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Health Technology Assessm

ent 2004;Vol. 8: No. 43

Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes


JL Colquitt, C Green, MK Sidhu, D Hartwell and N Waugh

Health Technology Assessment 2004; Vol. 8: No. 43

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Clinical and cost-effectiveness ofcontinuous subcutaneous insulininfusion for diabetes

JL Colquitt,* C Green, MK Sidhu, D Hartwell and N Waugh

Southampton Health Technology Assessments Centre, Southampton, UK

* Corresponding author

Declared competing interests of authors: none

Published October 2004

This report should be referenced as follows:

Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N. Clinical and cost-effectiveness ofcontinuous subcutaneous insulin infusion for diabetes. Health Technol Assess 2004;8(43).

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T

Objectives: To assess the clinical and cost-effectivenessof continuous subcutaneous insulin infusion (CSII)compared with multiple daily injections (MDI) in thedelivery of intensive insulin therapy for the treatmentof diabetes mellitus.Data sources: Electronic databases, references ofretrieved articles and manufacturer submissions.Experts in the field were consulted.Review methods: For the systematic review of clinicaland cost-effectiveness, studies were assessed forinclusion according to predefined criteria by tworeviewers. Data extraction and quality assessmentwere undertaken by one reviewer and checked by asecond reviewer. Data on clinical effectiveness weresynthesised through a narrative review with fulltabulation of all eligible studies, with meta-analysisperformed where appropriate.Results: Twenty studies comparing CSII with MDIwere identified. Quality was generally poor. In adultswith Type 1 diabetes, glycated haemoglobin improvedby 0.61% (95% CI –1.29 to 0.07) in longer termstudies, although this improvement was smaller when astudy using bovine ultralente was excluded. A reductionin insulin dose with CSII of about 12 units per day(–11.90, 95% CI –18.16 to 5.63) was found in short-term studies, with smaller differences in longer termstudies. Body weight and cholesterol levels weresimilar between treatments. Hypoglycaemic events didnot differ significantly between CSII and MDI in mosttrials, but some found fewer events with CSII and onefound more hypoglycaemia and hypoglycaemic comawith CSII. There was no consistency between thestudies in patient preference, but progress has beenmade both with insulin pumps and injector pens sincethe publication of many of the older studies. Nodifference in glycated haemoglobin between CSII andMDI was found in pregnancy; one study found lessinsulin was required by patients with CSII, but twoother studies found no significant difference. One study

of adolescents found lower glycated haemoglobin andinsulin dose with CSII whereas a second study found nosignificant difference. In CSII analogue insulin wasassociated with lower glycated haemoglobin levels thansoluble insulin. No economic evaluations comparingCSII with MDI were identified. The estimatedadditional cost of CSII compared to MDI varies from£1091 per annum to £1680 per annum, according tothe make of the insulin pump and the estimated life ofthe device. These estimates include the costs for theinsulin pump, the consumables associated with deliveryof CSII, and an allowance for the initial educationrequired when patients switch from MDI to CSII. The largest component of the annual cost for CSII is the cost of consumable items (e.g. infusion sets).Conclusions: When compared with optimised MDI,CSII results in a modest but worthwhile improvementin glycated haemoglobin in adults with Type 1 diabetes.It has not been possible to establish the longer termbenefits of such a difference in glycated haemoglobin,although there is an expectation that it would bereflected in a reduction in long-term complications.More immediate primary benefits from CSII may beassociated with an impact on the incidence ofhypoglycaemic events and the dawn phenomenon, andgreater flexibility of lifestyle. However, there is limitedevidence on this, and information presented to offercontext on quality-of-life is based on testimonies fromthose patients who have had a positive experience ofCSII. The estimated cost to the NHS per year for CSII would be around £3.5 million in England andWales if 1% of people with Type 1 diabetes used CSII,£10.5 million for 3%, and £17.5 million for 5%.Further research should focus on wider benefits ofCSII, such as flexibility of lifestyle and quality of life, and on the psychological impact of wearing a device for24 hours every day. Research into the use of CSII inchildren of different ages is also needed.


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Abstract

Clinical and cost-effectiveness of continuous subcutaneous insulininfusion for diabetes

JL Colquitt,* C Green, MK Sidhu, D Hartwell and N Waugh

Southampton Health Technology Assessments Centre, Southampton, UK* Corresponding author


v

Glossary and list of abbreviations ............. vii

Executive summary .................................... ix

1 Aim of the review ...................................... 1Subsidiary questions ................................... 1

2 Background ................................................ 3Introduction ............................................... 3Control of high blood glucose levels ......... 3Hypoglycaemia ........................................... 5Insulin treatment ........................................ 5Continuous subcutaneous insulin infusion ....................................................... 7Why are pumps little used in the UK? ....... 9Subsidiary questions ................................... 11

3 Clinical effectiveness .................................. 13Methods ...................................................... 13CSII versus MDI ......................................... 14Analogue versus soluble insulin in CSII ........................................................ 38Discontinuation rates ................................. 42

4 The patient’s perspective .......................... 45Caveats ....................................................... 45Reasons for switching to insulin by pump ..................................................... 46Hypoglycaemic events ................................ 46Control of blood glucose ............................ 47Flexibility of lifestyle .................................. 47Other comments ........................................ 48Disadvantages ............................................. 48Children and CSII ..................................... 49Common themes ........................................ 51Conclusions ................................................ 51

5 Economic analysis ...................................... 53Introduction ............................................... 53Literature review: economic evaluations and quality of life comparisons .................. 54Costs associated with CSII (versus MDI) ............................................... 55The benefits of CSII ................................... 59Economic models for Type 1 diabetes ....... 66Cost-effectiveness of CSII versus MDI ............................................................ 71

6 Implementation ......................................... 77Barriers to implementation ....................... 79

7 Discussion: analysis of uncertainties ......... 81Efficacy ....................................................... 81Comparators .............................................. 82Cost-effectiveness and cost per QALY .......................................................... 82Costs ........................................................... 83Duration of studies ..................................... 83Strengths and limitations of review ........... 83Research needs ........................................... 84

8 Conclusions ................................................ 85

Acknowledgements .................................... 87

References .................................................. 89

Appendix 1 Rapid review methods from the research protocol ......................... 97

Appendix 2 Sources of information, including databases searched and search terms ............................................... 101

Appendix 3 Quality assessment scale ............................................................ 103

Appendix 4 List of excluded studies ......................................................... 105

Appendix 5 List of recent abstracts ........... 107

Appendix 6 Summary of methodology: adults with Type 1 diabetes ...................................................... 109

Appendix 7 Summary of methodology: pregnancy ........................... 125

Appendix 8 Summary of methodology: adolescents .......................... 131

Appendix 9 Summary of methodology: analogue versus soluble insulin ............................................ 135

Appendix 10 Summary of results: adults with Type 1 diabetes ........................ 141

Appendix 11 Summary of results: pregnancy ................................................... 153

Contents

Appendix 12 Summary of results: adolescents ................................................. 161

Appendix 13 Summary of results: analogue versus soluble insulin .................. 165

Appendix 14 Calculations for NHS staff costs ............................................................ 171

Health Technology Assessment reportspublished to date ....................................... 173

Health Technology Assessment Programme ................................................ 183

Contents

vi

GlossaryTypes of diabetes The classifications ofdiabetes have changed in recent years, with theold terminology of insulin-dependent and non-insulin dependent being replaced by Type 1and Type 2. This was because many patientswith non-insulin-dependent diabetes are nowtreated with insulin. The new classification isbased on the aetiology and pathology ofdiabetes, rather than on treatment.

Type 1 diabetes Type 1 diabetes indicates thatthere has been a process of destruction of thebeta cells of the pancreas, leading to insulindeficiency. Eventually, insulin is required for

survival in order to prevent the development ofketoacidosis and death. There is usually aprocess of autoimmunity with autoantibodies,but these are not seen in all patients. The causeis unknown.

Type 2 diabetes Type 2 diabetes is morecommon, and is characterised by insulinresistance and insulin deficiency. Thedeficiency may be relative to insulin needs,rather than absolute, and there may be higherthan normal production of insulin at somestages. Type 2 diabetes is linked to overweightand obesity and to physical inactivity.


vii


Glossary and list of abbreviations

Technical terms and abbreviations are used throughout this report. The meaning is usually clear fromthe context, but a glossary is provided for the non-specialist reader. In some cases, usage differs in the

literature, but the term has a constant meaning throughout this review.

List of abbreviationsBDR background diabetic retinopathy

BMI body mass index

CI confidence interval

CRD Centre for Reviews andDissemination

CSII continuous subcutaneous insulininfusion, delivered with the aid ofan insulin pump

CT conventional therapy. In Type 1diabetes, conventional therapy inthe UK usually means that patientstake twice daily injections ofmixtures of short-acting andintermediate or long-acting insulin.

DC day case

DCCT Diabetes Control and ComplicationsTrial

DKA diabetic ketoacidosis, a life-threatening metabolic disturbancerelated to shortage of insulin. It isoften brought on by other illnessessuch as infections, which increasethe body’s insulin needs

DQOL diabetes quality of life

DSN diabetes specialist nurse

DTSQ Diabetes Treatment SatisfactionQuestionnaire

ELIP elective inpatient cost

FBR fixed basal rate

FCE finished clinical episode, i.e. ahospital admission to one unit

HbA1c glycated haemoglobin A1c

HFS Hypoglycaemia Fear Survey

continued

Glossary and list of abbreviations

viii

List of abbreviations continued

HOR higher overnight rate

HRG health-related resource group

hypo hypoglycaemic event

IDDM insulin-dependent diabetes mellitus

INPUT voluntary organisation promotingInsulin Pump Therapy

ITT intention-to-treat

MDI multiple daily injections

NELIP non-elective inpatient cost

NICE National Institute for ClinicalExcellence

p = ns not statistically significant

OR odds ratio

PDR proliferative diabetic retinopathy

PUMP Pump Management for Professionals

QALY quality-adjusted life-year

QoL quality of life

QWB quality of well-being scale

RCT randomised controlled trial

SCL-90R Symptom Checklist-90R

SD standard deviation

SF-36 Short Form with 36 Items

SG standard gamble

TTO time trade-off

UKPDS United Kingdom ProspectiveDiabetes Study

VAS visual analogue scale

WESDR Wisconsin Epidemiologic Study ofDiabetic Retinopathy

WMD weighted mean difference

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.


ix


Description of the proposedserviceThis systematic review examines the clinical andcost-effectiveness of continuous subcutaneousinsulin infusion (CSII) using insulin pumpscompared with multiple daily injections (MDI) fordiabetes.

Epidemiology and backgroundThere are two main types of diabetes. Type 1diabetes involves a process of destruction of thebeta cells of the pancreas, leading to severe insulindeficiency, so that insulin treatment is required forsurvival. It represents about 10–15% of all diabetesin England and Wales. Type 2 diabetes is muchmore common, and is characterised by insulinresistance and relative insulin deficiency. Type 2diabetes is linked to overweight and obesity and tophysical inactivity. The number of people withinsulin-treated diabetes has increased owing to themarked increase in the incidence of Type 1diabetes and also to a greater number of peoplewith Type 2 diabetes being treated with insulin toimprove diabetic control. There has also been anincrease in the prevalence of Type 2 diabetes,particularly among the Asian community. Poorcontrol of diabetes, reflected in high blood glucose levels, can in the short term result indiabetic ketoacidosis, a serious and potentiallyfatal condition, and in the long term increase the risk of complications such as diabeticretinopathy and nephropathy. However, studieshave shown that good diabetic control isassociated with a reduced risk of thesecomplications.

If insulin levels are too high and blood glucosefalls, hypoglycaemic episodes occur. The effects ofa hypoglycaemic episode depend on how low theblood glucose level falls, varying from mild andrapidly corrected by food or sugary drinks, tosevere where help is required. Severehypoglycaemia can lead to unconsciousness,convulsions or death.

There are several problems with currenttreatment. In the non-diabetic state, the body

needs a little insulin all the time (basal insulin)boosted by increased output after meals. This isdifficult to achieve with conventional insulininjections, and in particular good control of bloodglucose during the night is difficult. Intensiveinsulin regimens such as CSII aim to resemblemore closely the output of a normal pancreas byproviding basal insulin for fasting periods andadditional short-acting supplements to covermeals.

MethodsA systematic review of the literature and aneconomic evaluation were undertaken.

Data sourcesElectronic databases were searched, including theCochrane Library, MEDLINE, EMBASE, PubMed,Science Citation Index, Web of ScienceProceedings, DARE and HTA databases,PsycINFO, CIHAHL, NHS Economic EvaluationDatabase, EconLIT and Health ManagementInformation Consortium database. References ofall retrieved articles were checked for relevantstudies and experts were contacted for advice andpeer review and to identify additional publishedand unpublished references. Manufacturersubmissions to the National Institute for ClinicalExcellence (NICE) were reviewed.

Study selectionStudies were included if they fulfilled the followingcriteria:

� Interventions: CSII using insulin pumpscompared with optimised MDI (at least threeinjections per day). Analogue compared withsoluble insulin in CSII.

� Participants: people with insulin-treateddiabetes (Type 1 or Type 2). Newly diagnosedpatients were excluded.

� Outcomes: glycated haemoglobin, insulin dose,weight change, lipid levels, patient preference,quality of life, adverse effects.

� Design: parallel randomised controlled trials(RCTs) and randomised and non-randomisedcrossover studies with a minimum duration of10 weeks on each treatment.

Executive summary

x

Studies in non-English language or available only as abstracts were excluded from the main analysis.

For questions where no eligible studies wereidentified, information from selected observationalstudies was discussed.

Titles and summaries of studies being assessed forinclusion were checked by two reviewers. Full textsof selected studies were assessed for inclusion byone reviewer and checked by a second. Differencesin opinion were resolved through discussion.

Data extraction and quality assessmentData extraction and quality assessment wereundertaken by one reviewer and checked by asecond reviewer, with any disagreement resolvedthrough discussion. The quality of includedstudies was assessed in accordance with the Centrefor Reviews and Dissemination (CRD) Report 4quality assessment scale.

Data synthesisData on the clinical effectiveness of CSII fordiabetes were synthesised through a narrativereview with full tabulation of results of all eligiblestudies, with meta-analysis performed whereappropriate. Cost-effectiveness analysis examinedthe marginal costs of CSII compared with MDIand considered evidence on the marginal benefitssuch as improved control, adverse events andquality of life.

Number and quality of studiesSearching identified 20 studies comparing CSIIwith MDI. These included eight parallel RCTs,nine randomised crossover studies and three non-random crossover studies. Fourteen studiesincluded adults with Type 1 diabetes, four studiesincluded pregnant women and two studiesincluded adolescents. The quality of reporting andmethodology of the studies, many of which datedfrom many years ago, were often poor by today’sstandards, with just two studies having adequaterandomisation and none reporting adequateallocation concealment.

No RCTs or crossover studies were identified inchildren, on overnight use of CSII, in patientswith poorly controlled Type 2 diabetes or ondiscontinuation rates; therefore, selectedobservational studies were discussed in thesesections.

Six studies (one parallel RCT and five random crossover studies) were identifiedcomparing analogue with soluble insulin in CSII. Randomisation and allocationconcealment were adequate in the parallel RCT but not reported in the crossover studies.

No economic evaluations comparing CSII withoptimised MDI were found.

Summary of benefitsAdults with Type 1 diabetesIf all trials were included, a mean improvement in glycated haemoglobin of about 0.6% was found with CSII compared with MDI in both short-term [–0.64, 95% confidence interval (CI)–1.28 to 0.01] and longer term (–0.61, 95% CI–1.29 to 0.07) studies. This improvement wassmaller if a study which used bovine ultralente inthe control arm was excluded; the reduction inglycated haemoglobin A1c (HbA1c) is then only0.5%. Short-term studies show a reduction ininsulin dose of about 12 units (–11.90, 95% CI–18.16 to –5.63), with less difference in longer term studies. Body weight was similarduring treatment with CSII and MDI. The twostudies that reported data on cholesterol levelsfound no significant difference between thetreatments. There was no consistency between thestudies in patients preferring CSII or MDI,although many of the older studies used older,bulkier and less reliable pumps, and progress hasalso been made with discreet ‘pen’ injectors inMDI; therefore, these findings are probably notrelevant to the present devices. Hypoglycaemicepisodes did not differ significantly between CSII and MDI in most trials, but some foundfewer episodes with CSII and one study found more hypoglycaemia and hypoglycaemiccoma with CSII. In some observational studies, much greater reductions in the number of severe hypoglycaemic episodes were seen with CSII, which may be because these studiestend to select patients having particular problems.

PregnancyThree studies found no difference in glycatedhaemoglobin between CSII and MDI. Less insulin per kilogram was required by patients with CSII in one study, but two otherstudies found no significant difference. Patient preference and quality of life were notreported.

Executive summary

AdolescentsOne study found no significant difference between CSII and MDI, whereas the second studyfound lower glycated haemoglobin and insulindose with CSII. Over half of the patients chose tocontinue treatment with CSII in the former study.

ChildrenNo randomised trials were identified. Case seriessuggest that CSII has a place in treatment ofchildren with diabetes, but this needs to beconfirmed in randomised studies.

Overnight only CSIIThe combination of overnight CSII and daytimeMDI may help in children, by reducing nocturnalhypoglycaemic episodes and the dawnphenomenon, but no randomised trials wereidentified, and further research is necessary.

Short-term use in adults with poorlycontrolled Type 2 diabetesIt has been suggested that short-term CSII mayhelp in patients with Type 2 diabetes on highdoses of oral drugs and who are resistant toinsulin. No good evidence was found.

Analogue versus soluble insulinIn CSII, analogue insulin was associated withlower glycated haemoglobin levels than solubleinsulin and was preferred by patients. Nodifference in insulin dose or weight change wasobserved. Some studies found fewer hypoglycaemic episodes with analogue insulin,although this varied according to the definitionsused.

CostsThe additional cost of CSII compared with MDIvaries according to the make of pump and theestimated life of the device, from £1091 perannum using the cheapest pump and assuming an8-year life of the pump to £1680 per annum withthe most expensive model and assuming a life ofonly 4 years. These estimates include costs forconsumables and the initial education requiredwhen patients switch from MDI to CSII. Thelargest component of cost is the consumable items,such as infusion sets (tubing, etc.), with the capitalcost of the pump secondary. Initial education forthose switching to CSII is very important, and weestimated an additional cost per patient switching from MDI to CSII to be in the region of £150.

Costs per life year gainedThere are definite benefits of CSII over MDI,including improved control of diabetes, not just asreflected in glycated haemoglobin and in a slightlyreduced incidence of severe hypoglycaemic events,but also in flexibility of lifestyle and hence qualityof life. However, evidence on quality of life isreported in only one trial, and comes mainly fromtestimonies of pump users.

One would expect the improvement in HbA1c tobe reflected in reduced long-term complicationsand for that to be accompanied by reduced coststo the NHS. However, we have not found asatisfactory method of converting the observedbenefits into a cost per quality-adjusted life-year.

The main problem with the current evidence isthat it does not fully reflect the selection ofpatients for CSII. Most people on insulin therapywould not have much to gain from CSII, but thosewith particular problems such as recurrent severehypoglycaemia would. Their benefits wouldinclude not only fewer hypoglycaemic episodes,but also a reduction in fear of them. However, theutility effect of the reduction in fear ofhypoglycaemic episodes has not been quantified.The cost-effectiveness of CSII is likely to be muchbetter for certain subgroups.

Sensitivity analysisThe main costs are of consumables and pumps.The price of pumps might come down with bulkpurchase, but this is speculative. This would nothave much impact on the cost per annum.

ConclusionsControl of diabetes consists of more than justcontrol of blood glucose as reflected in glycatedhaemoglobin. Compared with optimised multipleinjection insulin therapy, CSII results in a modestbut worthwhile improvement in glycatedhaemoglobin, but its main value may be in reducing other problems such as hypoglycaemiaand the dawn phenomenon, and in improvingquality of life by allowing greater flexibility oflifestyle. Pumps appear to be a useful advance forpatients having particular problems, rather than adramatic breakthrough in therapy, and wouldprobably be used by only a small percentage ofpatients.


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Implications of approval of anincreased use of CSIIMany health authorities are not funding insulinpumps, and some of those that are have restrictedthe number. Many patients are funding their ownpumps. According to clinical consensus, it isunlikely that CSII would be used by more than asmall proportion of people with Type 1 diabetes,but the exact proportion is not known. We wouldnot expect any use in true Type 2 diabetes in theforeseeable future. The cost to the NHS per yearwould be around £3.5 million in England and Walesif 1% of people with Type 1 diabetes used CSII,£10.5 million for 3% and £17.5 million for 5%. Theeducational needs of patients starting CSII aresignificant, and it would usually be diabetesspecialist nurses who would provide this. However,there are many other demands on their time.

Need for further researchThe trials to date have focused on easilymeasurable outcomes such as glycatedhaemoglobin. The main benefits may be in termsof flexibility of lifestyle and quality of life, anddata on those would help with cost-effectivenessanalysis. Some of the implications for patientssuch as the psychological impact of wearing adevice for 24 hours every day have not beenquantified.

There appears to be no wholly satisfactoryeconomic model for diabetes, which would allowimprovements in diabetes control to be convertedinto a cost per quality-adjusted life-year. Researchis also needed into the use of CSII in children ofdifferent ages.

Executive summary

xii

The main aim of this review is to assess theclinical effectiveness and cost-effectiveness of

continuous subcutaneous insulin infusion (CSII)using insulin pumps, compared to intensivetreatment with multiple daily injections (MDI).The benefits could be improved control of bloodglucose levels as reflected in glycated haemoglobinA1c (HbA1c), or a similar level of control but withother advantages such as fewer problems withhypoglycaemic episodes (hypos), or greaterflexibility of lifestyle and hence better quality oflife (QoL).

Both CSII and MDI are forms of intensive insulintreatment. The benefit of intensive treatment, forthose whose diabetes is inadequately controlled onconventional insulin therapy, is not in doubtfollowing trials such as The Diabetes Control andComplications Trial (DCCT) and the UnitedKingdom Prospective Diabetes Study (UKPDS).Conventional insulin therapy (CT) is assumed to be twice daily injections usually of a mixture of short-acting and long-acting insulins. Thisreport assumes that Type 1 patients wouldnormally try twice-daily mixtures, and would then be treated with MDI before trying CSII, thatis, patients would not go directly fromconventional to CSII. However, increasingly,patients may start on MDI from diagnosis. Type 2patients would usually start with a once-dailyinjection of a long-acting insulin (ultralente or along-acting analogue such as glargine) or twice-daily NPH, and if not well-controlled wouldprogress next to CT, before going on, if necessary,to MDI and then CSII. This report thereforeexcludes the use of CSII in newly diagnosedpatients.

Intensive treatment with MDI is taken to meantreatment with a combination of short-actinginsulins (soluble or analogue) to cover meals, with long-acting insulin (intermediate, ultralenteor very long-acting analogues such as glargine) to provide basal insulin. In practice, MDI willmean a minimum of three injections a day, butmay involve more than that. It will also involveblood glucose testing. There will be varying levels

of intensity within MDI, and so the comparator forCSII is optimised MDI.

It should be noted that treatment of Type 1diabetes involves more than just injection ofinsulin:

“Modern insulin therapy is a package of insulinadministration according to basal and bolusprinciples, frequent blood glucose self monitoring,insulin adjustment according to blood glucoseresults and meal size, exercise, plus intake of ahealthy diet, and full diabetes education.” (Pickup J, Guy’s, King’s and St Thomas’ School ofMedicine, London: personal communication,2002)

Subsidiary questionsA number of subsidiary questions are alsoaddressed. Where eligible RCTs and crossoverstudies are lacking, evidence from selectedobservational studies will be sought.

1. Does CSII have advantages over MDI inwomen with Type 1 diabetes pre-conceptuallyand during pregnancy?

2. What is the role of CSII in adolescents andchildren?

3. What is the role of overnight-only CSII(injections taken as usual during the day)?

4. What is the value of short periods of CSII inpatients with Type 2 diabetes who are veryresistant to oral drugs such as thesulphonylureas?

5. In CSII, do analogue insulins have advantagesover older short-acting (soluble) insulins?

6. How many patients continue to use CSII(discontinuation rates)?

Implantable pumps are not covered by the review.

Insulin pumps are used for insulin therapy insome patients in hospital, for example thosehaving surgery. Such very short-term use is notrelevant to this review.


1


Chapter 1

Aim of the review

IntroductionThe number of people with insulin-treateddiabetes has increased over recent decades for tworeasons. Firstly, there has been a marked increasein the incidence of Type 1 diabetes mellitus[formerly called insulin-dependent diabetesmellitus (IDDM)].1–7 In some parts of the UK, theincidence of Type 1 diabetes has trebled over thelast 30 years.1,5 Rates in the UK are high ininternational terms,8 although more so inScotland. Second, more people with Type 2diabetes (formerly non-insulin-dependent diabetesmellitus) are being treated with insulin in order toachieve better control of blood glucose levels. Thistrend started before, but was probably acceleratedby the results of, the UKPDS.9 There has also beenan increase in the prevalence of Type 2diabetes,10,11 particularly among those from ethniccommunities.12 A recent study by the Office forNational Statistics shows a rise in prevalence from1994 to 1998.13

The need for insulin arises for different reasons inthe two main types of diabetes. Insulin is producedby the islet cells of the pancreas. In Type 1diabetes, there is a true insulin deficiency becausethe islet cells are destroyed as the result of anautoimmune process, for cause or causes unknown.In Type 2 diabetes, it is more common to have anormal or increased insulin production initially,with insulin resistance being a feature. However,over the years the pancreas may fail, leading toinsulin deficiency. Insulin production rates willhave fallen in patients to about 50% by the time ofdiabetes diagnosis in the UK, as was shown in oneof the UKPDS papers.14 It is probable that thisprogressive worsening would be much less, ormight not occur, if patients adhered to lifestylemeasures such as weight loss and exercise.

There are some patients who do not fit neatly intothe two groups, because at diagnosis they appearto have Type 2 diabetes, but then progress toinsulin treatment over the course of a few years;they may have slow onset Type 1 diabetes.15,16

The approximate prevalences of insulin-treateddiabetes in different age groups are shown inTable 1.

Control of high blood glucose levelsIf insulin levels are too low, blood glucose levelsare too high and there are other accompanyingmetabolic abnormalities. In the long run, poorcontrol of blood glucose increases the risk ofcomplications such as eye disease (diabeticretinopathy), which can potentially lead to loss ofvision. Diabetic retinopathy is the single mostcommon cause of blindness in people in theworking years of life in the UK and otherindustrial countries, and kidney disease (diabeticnephropathy) is now the leading cause of renalfailure, leading to the need for dialysis andtransplantation. Amputation rates are high indiabetes owing to the combination of peripheralvascular disease and neuropathy, and the care ofthose with severe peripheral vascular diseaseleading to amputation is one of the mostexpensive complications of diabetes.15 In the shortterm, poor diabetic control in Type 1 diabetes canresult in the metabolic derangement known asdiabetic ketoacidosis, which is a serious andoccasionally fatal condition, often referred to as‘diabetic coma’, because it can lead to reducedconsciousness and coma. Heart disease is morecommon amongst people with diabetes, but is lessclearly linked with blood glucose control.

Both randomised trials and large cohort studies haveshown that good control of blood glucose levels bytreatment is associated with reduced risk ofcomplications such as retinopathy and renal disease(older studies are in the meta-analysis by Wang andcolleagues,18 DCCT19 and Reichard andcolleagues20). For example, in the DCCT study, therewas a marked drop in the prevalence of serious eyedisease at 9 years, from 32% in the conventionaltreatment group to 9% in the intensive group.21 Inthis study, the intensive group maintained an averageHbA1c level of 7.2%, about 2% below those treatedconventionally (but note that the conventional groupwas better controlled than the US average). Therehas therefore been great emphasis on better(‘tighter’) control of blood glucose.

A meta-analysis by Egger and colleagues22

examined the risk of ketoacidosis during intensifiedtreatment compared with conventional treatment.For trials where patients could choose between


3


Chapter 2

Background

Background

4

TABLE 1 Prevalence of insulin treated diabetes per 1000 patients, by age, sex and year: 1994–98 in England and Wales

0–4 5–15 16–24 25–34 35–44 45–54 55–64 65–74 75–84 85+ Crude Age-rate standard-

(all ages) ised rate (all ages)

Males 1994Rate/1000 0.2 1.1 3.1 4.7 5.4 5.6 7.8 9.2 8.3 4.4 4.8 4.6LCL 0.1 0.9 2.7 4.3 4.9 5 7 8.3 7.1 2.7 4.6 4.4UCL 0.5 1.4 3.6 5.2 5.9 6.1 8.6 10.1 9.6 6.7 4.9 4.8No. of cases 7 86 171 388 393 375 390 372 163 20 2365 2365

Males 1995Rate/1000 0.2 1.4 3 4.5 5.5 5.8 8.3 9.7 9.4 5.9 5 4.8LCL 0.1 1.2 2.6 4.1 5 5.3 7.5 8.7 8.1 4 4.8 4.6UCL 0.5 1.7 3.5 5 6 6.4 9 10.6 10.7 8.5 5.2 4.9No. of cases 7 112 169 380 421 420 437 406 200 29 2581 2581

Males 1996Rate/1000 0.2 1.5 3.2 4.6 5.7 6.2 8.9 10 9.9 5.8 5.2 5LCL 0.1 1.2 2.7 4.2 5.2 5.7 8.1 9.1 8.6 3.9 5 4.8UCL 0.4 1.8 3.7 5.1 6.2 6.8 9.7 11 11.2 8.2 5.4 5.2No. of cases 7 125 184 401 463 481 495 439 227 30 2852 2852

Males 1997Rate/1000 0.3 1.6 3.3 4.7 5.8 6.9 9.5 11.4 10.2 6.9 5.6 5.3LCL 0.1 1.3 2.8 4.3 5.3 6.3 8.7 10.4 8.9 4.9 5.4 5.1UCL 0.6 1.9 3.7 5.2 6.3 7.4 10.2 12.3 11.4 9.4 5.8 5.5No. of cases 10 139 196 418 495 554 556 515 246 38 3167 3167

Males 1998Rate/1000 0.2 1.7 3.5 4.6 6.2 7.2 10 13.3 10.9 6.8 6 5.7LCL 0 1.4 3 4.1 5.7 6.6 9.3 12.3 9.7 4.9 5.8 5.5UCL 0.4 1.9 3.9 5 6.7 7.7 10.8 14.3 12.2 9.2 6.2 5.8No. of cases 5 151 219 413 565 609 634 627 282 41 3546 3546

Females 1994Rate/1000 0.1 1.7 3.2 3.4 4.4 4.5 7.7 8.3 8 4.7 4.4 4.1LCL 0 1.4 2.7 3 3.9 3.9 7 7.5 7 3.6 4.2 3.9UCL 0.3 2 3.6 3.8 4.9 5 8.5 9.1 9 6.1 4.6 4.3No. of cases 3 117 160 270 309 289 383 396 253 59 2239 2239

Females 1995Rate/1000 0.4 1.6 3.5 3.7 4.6 4.6 7.9 9.2 8.4 4.9 4.7 4.3LCL 0.2 1.3 3 3.3 4.1 4.1 7.2 8.3 7.5 3.8 4.5 4.1UCL 0.6 1.9 4 4.1 5 5.1 8.7 10 9.4 6.2 4.9 4.5No. of cases 11 120 178 305 340 323 415 450 289 65 2496 2496

Females 1996Rate/1000 0.3 1.7 3.3 3.8 4.8 5.1 8 9.5 8.8 4.5 4.8 4.5LCL 0.1 1.4 2.8 3.4 4.3 4.6 7.2 8.6 7.8 3.5 4.7 4.3UCL 0.6 2 3.8 4.2 5.3 5.6 8.7 10.3 9.8 5.8 5 4.6No. of cases 9 133 174 323 376 381 436 476 320 64 2692 2692

Females 1997Rate/1000 0.4 1.8 3.4 3.9 5 5.3 8.8 10.8 9.5 5.2 5.2 4.8LCL 0.2 1.5 2.9 3.5 4.5 4.8 8 9.9 8.5 4.1 5 4.6UCL 0.6 2.1 3.9 4.3 5.5 5.8 9.6 11.7 10.5 6.6 5.4 4.9No. of cases 11 147 189 340 410 412 508 558 362 78 3015 3015

Females 1998Rate/1000 0.3 1.9 3.2 4.3 5.2 5.7 9.4 12.1 9.4 5.9 5.5 5.1LCL 0.1 1.6 2.8 3.8 4.7 5.2 8.6 11.1 8.4 4.7 5.3 4.9UCL 0.5 2.2 3.7 4.7 5.6 6.2 10.1 13 10.3 7.2 5.7 5.2No. of cases 8 165 193 380 452 473 582 644 372 93 3362 3362

LCL, lower confidence limit; UCL, upper confidence limit.Source: Office for National Statistics.17

multiple injections or pump treatment, there wassome evidence of an increased risk of ketoacidosiswith intensified treatment, although this did notreach statistical significance [odds ratio (OR) 1.28,95% confidence interval (CI) 0.90 to 1.83, p =0.17]. For trials that randomised patients to pumps,there was a substantial increase in the risk ofketoacidosis (OR 7.20, 95% CI 2.95 to 17.58, p <0.0001). However, in the latter meta-analysis themost recent study was conducted in 1992, thereforethese results may no longer apply to newer pumps.

HypoglycaemiaHowever, insulin treatment may lead to bloodglucose levels falling below normal, potentiallyrobbing the brain of its essential glucose supply.This is called hypoglycaemia. Hypoglycaemicepisodes are usually known as ‘hypos’. Theconsequences vary depending on how low theblood glucose level falls. Mild hypoglycaemicevents may cause only a feeling of hunger andsweating, and can be rapidly corrected by food orsugary drinks. However, they may reduce theamount and quality of sleep when they occurduring the night (nocturnal hypoglycaemicevents). More serious or sustained falls in glucoselevel may mean that the diabetic person needshelp in order to recover, and severe hypoglycaemicevents can lead to behavioural disturbances,unconsciousness, convulsions or death. In youngchildren with frequent or severe hypoglycaemicevents, there may be some impairment ofintellectual function.23

People with Type 1 diabetes, especially youngerones, may be more afraid of hypoglycaemic eventsthan of long-term complications. As one of ourexpert advisers commented;

“Even though any single hypo event is short-livedin terms of its acute physiological effect, thepsychological effect on many patients is not at allshort-lived. It often has a very profound effect sothat the patient will do everything they can to avoida recurrence. Many patients have a greater fear ofhypos than they have of developing diabetes-relatedcomplications, and as a result will keep their bloodglucose levels higher than recommended in orderto avoid hypos. If they lost their fear of hypos,better glycaemic control could be achieved resultingin a reduced risk for complications.” (Tieszen K,Hope Hospital, Salford: personal communication)

Egger and colleagues22 reported that the incidenceof severe hypoglycaemia ranged from 0 to 33 per

100 person-years amongst conventionally treatedpatients and from 0 to 66 in intensively treatedpatients, in a meta-analysis of 14 randomisedcontrolled trials (RCTs) comparing conventionalwith intensive insulin regimens. The risk of severehypoglycaemia was three times as high in theintensive arms of the trials. However, because ofthe relative sizes of the trials, the result wasdominated by the DCCT study,24 which provided459 of the 531 hypoglycaemic events in theintensive group and 255 of the 315 in theconventional group, in the meta-analysis. Takingout DCCT would leave only 72 and 60hypoglycaemic events in the intensive andconventional groups, respectively. The risk ofsevere hypoglycaemia in the intensively treatedgroup fell after the first 2 years of the DCCTfeasibility study, suggesting a learning experiencein the trialists, but there was no reduction overtime in the annual rate of hypoglycaemic events inpatients recruited to the main study, suggestingthat hypoglycaemia will always be a risk inintensive therapy. Over an average follow-up of6.5 years, 65% of patients in the intensive and 35%of those in the conventional group had at least onesevere hypoglycaemic event.

In a representative group of people with IDDM,Muhlhauser and colleagues25 found that 10% ofconventionally treated patients and 9% of CSIItreated patients had at least one severehypoglycaemic event per year. The intensivelytreated group successfully improved their controlof blood glucose as reflected in HbA1 without anincreased risk of severe hypoglycaemia. There isgood evidence that although all patients with Type 1 diabetes are at some risk, the risk of severehypoglycaemia tends to be concentrated in arelatively small subset of individuals. Rewers andcolleagues26 found that 79% of severehypoglycaemic events occurred in the 14% ofchildren who had recurrent hypoglycaemic events.Thus, the strongest risk indicator for severehypoglycaemia is a history of an episode in thepast and this led the DCCT to modify theirrecruitment protocol after the first year to excludesuch patients. Loss of the warning symptoms of ahypoglycaemic events (see below) and deliberateor uniformed misuse of insulin also contribute torisk.

Insulin treatmentInsulin is ineffective if given by mouth, because itwould be digested. Therefore, at present, it has tobe given by injection. Inhaled forms are being


5


developed but bioactivity is low (10–20%) andvariable, and there have been problems withaccurate delivery.

There are many forms of insulin on the market,but they fall into a number of groupings byduration of action (Table 2).

There are several problems with current treatment.First, the body needs a little insulin all the time(‘basal insulin’, which accounts for about half of thetotal insulin production) with brief peaks ofincreased levels for an hour or two after meals.The basal insulin need is around 0.5–1.0 units/hourin adults. After meals blood levels normallyincrease 5–10-fold in the first 30 minutes,dropping back to basal after about 2 hours.27 It isdifficult to achieve this normal profile of insulinrelease with injected insulin. The rapid-actinganalogues are closest. Soluble insulin injectionsstart to act about 30 minutes after injection, rise toa peak of action over the next hour and fall 4–6hours later, although they can cause hypoglycaemiaup to 8 hours after injection, particularly in theearly part of the night. The newer analogueinsulins such as lispro and aspart start much morepromptly but are shorter lived in effect and still donot replicate the normal non-diabetic state. Iflarger doses of short-acting insulins are given tocontrol hyperglycaemia, which occurs 1–2 hoursafter meals, hypoglycaemic events may result at2–4 hours or even up to 8 hours later, particularlyduring the night.

Figure 1 illustrates some of the problems. In each,the dotted lines show the insulin requirements aftermeals, when in non-diabetic people there is a steepbut short-lived rise in insulin production. The darksolid lines show the timing of action of solubleinsulin and the light solid lines that of long-actinginsulin. The diagrams show that soluble insulin hasa longer but lower peak of action; it does not mimicnormal pancreatic function at all well, being

insufficient in the hour or so after the meal, butthen liable to have too much effect 3–4 hours afterthe meal. Giving two injections a day of a mixtureof short-acting and longer acting insulin fails tocontrol peaks of blood glucose (not shown, butrepresented by the dotted lines of insulin needs)but will provide too much insulin for much of theday (Figure 1a). Moving to MDI (several injectionsof short-acting insulin during the day with onelong-acting at night) still does not providesatisfactory cover (Figure 1b), nor does a yet morecomplicated regimen of three injections of short-acting and two of long-acting (Figure 1c). However,the MDI regimens do approximate more closely toinsulin needs. Using more rapid acting analogueinsulins (not shown, but shorter peaks than soluble)is an improvement but still does not replicatenormal pancreatic insulin production.

Background

6

TABLE 2 Insulin preparations

Duration of Type Time to onsetaction

Rapid-acting Analogues 15 minutes

Short-acting Soluble human 15–60 minutes

Intermediate NPH and human 2–4 hoursand porcine ultralentes

Long Long-acting analogues

Insulin replacement

Solubleinsulin

Intermediateinsulin

Insulin replacement – multipledaily injection therapy

Insulin replacement – multiple daily injection therapy with split basal insulin

(a)

(b)

(c)

FIGURE 1 Insulin profiles

Second, absorption rates from the injection sitesvary from day to day. Absorption is affected byinjection site and depth, adiposity, exercise,temperature, skin blood flow and insulinpreparation.28 Absorption varies in the sameindividual by about 25%.28 This can lead tounpredictable hypoglycaemic episodes, usuallyassociated with longer acting insulins.

Third, there is a problem with overnight control,when a low basal level is needed, but with a rise inthe morning to counteract the rise in bloodglucose which then occurs (before wakening).Isophane and lente insulins cannot maintainnormal blood glucose levels overnight withoutincreasing the risk of hypoglycaemic events.Nocturnal hypoglycaemic events may not besevere, but can be troublesome and disruptive ofsleep. If the dose is reduced to avoidhypoglycaemia, it is likely that glucose levels willbe high by morning. The rise in blood glucoselevels towards the end of the night and the loss ofcontrol which then occurs with long-acting insulininjections given the night before are sometimesreferred to as the ‘dawn phenomenon’.

Fourth, patients may not comply with advice, andit is known that some patients do not take all theirprescribed insulin.29 This may be partly because ofthe limitations placed on lifestyle by the diet andinsulin regimens still used in most places. Thelimitations are imposed by the need to have mealsat regular intervals. There may be other optionssuch as the intensive educational programme DoseAdjustment for Normal Eating (DAFNE), whichwill be covered by another National Institute forClinical Excellence (NICE) review.

The net effect of the limitations in conventionalinsulin therapy is that diabetes is not wellcontrolled in the majority of patients. In a recentaudit, only a minority of young people withdiabetes achieved good control.30

A recent review31 concluded that:

“A substantial advance in diabetes care would allowindividuals to have euglycaemia (normal bloodglucose) without risk of severe hypoglycaemia, andwith much less effort than is currently devoted tointensive therapy.”

Continuous subcutaneous insulininfusionThe first studies of CSII delivered via insulinpumps came from Guy’s Hospital, London, in

197832 and Yale in 1979.33 The aim of CSII is totry to approximate the insulin delivery profilemore closely to the pattern of output behaviour ofthe normal pancreas by providing continuouslyinfused, low-volume basal insulin for fastingperiods and the delivery of increased rate bolusesto cover meals. Only short-acting (crystalline orrapidly absorbed analogues) insulin is used.

There have been several reviews of CSII. Thorp,34

writing after a relatively short period of CSIIexperience in 1986, noted that: “Efforts toimprove insulin administration have resulted inthe development of a myriad of electromechanicalpump devices.” He noted that technical problemswere common. He also commented that 30% ofpatients in one of the studies discontinued use ofthe pump, and that: “All of those discontinuinguse of the pump identified the physician as thekey person involved in the decision to try thisform of treatment, rather than themselves.”

Davies and Baum in 198835 considered theevidence on CSII use in children, and noted a lackof enthusiasm amongst British paediatricians, butcommented that the recent advent of injectiondevices such as pens might be part of the answer,since those were being seen as an alternative wayof administering intensive insulin regimens.

Over the past decade, much effort has gone intoimprovement of both pump and insulintechnology and there have been several recentreviews. Lenhard and Reeves36 carried out areview, using MEDLINE only. They noted the risein popularity of CSII after the introduction ofpumps in the late 1970s and early 1980s, followedby a fall because of size, safety and efficacyconcerns, followed then by a rise in usage after thepublication of the DCCT study. They also notedthat the newer pumps, reduced to three in numberfrom the ‘myriad’ described by Thorp, weresmaller, more reliable and easier to use. Theyestimated that about 8% of all adults in NorthAmerica with Type 1 diabetes were using pumps.They concluded that there was good evidence forbenefits in adults (‘comparable or slightly superiorto MDI’), and some in pregnancy, but that therewas little good-quality evidence in children.

The annual position statement from the AmericanDiabetes Association for 200237 was cautious, andsaid that: “an insulin pump may provide greaterlifestyle flexibility, particularly with regard to mealschedules and travel but may be too demandingfor some individuals.” The statement did notmake any recommendation on the relative merits


7


of CSII and MDI, but said that: “pump therapy isas safe as multiple-injection therapy whenrecommended procedures are followed.”

Pickup and Keen,38 who were the originators ofCSII, reviewed the history of and evidence basefor CSII.39 They note the considerable world-wideuse of pumps (over 200,000 patients) and thedisproportionately low UK use. They concludethat on CSII, blood glucose and HbA1c are similaror slightly lower than with MDI, thathypoglycaemia is much less frequent and thatketoacidosis occurs at the same rate. They proposea set of clinical guidelines for identifying whichpatients should be considered for CSII, andconclude that the proportion of patients whowould be suitable is relatively small. They observethat individual patient choice and preference isnot possible unless the CSII option is available fora comparative trial, a condition rarely met in theUK. In a complementary study, Pickup andcolleagues40 carried out a meta-analysis of RCTscomparing CSII with MDI. They found that HbA1c

was about 0.5% better on CSII, but found that fewstudies reported hypoglycaemic events; noneappeared to report effect on QoL. The CSII groupneeded 14% less insulin.

Three health technology assessment reports haveexamined CSII. The Catalan Agency for HealthTechnology Assessment and Research (CAHTA)41

concluded that CSII was no more effective thanMDI, but appears to have based this only on theDCCT study. However, in the DCCT study patientswere not randomised to pumps or MDI; it was leftto individual centres to decide, and it would beunsafe to draw any comparison of the relativemerits of CSII and MDI.

The report from the Spanish Health TechnologyAssessment Agency [Agencia de Evaluacion deTecnologies Sanitarias (AETS)] came to similarconclusions.42 The US Agency for Health CarePolicy and Research (AHCPR, 1990)43 report issuperseded by new evidence.

It is always interesting to know what treatmentsclinicians with diabetes choose for themselves. A survey44 by the American Association ofDiabetes Educators (AADE) and the AmericanDiabetes Association (ADA) asked members if theyhad diabetes and, if so, how they were treated.About 6.4% of members had diabetes, of whom72% had Type 1. The survey found that 96% ofthose with Type 1 used an intensive insulinregimen, and that over half (60% of the AADEmembers with diabetes and 52% of the ADA

ones) used an insulin pump and, anecdotally, anumber of diabetic specialist physicians are known to have been on CSII for about 20 years.

Modern pumpsModern pumps are small and lightweightcompared with the early ones (Figures 2 and 3).The pumps are battery operated and hold enoughinsulin for several days, depending on daily need.The infusion rate can be programmed for bothdose and timing. Different basal rates can bepreset; for example, overnight could be lower thanduring the day or vice versa. Bolus boosts can begiven starting just before meals (if analogueinsulins are used), and infusion rates can bereduced during exercise.

The newer pumps are more reliable,38 and mayhave alarms for empty cartridges, low batteries,

Background

8

FIGURE 2 Disetronic H-TRON

FIGURE 3 Medtronic MiniMed 508

occlusion of tubing and faulty electronics, givingrise to less fear of undetected malfunction, whichwas a problem with some of the older pumps.There were isolated reports of pumps deliveringtoo much insulin (pump ‘run-away’, reported withthe Graseby MS3645) or being susceptible toelectrical forces.46 Mobile phones were thought tobe capable of upsetting pump function and thisappeared to be true with at least one older pump(the Microjet Quark) and one older phone, butonly when the phone was transmitting atmaximum power (8 W) and placed in directcontact with the pump.47 No such problem wasreported with the MiniMed pump regardless ofmodel of phone and direct contact. Modernphones have much lower maximum power, of1–2 W,47 and modern pumps have mechanisms toprotect against over-delivery.48

Why are pumps little used in the UK?Despite the invention of the technique in the UK,pumps are used much less there than in other

countries such as the USA, Germany, France andItaly (Table 3, Figure 4). The reasons for thisprobably include conservatism and cost concerns,but there have also been concerns about earlyreports of episodes of diabetic ketoacidosis (DKA)on CSII. A series of papers in the mid-1980sreported adverse events. Mecklenburg andcolleagues in 198449 found that diabetic controlimproved considerably on pump therapy but that42% of 161 patients experienced one or moreadverse events, the most serious being ketoacidosis(38 episodes in 26 patients; once in every 78patient months on CSII), which was commonerafter CSII than before, and commoner than in acomparison group on conventional insulininjections. The comparison group was notobtained by randomisation but some measureswere taken to make it reasonably well matched,except for pregnancies, with the pump group.Patients suffering DKA fell into three groups. Thelargest number had no DKA in the 5–25 monthsbefore starting pump therapy. The two othergroups consisted of those who had DKA bothbefore and after (pumps made little difference)and those who had DKA before but not after. Most


9


TABLE 3 Estimated pump use

Country Numbers Funding

USA 140,000 Fully funded by Medicare and private insuranceGermany 33,000 Fully reimbursed by insurance after 3-month trialFrance 9,500 Fully fundedItaly 5,700 Limited funding in 8 of 25 regionsThe Netherlands 4,700 Fully reimbursed by insurance after 1-month trialSweden 4,200 Fully fundedIsrael 1,900 Fully fundedJapan 1,500 No reliable informationCzech Republic 1,350 Fully fundedSwitzerland 1,300 Rental schemeUK 1,200 Random funding; no cohesive policyNorway 1,000 Fully fundedAustria 1,000 Fully funded by various schemesFinland 750 70% of cost refundedBelgium 750 Diabetic patients receive income support for 70% of costAustralia 500 Private insurance for pumps onlySpain 350 No fundingDenmark 350 Selective funding by hospital budgetsPoland 250 No funding, special cases onlyChina 250 Funded by hospital budgetsIrish Republic 100 Fully fundedSlovenia 50 Full funding for childrenHungary 20 No reliable informationGreece 20 No reliable informationNorthern Ireland 20 Health Boards looking at uniform policy and criteriaLatvia 20 No reliable informationRussia 10 No reliable informationKorea 20,000 No reliable information (pumps produced locally)

Source: INPUT, May 2002, reproduced with permission.

(128 of 161) patients did not have DKA on pumptherapy. The main cause of DKA was intercurrentillness; in half the episodes, patients had not beenchecking urine for ketones, which would havealerted them to the need to increase insulindosage; in half the episodes they had not followedinstructions about pump settings. Most of theepisodes of DKA happened in the first 5 monthsof CSII. Hence the failure may be partlyattributable to lack of education, or perhaps toomuch reliance on pumps, rather than CSII itself,although the authors reported pump malfunction,usually tubing problems, of some kind in 79% ofpatients. The commonest adverse event wasinjection site infection (once every 27 patientmonths)

Also in 1984, Teutsch and colleagues50 reportedthat there had been 35 deaths amongst theestimated 3500 pumps users in the USA at thattime, a rate no different from that expectedamongst non-CSII users. Two deaths appeared tobe directly attributable to pump therapy, onebeing due to pump malfunction and the other tobacterial endocarditis secondary to an infectedinjection site.

In the UK, Knight and colleagues51 in Sheffieldreported 13 episodes of DKA in 150 patient yearsof CSII. Nine of these occurred in the first year ofCSII. There were no instances of mechanicalfailure of the pump itself, but one episodefollowed disconnection of the cannula and anotherwhen the patient did not realise that there was noinsulin left. As in the Mecklenburg study, manyoccurrences of DKA followed other illnesses.

Knight and colleagues concluded that: “At present,the potential problem of severe hyperkalaemiaassociated with ketoacidosis during treatment witha pump creates doubt about the feasibility of CSII … .”

Also in 1984, the Kroc group reported anincreased risk of DKA in CSII compared withconventional therapy, but this time from arandomised study.52 However, the duration wasonly 8 months; eight patients had DKA.

Another adverse report came from Steel andWest,53 in the form of a case history of a pregnant diabetic woman whose baby diedin utero. This was related to incorrect use of thepump.

In 1986, the Sheffield group54 compared patientson CSII who had had DKA with those on CSIIwho had not. The main differences found werelength of full-time education and psychologicalmeasures such as locus of control. Those whosuffered DKA had left education 3 years earlier on average and were less likely to feel that theycould take control of their diabetes. The authors therefore concluded that it may bepossible to select out patients unsuitable for CSII or to provide better education and training.

In the DCCT, by contrast, there was no evidenceof increased DKA risk in pump users and this hasbeen the experience of groups with extensiveexperience of the use of CSII in the UK,55

Germany56 and the USA.57

Background

10

0

1

2

3

4

5

6

7

USA Germany Netherlands Israel France UK

Pum

p us

ers

(% T

ype

1 su

bjec

ts)

FIGURE 4 CSII use in different countries. Source: Pickup J, Guy’s, King’s and St Thomas’ School of Medicine, London: personalcommunication, 2002.

There have been two reports of CSII injection sitesbecoming infected with unusual organisms such asMycobacterium fortuitum58,59 and one set of authorswondered if the risk of infection with organismsfound in soil and water might be increased becauseusers could bathe and swim with some devices.59

The earlier reports nevertheless seem to have givenrise to a widespread belief in the UK that CSII isunsafe. For example, one hospital replying to apatient enquiry about funding a pump, said that:“Problems which arose from use of earlier CSIIsystems include reports of death due to diabeticketoacidosis following accidental disconnection ofthe pump and abscess formation at the site.”

One of the submissions received from patients forthis review said that doctors had old-fashionedopinions about pumps: “Many consultants I havespoken to have preconceived views on the pump.Because pumps were unreliable a few years agothey don’t seem to realise that technology moveson. Look at mobile phones 10 years ago. Look atthem now.”

There could be several reasons why the UK has hada much lower use of pumps than other countries:

� Experience with early, less reliable technologyand the ‘learning curve’

� ‘Migration’ of organised CSII research anddevelopment for want of resources in the UK(suggested by Keen H, Guy’s Hospital: personalcommunication, 2002).

� The fear of ketoacidosis.� Non-prescribability of pumps and adnexae

(perhaps partly based on the fear that largenumbers of patients with Type 1 diabetes wouldbe referred for CSII).

� Cost concerns and competition for fundingfrom other desirable developments. There maybe some clinics where there is support inprinciple for pump use, but where their priorityis lower than other items.

� Manpower resources, especially diabetesspecialist nurses (DSNs).

There is considerable interest in pumps amongstpatients and a growing interest from healthprofessionals, and two new groups have beenformed in the UK. The first is a users’ group,INPUT (Insulin Pump Therapy), which is: “… apatient led support group for diabetics usinginsulin pumps, run by pump users and theirfamilies, an information centre for people seekingfacts about insulin pumps, their use and how toobtain and fund them.”

The main aim of INPUT is to “increase theawareness and understanding of pump therapyand to have it funded by the Department ofHealth” (INPUT, October 2001,www.webshowcase.net/input).

The other group is an educational initiative forprofessionals in diabetes care, Pump Managementfor Professionals (PUMP),60 which organisestraining courses for medical and nursing staff.

Subsidiary questionsChildren, including overnight useGood control is difficult in children, and only aminority achieve it.30 Case series carried out in the1980s showed mixed results.61–64 A review in 1986summarised the finding of the early studies, andnoted conflicting results.65

Children at different ages need to be consideredseparately, perhaps grouped as follows;

� infants and toddlers under constant supervisionby parents

� young children attending nurseries or school,away from parents for part of the day

� older children who might be able to managepumps at school without supervision

� children old enough to look after themselves.

There has been debate about ages at whichchildren can manage their own pumps. It will varyamongst children according to their abilities.

One option that has been used, probablyinfrequently, is for children to have CSII onlyovernight,66,67 when they are under parentalsupervision. Overnight-only CSII has also beenused in adults.68,69

PregnancyCSII has been suggested as a way of normalisingdiabetic control in women with Type 1 diabetesduring pregnancy,70 or preconceptionally in orderto reduce the increased malformation rate seen inpoorly controlled diabetes.71 Various small earlystudies either had no control group72 or involvednon-randomised comparisons.73,74

In a 2000 review, Gabbe70 noted that CSII couldbe particularly useful in pregnancy because thebolus from pumps can be modified to fit with theslower absorption of nutrients associated with thedelayed gastric emptying seen in pregnancy.


11


However, he also noted that there is relativeinsulin resistance in the third trimester ofpregnancy, and that any interruption to insulinsupply could lead to an increased risk of DKA. Herecommended blood glucose testing at 2–3 a.m. inorder to check on insulin delivery.

In Auckland,75 CSII has been used for improvingcontrol in women with Type 2 diabetes andgestational diabetes, particularly those whorequired large (over 100 units per injection) dosesof insulin. These women were mainly Maori orSouth Sea Islanders. Insulin dosage and weightgain were greater on CSII but the comparison wasnot based on an RCT and numbers were small.

The key question for this review is whether CSIIhas any advantages over MDI when usedpreconceptually (for reducing malformations) orduring pregnancy (for improving outcomes for thebaby).

Insulin-resistant Type 2 diabetesA few studies have suggested that short periods ofCSII may be useful in patients with true Type 2diabetes who are poorly controlled on oral drugs.The rationale seems to be that improved controlwill reduce insulin resistance.

Analogue insulins in CSIIThere are theoretical advantages of short-actinganalogues in CSII because of the more rapid effectwhen used for bolus doses. The bolus could begiven when patients sit down to eat, rather than30 minutes before as with soluble, which may beuseful when the time of a meal is uncertain.

One implication is that in comparisons of MDIwith CSII, it is necessary to make sure that bothforms of intensive treatment use the same type ofinsulin. To compare CSII using analogues withMDI using soluble would introduce a confoundingfactor.

Background

12

MethodsThe a priori methods used for systematicallyreviewing evidence of clinical effectiveness weredescribed in the research protocol (Appendix 1),which was sent for expert comments to membersof the advisory panel for the review. Althoughmany helpful comments were received relating tothe general content of the research protocol, therewere none that identified specific problems withthe methods of review. Some changes, additions orpoints of clarification were made to the methodsdiscussed in the original protocol, and these areoutlined below.

� The evidence from the eligible RCTs andcrossover studies was supplemented withinformation from selected non-randomised andobservational studies, to provide information onareas where no evidence eligible for inclusionwas identified. A sensitive search forobservational studies was undertaken. Thesewere filtered by an information scientist andstudies for inclusion were then selected by anexperienced reviewer, looking specifically forstudies that could help answer questions 2, 3, 4and 6 on p. 1. An assessment of quality was notundertaken for these selected studies.

� Importantly it should be noted that the sections‘Quantity and quality of research’ (p. 14), ‘Resultsin adults with Type 1 diabetes’ (p. 16), ‘Pregnancy’(p. 32), ‘Adolescents’ (p. 36) and ‘Analogue versussoluble insulin in CSII’ (p. 38) are based on asystematic review of the evidence from eligibleRCTs and crossover studies, while informationfrom selected observational studies is discussed inthe sections ‘CSII in children’ (p. 37), ‘Overnight-only CSII in adults’ (p. 37), ‘Short-term CSII inpoorly controlled adults with Type 2 diabetes’ (p.37) and ‘Discontinuation rates’ (p. 42).

The methods outlined in the protocol aresummarised below.

Sources of information, search terms and a flowchart outlining the identification of studies aredescribed in Appendix 2. It was decided to run avery sensitive search in order to capture not onlyRCTs for efficacy, but also a wide range ofevidence, including:

� QoL studies� safety and side-effect studies, including a

selection of individual case reports that mightillustrate problems with pumps

� ‘real-life’ case series, especially those that gavedata on discontinuation rates

� a selection of reviews, old and new, partly tolook for reasons why the enthusiasm for pumpswaxed and waned in the last period of pumpactivity in the 1980s

� cost studies� studies on different types of insulin, such as

analogue versus soluble� studies using CSII for short periods to improve

insulin sensitivity in Type 2 diabetes� studies using CSII only for part of the day,

usually at night.

Background papers on the effect of improvedcontrol on long-term complications, mainly fromthe DCCT, Oslo, Stockholm and UKPDS studies,were also obtained. The search was carried out bya skilled information scientist. Abstracts (or justtitles in the minority of studies where no abstractwas available) were checked by two people. Of the3760 studies retrieved, 106 were selected forfurther scrutiny. Some of these were recentreviews, to give a check on completeness ofascertainment of RCTs and other studies. Otherswere exchanges of correspondence oncontroversial areas. A search of the electronic BMJwas carried out to capture correspondencefollowing the 2001 editorial,38 and the referencescited were checked. The Cochrane Library wassearched for RCTs, reviews and protocols and theCochrane Metabolic and Endocrine Group wasconsulted regarding any ongoing activity. Expertsin the field, including some of the pioneers ofpump use, were consulted as part of the advisorypanel. An unpublished meta-analysis andhistorical review were thus obtained.Manufacturers’ submissions to NICE werereviewed as a check on completeness of retrieval ofpublished trials.

The full text of relevant studies was examined andinclusion criteria were applied independently bytwo reviewers. An Access database was designedfor data extraction, which was carried out by onereviewer and checked by a second reviewer. The


13


Chapter 3

Clinical effectiveness

quality of eligible RCTs and crossover studies was assessed in accordance with chapter II.5 ofCRD Report 4 (2nd Edition) (Appendix 3).Quality criteria were applied by one reviewer and checked by a second reviewer. At each stage, any differences in opinion were resolvedthrough discussion or consultation with a thirdreviewer.

Inclusion criteriaStudies comparing CSII using insulin pumps withoptimised MDI (at least three injections per day)were included in the review. Comparisons ofanalogue and soluble insulin in CSII were alsoincluded. Comparisons of conventional therapy,implantable pumps and hospital inpatient pumpswere excluded.

The review includes people with insulin-treateddiabetes (Type 1 or Type 2), including adults,children, adolescents and pregnant women. Newlydiagnosed patients were excluded.

Parallel RCTs and randomised and non-randomised crossover studies were included in thereview. Studies with a duration of less than10 weeks on each treatment were excluded.

Studies were included if they reported one ormore of the following as primary outcomes:glycated haemoglobin, insulin dose, weightchange, lipid levels, patient preference, QoL oradverse effects.

Studies in non-English language or available only as abstracts were excluded from the mainanalysis.

Studies excluded from the review are listed inAppendix 4 and a list of recent studies reportedonly as abstracts is given in Appendix 5.

Data synthesisData were synthesised through a narrative reviewwith tabulation of all eligible studies. Data onglycated haemoglobin and insulin dose werecombined where appropriate in a meta-analysissummarising the weighted mean difference(WMD) using the random-effects model. Inassessing glycated haemoglobin, HbA1 and HbA1c

were considered sufficiently similar on clinicalgrounds to be combined within the meta-analysis,focusing on changes rather than absolute values.Further stratification by assay type was notundertaken owing to the lack of additional clarityprovided by the small number of studies reportingat each length of follow-up. A sensitivity analysis

was performed excluding non-randomisedcrossover studies.

CSII versus MDIQuantity and quality of researchTwenty studies comparing CSII and MDI met theinclusion criteria for the review and are shown inTables 4–15 and Appendices 6–13. These includedeight parallel RCTs, nine randomised crossoverstudies and three non-random crossover studies.Fourteen studies included adults with Type 1diabetes, four studies included pregnant women,and two studies included adolescents. One studywas reported in three publications.76–78 Only twoof the studies comparing CSII and MDI usedanalogue insulins for both groups.79,80

No RCTs or crossover studies were identified inchildren [see the section ‘CSII in children’ (p. 37)],CSII overnight only in adults [see the section‘Overnight-only CSII in adults’ (p. 37)] or inpoorly controlled adults with Type 2 diabetes [seethe section ‘Short-term CSII in poorly controlledadults with Type 2 diabetes’ (p. 37)]. Selectedobservational studies were discussed in thesesections, and no assessment of quality wasundertaken.

Adults with Type 1 diabetesThe quality of reporting and methodology of theincluded studies was generally poor by today’sstandards (Table 4). Of the 14 studies includingadults with Type 1 diabetes, the method ofrandomisation was adequate in just two, byBrinchmann-Hansen and colleagues76 and Tsuiand colleagues,79 both of which were parallelRCTs. The three non-randomised crossoverstudies were assessed as having an inadequatemethod of randomisation81–83 and the method wasnot reported in the remaining studies. Allocationconcealment was inadequate in four studies79,81–83

and unknown in 10 studies; therefore, they may besubject to selection bias. Moreover, the similarityof groups at baseline was reported by just fourstudies.76,79,84,85 Eligibility criteria for entry intothe study were reported in eightstudies76,79–81,83,84,86,87 but were not reported insix.82,85,88–91 Point estimates and measure ofvariability were presented for the primary outcomemeasure in most studies, but this was only partiallyreported in three studies where the data werepresented in figures only and had to beextrapolated.76,84,90 Data were analysed accordingto intention-to-treat (ITT) principles in fourstudies79,84–86 and withdrawals were adequately


14

reported in seven studies.76,80,83,85–87,90 Threestudies79,84,91 partially reported loss to follow-up(numbers but not reasons, or vice versa) and inone study88 the numbers were not specified foreither group. Three studies did not report loss tofollow-up.81,82,89

PregnancyTwo of the four parallel RCTs comparing CSII andMDI in pregnancy were thought to haverandomisation that was partially adequate,92,93 butallocation concealment was inadequate (Table 4).The method of randomisation was not stated inthe studies by Carta and colleagues94 and Burkartand colleagues,95 and therefore concealment ofallocation was unknown. The similarity of groupsat baseline was reported by just two of thestudies.93,94 Eligibility criteria for entry into thestudy were not clearly stated in three studies.92–94

Point estimates and measure of variability werepresented for the primary outcome measure in twostudies;92,93 however, this was only partiallyreported in the study by Carta and colleagues,94

where the data were presented in figures only andhad to be extrapolated, and by Burkart andcolleagues,95 where mean blood glucose or

glycated haemoglobin was not reported. ITTanalysis was not used in the studies and, althoughit may be assumed that no loss to follow-upoccurred, this was not clearly stated in any of thestudies.

