sajdvd volume 10, issue 1

Featured in this issue:

Volume 10 Number 1March 2013

SAJDVDThe South African Journal of DiAbeTeS & VASculAr DiSeASe

Reviews Ethics Focus Achieving Best Practice Diabetes Educator’s Focus News

The electronic version of the journal is available at

www.diabetesjournal.co.za

Medical management of type 2 diabetes

A healthcare funder’s perspective

Dietary management of type 2 diabetes

Insulin-related weight gain

Management of hypertriglyceridaemia

Painful diabetic peripheral neuropathy

Travelling on insulin

Second-generation sulphonylureas

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Dynator Advert A4.pdf 1 2013/02/13 10:07 AM

HYPERINSULINAEMIA

ISSN 1811-6515

THE SOUTH AFRICAN JOURNAL OF

Diabetes & vascular Disease

Corresponding EditorDr FA MAhoMeDGreys hospital, Pietermaritzburg

Consulting EditorDr L LoMbArD

National Editorial BoardDr A AMoDCentre for Diabetes, endocrinology and Metabolic Diseases, Life healthcare, Chatsmed Gardens hospital, Durban

Sr K beCKerTDiabetes Nurse, Paarl

ProF F boNNICIemeritus Professor, Faculty of health Sciences, University of Cape Town and President of Diabetes South Africa

ProF r DeLPorTDepartment of Family Medicine,University of Pretoria

Dr L DISTILLerDirector of the Centre of Diabetes and endocrinology, houghton, Johannesburg

Dr F MAhoMeDDepartment of endocrinology, Grey’s hospital, Pietermaritzburg

ProF WF MoLLeNTZehead of Department of Internal Medicine, University of the Free State, bloemfontein

ProF CD PoTGIeTerSpecialist Nephrologist, University of Pretoria and Jakaranda hospital, Pretoria

ProF K SLIWAAssociate Professor of Medicine and Cardiology, baragwanath hospital, University of the Witwatersrand, Johannesburg

ProF YK SeeDATemeritus Professor of Medicine and honorary research Associate, University of Natal, Durban

International Editorial BoardProF IW CAMPbeLLPhysician, Victoria hospital, Kircaldy, Scotland, UK

ProF PJ GrANTProfessor of Medicine and head of Academic Unit of Molecular Vascular Medicine, Faculty of Medicine and health, University of Leeds; honorary consultant physician, United Leeds Teaching hospitals NhS Trust, UK

ProF J-C MbANYAProfessor of endocrinology, Faculty of Medicine and biomedical Sciences, University of Yaounde I, Cameroon and President, International Diabetes Federation

ProF N PoULTerProfessor of Preventive Cardiovascular Medicine, Imperial College, School of Medicine, London, UK

Dr h PUrCeLLSenior research Fellow in Cardiology, royal brompton National heart and Lung hospital, London, UK

VOLUME 10 NUMBER 1 • MARCH 2013www.diabetesjournal.co.za

CONTENTS Editorial

3 The pendulum is swingingL Lombard

Funding Diabetes Care

4 Managing the world’s number one chronic disease: a healthcare funder’s perspectiveDiscovery Health

7 Medical management of type 2 diabetes mellitus: a frustrating battle with the fundersL Lombard

Reviews

9 Dietary management of type 2 diabetesW May

12 Insulin-related weight gain in patients with type 2 diabetes: case examples, mechanisms and an approach to managementD Webb, MAK Omar, A Kok

18 Hypertriglyceridaemia in type 2 diabetes: prevalence, risk and primary care managementA Sinclair

23 Painful diabetic peripheral neuropathyH Kaplan

Patients as Partners

32 Helping patients on insulin to travel safelyS Waddingham

Assistant Editor: Special AssignmentsJULIA AALberSTEL: 021 976 8129e-mail: [email protected]

Development Editor: GLeNDA hArDYTEL: 021 976 8129CELL: 071 819 6425FAX: 086 610 3395e-mail: [email protected]

Production EditorShAUNA GerMIShUIZeNTEL: 021 785 7178FAX: 086 628 1197e-mail: [email protected]

Production Co-ordinatorWeNDY WeGeNerTeL: 021 976 8129e-mail: [email protected]

Editorial Assistant and CirculationeLSAbÉ bUrMeISTerTEL: 021 976 8129FAX: 086 664 4202e-mail: [email protected]

Gauteng ContributorPeTer WAGeNAArCELL: 082 413 9954e-mail: [email protected]

Content ManagerMIChAeL MeADoN (Design Connection)TEL: 021 976 8129FAX: 086 655 7149e-mail: [email protected]

The South African Journal of Dia-betes and Vascular Disease is pub-lished four times a year for Clinics Cardive Publishing (Pty) Ltd and printed by Durbanville Commercial Printers. Online Services: Design Connection.

Articles in this Journal are sourced as per agreement with the British Journal of Diabetes and Vascular Disease

All correspondence to be directed to:The eDITorPO BOX 1013DUrbANVILLe7551or [email protected]

TEL: 021 976 8129FAX: 086 664 4202INT: 2721 976-8129

To subscribe to the journal or change address, email [email protected]

Full text articles available on: www.diabetesjournal.co.za via www.sabinet.co.za

The opinions, data and statements that appear in any articles published in this journal are those of the contributors. The publisher, editors and members of the editorial board do not necessarily share the views expressed herein. Although every effort is made to ensure accuracy and avoid mistakes, no liability on the part of the publisher, editors, the editorial board or their agents or employees is accepted for the consequences of any inaccurate or misleading information.

Diabetes News

35 Changing dietary habits and associated nutritional deficiencies impact on urban African patients living with heart failure in SowetoP Wagenaar

36 South African studies in the international literature: considerations of ethnicity and gender in chronic diseases of lifestyleG Hardy

Drug Trends

39 Sanofi diabetes specialist weekend 2012, Cape TownG Hardy

43 Second-generation sulphonylureas: gliclazide modified release (60 mg) reviewed in clinical practice for type 2 diabetes

J Aalbers

Page 11

Page 32

SA JOURNAL OF DIABETES & VASCULAR DISEASE EDITORIAL

VOLUME 10 NUMBER 1 • MARCH 2013 3

Correspondence to: Dr Landi LombardNetcare Kuils River Hospital, Cape TownTel: +27 0(21) 900-6350e-mail: [email protected]

S Afr J Diabetes Vasc Dis 2013; 10: 3

The pendulum is swingingLANDI LOMBARD

My endocrinology training at the Endocrine Unit of Tygerberg Hospital was under the supervision and watchful eye of Prof Stephen Hough. He deserves credit for having built

up this unit, mostly on his own, over many years. He used to love talking about how the pendulum swings in medicine, often from one extreme to the other.

I think it is swinging again. In the past decades, the pendulum swung towards private medicine and most doctors and specialists left the public sector for the private sector or life abroad. The most obvious reason was the poor salaries paid by the public sector, as well as poor working conditions and the unavailability of medicine and modern equipment.

In recent years however, public health has immensely improved remuneration packages for doctors and nurses. Working conditions have been upgraded and much money has been invested in improving equipment. On the other hand, private-sector earnings have not seen an inflation-related increase for a decade and consulting specialties struggle to match the current salaries of the public-sector health professionals. The risks they take and the huge increase in funders’ administrative burdens have escalated to unbearable levels.

Nursing care packages in the public sector have surpassed the salaries of private-care nurses and we are losing nurses from private hospitals. I expect many doctors to follow. The pendulum is surely swinging again, this time in favour of public health.

Healthcare funders have become the monster that is slowly devouring the noble profession of medicine. This frustration is voiced in my article on diabetes treatment in South Africa. An overview is given of the drugs available for diabetes care, compared to the USA, and how funders are limiting the funding of various options. I suggest a guideline for use in practice, based on the current SEMDSA guidelines (see page 7). The S Afr J Diabetes Vasc Dis asked Discovery Healthcare to state their perspective on how diabetes influences their business, how many diabetic people they look after, and the financial costs involved (see page 4).

Dr Webb and co-workers give case reports and advice in those patients with type 2 diabetes and insulin-induced weight gain, indeed a common phenomenon. They echo the view in my article, which suggests we should use more GLP-1 analogues and DPP-4 inhibitors (see page 12).

I’m often quizzed by colleagues on when to treat and which drugs to use. Prof Sinclair gives clear answers to these common questions in a good overview of hypertriglyceridaemia in type 2 diabetes. He gives practical advice on the management of this sometimes challenging problem, as well as discussing the NICE guidelines (see page 18).

A practical guide gives sound advice on travelling as a person with diabetes. It could be used as a hand-out or guide for diabetic patients travelling overseas (page 32).

There has been much controversy recently regarding diets for people with diabetes, especially after Prof Tim Noakes’ statements on diet in diabetes. Dr May gives an overview and published data to provide perspective on this difficult topic (see page 9).

I feel that private healthcare should reinvent itself by having meetings between private hospital groups, healthcare funders and private doctors (if possible) to discuss the future of private healthcare. The lack of positive communication between these large role players seriously hampers the potential of private healthcare.

4 VOLUME 10 NUMBER 1 • MARCH 2013

FUNDING DIABETES CARE SA JOURNAL OF DIABETES & VASCULAR DISEASE

Correspondence to: Discovery HealthWebsite: www.discovery.co.za

S Afr J Diabetes Vasc Dis 2013; 10: 4–6

Managing the world’s number one chronic disease: a healthcare funder’s perspectiveDISCOVERY HEALTH

Discovery Health provides a funder’s perspective on the management of diabetes. The Discovery Health Medical Scheme is South Africa’s largest open medical scheme.

Impact of chronic diseases of lifestyle Chronic diseases of lifestyle have rapidly snowballed into a global epidemic and are a leading cause of death and disability worldwide. The prevalence of chronic diseases is on a steep trajectory, with predictions that chronic diseases will be responsible for up to 73% of all deaths and 60% of the global disease burden by 2020.1

Type 1 and 2 diabetes mellitus are two of these many chronic diseases. Type 1 diabetes is an autoimmune disease that represents 5% of the population with diabetes, resulting from the body’s destruction of the pancreatic cells that produce insulin. On the other hand, type 2 diabetes is a chronic disease linked to poor lifestyle choices, including obesity, high cholesterol levels and physical inactivity; as well as a genetic predisposition to inheriting the disease. Type 2 diabetes accounts for 95% of all diabetes.2

International Diabetes Federation (IDF) statistics reflect there are 371 million people worldwide who have been diagnosed with diabetes and are living with the ill effects of the disease.2 It is also estimated that there are 187 million people worldwide who are unaware that they have diabetes. The IDF estimates that by 2030, there will be 552 million people worldwide living with diabetes, with the bulk of these people located in emerging economies. In South Africa, the Johannesburg-based Centre for Diabetes and Endocrinology approximates the number of South Africans diagnosed with diabetes at 3.5 million, with about 5 million more who are unaware that they have the disease.3

Economic costs of chronic diseasesThe high number of chronic diseases of lifestyle will continue to place an increasing burden on government and healthcare facilities in the years to come. This is particularly relevant as regions and industries are increasingly battling to address the high cost of healthcare and its impact on economic growth and human resource management. While many of these diseases can be avoided through preventative healthcare measures, the rising burden of chronic diseases worldwide presents a funding challenge for many healthcare funders. Globally, the cost of funding chronic diseases of lifestyle is expected to reach over $47 trillion by 2030, a massive financial burden.4

For healthcare funders, this high cost poses significant challenges. These include the increasing disease burden and benefit utilisation of a membership base, the high costs of

medical technologies and the high utilisation of expensive technology. At the same time, healthcare funders must manage resources responsibly and maintain affordable premiums to ensure sustainability and financial protection for members. These challenges provide a natural tension in how healthcare resources are managed, and funding decisions must therefore be made with the interests of all stakeholders at heart.

In light of the growing chronic diseases epidemic, Discovery Health’s role as the largest healthcare funder in South Africa is to fund healthcare of the highest quality for our members. Discovery Health has consistently increased its funding of chronic disease medication each year, from R1.08 billion to R1.74 billion in 2012.

In 2012, 325 157 Discovery Health members were registered with chronic diseases. Of this number, a total of 79 838 members were diagnosed with type 1 and 2 diabetes. At Discovery Health, diabetes mellitus accounts for 14.41% of the total patients registered on the chronic illness benefit (CIB), and represents 13.49% of the costs.

Table 1 and Fig. 1 show a comparison between the cumulative increase of all claims made by Discovery Health members with chronic diseases and members with chronic diabetes per 1 000 members during the period 2008 to 2012. The number of claims made by chronic members increased from 11.54 per 1 000 claimants in 2008 to 13.55 per 1 000 in 2012, while the number of claims made by chronic diabetics increased from 1.58 per 1 000 claimants in 2008 to 1.95 per 1 000 in 2012.

Table 1 and Fig. 1 show how, during the same period ending in 2012, those with diabetes made 6% more claims than other chronic members. This reflects how diabetes is increasing across all demographics, making it the world’s number one chronic disease, for which healthcare funders need to fund treatment.

