FOREWORD iPREFACE iiGUIDE OBJECTIVES iiiGUIDE WORKING COMMITTEE ivEXTERNAL REVIEWERS vSUMMARY OF TREATMENT ALGORITHM vi

SECTION 1 BACKGROUND 1

SECTION 2 RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES 4

SECTION 3 BARRIERS TO INSULIN THERAPY 10

SECTION 4 INSULIN TYPES AND REGIMENS 15 4.1 Insulin types 4.2 Insulin analogues 4.3 Insulin regimens

SECTION 5 INSULIN INITIATION AND OPTIMISATION (DOSE ADJUSTMENT) 22 5.1 Initiating and optimising with basal insulin 5.2 Initiating and optimising with premixed insulin 5.3 Initiating and optimising with prandial insulin 5.4 Initiating and optimising with basal and prandial insulin

SECTION 6 INSULIN INTENSIFICATION (SWITCHING INSULIN REGIMENS) 31 6.1 Switching from basal to basal plus regimen 6.2 Switching from basal to basal bolus regimen 6.3 Switching from basal to premixed regimen 6.4 Switching from premixed to basal bolus regimen 6.5 Switching from single to multiple premixed regimen 6.6 Intensifi cation of premixed regimen with addition of pre-meal bolus 6.7 Intensifi cation of prandial regimen with addition of basal insulin

TABLE OF CONTENTS

SECTION 7 TARGETS AND MONITORING 42 7.1 Glycemic targets 7.2 Monitoring insulin therapy

SECTION 8 PROBLEMS WITH INSULIN THERAPY 48 8.1 Hypoglycemia 8.2 Weight gain 8.3 Injection site problems 8.4 Insulin allergy and hypersensitivity

SECTION 9 SPECIAL SITUATIONS 55 9.1 Sick days 9.2 Travel 9.3 Exercise 9.4 Fasting (Ramadan) 9.5 Pregnancy

SECTION 10 PRACTICAL ISSUES 64 10.1 Insulin handling and storage 10.2 Insulin injection sites 10.3 Insulin pen devices 10.4 Insulin absorption 10.5 Insulin injection problems 10.6 Self Monitoring of Blood Glucose (SMBG)

APPENDIX Carbohydrate counting 75 INDEX 77

GLOSSARY OF TERMS 81

ACKNOWLEDGEMENTS 82

SOURCES OF FUNDING 82

TABLE OF CONTENTS

FOREWORD BYi

THE DIRECTOR GENERAL OF HEALTH OF MALAYSIA.

In Malaysia, the prevalence of diabetes mellitus among adults aged 30 years and abovehad risen by almost 80% in the last decade to 14.9%. This translates to one in six adultMalaysians above 30 years with diabetes, an estimated 1.4 million in number. It isestimated that 95% of those with diabetes in Malaysia have Type 2 Diabetes.

With increased duration of disease, oral anti-diabetic medications often lose effectiveness and consequently there is a need to add insulin to maintain glycemic control. Theuse of insulin therapy among patients with Type 2 diabetes within the Ministry of Healthhas continued to increase with the recognition of the need to maintain good glycaemiccontrol towards prevention of long-term diabetes-related complications, as recom-mended by recent local and international diabetes guidelines. However, insulin use inprimary care, both public and private, is still generally low in Malaysia and varies acrossdifferent states in the country. This may be due to poor acceptance of insulin therapy among patients and healthcare providers, probably due to lack of awareness, knowledgeand guidance. Diabetes-focused health education and counseling will defi nitely improveawareness, acceptance and adherence to insulin therapy among patients with diabetes.

Despite the increase in insulin use, the majority of insulin-treated patients are not ableto attain and maintain satisfactory long-term glycaemic control, as seen from recentaudits. I understand that one of the main reasons is the lack of a standardised way ininitiating, optimising and intensifying insulin therapy. There is therefore an urgent needto have a set of guidelines in place for this provision.

I would like to congratulate our MOH’s (Ministry of Health) endocrinologists who haveworked tirelessly to develop this practical guide for insulin therapy for patients withType 2 diabetes. I am sure this will provide simple and clear steps for all healthcareproviders to initiate insulin safely, optimise doses well and intensify insulin regimenspromptly to ensure that insulin therapy is administered in a cost effective manner inMOH. In addition I believe this will enable more patients to achieve and maintain goodglycaemic control, with reduction of the risk of long-term complications which equallypresents a huge economic burden.

I urge all of you to make full use of this new practical guide for insulin therapy in Type2 Diabetes, as it represents another important clinical tool for improving quality ofdiabetes care in the country.

TAN SRI DATO’ SERI DR. HJ. MOHD ISMAIL MERICAN

The prevalence of diabetes in Malaysia continues to increase at an alarming rate from1-2% in the 1960s and 1970s, 6.3% in 1986 (NHMS I), 8.2% in 1996 (NHMS II) to14.9% in 2006 (NHMS III). More recent studies have indicated that the prevalencehas risen to beyond 20%. This is largely contributed by a parallel increase in rates ofoverweight/obesity and high rates of physical inactivity among the adult populationtogether with population growth, aging and urbanization.

Oral anti-diabetic medications comprise the mainstay of treatment for patients withtype 2 diabetes in Malaysia. The majority of patients receiving treatment have suboptimal glycaemic control, often as a result of treatment inertia with lack of optimsation of oral medications and delay in insulin initiation. Insulin use in the management of type 2 diabetes is still seriously lacking especially in primary care. Currently insulin therapy is used in an estimated 20% of outpatients with diabetes inthe MOH Health facilities, noted from a survey done by Institute of Health Management(IHM) in 2008. This has increased compared to 13% in a similar survey by IHM in 2005.

The increase in insulin use is expected with current treatment guidelines (CPGManagement of Type 2 DM 2009) recommending earlier use of insulin therapy inpatients with sub-optimal glycemic control either at presentation or with failure of oralanti-diabetic agents.

Unfortunately, several local audits have shown that very few patients on insulin therapyare able to achieve good glycaemic control, as measured by HbA1c of less than 6.5%.Only 10 – 15% of patients on insulin therapy are able to achieve recommended glycaemic targets. Studies have also shown that in most instances insulin is prescribed using lessintensive regimens without good optimisation of dose.

The barriers to achieving good glycaemic control include poor medication adherence,hypoglycaemia, poor optimisation of insulin doses, lack of intensifi cation of insulinregimens, especially the use of more intensive insulin regimens that require morefrequent injections, the and use of both meal and basal insulin (basal bolus regimens).

In recent years, a large proportion of diabetes care in developed countries has movedfrom specialist units to primary care and insulin is now frequently and successfullyinitiated in the primary care setting. This change has been sponsored by governmentpolicies and guidelines which encourage providers of primary care to initiate and manage insulin.

This Practical Guide to Insulin Therapy has been developed to provide a clear andconcise approach to all health care providers on current concepts in the use of insulin in the management of type 2 diabetes (T2DM). I hope it will help to address the current shortfalls in the management of patients with T2DM requiring insulin therapy and it willbe fully utilised by all relevant health care providers, especially in primary care. Last but not least I would like to express my gratitude to everyone involved in the development of this practical guide and especially to the task force members for their immense support and contribution.

Dr Zanariah HusseinChairpersonWorking Committee

PREFACEii

ObjectivesThe aim of the practical guide is to assist health care providers, particularly primarycare physicians in making key decisions to initiate, optimise and intensify insulinmanagement and decrease long-term morbidity risk in patients with Type 2 diabetes.

Clinical QuestionsThe clinical questions of these guidelines are:1. Why is insulin therapy needed in Type 2 diabetes?2. How to initiate insulin therapy?3. How to optimize insulin doses?4. How to intensify insulin regimens?5. How to monitor glycemia in patients on insulin therapy?6. What are the problems and practical issues related to insulin therapy?

Target PopulationThis practical guide is applicable to children, adolescents and adults with T2DM

Target GroupThis practical guide is meant for all health care professionals involved in treatingpatients with T2DM which includes medical offi cers, family medicine specialists,primary care physicians, general practitioners, public health personnel, generalphysicians, endocrinologists, cardiologists, nephrologists, neurologists, geriatricians,obstetricians and gynaecologists, paediatricians, ophthalmologists, nurses, assistantmedical offi cers, podiatrists, pharmacists, dieticians and diabetic nurse educators.

GUIDE OBJECTIVESiii

CHAIRPERSON

MEMBERS (Alphabetical Order)

Dr. Zanariah HusseinSenior Consultant Endocrinologist,Hospital PutrajayaPutrajaya

Dr. Foo Siew HuiConsultant Endocrinologist,Hospital SelayangSelangor

Dr. Lim Siang ChinConsultant Endocrinologist,Hospital MelakaMelaka

Dr. Masni MohamadConsultant Endocrinologist,Hospital PutrajayaPutrajaya

Dr. Mohamed Badrulnizam Long BidinConsultant Endocrinologist,Hospital Kuala LumpurKuala Lumpur

Dr. Noor Lita AdamConsultant Endocrinologist,Hospital SerembanSeremban

Dr. Nurain Mohd. NoorConsultant Endocrinologist,Hospital PutrajayaPutrajaya

Dr. Shamita SharmaConsultant Endocrinologist,Hospital AmpangSelangor

Dr. Yong Sy LiangConsultant Endocrinologist,Hospital KlangSelangor

GUIDE WORKING COMMITTEEiv

Prof. Dato’ Paduka Dr. Wan Mohamad Wan BebakarSenior Consultant Endocrinologist,Hospital Universiti Sains Malaysia,Kubang Kerian, Kelantan

Prof. Dr. Nor Azmi KamaruddinPresidentMalaysian Endocrine and Metabolic Society (MEMS)Senior Consultant Endocrinologist,Pusat Perubatan Universiti Kebangsaan Malaysia,Kuala Lumpur

Dato. Dr. Santha KumariSenior Consultant PhysicianHospital KlangSelangor

Dr. G. R. Letchuman RamanathanSenior Consultant Physician,Hospital Taiping,Perak

Dr. Feisul Idzwan MustaphaPublic Health Physician,Disease Control Division,Department of Public Health,Ministry of Health Malaysia,Putrajaya

Dr. Mastura IsmailFamily Medicine Specialist,Klinik Kesihatan Ampangan,Negeri Sembilan

(The following external reviewers provided feedback on the draft)

EXTERNAL REVIEWERSv

SUMMARY OF TREATMENT ALGORITHMvi

Newly diagnosed DM & Type 2 DM• Symptomatic (osmotic symptoms) regardless HbA1c or FBS• HbA1c > 10% or FPG > 13 mmol/LType 2 DM on maximal OADs (single/double/triple)• HbA1c > 8%

Glycemicabnormality?

FPG, SMBG

Normal Fasting / prebreakfast BG High daytime BG

BASAL PLUS (premeal and

bedtime)Optimise dose Optimise dose Optimise dose

Sequential addition of

prandialinsulin

PREMIXED TDS* (premeals)

PREMIXED BD PLUS PRANDIAL

(prelunch)

StartPRANDIAL

only(usually TDSpremeals)

Optimisedose

StartBASAL BOLUS

(premeals, bedtime)

StartPREMIXED

BD (prebreakfast & predinner)

StartPREMIXED

OD(predinner)

StartBASAL

only(bedtime)

High Fasting /prebreakfast BG

Normal daytime BG

High Fasting /prebreakfast BG High daytime BG

Add

basa

l ins

ulin

Add

3 pr

andi

al in

sulin

BASAL BOLUS (prandial insulin at premeals, basal insulin at bedtime) Optimise dose

Note:1. Metformin should be continued while on insulin therapy unless contraindicated or intolerant2. Sulphonylureas / Meglitinides should be withdrawn once prandial insulin is used regularly with meals3. Insulin dose should be optimized prior to switching / intensifying regimens

* refers to insulin analogues only

Optimisedose

Optimisedose

Optimisedose

Optimisedose

BACKGROUND

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

Section1

In Malaysia, the Third National Health and Morbidity Survey (3rd NHMS) in 2006 showed that the prevalence of T2DM for adults aged 30 years old andabove had risen by almost 80% in the last decade to 14.9%1. In this populationsurvey of those with diabetes, 73.5% attended government health facilitiesand 20% received treatment from private health facilities. The majority, 77%were treated with oral anti-diabetic medications only and a mere 7% werereceiving insulin therapy at the time of the survey. The National Medicines UseSurvey (NMUS) in 2006 reported that insulin therapy contributed to only 8.2%of overall anti-diabetic drug utilisation for the country2. These fi gures representlow rates of insulin use when compared to other countries.

A nationwide audit done by the Institute of Health Management (IHM)3, MOH in2005 and 2008 showed that the use of insulin in MOH health facilities (primary,secondary and tertiary) was 13% and 19% respectively, mainly prescribed intertiary hospitals with low use in primary and secondary care. A recent MOHaudit in primary care (NCD Diabetes Clinical Audit 2009) found that insulin usein primary care was about 11.8% with marked differences between states. Useof insulin therapy in tertiary care was much higher at 54%4 (DiabCare 2009) andhas doubled compared to 28%5 (DiabCare 2003) in patients attending specialistclinics in MOH state hospitals and academic instituitions. The NMUS alsoshowed that insulin use was far greater in the public sector compared to theprivate sector refl ecting the burden of patients seen and managed by the publicsector.

Local audits and hospital based surveys have shown that more than 80% ofpatients were receiving less intensive insulin regimens. The most prescribedregimens were the ”basal only” insulin regimen (1 injection daily) in about 39%of patients and ”premixed” insulin regimen in 45% of patients. More intensiveregimens requiring 3 - 4 injections per day were prescribed in only 13% ofpatients attending physician practice (IDMPS 2006)6. The majority ( > 80%) ofpatients on insulin did not achieve HbA1c of less than 6.5%. There are manyproblems in our current practice with insulin therapy that represent barriers toachieving good glycaemic control such as poor patient acceptance, treatmentinertia, hypoglycemia, inadequate dosing, lack of optimisation of insulin regimens,inappropriate timing of injections, non-adherence to insulin regimens and others.