AdolescentsThe two studies comparing CSII and MDI96 orCSII, MDI and CSII during the night plus MDIduring the day97 in adolescents were of poormethodological quality (Table 4). The crossoverstudies were said to be randomised, but themethod of randomisation was not specified andallocation concealment was unclear.96,97 Thesimilarity of groups at baseline was not reportedby either study. Eligibility criteria were notreported in the study by Schiffrin and colleagues97

and point estimates and measure of variabilitywere only partially reported in that study as thedata were presented in figures and had to beextrapolated.97 ITT analysis was not used in eitherstudy and, although Schiffrin and colleaguesreported the numbers withdrawn from eachgroup, the reasons for withdrawal were not given97

and Tamborlane and colleagues did not reportloss to follow-up.96


15


TABLE 4 Quality assessment of studies comparing CSII versus MDI

Study Random Allocation Group Eligibility Point ITT Withdrawalsconcealment similarity estimates

Type 1 diabetesBak, 198787 Unknown Unknown Unknown Adequate Adequate Inadequate AdequateBode, 199681 Inadequate Inadequate Unknown Adequate Adequate Inadequate UnknownBrinchmann-Hansen, 198876 Adequate Unknown Reported Adequate Partial Inadequate AdequateChiasson, 198482 Inadequate Inadequate Unknown Unknown Adequate Inadequate UnknownHaakens, 199083 Inadequate Inadequate Unknown Adequate Adequate Inadequate AdequateHanaire-Broutin, 200080 Unknown Unknown Unknown Adequate Adequate Inadequate AdequateHome, 198288 Unknown Unknown Unknown Unknown Adequate Inadequate InadequateNathan, 198289 Unknown Unknown Unknown Unknown Adequate Inadequate UnknownNosadini, 198885 Unknown Unknown Reported Unknown Adequate Adequate AdequateSaurbrey, 198890 Unknown Unknown Unknown Unknown Partial Inadequate AdequateSchiffrin, 198291 Unknown Unknown Unknown Unknown Adequate Inadequate PartialSchmitz, 198986 Unknown Unknown Unknown Adequate Adequate Adequate AdequateTsui, 200179 Adequate Inadequate Reported Adequate Adequate Adequate PartialZiegler, 199084 Unknown Unknown Reported Adequate Partial Adequate Partial

PregnancyBurkart, 198895 Unknown Unknown Unknown Adequate Partial Inadequate UnknownCarta, 198694 Unknown Unknown Reported Unknown Partial Inadequate UnknownCoustan, 198693 Partial Inadequate Reported Unknown Adequate Inadequate UnknownNosari, 199392 Partial Inadequate Unknown Unknown Adequate Inadequate Unknown

AdolescentsSchiffrin, 198497 Unknown Unknown Unknown Unknown Partial Inadequate PartialTamborlane, 198996 Unknown Unknown Unknown Adequate Adequate Inadequate Unknown

See Appendix 3 for description of coding.

Results in adults with Type 1 diabetesFour randomised parallel,76,79,84,85 sevenrandomised crossover80,86–91 and three non-randomised crossover81–83 studies compared CSIIand MDI in adults with Type 1 diabetes, and areshown in Tables 4–10 and Appendices 6 and 10.Two of the 14 trials (one randomised crossover80

and one randomised parallel79) compared CSIIand MDI using the analogue insulin lispro,whereas the remaining studies compared CSII andMDI using regular insulin. Not all studies used theHbA1c that is standard today, but it is thedifference rather than the absolute values thatmatters. Six of the studies report HbA1,

76,82–84,88,91

seven report HbA1c79–81,85,86,89,90 and one reports

blood glucose only.87 Data are discussed in thisreview according to the reported length of follow-up. One caveat is that many of these studies arefairly old and used obsolete technologies.

Glycated haemoglobin and blood glucoseEight studies reported glycated haemoglobin at10 weeks to 4 months of follow-up(Table 5).76,78–80,82,88–91 A mean reduction in

glycated haemoglobin from baseline of between0.5% and 5.1% was found for CSII treatment, andbetween –1.0% to 4.8% for MDI treatment. Muchof this variation may be explained by differencesin baseline glycated haemoglobin between studies,which ranges from 7.7% for the CSII group in theparallel RCT by Tsui and colleagues79 to 13.2% inthe random crossover study by Schiffrin andcolleagues.91 At 10 weeks to 4 months follow-up,five studies found that glycated haemoglobin waslower with CSII than MDI, reporting a meanreduction of between 0.3% and 2.48%.79,80,88,89,91

This difference was statistically significant in justtwo of the studies (0.35%, p < 0.0001;80 1.7%,p = 0.02688), two other studies reported a non-significant reduction79,91 and one study89 did notreport statistical significance. Saurbrey andcolleagues found no difference in glycatedhaemoglobin between CSII and MDI at 10 weeksof follow-up,90 and two trials reported slightlyhigher glycated haemoglobin with CSII comparedwith MDI [8.9% versus 8.7%, p not reported;76,78

9.1% versus 8.7%, p = not statistically significant(ns)82]. Five of the eight studies provided data


16

TABLE 5 Glycated haemoglobin in adults with Type 1 diabetes

Study Mean glycated haemoglobin (SD) Difference

CSII MDI(MDI – CSII)

Bak, 198787 Glycated haemoglobin not reportedRandom crossover Blood glucose: Blood glucose:N: 20; end of study: 16 Month 6: 7.7 mmol/l (0.7) Month 6: 7.9 mmol/l (0.7), p = ns 0.2 mmol/lBaseline BG not reported

Bode, 199681 Month 12: 7.4% (1.2) 7.7% (1.5), p = ns 0.3%Non-random crossover Month 24: 7.7% (1.7) Not reportedN: 55. Month 36: 7.4% (1.7) Not reportedHbA1c data collected Month 48: 7.4% (1.2) Not reportedBaseline not reported

Brinchmann-Hansen, 198876,78 Month 3: 8.9% 8.7% –0.2%Parallel RCT Month 6: 9.2% 8.8% –0.4%CSII n: 15; MDI n: 15 Month 12: 8.5% 8.5% 0%HbA1 data collected Month 24: 8.7% (1.16) 9.1% (1.55) 0.4%Baseline CSII: 10.1% (1.55) Month 41: 9.1% 9.4% 0.3%Baseline MDI: 9.4% (1.55)

Chiasson, 198482 Month 3: 9.1% (1.04) 8.7% (1.39), p = ns –0.4%Non-random crossoverN: 12HbA1 data collectedBaseline: 11.9% (2.08)

Haakens, 199083 Month 6: 9.6% (2.47) 9.8% (1.85), p = ns 0.2%Non-random crossoverN: 52; end of study: 35HbA1 data collectedBaseline: 10.4% (1.85)

continued


17


TABLE 5 Glycated haemoglobin in adults with Type 1 diabetes (cont’d)

Study Mean glycated haemoglobin (SD) Difference


Hanaire-Broutin, 200080 Month 4: 7.89% (0.77) 8.24% (0.77), p<0.001 0.35%Random crossoverN: 41; end of study: 40HbA1c data collectedBaseline: 8.39% (0.87)

Home, 198288 Month 2.5: 10% (2.2) 11.7% (1.9), p = 0.026 1.70%Random crossoverN: 11; end of study: 10HbA1 data collectedBaseline: 10.7% (1.9)

Nathan, 198289 Month 3: 5.4% (0.34) 7.88% (1.37), p not reported 2.48%Random crossoverN: 5HbA1c data collectedBaseline: 9.03% (1.43)

Nosadini, 198885 CSII fixed night basal rate: MDI: 0.8% (MDI – Parallel RCT Month 12: 6.3% (0.7) 7.1% (0.9), p <0.01 (vs CSII fixed) CSII fixed)CSII fixed n: 19; MDI n: 15CSII variable n: 10 CSII with variable night basal rate: 1% (MDI – CSII HbA1c data collected Month 12: 6.1% (0.9), p < 0.01 variable)Baseline not reported (vs MDI)

Saurbrey, 198890 Month 2.5: 7.5% 7.5% 0%Random crossoverN: 21, end of study: 19HbA1c data collectedBaseline (CSII then MDI): 8.7% (1.74)Baseline (MDI then CSII) 8.8% (2.17)

Schiffrin, 198291 Month 3: 8.1% (0.6) 8.4% (0.7), p = ns 0.3%Random crossover. Month 6: 8.2% (0.5) 8.4% (0.5), p = ns 0.2%N: 20; end of study: 16HbA1 data collectedBaseline: 13.2% (1.1)

Schmitz, 198986 Month 6: 7% (1) 7.7% (1), p = 0.002 0.7%Random crossoverN: 10HbA1c data collectedBaseline: 7.6% (0.9)

Tsui, 200179 Month 3: 6.92% 7.55%. Treatment effect (adjusted 0.63%Parallel RCT for baseline HbA1c) = –0.21 CSII N:13; end of study: 12 (95% CI –0.59 to 0.17), p > 0.10MDI N: 14; end of study:14 Month 6: 7.19% 7.62%. Treatment effect (adjusted 0.43%HbA1c data collected for baseline HbA1c) = –0.01 Baseline CSII: 7.73% (0.6) (95% CI –0.44 to 0.42), p > 0.10Baseline MDI: 8.16% (0.7) Month 9: 7.38% 7.56%. Treatment effect (adjusted 0.18%

for baseline HbA1c) = 0.25 (95% CI –0.19, 0.68), p >0.10

Ziegler, 199084 Month 6: 8.2% 8.8%, p < 0.05 0.6%Parallel RCT Month 12: 8.5% 8.7%, p = ns 0.2%CSII N: 49; end of study: 36 Month 18: 8.5% 8.4%, p = ns –0.1%MDI N: 47; end of study: 37 Month 24: 8.6% 8.5%, p = ns –0.1%HbA1 data collectedBaseline CSII: 9.8%Baseline MDI: 9.5%, p = ns

BG, blood glucose; N, number of patients.

[means and standard deviations (SDs)] thatallowed them to be combined in a meta-analysis(Figure 5).80,82,88,89,91 Pooling the data using arandom-effects model (�2 test for heterogeneity15.68, df = 4, p = 0.0035) showed an overallreduction in glycated haemoglobin with CSIIcompared with MDI (–0.64, 95% CI –1.28 to 0.01).Because of the heterogeneity, these results shouldbe viewed with some caution, but theheterogeneity was around the effect size. Thestudy by Home and colleagues88 used a sub-optimal MDI regime with bovine ultralenteinsulin, and HbA1c actually worsened during MDIcompared with conventional treatment at baseline,thereby exaggerating the effects of CSII. Hencethere is an argument for excluding this study onthe grounds that the control arm did not receiveoptimal MDI. Repeating the meta-analysis without

this study (Figure 6) reduced the effect size (–0.52,95% CI –1.19 to 0.14, p = 0.12).

Six studies reported glycated haemoglobin at6 months follow-up (Table 5).76,78,79,83,84,86,91 Amean reduction from baseline of between 0.54%and 5% was found for CSII and between –0.1 and4.8% for MDI. Five of the studies found thatglycated haemoglobin was lower with CSII thanMDI, reporting a mean reduction of between 0.7%and 0.2%.79,83,84,86,91 This difference wasstatistically significant in just two of the studies(0.7%, p = 0.00286; 0.6%, p < 0.0584).Brinchmann-Hansen and colleagues found slightlyhigher glycated haemoglobin with CSII than withMDI (9.2% versus 8.8%), but significance was notreported.76,78 Three of the six studies reportingglycated haemoglobin at 6 months could be


18

01 2.5 to 4 monthsx Brinchmann, 1988

Chiasson, 1984Hanaire-Broutin, 2000Home, 1982Nathan, 1982

x Saurbrey, 1988Schiffrin, 1982

x Tsui, 2001Subtotal (95% CI)Test for heterogeneity χ2 = 15.68, df = 4, p = 0.0035Test for overall effect z = 1.93, p = 0.05

02 6 monthsx Brinchmann, 1988

Haakens, 1990Schiffrin, 1982Schmitz, 1989

x Tsui, 2001x Ziegler, 1990Subtotal (95% CI)Test for heterogeneity χ2 = 1.10, df = 2, p = 0.58Test for overall effect z = 1.67, p = 0.10

04 12 monthsBode, 1996

x Brinchmann, 1988Nosadini, 1988

x Ziegler, 1990Subtotal (95% CI)Test for heterogeneity χ2 = 2.57, df = 1, p = 0.11Test for overall effect z = 1.75, p = 0.08

15 8.90 (0.00) 14 8.70 (0.00) 12 9.10 (1.04) 12 8.70 (1.39) 40 7.89 (0.77) 40 8.24 (0.77) 10 10.00 (2.20) 10 11.70 (1.90) 5 5.40 (0.34) 5 7.88 (1.37) 19 7.50 (0.00) 19 7.50 (0.00) 16 8.10 (0.60) 16 8.40 (0.70) 12 6.92 (0.00) 14 7.55 (0.00)129 130

15 9.20 (0.00) 14 8.80 (0.00) 35 9.60 (2.47) 35 9.80 (1.85) 16 8.20 (0.50) 16 8.40 (0.50) 10 7.00 (1.00) 10 7.70 (1.00) 12 7.19 (0.00) 14 7.62 (0.00) 36 8.20 (0.00) 37 8.80 (0.00)124 126

55 7.40 (1.20) 55 7.70 (1.50) 15 8.50 (0.00) 14 8.50 (0.00) 19 6.10 (0.90) 10 7.10 (0.90) 36 8.50 (0.00) 37 8.70 (0.00)125 116

0.0 Not estimable18.5 0.40 (–0.58 to 1.38)29.7 –0.35 (–0.69 to –0.01)

9.2 –1.70 (–3.50 to 0.10)14.7 –2.48 (–3.72 to –1.24)

0.0 Not estimable27.9 –0.30 (–0.75 to –0.15)

0.0 Not estimable100.0 –0.64 (–1.28 to 0.01)

0.0 Not estimable9.0 –0.20 (–1.22 to 0.82)

78.7 –0.20 (–0.55 to 0.15)12.3 –0.70 (–1.58 to 0.18)

0.0 Not estimable0.0 Not estimable

100.0 –0.26 (–0.57 to 0.05)

55.8 –0.30 (–0.81 to 0.21)0.0 Not estimable

44.2 –1.00 (–1.69 to –0.31)0.0 Not estimable

100.0 –0.61 (–1.29 to 0.07)

–4 –2 2 40Favours CSII Favours MDI

Study mean (SD)CSII

n mean (SD)MDI

nWMD

(95% CI Random)Weight

%WMD(95% CI Random)

FIGURE 5 Meta-analysis of the effect of CSII versus MDI on glycated haemoglobin in adults with Type 1 diabetes. Note: HbA1 isreported by Brinchmann-Hansen, 1988,76 Chiasson, 1984,82 Haakans, 1990,83 Home, 1982,88 Schiffrin, 198291 and Ziegler, 1990.84

HbA1c is reported by Bode, 1996,81 Hanaire-Broutin, 2000,80 Nathan, 1982,89 Nosadini, 1988,85 Saurbrey, 1988,90 Schmitz, 198986

and Tsui, 2001.79

combined in a meta-analysis (Figure 5).83,86,91

Pooling the data using a random-effects model (�2

test for heterogeneity = 1.10, df = 2, p = 0.58)showed a non-significant reduction in glycatedhaemoglobin with CSII compared with MDI(–0.26, 95% CI –0.57 to 0.05).

Only one study reported glycated haemoglobin at9 months of follow-up79 (Table 5). Tsui andcolleagues found a reduction from baseline of0.35% with CSII and 0.60% with MDI. A non-significant difference between CSII and MDI wasfound (7.38% versus 7.56%) at 9 months of follow-up, with a treatment effect of 0.25 (95% CI –0.19to 0.68, p > 0.10) adjusted for baseline glycatedhaemoglobin.

Four studies reported glycated haemoglobin at12 months follow-up (Table 5).76,78,81,84,85 Only twostudies report baseline data, demonstrating amean reduction from baseline of 1.3%84 to1.6%76,78 for CSII and 0.8%84 to 0.9%76,78 forMDI. Nosadini and colleagues report significantlylower glycated haemoglobin with both fixed rate(6.3%) and variable rate (6.1%) CSII comparedwith MDI (7.1%, p < 0.01).85 However, threestudies report no difference between CSII andMDI (0% to 0.2%, p = ns).76,78,81,84 Two of the fourstudies provided data that allowed them to becombined in a meta-analysis (Figure 5).81,85 As thestudy by Nosadini and colleagues85 had twogroups with CSII, only the group with the variableinsulin rate was included in the meta-analysis, asthis had the lowest mean glycated haemoglobinlevel and may provide optimal control. Pooling thedata using a random-effects model (�2 test forheterogeneity 2.57, df = 1, p = 0.11) revealed anon-significant result in favour of CSII (–0.61,95% CI –1.29 to 0.07).

Two studies reported glycated haemoglobin at24 months of follow-up (Table 5), showing a meanreduction from baseline of between 1.2%84 and1.4%76,78 for CSII and between 0.3%76,78 and 1%84

for MDI. Brinchmann-Hansen and colleaguesreport lower glycated haemoglobin with CSII thanMDI (8.7% versus 9.1%), although significance isnot reported,76,78 and Ziegler and colleaguesreport no significant difference between CSII andMDI (8.6% versus 8.5%, p = ns) at 12 months.84

Studies could not be combined into a meta-analysis, as SDs were not presented.

Bode and colleagues81 reported glycatedhaemoglobin at 24 (7.7%, SD 1.7), 36 (7.4%, SD1.7) and 41 months (7.4%, SD 1.2) follow-up forCSII treatment only (Table 5). This was a

prospective non-randomised crossover study inwhich patients were switched to CSII after at least12 months with MDI.

Brinchmann-Hansen and colleagues76,78 reportedglycated haemoglobin at 41 months of follow-up(Table 5), demonstrating a mean reduction of 1.0% from baseline with CSII and no change withMDI. Glycated haemoglobin was lower with CSIIthan with MDI at 41 months of follow-up (8.7%versus 9.1%), but statistical significance was notreported.

Bak and colleagues87 did not report glycatedhaemoglobin, presenting blood glucose at12 months but not at baseline (Table 5). This studyshows a non-significant improvement in bloodglucose with CSII compared with MDI [7.7(SD 0.7) mmol/l versus 7.9 (SD 90.7) mmol/l, p = ns).

Glycated haemoglobin: sensitivity analysisA further meta-analysis was conducted without thethree non-randomised studies (Chiasson andcolleagues,82 3 months of follow-up; Haakens andcolleagues,83 6 months of follow-up; and Bode andcolleagues,81 12 months of follow-up), as there is agreater possibility of bias in non-randomised trials.

At 10 weeks to 4 months of follow-up, fourrandomised trials could be combined in a meta-analysis (Figure 7).80,88,89,91 Pooling the data usinga random-effects model (�2 test for heterogeneity12.95, df = 3, p = 0.0047) showed a significantreduction in glycated haemoglobin favouring CSIIcompared with MDI (–0.87, 95% CI –1.59 to–0.16). This shows a slightly greater reduction withCSII compared with the earlier meta-analysis(Figure 5). However, even with the non-randomstudies excluded, significant heterogeneity was stillpresent.

At 6 months of follow-up, two randomised trialscould be combined in a meta-analysis(Figure 7).86,91 Pooling the data using a random-effects model (�2 test for heterogeneity 1.08,df = 1, p = 0.3) showed that glycatedhaemoglobin was not significantly reduced withCSII compared with MDI at 6 months of follow-up(–0.28, 95% CI –0.64 to 0.08). This is similar tothe earlier meta-analysis (Figure 5).

Removing the study by Bode and colleagues81

at 12 months of follow-up leaves just onerandomised trial presenting means and standarddeviations; therefore, a meta-analysis cannot becarried out.


19


The shortage of long-term studies is unfortunate,since it is likely that it takes some time foroptimum dosage to be worked out and for patientsto become familiar with adjusting their insulindosages, and perhaps in particular experimentingwith different basal rates at different times of dayand night. Nevertheless, the limited amount ofdata from the trials does suggest that results mayimprove with longer duration.

SummaryThe evidence is consistent in showing animprovement in glycated haemoglobin on CSIIcompared with MDI, the difference averagingabout 0.5%.

CaveatAs has been pointed out to us (Home, PD,Department of Diabetes, The Medical School,


20


Chiasson, 1984Hanaire-Broutin, 2000Nathan, 1982



15 8.90 (0.00) 14 8.70 (0.00) 12 9.10 (1.04) 12 8.70 (1.39) 40 7.89 (0.77) 40 8.24 (0.77) 5 5.40 (0.34) 5 7.88 (1.37) 19 7.50 (0.00) 19 7.50 (0.00) 16 8.10 (0.60) 16 8.40 (0.70) 12 6.92 (0.00) 14 7.55 (0.00)119 120

0.0 Not estimable20.1 0.40 (–0.58 to 1.38)33.0 –0.35 (–0.69 to –0.01)16.0 –2.48 (–3.72 to –1.24)

0.0 Not estimable30.9 –0.30 (–0.75 to 0.15)

0.0 Not estimable100.0 –0.52 (–1.19 to 0.14)


Study mean (SD)CSII

n mean (SD)MDI

nWMD


%WMD(95% CI Random)

FIGURE 6 Meta-analysis of the effect of CSII versus MDI on glycated haemoglobin in adults with Type 1 diabetes, excluding Homeand colleagues.88 Note: HbA1 is reported by Brinchmann-Hansen, 1988,76 Chiasson, 1984,82 and Schiffrin, 1982.91 HbA1c is reportedby Hanaire-Broutin, 2000,80 Nathan, 1982,89 Saurbrey, 198890 and Tsui, 2001.79


Hanaire-Broutin, 2000Home, 1982Nathan, 1982



02 6 monthsx Brinchmann, 1988

Schiffrin, 1982Schmitz, 1989

x Tsui, 2001x Ziegler, 1990Subtotal (95% CI)Test for heterogeneity χ2 = 1.08, df = 1, p = 0.3Test for overall effect z = 1.52, p = 0.13

15 8.90 (0.00) 14 8.70 (0.00) 40 7.89 (0.77) 40 8.24 (0.77) 10 10.00 (2.20) 10 11.70 (1.90) 5 5.40 (0.34) 5 7.88 (1.37) 19 7.50 (0.00) 19 7.50 (0.00) 16 8.10 (0.60) 16 8.40 (0.70) 12 6.92 (0.00) 14 7.55 (0.00)117 118

15 9.20 (0.00) 14 8.80 (0.00) 16 8.20 (0.50) 16 8.40 (0.50) 10 7.00 (1.00) 10 7.70 (1.00) 12 7.19 (0.00) 14 7.62 (0.00) 36 8.20 (0.00) 37 8.80 (0.00) 89 91

0.0 Not estimable36.4 –0.35 (–0.69 to –0.01)11.3 –1.70 (–3.50 to 0.10)18.1 –2.48 (–3.72 to –1.24)

0.0 Not estimable34.2 –0.30 (–0.75 to 0.15)

0.0 Not estimable100.0 –0.87 (–1.59 to –0.16)

0.0 Not estimable83.8 –0.20 (–0.55 to 0.15)16.2 –0.70 (–1.58 to 0.18)

0.0 Not estimable0.0 Not estimable

100.0 –0.28 (–0.64 to 0.08)


Study mean (SD)CSII

n mean (SD)MDI

nWMD


%WMD(95% CI Random)

FIGURE 7 Meta-analysis of the effect of CSII versus MDI on glycated haemoglobin in adults with Type 1 diabetes, excluding non-random studies. Note: HbA1 is reported by Brinchmann-Hansen, 1988,76 Home, 1982,88 Schiffrin 1982,91 and Ziegler, 1990.84 HbA1cis reported by Hanaire-Broutin, 2000,80 Nathan, 1982,89 Saurbrey, 1988,99 Schmitz, 198986 and Tsui, 2001.79

Newcastle: personal communication, 2002), HbA1c

may not be a perfect guide to diabetes control inpeople who achieve good overall HbA1c levels butwho have problems with hypoglycaemia, since thehypoglycaemic events will reduce the HbA1c. IfCSII reduces the frequency of hypoglycaemia, ofwhatever degree, that will tend to increase HbA1c,and this may conceal the extent of theimprovement in control of hyperglycaemia.

Daily insulin doseInsulin dose was reported in the studies usingeither units per day (U/day) or units per kilogramper day (U/kg/day), and the data are discussedhere for each method separately, according to thereported length of follow-up.

Five studies reported insulin dose at 10 weeks to4 months follow-up (Table 6), with four studiespresenting insulin in units per day80,82,88,89 andone study presenting insulin units per kilogramper day.90 Compared with baseline, a meandecrease in insulin dose of 1.2–9 U/day wasobserved with CSII and a mean increase of3.7–20 U/day was observed with MDI.80,82,88,89

Three studies found significantly less insulin wasrequired with CSII than with MDI(8.80–29 U/day).80,82,88 The fourth study, byNathan and colleagues, found a lower daily insulindose with CSII compared with MDI [35.4 (SD11.5) U/day versus 48.8 (SD 13.18) U/day] but didnot report statistical significance.89 Pooling thesedata into a meta-analysis using a random-effectsmodel (�2 test for heterogeneity 3.78, df = 3,p = 0.29) shows an overall significant reduction ofabout 12 U/day in daily insulin dose after 10 weeksto 4 months of treatment on CSII compared withMDI (–11.90 units, 95% CI –18.16 to –5.63)(Figure 8). Repeating the meta-analysis without thestudy by Home and colleagues,88 which used asuboptimal MDI regime with bovine insulin,(Figure 9) slightly reduces the effect size (–9.73,95% CI –14.55 to –4.91), but the decrease ininsulin dose with CSII remains significant.

Saurbrey and colleagues90 found a mean reductionin insulin dose from baseline of 0.05 and0.03 U/kg/day at 10 weeks of follow-up for CSIIand MDI, respectively. Insulin use was slightlylower with CSII than MDI (0.62 versus0.64 U/kg/day), but statistical significance was notpresented.

Four studies83,86,87,91 reported insulin dose at6 months of follow-up (Table 6); two87,91 presentthe data as units per day and two83,86 units perkilogram per day. Insulin dose increased from

baseline in the study by Bak and colleagues (CSII0.6, MDI 5.9 U/day),87 but decreased in the studyby Schiffrin and colleagues (CSII –6, MDI–4 U/day).91 Haakens and colleagues reportedinsulin dose for MDI with isophane and withultralente, with a difference from baseline of –0.04and 0.03 U/kg/day (p = ns), respectively. Insulindose with CSII was significantly lower than atbaseline (0.64 versus 0.76 U/kg/day, p < 0.001).83

Schmitz and colleagues reported the meandifference from baseline for CSII as 0.05 U/kg/day(p = 0.03) and for MDI as 0 U/kg/day (p = ns).86

Daily insulin dose at 6 months of follow-up waslower with CSII than with MDI: between 2.0(p = ns)91 and 5.30 U/day (p < 0.05),87 andbetween 0.05 (p = 0.02)86 and 0.08 U/kg/day(p < 0.005) for isophane and 0.15 U/kg/day(p < 0.001) for ultralente.83 The differencebetween isophane and ultralente was alsostatistically significant (p < 0.01). A meta-analysisof insulin dose at 6 months of follow-up could not be performed as two studies did not present SDs.

Insulin dose was not often reported after 6 monthsof follow-up (Table 6). At 9 months of follow-up,Tsui and colleagues79 found little differencecompared with baseline (0.1 U/kg/day decrease forCSII and no change for MDI) or betweentreatments (0.1 U/kg/day, p = ns). Bode andcolleagues81 reported a non-significant decrease of6.50 U/day with CSII compared with MDI at12 months of follow-up, but did not reportbaseline values. As with glycated haemoglobin, theauthors also reported insulin dose for CSII at 24(36.6 U/day), 36 (37.7 U/day) and 48 months(37.8 U/day), but did not follow patients on MDIfor this length of time.

At 24 months of follow-up, Brinchmann-Hansenand colleagues78 found a decrease in insulin doseof 0.12 U/kg/day for CSII compared with baselineand no change for MDI (Table 6). There was nosignificant difference between CSII and MDI[0.68 U/kg/day (SD 0.19) versus 0.72 U/kg/day(SD 0.72), p = ns].

Daily insulin dose: sensitivity analysisA further meta-analysis was conducted without thenon-randomised study (Chiasson and colleagues82)at 10 weeks to 4 months follow-up (Figure 10).Pooling the three randomised studies80,88,89 thatreported data in units per day using a random-effects model (�2 test for heterogeneity 3.72, df = 2,p = 0.16) showed that the decrease in insulin dosewith CSII compared with MDI remained significant(WMD –13.63, 95% CI –23.62 to –3.64).


21



22

TABLE 6 Insulin dose in adults with Type 1 diabetes

Study Mean insulin dose (SD) Difference


Bak, 198787 Month 6: 46.6 U/day (10) 51.9 U/day (12.9), p < 0.05 5.3 U/dayRandom crossoverN: 20; end of study: 16Baseline: 46 U/day (16)

Bode, 199681 Month 12: 36.4 U/day (12.1) 42.9 U/day (17.9), p = ns 6.5 U/dayNon-random crossover Month 24: 39.6 U/day (14.4)N: 55 Month 36: 37.7 U/day (13.1)Baseline not reported Month 48: 37.8 U/day (14.2)

Brinchmann-Hansen, 198878 Month 24: 0.68 U/kg/day (0.19) 0.72 U/kg/day (0.12), p = ns 0.04 U/kg/dayParallel RCTCSII N: 15; MDI N: 15Baseline CSII: 0.8 U/kg/day (0.23)Baseline MDI: 0.72 U/kg/day (0.08)

Chiasson, 198482 Month 3: 43.9 U/day (10) 56.1 U/day (20.4), p < 0.01 12.2 U/dayNon-random crossoverN: 12Baseline: 44.7 U/day (14.6)

Haakens, 199083 Month 6: 0.64 U/kg/day (0.18) Month 6: MDI/human isophane 0.08 U/kg/dayNon-random crossover 0.72 U/kg/day (0.25), p < 0.005N: 52; end of study: 35 Month 6: MDI/human ultralente 0.15 U/kg/dayBaseline: 0.76 U/kg/day (0.25). 0.79 U/kg/day (0.25), p < 0.001

(isophane vs ultralente, p < 0.01)

Hanaire-Broutin, 200080 Month 4: 38.5 U/day (9.8) 47.3 U/day (14.9), p < 0.0001 8.8 U/dayRandom crossoverN: 41; end of study: 40Baseline: 43.6 U/day (13.5)

Home, 198288 Month 2.5: 51 U/day (15.8) 80 U/day (28.5), p = 0.004 29 U/dayRandom crossoverN: 11; end of study: 10Baseline: 60 U/day (18.97)

Nathan, 198289 Month 3: 35.4 U/day (11.5) 48.8 U/day (13.18) 13.4 U/dayRandom crossoverN: 5Baseline: 42.8 U/day (16.04)

Saurbrey, 198890 Month 2.5: 0.62 U/kg/day (0.17) 0.64 U/kg/day (0.13) 0.02 U/kg/dayRandom crossover (values collected during (values collected during N: 21; end of study: 19 treatment period) treatment period)Baseline: 0.67 U/kg/day (0.4)

Schiffrin, 198291 Month 6: 42 U/day 44 U/day, p = ns 2 U/dayRandom crossoverN: 20, end of study: 16Baseline: 48 U/day

Schmitz, 198986 Month 6: 0.55 U/kg/day (0.1) Month 6: 0.6 U/kg/day (0.11), 0.05 U/kg/dayRandom crossover p = 0.02N: 10Baseline: 0.6 U/kg/day (0.11)

Tsui, 200179 Month 9: 0.6 U/kg (0.2) 0.7 U/kg/day (0.2). Treatment 0.1 U/kg/dayParellel RCT effect (adjusted for baseline insulin):CSII N: 13; end of study: 12 –0.10 (95% CI–0.26 to 0.07),MDI N: 14, end of study: 14 p > 0.10Baseline CSII: 0.7 U/kg/day (0.2)Baseline MDI: 0.7 U/kg/day (0.1)

continued


23


TABLE 6 Insulin dose in adults with Type 1 diabetes (cont’d)



Ziegler, 199084 Values not reported, but it is Parallel RCT stated that daily insulin dose was CSII N: 49; end of study: 36 similar in CSII and MDI at entry MDI N: 47, end of study: 37 and during follow-upBaseline CSII: 49 U/day (17)Baseline MDI: 48 U/day (14)

01 2.5 to 4 months – U/dayChiasson, 1984Hanaire-Broutin, 2000Home, 1982Nathan, 1982

Subtotal (95% CI)Test for heterogeneity χ2 = 3.78, df = 3, p = 0.28Test for overall effect z = 3.72, p = 0.0002

12 43.90 (10.00) 12 56.10 (20.40) 40 38.50 (9.80) 40 47.30 (14.90) 10 51.00 (15.80) 10 80.00 (28.50) 5 35.40 (11.50) 5 48.80 (13.18) 67 67

19.3 –12.20 (–25.05 to 0.65)57.5 – 8.80 (–14.33 to –3.27)

8.8 –29.00 (–49.20 to –8.80)14.4 –13.40 (–28.73 to 1.93)

100.0 –11.90 (–18.16 to –5.63)

Study mean (SD)CSII

n mean (SD)MDI

nWMD


%WMD(95% CI Random)

–100 –50 0 50 100Favours MDIFavours CSII

FIGURE 8 Meta-analysis of the effects of CSII versus MDI on insulin dose (U/day) in adults with Type 1 diabetes

01 2.5 to 4 months – U/dayChiasson, 1984Hanaire-Broutin, 2000Nathan, 1982


12 43.90 (10.00) 12 56.10 (20.40) 40 38.50 (9.80) 40 47.30 (14.90) 5 35.40 (11.50) 5 48.80 (13.18) 57 57

14.1 –12.20 (–25.05 to 0.65)76.1 – 8.80 (–14.33 to –3.27)

9.9 –13.40 (–28.73 to 1.93)100.0 – 9.73 (–14.55 to –4.91)

Study mean (SD)CSII

n mean (SD)MDI

nWMD


%WMD(95% CI Random)


FIGURE 9 Meta-analysis of the effects of CSII versus MDI on insulin dose (U/day) in adults with Type 1 diabetes, excluding Home andcolleagues88

01 2.5 to 4 months – U/dayHanaire-Broutin, 2000Home, 1982Nathan, 1982


40 38.50 (9.80) 40 47.30 (14.90) 10 51.00 (15.80) 10 80.00 (28.50) 5 35.40 (11.50) 5 48.80 (13.18) 55 55

56.0 – 8.80 (–14.33 to –3.27)18.0 –29.00 (–49.20 to –8.80)26.1 –13.40 (–28.73 to 1.93)

100.0 –13.63 (–23.62 to –3.64)

Study mean (SD)CSII

n mean (SD)MDI

nWMD


%WMD(95% CI Random)


FIGURE 10 Meta-analysis of the effects of CSII versus MDI on insulin dose in adults with Type 1 diabetes, excluding non-random studies

SummaryIn short-term studies, insulin dose is lower onCSII than on MDI, by about 12 units (20–25%),but there is little difference in longer term studies.

Body weightEight of the studies included in this reviewreported data on change in body weight in adultswith Type 1 diabetes (Table 7).78,80,81,83,84,86–88

Two studies reported weight change at 10 weeks to4 months of follow-up, with a mean increase frombaseline of 0.580 to 1.3 kg88 and –0.688 to 0.8 kg80

for CSII and MDI, respectively. Home andcolleagues88 reported a significantly greater weightin individuals with CSII than with MDI (68.9

versus 67 kg, p = 0.023), whereas Hanaire-Broutinand colleagues80 report a non-significant decreaseof 0.3 kg with CSII.

Three studies reported weight change at 6months of follow-up.83,86,87 Body weight hadincreased from baseline in both groups, by 0.5 to 2.2 kg in CSII and by 0.4 to 2.0 kg inMDI.83,86,87 Haakens and colleagues83 reported a significantly lower weight with CSII comparedwith MDI (69.1 versus 70.6 kg, p < 0.05);conversely, Bak and colleagues87 found that weight was lower with MDI (76.6 versus 74.8 kg, p < 0.01). Schmitz and colleagues86 alsofound weight to be lower with MDI (73 versus72.8 kg), but this difference was not statisticallysignificant.


24

TABLE 7 Weight change in adults with Type 1 diabetes

Study Mean weight (SD) (kg) Difference

CSII MDI(MDI – CSII) (kg)

Bak, 198787 Month 6: 76.6 (9.6) 74.8 (9.7), p < 0.01 –1.8Random crossoverN: 20; end of study: 16Baseline: 74.4 kg (9.7)

Bode, 199681 Month 12: 68.1 (14.1) 67.4 (14.4), p = ns –0.7Non-random crossover Month 24: 69.7 (15.2)N: 55 Month 36: 70.0 (14.6)Baseline not reported Month 48: 68 (15.2)

Brinchmann-Hansen 198878 Month 24: 70.5 (8.9) 75.1 (11.2), p = ns 4.6Parallel RCTCSII N: 15; MDI N: 15Baseline: 68.6 kg (9.3)

Haakens, 199083 Month 6: 69.1 (8.63) 70.6 (8.63), p < 0.05 1.5Non-random crossoverN: 52; end of study: 35Baseline: 68.6 kg (8.63)

Hanaire-Broutin, 200080 Month 4: 68.7 (10) 69 (9.5), p = ns 0.3Random crossoverN: 41; end of study: 40Baseline: 68.2 kg (10)

Home, 198288 Month 2.5: 68.9 (9.2) 67 (9.2), p = 0.023 –1.9Random crossoverN: 11, end of study: 10Baseline: 67.6 kg (8.5)

Schmitz, 198986 Month 6: 73 (17.8) 72.8 (18.4), p = ns –0.2Random crossoverN: 10Baseline: 71.6 kg (17.2)

Ziegler, 199084 Final weight not reported Final weight not reportedParallel RCT Average weight gain after Average weight gain afterCSII N: 49; end of study: 36 2 years = 1.3 2 years = 2.8MDI N: 47; end of study: 37 BMI (months 6–24) 22.5 kg/m2 BMI (months 6–24) 24.2 kg/m2,Baseline BMI: 22.1 kg/m2 p < 0.05

At 12 months of follow-up, Bode and colleagues81

found no significant difference in body weightbetween CSII and MDI (68.1 versus 67.4 kg). Thestudy also reported mean weight for CSII only at24 (69.7 kg, SD 15.2), 36 (70.0 kg, SD 14.6) and48 months (68 kg, SD 15.2) of follow-up, but didnot follow MDI for this length of time.

Brinchmann-Hansen and colleagues78 reportedthat weight had increased from baseline by 1.9and 3.4 kg for CSII and MDI, respectively, at24 months of follow-up. No significant differencewas found between CSII and MDI (70.5 versus75.1 kg). Ziegler and colleagues84 also reported a non-significant mean weight gain from baseline (CSII 1.3, MDI 2.8 kg) at 24 months offollow-up. However, body mass index (BMI) wassignificantly lower in CSII than MDI (22.5 versus24.2 kg/m2, p < 0.05) after 6–24 months of follow-up, with a difference in BMI from baselineof –0.5 and +2.1 kg/m2 for CSII and MDI,respectively.84

SummaryThere was no consistent difference in weightbetween CSII and MDI treatment.

Lipid levelsThe majority of studies included in this review didnot report data on cholesterol or triglyceride levels(Table 8). Home and colleagues88 found nosignificant difference in cholesterol after 10 weeksof either CSII or MDI [5.0 mmol/l (SD 0.6) versus5.2 mmol/l (SD 0.6)].

Schiffrin and colleagues91 found cholesterol to besignificantly lower after 6 months of both CSIIand MDI compared with baseline [CSII 163 mg/dl(SD 15) versus 190 mg/dl (SD 9), p < 0.01; MDI

162 mg/dl (SD 12) versus 183 mg/dl (SD 8),p < 0.01]. The difference between CSII and MDIwas not statistically significant. Similarly, nodifference in triglyceride levels was found betweenCSII and MDI [82 mg/dl (SD 14) versus 81 mg/dl(SD 12), p = ns].

Ziegler and colleagues84 did not report data oncholesterol levels but stated that cholesterol levelsincreased within the normal range during thestudy without differences between groups.

SummaryThere is little evidence with which to compare theeffects on cholesterol levels of CSII and MDI.

Patient preferenceStudies reported various forms of patientpreference information, from patients’ treatmentpreference to reasons for preference such ascontrol, lifestyle, appearance or other reason.

Of the eight studies80,82,83,86–88,90,91 reportingpatient preference (Table 9), four studies80,82,83,88

reported a greater proportion of patientspreferring CSII to MDI treatment, rangingbetween 44% and 72.5%. Schiffrin andcolleagues91 reported no difference in the numberof patients preferring to continue with CSII orMDI, with 12.5% of patients reverting toconventional treatment at the end of the study.However, three studies86,87,90 reported a greaterproportion of patients (57%–80%) preferring MDIto CSII. Two further studies84,89 did not reportpatient preference but provided opinions ofpatients regarding treatments.

Reasons for preferring CSII included easierglycaemic control and greater flexibility of


25


TABLE 8 Cholesterol and triglyceride levels in adults with Type 1 diabetes

Study Mean cholesterol and triglyceride level (SD) Difference


Home, 198288 CholesterolRandom crossover 2.5 months: 5 (0.6) mmol/l 5.3 (0.6) mmol/l 0.3 mmol/lN: 11; end of study: 10

Schiffrin, 198291 CholesterolRandom crossover 6 months: 163 mg/dl (15) 162 mg/dl (12), p = ns –1 mg/dlN: 20; end of study: 16 Triglyceride

6 months: 82 mg/dl (14) 81 mg/dl (12), p = ns –1 mg/dl

Ziegler, 199084 Cholesterol levels increased within the normal range during the study without differences Parallel RCT between treatment groupsCSII N: 49; MDI N: 47


26

TABLE 9 Patient preference and quality of life for adults with Type 1 diabetes

Study Patient preference/QoL

CSII MDI

Bak, 198787

Random crossover.N: 20; end of study: 16

Preferring: 20%Reasons for preference: freedom frominjections: 44%

75% discomforted by butterfly needle (onCSII), 56% discomforted by infuser itself athome, 21% discomforted by infuser at work

QoL: not reported

80%

95% found pen easy to handle, 30% highfrequency of injections a disadvantage

Of total: independence of fixed mealtimes anadvantage with MDI and CSII by 85%

Chiasson, 198482

Non-random crossoverN: 12

Number preferring: 7 (58%)

QoL: not reported

5 (42%)

Haakens, 199083

Non-random crossoverN: 52; end of study: 35

Number preferring: 23/52 (44%) preferred CSII

Reasons:ControlFlexibility in terms of food intake allowedAvoid frequency injections: 2 (9%)Greater sense of well-being: 2 (9%)

QoL: not reported

20/52 (38%) preferred MDI

Reasons:Control: 17 (85%)More flexible lifestyle than CT without needto wear a devicePreferred human isophane at bedtime:16 (46%)Preferred human ultralente at bedtime:7 (20%)No preference between bedtime insulin:11 (31%)

Hanaire-Broutin, 200080

Random crossoverN: 41; end of study: 40

Number preferring: 29 (72.5%)Of these 29, 21 previously on CSII + regularinsulin and 8 on MDI

QoL: not reported

11 (27.5%)Of these 11, 10 previously on CSII and 1MDI

Home, 198288


8 (80%) preferred pump to MDI, 4 wished tocontinue with it. Universally regarded as toolarge and uncomfortable

QoL: not reported

None wished to continue with 3 dailyinjections owing to inconvenience

Nathan, 198289

Random crossoverN: 5

Number preferring: not reported

Ease of administering and adjusting insulin dosesnoted. A decrease in hypos and improvedfeeling of well-being contributed to acceptanceof pump.

Drawbacks: difficulty for women in dressing toaccommodate pump, and removal of pump forwatersports

QoL: not reported

Saurbrey, 198890


Number preferring for future treatment: 6(31.5%)

Reasons: freedom in daily life: 11 (42%)

QoL: not reported

12 (63%)1 (5%) was unsure of preference (either ICTor CSII)

Reasons: freedom in daily life: 11 (58%)

continued

meals83,91 and freedom from injections.87 Haakensand colleagues83 reported that two of the23 patients preferring CSII thought it wasimportant to avoid frequent injections and two felt a sense of greater well-being, whereas thepatients who preferred MDI found it practical andeasy to administer and that it allowed a moreflexible lifestyle than conventional treatmentwithout the need to wear a pump. Nathan andcolleagues89 did not report levels of patientpreference, but noted ease of administration and adjustment of insulin with CSII, and stated that a decreased number of hypoglycaemicepisodes and improved feeling of well-beingcontributed to acceptability of the CSII. Saurbreyand colleagues90 reported that 58% of patients felt that MDI gave the greatest freedom in dailylife, compared with 42% who felt that CSII gavemore freedom. Bak and colleagues87 reported that 85% of patients found the independence ofmealtimes with both CSII and MDI to beadvantageous.

Home and colleagues88 reported that eight of 10 patients preferred CSII to MDI and four ofthese wanted to continue with CSII rather thanreturn to conventional treatment. However theauthors noted that the pump was generallyregarded as too large and uncomfortable.Similarly, the reasons given by patients in thestudy by Schiffrin and colleagues for notpreferring CSII include the size of the device.However, both of these studies were published in 1982 when pumps were much larger than the present devices. Other drawbacks with thepump included discomfort from the needle orinfuser,87 problems of dressing to accommodatethe pump for women and in watersportsparticipation89 and discomfort, distortion of body image and feeling of dependency on thedevice.91

Ziegler and colleagues84 do not report level ofpatient preference, but do report that fourpatients changed to MDI from the CSII arm


27


TABLE 9 Patient preference and quality of life for adults with Type 1 diabetes (cont’d)

Study Patient preference/QoL

CSII MDI

Schiffrin, 198291



7/16 (44%) of pts chose CSII for easierglycaemic control and also greater flexibility formeal hours and meal size

CSII rejected for reasons of bulk, discomfort, afeeling of dependency on the machine anddistortion of body image

70% would recommend CSII to a diabeticfriend

QoL: not reported

7 (44%)[2 pts reverted to conventional]

30% would recommend MDI to a diabeticfriend

Schmitz, 198986



QoL: not reported

6 (60%)

Tsui, 200179

Parallel RCTCSII N:13; end of study: 12MDI N: 14 end of study: 14


QoL score: (mean)Satisfaction 75.6Impact: 69.9Diabetic worry: 85.2Social worry: 89.6Global health: 68.2Response rate 85%

QoL score (mean):68.368.479.894.067.3 (p = ns for any of the subscales)Response rate 100%

Ziegler, 199084

Parallel RCTCSII N: 49; end of study: 36MDI N: 47; end of study: 37

pts, Patients.


4 pts changed to MDI during study owing totechnical problems with pump

QoL: not reported

7 pts changed treatment group during studyowing to explicit request to have a pump

owing to technical problems with the pump, andseven MDI patients explicitly requested a pumpduring the study.

SummaryFour of the eight studies reported that a greaterproportion of patients preferred CSII, threestudies found a greater proportion preferred MDIand one study found no difference. However, sincesome of these studies were done with older andbulkier pumps, their findings may not be relevantto today’s pumps. Progress has also been madewith MDI, for example the introduction of discreet‘pen’ injectors. The three studies that reportedthat greater proportions preferred MDI were from 1987 to 1989; those where the majoritypreferred CSII were from 1982, 1984, 1990 and 2001.

Quality of lifeOnly one study (Tsui 2001)79 reported on QoL(Table 9). Information was collected using theDiabetes Quality of Life (DQOL) tool. Twoparticipants did not complete the DQOL, givingresponse rates of 85% for CSII and 100% for MDI,and just three of 1128 items were missing. Nosignificant differences between CSII and MDI werefound overall or on any of the subscales:satisfaction (7.3), impact (1.5), diabetic worry (5.4),global health (0.9) or social worry (–4.4).

SummaryThere is little evidence with which to compare theeffects of CSII and MDI on QoL.

Adverse effectsThe definition of hypoglycaemic episodes varied,making comparison between studies difficult.Significantly fewer hypoglycaemic episodes with CSII therapy were observed in threestudies,81,85,87 but most studies found no statisticaldifference between CSII and MDI78–80,83,89–91

(Table 10). Ziegler and colleagues reportedsignificantly more episodes of blood glucose<50 mg/dl and reported symptoms ofhypoglycaemia with CSII than MDI at 1–6 and7–12 months of follow-up, but these tended todecrease in CSII so that at 19–24 months offollow-up the differences were no longersignificant.84

Severe hypoglycaemic episodes differed littlebetween treatments in most studies,79,80,83,85–88,90,91

with no severe episodes occurring in twostudies.86,90 Significantly fewer severehypoglycaemic episodes per 100 patients years occurred with CSII compared with

MDI in the study by Bode and colleagues,81

and similarly Brinchmann-Hansen and colleagues found hypoglycaemic coma occurredless frequently with CSII.78 Ziegler and colleagues, however, found that hypoglycaemiccoma was about twice as common in CSII than MDI.84

Two studies reported no occurrences of DKA with either treatment,86,87 and another threestudies reported no events with MDI78,83,90

and one83,90 or two78 episodes with CSII. Bodeand colleagues found rates of DKA to be less with CSII than MDI, although the differencewas not significant (7.2 versus 14.6 events per 100 patient years). Nosadini and colleagues,however, reported significantly more ketotic eventswith both fixed-rate and variable rate CSIIcompared with MDI. About 20% of these episodeswere caused by pump malfunction, and 23% ofthose with fixed basal rate and 27% of those withvariable basal rate were caused by infectivedisease.85 Ziegler and colleagues found anincidence of DKA of 9.7 events per 100 years inpatients assigned to CSII and 8.1 events per100 years in patients assigned to MDI; however,when the true therapy at the time of the event was analysed, more events occurred with CSII(14.1 versus 2.9 events per 100 years). However, it should be noted that the studies thatreport significant problems with DKA are theolder ones.

The presence or absence of other adverse events was poorly reported in many of the studies.Pump malfunctions were reported in three studies, specified as the cause of about 20% ofketotic episodes by one study,85 but occurring only once88 or twice89 in the other studies.Problems with catheters were reported in onestudy, in which the catheter became dislodged atnight on six occasions.89 Subcutaneous abscessoccurred in one patient with CSII in twostudies83,89 and abscesses occurred in eightpatients with CSII in the study by Brinchmann-Hansen and colleagues.78 Subcutaneous infectionoccurred three times in one patient in anotherstudy.90

CaveatsIn most of the RCTs, there was little difference in the frequency of severe hypoglycaemia. Thisevidence is in conflict with that from three othersources, namely observational studies, clinicalopinion and patient experiences reported to usduring this review. The observational studiesinclude:


28


29


TABLE 10 Adverse events for adults with Type 1 diabetes

Study Adverse events

CSII MDI

Bak, 198787


Frequency of BG values <4 mmol/l: 2.3%Severe hypos: 1 (requiring hospital treatment)DKA: 0

Frequency of background values <4 mmol/l:4.1%, p < 0.02

Severe hypos: 0

DKA: 0

Bode, 199681

Non-random crossoverN: 55

Severe hypos: 12 episodes (12 months)

Severe hypos per 100 patient-years (n),significance from MDI: 12 months: 22 (55) p < 0.000124 months: 26 (50) p < 0.0136 months: 39 (33) p < 0.000148 months: 36 (25) p < 0.01

Of 25 pts with HbA1c ≥ 8.0%, rate of severehypos declined from 84 events per 100 patientyears at baseline (MDI) to 8 events in year 1(p < 0.0001). The 30 pts with baseline HbA1c<8.0% also experienced a decline, from 183 to33 severe hypos per 100 patient years(p = 0.0005).

DKA rates were not significantly differentbetween MDI and CSII phases (14.6 vs 7.2events per 100 patient years, respectively)

Severe hypos: 76 episodes (12 months)Severe hypos per 100 patient years (n):138(55)

Brinchmann-Hansen,198878

Parallel RCT.CSII N: 15; MDI N: 15

Hypoglycaemia: mean (SEM):% of home BG <2.5 mmol/l: at randomisation= 6 (2); after 2 years = 11 (2)

Symptomatic episodes/week/patient: At randomisation = 2.3 (0.6); at 2 years = 1.7(0.3)

Hypo coma: 2 (2)DKA: 2 (2)Subcutaneous abscess: 8 (6)

Retinopathy: improved (14%), unchanged(29%), worsened (57%) (one patient had anallergy to fluorescein)

Hypoglycaemia: mean (SEM):% of home BG <2.5 mmol/l: atrandomisation = 8 (3); after 2 years = 7 (1),vs CSII p = ns

Symptomatic episodes/week/patient: At randomisation = 1.5 (0.3); at 2 years =1.2 (0.2), vs CSII, p = ns.Hypo coma 14 (6), vs CSII p < 0.001.DKA 0, vs CSII p = nsSubcutaneous abscess 0, vs CSII p < 0.01

Retinopathy: Improved (7%), unchanged(43%), worsened (50%) (one patient had anallergy to fluorescein)

Haakens, 199083

Non-random crossoverN: 52; end of study: 35

Subcutaneous abscess: 1

DKA: 1 requiring hospitalisationSevere hypos (episodes/patient/month):Total 1/7.5 (requiring glucose i.v./glucagon 1/96;assistance but not requiring glucose i.v./glucagon1/8).

No. of mild subjective hypos/week: 1.4 (SD0.92)

Subcutaneous abscess: 0

DKA: 0

Severe hypos (episodes/patient/months): Total 1/5 (requiring glucose i.v./glucagon 1/79;assistance but not requiring glucosei.v./glucagon 1/5). CSII vs MDI p = ns.

No. of mild subjective hypos/week: isophane1.4 (SD 0.92), ultralente 1.5 (SD 1.17). CSIIvs MDI p = ns.

Hanaire-Broutin, 200080


Severe hypos: 2 pts, 3 events (severe hypos didnot result in coma or seizures, external helpneeded to take sugar, but glucagon or glucoseinjection not required)

Hypos during last 14 days of each treatmentperiod: 3.9 (4.2)

Severe hypo: 1 patient, 1 event

Hypos during last 14 days of each treatmentperiod: 4.3 (3.9), p = ns

continued


30

TABLE 10 Adverse events for adults with Type 1 diabetes (cont’d)


CSII MDI

Home, 198288

Random crossover.N: 11; end of study: 10Baseline hypo 1.1 (0–4)episodes per pt biweekly

Hypos: 0.6 (0–3) episodes per pt biweekly.Pump malfunction: 1 (1 pt × 3 hypo episodes in16 h due to faulty pump)

1 patient required intravenous glucose

Hypos: 0.8 (0–7) episodes per pt biweekly

Nathan, 198289


During 2.5 patient years CSII: subcutaneousabscess needing oral antibiotics (1), pumpmalfunctions (2) catheter dislodged at night (6)

Hypo reactions n/week at 3 months: 1 (0.25)

Hypo reactions n/week at 3 months: 2.5(0.61), p = ns

Nosadini, 198885

Parallel RCTCSII fixed N: 19;MDI N: 15;CSII variable N: 10

Mean events/pt/yr:CSII with fixed night basal rate:Hyper: 18 (5) vs MDI, p = nsKetotic events: 0.13 (0.02) vs MDI, p < 0.01Mild hypos: 36 (10) vs MDI, p < 0.01Severe hypos: 0.14 (0.05) vs MDI, p < 0.01Sudden death: 0.04 (1 pt dead in bed)

CSII with variable night basal rate):Hyper: 17 (4) vs MDI, p = nsKetotic events: 0.16 (0.03) vs MDI, p < 0.05Mild hypos: 30 (11) vs MDI, p < 0.01Severe hypos: 0.16 (0.09) vs MDI, p < 0.01[CSII–HOR vs CSII–FBR, all p = ns]

Malfunction of pump caused about 20% ofketotic episodes in both CSII groups. 23% (CSIIfixed) and 27% (CSII variable) caused byinfective disease

Hyper: 20 (3) Ketotic events: 0.03 (0.01) Mild hypos: 59 (12) Severe hypos: 0.42 (0.15)

Saurbrey, 198890


Severe hypos: 0

No. of subjective or biochemical (BG<2.5 mmol/l) hypos in each group, p = ns(values not given).

Ketoacidosis = 1 (due to acute gastroenteritisand failure to take extra insulin, not pumpmalfunction)

Subcutaneous infection (3 times) in samepatient, one required surgical incision

Severe hypos: 0

Schiffrin, 198291


Mild hypos: 186Moderate hypos: 10Severe hypos: 1 (due to delaying meal afterbolus insulin taken – intravenous glucose wasadministered)

Mild hypos: 189, p = nsModerate hypo: 11, p = nsSevere hypos: 0, p = ns

Schmitz, 198986


Severe hypos: 0DKA: 0


Tsui, 200179

Parallel RCTCSII N:13; end of study: 12MDI N: 14; end of study: 14

Severe hypos: 6

Mean number of hypos each month, 8.9(3 months), 7.2 (6 months), 7.0 (9 months), 8.0 (overall)

Severe hypos: 4, p > 0.10

Mean number of hypos each month, 5.0(3 months), 9.0 (6 months), 9.2 (9 months),7.4 (overall), all = ns vs CSII

Relative treatment effect (CSII-MDI)/MDI foroverall no. of hypos: +9% (95% CI –37 to+87), p > 0.10

continued

� Boland and colleagues,98 who reported a dropin hypoglycaemic events requiring assistancefrom 134 per 100 person years on MDI to 76 per 100 person years on CSII, inadolescents.

� Mack-Fogg and colleagues,99 in abstract only,report a reduction in severe hypoglycaemicevents in children after transfer from MDI toCSII, from a mean of 0.55 to 0.25 per child peryear.

� Rudolph and Hirsch100 found that there were73 severe hypoglycaemic events per 100 patientyears on MDI, but only 19 on CSII.

� Haardt and colleagues,101 in a retrospectiveanalysis of the Hotel–Dieu cohort, found that glycated haemoglobin levels decreased‘only modestly’ (from 9.3% on injections to 8.6% on CSII), but that the number of severe hypoglycaemic events fell by over 75%.

A possible explanation is that patients recruited tothe trials may be roughly representative of thoseseen in clinics, although with a bias to the mostcooperative (because of the demands of trials) whomay have better control than average, whereas inroutine care as reflected more in the observationalstudies, CSII may be used mostly in those who arehaving considerable problems with control, eitherhigh glycated haemoglobin or frequenthypoglycaemic events.

SummaryHypoglycaemic events did not differ significantlybetween CSII and MDI in most trials, but threefound fewer hypoglycaemic episodes with CSIIand one study found more hypoglycaemia andhypoglycaemic coma with CSII. Observationalstudies found much greater reductions in thefrequency of severe hypoglycaemia with CSII, butare more prone to bias.

PregnancyFour parallel RCTs92–95 compared the effects ofCSII with MDI in pregnancy (Tables 4 and 11–14,Appendices 7 and 11), although the sample size inthree of the studies was small (14–32).92–94 Cartaand colleagues94 included women with Type 1 andType 2 diabetes diagnosed before pregnancy andanalysed these groups separately. Nosari andcolleagues92 and Coustan and colleagues93

included women with Type 1 diabetes who werepregnant or planning pregnancy, and Burkart andcolleagues included women with Type 1 diabetesattending no later than the first trimester.95

Glycated haemoglobinBurkart and colleagues did not report data onglycated haemoglobin, simply stating that patientsin both groups had normal mean glucose andHbA1 <7.5% at least from the end of the firsttrimester on.95 During the first trimester in theother studies, glycated haemoglobin was lower


31


TABLE 10 Adverse events for adults with Type 1 diabetes (cont’d)


CSII MDI

Ziegler, 199084

Parallel RCTCSII N: 49; end of study:36.MDI N: 47; end of study: 37

FBR, fixed basal rate; HOR, higher overnight rate; SEM, standard error of mean.

No. of metabolic complications/6 months mean(range). Reviewer has calculated mean of the 4 × 6 month periods to give totals below.Mild hypos (BG <50 mg/dl): 15.5 (0–70)Mild hypos (symptoms): 19.8 (0–104)Severe hypos (req. assistance): 0.091 (0–7)Severe hypos (coma): 0.101 (0–4)Ketosis (BG >200 mg/dl and ketonuria): 6.5(0–57)Ketoacidosis: 0.046 (0–1)

Frequency of pts (no. of events/100 years):Hypos requiring assistance: 13.9 (18.1)Hypos (coma): 30.6 (19.4)DKA: 13.9 (9.7) [true therapy at time of event:15.4 (14.1)]

Mild hypos (BG <50 mg/dl): 10.6 (0–53)Mild hypos (symptoms): 10.1 (0–81)Severe hypos (requiring assistance): 0.070(0–2)Severe hypos (coma): 0.048 (0–1)Ketosis (BG >200 mg/dl and ketonuria): 7.8(0–85)Ketoacidosis: 0.040 (0–3)

Frequency of pts (no. of events/100 years):Hypos requiring assistance: 16.2 (13.5)Hypos (coma): 13.5 (9.5)DKA: 8.1 (8.1) [true therapy at time ofevent: 5.9 (2.9)]

with CSII than MDI (0.2–1.1%) in both Type 1diabetes92,94 and Type 2 diabetes,94 but thesedifferences were not statistically significant (Table11). Similarly, there were no significant differencesbetween CSII and MDI during the second trimester(–0.7 to 0.75%)92,94 or term (–0.1 to 0.7%).94

Insulin doseThere was no significant difference between CSIIand MDI in total daily insulin dose in Type 1diabetes92,94 or Type 2 diabetes94 during the first,second or third trimesters (Table 12). However,Coustan and colleagues93 found that fewer insulinunits per kilogram per day were required withCSII than with MDI [first trimester, 0.71 U/kg/day(SD 0.16) versus 1.01 U/kg/day (SD 0.28), p = 0.101; second trimester 1.02 U/kg/day (SD0.53) versus 1.40 U/kg/day (SD 0.4), p = 0.027;third trimester, 1.26 U/kg/day (SD 0.49) versus1.63 U/kg/day (SD 0.51), p = 0.041]. Daily insulin

dose was not reported by Burkart andcolleagues.95

Pregnancy outcomesThe mean duration of pregnancy was38.1–38.9 weeks in CSII and 37.7–38.8 weeks inMDI, with no significant differences between thegroups for Type 1 or Type 2 diabetes92–95

(Table 13). Nosari and colleagues92 reported threeintrauterine deaths: two in the CSII group andone in the MDI group. In one case from eachgroup, the cause of death was a severe reductionin placental blood flow; the cause of the thirddeath was unknown. Burkart and colleaguesreported two deaths in the CSII group, oneintrauterine death due to cause unknown and onedeath at 3 months postpartum followingpremature delivery and maternal ketoacidosis.Three deaths occurred in the MDI group at3 days, 5 days and 3 months postpartum due to


32

TABLE 11 Glycated haemoglobin in pregnant women

Study Mean glycated haemoglobin (%) (SD) Difference


Burkart, 198895 Data not reported. States that patients selected in the CSII or MDI group had normal Parallel RCT mean glucose and HbA1 <7.5% at least from the end of the first trimester on.CSII N: 48; MDI N: 41Baseline not reported

Carta, 198694 Weeks 9–11: 7.8 8.5, p = ns 0.7Parallel RCT Weeks 19–21: 7 7.75, p = ns 0.75Type 1 Weeks 33–35: 7 6.95, p = ns –0.05CSII N: 8; MDI N: 7 Weeks ≥ 37: 6.5 6.45, p = ns –0.05HbA1 data collectedBaseline CSII: 8.75%Baseline MDI: 9.1%, p = ns

Carta, 198694 Weeks 9–11: 7 8.1, p = ns 1.1Parallel RCT. Weeks 19–21: 6.75 7.2, p = ns 0.45Type 2 Weeks 33–35: 6.5 6.7, p = ns 0.2CSII N: 6, MDI N: 8. Weeks ≥ 37: 6 6.7, p = ns 0.7HbA1 data collectedBaseline CSII: 8.1%Baseline MDI: 8.2%, p = ns

Coustan, 198693 Therapy week 8: 7 7.5, p = ns 0.5Parallel RCT Term: 6.3 (0.6) 6.4 (0.4), p = ns 0.1CSII N: 11; MDI N: 11HbA1 data collectedBaseline CSII: 8.6% (1.7)Baseline MDI: 9.1% (1.5), p = ns

Nosari, 199392 1st trimester: 6 (3.6) 6.2 (1.6), p > 0.5 0.2Parallel RCT 2nd trimester: 6.8 (5.6) 6.1 (2.4), p > 0.5 –0.7CSII N: 16; MDI N: 16 3rd trimester: 6.3 (2) 6.2 (0.8), p > 0.5 –0.1HbA1c data collectedBaseline not reported

toxoplasma infection, hypoplastic left heart andrenal vein thrombosis, respectively.95 Nointrauterine deaths occurred in the other twostudies.93,94 The proportion of babies delivered byCaesarean section varied between the studies, buttended to be similar between CSII and MDI inType 1 diabetes. Carta and colleagues,94 however,reported that in Type 2 diabetes, one of nine(16.7%) women with CSII underwent Caesareansection compared with three of eight (37.5%)women with MDI. There was no significantdifference in birthweight between CSII and MDI in any of the studies. A small number ofpreterm, small for gestational age or large forgestational age infants were observed in both groups, with little apparent differencebetween the groups.

Patient preference and quality of lifePatient preference and QoL were not reported bythe four studies comparing CSII and MDI inpregnancy.