How Discovery Health funds medication for chronic diseases As a medical scheme that manages funds for members, Discovery Health embraces new technology that is of proven benefit to our members in a responsible manner, taking into consideration the

Table 1. Cumulative increase of all chronic diabetics vs all chronic members from 2008.

Year

All chronic claimants

per 1 000 lives

All diabetic claimants

per 1 000 lives

Cumulative increase:

all chronic claimants (%)

Cumulative increase: all

chronic diabetics (%)

2008 11.54 1.58 100 100

2009 12.01 1.63 104 103

2010 12.68 1.74 110 110

2011 13.15 1.85 114 117

2012 13.55 1.95 117 123


SA JOURNAL OF DIABETES & VASCULAR DISEASE FUNDING DIABETES CARE

affordability and sustainability of the Discovery Health Medical Scheme. The Scheme must be sustainable and provide our members with peace of mind that they will be covered when they need it.

We understand the importance of managing chronic diseases of lifestyle through co-ordinated chronic care management and offer our members full cover for diabetes. Discovery Health has a comprehensive, flexible and holistic approach to providing cover for medicines for chronic diseases across the board. This approach is fully compliant with the prescribed minimum benefits and all other applicable aspects of the Medical Schemes Act.

The prescribed minimum benefits state that all medical schemes are by law obliged to cover costs related to the diagnosis, treatment and care of any life-threatening emergency medical conditions, as defined in the Medical Schemes Act of 1998. This set of conditions includes 270 defined diagnoses, their associated treatments and 27 chronic conditions, including type 1 and 2 diabetes mellitus. Patients who have been diagnosed with type 2 diabetes are also eligible for the funding of treatment with lipid-lowering drugs.

To manage these funding challenges, Discovery Health funds all chronic medications for chronic diseases through the CIB. Members who want to register on the CIB need to ask their doctor to complete an application form, which includes the clinical entry criteria requirements for them to be accepted on the benefit. Each chronic condition has clinical entry criteria and if a member does not meet these criteria, he/she will be unable to access the CIB for this particular medicine.

We offer our members extensive and flexible cover for approved chronic medicine. Members on the CIB have two options when it comes to selecting their medicine. They can either select and claim for medicine that is included on the formulary and which Discovery Health will pay in full, or they can choose to use a medicine that is not on the list, for which Discovery Health will pay the chronic drug amount for that medicine. If the medicine costs more, members may need to make a co-payment.

Through the CIB, Discovery Health provides members with comprehensive, holistic care and management for their chronic diseases. Discovery Health has added specific benefits to assist members who want to access additional cover. Discovery Health Medical Scheme provides members on the top-end Executive and Comprehensive health plans access to the Specialised Medicine

and Technology benefit, which provides them with additional cover for certain innovative medical technologies and expensive medicines. Members who require access to medication that is not on the formulary can request that their case be considered on appeal, through which a doctor can demonstrate and motivate why the member should be allowed to access the required medication and be covered for it.

Discovery Health formulary The Discovery Health formulary is fully compliant with the Council of Medical Schemes’ algorithms and is designed to cater for the patient with mild to moderate disease. Patients with a greater severity of disease or any other complicating factors need to go through the appeals process. Any newer drug classes which are not currently listed on the Council of Medical Schemes’ algorithms are not included in the Discovery Health formulary.

Any member, who may, for clinical reasons, require a medicine that cannot be covered within the Chronic Drug amount can apply for a clinical exception, and the application will be reviewed and assessed by a clinical team. Medicine approved to treat conditions included in the Chronic Disease list and the Additional Disease list, which are listed in the Discovery Health formulary, are funded in full up to the Discovery Health medicine rate if they are obtained from one of our network pharmacies.

Negotiating with pharmaceutical companies to lower costsDiscovery Health continuously negotiates with pharmaceutical companies and drug manufacturers to reduce the cost of medicine for our members and the single exit price of medicines for South Africa. All these formularies are reviewed by external specialists in the relevant clinical fields and by our clinical unit twice yearly.

Approving drugs and new technologiesOne of the funding challenges medical schemes experience is in funding new medical technologies for chronic diseases, which may improve patient outcomes in sustainable ways. Such new technologies come with high costs, and because of these costs, some medical schemes have made a decision not to fund the latest treatments.

Discovery Health’s Clinical Policy Unit reviews and assesses new technologies and determines whether they should be funded or not. The Clinical Policy Unit has a rigorous process to assess new technologies and new indications for current technologies, such as drugs, devices and technology. This process includes the evaluation of published clinical evidence, referred to as evidence-based medicine, the financial impact on the scheme, and a health economics analysis. The first phase of this process is the clinical assessment, and if the clinical evidence is sufficient to support the recommendation for funding, the process will continue to a financial assessment of the technology, which might include a health economics model before being approved for funding.

Centre for Diabetes and Endocrinology’s Diabetes Management ProgrammeIn addition to being able to access chronic medication through the CIB, members who are registered on the CIB are able to register on the Diabetes Management Programme, which is a nationwide

Figure 1. Graph portraying cumulative increase of all chronic diabetics vs all chronic members from 2008.



programme run by the Centre for Diabetes and Endocrinology. They learn more about diabetes and how to manage their diabetes more effectively. The value of this programme to members is that it enables them to take an active role in their own health and wellbeing, and live healthier lives.

Discovery Vitality Discovery Health funds approved treatment and medication for members with diabetes. However, if members’ blood glucose levels are high but not high enough to be diagnosed as diabetes, we encourage our members to adjust their lifestyles and lead healthier, more active lifestyles rather than go on medication. In this way, members are able to take responsibility for their own health and wellbeing.

Our internationally recognised wellness programme, Vitality, helps them to do this. LivingVitality, an online platform, has made it easier for them to monitor their health and wellness. LivingVitality empowers our members to understand, track, connect, learn more about and manage their diabetes and any other medical conditions they may have through being able to ask experts questions, and make use of online tools and social media.

Telemetry pilot for blood glucose readingsFollowing the successful launch of the HealthID application, which enables doctors (with their patients’ consent) to access their electronic healthcare records, a pilot study with a telemetric glucometer was initiated. The glucometer enables diabetic patients to view and understand their blood glucose trends more easily, and empowers them to manage their diabetes more successfully.

The glucometer is designed to transmit the patient’s blood glucose readings directly to an application on their cellphone via Bluetooth, from where they are sent to a website that can be accessed by their caregiver. The system means that there is no need for diabetic patients to wait for a doctor’s visit to download their readings and view the trends, or to manually transcribe their readings onto a worksheet or into a logbook. All of their readings are easy to view and interpret in graphic format on their cellphone, allowing patients to understand how their actions affect their blood glucose levels and to adjust their behaviour in a positive way.

In addition, caregivers can access the results at any time to ensure that patients are testing regularly enough, and to check on

their blood glucose readings and whether they are improving over time. Further versions of the application will also enable patients to record the number of carbohydrates they have consumed during the day, as well as how much insulin they have injected.

The pilot group consisted of 50 Discovery Health members aged between six and 74 years who were primarily type 1 diabetes and insulin-dependent type 2 diabetes patients. After a trial run of five months, 82% of patients who provided feedback about the telemetric device rated their experience as an 8 or above out of 10; 82% of these patients also stated that they would purchase the device for themselves, and all of them said they would recommend the device to other diabetic patients. One patient even commented that ‘It has really helped me. My sugar levels are below what they have ever been and I owe part of that to this system. Thank you’.

Following the successful pilot study, Discovery Health is exploring solutions whereby they can enable diabetic patients and their caregivers to access this telemetric device and application. Ideally, a link to this application will be created on LivingVitality and within HealthID to facilitate a diabetes technological ecosystem, which both members and caregivers can tap into. This innovation shows how Discovery Health is continuously researching and funding new, innovative technologies that will best benefit members.

All the processes mentioned above show that Discovery Health is actively funding treatment and medication for diabetes mellitus and other chronic diseases, and this is in line with the Council of Medical Schemes. We are also bringing useful tools that enable the members to take control of the ongoing monitoring of their condition. We are aware of the multifaceted challenges around healthcare and funding chronic conditions, and we continue to implement mechanisms that will allow us to fund chronic conditions and provide our members with the highest quality healthcare while remaining sustainable.

References1. Discoverer, September 2012. Comprehensive chronic disease management: 4.2. SEMDSA 2012 Guideline for the Management of Type 2 Diabetes. J Endocrinol

Metab Diabetes S Afr 2012; 17(1); 51–5943. Diabetes worldwide at a record high http://www.health24.com/news/Diabetes/1-

904,77850.asp4. Diabetes ‘tsunami’ hits South Africa. http://www.health24.com/medical/

Condition_centres/777-792-808-1657,77805.asp5. Chronic disease to cost $47 trillion by 2030. http://www.reuters.com/article/

2011/09/18/us-disease-chronic-costs-idUSTRE78H2IY20110918


SA JOURNAL OF DIABETES & VASCULAR DISEASE FUNDING DIABETES CARE

Correspondence to: Dr Landi LombardNetcare Kuils River Hospital, Cape TownTel: +27 0(21) 900-6350e-mail: [email protected]


There is currently a worldwide pandemic of type 2 diabetes that is spiralling out of control and threatening to overwhelm healthcare systems. South Africa is no exception, and the

escalating incidence of obesity here suggests that it will get worse. The brunt of this pandemic will have to be managed at a primary-care level where general practitioners and primary-care nurses will play a vital role.

Healthcare professionals work under huge pressure to accommodate all their patients. We try to manage these patients optimally, taking into account efficacy, side effects and cost. At the specialist level, each drug is carefully selected according to individual characteristics and needs.

However healthcare funders make it difficult for us by each having their own set of rules and recommended drugs, which change periodically. They also show little insight into the variety of options available to diabetics and only consider the cheapest options. If we don’t address this, we might soon find ourselves only generating an ICD-10 code and the funders will decide which medicine will be allowed. This is causing huge frustration in daily practice and contributing to the emigration of many of our doctors.

National and international guidelines are published, drawn up by the best and most knowledgeable people in the world. The funders seem to ignore these and have their own ‘experts’ draw up their guidelines. In my opinion this should not be allowed by the Council for Medical Schemes. The national guidelines should be enforced by law.

The other side of the coin unfortunately is that with the marked increase in incidence of diabetes, there is also a dramatic increase in cost for the funders. Medical aid premiums are also increasing at an alarming rate and soon most people will not be able to afford them. Physicians must be cost effective, but not at the cost of efficacy or side effects.

I am of the opinion that we should manage chronic illness at the optimum level to prevent complications down the line. Money could be saved on expensive procedures if a national guideline could be drawn up to regulate the implementation of these procedures, for example, chronic haemodialysis, cardiac defibrillators, TAVIs, ventilation withdrawal protocols, and admissions for diabetes. All medical aids should have to cover the same benefits.

Table 1 shows the drugs currently registered with the Food and Drug Administration, as well as their availability in South Africa.1 We

Medical management of type 2 diabetes mellitus: a frustrating battle with the fundersLANDI LOMBARD

Table 1. Drugs currently registered with the FDA as well as their availability in South Africa.1

Brand name Generic name Approval date Yes/noACTOplus met pioglitazone hydrochlo-

ride and metformin hydrochloride

August 2005 N

Apidra insulin glulisine February 2004 YAvandamet rosiglitazone maleate

and metformin HClOctober 2002 N

Bydureon exenatide synthetic January 2012 NByetta exenatide April 2005 YHumalog insulin lispro June 1996 YHumalog 50/50 50% insulin lispro pro-

tamine and 50% insulin lispro

June 1996 Y

Humalog 75/25 75% insulin lispro pro-tamine and 25% insulin lispro

December 1999 N

Humulin N NPH (N) October 1982 YHumulin 70/30 70% NPH and 30%

regularApril 1989 Y

Humulin R 100 U regular (R) Insulin October 1982 Y

Humulin R 500 U regular (R) Insulin (5 times concentration)

October 1982 N

Janumet sitagliptin/metformin HCl

March 2007 Y

Janumet XR sitagliptin and met-formin HCl extended-release

February 2012 N

Januvia sitagliptin phosphate October 2006 YJantadueto linagliptin plus met-

formin hydrochlorideFebruary 2012 N

Juvisync sitagliptin and simvas-tatin

October 2011 N

Kombiglyze XR saxagliptin/metformin hydrochloride extended release

November 2010 N

Lantus insulin glargine April 2000 YLevemir insulin detemir June 2005 YLucentis ranibizumab August 2012 NMetaglip glipizide/metformin HCl October 2002 NNovolin N NPH (N) July 1991 YNovolin R regular (R) June 1991 YNovolin 70/30 70% NPH and 30%

regularJune 1991 Y

Novolog Insulin aspart November 2001 YNovolog 70/30 70% insulin aspart

protamine and 30% insulin aspart

November 2001 Y

Onglyza saxagliptin July 2009 YPrandiMet repaglinide/metformin

hydrochlorideJune 2008 N

Symlin pramlintide March 2005 NTradjenta linagliptin May 2011 NVictoza liraglutide January 2010 Y

Welchol colesevelam hydro-chloride

January 2008 N



also have a good variety of anti-diabetic agents registered in South Africa (Table 2). Physicians can therefore opt for combinations of oral agents, or combine them with insulin or newer GLP-1 analogues.