BACKGROUND2

3REFERENCES

1. The Third National Health and Morbidity Survey 2006 (NHMS III). Institute for Public Health, National Institute of Health, Ministry of Health, Malaysia.

2. GR Letchumanan, P.K.Yap Muruga V, SP CHan, Oiyammal C, Loh KM, Ariza Z, Emieda MH, Selva Malar, Zanariah H, M Badrulnizam. Chapter 5 Use Antidiabetics.-Report of National Medicines Use Survey. Malaysian Statistics on Medicine 2004 Pg 9-11. (Published April 2006).

3. Haliza AM et al. Management of patients with type 2 diabetes mellitus in Ministry of Health hospitals and health centres. Journal of Health Management. Vol 4 no 1/ 2008 Institute of Health Management, Malaysia.

4. Results of Diabcare(Malaysia) 2009. Novo Nordisk data on fi le.

5. Mafauzy M. Diabetes Control and Complications in Public Hospitals in Malaysia. For the Diabcare-Malaysia Study Group. Med J Malaysia Vol 61 No 4 October 2006.

6. Juliana Chan et al. Multifaceted Determinants for Achieving Glycemic Control. The International Diabetes Management Practice Study (IDMPS). Diabetes Care 2009; (32):227-233.

RATIONALE FOR INSULIN THERAPY IN T2DM

Section2

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

Insulin resistance and impaired insulin secretion form the two key factors to developing T2DM. These two factors are already present at an early stage inthose with pre-diabetes, and worsen with time. At diagnosis, as seen in the UKPDS, pancreatic beta cell function was found to be approximately 50 % ofnormal, with a decline of approximately 5% per year1. It was estimated that thereduction in beta-cell function begins 10-12 years prior to diagnosis and approached less than 25 % of normal function 6 years after diagnosis2. (Figure 2.1)

ß-C

ell F

unct

ion

(%)

100

75

50

25

0-12 -10 -2 0 2 6 10 14

Years From Diagnosis

IGT PostprandialHyperglycemia

Type 2Diabetes

Figure 2.1Progressive Decline in Beta-cell Function in Type 2

T2DM is a progressive disease characterised by worsening glycemia. There aremany reasons why beta cells continue to decline. One of the important reasonsis glucose toxicity (Figure 2.2)3.The progressive decline in beta cell functionultimately renders oral agents ineffective and the majority of patients withT2DM will require exogenous insulin treatment. Besides restoring circulatinghormone levels, insulin treatment has benefi cial effects on insulin sensitivity,vascular function, dyslipidemia and biomarkers that predict vascular damage.

RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

5

Insulin is widely accepted as the most effective treatment option available to helppeople with T2DM achieve treatment targets for glycemic control. Insulin therapyis suitable at all stages of T2DM, for all ages, and with a wide range of treatmentoptions and regimens. Insulin has a well documented safety profi le and is generallywell tolerated in those with T2DM. The glucose lowering effects of insulin areunmatched and no maximum dose exists. Insulin can be usefully combined withother oral anti-diabetic agents and recently has also been shown to give improved glycemic control when combined with the other injectable agents, GLP-agonists or mimetics4.

Numerous randomised controlled trials and large observational studies haveshown that good glycemic control can be achieved in patients with T2DM whoare treated with insulin or insulin analogues using treatment algorithms5,6.

As most people with T2DM will ultimately require long-term insulin therapy dueto the progressive nature of the disease, it seems rational to add insulin therapyearlier rather than later. Therefore, the Malaysian CPG on Management of T2DM2009 recommends to initiate insulin in those newly diagnosed with HbA1c ofmore than 10% or fasting blood glucose (FBS) > 13mmol/L or in those oncombination OADs who are unable to achieve target HbA1c (See Figure 2.3).

Figure 2.2Overview of factors infl uencing stages from insulin resistance to progressionof T2DM

Lifestyle factors:diet, exercise,

smoking, alcohol

Insulinresistance

Geneticfactors

Lipotoxicity

Amyloid deposition

Beta celldysfunction

Glucosetoxicity

Progression oftype 2 diabetes

Genetic andenvironmentalfactors causesusceptibility

Declining betacell function

RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

6

7

Figure 2.3Treatment Algorithm for the Management of Type 2 Diabetes Mellitus(From Management of T2DM CPG 2009)

Diagnosis of Type 2 DiabetesAll patients advised LIFESTYLE

HbA1c < 6.5% ORFPG < 6 mmol/L

LIFESTYLE APPROACH*

Follow-up with HbA1c after3 months

If HbA1c ≤ 6.5% continue with Lifestyle Approach.

If HbA1c > 6.5% on follow-up, consider OAD monotherapy

HbA1c 6.5 - < 8.0%OR FPG 6 - < 10 mmol/L

OAD MONOTHERAPY

Metformin**ORAGI / DPP-4 Inhibitor / Glinides / SU / TZDs

Optimise dose ofOAD agent in the subsequent 3-6 months

Follow-up withHbA1c after 3-6 months

If HbA1c ≤ 6.5%, continue therapy

If HbA1c > 6.5%, consider COMBINATION OAD Therapy

HbA1c 8.0 - 10.0% OR FPG 10 - 13mmol/L

COMBINATION THERAPY***

Metformin with other OAD agents (AGI / DPP-4 Inhibitor / Glinides / Incretin Mimetic / SU / TZDs) or with insulin

Optimise dose of OAD agents in the subsequent 3-6 months

Follow-up with HbA1c after 3-6 months

If HbA1c ≤ 6.5%, continue therapy

If HbA1c > 6.5%, consider addition of INSULIN THERAPY

HbA1c > 10.0% OR FPG > 13 mmol/L

COMBINATION THERAPY + BASAL / PREMIXED INSULIN THERAPY

OR

INTENSIVE INSULIN THERAPY, continue Metformin

Footnote:If symptomatic (weight loss, polyuria, etc) at any HbA1c and FPG level, consider insulin therapy.Try to achieve as near normal glycaemia without causing hypoglycaemia* Consider metformin/AGI/other insulin sensitiser in appropriate patients** Metformin is the preferred 1st line agent, and SU should preferably not be used as 1st line*** Although 3 oral agents can be used, initiation and intensifi cation of insulin therapy is preferred based on effectiveness and expense

It is important to discuss the role of insulin therapy with your patients even at thetime of diagnosis of T2DM. (Refer Table 2.1)

Table 2.1Issues for patient discussion at time of diagnosis - role of insulintherapy

Introduce your patient to the eventual need for insulin so that it isnot used as a punishmnent

• Type 2 DM results from insuffi cient insulin secretion due to beta cell dysfunction

• Over time beta cell function continues to deteriorate resulting in increasing blood glucose levels

• Elevated glucose levels can lead to diabetes complications, progression of disease and deteriorating health

• Treatment of elevated blood sugars slows the gradual worsening of health

• Insulin injections will eventually be required to replace the body’s own insulin, control blood sugar and slow disease progression

(derived from Practical Guidance to Insulin Management – Primary Care Diabetes 4 Supplement 1 ( 2010) S43 – 56)

Short term use of insulin therapy in patients with T2DM may also be consideredin the following conditions:

• Acute illness, surgery, stress and emergencies

• Pregnancy

• Breast-feeding

• As initial therapy in T2DM with marked hyperglycemia

• Severe metabolic decompensation (eg. DKA, HHS)

8 RATIONALE FOR INSULIN THERAPY IN TYPE 2 DIABETES MELLITUS

9REFERENCES

1. UKPDS Group. UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes-A progressive Disease. Diabetes 1995; 44:1249-1256.

2. Holman RR. Assessing the potential for Alpha-glucosidase Inhibitors in Prediabetes States. Diabetes Res Clin Pract 1998;40(suppl.):S21-S25.

3. Vincent P et al. Glucolipotoxicity: Fuel Excess and Beta Cell dysfunction. Endocrine Review, 2008.

4. Maria Tzafos et al. Glucagon-Like Peptide-1 Analog and Insulin Combination Therapy in the management of adults with type 2 Diabetes Mellitus. The Annals of Pharmacotherapy. 2010. 44(7); 1294-1300.

5. Ryuza Kawamori et al. IMPROVE Observational Study of Biphasic Insulin Aspart 30/70 in Patients with Type 2 Diabetes Mellitus. Expert Rev Endocrinol Metab. 2010; 5(4):507-516.

6. Schreiber SA et al. The long term effi cacy of insulin Glargine plus oral antidiabetic agents in a 32-month observational study of every day clinic practice. Diabetes Technol Ther. 2008. Apr;10(2):121-127.

Section3

BARRIERS TO INSULIN THERAPY

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

Insulin is the most effective drug available to achieve glycemic targets in patientswith T2DM yet there is reluctance among patients and physicians to initiateinsulin. There are many barriers to insulin treatment among health care providersand patients.

3.1 Patient barriers

In a recent survey the International Diabetes Management Practises Study (IDMPS), which is a global registry performed to assess the current managementpractices in patients with diabetes, it was shown that one of the reasons forpatients not reaching target is fear of injection1.

Another recent global survey entitled the Global Attitudes of Patients and Physicians in Insulin Therapy (GAPPTM), conducted specifi cally to assess needsand challenges relating to insulin treatment, found that more than one in threediabetes patients skip doses or fail to take their insulin as prescribed, on averagethree times in the last month. Being too busy or simply forgetting to take theinsulin are the main reasons cited by patients missing insulin doses. Two thirdsof patients taking insulin in the study were concerned about experiencing a hypoglycemic event in the future. Nine in 10 patients wished for less invasiveinsulin regimens where insulin could be dosed less than once a day.2

It is important to address the patient’s concerns regarding insulin by enquiringabout the following prior to initiating insulin2:• What do you need to know to consider insulin?• What problems do you think you can encounter?• What do you think are the benefi ts and the negative effects of insulin?• What will help you to overcome the concerns?• Are you willing to consider insulin? If not, what would cause you to consider insulin?

As healthcare providers, it is important to identify the patient’s barriers to insulintherapy and implement strategies to overcome or decrease these barriers as thiswill assist the patient in the decision-making process to accept and adhere toinsulin therapy (Refer Table 3.1)

To provide encouragement and support for insulin use it may be useful to do thefollowing;• Give your patient materials that they can use at home, such as information sheets, patient diary, and contact information for diabetes support groups or websites• Involve family and friends for support• Recommend that the patient join a local diabetes support group• Encourage your patient to talk to someone who has been successfully treated with insulin therapy

BARRIERS TO INSULIN THERAPY 11

Possible barriers Suggested solutions and issues for patient discussion

Insulin as a personal failure

Insulin causes complicationsand death

Insulin injectionsare painful

Fear ofhypoglycaemia

Change in lifestyle1) Restricts independence2) Concern of injecting insulin in public places

Insulin is noteffective

Insulin causes weight gain

• Reassure your patient they have done nothing wrong• Emphasize the pathophysiology of Type 2 DM Diabetes progression means insulin will be needed eventually• Explain that starting insulin at the right time will help with glycemic control and slow disease progression

• Provide information to counteract this belief• Acknowledging the patients fear and informing the provider’s experience is helpful• Discuss that adding insulin does not mean health is deteriorating; rather, it is an effective step to prevent diabetes progression and complications

• Explain the benefi ts of using pen / injection devices• Demonstrate insulin injection technique for subcutaneous injections with a practice pen to the patients. Highlight sites of injection• Let the patient try an injection test / placebo injection

• Reassure them that there are strategies to prevent, recognize and treat hypoglycaemia and thus avoid severe events• Basal insulins have minimal risks

Provide information and discuss about insulin and pen. • Modern injection devices (insulin pens) are convenient, discreet and simple to use• Insulin can fi t in with daily life • Selection of insulin type and regimens with maximum fl exibility

• Inform that diabetes is an insulin-related problem and the insulin used is very similar to that produced naturally• Offer a 3-month trial to get the patient used to the idea• Once patients try insulin they rarely want to change, because it is successful

• Consult a dietician and discuss strategies to prevent weight gain• Lifestyle interventions with diet and exercise continue to be important

Table 3.1: Barriers to insulin therapy and suggested solutions

12 BARRIERS TO INSULIN THERAPY

13

3.2 Provider barriers

Barriers to insulin therapy are also seen among health care providers. Thisalso leads to delayed initiation of insulin therapy3.

Some barriers are listed below:• Lack of resources — drug costs, staff, skills• Time constraints• Lack of familiarity/experience• Lack of tools/algorithm• Effi cacy concern• Risk of severe hypoglycaemia /adverse effects on quality of life (QoL)• Concerns about patient refusal and non-compliance • Concerns relating to educating patients• Excess weight gain in already overweight patients• Too demanding for elderly patients

Convincing patients to be on insulin therapy can be challenging. Good communication between patients and health care providers is the key to overcoming psychological barriers to insulin therapy.

Strategies to overcome these barriers among health care providers include:

• Building knowledge, experience and confi dence by continuous training and education of health care providers• Discuss challenging and/or successful insulin initiation cases with health care provider peers• Networking between diabetes educators, pharmacists and diabetes support groups• Providing comprehensive patient education• Arrange for timely patient follow-up to ensure patient adherence and identify and resolve potential diffi culties and challenges• Development and implementation of comprehensive algorithms for optimi- sation and intensifi cation of insulin

14 REFERENCES

1. Juliana Chan et al. Multifaceted Determinants for Achieving Glycemic Control. The International Diabetes Management Practice Study (IDMPS). Diabetes Care 2009; (32):227-233.

2. New Global Survey Reveals Over One in Three Patients Fail to Take Insulin as Prescribed -Global Attitudes of Patients and Physicians in Insulin Therapy (GAPPTM) Survey - Press Release by Newswire 21st September 2010.

3. Martha M et al. Overcoming barriers to the initiation of insulin therapy. Clinical diabetes. Vol 25, No 1, 2007.

4. Mark Peyrot el al . Resistance to Insulin therapy among patients and providers. Results of the cross national Diabetes, Attitude, Wishes and Needs ( DAWN) Study. Diabetes Care. Vol 28, No 11, 2005.