Adverse eventsNo pump malfunctions were reported, althoughone study reported three catheter disconnections94

and another stated that catheter leakage or

occlusion occurred infrequently and resolvedquickly93 (Table 14). Carta and colleagues94

reported that among Type 2 diabetes patients,episodes of mild hypoglycaemia were few and didnot occur in all patients. One severehypoglycaemic episode occurred among the Type1 diabetes patients, but the treatment group wasnot specified. Coustan and colleagues93 foundmore severe hypoglycaemic episodes in the MDIgroup than in the CSII group (45% versus 27%),although the authors noted that the groups weretoo small to attain statistical significance. Twoother studies, however, found slightly more severeepisodes92 and undefined hypoglycaemia95 withCSII. Ketoacidosis occurring in CSII group butnot the MDI group was reported by two studies.92

It is important to bear in mind that even oneepisode of ketoacidosis could lead to fetal death.95

SummaryThere is insufficient evidence from these studiesthat CSII is better than MDI in pregnancy forachieving glycaemic control. If CSII or any otherform of intensified therapy is to be optimallyeffective in pregnancy, it would have to startbefore conception, partly to minimise risk of


33


TABLE 12 Insulin dose in pregnant women



Carta, 198694 Month 3: 37 U/day 32 U/day, p = ns –5 U/dayParallel RCT Month 6: 42 U/day 47 U/day, p = ns 5 U/dayType 1 Month 9: 49.1 U/day 60.4 U/day, p = ns 11.3 U/dayCSII N: 8; MDI N: 7Baseline CSII: 31.5 U/dayBaseline MDI: 27.8 U/day, p = ns

Carta, 198694 Month 3: 23.1 U/day 28 U/day, p = ns 4.9 U/dayParallel RCT Month 6: 36 U/day 49 U/day, p = ns 13 U/dayType 2 Month 9: 52.8 U/day 51.2 U/day, p = ns –1.6 U/dayCSII N: 6; MDI N: 8Baseline not reported

Coustan, 198693 1st trimester: 0.71 U/kg/day (0.16) 1.01 U/kg/day (0.28), p = 0.101 0.3 U/kg/dayParallel RCT 2nd trimester: 1.02 U/kg/day (0.53) 1.4 U/kg/day (0.4), p = 0.027 0.38 U/kg/dayCSII N: 11; MDI N: 11 3rd trimester: 1.26 U/kg/day (0.49) 1.63 U/kg/day (0.51), p = 0.041 0.37 U/kg/dayBaseline CSII: 0.9 U/kg/day (0.42)Baseline MDI: 1.05 U/kg/day (0.38), p = 0.381

Nosari, 199392 1st trimester: 39.6 U/day (22.8) 36 U/day (24.4), p > 0.5 –3.6 U/dayParallel RCT 2nd trimester: 48.1 U/day (20.8) 43.7 U/day (35.6), p > 0.5 –4.4 U/dayCSII N: 16; MDI N: 16 3rd trimester: 57.3 U/day (21.6) 54.7 U/day (39.2), p > 0.5 –2.6 U/dayBaseline not reported


34

TABLE 13 Outcomes of pregnancy

Study CSII MDI

Burkart, 198895

Parallel RCT

CSII N: 48MDI N: 41

Duration: mean 38.4 weeks Live births: 47/48 (97.9%)Birth weight: mean 3082.7 (units not specified)No. Caesarean: 24/48 (50%)

Complications in pregnancy:Pyelonephritis 5Premature labour 4 Premature rupture 2Premature delivery 7 Pre-eclampsia 3Growth retardation 3Hypoglycaemia 5 Still birth 1 Ketoacidosis 1Total: 12/48 pregnancies had one or morecomplications

Fetal outcome:Healthy newborns 40Minor symptoms 8 Major symptoms 0Glucose i.v. 14Overall mortality up to age 1 year = 2/48 (4.2%)

Duration: mean 38.2 weeksLive births: 100%Birth weight: mean 3319.5 (units not specified)No. Caesarean: 15/41 (36.6%), p = ns

Complications in pregnancy:Pyelonephritis 6Premature labour 3Premature rupture 1Premature delivery 4Pre-eclampsia 3 Growth retardation 1Hypoglycaemia 3Still birth 0Ketoacidosis 0Total: 13/41 pregnancies had one or morecomplications (vs CSII p = ns)

Fetal outcome:Healthy newborns 34Minor symptoms 5Major symptoms 2 Glucose i.v. 9 (all p = ns vs CSII)Overall mortality up to age 1 year = 3/41(7.3%), vs CSII p < 0.05a

Incidence of complications in both groups islinked to the severity of maternal diabetes(White’s criteria). Birthweight reportedaccording to White’s criteria decreases withseverity. Differences in mean birthweights, p = ns.

Carta, 198694

Parallel RCT

Type 1CSII N: 8MDI N: 7

Duration: mean 266.7 days (SD 7.6)Live births: 100%Birth weight: mean 3395 g (SD 407)No. Caesarean: 3 (37.5%)

1 preterm due to hydramnios and fetalmegalosomnia. 1 large for gestational age. 1 macrosomnic (>4000 g).[CSII or MDI group not specified: 2 infantsdepressed, 5 metabolic morbidity (hypoglycaemia,hypocalcaemia, hyperbilirubinaemia), 2 congenitalcardiac malformations]

Duration: mean 263.6 days (SD 17.7)Live births: 100%Birth weight: mean 2906 g (SD 553), CSII vsMDI p = nsNo. Caesarean: 3 (42.9%)

1 preterm due to metrotthagia caused by centralplacenta previa

Carta, 198694

Parallel RCT


Duration: mean 272 days (SD9)Live births: 100%Birth weight: mean 3292 g (SD 578)No. Caesarean: 1 (16.7%)

1 preterm due to premature rupture of membranes.1 large for gestational age

Duration: mean 269 days (11.7)Live births: 100%Birth weight: mean 2994 g (SD 512), CSII vsMDI p = nsNo. Caesarean: 3 (37.5%)

1 preterm due to premature rupture ofmembranes. 1 small for gestational age

Coustan, 198693

Parallel RCT

CSII N: 11MDI N: 11

Duration: mean 38.1 weeks (SD 2.1)Live births: 100%Birth weight: mean 3050 g (SD 675)No. Caesarean: 7 (63.6%)

One birthweight above 90th percentile, 2 small forgestational age babies. Neonatal hypoglycaemia inone

Duration: mean 38.8 weeks (SD 1.4)Live births: 100%Birth weight: mean 3324 g (SD 475), CSII vsMDI p = nsNo. Caesarean: 7 (63.6%)

1 baby moderate respiratory distress syndrome.Neonatal hypoglycaemia in one

continued


35


TABLE 13 Outcomes of pregnancy (cont’d)

Study CSII MDI

Nosari, 99392

Parallel RCT

CSII N: 16MDI N: 16

a The p-value reported in the paper appears to be incorrect, and should be statistically insignificant.

Duration: mean 38.9 weeks (SD 7.6)Live births: 87.5%Birth weight: mean 3130 g (SD 1480)No. Caesarean: 9 (56.3%)

2 intrauterine deaths. No fetal congenitalmalformations, macrosomia or low Apgar scores(<7 at 5 minutes)1 CSII large for age. Respiratory distress in 1 CSIIinfant. Neonatal hypo (plasma glucose <30 mg/dl) inone CSII

Duration: mean 38.2 weeks (SD 10), CSII vsMDI p > 0.5Live births: 93.8%Birth weight: mean 3010 g (SD 1728), CSII vsMDI p > 0.5No. Caesarean: 7 (43.8%)

1 intrauterine death. 2 MDI small for age. 1premature MDI birth. Neonatal hypo (plasmaglucose < 30 mg/dl) in one MDI

TABLE 14 Adverse events in pregnant women

Study details CSII MDI

Burkart, 198895

Parallel RCT

CSII N: 48MDI N: 41

Hypoglycaemia: 5Ketoacidosis: 1

Hypoglycaemia: 3 Ketoacidosis: 0

Coustan, 198693

Parallel RCT

CSII N: 11MDI N: 11

Injection site infection: 0Pump malfunction: 0Mild hypos: 11 patientsModerate hypos: 6 patientsSevere hypos: 3 patients (8 episodes)DKA: 0Other: 1 hyperglycaemia and ketonuria (2 days)during viral infectionCatheter leakage or occlusion occurred infrequentlyand resolved quickly

Mild hypo: 11 patientsModerate hypos: 10 patientsSevere hypos: 5 patients (23 episodes)DKA: 0

one subject had 17 hypos related to dietaryirregularities

Nosari, 199392

Parallel RCT

CSII N: 16MDI N:16


Severe hypos: 1, CSII vs MDI p > 0.5DKA: 0, CSII vs MDI p > 0.1

Carta, 198694

Parallel RCT


Episodes of mild hypos were few and did not occur in all patients

Carta, 198694

Parallel RCT


Injection site infection: 0Pump malfunction: 0Other: catheter disconnection: 3In all pts, no hypo coma. One severe hypo (group not stated). Mild hypos occurred on average onceevery 15–20 days.

malformation and partly because it may take a fewmonths to learn how to use the intensifiedregimen.

AdolescentsTwo randomised crossover studies compared theeffects of MDI and CSII in adolescents aged up to20 years with Type 1 diabetes,96,97 one of whichalso included treatment with CSII overnight plusMDI during the day (CSII + MDI)97 (Tables 4, 15and 16, Appendices 8 and 12).

Glycated haemoglobinAfter 1 month, glycated haemoglobin wassignificantly lower than baseline [13% (SD 1),p < 0.001] in all three groups (Table 15) in thestudy by Schiffrin and colleagues.97 At 4 months offollow-up, glycated haemoglobin was significantlylower with CSII (8.8%) than with MDI (9.6%,p < 0.05) or CSII + MDI (9.3%, p < 0.05). Thedifference between CSII + MDI and MDI was notstatistically significant.97 However, althoughTamborlane and colleagues also found a decreasein glycated haemoglobin with both CSII and MDIcompared with baseline (p < 0.05), they found nosignificant difference between CSII and MDI after6 months of follow-up (8.5% versus 8.7%,p = ns).96

InsulinTotal daily insulin dose was significantly lowerduring both CSII (44 U/day) and CSII + MDI(48 U/day) than at baseline [64 U/day (SD 14),p < 0.001] or during MDI (60 U/day, p < 0.001)in the study by Schiffrin and colleagues97

(Table 15). Conversely, Tamborlane and colleagues

found an increase in insulin dose with both CSIIand MDI compared with baseline (p < 0.05), butno significant difference between CSII and MDIafter 6 months of follow-up (1.3 versus 1.4 U/day,p = ns).96

Patient preference and quality of lifeQoL was not reported by either study.96,97 At theend of the study by Schiffrin and colleagues, overhalf of patients (55%) chose to be treated withCSII and all patients stated that they wouldrecommend this treatment to a friend (Table 16).Four patients (20%) chose to continue with MDI and three (15%) with CSII + MDI, and two(10%) patients returned to using twice dailyinjections. MDI and CSII + MDI would berecommended to others by 66% and 70% ofpatients respectively.97

Adverse eventsBoth studies reported few severe hypoglycaemicepisodes96,97 (Table 16). Schiffrin and colleagues97 reported that there was no differencein the number of hypoglycaemic events between treatments, although numbers are not stated, and that they were mostly mild and averaged one per week per patient. Similarly, Tamborlane and colleagues reportedthat episodes of mild hypoglycaemia werecommon during each treatment.96 No otheradverse events were reported by either study.

SummaryOne study found no significant difference betweenCSII and MDI, whereas the other study showed a


36

TABLE 15 Glycated haemoglobin and daily insulin dose in adolescents

Study Mean HbA1 (SD) (%) Mean daily insulin dose (SD) (U/day)

CSII MDI CSII + MDI CSII MDI CSII + MDI

Schiffrin, 198497 Month 3: 8.75 9.5 9Random crossover Month 4: 8.8 9.6 9.3 Month 4: 44 60 48N: 20Baseline HbA1: 13% (1) CSII vs MDI p < 0.05 CSII vs MDI p <0 .001Baseline daily insulin dose: CSII vs CSII + MDI p < 0.05 CSII + MDI vs MDI p < 0.00164 U/day (14)

Tamborlane, 198996 Month 6: 8.5 (1.26) 8.7 (1.58), p = ns Month 6: 1.3 (3.16) 1.4 (0.32), p = nsRandom crossoverN: 10Baseline HbA1: 12.2% (4.11)Baseline daily insulin dose: 1.1 U/day (0.32)

clear benefit of CSII on glycated haemoglobin andinsulin dose.

CSII in childrenNo published randomised trials were found eitherby our searches or in published reviews.65,102–104

Table 17 summarises results from some case series.Some include both adolescents and children.

Two recent abstracts from the ADA 2002conference were found. The first, by Fox andcolleagues,109 gives only sparse data, and it is notclear what treatment patients were on beforestarting CSII. They may have been newlydiagnosed. Numbers are small, 10 patients todate. This study was excluded. The secondabstract, by Weintrob and colleagues,110 is furtheradvanced, with 23 children aged 9–14 years. It is acrossover study with 3.5 months on each of CSIIand MDI. There was no difference in HbA1c butthere were fewer hypoglycaemic episodes on CSII.

These studies suggest that CSII has a place intreatment of children with diabetes, but case seriesare more susceptible to bias than RCTs and betterevidence is needed. In most cases, children wereswitched directly from CT to CSII. Nowadays,children are more likely to go from MDI to CSII.Some may have problems running out of skin siteswith MDI. One small study in 10 children aged7–10 years studied a combination of CSII fromdinner until dawn and prebreakfast lispro andNPH; the comparator was three-injection MDI.66

The study was very short, with only 4 weeks stable

on each treatment. HbA1c results were notavailable given those durations. Blood glucoseresults improved. For children unable to use 24-hour CSII, this may be a useful option, butfurther research is needed.

Overnight-only CSII in adultsThere is little evidence on overnight-only CSII inadults. Olsson and colleagues in 198768 compareda bedtime injection of intermediate acting insulinwith overnight CSII in 10 patients, but on onlyfour nights. Kanc and colleagues69 carried out a 2-month crossover study and reported lesshypoglycaemia and improved hypoglycaemicepisode awareness.

Short-term CSII in poorly controlledadults with Type 2 diabetesThere is little evidence for this. Valensi andcolleagues111 carried out a short-term study,duration 8–23 days, but CSII was combined withmetformin, and with strict diet, in patientsadmitted to hospital. Little can be deduced aboutCSII from this study.

Another paper from France112 studied all theirType 2 diabetes patients with poor control onmaximal oral therapy. Many needed permanentinsulin treatment, but a group of 111 remained onoral treatment apart from two 3-day periods onCSII, and their HbA1c improved from 8.76% at thestart of the period to 7.82% at the end, with slightweight loss. Hence there may be a place for short-term use of CSII, but further research is required.


37


TABLE 16 Patient preference and adverse events among adolescents

Study CSII MDI CSII + MDI

Patient preferenceSchiffrin, 198497 No. preferring: 11 (55%) No. preferring: 4 (20%) No. preferring: 3 (15%)Random crossover 100% would recommend 66% would recommend MDI to 70% would recommend N: 20 CSII to a friend a friend CSII + MDI to a friend

(2 of 20 completing studyreverted to twice dailyinjections)

Adverse eventsSevere hypos: 1 Severe hypos: 1 (due to Severe hypos: 0

inadvertent administration of extra NPH dose)

Note: No difference in hypos between treatments. Mostly mild and averaged one per week perpatient. Same pt had severe hypos on CSII and MDI.

Tamborlane, 198996 Mild hypos were common during each treatment. States that there was only one severe Random crossover hypo requiring assistance during each 6-month treatment periodN: 10

Analogue versus soluble insulin in CSIIQuantity and quality of researchSix studies (one parallel RCT113 and fiverandomised crossover studies114–118) comparingrapid-acting analogues with soluble insulin in CSIIwere included in the review and are reported inTables 18–23 and Appendices 9 and 13. Bode andcolleagues113 compared two analogue insulins,lispro and aspart, whereas the other studiesincluded insulin lispro. Randomisation andallocation concealment were adequate in theparallel RCT,113 but the method of randomisationwas not reported in the five crossover studies114–118

(Table 18). The similarity of the groups at baselinewas reported in two studies,113,117 and all studiesreported eligibility criteria. Fivestudies113,114,116–118 reported point estimates andmeasures of variability for the primary outcomemeasure; however, Schmauss and colleagues115

reported the mean and standard error of glycatedhaemoglobin for each treatment at crossover andend of study, but did not combine the two periods.Raskin and colleagues117 were the only group toperform ITT analysis. Loss to follow-up wasadequately reported in two studies,115,118 partially

reported (number but not reasons, or vice versa)in one study113 and inadequately reported(numbers not stated for each group) in twostudies.116,117 Loss to follow-up was not reportedby Renner and colleagues.114

Adults with Type 1 diabetesGlycated haemoglobinGlycated haemoglobin was reported in allincluded studies (Table 19), which were combinedin a meta-analysis (Figure 11). Pooling these data(final values and changes from baseline includedas separate subgroups119) using a random effectsmodel (�2 test for heterogeneity 9.09, df = 5,p = 0.11) showed a significant decrease in glycatedhaemoglobin with the analogue insulin lisprocompared with soluble (–0.26%, 95% CI –0.47 to–0.06). The study by Bode and colleaguesincluded a third group with insulin aspart.113

Replacing lispro with aspart for this study in themeta-analysis made little difference to the overalltreatment effect (–0.27%, 95% CI 0.44 to –0.10).

Insulin doseInsulin requirement varied between the studies(Table 20); however, none of the five studiesreporting insulin dose found a significant


38

TABLE 17 CSII in children: case series

Study No. of Previous Reason for starting HbA1(c) HbA1(c) Discontinuation patients treatment CSII before after (%) rate (%)

Brink, 198661 24 CT Poor control 14.8 13.3 30

Levy-Marchal, 198862 7 CT Trial 9.3 7.3 43 (3 pts)

Steindel, 1995105 6 CT Non-compliance and 9.2 9.0 –brittle diabetes

Maniatis, 2001106 56, aged Unclear Poor control, flexibility 8.5 8.3 –7–23 of lifestyle, avoiding MDI

Bougneres, 198464 6, aged CT Poor control 11.7 9.3 –1–4 years

Conrad, 2002107 65 MDI Various, including poor 8.4 No significant –control, patient differencepreference, hypos, dawn phenomenon

Boland, 199998 75, allowed CT Post-DCCT research 8.3 on Almost all choice study MDI; 7.5 on continued CSII

CSII

Ahern, 2002108 161, aged CT? but Offered to those 7.1 in 6.5 98% remained18 months– with some interested pre- on CSII18 years intensive schoolers

features such 7.8 in 7.3as BG 7–11 year-monitoring olds

8.1 in 8.112–18 year-olds


39


TABLE 18 Quality assessment of studies comparing analogue versus soluble insulin

Study Random Allocation Group Eligibility Point ITT Withdrawalsconcealment similarity criteria estimates

Bode, 2002113 Adequate Adequate Reported Adequate Adequate Inadequate PartialMelki, 1998116 Unknown Unknown Unknown Adequate Adequate Inadequate InadequateRaskin, 2001117 Unknown Unknown Reported Adequate Adequate Adequate InadequateRenner, 1999114 Unknown Unknown Unknown Adequate Adequate Inadequate UnknownSchmauss, 1998115 Unknown Unknown Unknown Adequate Partial Inadequate AdequateZinman 1997118 Unknown Unknown Unknown Adequate Adequate Inadequate Adequate

See Appendix 3 for description of coding.

TABLE 19 Glycated haemoglobin with analogue and soluble insulin

Study Mean HbA1c (SD)

Analogue Soluble

Bode, 2002113

Parallel RCTLispro N: 28; end of study: 27Regular N: 59; end of study: 50Aspart N: 59; end of study: 55Baseline lispro: 7.3% (0.7).Baseline aspart: 7.3% (0.7).Baseline soluble: 7.5% (0.8)

LisproMonth 4: mean change from baseline0.18% (0.84)

AspartMonth 4: mean change from baseline0.00% (0.51)

SolubleMonth 4: mean change from baseline 0.15%(0.63)

(mean changes from baseline notsignificantly different between the threegroups)

Melki, 1998116

Random crossoverN: 39; end of study: 38Baseline: 7.84% (0.75)Baseline analogue: 7.74% (1.23)Baseline soluble: 7.97% (0.8)

Month 3: 7.11% (SD 0.92)

Change from baseline –0.62 (0.8)

7.88% (SD 0.99)

Change from baseline –0.09 (0.92)Lispro vs regular p = 0.01

Raskin, 2001117

Random crossoverN: 59; end of study: 58Baseline analogue: 7.9% (1.1)Baseline soluble: 7.6% (0.8),p = 0.234

Month 3: 7.41% (SD 0.97)

Change from baseline –0.34 (0.59)

7.65% (SD 0.85), p = 0.004

Change from baseline –0.09 (0.63), lispro vsregular p = 0.004

Renner, 1999114

Random crossoverN: 113Baseline: 7.24% (1)

Month 4: 6.77% (SD 0.88) 6.9% (SD 0.97), p < 0.02

Schmauss, 1998115

Random crossoverN: 11Baseline analogue: 6.3% (0.7)Baseline soluble: 6.7% (1.3),p = ns

Month 3: 6% (SD 0.99)(Mean HbA1c estimated by reviewer)

6.35% (SD 0.83), p = ns

Zinman, 1997118

Random crossoverN: 30Baseline: 8.03% (0.71)

Month 3: 7.66% (SD 0.71) 8% (SD 0.88), p = 0.0041


40

01 Final valuesMeiki, 1998Raskin, 2001Renner, 1999Schmauss, 1998Zinman, 1997


02 Change from baselineBode, 2002

Subtotal (95% CI)Test for heterogeneity χ2 = 0.00, df = 0Test for overall effect z = 0.16, p = 0.9


38 7.11 (0.92) 38 7.88 (0.99) 58 7.41 (0.97) 56 7.65 (0.85)113 6.77 (0.88) 113 6.90 (0.97) 11 6.00 (0.99) 11 6.35 (0.83) 30 7.66 (0.71) 30 8.00 (0.88)250 250

27 0.18 (0.84) 50 0.15 (0.63) 27 50

277 300

14.7 –0.77 (–1.20 to –0.34)19.6 –0.24 (–0.57 to 0.09)25.6 –0.13 (–0.37 to 0.11)

6.3 –0.35 (–1.11 to 0.41)15.8 –0.34 (–0.74 to 0.06)82.0 –0.32 (–0.55 to –0.10)

18.0 0.03 (–0.33 to 0.39)18.0 0.03 (–0.33 to 0.39)

100.0 –0.26 (–0.47 to –0.06)

Study mean (SD)Lispro

n mean (SD)Soluble

nWMD


%WMD(95% CI Random)

–1 –0.5 0.5 10Favours Lispro Favours soluble

FIGURE 11 Meta-analysis of the effect of lispro versus soluble insulin on glycated haemoglobin in Type 1 diabetes. Note: subgroup 1‘final values’ include studies reporting mean HbA1c at crossover or end of study (3 months with treatment). Subgroup 2 ‘change frombaseline’ includes one study reporting mean change in baseline HbA1c at end of study (4 months with treatment).

TABLE 20 Insulin dose with analogue and soluble insulin

Study Mean insulin (SD)

Analogue Soluble

Melki, 1998116 Month 3: 0.53 (0.12) U/kg/day 0.55 (0.12) U/kg/day, p = nsRandom crossoverN: 39; end of study: 38Baseline: 0.57 U/kg/day (0.12)

Raskin, 2001117 Month 3: Bolus 0.28 U/kg Basal 0.34 U/kgRandom crossover Basal 0.35 U/kg Bolus 0.30 U/kgN: 59; end of study: 58Baseline not reported

Renner, 1999114 Month 4: 83.1 U/day 85.4 U/day, p = nsRandom crossoverN: 113Baseline: 8.34 U/day

Schmauss, 1998115 Month 3: Basal 19 (6.6) U/day Basal 20 (3.3) U/day, p = nsRandom crossover Bolus 1.4 (0.3) IU/12 g carbohydrate Bolus 1.5 (0.3) U/12 g carbohydrate, p = nsN: 11Baseline not reported

Zinman, 1997118 Month 3: 40.4 (9.3) U/day 40.8 (8.8) U/day, p = nsRandom crossoverN: 30Baseline not reported

difference between analogue and soluble insulingroups. Daily insulin dose for analogue and solubleinsulin varied between 40.4118 and 83.1 U/day114

and between 40.8118 and 85.4 U/day,114

respectively, and between 0.53116 and 0.62 U/kg117

and between 0.55116 and 0.65 U/kg,117 respectively.

WeightThree studies116–118 presented data on weight (Table21). No significant difference in weight gain116 orweight at the end of the treatment period117,118 wasfound between analogue and soluble insulin.

Patient preference and quality of lifeQoL was not reported in any of the studiescomparing analogue and soluble insulin.

Three studies reported patient preference. The majority of patients preferred treatment with analogue insulin than soluble, with 95–100% choosing to continue their treatmentwith lispro, generally owing to its greaterflexibility115,116 (Table 22). Although Schmauss and colleagues115 reported that there was nosignificant difference in treatment satisfaction(method not stated), Renner and colleagues114

found a statistically significant result in favour oflispro with the validated Diabetes TreatmentSatisfaction Questionnaire (DTSQ).

Adverse eventsSevere hypoglycaemic events occurred in 0–8% ofpatients using analogue insulin and 0–10% of


41


TABLE 21 Weight change with analogue and soluble insulin

Study Mean weight (SD) (kg)

Analogue Soluble

Melki, 1998116 Month 3: gain 0.04 (1.79) Gain 0.48 (SD 1.6), p = nsRandom crossoverN: 39; end of study: 38Baseline: 24.4 kg/m2 (2.5)

Raskin, 2001117 Month 3: 79.2 (17.1) 78.8 kg (17.3), p = 0.78Random crossover (1 kg gained at end of period 1, (1 kg gained at end of period 1, N:59, end of study: 58 vs baseline p = ns) vs baseline p = ns)Baseline analogue: 78.3 kg (17.9)Baseline soluble: 77.3 kg (16.7)

Zinman, 1997118 Month 3: 72.6 (9.9) 72.8 (9.9), p = nsRandom crossoverN: 30Baseline: 72.8 kg (9.9)

TABLE 22 Patient preference with analogue and soluble insulin

Study details Analogue Soluble

Melki, 1998116 With which insulin:Random crossover Do you feel better? 34 (89.4%) 2 (5.3%)N: 39; end of study: 38 Are daily activities easier? 32 (84.2%) 2 (5.3%)

Do you prefer? 35 (92.1%) 2 (5.3%)Would you use in future? 36 (94.7%) 2 (5.3%)Gives most flexibility eating at home? 33 (86.8%) 2 (5.3%)Gives most flexibility eating outside? 32 (84.2%) 3 (7.9%)Best balance of glycaemia during study? 34 (89.4%) 2 (5.3%)

Renner, 1999114 Diabetes Treatment Satisfaction Diabetes Treatment Satisfaction QuestionnaireRandom crossover Questionnaire (total score possible 48): (total score possible 48): 32.36 (5.87), p < 0.001N: 113 35.16 (4.25)

Schmauss, 1998115 Continue with treatment: 11 (100%) Continue with treatment: 0Random crossover (owing to greater flexibility with lispro)N: 11 Reports that no significant difference in

treatment satisfaction was noted

patients using soluble insulin, with little differenceapparent between the groups113,115–118 (Table 23).Bode and colleagues113 observed a significantlylower rate of hypoglycaemic events according to symptoms (but not necessarily confirmed byblood glucose <50 mg/dl) in patients in the aspartgroup (6.7 episodes/patient/30 days, SD 5.4)compared with lispro (10.5 episodes/patient/30 days, SD 8.1, p = 0.044) or soluble (10.5episodes/patient/30 days, SD 8.9, p = 0.034)groups. Nocturnal hypoglycaemia with bloodglucose <50 mg/dl was also significantly lower inthe aspart group than the soluble group.113 Melkiand colleagues116 found fewer episodes of bloodglucose <2.0 mmol/l with lispro [0.05 (SD 0.31)per month] than soluble [0.47 (SD 1.17) permonth, p < 0.05], but not of episodes of bloodglucose <3.0 mmol/l. Other studies found nosignificant difference in the number ofhypoglycaemic events defined by patientsymptoms or blood glucose <3 mmol/l,117 meannumber of episodes per patient defined bysymptoms or blood glucose <3.5 mmol/l,114

episodes per 30 days defined by blood glucose<3.5 mmol/l115 or episodes per 30 days defined bysymptoms or blood glucose <3.0 mmol/l.118

No episodes of DKA were reported in four studies.Ketosis was reported in two studies, occurring in1.7–4.4% of patients in the lispro group and0–3.5% of patients in the soluble group.114,117 Nosignificant differences in hyperglycaemia (bloodglucose >350 mg/dl) between aspart, lispro andsoluble insulin were reported by Bode andcolleagues.113 A similar proportion (18–23%) ofpatients in each group experienced catheterobstructions.114,116 In addition, Raskin andcolleagues117 reported that eight (14%) patientsusing lispro and 12 (20%) patients using solubleinsulin experienced 16 and 23 episodes ofhyperglycaemia, respectively, caused byocclusion.117

SummaryAnalogue insulin was associated with a 0.26%lower glycated haemoglobin levels than solubleinsulin and was preferred by patients. Nodifference in insulin dose or weight change wasobserved. Some studies found fewerhypoglycaemic events with analogue insulin,although this varied according to the definitionsused.

Discontinuation ratesOne way of assessing acceptability to patients is toexamine how many patients continue to use

pumps. However, there is a wide range ofdiscontinuation rates and the studies need to beinterpreted with care. Schifferdecker andcolleagues120 noted that discontinuation rates werehigher in studies from the USA, and higher inpatients with poorer control (by HbA1) at the start.They suggest that those with poorer control wereless likely to have been experienced in bloodglucose self-control and insulin dose adjustment,and that discontinuation is less likely if patientshave had a spell on MDI first. This is supportedby Wredling and colleagues,121 who recommendthat patients be selected and prepared for CSII bymeans of at least 6 months of MDI, adequateexperience with blood glucose self-testing, andgood compliance with diabetes management.

Schifferdecker and colleagues also note acorrelation between the discontinuation rate andthe proportion of people with Type 1 diabetes onpumps, with a low rate in European countries suchas Germany, where only 2% of Type 1 diabetespatients were on CSII,120 but a high rate in clinicswith up to 30% of Type 1 diabetes patients onpumps.122 In the study by Knight and colleagues,122

all patients attending the clinic were offered CSII orMDI, and most pump users (101 of 116) wentstraight from conventional insulin treatment withone or two injections per day to CSII. With thisunselective approach, there was a high uptake(30%) of CSII but also a high early discontinuationrate by 12 months, with most of these stoppingwithin 2 months. However, the pump used was theGraseby, and the authors comment that there wasreluctance amongst patients to ‘walking around witha large box attached to me all the time’. Thecommonest reasons for early discontinuation werepump size and discomfort. Another reason washypoglycaemia, in patients who had been poorlycontrolled before CSII, had rarely experiencedhypoglycaemia, and who found occasionalhypoglycaemic episodes unacceptable.

Floyd and colleagues123 reported that 33 (49%) of68 adults starting on CSII stopped, about halfwithin 6 months. A variety of pumps were used,including larger older ones. Factors predictingdiscontinuation included a high baseline HbA1

and a low estimation by users of their ability toself-manage diabetes.

Bell and colleagues124 found in 1988 that one ofthe major reasons (40%) for discontinuation wasneedle site abscess, but in a later paper (1993)125

they report that the cause of the infections hadbeen found to be the diluting fluid, and that therewere no discontinuations due to abscesses in thesecond study.


42


43


TABLE 23 Adverse events with analogue and soluble insulin


Analogue Soluble

Bode, 2002113

Parallel RCTLispro N: 28; end of study: 27Soluble N: 59; end of study: 50Aspart N: 59; end of study: 55

LisproSevere hypos: 0DKA: 0Hyperglycaemia (BG >350 mg/dl): 10, p = ns

≤ 3 clogs or blockages: 64%Hypos [episodes, rate/pt/30days (SD)]:All reported: 872, 10.5 (8.1) vs aspartp = 0.044.Hypos BG <50 mg/dl: 359, 4.4 (4.7) vsaspart p = 0.841Nocturnal hypos BG < 50 mg/dl: 64, 0.6(0.61) vs aspart p = 0.189

AspartSevere hypos: 0DKA: 0Hyperglycaemia (BG >350 mg/dl): 16, p = ns

3 clogs or blockages: 75%Herpes zoster: 1Hypos [episodes, rate/pt/30 days (SD)]:All reported: 1126, 6.7 (5.4)Hypos BG <50 mg/dl: 610, 3.7 (3.6)Nocturnal hypos BG <50 mg/dl: 96, 0.5(0.83)

Severe hypos: 1 (1.7%)DKA: 0Hyperglycaemia (BG > 350 mg/dl): 24, p = ns

≤ 3 clogs or blockages: 78%Hypos [episodes, rate/pt/30days (SD)]:All reported: 1663, 10.5 (8.9) vs aspartp = 0.034Hypos BG <50 mg/dl: 770, 4.8 (4.2) vsaspart p = 0.175.Nocturnal hypos BG <50 mg/dl: 207, 0.9(0.97) vs aspart p = 0.004

Melki, 1998116


Catheter obstructions: 9Severe hypos: 3 (7.9%)DKA: 0Insulin precipitation in catheter: 1

BG <3.0 mmol/l: 7.03 (5.79) per monthBG <2.0 mmol/l: 0.05 (0.31) per month

Catheter obstructions: 9 Severe hypos: 4 (10.5%) patients(7 episodes)DKA: 0Insulin precipitation in catheter: 4

BG <3.0 mmol/l: 7.94 (5.42) per month,p = nsBG <2.0 mmol/l: 0.47 (1.17) per month,p < 0.050 hypos resulted in coma or seizures

Raskin, 2001117


Severe hypos: 3 (5.1%) patients (3 episodes)Ketosis: 1Hyper due to occlusion: 8 pts (16 episodes).

Hypos as defined: 7 pts (8 episodes)

Severe hypos: 2 (3.4%) patients (3 episodes)DKA: 0Hyper due to occlusion: 12 pts (23episodes)[During study 38 pts reported 109 episodesof hyper: 39 caused by occlusion, 47 causedby other reasons, 23 no identifiable cause.Groups not specified]

Hypos as defined: 7 pts (11 episodes).1 hospitalised: fever, vomiting, dehydration

Renner, 1999114


Injection site infection: 4

Serious adverse event not related to drug: 1

Hypos: mean 12.4 (13.9), median 8episodes/ptInfection (cold): 19.4%Rhinitis: 15.8%Catheter occlusion: 20 (42 episodes)Ketosis: 5

Injection site infection: 2

Serious adverse event not related to drug: 6

Hypos: mean 11.0 (11.2), median8 episodes/pt, p = nsInfection (cold): 21.1%Rhinitis: 13.8%Catheter occlusion: 21 (45 episodes), p = nsKetosis: 4

continued


44

TABLE 23 Adverse events with analogue and soluble insulin (cont’d)


Analogue Soluble

Schmauss, 1998115


Severe hypos: 0DKA: 0Hypos per 30 days: 4 (2.98)

Note: no severe adverse events registeredby either treatment

Severe hypos: 0DKA: 0Hypos per 30 days: 3.2 (2.3), p = ns

Zinman, 1997118


Skin reaction: 16Severe hypos: 0

Discoloration of insulin in reservoir orcatheter (did not lead to obstruction orsignificant hyperglycaemia): 2

Hypos: 8.6 (7.7)/30 days (vs baselinep = 0.035)Hypos confirmed by BG: 6.0 (4.9)/30 days(vs baseline p = 0.03)

Skin reaction: 15Severe hypos: 0

Discoloration of insulin in reservoir orcatheter (did not lead to obstruction orsignificant hyperglycaemia): 2

Hypos 10.8 (9.9)/30 days (vs baseline andlispro p = ns)Hypos confirmed by BG: 7.6 (7.1)/30 days(vs baseline p = ns, vs lispro p = ns)

The purpose of this chapter is to give anappreciation of what it means to have Type 1

diabetes that is not well controlled on insulin byinjections and how CSII can change that.Although this chapter gives us access to a widerrange of data than is available from the trials, it isnot methodologically rigorous and findings maynot be generalisable.

CaveatsThe patient’s perspective section is based largelyon written statements from pump users, andseveral caveats are required. First, most commentscome from people who are members of INPUTwho have responded to a request for comments.They are likely to be a more highly motivatedgroup than average and some are clearly highlyorganised individuals. This does not affect thevalidity of their comments, but may haveimplications for generalisability. Second, they aresuccessful pump users and tend to be enthusiastsfor the technology. That is less important becausethose who do not succeed will not incur the on-going costs of pumps. Third, most have had topay for the pumps and consumables themselves,and this creates another selection bias. Fourth,because pumps are little used in the UK, itappears that most of those who have gone on toCSII have done so because they have had a lot oftrouble with control of blood glucose or frequenthypoglycaemic episodes, that is, a severity bias.They may have more to gain than the averageperson with insulin-treated diabetes. It isapparent, for example, that some of theimprovements in HbA1c reported by the INPUTrespondents are greater than seen in the trials.Again, this does not affect the validity of thefindings, but will be relevant to discussions aboutthe proportion of people with Type 1 diabetes whoshould be considered for CSII. It may also meanthat CSII might be more cost-effective in ‘real-lifepractice’ than would be expected from HbA1c

differences seen in the trials.

The term ‘control’ is used in different ways. Theusual use refers to control of blood glucose levels,but we need to distinguish that fairly narrow usagefrom control of diabetes. The broader use includes

control of symptoms, hypoglycaemic episodes andother metabolic disturbances such as highcholesterol levels. Or as one of the INPUTmembers said, “Good diabetic control does notequal normal life.”

Most of the published studies have used outcomemeasures such as HbA1c. Some have includedfrequency and severity of hypoglycaemic episodes,but only one has included QoL.

It may be useful to think in terms of a spectrum ofbenefits in terms of ease of measurement, with themore easily measured such as HbA1c at one end andbenefits such as greater flexibility of lifestyle at theother. Published research tends to focus on themore easily measurable end of the spectrum,whereas it may be that the greatest amount ofbenefit lies at the less easily measurable, or perhapsjust less frequently studied, end of the spectrum.

Since the published studies did not providesufficient data on all outcomes of importance topatients, we have sought information from pumpusers, sometimes directly from individual users,but more from the pump users’ group INPUT.This information has usually come from the user,but sometimes has come from their spouse orparent. For example, few of the trials haveincluded children, and so we have specificallysought advice from a number of parents.

Such information may be from successful pumpusers, but when considering the resource impact,that is appropriate, since those who do not like CSIIwill probably cease to use it and will thereby ceaseto incur the extra costs. Hence the economicanalysis differs from, for example, that of a druggiven to a number of patients, some of whom willbenefit and some not. Those who do not benefitfrom pumps will probably stop using them fairlyquickly. The cost-effectiveness therefore depends onthe costs and benefits for successful long-term users.

Space does not permit the inclusion of commentsfrom all those members of INPUT whoresponded. In the quotations below, they andother pump users are identified only as ‘pumpuser (PU)’ and number. Parents are identified as,for example, ‘Parent 1’.


45


Chapter 4

The patient’s perspective

Reasons for switching to insulin bypumpThe reasons for starting CSII given in publishedstudies have been reviewed by Pickup and Keen39

and range from improving poor control to patientpreference.

The meaning of ‘poor control’ and the emphasison HbA1c have been mentioned above. However,as one of our panel of experts noted:

“HbA1c is only an average of what the patient’s bloodglucose has been. It does not show the variations ofblood glucose that any person treated with insulin willexperience. These variations can often be quite wide.An HbA1 measurement cannot show whether thepatient has frequent hypoglycaemia, which is onereason for a person to opt for CSII therapy.” (PU1)

Because HbA1 is only an average, it could reflecteither perfect control with blood glucose alwaysunder tight control, or a situation with both highand low blood glucose levels. As our adviser said:

“From my own personal experience as a pump user of20 months, if only HbA1 was used as the measure ofcontrol, one would not be able to see how CSIItherapy has altered my diabetes control. I managed tomaintain a perfect, i.e. non-diabetes level using MDItreatment for a good 10 years before changing toCSII, and my HbA1 level has not altered with pumptherapy. However, CSII has had a dramatic effect onmy control by reducing the frequency ofhypoglycaemia.” (PU1)

The value of HbA1c is not in doubt as an indicatorof risk of long-term complications of diabetes suchas eye or kidney disease. It is less useful for large-vessel disease such as ischaemic heart disease.

The reasons given by pump users for switching toCSII included:

� To reduce problems with hypoglycaemic events;this was especially the case amongst those whohad lost awareness of developinghypoglycaemia.

� To control hyperglycaemia and improve HbA1c,in order to prevent longer term complications.

� To give control of wide fluctuations in glucoselevels (in effect, the combination of the previoustwo reasons).

� To allow more flexibility in diet and insulin,particularly for those whose schedule may varyfrom day to day or be unpredictable (such asbusiness people, junior doctors andschoolchildren).

� To ‘regain a more normal lifestyle’.� Less painful than multiple injections.� To lose weight, which had been difficult on MDI

because hypoglycaemic events were avoided byregular eating plus snacks when symptoms ofhypoglycaemia occurred, or blood glucosetesting showed lowish results.

� To control the ‘dawn phenomenon’, whichoccurs when the effect of insulin taken theevening before wears off by morning, allowingblood glucose levels to rise to high levels.

� To ensure very good control of blood glucoselevels during pregnancy. (Tight control beforeconception and during pregnancy reduces therisk of malformation and other adverse events.)

One mother reported that her son “likes gadgetsand computers” and wanted to administer hisinsulin with one.

Hypoglycaemic eventsThis was one of the main reasons for switchingfrom MDI to pumps, and a number of respondentscommented on the frequency of hypoglycaemicevents on MDI and the unpredictability of theeffect of long-acting insulin:

“My quality of life has definitely improved mainly dueto the reduction in hypoglycaemia. One very importantimprovement is that my hypoglycaemic warning signsare now much more evident, allowing me to takeappropriate action in reducing the risk of severehypoglycaemia. On MDI therapy, I had problemscontrolling my post-prandial blood glucose even whenusing the quick acting lispro insulin. The choice waseither to take less insulin at meal times to avoid goinghypoglycaemic several hours later, which resulted inpost-prandial highs, or to take more insulin at mealtimes to prevent the post-prandial highs but then riskgoing hypo later and having to eat more food whetherI was hungry or not. The pump solves this problemwith the use of the different boluses available and withthe continuous basal infusion.” (PU1)

“On MDI therapy, I averaged approximately 3admissions yearly to Accident and Emergency byambulance for severe hypoglycaemia. My wife had toadminister glucagon to me on average twice a month;I have only needed one glucagon injection in20 months since being on the pump.” (PU1)

A glucagon kit, with drug, syringe and sterile waterfor injection, costs about £20.126 Hence twice-monthly glucagon would cost about £480 per year.

“At the age of 14 I began to use a basal-bolusinjection regimen. . . . I remember battling exhaustion


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at school due to fatigue as the result of sleepdisturbance due to nocturnal hypoglycaemia. . . . Ifound that however hard I tried, if I aimed fornormoglycaemia, I would experience frequent hypos,which left me feeling exhausted. . . . Over the next 3years control improved again but I still suffered fromfrequent nocturnal hypos during which I woke upbathed in sweat. I found that reducing long-actinginsulin by 2 units often had little effect and any largerreduction often resulted in morning hyperglycaemia.During my first year employed as a doctor I struggledwith frequent hypos. . . . [On pump therapy] I stillexperience a few hypos but not to the extent of mypre pump days. . . . Overall the pump has enabled meto regain a degree of control over the condition.”(PU2)

“I really do feel that for the first time in my life that Iam actually controlling my diabetes rather than justletting it run constantly high so that I didn’t go hypo.My hypos have become much milder and so mucheasier to control, so that I am not frightened to runmy blood glucose in the normal range.” (PU3)

“I changed to four daily injections for three years.The new regime did not help night time hypos ordawn phenomenon. I experienced severe hypos whichended up with either ambulance call-outs oremergency visits to A and E (12 in two years). . . . Thepump corrected my hypos in the middle of the nightand also my dawn phenomenon. Over a few monthsmy hypo awareness returned in that I would knowwhen my sugar levels started to drop and be able totake glucose without becoming unconscious as before.I have now been using a pump for 6 years and havenot been admitted to A&E since starting on thepump.” (PU4)

Several users commented that awareness ofimpending hypoglycaemia (see ‘Introduction’ forexplanation) had returned once they had been onCSII for a couple of months, probably becausethey had had periods of relative freedom fromhypoglycaemic episodes.

Control of blood glucoseA number of respondents commented that MDIdid not provide satisfactory control.

“I was diagnosed age 12. Years ago I went on to amultiple injection regime, which used long-actinginsulin as a background dose, with injections of short-acting insulin before each meal – a total of sixinjections a day. My diabetes has always been difficultto control. Six injections a day and very regular bloodtesting (5–7 tests a day) backed up by sensible andregular eating and hardly any lifestyle ‘excesses’ didnot enable me to achieve reasonable blood sugarcontrol. Every single day I would have a problem with

either high or low blood sugars. On pump therapyalthough my sugars still fluctuate, on most days I canhope to get through the day without a significantproblem.” (PU 5)

“My diabetes control had been erratic for some yearsdue to problems with insulin absorption after 28 yearsof injections. After I had used the pump for 4months, blood test results decreased by some 20%,which if sustained should lead to decreased morbidityand risk of complications. . . .” (PU6)

“When I was on MDI blood glucoses were erratic. Inone day I could easily go from being hypo to beingover 20. On the pump, I have very few highs andlows. When I do, I can explain each and every one. Ican look back and see that I have misjudged a mealbolus, or that I didn’t reduce my basal rate enoughwhile exercising. Diabetes is a constant balancingact. . . . because of this you have to make small changesto your diabetes control all the time and with pumptherapy this is very simple and very easy.” (PU7)

“My HbA1c results, which date back 4 years beforestarting pump therapy, were at best 7.4% and at worst11.8%, with an average of 8.9%. Within 3 months ofcommencing pump therapy, I achieved 6.8%, and onmy last test it was down to 6.1% – excellent control.”(PU8)

Some respondents had additional comments onthe difference between MDI and CSII:

“To a certain extent some of these things could bepartially accomplished using lispro insulin on MDItherapy. However, the difficulty lies with the injectionof intermediate/long acting basal insulin. For me, Ifound that its action from day to day would peak atimprecise times probably due to the variableabsorption of the unused injected insulin. It is alsoimpossible with this insulin to adjust for changes ininsulin needs and sensitivity throughout the day, e.g.dawn phenomenon. For myself with the pump, I setfour different basal rates throughout a 24 hour day,ranging from 0.1 units/hour for most of my workingday, to 0.4, 0.5 and 0.6 units for the evening, nightand early morning, respectively. This would be verydifficult to do with MDI therapy.” (PU1).

Flexibility of lifestyleThe advantages of pumps in allowing greaterflexibility of lifestyle and working patterns werereferred to by a number of respondents:

“Living with diabetes is not an easy situation.Anything that allows the individual person to takecontrol and manage a medical condition must bebeneficial both to the patient and the carers. Theproper use of an insulin pump allows this to happen.


47


From my own perspective the pump has allowed meto lead a full and active life where I control mydiabetes rather than the diabetes control me. I havebeen able to travel extensively on business and forpleasure without worrying about changing time zones,strange local eating customs and where/when the nextmeal might come from.” (PU9)

“Freedom, flexibility, pleasure and peace of mind inone’s daily life, almost like being a non-diabetic,compared with the uncertainty of the MDI regime.”(PU10).

“I can live a much more flexible lifestyle where I havethe freedom to eat when and what I please withoutcompromising on my glycaemic control, whereasbefore, on MDI, the insulin was controlling my eatinghabits. Now I can more easily regulate the insulin bytaking whatever is needed according to when andwhat I eat. I can even skip meals or take a secondhelping.” (PU1)

“As I have a very busy life the remote control of mypump helps me to be able to eat on the go and give acouple of units of insulin for the carbohydrate that Ieat.” (PU3)

“I have experience of both injection (19 years) andinsulin pump (6 years) therapy. I find pump therapyto be preferable as it gives me far more control of myinsulin input and daily activities. I am now able to livea near normal lifestyle with better control of mydisease.” (PU4).

“I have just completed the first 6 months of anintensive degree course, which has meant balancingfamily life with controlling my blood sugars andworking literally all hours in order to complete myprojects in time. My last three projects involved myworking through the night. . . . I couldn’t imaginedoing that without the support of a pump.” (PU5; aworking mother with young children).

Other commentsThe respondents mentioned a number of benefitsrelating to their reasons for going on to pumptherapy, but they also gave details of benefits thatthey did not seem to have expected:

“ I feel more energetic and more able to cope withthe demands of work.”

“The pump is extremely predictable; I have neverhad a problem with mine. Using the pen, theabsorption of insulin was erratic and everything wasleft to guesswork. . . . ”

“For the first time in my life I almost feel normal. Iam not constantly looking for drink and food.”

“My injection sites were hard and painful and I wouldhave to alternate these. With the pump I do not havethese.”

“I do not have to carry syringes with me everywhereor inject in restaurants or loos before eating”.

“My condition is much less visible, in that I can takeinsulin without anyone being aware of what I amdoing.”

“On the pump I backpacked through Guatemala,Belize and Honduras for 3 months, scuba diving,climbing volcanoes, doing all sorts of activities for thefirst time. I could apply my pump knowledge to anysituation and come out the other end with good BGs.I could conceal my pump so didn’t get needles outwhere locals may have seen and suspected. It wouldhave been a lot harder on injections and moreworrying and stressful.”

“It all goes back to being in control of your conditionrather than the condition controlling you”.

“The extra weight has been lost.”

DisadvantagesThe commonest reported problem was cost.

Other problems included concern about beingattached to a pump 24 hours per day every day:

“At first I was very apprehensive about this form oftherapy since it would mean being connected to apump for 24 h/7 days a week which I didn’t reallythink was for me,” but after being on the pump,“Always being connected to a device is certainly notan ideal way to live. Its advantages however faroutweigh the inconvenience of wearing it. It can easilyand quickly be removed for taking a shower, bath,and swimming or for sex.”

“It certainly made me more aware of my diabetes. Infact to be honest, I had the feeling that I was adisabled person, something I had never felt before.This feeling of being disabled is no longer present.”

“In the 20 months since using the pump, I haveexperienced on 3–4 occasions interruptions of insulindelivery which were not detected by the pump’ssecurity alarm system, and only later detected bytesting my blood sugar and finding an unexpectedhigh. I later discovered the causes for these as eitherbeing a large bubble forming in the infusion line orthat the infusion site cannula had slipped out. Thishas reinforced the need for frequent monitoring ofmy blood sugar.”

“The only problems that I see with the pumps are thered marks that the infusion sets leave on myabdomen, and that I can’t swim with it.”


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“Curiously enough, I have never found the actualwearing of the pump to be the slightest problem. Thepump and its tubing are easily disconnected at thesite (this takes about a second) should I wish to bewithout it for a short period. It is small and clips tothe waistband of whatever I am wearing and the shortlength of tubing is simply tucked under my clothes.The only time I have found the wearing of the pumpto be a problem was when I was on holiday, wearing aswimsuit and having to keep the pump in a smallcoolbag so that the sun did not overheat the insulin.”

“The only problem occurred shortly after I startedusing it and was unused to it. One evening Iinadvertently knocked out the cannula from under myskin and went to bed. I then had no insulin deliveryuntil the morning.”

The alarm on the pump will go off if the pumpfails to pump out insulin, but as long as the insulinis being pumped out, whether into the patient orthe bed, the alarm will not go off.

Pump users need to remember that they have noreserves of insulin:

“Anyone contemplating pump therapy needs tounderstand that, because one is using only short-acting insulin, if for any reason the supply of insulinis unexpectedly interrupted, the body has no reserveof long-acting insulin, and so sugars can rise sharply.”

and that they have to monitor their blood sugarlevels:

“Anyone on a pump has to accept that they have tokeep a reasonably close eye on their blood sugars, bydoing regular blood tests during the day. This way,any unexpected fluctuations can be investigated.”

and

“If the pump is to work for you, you need to beprepared to work with it. It relies on goodprogramming by the user and you need to bemotivated in order to get the best out of it, as it willnot solve all your problems without any input fromyou”.

With CSII, there is a needle through the skin allthe time, although the site will be changed everyfew days. There is therefore a small but real risk ofinfection:

“The only disadvantage I have found is the very rareoccurrence of infection at the insertion site. In mycase I have suffered this on four occasions in 20 yearswhen I have needed antibiotics. However, it is easy torecognise how I got infections. It was the direct resultof leaving the infusion line in place for too long. This

of course happens because I have to pay for all theancillary supplies, costing about £1200 per annum, acost that would double if I changed the reservoirs andinfusion lines as often as recommended by thesuppliers.”

Children and CSIIAll the comments above came from adult pumpusers. Fourteen submissions were obtained byINPUT from parents of children (some now olderteenagers) with experience of pumps. The numberof children on pumps in the UK appears to be low[currently over 100 children on pumps (Davis J,INPUT: personal communication, 2002)] and thishas been a problem for some families:

“Because there are currently so few others in the samesituation, we had to follow a steep learning curve forthe first few weeks, making up a number of groundrules for ourselves. We have joined a growing supportgroup of pump users. . . . ” (P1)

Space prohibits more than a few quotations fromthe submissions, but a few examples give anillustration of before and after pump therapy.

Before:

“The two words that best summed up living with thecondition are ‘discipline’ and ‘stress’. Disciplinerelates to the way our lives had to be structuredaround Sam’s diabetes. This included arranginginjections to fit in with meal times (i.e. just beforebreakfast and just before tea, in general), working outa fairly rigid regime of snacks and regular meals,trying to ensure that a young child eats just the rightamount at just the right time, forward planning tomake sure that all trips away from home wereadequately prepared for any eventuality. . . . It hadbeen very frustrating to put so much effort intolooking after him, only to see wide fluctuations in hisblood glucose levels partly due to the uncertainties ininsulin absorption from injections.”

(This child developed diabetes at the age of two,and switched to the pump when he was 7.)

After:

“We can definitely say that it has been beneficial forall of us. The first few weeks were very hard work, butonce the various insulin delivery rates had beenestablished, we quickly settled into a routine.

Meal times are no longer rigid or stressful. Sam caneat what he wants (within reason) whenever he wants– we simply add up the amount of carbohydrate ineach meal, convert this to an insulin amount using


49


our own conversion chart, and program the bolus onthe pump. It did not take Sam very long to work outhow to do this himself and it has made an enormousdifference to his independence and self-esteem.” (P1)

From a child switched to CSII from MDI:

“better control on multiple injections than on two aday (HbA1 8.6%) but even better on pump (7%).Pump gives back part of the quality of life that wasdestroyed when he first became diabetic – he may notbe ‘normal’ or ‘better’, but he can live a more or lessnormal life with a pump.”

This child had severe problems with hypoglycaemicunawareness and hypoglycaemic events, had hadhypoglycaemic event-induced seizures and hadepisodes of unconsciousness at school events:

“He was deeply affected by having collapsed at school,in a public hall, on stage in front of all the otherschools in the town with everyone having seen.” [He isa saxophone player.] “He was not allowed his snack ona school trip and he collapsed hypo on the outing.”

After:

“I no longer have the child alarm in his room in casehe goes hypo in his sleep because I am confident he isnot likely to. Having spoken to other parents whosechild has fitted [i.e. had an epileptic-like convulsiondue to hypoglycaemia], it is an experience you never,ever, forget, but on a pump you are able to sleepnights, and so is your child, confident that he willwake up in the morning.” (P2)

Hypoglycaemic episodes affect not just the childbut the family. From the parent of a child whodeveloped diabetes at 1 year old and is now4 years old:

“I have found it hard to go back to work as I seem tobe on call for him all the time. For example, I willdrop him off at 9.30 and by 11 am they can phoneme up because he has gone low, and I have to go backto the school.” (P3)

Most of the respondents noted improvements inHbA1c, but it should be noted that half thechildren were on conventional insulin treatmentwith two injections a day:

“Her HbA1c levels dropped from 10.6 to 8.2, and hermood and personality dramatically changed – we gotour little girl back again.” (P8).

In some cases, treatment with conventionaltherapy rather than MDI was preferred by thehospital clinic, and one parent switched to MDIherself after studying Internet sites and books:

“In a 12 week period, I listed all Jamie’s readings – 78hypers, 63 hypos and 69 normal readings. Went onmultiple injections – I telephoned the hospital and saidthat I would be starting it, as they had failed to respondto my requests for many weeks, and it would be helpfulif they could tell me how to work out the dosage, butthat even if they did not, we would be doing it.” (P2)

Several commented on reduced emergencyhospital visits:

“. . . Has not been admitted to hospital since going onthe pump. On four injections a day had fouradmissions over 2 years.” (P6)

There were comments on the pros and cons ofMDI versus CSII:

“We wouldn’t consider having 12 injections every 3days when we can have only 1 and the ability tocorrect a hyper at the touch of a button with no moreinjections.” (P8)

“I don’t think multiple injections do anything for achild’s mental state. Their lives would be governed bythe clock. Syringes would always have to be carried onthe person which is not socially acceptable (school,discos, etc.) plus the safe carriage of a vial of insulin.”(P9)

Some of the benefits are social rather than medical:

“Steven feels more like his peers now [on the pump].He can eat with them [instead of going in to dinnerearly] and he can eat the same things as them.” (P10)

“Had to move school due to bullying as other pupilscould not accept Nicola eating at certain times of theday. . . .”

“Diabetes [on pump] is now not obvious to anyone asNicola does not need to eat during class and does nothave so many hypo attacks.” (P9)

Some children had snacks stolen; one had hisblood glucose meter stolen.

Disadvantages mentioned included:

� more daily blood tests than on CT, and moreparental input to collate tests and insulin boluses

� cost� the need for vigilance in case any thing goes

wrong with the pump� misunderstandings by other people – “On a few

occasions, people have thought he was playingwith a Game Boy while he was programming abolus”

� being connected to a device 24 hours a day.

However, most respondents said there were nodisadvantages.


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Common themesSources of informationThe majority of parents got their informationfrom non-NHS sources, the two main ones beingthe Internet, and Balance, the magazine ofDiabetes UK (formerly the British DiabeticAssociation). Several encountered resistance fromthe NHS, and sometimes wrong information:

“We had to go to a private doctor instead of theNHS.” (P4)

“Every avenue had been explored to try to stabiliseher condition (different insulins and regimes) butnothing worked. The pump was a plea from me to seewhether or not it would help, as the consultant didnot know what else to try. Nurse educator fromcompany put her on the pump; hospital consultantdid not get involved as he has no knowledge of thistherapy. It worked, thankfully.” (P9)

“Consultant was patronising, dismissive andcombative.” (P11).

“Consultant thought pumps were dangerous.” (P2)

Training needsMost parents commented that much support wasneeded in the first few weeks. This was sometimesprovided by the local clinic, but often by nursesfrom the pump companies.

Training needs sometimes varied between parentsand children:

“Started pump therapy after a week of training for meand his father – Jamie of course had already workedout how to use the pump from talking to another childwith one and from reading all the manuals.” (P2).

Jamie started using the pump aged 11 years; helikes computers and other gadgets.

FundingOf the 14 respondents, eight were funding thepump and consumables themselves; one hadsupport from a hospital league of friends; fivewere funded by the NHS, some with little trouble,others after much correspondence with the NHS,MPs and the media. It appears that most healthauthorities do not fund pumps for children. Onehealth authority funded the pump for 2 years thenstopped funding.

Problems with schoolsThere were many problems with schools. Some are not relevant to this review, but the testimoniesare consistent in reporting that schools cope much better with children on pumps than those on injections – although to some extent this is because the children find it easier to lookafter themselves, have fewer hypoglycaemicepisodes, do not need to eat at special times, canmiss meals if necessary and do not need to carryinsulin syringes and vials.

ConclusionsThe evidence above differs in type from that seen in traditional systematic reviews, beinganecdotal and subject to selection biases, but itdoes provide valuable information that is notavailable from the published literature, and is very useful. Data on many of the outcomes could be collected in trials. The problem for thisreview is that such data have not been collected ingood-quality studies from which one can extractutility data to feed into cost per QALYcalculations.

Nevertheless, the submissions have been veryuseful, and provide information that is currentlynot available anywhere else.


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IntroductionThe economic assessment of CSII versus MDI is anevaluation of differing forms of delivery forintensive insulin therapy, and this type ofcomparison has received little, if any, attention inthe scientific literature in terms of cost-effectiveness analysis. Much of the economicsliterature pertaining to diabetes is related to eithercost-of-illness studies127,128 or the cost-effectivenessof intensive diabetic therapy versus conventionaldiabetic therapy (e.g. DCCT129 UKPDS130). Wehave not identified any studies informing on theeconomic consequences of CSII versus MDI.Therefore, we have to see what can be extrapolatedfrom the studies of the benefits of improvedcontrol, and we begin by outlining some of the keystudies, both trials and epidemiological literature,which have been used to support economic analysisin diabetes, and Type 1 diabetes in particular.

A brief outline of the DCCT,19 UKPDS131 andWisconsin Epidemiologic Study of DiseaseRetinopathy (WESDR)132 studies is given below,and in the section ‘Economic models for Type 1diabetes’ (p. 66) we review the main economicmodelling approaches published to date. Thesestudies are used to illustrate the problems ofcreating an economic model to estimate the cost-effectiveness of CSII.

The section ‘Literature review: economicevaluations and quality of life comparisons’ (p. 54)refers to the methodology and findings of theliterature search to identify economic studiesrelevant to the evaluation of CSII versus MDI. Thesection ‘Costs associated with CSII (versus MDI)’(p. 55) presents the cost analysis for CSII. Thesection ‘The benefits of CSII’ (p. 59) provides anassessment of the benefits and QoL issuesassociated with CSII. The sections ‘Economicmodels for Type 1 diabetes’ (p. 66) and ‘Cost-effectiveness of CSII versus MDI’ (p. 71) explorethe opportunities to estimate the cost-effectivenessof CSII using available models and through thesynthesis of available cost and outcome data.

The Diabetes Control andComplications Trial (DCCT)The DCCT19 was a multi-centre randomised

clinical trial designed to compare the effects ofintensive diabetes therapy with those ofconventional diabetes therapy on the developmentand/or long-term progression of diabetescomplications of IDDM. The intensive therapy wasdesigned to achieve blood glucose values as closeto normal range as possible with three or moredaily insulin injections or treatment with aninsulin pump. Conventional therapy consisted ofone or two insulin injections per day (note thatconventional insulin therapy was probably lessthan in the UK, where most patients would get twoinjections of mixtures per day). Two cohorts ofpatients were studied, a primary preventioncohort, to consider whether intensive therapywould prevent the development of complications,and a secondary cohort, to consider whetherintensive therapy would affect the progression ofearly complications. Retinopathy was the principalstudy outcome, but renal, neurological andcardiovascular outcomes were also studied, as werethe adverse effects of the two regimens. Theresults of the DCCT demonstrated that intensivetreatment led to a significant risk reduction in theonset and progression of retinopathy, nephropathyand neuropathy. However, intensive therapy(compared with conventional therapy) wasassociated with a threefold increase in the risk ofsevere hypoglycaemia.19 Analyses did notdemonstrate differences in the QoL outcomesbetween the treatment groups. Most economicsassessments in the field of diabetes have beenundertaken using largely homogeneous modellingmethods, which utilise the data from the DCCT.

The model developed and presented by theDCCT Research Group129 examined the cost-effectiveness of alternative approaches to themanagement of IDDM. The model was used toconsider all persons with IDDM in the USA whowould meet the DCCT eligibility criteria, in orderto provide estimates of the lifetime benefits andcosts of intensive therapy, and to address whethermore costly intensive therapy would be preferableto conventional therapy from the perspective ofthe healthcare system. The model used datacollected as part of the DCCT, together with datafrom other clinical trials and epidemiologicalstudies – detail on the model is presented later inTable 35. The DCCT Research Group present


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Chapter 5

Economic analysis

findings from the model to demonstrate thatintensive therapy reduces complications and canbe expected to increase length of life. The authorsalso state that from a healthcare systemperspective, intensive therapy is well within therange of cost-effectiveness considered to representgood value129 – although the marginal benefits ofthe intensified treatment will vary depending onthe level of control achieved with whateverconventional treatment is used.

The DCCT data are not appropriate to assess therelative benefits of CSII and MDI, because theintensive treatment group was treated with eitherMDI or CSII with non-randomised allocation.However, the study does provide evidence on therelationship between HbA1c and health outcomes(long-term complications), and on some of theQoL issues related to intensive therapy andhypoglycaemia. The DCCT also offers a generalfoundation for modelling the cost-effectiveness oftherapies in IDDM.

The United Kingdom ProspectiveDiabetes Study (UKPDS)The UKPDS, started in 1977, was designed toestablish whether, in patients with Type 2 diabetes,intensive blood glucose control reduced the risk ofmacro- or microvascular complications, and toinvestigate the benefits of the therapeutic options.Studies within the UKPDS have reported on bloodglucose control with sulphonylureas or insulincompared with conventional therapy,9 control withmetformin on complications in overweightpatients133 and cost-effectiveness analysis for bothof these comparisons,130,134 amongst others. TheUKPDS has reported that intensive blood glucosecontrol in patients with Type 2 diabetes cansubstantially reduce the cost of diabeticcomplications and increase the time free ofcomplications. Findings from the UKPDS supportthose findings presented in the DCCT concerningthe benefits of improved control.