When we treat type 2 diabetes we should all have the recently published SEMDSA guidelines in mind,2 as well as individualised goals for specific patients. This will help us to select the best option for each patient. Discussion with the patient is necessary because of cost implications of the medication as well as individual preferences.

All patients should be on a lifestyle programme, including an exercise routine, as well as metformin. If gastrointestinal side effects are experienced, the glucophage XR formulation will often prevent this. Metformin should be stopped for a week and re-challenged with glucophage XR, starting with one tablet after supper and increasing by one tablet every five to seven days. Two tablets are a good dose and three are optimal. This is the easy part; from here there are many options. I seldom use metformin in a twice-daily dosing regimen.

The best for beta-cell preservation and prevention of hypoglycaemia is adding a GLP-1 analogue or a DDP-IV inhibitor in early diabetes. Funders do not agree with this strategy because it is not the cheapest. They will however often pay for insulin as a second step, with similar cost and more risk.

The risk–benefit ratio of the thiazoledinediones is very small and they should not be used routinely, only at the specialist level. In the sulphonylurea class, I mainly use gliclazide MR and sometimes glimeperide. Glibenclamide should, in my opinion, not be used because of the much higher hypoglycaemic risk, except in the fixed combination, Glucovance, and then only in younger patients.

The meglitinides are in a separate class, with similar effects to the sulfonylureas but no other benefits, and are much more expensive. I therefore seldom use them.

The DPP-4 inhibitors, which were recently reviewed in this journal, are well priced and combine well with metformin.3 They should be used early in type 2 diabetes and always in combination. Fixed combinations were recently launched (GalvusMet and Janumet). These drugs have very low side-effect profiles, low hypoglycaemic risk and are weight neutral. Multiple cardiovascular outcome trials are currently on-going for these medications.

Triple therapy could be considered, but only if the HbA1c level is close to target. The next step is insulin, usually with a basal insulin at bedtime. One could also start with a premix with supper. Starting dose is usually 14 to 16 units, up-titrated to achieve the specified fasting glucose level. Titration can be done twice a week. When the target fasting level (which should be either 6 or 7 mmol/l) is achieved, pre-supper values should be monitored as well.

Determination of HbA1c levels should be repeated at this stage to see if control has been achieved. If not controlled despite achieving a fasting glucose level of 6 mmol/l or below, further therapy should be added. This will require a daytime insulin, either mixed (if already used with supper) or the basal plus short-acting insulin, and adding short-acting analogue insulin with the main meal. Using short-acting insulin will require more testing and patient insight, so careful patient selection is necessary. This additional short-acting insulin might end up as a full basal-bolus regime, always combined with metformin.

When insulin is used twice or more a day, sulfonylureas and DDP-4 inhibitors should be stopped. The problem is that these patients will often require huge doses of insulin and need the maximum tolerated dose of metfomin. The use of GLP-1 analogues can contribute to significant insulin saving and prevention of weight gain, which is often a problem if large doses of insulin are used.

New strategies are needed for the severely insulin-resistant patient. The Centre for Diabetes and Endocrinology in Johannesburg has recently studied U-500 insulin in a randomised trial, and we are awaiting the results.

Currently we have a wide range of drugs available in this country to fight the diabetes pandemic. Our drug availability compares well with many European countries, however in practice, when the clinician wants to prescribe many of these drugs, they are severely restricted by the funders. This may be contributing to the sub-optimal control of diabetes in this country.

References1. FDA website: www.fda.gov/.2. Amod A, Ascott-Evans BH, Berg GI, et al. The 2012 SEMDSA guidelines for the

management of type 2 diabetes (Revised). JEMDSA 2012; 17(suppl 1): S1–S95.3. Lombard L. DDP-4 inhibitors (gliptins) in the management of type 2 diabetes.

S Afr J Diabetes Vasc Dis 2012; 9(1): 10.

Table 2. Registered anti-diabetic agents.

Class Generic name *Trade name Maximun dose

Biguanides metformin Glucophage 3 g/dayXR 2 g/day

Sulfonylureas gliclazide

glimepirideglibenclamideglipizide

DiamicronDiamicron MRAmarylDaonilMinidiab

160 mg bid120 mg/day8 mg/day7.5 mg bid

Alpha-glucosi-dase inhibitors

acarbose Glucobay 200 mg tds

Meglitinides nategliniderepaglanide

StarlixNovonorm

120 mg tds4 mg qid

DPP-4 inhibitors vildagliptinsaxagliptinsitagliptin

GalvusOnglyzaJanuvia

50 mg bid5 mg/day100 mg/day

GLP-1 analogues exenatideliraglutide

ByettaVictoza

10 ug bid1.8 mg/day

Thiazoledine-diones

pioglitazone Actos 45 mg/day

Basal insulin

Analogues

NPH

zinc insulindetemirglargine

Humulin NProtaphaneBiosulin NBiosulin LLevemirLantus

unlimited

Pre-mix insulin ActraphaneHumulin 30/70Biosulin 30/70Novomix-30Humalog mix-25 and Mix-50Insuman comb

unlimited

Short-acting insulin(analogue)

lisproaspartglulisine

HumalogNovorapidApidra

unlimited

Human insulin Humulin RBiosulin R

unlimited

Combinations GlucovanceGalvusMetJanumet

different com-binations and doses

*Generic oral agents not mentioned


SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW

Correspondence to: Dr Wayne MayEndocrinologist, Kingsbury Hospital, Cape Towne-mail: [email protected]


T he management of diabetes has evolved over the years and has become more individualised with time. As we learn more we have come to understand that we need better approaches

if we are to reduce the incidence of diabetes and its complications, no more so than with regard to diet. Recently there has been much controversy with regard to the ideal diet, and the aim of this article is to look critically at the evidence to see if there is one ideal diet.

One diet that is receiving attention is the low-carbohydrate diet (LCD). This diet has been around for centuries. One of the first reports was by John Rollo and William Cruickshank, who put two soldiers with diabetes onto a vegetable-free diet, low in carbohydrates and high in protein and fat.1 They were able to show a reduction in body weight and glycosuria.

In 1825, a French lawyer and gourmand, Brillant-Savarin published The Physiology of Taste, in which he said he had identified the cure for obesity: ‘More or less rigid abstinence from everything that is starchy or floury.’ A more well-known account is that of William Banting,2 who in 1863 was advised by William Harvey to give up beer, potatoes and bread, which he did successfully. Since then there have been numerous reports of the LCD being used to treat type 1 diabetes before the advent of insulin.

Without doubt, the most popular version of the LCD is the Atkins diet, first published in 1972.3 He initially studied the LCD in patients to control seizures, and then on himself. Since his initial book, there have been multiple other LCD books published. There are various classifications of what constitutes a LCD, but one common one is as follows: low-carb ketogenic diet < 50 g daily, low-carb diet 50–130 g daily, moderately low-carb diet 130–225 g daily.

The traditional diet that has been advocated for the last couple of decades has been the low-fat diet (LFD). The origin of this dates back to 1951 when Ancel Keys, a professor at the University of Minnesota, attended a conference in Rome on nutrition and disease and learned that heart disease was rare in some Mediterranean populations who consumed a low-fat diet. He noted, too, that the Japanese had low-fat diets and low rates of heart disease. He hypothesised from these observations that fat was the cause of heart disease. In 1953 he published his Seven Country analysis, suggesting an association between dietary fat and mortality from heart disease.4

Following on this, in 1956, the American Heart Association (AHA) conducted a TV fundraiser on all three networks urging Americans to reduce their intake of total fat, saturated fat and cholesterol. In 1961, Keys made the cover of Time magazine, and from then on the media pushed the low-fat diet as the healthy option.

In 1961, the Framingham Heart study showed that men under 50 years with elevated cholesterol and other risk factors were at greater risk of heart disease.5 These became the famous

Dietary management of type 2 diabetesWAYNE MAY

Framingham ‘risk factors’, and elevated cholesterol was at the top of the list. It is important to note that these were associations, not cause and effect.

In 1977, after conducting six additional hearings, Senator McGovern’s Senate Select Committee issued the final version of the Dietary guidelines for Americans. For the first time, an agency of the USA federal government told the American people to eat less fat. In 1988, the National Institutes of Health and the American Heart Association established the National Cholesterol Education Program.6 Guidelines were issued the following year, and blood cholesterol levels over 5.147 mmol/l were treated as a disease.

Following on the above, a LFD has become entrenched in all dietary guidelines, and so the question is ‘how strong is the cholesterol evidence?’ Firstly, cholesterol is an essential molecule, playing an important role in multiple physiological functions, and life cannot exist without it. There certainly is, however, no lack of association in studies such as the Seven Countries, Framingham Heart and INTERHEART8 studies showing a link between cholesterol and heart disease, but when one looks for direct cause and effect studies, these are not as strong.

There are some animal studies, and one of the first was by Anitschkow in 1913, showing that rabbits fed cholesterol in sunflower oil developed lesions resembling human atherosclerosis, whereas the ones fed only sunflower oil developed no lesions. Unfortunately other researchers were unable to replicate the findings. Certainly, some of the best clinical evidence comes from patients with familial hypercholesterolaemia,7 as these patients are at high risk of heart disease.

The next question is ‘does lowering cholesterol impact on reducing the incidence of heart disease?’. There is no doubt that statins reduce incidence of heart disease, as this has been replicated in numerous studies, but the same cannot be said for dietary interventions, i.e. can a low-fat diet and blood cholesterol lowering reduce the incidence of heart disease.

The Finnish Mental Hospital study showed that by reducing saturated fat intake in an in-patient population, the patients were able to reduce cholesterol levels and death from coronary heart disease by more than 50%.9 In other studies, the results have not always been the same as in the Women’s Health initiative.10 We are therefore left with those who believe that high cholesterol levels are harmful and should be treated, and those who doubt the evidence and are unconvinced.

The next aspect to focus on is how carbohydrates have become so entrenched in the guidelines. To do this we need to look at the evolution of the food pyramid.11 It is important to note that the main driving force behind the food pyramid is the American Agriculture Department, and hence there is an in-built bias. The forerunner of the eventual food pyramid and subsequent ‘My Plate’ started with ‘Food for young children’ published in the Farmer’s Weekly in 1916, followed a year later by ‘How to select foods’. This was followed by the ‘Basic seven’ in 1943 and then the ‘Basic four‘ in 1956.

In 1980 in the Dietary Guidelines for Americans, sparsely named Food, the US Department of Agriculture addressed the link between


REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE

too much of certain foods and chronic disease. In 1984, the ‘food wheel’ was published and for the first time carbohydrates were depicted to form the bulk of the food we were to eat. This was replaced by the ‘pyramid’ in 1992, and then by the ‘mypyramid’ in 2005. In both pyramids, carbohydrates formed the main source of food.

The latest incarnation is the ‘MyPlate’, replacing the pyramid with two plates, one containing fruits, vegetables, grains and proteins and then a second smaller plate for dairy, with carbohydrates again forming the bulk. At this point it should be noted that there are no trials showing that by following a ‘MyPlate’ diet, one can reduce incidence of heart disease. Hence it reflects the summary of various bits of evidence put together as a best-fit diet, with some interplay between science and the food industry.

Given the above as a background, it is appropriate to look at the evidence for various diets, but specifically the LCD vs LFD with regard to weight, surrogate markers, diabetes and diabetes-related complications. Focusing first on weight, the trials show that in the short term, i.e. less than six months, the LCD is better than the LFD, but that over the longer term, there is no difference.12,13 Sacks et al. compared weight-loss diets with different compositions of fat, protein and carbohydrates, and showed that over two years, it made no difference in terms of weight loss.14

With regard to metabolic parameters, the LCD has an advantage with regard to raising high-density lipoprotein (HDL) levels, but fares worse with regard to low-density lipoprotein (LDL) levels.13

When it comes to diabetes prevention, the main studies in this area have used a LFD, and have showed a 58% reduction in the progression from pre-diabetes to diabetes.15 There are no formal large-scale studies looking at preventing diabetes using a LCD.

When it comes to dietary manipulation in patients with diabetes, one of the earliest and most well-quoted studies is by Westman,16

where he compared a LCD to a low glycaemic index diet. He showed that over 24 weeks, the LCD reduced HbA1c levels by 1.55% as opposed to the low-glycaemic index diet, which reduced HbA1c

levels by 0.5%. More weight loss occurred in the LCD diet, but the authors were statistically able to show that the improvement in HbA1c level was not dependent on weight loss.