Section4

INSULIN TYPES AND REGIMENS

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

4.1 Insulin Preparations

The insulin currently used in Malaysia is recombinant human insulin, eitherdirectly derived from the native human insulin, i.e. regular human insulin orstructurally modifi ed, i.e. insulin analogue. Both types of insulin are furtherdivided into prandial, basal and premixed insulin according to their pharmacoki-netic profi les (Table 4.1a).

• Prandial insulin is administered pre-meal because of its short or rapid onset of action for controlling the post-prandial glucose excursion. It is also used in insulin pumps.• Basal insulin is administered once or twice daily. The intermediate or long-acting pharmacokinetic profi le covers the basal insulin requirements in between meals and overnight due to endogenous hepatic glucose production. • Premixed insulin is biphasic insulin that incorporates the combination of short or rapid-acting insulin with its intermediate-acting counterpart into a single preparation to cover for both postprandial glucose excursion as well as basal insulin needs simultaneously (Table 4.1b).

Table 4.1a Insulin Preparations available in Malaysia

Rapid-acting- Novorapid® (Aspart)- Humalog® (Lispro)- Apidra® (Glulisine)

Long-acting- Lantus® (Glargine)- Levemir® (Detemir)

Combination of rapid-acting & protaminated analogue- NovoMix® 30 (30% aspart + 70% aspart protamine)- Humalog Mix® 25 (25% lispro + 75% lispro protamine)

INSULIN TYPES AND REGIMENS

InsulinType Conventional

Short-acting regular human insulin- Actrapid®

- Humulin R®

Intermediate-acting or Neutral Protaminated Hagedorn (NPH) Insulin- Insulatard®

- Humulin N®

Combination of short & intermediate-acting: 30% regular insulin + 70% NPH- Mixtard® 30- Humulin® 30/70

Analogue

Prandial

Basal

Premixed

16

17

Table 4.1b Pharmacokinetic profi les of various types of insulin1

a) Short-acting, regular- Actrapid®*- Humulin R®*

c) Intermediate-acting, NPH - Insulatard®*- Humulin N®*

e) Premixed human (30% regular insulin+ 70% NPH)- Mixtard® 30*- Humulin® 30/70*

f) Premixed analogue- NovoMix® 30 (30% aspart + 70% aspart protamine)*- Humalog Mix® 25 (25% lispro + 75% lispro protamine*

d) Long-acting analogue- Glargine®*- Detemir®*

b) Rapid-acting analogue- Novorapid® (Aspart)*- Humalog® (Lispro)*- Apidra® (Glulisine)

30 mins before meal

Pre-breakfast / Pre-bed

30-60 minsbefore meals

5-15 minsbefore meals

Same time everyday at

anytime of the day

5-15 mins before or

immediately after meals

30 min30 min

1.5 Hr1 Hr

30 min30 min

10-20 min

0-15 min

2-4 Hr1 Hr

10-20 min0-15 min5-15 min

1-32-4

4-124-10

dualdual

dual

dual

peaklesspeakless

1-31

1-2

86-8

18-2316-18

18-2316-18

18-23

16-18

20-2417-23

3-53.5-4.5

3-5

N.B. The time course of action of any insulin may vary in different individuals, or at different times, or at different injection locations in the same individual. Due to such variations the time periods described above should be used as general guidelines only.The short-acting and the intermediate-acting insulin can be self mixed as an alternativeto the human premixed insulin although this is not encouraged due to signifi cant reductionin the reproducibility of insulin action.

* Available at Ministry of Health, Malaysia.

Brand (Generic) Name Onset Peak (Hr) Duration

(Hr)Timing of

insulin

4.2 Comparison of Conventional Insulin and Insulin Analogues

Insulin analogue is derived from human insulin in which the amino acid sequenceis intentionally altered to produce an improved pharmacokinetic profi le thatmimics physiological insulin secretion better.

• Prandial analogue mimics the fi rst phase of insulin secretion in response to a meal• Basal analogue mimics the physiological basal insulin secretion in-between meals and overnight• Premixed analogue consists of both rapid-acting and intermediate-acting insulin analogues and was developed to more closely mimic physiological endogenous insulin secretion and meet the needs of patients who require both basal and prandial insulin but wish to limit the number of daily injections

The differences between prandial, basal & premixed analogues compared tohuman insulin are summarized in Table 4.2.

Individuals with the following situations should be considered for insulin analoguetherapy:

a) Rapid-acting analogue- Delayed inter-meal hypoglycemia preventing achievement of postprandial glycemic target on regular short-acting insulin- Lifestyle restriction, the need to eat immediately after insulin injection due to job schedule etc.- Variable carbohydrate intake

b) Long-acting analogue- Nocturnal hypoglycemia on intermediate-acting insulin (NPH) preventing achievement of target fasting blood glucose- Inadequate basal insulin coverage with once daily intermediate-acting insulin (NPH) and not willing to go on NPH twice daily

INSULIN TYPES AND REGIMENS18

19

Characteristics

Onset

Administration

Postprandial glycemic control

Inter-meal hypoglycemia

Inter-meal hyperglycemia

Dosing fl exibility

Pharmacokinetics

Cost

Delayed

30 min before meals

+

++

+

+

Less physiological

Lower

Immediate

With meals

++

+

++

++

More physiological

Higher

Duration

Peak

Nocturnal hypoglycemia

Absorption

Weight gain

Pharmacokinetics

Cost

< 24Hr

Pronounced

++

Variable

++

Less physiological

Lower

~24Hr

Absent / minimal

+

Reproducible

+/- (detemir)

More physiological

Higher

Administration

Postprandial glycemic control

Inter-meal hypoglycemia

Dosing fl exibility

Dosing interval

Pharmacokinetics

Cost

30min before meals

+

++

+

Once to twice daily

Less physiological

Lower

With meals

++

+

++

Once to thrice daily

More physiological

Higher

Conventional

PRANDIAL INSULIN

BASAL INSULIN

PREMIXED INSULIN

Analogue

Table 4.2 Comparison of conventional and analogue insulin2,3,4

BASAL

BASAL

BASAL-PLUS (2)

BASAL

PREMIXED BD

PRANDIAL

PREMIXED-PLUS

PREMIXED TDS

PREMIXED-PLUS

BASAL-BOLUS

BASAL-BOLUS

PREMIXED OD

BASAL-PLUS (1)

1

2

3

4

5

Intermediate acting (NPH) insulin pre-bed

Intermediate acting (NPH) pre-breakfast and pre-dinner

Basal insulin once daily + 2 prandial insulin

Long-acting analogue once daily

Premixed insulin pre-breakfast and pre-dinner

Prandial insulin pre-breakfast, pre-lunch and pre-dinner

Premixed insulin pre-breakfast, pre-dinner + 1 prandial insulin pre-lunch

Premixed analogue pre-breakfast, pre-lunch and pre-dinner

Prandial insulin pre-breakfast and pre-lunch + premixed insulin pre-dinner

Basal insulin once daily + prandial insulin pre-breakfast, pre-lunch and pre-dinner

Intermediate acting (NPH) insulin pre-breakfastand pre-dinner + prandial insulin pre-breakfast, pre-lunch and pre-dinner

Premixed/ premixed analogue pre-dinner

Basal insulin once daily + 1 prandial insulin

4.3 Insulin Regimen

4.4 An ideal insulin regimen should mimic the physiological insulin response tomeals and endogenous hepatic glucose production. The various types of insulinregimen can be classifi ed as below (Table 4.3).

The choice of insulin regimen should be individualised, based on the patient’sglycemic profi le, dietary pattern, personal lifestyle as well as desired fl exibility.

Table 4.3 Insulin regimens and frequency of injections per day

Apart from insulin pump therapy, basal bolus therapy using the combination oflong-acting basal and rapid-acting analogue offers the regimen that most closelymimics the endogenous insulin action at the expense of increased number ofinjections.

No. ofinjections per day

Insulin regimen Type of insulin and timing

20

21REFERENCES

1. DeWitt DE et al. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: Scientifi c review. J Am Med Assoc. 2003; 289:2254-64.

2. Raskin P et al. Use of insulin aspart, a short-acting insulin analogue as the meal time insulin in the management of patients with type 1 diabetes. Diabetes Care. 2000; 23:583

3. Manucci E et al. Short-acting insulin analgues versus regular human insulin in type 2 diabetes: a meta-analysis. Diabetes, Obes & Metab. 2009; 11:53-59.

4. Qayyum R et al. Systematic review: Comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes. Ann Intern Med. 2008; 149: 549-59.

Section5

INSULIN INITIATION AND OPTIMISATION

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

Normal High

Implementing successful insulin therapy requires a 3 stage process;

1. Initiation – Starting insulin. Requires selection of appropriate insulin regimen, insulin type and starting dose to address the individual’s main glycemic abnormality.

2. Optimisation1 – Dose titration / adjustment. Requires gradual, safe and prompt titration of insulin dose according to self blood glucose monitoring (SMBG), towards an optimal dose to ensure maximum benefi t from prescribed treatment. The insulin dose should be adjusted at least weekly to get the monitored readings to target. Optimisation of the insulin dose should be an interactive process between the healthcare provider and the patient. This can be done at the diabetic resource centre or via telephone calls. It should be done within the fi rst few months of starting insulin.

3. Intensifi cation – Modifi cation of an insulin regimen to achieve better glycemic control requires switching to more intensive insulin regimens for better glycemic control. There are a few choices when starting insulin (Table 4.1a). The insulin regimen and insulin doses initiated are individualized, based on blood glucose profi le, patient’s lifestyle and preferences (Table 5.1).

Starting T2DM patients on basal insulin is a well established treatment option forimproving glycemic control when OADs fail2. Supplementation with basal insulinallows the reduction of HbA1c, primarily by targeting fasting plasma glucose(FPG) – concept of 3Fs – “Fixing the Fasting First”.

For those patients who desire an easier insulin regimen but can cope with rigidityof lifestyle, a premixed insulin regimen can be initiated2.

Blood Glucose Profi le

Pre-Breakfast Daytime

High Normal Pre-bed intermediate / long acting insulin (BASAL)

High

Pre-bed intermediate / long-acting insulin and lateradd on prandial short / rapid acting insulin (BASAL → BASAL PLUS / BASAL BOLUS) or(PRE-BREAKFAST AND PRE-DINNERPREMIXED INSULIN)

Prandial short / rapid acting insulin and later addon basal insulin(PRANDIAL → BASAL PLUS / BASAL BOLUS)

High

Preferred insulin regimen

INSULIN INITIATION AND OPTIMISATION

Table 5.1 Selecting initial insulin regimen based on blood sugar profi le:

23

5.1 Initiating and Optimising Pre-bed Intermediate / Basal insulin

We can simply start the pre-bed intermediate/basal insulin at 10 units per day,or alternatively, start based on body weight at 0.2 units/kg3. (In those patientswho are elderly, leaner or have milder fasting hyperglycemia, an initial dose of0.1units/kg may be reasonable to ensure lower risk of hypoglycemia)

Patients are advised to perform SMBG at pre-breakfast. There should be at least3 consecutive values before adjusting insulin dose. Monitoring-based doseadjustment should be done after 3 to 7 days of initiating the last dose. The targetblood glucose is at 4 – 6 mmol/L.

If more than 1 of 3 pre-breakfast blood glucose values are less than 4 mmol/L,reduce intermediate/basal insulin by 2 units. If all 3 values are within the targetsof 4-6 mmol/L, maintain current intermediate/basal insulin dose. If more than 1reading of blood glucose is more than 6 mmol/L without any hypoglycemia, basal insulin dose may be increased by 2 units (Table 5.2). Subsequently insulindoses are gradually increased until target blood glucose is achieved.

The optimal dose of bedtime intermediate/basal insulin is generally at:• Lean patient : 0.2 – 0.3 units/kg• Most patients : 0.4 – 0.5 units/kg• Obese patient : up to 0.7 units/kg

Table 5.2 Initiating insulin with basal insulin3,4

Treatment Dose

Initiation 10 units or 0.2U/kg at bedtime(0.1 units / kg if higher risk for hypos)

Monitoringand targets

Optimisation

Optimal dose

Caution

Monitor pre-breakfast BGTarget pre-breakfast BG is at 4 - 6 mmol/L

Adjust insulin doses after 3 consecutive BG values obtained (every 3 – 7 days)- < 4 mmol/L ( > 1 value ) → reduce dose by 2 units- 4-6 mmol/L ( all values ) → maintain current dose- > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

0.2 – 0.3 units/kg in lean patients0.4 – 0.5 units/kg in most patientsUp to 0.7 units/kg in obese patients

Watch for nocturnal hypoglycaemia. If hypoglycemia is the limitingfactor to achieve optimum dose, conventional intermediate-actinginsulin may be switched to basal insulin analogue.

INSULIN INITIATION AND OPTIMISATION24

25

5.2 Initiating and Optimising Premixed Insulins3,4

Premixed insulin may be initiated once daily, usually at pre-dinner or twice dailyat pre-dinner and pre-breakfast (Table 5.3).

5.2.1 Premixed insulin once dailyThe initial dose for once daily premixed insulin is usually 10 units or 0.2 units/kgadministered usually pre-dinner.

Patients are advised to perform SMBG at pre-breakfast. Titration is based on 3 consecutive readings of blood glucose (similar as for titrating intermediate/basal insulin). The insulin dose should be adjusted weekly to get the monitoredreadings to target.

During optimisation of pre-dinner premixed insulin:

• If more than 1 of 3 pre-breakfast BG is less than 4 mmol/L, reduce pre-dinner premixed insulin by 2 units.• If all 3 pre-breakfast BG are within the targets of 4-6 mmol/L, maintain current pre-dinner premixed insulin dose.• If more than 1 pre-breakfast BG is more than 6 mmol/L without any hypoglycemia, may increase pre-dinner premixed insulin dose by 2 units.

5.2.2 Premixed insulin twice dailyThe initial dose for twice daily premixed insulin is usually 10 units or 0.2 units/kgtwice daily administered at pre-breakfast and pre-dinner.