As with the DCCT, the UKPDS presents findingsfrom comparisons of intensive versus conventionaltherapy. For example, the UKPDS9 reports a 0.9%difference in HbA1c between intensive (7.0%) andconventional (7.9%) groups over 10 years (an 11%reduction), and data showed a significant 25%reduction in microvascular endpoints(p = 0.0099), most of which was a risk reduction of21% for retinopathy. The study suggests that therisk reduction is due to improved glycaemiccontrol, rather than the method by which it wasachieved, as there were no significant differencesbetween the three types of drug treatment.

However, the link between glycaemic control andoutcome is complex as the HbA1c levelsprogressively increased over time, although thedifferences between the more intensively treatedand control groups was maintained.9

As part of the UKPDS,130 a model was developedto estimate cost and effect. The model is a discreteevent simulation model, looking at cost per event-free year; however, it does not have a direct link tothe HbA1c input variable.

The Wisconsin Epidemiologic Study ofDiabetic Retinopathy (WESDR)The WESDR is a population-based study of theprevalence and incidence of diabeticretinopathy.129 The study population consisted ofa sample selected from 10,135 patients withdiabetes who received primary care in an 11-county area in southern Wisconsin from 1979 to1980. The study reports on ‘younger onset’ Type 1diabetic patients diagnosed before 30 years of age.The study provides unique long-term population-based information. Within the sample studied the14-year rate of progression of retinopathy was86%, regression of retinopathy was 17%,progression of proliferative retinopathy (PDR) was37% and the incidence of macular oedema was26%. Data from the study suggest relatively high14-year rates of progression of retinopathy andthat a reduction of hyperglycaemia andhypertension may result in a beneficial decrease inthe progression to proliferative retinopathy. Datafrom WESDR have been applied in diseaseprogression models used for the purpose ofeconomic evaluation [e.g. Palmer andcolleagues,135 discussed further in the section‘Economic models for Type 1 diabetes’ (p. 66)].

Literature review: economicevaluations and quality of lifecomparisonsMethodsLiterature searches were undertaken using searchterms related to the technology and to economicsand QoL. Searches were carried out in a range ofdatabases (see Appendix 2).

Summary of findings on cost-effectivenessThere were no studies identified via the literaturesearch that reported on the cost-effectiveness ofCSII versus MDI. Experts were also consulted inorder to identify any literature on the cost-effectiveness of CSII, but no further studies were

Economic analysis

54

identified. Furthermore, we did not identify anyliterature covering the costs associated with CSII.

Summary of findings on quality of lifecomparisons The literature searches provided only one RCTcomparing QoL outcomes of CSII versus MDI.This study79 found no significant differencesbetween the two interventions [see the section‘CSII versus MDI’ (p. 14)]. Some descriptive andobservational studies that assist with theunderstanding of the QoL consequences of CSIIare discussed in the section ‘The benefits of CSII’(p. 59).

Costs associated with CSII (versus MDI)Additional costs associated with CSII have beenestimated based on the perspective of the NHSand personal social services sector. The costanalysis here aims to identify cost differencesbetween CSII and MDI. Costs componentscomprise (i) intervention costs, (ii) differences ininsulin costs, (iii) differences in the generalmanagement of patients, (iv) the costs associatedwith additional education for pump users and (v) costs associated with adverse events andcomplications. From these, we provide an overallestimate of the additional costs associated withCSII. Cost estimates are based on data from a

number of sources (i.e. manufacturers, patientgroups and expert opinion from two diabetescentres with expertise in management of patients on CSII therapy). As previouslymentioned, we found no cost data in thepublished literature.

Intervention costsTable 24 shows the differences in the suppliesrequired for CSII and MDI therapy, indicatingwhere the intervention costs differ.

Insulin pump costsIn the UK there are currently three insulin pumps available for diabetic patients, DisetronicH-Tron, Disetronic D-Tron and MiniMed 508.Table 25 provides the costs associated with thepurchase and maintenance of the insulin pumpsavailable.

One aspect of the cost analysis is the assumptionon the expected life of the insulin pump. Theguaranteed life of those insulin pumps available inthe UK is 4 years, whereas indications fromINPUT and insulin pump manufacturers arearound an expected life of 7–8 years. This analysiswill use as a base case a pump life of 4 years,reflecting the guaranteed life where nomaintenance costs are payable. Further costcomparisons and sensitivity analysis will explorealternative periods of expected pump life (e.g.8 years).


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TABLE 24 Supplies used in diabetes treatment by intensive MDI therapy or CSII therapy

Supply item Needed for MDI? Needed for CSII? Additional costs for CSII compared with MDI

Lancets Yes, ≥ 3 per day Yes, ≥ 4 per day No

Glucose test strips Yes, ≥ 3 per day Yes, ≥ 4 per day No

Glucometer Yes Yes No

Insulin Yes, short-acting and other Yes, short-acting insulin; unit Reduced insulin use in CSII intermediate- and long-acting requirements vary userspreparations; unit requirements vary

Insulin syringes or insulin Yes, ≥ 3 per day Yes No (minor cost saving in CSII pen users)

Insulin infusion pump No Yes (see pump costs for Yesdetails)

Insulin cartridge/reservoirs No Yes Yes

Adaptors for insulin No Yes, depending on type of Yescartridge/reservoirs insulin pump

Infusion sets No Yes, one set every 3 days Yes

Batteries No Yes, battery life varies by Yespump type

Estimates of the cost for consumable itemsrequired as part of CSII therapy are presented inTable 26. All pumps require batteries, infusion setsand insulin cartridges and/or adaptors.

Insulin costsThe clinical review has shown a reduction in thedaily insulin dose with CSII. Table 27 uses thefindings from the meta-analysis [see the section‘CSII versus MDI’ (p. 14)] to estimate the costimplications of the reduced insulin requirement.

Cost for general patient managementDiabetic patients on MDI are typically managedon an outpatient basis at a local diabetes centre.Patients typically (where no complications occur)attend for a regular annual outpatientappointment with the consultant physician, and at6-monthly intervals they attend for anappointment with a DSN (two visits per year).They should be able to have HbA1c measuredevery 3–4 months. Patients also have access toadvice by telephone to the medical team at their

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TABLE 25 Costs associated with purchase and maintenance of insulin pumps

Type of insulin pump Initial cost (£) Expected life Guaranteed pump Maintenance cost: (years) life (years) average cost per year

following warranty life (£)

Disetronic H-Tron 2350 4–8 2 pumps at 2 years each 176.25(total 4)

Disetronic D-Tron 2468 4–8 4 176.25

MiniMed 508 2562 4–8 4 381.88 for 2 years

Costs are inclusive of VAT.Source: INPUT136 and pump manufacturers.

TABLE 26 Cost for consumable items required by insulin pump users

Item Unit cost Requirements Cost per year (excluding VAT) (£) (including VAT) (£)

Insulin cartridge/reservoirs:Disetronic H-Tron 41.25 per 25 Depend on dose 51.47Disetronic D-Tron 35.00 per 10 Depend on dose N/Aa

MiniMed 508 40.80 per 24 Depend on dose 53.60

Adaptors for insulin cartridge/reservoirs:Disetronic D-Tron 35.00 per 10 Weekly (approx.) 220.10

Infusion sets:Disetronic H-Tron and D-Tron Varies: 4.04/4.96/5.25 1 every 2 or 3 days 950.15b

MiniMed 508 Varies: 3.70–7.05 1 every 2 or 3 days 847.60c

Batteries:Disetronic H-Tron 10.30 per set 1 set every 5 weeks 126.21Disetronic D-Tron 11.00 per set 1 set every 12 weeks 56.17MiniMed 508 4.50 per set 1 set every 6 weeks 45.95

Estimated annual cost for consumable items (including VAT):Disetronic H-Tron 1127.83Disetronic D-Tron 1226.42MiniMed 508 947.15

a Disetronic D-Tron is able to use 3-ml Humalog insulin cartridges.b Weighted annual cost from Disetronic/Abacus.c Weighted annual cost based on average cost for Teflon needles and proportions of 0.55 and 0.45 for Teflon and steel

needles used.Source: cost data from INPUT 2001,136 unless stated otherwise.

diabetes centre (normally their DSN). This level ofcare is not expected to be any different once apatient has started CSII therapy (assuming thateducation support is adequate for those on MDI,otherwise there would be an added cost) and hasbeen through the education and training requiredas part of CSII therapy. However, in the earlystages of CSII therapy it would be reasonable toexpect that one extra visit to the DSN may benecessary (in addition to the education required atthe start of CSII therapy), at 3 months after thestart of pump therapy (source: expert opinion)(Table 28). These extra visits probably do not applyin the case of children, who are usually seen moreoften (every 3 months).

Where complications do occur, the treatmentpatterns/care pathways will be the same for bothMDI and CSII patients.

Costs associated with education forCSIIEducation for CSII: patient levelWhere patients are switched from MDI to CSIIthey must undertake a programme of education tofamiliarise themselves with the use of the insulinpump and its use in the management of theirdiabetes. There are no published data on the costsassociated with insulin pump education. Weconsulted Bournemouth Diabetes and Endocrine

Centre, a leading centre for insulin pump use, andtheir practice indicates that all patients on MDIshould have been through diabetes education aspart of the management of their diabetes. Thetypical education package at the BournemouthCentre, for MDI, would entail an educationprogramme comprising attendance at four 6-hoursessions, in a consecutive 4-week programme.These programmes typically cater for groups of5–6 patients and involve a DSN and dietitianthroughout the programme, with a consultantphysician devoting up to 3 hours of contact timeover the complete programme.

Diabetic education will differ across centres fromformal packages of education, as provided inBournemouth, to more informal and ad hocpatient education programmes. The issue in thisreview is the additional education required bypatients when switching to CSII. Again we havedrawn on current practice at the BournemouthCentre, which we believe provides a reasonableestimate (a relatively thorough package ofeducation and training) of the education necessaryfor insulin pump users. When a patient initiatesCSII, additional education is provided at bothgroup and individual patient levels. Patientsattend for both group and individual educationsessions. Education is delivered to groups of3–5 patients (minimum, maximum) and comprisesinput from a DSN, at 9-hour group level, andthereafter patients typically attend for 3 hours ofeducation with the DSN at an individual patientlevel. The typical programme would comprise a 6-hour group session, a 3-hour group session andindividual education (3 hours) thereafter. Inputfrom a dietitian would be variable, from0–6 hours, depending on the level of prioreducation within the group (i.e. MDI educationpackage outlined above) and the time that had


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TABLE 27 Reduction in insulin dose and associated costs

Reduction in daily insulin dose: Source Insulin/cost per unita Annual cost mean (95% CI) reduction (£)

–9.73 (–14.5 to –4.91) Meta-analysis 2.5–4 months Humalog: 5 × 3-ml cartridge 66.33(all appropriate trials) (100 units per ml) = £26.78

Soluble: Actrapid, 10-ml vial 37.29(100 units per vial) = £10.50

–13.63 (–23.62 to –3.64) Meta-analysis 2.5–4 months Humalog: 5 × 3-ml cartridge 88.72(RCT data only) (100 units per ml) = £26.78

Soluble: Actrapid, 10-ml vial 52.57(100 units per vial) = £10.50

a Source of cost data: BNF, March 2002.

TABLE 28 Additional resources for general patientmanagement: CSII versus MDI

Additional resource items Additional cost (£)

1 additional outpatient 74appointment in year 1

Source: PSSRU, 2001.

lapsed since the delivery of prior educationprogrammes. In the estimate provided in Table 29we assume the maximum expected 6 hours ofdietitian input. In paediatric care, because ofsmaller numbers, group sessions may not bepossible.

Education for CSII: institutional levelStaff in diabetes centres providing CSII therapywill also require additional education and trainingwhere it is lacking. There is an organisation set upin the UK, Pump Management for Professionals(PUMP), a collaboration between BournemouthDiabetes and Endocrine Centre and the HarrogateDiabetes Centre, that delivers education toprofessionals to facilitate the wider use of insulinpump therapy. PUMP recommends that for eachcentre managing patients on insulin pumps aminimum of three persons be educated on CSII:one physician, one dietitian and one DSN. Theeducational programmes offered currentlycomprise a 3-day teaching programme. Table 30presents details of the costs associated with theeducation of diabetes centres.

Information from PUMP indicates that 90 diabetescentres currently have some patients (one or more)on CSII and 25 centres have 10 or more patients.It is difficult to estimate the number of centresthat would require CSII education for health careprofessionals. It may be that some of those centresalready managing CSII patients would still require

some degree of professional education. At one endof the spectrum we could assume that all 218 NHSTrusts in England and Wales that offer diabeticcare, as listed in the Directory of Diabetes Care,137

require the minimum education detailed in Table 30. This would result in an estimate of about£590,000 to cover education as described in theabove table. However, it is unlikely that all centreswould be responsible for the management of CSIIpatients, with the setting up of local or regionalCSII centres being a possibility, which wouldreduce costs.

Costs associated with severe hypoglycaemiaThe clinical review suggests that there will beslightly fewer severe hypoglycaemic events on CSIIthan MDI. Severe hypoglycaemia could have aneconomic impact, owing to the costs associatedwith treatment and the potential impact onpatient QoL. However, indications from the twodiabetes centres assisting with our review(Bournemouth and Harrogate) are that mostinstances of severe hypoglycaemia are treated bypatients and carers and do not result in significantNHS resource implications. There is littleliterature on the cost consequences of severehypoglycaemia. We detail below the insightsavailable from the limited literature and thefindings from consultation with two diabetescentres. We use these in Table 31 to give anestimate of the cost per severe hypoglycaemicevent, based on the assumptions on treatment

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TABLE 29 Patient-level education for CSII therapy

Input to education programme Hours Staff inputs: cost per houra (£) Cost per patient (assuming a group of 4 patients) (£)

DSN – group 9 21.75 48.94Dietitian – group 6 22.23 33.35DSN – individual 3 21.75 65.25Additional education cost per patient switching to CSII 147.54

a See Appendix 14 for details.

TABLE 30 CSII – education and training for professionals

Cost/resource inputs Number (minimum) Cost per daya (£) No. of days Cost estimate (£)per centre

Physician 1 578 3 1734DSN 1 163 3 489Dietitian 1 164 3 492Course fees (NHS transfers) N/A N/AEstimate of the costs associated with education for professionals 2715

a See Appendix 14 for details.

given in the third column. Based on discussionwith the diabetes centres the cost profile for severehypoglycaemic events assumes that in most casesthere is no input from NHS staff, with patients orcarers administering glucagon. In a number ofinstances patients are expected to attend or reportthe event to a DSN and we have made anassumption that this occurs in 10% of cases. Also,we have made an assumption that in 5% of casesan ambulance is called out to a patientexperiencing an event, although these cases donot result in a hospital admission. These areconservative assumptions, and in reality there maybe fewer instances of glucagon use, fewervisits/reports to the DSN and fewer ambulancecallouts than those detailed in the cost profile.

The NHS Reference Costs Data139 offer estimatesfor two health-related resource groups (HRGs)(K11, K12) associated with emergencyhypoglycaemia in diabetic patients. K11 refers to‘Diabetes with Hypoglycaemic Emergency >69 orw cc’ and K12 refers to ‘Diabetes withHypoglycaemic Emergency <70 w/o cc’. The costdatabase provides estimates for elective inpatient(ELIP) costs, non-elective inpatient (NELIP) costsand day case (DC) costs. Although electiveinpatients stays (costing £1395 for K11 and £796for K12) do not seem correct for emergencyhypoglycaemia, 48 such events are listed asfinished clinical episodes (FCEs) in the ReferenceCosts Database and 198 for K12. It is possible thatthey have been mis-coded as elective, or thatpatients have been admitted as semi-elective cases in order to review treatment and improvecontrol. For NELIP costs are £954 and £567,respectively (activity data show 3027 and 2416FCEs). For DC cost estimates are £222 and £352,respectively (16 and 97 FCEs). These HRG costsdo not reflect the costs of the average severehypoglycaemic event. It is possible that the costestimates given in the NHS Reference Costs referto severe hypoglycaemia complicated byuncommon related events, possibly hypoglycaemiaassociated with seizure or coma. Althoughrelevant, they are probably sufficiently rare to

have little effect on the average cost of a severehypoglycaemic event.

A Scandinavian study by Nordfelt and Jonsson140

reports a 12-month prospective follow-up ofdiabetic patients and estimates the costs associatedwith diabetes, providing an estimate of the costsassociated with severe hypoglycaemia. The studyassesses costs and other short-term effects ofsevere hypoglycaemia in 129 children andadolescents with Type 1 diabetes. Data werecollected on 111 events of severe hypoglycaemia(16 were events involving unconsciousness and 95were non-unconscious events). The average costper event is reported at €239 (2047 SEK) forevents involving unconsciousness and €63 (543SEK) for events not involving unconsciousness (n= 95). These estimates include indirect costs (e.g.time lost from the workplace), and the estimateswith healthcare costs only are substantially lower at€151 and €28, respectively (approximately £94and £17.50, using an exchange rate of €1.6 per £).The study by Nordfelt and Jonsson, although inchildren and adolescents, adds support to our costassumptions for severe hypoglycaemia (as above).

In a study available in abstract only, Leese andcolleagues from the population-based DARTScollaboration reported that over a 12-monthperiod, 7% of patients with Type 1 diabetes hadsevere hypoglycaemic events (‘severe’ beingdefined as needing emergency assistance fromNHS personnel). One in three episodes (of allcases, Type 1 and Type 2 diabetes) were dealt withsolely by the ambulance crew. The average costwas around £377.141

Estimated marginal cost for CSIIBased on the cost estimates presented above, theadditional costs of CSII are as given in Table 32.

The benefits of CSIIFrom the clinical effectiveness evidence and theusers’ submissions, the benefits of CSII over MDIinclude:


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TABLE 31 Cost estimate for treatment of severe hypoglycaemic event

Treatment Unit cost (£) (source) Proportion of events Proportionate cost (£)treated in this way (%)

Glucagon 19.95 (BNF126) 100 19.95DSN/outpatient attendance 74.00 (PSSRU138) 10 7.40Paramedic/ambulance attendance 247.00 (PSSRU138) 5 12.35Average cost for severe hypo 39.70

� QoL gains from greater lifestyle flexibility� improved diabetes control as reflected in HbA1c,

which might be expected to reduce long-termcomplications

� a reduction in hypoglycaemic events, whichwould be expected to be associated with areduction in the fear of hypoglycaemic events

� an improvement in hypoglycaemic eventawareness, which will feed into both theprevious benefits.

However, all these benefits can feed into animproved quality and quantity of life.

This section starts with an overview of diabetesand QoL and then considers individual benefits.

Diabetes and quality of lifeA recent review of QoL associated with diabetes142

characterises the nature of diabetes (generally) byreporting that people with diabetes often feelchallenged by their disease and its day-to-day

management demands, finding that thesedemands are substantial. Patients with diabetesmust deal with their diabetes all day, every day,making countless decisions in an often futile effortto approximate the non-diabetic metabolic state.Diabetes therapy, such as taking insulin, cansubstantially affect QoL either positively, byreducing symptoms of high blood sugar, ornegatively, by symptoms of low blood sugar. Thepsychosocial toll of living with diabetes is often aheavy one, and this toll can often affect self-carebehaviour and, ultimately, long-term glycaemiccontrol, the risk of developing long-termcomplications and overall QoL.142

However, to place diabetes in context, the authorsof the above review report that ‘people withdiabetes have a worse QoL than people with nochronic illness, but a better QoL than people withmost other serious chronic diseases’ (p. 205). Thereview is a useful one, albeit general, and presentsfindings on a range of issues affecting the

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TABLE 32 Estimated marginal cost associated with CSII compared with MDI

Cost consequence of CSII versus MDI Disetronic D-Tron (£) Disetronic H-Tron (£) MiniMed 508 (£)

Intervention costs:Pump 2,468 2,350 2,562Consumables 1,226.42 1,127.83 947.15

General patient management 74 74 74

Patient education costs 147.54 147.54 147.54

Difference in treatment cost for severe hypos –39.70 –39.70 –39.70(assuming a reduction of 1 event per year)

Difference in insulin costa –88.72 –88.72 –88.72

Total net cost for CSII:

Year 1 3,878 3,571 3,602

Cumulative cost, assuming 4-year pump life:

Years 1–4 (discounted)b 7,081 (6,722) 6,569 (6,242) 6,058 (5,790)

Mean non-discounted cost per year 1,770 1,642 1,514(costs spread over 4 years)



Cumulative cost, assuming 8-year pump life:



Education for professionals ~2,715 per centre, ~2,715 per centre, ~2,715 per centre, year 1 only year 1 only year 1 only

a Using data from meta-analysis including RCTs alone.b Figures in parentheses indicate where discounting of future costs has been undertaken using a discount rate of 6%.

relationship between QoL and diabetes, forexample, type of diabetes, treatment regimen,glycaemic control, demography and patientcharacteristics. The review highlights some of theassociations and uncertainties evident in theliterature covering the assessment of QoL indiabetic patients generally.

A number of the above issues impact on theassessment of CSII, which may affect glycaemiccontrol, adverse events and lifestyle issuesassociated with managing diabetes. Within thisassessment of CSII versus MDI, the prime concernis the difference between the two therapeuticoptions. With respect to QoL, there are fewinsights as to any potential differences between thetwo options. From the clinical review only onestudy has reported QoL as a trial outcome, by Tsuiand colleagues,79 and that study failed to find asignificant difference between CSII and MDI(using DQOL). Further literature searches did notidentify any studies (randomised or crossoverstudies) comparing QoL outcomes in CSII andMDI. A number of descriptive studies may assist informing a view on the QoL consequences of CSII,and these are discussed below. However, we mustbe aware that the findings from these studies maynot be generalisable and may introduce bias froma variety of sources, such as patient selection andstudy design.

From the clinical review findings in Chapter 3, thesmall, but significant, difference in HbA1c and thereduction in the event rate for severehypoglycaemia are deserving of attention in terms of their impact on the QoL of patients (CSII versus MDI). These issues are discussedbelow.

Glycaemic control (HbA1c)Data from long-term trials and epidemiologicalstudies have provided evidence that ‘good’metabolic control protects diabetic patients againstchronic complications (e.g. DCCT ResearchGroup,19 WESDR132 and UKPDS130).

The DCCT Research Group143 have presentedfindings on the relationship of glycaemic exposure(glycated haemoglobin/HbA1c) to the risk ofdevelopment of progression of retinopathy in theDCCT. The DCCT demonstrated a markedreduction in the risks of development andprogression of retinopathy and othercomplications of IDDM with intensive treatmentcompared with conventional treatment. They alsopresent findings143 from an epidemiologicalassessment of the association between levels of

HbA1c, before and during the DCCT, with the riskof retinopathy progression. The DCCT data donot provide a definitive assessment of the causalrelationship between specific levels of glycaemicexposure (HbA1c) and the risk of complications,143

as confounding is possible from a number ofsources. However, the findings from theepidemiological assessment lead the DCCT groupto believe that the mean HbA1c (i.e. improvedHbA1c) is the dominant predictor of the reducedrisk of complications in the intensive treatmentgroup, and that data on the total exposure toglycaemia (based on HbA1c at screening and thelevel during the trial), the baseline duration ofIDDM and the time in the study provide a strong,although indirect, affirmation of the glucosehypothesis (i.e. lower levels of glycaemia wouldreduce the development and progression ofcomplications).

The DCCT Research Group use a number ofdifferent statistical models (proportional hazards,Poisson and Logit models) to show that the risk ofcomplications increases with increases in themodel variables reflecting glycaemic exposure. It isfrom these sources that the recent meta-analysis byPickup and colleagues,40 comparing CSII withMDI, postulates that a difference in HbA1c of 0.5%approximates to a reduction of 0.5 cases ofsustained retinopathy progression per 100 patientyears (such a difference would be reflected by areduction in the probability of sustainedretinopathy progression of p = 0.005, or 0.5% perpatient per year). Although these statistical modelsare helpful, they do not lend themselves to anapplication in economic models, as the differencein HbA1c cannot be translated into a transitprobability from meaningful health statedescriptions [i.e. a Markov or decision analyticmodel requires a pathway of disease from onehealth state to another and the DCCT statisticalmodels do not offer this opportunity, based on thepublished literature. This point is discussedfurther below, in the section ‘Cost-effectiveness ofCSII versus MDI’ (p. 71), as we assess the generalfindings from the DCCT statistical models thatpredict the absolute risk of onset of sustainedretinopathy progression].

Data from WESDR demonstrated the generalrelationship of glycaemic control to the incidence of diabetic complications.144 WESDRhealth outcomes data suggest that higher levels of glycaemia are related to a decreasingQoL, but the investigators expect this to bebecause of the increased incidence ofcomplications.145


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HypoglycaemiaHypoglycaemia is the most common complicationof therapy for Type 1 diabetes, and the reportedincidence varies considerably (from four to 65episodes per 100 patient years).146 Theconsequences of hypoglycaemia vary from mildsymptoms and signs to profound sequelae ofneuroglycopenia including coma and seizures.146

Effects on motor coordination, cognitive functionand judgement can impair performance ofcomplex functions such as driving a car, and alsosimple tasks, such as treating hypoglycaemia withoral carbohydrate. Mild hypoglycaemia can berapidly corrected by food intake or sugary drinks,and has little clinical impact. However, severehypoglycaemia, generally defined as requiringassistance from another person, can be serious,involving the potential for harm to patients andothers. Severe hypoglycaemic events may alsoresult in coma or seizure.

Severe hypoglycaemia is common in all patientswith Type 1 diabetes with almost one-third ofpatients experiencing one or more episodes eachyear (EURODIAB IDDM Complications StudyGroup147). Severe hypoglycaemic events arethemselves short-term events, with acute effectslasting no more than 1–2 days in most cases.However, the fear of experiencing a hypoglycaemicevent is a further characteristic of the disease.

The clinical review [see the section ‘Results inadults with Type 1 diabetes’ (p. 16)] found that therate of severe hypoglycaemic episodes differedlittle between treatments in moststudies,79,80,83,85–88,90,91 with no severe episodesoccurring in two studies.86,90 However,significantly fewer severe hypoglycaemic eventsper 100 patients years occurred with CSIIcompared with MDI in the study by Bode andcolleagues.81 Therefore, the impact of thispotential reduction in the rate of severe events onthe QoL of patients may be an important factor inthe comparison of the two treatment options. Asdiscussed in Chapter 3, it is possible that the RCTsunderestimate the benefits of CSII for those withrecurrent severe hypoglycaemia.

Findings from the DCCT showed that althoughhypoglycaemia is an important adverse event forIDDM, the relationship between hypoglycaemiaand QoL is not clear. The DCCT presents findingson the relationship between hypoglycaemia andQoL as measured within the trial. QoL in theDCCT was assessed through the completion of theDQOL measure, the Symptom Checklist-90R(SCL-90R), the Short Form with 36 Items (SF-36)

and psychosocial events observed in the trial. QoLdata were collected from patients at annual visits.Initial analyses did not demonstrate differences inthe QoL of outcomes between the treatmentgroups,19 even though there was a markedincrease in hypoglycaemia in the intensiveintervention group. Subsequent analyses havesupported this finding.148 End of studyassessments showed that the scores on all scalesdid not differ between the treatment groups.Subsequent analyses were undertaken to assess therelationship between hypoglycaemia and QoLoutcomes. The DCCT Research Group148

modelled the relationship of hypoglycaemia to theSCL-90R and DQOL outcomes. Data showed thatthe occurrence of severe hypoglycaemia was notconsistently associated with a subsequent increasein symptomatic distress or decline in diabetes-related QoL. Models using the SCL-90R showedthat only where patients had repeated severehypoglycaemia, resulting in coma or seizure, didthey tend to be at increased risk of measurablesymptomatic distress. The models using theDQOL score as the outcome did not demonstratean association of hypoglycaemia with an adversechange in QoL. The authors draw attention tosome of the factors that may account for thesefindings (e.g. lack of power to detect anassociation between hypoglycaemia and QoL asmeasured by the DQOL), but present the findingsas an indication that patients on intensive therapydid not face a deterioration in QoL, despiteincreasing demands of their diabetes care and thefrequency of hypoglycaemia (for further detail, seethe DCCT references listed).

Although severe hypoglycaemia is seen as a majorcomplication by diabetic patients, other studiesseem to support the supposition from the DCCTanalysis that hypoglycaemia may not have asignificant impact on the patients’ reported QoLassessments. Ferguson and colleagues149 in a studyto investigate the potential of insulin Lispro tolimit the frequency of severe hypoglycaemia, in acohort of patients with Type 1 diabetes who are ata high risk of severe hypoglycaemia, present someindicative findings on the relationship betweensevere hypoglycaemia and QoL. The study (anopen-label design) used the DTSQ andHypoglycaemia Fear Survey (HFS) to assess QoL,and reported that overall, considering bothtreatment groups together, the 55% of studyparticipants (18 of 33 patients) who experiencedsevere hypoglycaemia during the 48 weeks of studyfollow-up scored significantly higher on the HFSscales for worry (p = 0.049) and behaviour (p =0.015), and these patients also had significantly

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lower DTSQ scores (p = 0.040). Analysis across allpatients in the study showed an increase inexposure to severe hypoglycaemia correlated withgreater anxiety (r = 0.55, p = 0.001) and worry (r= 0.58, p = 0.001), depression (r = 0.45, p =0.010) and lower levels of energy (r = –0.52, p =0.002). However, where one treatment groupshowed a reduced incidence of severehypoglycaemia (insulin Lispro treatment), therewere no significant improvements in QoL measuresbetween the two treatment groups.

Boland and colleagues98 present findings from aprospective follow-up study in 75 adolescents andyoung adults with Type 1 diabetes, where patientschose between CSII and MDI prior to follow-up inthe study. Rates for all hypoglycaemic eventsrequiring assistance or resulting in coma werereduced by almost 50% in the CSII group (134versus 76 per 100 patient years, p < 0.05), andpatients in the CSII group found coping withdiabetes to be less difficult than patients usingMDI (p = 0.05). However, QoL assessed using theDQOLY (a version of the DCCT DQOLinstrument) showed no differences between thetwo groups. The study also reports no differencebetween groups in terms of depression (assessedusing psychosocial assessments), and self-efficacyassessments. (Note that this study was a non-randomised prospective study, and subject toselection bias, and so was not included in ourclinical review.)

Nordfelt and Jonsson140 present findings from adescriptive study to describe costs and other short-term effects of severe hypoglycaemia in childrenand adolescents with Type 1 diabetes. The study ispredominantly a cost-of-illness study, with a 12-month prospective follow-up. The study doesnot assess CSII and the study sample group(n = 129) are patients treated intensively withmultiple insulin therapy, based on active self-control, problem-based learning and psychosocialsupport. The interest in this study is the focus onhypoglycaemia and general comments on QoLissues associated with severe hypoglycaemia. Thestudy used a questionnaire containing 20 detailedquestions regarding short-term effects after eachevent of severe hypoglycaemia (during January toDecember 1988). Questionnaires were obtainedfrom 50 patients who had reported one or moreevents of severe hypoglycaemia. Nine patients(7%) reported severe hypoglycaemia withunconsciousness (U) and 45 (35%) reported severehypoglycaemia without unconsciousness butneeding assistance of another person (NU). Fourpatients had both U and NU events. Data were

collected on 111 events of severe hypoglycaemia(16 were U and 95 were NU events). With respectto QoL, patients indicated cancellations ofplanned activities in 11 events (10%),tiredness/headache in seven events (6%),schoolwork affected in five events (5%) and anger,sadness, minor wounds or bed/clothes wetting intwo events. Other effects were reported forparents/families; increased worry after nine events(8%), poor sleep/tired during the day after eightevents. As can be seen from the questionnaireresponse data, the assessment appears to havebeen primarily assessing QoL issues related toactivities of daily living and psychosocial impacts;the authors do not offer further detail on thequestionnaire administered.

Nordfelt and Jonsson140 also present brief detail ona health state valuation exercise undertaken as partof their study. The study used the EQ-5Dinstrument in a postal survey of patients with aduration of diabetes longer than 1 year. The EQ-5Dscores indicated lower global QoL for the patientswith severe hypoglycaemia in 1997 compared withthose without the severe hypoglycaemia: median0.85 versus 1.0, p = 0.0114. The authors do notoffer further detail on their findings or methods.The EQ-5D typically measures QoL on a scale of0–1, with 0 representing the worst imaginablehealth and 1 reflecting the best imaginable health,whereby respondents are asked to place a rating fortheir own health state on a visual analogue scale(VAS) from 0 to 100. Further detail is required onthis paper before findings can be generalised, assome ambiguities exist as to the comparator groupsand the methods employed to obtain values(presumably the study used the VAS section of theEQ-5D instrument).

The association between severe hypoglycaemiaand QoL differences is not apparent from theliterature. The literature does not offer areasonable estimate of health state values/utilitiesassociated with health states involving severehypoglycaemia. Some insights are available andthese will be explored in the section ‘Economicmodels for Type 1 diabetes’ (p. 66).

Fear of hypoglycaemiaBecause of the ever-present threats fromhypoglycaemia (physical symptoms, negativemood states, cognitive dysfunction and the risk ofseizures or death), many patients acknowledgesubstantial anxiety and fear concerninghypoglycaemia.150 Fear of hypoglycaemia mayitself be associated with poor metabolic control(e.g. deliberately maintaining high glucose levels


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or over-treating early symptoms).150 A surveyinstrument, the Hypoglycaemia Fear Survey(HFS),151 has been developed to assess patients’fear. The HFS is a 27-item questionnaire, with afive-point Likert scale format. The HFS was usedin a study by Ferguson and colleagues,149 discussedabove. However, the literature on the relativeeffectiveness of CSII versus MDI does not offerany detail on any differences in hypoglycaemicfear between the treatment groups.

In the appraisal of long-acting insulin analogues(insulin glargine), the NICE Appraisal Committeeaccepted that episodes of hypoglycaemia aredetrimental to QoL, partly owing to fear of suchepisodes. The Committee accepted that reductionin fear of hypoglycaemia could have a significanteffect on QoL, additional to that obtained fromreducing the QoL losses from the actual episodes.Specific QoL and utility values are not given in theappraisal consultation document for long-actinganalogues, but it appears that the cost-effectiveness estimates were significantlyinfluenced by a reduction in fear of hypoglycaemia(NICE website at www.nice.org.uk, accessed 18 October 2002).

Hypoglycaemic awarenessImpaired awareness of hypoglycaemia, defined asa reduced ability to perceive the onset ofhypoglycaemia, is common in patients with Type 1diabetes, affecting around 25% of patients,152 withprevalence increasing with duration of diabetes.149

Up to 50% of IDDM patients 15–20 years post-diagnosis report having lost their ability toperceive autonomic symptoms associated with lowblood glucose levels and thus often fail to act toprevent severe hypoglycaemia.152 Severehypoglycaemia has been reported to occur up tofive times more frequently in patients withreduced awareness of hypoglycaemia. One of thebenefits of better control through CSII may be thereturn of awareness of impending hypoglycaemia.

Clarke and colleagues152 have developed a surveyinstrument to assess patient awareness ofhypoglycaemia, and report a prospective study in78 IDDM patients. The study concluded thatIDDM subjects who believed they had reducedawareness of hypoglycaemia were generallycorrect. As part of this work, Clarke andcolleagues152 report that reduced awareness led toa greater number of moderate and severehypoglycaemic events (results were fromprospective diary records and were statisticallysignificant at p values of 0.026 and 0.0062,respectively). In support of this finding, Gold and

colleagues153 (cited by Bode and colleagues81)report a sixfold higher incidence of severehypoglycaemia in patients with hypoglycaemicunawareness compared with patients withoutimpaired awareness. The literature review on theeffectiveness of CSII versus MDI does not offerany detail on differences in hypoglycaemicawareness between the treatment groups.

CSII versus MDI: quality of lifeassessmentThe search of the literature on QoL associated withCSII identified only one study that included QoLas an outcome in a randomised trial comparingCSII with MDI.79 Tsui and colleagues79 randomlyassigned 27 patients with Type 1 diabetes to CSIIor MDI. This study reports a QoL assessment atbaseline and 9 months, as a secondary outcome,using the DQOL questionnaire. The study did notobserve any significant differences in DQOL scoresbetween the two groups (see detail on the study inAppendices 6 and 10).

There were no further findings on QoLcomparisons between CSII and MDI fromrandomised or controlled trials, identified as partof the literature review. However, we haveconsulted a number of general and cross-sectionalstudies to provide an insight to the health statusassociated with CSII treatment. We have discussedabove a number of studies that address issuesrelated to severe hypoglycaemia and QoL andoffer brief detail below of studies by Chantelauand colleagues154 and Lewis and colleagues155 thatconsidered general QoL issues in the context ofCSII. However, these studies are not randomisedor crossover designs, and the quality of the studies(often descriptive in nature) is variable; cautionshould be exercised in the interpretation andgeneralisation of any findings.

The study by Chantelau and colleagues154 presentsfindings from a prospective cohort study with a 6-month follow-up. The study uses the DCCTDQOL questionnaire to consider QoL in IDDM.The study considers two groups. Group A werepatients who had moved to a more intensivetherapy (one group is CSII). The study reports nochange on scales for social worries or diabetes-related worries, the scale for impact of diseaseshowed a reduction and the score for patientsatisfaction increased. CSII indicated fewerhypoglycaemic events. (The DQOL instrument has46 items, four subscales, scored on five-pointLikert scales.) Group B comprised a comparison ofpens versus pumps, and pen therapy scoredrelatively low on the satisfaction subscale, mean

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64

3.61 (SD 0.06), and higher on the impact subscale,mean 2.20 (SD 0.06). CSII significantly improved(p = 0.02) these subscale scorings only [satisfactionup to 4.02 (SD 0.06) and impact down to 2.03(SD 0.05)], with the scales for social worries anddiabetes-related worries unchanged.

Within subgroup analysis, pump users (Group Bsubgroup B1) scored significantly improved QoLwith regard to hypoglycaemia, whereas pen users(Group A subgroup A1) did not (those changingfrom pen to pump, B1, reported less frequenthypoglycaemia, as opposed to those changing fromtraditional therapy to intensive pump therapy whoreported hypoglycaemia as ‘unchanged’).

Lewis and colleagues155 present a TreatmentSatisfaction Scale for IDDM diabetes, with threesubscales. The authors offer support for the scaleand some experimental results, which indicate thatCSII has better QoL than other treatment groups.However, the authors also raise concerns over thegeneralisability of the study findings.

In a general review of QoL issues associated withdiabetes, Rubin and Peyrot142 state that it is notpossible to conclude that QoL differences (i.e.diabetes versus non-diabetes) are due to diabetesper se rather than some other characteristicsassociated with diabetes. The authors sum up bystating that better glycaemic control is associatedwith better QoL, but it is the complications ofdiabetes that are the most important disease-specific determinant of QoL. This position appearsto be the position of the WESDR and DCCTinvestigators also. Based on findings on QoL fromthese long-term studies, and from what we canlearn from the limited empirical evidence availableelsewhere, it would seem reasonable to assumethat differences between CSII and MDI in terms ofthe rates of severe hypoglycaemia may not inthemselves result in a difference in QoL, as assessedusing instruments such as DQOL and SCL-90R.

As highlighted in the patients’ perspective sectionof this report, hypoglycaemia is undoubtedly aserious concern for diabetic patients, withpotentially severe consequences, yet the overallimpact does not appear to be captured in thegeneral assessment of QoL. This may be due tothe lack of sensitivity in the instruments used, or itmay be due to the short-term nature of the eventsthemselves, or the fact that the difference betweenCSII and MDI may, on average, only reflect areduction of one event or less per patient per year.These considerations are mere speculation andshould be the subject of further research efforts.

CSII may result in a more flexible lifestyle withregard to meal schedules, work and recreation,with flexibility over the timing and content ofmeals. CSII may offer variability in timing anddose selection for insulin therapy and it may allowpatients to follow a flexible lifestyle, offering thecapability easily to correct blood glucose values byaltering infusion rates to meet swings in thesevalues.156 However, there is no evidence base todemonstrate how a reduction in the rate of severehypoglycaemia impacts on patients’ QoL.Likewise, although the fear of hypoglycaemia andthe reduced awareness of hypoglycaemia are veryreal issues for a number of patients, it is notpossible at present to quantify the impact of CSIIon the fear of hypoglycaemia or the effect of CSIIon the ability of patients to perceive the onset ofhypoglycaemia (let alone the QoL issuesassociated with such impacts).

Health state values/utilities for CSIIThe literature identified did not contain anyinsight as to the values, or health state utilities,that patients ascribe to the use of CSII.Furthermore, we found more generally that theliterature on health state values associated withdiabetes was also sparse, although this was subjectto ad hoc searches only and by a systematic reviewof the literature.

Wu and colleagues157 present analyses on healthstate values for diabetes derived via a mappingprocess, from SF-36 responses to the valuesavailable from the QWB Scale. The findings arebased on analysis from a sample of 89 (non-diabetic) respondents completing the SF-36. Thepaper is a methods paper and can be classed asexperimental; however, the presentation ofestimates of QWB scores associated with a movefrom ‘general population health state values’ to acondition in which patients are ‘Type 1 diabetics,with no complications’, and from the ‘nocomplications’ diabetic state to a state involving‘diabetic retinopathy’ may be helpful for thedevelopment of illustrative analysis within thisreview. Table 33 presents outline findings from thestudy by Wu and colleagues. Caution must beexercised when considering the data presented inthis study.

Data from Wu and colleagues157 indicate thathealth state values associated with different statesshow only small differences in valuations (e.g. fora move from ‘no complications’ to ‘retinopathystate’ we see a change of 0.03, 0.04 and 0.02 forthe groups in Table 33). The clinical significance ofthese differences is dubious, and retinopathy


65


would only affect QoL if it impaired vision, or if itled to anxiety though the diagnosis per se, or fromdisutility from treatment given.

With regard to diabetic retinopathy, Brown andcolleagues158 assessed the utility values associatedwith varying degrees of visual loss due to diabeticretinopathy. The study presents utility values,elicited using standard gamble (SG) and timetrade-off (TTO) techniques, across five subgroupswith varying degrees of visual loss, ranging from0.85 to 0.59 for TTO and from 0.70 to 0.90 for SGscores. Overall, in the sample of 95 respondentsthe TTO values were 0.77 and the SG scores were0.88 (with visual acuity ranging from 20/20 visionto hand motion visual acuity in the best eye).

Kiberd and Jindal,159 in a study on screening toprevent renal failure in insulin-dependent diabeticpatients, present an estimate of the health stateutility for patients with diabetes; they report avalue of 0.838, commenting that traditionallyutilities vary between 1.0 (perfect health) and 0(death). The authors, finding no publishedliterature to inform on health state values,determined these values using a TTO format in asample of 17 healthcare workers not associatedwith their study (this sample consisted ofnephrologists, clinical house staff, nurses and onesocial worker). The sample of healthcare workersestimated values for six health states, one of whichwas ‘insulin-dependent diabetes alone’. Theauthors do not report any further detail on thehealth state valuation exercise.

The above studies have no direct relevance to thecomparison of CSII and MDI, but they do offersome idea of the magnitude of the health statevaluation differences between diabetes-relatedhealth states, and may offer an opportunity toconsider how the difference between CSII andMDI might relate to the differences associatedwith (i) a non-diabetic state versus a diabetic stateor (ii) a diabetic state with no complications versus

a diabetic state with retinopathy complications.Once again, in raising these matters forconsideration we stress that caution must beexercised in generalising from these essentiallyexperimental studies or using the information foranything other than illustrative purposes.

Economic models for Type 1diabetesReview of economic models for Type 1diabetes mellitus (IDDM)Given the limited data available to inform on thecost-effectiveness of CSII versus MDI, a generaltopic search of the diabetes literature wasundertaken to identify literature on the model-based economic assessments within Type 1diabetes (IDDM). Only a limited number ofmodel-based approaches have been identified thatassess economic outcomes for Type 1 diabetes.Table 34 provides summary detail on themodelling approaches associated with Type 1diabetes. Models are described in outline, with aparticular focus on diabetic retinopathy andhypoglycaemia, where they form part of the modelstructure. The models are described to offerbackground to the assessment of CSII but do notdirectly assist with the assessment of CSII versusMDI.

DCCT Research GroupThe DCCT has been discussed above. The DCCTmodel129 describes and compares the lifetimebenefits and costs of conventional and intensivetherapy as implemented in the DCCT. The modelis a Monte Carlo simulation model, used topredict the incidence of microvascular andneurological complications in a hypotheticalsample of 10,000 persons with IDDM. It randomlyselects from the hypothetical population (either aprimary prevention cohort, or secondaryprevention) and assigns characteristics (e.g. age,disease characteristics). It then uses 12 health

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TABLE 33 Age- and health-specific QWB scores. (Copyright © 1998 American Diabetes Association. From Diabetes Care 1998; 21:275–31.157 Reprinted with permission from The American Diabetes Association.)

Age (years) General populationa Type 1 diabetic, Type 1 diabetic, Otherb

no complications with retinopathy only

<45 0.82 0.73 ± 0.07 0.76 ± 0.05 0.70 ± 0.0845–64 0.75 0.68 ± 0.09 0.72 ± 0.09 0.66 ± 0.07≥ 65 0.70 0.64 ± 0.08 0.62 ± 0.07 0.55 ± 0.05

a Data on general population are from previous studies; see Wu et al.157 for detail.b Type 1 diabetic individuals with diabetic neuropathy or nephropathy alone, or with other complications.

states to capture disease characteristics, groupedaccording to the three major complicationsstudied in the DCCT (retinopathy, neuropathy,nephropathy). The model simulates the course ofthe patient’s disease over their expected lifetime.The model uses 1-year cycles and at each cycle anindividual is in one of five retinopathy healthstates, one of four nephropathy health states andone of three neuropathy health states. Theprobability that a patient will advance to a moresevere stage of disease in a given year depends onthe patient’s current state of health, treatmentregime (i.e. intensive versus conventional insulintherapy) and treatment duration. The modelcycles through time at a patient level, until thepatient exits the model (due to death) and thenthe next patient is selected from the hypotheticalsample. This process is repeated in the DCCTanalysis for a sample of 10,000 individuals. At theend of the modelling process (the simulation), thetime spent in each of the treatments and healthstates and the time spent alive are calculated, costsare assigned and mean statistics are calculated bytreatment group (conventional versus intensive).The DCCT model does not considerhypoglycaemic events.

The DCCT model uses empirical data on diseaseprogression, over 9 years, from the DCCT and aseries of statistical models (Weibull models) topredict the probability of patients advancing tobackground diabetic retinopathy (BDR) andproliferative diabetic retinopathy (PDR) [e.g.Weibull model, � × � × t(� – 1), where � and � arestatistical parameters determined by the study andt is the parameter for duration of treatment;different � and � parameters were determined toreflect conventional and intensive treatmentprobabilities of progression of disease]. Thesemethods are not transferable to the assessment ofCSII versus MDI. Table 35 offers outline detail onthe DCCT model structure.

Palmer and colleaguesThe diabetes disease model developed by Palmerand colleagues135 considers the cost-effectiveness

of a range of intensive interventions for Type 1diabetes (IDDM) compared with conventionaltherapy, to consider optimal lifetime treatmentpatterns. A variant of this model has been used inan earlier NICE submission on pioglitazone inType 2 diabetes.171 (Chilcott and colleagues,2001). The Type 1 model of Palmer andcolleagues is a microsimulation model, simulatingthe experiences of individual patients (themodelling process is similar to the processdescribed above for the DCCT model). The datafor the model are generally drawn from the DCCTand WESDR studies. The authors cite an earlyWESDR study144 and the main DCCT study19 asevidence that the rate of disease progression fromno retinopathy to BDR is dependent on durationof diabetes and the HbA1c value;135 yet the modeluses DCCT methods surrounding duration ofdiabetes to predict transit probabilities for BDR.19

Palmer and colleagues’ model comprises a seriesof Markov submodels, representing thedevelopment and consequences of renal disease,retinopathy, amputation, myocardial infarction,stroke, major hypoglycaemic events and DKA. Thedata used in the model on hypoglycaemic eventsare data (event rates) from the DCCT, reflecting agreater risk of severe hypoglycaemic events for theintensive treatment group versus conventionaltherapy.

The submodel for hypoglycaemia (Figure 12) is asimple transition from an entry state involving nomajor hypoglycaemic event to a health statewhereby patients experience an event requiringassistance (severe hypoglycaemia) and then transitback to either the health state of no hypoglycaemiaor hypoglycaemic death (the model assumes a verysmall probability of death as a consequence ofhypoglycaemia, a death rate of 0.0001).

The submodel for diabetic retinopathy is describedin Figure 13.

For retinopathy, the pattern of disease progressionis from no retinopathy to BDR, to PDR and on to


67


TABLE 34 Approaches to model the cost-effectiveness of Type 1 diabetes

Study Study design Approach Intervention

DCCT, 1996129 Modelling Cost-effectiveness Conventional versus intensive therapy

Palmer, 2000135 Modelling Cost-effectiveness Conventional versus intensive therapy(various treatment options)

Tomar, 1998160 Modelling (based on Cost-effectiveness Conventional versus Intensive therapyDCCT model above) (plus costing study)

blindness (Figure 13). As the simulation progresseseach year (1-year model cycles), patients maycontinue in their present health states or transit tothe next stage of disease progression or a non-specific mortality state. Transit probabilities arebased on DCCT data and are dependent onduration of diabetes. Therefore, the methodologyis not transferable to an evaluation of CSII versusMDI. The retinopathy submodel does not includemacular oedema. The retinopathy submodelmakes assumptions surrounding screening andtreatment for diabetic retinopathy.

The model examines the course of thedevelopment of diabetes complications under a set

of intervention scenarios and examines thetreatment effects in terms of a time series ofclinical events and outcomes (e.g. incidence ofcomplications, mortality). It produces results for atypical cohort of 19-year-old diabetic patients, withno baseline complications (to reflect a typicalcohort of Swiss male patients). It does not have aseparate submodel for mortality, as mortality isincluded within each of the complication specificsubmodels. However, it is not clear how themortality rates have been determined. Table 35offers outline detail on the model structure.

Tomar and colleaguesThe model by Tomar and colleagues160 is notdescribed in this report as it is based on theapproach documented by the DCCT ResearchGroup (as above), and does not offer additionaldata to inform on the modelling of diabetes forCSII versus MDI. See the cited reference forfurther detail.

Suitability of economic models forevaluation of CSII versus MDIThe modelling approaches discussed above do notoffer an opportunity to transfer methods to theassessment of CSII versus MDI. The model-basedapproaches described for Type 1 diabetes (andmuch of the Type 2 diabetes literature) areconfigured to assess the impact of intensivetherapy compared with conventional therapy,whereas the assessment of CSII versus MDI is acomparison of different treatment options for thedelivery of intensive therapy.

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68

Nohypoglycaemic

event

Severe hypoglycaemiarequiring medical

assistance

Death fromhypoglycaemic

event

FIGURE 12 Hypoglycaemia submodel from Palmer andcolleagues135

No retinopathy

Backgroundretinopathy

Non-specificmortality

Blind

Proliferativeretinopathy

FIGURE 13 Retinopathy submodel from Palmer and colleagues135

Illustrative analysis of the relationshipbetween HbA1c reductions and theincidence of diabetic retinopathyGiven the lack of models with which to comparedirectly the cost-effectiveness of CSII with MDI,one option is to use the observed mean reductionin HbA1c in combination with the DCCT modelfor a somewhat speculative estimate of reductionin future retinopathy.

The DCCT Research Group demonstrated that aregimen of intensive therapy aimed at maintainingnear normal blood glucose values markedlyreduces the risk of development and progressionof retinopathy and other complications of IDDMwhen compared with a conventional treatmentregimen.19 The DCCT Research Group alsopresent a further epidemiological assessment ofthe association between levels of glycaemicexposure (HbA1c) before and during the DCCTwith risk of retinopathy progression within eachtreatment group.143 Total glycaemic exposure(HbA1c and the duration of exposure) was thedominant factor associated with the risk ofretinopathy progression.143 When examinedsimultaneously within each treatment group, eachof the components of pre-DCCT HbA1c, pre-DCCT duration of IDDM, mean HbA1c during the

study, time in the study and their interaction, wassignificantly associated with risk of retinopathyprogression.143 However, the DCCT data cannotprovide a definitive assessment of the causalrelationship between specific levels of glycaemicexposure and the risk of complications. The studywas designed to assess whether an intensiveregimen aimed at lower levels of glycaemia wouldyield the desired effects (i.e. reducedcomplications), recognising that any effectsobserved could theoretically be attributable to anyof the effects of such therapy.143 However, theDCCT Group do state that the epidemiologicalassessment of data conclusively demonstrates thatthe updated mean HbA1c (i.e. followingintervention) during the trial and the years offollow-up in the study are the most importantpredictors of the risk of complications in theconventional treatment group, and that theupdated mean HbA1c was the dominant predictorof risk of complications in the intensive treatmentgroup. Although glycaemic exposure was thedominant predictor, the updated mean HbA1c didnot completely explain the risk of progression.

The DCCT Research Group143 investigatedwhether there was a threshold for glycaemia belowwhich there was no further reduction in risk of


69


TABLE 35 Models for IDDM and model characteristics

Modelling studies

Detail DCCT Research Group129 Palmer and colleagues135

Study design Modelling Modelling

Economic outcomes Cost-effectiveness Cost-effectiveness

Intervention Intensive insulin therapy Intensive therapy combinations

Type of modelling Microsimulation (Monte Carlo, Microsimulation (Monte Carlo, patient level, 1-year cycles) patient level, 1-year cycles)

Markov model Markov model

Decision analysis Yes Yes

Cohort/age Two cohorts aged 13–39 years Swiss cohort of 19-year-old diabetics (primary/secondary prevention) patients

Source of cohort information WESDR

Complications:Retinopathy � �Neuropathy � �Nephropathy � �Heart Disease – �Stroke – �Hypoglycaemia – �Ketoacidosis – �Data inputs for retinopathy WESDR DCCT/WESDRData inputs for hypo – DCCT

complications, finding that over the range ofvalues for intensive treatment, there was a gradualdecline in risk with each additional reduction inHbA1c (i.e. no threshold was seen below which therisk of retinopathy was eliminated entirely). Theauthors present a number of statistical models(regression models) used to predict the risk ofretinopathy progression. In Figure 14 we apply oneof these models in an illustrative analysis to assessthe predicted risk of retinopathy progressionamongst patient groups subject to CSII or MDI.

Coefficients for this model are presented by theDCCT Group as shown in Table 36.

The exploratory model (see Figure 15), uses a timehorizon of 10 years (10 years has been used as theanalysis does not accommodate mortalityconcerns) to simulate patient level experiences forCSII and MDI therapies against differing HbA1c

profiles, to reflect the efficacy parametersexpected from CSII versus MDI. A simple Excelspreadsheet model has been used, using CrystalBall software (Decisioneering®) to produce asimulation.

We have applied the above statistical model[equation (1)] to predict the probability of onset ofsustained progression of diabetic retinopathy in a

population defined by baseline HbA1c andduration of IDDM at the start of therapy. Thecohort is assumed to be a primary preventioncohort, free from diabetic retinopathy. Cohort datahave been gathered from studies within theclinical review described above (see Figure 15 fordetail). The efficacy data from the clinical reviewhave been used to reflect a difference in baselineHbA1c and follow-up HbA1c. To simulate theprogression of disease over time, the model usesthe transit probabilities determined through use ofthe statistical model and appropriate modelcoefficients, together with a series of randomnumbers, with the onset of disease based on thebalance of probabilities within the patient cohort.The onset of sustained progression of disease is asdefined in the DCCT study.

A simple simulation has been run over the 10-yeartime frame, to predict the experiences of a patientcohort with CSII (reflecting a reduced level ofHbA1c) and a patient cohort on MDI (i.e. noreduction in HbA1c), using the same series ofrandom numbers to cycle both patient groupsthrough the model/simulation. A simulation hasbeen carried out using a group of 10,000 patients.Results generated from specific input parameters(i.e. HbA1c and duration of IDDM) are presentedin Table 37, for illustrative purposes only [this

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Absolute risk at time (t) = f (HbA1c, log of duration of IDDM on entry to the study, time)

�(t) = exp{� + �1 (H) + �2 ln(D) + �3 (t) + �4 ln(A) + [�5(t) × ln(A)]} (1)

where �(t) is the absolute risk at time t, � is an intercept term, �1 is the screen HbA1c coefficient, H is the screeningHbA1c, �2 is the duration coefficient, D is the duration of IDDM (in years) on entry, �3 is the time coefficient, t is thestudy time and �4 and �5 are interaction coefficients. Hence,

� (risk of onset of sustained retinopathy progression at t) = exp{� + �1 (screen HbA1c) + �2 (log duration of IDDMon entry) + �3 (time) + �4 (log mean updated HbA1c) + [(�5 × time) × (log mean HbA1c)]} (2)

FIGURE 14 DCCT regression model used for illustrative analysis

TABLE 36 From DCCT143 Table 9: regression models of sustained retinopathy progression as a function of total glycaemic exposure

Intensive – treatment

Total glycaemic exposure, Poisson model Estimate 95% CI p

Intercept –10.871 –16.964 to –4.779 <0.001Screening HbA1c (%) 0.215 0.061 to 0.37 –Log (duration) (years) 1.055 0.656 to 1.454 –Pre-DCCT exposure (2 df) – – <0.001Time (years) – 1.710 –3.120 to –0.300 –Log (mean HbA1c) 1.541 –1.46 to 4.541 –Log (mean HbA1c) × time 0.809 0.136 to 1.483 <0.019

exploratory analysis is based on an assumption ofprimary prevention cohorts (diabetic retinopathy),assuming that patient cohorts are free fromdisease].

Cost-effectiveness of CSII versusMDI We have discussed above the difficulties associatedwith modelling cost-effectiveness via a diseaseprogression model using glycated haemoglobin(HbA1c), the main effectiveness outcome from thecomparison of CSII and MDI. From ourexploration of the literature and availablemodelling technologies, it is not possible toproduce a meaningful incremental cost-effectiveness ratio. We have produced a costanalysis to determine the short-term and medium-term costs associated with CSII. However, we havenot been able to identify comprehensive estimatesof meaningful health outcomes from the clinicalevidence available. The link between HbA1c andlonger term complications (e.g. eye and kidneydisease) would have to be assumed. There is anabsence of data linking the use of pumps with anylonger term complication or mortality data. Toour knowledge there are no long-term trials ofCSII versus MDI planned for the future.

Below we make some assumptions surrounding thebenefits associated with CSII. However, based onthe lack of an evidence base to support theseassumptions, the examples are purely illustrative.

Outcomes associated with CSIILong-term complicationsWe have discussed above the general belief that areduction in HbA1c is a good thing, with areduction in HbA1c expected to contribute to areduction in the incidence of complications suchas diabetic retinopathy (DCCT,19 UKPDS,131

WESDR132). However, in previous studies assessingthe cost-effectiveness of interventions for Type 1diabetes (DCCT,129 Palmer and colleagues135),hazard rates and statistical parameters have beenused that have been determined from particularstudy and intervention groups, in order toestimate future rates for complications and thesubsequent reduction in risk associated withdiabetic interventions (e.g. intensive therapyversus conventional therapy). Pickup andcolleagues40 in a recent meta-analysis of CSII havealluded to a potential reduction in the onset ofsustained retinopathy progression and we haveundertaken some exploratory analysis to assesswhether their claims are supported by the datafrom the DCCT. Using a statistical model to assessthe absolute risk of sustained onset of retinopathy


71


Assign patient-levelcharacteristicsfrom cohort data

Simulation (10,000 patients)

No DR

Patients go through 10 × 1-year cycles with risk of onset of sustained progression of DR

NoYesOnset of DR(or cycle = 10)

Patients either exit the model free of DR or subject to onset of DR

Ass

ign

next

pa

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CohortDescription– HbA1c (entry)– Duration of DM (on entry)

FIGURE 15 Structure of exploratory model to assess risk of onset of sustained progression of diabetic retinopathy (DR)

Economic analysis

72 TA

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progression, a Poisson model detailed by theDCCT Research Group, we would concur with thesuggestion of Pickup and colleagues that a 0.5%reduction in HbA1c would result in a reduction inthe region of 0.5 cases of sustained retinopathyprogression per 100 patient years.

The analysis we have undertaken to relate theeffect of HbA1c changes to the incidence of long-term complications is illustrative. The statisticalmodel used does not differentiate between thenature of the outcome expected, sustainedretinopathy progression. BDR, which wouldcomprise most, if not all, of this forecast reductionin the risk of diabetic retinopathy, is very differentfrom PDR in terms of both its economicimplications and the implications for the diabeticpatient. The onset of BDR does not involveadditional NHS resources as there is no treatmentother than insulin therapy to manage glycaemiccontrol. All diabetic patients should be subject toeye screening to detect onset and progression ofdiabetic retinopathy. The probability of onset ofBDR is relatively high compared to the progressionfrom BDR to PDR, hence our concern over theability of the statistical model available to modeldisease progression. Our exploratory analysis ofthe methods presented by the DCCT ResearchGroup143 involved a simulation of patient groupsdefined by levels of HbA1c and duration of diabetesover a 10-year period to detect onset of BDR froma population assumed to be free from BDR. Fromthe clinical studies identified to inform on theeffectiveness of CSII versus MDI we used patientcharacteristics, together with the mean effectivenesson HbA1c identified via the meta-analysis reportedabove (we assume a reduction in HbA1c of 0.52%).Findings indicate that a reduction in the risk ofonset of BDR is somewhere between 0.5% and 1%per patient per year. The effect of such areduction in the onset of sustained retinopathyprogression requires consideration in the contextof the overall incidence of disease and the impactof disease. The incidence of BDR is reported to bedependent on the duration of diabetes(WESDR,132 DCCT19), and an estimate of theannual incidence of BDR from ‘no retinopathy’would be in the region of 22% per year, based ondata from WESDR, reported in their study on the4-year incidence of diabetic retinopathy (datashowed an incidence rate of 59% over 4 years).The DCCT Research Group19 report in theirprimary prevention cohort a rate of 1.2 events per100 patient years for onset of BDR. However, thisgroup consisted of recently diagnosed patientswith a mean duration of diabetes of 2.6 years(±1.4), hence a low-risk group.

In our opinion, it would seem reasonable toassume a small reduction in the onset of sustainedretinopathy progression, predominantly from nodisease to BDR; however, the impact of any sucheffect would be small on any cost-effectivenessfindings for a population or patient analysis.Further effects on other long-term complicationssuch as nephropathy (kidney disease) may berelevant, although we are not able to identify anyliterature concerning the consequences for suchevents in the context of the size of difference inHbA1c related to the comparison of CSII and MDI.

It might also be worth noting that the move tosystematic screening for early retinopathy,followed by laser photocoagulation, will diminishthe incidence of visual loss. Hence the benefits oftighter control will, at least for retinopathy, be lessthan in past decades.

Adverse events – severe hypoglycaemiaThe impact of severe hypoglycaemic events onQoL is not known. Indications from the limitedliterature indicate that overall QoL, as measuredby instruments such as the DQOL, is not affectedby events. Events are very short term, with theacute impact of a severe hypoglycaemic eventlasting for 24 hours, at most, in most cases.

In order to assess the impact of severehypoglycaemic events on the health state utilityexperienced by the diabetic patient, we canconsider illustrative examples in a number of ways:

1. We could take the data reported by Nordfeltand Jonsson140 showing a reduction of 0.15 (ona health metric scale of 0–1), between a statecharacterised by severe hypoglycaemia and onewhich is not. As mentioned earlier, these dataare not supported by detail on methods withinthe paper, so caution must be exercised.However, it could be assumed that the healthgain associated with preventing one eventcould be characterised by dividing 0.15 (thehealth gain) by 365 days to ascertain theassociated impact for the 24-hour acute period.This obviously results in a very small differencein overall health utility, and even assuming thatthe effect of the severe hypoglycaemic eventcovered a period of 4 days, the health utilitygained from preventing an event would be0.00164, less than a 0.2% difference.

2. We could consider the health state valuesoffered as part of the EQ-5D tariff161 andassume that the effect of a severehypoglycaemic event would be reflected in a movement in the EQ-5D health


73


descriptive system against the dimensions ofanxiety/depression and/or usual activities, asintuitively both dimensions may be affected byan episode of severe hypoglycaemia.Considering that an event may cause amovement on the EQ-5D algorithm from amoderate to a severe level (level 2 to level 3),or from a level associated with no problems oranxiety to a level associated with a moderatelevel of anxiety/depression and/or someproblems with usual activities (level 1 to level2). In such a way we can estimate the healthgain associated with preventing one severehypoglycaemic event. The health gainidentified in this hypothetical manner wouldstill be very small, assuming that an acute affectfrom an event covers a 24-hour period.Assuming that a patient moves from an EQ-5Dhealth state described as having no anxiety anddepression and no problems with usualactivities to a health state characterised byextreme anxiety/depression and unable to dousual activities (all other dimensions remainingconstant), the EQ-5D tariff values would reflecta difference in health utility/value of 0.294quality-adjusted life-years (QALYs). Applyingsuch a change to a short-term experience suchas a severe hypoglycaemic event lasting24 hours, we have 0.294/365, which is 0.0008QALYs per event.