Further studies however by Davis et al.17, Iqbal et al.18 and Guldbrand et al.19 did not show a difference between a LCD and LFD with regard to HbA1c level specifically over longer periods such as two years. The Diabetes Excess Weight Loss (DEWL) trial20 compared a high-protein diet with a high-carbohydrate diet and showed that over two years, neither diet was superior to the other with regard to HbA1c levels or other metabolic parameters such as weight or lipid levels. There is therefore no good evidence to show that a LCD diet is better than a LFD or any other diet with regard to HbA1c lowering

Recently there has been much interest in reversing diabetes, as this has been noticed in bariatric studies. There was an interesting study by Lim et al.21 that showed calorie reduction (600 calories over eight weeks) in 11 patients with diabetes could reverse the abnormalities in diabetes. The dietary breakdown in the study was 46.4% carbohydrate, 32.5% protein and 20.1% fat. The question with this low-calorie intake is whether to call this a low-fat or low-carbohydrate diet, as both could apply. It then begs the question whether the main dietary benefits of diets are via the alteration of the macronutrients or the total calorie content.

It can be argued that it is virtually impossible to design and conduct an adequate dietary trial. The alteration of any one

component of a diet will lead to alterations in others. Dietary trials cannot generally be blinded and changes in the diet of the ‘control’ population are frequently seen. It is also recognised that adherence to dietary advice over many years by large population samples, as for most individuals in real life, is poor and the stricter the diet, the worse the compliance. Finally, the impact of weight loss and exercise is difficult to separate from the change in macronutrients. A review by Wheeler et al. in Diabetes Care on multiple studies of diet and diabetes concluded similarly to the above.22

Ultimately, the main reasons for treating diabetic patients are to reduce macro- and microvascular complications, as well as incidence of death and cancer. To date there are no studies showing a benefit with regard to any of these outcomes. In keeping with this, a Cochrane meta-analysis concluded that no high-quality data on the efficacy of diet alone exist for treatment of type 2 diabetes mellitus and that no data were found on micro- or macrovascular diabetic complications, mortality or quality of life.23 Recently, the LOOK AHEAD study,24 which employed a low-fat diet (< 30% of kCal from fat with < 10% saturated fat) along with a 7–10% weight loss and an increase in exercise to 175 minutes per week, was stopped in view of futility, as it showed no reduction in incidence of cardiovascular disease.

With all this information, what do the current guidelines say? The American Diabetes Association suggests the mix of carbohydrate, protein and fat may be adjusted to meet the metabolic goals and individual preferences of the person with diabetes.25 Saturated fat intake should be < 7% of total calories. For weight loss, either low-carbohydrate, low-fat calorie-restricted, or Mediterranean diets may be effective in the short term (up to two years).

The South African Guidelines (SEMDSA) prescribe that fat intake should be restricted to < 35% of the total energy intake.26 The saturated fat intake should be restricted to < 7% of the total energy intake. Carbohydrates should make up 45–60% of the total energy intake. Proteins should make up 15–20% of the total energy intake. For weight loss, optional diets include the low-fat, low-carbohydrate and Mediterranean diets.

In conclusion, LCDs help with weight loss and are better than LFDs over the short term for weight loss, but are no better for weight loss over the longer term. Over the long term, LCDs are no better for metabolic parameters (except HDL) or diabetes. Current carbohydrate intake is too high, but the question is ‘what is the optimal amount?’ There are currently no outcomes data. Food sustainability doesn’t support a universal low-carbohydrate diet. My recommendation is that dietary advice should be individualised and metabolic parameters monitored. With regard to weight loss, the main emphasis is more about cutting calories than altering macronutrients.

References1. Rollo J, Cruikshank W. An Account of Two Cases of the Diabetes Mellitus. Vol I

and Vol II. T Gillet for C Dilly. London, UK, 1797.2. Banting W. Letter on corpulence, addressed to the public, 1864.3. Atkins RC. Dr Atkins’ Diet Revolution. Bantam, 1972.4. Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E. Coronary

Heart Disease among Minnesota Business and Professional Men Followed Fifteen Years. Circulation 1963; 28: 381–395.

5. Dawber TR, Kannel WB, Revotskie N, et al. Some factors associated with the development of coronary heart disease. Six years’ follow-up experience in the Framingham Study. Am J Public Health 1959; 49(10): 1349–1356.

6. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: the Expert Panel. Arch Intern Med 1988: 14836–14869.



7. Yusuf S, Hawken S, Ounpuu S, et al. On behalf of the INTERHEART study investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937–952.

8. Müller C. 1939. Angina pectoris in hereditary xanthomatosis. Arch Intern Med 1939; 64: 675–700.

9. Turpeinen O, Karvonen MJ, Pekkarinen M, et al. Finnish Mental Hospital study. Int J Epidemiol 1979, 8: 99–118.

10. Howard BV, van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease. The Women’s Health Initiative Randomized Controlled Dietary Modification Trial. J Am Med Assoc 2006; 295(6): 655–666.

11. The history of the food pyramid. http://www.washingtonpost.com/wp-srv/special/health/food-pyramid/. Accessed 29 Jan 2013.

12. Hession M, Rolland C, Kulkarni U, et al. Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities. Obesity Rev 2009; 10: 36–50.

13. Foster GD, Wyatt HR, Hill JO, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet. Ann Intern Med 2010; 153(3): 147–157.

14. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 360: 859–873.

15. uomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–1350.

16. Westman EC, Yancy WS, Jr, Mavropoulos JC, et al. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus – 24 weeks. Nutr Metab (Lond) 2008; 5: 36.

17. Davis NJ, Tomuta N, Schechter C, et al. Comparative study of the effects of a 1-year dietary intervention of a low-carbohydrate diet versus a low-fat diet on

weight and glycemic control in type 2 diabetes. Diabetes Care 2009; 32(7): 1147–1152.

18. Iqbal N, Vetter ML, Moore RH, et al. Effects of a low-intensity intervention that prescribed a low-carbohydrate vs. a low-fat diet in obese, diabetic participants – 2 year. Obesity 2010; 18(9): 1733–1738.

19. Guldbrand H, Dizdar B, Bunjaku B, et al. In type 2 diabetes, randomisation to advice to follow a low-carbohydrate diet transiently improves glycaemic control compared with advice to follow a low-fat diet producing a similar weight loss. Diabetologia 2012; 55(8): 2118–2127.

20. Krebs JD, Elley CR, Parry-Strong A, et al. The Diabetes Excess Weight Loss (DEWL) trial: a randomised controlled trial of high-protein versus high-carbohydrate diets over 2 years in type 2 diabetes Diabetologia 2012; 55: 905–914.

21. Lim EL, Hollingsworth KG, Aribisala BS, et al. Reversal of type 2 diabetes: normalisation of beta-cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506–2514.

22. Wheeler ML, et al. Is there an optimal macronutrient ratio for glycemic management and cardiovascular risk reduction in people with diabetes? Diabetes Care 2012; 35(2): 434–445.

23. Nield L, Moore H, Hooper L, et al. Dietary advice for treatment of type 2 diabetes mellitus in adults. Published online: January 21, 2009.

24. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 2011; 34(7): 1481–1486

25. American Diabetes Association. Standards of medical care in diabetes 2013. Diabetes Care 2013; 36: S11–S66. doi:10.2337/dc13-S011.

26. Amod A, Ascott-Evans BH, Berg GI, Blom DJ, Brown SL, Carrihill MM, et al.; Guideline committee. The 2012 SEMDSA guideline for the management of type 2 diabetes. J Endocrinol Metabol Diabetes S Afr 2012; 17(1): S1–S94.

More reasons to encourage smokers to quitTwo new articles confirm that, despite comprehensive

knowledge that smoking is hazardous, it remains a major threat to public health.1,2

The first study was a review of data from the US National Health Interview Survey, which included nearly 200 000 people over 25 years of age.1 It revealed the on-going impact of smoking on health, including a three times higher mortality rate compared with those that had never smoked. Diseases attributable to smoking accounted for about 60% of smokers’ deaths.

The survey also revealed changes in smoking patterns with many people beginning smoking after the age of 20 and 15% of women beginning after age 25, which is later than previously assumed. The mortality risk for women who smoke is 50% higher than the estimates reported in the 1980s.

The benefits of quitting smoking were dramatic for all age groups, with substantial gains in life expectancy compared with those who had continued to smoke. For example, those who quit between the ages of 25 and 34 years lived 10 years longer whereas even those who quit between ages 55 and 64 gained four years.

The second study focused on the mortality rates in females in seven USA population surveys.2 During the 50-year span of the survey, overall mortality dropped by 50% in the general population, by 24% in male smokers, but not at all in females. Whereas lung cancer mortality was nearly five times as high in men than in women in in the early 1960s, today the risks are the same, and are 25 times that in the non-smoking population. Overall, the risk of death from cigarette smoking continues to increase among women and is now almost identical to the rate for men.

SAJDVD recommended action These two articles confirm the benefits of quitting smoking at any age, and health professionals should do as much as possible to encourage patients to stop smoking. With more women dying of lung cancer than breast cancer, the need for further efforts to support women in quit attempts are a public health necessity.

References1. Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century hazards of

smoking and benefits of cessation in the United States. N Engl J Med 2013; 368: 341–350.

2. Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-related mortality in the United States. N Engl J Med 2013; 368: 351–364.

EVIDENCE IN PRACTICE



Correspondence to: Dr David WebbGauteng medical writere-mail: [email protected]

Prof MAK OmarDepartment of Endocrinology, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban

Dr Adri Kok Union Hospital, Alberton, GautengTel: +27 (0) 11 907 8827


Insulin-related weight gain in patients with type 2 diabetes: case examples, mechanisms and an approach to managementDAVID WEBB, MAK OMAR, ADRI KOK

IntroductionIn patients with type 2 diabetes, tight glucose control is associated with a significant reduction in the risk of diabetes-related complications. In the United Kingdom Prospective Diabetes study (UKPDS), each 1% reduction in HbA1c level was associated with a 21% reduction in risk for diabetes-related endpoints, 21% for deaths related to diabetes, 14% for myocardial infarction and 37% for microvascular complications, with no obvious threshold of HbA1c below which risk no longer decreased.1 Compared to patients with

Case study 1A 64-year-old male who has had type 2 diabetes for 19 years came for an assessment. His other problems were hypertension, dyslipidaemia and silent cardiac ischaemia. Up to seven years ago he had been on gliclazide, but, because of poor glycaemic control (HbA1c = 8.1%), insulin glargine was added as a basal insulin. His weight at the time was 92.8 kg. Since then he had steadily gained weight, having put on 5 kg. He then went on a strict diet and exercise programme, while metformin was substituted for gliclazide and insulin glargine was continued. He lost 2 kg with these measures and the weight remained stable at 94.6 kg for three months. His HbA1c level was 9.2 % at this visit.

A GLP-1 analogue was then added. This resulted in steady weight loss as well as improvement in glycaemic control so that a year later his weight was 84.4 kg and HbA1c level was 6%. Meanwhile, over this period, the dose of his basal insulin had to be reduced from 66 to 30 units nocte.

Case study 2Mr B is a 60-year-old male patient, diagnosed with type 2 diabetes 10 years ago. For the last six years he has been treated with oral hypoglycaemic drugs and high doses of insulin. On a regimen of aspart/protamine aspart 30/70, 102 units daily in split doses, his HbA1c level was 8.1% and his weight had steadily increased to 158.9 kg. He was switched to basal bolus insulin plus pioglitazone and metformin. On a total daily dose of glargine 50 units plus aspart 48 units in divided doses, his HbA1c level improved to 6.1%, but his weight increased further to 165.4 kg (body mass index > 45 kg/m2).