Patients are advised to perform SMBG at pre-breakfast and pre-dinner. Titrationis based on 3 consecutive readings of blood glucose (similar as for titratingintermediate/basal insulin). The insulin dose should be adjusted weekly to get themonitored readings to target.

During optimisation of pre-breakfast premixed insulin:

• If more than 1 of 3 pre-dinner BG is less than 4 mmol/L, reduce pre-breakfast premixed insulin by 2 units• If all 3 pre-dinner BG are within the targets of 4 - 6 mmol/L, maintain current pre-breakfast premixed insulin dose• If more than 1 pre-dinner BG is more than 6mmol/L without any hypoglycemia, may increase pre-breakfast premixed insulin dose by 2 units

Titration for pre-dinner premixed insulin dose is similar as above.

5.3 Initiating and Optimising Prandial Insulin

Prandial insulin therapy can be initiated at a dose of 6 units per meal, or altern-tively, started based on body weight at 0.1units/kg per meal administered 30minutes prior (short-acting insulin) or just before (rapid-acting analogue) the meal(Table 5.4). Optimisation of prandial insulin doses are dependent on:

• Meal types and amount• Pre-meal blood glucose levels on SMBG

Table 5.3 Initiating insulin with premixed insulin3

Initiation Once daily : 10 units or 0.2U/kg at pre-dinnerTwice daily : 10 units or 0.2U/kg at pre-breakfast andpre-dinner(0.1units/kg if higher risk for hypos)

Monitoringand targets

Optimisation

Optimal dose

Caution

Once daily : Monitor pre-breakfast BGTwice daily : Monitor pre-breakfast and pre-dinner BGTarget pre-meal BG is at 4-6mmol/L

Adjust insulin doses after 3 consecutive BG values obtained (every 3 – 7 days)- < 4 mmol/L ( > 1 value ) → reduce dose by 2 units- 4-6 mmol/L ( all values ) → maintain current dose- > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

Pre-breakfast BG determine pre-dinner premixed dose adjustment Pre-dinner BG determine pre-breakfast premixed dose adjustment

Total daily dose of 0.5 – 1.0 units/kg in most patients(Maybe more than 1.0 units/kg/day in obese, insulinresistant patients)

Watch for in between meal hypoglycaemia. If hypoglycemia is thelimiting factor to achieve optimum dose, conventional premixedinsulin may be switched to premixed analogue.

Treatment Dose

INSULIN INITIATION AND OPTIMISATION26

27

If conventional short-acting insulin is used, SMBG should be performed pre-mealsat pre-lunch, pre-dinner and pre-bed. But, if rapid-acting insulin analogue isused, BG may be monitored 1.5 - 2 hours post-meals. Following 3 consecutivereadings, insulin dose adjustment should be done on a weekly basis until theglycemic targets are met.

During optimisation of prandial insulin, insulin dose is titrated to next pre-meal(& bedtime) target:

• If the pre-lunch BG levels are not to target, pre-breakfast insulin dose is adjusted. (Post-breakfast BG level may be used for rapid-acting analogue)• If the pre-dinner BG levels are not to target, pre-lunch insulin dose is adjusted. (Post-lunch BG level may be used for rapid-acting analogue)• If the pre-bed blood BG levels are not to target, pre-dinner dose is adjusted. (Post-dinner BG level may be used for rapid-acting analogue)

Prandial insulin dose may be adjusted as the following4:

• If more than one BG level is less than 4 mmol/L, reduce the prior pre-meal prandial insulin by 1- 2 units• If more than one BG level is more than 6mmol/L without any hypoglycemia, may increase prior pre-meal insulin dose by 2 units• If all pre-meal BG on target, dose of prior pre-meal prandial insulin is maintained

Patients on prandial insulin should ideally be instructed in the following skills:

• Carbohydrate counting by a certifi ed dietician. Carbohydrate counting is a recommended method of meal planning for patient who have diabetes. Carbohydrate counting allows patients to adjust the amount of prandial insulin administered based on how many grams of carbohydrate they eat at a meal or snack• Insulin to carbohydrate ratio (I:C ratio) specifi es how many grams of carbohydrate are “covered” by each unit of insulin. For example, a 1-unit- per-10-grams-of-carb (1:10) ratio means that one unit of insulin covers 10 grams of carbohydrate• Correctional dose adjustment for pre-meal hyperglycemia. This will allow patients to adjust pre-meal prandial insulin dose in case BG levels are already elevated or low prior to meals

5.4 Initiating and Optimising Basal Bolus Regimen

We can simply start this regimen by initiating prandial insulin at 0.1 U/kg or 6units before each meal and basal insulin at 0.2 unit/kg or 10 units at bedtime (Table 5.5).

SMBG should be performed pre-meals at pre-breakfast, pre-lunch, pre-dinnerand at bedtime/pre-bed for 3 consecutive readings and insulin dose can then be adjusted accordingly.

Insulin dose adjustment for prandial and basal insulin is similar as that mentionedin the prior sections 5.1 and 5.3. Aim for normal pre-breakfast BG fi rst byadjusting the dose of bedtime basal insulin before adjusting the prandialinsulin dose. Repeat this monitoring on a weekly basis until glycemic targets aremet.

Table 5.4 Initiating with prandial insulin

Initiation 6 units or 0.1units/kg for each meal with short-acting orrapid-acting analogue.

Monitoringand targets

Optimisation

Optimal dose

Caution

Pre-meals and pre-bed. (Postmeals 1.5 - 2 hours if using rapid-acting analogue)Target pre-meal BG is at 4 – 6 mmol/L Target post-meals and pre-bed 4 – 8 mmol/L

Adjust insulin doses after 3 consecutive pre-meal BG values obtained - < 4 mmol/L ( > 1 value ) → reduce dose by 2 units- 4-6 mmol/L ( all values ) → maintain current dose- > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

Adjust the dose of prandial insulin of the preceding meal(eg: if pre lunch BG is high, adjust pre breakfast prandial insulin)

Prandial dose for each meal will vary according to carbohydratecontent and amount.Dose should ideally not exceed 0.5U/kg/dose.

Watch for in-between meal hypoglycaemia. If hypoglycemia is thelimiting factor to achieve optimum dose, conventional short-actinginsulin may be switched to rapid-acting analogue.

Treatment Dose

INSULIN INITIATION AND OPTIMISATION28

29

Table 5.5 Initiating with basal-bolus regimen3,4

Initiation Prandial Insulin : 6 units or 0.1U/kg before each mealBasal insulin : 10 units or 0.2U/kg at bedtime

Monitoringand targets

Optimisation

Optimal dose

Preferably 4 times per day upon initiationPre-meals at pre-breakfast, pre-lunch and pre-dinner and at bedtimeTarget pre-meals BG at 4 – 6 mmol/L Target bedtime BG at 4 – 8 mmol/L

i: Prandial insulin:Adjust insulin doses after 3 consecutive pre prandial BG values obtained - < 4 mmol/L ( > 1 value ) → reduce dose by 2 units- 4-6 mmol/L ( all values ) → maintain current dose- > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

Adjust the dose of prandial insulin of the preceding meal(eg: if pre-lunch BG is high, adjust pre-breakfast prandial insulin)

ii: Basal insulin :Adjust insulin doses after 3 consecutive BG values obtained (every 3 – 7 days)- < 4 mmol/L ( > 1 value ) → reduce dose by 2 units- 4-6 mmol/L ( all values ) → maintain current dose- > 6 mmol/L ( >1 value, no hypos ) → increase by 2 unit Aim for normal pre-breakfast BG fi rst by adjusting the dose of bed-time basal insulin before adjusting the prandial (bolus) insulin dose.

Generally basal insulin would contribute 50% of total daily insulindose and prandial insulin would contribute remaining 50%(distributed over three main meals).

Prandial insulin: Dose for each meal will vary according to meal carbohydratecontent.Normal prandial dose should not exceed 0.5u/kg/dose.

Basal insulin:0.4 - 0.5 units/kg in most patientsLean patients : 0.2 – 0.3 units/kg Obese patients : Up to 0.7 units/kg

Treatment Dose

There is no limitation for insulin dose5, however, requirement of high insulin dose (>1.5unit / kg per day) should prompt a search for an underlying cause or secondary problemssuch as: non-compliance, incorrect dosing and administration timing, hypertrophy ofinjection area, inter–meal hypoglycemia with rebound hyperglycemia pre-meal, expiredinsulin, inappropriate insulin or inaccurate BGM and occult infections.

30 REFERENCES

1. Arshag DM et al Narrative Review: A Rational Approach to Starting Insulin Therapy. Ann Intern Med. 2006;145:125-134.

2. Holman R et al. Three Year Effi cacy of Complex Insulin Regimens in Type 2 Diabetes. N Engl J Med 2009;361:1736-47.

3. Bu BY. Type 2 diabetes mellitus-Guidelines for initiating insulin therapy. Australian Family Physician 2007; 36(7):549-553.

4. Swinnen SGHA et al. Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes. Diabetologia 2009; 52(11):2324-2327.

5. Clinical Practice Guidelines (CPG) on Management of type 2 Diabetes Mellitus (4th Edition) 2009.

Section6

INSULININTENSIFICATION

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

T2DM is a progressive disease. With increasing duration of disease, there isincreasing fasting and postprandial hyperglycemia as a result of progressivepancreatic beta-cell failure. Therefore insulin therapy needs to be a dynamicprocess, to address progressive insulin defi ciency.

The use of a single insulin regimen may often not ensure durable glycemic control over time despite optimisation of insulin doses. Many patients are left on aninadequate insulin regimen for too long resulting in sub-optimal glycemic control.Intensifi cation enables modifi cation of an insulin regimen, either with additionalinjections or switching to different insulin types, towards achieving better glycemic control.

Key elements for successful insulin intensifi cation

• Patient education

• Dedicated diabetes team - diabetes educator, pharmacist, dietician

• Self-blood glucose monitoring (SMBG)

• Frequent contact with health care team

• Support group

Insulin intensifi cation can be done in many ways. The choice would dependon the pre-existing insulin regimen, the abnormal glycemic pattern, patient acceptance and lifestyle issues.

INSULIN INTENSIFICATION32

33

Premixed insulin regimens can be intensifi ed by any of the following ways(Figure 6.1b)

• Additional injections of premixed insulin (twice and three times daily)• Addition of pre-meal rapid / short-acting at lunch

Figure 6.1a Insulin Intensifi cation from basal regime

BASAL

PREMIXED BD BASAL BOLUSBASAL PLUS(1 PRANDIAL)

BASAL PLUS(2 PRANDIAL)

BASAL BOLUS(3 PRANDIAL)

Figure 6.1b Insulin Intensifi cation from premixed regime

PREMIXED OD

PREMIXED TDS(FOR ANALOGUES)

PREMIXED BDPLUS

PRELUNCH / PRANDIAL

PREMIXED BD

Basal insulin regimens can be intensifi ed by any of the following ways(Figure 6.1a)

• Switching to premixed regimen (usually twice daily)• Addition of three pre-meal rapid / short-acting insulin – basal-bolus regimen• Sequential addition of pre-meal rapid / short-acting insulin – basal-plus regimen

Figure 6.2 Intensifi cation from Basal to Basal – Plus regimen

• Fix Fasting Blood Glucose (FBG) fi rst using basal insulin (dose optimisation)• Goal FBG 4 – 6 mmol/L• Consider adding bolus / meal insulin when: Hb A1c > 7% and FBG at goal or basal insulin dose > 0.5U/kg

If A1c > 6.5 - 7% after 3 months despite titrating doses, or prandial dose > 30 U per meal, consider:• Add second prandial insulin at 6 units or 0.1 unit/kg at 2nd largest meal and titrate as before• Repeat 3rd prandial insulin dose at fi nal meal of the day

• Add prandial insulin 6 units or 0.1unit/ kg at largest meal• Titrate to next pre-meal / bedtime BG target daily• If subsequent premeals BG are - < 4 mmol/L ( > 1 value ) → reduce dose by 2 units - 4-6 mmol/L ( all values ) → maintain current dose - > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units• Discontinue SU on addition of prandial insulin• Continue metformin • Patients may need to perform SMBG up to 4 times per day

6.1 Switching from Basal to Basal plus regimen

For those patients on combination OADs and basal insulin not achieving HbA1ctargets despite optimal fasting BG, addition of prandial insulin to addresspostprandial hyperglycemia will help improve overall glycemic control. This canbe initiated with addition of single prandial insulin prior to the largest meal of theday or to address the highest postprandial BG of the day1,2.

With time, additional prandial insulin can be added prior to other meals to addresspostprandial hyperglycemia. (Figure 6.2). Intensifi cation of the Basal – Plusregimen (sequential addition of prandial insulin) will ultimately lead to Basal –Bolus regime.

INSULIN INTENSIFICATION34

35

Figure 6.3. Intensifi cation from Basal to Basal – Bolus regimen

• Fix Fasting Blood Glucose (FBG) fi rst using basal insulin (dose optimisation)• Goal FBG 4 – 6 mmol/L• Consider adding bolus / meal insulin when: Hb A1c > 7% and FBG at goal or basal insulin dose > 0.5U/kg

If HbA1c > 6.5 - 7% after 3 months despite titrating prandial doses or prandial doses > 30 units per meal, consider:• Resume titration / optimisation of basal insulin up to 0.7 U/kg• Perform 7- point BG profi le

• Add bolus / prandial insulin 6 units or 0.1unit/kg at each meal• Monitor BG up to 4 times per day• Titrate to next pre-meal / bedtime BG target daily

• If subsequent pre-meals BG are

- < 4 mmol/L ( > 1 value ) → reduce dose by 2 units - 4-6 mmol/L ( all values ) → maintain current dose - > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units• Stop SU and continue metformin

6.2 Switching from Basal to Basal bolus regimen

For those patients on combination OADs and basal insulin not achieving HbA1ctargets despite optimal fasting BG, with post-prandial hyperglycemia identifi edfollowing all main meals, addition of prandial insulin prior to each meal will helpimprove overall glycemic control. (Figure 6.3). Sulphonylureas should be stoppedbut Metformin should be continued.