3. Even if we were crudely to assume that apatient experiencing a severe hypoglycaemicevent were to move, on the health metric scaleof 0–1 (where 1 represents full health), fromfull health (score of 1) to worst imaginablehealth (score of 0), it would still only reflect ahealth gain (QALY value) of 0.00274 per event(assuming the event were to last for 24 hours).

The above considerations are purely speculativeand have no basis in the published literature, andcombining these assumptions with available costestimates (in effect assuming that the reduction in

hypoglycaemic events was the only benefit of CSII)would result in very extreme, and potentiallyunrealistic, cost-effectiveness findings(~£400,000–500,000 per QALY).

Other benefits of CSIIChapter 4 indicated that CSII is reported by somepatients to offer lifestyle benefits andopportunities to manage their diabetes in a moreflexible way. In this review we have been unable toquantify such benefits for the purpose of economicanalysis. This does not mean that such benefits arenot of importance for the patients themselves, butjust that the research necessary to quantify anyrelative utility values has not been undertaken.

Estimating the cost-effectiveness ofCSII versus MDICost estimates have been detailed above (seesummary in Table 38). In order to present cost-effectiveness estimates, data on meaningful healthoutcomes are required. We have been unable toidentify health outcomes that can be quantified forthe purposes of cost-effectiveness analysis. Basedon the cost estimates calculated as part of thisreview, and the speculation as to the health gainassociated with the prevention of severehypoglycaemia (for example, a reduction of oneevent per year), with estimated QALY values perevent ranging from 0.00164 to 0.00274, any cost-effectiveness estimates would be circa~400,000–500,000 per QALY. A summary ofbenefits/outcomes from CSII versus MDI ispresented in Table 39.

Cost-effectivenessCost per severe hypoglycaemic event avoidedThe evidence on the rate of severe hypoglycaemicevents, CSII versus MDI, is conflicting. Using datafrom Bode and colleagues,81 which cover thereduction in events associated with CSII in apatient group that has a relatively high risk ofevents (i.e. a relatively high estimate of

Economic analysis

74

TABLE 38 Estimated additional costs associated with CSII versus MDI: mean patient-level costs for 1, 4 and 8 years (figures inparentheses where future costs have been discounted at 6%)

Total net cost for CSII Disetronic D-Tron (£) Disetronic H-Tron (£) MiniMed 508 (£)

Year 1 3,878 3,571 3,602

Assuming 4-year pump life:Years 1–4 (discounted) 7,081 (6,722) 6,569 (6,242) 6,058 (5,790)Years 1–8 (discounted) 13,941 (11,871) 12,917 (11,011) 11,894 (10,201)

Assuming 8-year pump life:years 1–8 (discounted) 12,178 (10,429) 11,272 (9,663) 10,096 (8,728)

effectiveness), there is an assumed reduction of1.16 severe hypoglycaemic events per patient peryear (12-month data showed 22 events for CSIIcompared with 138 events for MDI). Applying thecost data in Table 38 to the data on severehypoglycaemia from Bode and colleagues offersan estimate of the cost per severe hypoglycaemicevent avoided. However, this is an intermediateoutcome and does not describe the health impactwith respect to a severe hypoglycaemic event.

Estimates are also presented based on an estimateof effectiveness that is expected to be at the highend of the expected benefits from CSII therapy.

Cost per severe hypoglycaemic event avoided ispresented in Table 40.

Further estimates on the cost-effectiveness of CSIIversus MDI are not possible given the dataavailable.


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TABLE 39 Summary of benefits/outcomes from CSII versus MDI

Benefit/outcome Quantifiable Related to cost-effectiveness

Reduction in HbA1c Yes Not able to link directly to diabetic complications

Reduction in severe hypoglycaemia Yes Not able to link to cost-effectiveness in a meaningful manner (i.e.only able to consider cost per event avoided). Not able toestablish QoL impact associated with the reduction in severehypoglycaemic events

Long-term complications No Not able to link HbA1c directly to diabetic complications (e.g. diabetic retinopathy) (illustrative analysis provided). Small reduction in incidence of

microvascular complications expected

QoL benefits No Insufficient data to make a judgement on overall QoL differencesbetween CSII and MDI

Lifestyle benefits/flexibility No No research available with quantifiable utility effects

TABLE 40 Cost per severe hypoglycaemic event avoided

Time horizon for analysis Cost per severe hypoglycaemic event avoided (£)a

Year 1 3078–32644-year time horizon (years 1–4)b 1305–1526 [1275–1481]c

8-year time horizon (years 1–8)b 1281–1502 [1157–1346]c

a Range reflects the differences between the three insulin pumps available.b Assuming an insulin pump life of 4 years.c Where future costs have been discounted at 6% and future outcomes discounted at 1.5%.

The cost to the NHS would depend mainly onthe proportion, and therefore the number, of

patients who used pumps. The largest cost, asshown in Chapter 5, would be those of theconsumables such as infusion sets, with the pumpbeing second. These two together cost fromaround £1075 per annum assuming an 8-year lifeof pump and the cheapest of the three, to £1423per annum assuming a 4-year life and the mostexpensive model.

Numbers would be limited. CSII is not just apump, but a package of self-care involvingfrequent self-monitoring of blood glucose andwillingness to accept further training andresponsibility. The presence of the device for24 hours will deter some people. Conversely, theyounger generation of children familiar withpocket technologies such as games, phones andhand-held computers might have a faster uptake.

Various guides to identifying patients most able tobenefit have been produced. Those from theDiabetes Federation of Ireland note that thedecision is often made by patients:

“Patient selection

� Patients tend to self-select for pumps. They areexclusively patients with Type 1 diabetes who arehighly motivated and have developed an expertisein their own condition.

� Most will have been using MDI but have notachieved their desired level of control.

� Many have early complications such as retinopathy,nephropathy or large vessel disease, whichcontribute to the patient’s personal motivation totake control of the condition. This is a motivator,not a criterion, as ideally intensive insulin therapyshould aim to prevent complications.

� Patients make an important trade-off in acceptingthe long-term attachment to the pump in exchange for better control and a lower risk ofcomplications.”

T. O’Sullivan, Diabetes Federation of Ireland,September 2001

Similar thoughts were expressed by Gerich in1985,162 who added that patients must be capableof accurate self-monitoring of blood glucose levelsand must be willing to do this several times a day.

It is unlikely that more than a small proportion ofpeople with Type 1 diabetes would become pumpusers, but this proportion is not known withaccuracy. Experience from the first few years ofthe West Kent service, provided by the Guy’sHospital trust, suggests that perhaps only 2% willmove to CSII (Pickup J: personal communication).It is likely that CSII would be used mainly by thosewith particular problems with control ofhypoglycaemia, rather than high HbA1c. It seemssafe to assume that patients with Type 2 diabeteswill not be treated with CSII, except as part ofresearch projects on reversing insulin resistance.Figure 16 shows the system used in the serviceprovided to West Kent Health Authority (Pickup J:personal communication) and Table 41 gives thecriteria used to assess suitability.

There are about 330,000 people with Type 1diabetes in England and Wales. The annual costsfor varying percentages are shown in Table 42.However these figures may be too conservative. Itis reported that in Sweden in 1999, 7.5% ofchildren and teenagers were on CSII, but that thishas now increased to 12%.163

Costs other than disposables and pumps areminor. There will be modest savings in insulindosage and from reduced hypoglycaemic events.In the longer term, there will probably be savingsfrom reduced long-term complications, althoughthese are difficult to quantify (see Chapters 5 and7). There will also be education costs, for bothpatients and staff. We have included these in ourcostings.

One issue would be the number of centres thatprovide a CSII service. Should all large diabetesclinics provide a service, or should there be alimited number, with perhaps one pumps clinicper 500,000 population, except in less denselypopulated areas where that would impose travelcosts on patients? One might expect that serviceswould be better if they looked after a minimumnumber of pump users, but there is no hardevidence for that, or for what the minimumnumber should be. The converse argument is thatall hospitals providing a diabetes clinic shouldoffer pump therapy, since it is just another way ofgiving insulin. Furthermore, if pump services were


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Chapter 6

Implementation

Implementation

78

Hospital consultantGPAssessment atPump Clinic byConsultant(15 pts/yr/HA)

Poor control on MIT(two-thirds)– frequent hypo– dawn phenomenon

Pump nurse/dietitianOptimisation of controlon MIT

Unsuitable for CSII (one-third)– non-compliant– psychological problems– good control on MIT

Further treatment(e.g. psychotherapy)General Diabetic Clinic

Trial of CSII

Improved controlcontinued CSII(~10 pts/yr/HA)

FIGURE 16 Strategy for management of potential insulin pump patients

TABLE 41 Selection criteria for a trial of CSII

Type 1 diabetic patients who have failed to achieve good glycaemic control after a 3-month trial of intensive insulin injectiontherapy, including re-education in injection technique, dietary advice and blood glucose self-monitoring), because of:

� frequent unpredictable hypoglycaemia or� a marked dawn blood glucose increase.

NB. We find that in patients with unpredictable and wide swings in blood glucose levels during injection therapy, disablinghypoglycaemia may develop as injection therapy is intensified. These patients would then become candidates for CSII, asindicated above.

Prerequisites for insulin pump therapy

All patients should be:

� willing to undertake CSII� motivated� compliant in diabetes management� able to perform CSII procedures� able to perform frequent blood glucose self-monitoring� meet clinical indications for CSII� free of major psychological and psychiatric problems.

Patients who are likely to do poorly on pump therapy

� ‘brittle’ diabetic subjects characterised by recurrent DKA� patients who are poorly compliant on injection therapy� patients with significant psychological and psychiatric problems, or those who otherwise do not meet the prerequisites.

Source: Pickup and Keen, 2001.38

provided at a limited number of ‘area’ locations,this would disadvantage those living in rural areaswith poor public transport, particularly bearing inmind that they are more likely to be unable todrive than people without diabetes. One optionwould be for each area to start with one centre androll out the service according to demand.

Barriers to implementationUse of CSII in the UK appears to have beenlimited by two main factors. First, the cost haslimited use in those diabetes clinics whereconsultants believed in their value. Second, theprevailing clinical impression seems to have beenthat the risks might outweigh the benefits. Thatimpression probably dates from the days of theearly pumps, but has not been supersededperhaps because there has been little experiencewith newer and more reliable pumps. A circularscenario may have been operating: because thevalue of CSII was doubted by many diabetologists,there has been little pressure for more funds;because funds have been limited, there has beenlittle experience with newer pumps, and theconservative attitude has not been countered bynew experience.

Unpublished (as of early August 2003; Matsuoka K, Oxford: personal communication,2003) research from one English health authorityprovides very useful information on the barriers to

implementation if NICE approved the use ofinsulin pumps in selected individuals. Theproblems include:

� A lack of knowledge about CSII. � A perception amongst many in diabetes care

that the evidence base for CSII was weak; thisseemed to be based on knowledge of the earlytrials. The diabetologists with this belief did notthink that pumps had improved, or did notknow whether they had or not.

� Lack of resources, coupled with competingdemands, so that CSII would not be a toppriority even if funding became available.

� Concern about the training needs – it wasbelieved that heavy initial investment would berequired for education and backup in the firstfew weeks.

The three barriers reported most often were lackof a skills base (80%), insufficient staff for follow-up care (63%) and lack of funding. There wasparticular concern about a shortage of DSNs,which was not just about funding, but about theavailability of trained people.

This research project also noted that there was aninequitable distribution of pumps users acrosssocioeconomic areas, with very little use in themore deprived areas. This is only partly explainedby the fact that 50% of users fund their ownpumps.


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TABLE 42 Annual costs of Type 1 diabetes

All Type 1s (including children) (%) Number Annual cost (£)

1 3,300 3.5 million3 9,900 10.5 million5 16,500 17.5 million

This chapter reviews the key issues, and whereappropriate, the uncertainties involved in each.

EfficacyThe potential benefits of CSII are threefold:

1. Glycaemic control: the evidence suggests amodest improvement in control of high bloodglucose levels, as reflected in glycatedhaemoglobin. This may lead to reduced long-term complications, but evidence is lackingfrom the studies included in this review.

2. Frequency of hypoglycaemic episodes: althoughmost studies found no difference in thefrequency of hypoglycaemia between CSII andMDI, some found decreases with CSII and onestudy found an increase with CSII. There mayalso be benefits from reduced fear ofhypoglycaemia, but this has not beenquantified by the studies.

3. Well-being and QoL: QoL was assessed by justone eligible study, which reported nodifferences between CSII and MDI. Statementsfrom patients who are successful pump userssuggest an improvement in well-being andQoL, partly from greater flexibility of lifestyle.The effects have not been quantified in utilityterms.

There is good evidence that CSII is acceptable tousers (partly because those who do not like using itstop, and thereby incur no further added costs).The fact that many pump users are meeting thecosts themselves implies that they value it. Thereis also good evidence of a useful reduction inglycated haemoglobin levels and of a small dropin the frequency of serious hypoglycaemia.

There is strong anecdotal evidence from usersfrom INPUT and elsewhere that CSII improvesQoL, but the RCTs have neglected this and havefocused on measuring the more easily measurableoutcomes such as HbA1c. This is unfortunate: asone of our users commented, “there is more tocontrol of diabetes than HbA1”.

One problem with assessing the effect of CSII onglycated haemoglobin is that those who take part

in trials, or whose results are reported in someobservational studies, may be highly motivatedindividuals whose HbA1c is already better thanaverage, so that there is less scope forimprovement. Conversely, in some studies patientsmay have been poorly controlled with more togain, both in terms of glycated haemoglobin andreduction in hypoglycaemic events. For example,in the study by Boland and colleagues,98 the rateof severe hypoglycaemic episodes was reduced by50% (p = 0.01), and Bode and colleagues81 alsoreported much greater reductions inhypoglycaemia with CSII compared with MDI.Hence in routine care results may be better thanin the trials, because there is greater selection of patients with problems. Numbers of patientsgoing on to CSII may be small partly because the clinics that use CSII most are also vigorous in trying to achieve better control on MDI, so that only those who still have problems go on to CSII.

Two studies included in the meta-analysis byPickup and colleagues40 were excluded from the present meta-analysis. In the study by Marshall and colleagues,164 most patients (10 out of 12) used twice-daily injections while on the injection phase of the crossover study,and although the authors described the trial asbeing of “CSII versus optimised injectiontherapy”, it seemed more like optimisedconventional therapy rather than optimisedmodern MDI, and was therefore excluded.Because it was a very small study of only 10patients, inclusion would not have changed theresults of our meta-analysis.

The other study, by Helve and colleagues,165 wasagain of conventional therapy versus CSII.Although the authors say that conventionaltherapy could be optimised by changing thenumber and timing of daily injections, no data aregiven to show the extent to which this was done.They report that daily insulin dose did not changeduring the conventional phase (whereas itdropped during CSII), suggesting that in practicethere was little change in the intensity of theconventional treatment. Most patients were on twoinjections per day at the start, and a few were ononly one.


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Chapter 7

Discussion: analysis of uncertainties

ComparatorsWe have assumed that patients progress fromconventional insulin treatment to MDI and then toCSII, and that the key comparator for CSII isoptimised MDI. However, given that there arevarying intensities of MDI, it is possible that interms of convenience to patients, changing to CSIImight be worthwhile for some patients before alloptions with MDI had been tried. That is, thatsome patients might be able to achieve goodcontrol, as reflected in HbA1c, on MDI but only ata level of inconvenience that made it worthwhileswitching to CSII before that level of control wasreached. This implies that patient conveniencebecomes an independent indicator for CSII. Theexpectation is that that would only apply topatients on MDI, but there could be some onconventional therapy (twice-daily mixtureinjections) who would request a change to CSII.

We do not have good data on the proportions ofpeople with Type 1 diabetes who achieve adequatecontrol at present. Data from young people withdiabetes in Scotland (SSGCYD) indicates that onlya minority succeed, but the proportion would beexpected to be higher in adults, especially theover-30s. Nevertheless, it may be worth bearing inmind that most people (perhaps 80%) with Type 1diabetes are not adequately controlled.166

There is a new, long-acting analogue insulin,glargine, on the market and another, detemir, isfollowing. Glargine has been the subject ofanother review.167 It may have advantages over thecurrent long-acting insulins,168 and might beregarded as a stronger competitor to CSII, byproviding a better (less hypoglycaemia) form ofMDI. However, CSII has the advantage of beingable to provide several different basal insulin ratesover 24 hours, whereas glargine provides only aconstant basal level. A recent abstract reportedthat CSII gave better glycaemic control thanglargine, but conclusions must await the full study,which was not an RCT.169

Cost-effectiveness and cost perQALYThere is general agreement that reducing HbA1c

improves long-term outcomes, and this has beenshown in the meta-analysis of smaller trials by Wangand colleagues18 (which pooled results from 681patients) and by the DCCT study19 (1441 patients).One problem in many of these studies is that theyreport changes in relative risks, rather than giving

absolute differences. However, they do provideevidence of delays in the onset of complicationssuch as renal disease, which should lead to life yearsgained in due course, although these may be20 years down the line and hence offset by the ruleson discounting. There should also be future savingsin healthcare, but these will be much more reducedby discounting at 6%. It may be worth noting thatthe main evidence to date from the DCCT was ofdelaying rather than preventing complications.

However, it has not proved possible to go fromreduction in HbA1c to a simple cost per QALY forseveral reasons. First, there is insufficient evidenceon the utility value of some of the benefits mostappreciated by patients, such as flexibility oflifestyle and freedom from the fear ofhypoglycaemic events.

Second, there is the issue of the improvement inHbA1c and the expected consequent reduction inthe risk of long-term complications. There areseveral problems with estimating the cost-effectiveness implications of these factors:

� Trials such as DCCT compare packages of care.The intensive arm of DCCT had CSII or MDI,more intensive self-monitoring of blood glucosewith targets to achieve, more education on dietand exercise, more visits to clinics and frequentadvice by telephone. It is unsafe to attribute allthe benefits seen in the intensive group to thereduction in HbA1c. For example, theircholesterol results were better; it may be thatsome benefits were due to aspects other thanthe insulin regimen. What other confoundingfactors are there in each trial? Did smokingrates or blood pressure levels change?

� There were clear differences in HbA1c levels.However, can we extrapolate from the benefitsof, a drop of, for example, 1.4% (from Wangand colleagues’ meta-analysis) to one of 0.6%(in the CSII analysis here)? If a drop of 1.4% inHbA1c gives an odds ratio of 0.32 for renaldisease progression, would the odds ratio for adrop of 0.65 be in proportion?

� There are differences in how these drops inHbA1c were obtained. Does a drop based on aswitch from conventional twice daily insulin toCSII have the same implication as one achievedby switching from MDI to CSII?

� There is also the issue of baseline HbA1c. Woulda drop from 10% to 9.4% carry the sameimplications as one from 8.0 to 7.4%? Even ifthe relative risk reduction was the same, thelower absolute risks would affect the cost-effectiveness equations.


82

A third problem in producing a cost per QALY isthat we do not have good data on therepresentativeness of patients in the trials. Thosepatients who enter trials may do better whatevertreatment they use. If their results on MDI arebetter than average, there may be less scope forimprovement on CSII, which would reduce thepower of the studies to show benefits with CSII. Itmay be that there are other patients who wouldstruggle with an intensive MDI regimen but whowould cope with a pump. Pumps would be morecost-effective in the latter group because therewould be a greater potential gain in HbA1c.

A fourth problem might be that CSII is not just apump, but a package. However, since this alsoapplies to MDI, this should not invalidate themeta-analysis of CSII versus MDI.

CostsThe costs and uncertainties involved include thefollowing:

� The NHS costs of those with inadequate controlon MDI – will there be savings after transfer toCSII? Possibly, but probably small in the short-term. The cost to the NHS of hypoglycaemicevents is small in monetary terms.

� The cost of pumps. The number of pump usersin the UK is small at present. If a much greaternumber were to be used, could the NHS securesignificantly lower prices by bulk purchase?

� The cost of disposables such as infusion sets.Could these be reduced, perhaps by longer use?How much would that increase the risk ofinfections?

� The cost of insulin – good evidence of a modestbut useful reduction in the short term leadingto savings of around £90 per patient per annum

Duration of studiesMost of the present studies are fairly short term.We do not know what benefits will accrue after, forexample, 20 years of CSII.

Strengths and limitations ofreviewThe systematic review has the following strengths:

� The systematic review is independent of anyvested interests.

� The systematic review brings together theevidence for the effectiveness of insulin pumpsapplying consistent methods of criticalappraisal.

� The review was guided by the principles forundertaking systematic reviews. Beforeundertaking the review the methods were setout in research protocol (Appendix 1), whichwas commented on by an advisory group. Theprotocol defined the research question,inclusion criteria, quality criteria, dataextraction process and methods used toundertake the different stages of the review.

� An advisory group has informed the reviewfrom its initiation, through the development ofthe research protocol and completion of thereport.

In contrast, there were certain limitations placedupon the review:

� Owing to time constraints placed upon thereview, there was a lack of follow-up withauthors of studies to clarify methodologicaldetails and results from the primary studies.

� The systematic review was limited to parallelRCTs and randomised and non-randomisedcrossover studies. However, for areas where noeligible studies were identified, selectedobservational studies were discussed [see thesections ‘CSII in children’ (p. 37), ‘Overnight-only CSII in adults’ (p. 37), ‘Short-term CSII inpoorly controlled adults with Type 2 diabetes’(p. 37) and ‘Discontinuation rates’ (p. 42)].

� Abstracts and conference proceedings wereexcluded from the review as these usually fail toprovide adequate details of the methods of thestudy and their results, and inclusion waslimited to English language due to timeconstraints. A previous meta-analysis foundevidence of some publication bias for glycatedhaemoglobin.40

Other issues� Parallel RCTs and crossover studies have been

combined in meta-analyses in this systematicreview. In a recently published paper, Elbourneand colleagues suggest that combining crossoverand parallel trials in this way is conservative, asit ignores the within-patient correlation.170

� Due to the nature of the interventionscompared, blinding of patients and treatingclinicians in clinical trials is difficult, if notimpossible. Although a lack of blinding mayprovide the opportunity for observer bias, it wasfelt that as the primary outcome measureassessed was an objective measure, that of


83


glycated haemoglobin, any potential bias wouldhave a limited effect.

� As part of a new development to help supportthe NICE appraisal process, the report includeda section examining the patients’ perspective onthe condition suffered and their reflections onthe different technologies assessed. Althoughconsidered useful, it should be recognised thatit is not methodologically rigorous and haslimitations that mean it is not generalisable.The information originates from members of aspecific user group, who are enthusiasts for thetechnology, may have paid for it themselves andhave had problems with previous forms ofmanaging the condition. Research is under wayto provide guidance on the most appropriatemethods for representing such patient views inhealth technology assessments.

Research needs1. We need much more evidence on the gains in

QoL from CSII, which was one of thehindrances in analysing cost-effectiveness. In particular, there is a need for trials

focused on patients with good control asrecorded by glycated haemoglobin, but withspecific problems such as recurrent severehypoglycaemia.

2. There is a need for good randomised trials inchildren, of different ages, and of differentpatterns of use, such as 24-hour use underparental supervision for the 0–4-years-olds,overnight only use in the 4–8-years age range and independent use in the over-8-years-olds.

3. Research is needed on the role of CSII inteenagers, who often have poor diabeticcontrol. Could pumps improve compliance withtreatment?

4. We need RCTs in pregnancy, startingpreconceptually, and compared with MDI.

5. There may be a place for short-term use ininsulin-resistant adults with Type 2 diabetes,but this is unproven. Trials should control forother interventions such as diet, and should bedone on outpatients.

6. There may be a need for further trials of CSIIversus MDI using longer acting analogues suchas glargine, but we need to see the full detailsof the current glargine trials first.


84

Pump technology has advanced considerablysince the early days, and pumps are now

much more portable and reliable. In randomisedtrials, they show definite but modest benefits. In observational studies, greater benefits arereported, probably because the patients in those are selected because of particular problemsand have more scope to benefit. In routinepractice, patients who go on to pumps arecarefully selected and to a large degree self-selected.

However, pumps are used much less in the UKthan in other Western nations. This may be partlybecause of cost and partly because of early adverseexperiences. The lack of use may mean that theadverse experiences have in most centres not beenreplaced by positive ones, hence allowingpessimism to prevail.

It is unlikely that insulin pumps would be used bymore than a small percentage of people with Type1 diabetes, but the exact proportion is uncertain.


85


Chapter 8

Conclusions

We are grateful to the advisory panel whoprovided expert advice and comments on the

research protocol and/or a draft of this report:

Professor Stephanie Amiel (Professor of DiabeticMedicine), King’s College School of Medicine,London. Miss Ann Brooker (Paediatric DiabetesClinical Nurse Specialist), St Luke’s Hospital,Bradford. Mr John Davis, INPUT, Lymington,Hampshire. Sister Joan Everett (DiabetesSpecialist Nurse), Royal Bournemouth Hospital,Dorset. Dr Stephen Greene (Reader in Child andAdolescent Health ), Tayside Institute of ChildHealth, Ninewells Hospital and Medical School,Dundee. Professor Philip Home, Department ofDiabetes, The Medical School, Newcastle uponTyne. Dr Abigail King, Haverfordwest,Pembrokeshire. Dr John Pickup (Reader) Guy’s,King’s and St Thomas School of Medicine,London. Mrs Gill Salt (Paediatric Diabetes NurseSpecialist), New Cross Hospital, Wolverhampton.Dr Ken Tieszen, Department of Diabetes, HopeHospital, Salford.

We would like to thank the following people andorganisations for information or other assistance:Dr Pam Royle (Senior Researcher/InformationScientist), Wessex Institute of Health Research andDevelopment. Professor Harry Keen, Guy’sHospital, London. Karen Matsuoka, Oxford.Lorraine Rothery, Halifax. Professor WilliamTamborlane, School of Medicine, Yale University.Bournemouth Diabetes and Endocrine Centre.Diabetes Resource Centre, Harrogate DistrictHospital. INPUT, UK, and in particular all those

pump users who provided personal experiences.Royal College of Nursing Paediatric andAdolescent Diabetes group. Royal College ofPhysicians of London.

We are also grateful to Disetronic and Medtronicfor kindly supplying photographs of their insulinpumps.

This report was commissioned by the NHS R&DHTA Programme on behalf of NICE. The viewsexpressed in this report are those of the authorsand not necessarily those of the NHS R&D HTAProgramme. The report remains the responsibilityof the Southampton Health TechnologyAssessments Centre, Wessex Institute for HealthResearch and Development, University ofSouthampton. Any errors are the responsibility ofthe authors.

Contributions of authorsJL Colquitt (Senior Researcher) assessed studiesfor inclusion, extracted and synthesised clinicaleffectiveness data, and contributed to drafting thereport. C Green (Senior Research Fellow) wasresponsible for the cost-effectiveness section, andcontributed to drafting the report. MK Sidhu(Researcher) assisted with study selection, dataextraction and drafting the clinical effectivenesssection. D Hartwell (Researcher) assisted withstudy selection, data extraction and drafting thereport. N Waugh (Professor of Public Health)drafted the protocol, contributed to drafting thereport, and was responsible for writing thepatient’s perspective chapter.


87


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135. Palmer AJ, Weiss C, Sendi PP, Neeser K, Brandt A,Singh G, et al. The cost-effectiveness of differentmanagement strategies for type I diabetes: a Swissperspective. Diabetologia 2000;43:13–26.

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Full title of research questionResearch aim: to assess the clinical effectivenessand cost-effectiveness of continuous subcutaneousinsulin infusion (CSII) using insulin pumps in thetreatment of patients with insulin-treated diabetes,whether Type 1 or Type 2, in whom diabetescontrol is unsatisfactory, and to consider whichgroups of patients could benefit most.

Clarification of research questionand scopeConventional insulin treatment in people withType 1 diabetes involves two injections per day,usually giving a mixture of short- and longeracting insulins [this will be referred to henceforthas conventional therapy (CT)]. CT providessatisfactory control as assessed by glycosylatedhaemoglobin (HbA1c) in only a minority ofpatients. Furthermore, some of those who doachieve an acceptable average blood glucose levelonly do so by having a mixture of high and lowglucose levels, and may have lives made difficultby hypoglycaemic attacks. The HbA1c level cantherefore be used only as a guide and needs to beused in conjunction with information onfluctuations in blood glucose, such as number ofhypoglycaemic episodes, and results of blood tests,in order to establish how the HbA1c level has beenachieved.

After CT, the current next best regimen is ‘basalplus bolus’, now often referred to as ‘meal-timeplus basal’, wherein patients receive one or twoinjections of long-acting insulins to provide thelow level of insulin needed throughout the dayand night, with additional injections of short-acting insulins to cover the steep rises in bloodglucose that would otherwise occur after meals.This is sometimes referred to as MDI, for multipledaily injections, and can be regarded as a form ofintensified treatment. However, there can bedifferent degrees of intensity. Our initial searchesshow variations in the meanings of conventionaland intensive. The term ‘optimised MDI’ has beenused to describe the situation where control withMDI is thought to be as good as can be achieved.This may involve four or more injections each day,

usually accompanied by frequent self-testing ofblood sugar levels using reagent strips and meters.

CSII is usually used to provide intensive treatmentin a different way to MDI, with a needle under theskin all day long, but with different amounts ofinsulin being given at different times – a slowbasal infusion all day long, but with the infusionrate being boosted to cover meals. It is thereforeanother way of providing basal plus bolus, but hasadvantages in that both basal and bolus dosagecan be adjusted more easily and that because only short-acting insulin is used, there is lesschance of hypoglycaemic episodes fromunpredictable absorption from injections of long-acting insulins. There can also be different basalrates at different times of day.

The main clinical question is the extent to whichCSII using insulin pumps provides any clinicaladvantages over management of Type 1 diabeteswith optimised MDI. The benefits could be bettercontrol of blood glucose as reflected in HbA1, or asimilar level of control but with other advantagessuch as fewer problems with hypoglycaemia, orgreater flexibility of lifestyle and hence betterQoL. If MDI is particularly intensive (e.g.5–7 injections a day), then CSII may in effect beless intensive.

Multiple injections can be given by syringe ormore often by insulin pen injectors or acombination thereof.

It is expected that CSII will be part of a packageof care delivered by specialist clinics.

The cost-effectiveness question is whether thebenefits are commensurate with the marginal cost.

Subsidiary questions to be addressed include:

� Do rapid-acting analogue insulins haveadvantages over older short-acting (soluble)insulins?

� Should CSII be used for women with Type 1diabetes preconceptually and during pregnancy?

Where possible, cost issues will be considered forthese questions.


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Appendix 1

Rapid review methods from the research protocol

Studies giving data on discontinuation rates will beused as a guide to patient acceptability and otherdata on patient experiences and perspective willbe obtained from users and past users.

Studies on safety with modern pumps will besought. With the older pumps in the past, therewere problems with device failure leading to DKA.

Two other possible questions have been identifiedduring initial literature searches, but where littleresearch seems to have been done. These will onlybe addressed if time, resources and evidencepermit. Our initial impression is that the presentevidence will be insufficient as a basis for guidanceand that these may be topics to be identified onlyas areas for future research. They are:

� What is the value of short periods of CSII inpatients with Type 2 diabetes who are veryresistant to oral drugs?

� What is the role of overnight-only CSII (inpatients who would take injections as usual byday)? This method might be particularlyrelevant to children, but could apply to someadults as well.

These questions will not be subjected to economicanalysis.

Implantable pumps will not be covered by thereview. We believe these to be a differenttechnology at an earlier stage of application.Pumps used for external intravenous infusion inhospital care will also be excluded.

It is assumed that the usual sequence is to start onconventional insulin treatment and to move tointensive treatment with MDI if control isinadequate, and so the main question for thisreview is whether it is worth moving fromoptimised MDI to CSII.

We will define intensive or MDI as a combinationof short-acting insulins (soluble or analogue) tocover meals with long-acting insulins(intermediate ultralente or long-acting analoguessuch as glargine) to provide basal insulin. Inpractice, MDI will mean a minimum of threeinjections per day.

Report methodsSearch strategyIn order to capture not only RCTs for efficacyanalysis, but also information on problems with

pumps and reasons for discontinuation, economicstudies, patient experiences and long-termoutcomes, a very sensitive search will be carriedout. Filtering will then be done by reading theabstracts (this has been done for MEDLINE; 1349abstracts have been checked, and about 110studies identified for review of the full paper).Reference lists of retrieved studies will be checkedfor others. Our expert advisers will be asked tocomment on the comprehensiveness of our review.The Cochrane Metabolic and Endocrine DiseasesGroup based in Düsseldorf will be consulted.

Inclusion and exclusion criteriaExclusions will include: conventional therapy;treatment of newly diagnosed patients;implantable pumps; very short-term studies; andhospital in-patient pumps.

Because the key measure of blood glucose controlis glycosylated haemoglobin (HbA1c), studies of<10 weeks duration on each treatment will beexcluded from any HbA1c analysis.

Inclusion and exclusion criteria will be applied byone reviewer and checked by a second. Anydisagreement will be resolved by discussion.

Data extraction strategyData will be extracted by one person and checkedby a second. Any discordances will be resolved bydiscussion or by checking by a third person.

Quality assessment strategyThis will be done in accordance with Chapter II.5of CRD Report 4 (2nd edition). A locallydeveloped system will be used to assess QoLstudies. Criteria will be applied by one reviewerand checked by a second.

Patient perspectivesOur expert panel will include several users of CSII,and we will explore with INPUT how best to includeinformation on patient experiences with CSII.

Methods of analysis/synthesisClinical effectiveness will be synthesised through anarrative review with tabulation of results ofincluded studies.

Combination of studies into a Review Managermeta-analysis will be considered. This could formthe basis for a collaborative Cochrane review.

Economic appraisalThe costs and effects of CSII will be comparedwith MDI in Type 1 diabetes patients. Costs will be

Appendix 1

98

obtained from published literature, NHS sources,ad hoc studies and industry submissions. Costs tobe considered will include NHS resource usebefore and after CSII (e.g. insulin pumps, pumpmaintenance, disposables, extra hospital contacts);educational needs (at both institutional andpatient level); and insulin requirements. If there isevidence of differences in long-term outcomessuch as eye or kidney disease, the economicconsequences of these outcomes will beconsidered. The likely numbers of patients whomight be treated with CSII will be considered. Theperspective of the economic analysis will be that ofthe NHS and Personal and Social Servicesdecision-maker.

Data on clinical and QoL benefits will be soughtfrom the literature. Cost-effectiveness analysis willcompare CSII and MDI on the basis of theprimary outcome measures specified as part of theliterature review (e.g. HbA1c, severe hypoglycaemicevents and diabetes-related complications) andadditional QoL outcomes where documented aspart of the review findings. Information from thepatient impact assessment will also be considered.

Economic analysis will consider� Short-term benefits such as reduction in

hypoglycaemic events, greater flexibility oflifestyle and quality of life

� Short-term disbenefits such as acute events dueto pump failure, cosmetic problems,interference with leisure activities

� Intermediate benefits such as improved blood glucose control as measured by HbA1c,likely to lead to a reduction in long-termcomplications.

If evidence showed that CSII was cost-effective onshort-term outcomes alone, the benefits of longerterm outcomes would not need to be preciselyquantified and they would simply be listed asadditional benefits.

Cost per QALY values will be estimated if the dataprovide evidence of cost-effectiveness gains.

Published cost-effectiveness studies will bereviewed. All papers that present findings on thecost-effectiveness of CSII when compared withMDI (as defined above) will be reviewed in detail,comprising a narrative review with tabulation ofresults where appropriate.

Company submission(s)We will use company and other submissions tocheck on completeness of ascertainment of relevanttrials, for costs of pumps and CSII and for data oncurrent use of insulin pumps in England andWales. We will compare results of cost-effectivenessanalysis from industry models with theSouthampton Health Technology AssessmentCentre one, but in line with our contract the timespent on industry models may be limited to 5person days. This may not allow sufficient time fora detailed critique of industry models.


99


The databases were searched for publishedstudies and recently completed and ongoing

research. All searches were limited to Englishlanguage only.

Clinical effectiveness searchstrategiesCochrane Library (Issue 2, 2002) and NationalResearch Register (Issue 2, 2002):#1 (INSULIN near PUMP*)#2 CSII#3 ((CONTINUOUS near INSULIN) nearINFUSION)#4 ((SUBCUTANEOUS near INSULIN) nearINFUSION)#5 ((EXTERNAL and PUMP*) AND (DIABET*

near INSULIN*))#6 ((((#1 or #2) or #3) or #4) or #5)

MEDLINE (WebSPIRS), 1985–June 2002:((explode ‘Diabetes-Mellitus-Insulin-Dependent’ /all subheadings in MIME,MJME) and ((insulinnear pump*) or (csii) or (continuous near insulinnear infusion) or (subcutaneous near insulin nearinfusion) or (external pump* and diabet* andinsulin*))) and (English in la)

Embase (WebSPIRS), 1980–May 2002:(((insulin near3 pump*) or ((pump* near therapy)and diabet*) or (csii) or (subcutaneous near insulinnear infusion) or (external pump near insulin) or(continuous near insulin near infusion) or (externalpump near diabet*)) and (English in la)) or((external pumps near insulin) and (English in la))

PubMED (Internet version), records added from20 June 2001 to 25 June 2002:insulin pumps* OR CSII OR continuous insulininfusion OR subcutaneous insulin infusion

Science Citation Index, 1990–26 June 2002:insulin pump* or csii or insulin infusion (restrictedto document type = meeting abstracts)

BIOSIS, 1999–26 June 2002:((insulin and pump*) or csii or continuous

subcutaneous insulin)) and random* (restricted todocument type = meeting abstracts)

Web of Science Proceedings,1990–26 June 2002:(insulin pump* or csii or insulin infusion) andrandom*

DARE and HTA Databases (web version), searchedon 29 June 2002:csii or insulin pump$ or insulin infusion

Libcat (in-house library catalogue):insulin pump* or csii or insulin infusion

A flowchart of identification of studies forinclusion in the review of clinical effectiveness isgiven in Figure 17.

Cost effectiveness and quality oflife searchesMEDLINE (WebSPIRS), 1981–June 2002:((insulin near3 pump*) or csii or (insulin nearinfusion)) and ((cost* or economic*) or (explode‘Economics-’ / all subheadings in MIME,MJME) or(explode ‘Health-Status’ / all subheadings inMIME,MJME) or (explode ‘Outcome-Assessment-Health-Care’ / all subheadings in MIME,MJME) or(explode ‘Quality-of-Life’ / all subheadings inMIME,MJME) or (wellbeing or well-being) or(health near3 outcome*))

EMBASE (WebSPIRS), 1980–May 2002:(((insulin near pump*) or (csii or (insulin nearinfusion))) and (((explode ‘health-economics’ / allsubheadings) or (explode ‘economics-’ / allsubheadings) or (explode ‘quality-of-life’ / allsubheadings) or (quality near3 life) or (cost* oreconomic*) or (health near3 status) or (healthnear3 outcome*)) or (wellbeing or well-being)))and (English in la)

PubMED (Internet version, records added from20 June 2001 to 29 June 2002:insulin pumps* OR CSII OR continuous insulininfusion OR subcutaneous insulin infusion


101


Appendix 2

Sources of information, including databases searchedand search terms

PsycINFO (WebSPIRS), 1984–June 2002:(insulin near pump*) or (csii or (insulin nearinfusion))

CINAHL (WebSPIRS), 1982–December 2001:((insulin near pump*) or csii or (insulin nearinfusion)) and ((cost* or economic*) or (explode‘Economics-’ / all topical subheadings / all agesubheadings in DE) or (explode ‘Health-Status’ /all topical subheadings / all age subheadings inDE) or (explode ‘Quality-of-Life’ / all topicalsubheadings / all age subheadings in DE) or(wellbeing or well-being) or (explode ‘Outcomes-Health-Care’ / all topical subheadings / all agesubheadings in DE) or (health near3 outcome*))

NHS EED (web version), searched on 29 June2002:csii or insulin pump$ or insulin infusion

EconLit (WebSPIRS): 1969–May 2002csii or insulin pump* or insulin infusion

Additional searchingBibliographies: all references of articles for whichfull papers were retrieved were checked to ensurethat no eligible studies had been missed.

Industry submissions to NICE were examined forany further studies that met the inclusion criteria.

Appendix 2

102

Total identified on searchingn = 3760

Abstracts inspected

Full copies retrievedn = 106

Papers inspected

Papers for appraisal and data extractionCSII vs MDI: n = 22 (20 trials)

Analogue vs soluble: n = 6

Excludedn = 78

Excludedn = 3654

FIGURE 17 Flowchart of identification of studies for inclusion in the review of clinical effectiveness

This is adapted from CRD Report 4 (2nd edition).

Quality criteria for assessment of experimental studies


103


Appendix 3

Quality assessment scale

1. Was the assignment to the treatment groups really random?2. Was the treatment allocation concealed?3. Were the groups similar at baseline in terms of prognostic factors?4. Were the eligibility criteria specified?5. Were the point estimates and measure of variability presented for the primary outcome measure?6. Did the analyses include an intention-to-treat analysis?7. Were withdrawals and dropouts completely described?

Some instructions for using a checklist for RCTs

Quality item Coding Explanation

1. Was the assignment to the treatment groups really random?

Random sequence generation Adequate Adequate: random numbers table or computer Partial and central office or coded packagesInadequate Partial: (sealed) envelopes without further Unknown description or serially numbered opaque, sealed

envelopes Inadequate: alternation, case record number, birthdate or similar proceduresUnknown: just the term ‘randomised’ or ‘randomlyallocated’ etc.

2. Was the treatment allocation concealed?

Concealment of randomisation Adequate Adequate: when a paper convinces you that The person(s) who decide on eligibility should Inadequate allocation cannot be predicted [separate persons, not be able to know or be able to predict with Unknown placebo really indistinguishable, clever use of block reasonable accuracy to which treatment group sizes (large or variable)]. Adequate approaches might a patient will be allocated. In trials that use include centralised or pharmacy-controlled good placebos this should normally be the case; randomisation, serially numbered identical however, different modes or timing of drug containers, on-site computer-based system with a administration in combination with the use of randomisation sequence that is not readable until small block sizes of known size may present allocation and other approaches with robust opportunities for clinicians who are also involved methods to prevent foreknowledge of the allocation in the inclusion procedure to make accurate sequence to clinicians and patientsguesses and selectively exclude eligible patients Inadequate: this option is often difficult. You have to in the light of their most likely treatment visualise the procedure and think how people might allocation; in centres with very low inclusion be able to circumvent it. Inadequate approaches frequencies combined with very brief follow-up might include use of alternation, case record times this may also present a potential problem numbers, birth dates or week days, open random because the outcome of the previous patient numbers lists, serially numbered envelopes (even may serve as a predictor of the next likely sealed opaque envelopes can be subject to allocation manipulation) and any other measures that cannot

prevent foreknowledge of group allocationUnknown: no details in text. Disagreements or lackof clarity should be discussed in the review team

continued

Appendix 3

104

Quality item Coding Explanation

3. Were the groups similar at baseline regarding the prognostic factors?

Baseline characteristics Reported Consult the list of prognostic factors or baseline Main aim is to enable the reviewer to see Unknown characteristics (not included in this Appendix).which patients were actually recruited. It Reviewer decidesenables one to get a rough idea on prognostic comparability. A real check on comparability requires multivariable stratification (seldom shown)

4. Were the eligibility criteria specified?

AdequatePartialInadequateUnknown

5. Were the point estimates and measure of variability presented for the primary outcome measure?

Results for the primary outcome measure Adequate Adequate: mean outcome in each group together Partial with mean difference and its standard error (SE) or Inadequate standard deviation (SD) or any CI around it or the Unknown possibility to calculate those from the paper. Survival

curve with log-rank test and patient numbers at latertime pointsPartial: partially reportedInadequate: no SE or SD, or SD without N (SE =SD/N)Unknown: very unlikely

6. Did the analysis include an intention to treat analysis?

Intention-to-treat analysis (ITT) Adequate Reviewers should not just look for the term ITT but Early dropout can make this very difficult. Inadequate assure themselves that the calculations were Strictest requirement is sensitivity analysis according to the ITT principleincluding early dropouts

7. Loss to follow-up

This item examines both numbers and reasons; Adequate Adequate: number randomised must be stated. typically an item that needs checking in the Partial Number(s) lost to follow-up (dropped out) stated or methods section and the marginal totals in the Inadequate deducible (from tables) for each group and reasons tables. Note that it may differ for different Unknown summarised for each groupoutcome phenomena or time points. Some Partial: numbers, but not the reasons (or vice versa) reasons may be reasons given by the patient Inadequate: numbers randomised not stated or not when asked and may not be the true reason. specified for each groupThere is no satisfactory solution for this Unknown: no details in text

Arias P, Kerner W, Zier H, Navascues I, Pfeiffer EF.Incidence of hypoglycemic episodes in diabetic patientsunder continuous subcutaneous insulin infusion andintensified conventional insulin treatment: assessmentby means of semiambulatory 24-hour continuous bloodglucose monitoring. Diabetes Care 1985;8:134–40. [Studydesign]

Barbosa J, Menth L, Eaton J, Sutherland D, Freier EF,Najarian J. Long-term, ambulatory, subcutaneousinsulin infusion versus multiple daily injections in brittlediabetic patients. Diabetes Care 1981;4:269–74.[Insufficient follow-up]

Beck-Nielsen H, Richelsen B, Schwartz-Sorensen N,Hother-Nielsen O. Insulin pump treatment: effect onglucose homeostasis, metabolites, hormones, insulinantibodies and quality of life. Diabetes Res 1985;2:37–43.[Not intensive therapy]

Bell DS, Ovalle F. Improved glycemic control with use ofcontinuous subcutaneous insulin infusion compared withmultiple insulin injection therapy. Endocr Pract 2000;6:357–60. [Study design]

Blackett PR. Insulin pump treatment for recurrentketoacidosis in adolescence. Diabetes Care 1995;18:881–2. [Study design]

Bode BW, Strange P. Efficacy, safety, and pumpcompatibility of insulin aspart used in continuoussubcutaneous insulin infusion therapy in patients withtype 1 diabetes. Diabetes Care 2001;24:69–72.[Insufficient follow-up]

Boland EA, Grey M, Oesterle A, Fredrickson L,Tamborlane WV. Continuous subcutaneous insulininfusion. A new way to lower risk of severehypoglycemia, improve metabolic control, and enhancecoping in adolescents with type 1 diabetes. Diabetes Care1999;22:1779–84. [Study design]

De Beaufort CE, Houtzagers CM, Bruining GJ, Aarsen RS, den Boer NC, Grose WF, et al. Continuoussubcutaneous insulin infusion (CSII) versus conventionalinjection therapy in newly diagnosed diabetic children:two-year follow-up of a randomized, prospective trial.Diabet Med 1989;6:766–71. [Not intensive therapy]

Garg SK, Anderson JH, Gerard LA, Mackenzie TA,Gottlieb PA, Jennings MK, et al. Impact of insulin lisproon HbA1c values in insulin pump users. Diabetes ObesityMetab 2000;2:307–11. [Study design]

Helve E, Koivisto VA, Lehtonen A, Pelkonen R,Huttunen JK, Nikkila EA. A crossover comparison ofcontinuous insulin infusion and conventional injectiontreatment of type I diabetes. Acta Med Scand 1987;221:385–93. [Not intensive therapy]

Jennings AM, Lewis KS, Murdoch S, Talbot JF, Bradley C, Ward JD. Randomized trial comparingcontinuous subcutaneous insulin infusion andconventional insulin therapy in type II diabetic patientspoorly controlled with sulfonylureas. Diabetes Care1991;14:738–44. [Not intensive therapy]

Johansson UB, Adamson UC, Lins PE, Wredling RA.Improved blood glucose variability, HbA1c insumanInfusat and less insulin requirement in IDDM patientsusing insulin lispro in CSII. The Swedish MulticenterLispro Insulin Study. Diabetes Metab 2000;26:192–6.[Insufficient follow-up]

Laatikainen L, Teramo K, Hieta-Heikurainen H,Koivisto V, Pelkonen R. A controlled study of theinfluence of continuous subcutaneous insulin infusiontreatment on diabetic retinopathy during pregnancy.Acta Med Scand 1987;221:367–76. [Not intensivetherapy]

Lauritzen T, Frost LK, Larsen HW, Deckert T. Effect of 1year of near-normal blood glucose levels on retinopathyin insulin-dependent diabetics. Lancet 1983;i:200–4.[Not intensive therapy]

Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al. Pharmacokinetics andpharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, andultralente human insulin and continuous subcutaneousinfusion of insulin lispro. Diabetes 2000;49:2142–8.[Insufficient follow-up]

Mancuso S, Caruso A, Lanzone A, Bianchi V, Massidda M, Codipietro F, et al. Continuoussubcutaneous insulin infusion (CSII) in pregnantdiabetic women. Acta Endocrinol Suppl (Copenh) 1986;277:112–16. [Study design]

Marshall SM, Home PD, Taylor R, Alberti KG.Continuous subcutaneous insulin infusion versusinjection therapy: a randomised cross-over trial underusual diabetic clinic conditions. Diabet Med1987;4:521–5. [Not intensive therapy]

Ng-Tang FS, Pickup JC, Bending JJ, Collins AC, Keen H, Dalton N. Hypoglycemia andcounterregulation in insulin-dependent diabeticpatients: a comparison of continuous subcutaneousinsulin infusion and conventional insulin injectiontherapy. Diabetes Care 1986;9:221–7. [Not intensivetherapy]

Olsen T, Ehlers N, Nielsen CB, Beck-Nielsen H.Diabetic retinopathy after one year of improvedmetabolic control obtained by continuous subcutaneousinsulin infusion (CSII). Acta Ophthalmol (Copenh)1985;63:315–19. [Not intensive therapy]


105


Appendix 4

List of excluded studies

Olsen T, Richelsen B, Ehlers N, Beck-Nielsen H.Diabetic retinopathy after 3 years’ treatment withcontinuous subcutaneous insulin infusion (CSII). ActaOphthalmol (Copenh) 1987;65:185–9. [Not intensivetherapy]

Ooi C, Mullen P, Williams G. Insulin lispro: the idealpump insulin for patients with severe hypoglycemicunawareness? Diabetes Care 1999;22:1598–9. [Studydesign]

Reeves ML, Seigler DE, Ryan EA, Skyler JS. Glycemiccontrol in insulin-dependent diabetes mellitus.Comparison of outpatient intensified conventionaltherapy with continuous subcutaneous insulin infusion.Am J Med 1982;72:673–80. [Insufficient follow-up]

Rizza RA, Gerich JE, Haymond MW, Westland RE, Hall LD, Clemens AH, et al. Control of blood sugar ininsulin-dependent diabetes: comparison of an artificialendocrine pancreas, continuous subcutaneous insulininfusion, and intensified conventional insulin therapy. N Engl J Med 1980;303:1313–8. [Insufficient follow-up]

The Diabetes Control and Complications Trial ResearchGroup. The effect of intensive treatment of diabetes onthe development and progression of long-termcomplications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [Study design]

Appendix 4

106

Bode B, McCulloch K, Strange P. Insulin aspart efficacyand safety compared to buffered regular insulin(Velosulin®) for continuous subcutaneous insulininfusion. Diabetes 2000;49:394.

Chase HP, Saib SZ, MacKenzie T, Hansen M, Garg SK.Postprandial glucose excursions following four methodsof bolus insulin administration using an insulin pump.Diabetes 2001;50:A92.

Conway RJ, Milliken JA. Option or essential tool?Insulin pump therapy in young women. Diabetes2002;51 (Suppl 2):1921.

Devries JH, Snoek FJ, Kostense PJ, Masurel N, HeineRJ. CSII improves glycaemic control and quality of lifein type 1 diabetic patients with long standing poorglycaemic control. A randomized trial. Diabetes 2002;51 (Suppl 2):520.

Galatzer A, Weintrob N, Cohen D, Benzaquen H, RimerA, Ofan R, et al. Treatment satisfaction of type 1 diabeticpatients: CSII v MDI. Diabetes 2002;51 (Suppl 2):2570.

Laffel L, Loughlin C, Ramchandani N, Butler D, Laffel N, Levine BS, et al. Glycemic challenges of pumptherapy (CSII) in youth with type 1 diabetes (T1DM).Diabetes 2001;50:A66–7.

Lenhard MJ, Maser RE. Continuous subcutaneousinsulin infusion (CSII) in patients with type 2 diabetes.Diabetes 2001;50:A440–1.

Lepore M, Pampanelli S, Fanelli CG, Porcellati F,Brunetti P, Bolli GB. Pharmacokinetics and dynamics ofs.c. injection of insulin glargine, NPH and ultralente inT1DM: comparison with CSII. Diabetes 2000;49:36.

Linkeschova R, Raoul M, Bott U, Berger M, Spraul M.Better diabetes control, quality of life and less severehypoglycaemias with insulin pump treatment.Diabetologia 2000;43:748.

Litton J, Rice A, Friedman N, Oden J, Lee M, FreemarkM. Insulin pump therapy in infants and preschoolchildren with type 1 diabetes. Paediatr Res 2002;51(Suppl 1):748.

Mack-Fogg J, Bates S, Faro B, Sciera M, Ippolito K,Orlowski CC, et al. Safe and effective use of CSII in

young children with type 1 diabetes mellitus: PaediatrRes 2002;51 (Suppl 1):712.

Raskin P, Bode B, Marks JB, Hirsch IB, Weinstein R,McGill J, et al. Insulin aspart (IAsp) is as effective incontinuous subcutaneous insulin infusion as in multipledaily injections for patients with type 2 diabetes. Diabetes2001;50:A128.

Reid SM, Lawson ML. Comparison of CSII versusconventional treatment of diabetes with respect tometabolic control. Quality of life and treatmentsatisfaction. Paediatr Res 2002;51 (Suppl 1):713.

Rudolph JW, Hirsck IB. An assessment of continuoussubcutaneous insulin infusion therapy in an academicdiabetes clinic. Diabetes 2000;49:501.

Tubiana-Rufi N, Coutand R, Bloch J, Munz-Licha G,Delcroix C, Limal JM, et al. Efficacy and tolerance ofinsulin lispro in young diabetic children treated withCSII. Diabetologia 2000;43:762.

Turrentine LA, Wallander JL, Roth DL, Bode BW,Trippe BS, Bell DS. The influence on quality of life ofcontinuous subcutaneous insulin infusion (CSII) therapy.Diabetes 2001;50:A49.

Wainstein J, Cohen Y, Gilad R, Raz I, Wexler ID.Treatment of severe insulin resistance in type 2 diabeticswith insulin pumps. Diabetologia 2000;43:789.

Wainstein J, Metzger M, Menuchin O, Cohen Y, Yaffe A,Ravid M, et al. Insulin pump therapy versus multipledaily injections in obese type 2 diabetic patients.Diabetologia 2001;44:94.

Weintrob N, Benzaquen H, Shalitin S, Fayman G,Galatzer A, Dickerman Z, et al. Continuoussubcutaneous insulin infusion versus multiple dailyinjections in children with type 1 diabetes. Diabetologia2001;44:95.

White NH, Hollander AS, Sadler M, Daniels L. Risks and benefits of continuous subcutaneous insulininfusion (CSII) therapy in children. Diabetes 2001;50:A66.

Zloczower M, Cohen J, Zaidise I, Kanter Y. Insulin pump in pregnancy. Diabetes 2000;49:1885.


107


Appendix 5

List of recent abstracts


109


Appendix 6

Summary of methodology: adults with Type 1 diabetes

Appendix 6

110

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Bak

et a

l.,19

8787

Den

mar

k,sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

6m

onth

s, M

DI

6m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

.G

rase

by M

S36

Trea

tmen

t 2:

MD

I+

reg

ular

(3 ×

solu

ble,

1 ×

NPH

).Pe

n in

ject

or(N

ovoP

en)

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:hy

pos

estim

ated

by

the

M-

valu

e of

Sch

lictk

rull,

and

also

freq

uenc

y of

BG

valu

es <

4m

mol

/l –

both

calc

ulat

ed fr

om h

ome-

reco

rded

BG

pro

files

durin

g la

st 3

mon

ths

onea

ch t

reat

men

t re

gim

en.

Patie

nt p

refe

renc

e by

ques

tionn

aire

at

end

ofst

udy

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d, h

alf t

o ea

ch t

reat

men

t.N

o fu

rthe

r de

tails

Run-

in/w

ash-

out

perio

d: t

rans

ition

to

CSI

I or

MD

I mad

e du

ring

hosp

italis

atio

n. N

o ru

n-in

or

was

h-ou

t pe

riod

spec

ified

C

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: W

ilcox

on’s

tes

t fo

r pa

ired

diffe

renc

es (2

-tai

led)

. Mea

ns (S

D)

pres

ente

dSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: m

ainl

y yo

ung

mal

e ad

ults

with

Typ

e 1

Out

com

e m

easu

res:

HbA

1no

t re

port

ed. D

urat

ion

of d

iabe

tes

repo

rted

in m

onth

s. M

ean

gluc

ose

valu

es d

urin

g la

st 3

mon

ths

ofea

ch t

reat

men

t re

gim

en r

epor

ted.

Ave

rage

dai

ly in

sulin

req

uire

men

tat

opt

imum

insu

lin d

osag

e re

port

edRe

ason

s fo

r w

ithdr

awal

s: in

com

patib

ility

with

pum

p re

gim

en (4

CSI

I)Pa

tient

pre

fere

nce:

% w

antin

g to

con

tinue

with

tre

atm

ent

pres

ente

d, n

umer

ator

and

den

omin

ator

not

rep

orte

dC

onfli

ct o

f int

eres

t: N

OVO

Indu

stri,

Den

mar

k pr

ovid

ed N

ovoP

enin

ject

ors

and

infu

sers

, and

per

form

ed la

bora

tory

ana

lyse

s. S

uppo

rted

by A

arus

Uni

vers

ity, D

anish

Dia

betic

Ass

ocia

tion

and

Dan

ish M

edic

alRe

sear

ch C

ounc

il

Popu

latio

n: y

oung

adu

lts; I

DD

M w

ithdu

ratio

n of

>2.

5 y,

dia

gnos

ed b

efor

e th

eag

e of

30

y.C

riter

ia: n

o sig

n of

neu

ropa

thy,

hype

rten

sion

or a

dvan

ced

retin

opat

hy,

abse

nce

of a

lbum

inur

ia, d

iast

olic

blo

odpr

essu

re <

95m

mH

g, a

bsen

ce o

f cat

arac

t,re

tinal

pro

lifer

atio

ns, h

aem

orrh

ages

or

exud

ates

, <5

mic

ro-a

neur

ysm

s in

the

retin

a. C

-pep

tide

–ve

Part

icip

ants

: N

: 20

End

of s

tudy

: 16

Fem

ale:

6.2

5%M

ean

age

(±SD

): 24

(±2)

yD

iabe

tes

dura

tion

mea

n (±

SD):

5.8

(±3.

8) y

Base

line

valu

es: m

ean

(±SD

):In

sulin

: 46

(±16

)IU

/day

Wei

ght:

74.4

(±9.

7)kg

Prev

ious

reg

imen

: pre

viou

sly t

reat

edco

nven

tiona

lly w

ith in

term

edia

te in

sulin

alon

e or

in c

ombi

natio

n w

ith s

hort

-act

ing

insu

lin o

nce

or t

wic

e da

ily

cont

inue

d


111


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Bode

et

al.,

1996

81

USA

, sin

gle-

cent

re, n

on-

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

mea

n 37

mon

ths,

MD

I min

. of

12m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

Min

imed

506

/504

Trea

tmen

t 2:

MD

I+

reg

ular

Reas

on fo

r C

SII:

(1) s

ubop

timal

glyc

aem

ic c

ontr

olas

sho

wn

byflu

ctua

ting

BGle

vels

thou

ght

tobe

ass

ocia

ted

with

poor

res

pons

e to

inte

rmed

iate

actin

g in

sulin

; (2

) HbA

1c>

8.0%

;(3

) a h

istor

y of

recu

rren

t se

vere

hypo

glyc

aem

ia(d

efin

ed a

s≥

1ep

isode

s/y

ofhy

pos

requ

iring

assis

tanc

e); o

r(4

)hyp

ogly

caem

icun

awar

enes

s

Ass

essm

ent

of o

utco

mes

:w

eigh

t an

d H

bA1c

reco

rded

qua

rter

ly a

t ea

chvi

sit. B

G r

ecor

ded

whe

nse

vere

hyp

o ex

perie

nced

.H

ypos

/dai

ly in

sulin

/sel

f-m

onito

ring

freq

uenc

y/D

KA

= o

btai

ned

at e

ach

visit

from

pat

ient

s’ p

erso

nal l

ogsh

eet

Allo

catio

n to

tre

atm

ent

grou

ps: p

atie

nts

not

rand

omise

dRu

n-in

/was

h-ou

t pe

riod:

all

star

ted

on C

SII a

s in

-pat

ient

s on

dia

bete

sun

it; n

o w

asho

ut p

erio

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: b

asel

ine

valu

es =

last

HbA

1c, b

ody

wei

ght

and

tota

l dai

lyin

sulin

dos

e re

cord

ed w

hen

patie

nts

on M

DI b

efor

e cr

ossin

g ov

er t

oC

SII (

at le

ast

12m

onth

s). S

ingl

e-sa

mpl

e St

uden

t’s t

-tes

t to

eva

luat

ech

ange

from

bas

elin

e. S

ign

test

to

eval

uate

cha

nges

in e

vent

rat

es o

fhy

pos

and

DK

A fr

om t

he M

DI t

o th

e C

SII p

erio

dSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

pre

viou

sly o

n M

DI c

hang

ed t

o C

SII.

Hist

ory

ofse

vere

hyp

os a

nd/o

r hy

po u

naw

aren

ess

Out

com

e m

easu

res:

HbA

1c, b

ody

wei

ght

and

tota

l ins

ulin

dos

eva

lues

. Num

ber

of s

ever

e hy

pos

and

DK

A e

piso

des

durin

g M

DI y

ear

and

durin

g ea

ch C

SII y

ear

Con

flict

of i

nter

est:

1 au

thor

has

rec

eive

d ho

nora

ria fo

r sp

eaki

ngen

gage

men

ts fr

om M

inim

ed, I

nc.,

and

has

rece

ived

gra

nt s

uppo

rt fo

rth

e M

inim

ed Im

plan

tabl

e Pu

mp

stud

y

Popu

latio

n: P

atie

nts

curr

ently

on

CSI

IC

riter

ia: f

rom

a p

opul

atio

n of

255

pts

usin

gC

SII:

min

. of 1

2m

onth

s on

inte

nsiv

eth

erap

y w

ith M

DIs

bef

ore

switc

hing

to

CSI

I; an

d a

min

. of 1

2m

onth

s on

CSI

I afte

rcr

osso

ver

Part

icip

ants

: N

: 55

End

of s

tudy

: 55

Fem

ale:

64%

Mea

n ag

e (±

SD):

39.2

(±12

.9) y

Dia

bete

s du

ratio

n m

ean

(±SD

): 22

.2(±

9.7)

y

Prev

ious

reg

imen

: MD

I

cont

inue

d

Appendix 6

112

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Brin

chm

ann-

Han

sen

et a

l.,19

8876

Oth

erpu

blic

atio

ns:

Dah

l-Jo

rgen

sen

et a

l.,19

8877

and

Dah

l-Jo

rgen

sen

et a

l., 1

98678

Nor

way

, mul

ti-ce

ntre

, RC

T(p

aral

lel)

(Stu

dy =

conv

entio

nal v

sM

DI v

s C

SII;

data

extr

acte

d on

MD

I and

CSI

Ion

ly)

Dur

atio

n: C

SII

mea

n 40

mon

ths

(ran

ge 2

4–60

),M

DI m

ean

41m

onth

s (r

ange

21–4

7)

Trea

tmen

t 1:

CSI

I+

sol

uble

.N

ordi

sk In

fuse

r,A

utos

yrin

ge A

S6C

,Eu

lgy,

Gra

seby

MS3

6 an

d N

ipro

.

Trea

tmen

t 2:

MD

I+

reg

ular

(4 ×

solu

ble,

1 ×

long

-ac

ting)

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

me:

subj

ectiv

e hy

pos

reco

rded

by p

atie

nt. H

bA1

dete

rmin

ed e

very

mon

thfo

r fir

st y

ear

and

ever

yse

cond

mon

th t

here

afte

r

Allo

catio

n to

tre

atm

ent

grou

ps: b

lock

ran

dom

isatio

n w

ithco

mpu

teris

ed m

atch

ing

of c

linic

al b

ackg

roun

d ch

arac

teris

tics

Run-

in/w

ash-

out

perio

d: h

ome

gluc

ose

mon

itorin

g du

ring

2m

onth

sbe

fore

ran

dom

isatio

n sig

nific

antly

red

uced

HbA

1(p

< 0

.01)

in a

llgr

oups

.C

ompa

rabi

lity

of t

reat

men

t gr

oups

: HbA

1, b

ody

wei

ght,

insu

linre

quire

men

t, ag

e, s

ex a

nd d

urat

ion

of d

iabe

tes

com

para

ble

Ana

lysis

: 2-s

ided

Wilc

oxon

ran

k-su

m t

est

to c

ompa

re v

alue

s be

twee

ntr

eatm

ent

grou

ps a

nd 2

-sid

ed W

ilcox

on s

igne

d ra

nk t

est

to c

ompa

reva

lues

with

in t

reat

men

t gr

oups

. Lev

el o

f sig

nific

ance

= 5

%. H

bA1

data

ext

ract

ed fr

om fi

gure

by

revi

ewer

(exc

ept

2-y

data

). SE

Mpr

esen

ted,

SD

cal

cula

ted

by r

evie

wer

. Dat

a at

2y

extr

acte

d fr

omD

ahl-

Jorg

ense

n, 1

986

(tab

le).