Six months ago he was started on a GLP 1 analogue. On a current regimen of insulin detemir 14 units nocte, with aspart as required, a GLP1 analogue and metformin 1 g twice daily, his weight has decreased to 141.8 kg, and waist circumference from 146 cm in 2006 to 137 cm in 2012. His HbA1c level is 7.4%. Subjectively, he feels better and reports improved quality of life in terms of energy and effort tolerance, improved sleep, and less joint pain. He is motivated to continue with his weight loss and improving his diabetes control.

less stringent glycaemic goals and despite a loss of between-group differences in glycated haemoglobin concentrations after one year, relative risk reductions in those randomised to tight control with a sulphonylurea or insulin persisted after 10 years, with 9% risk reduction for any diabetes-related endpoint, 24% for microvascular disease, 15% for myocardial infarction and 13% for death due to any cause.2

Consequently, current treatment guidelines recommend ambitious targets for HbA1c levels. The 2012 guidelines from the American Diabetes Association and European Association for the Study of Diabetes (ADA/EASD) and also from the Society of Endocrinology Metabolism and Diabetes of South Africa (SEMDSA) recommend maintaining HbA1c levels below 7% for the majority of patients.3,4 This may be achieved by maintaining fasting or pre-meal glucose levels between 4.0 and 7.0 mmol/l.4

However, these goals may be difficult to achieve and even harder to maintain. Various studies indicate that fewer than 40 to 60% of patients achieve HbA1c < 7%.5 Even in those who do, because of progressive decline in pancreatic beta-cell function and increasing insulin resistance in the presence of obesity, poor dietary intake and a lack of physical activity, a fasting plasma glucose of less than 7.8 mmol/l will be maintained in less than 50% of patients on oral hypoglycaemic monotherapy after three years, and in less than a third of patients after six years.6,7



Early initiation of insulinIn patients who do not achieve or maintain their HbA1c target with oral hypoglycaemic monotherapy, guidelines recommend the addition of a second oral medication or early initiation of insulin.3,4 In contrast to oral hypoglycaemic agents, insulin is the most effective treatment to lower glycaemia and there is no maximum dose of insulin beyond which a therapeutic effect will not occur. When used in adequate doses, insulin will decrease any level of elevated HbA1c to, or close to, target values.8

Indeed, delaying insulin initiation in patients who progressively fail stepwise treatment and progress through lifestyle modification to oral monotherapy to combination oral therapy is associated with further deterioration in HbA1c values and exposes patients to prolonged periods of uncontrolled glycaemia, which increases the risk of diabetes-related complications.7,9 Conversely, early initiation of insulin reduces the risk of diabetes-related complications and potentially helps to preserve beta-cell function, without compromising quality of life or treatment satisfaction.7

However, both physicians and patients demonstrate reluctance to initiate insulin, resulting in delay of treatment until late into the progression of the disease when the opportunity for optimal micro- and macrovascular protection has been missed. Patients’ concerns regarding insulin include anxiety about injections, fear of hypoglycaemia and other adverse health effects, a belief that their disease has progressed because they have managed their condition poorly (feelings of failure), social stigma of having to inject in public, and fear of weight gain. Concerns about insulin-related hypoglycaemia and weight gain may also underlie physicians’ reluctance to commence insulin earlier.10,11

Overweight and diabetesWeight gain is a specific concern among patients with diabetes. Obesity, particularly abdominal obesity, plays a pivotal role in the development of type 2 diabetes and more than 80% of patients with type 2 diabetes are overweight or obese, many at the time of diagnosis. Both diabetes and obesity are independently associated with additional cardiovascular risk factors, including hypertension and an atherogenic lipid profile and, compared to individuals without diabetes, diabetics have a significantly higher risk of cardiovascular events and death from cardiovascular causes.12

Even in combination with metformin, most treatments for type 2 diabetes, including sulphonylureas, glinides, thiazolidinediones, and basal and biphasic insulins are associated with modest weight gain.13 Compared to alternative treatments, intensive glucose control with insulin is associated with the greatest gain in body weight, with an average increase of 4.3 ± 2.74 kg (mean ± SD, range –2.76 to 14.7 kg, 95% CI: 4.32–4.38) during the first year of treatment.14-16 Most of the weight gain occurs during this first year after insulin initiation, but it is progressive after that.

In the UKPDS, insulin-treated patients had gained an average of 6.5 kg during 10 years of follow up.15 Higher doses of insulin, lower HbA1c targets and lower achieved levels of HbA1c were associated with greater increases in body weight. Possibly as a consequence of the lower doses that are used, basal insulin regimens are associated with less weight gain than prandial or twice-daily regimens.16 Although, in general, all types of insulins are associated with weight gain, an exception appears to be detemir, which is associated with significantly less or no weight

gain compared with alternatives. Its weight-sparing benefits are especially evident in patients with a higher body mass index.16,17

Although the exact mechanisms underlying this weight-sparing effect are uncertain, a number of theories have been proposed. It has been suggested that because detemir is associated with sig-nificantly less hypoglycaemia than isophane insulin (NPH), patients may be less prone to defensive snacking.17 However, while hypogly-caemia is predictive of weight gain with NPH insulin, no such asso-ciation could be demonstrated with detemir, so it seems likely that less hypoglycaemia does not fully explain less weight gain.18

Because it is highly bound to albumin, detemir may have limited access to peripheral compartments and therefore may influence hepatic glucose to a greater extent than in adipose tissue and muscle. Decreased peripheral glucose uptake in comparison with NPH may contribute to lower weight gain. Detemir may also cross the blood–brain barrier more efficiently. Therefore it may be more effective at communicating satiety signals in the central nervous system than other insulins. Lastly, detemir may be less adipogenic than human insulin and may have direct effects on adipocytes, influencing the expression of adiponectin. Adiponectin and leptin are derived from adipose tissue and influence food intake, insulin resistance and lipolysis.19

Mechanisms of insulin-related weight gainVarious mechanisms have been proposed to account for weight gain associated with insulin therapy:

Improved glycaemic control may lower blood glucose levels • to below the renal threshold, thereby reducing or eliminating glycosuria and improving conservation of ingested calories. Insulin itself is an anabolic hormone that inhibits lipolysis and • protein catabolism and stimulates lipogenesis and fatty acid conversion into triglycerides in adipose tissue, favouring an increase in adipose mass. Improved glycaemic control is also associated with reduced • resting energy expenditure per lean body mass, which suggests a role for increased efficiency of fuel usage. Fear of insulin-related hypoglycaemia may result in ‘defensive • snacking’, contributing to increased carbohydrate intake and increasing total calorie intake. In addition, ‘new’ low glucose levels may also be associated with an involuntary adaptive increase in appetite. ‘Central insulin resistance’ associated with a defect in insulin • and leptin signalling pathways in the hypothalamus may disrupt normal catabolic and anorectic signalling pathways in the central nervous system that promote satiety and balance the anabolic actions of circulating insulin. Exogenous insulin administration is unphysiological in that • dosing schedules create an unpredictable imbalance between insulin supply and insulin need, leading to periods of over- and undersupply and consequently hyper- and hypoglycaemia interspersed throughout the day. Furthermore, unlike physio-logically secreted insulin, subcutaneous insulin circulates systemically before passing through the liver, so it exerts a disproportionate influence on muscle and adipose tissue.20,21

Does weight gain associated with intensive glucose control matter?While obesity is undoubtedly a factor that increases the risk of cardiovascular events, the role of weight gain consequent to



intensive glucose control in cardiovascular mortality is controversial. Higher body mass index (BMI) in type 2 diabetes has not been consistently associated with a higher risk for cardiovascular events. On the contrary, several studies have demonstrated a lower risk for cardiovascular mortality in overweight compared to leaner diabetics, even in patients at very high cardiovascular risk.22,23

In the UKPDS, despite a significant increase in weight compared to conventional therapy, intensive glucose control with insulin was asso-ciated with fewer microvascular complications without an increase in cardiovascular mortality.15 One observation that might explain this paradox is that weight accumulation related to intensive glu-cose control is not limited to the abdomen, but rather is generalised, being distributed between fat mass and lean mass. Furthermore, the increase in fat mass is predominantly peripheral rather than central, so it may not result in an overall increase in cardiovascular risk.21,24

Nevertheless, there is direct evidence that intentional weight loss among overweight patients with type 2 diabetes is associated with an improvement in glycaemia, blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C) and other markers of cardiovascular risk, such as C-reactive protein (CRP), and with a reduction in cardiovascular mortality.25-27 In a 12-year, prospective observational study including 4 970 overweight individuals with type 2 diabetes aged 40 to 64 years of age, intentional weight loss was associated with a 25% reduction in total mortality and a 28% reduction in cardiovascular and diabetes-related mortality.27

Compared to patients who did not try to lose weight, the intention to lose weight was associated with reductions in mortality regardless of whether weight loss actually occurred.

In another prospective, observational study including 1 401 type 2 diabetes subjects over the age of 35 years, individuals who reported trying to lose weight had a 23% lower mortality rate than those who did not and this was the same regardless of whether attempts at weight loss were successful.28 These results suggest that lifestyle changes and behaviours associated with weight loss attempts improve longevity irrespective of the degree of weight loss, or they may reflect that achieved weight loss is difficult to maintain, but nevertheless may be associated with improved long-term health.

Excess adiposity and weight gain in type 2 diabetes are associated with a number of physical and psychological consequences that affect adherence and response to therapy, and long-term glucose

control. Increased fat mass is associated with insulin resistance, which exacerbates beta-cell dysfunction and increases requirement for insulin and further weight gain.20 Higher BMI at initiation of treatment predicts a poorer response to insulin therapy.29,30

Weight gain may compound feelings of depression and anxiety, which are already common in patients with diabetes and which are associated with poor adherence and self-care.5 In the Diabetes Attitudes Wishes and Needs (DAWN) study, which surveyed the perceptions surrounding diabetes care and self management among more than 5 000 type 2 diabetes subjects, 50% of patients expressed anxiety about their body weight, which contributed to a common poor sense of wellbeing.11 The fear of weight gain discourages both initiation of and adherence to insulin therapy. Patients concerned about weight gain are more likely to omit insulin doses or adjust their insulin dose in order to aim for higher blood glucose targets and to avoid normoglycaemia in an attempt to manage their body weight. This behaviour is associated with a significant increase in risk of diabetes-related emergency room visits and hospitalisations, and higher rates of retinopathy and neuropathy.31

So, while concerns about weight gain should not discourage insulin use in patients who require more intensive glucose control, it would make sense to seek out strategies to limit the impact of treatment on body weight.

Limiting treatment-related weight gainLifestyle modificationBecause insulin-related weight gain is dose dependent, one broad strategy to limit weight gain is to use less insulin. Diet and exercise form the cornerstone of management for type 2 diabetes, improving cardiovascular health, helping to control weight and glycaemia and improving insulin sensitivity. Because adiposity is inversely associated with insulin sensitivity, diet and exercise can help to break the cycle of higher insulin use and increasing weight.20

A healthy diet comprises reduced calorie intake and consumption of less saturated fats, trans fats, cholesterol and sodium.4 However, because dietary lifestyle change is one that needs to be continued for life, it is very important that the diet be tailored to individual patients according to their personal and cultural preferences in order to achieve long-term success. Regular follow up and counselling is also beneficial to help maintain compliance.32

Table 1. Lifestyle advice to help achieve and maintain weight loss4,34-36

Avoid soft drinks and other sweet beverages.• Avoid fast food.• Do not skip breakfast.• Eat regular, evenly distributed meals throughout the day.• Keep a record of your weight, what you eat and what you do for physical activity.• Eat family meals at the table and not in front of the television.• Cut down on the amount of time you spend watching television.• Do not use food as a way to reward yourself.• Find fun and easy activities that require minimal preparation; e.g. walking outside, running on a treadmill or riding a stationary bicycle in front of the television • or while listening to music.If time is a barrier, two or three short exercise sessions still have benefit. Activity may be accumulated throughout the day with a minimum of 10 minutes or • more for each exercise session.Exercise when your energy levels are at their highest.• Join a health club and seek professional advice from a personal fitness trainer or join an exercise class.• If you prefer to train at home, make use of fitness DVDs and home exercise equipment.• Set realistic time-related goals.• Exercising with friends or family is more fun and will help to keep you motivated.• The internet is a useful source of information, including menu planning, recipes, healthy eating guides, shopping tips, record keeping (food intake, physical • activity, carbohydrate and/or caloric balance, blood glucose monitoring, body weight and body mass index) and physical activity programmes.



In patients with type 2 diabetes, regular physical activity is associated with increased cardiovascular fitness, decreased insulin resistance and improved glucose control, blood lipid profile and blood pressure. It helps to maintain weight loss, decreases stress and anxiety and improves general well-being. Patients should be advised to perform at least 150 minutes of moderate-intensity aerobic physical activity and, provided there are no contraindications, resistance training three times per week.4 Additional lifestyle advice that may be beneficial for achieving and maintaining weight loss is listed in Table 1.

Despite the health benefits of diet and exercise, weight loss with lifestyle change alone is often modest and is difficult to achieve and maintain.33

An additional approach is to combine insulin with other insulin-sparing treatments that do not exacerbate weight gain. In two separate studies, metformin, when added to insulin, was able to reduce insulin requirements by almost 30% within a year and was associated with at least as good, or better control of HbA1c levels.37,38 However, patients on metformin still continue to gain weight, albeit in one study at a lower rate than those on insulin monotherapy (mean 6.1 vs 7.6 kg; p = 0.02).38

Incretin-based therapiesRecently a new class of medication has been introduced for the treatment of type 2 diabetes. These incretin-based therapies potentiate or mimic the actions of glucagon-like peptide 1 (GLP-1), an incretin hormone that is released by the intestine shortly after ingestion of food. GLP-1 has a potent blood glucose-lowering action and inhibits glucagon release in a glucose-dependent manner. It also induces weight loss by acting on receptors in the central nervous system that induce perceptions of satiety regardless of the presence of food in the gastric system.39 In vivo, the half-life of GLP-1 is very short, because it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).