6.3 Switching from Basal to Premixed regimen

For those patients on combination OADs and basal insulin not achieving HbA1ctargets despite optimal fasting BG, with post-prandial hyperglycemia, anotheroption for intensifi cation would be to switch to a premixed regimen.

This option is usually appropriate for patients who prefer a simpler regimen andare unable to accept 3 – 4 injections per day. This regimen is more suitable forthose with a rigid lifestyle. Sulphonylureas should be stopped but Metforminshould be continued.

Dose for dose transfer can be used where the total daily dose of basal insulin isused to determine premixed total daily dose. Premixed is then administered intwo divided doses, usually equal in amount ie: split dose 50: 50 at pre-breakfastand pre-dinner (Figure 6.4).

Premixed analogues may be considered in patients experiencing hypoglycaemiawith conventional premixed insulin and in those who desire greater fl exibility asadministration of premixed analogue does not require specifi c timing prior tomeals and may be injected just prior to, during, or immediately after, a meal.

BASAL OD or BD

HbA1c 6.5 – 8%FPG > 6 mmol/L

Titrate basal insulin to achieve FPG < 6mmol/L• Optimal dose 0.4 – 0.5 u / kg• Continue OADs

Switch to PREMIXEDTWICE DAILY• Total dose transfer• Split dose 50:50 pre-breakfast : pre-dinner• Titrate dose once / twice a week to next preprandial goal• Stop SU, continue metformin• Consider premixed analogue

HbA1c > 6.5 – 7%FPG 4-6 mmol/L

Figure 6.4 Intensifi cation from basal to premixed regimen

INSULIN INTENSIFICATION36

37

6.4 Switching from Premixed to Basal bolus regimen

For those patients on premixed regimen (twice or three times daily) and not achieving HbA1c targets despite optimised dose, another option for intensifi cationwould be to switch to basal-bolus regimen.

This option is appropriate for patients who require greater fl exibility in doseadjustment as it potentially allows pre-meal rapid / short-acting insulin to beadjusted individually according to blood glucose level (correctional bolus) as wellas the carbohydrate meal content of the meal.

The initial total daily dose following the switch may be guided by using a simpledose calculation of 0.5units/kg or by a total dose for dose transfer from the priortotal daily dose on the previous regimen. Following determination of total daily-dose requirement, proportion of basal to prandial insulin requirement may beestimated using a ratio of 50:50. A smaller proportion of basal insulin may alsobe used such as between 25 – 40% of total daily dose in certain circumstances.The basal dose is usually administered at bedtime (conventional insulin) and theprandial portion is divided into three to cover the three main meals, administeredpre-meals. Estimation of the pre-meal dose should take into consideration thesize of the meal, in terms of the carbohydrate content. Subsequently the basaland pre-meal insulin should be titrated or optimised accordingly towards attainingglycemic targets (Figure 6.5).

PREMIXED INSULIN BD or TDS (Insulin analogue)

FPG / premeals > 6 mmol/LHbA1c > 6.5 – 7%

Switch to BASAL BOLUS REGIMEN• Starting dose 0.5units/kg/day or total dose transfer• Split dose 50:50 for basal and prandial insulin• Divide prandial doses into 3 main meals• Fix FPG < 6mmol/L using basal insulin• Titrate bolus dose once / twice a week to achieve FP and preprandial goal < 6mmol/L• Stop SU, continue metformin

Figure 6.5 Intensifi cation from premixed regimen to basal bolus regimen

6.5 Switching from single to multiple premixed regimen

For those patients already on a single premixed insulin regimen, usually in combination with single or multiple OADs and not achieving blood glucose andHbA1c targets despite optimising insulin and OAD doses, an option for intensifi cation would be to initiate additional pre-meal doses of premixed insulin.

For those on single dose conventional premixed insulin, usually prior to eveningmeals, one additional dose may be initiated prior to the morning meal. In thosereceiving premixed analogue insulin, additional doses may be initiated at bothmorning and midday meals, either sequentially or simultaneously. It is not usualto administer conventional premixed insulin more than twice daily in view ofconcern for between-meal hypoglycaemia3,4,5,6.

Figure 6.6 Intensifi cation of premixed regimen

PREMIXED OD (pre-dinner) or BD

FPG and / or pre-dinner 4-6 mmol/L FPG and / or pre-dinner > 6 mmol/L

HbA1c > 6.5 – 8% Titrate Premix OD or BD to achieve FPG and / or predinner < 6mmol/L

DAILY (OD) → TWICE DAILY (BD)• Starting dose 0.3units/kg/day or total dose transfer• Split the dose 50:50 pre-breakfast and pre-dinner• Titrate insulin dose to achieve FPG and pre-dinner<6mmol/L

TWICE DAILY (BD) → THREE TIMESDAILY (TDS)• Add 6 units or 10% total daily dose at lunch• Titrate dose once or twice a week to next pre prandial goal < 6mmol/L• Down titrate morning dose ( 2 – 4 units ) may be needed after adding lunch dose• Continue metformin• Consider premixed analogues if hypos

SWITCH TO PREMIXED BD OR TDS (analogues only)

INSULIN INTENSIFICATION38

39

6.6 Intensifi cation of premixed regimen with addition of pre-meal bolus

For those patients already on a premixed daily regimen usually in combinationwith single or multiple OADs and not achieving blood glucose and HbA1c targetsdespite optimising insulin and OAD doses, an option for intensifi cation would beto initiate additional injections of pre-meal rapid or short-acting insulin.

Whereas for those patients already on premixed twice daily regimen and notachieving blood glucose and HbA1c targets despite optimising insulin doses,an option for intensifi cation would be to initiate pre-lunch rapid or short-actinginsulin.

Figure 6.7 Intensifi cation of premixed regimen with addition of prandial insulin

PREMIXED OD (pre-dinner) or BD

PREMIXED ONCE DAILY (pre-dinner)

FPG 4-6 mmol/L, pre-lunchand pre-dinner > 6mmol/LAdd PRANDIAL INSULIN (at morning and midday meal)

PREMIXED TWICE DAILY (pre-breakfast, pre-dinner)

Pre-dinner >6 mmol/LAdd PRANDIAL INSULIN

(at midday meal)

• Add prandial insulin 6 units or 0.1unit/kg at lunch• Titrate to pre-dinner BG target daily• If subsequent pre-meal BG is - < 4 mmol/L ( > 1 value ) → reduce dose by 2 units - 4-6 mmol/L ( all values ) → maintain current dose - > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

6.7 Intensifi cation of prandial regimen with addition of basal insulin

For those patients already on prandial only regimen usually with each mealand not achieving HbA1c and blood glucose targets (particularly fasting BG despite optimising doses of prandial insulin), an option for intensifi cation wouldbe to initiate basal insulin, usually at bedtime. Basal insulin analogue may beadded in the daytime as an alternative to bedtime dosing. Therefore the prandialregimen is intensifi ed to a basal bolus regimen (Figure 6.8)7.

PRANDIAL TDSOptimised prandial doses

FPG > 6 mmol/LHbA1c > 6.5 – 8%

Addition of BASAL INSULIN → BASAL BOLUS REGIMEN• 10 units or 0.2U / kg at pre-dinner • Monitor FPG , target 4-6 mmol/L• Adjust basal insulin doses after 3 consecutive BG values obtained (every 3 – 7 days)

- < 4 mmol/L ( > 1 value ) → reduce dose by 2 units - 4-6 mmol/L ( all values ) → maintain current dose - > 6 mmol/L ( >1 value, no hypos ) → increase by 2 units

Figure 6.8 Intensifi cation of prandial regimen with addition of basal insulin

40 INSULIN INTENSIFICATION

41REFERENCES

1. Insulin intensifi cation strategies in type 2 diabetes: when one injection is no longer suffi cient A. J. Garber Diabetes, Obesity and Metabolism Special Issue: Perspectives in Type 2 Diabetes: Incorporating the Latest Insulin Analogue Strategies to Achieve Treatment Success Volume 11, Issue Supplement s5, pages 14–18, November 2009.

2. Options for the intensifi cation of insulin therapy when basal insulin is not enough in type 2 diabetes mellitus D. Raccah Diabetes, Obesity and Metabolism Special Issue: Insulin Glargine: Cornerstone Treatment for Type 2 Diabetes Patients Volume 10, Issue Supplement s2, pages 76–82, July 2008 (basalplus).

3. Garber AJ, Wahlen J, Wahl T et al. Attainment of glycemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab 2006; 8: 58-66.

4. Bebakar WM, Chow CC, Kadir KA et al. Adding biphasic insulin aspart 30 once or twice daily is more effi cacious than optimizing oral antidiabetic treatment in patients with type 2 diabetes. Diabetes Obes Metab 2007; 9: 724-32.

5. A. G. Unnikrishnan,1 J. Tibaldi,2 M. Hadley-Brown,3 A. J. Krentz,4 R. Ligthelm,5 T. Damci,6 J. Gumprecht,7 L. Gerö,8 Y. Mu,9 I. Raz10 Practical Guidance on Intensifi cation of Insulin Therapy With BIAsp 30: A Consensus StatementInt J Clin Pract. 2009;63(11):1571-1577.

6. Intensifi cation lessons with modern premixes: From clinical trial to clinical practice Serdar Gulera, Julius A. Vazb, Robert Ligthelmc Volume 81, Supplement 1, Pages S23-S30 (1 September 2008).

7. Intensifi cation with prandial insulin. Pfützner A, Forst T .Int J Clin Pract Suppl. 2009 Oct;(164):11-4.

TARGETS AND MONITORING

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

Section7

Achieving glycaemic targets is central to reducing diabetes-related complications. In most patients insulin given in suffi cient doses and carefully titrated will achieve those targets, and often more readily than with oral agents.

As a general rule, therapy should be directed to achieve an HbA1c of below 6.5% as this has been shown to reduce both microvascular and macrovascular complications. It is increasingly recognised however that glycaemic targetsshould be individualised.

Long-term follow-up of UKPDS and DCCT cohorts suggests that patients withlittle co-morbidity and a long life expectancy may benefi t from stringent glycaemic targets early in the disease1,2,3.

Other recent studies4,5 assessing macrovascular outcomes indicate that less stringent targets may be appropriate in the following situations:

• A history of severe hypoglycaemia• Patients with limited life expectancy• Advanced microvascular or macrovascular complications• Extensive co-morbidities• Long-standing diabetics in whom glycaemic control remains diffi cult despite optimising patient education, adherence and dosage6.

Individualised targets for self-monitoring of blood glucose may be discussed andagreed upon after taking patient factors and limitations into consideration.

7.1 Glycaemic targets for diabetes mellitus7

Fasting Blood Glucose (FBG) 4.4-6.1 mmol/L

4.4-8.0 mmol/L

< 6.5%

Non-fasting Blood Glucose

HbA1c

Glycemic Measures Targets

Malaysian Ministry of Health CPG, Management of T2DM 2009

TARGETS AND MONITORING 43

7.2 Monitoring insulin therapy

Techniques of monitoring insulin therapy include:• Fasting Plasma Glucose (FPG)• Glycosylated haemoglobin (HbA1c)• Self-monitoring of blood glucose (SMBG)• Continuous glucose monitoring (CGM)

7.2.1 Fasting Plasma Glucose (FPG)

Measurement of FPG is an established component of glycemic monitoring in mostoutpatient settings. It is inexpensive and widely available. However single-pointglucose measurements may not accurately depict overall glycaemic control. Thisis important to bear in mind when making therapeutic decisions.

7.2.2 Glycosylated haemoglobin (HbA1c)

HbA1c levels refl ect average glycaemic control over 2-3 months. This affords anadvantage over single-point glucose measurements, however it may not refl ectglucose variability.

HbA1c should be performed at least 6-monthly in patients who are on stabletreatment and are meeting glycaemic targets. In patients’ not meeting targetsor in whom there has been a change in therapy, HbA1c levels should be performed 3-monthly. Special situations may require monitoring at closer intervals e.g. in pregnant diabetics requiring intensive insulin therapy.

7.2.3 Self-Monitoring of Blood Glucose (SMBG)

SMBG allows patients to evaluate their individual response to lifestyle, meals andtherapy, and to assess whether glycaemic targets are being achieved. It is particularly important in insulin self-titration and may help minimise hypoglycae-mia. As self-monitoring is both instrument and user-dependent, involvement ofa diabetes educator is crucial.

SMBG should be carried out at least 3-4 times daily in patients on multiple insulininjections or insulin pump therapy i.e. before each meal and before bed (10-11pm). Once pre-prandial glucose targets are achieved, post-prandial BG testingis recommended for fi ne-tuning of insulin therapy.

TARGETS AND MONITORING44

45

Recommended timing of SMBG in different insulin regimens

Please refer to tables 7.2.3a and 7.2.3b

Table 7.2.3a SMBG in Basal / Basal bolus Regimen

Note• Pre-breakfast glucose readings refl ect adequacy of pre-bed basal insulin• Pre-lunch readings refl ect adequacy of pre-breakfast short-acting insulin • Pre-dinner readings refl ect adequacy of pre-lunch short-acting insulin• Pre-bed readings refl ect adequacy of pre-dinner short-acting insulin• Post-prandial glucose readings refl ect the respective pre-meal rapid-acting insulin (Aspart/Lispro/Glulisine) and can also be used to fi ne-tune short-acting insulin

NoteSMBG in Premixed regimen• Pre-breakfast glucose readings refl ect pre-dinner premixed insulin• Pre-lunch and pre-dinner readings refl ect pre-breakfast premixed insulin• Pre-bed readings refl ect pre-dinner premixed insulin• Post-prandial testing may be recommended for fi ne-tuning of pre-mixed insulin

Breakfast

Breakfast

Bedtime

Bedtime

Dinner

Dinner

Lunch

Lunch

Basal only

Basal bolus (short-acting)

Pre-mixed Analogues BD

Pre-mixedHuman BD

Basal bolus (rapid-acting)

Pre-mixed Analogues TDS

Pre

Pre

Pre

Pre

Pre

Pre

Pre

Pre

Post

Post

Post

Post

Post

Post

X

X

X

X X X

X

X

X

X

X

X

X

X

X

X

X X X

X

X

X

X

Table 7.2.3b SMBG in Premixed Regimen

Table 7.2.3 c SMBG and Insulin Titration

SMBG pattern management

This is a systematic approach to identifying patterns within SMBG data and then taking appropriate action based upon results. It consists of four basic steps:

Step 1 Identify glycemic abnormality: • Priority 1 – Hypoglycaemia • Priority 2 – Fasting hyperglycemia • Priority 3 – Postprandial hyperglycemia

Step 2 Determine timing and frequency of occurrence • Prior to meals, after meals, during night? • Occurs frequently or intermittently?