Mul

ticen

tre

varia

bilit

y no

t as

sess

edSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dult

insu

lin d

epen

dent

dia

betic

sO

ther

: fre

quen

cy o

f hom

e BG

mon

itorin

g w

as r

educ

ed a

fter

1st

12m

onth

s an

d ca

used

a t

rend

for

incr

ease

in H

bA1

in a

ll gr

oups

Reas

ons

for

with

draw

als:

sev

ere

hypo

glyc

aem

ia (1

MD

I)C

onfli

ct o

f int

eres

t: st

udy

supp

orte

d by

gra

nts

from

the

Nor

weg

ian

Cou

ncil

for

Scie

nce

and

Hum

aniti

es, O

slo; t

he N

orw

egia

n D

iabe

tes

Ass

ocia

tion,

Oslo

; the

Nor

weg

ian

Cou

ncil

on C

ardi

ovas

cula

rdi

seas

es, O

slo; t

he U

nive

rsity

of O

slo; t

he A

nder

s Ja

hres

Med

ical

Foun

datio

n, O

slo; a

nd N

ordi

sk G

ento

fte A

/S

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

ticpa

tient

sIn

clus

ion

crite

ria: a

ge 1

8–45

y, d

iabe

tes

befo

re 3

0y

old;

dur

atio

n of

dise

ase

>6

and

<30

y; n

o cl

inic

al s

igns

of n

ephr

opat

hyor

sys

tem

ic h

yper

tens

ion;

no

hist

ory

ofne

urop

athy

; tes

ted

nega

tive

for

C-p

eptid

e.Pt

s w

ith p

rolif

erat

ive

retin

opat

hy w

ere

not

incl

uded

CSI

I par

ticip

ants

: N

: 15

End

of s

tudy

: 15

Fem

ale:

53%

Mea

n ag

e (m

in.–

max

.): 2

6 (1

8–38

) yD

iabe

tes

dura

tion

mea

n (m

in.–

max

.): 1

2.8

(6.4

–23.

3) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

10.

1 (±

1.55

)% ,

rang

e 8.

0–12

.9In

sulin

: 0.8

(±0.

23)U

/kg

Wei

ght:

68.6

(±9.

3)kg

MD

I par

ticip

ants

:N

: 15

End

of s

tudy

: 14

Fem

ale:

53%

Mea

n ag

e (m

in.–

max

.): 2

6 (1

9-42

) yD

iabe

tes

dura

tion

mea

n (m

in.–

max

.): 1

2.8

(6.8

–20.

8) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

9.4

(±1.

55)%

, ra

nge

7.0–

11.7

,p

=ns

Insu

lin: 0

.72

(±0.

08)U

/kg

Wei

ght:

71.7

(±10

.1) k

g, p

= n

s

Prev

ious

reg

imen

: tw

o in

ject

ions

of i

nsul

in

cont

inue

d


113


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Chi

asso

n et

al.,

1984

82

Can

ada,

sin

gle-

cent

re, n

on-

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

3m

onth

s, M

DI

3m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

. Mill

Hill

infu

ser

Trea

tmen

t 2:

CSI

I+

sol

uble

(sol

uble

,pl

us 1

ultr

alen

te).

MD

I adm

inist

ered

by a

utom

atic

jet

inje

ctor

(Med

i-Je

ctor

). Bo

luse

sbe

fore

mea

ls an

dsn

ack

with

>20

gca

rboh

ydra

te

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:di

abet

ic d

iary

: inc

l. in

sulin

dose

(col

lect

ed b

efor

est

art

of s

tudy

and

at

end

of3-

mon

th p

erio

d).

Gly

cosy

late

d ha

emog

lobi

nm

easu

red

at e

nd o

f eac

h 3-

mon

th p

erio

d

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

misa

tion

men

tione

d in

abs

trac

tbu

t no

t in

pap

er, w

hich

sta

tes

half

star

ted

with

CSI

I and

hal

f with

MD

I. M

etho

d no

t st

ated

Run-

in/w

ash-

out

perio

d: n

o w

ash-

out

perio

d in

dica

ted.

Pat

ient

s w

ere

hosp

italis

ed (u

nkno

wn

perio

d) w

here

the

y le

arne

d to

ope

rate

the

inte

rven

tion,

mod

ify in

sulin

and

cal

cula

te c

arbo

hydr

ate

cont

ent

Com

para

bilit

y of

tre

atm

ent

grou

ps: i

ndiv

idua

l pat

ient

dat

a pr

esen

ted

for

age,

sex

, dur

atio

n of

dia

bete

s, b

ut t

reat

men

t gr

oup

not

give

nA

naly

sis: s

tatis

tical

com

paris

ons

wer

e m

ade

by m

eans

of p

aire

d t-

test

SEM

pre

sent

ed, S

D c

alcu

late

d by

rev

iew

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

insu

lin-d

epen

dent

dia

bete

s w

ith s

igns

of

retin

opat

hy, p

revi

ously

on

conv

entio

nal t

hera

pyO

utco

me

mea

sure

s: H

bA1,

dai

ly in

sulin

dos

eO

ther

: num

ber

of in

ject

ions

in M

DI n

ot s

tate

dC

onfli

ct o

f int

eres

t: st

udy

fund

ed in

par

t by

gra

nts

from

Med

ical

Rese

arch

Cou

ncil

(MA

721

1), t

he C

onse

il de

la R

eche

rché

en

Sant

édu

Qué

bec

and

the

NIH

(2R0

1 A

M 2

199-

05)

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

tics,

all

had

signs

of r

etin

opat

hy, a

ll w

ithin

20%

of

idea

l bod

y w

eigh

tIn

clus

ion

crite

ria: n

ot r

epor

ted

Part

icip

ants

: N

: 12

End

of s

tudy

: 12

Fem

ale:

58.

3%M

ean

age

(min

.–m

ax.):

26.

8 (1

8–40

) yD

iabe

tes

dura

tion

mea

n (m

in.–

max

.): 1

5.3

(4–2

3) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

11.

9 (±

2.08

)%

Insu

lin: 4

4.7

(±14

.6)I

U/d

Prev

ious

reg

imen

: con

vent

iona

l the

rapy

cont

inue

d

Appendix 6

114

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Haa

kens

et

al.,

1990

83

Nor

way

, sin

gle-

cent

re, n

on-

rand

omise

dcr

osso

ver

(Stu

dy =

conv

entio

nal v

sM

DI v

s C

SII;

data

extr

acte

d on

MD

I and

CSI

Ion

ly)

Dur

atio

n: C

SII

6m

onth

s, M

DI

6m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

.N

ordi

sk in

fuse

r/(n

= 5

0),

auto

syrin

ge A

S8M

P (n

= 2

)

Trea

tmen

t 2:

MD

I+

reg

ular

[4

×so

lubl

e (v

iaN

ovop

en);

1 ×

inte

rmed

iate

(ultr

alen

te a

ndiso

phan

e us

ed v

iasy

ringe

)]

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

: ou

tpat

ient

clin

ic v

isits

=6

wee

ks, o

ccur

renc

e of

mild

and

ser

ious

hyp

os,

DK

A, i

njec

tion/

infu

sion

site

infe

ctio

ns, r

esul

ts o

f hom

eBG

mon

itorin

g re

cord

ed

Allo

catio

n to

tre

atm

ent

grou

ps: i

ndiv

idua

ls no

t ra

ndom

ised

Run-

in/w

ash-

out

perio

d: r

un-in

per

iod

= 3

–9 m

onth

sC

ompa

rabi

lity

of t

reat

men

t gr

oups

: no

base

line

char

acte

ristic

spr

ovid

ed t

o al

low

com

paris

ons.

No

stat

istic

al s

igni

fican

ce b

etw

een

subj

ects

who

ent

ered

the

stu

dy a

nd t

hose

who

did

n’t

with

reg

ard

toH

bA1

(11.

1 ±

0.29

% v

s. 1

0.9

±0.

16%

) or

age

(24.

4 ±

1.0

y vs

25.

5±

0.5

y)A

naly

sis: n

ot IT

T a

naly

sis. R

esul

ts g

iven

as

mea

ns ±

SEM

. Rev

iew

erca

lcul

ated

SD

. 2-s

ided

Wilc

oxon

sig

ned-

rank

tes

t fo

r pa

ired

data

use

dto

com

pare

diff

eren

t tr

eatm

ent

mod

es. S

pear

man

’s r

ank

corr

elat

ion

coef

ficie

nt u

sed.

Sta

tistic

al s

igni

fican

ce s

et t

o p

< 0

.05.

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted.

Gen

eral

isabi

lity:

adu

lts (1

6–50

y) w

ith in

sulin

-dep

ende

nt d

iabe

tes

for

>1

y, w

ith n

o pr

olife

rativ

e/pr

epro

lifer

ativ

e re

tinop

athy

Out

com

e m

easu

res:

sta

ble

HbA

1=

ref

eren

ce r

ange

5.4

–7.6

%Re

ason

s fo

r w

ithdr

awal

s: s

erio

us h

ypo

(1 M

DI),

una

ble

to c

ontr

ol B

G(2

MD

I), d

iscon

tinue

d af

ter

1.5

mon

ths

– un

com

fort

able

(6 C

SII),

med

ical

rea

sons

(2 C

SII),

ref

used

to

give

up

pum

p to

go

on M

DI (

4),

refu

sed

tria

l of C

SII (

2)C

onfli

ct o

f int

eres

t: N

orw

egia

n D

iabe

tic A

ssoc

iatio

n pr

ovid

edfin

anci

al s

uppo

rt

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

ticpa

tient

s ag

ed 1

6–50

y, a

tten

ding

out

patie

ntcl

inic

at

hosp

ital

Excl

usio

n cr

iteria

: on

inte

nsifi

ed in

sulin

ther

apy;

pre

gnan

t or

pla

nnin

g pr

egna

ncy;

diab

etes

dur

atio

n <

1y;

tot

al d

aily

insu

lindo

se <

24U

; ser

um c

reat

inin

e>

150

µmol

/l; p

rolif

erat

ive/

prep

rolif

erat

ive

retin

opat

hy; m

acro

vasc

ular

com

plic

atio

ns;

seve

rely

affe

cted

abi

lity

to r

ecog

nise

hypo

glyc

aem

ia, a

s ev

iden

ced

by m

ultip

lehy

pogl

ycae

mic

com

as w

ithou

t w

arni

ngsy

mpt

oms

durin

g th

e la

st fe

w y

ears

;m

alig

nant

dise

ase;

kno

wn

alco

hol/d

rug

abus

e; p

sych

osis;

men

tal r

etar

datio

n

Part

icip

ants

: N

: 52

End

of s

tudy

: 35

Fem

ale:

63%

Mea

n ag

e (±

SD):

24.9

(±6.

78) y

Dia

bete

s du

ratio

n m

ean

(±SD

): 9.

2(±

5.55

) yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1: 1

0.4

(±1.

85)%

.In

sulin

: 0.7

6 (±

0.25

)IU

/day

BMI:

23.2

(±2.

47)k

g/m

2(a

t en

try

to s

tudy

)W

eigh

t: 68

.6 (±

8.63

)kg.

HbA

1at

beg

inni

ng o

f pre

-per

iod

=10

.7(±

2.47

)

cont

inue

d


115


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Han

aire

-Bro

utin

et a

l., 2

00080

Fran

ce, s

ingl

e-ce

ntre

,ra

ndom

ised

cros

sove

r

Dur

atio

n: C

SII

4m

onth

s, M

DI

4m

onth

s

Trea

tmen

t 1:

CSI

I+

lisp

ro. M

inim

ed50

6/50

7,D

isetr

onic

Htr

onD

/V

Trea

tmen

t 2:

MD

I+

lisp

ro [3

×lis

pro,

2 ×

NPH

(mea

n 2.

65in

ject

ions

at

end

of M

DI)]

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:da

ily B

G m

easu

rem

ents

–in

eve

nt o

f hyp

ogly

caem

icsy

mpt

oms.

Pts

rec

orde

d al

lep

isode

s of

hyp

ogly

caem

iaan

d an

y ot

her

tech

nica

l or

met

abol

ic in

cide

nt. V

isits

ever

y 2

mon

ths,

insu

lindo

se a

nd a

dver

se e

vent

sno

ted.

Pat

ient

pre

fere

nce

at e

nd o

f stu

dy. H

bA1c

dete

rmin

ed a

t en

d of

eac

hpe

riod

Hyp

os (B

G <

60m

g/dl

)du

ring

last

14

days

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

run-

in p

erio

d,m

etho

d no

t st

ated

. Allo

catio

n co

ncea

lmen

t un

clea

r, op

en-la

bel d

esig

nRu

n-in

/was

h-ou

t pe

riod:

all

pts

had

6w

eeks

run

-in w

ith C

SII +

regu

lar

insu

lin. N

o w

ash-

out

perio

d. S

tate

s th

at n

o ca

rryo

ver

effe

ctw

as o

bser

ved

Com

para

bilit

y of

tre

atm

ent

grou

ps: n

ot r

epor

ted

Ana

lysis

: res

ults

giv

en a

s m

eans

and

SD

. All

test

s w

ere

2-ta

iled,

and

pva

lues

<0.

05 =

sta

tistic

ally

sig

nific

ant.

Cha

nges

in c

ontin

uous

crit

eria

stud

ied

by a

naly

sis o

f var

ianc

e ap

plie

d to

cro

ssov

er s

tudy

with

perio

d, t

reat

men

t gr

oup,

and

inte

ract

ion

fact

ors.

Cat

egor

ical

crit

eria

(adv

erse

eve

nts)

wer

e co

mpa

red

with

χ2

test

.Sa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

Typ

e I d

iabe

tes

and

expe

rienc

e of

inte

nsifi

ed t

hera

py (C

SII o

r M

DI)

Out

com

e m

easu

res:

HbA

1cat

4 m

onth

s, in

sulin

dos

e, h

ypo

episo

des

durin

g la

st 1

4da

ysRe

ason

s fo

r w

ithdr

awal

s: d

iffic

ultie

s w

ith M

DI (

pts

on C

SII b

efor

een

rolm

ent)

(1 M

DI)

Con

flict

of i

nter

est:

stud

y w

as s

uppo

rted

by

Lilly

Fra

nce

and

Baye

rFr

ance

Popu

latio

n: T

ype

1 di

abet

ic p

atie

nts

aged

21–6

5y.

Incl

usio

n cr

iteria

: HbA

1c<

10.

0%,

C-p

eptid

e –v

e an

d ex

perie

nce

ofin

tens

ified

insu

lin t

hera

py. N

one

had

untr

eate

d re

tinop

athy

, im

paire

d re

nal

func

tion,

gas

tric

neu

ropa

thy,

BMI>

30kg

/m2 , d

aily

insu

lin d

ose

>2

U/k

g, h

istor

y of

hyp

ogly

caem

iaun

awar

enes

s, o

r an

y se

vere

dise

ase

Part

icip

ants

: N

: 41

End

of s

tudy

: 40

Fem

ale:

48.

8%M

ean

age

(±SD

): 43

.5 (±

10.3

)y, m

in. 2

1,m

ax. 6

5.4

yD

iabe

tes

dura

tion

mea

n (±

SD):

20(±

11.3

y), m

in. 4

, max

. 42

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 8

.39

(±0.

87)%

Insu

lin: 4

3.6

(±13

.5) U

/day

BMI:

24 (±

2.4)

kg/m

2

Wei

ght:

68.2

(±10

)kg

Prev

ious

reg

imen

: at

enro

lmen

t 32

wer

etr

eate

d w

ith C

SII +

reg

ular

insu

lin a

nd 9

by

MD

I with

reg

ular

insu

lin o

r lis

pro

cont

inue

d

Appendix 6

116

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Hom

e et

al.,

1982

88

UK

, sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

2.5

mon

ths,

MD

I2.

5 m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

. Mill

Hill

1001

HM

,A

utos

yrin

geA

S*6C

Trea

tmen

t 2:

MD

I+

reg

ular

(2 ×

solu

ble,

1 ×

ultr

alen

te)

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:nu

mbe

r of

hyp

os r

equi

ring

oral

glu

cose

rec

orde

d at

biw

eekl

y cl

inic

visi

tsPa

tient

pre

fere

nce

byqu

estio

nnai

re a

t en

d of

stud

y

Allo

catio

n to

tre

atm

ent

grou

ps: s

tate

s re

gim

ens

in ‘r

ando

m o

rder

’bu

t no

furt

her

deta

ilsRu

n-in

/was

h-ou

t pe

riod:

not

rep

orte

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: n

ot IT

T. D

ata

pres

ente

d on

10

pts

who

com

plet

ed s

tudy

.M

ean

(SE)

pre

sent

ed. S

D c

alcu

late

d by

rev

iew

er. S

tude

nt’s

pai

red

t-te

stSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

insu

lin-d

epen

dent

dia

bete

sO

utco

me

mea

sure

s: b

lood

tak

en fo

r H

bA1

biw

eekl

y an

d fo

rch

oles

tero

l at

end

of e

ach

trea

tmen

t. H

ypos

rec

orde

d at

clin

ic v

isit,

ther

efor

e su

bjec

t to

rec

all b

ias.

Que

stio

nnai

re fo

r pa

tient

pre

fere

nce.

Reas

ons

for

with

draw

als:

1 p

t ex

clud

ed b

ecau

se o

f isc

haem

ic h

eart

dise

ase

(not

cle

ar w

heth

er t

his

was

bef

ore

or a

fter

rand

omisa

tion)

;1

pt h

ad m

yoca

rdia

l inf

arct

ion

befo

re c

ompl

etin

g st

udy

Con

flict

of i

nter

est:

pers

onal

sup

port

from

Nov

o La

bora

torie

sLi

mite

d. F

inan

cial

sup

port

from

Brit

ish D

iabe

tic A

ssoc

iatio

n

Popu

latio

n: in

sulin

-dep

ende

nt, C

-pep

tide

–ve,

adu

lts w

hose

con

trol

had

bee

npr

evio

usly

opt

imise

d on

tw

ice-

daily

inje

ctio

n th

erap

y.C

riter

ia: n

ot s

peci

fied.

1 (o

f 12)

pat

ient

excl

uded

due

to

ischa

emic

hea

rt d

iseas

e

Part

icip

ants

: N

: 12

cons

ente

d (s

ee m

etho

dolo

gy)

End

of s

tudy

: 10

Fem

ale:

40%

Mea

n ag

e (m

in.–

max

.): 4

0.4

(29–

52) y

Dia

bete

s du

ratio

n m

ean

(min

.–m

ax.):

22.

3(7

–34)

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1: 1

0.7

(±1.

9)%

Insu

lin: 6

0 (±

18.9

7) IU

/day

Wei

ght:

67.6

(±8.

5)kg

Prev

ious

reg

imen

: opt

imise

d on

tw

ice-

daily

inje

ctio

ns

cont

inue

d


117


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Nat

han

and

Lou,

1982

89

USA

, sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: e

ach

perio

d8–

12w

eeks

dura

tion;

1su

bjec

t on

MD

Ifo

r <

10w

eeks

.

1 su

bjec

tcr

osse

d-ov

er3

times

(M

DI 8

wee

ks,

CSI

I 12

wee

ks,

MD

I 8w

eeks

,C

SII 4

wee

ks

Trea

tmen

t 1:

CSI

I+

sol

uble

.A

utos

yrin

geA

S*6C

Trea

tmen

t 2:

MD

I+

reg

ular

(3 ×

solu

ble,

2 ×

NPH

or 1

×ul

tral

ente

).

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:di

ary:

insu

lin d

ose

adju

stm

ents

,hy

pogl

ycae

mic

rea

ctio

ns,

unus

ual a

ctiv

ities

,co

mpl

icat

ions

of t

hera

py.

Hyp

ogly

caem

ia:

com

bina

tion

of s

ympt

oms

of p

alpi

tatio

ns, d

iaph

ores

is,hu

nger

, lig

ht-h

eade

dnes

s or

conf

usio

n oc

curr

ing

with

BG <

60m

g/dl

and

relie

ved

by c

arbo

hydr

ate

inge

stio

nA

ccep

tabi

lity

of t

reat

men

tas

sess

ed w

ithqu

estio

nnai

re

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

base

line

data

obta

ined

. Met

hod

not

stat

ed. C

once

alm

ent

of a

lloca

tion

not

indi

cate

d1

pt p

artic

ipat

ed in

a d

oubl

e-bl

ind

cros

sove

r tr

ial o

f bot

h th

erap

ies

(3w

eeks

per

arm

)Ru

n-in

/was

h-ou

t pe

riod:

No

indi

catio

n of

was

h-ou

t pe

riod.

Pts

adm

itted

to

IP fo

r 2–

3da

ys a

fter

each

tre

atm

ent

star

ted

and

afte

rcr

osso

ver.

Afte

r co

mpl

etin

g fir

st le

g of

tria

l, pt

s ha

d al

l bas

elin

est

udie

s ag

ain,

inpa

tient

mon

itorin

g w

as c

arrie

d ou

t an

d pt

s w

ere

swap

ped

over

to

the

alte

rnat

ive

ther

apy

Com

para

bilit

y of

tre

atm

ent

grou

ps: b

asel

ine

data

tab

le g

iven

, tho

ugh

com

para

bilit

y be

twee

n gr

oups

(tho

se o

n M

DI f

irst

vs C

SII f

irst)

not

give

nA

naly

sis: S

tude

nt’s

pai

red

2-ta

iled

t-te

st. I

ndiv

idua

l pt

data

pre

sent

ed,

mea

ns c

alcu

late

d by

rev

iew

er. B

asel

ine

and

insu

lin a

nd H

bA1c

(for

trea

tmen

ts) S

D c

alcu

late

d by

rev

iew

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: m

otiv

ated

adu

lts w

ith T

ype

I dia

bete

s, p

revi

ously

on

NPH

and

reg

ular

insu

lin r

egim

esO

utco

me

mea

sure

s: a

ppro

pria

te o

utco

me

mea

sure

s ( H

bA1c

,hy

pogl

ycae

mic

epi

sode

s) u

sed

Con

flict

of i

nter

est:

gran

t su

ppor

t: in

par

t by

Cor

ning

Med

ical

and

Scie

ntifi

c, M

edfie

ld, M

A; t

he M

uria

l McL

auth

lin F

und,

Mas

sach

uset

tsG

ener

al H

ospi

tal;

and

the

Gen

eral

Clin

ical

Res

earc

h C

entr

e gr

ant

RR01

066,

Nat

iona

l Ins

titut

es o

f Hea

lth. O

ne a

utho

r is

the

Cap

psSc

hola

r of

Har

vard

Uni

vers

ity; o

ne a

utho

r is

an in

vest

igat

or fo

r th

eH

owar

d H

ughe

s M

edic

al In

stitu

te

Popu

latio

n: m

otiv

ated

adu

lts w

ith T

ype

Idi

abet

esC

riter

ia: p

ts h

ad h

istor

y of

ket

osis-

pron

e,in

sulin

-dep

ende

nt d

iabe

tes.

Non

e ha

dsig

nific

ant

neur

opat

hy n

ephr

opat

hy,

retin

opat

hy o

r va

scul

ar d

iseas

e at

stu

dyou

tset

. All

pts

with

in 1

0% o

f ide

al b

ody

wei

ght

Part

icip

ants

: N

: 5En

d of

stu

dy: 5

Fem

ale:

60%

Mea

n ag

e (m

in.–

max

.): 3

1 (2

7–41

) yD

iabe

tes

dura

tion

mea

n (m

in.–

max

.):7.

4(5

–9) y

Base

line

valu

es: m

ean

(±SD

):H

bA1c

: 9.0

3 (±

1.43

)%.

Insu

lin: 4

2.8

(±16

.04)

IU/d

ayH

ypog

lyca

emic

rea

ctio

ns (n

/wee

k) =

1.8

(±0.

84)

Prev

ious

insu

lin r

egim

en: r

egul

ar +

NPH

(2 ×

daily

) (3

pts)

; NPH

(2 ×

daily

) (1

pt);

regu

lar

+ N

PH (1

pt)

cont

inue

d

Appendix 6

118

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Nos

adin

i et

al.,

1988

85

Italy,

sin

gle

cent

re, R

CT

(par

alle

l)

[4 a

rms:

conv

entio

nal v

sM

DI v

s C

SII w

ithfix

ed b

asal

rat

e(F

BR) v

s C

SII

with

hig

her

daw

nin

sulin

(HO

R).

Dat

a on

conv

entio

nal a

rmno

t ex

trac

ted]

Dur

atio

n:12

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

(FBR

).M

icro

jet

MC

20

Trea

tmen

t 2:

MD

I+

reg

ular

(3 ×

solu

ble,

1 ×

long

-ac

ting)

Trea

tmen

t 3:

CSI

I+

sol

uble

(HO

R).

Beta

tron

II

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:BG

mea

sure

d w

hen

hype

ran

d hy

po e

piso

des

susp

ecte

d. E

vent

s as

sess

edfr

om t

wic

e-w

eekl

ypr

ofile

s, h

ospi

tal B

G a

nd p

tre

cord

s of

sus

pect

edev

ents

. Hyp

er =

BG

up

to35

0m

g/dl

with

ace

tonu

riaas

sess

ed b

y pt

, no

med

ical

advi

ce. K

etot

ic e

vent

s =

BG >

400

mg/

dl a

ndke

tone

bod

y le

vels

>1.

5m

mol

/l w

ith c

linic

alsy

mpt

oms

requ

iring

adm

issio

n to

war

d. H

ypo

= B

G<

60m

g/dl

with

clin

ical

sym

ptom

s w

ithou

the

lp fr

om o

ther

s. S

ever

ehy

po =

BG

<60

mg/

dlre

quiri

ng g

luca

gon

orgl

ucos

e pa

rent

eral

adm

inist

ratio

n fr

om o

ther

s

Allo

catio

n to

tre

atm

ent

grou

ps: 9

6 pt

s re

crui

ted

and

divi

ded

into

4gr

oups

: mal

e, fe

mal

e, d

urat

ion

of d

iseas

e >

5y,

<5

y. S

ubje

cts

ofea

ch g

roup

wer

e as

signe

d ‘b

lindl

y’ t

o ea

ch o

f 4 t

reat

men

ts. M

etho

dno

t st

ated

. Sea

led

enve

lope

s op

ened

by

pts.

Con

sent

obt

aine

d af

ter

rand

omisa

tion

Run-

in/w

ash-

out

perio

d: a

fter

rand

omisa

tion,

met

abol

ic d

ata

colle

cted

for

3 m

onth

s on

pre

viou

s tr

aditi

onal

the

rapy

. A w

eek

inho

spita

l was

spe

nt t

each

ing

self-

mon

itorin

g an

d se

lf-re

gula

tion

ofin

sulin

Com

para

bilit

y of

tre

atm

ent

grou

ps: s

tate

s sim

ilar

insu

lin d

aily

dos

ean

d nu

mbe

r of

inje

ctio

ns, a

nd H

bA1c

Ana

lysis

: no

cros

sove

r w

ithin

tre

atm

ents

occ

urre

d. M

ultiv

aria

teA

NO

VA fo

r re

peat

ed m

easu

res

used

for

diffe

renc

es w

ithin

the

4in

sulin

reg

imen

s an

d be

twee

n tim

e 0

and

each

reg

imen

. Unp

aire

d t-

test

ana

lysis

and

Bon

ferr

oni t

-tes

t fo

r di

ffs b

etw

een

singl

e va

lues

whe

n A

NO

VA r

evea

led

signi

fican

t di

ffere

nce

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted

Gen

eral

isabi

lity:

insu

lin-d

epen

dent

dia

betic

s re

ceiv

ing

conv

entio

nal

ther

apy

Out

com

e m

easu

res:

bas

elin

e va

lues

col

lect

ed in

mon

th p

rece

ding

time

0. H

ypos

exp

ress

ed a

s m

ean

valu

e/pt

/yea

rC

onfli

ct o

f int

eres

t: su

ppor

ted

by C

NR

gran

ts a

nd C

NR

Inte

rnat

iona

lRe

sear

ch P

rogr

amm

e

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

tics

Incl

usio

n cr

iteria

: C-p

eptid

e –v

e

CSI

I FBR

par

ticip

ants

: N

: 19

End

of s

tudy

: 19

Fem

ale:

42.

1%M

ean

age

(±SD

): 36

(±6)

yD

iabe

tes

dura

tion

mea

n (±

SD):

8 (±

3)y

Base

line

valu

es: m

ean

(±SD

):W

eigh

t: 77

(±7)

kg

MD

I par

ticip

ants

:N

: 15

End

of s

tudy

: 15

Fem

ale:

26.

7%M

ean

age

(±SD

): 32

(±9)

yD

iabe

tes

dura

tion

mea

n (±

SD):

7 (±

4)y

Base

line

valu

es: m

ean

(±SD

):W

eigh

t: 71

(±6)

kg

CSI

I HO

R pa

rtic

ipan

ts:

N: 1

0En

d of

stu

dy: 1

0Fe

mal

e: 4

0%M

ean

age

(±SD

): 34

(±3)

yD

iabe

tes

dura

tion

mea

n (±

SD):

7 (±

3)y

Base

line

valu

es: m

ean

(±SD

):W

eigh

t: 70

(±7)

kg

Prev

ious

reg

imen

: 2–3

inje

ctio

ns/d

ay,

mix

ed r

egul

ar a

nd lo

ng-a

ctin

g in

sulin

prep

arat

ions

cont

inue

d


119


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Saur

brey

et

al.,

1988

90

Den

mar

k, s

ingl

e-ce

ntre

,ra

ndom

ised

cros

sove

r

Dur

atio

n: C

SII

2.5

mon

ths,

MD

I2.

5m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

.A

utos

yrin

ge A

S-6C

(n=

6),

Med

ix20

9 (n

= 1

3).

Trea

tmen

t 2:

MD

I+

reg

ular

[3

×so

lubl

e(N

ovop

en),

1 ×

inte

rmed

iate

(syr

inge

)].

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:tw

ice

wee

kly

= 7

-poi

ntBG

pro

files

. Num

ber

ofhy

pos

reco

rded

. No

furt

her

deta

ils.

Bloo

d sa

mpl

es fo

r H

bA1c

take

n af

ter

run-

in a

nd a

fter

each

tre

atm

ent

perio

dA

t al

l out

patie

nt v

isits

=in

ject

ions

site

s in

spec

ted

and

body

wei

ght

reco

rded

.Pa

tient

att

itude

ques

tionn

aire

com

plet

ed a

ten

d of

stu

dy

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d, b

ut n

o in

dica

tion

ofm

etho

d of

ran

dom

isatio

n. N

o m

entio

n of

con

ceal

men

t of

allo

catio

nRu

n-in

/was

h-ou

t pe

riod:

pts

had

a 3

-wee

k ru

n-in

Com

para

bilit

y of

tre

atm

ent

grou

ps: n

ot r

epor

ted

Ana

lysis

: Mea

n an

d ±

SE v

alue

s pr

ovid

ed. R

evie

wer

cal

cula

ted

SD fo

rH

bA1c

and

insu

lin. R

esul

ts c

ompa

red

stat

istic

ally

by

Stud

ent’s

t-t

est

and

diffe

renc

es r

esul

ting

in p

-val

ues

<0.

05 w

ere

cons

ider

edsig

nific

ant.

HbA

1cda

ta e

xtra

cted

from

figu

re b

y re

view

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

insu

lin-d

epen

dent

dia

bete

s w

ho h

adpr

evio

usly

bee

n on

inje

ctio

n in

sulin

the

rapy

.O

utco

me

mea

sure

s: a

ppro

pria

te o

utco

me

mea

sure

s us

ed (H

bA1c

and

hypo

s), a

lthou

gh n

o in

dica

tion

of r

ecor

ding

met

hod

of h

ypos

Reas

ons

for

with

draw

als:

pum

p w

earin

g un

acce

ptab

le (2

)C

onfli

ct o

f int

eres

t: N

ovo

Indu

stri

A/S

sup

plie

d N

ovoP

ens

Popu

latio

n: a

dults

with

insu

lin d

epen

dent

diab

etes

; ass

umed

tha

t m

ost

of t

he p

ts C

-pe

ptid

e –v

e. A

ll w

ere

trea

ted

with

tw

ice

daily

inje

ctio

ns o

f sho

rt-a

ctin

g pl

usin

term

edia

te-

or lo

ng-a

ctin

g in

sulin

.Ba

ckgr

ound

ret

inop

athy

(12)

, pro

lifer

ativ

ere

tinop

athy

(0),

inci

pien

t se

nsor

yne

urop

athy

(4),

inte

rmitt

ent

prot

einu

ria (3

)In

clus

ion

crite

ria: i

nsul

in-d

epen

dent

diab

etes

; abl

e to

com

ply

with

inte

nsiv

ein

sulin

reg

ime

Part

icip

ants

: N

: 21

End

of s

tudy

: 19

Fem

ale:

43%

Mea

n ag

e (±

SD):

32 (±

2.1)

y, m

in. 2

0,m

ax. 5

3D

iabe

tes

dura

tion

mea

n (±

SD):

14.5

(±1.

4) y

Base

line

valu

es: m

ean

(±SD

):G

roup

sta

rtin

g w

ith C

SII,

HbA

1c: 8

.7(±

1.74

)%G

roup

sta

rtin

g w

ith M

DI H

bA1c

: 8.8

(±2.

17)%

, p=

ns

Insu

lin: 0

.67

(±0.

4) IU

/day

cont

inue

d

Appendix 6

120

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Schi

ffrin

and

Belm

onte

, 198

291

Can

ada,

sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

6m

onth

s, M

DI

6m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

. Mill

Hill

1001

GM

Trea

tmen

t 2:

MD

I+

reg

ular

(3 ×

solu

ble,

1 ×

NPH

).

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:H

ypos

: mild

= r

ecog

nise

dby

sen

satio

n of

hun

ger,

fatig

ue, i

rrita

bilit

y,he

adac

he. M

oder

ate

=co

ld s

wea

ting,

pal

pita

tions

,tr

emou

rs, b

lurr

ed v

ision

,im

paire

d vo

lunt

ary

mov

emen

ts o

r m

emor

ylo

ss. S

ever

e =

loss

of

cons

ciou

snes

s. M

etho

d of

colle

ctin

g pt

pre

fere

nce

data

not

rep

orte

d. H

bA1

and

chol

este

rol m

easu

red

mon

thly

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d, h

alf t

o ea

ch t

hera

py,

but

no in

dica

tion

of m

etho

d of

ran

dom

isatio

n. A

lloca

tion

conc

ealm

ent

uncl

ear

Run-

in/w

ash-

out

perio

d: p

ts r

emai

ned

on c

onve

ntio

nal t

reat

men

tpr

ior

to s

tudy

. Pts

sta

rtin

g on

CSI

I wer

e gi

ven

prac

tice

for

1w

eek

prio

r to

stu

dy. N

o w

ash-

out

perio

d re

port

edC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: n

ot IT

T a

naly

sis. M

ean

±SD

pro

vide

d. D

ata

anal

ysed

by

paire

d St

uden

t’s t

-tes

t. W

hen

valu

es d

id n

ot h

ave

a no

rmal

dist

ribut

ion,

a p

aire

d t-

test

was

per

form

ed o

n th

e lo

garit

hmic

tran

sfor

m o

f the

dat

a. B

asel

ine

and

6-m

onth

insu

lin v

alue

sex

trap

olat

ed fr

om g

raph

(Fig

ure

4) b

y re

view

er. B

asel

ine

wei

ght

and

BMI c

alcu

late

d fr

om T

able

1 b

y re

view

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: in

sulin

-dep

ende

nt d

iabe

tics

aged

14–

41 y

who

had

prev

ious

ly b

een

on c

onve

ntio

nal i

njec

tion

insu

lin t

hera

pyO

utco

me

mea

sure

s: H

bA1

repo

rted

mon

thly

for

mon

ths

0–6.

Dat

aex

trac

ted

for

mon

ths

0, 3

and

6 o

nly.

Met

hod

of r

ecor

ding

hyp

os n

otcl

ear.

Pts

follo

wed

the

ir us

ual d

iabe

tic d

iet:

30–4

0% fa

t, 15

–20%

prot

ein,

40–

45%

CH

O in

the

form

of 3

mea

ls an

d be

dtim

e sn

ack.

Reas

ons

for

with

draw

als:

1 C

SII,

1 M

DI a

fter

4w

eeks

of t

hera

py(r

easo

n no

t sp

ecifi

ed);

1 af

ter

2 w

eeks

and

1 a

fter

2m

onth

s of

bot

hC

SII a

nd M

DI

Con

flict

of i

nter

est:

Boeh

ringh

er M

annh

eim

Can

ada

loan

ed t

here

flect

ance

met

ers

(for

BG m

easu

rem

ent)

. Fun

ded

by D

iabe

ticC

hild

ren’

s Fo

unda

tion,

Que

bec

and

the

Mon

trea

l Chi

ldre

n’s

Hos

pita

lRe

sear

ch In

stitu

te

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

tics

with

sev

ere

insu

lin d

efic

ienc

y do

cum

ente

dby

abs

ent

C-p

eptid

e re

spon

se t

o gl

ucag

onst

imul

atio

n. A

ged

14–4

1 y.

Incl

usio

n cr

iteria

: not

rep

orte

d

Part

icip

ants

: N

: 20

End

of s

tudy

: 16

Fem

ale:

70%

Mea

n ag

e (m

in.–

max

.): 2

4.95

(14–

41) y

Dia

bete

s du

ratio

n m

ean

(min

.–m

ax.):

10.3

5 (6

–21)

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1: 1

3.2

(±1.

1)%

Insu

lin: 4

8 IU

/day

BMI:

22.8

1 kg

/m2

Wei

ght:

61.8

6kg

Prev

ious

reg

imen

: con

vent

iona

l tre

atm

ent

of r

egul

ar a

nd in

term

edia

te-a

ctin

g in

sulin

. 2

inje

ctio

ns/d

ay (n

= 1

6), 3

inje

ctio

ns/d

ay(n

= 3

), 4

inje

ctio

ns/d

ay (n

= 1

)

cont

inue

d


121


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Schm

itz e

t al

.,19

8986

Den

mar

k, s

ingl

e-ce

ntre

,ra

ndom

ised

cros

sove

r

Dur

atio

n: C

SII

6m

onth

s, M

DI

6m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

.N

ordi

sk

Trea

tmen

t 2:

MD

I+

reg

ular

(3–4

×so

lubl

e, 1

×N

PH.

Insu

ject

pen

+)

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

of o

utco

mes

:M

etho

d of

rec

ordi

ng h

ypos

not

reco

rded

. Pts

cho

seth

eir

pref

eren

tial

trea

tmen

t at

end

of s

tudy

;m

etho

d no

t re

cord

ed

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d, b

ut n

o in

dica

tion

ofm

etho

d of

ran

dom

isatio

n. A

lloca

tion

conc

ealm

ent

uncl

ear

Run-

in/w

ash-

out

perio

d: n

ot r

epor

ted

Com

para

bilit

y of

tre

atm

ent

grou

ps: n

ot r

epor

ted

Ana

lysis

: Mea

ns ±

assu

me

SD (n

ot s

peci

fied)

. Diff

eren

ces

judg

ed b

ySt

uden

t’s p

aire

d t-

test

. HbA

1cm

easu

red

at 0

mon

ths

and

mon

thly

and

mea

n of

val

ues

durin

g la

st 3

mon

ths

of e

ach

stud

y pe

riod

calc

ulat

ed. W

eigh

t an

d in

sulin

dos

e ca

lcul

ated

as

mea

n of

val

ues

durin

g 3

mon

ths

prio

r to

stu

dy a

nd d

urin

g la

st 3

mon

ths

of e

ach

stud

y pe

riod

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted

Gen

eral

isabi

lity:

adu

lts w

ith lo

ng-t

erm

unc

ompl

icat

ed in

sulin

-de

pend

ent

diab

etes

. In

good

con

trol

bef

ore

entr

ance

to

stud

yO

utco

me

mea

sure

s: p

ts s

een

mon

thly

in o

utpa

tient

clin

ic. V

ery

little

info

rmat

ion

on h

ypos

– o

nly

repo

rts

that

‘no

seve

re h

ypos

occ

urre

d’C

onfli

ct o

f int

eres

t: no

ne r

epor

ted

Popu

latio

n: o

ther

wise

hea

lthy

insu

lin-

depe

nden

t di

abet

ics,

age

d 26

–50

y.D

iabe

tes

in ‘g

ood

cont

rol’

befo

re e

ntra

nce

to t

he s

tudy

Incl

usio

n cr

iteria

: dia

bete

s du

ratio

n ≥

20y,

abse

nce

of s

ever

e di

abet

ic c

ompl

icat

ions

,i.e

. urin

ary

albu

min

exc

retio

n ra

te≤

20µg

/min

, nor

mal

blo

od p

ress

ure

and

seru

m c

reat

inin

e an

d no

pro

lifer

ativ

ere

tinop

athy

. Also

, no

med

icat

ion

othe

rth

an in

sulin

tak

en

Part

icip

ants

: N

: 10

End

of s

tudy

: 10

Fem

ale:

60%

Mea

n ag

e (±

SD):

36.5

(±7.

9) y

, min

. 26,

max

. 50

Dia

bete

s du

ratio

n m

ean

(±SD

): 23

.7(±

2.9)

y, m

in. 2

1, m

ax. 3

0Ba

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.6 (±

0.9)

%

Insu

lin: 0

.6 (±

0.11

) IU

/kg/

day

BMI:

23kg

/m2

(cal

cula

ted

by r

evie

wer

)W

eigh

t: 71

.6 (±

17.2

)kg

Prev

ious

reg

imen

: con

vent

iona

l tre

atm

ent

(no

furt

her

deta

ils)

cont

inue

d

Appendix 6

122

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Tsui

et

al.,

2001

79

Can

ada,

sin

gle-

cent

re, R

CT

(par

alle

l)

Dur

atio

n:9

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro. M

inim

ed50

7

Trea

tmen

t 2:

MD

I+

lisp

ro (a

lso 1

×N

PH).

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: A

dver

seev

ents

suc

h as

DK

Are

cord

ed b

y pa

tient

s.H

bA1c

mea

sure

dm

onth

ly.H

ypog

lyca

emia

:sy

mpt

oms

relie

ved

byin

gest

ion

of g

luco

sean

d/or

BG

≤3

mm

ol/l;

seve

re h

ypog

lyca

emia

:re

quire

s as

sista

nce

orin

com

a

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d af

ter

a 2-

wee

k sc

reen

ing

perio

d by

sea

led

enve

lope

s, p

repa

red

inde

pend

ently

usin

g co

mpu

ter-

gene

rate

d ra

ndom

isatio

nsc

hedu

leRu

n-in

/was

h-ou

t pe

riod:

not

rep

orte

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: pts

sim

ilar

at b

asel

ine

Diff

eren

ce in

HbA

1c: n

ot s

tatis

tical

ly s

igni

fican

tA

naly

sis: H

bA1c

anal

ysed

by

rand

om-e

ffect

s re

gres

sion

mod

el; m

onth

ly h

ypos

ana

lyse

d by

Poi

sson

reg

ress

ion,

base

line

HbA

1cus

ed a

s a

cova

riate

in m

odel

. Mul

tivar

iate

linea

r m

odel

ling

used

for

subs

cale

of D

QO

L an

d m

ultiv

aria

tean

alys

is of

var

ianc

e gl

obal

ly, e

ach

trea

tmen

t gr

oup

test

ed o

nits

ow

n an

d w

ith a

ge, s

ex, d

iseas

e du

ratio

n, b

asel

ine

HbA

1c,

tota

l no.

of h

ypos

, and

no.

of s

ever

e hy

pos

incl

uded

sepa

rate

ly a

nd c

ombi

ned

as c

ovar

iate

s. 9

5% C

I and

p-v

alue

sca

lcul

ated

. p-v

alue

of 0

.05

used

as

signi

fican

ce, n

ot a

djus

ted

for

mul

tiple

com

paris

ons.

Pts

ana

lyse

d ac

cord

ing

tora

ndom

isatio

n gr

oup

Sam

ple

size/

pow

er c

alcu

latio

n: 2

8 pt

s re

crui

ted

but

only

27

rand

omise

d –

1 w

as u

nsui

tabl

e. S

tatis

tical

pow

er o

f 86%

to

dete

ct a

clin

ical

ly im

port

ant

over

all d

iffer

ence

of ±

0.5

inH

bA1c

betw

een

two

trea

tmen

t gr

oups

usin

g tw

o-ta

iled

alph

aof

0.0

5G

ener

alisa

bilit

y: a

dults

age

d 18

–60

y w

ith in

sulin

-dep

ende

ntdi

abet

esO

utco

me

mea

sure

s: r

ecor

ded

adve

rse

even

ts s

uch

as D

KA

,H

bA1c

, mon

thly

Oth

er: A

t en

d of

9m

onth

s st

udy

12 M

DI c

ross

ed t

o C

SII a

ndfo

llow

ed fo

r 6

mon

ths.

Firs

t 3

mon

ths

excl

uded

from

anal

ysis,

but

stu

dy d

one

post

hoc

and

pote

ntia

l for

bia

s du

e to

perio

d ef

fect

Reas

ons

for

with

draw

als:

1 C

SII d

ropp

ed o

ut a

fter

3m

onth

s(r

easo

n no

t gi

ven)

Con

flict

of i

nter

est:

1 au

thor

rec

eive

d re

sear

ch s

uppo

rt,

hono

raria

and

con

sulta

nt fe

es fr

om E

li Li

lly, o

ne a

utho

r is

ace

rtifi

ed t

rain

er fr

om M

iniM

ed. S

tudy

sup

port

ed b

y re

sear

chgr

ant

from

Eli

Lilly

. Pum

ps a

nd d

ispos

able

sup

plie

s by

Min

iMed

. Hum

alog

and

NPH

by

Eli L

illy

Popu

latio

n: a

dults

age

d 18

–60

y w

ith e

ndoc

rine

diag

nose

d Ty

pe I

diab

etes

Incl

usio

n cr

iteria

: dia

betic

for

>2

y, on

set o

f dia

bete

s on

or b

efor

e 40

y, ab

le to

com

ply

with

trea

tmen

t reg

imen

,cu

rren

tly r

ecei

ving

two

or m

ore

inje

ctio

ns p

er d

ay a

ndin

tere

sted

and

mot

ivat

ed to

use

CSI

IEx

clus

ion:

hist

ory

of >

2 se

vere

hyp

os (c

oma,

sei

zure

,lo

ss o

f con

scio

usne

ss) i

n th

e la

st y

ear,

haem

oglo

bino

path

y, in

sulin

res

istan

ce, e

xtre

me

obes

ity(B

MI>

35),

seve

re la

te c

ompl

icat

ions

of d

iabe

tes,

evid

ence

of s

igni

fican

t car

diov

ascu

lar,

hepa

tic d

iseas

e,ca

ncer

, or

cere

brov

ascu

lar

or s

ever

e pe

riphe

ral v

ascu

lar

dise

ase,

alc

ohol

or

drug

abu

se, a

nd/o

r pa

rtic

ipat

ion

inan

othe

r cl

inic

al tr

ial i

n pa

st 4

wee

ks. P

regn

ant w

omen

or

thos

e lik

ely

to b

ecom

e pr

egna

nt. 1

exc

lude

d as

too

hirs

ute

for

pum

p ad

hesiv

e to

stic

kC

SII p

artic

ipan

ts:

N: 1

3En

d of

stu

dy: 1

2Fe

mal

e: 3

8%M

ean

age

(±SD

): 36

(±12

) yrs

Med

ian

age

(min

-max

): 38

(19-

57)y

Dia

bete

s du

ratio

n m

ean

(±SD

): 17

(±10

), m

in. 8

, max

.37

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.73

(±0.

6)%

In

sulin

: 0.7

(±0.

2) IU

/day

BMI:

27 (±

4) k

g/m

2

MD

I par

ticip

ants

:N

: 14

End

of s

tudy

: 14

Fem

ale:

29%

Mea

n ag

e (±

SD):

36 (±

10) y

Med

ian

age

(min

-max

): 35

(21–

58) y

Dia

bete

s du

ratio

n m

ean

(±SD

): 15

(±9)

, min

. 4, m

ax.

28 y

rsBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 8

.16

(±0.

7)%

, 95

% C

I –0.

94 to

+0.

09, p

>0.

10.

Insu

lin: 0

.7 (±

0.1)

IU/d

ayBM

I: 26

(±3)

kg/

m2

cont

inue

d


123


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Zie

gler

et

al.,

1990

84

Ger

man

y, s

ingl

e-ce

ntre

, RC

T(p

aral

lel)

Dur

atio

n:24

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

.N

ordi

sk In

fuse

r,Be

tatr

on I

and

II,au

tosy

ringe

8M

P,or

Pro

med

os E

1

Trea

tmen

t 2:

MD

I+

reg

ular

(2–4

inje

ctio

ns d

aily

: 2in

ject

ions

(sta

ndar

d) =

com

bina

tions

of

regu

lar

and

NPH

.3

inje

ctio

ns(in

crea

sed

fast

ing

BG) =

2 ×

NPH

+ r

egul

ar, a

nd

2–3

×re

gula

r. 4

inje

ctio

ns(ir

regu

lar

lifes

tyle

)=

1–2

×N

PH a

nd3–

4 ×

regu

lar)

.

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: s

yste

mat

icas

sess

men

t of

hyp

o-an

d hy

perg

lyca

emic

episo

des

base

d on

pts

’da

ily r

ecor

ds a

nd o

nin

quiri

es a

t ea

chm

onth

ly c

linic

visi

t.M

ild h

ypo

= B

G<

50m

g/dl

with

out

sym

ptom

s, o

r th

eap

pear

ance

of t

ypic

alsy

mpt

oms

that

cou

ldbe

sel

f-m

anag

ed.

Seve

re h

ypo

= e

vent

sre

quiri

ng a

ssist

ance

by

othe

r pe

rson

s, o

rco

ma

whe

n gl

ucos

e or

gluc

agon

inje

ctio

nsw

ere

requ

ired.

Hyp

ergl

ycae

mic

keto

sis =

BG

>20

0m

g/dl

and

posit

ive

urin

e ac

eton

e.Ke

toac

idos

is =

ven

ous

bloo

d pH

<7.

3 at

hosp

ital a

dmiss

ion.

HbA

1de

term

ined

mon

thly

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d, b

ut n

oin

dica

tion

of m

etho

d of

ran

dom

isatio

n. A

lloca

tion

conc

ealm

ent

uncl

ear

Run-

in/w

ash-

out

perio

d: fo

r 1

mon

th p

rior

to r

ando

misa

tion,

all p

ts w

ere

put

on in

tens

ified

con

vent

iona

l inj

ectio

n th

erap

y.A

lso 1

-wee

k te

achi

ng p

rogr

amm

eC

ompa

rabi

lity

of t

reat

men

t gr

oups

: clin

ical

cha

ract

erist

ics

atra

ndom

isatio

n gi

ven

for

both

gro

ups.

Sim

ilar

age,

BM

I,du

ratio

n of

dia

bete

s, in

sulin

dos

e an

d H

bA1.

Ana

lysis

: met

hod

stat

es d

ata

are

mea

n ±

SD, b

ut g

raph

s ar

eSE

. Adv

erse

effe

cts

are

mea

n (r

ange

). Ba

selin

e da

ta a

rem

edia

n (m

in.–

max

.). S

tude

nt’s

t-t

est

(2-s

ided

) for

inde

pend

ent

grou

ps. F

isher

’s e

xact

pro

babi

lity

test

(2-s

ided

)to

ana

lyse

qua

litat

ive

varia

bles

. Rev

iew

er h

as e

xtra

pola

ted

grap

h fo

r al

l HbA

1va

lues

. Whe

re p

ts c

hang

ed t

reat

men

tgr

oup,

the

y w

ere

reta

ined

in t

he o

rigin

ally

ass

igne

d gr

oup

for

stat

istic

al a

naly

sisSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: p

oorly

con

trol

led

Type

1 p

ts w

ith c

linic

alsy

mpt

oms

of a

t le

ast

1 ch

roni

c di

abet

ic c

ompl

icat

ion

Out

com

e m

easu

res:

HbA

1ex

amin

ed a

t ba

selin

e an

d m

onth

lyth

erea

fter.

No.

of a

dver

se e

vent

s ca

lcul

ated

for

each

pt

per

6m

onth

s. T

otal

no.

of s

ever

e hy

po a

nd D

KA

per

24

mon

ths

extr

apol

ated

to

100

y (n

o ev

ents

/100

y).

Reas

ons

for

with

draw

al: p

artic

ipat

ion

offe

red

to 2

08, 1

08re

fuse

d du

e to

stu

dy p

roto

col o

r di

stan

ce t

o ce

ntre

. 4ex

clud

ed a

t en

d of

rec

ruitm

ent

phas

e as

did

not

mee

tcr

iteria

. With

draw

als:

adv

erse

effe

cts

(not

spe

cifie

d) (1

CSI

I);re

fusa

l to

cont

inue

on

ther

apy

(1 C

SII,

1 M

DI);

bur

den

ofst

udy

(e.g

. reg

ular

BG

sel

f-m

onito

ring)

(6 C

SII,

5 M

DI);

reas

ons

unre

late

d to

stu

dy (e

.g. m

oved

hou

se) (

5 C

SII,

4M

DI)

Oth

er: 1

1 pt

s (4

CSI

I, 7

MD

I) ch

ange

d to

oth

er t

reat

men

t. In

both

gro

ups

chan

gers

equ

ally

dist

ribut

ed t

hrou

ghou

t st

udy

perio

d. 1

pt

with

aut

onom

ic n

euro

path

y di

ed fr

om s

udde

nde

ath

with

out

evid

ence

of h

ypo

of D

KA

– a

ssum

ed t

hey

are

incl

uded

in t

he g

roup

of w

ithdr

awal

s ‘u

nrel

ated

to

stud

y’C

onfli

ct o

f int

eres

t: su

ppor

ted

by g

rant

s fr

om D

euts

che

Fors

chun

gsge

mei

nsch

aft,

Bonn

FRG

(SFB

113

), th

eBu

ndes

min

ister

für

Ges

undh

eit

and

the

Min

ister

für

Wiss

ensc

haft

und

Fors

chun

g, N

RW

Popu

latio

n: C

-pep

tide

–ve,

poo

rly c

ontr

olle

d Ty

pe 1

diab

etes

pts

with

clin

ical

sym

ptom

s of

at

leas

t 1

chro

nic

diab

etic

com

plic

atio

n, w

ho w

ere

unse

lect

ed a

sto

inte

llige

nce

and

educ

atio

n. A

ged

18–6

0 y.

Incl

usio

n cr

iteria

: ≥18

y an

d ≤

60 y

; Typ

e 1

diab

etes

;m

anife

stat

ion

of d

iabe

tes

<35

y of

age

; dia

bete

sdu

ratio

n >

1y,

stim

ulat

ed s

erum

C-p

eptid

e<

0.3

ng/m

l; H

bA1

≥8.

0% u

nder

con

vent

iona

l ins

ulin

ther

apy;

at

leas

t 1

chro

nic

diab

etic

com

plic

atio

n(r

etin

opat

hy, n

ephr

opat

hy o

r ne

urop

athy

)Ex

clus

ion:

mal

igna

ncie

s; p

revi

ous

card

iac

infa

rctio

n;en

docr

ine

diso

rder

s; p

rimar

y dy

slipo

prot

eina

emia

;am

auro

sis; h

ypog

lyca

emic

una

war

enes

s; s

erum

crea

tinin

e >

3m

g/dl

; psy

chos

is; c

hron

ic a

lcoh

ol a

buse

;in

form

ed c

onse

nt r

efus

edC

SII p

artic

ipan

ts:

N: 4

9En

d of

stu

dy: 3

6Fe

mal

e: 3

8.8%

Med

ian

age

(min

.–m

ax.):

32

(18–

54) y

Dia

bete

s du

ratio

n m

edia

n (m

in.–

max

.): 1

8.0

(3–4

4) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

9.8

%

HbA

11

mon

th p

rior

to r

ando

misa

tion

10.6

(±2.

2)In

sulin

: 49

(±17

) IU

/day

BMI:

23 k

g/m

2

MD

I par

ticip

ants

:N

: 47

End

of s

tudy

: 37

Fem

ale:

51.

1%M

edia

n ag

e (m

in.–

max

.): 3

2 (1

8–55

) yD

iabe

tes

dura

tion

med

ian

(min

.–m

ax.):

14.

8 (3

–42)

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1: 9

.5%

, p=

ns

HbA

11

mon

th p

rior

to r

ando

misa

tion

10.2

(±1.

6),

p=

nsIn

sulin

: 48

(±14

) IU

/day

, p=

nsBM

I: 22

.1 k

g/m

2

Prev

ious

reg

imen

: con

vent

iona

l ins

ulin

the

rapy

, def

ined

as d

aily

inje

ctio

ns o

f lon

g-ac

ting

or fi

xed

com

bina

tions

of in

term

edia

te-

and

shor

t-ac

ting

insu

lin a

t gi

ven

dose

sw

ithou

t re

gula

r BG

sel

f-m

onito

ring

and

self-

adju

stm

ent

of t

hera

py

AN

OVA

, ana

lysis

of v

aria

nce.


125


Appendix 7

Summary of methodology: pregnancy

Appendix 7

126

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Burk

art

et a

l.,19

8895

Ger

man

y, s

ingl

e-ce

ntre

, RC

T(p

aral

lel)

Dur

atio

n:9

mon

ths

(Also

com

pare

dw

ith a

conv

entio

nal

trea

tmen

t gr

oup

– da

ta n

otex

trac

ted)

Trea

tmen

t 1:

CSI

I+

sol

uble

. ‘O

pen

loop

infu

sion

syst

em’ –

no

furt

her

deta

ils

Trea

tmen

t 2:

MD

I+

reg

ular

.D

escr

ibed

as

‘inte

nsifi

ed in

sulin

ther

apy’

by

‘con

vent

iona

lsy

ringe

tec

hniq

ue’.

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es:

Dat

a pr

esen

ted

acco

rdin

g to

sev

erity

of m

ater

nal d

iabe

tes

(Whi

te’s

cla

ssifi

catio

n).

Mea

n bi

rthw

eigh

t an

dge

stat

iona

l age

for

each

gro

up e

stim

ated

from

the

mea

nsre

port

ed fo

r ea

ch o

fW

hite

’s c

lass

ifica

tion.

Feta

l mor

bidi

ty:

heal

thy

new

born

s –

i.v. g

luco

se <

48 h

,1

min

or s

ympt

om;

min

or s

ympt

oms

– i.v

.gl

ucos

e >

48 h

,<

5da

ys, o

ne o

r m

ore

of p

olyc

ytha

emia

,hy

perb

iliru

bina

emia

,hy

poca

lcae

mia

, lig

htre

spira

tory

dist

ress

synd

rom

e, b

irthw

eigh

t>

90th

per

cent

ile;

maj

or s

ympt

oms

– 2

or m

ore

sym

ptom

s of

birt

hwei

ght

>95

thpe

rcen

tile,

card

iom

yopa

thy,

hepa

tosp

leno

meg

aly,

seve

re r

espi

rato

rydi

stre

ss s

yndr

ome,

spas

ms,

i.v.

glu

cose

usua

lly >

5 da

ys.

Prem

atur

e -

deliv

ery

befo

re e

nd o

fge

stat

iona

l wee

k 37

Allo

catio

n to

tre

atm

ent

grou

ps: p

atie

nts

‘rand

omly

sel

ecte

dto

eac

h of

the

pro

cedu

res’

. No

furt

her

deta

ils. N

o de

tails

of

allo

catio

n co

ncea

lmen

tRu

n-in

-was

h ou

t pe

riod:

not

app

licab

leC

ompa

rabi

lity

of t

reat

men

t gr

oups

: age

and

dur

atio

n of

diab

etes

sim

ilar.

CSI

I had

mor

e cl

ass

D (p

<0.

05) a

nd le

sscl

ass

B (p

<0.

005)

tha

n M

DI (

Whi

te’s

cla

ssifi

catio

n).

Sim

ilarit

y of

bas

elin

e H

bA1

and

othe

r va

riabl

es n

ot r

epor

ted

Ana

lysis

: Sta

tes

‘rout

ine

stat

istic

al m

etho

ds’ u

sed.

No

furt

her

deta

ils. U

nits

for

birt

hwei

ght:

not

give

nSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: p

regn

ant

wom

en w

ith T

ype

1 di

abet

esO

utco

me

mea

sure

s: p

regn

ancy

com

plic

atio

ns, f

etal

out

com

e.Bl

ood

gluc

ose,

HbA

1an

d in

sulin

dos

e no

t re

port

edC

onfli

ct o

f int

eres

t: no

ne s

tate

d

Popu

latio

n: p

regn

ant

wom

en w

ith T

ype

1 di

abet

esw

ho a

tten

ded

the

hosp

ital n

o la

ter

than

the

firs

ttr

imes

ter

Excl

usio

n cr

iteria

: Typ

e 2

and

gest

atio

nal d

iabe

tes,

patie

nts

who

att

ende

d th

e ho

spita

l lat

er t

han

in t

hefir

st t

rimes

ter

CSI

I par

ticip

ants

:N

: 48

End

of s

tudy

: 48

Fem

ale:

100

%M

ean

age

(±SD

): 28

.4 (±

5.3)

yD

iabe

tes

dura

tion

mea

n (±

SD):

11.7

(±7.

4)y

MD

I par

ticip

ants

:N

: 41

End

of s

tudy

: 41

Fem

ale:

100

%M

ean

age

(±SD

): 28

.7 (±

4.7)

yD

iabe

tes

dura

tion

mea

n (±

SD):

9.9

(±8.

9) y

Base

line

valu

es: n

ot g

iven

. Sta

tes

that

pat

ient

s se

lect

edin

the

CSI

I or

MD

I gro

up h

ad n

orm

al m

ean

gluc

ose

and

HbA

1<

7.5%

at

leas

t fr

om t

he e

nd o

f the

firs

ttr

imes

ter

on.

Prev

ious

reg

imen

: not

sta

ted

for

eith

er g

roup

cont

inue

d


127


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Car

ta e

t al

.,19

8694

Italy,

sin

gle-

cent

re, R

CT

(par

alle

l)

Dur

atio

n:9

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

.M

icro

jet

MC

20

Trea

tmen

t 2:

MD

I+

reg

ular

(Act

rapi

d ×

4on

ly).

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: H

bA1

mea

sure

d ea

chtr

imes

ter

Allo

catio

n to

tre

atm

ent

grou

ps: n

o in

dica

tion

of m

etho

d of

rand

omisa

tion

Run-

in/w

ash-

out

perio

d: n

ot a

pplic

able

Com

para

bilit

y of

tre

atm

ent

grou

ps: s

imila

r ag

e. B

asel

ine

HbA

1no

t sig

nific

antly

diff

eren

t fo

r C

SII v

s M

DI a

rms

in b

oth

Type

1 a

nd T

ype

2. B

asel

ine

insu

lin r

equi

rem

ents

not

signi

fican

tly d

iffer

ent

in T

ype

1, b

ut n

ot p

rese

nted

for

Type

2A

naly

sis: s

igni

fican

ce o

f diff

eren

ce b

etw

een

resu

lts a

sses

sed

by m

eans

of 2

-tai

led

Stud

ents

t-t

est

for

unpa

ired

data

.Ba

selin

e H

bA1

and

HbA

1an

d so

me

insu

lin v

alue

s ex

trac

ted

from

figu

re b

y re

view

er. I

ndiv

idua

l pat

ient

bas

elin

e da

tapr

esen

ted,

mea

ns c

alcu

late

d by

rev

iew

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: P

regn

ant

wom

en w

ith T

ype

1 an

d 2

diab

etes

(ana

lyse

d se

para

tely

) who

had

dia

bete

s be

fore

pre

gnan

cyO

utco

me

mea

sure

s: in

sulin

req

uire

men

t, pe

rinat

al o

utco

me

and

glyc

aem

ic c

ontr

ol. W

eekl

y vi

sits

to o

utpa

tient

s w

here

insu

lin d

ose

adju

sted

Con

flict

of i

nter

est:

supp

orte

d by

Gra

nt o

f Reg

ione

Pie

mon

te

Popu

latio

n: p

regn

ant

diab

etic

wom

en –

cla

ssifi

ed a

sTy

pe 1

(15)

and

Typ

e 2

(14)

bef

ore

preg

nanc

yC

riter

ia: n

ot r

epor

ted

Type

I C

SII p

artic

ipan

ts:

N: 8

End

of s

tudy

: 8Fe

mal

e: 1

00%

Mea

n ag

e (m

in.–

max

.): 2

4.6

(17-

37) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

8.7

5%

Insu

lin: 3

1.5

IU/d

ay

Type

I M

DI p

artic

ipan

ts:

N: 7

End

of s

tudy

: 7Fe

mal

e: 1

00%

Mea

n ag

e (m

in.–

max

.): 2

5.9

(19–

32) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

9.1

%, p

= n

sIn

sulin

: 27.