The incretin-based therapies include the oral DPP-4 inhibitors (sitagliptin, saxagliptin and vildagliptin) and the GLP-1 agonists, exenatide and liraglutide, which are injected subcutaneously. All of these therapies reduce plasma glucose with a low risk of hypoglycaemia, but they have different effects on body weight; the DPP-4 inhibitors are weight neutral, whereas exenatide and liraglutide are associated with weight loss.5,40

Clinical studies have demonstrated that the GLP-1 agonists significantly reduce HbA1c levels, both when administered as monotherapy and in combination with oral antidiabetic drugs, without increasing the risk of hypoglycaemia and with concomitant weight loss.5,13 When used as second-line therapy in combination with metformin, these drugs reduce HbA1c levels to a greater degree than sulphonylureas, glinides, thiazolidinediones, alpha-glucosidase inhibitors and DPP-4 inhibitors, and to a degree comparable with basal insulin and biphasic insulin.13,41

In a recent meta-analysis comparing liraglutide to other commonly used antidiabetic medications, including glimepiride, rosiglitazone, glargine, exenatide and sitagliptin, the GLP-1 agonist was found to be 2.0- to 10.5-fold more likely to achieve a composite outcome of HbA1c < 7%, with no hypoglycaemia and no weight gain.42 Furthermore, liraglutide induced greater weight loss in patients with higher BMI, primarily due to a decrease in abdominal subcutaneous and visceral adipose tissue.39,43

The addition of liraglutide to insulin therapy in obese, poorly controlled type 2 diabetes patients has been compared to

intensification of insulin therapy.44 Adding liraglutide was associated with a reduction in HbA1c level that was comparable to increasing the dose of insulin (–1.9 vs –1.77%, p > 0.05), but with a higher percentage of patients achieving HbA1c ≤ 7%, with no weight gain and no hypoglycaemia (67 vs 19%, p < 0.001).

Body weight, waist circumference, body mass index and total daily insulin dose were significantly decreased after the addition of liraglutide, while all of these parameters increased significantly after increasing the dose of insulin. Sixty-two per cent of patients in the liraglutide group achieved at least 5% reduction in body weight. Severe hypoglycaemia was reported in two patients in the insulin-intensification group and none in the liraglutide group, while minor hypoglycaemic episodes occurred in 31.0 and 11.9%, respectively (p = 0.033).

In another study, insulin detemir was added to therapy in patients uncontrolled on metformin plus liraglutide (HbA1c ≥ 7%).45 After 26 weeks, HbA1c level was decreased by 0.5%, with 43% of patients achieving HbA1c < 7%. Mean body weight was decreased by 0.16 kg. There were no episodes of severe hypoglycaemia after the addition of insulin detemir, although minor hypoglycaemic events were more common than in patients who did not receive insulin (9.2 vs 1.3%). On the basis of this study, in 2012 the American Food and Drug Administration (FDA) approved a label update for liraglutide to include combination therapy with basal insulin for the treatment of adults with type 2 diabetes.46

When used in combination with basal insulin (with or without metformin ± thiazolidinedione), exenatide was associated with significant reductions in HbA1c level and postprandial glucose (with or without a decrease in fasting plasma glucose), compared to control groups receiving basal insulin with or without metformin ± thiazolidinedione. More patients in the GLP-1 agonist groups reached target HbA1c ≤ 7%. Furthermore, these results were achieved with lower doses of insulin than in control groups and with mild, infrequent or no additional risk of hypoglycaemia.47 Body weight increased in the control groups, but decreased or remained stable in the exenatide groups.

The most common adverse effects associated with GLP-1 agonists are nausea, vomiting, diarrhoea, headache and constipation. However, these gastrointestinal adverse effects tend to become less frequent with continued use.5,47

In addition to their metabolic benefits, GLP-1 agonist therapy has also been shown to be associated with variable improvements in systolic blood pressure, serum cholesterol and triglyceride levels and cardiovascular biomarkers, including brain natriuretic peptide, plasminogen activator-1 and high-sensitivity CRP.42,47,48 The effect of GLP-1 agonists on cardiovascular events is being studied in large, long-term outcomes studies, which are ongoing.

ConclusionAchieving adequate long-term control of plasma glucose remains a problem in patients with type 2 diabetes. Almost all require intensification of treatment over time, which is associated with major challenges, including treatment-related adverse effects, maintenance of patient compliance and adherence to treatment, psychological co-morbidities and treatment-associated weight gain. Involving the patient in treatment decisions and appropriate patient education is essential to overcome some of these obstacles. Using a GLP-1 agonist as add-on therapy has significant advantages, including further reductions in HbA1c level and postprandial glucose, while reducing basal insulin requirements. GLP-1 agonists



are associated with a low risk of hypoglycaemia and, importantly, help minimise treatment-related weight gain.

In South Africa GLP1 agonists are not yet registered for add-on therapy to insulin in type 2 diabetes.49,50 In the case studies, off-label use in conjunction with insulin was at the discretion of the treating physician in consultation with the patient.

References1. Stratton IM, Adler AI, Neil AW, et al. Association of glycemia with macrovascular

and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. Br Med J 2000; 321: 405–412.

2. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577–1589.

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012. Published online 19 April 2012. DOI: 10.2337/dc12-0413.

4. Amod A, Motala A, Levitt N, et al. The 2012 SEMDSA guideline for the management of type 2 diabetes. J Endocrinol Metabol Diabetes S Afr 2012; 17(1): S1–S94.

5. Khunti K, Davies M. Glycemic goals in patients with type 2 diabetes: current status, challenges and recent advances. Diab Obesity Metab 2010; 12: 474–484.

6. Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulphonylurea, metformin, or insulin in patients with type 2 diabetes mellitus. Progressive requirement for multiple therapies (UKPDS 49). J Am Med Assoc 1999; 281: 2005–2012.

7. Asche CV, Bode B, Busk, AK, Nair SR. The economic and clinical benefits of adequate insulin initiation and intensification in people with type 2 diabetes mellitus. Diab Obesity Metab 2012; 14: 47–57.

8. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the study of Diabetes. Diabetes Care 2009; 32(1): 1–11.

9. Brown, JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004; 27: 1535–1540.

10. Hunt LM, Valenzuela MA, Pugh JA. NIDDM patients’ fears and hopes about insulin therapy. Diabetes Care 1997; 20(3): 292–298.

11. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obesity 2002; 26(Suppl 3): S18–S24.

12. Niswender K. Diabetes and obesity: therapeutic targeting and risk reduction – a complex interplay. Diab Obesity Metab 2010; 12: 267–287.

13. Liu S-C, Tu Y-K, Chien M-N, Chien K-L. Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diab Obesity Metab 2012; 14: 810–820.

14. Van Dieren S, Czernichow S, Chalmers J, et al. Weight changes and their predictors amongst 11 140 patients with type 2 diabetes in the ADVANCE trial. Diab Obesity Metab 2012; 14: 464–469.

15. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.

16. Pontiroli AE, Miele L, Morabito A. Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis. Diab Obesity Metab 2011; 13: 1008–1019.

17. Hermansen K, Davies M. Does insulin detemir have a role in reducing risk of insulin-associated weight gain? Diab Obesity Metab 2007; 9: 209–217.

18. Davies MJ, Derenski T, Pedersen CB, Clauson P. Reduced weight gain with insulin detemir compared to NPH insulin is not explained by a reduction in hypoglycaemia. Diabetes Technol Ther 2008; 10(4): 273–277.

19. Hollander PA. Insulin detemir for the treatment of obese patients with type 2 diabetes. Diabetes, Metab Syndr Obesity: Targets Ther 2012; 5: 11–19.

20. Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes – causes, effects and coping strategies. Diab Obesity Metab 2007; 9: 799–812.

21. Jacob AN, Salinas K, Adams-Huet B, Raskin P. Weight gain in type 2 diabetes mellitus. Diab Obesity Metab 2007; 9: 386–93.

22. Chaturvedi N, Syevens LK, Fuller JH, for the WHO Multinational Study Group. Mortality and morbidity associated with body weight in people with IDDM. Diabetes Care 1995; 18(6): 761–765.

23. Aas A-M, Öhrvik J, Malmberg K, Rydén L, Birkeland KI, for the DIGAMI 2 investigators. Insulin-induced weight gain and cardiovascular events in patients with type 2 diabetes. A report from the DIGAMI 2 study. Diab Obesity Metab 2009; 11: 323–329.

24. Bagg W, Plank LD, Gamble G, et al. The effects of intensive glycaemic control on body composition in patients with type 2 diabetes. Diab Obesity Metab 2001; 3: 410–416.

25. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 2011; 34: 1481–1486.

26. Belalcazar LM, Reboussin DM, Haffner SM, et al. A 1-year lifestyle intervention for weight loss in individuals with type 2 diabetes reduces high C-reactive protein levels and identifies metabolic predictors of change. Diabetes Care 2010; 33: 2297–2303.

27. Williamson DF, Thompson TJ, Thun M, et al. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23: 1499–1504.

28. Gregg EW, Gerzoff RB, Thompson TJ, Williamson DF. Trying to lose weight, losing weight, and 9-year mortality in overweight U.S. adults with diabetes. Diabetes Care 2004; 27: 657–662.

29. Owen V, Seetho I, Idris I. Predictors of responders to insulin therapy at 1 year among adults with type 2 diabetes. Diab Obesity Metab 2010; 12: 865–870.

30. Watson L, Wilson BP, Alsop J, Kumar S. Weight and glycaemic control in type 2 diabetes: what is the outcome of insulin initiation? Diab Obesity Metab 2011; 13: 823–831.

31. Polonsky WH, Anderson BJ, Lohrer PA, et al. Insulin omission in women with IDDM. Diabetes Care 1994; 17(10): 1178–1185.

32. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009; 360(9): 859–873.

33. Norris SL, Zhang X, Avenell A, et al. Long-term non-pharmacological weight loss interventions for adults with type 2 diabetes mellitus. Cochrane Database of Sys-tematic Reviews 2005, Issue 2. Art. No.: CD004095. DOI: 10.1002/14651858.CD004095.pub2.

34. Rao G. Office-based strategies for the management of obesity. Am Fam Physician 2010; 81(12): 1449–1455.

35. Powers MA, March SB, Evert A. Use of internet technology to support nutrition and diabetes self-management care. Diabetes Spectrum 2008; 21(2): 91–99.

36. Shahar J. Helping your patients become active. Diabetes Spectrum 2008; 21(1): 59–62.

37. Biesenbach G, Raml A, Alsaraji N. Weight gain and insulin requirement in type 2 diabetic patients during the first year after initiating insulin therapy dependent on baseline BMI. Diab Obesity Metab 2006; 8: 669–673.

38. Douek IF, Allen SE, Ewings P, et al, for the Metformin trial group. Continuing metformin when starting insulin in patients with type 2 diabetes: a double blind randomized placebo-controlled trial. Diabet Med 2005; 22: 634–640.

39. Sesti G. Harnessing the weight-regulating properties of glucagon-like peptide-1 in the treatment of type 2 diabetes. Diab Obesity Metab 2009; 11(Suppl 3): 4–10.

40. Lombard L. DPP-4 inhibitors (gliptins) in the management of type 2 diabetes. S Afr J Diabetes Vasc Dis 2012; 9: 9–12.

41. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375: 1447–1456.

42. Zinman B, Schmidt WE, Moses A, et al. Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme. Diab Obesity Metab 2012; 14: 77–82.

43. Niswender K, Pi-Sunyer X, Buse J, et al. Weight change with liraglutide and comparator therapies: an analysis of seven phase 3 trials from the liraglutide diabetes development programme. Diab Obesity Metab 2012. Doi: 10.1111/j.1463-1326.2012.01673.x.

44. Li C-J, Li J, Zhang Q-M, et al. Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity. Cardiovasc Diabetol 2012; 11:142 Published online at http://www.cardiab.com/content/11/1/142.

45. DeVries JH, Bain SC, Rodbard HW, et al. Sequential intensification of metformin treatment in type 2 diabetics with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care 2012; 35(7): 1446–1454.

46. http://www.multivu.com/mnr/55639-novo-nordisk-fda-approval-victoza-product-label-update-blood-sugar-control.

47. Berlie H, Hurren KM, Pinelli NR. Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. Diabetes, Metab Syndr Obesity: Targets Ther 2012; 5: 165–174.

48. Horton ES, Solberman C, Davis KL, Berria R. Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care 2010; 33(8): 1759–1765.

49. Victoza package insert. Novo Nordisk (Pty) Ltd; 2011.50. Byetta package insert. Eli Lilly (SA) (Pty) Ltd; 2009.

References: 1. The ACCORD Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med. 2010;362;1563-1574. 2. Elam MB, Lovato LC, Byington RP, Bonds D, Leiter L, Crouse JR et al. Hypertriglyceridemia and Low HDL-C Predicts Fenofibrate Response in the ACCORD-Lipid Trial. Abstract 19724 AHA 2010

LIPANTHYL® 200 mg. Each capsule contains 200 mg fenofibrate (micronised). Reg. No. 30/7.5/0494.

For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority. Date of Publication of this Promotional Material: September 2012. Abbott Laboratories S.A. (Pty) Limited, Abbott Place, 219Golf Club Terrace, Constantia Kloof, 1709 Tel No 011 858 2000. Promo. No: 0001-0912-K435-A-2218.