Step 3 Investigate potential causes • Insulin and OADs, food and/or physical activity

Step 4 Take action • Insulin and OADs, food and/or physical activity

SMBG and insulin titration / adjustment

Pre Breakfast BG

2 hours Post-lunch BG

Pre-bed intermediate/long-acting insulin or pre-dinner premixed

Pre-lunch rapid-acting or pre-breakfast premixed insulin.

Pre-breakfast rapid-acting or premixed insulin analogue.

Pre-lunch short-acting or pre-breakfast premixed insulin.

Pre-breakfast short-acting or premixed insulin.

Pre-dinner rapid-acting or pre-dinner premixed insulin.

2-hours Post-breakfast BG

Pre-dinner BG

Pre-lunch BG

Post-dinner/Pre-bed BG

TO CONTROL ADJUST

7.2.4 Continuous Glucose Monitoring (CGM)

CGM is not widely available but is an evolving technology which may benefi tselected patients. It employs interstitial glucose measurement via sensors placedsubcutaneously in the abdomen. These readings are transmitted to a monitorand generally correlate well with plasma glucose. However, SMBG is still recommended to calibrate CGM and for making acute treatment decisions.Studies using CGM suggest some benefi t for patients with Type 1 diabetes.

46 TARGETS AND MONITORING

47REFERENCES

1. UKPDS Study Group. UKPDS 16. Overview of six years’ therapy of type 2 diabetes – a progressive disease. Diabetes 44, 1249–1258 (1995).

2. Diabetes Control and Complications Trial, NEJM 329(14), September 30, 1993.

3. The Epidemiology of Diabetes Interventions and Complications Trial, NEJM 353(25), December 22, 2005.

4. Effects of Intensive Glucose Lowering in Type 2 Diabetes, the ACCORD study group, NEJM 2008.

5. Dluhy RG et al. Intensive Glycemic Control in the ACCORD and ADVANCE Trials; NEJM 2008.

6. Standards of Medical Care in Diabetes 2010, American Diabetic Association.

7. Clinical Practice Guidelines (CPG) on Management of type 2 Diabetes Mellitus (4th Edition) 2009.

Section8

PROBLEMS WITHINSULIN THERAPY

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

PROBLEMS WITH INSULIN THERAPY

8.1 Hypoglycaemia

Hypoglycaemia is less common in people with T2DM than in those with T1DM.However, this problem has become progressively more frequent with advancedduration of T2DM and the use of intensive insulin therapy1. In a recent T2DMsurvey, 50% of insulin-treated patients with T2DM self-reported hypoglycaemic events in the preceding month2. In the UKPDS, intensive SU and insulin therapyin non-obese, newly-diagnosed patients with T2DM was associated with thehighest cumulative incidences of hypoglycaemia over a six-year period, occurringin approximately three-quarter of patients receiving insulin therapy and almosthalf of those receiving SU. The incidence of major hypoglycaemia was muchgreater with insulin therapy (11.2%) compared to SU therapy (3.3%)3.

Hypoglycaemia has a negative impact on physical and psychological well-being.Hypoglycaemic episodes are associated with several serious consequences suchas cardiovascular death, MI, cardiac arrhythmias, cardiac ischaemia, progressiveneuroglycopenia and autonomous nervous system abnormalities4. Hypoglycaemiaand fear of hypoglycaemia are important limiting factors in glycemic managementand may become signifi cant barriers to treatment adherence. For instance, patients may stop taking their anti-diabetic medication resulting in poor glycemiccontrol. In the Diabcare-Asia 2003 survey involving 15,549 patients with diabetes(96% had T2DM), 54% of patients were anxious about the risk of hypoglycaemiamost of the time5.

There is no current consensus on a defi nition for hypoglycaemia. Recent defi nitions by the American Diabetes Association (ADA), Canadian DiabetesAssociation (CDA) and the European Medicines Agency (EMEA) have assigneda threshold for the diagnosis of hypoglycaemia as a blood glucose level less than3.9 mmol/L6.

Hypoglycaemia manifests as neuroglycopenic or neurogenic symptoms or both.4,7

(Table8.1a)

Table 8.1a Clinical manifestations of hypoglycaemia

Neurogenic / Autonomic Neuroglycopenic

AdrenergicPalpitationsTremorAnxiety/arousal

CholinergicSweatingHungerParesthesia

Cognitive dysfunctionBehavioral changesPsychomotor abnormalitiesSeizureComaBrain damageDeath

49

The severity of hypoglycaemia can be defi ned by its clinical manifestations. • Mild - Autonomic symptoms present and the individual is able to self-treat • Moderate - Autonomic and neuroglycopenic symptoms present and the individual is able to self-treat • Severe - Unconsciousness may occur. Plasma glucose is typically < 2.8 mmol/L and the individual requires the assistance of another person

Severe hypoglycaemia requiring hospitalisation is more common in elderlypatients with T2DM. These events can have serious, sometime life-threatening,cardiovascular and neurological consequences resulting in increased healthcarecosts. Elderly patients have a higher risk of complications such as falls and injury,cognitive decline, depression and deteriorating quality-of-life.

Asymptomatic hypoglycaemia is the presence of biochemically low blood glucoselevel without any symptoms. This can be seen in some insulin-treated patientswith advanced duration of diabetes or some patients who suffer from autonomicdysfunction and frequent exposure to hypoglycaemia episodes. Symptoms ofhypoglycaemia may be absent despite signifi cantly low blood glucose levels. This phenomenon is described as hypoglycaemic unawareness. Hypoglycaemicunawareness predisposes the patients to have recurrent hypoglycaemia eventswhich can be life threatening7.

Risk factors for hypoglycaemia in people with T2DM are • Concomitant use of insulin secretagogues and insulin therapy• Missed or irregular meals• Alcohol consumption (in the absence of suffi cient carbohydrate intake)• Excessive physical activity• Advanced age• Longer duration of diabetes• Impaired renal or liver function• Impaired awareness of hypoglycaemia• Lack of patient and care-giver education on hypoglycaemia

PROBLEMS WITH INSULIN THERAPY50

51

Prevention of hypoglycaemia requires risk factor reduction and individualised treatment regimens. This will include therapy adjustment, fl exibility in treatment or a change in regimen adapting to each person’s needs and lifestyle. It is veryimportant to educate patients with diabetes to recognize the signs and symptomsof hypoglycaemia and how to treat hypoglycaemia (Table 8.1b). Improved educationand recognition could prevent and reduce frequency of hypoglycaemic events.

Table 8.1b Treatment of hypoglycaemia

1. Assess the cause and severity of hypoglycaemia2. Treat hypoglycaemia according to BG level

Mild ( BG 3.3 – 3.9 mmol/L ): Give 15g carbohydrate 4 ounces (120mls) orange juice or other fruit juices OR Hard candy OR 3 glucose tablets

Moderate ( BG 2.5 – 3.2mmol/L ): Give 20g carbohydrate 6 ounces (180mls) orange juice or other fruit juices OR 4 glucose tablets OR Dextrose 50% 25 ml iv

Severe ( BG < 2.5 mmol/L ): Give 30g carbohydrate 8 ounces (240ml) orange juice or other fruit juices OR 6 glucose tablets OR Dextrose 50% 25 ml iv

Unconscious with severe hypoglycaemia ( BG< 2.5 mmol/L ) Dextrose 50% 25 ml IV OR Glucagon 1 mg subcutaneous or intramuscular (0.5 mg for child) - Vomiting and aspiration risk - Roll patient onto their side when used

3. Monitor BG level every 15 minutes until > 5.6 mmol/L4. Redose glucose replacement as above every 15 minutes as necessary (PRN)

8.2 Weight gain

Most patients with T2DM are overweight or obese. Many anti-diabetic medications contribute to weight gain over time. In the UKPDS study (UKPDS34)9: regardless of treatment, patients gained weight. Patients who were treatedwith insulin showed the largest weight increase, with an average gain of 4 kgmore than conventional therapy at 10 years (UKPDS 33)10.

In other studies involving basal insulin use, weight gain of 2 to 3 kg has beenobserved. Weight gain with insulin therapy is dose related. Use of more intensiveinsulin regimens with increased total daily insulin requirement generally contributes to greater magnitude of weight gain. The combination of insulin withoral anti-diabetic agents such as TZDs and SUs result in greater weight gainwhereas combined use of insulin with metformin may help minimize weight gain. Weight gain in insulin-treated patients may be a consequence of several factors:

• Improving metabolic control reduces glycosuria, thus fewer calories are lost in this manner• Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake• Use of insulin can increase lean body mass through its anabolic nature.• Insulin use can also cause salt and water retention

It is important to provide patient education on measures to counter weight gainwhile on insulin therapy. Important steps would be as follows

• Restrict calories and portion control, particularly carbohydrate and fats• Appropriate advice from dietician• Keep physically active and practise regular exercise• Avoid high doses of insulin. Reducing carbohydrate intake and being physically active reduces insulin requirement• Prevent hypoglycaemia which leads to defensive eating / snacking

PROBLEMS WITH INSULIN THERAPY52

53

8.3 Injection site problems

Skin irregularities can sometimes occur at injection sites due to changes in thesubcutaneous fat, of which there are three types.

Fat hypertrophy (“lipohypertrophy”) appears as soft lumps at the injection sites.This unusual condition may be caused by the natural effects of insulin (one ofwhich is to cause fat to grow) or by reuse of needles. To prevent further development of hypertrophy, rotate injection sites and avoid reuse of needles.

Fat atrophy (“lipoatrophy”) is a loss of fat under the skin’s surface. This rarecondition appears as a dip in the skin and has a fi rm texture. It occurs much more commonly with impure insulins.

Scarring of the fat (also known as “lipodystrophy”) is caused when you injecttoo many times into the same site or when you reuse a needle.

8.4 Insulin allergy and hypersensitivity

In the past, when unpurifi ed insulins were used, allergic reactions were reportedin 10% to 56% of patients. Since human insulin and analogues have beenintroduced, insulin allergies are rare and currently reported in only 0.1% to 2% of all patients treated with insulin. In most cases, allergic reactions are restrictedto the skin and are either of a local immediate or delayed reaction type. Theseskin reactions are often self-limited with continuation of therapy. However, systemic reactions such as urticaria or anaphylaxis have also been reported.

Both types of hypersensitivity may result from the insulin molecule itself, and also from protamine, which is used in many preparations to delay insulinabsorption. In patients with diabetes mellitus, subcutaneous administration ofprotamine-containing insulin preparations can provoke delayed, T-cell mediatedskin reactions or granulomatous hypersensitivity. In addition to protamine, cresoland phenol, both preservatives in pharmaceutical products, may provoke allergicreactions. Successful treatment of insulin allergies have been reported whenpatients were using a continuous subcutaneous pump infusion of insulin andswitching from human insulin to insulin analogues such as aspart or lispro.

REFERENCES

1. UK Hypoglycemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50(6):1140–1147.

2. Lundkvist J et al. The economic and quality of life impact of hypoglycemia. Eur J Health Econom. 2005;6(3):197–202.

3. UKPDS Research Group: Overview of 6 years of therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258, 1995

4. Cryer PE. Hypoglycemia, functional brain failure, and brain death. J Clin Invest. 2007;117(4):868–870.

5. Mohamed M. An audit on diabetes management in Asian patients treated by specialists: the Diabcare-Asia 1998 and 2003 studies Curr Med Res Opin 2008; Vol 24 No 2: 507–514.

6. Workgroup on Hypoglycemia, American Diabetes Association: Defi ning and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 28:1245–1249, 2005.

7. Cryer PE et al. Hypoglycemia in diabetes. Diabetes Care 26:1902–1912, 2003.

8. Amiel SA et al. Hypoglycaemia in Type 2 diabetes . Diabet Med. 2008;25(3):245–254.

9. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood- glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 Sep 12 352 854-865.

10. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837–53.

54

SPECIAL SITUATIONS

Section9

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

SPECIAL SITUATIONS

9.1 Sick Days

There may be times when the patient cannot eat solid food or follow their regularmeal plan because of concurrent illness, dental or outpatient surgery. Maintainingglycemic control during periods of short-term illness is important to preventcomplications.

Potential problems during sick days are the following: • dehydration • ketoacidosis • hyperglycemia • hypoglycaemia

9.1.1 Hyperglycaemia

These are more common during illness particularly in viral illnesses with fever(such as infl uenza or upper respiratory tract infection) or in bacterial illnesses(such as tonsillitis or otitis media). BG levels will often still be high even if thepatient’s appetite is poor because of continuing release of glucose from the liverand insulin resistance secondary to infection.

9.1.2 Hypoglycaemia

Gastroenteritis (vomiting and diarrhoea) often cause low BG levels even withoutfever. The BG levels are low because the patient’s appetite is often decreased andthe food and drink that is taken is not being well absorbed.

During acute inter-current illness, insulin-treated patients will need to pay specialattention to monitoring and self-care practices. The following table indicatesprinciples in managing insulin-treated patients with acute intercurrent illness (Table 9.1)

• Treat underlying illness• Symptomatic treatment eg: paracetamol for headache• More frequent SMBG• Maintain positive fl uid balance: plenty of fl uids, especially those with high temperatures and high glucose• Maintain adequate nutrition• Insulin treatment may need adjustment - Start out with usual insulin dose (except if AGE) - Monitor BG pre-meals and between meals when needed - Adjust insulin doses according to SMBG - Additional rapid-acting insulin if blood glucose more than 15-16 mmol/L

Table 9.1 “Sick Days” Rules. Patients are instructed on the following self-care.