8 IU

/day

, p=

ns

Type

1 p

revi

ous

regi

men

: 13

prev

ious

ly o

nco

nven

tiona

l, 2

CSI

I sta

rted

3–4

mon

ths

befo

reco

ncep

tion

Type

2 C

SII p

artic

ipan

ts:

N: 6

End

of s

tudy

: 6Fe

mal

e: 1

00%

Mea

n ag

e (m

in.–

max

.): 3

1.3

(25-

39) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

8.1

%

Type

2 M

DI p

artic

ipan

ts:

N: 8

End

of s

tudy

: 8Fe

mal

e: 1

00%

Mea

n ag

e (m

in.–

max

.): 2

9.4

(20–

46) y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

8.2

%, p

= n

s

Type

2 p

revi

ous

regi

men

: 4 t

akin

g or

al h

ypog

lyca

emic

sbe

fore

pre

gnan

cy, 1

0 tr

eate

d by

die

tary

mea

sure

s on

ly

cont

inue

d

Appendix 7

128

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Cou

stan

et

al.,

1986

93

USA

, sin

gle-

cent

re, R

CT

(par

alle

l)

Dur

atio

n:9

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

.A

utos

yrin

ge A

S-2C

, 6C

,6C

(U10

0); L

illy

CPI

-910

0

Trea

tmen

t 2:

MD

I+

reg

ular

(2–4

inte

rmed

iate

or

rapi

d-ac

ting

insu

lin)

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: s

ubje

ctiv

ehy

pos

reco

rded

indi

ary:

mild

(res

pond

edto

sel

f-ad

min

ister

edsn

ack)

, mod

erat

e(r

equi

ring

anot

her

pers

on’s

ass

istan

ce),

seve

re (r

equi

red

gluc

agon

or

intr

aven

ous

gluc

ose,

usua

lly in

em

erge

ncy

room

set

ting)

. HbA

1m

easu

red

at w

eekl

ycl

inic

visi

ts. P

tssw

itche

d to

cont

inuo

usin

trav

enou

s gl

ucos

ean

d in

sulin

infu

sion

whe

n ad

mitt

ed t

ola

bour

, ele

ctiv

e la

bour

or C

aesa

rean

sec

tion

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts r

ando

mise

d us

ing

seal

eden

velo

pes.

The

sub

ject

stu

died

dur

ing

2 pr

egna

ncie

s w

asra

ndom

ised

inde

pend

ently

eac

h tim

e an

d tr

eate

d w

ith C

SII

durin

g on

e pr

egna

ncy

and

MD

I dur

ing

othe

rRu

n-in

/was

h-ou

t pe

riod:

48

h on

exi

stin

g re

gim

en a

sin

patie

nt fo

r ba

selin

e da

ta. A

fter

rand

omisa

tion

rem

aine

d in

inpa

tient

for

up t

o 7

days

to

optim

ise c

ontr

ol o

n as

signe

dtr

eatm

ent

Com

para

bilit

y of

tre

atm

ent

grou

ps: t

able

of b

asel

ine

char

acte

ristic

s sh

ows

grou

ps t

o be

com

para

ble,

rep

orts

no

signi

fican

t di

ffere

nces

.A

naly

sis: m

eans

and

SD

pre

sent

ed. S

tude

nt’s

t-t

est

(pai

red

and

unpa

ired)

. Wilc

oxon

non

-pai

red

rank

-sum

tes

t. H

bA1

mon

th 2

dat

a ex

trac

ted

from

figu

reSa

mpl

e siz

e/po

wer

cal

cula

tion:

sam

ple

size

22 p

regn

anci

esal

low

ing

dete

ctio

n of

a d

iffer

ence

in a

vera

ge c

ircul

atin

ggl

ucos

e le

vels

betw

een

the

two

grou

ps o

f 17.

9m

g/dl

at

0.05

leve

l of s

igni

fican

ce a

nd 8

0% p

ower

, ass

umin

g an

SD

of

15m

g/dl

. Gro

ups

too

smal

l for

sta

tistic

ally

sig

nific

ant

diffe

renc

e in

mod

erat

e an

d se

vere

hyp

os t

o be

att

aine

d –

with

a p

ower

of 8

0% if

50%

in o

ne g

roup

and

90%

in t

heot

her

grou

p re

port

ed s

ympt

oms

29 p

atie

nts

wou

ld b

ere

quire

d in

eac

h gr

oup

Gen

eral

isabi

lity:

pre

gnan

t in

sulin

dep

ende

nt w

omen

Out

com

e m

easu

res:

HbA

1re

port

ed. H

ypos

rec

orde

d by

patie

nts.

Con

flict

of i

nter

est:

stud

y su

ppor

ted

by g

rant

6-2

60 fr

om t

heM

arch

of D

imes

Birt

h D

efec

ts F

ound

atio

n, g

rant

s RR

125

and

AM

2049

5 fr

om t

he N

IH a

nd g

rant

s fr

om t

he Ju

veni

leD

iabe

tes

Foun

datio

n, A

mer

ican

Dia

bete

s A

ssoc

iatio

n an

d th

eD

iabe

tes

Ass

ocia

tion

of G

reat

er F

all R

iver

, Mas

sach

uset

ts.

Insu

lin p

rovi

ded

by S

quib

b-N

ovo

Popu

latio

n: in

sulin

-dep

ende

nt d

iabe

tes.

Wom

en –

preg

nant

(15)

or

plan

ning

pre

gnan

cy (7

). 21

wom

enw

ith 2

2 pr

egna

ncie

sC

riter

ia: n

ot s

peci

fied

CSI

I par

ticip

ants

: N

: 11

End

of s

tudy

: 11

Fem

ale:

100

%M

ean

age

(±SD

): 29

(±3)

yrs

, min

. 26,

max

. 32

Base

line

valu

es: m

ean

(±SD

):H

bA1:

8.6

(±1.

7) %

In

sulin

: 0.9

(±0.

42) I

U/d

ay%

obe

se (>

20%

ove

r id

eal b

ody

wei

ght)

= 2

MD

I par

ticip

ants

:N

: 11

End

of s

tudy

: 11

Fem

ale:

100

%M

ean

age

(±SD

): 28

(±4)

y, m

in. 2

4, m

ax. 3

2Ba

selin

e va

lues

: mea

n (±

SD):

HbA

1: 9

.1 (±

1.5)

% ,

p=

ns

Insu

lin: 1

.05

(±0.

38) I

U/d

ay, p

= 0

.381

% o

bese

(>20

% o

ver

idea

l bod

y w

eigh

t) =

2

Prev

ious

reg

imen

: at

leas

t 2

daily

inje

ctio

ns o

f am

ixtu

re o

f rap

id-

and

inte

rmed

iate

-act

ing

insu

lins

(100

%)

cont

inue

d


129


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Nos

ari e

t al

.,19

9392

Italy,

sin

gle-

cent

re, R

CT

(par

alle

l)

Dur

atio

n:9

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

.M

icro

jet

20 o

rD

ahed

i BV

Trea

tmen

t 2:

MD

I+

reg

ular

(3 ×

solu

ble,

1 ×

inte

rmed

iate

)

Reas

on fo

r C

SII:

refe

rred

for

inte

nsiv

etr

eatm

ent

beca

use

preg

nant

(28)

or

plan

ning

to

beco

me

preg

nant

(4)

Ass

essm

ent

ofou

tcom

es: h

ypos

clas

sifie

d as

sev

ere

whe

n ch

arac

teris

ed b

yco

ma

or s

eizu

re o

rre

quiri

ngho

spita

lisat

ion

orin

trav

enou

s gl

ucos

e or

gluc

agon

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mly

allo

cate

d us

ing

seal

ed e

nvel

opes

. No

furt

her

info

rmat

ion

repo

rted

Run-

in/w

ash-

out

perio

d: n

ot a

pplic

able

Com

para

bilit

y of

tre

atm

ent

grou

ps: s

imila

r ag

e an

d BM

I, bu

tba

selin

e H

bA1c

, mea

n in

sulin

dos

e, d

urat

ion

of p

regn

ancy

of

rand

omisa

tion

not

repo

rted

Ana

lysis

: stu

dent

’s t

-tes

t or

χ2

anal

ysis

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted

Gen

eral

isabi

lity:

pre

gnan

t w

omen

with

Typ

e 1

diab

etes

Out

com

e m

easu

res:

HbA

1cre

port

ed. B

irthw

eigh

t as

sess

ed in

rela

tion

to g

esta

tiona

l age

, acc

ordi

ng t

o th

e na

tiona

lno

mog

ram

of i

ntra

uter

ine

feta

l gro

wth

Oth

er: 2

8 w

omen

wer

e pr

egna

nt w

hen

refe

rred

, but

dura

tion

of p

regn

ancy

whe

n ra

ndom

ised

not

repo

rted

Con

flict

of i

nter

est:

none

sta

ted

Popu

latio

n: c

lass

ified

with

Typ

e 1

diab

etes

bef

ore

preg

nanc

y. 3

1 w

omen

with

32

preg

nanc

ies

(16

in e

ach

arm

) inc

lude

d.C

riter

ia: n

ot r

epor

ted

CSI

I par

ticip

ants

: N

: 16

End

of s

tudy

: 16

Mea

n ag

e (±

SD):

25.5

(±7.

2) y

Dia

bete

s du

ratio

n: m

in. 3

.0, m

ax. 1

6.0

yBa

selin

e va

lues

: mea

n (±

SD):

BMI:

21.8

(±1.

6)kg

/m2

MD

I par

ticip

ants

:N

: 16

End

of s

tudy

: 16

Mea

n ag

e (±

SD):

27.3

(±12

) yD

iabe

tes

dura

tion:

min

. 3.0

, max

. 16.

0 y

Base

line

valu

es: m

ean

(±SD

):BM

I: 21

.6 (±

2.4)

kg/m

2

Prev

ious

reg

imen

: one

sta

rted

CSI

I 2–4

mon

ths

prio

rto

con

cept

ion,

15

had

at le

ast

2 da

ily in

ject

ions


131


Appendix 8

Summary of methodology: adolescents

Appendix 8

132

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Schi

ffrin

et

al.,

1984

97

Can

ada,

sin

gle-

cent

re,

rand

omise

dcr

osso

ver

[3 a

rms

– M

DI,

CSI

I, or

CSI

I at

nigh

t w

ithpr

epra

ndia

lsh

ort-

actin

gin

sulin

dur

ing

the

day

(CSI

I +M

DI)]

Dur

atio

n: C

SII 4

mon

ths,

MD

I4

mon

ths,

CSI

I+M

DI

4m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

. Mill

Hill

2703

Trea

tmen

t 2:

MD

I+

reg

ular

(3–4

×so

lubl

e, 1

×N

PH).

Trea

tmen

t 3:

CSI

I+

MD

I. C

SII

over

nigh

t w

ithpr

epra

ndia

lin

ject

ions

of s

hort

-ac

ting

insu

lindu

ring

the

day.

Pum

p us

ed fo

rpr

ebre

akfa

st b

olus

Oth

erin

terv

entio

ns: p

tsfo

llow

ed t

heC

anad

ian

Dia

bete

sA

ssoc

iatio

n Fo

odch

oice

s di

etsy

stem

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: o

nce-

mon

thly

fast

ing

bloo

dsa

mpl

es o

btai

ned

for

HbA

1Se

vere

hyp

os –

requ

ired

gluc

agon

Allo

catio

n to

tre

atm

ent

grou

ps: p

ts w

ere

said

to

bera

ndom

ised,

but

no

indi

catio

n of

ran

dom

isatio

n m

etho

d. N

oin

dica

tion

of a

lloca

tion

conc

ealm

ent

Run-

in/w

ash-

out

perio

d: n

one

Com

para

bilit

y of

tre

atm

ent

grou

ps: n

ot r

epor

ted

Ana

lysis

: tre

atm

ent

com

paris

ons

wer

e do

ne b

y 2-

way

AN

OVA

follo

wed

by

the

New

man

–Keu

ls te

st a

nd S

tude

nt’s

t-te

st fo

r pa

ired

data

. IT

T a

naly

sis n

ot c

arrie

d ou

t. H

bA1

data

pres

ente

d in

figu

re o

nly.

HbA

1da

ta e

xtra

cted

from

figu

re b

yre

view

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dole

scen

ts w

ith T

ype

1 di

abet

esO

utco

me

mea

sure

s: H

bA1

repo

rted

Reas

ons

for

with

draw

al: 1

CSI

I afte

r 3

mon

ths

and

1 M

DI

afte

r 1

wee

k (r

easo

n no

t sp

ecifi

ed);

refu

sed

to c

ross

ove

rfr

om C

SII (

n=

2)

Con

flict

of i

nter

est:

gran

t fr

om t

he Ju

veni

le D

iabe

tes

Foun

datio

n an

d th

e C

anad

ian

Dia

bete

s A

ssoc

iatio

n

Popu

latio

n: T

ype

1 pt

s ag

ed 1

3–20

y. P

revi

ously

had

faile

d to

res

pond

to

twic

e-da

ily in

ject

ions

with

hom

eBG

mon

itorin

g re

gim

e. P

ts h

ad n

ot b

een

on in

tens

ive

ther

apy

in t

he p

ast

and

wer

e no

t sig

nific

antly

obe

seC

riter

ia: n

ot r

epor

ted

Part

icip

ants

: N

: 24

End

of s

tudy

: 20

Age

(min

.–m

ax.):

13–

20 y

Dia

bete

s du

ratio

n, m

ean:

9 y

Base

line

valu

es: m

ean

(±SD

):H

bA1:

13

(±1)

%In

sulin

: 64

(±14

) IU

/day

Prev

ious

reg

imen

: tw

ice-

daily

inje

ctio

ns

cont

inue

d


133


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Tam

borla

ne e

tal

., 19

8996

USA

, sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: C

SII

6m

onth

s, M

DI

6m

onth

s

Trea

tmen

t 1:

CSI

I+

sol

uble

. Pum

pty

pe n

ot r

epor

ted

Trea

tmen

t 2:

MD

I+

reg

ular

. Ins

ulin

type

and

freq

uenc

y no

tre

port

ed

Reas

on fo

r C

SII:

not

repo

rted

Not

rep

orte

dA

lloca

tion

to t

reat

men

t gr

oups

: ran

dom

ly a

ssig

ned

to C

SII o

rM

DI a

fter

base

line

asse

ssm

ents

obt

aine

d an

d pt

s ad

mitt

ed t

oYa

le C

hild

ren’

s C

linic

al R

esea

rch

Cen

tre.

No

furt

her

deta

ils.

Allo

catio

n co

ncea

lmen

t no

t re

port

edRu

n-in

/was

h-ou

t pe

riod:

pts

rem

aine

d in

hos

pita

l 5–7

day

s to

optim

ise c

ontr

ol o

n as

signe

d tr

eatm

ent

regi

men

. Pts

read

mitt

ed t

o re

sear

ch c

entr

e to

cro

ssov

er t

reat

men

ts. N

ow

ash-

out

perio

d or

ana

lysis

of t

reat

men

t ef

fect

sC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: d

ata

pres

ente

d as

mea

n (S

E). S

E co

nver

ted

to S

Dby

rev

iew

er. A

naly

sis o

f var

ianc

e us

edSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: n

on-o

bese

ado

lesc

ents

who

wer

e pr

evio

usly

taki

ng ≤

2 da

ily in

sulin

inje

ctio

ns a

nd n

ot p

erfo

rmin

g fr

eque

ntbl

ood

gluc

ose

mon

itorin

g, t

here

fore

like

ly t

o be

poo

rlyco

ntro

lled

Out

com

e m

easu

res:

HbA

1an

d da

ily in

sulin

dos

e re

port

edD

ropo

uts/

with

draw

als:

not

rep

orte

dC

onfli

ct o

f int

eres

t: su

ppor

ted

by g

rant

s fr

om t

he N

atio

nal

Inst

itute

s of

Hea

lth a

nd t

he Ju

veni

le D

iabe

tes

Foun

datio

nIn

tern

atio

nal

Popu

latio

n: n

on-o

bese

ado

lesc

ents

with

Typ

e 1

diab

etes

,age

d 11

–20

y, h

ad d

iabe

tes

for

2–12

y.

Hei

ghts

wer

e w

ithin

ran

ge o

f nor

mal

with

one

exce

ptio

n. O

ne s

ubje

ct h

ad a

ttai

ned

full

pube

rtal

deve

lopm

ent

Incl

usio

n cr

iteria

: pts

wer

e dr

awn

from

the

Yal

eC

hild

ren’

s D

iabe

tes

Clin

ic a

nd w

ere

incl

uded

if t

hey

wer

e de

emed

to

be a

ble

to c

arry

out

the

tas

ks a

ndre

spon

sibili

ties

dem

ande

d by

the

stu

dy p

roto

col

Excl

usio

n cr

iteria

: pts

tak

ing

mor

e th

an 2

dai

ly in

sulin

inje

ctio

ns o

r pe

rfor

min

g fr

eque

nt s

elf-

bloo

d gl

ucos

em

easu

rem

ents

prio

r to

enr

olm

ent

Part

icip

ants

: N

: 10

Fem

ale:

50%

Age

(min

.–m

ax.):

11–

20 y

Dia

bete

s du

ratio

n (m

in.–

max

.): 2

–12

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1: 1

2.2

(±4.

1)%

In

sulin

: 1.1

(±0.

32) U

/day

Prev

ious

reg

imen

: con

vent

iona

l ins

ulin

tre

atm

ent

of n

otm

ore

than

2 in

ject

ions

/day


135


Appendix 9

Summary of methodology: analogue versus soluble insulin

Appendix 9

136

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Bode

et

al.,

2002

113

USA

, mul

ti-ce

ntre

, RC

T(p

aral

lel)

Dur

atio

n:4

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro

Trea

tmen

t 2:

CSI

I+

buf

fere

d re

gula

r

Trea

tmen

t 3:

CSI

I+

asp

art

Min

imed

/D

isetr

onic

506

or

507

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es:

HbA

1cta

ken

at w

eek

16. T

otal

dai

ly in

sulin

dose

for

wee

k be

fore

base

line

and

last

wee

kof

tre

atm

ent.

Hyp

osy

mpt

oms

and

adve

rse

even

ts r

ecor

ded

indi

ary.

Min

or h

ypo

=sy

mpt

oms

(pal

pita

tions

,tir

edne

ss, s

wea

ting,

stro

ng h

unge

r,di

zzin

ess,

tre

mor

, etc

.)co

nfirm

ed b

y BG

<50

mg/

dl a

nd a

ble

tode

al w

ith it

on

own.

Maj

or h

ypo

= B

G<

50 m

g/dl

and

sev

ere

cent

ral n

ervo

ussy

stem

dys

func

tion

prev

entin

g th

emtr

eatin

g th

emse

lves

or

adm

inist

ratio

n of

pare

nter

al g

luco

se o

rgl

ucag

on

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mly

ass

igne

d af

ter

run-

in (2

:2:1

) to

low

est

avai

labl

e ra

ndom

isatio

n nu

mbe

r to

aspa

rt, l

ispro

or

regu

lar.

Rand

omisa

tion

code

pro

vide

d by

Nov

o N

ordi

sk t

o en

sure

tha

t in

vest

igat

or a

nd s

ubje

ct w

ere

blin

ded

at p

oint

of r

ando

misa

tion

Run-

in/w

ash-

out

perio

d: 4

-wee

k ru

n-in

with

buf

fere

d re

gula

r.D

ose

adju

stm

ent

perio

d du

ring

4w

eeks

afte

r ra

ndom

isatio

n.C

ompa

rabi

lity

of t

reat

men

t gr

oups

: pat

ient

s ap

pear

sim

ilar

inag

e, s

ex, B

MI,

HbA

1c, i

nsul

in d

ose

but

stat

istic

s no

tpr

esen

ted

Ana

lysis

: bet

wee

n-tr

eatm

ent

com

paris

ons,

exc

ept

insu

linus

ed, m

ade

with

AN

CO

VA m

odel

with

tre

atm

ent

and

cent

reas

fixe

d ef

fect

s an

d co

rres

pond

ing

base

line

mea

sure

men

t as

cova

riate

. Las

t ob

serv

atio

n ca

rrie

d fo

rwar

d us

ed in

ana

lysis

of H

bA1c

, wei

ght

and

lipid

pro

file.

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted.

Gen

eral

isabi

lity:

adu

lts w

ith T

ype

1 di

abet

es w

ith a

t le

ast

3m

onth

s C

SII e

xper

ienc

eO

utco

me

mea

sure

s: fi

nal H

bA1c

mea

sure

s an

d SD

/SEM

/CI

not

pres

ente

d, c

hang

es fr

om b

asel

ine

only.

Rat

e of

hyp

os =

mea

n nu

mbe

r (S

D) o

f hyp

os r

epor

ted

by s

ubje

ct p

er 3

0da

ysfo

r al

l sub

ject

s in

the

tre

atm

ent

grou

p. ‘A

ll re

port

ed h

ypos

’ =re

gard

less

of B

G v

alue

. Dat

a ex

trac

ted

for

mai

nten

ance

perio

d on

ly (e

ntire

tria

l and

dos

e-ad

just

men

t pe

riod

valu

esal

so r

epor

ted)

Reas

ons

for

with

draw

al: w

ithdr

awal

of c

onse

nt, l

ack

ofco

mpl

ianc

e, lo

ss t

o fo

llow

-up,

inef

fect

ive

ther

apy

(num

bers

for

each

rea

son

not

spec

ified

): lis

pro

(1),

buffe

red

regu

lar

(9),

aspa

rt (3

); ad

vers

e ev

ent

– he

rpes

zos

ter

(1 a

spar

t).

Con

flict

of i

nter

est:

spon

sore

d by

Nov

o N

ordi

skPh

arm

aceu

tical

s, P

rince

ton,

NJ

Popu

latio

n: a

dults

age

d 18

–71

y w

ith T

ype

1 di

abet

es>

12m

onth

s an

d tr

eate

d w

ith C

SII c

ontin

uous

ly fo

rpr

evio

us 3

mon

ths

Excl

usio

n cr

iteria

: im

paire

d he

patic

, ren

al, o

r ca

rdia

cfu

nctio

n or

rec

urre

nt h

ypog

lyca

emia

. Wom

enpr

egna

nt, b

reas

t-fe

edin

g, o

r no

t us

ing

cont

race

ptio

n

Lisp

ro p

artic

ipan

ts:

N: 2

8En

d of

stu

dy: 2

7Fe

mal

e: 6

8%M

ean

age

(±SD

): 39

.9 (±

11.1

) yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.3 (±

0.7)

%

Insu

lin: 0

.5 (±

0.19

) U/k

gBM

I: 26

.3 (±

3.2)

kg/

m2

Buffe

red

regu

lar

part

icip

ants

:N

: 59

End

of s

tudy

: 50

Fem

ale:

68%

Mea

n ag

e (±

SD):

43.1

(±9.

4) y

Base

line

valu

es: m

ean

(±SD

):H

bA1c

: 7.5

(±0.

8)%

.In

sulin

: 0.6

(±0.

18) U

/kg

BMI:

25.9

(±3.

8) k

g/m

2

Asp

art

part

icip

ants

:N

: 59

End

of s

tudy

: 55

Fem

ale:

61%

Mea

n ag

e (±

SD):

42.3

(±12

) yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.3 (±

0.7)

%.

Insu

lin: 0

.7 (±

0.76

) U/k

gBM

I: 26

.7 (±

3.8)

kg/

m2

cont

inue

d


137


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Mel

ki e

t al

.,19

9811

6

Fran

ce, m

ulti-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: s

olub

le3

mon

ths,

lisp

ro3

mon

ths

Trea

tmen

t 1:

CSI

I+

sol

uble

(Act

rapi

d)

Trea

tmen

t 2:

CSI

I+

lisp

ro(H

umal

og)

Min

imed

506

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: h

ypos

,te

chni

cal o

r m

etab

olic

inci

dent

s, e

.g.

keto

nuria

, rec

orde

d in

note

book

. Num

ber

ofhy

pos

defin

ed b

y BG

<3.

0m

mol

/l or

ver

ylo

w B

G <

2.0

mm

ol/l

note

d at

mon

thly

visit

s. S

atisf

actio

nqu

estio

nnai

re a

t en

dof

stu

dy. L

ast

30 d

ays

of 1

st p

erio

d an

alys

ed

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

run-

in. N

ofu

rthe

r de

tails

Run-

in/w

ash-

out

perio

d: 4

wee

k ru

n-in

of C

SII +

reg

ular

prio

r to

ran

dom

isatio

n. A

naly

sis o

f HbA

1cpe

rfor

med

onl

ydu

ring

first

per

iod

due

to a

car

ryov

er e

ffect

. Ana

lysis

of

hypo

s re

stric

ted

to la

st 3

0 da

ys o

f firs

t pe

riod

to a

void

conf

usio

n du

e to

car

ryov

er e

ffect

Com

para

bilit

y of

tre

atm

ent

grou

ps: H

bA1c

repo

rted

for

each

grou

p at

bas

elin

e, n

o fu

rthe

r de

tails

. Pos

sibili

ty o

f bia

s as

seco

nd p

erio

d ig

nore

d fo

r an

alys

is of

hyp

os a

nd H

bA1c

Ana

lysis

: not

ITT

ana

lysis

. Mea

ns (S

E) r

epor

ted.

SD

calc

ulat

ed b

y re

view

er. A

ll te

sts

2-ta

iled.

Com

paris

ons

for

base

line

char

acte

ristic

s us

ed χ

2or

Fish

er’s

exa

ct t

est.

AN

OVA

for

cont

inuo

us v

aria

bles

app

lied

for

cros

sove

r st

udy

with

per

iod,

tre

atm

ent

grou

p an

d in

tera

ctio

n fa

ctor

s. In

cas

eof

sig

nific

ant

inte

ract

ion

or c

arry

over

effe

ct, o

nly

the

first

perio

d w

as u

sed

in c

ompa

rison

s. C

ateg

oric

al d

ata

com

pare

dby

sig

n te

st b

etw

een

perio

ds a

nd b

etw

een

trea

tmen

t gr

oups

.St

udy

cond

ucte

d in

5 c

entr

es, i

nter

cent

re v

aria

bilit

y no

tas

sess

edSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

Typ

e 1

diab

etes

who

hav

e us

ed a

pum

p fo

r at

leas

t 1

year

Reas

ons

for

with

draw

al: p

erso

nal r

easo

ns a

nd la

ck o

fpr

otoc

ol c

ompl

ianc

e (n

= 1

)C

onfli

ct o

f int

eres

t: st

udy

supp

orte

d by

Lill

y Fr

ance

Popu

latio

n: a

dults

with

Ty

pe 1

dia

bete

s ag

ed 1

8–60

y, t

reat

ed b

y C

SII w

ithre

gula

r in

sulin

for

at le

ast

1 y

befo

re e

nrol

men

tC

riter

ia: H

bA1c

<8.

5%, n

egat

ive

C-p

eptid

e re

spon

se,

anti-

insu

lin a

ntib

odie

s <

70%

. Non

e ha

d un

trea

ted

retin

opat

hy, i

mpa

ired

rena

l fun

ctio

n, g

astr

icne

urop

athy

, BM

I>30

, dai

ly in

sulin

dos

e >

2IU

/kg,

hist

ory

of h

ypo

unaw

aren

ess

or s

ever

e di

seas

e th

atco

uld

inte

rfer

e w

ith s

tudy

Part

icip

ants

: N

: 39

End

of s

tudy

: 38

Fem

ale:

43.

6%M

ean

age

(±SD

): 39

.4 (±

9.4)

yD

iabe

tes

dura

tion

mea

n (±

SD):

22.5

(±10

) yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.84

(±0.

75)%

(HbA

1cso

lubl

e 7.

74 ±

1.23

; lisp

ro 7

.97

±0.

8)In

sulin

: 0.5

7 (±

0.12

) IU

/day

BMI:

24.4

(±2.

5) k

g/m

2

cont

inue

d

Appendix 9

138

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Rask

in e

t al

.,20

0111

7

USA

,m

ultic

entr

e,ra

ndom

ised

cros

sove

r

Dur

atio

n: li

spro

3m

onth

s, s

olub

le3

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro(H

umal

og)

Trea

tmen

t 2:

CSI

I+

sol

uble

(Vel

osul

in)

Min

imed

504

,50

4-S,

506

or

507

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: h

ypos

reco

rded

in d

iary

: pt

belie

ved

(or

othe

rpe

rson

obs

erve

d) t

hey

wer

e ex

perie

ncin

g at

leas

t on

e sig

n or

sym

ptom

ass

ocia

ted

with

hyp

o, o

r BG

<3.

0m

mol

/l. H

yper

= 2

or

mor

e BG

>13

.8m

mol

/l in

2–4

hno

t re

spon

ding

to

insu

lin b

olus

es o

rot

herw

ise u

nexp

lain

ed

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

run-

in.

Stat

es t

hat

‘rand

omisa

tion

was

suc

h th

at t

here

wou

ld b

eap

prox

imat

ely

equa

l num

bers

of p

ts in

eac

h tr

eatm

ent

sequ

ence

at

each

inve

stig

ativ

e sit

e’. N

o fu

rthe

r de

tails

giv

enRu

n-in

/was

h-ou

t pe

riod:

2–4

wee

k ru

n-in

with

reg

ular

insu

lin. N

o w

ash-

out

perio

d. N

o ca

rryo

ver

or in

vest

igat

oref

fect

s di

scov

ered

by

AN

OVA

, the

refo

re d

ata

from

trea

tmen

t pe

riods

com

bine

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: dat

a pr

esen

ted

for

both

grou

ps. S

imila

r in

pro

port

ion

of fe

mal

es, a

ge, w

eigh

t an

ddu

ratio

n of

dia

bete

s, b

ut s

tatis

tical

ana

lysis

not

pre

sent

ed.

No

signi

fican

t di

ffere

nce

in H

bA1c

Ana

lysis

: sta

tes

that

ITT

ana

lysis

per

form

ed. 2

-tai

led

test

s,sig

nific

ance

leve

l 0.0

5. A

NO

VA u

sed

to e

xam

ine

for

carr

yove

r, in

vest

igat

or o

r tr

eatm

ent

effe

cts.

Mul

ticen

tre:

inve

stig

ator

effe

cts

asse

ssed

by

AN

OVA

and

non

e id

entif

ied

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted

Gen

eral

isabi

lity:

Typ

e 1

diab

etes

with

acc

epta

ble

com

plia

nce

and

at le

ast

6 m

onth

s w

ith C

SII

Out

com

e m

easu

res:

HbA

1cm

easu

red

at e

nd o

f eac

htr

eatm

ent

perio

d. In

sulin

dos

es u

sed

on d

ay b

efor

e ea

chcl

inic

visi

t (e

very

6 w

eeks

) rec

orde

d in

dia

ryRe

ason

s fo

r w

ithdr

awal

: per

sona

l rea

sons

(n=

1).

Con

flict

of i

nter

est:

Spon

sore

d by

Eli

Lilly

and

Com

pany

Popu

latio

n: T

ype

1 di

abet

es a

ge 1

3–60

y w

ho h

adac

hiev

ed a

ccep

tabl

e co

mpl

ianc

e w

ith in

sulin

pum

psth

erap

y an

d a

nutr

ition

al r

egim

en a

nd h

ad b

een

trea

ted

with

CSI

I for

at

leas

t 6

mon

ths

Excl

usio

n cr

iteria

: tot

al g

lyca

ted

haem

oglo

bin

valu

es o

rH

bA1c

>2.

0 tim

es u

pper

lim

it of

nor

mal

ran

ge,

clin

ical

ly s

igni

fican

t re

nal,

hepa

tic o

r ca

rdia

c di

seas

e,ca

ncer

, dru

g or

alc

ohol

abu

se, i

nsul

in a

llerg

y, r

ecur

rent

seve

re h

ypog

lyca

emia

, ana

emia

, life

exp

ecta

ncy

<3

y,la

ctat

ing,

pre

gnan

t or

inte

ndin

g to

bec

ome

preg

nant

or

requ

ire d

ilutio

n of

insu

lin in

pum

p. 3

pts

disc

ontin

ued

befo

re r

ando

misa

tion

(2 fo

r pe

rson

al r

easo

ns, 1

faile

dto

mee

t cr

iteria

)

N: 5

9En

d of

stu

dy: 5

8.Se

quen

ce li

spro

the

n re

gula

r in

sulin

: En

d of

stu

dy: 2

8Fe

mal

e: 4

2.9%

Mea

n ag

e (±

SD):

40.5

(±8.

7) y

Dia

bete

s du

ratio

n m

ean

(±SD

): 18

.8 (±

7.6)

yBa

selin

e va

lues

: mea

n (±

SD):

HbA

1c: 7

.9 (±

1.1)

%

Wei

ght:

78.3

(±17

.9) k

g.

Sequ

ence

reg

ular

the

n in

sulin

lisp

ro:

End

of s

tudy

: 30

Fem

ale:

53.

3%M

ean

age

(±SD

): 37

.8 (±

9.7)

yD

iabe

tes

dura

tion

mea

n (±

SD):

17.4

(±8.

5) y

Base

line

valu

es: m

ean

(±SD

):H

bA1c

: 7.6

(±0.

8)%

, p=

0.2

34.

Wei

ght:

77.3

(±16

.7) k

g

Prev

ious

reg

imen

: 2–4

wee

ks r

un-in

with

CSI

I +re

gula

r in

sulin

cont

inue

d


139


Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Renn

er e

t al

.,19

9911

4

Ger

man

y,m

ultic

entr

e,ra

ndom

ised

cros

sove

r

Dur

atio

n: li

spro

4m

onth

s, s

olub

le4

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro(H

umal

og).

Min

imed

506

Trea

tmen

t 2:

CSI

I+

sol

uble

(Hum

insu

lin).

Dise

tron

ic H

tron

-10

0

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: h

ypo:

<3.

5m

mol

/l an

d/or

sym

ptom

s, r

ecor

ded

in d

iary

. Dia

bete

sTr

eatm

ent

Satis

fact

ion

Que

stio

nnai

reco

mpl

eted

at

begi

nnin

g an

d en

d of

each

tre

atm

ent

arm

,m

axim

um s

core

48

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

run-

in. N

ofu

rthe

r de

tails

Run-

in/w

ash-

out

perio

d: 4

wee

ks r

un-in

with

CSI

I + r

egul

arin

sulin

. No

was

h-ou

t. Tr

eatm

ent

orde

r ef

fect

not

rep

orte

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: A

NO

VA w

ith p

ts, t

reat

men

t an

d pe

riod

term

s.Fr

iedm

an’s

ran

k-su

m t

est

if no

t no

rmal

ly d

istrib

uted

(HbA

1c,

patie

nt p

refe

renc

e). F

requ

ency

of h

ypos

and

cat

hete

roc

clus

ions

use

d M

cNem

ar’s

tes

t. In

sulin

dos

e ca

lcul

ated

by

revi

ewer

from

mea

ns o

f 7 r

epor

ted

mea

l-rel

ated

bas

al a

ndbo

lus

valu

es. T

otal

bas

elin

e an

d 4-

mon

th in

sulin

cal

cula

ted

byre

view

erSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: w

ell-c

ontr

olle

d Ty

pe 1

dia

bete

s w

ith a

t le

ast

6 m

onth

s C

SII u

seO

utco

me

mea

sure

s: D

iabe

tes

Trea

tmen

t Sa

tisfa

ctio

nQ

uest

ionn

aire

rep

orte

d to

be

valid

ated

Oth

er: t

otal

insu

lin d

ose

calc

ulat

ed b

y re

view

er fr

om b

asal

brea

kfas

t, lu

nch

and

dinn

er; b

olus

bre

akfa

st lu

nch

and

dinn

er;

and

snac

ksC

onfli

ct o

f int

eres

t: 2

auth

ors

hold

sto

ck in

and

/or

rece

ived

hono

raria

from

Min

iMed

and

/or

Eli L

illy.

A 3

rd a

utho

rre

ceiv

ed g

rant

and

res

earc

h su

ppor

t fr

om E

li Li

lly

Popu

latio

n: T

ype

1 di

abet

es >

2 y

and

trea

tmen

t w

ithC

SII f

or a

t le

ast

6 m

onth

sEx

clus

ion

crite

ria: k

now

n in

sulin

alle

rgy,

car

diov

ascu

lar

or c

ereb

rova

scul

ar s

ympt

oms

of a

ther

scle

rosis

, can

cer,

rena

l or

hepa

tic fa

ilure

, sig

ns o

f dru

g ab

use,

life

-th

reat

enin

g di

seas

e, p

regn

ant,

lact

atin

g or

pla

nnin

gpr

egna

ncy

Part

icip

ants

: N

: 113

End

of s

tudy

: 113

Fem

ale:

46.

9%M

ean

age

(±SD

): 37

.1 (±

11.6

) yD

iabe

tes

dura

tion

mea

n (±

SD):

19.1

(±9.

2) y

Base

line

valu

es: m

ean

(±SD

):H

bA1c

: 7.2

4 (±

1)%

Insu

lin: 8

3.4

IU/d

ay (c

alcu

late

d by

rev

iew

er)

BMI:

24.7

(±1.

1) k

g/m

2

Prev

ious

reg

imen

: CSI

I, du

ratio

n 5.

3 ±

3.9

y

cont

inue

d

Appendix 9

140

Stud

yIn

terv

enti

ons

Subj

ects

Out

com

e m

easu

res

Met

hodo

logy

Zin

man

et

al.,

1997

118

Can

ada,

sin

gle-

cent

re,

rand

omise

dcr

osso

ver

Dur

atio

n: li

spro

3m

onth

s, s

olub

le3

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro

Trea

tmen

t 2:

CSI

I+

sol

uble

(Hum

ulin

)

Dise

tron

ic H

tron

V100

.

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es: i

nsul

in d

ose

and

hypo

s re

cord

ed in

diar

y. H

bA1c

mea

sure

dm

onth

ly. H

ypo

= B

G<

3m

mol

/l or

sym

ptom

s. B

efor

era

ndom

isatio

nfr

eque

ncy

12.7

(8.8

)ep

isode

s/30

day

s, o

r if

conf

irmed

by

BG 8

.4(7

.1)/

30da

ys. S

ever

ehy

pos

as d

efin

ed b

yD

CC

T

Allo

catio

n to

tre

atm

ent

grou

ps: d

oubl

e-bl

ind.

Ran

dom

ised

afte

r ru

n-in

Run-

in/w

ash-

out

perio

d: 1

6 pt

s on

MD

I sw

itche

d to

CSI

I +re

gula

r 3

mon

ths

befo

re r

ando

misa

tion.

All

pts

rece

ived

CSI

I+

reg

ular

for

1 m

onth

run

-inC

ompa

rabi

lity

of t

reat

men

t gr

oups

: not

rep

orte

dA

naly

sis: A

NO

VA u

sed

mod

els

with

tre

atm

ent

sequ

ence

(stu

dy g

roup

), pe

riod

and

trea

tmen

t te

rms.

Ord

inal

var

iabl

esw

ith W

ilcox

on’s

ran

k-su

m t

est

(tre

atm

ent

sequ

ence

, per

iod

and

trea

tmen

t te

rm e

valu

ated

in t

hree

sep

arat

e an

alys

es).

Cat

egor

ical

var

iabl

es u

sed

χ2 , McN

emar

’s a

nd/o

r Fi

sher

’sex

act

test

sSa

mpl

e siz

e/po

wer

cal

cula

tion:

not

rep

orte

dG

ener

alisa

bilit

y: a

dults

with

Typ

e 1

diab

etes

pre

viou

sly o

nin

tens

ive

insu

lin t

hera

py o

r C

SII

Con

flict

of i

nter

est:

supp

orte

d by

an

unre

stric

ted

rese

arch

gran

t fr

om E

li Li

lly C

anad

a

Popu

latio

n: a

dults

with

Typ

e 1

diab

etes

and

at

leas

t 3

mon

ths

with

CSI

I. N

one

had

signi

fican

t en

doge

nous

insu

lin s

ecre

tion

as a

sses

sed

by t

he m

easu

rem

ent

offa

stin

g C

-pep

tide

(<0.

02 n

mol

/l)Ex

clus

ion

crite

ria: s

ever

e re

tinop

athy

or

neur

opat

hy,

>1

seve

re p

ast

year

. Mild

to

mod

erat

e re

tinop

athy

was

pre

sent

in 1

6 (5

3%),

mild

to

mod

erat

ene

urop

athy

in 1

2 (4

0%)

Part

icip

ants

: N

: 30

End

of s

tudy

: 30

Fem

ale:

56.

7%M

ean

age

(±SD

): 35

.1 (±

8.2)

y, m

in. 2

6, m

ax. 5

1D

iabe

tes

dura

tion

mea

n (±

SD):

17.5

(±8.

8) y

, min

. 6,

max

. 44

Base

line

valu

es: m

ean

(±SD

):H

bA1c

: 8.0

3 (±

0.71

)%

BMI:

24.8

(±2.

7) k

g/m

2

Wei

ght:

72.7

(±9.

9) k

gPr

evio

us r

egim

en: 1

4 on

CSI

I>3

mon

ths.

Inte

nsifi

edin

sulin

the

rapy

with

pen

(7) o

r sy

ringe

(9) b

efor

esw

itchi

ng t

o C

SII +

reg

ular

insu

lin 3

mon

ths

prio

r to

rand

omisa

tion

Schm

auss

et

al.,

1998

115

Ger

man

y, s

ingl

e-ce

ntre

,ra

ndom

ised

cros

sove

r

Dur

atio

n: li

spro

3m

onth

s, s

olub

le3

mon

ths

Trea

tmen

t 1:

CSI

I+

lisp

ro(H

umal

og)

Trea

tmen

t 2:

CSI

I+

sol

uble

(Hum

ulin

)

Dise

tron

ic H

tron

V100

Reas

on fo

r C

SII:

not

repo

rted

Ass

essm

ent

ofou

tcom

es:

hypo

s an

d ad

vers

eev

ents

rec

orde

d at

clin

ic v

isits

.H

ypos

= B

G<

3.5

mm

ol/l

Allo

catio

n to

tre

atm

ent

grou

ps: r

ando

mise

d af

ter

run-

in, n

ofu

rthe

r de

tails

Run-

in/w

ash-

out

perio

d: r

un-in

per

iod

4w

eeks

. No

was

h-ou

tTr

eatm

ent

orde

r ef

fect

: not

disc

usse

dC

ompa

rabi

lity

of t

reat

men

t gr

oups

: HbA

1cat

ran

dom

isatio

ngi

ven

for

each

gro

up, n

o fu

rthe

r de

tails

Ana

lysis

: AN

OVA

with

rep

eate

d m

easu

res

appl

ied

toev

alua

te t

he in

fluen

ce o

f gro

up a

nd t

ime

on c

ontin

uous

varia

bles

. Wilc

oxon

ran

k te

st fo

r hy

pos.

Mea

n (S

EM)

pres

ente

d. S

D c

alcu

late

d by

rev

iew

er. H

bA1c

at e

nd o

fpe

riods

1 a

nd 2

for

each

tre

atm

ent

aver

aged

by

revi

ewer

Sam

ple

size/

pow

er c

alcu

latio

n: n

ot r

epor

ted

Gen

eral

isabi

lity:

adu

lts w

ith w

ell-c

ontr

olle

d Ty

pe 1

dia

bete

s,w

ith a

t le

ast

6 m

onth

s C

SII u

se a

nd n

o se

vere

dia

betic

com

plic

atio

nsO

utco

me

mea

sure

s: H

bA1c

reco

rded

at

end

of r

un-in

,cr

osso

ver

and

end

of s

tudy

Con

flict

of i

nter

est:

supp

orte

d by

an

unre

stric

ted

rese

arch

gran

t fr

om E

li Li

lly, G

erm

any

Popu

latio

n: w

ell-c

ontr

olle

d Ty

pe 1

dia

bete

s, u

se o

fin

tens

ified

insu

lin t

hera

py a

t le

ast

2y,

with

CSI

I for

at

leas

t 6

mon

ths

prio

r to

stu

dy. A

ge 1

8–65

y.

Excl

usio

n cr

iteria

: kno

wn

alle

rgy

to in

sulin

, sev

ere

com

plic

atio

ns o

f dia

bete

s, in

adeq

uate

met

abol

icco

ntro

l (H

bA1c

>10

%),

life-

thre

aten

ing

dise

ase,

dru

gab

use,

wom

en p

regn

ant

or p

lann

ing

preg

nanc

y

Part

icip

ants

: N

: 11

End

of s

tudy

: 11

Fem

ale:

54.

5%M

ean

age

(±SD

): 30

(±8.

3) y

Dia

bete

s du

ratio

n m

ean

(±SD

): 14

(±3.

3) y

Base

line

valu

es: m

ean

(±SD

):Li

spro

HbA

1c: 6

.3 (±

0.7)

%

Solu

ble

HbA

1c: 6

.7 (±

1.3)

%, p

= n

sBM

I: 24

(±3.

3) k

g/m

2


141


Appendix 10

Summary of results: adults with Type 1 diabetes

Appendix 10

142

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Bak

et a

l.,19

8787

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

6m

onth

s,M

DI

6m

onth

sN

: 20

End

of s

tudy

:16

CSI

I + s

olub

leM

onth

: 6M

ean:

46.

6U

/day

SD: 1

0

Mon

th: 6

Mea

n: 7

6.6

kgSD

: 9.6

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dFr

eedo

m fr

om in

ject

ions

: 44%

75%

disc

omfo

rted

by

butt

erfly

nee

dle

(on

CSI

I), 5

6% d

iscom

fort

ed b

y in

fuse

rits

elf a

t ho

me,

21%

disc

omfo

rted

by

infu

ser

at w

ork

QoL

: not

rep

orte

d

Mod

erat

e hy

po: 2

.3 (%

of B

Gva

lues

bel

ow 4

mm

ol/l)

Seve

re h

ypo:

1 (r

equi

ring

hosp

ital t

reat

men

t)D

KA

: 0

Gly

cate

d H

b: n

otre

port

edBl

ood

gluc

ose:

Mon

th: 6

Mea

n: 7

.7SD

: 0.7

Bode

et

al.,

1996

81

Non

-ra

ndom

ised

cros

sove

rD

urat

ion:

MD

I min

. of

12 m

onth

s.C

SII m

ean

37m

onth

s.N

: 55

CSI

I + s

olub

leM

onth

: 12

Mea

n: 3

6.4

U/d

aySD

: 12.

1M

onth

: 24

Mea

n: 3

9.6

U/d

aySD

: 14.

4M

onth

: 36

Mea

n: 3

7.7

U/d

aySD

: 13.

1M

onth

: 48

Mea

n: 3

7.8

U/d

aySD

: 14.

2N

ote:

N=

54

(12

mon

ths)

; 38

(24

mon

ths)

; 25

(36

mon

ths)

; 19

(48

mon

ths)

Mon

th: 1

2M

ean:

68.

1kg

SD: 1

4.1

Mon

th: 2

4M

ean:

69.

7kg

SD: 1

5.2

Mon

th: 3

6M

ean:

70.

0kg

SD: 1

4.6

Mon

th: 4

8M

ean:

68

kgSD

: 15.

2N

ote:

N=

55

(12

mon

ths)

; 41

(24

mon

ths)

; 25

(36

mon

ths)

; 19

(48

mon

ths)

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dQ

oL: n

ot r

epor

ted

Seve

re h

ypo:

12

Not

e: h

ypo

even

ts p

er 1

00pa

tient

yea

rs (n

), sig

nific

ance

from

MD

I: 12

mon

ths

22 (5

5),

p<

0.00

01; 2

4m

onth

s 26

(50)

, p<

0.01

; 36

mon

ths

39(3

3), p

<0.

0001

; 48

mon

ths

36 (2

5), p

<0.

01.

Of 2

5 pt

s w

ith H

bA1c

≥8.

0%,

rate

of s

ever

e hy

pos

decl

ined

signi

fican

tly, f

rom

84

even

tspe

r 10

0 pa

tient

yea

rs a

tba

selin

e (M

DI)

to 8

eve

nts

inye

ar 1

(p<

0.00

01).

The

30

pts

with

bas

elin

e H

bA1c

<8.

0% a

lso e

xper

ienc

ed a

decl

ine,

from

183

to

33se

vere

hyp

os p

er 1

00 p

atie

ntye

ars

(p=

0.00

05).

DK

A r

ates

wer

e no

tsig

nific

antly

diff

eren

t be

twee

nM

DI a

nd C

SII p

hase

s (1

4.6

vs7.

2ev

ents

per

100

pat

ient

year

s, r

espe

ctiv

ely)

HbA

1cre

port

edM

onth

: 12

Mea

n: 7

.4%

SD: 1

.2M

onth

: 24

Mea

n: 7

.7%

SD: 1

.7M

onth

: 36

Mea

n: 7

.4%

SD: 1

.7M

onth

: 48

Mea

n: 7

.4%

SD: 1

.2N

ote:

N=

55

(12

mon

ths)

; 41

(24

mon

ths)

; 26

(36

mon

ths)

; 20

(48

mon

ths)

MD

I +re

gula

rM

onth

: 6M

ean:

51.

9 U

/day

SD: 1

2.9

Sign

ifica

nce:

p<

0.0

5

Mon

th: 6

Mea

n: 7

4.8

kgSD

: 9.7

Sign

ifica

nce:

p<

0.0

1

Not

repo

rted

Pref

errin

g: 8

0% w

ante

d to

con

tinue

with

MD

I95

% fo

und

pen

easy

to

hand

le, 3

0%hi

gh fr

eque

ncy

of in

ject

ions

disa

dvan

tage

Of t

otal

: ind

epen

denc

e of

fixe

dm

ealti

mes

an

adva

ntag

e w

ith M

DI a

ndC

SII b

y 85

%Q

oL: n

ot r

epor

ted

Mod

erat

e hy

po: 4

.1 (%

of B

Gva

lues

bel

ow 4

mm

ol/l)

, p

< 0

.02

Seve

re h

ypo:

0D

KA

: 0

Bloo

d G

luco

se:

Mon

th: 6

Mea

n: 7

.9SD

: 0.7

Sign

ifica

nce:

p=

ns

cont

inue

d


143


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

MD

I +re

gula

r M

onth

: 12

Mea

n: 4

2.9

U/d

aySD

: 17.

9Si

gnifi

canc

e: p

= n

s

Mon

th: 1

2M

ean:

67.

4kg

SD: 1

4.4

Sign

ifica

nce:

p=

ns

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

d Q

oL: n

ot r

epor

ted

Seve

re h

ypo:

76

MD

I: hy

po e

vent

s pe

r 10

0pa

tient

yea

rs (n

):138

(55)

HbA

1cre

port

ed

Mon

th: 1

2M

ean:

7.7

%SD

: 1.5

Sign

ifica

nce:

p=

ns

Not

e: a

sig

nific

ant

impr

ovem

ent

in m

ean

HbA

1cfr

om b

asel

ine

(MD

I) to

yea

r 1

was

seen

with

pat

ient

s w

hoha

d un

acce

ptab

legl

ycae

mic

con

trol

at

base

line

(MD

I), d

efin

edas

HbA

1c≥

8.0%

(8.9

±0.

8% v

s 8.

1 ±

1.0%

,p

= 0

.000

4). I

n co

ntra

st,

the

30 p

atie

nts

who

had

bett

er g

lyca

emic

con

trol

at b

asel

ine,

def

ined

as

HbA

1c<

8.0%

sho

wed

no s

igni

fican

t di

ffere

nce

in c

ontr

ol fr

om b

asel

ine

to y

ear

1 (6

.7 ±

1.1%

vs 6

.8 ±

1.2%

, p=

ns)

cont

inue

d

Appendix 10

144

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Brin

chm

ann-

Han

sen

et a

l.,19

8876

,78

RCT

(par

alle

l)D

urat

ion:

CSI

I mea

n40

mon

ths

(24–

60).

MD

I mea

n41

mon

ths

(21–

47)

CSI

I N: 1

5M

DI N

: 15

CSI

I + s

olub

leM

onth

: 24

Mea

n: 0

.68

U/k

gSD

: 0.1

9 (S

EM 0

.05)

Mon

th: 2

4M

ean:

70.

5kg

SD: 8

.9 (S

EM 2

.3)

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dQ

oL: n

ot r

epor

ted

Hyp

ogly

caem

ia m

ean

(SEM

)va

lues

: (%

of h

ome

BG<

2.5

mm

ol/l)

: at

rand

omisa

tion

= 6

(2),

afte

r2

year

s =

11

(2),

p<

0.05

.Sy

mpt

omat

icep

isode

s/w

eek/

patie

nt: a

tra

ndom

isatio

n =

2.3

(0.6

); at

2ye

ars

= 1

.7 (0

.3)

Hyp

o co

ma:

2 (2

) D

KA

: 2Su

bcut

aneo

us a

bsce

ss: 8

(6)

Retin

opat

hy =

impr

oved

(14%

), un

chan

ged

(29%

),w

orse

ned

(57%

) (on

e pa

tient

had

an a

llerg

y to

fluo

resc

ein)

HbA

1re

port

ed

Mon

th: 3

Mea

n: 8

.9%

Mon

th: 6

Mea

n: 9

.2%

Mon

th: 1

2M

ean:

8.5

%M

onth

: 24

Mea

n: 8

.7%

SD: 1

.16

Mon

th: 4

1 M

ean:

9.1

%

MD

I +re

gula

rM

onth

: 24

Mea

n: 0

.72

U/k

gSD

: 0.1

2 (S

EM 0

.03)

Sign

ifica

nce:

p=

ns

Mon

th: 2

4M

ean:

75.

1kg

SD: 1

1.2

(SEM

2.9

)Si

gnifi

canc

e: p

= n

s

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dQ

oL: n

ot r

epor

ted

Hyp

ogly

caem

ia m

ean

(SEM

)va

lues

: (%

of h

ome

BG<

2.5

mm

ol/l)

: at

rand

omisa

tion

= 8

(3),

afte

r2

year

s =

7 (1

), p

= n

s.Sy

mpt

omat

icep

isode

s/w

eek/

patie

nt: a

tra

ndom

isatio

n =

1.5

(0.3

); at

2ye

ars

= 1

.2 (0

.2).

Hyp

o co

ma:

14

(6) v

s C

SII,

p<

0.00

1.D

KA

: 0 (v

s C

SII,

p=

ns)

Subc

utan

eous

abs

cess

: 0 v

sC

SII,

p <

0.0

1Re

tinop

athy

= im

prov

ed(7

%),

unch

ange

d (4

3%),

wor

sene

d (5

0%) (

one

patie

ntha

d an

alle

rgy

to fl

uore

scei

n)

HbA

1re

port

ed

Mon

th: 3

Mea

n: 8

.7%

Mon

th: 6

Mea

n: 8

.8%

Mon

th: 1

2M

ean:

8.5

%M

onth

: 24

Mea

n: 9

.1%

SD: 1

.55

Mon

th: 4

1M

ean:

9.4

%

cont

inue

d


145


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Chi

asso

n,

et a

l., 1

98482

Non

-ra

ndom

ised

cros

sove

rD

urat

ion:

CSI

I3

mon

ths,

MD

I3

mon

ths

N=

12

CSI

I + s

olub

leM

onth

: 3M

ean:

43.

9 U

/day

SD: 1

0

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: 7

(58%

)Q

oL: n

ot r

epor

ted

Not

rep

orte

dH

bA1

repo

rted

M

onth

: 3M

ean:

9.1

%SD

: 1.0

4

Haa

kens

et

al.,

199

083

Non

-ra

ndom

ised

cros

sove

rD

urat

ion:

CSI

I6

mon

ths,

MD

I 6m

onth

sN

: 52

End

of s

tudy

:35

CSI

I + s

olub

leM

onth

: 6M

ean:

0.6

4 U

/kg/

day

SD: 0

.18

CSI

I sig

nific

antly

low

erth

an d

urin

g C

T(p

<0.

001)

,M

DI/h

uman

ultr

alen

te(p

<0.

001)

,M

DI/h

uman

isop

hane

(p<

0.00

5)

Mon

th: 6

Mea

n: 6

9.1

kgSD

: 8.6

3St

art

of C

SII v

s en

d of

CSI

I (st

art

of M

DI),

p

= n

s

Not

repo

rted

23/5

2 (4

4%) p

refe

rred

CSI

I: Re

ason

s:C

ontr

olFl

exib

ility

in t

erm

s of

food

inta

keal

low

edA

void

freq

uent

inje

ctio

ns: 2

(9%

)G

reat

er s

ense

of w

ell-b

eing

: 2 (9

%)

QoL

: not

rep

orte

d

Inje

ctio

n sit

e in

fect

ion:

1D

KA

: 1Se

vere

hyp

os(e

piso

des/

patie

nt/m

onth

) =1/

7.5;

req

uirin

g gl

ucos

ei.v

./glu

cago

n =

1/9

6,as

sista

nce

but

not

requ

iring

gluc

ose

i.v./g

luca

gon

= 1

/8.

No.

of m

ild s

ubje

ctiv

ehy

pos/

wee

k: 1

.4 (S

D 0

.92)

HbA

1re

port

ed

Mon

th: 6

Mea

n: 9

.6%

SD: 2

.47

MD

I +re

gula

rM

onth

: 6M

DI/h

uman

isop

hane

Mea

n: 0

.72

SD: 0

.25

Sign

ifica

nce:

p<

0.0

05M

I/hum

an u

ltral

ente

Mea

n: 0

.79

SD: 0

.25

Sign

ifica

nce:

p>

0.0

01(is

opha

ne v

sul

tral

ente

, p<

0.0

1)

Mon

th: 6

Mea

n: 7

0.6

kgSD

: 8.6

3Si

gnifi

canc

e: p

< 0

.05

Star

t of

CSI

I vs

end

ofM

DI,

p <

0.0

2

Not

repo

rted

20/5

2 (3

8%) p

refe

rred

MD

I. Re

ason

s:C

ontr

ol: 1

7M

ore

flexi

ble

lifes

tyle

tha

n C

T w

ithou

tne

ed t

o w

ear

a de

vice

Pref

erre

d hu

man

isop

hane

at

bedt

ime:

16 (4

6%)

Pref

erre

d hu

man

ultr

alen

te a

t be

dtim

e:7

(20%

)N

o pr

efer

ence

bet

wee

n be

dtim

ein

sulin

: 11

(31%

)Q

oL: n

ot r

epor

ted

Inje

ctio

n sit

e in

fect

ion:

0D

KA

: 0Se

vere

hyp

os(e

piso

des/

patie

nt/m

onth

) =1/

5; r

equi

ring

gluc

ose

i.v./g

luca

gon

= 1

/79,

assis

tanc

e bu

t no

t re

quiri

nggl

ucos

e i.v

./glu

cago

n =

1/5

.N

o. o

f mild

sub

ject

ive

hypo

s/w

eek:

isop

hane

1.4

(SD

0.92

), ul

tral

ente

1.5

(SD

1.1

7)

HbA

1re

port

ed

Mon

th: 6

Mea

n: 9

.8%

SD: 1

.85

Sign

ifica

nce:

p=

ns

cont

inue

d

MD

I +re

gula

rM

onth

: 3M

ean:

56.

1 U

/day

SD: 2

0.4

Sign

ifica

nce:

p<

0.0

1

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: 5

(42%

)Q

oL: n

ot r

epor

ted

Not

rep

orte

dH

bA1

repo

rted

M

onth

: 3M

ean:

8.7

%SD

: 1.3

9Si

gnifi

canc

e: p

= n

s

Appendix 10

146

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Han

aire

-Br

outin

et

al.,

2000

80

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

4m

onth

s,M

DI

4m

onth

sN

: 41

End

of s

tudy

:40

CSI

I + li

spro

Mon

th: 4

Mea

n: 3

8.5

U/d

aySD

: 9.8

Not

e: m

ean

valu

eov

er 4

mon

ths

Mon

th: 4

Mea

n: 6

8.7

kgSD

: 10

Not

repo

rted

No.

pre

ferr

ing:

29

(72.

5%)

Of t

hese

29,

21

prev

ious

ly o

n C

SII +

regu

lar

and

8 on

MD

IQ

oL: n

ot r

epor

ted

Seve

re h

ypo:

3 e

vent

s, 2

pts

Not

e: h

ypos

dur

ing

last

14da

ys o

f eac

h tr

eatm

ent

perio

d: 3

.9 (4

.2).

Seve

re h

ypos

did

not

res

ult

inco

ma

or s

eizu

res,

ext

erna

lhe

lp n

eede

d to

tak

e su

gar,

but

gluc

agon

or

gluc

ose

inje

ctio

nno

t re

quire

d

HbA

1cre

port

ed

Mon

th: 4

Mea

n: 7

.89%

SD: 0

.77

Not

e: m

ean

valu

e ov

er4

mon

ths

Hom

e et

al.,

1982

88

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

2.5

mon

ths,

MD

I 2.5

mon

ths

N: 1

1En

d of

stu

dy:

10

CSI

I + s

olub

leM

onth

: 2.5

Mea

n: 5

1 U

/day

SD: 1

5.8

Not

e: In

divi

dual

chan

ges

+21

% t

o–4

3% o

f tw

ice-

daily

inje

ctio

n do

se.

Requ

irem

ents

rem

aine

d st

eady

from

2nd

wee

k

Mon

th: 2

.5M

ean:

68.

9kg

SD: 9

.2N

ote:

wei

ght

gain

clin

ical

ly s

igni

fican

tpr

oble

m o

n C

SII,

onoc

casio

n lim

iting

adju

stm

ent

of in

sulin

dosa

ge

Cho

lest

erol

:en

d of

stu

dyM

ean:

5SD

: 0.6

No.

pre

ferr

ing:

8 (8

0%) p

refe

rred

pum

p to

MD

I, 4

wish

ed t

o co

ntin

uew

ith it

. Uni

vers

ally

reg

arde

d as

too

larg

e an

d un

com

fort

able

QoL

: not

rep

orte

d

Pum

p m

alfu

nctio

n: 1

(1 p

t ×

3ep

isode

s in

16

h du

e to

faul

typu

mp)

Seve

re h

ypo:

0.6

(0–3

)ep

isode

s pe

r pt

biw

eekl

y[B

asel

ine

hypo

1.1

(0–4

)ep

isode

s pe

r pt

biw

eekl

y]1

pt r

equi

red

intr

aven

ous

gluc

ose

HbA

1re

port

ed

Mon

th: 2

.5M

ean:

10%

SD: 2

.2N

ote:

5 r

each

ed n

orm

al(<

8.2%

) at

som

e po

int

durin

g pu

mps

MD

I +re

gula

rM

onth

: 2.5

Mea

n: 8

0 U

/day

SD: 2

8.5

Sign

ifica

nce:

p=

0.0

04N

ote:

diff

eren

ce C

SII

– M

DI d

ue t

odi

ffere

nce

in b

asal

insu

lin r

equi

rem

ents

[CSI

I 29

(3) U

/day

vs

MD

I 53

(9) U

/day

,p

=0.

013]

. Ind

ivid

ual

incr

ease

s co

mpa

red

with

pum

p: +

20%

to

+12

0%, t

wic

e da

ily:

+14

% t

o +

74%

Mon

th: 2

.5M

ean:

67

kgSD

: 9.2

Sign

ifica

nce:

p=

0.0

23

Cho

lest

erol

:En

d of

stu

dyM

ean:

5.3

SD: 0

.6

No.

pre

ferr

ing:

0N

one

wish

ed t

o co

ntin

ue w

ith 3

×in

ject

ions

due

to

inco

nven

ienc

eQ

oL: n

ot r

epor

ted

Seve

re h

ypo:

0.8

(0–7

)ep

isode

s pe

r pt

biw

eekl

yH

bA1

repo

rted

M

onth

: 2.5

Mea

n: 1

1.7%

SD: 1

.9Si

gnifi

canc

e: p

= 0

.026

Not

e: 1

pt

reac

hed

norm

al d

urin

g M

DI

MD

I + li

spro

Mon

th: 4

Mea

n: 4

7.3

U/d

aySD

: 14.

9Si

gnifi

canc

e: p

< 0

.000

1N

ote:

mea

n nu

mbe

r of

NPH

inje

ctio

ns =

2.65

day

at e

nd o

f MD

Ipe

riod

Mon

th: 4

Mea

n: 6

9kg

SD: 9

.5Si

gnifi

canc

e: p

= n

s

Not

repo

rted

No.

pre

ferr

ing:

11

(27.

5%)

Of t

hese

11,

10

prev

ious

ly o

n C

SII a

nd1

MD

IQ

oL: n

ot r

epor

ted

Seve

re h

ypo:

1 e

vent

, 1 p

tN

ote:

hyp

os d

urin

g la

st14

days

of e

ach

trea

tmen

tpe

riod

= 4

.3 (3

.9),

p=

ns.

Seve

re h

ypos

did

not

res

ult

inco

ma

or s

eizu

res,

ext

erna

lhe

lp n

eede

d to

tak

e su

gar,

but

gluc

agon

or

gluc

ose

inje

ctio

nno

t re

quire

d

HbA

1cre

port

ed

Mon

th: 4

Mea

n: 8

.24%

SD: 0

.77

Sign

ifica

nce:

p<

0.0

01N

ote:

mea

n va

lue

over

4m

onth

s

cont

inue

d


147


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Nat

han

and

Lou,

198

289

Rand

omise

dcr

osso

ver

Dur

atio

n:Ea

ch p

erio

d8–

12 w

eeks

N: 5

CSI

I + s

olub

leM

onth

: 3M

ean:

35.