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Patients with type 2 diabetes with TG ≥2.30 mmol/l and HDL-C ≤0.88 mmol/l

17.3%

GO BEYOND the STATIN QUOAim for Broader Lipid Management

Effective in reducing residual CV risk associated with elevated triglyceridesand low HDL-C in your statin-treated patients with type 2 diabetes1

Abbott Lipanthyl Advert_Layout 1 2012/09/14 1:22 PM Page 1



Correspondence to: Prof Alan SinclairInstitute of Diabetes for Older People, Bedfordshire and Hertfordshire Postgraduate Medical School, Putteridge Bury Campus, Hitchin Road, Luton LU2 8LE, Bedfordshire, UK.Tel: +44(0) 1582 743285E-mail: [email protected]

Originally in: Br J Diabetes Vasc Dis 2012; 12: 65–70

S Afr J Diabetes Vascular Dis 2013; 10: 18-22

Hypertriglyceridaemia in type 2 diabetes: prevalence, risk and primary care managementALAN SINCLAIR

AbstractCardiovascular disease (CVD) associated with type 2 diabetes will impose an increasing burden on primary care over the next few decades. Several mutually reinforcing factors account for the increased CVD risk among patients with diabetes, including hypertriglyceridaemia, the importance of which has been generally underestimated. A consensus from the literature suggests that fasting triglyceride levels of 1.7 mmol/l or above may be a cause for cardiovascular concern and warrant further investigation. Apart from CVD, hypertriglyceridaemia can increase the risk of pancreatitis. Clinicians in primary care should become active in identifying and managing secondary causes of hypertriglyceridaemia and encourage patients with diabetes to implement lifestyle changes. Statins are the mainstay of treatment for diabetic dyslipidaemia that remains inadequately controlled. However, the National Institute for Health and Clinical Excellence (NICE) suggests prescribing a fibrate if triglyceride levels remain > 4.5 mmol/l after addressing secondary causes. Clinicians could consider adding a fibrate if triglyceride levels remain between 2.3 and 4.5 mmol/l despite statin monotherapy for patients at high CVD risk. NICE advocates a trial of highly concentrated, licensed omega-3 fish oils if lifestyle measures and fibrate fail to adequately reduce hypertriglyceridaemia.

Keywords: cardiovascular disease, hypertriglyceridaemia,type 2 diabetes mellitus, pancreatitis, primary care

IntroductionCVD in people with type 2 diabetes is likely to impose a growing burden. The National Heart Forum predicts that rates of diabetes will rise by 98% between 2006 (2 869 cases per 100 000 of the population) and 2 050 (7 072 per 100 000).1 Type 2 diabetes accounts for 85–95% of cases of diabetes.2

Patients with diabetes are at markedly higher risk of CVD,3,4 partly because of an increased incidence of hypertriglyceridaemia,5-7 a key component of diabetic dyslipidaemia that is also associated

with pancreatitis.8,9 The paper attempts to stimulate primary care physicians to manage lipid disorders in diabetes more proactively and take evidence-based decisions when treating patients with both diabetes and hypertriglyceridaemia.

Hypertriglyceridaemia and diabetesTriglycerides evolved as an energy store and are found predominately in adipose tissue. Chylomicrons and VLDLs transport most triglycerides in the blood.10 Chylomicrons are the main component of postprandial lipoproteins,11 while VLDL reflects hepatic synthesis.5

In general, VLDL cholesterol begins rising substantially at triglyceride concentrations of 2.26 mmol/l or higher.5 Primary care physicians can include triglycerides in a standard lipid profile request. While treatment decisions should be based on fasted samples (which reflects hepatic production), a non-fasted sample may offer some indication of prevailing postprandial levels.

Hypertriglyceridaemia potentially results from increased production of VLDL, reduced clearance of VLDL or chylomicrons, or a combination of both mechanisms.8 For example, insulin modulates triglyceride levels, partly by inducing lipoprotein lipase, which contributes to clearance of chylomicron triglycerides. The rate of chylomicron clearance largely determines fasting and postprandial triglyceride levels in patients with diabetes. However, several other metabolic abnormalities appear to contribute to diabetic hypertriglyceridaemia, including increased plasma VLDL concentrations (with or without chylomicronaemia), increased cholesterylester transfer protein activity and increased hepatic flux of free fatty acids.12 Moreover, many components of dyslipidaemia

Abbreviations and acronyms

AUC area under the curveBMI body mass indexCAD coronary artery diseaseCHD coronary heart diseaseCVD cardiovascular diseaseDHA docosahexaenoic acidEPA eicosapentaenoic acidFIELD Fenofibrate Intervvention and Event Lowering in DiabetesHbA1C glycated haemoglobin A1C

HDL high-density lipoproteinJELIS Japan Eicosapentaenoic acid (EPA) Lipid Intervention StudyLDL low-density lipoproteinMI myocardial infarctionNICE National Institute for Health and Clinical ExcellencePUFA polyunstaturated fatty acidRR relative riskVLDL very low-density lipoprotein



in type 2 diabetes – including low HDL concentrations, the predominance of small dense LDL and high postprandial fat levels – might arise as sequelae of hypertriglyceridaemia.11

Against this background, normotriglyceridaemia type 2 diabetes patients with microalbuminuria are almost three times more likely to show postprandial triglyceridaemia than normoalbuminuric diabetic patients. (This study excluded patients with macroalbuminuria or abnormal liver or thyroid function.13) Hypertriglyceridaemia is also associated with prothrombotic haemostatic changes,13 although several mechanisms contribute to enhanced prothrombosis in diabetes, including impaired fibrinolysis and coagulation, as well as endothelial and platelet dysfunction.14

Hypertriglyceridaemia-related risk in diabetesCompelling evidence suggests that hypertriglyceridaemia increases CVD risk in diabetes. For instance, Schulze et al. followed 921 women with type 2 diabetes who did not show CVD at baseline for 10 years. Of these, 122 women developed incident CHD. At baseline, the mean age (60.6 years) and the mean fasting triglyceride level (2.56 mmol/l) among women who developed CHD differed significantly from those who remained free of CHD (58.0 years; 2.15 mmol/l). The relative risk of CHD (adjusted for various confounders including age, hypertension, BMI and aspirin use) showed a trend towards an increased risk from low (median 0.98 mmol/l) to high (median 3.45 mmol/l) levels of fasting triglycerides (relative risk 1.42; 95% CI 0.79–2.54), although this was not statistically significant. High levels of fasting triglycerides increased CVD risk among women with low HbA1C concentrations. The relative CVD risk comparing the bottom and top fasting triglyceride tertiles was 3.32. This association was not present among women with high HbA1C concentrations (Fig. 1), possibly suggesting that poor glycaemic control may mask the effects of HDL and triglyceride levels.5

Laakso et al. followed 153 men (mean age 56 years) and 160 women (mean age 58 years) with non-insulin-dependent diabetes for up to seven years. Total triglyceride levels > 2.3 mmol/l approximately doubled the risk of age-adjusted death from CHD (OR 2.2; 95% CI 1.2–4.0) and all CHD events (OR 1.6; 95% CI 1.0–2.8) compared with lower concentrations. The independent association between total triglycerides and CHD events disappeared on multivariate logistical regression analysis that controlled for high LDL (< 4.3 mmol/l) and HDL (> 1.2 mmol/l). However, in patients with low LDL cholesterol (≤4.3 mmol/l; unstandardised β-coefficient 1.0266) and low HDL cholesterol (≤ 1.12 mmol/l; unstandardised β-coefficient 0.8129) VLDL triglycerides were significantly associated with CHD events, suggesting an independent relationship.6

The Strong Heart Study followed 2 108 Native Americans with type 2 diabetes and 2 060 non-diabetic controls, all of whom were free from CVD at baseline. After an average of 9 years, 521 and 145 of the diabetic and non-diabetic patients respectively had developed CVD. Based on a Cox multivariate regression model, compared with triglyceride levels < 1.20 mmol/l, men with concentrations of 1.20–1.98 mmol and > 1.98 mmol were 40% (95% CI 0.94–2.07) and 39% (95% CI 1.00–1.98) respectively more likely to develop CVD, after adjusting for several non-lipid confounding variables such as age, BMI, HbA1C and insulin use. Compared with triglyceride levels< 1.28 mmol/l, women with concentrations of 1.28–1.98 mmol and > 1.98 mmol were 36% (95% CI 0.99-–1.87) and 61% (95% CI 1.17–2.22) respectively more likely to develop CVD.7

Figure 1. Relative risk of coronary heart disease by tertiles of HbA1C (%) and fasting triglycerides (mmol/l)5

Diabetes and pancreatitisChronic pancreatitis causes between 0.5 and 1% of cases of diabetes, and between 40 and 60% of patients with chronic pancreatitis, show concurrent diabetes.15 Hypertriglyceridaemia may partly account for this overlap. Indeed, hypertriglyceridaemia causes up to 10% of acute pancreatitis and up to half of gestational pancreatitis cases.16 The mechanism linking hypertriglyceridaemia and pancreatitis remains unclear. However, an increase in pancreatic free fatty acid levels could induce inflammation. Alternatively, hyperviscosity due to elevated chylomicron levels could cause capillary ischaemia and acidosis.8

Hypertriglyceridaemia tends to be a primary cause of pancreatitis only at relatively high concentrations. In a Canadian study, 15 of 95 patients (mean age 54.2 years; 73.7% male; 41.1% with diabetes) presenting with non-acute pancreatitis showed triglyceride levels > 20 mmol/l (mean 38.1 mmol/l). In contrast, none of the control group of 91 patients showed pancreatitis despite triglyceride levels between 10 and 20 mmol/l.9

Defining hypertriglyceridaemia in type 2 diabetesThere is a broad consensus that very high levels of triglycerides (typically > 10–11 mmol/l) increase the risk of acute pancreatitis.9,12,17 There is less agreement about the levels of triglycerides that increase cardiovascular risk. Indeed, NICE did not set a target for, or specifically define, hypertriglyceridaemia in the lipid modification or type 2 diabetes treatment guidelines in a manner analogous to HDL and LDL. However, a UK consensus panel recently agreed a quadripartite stratification, based on fasting levels.18

Desirable: < 1.7 mmol/l• Abnormal, moderately high: 1.7–9.9 mmol/l• Abnormal, very high: 10–20 mmol/l• Abnormal, extremely high: >20 mmol/l.•

Similarly, Jialal et al., for example, proposed that fasting triglyceride concentrations of 1.69–5.6 mmol/l represent mild to moderate hypertriglyceridaemia. Triglyceride levels of at least 5.6 mmol/l indicate severe hypertriglyceridaemia.19 A consensus panel suggested a bipartite classification where non-fasting triglyceride levels ≥ 2 mmol/l and that postprandial levels following



a fat tolerance test should be ≤ 2.5 mmol/l.20 The Joint British Societies’ guidelines recommend increasing CVD risk by a factor of 1.3 when using the charts in patients with fasting triglycerides > 1.7 mmol/l.21 Therefore, a triglyceride level of 1.7 mmol/l seems to be a suitable threshold for intervention.