56

57

9.1.3 Indications for hospital referral / admissionThe following circumstances may indicate the need for hospital referral andadmission in insulin-treated patients with acute inter-current illness

• Voluminous or repeated vomiting• Increasing levels of ketones in the blood or urine or labored breathing• Blood glucose remains high despite extra insulin• Absence of obvious precipitating factors• Severe or unusual abdominal pain• Confusion or deterioration in well being• Presence of concurrent illnesses besides diabetes• Exhaustion on the part of other person or their carer, eg: repeated night waking

9.2 Travel1

During long distance travel, patients requiring insulin therapy will need to plantravel and holidays in advance and seek advice wherever necessary. Ideallyglycaemia, blood pressure and lipids should be under control. It is important tofi nd out the types, formulations and strengths of insulin which are available in thearea of destination. The following table indicates the appropriate advice andinstructions to be given to insulin-treated patients who are intending to travellong distance. (Table 9.2)

• Take twice as much insulin, syringes or pens, needles or tablets as will be needed• If travelling with others, split the amount between each passenger’s hand luggage just in case one of the bags is lost• Bring a cool bag for storing insulin• Bring adequate BG monitoring equipment (with strips, lancets, spare battery) • High altitude, heat and humidity can sometimes affect meters and test strips. Be aware of possible false readings• Bring carbohydrate (glucose tablets, sweets, snacks and juices) in the hand luggage to cover any travelling delays in case of hypoglycaemia• A diabetes identity card or medic alert bracelet.

Table 9.2 Preparations for long distance travel for insulin users

• Increases calorie expenditure with weight loss and maintenance of healthy weight• Increases insulin sensitivity and reduces insulin resistance, improves glycemic control• Reduces insulin requirement • Improves lipid profi le, reduces LDL-cholesterol and increases HDL- cholesterol• Lowers BP and reduces risks of CV disease and CV mortality• Increases endorphin release, thereby reduces stress and improves mood• Improves muscle strength• Increases bone density and strength

Adjustment of insulin doses during long distance air travel

With long haul fl ights and crossing of time zones, there may need to adjust insulindoses due to changes in mealtimes and activity during the fl ight. Travelling Northor South does not require any changes in 24 hour schedule.

Travelling East will shorten the day and therefore the need for less insulin, meanwhile travelling West will lengthen the day and the need for more insulin.

During travelling, the insulin-treated patient is advised the following:

• Frequent blood glucose monitoring • Planning of activities to match the insulin and meals• Careful observation and selection of food and drinks to avoid food-borne infection• Advice on appropriate footwear and foot care

9.3 Exercise2

Physical activity / exercise is an integral part of the overall management ofinsulin-treated patients. The following table states the benefi ts of exercise ininsulin-treated patients (Table 9.3a).

Prior to exercise, insulin-treated patients should undergo the following evaluation:

• Complete Physical Exam, including foot, respiratory, cardiovascular• Diabetic complication screening with assessment for proliferative retinopathy, autonomic and peripheral neuropathy and nephropathy

Table 9.3aBenefi ts of exercise in insulin-treated patients

SPECIAL SITUATIONS58

59

Insulin-treated patients may experience unstable blood glucose levels in relationto exercise with an increase risk of both hypoglycaemia and hyperglycaemia. Risk of hypoglycaemia is due to reduced insulin resistance and reduced insulin requirement while risk of hyperglycemia is a result of stress hormone release.Advice is given to patients with regards to monitoring, lifestyle and insulin doseadjustment prior to, during and after exercise as stated in Table 9.3b.

• Optimal time for exercise would preferably be 1-3 hours following meal• SMBG should be performed before, during and after exercise BG target at the start - between 5.5mmol/L to 11.1 mmol/L If BG is < 4.4 mmol/L – advise to consume 15-20 grams carbohydrate • 15-20 grams carbohydrate for prevention of hypoglycaemia, may need additional consumption every 30-60 minutes. Carry sweet or snacks in case of hypoglycaemia.• Consider need for insulin dose reduction, vary between 25-75% reduction• Watch for post-exercise hypoglycaemia• If heavy exercise is planned, such as aerobics, running or handball, extra calories should be consumed.• Exercise should be avoided in the following circumstances; Elevated BG > 16mmol/L Acute inter-current illness Positive ketonuria Dyspnoea. Symptomatic peripheral neuropathy - tingling, pain or numbness in the legs

Table 9.3b Recommendations on self-care and lifestyle adjustment with exercisefor insulin users

9.4 Fasting and Ramadan3

Insulin-treated patients who perform fasting are at risk of hypoglycaemia, hyperglycaemia, diabetic ketoacidosis, dehydration and thrombosis. The severityof risk for developing these complications differ according to several patient factors as mentioned in Table 9.4a.

Table 9.4a Severity of risk for complications during fasting for patients withdiabetes3

Very high risk group• Type 1 diabetes• Severe hypoglycaemia within the last 3 months prior to Ramadan• Patient with a history of recurrent hypoglycaemia or hypoglycaemia unawareness• Ketoacidosis or Hyperosmolar hyperglycaemia within the last 3 months prior to Ramadan• Patients with sustained poor glycaemic control• Patients with renal insuffi ciency, advanced macrovascular complications or co-morbid conditions that present additional risk factors• Acute concurrent or recent illness such as infection• Poor compliance to anti-diabetic medications• Pregnancy

Moderate risk• Patients with moderate hyperglycaemia • People living alone that are treated with insulin • Patients living alone with ill health• Old age with ill health• Drugs that may affect mentation • Patients who perform intense physical work

Low risk• Well controlled patients treated with diet alone, metformin, or a thiazolidinedione, who are otherwise healthy• Well-controlled patients treated with prandial glucose regulators such as repaglinide or nateglinide

SPECIAL SITUATIONS60

61

All patients must always and immediately end their fast if:

• Hypoglycaemia (BG <3.5 mmol/l)• BG reaches < 3.9 mmol/l in the fi rst few hours after the start of the fast, especially if insulin, has been taken at pre-dawn• Blood glucose exceeds 16 mmol/l as higher risk for acute hyperglycaemic complications and dehydration

Table 9.4bDose adjustments for insulin regimens during fasting

Insulin Regimen

Bedtime basal insulin with OADs

Premixed insulintwice daily

Basal bolus

• Reduce basal insulin dose by 20% • Insulin administered at Iftar time (sunset) • Reverse OAD dose - morning to evening dose and vice versa

• Reverse doses – morning dose given at Iftar (sunset) and evening dose at sahur • Insulin dose at sahur reduced by 20-50% to prevent daytime hypoglycaemia

• Basal dose given at Iftar, dose reduced by 20%• Sahur/ morning dose of prandial insulin reduced by 25%• Mid-day/ lunch prandial insulin omitted• Iftar prandial dose maintained, may be adjusted according to carbohydrate content in meals

Insulin Dose Adjustment

Those patients at very high risk of complications are strongly advised to avoidfasting whilst those insulin-users with satisfactory glycemic control and low riskof severe hypoglycaemia may be allowed to perform fasting with strongrecommendations for more frequent blood glucose monitoring and appropriateinsulin dose adjustments. Use of insulin analogues (basal, short acting or premixanalogues) during fasting has been associated with less hypoglycaemia andmore effective postprandial BG control.

SMBG is advised for the following times• Pre Sahur (pre-dawn meal) and 2 hours post Sahur• Pre Iftar (Sunset) and 2 hours post Iftar

Insulin dose adjustments during fasting are as recommended in Table 9.4b4.

TimingPre-prandial1 hour post-prandial2 hours post-prandial0200-0400H

3.5-5.9<7.8

4.4-6.73.9

Glucose Levels (mmol/L)

Table 9.5b Glycaemic Targets in Pregnancy

(ADA recommends pre-prandial BG <5.3 mmol/L)

9.5 Pregnancy

Diabetes during pregnancy presents major risks for poor fetal, neonatal, andmaternal outcomes. However, the risk can be greatly reduced by early institutionof medical nutritional therapy and insulin treatment. In a T2DM patient planningto get pregnant, preconception counselling with optimisation of glycaemic controlprior to conception is of utmost importance. There is a need to consider initiatinginsulin prior to conception and work towards achieving and maintaining targetHbA1c < 6.5%. Maintaining maternal glycaemia as near to normal as possiblereduces the risk of congenital anomalies, macrosomia, neonatal hypoglycaemia,and large-for-gestational-age infants.

Insulin is considered the “gold standard” treatment in managing gestational diabetes mellitus (GDM) and T2DM during pregnancy. In pregnancy, the commoninsulin regime is basal bolus regime which enables easier insulin dose adjustment and potentially better glycaemic control. The prandial insulins that canbe used are short-acting regular human insulin and the rapid-acting insulin analogues. The basal insulin used in pregnancy is usually NPH as the evidencefor the use of long- acting insulin analogues in pregnancy is not as extensive5.

When estimating the starting insulin dose, the maternal weight and the pregnancygestation / trimester should be considered (Table 9.5). There is increased insulinrequirement as pregnancy progresses as a result of insulin resistance. In somepatients there may be a need for more than 1 unit / kg day total daily dose duringpregnancy, especially in obese women with T2DM and other features of metabolicsyndrome6.

Pregnancy gestation

1st trimester2nd trimester3rd trimester

0.7 units/kg/day0.8 units/kg/day0.9 units/kg/day

Total daily insulin requirement

The insulin regimes used must be able to maintain good glycaemic control withouthypoglycaemia. SMBG is an important aspect in managing diabetes in pregnancy.The targets of blood glucose during pregnancy are as outlined in CPG Managementof T2DM 2009 (Table 9.5b).

Table 9.5a Estimation of total daily insulin requirement by gestation / trimester

62 SPECIAL SITUATIONS

Pregnancy gestation

63REFERENCES

1. National diabetes education program. Available from http://www.nedep.nih. gov/media/diabetes_travel_article,pdf.

2. Diabetes and Exercise association. Available from http://www.diabetes- exercise.org/presentaion/Horton_2009,pdf.

3. A population-based study of diabetes and its characteristics during the fasting month of Ramadan in 13 countries: results of the epidemiology of diabetes and Ramadan 1422/2001 (EPIDIAR) study. Diabetes Care. 2004 Oct;27(10):2306-11.

4. Recommendations for Management of Diabetes During Ramadan. Diabetes Care,2010 Aug;33(8):1895-1902.

5. Angeline L et al .Insulin analogue and pregnancy .Diabetes Spectrum Vol 2, 2007.

6. Boyd et al.Summary and Recommendations of the 5th International Workshop Conference on Gestational Diabetes Mellitus .Diabetes Care, Vol 30, Supplement 2, July 2007.

Section

PRACTICALISSUES

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

10

PRACTICAL ISSUES

10.1 Insulin handling and storage

Insulin comes from drug manufacturers in three basic packages; vials, pens andcartridges/ penfi lls. Insulin vials, either open or unopened, generally last for onemonth when stored at room temperature (15 – 30oC). All unopened vials shouldbe stored in the refrigerator (2 – 8oC) away from the freezer, and are good untilthe expiration date printed on the label. A vial is considered open if its seal hasbeen punctured. Once opened and stored in a refrigerator the insulin should beused within one month of being opened and discarded thereafter, regardless ofthe expiration date, as there may be loss in potency. Vials that are currently in usecan be kept at room temperature as injecting cold insulin can be painful. Insulinpast the expiration date printed on the label should not be used. Patients areadvised to write the date the vial was opened on the label.

With insulin pens and their cartridges / penfi lls, storage life ranges from sevendays to one month1. There are different storage indications for every type ofinsulin available, depending on the particular formulation of insulin, its methodof manufacture, its container and ambient storage conditions. In-use datingrecommendations for insulin in vials differ from cartridges or prefi lled insulinpens. Pens and cartridges have shorter in-use duration than those for vials,refl ecting the reduced volumes and the environment to which these productsmight be exposed.2,3

65

Product name

Humulin® N

Humulin® 30/70

Humalog®

Humalog® 25/75

Actrapid®

Insulatard®

Mixtard® 30/70

Novorapid®

Lantus®

Levemir®

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

Do not refrigerate

28282828424242283042

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Until Expiration Date Stamp

Roomtemperature

Opened / Unopened

(Days)

Refrigerated

Maximum storage duration for insulin pens

Opened Unopened

The following tips are useful for insulin storage

• Protect insulin (vials, pens, and cartridges) from extremes of hot and cold

• Keep insulin out of direct sunlight

• Never store insulin in the freezer - once insulin is frozen, it loses its potency

• Don’t store insulin near radiators, heat-vents, ovens, air conditioners, etc.

• Don’t leave insulin in a closed car during very warm or cold weather

• If going outdoors for a while in hot or cold weather, store your insulin in an insulated case

• Inspect insulin prior to each use. Observe for unusual appearance of insulin- cloudy instead of clear, clumping, stringy or has changed in color. These changes will probably lead to ineffective insulin and should be discarded immediately and a new vial / cartridge / pen should be used

PRACTICAL ISSUES66

67

10.2 Insulin injection sites

The site of insulin injection greatly infl uences the absorption level and effective-ness of the insulin. Insulin injection site rotation is as important as the amount of insulin taken.

General tips with regards to injection sites.

1. Give injections in the abdomen, thighs and back of the upper arm whenever possible. Insulin is most rapidly absorbed when injected in the abdomen, followed by the upper arm and thigh area. Injections in hip and buttock areas are more slowly absorbed. Never inject within two inches of navel.

2. Choose a slightly new location for each injection. This is called site rotation. For example, if all injections are given in the abdomen, note of where the last injection was given and move the next one about an inch to one side or the other. Continue to move the injection site until all the available sites are covered before starting a new area.

3. Always inject insulin into fatty tissue instead of muscle. That’s why the abdomen, upper back of the arms and outer thigh are preferred. These areas are easy to reach and have ample amounts of fatty tissue (called subcutaneous fat). These areas also reduce the risk of injecting insulin too close to a large blood vessel or nerve.

4. Give your injections in the same general area at the same time each day. For example, take the morning insulin in the abdomen and the afternoon or evening insulin in the arm. This consistency helps the body better absorb the insulin over random injections.