4 U

/day

SD: 1

1.5

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: n

ot r

epor

ted

Not

e: e

ase

of a

dmin

ister

ing

and

adju

stin

g in

sulin

dos

es –

not

ed. A

decr

ease

in h

ypos

and

impr

oved

feel

ing

of w

ell-b

eing

con

trib

uted

to

acce

ptan

ce o

f pum

p; d

raw

back

s =

diffi

culty

for

wom

en in

dre

ssin

g to

acco

mm

odat

e pu

mp

and

rem

oval

of

pum

p fo

r w

ater

spo

rts

QoL

: not

rep

orte

d

Dur

ing

2.5

patie

nt-y

ears

CSI

I=

sub

cuta

neou

s ab

sces

sne

edin

g or

al a

ntib

iotic

s (1

),pu

mp

mal

func

tions

(2)

cath

eter

disl

odge

d at

nig

ht (6

)H

ypo

reac

tions

n/w

eek

at3

mon

ths

= 1

(0.2

5)

HbA

1cre

port

ed

Mon

th: 3

Mea

n: 5

.4%

SD: 0

.34

Nos

adin

i et

al.,

198

885

RCT

(par

alle

l)D

urat

ion:

12m

onth

sC

SII f

ixed

basa

l rat

e(F

BR):

19M

DI:

15C

SII h

ighe

rda

wn

insu

lin(H

OR)

: 10

CSI

I + s

olub

le(F

BR)

Not

rep

orte

dN

ot r

epor

ted

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dQ

oL: n

ot r

epor

ted

Mea

n ev

ents

/pt/

y:H

yper

18

(5)

Keto

tic e

vent

s 0.

13 (0

.02)

Mild

hyp

o 36

(10)

Seve

re h

ypo

0.14

(0.0

5)Su

dden

dea

th 0

.04

(1pt

dea

din

bed

). M

alfu

nctio

n of

pum

pca

used

abo

ut 2

0% o

f ket

otic

episo

des

in b

oth

CSI

I gro

ups.

23%

(FBR

) and

27%

(HO

R)ca

used

by

infe

ctiv

e di

seas

e

HbA

1cre

port

ed

Mon

th: 1

2M

ean:

6.3

%SD

: 0.7

MD

I +re

gula

rN

ot r

epor

ted

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: n

ot r

epor

ted

QoL

: not

rep

orte

dH

yper

20

(3),

p=

ns.

Ke

totic

eve

nts

0.03

(0.0

1),

p<

0.01

Mild

hyp

o 59

(12)

, p<

0.01

Seve

re h

ypo

0.42

(0.1

5),

p<

0.01

(all

vs C

SII–

FBR)

HbA

1cre

port

ed

Mon

th: 1

2M

ean:

7.1

%SD

: 0.9

Sign

ifica

nce:

p<

0.0

1M

DI v

s C

SII–

FBR

and

CSI

I–H

OR,

p<

0.0

1

MD

I +re

gula

rM

onth

: 3M

ean:

48.

8 U

/day

SD: 1

3.8

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: n

ot r

epor

ted

QoL

: not

rep

orte

dH

ypo

reac

tions

n/w

eek

at3

mon

ths

= 2

.5 (0

.61)

HbA

1cre

port

ed

Mon

th: 3

Mea

n: 7

.88%

SD: 1

.37

Sign

ifica

nce:

pno

tre

port

edN

ote:

n=

4

cont

inue

d

Appendix 10

148

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

CSI

I + s

olub

le(H

OR)

Not

rep

orte

dN

ot r

epor

ted

Not

repo

rted

No.

pre

ferr

ing:

not

rep

orte

dQ

oL: n

ot r

epor

ted

Hyp

er 1

7 (4

) vs

MD

I, p

= n

sKe

totic

eve

nts

0.16

(0.0

3) v

sM

DI,

p<

0.0

5M

ild h

ypo

30 (1

1) v

s M

DI,

p<

0.0

1Se

vere

hyp

o 0.

16 (0

.09)

vs

MD

I, p

< 0

.01

CSI

I–H

OR

vs C

SII-F

BR, a

llp

=ns

HbA

1cre

port

ed

Mon

th: 1

2M

ean:

6.1

%SD

: 0.9

Not

e: v

s M

DI p

< 0

.01

Saur

brey

etal

., 19

8890

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

2.5

mon

ths,

MD

I2.

5m

onth

sN

: 21

End

of s

tudy

:19

CSI

I + s

olub

leC

olle

cted

dur

ing

trea

tmen

t pe

riod

Mea

n: 0

.62

U/d

aySD

: 0.1

7

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: 6

(31.

5%)

Reas

ons

Life

styl

e: 4

2Q

oL: n

ot r

epor

ted

Seve

re h

ypo:

0N

o. o

f sub

ject

ive

orbi

oche

mic

al (B

G <

2.5

mm

ol/l)

hypo

s in

eac

h gr

oup,

p=

ns

Keto

acid

osis

= 1

(due

to

acut

e ga

stro

ente

ritis

and

failu

re t

o ta

ke e

xtra

insu

lin,

not

pum

p m

alfu

nctio

n)Su

bcut

aneo

us in

fect

ion

(3tim

es) i

n sa

me

patie

nt, o

nere

quire

d su

rgic

al in

cisio

n

HbA

1cre

port

edM

onth

: 2.5

Mea

n: 7

.5%

MD

I +re

gula

rC

olle

cted

dur

ing

stud

yM

ean:

0.6

4 U

/day

SD: 0

.13

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: 1

2 (6

3%)

Reas

ons:

Life

styl

e: 5

81

(5%

) wer

e un

sure

of p

refe

renc

e(e

ither

ICT

or

CSI

I)Q

oL: n

ot r

epor

ted

Seve

re h

ypo:

0H

bA1c

repo

rted

M

onth

: 2.5

Mea

n: 7

.5%

cont

inue

d


149


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Schi

ffrin

and

Belm

onte

,19

8291

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

6m

onth

s,M

DI

6m

onth

s.N

: 20

End

of s

tudy

:16

CSI

I + s

olub

leM

onth

: 6M

ean:

42

U/d

ayN

ot r

epor

ted

Cho

lest

erol

:En

d of

stu

dyM

ean:

163

mg/

dlSD

: 15

Base

line:

190

(9) m

g/dl

Trig

lyce

ride:

end

of s

tudy

Mea

n:82

mg/

dl

SD: 1

5

No.

pre

ferr

ing:

7/1

6 (4

4%) o

f pts

chos

e C

SII f

or e

asie

r gl

ycae

mic

con

trol

and

also

gre

ater

flex

ibili

ty fo

r m

eal

hour

s an

d m

eal s

ize

CSI

I rej

ecte

d fo

r re

ason

s of

bul

k,di

scom

fort

, a fe

elin

g of

dep

ende

ncy

onth

e m

achi

ne &

dist

ortio

n of

bod

yim

age

70%

wou

ld r

ecom

men

d C

SII t

o a

diab

etic

frie

ndQ

oL: n

ot r

epor

ted

Mild

hyp

o: 1

86M

oder

ate

hypo

: 10

Seve

re h

ypo:

1(s

ever

e hy

po in

1 p

t du

e to

dela

ying

mea

l afte

r bo

lus

insu

lin t

aken

– in

trav

enou

sgl

ucos

e w

as a

dmin

ister

ed)

HbA

1re

port

ed

Mon

th: 3

Mea

n: 8

.1%

SD: 0

.6M

onth

: 6M

ean:

8.2

%SD

: 0.5

Not

e: H

bA1

repo

rted

mon

thly.

Dat

a fo

rm

onth

s 3

and

6ex

trac

ted

only

MD

I +re

gula

rM

onth

: 6M

ean:

44

U/d

aySi

gnifi

canc

e: p

= n

s

Not

rep

orte

dC

hole

ster

ol:

end

of s

tudy

Mea

n: 1

62m

g/dl

SD: 1

2Ba

selin

e: 1

83(8

)mg/

dl.

Mea

nba

selin

ech

oles

tero

lfo

r w

hole

grou

p: 1

86.5

(70–

200)

.Ba

selin

eva

lue

vs C

SII

and

MD

I at

end

of s

tudy

,p

<0.

01Tr

igly

cerid

e:en

d of

stu

dyM

ean:

81m

g/dl

SD

: 12,

p

= n

s

No.

pre

ferr

ing:

7 (4

4%)

30%

wou

ld r

ecom

men

d M

DI t

o a

diab

etic

frie

nd.

(2 p

ts r

ever

ted

to c

onve

ntio

nal)

QoL

: not

rep

orte

d

Mild

hyp

o: 1

89, p

= n

sM

oder

ate

hypo

: 11

p=

ns

Seve

re h

ypo:

0, p

= n

s

HbA

1re

port

ed

Mon

th: 3

Mea

n: 8

.4%

SD: 0

.7Si

gnifi

canc

e: p

= n

sM

onth

: 6M

ean:

8.4

%SD

: 0.5

Sign

ifica

nce:

p=

ns

cont

inue

d

Appendix 10

150

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Schm

itz

et a

l., 1

98986

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

6m

onth

s,M

DI

6m

onth

sN

= 1

0

CSI

I + s

olub

leM

onth

: 6M

ean:

0.5

5 U

/kg/

day

SD: 0

.1Ba

selin

e vs

CSI

I,p

=0.

03

Mon

th: 6

Mea

n: 7

3kg

SD: 1

7.8

Base

line

vs C

SII,

p=

0.01

Not

repo

rted

No.

pre

ferr

ing:

4 (4

0%)

QoL

: not

rep

orte

dSe

vere

hyp

o: 0

DK

A: 0

HbA

1cre

port

ed

Mon

th: 6

Mea

n: 7

%SD

: 1Ba

selin

e vs

CSI

I, p

= 0

.03

Tsui

et

al.,

2001

79

RCT

(par

alle

l)D

urat

ion:

9m

onth

s.C

SII:

13En

d of

stu

dy:

12 MD

I: 14

End

of s

tudy

:14

CSI

I + li

spro

Mon

th: 9

Mea

n: 0

.6 U

/kg

SD: 0

.2

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: n

ot r

epor

ted

QoL

sco

re:

Satis

fact

ion

75.6

Impa

ct: 6

9.9

Dia

betic

wor

ry: 8

5.2

Soci

al w

orry

: 89.

6G

loba

l Hea

lth :

68.2

Resp

onse

rat

e: 8

5%

Seve

re h

ypo:

6M

ean

num

ber

of h

ypos

eac

hm

onth

, 8.9

(3 m

onth

s), 7

.2(6

mon

ths)

, 7.0

(9 m

onth

s),

8.0

(ove

rall)

, all

p=

ns

HbA

1cre

port

edM

onth

: 3M

ean:

6.9

2%M

onth

: 6M

ean:

7.1

9%M

onth

: 9M

ean:

7.3

8%Po

oled

est

imat

es o

fpa

ralle

l and

cro

ssov

erst

udy:

diff

eren

ce C

SII

and

MD

I = 0

.09%

(95%

CI –

0.09

to

+0.

26),

p>

0.1

.Pr

obab

ility

tha

t tr

uetr

eatm

ent

effe

ct is

mor

eex

trem

e th

an ±

0.5%

is<

0.00

001

MD

I +re

gula

rM

onth

: 6M

ean:

0.6

U/k

g/da

ySD

: 0.1

1Si

gnifi

canc

e: p

= 0

.02

Not

e: b

asel

ine

vs M

DI,

p=

ns

Mon

th: 6

Mea

n: 7

2.8

kgSD

: 18.

4Si

gnifi

canc

e: p

= n

sBa

selin

e vs

MD

I,p

=ns

Not

repo

rted

No.

pre

ferr

ing:

6 (6

0%)

QoL

: not

rep

orte

dSe

vere

hyp

o: 0

DK

A: 0

HbA

1cre

port

ed

Mon

th: 6

Mea

n: 7

.7%

SD: 1

Sign

ifica

nce:

p=

0.0

02Ba

selin

e vs

MD

I, p

= n

s

cont

inue

d


151


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

MD

I + li

spro

Mon

th: 9

Mea

n: 0

.7 U

/kg

SD: 0

.2Tr

eatm

ent

effe

ct(a

djus

ted

for

base

line)

:–0

.10

(85%

CI –

0.26

to 0

.07)

, p>

0.1

0Si

gnifi

canc

e gi

ven

for

diffe

rent

CSI

I – M

DI

–0.1

0

Not

rep

orte

dN

otre

port

edN

o. p

refe

rrin

g: n

ot r

epor

ted

QoL

: Sa

tisfa

ctio

n: 6

8.3

Impa

ct: 6

8.4

Dia

betic

wor

ry: 7

9.8

Soci

al w

orry

: 94.

0G

loba

l Hea

lth :

67.3

p=

ns

for

any

of t

he s

ubsc

ales

Resp

onse

rat

e: 1

00%

Seve

re h

ypo:

4, p

> 0

.10

Mea

n nu

mbe

r of

hyp

os e

ach

mon

th, 5

.0 (3

mon

ths)

, 9.0

(6m

onth

s), 9

.2 (9

mon

ths)

,7.

4 (o

vera

ll), a

ll p

= n

s vs

CSI

I Re

lativ

e tr

eatm

ent

effe

ct(C

SII–

MD

I)/M

DI f

or o

vera

llno

. of h

ypos

= +

9% (9

5% C

I–3

7 to

+87

) p>

0.1

0

HbA

1cre

port

ed

Mon

th: 3

Mea

n: 7

.55%

Trea

tmen

t ef

fect

(adj

uste

d fo

r ba

selin

e):

–0.2

1 (9

5% C

I –0.

59 t

o0.

17),

p>

0.1

0M

onth

: 6M

ean:

7.6

2%Tr

eatm

ent

effe

ct(a

djus

ted

for

base

line)

:–0

.01

(95%

CI –

0.44

to

0.42

), p

> 0

.10

Mon

th: 9

Mea

n: 7

.56%

Trea

tmen

t ef

fect

(adj

uste

d fo

r ba

selin

e):

0.25

(95%

CI –

0.19

to

0.68

), p

> 0

.10

Not

e: t

reat

men

t ef

fect

CSI

I – M

DI s

how

nco

rrec

ted

for

base

line

diffe

renc

es

cont

inue

d

Appendix 10

152

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tLi

pids

Pati

ent

pref

eren

ce/q

ualit

y of

life

Adv

erse

eve

nts

Zie

gler

et

al.,

1990

84

RCT

(par

alle

l)D

urat

ion:

24m

onth

sC

SII:

49En

d of

stu

dy:

36 MD

I: 47

End

of s

tudy

:37

CSI

I + s

olub

leN

o va

lues

giv

en, b

utp

=ns

dur

ing

follo

w-

up

No

valu

es g

iven

, but

note

d in

disc

ussio

nth

at a

vera

ge w

eigh

tga

in a

fter

2 y

=1.

3kg

. BM

I at

mon

ths

6–24

= 2

2.5

No

valu

esgi

ven,

but

note

d in

disc

ussio

nth

atch

oles

tero

lle

vels

incr

ease

dw

ithin

the

norm

al r

ange

durin

g th

est

udy

with

out

diffe

renc

esbe

twee

ntr

eatm

ent

grou

ps

No.

pre

ferr

ing:

not

rep

orte

d4

pts

chan

ged

to M

DI d

urin

g st

udy

due

to t

echn

ical

pro

blem

s w

ith p

ump

QoL

: not

rep

orte

d

No.

of m

etab

olic

com

plic

atio

ns/6

mon

ths

mea

n(r

ange

). Re

view

er h

asca

lcul

ated

mea

n of

the

4

×6-

mon

th p

erio

ds t

o gi

veto

tals

belo

wM

ild h

ypo

(BG

<50

mg/

dl):

15.5

(0–7

0)M

ild h

ypo

(sym

ptom

s): 1

9.8

(0–1

04)

Seve

re h

ypo

(req

uirin

gas

sista

nce)

: 0.0

91 (0

–7)

Seve

re h

ypo

(com

a): 0

.101

(0–4

)Ke

tosis

(BG

>20

0m

g/dl

and

keto

nuria

): 6.

5 (0

–57)

Keto

acid

osis:

0.0

46 (0

–1)

Freq

uenc

y of

pts

(no.

of

even

ts/1

00 y

)H

ypo

requ

iring

ass

istan

ce:

13.9

(18.

1)H

ypo

com

a: 3

0.6

(19.

4)D

KA

: 13.

9 (9

.7) [

true

the

rapy

at t

ime

of e

vent

: 15.

4 (1

4.1)

]

HbA

1re

port

ed

Mon

th: 6

Mea

n: 8

.2%

Mon

th: 1

2M

ean:

8.5

%M

onth

: 18

Mea

n: 8

.5%

Mon

th: 2

4M

ean:

8.6

MD

I +re

gula

rN

o va

lues

giv

en, b

ut

p=

ns

durin

g fo

llow

-up

As

for

CSI

I, av

erag

ew

eigh

t ga

in a

fter

2y

= 2

.8kg

. BM

I at

mon

ths

6–24

= 2

4.2,

p<

0.05

No.

pre

ferr

ing:

not

rep

orte

d7

pts

chan

ged

trea

tmen

t gr

oup

durin

gst

udy

due

to e

xplic

it re

ques

t to

hav

e a

pum

pQ

oL: N

ot r

epor

ted

Mild

hyp

o (B

G <

50m

g/dl

):10

.6 (0

–53)

Mild

hyp

o (s

ympt

oms)

: 10.

1(0

–81)

Seve

re h

ypo

(req

uirin

gas

sista

nce)

: 0.0

70 (0

–2)

Seve

re h

ypo

(com

a): 0

.048

(0–1

)Ke

tosis

(BG

>20

0 m

g/dl

and

keto

nuria

): 7.

8 (0

–85)

Keto

acid

osis:

0.0

40 (0

–3)

Freq

uenc

y of

pts

(no.

of

even

ts/1

00 y

)H

ypo

requ

iring

ass

istan

ce:

16.2

(13.

5)H

ypo

com

a: 1

3.5

(9.5

)D

KA

: 8.1

(8.1

) [tr

ue t

hera

pyat

tim

e of

eve

nt: 5

.9 (2

.9)]

HbA

1re

port

ed

Mon

th: 6

Mea

n: 8

.8%

Sign

ifica

nce:

p<

0.0

5M

onth

: 12

Mea

n: 8

.7%

Sign

ifica

nce:

p=

ns

Mon

th: 1

8M

ean:

8.4

%Si

gnifi

canc

e: p

= n

sM

onth

: 24

Mea

n: 8

.5Si

gnifi

canc

e: p

= n

s


153


Appendix 11

Summary of results: pregnancy

Appendix 11

154

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Burk

art

etal

., 19

8895

RCT

(par

alle

l)

Dur

atio

n:9

mon

ths

CSI

I: 48

MD

I: 41

CSI

I +so

lubl

eN

ot r

epor

ted

Mea

n du

ratio

n: 3

8.4

wee

ks

Live

birt

hs: 4

7/48

(97.

9%)

Mea

n bi

rth

wei

ght:

3082

.7 (u

nits

not

spec

ified

)

No.

Cae

sare

an: 2

4/48

Com

plic

atio

ns in

pre

gnan

cy:

Pyel

onep

hriti

s: 5

Prem

atur

e la

bour

: 4

Prem

atur

e ru

ptur

e: 2

Prem

atur

e de

liver

y: 7

Pr

e-ec

lam

psia

: 3G

row

th r

etar

datio

n: 3

Hyp

ogly

caem

ia: 5

St

ill b

irth:

1

Keto

acid

osis:

1To

tal:

12/4

8 pr

egna

ncie

s ha

d on

e or

mor

e co

mpl

icat

ions

Inci

denc

e of

com

plic

atio

ns in

bot

hgr

oups

is li

nked

to

the

seve

rity

ofm

ater

nal d

iabe

tes

(Whi

te’s

crit

eria

).Bi

rthw

eigh

t de

crea

ses

with

sev

erity

.D

iffer

ence

s in

mea

n bi

rthw

eigh

ts, p

=ns

Feta

l out

com

e:H

ealth

y ne

wbo

rns:

40

Min

or s

ympt

oms:

8

Maj

or s

ympt

oms:

0I.v

. glu

cose

: 14

Ove

rall

mor

talit

y up

to

age

1 y

= 2

/48

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

See

com

plic

atio

ns in

preg

nanc

yN

ot r

epor

ted.

Sta

tes

that

patie

nts

sele

cted

in t

heC

SII o

r M

DI g

roup

had

norm

al m

ean

gluc

ose

and

HbA

1<

7.5%

at

leas

t fr

omth

e en

d of

the

firs

ttr

imes

ter

on

cont

inue

d


155


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

CSI

I +re

gula

rN

ot r

epor

ted

Mea

n du

ratio

n: 3

8.2

wee

ks

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

3319

.5 (u

nits

not

spec

ified

)

No.

Cae

sare

an: 1

5/41

(p =

ns)

Com

plic

atio

ns in

pre

gnan

cy:

Pyel

onep

hriti

s: 6

Prem

atur

e la

bour

: 3Pr

emat

ure

rupt

ure:

1Pr

emat

ure

deliv

ery:

4Pr

e-ec

lam

psia

: 3

Gro

wth

ret

arda

tion:

1H

ypog

lyca

emia

: 3St

ill b

irth:

0Ke

toac

idos

is: 0

Tota

l: 13

/41

preg

nanc

ies

had

one

orm

ore

com

plic

atio

ns (v

s C

SII,

p=

ns)

Feta

l out

com

e:H

ealth

y ne

wbo

rns:

34

Min

or s

ympt

oms:

5M

ajor

sym

ptom

s: 2

I.v

. glu

cose

9 (a

ll p

= n

s vs

CSI

I)O

vera

ll m

orta

lity

up t

o ag

e 1

y =

3/4

1,vs

CSI

I p<

0.0

5. (N

ote:

the

p-v

alue

repo

rted

by

the

pape

r ap

pear

s to

be

inco

rrec

t, an

d sh

ould

be

insig

nific

ant)

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

See

com

plic

atio

ns in

preg

nanc

y

cont

inue

d

Appendix 11

156

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Car

ta e

t al

.,19

8694

RCT

(par

alle

l)

Dur

atio

n:9

mon

ths

Type

1di

abet

es:

CSI

I: 8

MD

I:7

CSI

I +so

lubl

eM

onth

: 3M

ean:

37

U/d

ay

Mon

th: 6

Mea

n: 4

2 U

/day

Mon

th: 9

Mea

n: 4

9.1

U/d

ay

Mea

n du

ratio

n: 2

66.7

day

sSD

: 7.6

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

3395

gSD

: 407

No.

Cae

sare

an: 3

(37.

5%)

1 pr

eter

m d

ue t

o hy

dram

nios

and

feta

lm

egal

osom

nia.

1 la

rge

for

gest

atio

nal

age.

1 m

acro

som

nic

(>40

00g)

.[A

rms

not

spec

ified

: 2 in

fant

s de

pres

sed,

5 m

etab

olic

mor

bidi

ty (h

ypog

lyca

emia

,hy

poca

lcae

mia

, hyp

erbi

lirub

inae

mia

), 2

cong

enita

l car

diac

mal

form

atio

ns]

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Inje

ctio

n sit

e in

fect

ion:

0Pu

mp

mal

func

tion:

0C

athe

ter

disc

onne

ctio

n: 3

In a

ll pt

s: n

o hy

po c

oma.

1se

vere

hyp

o (g

roup

not

stat

ed).

Mild

hyp

osoc

curr

ed o

n av

erag

e on

ceev

ery

15–2

0 da

ys

Mon

th: 3

Mea

n: 7

.8%

Mon

th: 5

Mea

n: 7

%

Mon

th: 8

Mea

n: 7

%

Mon

th: 9

Mea

n: 6

.5%

MD

I +re

gula

rM

onth

: 3M

ean:

32

U/d

aySi

gnifi

canc

e: p

= n

s

Mon

th: 6

Mea

n: 4

7 U

/day

Sign

ifica

nce:

p=

ns

Mon

th: 9

Mea

n: 6

0.4

U/d

aySi

gnifi

canc

e: p

= n

s

Mea

n du

ratio

n: 2

63.6

day

sSD

: 17.

7

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

2906

gSD

: 553

Sign

ifica

nce:

p=

ns

No.

Cae

sare

an: 3

(42.

9%)

1 pr

eter

m d

ue t

o m

etro

ttha

gia

caus

edby

cen

tral

pla

cent

a pr

evia

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Mon

th: 3

Mea

n: 8

.5%

Sign

ifica

nce:

p=

ns

Mon

th: 5

Mea

n: 7

.75%

Sign

ifica

nce:

p=

ns

Mon

th: 8

Mea

n: 6

.95%

Sign

ifica

nce:

p=

ns

Mon

th: 9

Mea

n: 6

.45%

Sign

ifica

nce:

p=

ns

cont

inue

d


157


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Car

ta e

t al

.,19

8694

RCT

(par

alle

l)

Dur

atio

n:9

mon

ths

Type

2di

abet

es:

CSI

I: 6

MD

I: 8

CSI

I +so

lubl

eM

onth

: 3M

ean:

23.

1U

/day

Mon

th: 6

Mea

n: 3

6U

/day

Mon

th: 9

Mea

n: 5

2.8

U/d

ay

Mea

n du

ratio

n: 2

72 d

ays

SD: 9

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

3292

gSD

: 578

No.

Cae

sare

an: 1

(16.

7%)

1 pr

eter

m d

ue t

o pr

emat

ure

rupt

ure

ofm

embr

anes

. 1 la

rge

for

gest

atio

nal a

ge

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Episo

des

of m

ild h

ypos

wer

e fe

w a

nd d

id n

otoc

cur

in a

ll pt

s

Mon

th: 3

Mea

n: 7

%

Mon

th: 5

Mea

n: 6

.75%

Mon

th: 8

Mea

n: 6

.5%

Mon

th: 9

Mea

n: 6

%

MD

I +re

gula

rM

onth

: 3M

ean:

28

U/d

aySi

gnifi

canc

e: p

= n

s

Mon

th: 6

Mea

n: 4

9 U

/day

Sign

ifica

nce:

p=

ns

Mon

th: 9

Mea

n: 5

1.2

U/d

aySi

gnifi

canc

e: p

= n

s

Mea

n du

ratio

n: 2

69 d

ays

SD: 1

1.7

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

2994

gSD

: 512

Sign

ifica

nce:

p=

ns

No.

Cae

sare

an: 3

(37.

5%)

1 pr

eter

m d

ue t

o pr

emat

ure

rupt

ure

ofm

embr

anes

. 1 s

mal

l for

ges

tatio

nal a

ge

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Mon

th: 3

Mea

n: 8

.1%

Sign

ifica

nce:

p=

ns

Mon

th: 5

Mea

n: 7

.2%

Sign

ifica

nce:

p=

ns

Mon

th: 8

Mea

n: 6

.7%

Sign

ifica

nce:

p=

ns

Mon

th: 9

Mea

n: 6

.7%

Sign

ifica

nce:

p=

ns

cont

inue

d

Appendix 11

158

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Cou

ston

et

al.,

198

693

RCT

(par

alle

l)

Dur

atio

n:9

mon

ths

CSI

I: 11

MD

I: 11

CSI

I + li

spro

Mon

th: 3

Mea

n: 0

.71

U/k

g/da

ySD

: 0.1

6

Mon

th: 6

Mea

n: 1

.02

U/k

g/da

ySD

: 0.5

3

Mon

th: 9

Mea

n: 1

.26

U/k

g/da

ySD

: 0.4

9

Mea

n du

ratio

n: 3

8.1

wee

ksSD

: 2.1

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

3050

gSD

: 675

No.

Cae

sare

an: 7

(63.

6%)

1bi

rthw

eigh

t ab

ove

90th

per

cent

ile,

2sm

all f

or g

esta

tiona

l age

bab

ies.

Neo

nata

l hyp

ogly

caem

ia in

1

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Inje

ctio

n sit

e in

fect

ion:

0Pu

mp

mal

func

tion:

0M

ild h

ypo:

11

pts

Mod

erat

e hy

po: 6

pts

Seve

re h

ypo:

3 p

ts(8

episo

des)

DK

A: 0

1 hy

perg

lyca

emia

and

keto

nuria

(2da

ys) d

urin

gvi

ral i

nfec

tion.

Cat

hete

r le

akag

e or

occl

usio

n oc

curr

edin

freq

uent

ly a

nd r

esol

ved

quic

kly

Mon

th: 2

Mea

n: 7

%M

onth

: 9M

ean:

6.3

%SD

: 0.6

Not

e: S

igni

fican

cere

duct

ion

from

bas

elin

e(p

<0.

05)

MD

I + li

spro

Mon

th: 3

Mea

n: 1

.01

U//k

g/da

ySD

: 0.2

8Si

gnifi

canc

e: p

= 0

.101

Mon

th: 6

Mea

n: 1

.4 U

//kg/

day

SD: 0

.4Si

gnifi

canc

e: p

= 0

.027

Mon

th: 9

Mea

n: 1

.63

U//k

g/da

ySD

: 0.5

1Si

gnifi

canc

e: p

= 0

.041

Mea

n du

ratio

n: 3

8.8

wee

ksSD

: 1.4

Live

birt

hs: 1

00%

Mea

n bi

rth

wei

ght:

3324

gSD

: 475

Sign

ifica

nce:

p=

ns

No.

Cae

sare

an: 7

(63.

6%)

1 ba

by m

oder

ate

resp

irato

ry d

istre

sssy

ndro

me.

Neo

nata

l hyp

ogly

caem

ia in

1

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Mild

hyp

o: 1

1 pt

sM

oder

ate

hypo

: 10

pts

Seve

re h

ypo:

5 p

ts (2

3ep

isode

s)D

KA

: 0

1 su

bjec

t ha

d 17

hyp

osre

late

d to

die

tary

irreg

ular

ities

Mon

th: 2

Mea

n: 7

.5%

Sign

ifica

nce:

p=

ns

Mon

th: 9

Mea

n: 6

.4%

SD: 0

.4Si

gnifi

canc

e: p

= n

s

Not

e: s

igni

fican

cere

duct

ion

from

bas

elin

e(p

< 0

.05)

cont

inue

d


159


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eP

regn

ancy

out

com

esPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Nos

ari e

t al

.,19

9392

RCT

(par

alle

l)

Dur

atio

n:9

mon

ths

CSI

I: 16

MD

I: 16

CSI

I +so

lubl

eM

onth

: 3M

ean:

39.

6 U

/day

SD: 2

2.8

Mon

th: 6

Mea

n: 4

8.1

U/d

aySD

: 20.

8

Mon

th: 9

Mea

n: 5

7.3

U/d

aySD

: 21.

6

Not

e: d

ata

at 1

st, 2

nd, 3

rdtr

imes

ter

Mea

n du

ratio

n: 3

8.9

wee

ksSD

: 7.6

Live

birt

hs: 8

7.5%

Mea

n bi

rth

wei

ght:

3130

gSD

: 148

0

No.

Cae

sare

an: 9

(56.

3%)

2 in

trau

terin

e de

aths

. Ges

tatio

nal a

ge a

tde

liver

y (p

regn

ancy

dur

atio

n) p

> 0

.5,

birt

hwei

ght

p>

0.5

. Fet

al c

onge

nita

lm

alfo

rmat

ions

, mac

roso

mia

, low

Apg

arsc

ores

(<7

at 5

min

utes

) not

obs

erve

d.1

CSI

I lar

ge fo

r ag

e. R

espi

rato

ry d

istre

ssin

1 C

SII i

nfan

t. N

eona

tal h

ypo

(pla

sma

gluc

ose

<30

mg/

dl) i

n 1

CSI

I.

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Seve

re h

ypo:

3D

KA

: 3M

onth

: 3M

ean:

6%

SD: 3

.6

Mon

th: 6

Mea

n: 6

.8%

SD: 5

.6

Mon

th: 9

Mea

n: 6

.3%

SD: 2

Not

e: d

ata

at 1

st, 2

nd, 3

rdtr

imes

ter

MD

I +re

gula

rM

onth

: 3M

ean:

36

U/d

aySD

: 24.

4Si

gnifi

canc

e: p

> 0

.5

Mon

th: 6

Mea

n: 4

3.7

U/d

aySD

: 35.

6Si

gnifi

canc

e: p

> 0

.5

Mon

th: 9

Mea

n: 5

4.7

U/d

aySD

: 39.

2Si

gnifi

canc

e: p

> 0

.5

Mea

n du

ratio

n: 3

8.2

wee

ksSD

: 10

Live

birt

hs: 9

3.8%

Mea

n bi

rth

wei

ght:

3010

gSD

: 172

8

No.

Cae

sare

an: 7

(43.

8%)

1 in

trau

terin

e de

ath.

2 M

DI s

mal

l for

age.

1 p

rem

atur

e M

DI b

irth.

Neo

nata

lhy

po (p

lasm

a gl

ucos

e <

30m

g/dl

) in

1M

DI

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Seve

re h

ypo:

1, C

SII v

sM

DI,

p>

0.5

DK

A: 0

, CSI

I vs

MD

I,p

>0.

1

Mon

th: 3

Mea

n: 6

.2%

SD: 1

.6Si

gnifi

canc

e: p

>0.

5

Mon

th: 6

Mea

n: 6

.1%

SD: 2

.4Si

gnifi

canc

e: p

> 0

.5

Mon

th: 9

Mea

n: 6

.2%

SD: 0

.8Si

gnifi

canc

e: p

> 0

.5


161


Appendix 12

Summary of results: adolescents

Appendix 12

162

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

ePa

tien

t pr

efer

ence

Adv

erse

eve

nts

Schi

ffrin

et

al.,

198

497

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

4m

onth

s,M

DI

4m

onth

s,C

SII+

MD

I4

mon

ths

N: 2

4

CSI

I +so

lubl

eM

onth

: 4M

ean:

44

U/d

aySD

: 12

Not

e: t

otal

insu

lin/d

ay d

urin

gtr

eatm

ent

– no

tim

e po

int

give

nC

SII v

s IC

T a

nd b

asel

ine,

p<

0.0

01

No.

pre

ferr

ing:

11

100%

wou

ldre

com

men

d C

SII t

o a

frie

nd.

QoL

: not

rep

orte

d

Seve

re h

ypo:

1

No

diffe

rent

in h

ypos

from

oth

ertr

eatm

ents

. Mos

tly m

ild a

nd a

vera

ged

one

per

wee

k pe

r pt

. Sam

e pt

s ha

dse

vere

hyp

o on

CSI

I and

ICT

– t

hela

tter

due

to

inad

vert

ent

adm

inist

ratio

n of

ext

ra N

PH d

ose

Mon

th: 3

Mea

n: 8

.75%

M

onth

: 4M

ean:

8.8

%N

ote:

red

uctio

n is

signi

fican

t fr

om b

asel

ine

(p<

0.0

01)

CSI

I vs

CSI

I-IC

T, p

< 0

.05

CSI

I vs

ICT,

p<

0.0

5

MD

I +re

gula

rM

onth

: 4M

ean:

60

U/d

aySD

: 16

Sign

ifica

nce:

p<

0.0

01

Not

e: t

otal

insu

lin/d

ay d

urin

gtr

eatm

ent

– no

tim

e po

int

give

n

No.

pre

ferr

ing:

466

% w

ould

rec

omm

end

ICT

to

a fr

iend

QoL

: not

rep

orte

d

Seve

re h

ypo:

1 (d

ue t

o in

adve

rten

tad

min

istra

tion

of e

xtra

NPH

dos

e)M

onth

: 3M

ean:

9.5

%Si

gnifi

cant

: p<

0.0

5M

onth

: 4M

ean:

9.6

%Si

gnifi

canc

e: p

< 0

.05

Not

e: r

educ

tion

is sig

nific

ant

from

bas

elin

e(p

<0.

001)

CSI

Iov

erni

ght

with

MD

Idu

ring

day

Mon

th: 4

Mea

n: 4

8U

/day

SD: 1

6N

ote:

dur

ing

who

le s

tudy

CSI

I–IC

T v

s IC

T a

nd b

asel

ine,

p

< 0

.001

No.

pre

ferr

ing:

370

% w

ould

rec

omm

end

CSI

I–IC

T t

o a

frie

nd(2

of 2

0 co

mpl

etin

gst

udy

reve

rted

to

twic

eda

ily in

ject

ions

)

QoL

: not

rep

orte

d

Mon

th: 3

Mea

n: 9

%

Mon

th: 4

Mea

n: 9

.3%

Not

e: r

educ

tion

signi

fican

t fr

om b

asel

ine

(p<

0.0

01)

CSI

I vs

CSI

I–IC

T, p

< 0

.05

cont

inue

d


163


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

ePa

tien

t pr

efer

ence

Adv

erse

eve

nts

Tam

borla

neet

al.,

198

996

Rand

omise

dcr

osso

ver

Dur

atio

n:C

SII

6m

onth

s,M

DI

6m

onth

s

N: 1

0

CSI

I +re

gula

rM

onth

: 6M

ean:

1.3

U/d

aySD

: 3.1

6

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Episo

des

of m

ild h

ypos

wer

e co

mm

ondu

ring

each

tre

atm

ent.

Stat

es t

hat

ther

e w

as o

nly

one

seve

re h

ypo

requ

iring

ass

istan

ce d

urin

g ea

ch

6-m

onth

tre

atm

ent

perio

d

Mon

th: 6

Mea

n: 8

.5%

SD: 1

.26

MD

I +re

gula

rM

onth

: 6M

ean:

1.4

U/d

aySD

: 0.3

2Si

gnifi

canc

e: p

=ns

Mon

th: 0

Mea

n: 0

U/d

ay

Insu

lin d

ose

(U/d

ay) w

as in

crea

sed

durin

g bo

th M

DI a

nd C

SII

com

pare

d w

ith b

asel

ine,

p<

0.0

5

No.

pre

ferr

ing:

not

repo

rted

QoL

: not

rep

orte

d

Mon

th: 6

Mea

n: 8

.7%

SD: 1

.58

Sign

ifica

nce:

p=

ns

HbA

1sig

nific

antly

red

uced

com

pare

d w

ithba

selin

e du

ring

both

CSI

I and

MD

I, p

< 0

.05


165


Appendix 13

Summary of results: analogue versus soluble insulin

Appendix 13

166

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Bode

et

al.,

2002

113

RCT

(par

alle

l)

Dur

atio

n:4

mon

ths

Lisp

ro: 2

8(e

nd o

fst

udy

27)

Regu

lar:

59

(end

of

stud

y 50

)A

spar

t: 59

(end

of

stud

y 55

)

CSI

I + li

spro

Not

rep

orte

dN

ot r

epor

ted

Not

rep

orte

dSe

vere

hyp

o: 0

DK

A: 0

Hyp

ergl

ycae

mia

(>35

0m

g/dl

): 10

≤3

clog

s or

blo

ckag

es: 6

4%H

ypos

[epi

sode

s, r

ate

(SD

)]:

All

repo

rted

: 872

, 10.

5 (8

.1),

vs a

spar

t p

= 0

.044

Hyp

o BG

<50

mg/

dl: 3

59, 4

.4 (4

.7),

vs a

spar

tp

=0.

841

Noc

turn

al h

ypo

BG <

50m

g/dl

: 64,

0.6

(0.6

1), v

sas

part

p=

0.18

9

Mon

th: 4

Mea

n ch

ange

from

base

line:

0.1

8 (0

.84)

%

CSI

I +bu

ffere

dre

gula

r

Not

rep

orte

dN

ot r

epor

ted

Not

rep

orte

dSe

vere

hyp

o: 1

(1.7

%)

DK

A: 0

Hyp

ergl

ycae

mia

(>35

0m

g/dl

): 24

≤3

clog

s or

blo

ckag

es: 7

8%H

ypos

[epi

sode

s, r

ate

(SD

)]:

All

repo

rted

: 166

3, 1

0.5

(8.9

), vs

asp

art

p=

0.0

34H

ypo

BG<

50m

g/dl

: 770

, 4.8

(4.2

), vs

asp

art

p=

0.17

5.N

octu

rnal

hyp

o BG

<50

mg/

dl: 2

07, 0

.9 (0

.97)

, vs

aspa

rt p

=0.

004

Mon

th: 4

Mea

n ch

ange

from

base

line:

0.1

5 (0

.63)

%

CSI

I + a

spar

tN

ot r

epor

ted

Not

rep

orte

dN

ot r

epor

ted

Seve

re h

ypo:

0D

KA

: 0H

yper

glyc

aem

ia (>

350

mg/

dl):

16 (p

=ns

bet

wee

nal

l tre

atm

ents

)

≤3

clog

s or

blo

ckag

es: 7

5%H

erpe

s zo

ster

= 1

Hyp

os [e

piso

des,

rat

e (S

D)]

:A

ll re

port

ed: 1

126,

6.7

(5.4

)H

ypo

BG<

50m

g/dl

: 610

, 3.7

(3.6

)N

octu

rnal

hyp

o BG

<50

mg/

dl: 9

6, 0

.5 (0

.83)

Mon

th: 4

Mea

n ch

ange

from

base

line:

0.0

0 (0

.15)

%

p=

ns

betw

een

grou

ps

cont

inue

d


167


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Mel

ki e

t al

.,19

9811

6

Rand

omise

dcr

osso

ver

Dur

atio

n:So

lubl

e3

mon

ths,

lispr

o3

mon

ths

N: 3

9En

d of

stud

y: 3

8

CSI

I +so

lubl

eM

onth

: 3M

ean:

0.5

3 U

/kg/

day

SD: 0

.12

Mon

th: 3

Mea

n: 0

.04

kgSD

: 1.7

9

No.

pre

ferr

ing:

36

(94.

7%)

Reas

ons:

Con

trol

: 89.

4%Li

fest

yle:

84.

2%

% o

f fav

oura

ble

resp

onse

s fo

rlis

pro

varie

d fr

om 8

4 to

92%

acco

rdin

g to

the

que

stio

ns

QoL

: not

rep

orte

d

Cat

hete

r ob

stru

ctio

ns :

9 Se

vere

hyp

o: 3

(7.9

%)

DK

A: 0

Insu

lin p

reci

pita

tion

in c

athe

ter:

1

BG<

3.0

mm

ol/l:

7.0

3 (5

.79)

per

mon

thBG

<2.

0 m

mol

/l: 0

.05

(0.3

1) p

er m

onth

Mon

th: 3

Mea

n: 7

.11%

SD: 0

.92

Not

e: r

educ

tion

from

base

line:

0.6

2 (0

.8)

CSI

I + li

spro

Mon

th: 3

Mea

n: 0

.55

U/k

g/da

ySD

: 0.1

2

Sign

ifica

nce:

p=

ns

Mon

th: 3

Mea

n: 0

.48

kgSD

: 1.6

Sign

ifica

nce:

p

= n

s

No.

pre

ferr

ing:

2 (5

.3%

)

Reas

ons

Con

trol

: 5.3

%Li

fest

yle:

5.3

%

QoL

: not

rep

orte

d

Cat

hete

r ob

stru

ctio

ns: 9

Seve

re h

ypo:

4 (1

0.5%

) pts

, 7 e

vent

sD

KA

: 0In

sulin

pre

cipi

tatio

n in

cat

hete

r: 4

BG<

3.0

mm

ol/l:

7.9

4 (5

.42)

per

mon

th, p

=ns

BG<

2.0

mm

ol/l:

0.4

7 (1

.17)

per

mon

th, p

<0.

050

resu

lted

in c

oma

or s

eizu

res

Mon

th: 3

Mea

n: 7

.88%

SD: 0

.99

Not

e: r

educ

tion

from

base

line:

0.0

9 (0

.92)

Lisp

ro v

s re

gula

r, p

= 0

.01

CSI

I + li

spro

Basa

l 0.3

4 U

/kg,

bolu

s 0.

28 U

/kg

Mon

th: 3

Mea

n: 7

9.2

kgSD

: 17.

1

Not

e: 1

kgga

ined

at

end

of p

erio

d 1,

vs

base

line

p=

ns

Not

rep

orte

dSe

vere

hyp

o: 3

(5.1

%) p

ts (3

epi

sode

s)H

yper

due

to

occl

usio

n: 8

pts

(16

episo

des)

Keto

sis: 1

Hyp

o as

def

ined

: 7 p

ts (8

epi

sode

s)

Mon

th: 3

Mea

n: 7

.41%

SD: 0

.97

Not

e: c

hang

e fr

omba

selin

e: 0

.34

(0.5

9)

CSI

I +so

lubl

eBa

sal 0

.35

U/k

g,bo

lus

0.30

U/k

gM

onth

: 3M

ean:

78.

8kg

SD: 1

7.3

Sign

ifica

nce:

p=

0.78

Not

e: 1

kgga

ined

at

end

of p

erio

d 1,

vs

base

line:

p=

ns

No.

pre

ferr

ing:

not

rep

orte

d

QoL

: not

rep

orte

d

Seve

re h

ypo:

2 (3

.4%

) pts

(3 e

piso

des)

DK

A: 0

Not

e: h

yper

due

to

occl

usio

n: 1

2 pt

s (2

3 ep

isode

s)H

ypo

as d

efin

ed: 7

pts

(11

episo

des)

1 ho

spita

lised

with

feve

r, vo

miti

ng, d

ehyd

ratio

n

(38

pts

repo

rted

109

epi

sode

s of

hyp

er: 3

9 ca

used

by o

cclu

sion,

47

caus

ed b

y ot

her

reas

ons,

23

noid

entif

iabl

e ca

use.

Gro

ups

not

spec

ified

)

Mon

th: 3

Mea

n: 7

.65%

SD: 0

.85

Sign

ifica

nce:

p=

0.0

04

Not

e: c

hang

e fr

omba

selin

e: 0

.09

(0.6

3),

lispr

o vs

reg

ular

p=

0.00

4

cont

inue

d

Rask

in e

t al

.,20

0111

7

Rand

omise

dcr

osso

ver

Dur

atio

n:lis

pro

3m

onth

s,so

lubl

e3

mon

ths

N:5

9 En

d of

stud

y: 5

8

Appendix 13

168

Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

dos

eW

eigh

tPa

tien

t pr

efer

ence

Adv

erse

eve

nts

Renn

er

et a

l.,19

9911

4

Rand

omise

dcr

osso

ver

Dur

atio

n:lis

pro

4m

onth

s,so

lubl

e4

mon

ths

N: 1

13

CSI

I + li

spro

Mon

th: 4

Mea

n: 8

3.1

U/d

ayN

ot r

epor

ted

No.

pre

ferr

ing:

not

rep

orte

d

DT

SQ p

atie

nt s

atisf

actio

n (m

ax.

scor

e of

48

poss

ible

):35

.16

(4.2

5)

QoL

: not

rep

orte

d

Inje

ctio

n sit

e in

fect

ion:

4Se

rious

adv

erse

eve

nt n

ot r

elat

ed t

o dr

ug: 1

Hyp

o: m

ean

12.4

(13.

9), m

edia

n 8,

epi

sode

s/pt

.In

fect

ion

(col

d): 1

9.4%

Rhin

itis:

15.

8%C

athe

ter

occl

usio

n: 2

0 (4

2 ep

isode

s)Ke

tosis

: 5

Mon

th: 4

Mea

n: 6

.77%

SD: 0

.88

Schm

auss

et

al.,

1998

115

Rand

omise

dcr

osso

ver

Dur

atio

n:lis

pro

3m

onth

s,so

lubl

e3

mon

ths

N: 1

1

CSI

I + li

spro

Basa

l 19

(6.6

) IU

/day

Bolu

s 1.

4 (0

.3)

IU/1

2g

carb

ohyd

rate

Not

rep

orte

dN

o. p

refe

rrin

g: 1

1 (1

00%

)G

reat

er fl

exib

ility

with

lisp

ro

No

signi

fican

t di

ffere

nce

intr

eatm

ent

satis

fact

ion

note

d

QoL

: not

rep

orte

d

Seve

re h

ypo:

0D

KA

: 0H

ypos

per

30

days

: 4 (2

.98)

No

seve

re a

dver

se e

vent

s re

gist

ered

by

eith

ertr

eatm

ent

Mon

th: 3

Mea

n: 6

%SD

: 0.9

9

CSI

I +so

lubl

eBa

sal 2

0 (3

.3) I

U/d

ay,

p=

nsBo

lus

1.5

(0.3

)IU

/12

gca

rboh

ydra

te, p

=ns

Not

rep

orte

dN

o. p

refe

rrin

g: 0

QoL

: not

rep

orte

d

Seve

re h

ypo:

0D

KA

: 0H

ypos

per

30

days

: 3.2

(2.3

), p

=ns

Mon

th: 3

Mea

n: 6

.35%

SD: 0

.83

Sign

ifica

nce:

p=

ns

Not

e: H

bA1c

at e

nd o

fea

ch t

reat

men

t pe

riod

not

com

bine

d in

pap

er

CSI

I +so

lubl

eM

onth

: 4M

ean:

85.

4 U

/day

Sign

ifica

nce:

p=

ns

Not

rep

orte

dN

o. p

refe

rrin

g: n

ot r

epor

ted

DT

SQ p

atie

nt s

atisf

actio

n (m

ax.

scor

e of

48

poss

ible

): 32

.36

(5.8

7), v

s lis

pro

p<

0.0

01

QoL

: not

rep

orte

d

Inje

ctio

n sit

e in

fect

ion:

2Se

rious

adv

erse

eve

nt n

ot r

elat

ed t

o dr

ug :

6H

ypo:

mea

n 11

.0 (1

1.2)

, med

ian

8, e

piso

de/p

t,p

=ns

.In

fect

ion

(col

d): 2

1.1%

Rhin

itis:

13.

8%C

athe

ter

occl

usio

n: 2

1 (4

5 ep

isode

s), p

= n

sKe

tosis

: 4

Mon

th: 4

Mea

n: 6

.9%

SD: 0

.97

Sign

ifica

nce:

p<

0.0

2

cont

inue

d


169


Stud

yTr

eatm

ent

Gly

cate

d H

bIn

sulin

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tPa

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t pr

efer

ence

Adv

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eve

nts

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man

et

al.,

1997

118

Rand

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dcr

osso

ver

Dur

atio

n:lis

pro

3m

onth

s,so

lubl

e3

mon

ths

N: 3

0

CSI

I + li

spro

Mon

th: 3

Mea

n: 4

0.4

U/d

aySD

: 9.3

Mon

th: 3

Mea

n: 7

2.6

kgSD

: 9.9

No.

pre

ferr

ing:

not

rep

orte

d

Qua

lity

of li

fe: n

ot r

epor

ted

Skin

rea

ctio

n: 1

6Se

vere

hyp

o: 0

Disc

olou

ratio

n of

insu

lin in

res

ervo

ir or

cat

hete

r (d

idno

t le

ad t

o ob

stru

ctio

n or

sig

nific

ant

hype

rgly

caem

ia):

2

Hyp

os: 8

.6 (7

.7)/

30 d

ays

(vs

base

line

p=

0.0

35)

Hyp

os c

onfir

med

by

BG: 6

.0 (4

.9)/

30 d

ays

(vs

base

line

p=

0.03

)

Mon

th: 3

Mea

n: 7

.66%

SD: 0

.71

CSI

I +so

lubl

eM

onth

: 3M

ean:

40.

8 U

/day

SD: 8

.8Si

gnifi

canc

e: p

= n

s

Mon

th: 3

Mea

n: 7

2.8

kgSD

: 9.9

Sign

ifica

nce:

p

= n

s

No.

pre

ferr

ing:

not

rep

orte

d

QoL

: not

rep

orte

d

Skin

rea

ctio

n: 1

5Se

vere

hyp

o: 0

Disc

olou

ratio

n of

insu

lin in

res

ervo

ir or

cat

hete

r (d

idno

t le

ad t

o ob

stru

ctio

n or

sig

nific

ant

hype

rgly

caem

ia):

2

Hyp

os: 1

0.8

(9.9

)/30

day

s (v

s ba

selin

e an

d lis

pro

p=

ns).

Hyp

os c

onfir

med

by

BG: 7

.6 (7

.1)/

30 d

ays

(vs

base

line

p=

ns, v

s lis

pro

p=

ns)

Mon

th: 3

Mea

n: 8

%SD

: 0.8

8Si

gnifi

canc

e:p

=0.

0041

Sign

ifica

nce

is fo

r C

SII v

s M

DI e

xcep

t w

here

sta

ted.


171


Appendix 14

Calculations for NHS staff costs

Costs/staff Consultant physician Diabetes specialist nurse Dietitian (assuming (assuming discretionary (assuming G grade nurse; senior dietitian, grade 1; point 3 on salary scale) top of salary scale, top of salary scale,

point 5) point 6)

Annual salary (£) 76,700 26,056 25,145Employer’s National Insurance (£) 8,119 1,994 1,910Employer’s pension contribution (£) 5,262 1,730 1,675Overheadsa 24,320 2,216 2,216Capital overheadsa 4,161 2,263 3,606Total annual costs (£) 118,562 34,259 34,552Working time 41 weeks × 40 h 42 wks × 37.5 h 42 weeks × 37 hCost per hour (£) 72.29 21.75 22.23Cost per day (£) 578.35 163.14 164.53

a Overhead estimates based on data from PSSRU.138

Source: Salary scales from Southampton General Hospital Trust (2001–2002).


183

Health Technology AssessmentProgramme

Prioritisation Strategy GroupMembers

Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital

Professor Shah Ebrahim,Professor in Epidemiology of Ageing, University of Bristol

Dr John Reynolds, ClinicalDirector, Acute GeneralMedicine SDU, RadcliffeHospital, Oxford

Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

HTA Commissioning BoardMembers

Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Chair,Professor Shah Ebrahim,Professor in Epidemiology ofAgeing, Department of SocialMedicine, University of Bristol

Deputy Chair, Professor Jenny Hewison,Professor of Health CarePsychology, Academic Unit ofPsychiatry and BehaviouralSciences, University of LeedsSchool of Medicine

Dr Jeffrey AronsonReader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford

Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London

Professor Andrew Bradbury,Professor of Vascular Surgery,Department of Vascular Surgery,Birmingham HeartlandsHospital

Professor John Brazier, Directorof Health Economics, Sheffield Health EconomicsGroup, School of Health &Related Research, University of Sheffield

Dr Andrew Briggs, PublicHealth Career Scientist, HealthEconomics Research Centre,University of Oxford

Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork

Dr Andrew Farmer, SeniorLecturer in General Practice,Department of Primary HealthCare, University of Oxford

Professor Fiona J Gilbert,Professor of Radiology,Department of Radiology,University of Aberdeen

Professor Adrian Grant,Director, Health ServicesResearch Unit, University ofAberdeen

Professor F D Richard Hobbs,Professor of Primary Care &General Practice, Department ofPrimary Care & GeneralPractice, University ofBirmingham

Professor Peter Jones, Head ofDepartment, UniversityDepartment of Psychiatry,University of Cambridge

Professor Sallie Lamb, ResearchProfessor in Physiotherapy/Co-Director, InterdisciplinaryResearch Centre in Health,Coventry University

Professor Julian Little,Professor of Epidemiology,Department of Medicine andTherapeutics, University ofAberdeen

Professor Stuart Logan,Director of Health & SocialCare Research, The PeninsulaMedical School, Universities ofExeter & Plymouth

Professor Tim Peters, Professorof Primary Care Health ServicesResearch, Division of PrimaryHealth Care, University ofBristol

Professor Ian Roberts, Professorof Epidemiology & PublicHealth, Intervention ResearchUnit, London School ofHygiene and Tropical Medicine

Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh

Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York

Professor Martin Severs,Professor in Elderly HealthCare, Portsmouth Institute ofMedicine

Dr Jonathan Shapiro, SeniorFellow, Health ServicesManagement Centre,Birmingham

Ms Kate Thomas,Deputy Director,Medical Care Research Unit,University of Sheffield

Professor Simon G Thompson,Director, MRC BiostatisticsUnit, Institute of Public Health,Cambridge

Ms Sue Ziebland,Senior Research Fellow,Cancer Research UK,University of Oxford

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org)


Health Technology Assessment Programme

184

Diagnostic Technologies & Screening PanelMembers

Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Ms Norma Armston,Freelance Consumer Advocate,Bolton

Professor Max BachmannProfessor Health Care Interfaces, Department of Health Policy and Practice,University of East Anglia

Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust

Dr Paul Cockcroft, Consultant MedicalMicrobiologist/LaboratoryDirector, Public HealthLaboratory, St Mary’s Hospital, Portsmouth

Professor Adrian K Dixon,Professor of Radiology,Addenbrooke’s Hospital,Cambridge

Dr David Elliman, Consultant in Community Child Health, London

Professor Glyn Elwyn,Primary Medical Care Research Group,Swansea Clinical School,University of WalesSwansea

Dr John Fielding,Consultant Radiologist,Radiology Department,Royal Shrewsbury Hospital

Dr Karen N Foster, ClinicalLecturer, Dept of GeneralPractice & Primary Care,University of Aberdeen

Professor Antony J Franks,Deputy Medical Director, The Leeds Teaching HospitalsNHS Trust

Mr Tam Fry, HonoraryChairman, Child GrowthFoundation, London

Dr Edmund Jessop,Medical Adviser,National SpecialistCommissioning Advisory Group(NSCAG), Department ofHealth, London

Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist,National PerinatalEpidemiology Unit,Oxford

Dr Susanne M Ludgate, MedicalDirector, Medical DevicesAgency, London

Dr William Rosenberg, SeniorLecturer and Consultant inMedicine, University ofSouthampton

Dr Susan Schonfield, CPHMSpecialised ServicesCommissioning, CroydonPrimary Care Trust

Dr Margaret Somerville,Director of Public Health,Teignbridge Primary Care Trust

Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull

Professor Martin J Whittle,Head of Division ofReproductive & Child Health,University of Birmingham

Dr Dennis Wright, ConsultantBiochemist & Clinical Director,Pathology & The KennedyGalton Centre, Northwick Park& St Mark’s Hospitals, Harrow

Pharmaceuticals PanelMembers

Chair,Dr John Reynolds, ClinicalDirector, Acute GeneralMedicine SDU, OxfordRadcliffe Hospital

Professor Tony Avery, Professor of Primary HealthCare, University of Nottingham

Professor Stirling Bryan,Professor of Health Economics,Health Services Management Centre,University of Birmingham

Mr Peter Cardy, ChiefExecutive, Macmillan CancerRelief, London

Dr Christopher Cates, GP andCochrane Editor, Bushey HealthCentre

Professor Imti Choonara,Professor in Child Health,University of Nottingham,Derbyshire Children’s Hospital

Mr Charles Dobson, SpecialProjects Adviser, Department ofHealth

Dr Robin Ferner, ConsultantPhysician and Director, WestMidlands Centre for AdverseDrug Reactions, City HospitalNHS Trust, Birmingham

Dr Karen A Fitzgerald,Pharmaceutical Adviser, Bro TafHealth Authority, Cardiff

Mrs Sharon Hart, ManagingEditor, Drug & TherapeuticsBulletin, London

Dr Christine Hine, Consultant inPublic Health Medicine, Bristol South & West PrimaryCare Trust

Professor Stan Kaye,Professor of Medical Oncology,Consultant in MedicalOncology/Drug Development,The Royal Marsden Hospital

Ms Barbara Meredith,Project Manager ClinicalGuidelines, Patient InvolvementUnit, NICE

Dr Frances Rotblat, CPMPDelegate, Medicines ControlAgency, London

Professor Jan Scott,Professor of PsychologicalTreatments,Institute of Psychiatry,University of London

Mrs Katrina Simister, NewProducts Manager, NationalPrescribing Centre, Liverpool

Dr Richard Tiner, MedicalDirector, Association of theBritish Pharmaceutical Industry

Dr Helen Williams,Consultant Microbiologist,Norfolk & Norwich UniversityHospital NHS Trust



185

Therapeutic Procedures PanelMembers

Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Royal Devon& Exeter Hospital

Dr Mahmood Adil, Head ofClinical Support & HealthProtection, Directorate ofHealth and Social Care (North),Department of Health,Manchester

Dr Aileen Clarke,Reader in Health ServicesResearch, Public Health &Policy Research Unit,Barts & the London School ofMedicine & Dentistry,Institute of Community HealthSciences, Queen Mary,University of London

Mr Matthew William Cooke,Senior Clinical Lecturer andHonorary Consultant,Emergency Department,University of Warwick, Coventry& Warwickshire NHS Trust,Division of Health in theCommunity, Centre for PrimaryHealth Care Studies, Coventry

Dr Carl E Counsell, SeniorLecturer in Neurology,University of Aberdeen

Dr Keith Dodd, ConsultantPaediatrician, DerbyshireChildren’s Hospital

Professor Gene Feder, Professorof Primary Care R&D, Barts &the London, Queen Mary’sSchool of Medicine andDentistry, University of London

Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofOrthopaedic Surgery,South Tees Hospital NHS Trust

Ms Bec Hanley, FreelanceConsumer Advocate,Hurstpierpoint

Ms Maryann L. Hardy,Lecturer, Division of Radiography,University of Bradford

Professor Alan Horwich,Director of Clinical R&D, TheInstitute of Cancer Research,London

Dr Phillip Leech, PrincipalMedical Officer for PrimaryCare, Department of Health,London

Dr Simon de Lusignan,Senior Lecturer, Primary CareInformatics, Department ofCommunity Health Sciences,St George’s Hospital MedicalSchool, London

Dr Mike McGovern, SeniorMedical Officer, Heart Team,Department of Health, London

Professor James Neilson,Professor of Obstetrics andGynaecology, Dept of Obstetricsand Gynaecology,University of Liverpool,Liverpool Women’s Hospital

Dr John C Pounsford,Consultant Physician, NorthBristol NHS Trust

Dr Vimal Sharma,Consultant Psychiatrist & HonSnr Lecturer,Mental Health Resource Centre,Victoria Central Hospital,Wirrall

Dr L David Smith, ConsultantCardiologist, Royal Devon &Exeter Hospital

Professor Norman Waugh,Professor of Public Health,University of Aberdeen


Health Technology Assessment Programme

186Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.ncchta.org)

Expert Advisory NetworkMembers

Professor Douglas Altman,Director of CSM & CancerResearch UK Med Stat Gp,Centre for Statistics inMedicine, University of Oxford,Institute of Health Sciences,Headington, Oxford

Professor John Bond,Director, Centre for HealthServices Research,University of Newcastle uponTyne, School of Population &Health Sciences,Newcastle upon Tyne

Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury

Mrs Stella Burnside OBE,Chief Executive,Office of the Chief Executive.Trust Headquarters,Altnagelvin Hospitals Health &Social Services Trust,Altnagelvin Area Hospital,Londonderry

Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London

Mr John A Cairns, Professor of Health Economics,Health Economics ResearchUnit, University of Aberdeen

Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton

Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale

Professor Collette Mary Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham

Professor Barry Cookson,Director, Laboratory of HealthcareAssociated Infection,Health Protection Agency,London

Professor Howard Stephen Cuckle, Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds

Professor Nicky Cullum, Director of Centre for EvidenceBased Nursing, University of York

Dr Katherine Darton, Information Unit, MIND – TheMental Health Charity, London

Professor Carol Dezateux, Professor of PaediatricEpidemiology, London

Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge

Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester

Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne

Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield

Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust

Professor David Field, Professor of Neonatal Medicine,Child Health, The LeicesterRoyal Infirmary NHS Trust

Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield

Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham

Ms Grace Gibbs, Deputy Chief Executive,Director for Nursing, Midwifery& Clinical Support Servs, West Middlesex UniversityHospital, Isleworth

Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol

Professor Alastair Gray,Professor of Health Economics,Department of Public Health,University of Oxford

Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester

Professor F D Richard Hobbs, Professor of Primary Care &General Practice, Department ofPrimary Care & GeneralPractice, University ofBirmingham

Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield

Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame

Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London

Mr George Levvy,Chief Executive, MotorNeurone Disease Association,Northampton

Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital

Professor Rajan Madhok, Medical Director & Director ofPublic Health, Directorate ofClinical Strategy & PublicHealth, North & East Yorkshire& Northern Lincolnshire HealthAuthority, York

Professor David Mant, Professor of General Practice,Department of Primary Care,University of Oxford

Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds

Dr Chris McCall, General Practitioner, The Hadleigh Practice, Castle Mullen

Professor Alistair McGuire, Professor of Health Economics,London School of Economics

Dr Peter Moore, Freelance Science Writer,Ashtead

Dr Andrew Mortimore, Consultant in Public HealthMedicine, Southampton CityPrimary Care Trust

Dr Sue Moss, Associate Director, CancerScreening Evaluation Unit,Institute of Cancer Research,Sutton

Professor Jon Nicholl, Director of Medical CareResearch Unit, School of Healthand Related Research,University of Sheffield

Mrs Julietta Patnick, National Co-ordinator, NHSCancer Screening Programmes,Sheffield

Professor Robert Peveler,Professor of Liaison Psychiatry,University Mental HealthGroup, Royal South HantsHospital, Southampton

Professor Chris Price, Visiting Chair – Oxford, Clinical Research, BayerDiagnostics Europe, Cirencester

Ms Marianne Rigge, Director, College of Health,London

Dr Eamonn Sheridan,Consultant in Clinical Genetics,Genetics Department,St James’s University Hospital,Leeds

Dr Ken Stein,Senior Clinical Lecturer inPublic Health, Director,Peninsula TechnologyAssessment Group, University of Exeter

Professor Sarah Stewart-Brown, Director HSRU/HonoraryConsultant in PH Medicine,Department of Public Health,University of Oxford

Professor Ala Szczepura, Professor of Health ServiceResearch, Centre for HealthServices Studies, University ofWarwick

Dr Ross Taylor, Senior Lecturer, Department of General Practiceand Primary Care, University of Aberdeen

Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network

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HTA

Health Technology Assessm

ent 2004;Vol. 8: No. 43



JL Colquitt, C Green, MK Sidhu, D Hartwell and N Waugh


HTAHealth Technology AssessmentNHS R&D HTA Programme

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.ncchta.org ISSN 1366-5278

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your comments. If you prefer, you can send your comments to the address below, telling us whether you would like

us to transfer them to the website.

We look forward to hearing from you.

October 2004

nhs r&d hta programme - university of warwickwrap.warwick.ac.uk/49877/1/wrap_waugh_csii...

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