5. Keep accurate records of site rotation. This will help avoid injecting the same area repeatedly. Doing so is likely to result in the development of fat deposits that can make skin look lumpy and delay the absorption of insulin.

Abdomen Abdomen

Front

Back

Frontand sideof thigh

Upper and outer arm

Buttocks Buttocks

Side of thigh

Upper and outer arm

Frontand sideof thigh

Side of thigh

68 PRACTICAL ISSUES

69

10.3 Insulin pen devices and needles

Insulin injections can be given using an insulin syringe and appropriate syringeneedles or with an insulin pen device and appropriate pen needles.

An insulin pen is a type of delivery system for administering insulin doses that is used as an alternative to a syringe. Insulin pens use short and thin needles thatusually guard against any air fl owing through. Insulin pens have made dispensinginsulin simple for patients at home or on the go, and can generally provide a more accurate dosage than a syringe. There are a number of different brandsand models of insulin pens available. Most insulin pens fall into one of twogroups: reusable pens and disposable pens.

• A reusable insulin pen must be loaded with a cartridge / penfi ll of insulin (available / sold in boxes of fi ve cartridges). Cartridges / penfi lls hold 300 units of insulin and may give enough insulin to last for several days. When the cartridge is empty a new cartridge is loaded. With good care a reusable pen can often be used for several years.

• Disposable insulin pens come pre-fi lled with insulin and are thrown away when they are empty. Most disposable pens used hold 300 units of insulin and are available / sold in boxes of fi ve. Disposable pens are generally more convenient because there is no need to load any cartridges, but usually cost more to use than reusable pens and cartridges.

HumaPen® (Ergo)

Novolet®

Flexpen®

SoloSTAR®

Novopen® 3 Novopen® 4

Reusable

Pre-fi lled / disposable

Pre-fi lled / disposable

Pre-fi lled / disposable

Reusable

- Humulin R®

- Humulin N®

- Humulin® 30/70- Humalog® - Humalog® 25/75

- Actrapid®

- Insulatard®

- Mixtard® 30/70

- Novorapid®

- Novomix® 30- Detemir®

- Lantus®

- Apidra®

- Actrapid®

- Insulatard®

- Mixtard® 30/70- Novorapid®

Insulin Pen

Table 10.3 Insulin pens available in Malaysia1

Pen Type Insulin Type

n® (Ergo)

PRACTICAL ISSUES70

71

10.4 Insulin Absorption

Variability of insulin absorption is perhaps the greatest barrier to replicatingphysiologic insulin secretion4. The inter-individual and intra-individual insulinabsorption can pose a signifi cant challenge to the health care provider duringinsulin optimisation. Day-to-day intra-individual variation in insulin absorption is approximately 25%, and the variation between individuals may be as highas 50%5. Factors that may affect insulin absorption include the following (Table10.4):

Factors

1. Site of injection

2. Injection volume

3. Injection depth

4. Needle length

5. Insulin type

6. Injection route

7. Exercise

8. Heat application or Massage

Abdominal injection (particularly if above theumbilicus) results in the quickest absorption; arminjection results in quicker absorption than thighor hip injection

Large volume injection is absorbed in a moreunpredictable manner compared to small volumeinjection (i.e. < 10u)

Patients should be advised to inject insulin at aconsistent depth to avoid unpredictable absorption

Absorption may be compromised if short needlesare used for a relatively thick subcutaneous tissue.There are three needle sizes available in Malaysia,i.e. 5mm, 6mm and 8mm

Insulin analogue is generally absorbed in a morepredictable manner than conventional human insulin

Insulin is absorbed faster when administeredintravenously compared to intramuscular orsubcutaneously in a descending order

Exercising a muscle group before injecting insulin into that area increases the rate of insulin absorption

Local application of heat or massage after an insulin injection increases the rate of insulin absorption

Comment

Table 10.4 Factors infl uencing insulin absorption

10.5 Insulin Injection problems

Beginning insulin therapy requires proper education regarding injection technique.However, even with proper education by a certifi ed diabetes educator problems can still occur. Injection problems can occur with the use of a vial and syringe or a pen device (Table 10.5)

Problems

Painful injections

Bleeding at site of injection

Insulin isdripping fromthe pen needleafter injection

The injectiondevice is clogged

Insulin leakingfrom injection site

• Review injection technique• Try injecting at a 45° angle; to prevent hitting muscle • Inject quickly• Check that needle is not bent• Inject insulin when it is at room temperature. Cold insulin hurts• Try injecting in different site• Do not use needles more than once. Reusing needles can bend and dull the tip and increase pain• Keep the muscles at injection area relaxed• Larger doses hurt more. May benefi t from more frequent injection with smaller amount

• Do not rub the injection site• Apply light pressure with fi nger to prevent bruising• If bruising, avoid that injection site again until the bruise resolves• Frequent bleeding may indicate poor technique or another medical problem; inform healthcare provider and/or diabetes educator

• Wait at least 10 seconds after injecting before removing the needle.• Do not carry a pen with the needle attached. This causes air to enter the cartridge, thus slowing the time it will take to get the insulin dose

• Small amounts of insulin may be caught in the needle from a previous use. Never re-use needles• There may be a clump in the insulin: If using cloudy insulin, be sure to properly mix insulin before drawing it up• Cloudy insulin can dry inside the needle or syringe if drawn up too far before the time of injection. Fill syringe closer to the time of injection

• Try using a longer needle (8mm).• Try a different injection site

Solutions

Table 10.5 Common insulin injection problems

Pen needles should be removed after each use to prevent air from entering thecartridge and to prevent insulin from leaking out.

PRACTICAL ISSUES72

73

10.6 Self monitoring of Blood Glucose (SMBG)

Glucose meters play a central role in the management of diabetes particularly for insulin- treated patients as insulin dose adjustment is reliant on SMBG. TheADA consensus panel reported that up to 50% of SMBG determinations mightvary more than 20% from the true value4

The following table (Table 10.6) describes factors to be considered to assure theaccuracy of home glucose monitoring5

Table 10.6

1. Code on monitor matches code on glucose test strip vial2. Glucose test strips stored in original container3. Test strips within expiry date4. Lateral side of fi nger pricked with puncture device5. First drop of blood is wiped off, then hanging drop is tested6. Blood is applied correctly to cover all of test strip7. Strip is inserted at appropriate time8. Monitor is cleaned weekly or as needed9. Blood glucose value properly recorded10. Control solution is used and control solution is within expiry date11. Control values are within 10% of expected

REFERENCES

1. Grajower m et al. How Long Should Insulin Be Used Once a Vial Is Started? Diabetes Care September 2003 26:2665-2669;

2. Insulin Storage in Europe: A comment to Grajower et al., Eli Lilly, and Novo Nordisk Diabetes Care May 1, 2004 27:1225-1226.

3. Holcombe JH et al : How Long Should Insulin Be Used Once a Vial Is Started? Response to Molitch. Diabetes Care May 2004 vol. 27 no. 5 1241-1242.

4. Heinemann L. et al. Variability of insulin absorption and insulin action. Diabetes Technol Ther. 2002;4(5):673-82.

5. Self-monitoring of blood glucose. American Diabetes Association. Diabetes Care 1990;13(Suppl 1):S41–6.

6. William A et al. Assuring the Accuracy of Home Glucose Monitoring. J Am Board Fam Pract 2002; 15:1–6.

74

Practical Guide toInsulin Therapy inType 2 Diabetes Mellitus

APPENDIX

Fried noodles (mee/mee hoon) 1 plate (170g) 281 41 3

Bread (white/wholemeal) 1 slice (30g) 70 15 1

Biscuits, unsweetened 2 pieces (18g) 80 14 1

Condensed milk, sweetened 2 tablespoon (40g) 126 21 1.5

Banana (pisang mas) 1 small (50g) 40 9 <1

Langsat/ grapes/longan 8 small (233 g) 52 12 1

Watermelon/ papaya/ pineapple 1 slice ( 160g) 56 11 1

Foods Serving Calories (kcal)

Carbohydrate content (g)

Approx. Carbohydrate Exchanges**1 carbohydrate food exchange = 15 g

Carbohydrate Content of Common Malaysian Foods

Cooked rice 1 bowl (159g) 207 48 3

Roti canai 1 piece (95g) 301 46 3

Chappati 1 piece(100g) 300 47 3

Curry mee 1 bowl (450g) 549 55 4

Curry puff 1 piece (40g) 128 17 > 1

Potato 1 medium (90g) 90 16 1

Dhall (raw) ½ cup (98g) 98 64 4

Full cream milk 1 cup (250 ml) 187 18 1

Low fat milk 1 cup (250 ml) 131 12 1

Skim milk powder 4 tablespoon (28g) 100 16 1

Apple/ orange 1 medium (114g) 40 9 < 1

Star fruit 1 medium (260g) 56 11 1

Guava ½ fruit (100g) 50 11 1

Mango 1 small ( 100g) 50 11 1

76 APPENDIX

INDEX 77

References are to page numbers within the booklet.

PageBarriers insulin absorption 71 insulin therapy 2; 11; 12 - solutions 12 patient barriers 11 provider barriers 12 - solutions 13 Basal bolus regimen initiation and optimisation 28; 29 Basal insulin basal bolus regimen 35 initiation and optimisation 24 intensifi cation 33 basal plus regimen 34 premix regimen 36

Beta cells progressive decline 5; 8

Diagnosis role of insulin therapy 8Exercise benefi ts 58 insulin dose adjustment 59

Fasting and Ramadan insulin therapy - complications 60 - insulin dose adjustments 61 - severity of risk 60

Handling and storage insulin 65; 66

78 INDEX

References are to page numbers within the booklet.

PageHypoglycaemia clinical manifestations 49 insulin therapy 49 prevention 51 risk factors 50 severity 50

Injection site practical issues 67 problems 53

Insulin absorption 71 comparison of conventional insulin and insulin analogues 18; 19 effectiveness 6 handling and storage 65; 66 initiation and optimisation 23; 24 intensifi cation 32 pen devices and needles 69 preparations 16 regimen 20 types 16 - pharmacokinetic profi les 17

Insulin absorption 71 affecting factors 71

Insulin analogues 18

Insulin injection problems 72

Insulin regimen 20

Insulin resistance progression of T2DM 6

INDEX 79

References are to page numbers within the booklet.

PageInsulin therapy barriers 2; 11; 12 - solutions 12; 13 current practice 2 implementation 23 intensifi cation 32 monitoring 44 practical issues - injection site 67 - insulin absorption 71 - insulin handling and storage 65; 66 - pen devices and needles 69 problems - allergy and hypersensitivity 53 - hypoglycaemia 49 - injection site 53 - insulin injection 72 - weight gain 52 rationale 5; 6; 8 role 8 short-term use 8 special situations 56 - exercise 58 - fasting and Ramadan 60 - pregnancy 62 - travel 57 utilisation 2

Intensifi cation basal bolus regimen 37 basal regimen 35 multiple premixed regimen 38 basal plus regimen 34 prandial regimen 40 premix regimen 36

Monitoring continuous glucose monitoring 46 insulin therapy 44 self-monitoring of blood glucose 44 - accuracy 73 - glucose meters 73

Pen devices and needles 69

80 INDEX

References are to page numbers within the booklet.

PagePharmacokinetic profi les insulin 17

Prandial insulin initiation and optimisation 26; 27; 28 intensifi cation 40

Pregnancy insulin therapy 62 - management 62 - risks 62

Premixed insulins addition of prandial insulin 39 basal bolus regimen 37 initiation and optimisation 25; 26 intensifi cation 33 multiple premixed regimen 38

Self-monitoring of blood glucose 44 accuracy 73 - glucose meters 73 insulin titration/adjustment 46 pattern management 46 timing in different insulin regimens 45

Sick days hyperglycaemia 56 hypoglycaemia 56 ‘sick days’ rules 56

Targets glycaemic targets 43

Travel insulin therapy - long distance air travel 58 - preparations 57

Type 2 Diabetes Mellitus diagnosis - role of insulin therapy 8 - treatment and management 7

Weight gain insulin therapy 52

81GLOSSARY OF TERMS

BD Twice Daily (Bis Die)BG Blood GlucoseBMI Body Mass IndexBP Blood PressureCHD Coronary Heart DiseaseCVD Cardiovascular DiseaseDCCT Diabetes Control and Complications TrialDKA Diabetes KetoacidosisDM Diabetes MellitusDN Diabetic NephropathyDPP-4 Dipeptidyl peptidase-4ECG ElectrocardiogramED Erectile DysfunctionFPG Fasting Plasma GlucoseGDM Gestational Diabetes MellitusGI Glycaemic IndexHbA1c Glycosylated HaemoglobinHDL High Density LipoproteinIDF International Diabetes FederationIFG Impaired Fasting GlucoseIGT Impaired Glucose ToleranceLDL Low Density LipoproteinMNT Medical Nutrition TherapyNCEP National Cholesterol Education ProgramNPH Neutral Protamine HagedornOAD Oral Anti-diabeticOD Once Daily (Omni Die)OGTT Oral Glucose Tolerance TestOM On Morning (Omni Mane)ON On Night (Omni Nocte)PPAR-Y Peroxisome Proliferator-Activated Receptor-GammaPPG Post-prandial Plasma GlucoseRPG Random Plasma GlucoseS/C SubcutaneousSMBG Self Monitoring Blood GlucoseSU SulphonylureaT1DM Type 1 Diabetes MellitusT2DM Type 2 Diabetes MellitusTDS Three Times Daily (Ter Die Sumendus)TG TriglyceridesTZD ThiazolidinedioneUKPDS United Kingdom Prospective Diabetes StudyWC Waist CircumferenceWHO World Health Organisation

ACKNOWLEDGEMENTS82

The members of the working committee of this guide would like toexpress their gratitude and appreciation to the following for theircontributions:

• Panel of external reviewers who reviewed the draft

• All those who have contributed directly or indirectly to the development of this guide

The development of this guide was supported by an educational grant from sanofi -aventis

SOURCES OF FUNDING