Managing hypertriglyceridaemia in diabetesFinding hypertriglyceridaemia should alert clinicians to search for secondary causes, such as hypothyroidism, renal impairment, liver inflammation (particularly from alcohol abuse) and poor blood glucose control.22 Indeed, some oral hypoglycaemics may attenuate the rise in triglyceride levels. For example, a relatively small study of treatment-naïve type 2 diabetic patients found that glibenclamide reduced postprandial hypertriglyceridaemia compared with placebo (AUC 687 and 821 mM/h respectively). However, glibenclamide attenuated the increase in chylomicron triglycerides only compared with placebo (AUC 344 and 487 mM/h respectively) rather than VLDL. Therefore, a reduction in triglycerides of intestinal origin seems to account for most of the decrease in postprandial levels induced by glibenclamide. Further studies need to ascertain whether the reduction in triglyceride levels is a pharmacodynamic effect of glibenclamide or a reflection of improved postprandial glycaemia and increased insulin-induced lipoprotein lipase activity.11

Lifestyle changesClinicians should encourage diabetic patients with hypertri-glyceridaemia to implement lifestyle changes, such as controlling body weight, taking regular physical activity, avoiding tobacco and high-carbohydrate foods, and eating a diet low in saturated fat and sugar.23,24 Patients with triglyceride levels > 11.30 mmol/l should immediately start a very low-fat diet, in which fat accounts for ≤ 15% of calories.24

There is currently no standardised treatment protocol for severe hypertriglyceridaemia (e.g. > 10 mmol/l). In patients with diabetes, fenofibrate may be the preferred treatment, usually combined with a statin.8 According to NICE, patients at high risk of pancreatitis should commence treatment with a fibrate before starting a statin.22 Omega-3 PUFAs, which can reduce triglyceride levels by up to 45% in patients with severe hypertriglyceridaemia, enrolled patients who had fasting triglycerides < 4.5 mmol/l. Nicotinic acid (niacin) and fibric acid derivatives (fibrates) are more effective, reducing triglycerides by up to 50 and 60% respectively. The choice depends on other considerations, such as the need to reduce and increase concentrations of LDL and HDL cholesterol respectively. (Bile acid sequestrants either produce no in change or increase triglycerides.)23,24

FibratesStatins are the mainstay of treatment for diabetic dyslipidaemia.19

However, NICE suggests prescribing a fibrate (fenofibrate first-line) if triglyceride levels remain above 4.5 mmol/l despite addressing secondary causes.22 Clinicians could consider adding a fibrate if triglyceride levels remain between 2.3 and 4.5 mmol/l after 6 months of treatment with a statin and optimal glucose control, especially in patients at high cardiovascular risk – which is usually the case in type 2 diabetes.22 Fibric acid derivatives (fibrates) reduce triglycerides by up to 60%.24

However, fenofibrate did not significantly reduce the primary endpoint in the FIELD study25 and ‘considerable controversy’

still surrounds fibrates’ clinical efficacy.26 FIELD enrolled 9 795 patients with type 2 diabetes (37% women; mean age at baseline 62.2 years), total cholesterol levels of 3.0–6.5 mmol/l and a total-cholesterol/HDL ratio of ≥ 4.0, or plasma triglyceride concentrations of between 1.0 and 5.0 mmol/l. Of these, 59% showed low HDL levels (< 1.03 mmol/L in men and < 1.29 mmol/l in women), 52% high triglyceride levels (> 1.7 mmol/l) and 38% both. At baseline, triglyceride levels were 1.93 mmol/l (standard deviation [SD] 0.88) in the placebo arm, and 1.95 mmol/l in the micronised fenofibrate (200 mg daily) arm. Four months after the start of treatment fenofibrate reduced triglycerides by 0.56 mmol/l (–28.6%) compared with placebo, which was broadly maintained until the end of the study (median five years; –0.41 mmol/l; –21.9%).25

Fenofibrate reduced the RR of a coronary event by 11% compared with placebo (5.2 and 5.9% respectively; p = 0.16), this difference was not statistically significant. The risk of non-fatal MI (RR 0.76; p = 0.010), total CVD events (RR 0.89; p = 0.035) and coronary revascularisation (RR 0.79; p = 0.003) significantly declined in the fenofibrate arm.25 Nevertheless, whether adding a fibrate to statin reduces cardiovascular risk in type 2 diabetic patients ‘remains unproven’, although the possibility of a clinically relevant improvement in those with elevated triglyceride and low HDL levels cannot be excluded.26

As mentioned above, in patients with low HDL cholesterol VLDL triglycerides were independently associated with CHD events.6 A meta-analysis of five studies, including FIELD, found that in patients with dyslipidaemia (defined as triglyceride ≥ 2.3 mmol/l and HDL ≤ 0.9 mmol/l) fibrates reduced the rate of coronary heart disease by 35% (95% CI 22–46). In contrast, in patients who failed to meet the criteria for dyslipidaemia, fibrates reduced the rate of coronary heart disease by 6%, which was not statistically significant (95% CI –5–16).27 Therefore, fibrates may be effective in patients with the combination of low HDL and high triglycerides.

Nicotinic acid preparationsNicotinic acid (niacin) reduces triglyceride levels by up to 50%.23,24

However, NICE advises against using nicotinic acid preparations and derivatives routinely in type 2 diabetes. Nicotinic acid may be suitable for some people intolerant of other therapies who have ‘more extreme disorders’ of lipid metabolism. Such patients should be managed by specialists.22 Specialist referral may also be appropriate in cases of acute pancreatitis, difficult-to-manage

Table 1. Effect of lipid lowering medication on triglyceride, LDL andHDL levels23,24

Author Triglyceride reduction

(%)

LDL change(%)

HDL increase

(%)

Statins Oh et al.Solano et al.

20 – 40 7 – 30

18 – 55 i18 – 55 i

5 – 155 – 15

Ezetimibe Solano et al. 5 – 10 15 – 20 i 1 – 4

Fibrates Oh et al.Solano et al.

40 – 6020 – 50

5 – 30 5 – 20 i

15 – 2510 – 20

Nicotinic acid Oh et al.Solano et al.

30 – 5020 – 50

5 – 25 i 5 – 25 i

20 – 3015 – 35

Fish oil Oh et al. 30 – 50 5 – 10 5 – 10

Key: HDL = high-density lipoprotein; LDL = low-density lipoprotein



chronic pancreatitis and when an adequate trial of statins, in combination with, as appropriate ezetimibe, fibrates and omega-3 PUFAs, fail to adequately reduce levels of triglycerides.

Omega 3 PUFA supplementsOmega 3 PUFA supplements offer a further alternative. Consuming fish oil containing 2–4 g EPA and DHA daily can lower triglycerides by 30–50%. Combining fish oil and statin reduces triglycerides by an additional 30% compared with monotherapy.24 Side effects associated with omega 3 PUFA supplements – such as fishy aftertaste and mild gastrointestinal upset – are usually minimal, while bleeding effects are not clinically significant even at large doses.24 Some patients with hypertriglyceridaemia require triple therapy with a fibrate, niacin, and omega-3 PUFAs, the latter at doses between 4 and 10 g daily.19

The JELIS study treated 18 645 Japanese patients (mean age 61 years; 69% women; 16% with diabetes) with total cholesterol of ≥ 6.5 mmol/l using 1.800 mg EPA daily plus statin or statin monotherapy. After a mean follow up of 4.6 years, triglyceride levels decreased significantly from baseline (mean 1.7 mmol/l) by 9% in the EPA group and by 4% in controls. The primary endpoint (any major coronary event) occurred in 2.8% of the EPA group and 3.5% of controls, equivalent to a 19% relative reduction. The number of unstable angina cases and non-fatal coronary events declined by 24 and 19% respectively. In patients with a history of CAD, EPA significantly reduced the rate of major coronary events by 19% compared with controls (8.7 and 10.7% respectively). In patients without a history of CAD, EPA reduced major coronary events by a similar amount (18%), although the reduction was not statistically significant (1.4 and 1.7% respectively). EPA did not significantly alter LDL cholesterol. Therefore, the 19% reduction in major coronary events seems to be independent of changes in LDL.28

In general, NICE advises against prescribing fish oil for primary CVD prevention in type 2 diabetes. However, this does not apply to diabetic patients with hypertriglyceridaemia who are receiving advice from a healthcare professional with special expertise. Indeed, NICE recommends a trial of highly concentrated, licensed omega-3 fish oils for hypertriglyceridaemia if lifestyle measures and fibrate fail to adequately reduce levels.22 Furthermore, Omacor, which contains 460 mg EPA ethyl ester and 380 mg DHA ethyl ester, is approved in combination with statins for type IIb/III hypertriglyceridaemia as well as for type IV hypertriglyceridaemia as monotherapy.29

Due to increased risk of CVD, many patients with diabetes experience acute coronary syndrome. NICE advises eating ≥ 7 g

of omega 3 PUFA a week from two to four portions of oily fish as secondary prevention after MI. Patients who suffered an MI within the last 3 months and who cannot consume sufficient fish could receive ≥1 g daily of omega 3-acid ethyl esters licensed for secondary prevention after MI. Treatment should last for up to 4 years.30

ConclusionCVD in type 2 diabetes is likely to impose a growing burden on primary care.1 Several studies confirm that hypertriglyceridaemia contributes to the increased likelihood of suffering CVD among patients with diabetes5–7 and pancreatitis.8,9 Indeed, many components of dyslipidaemia in type 2 diabetes might arise as metabolic sequelae of hypertriglyceridaemia.11 Fortunately, several treatments effectively lower triglyceride levels, although patients may need more than one drug.19,23,24 Raising awareness of the burden imposed by hypertriglyceridaemia and proactive, effective management of this common dyslipidaemia should help reduce the cardiovascular morbidity and mortality associated with type 2 diabetes.

AcknowledgementsProfessor Sinclair has received a fee for preparing this article as part of the educational support provision available but the content, emphasis and direction of the article is solely due to him.

The author would like to acknowledge the assistance of Mark Greener, medical writer, and Rock Medical Communications in the preparation of this manuscript. The author is responsible for the final version of the review.

FundingThe preparation of this manuscript was supported by a grant from Abbott Healthcare Products.

Conflict of interest statementThe author declares that there is no conflict of interest.

References1. Brown M, Byatt T, Marsh T, McPherson K. National Heart Forum: micro

simulation of Obesity Trends 2006 – 2050: Obesity Trends for Adults Analysis from the Health Survey for England 1993 – 2007 February 2010. London: National Heart Forum, 2010. http://www.heartforum.org.uk/resources/nhf-publications/?entryid30=3985 (Accessed 10 October 2010)

2. Diabetes UK. What is Type 2 diabetes? London: Diabetes UK, 2010. http://www.diabetes.org.uk/Guide-to-diabetes/Introduction-to-diabetes/What_is_diabetes/What-is-Type-2-diabetes/ Accessed 10 October 2010

3. Haffner SM, Lehto S, Rönnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.

4. Donahoe SM, Stewart GC, McCabe CH et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765-75.

5. Schulze MB, Shai I, Manson JE et al. Joint role of non-HDL cholesterol and glycated haemoglobin in predicting future coronary heart disease events among women with type 2 diabetes. Diabetologia 2004;47:2129-36.

6. Laakso M, Lehto S, Penttilä I, Pyörälä K. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993;88(part 1):1421-30.

7. Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabetes Care 2003;26:16-23.

8. Schaefer EW, Leung A, Kravarusic J, Stone NJ. Management of severe hypertriglyceridemia in the hospital: A review. J Hosp Med 2011 Nov 29. doi: 10.1002/jhm.995.

Key messagesHypertriglyceridaemia contributes to the increased risk of • CVD and pancreatitis in diabetesFasting triglycerides ≥ 1.7 mmol/l requires further review • and may be abnormalFinding hypertriglyceridaemia should prompt a search for • secondary causesNICE suggests a fibrate if triglycerides are > 4.5 mmol/l • after addressing secondary causes or if 2.3–4.5 mmol/l despite statin useConsider highly concentrated, licensed omega-3 PUFAs • if lifestyle measures and a fibrate (± a statin) fail to adequately reduce triglycerides



9. Sandhu S, Al-Sarraf A, Taraboanta C et al. Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study. Lipids Health Disease 2011;10:157 http://www.lipidworld.com/content/10/1/157.

10. Sarwar N, Danesh J, Eriksdottir G et al. Triglycerides and the risk of coronary heath disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation 2007;115:450-8.

11. Skrapari I, Perrea D, Ioannidis I et al. Glibenclamide improves postprandial hypertriglyceridaemia in Type 2 diabetic patients by reducing chylomicrons but not the very low-density lipoprotein subfraction levels. Diabet Med 2001;18:781-5.

12. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 2007;176:1113-20.

13. Tentolouris NA, Stylianou E, Lourida D et al. High postprandial triglyceridemia in patients with type 2 diabetes and microalbuminuria. J Lipid Res 2007;48:218-25.

14. Angiolillo DJ, Roffi M, Fernandez-Ortiz A. Tackling the thrombotic burden in patients with acute coronary syndrome and diabetes mellitus. Expert Rev Cardiovasc Ther 2011;9:697-710.

15. Choudhuri G, Lakshmi CP, Goel A. Pancreatic diabetes. Trop Gastroenterol 2009;30:71-5.

16. Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol 2009;20:497-504.

17. Tonsi AF, Bacchion M, Crippa S et al. Acute pancreatitis at the beginning of the 21st century: The state of the art. World J Gastroenterol 2009;15:2945-59.

18. Nair D, Merriman H, Morrell J et al. Consensus guideline on reducing cardiovascular events and pancreatitis through the effective management of triglycerides. In: Foord-Kelcey G (ed.). Guidelines: summarising clinical guidelines for primary care. 42nd ed. Berkhamsted: MGP Ltd, 2010;91-95.

19. Jialal I, Amess W and Kaur M. Management of hypertriglyceridaemia in the diabetic patient. Curr Diab Rep 2010;10:316-20.

20. Kolovou GD, Mikhailidis DP, Kovar J et al. Assessment and clinical relevance of

non-fasting and postprandial triglycerides: an expert panel statement. Current Vascular Pharmacology 2011;9:258-70.

21. British Cardiac Society; British Hypertension Society; Diabetes UK; HEART UK; Primary Care Cardiovascular Society; Stroke Association. JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(suppl 5):v1-52.

22. The National Collaborating Centre for Chronic Conditions (NCCCC). Type 2 diabetes. National clinical guidance for management in primary and secondary care (update). London: Royal College of Physicians, 2008. http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf (Accessed 8 March 2012)

23. Solano MP, Goldberg RB. Lipid management in type 2 diabetes. Clin Diab 2006;24;27-32.

24. Oh R, Lanier J. Management of hypertriglyceridemia. Am Fam Physician 2007;75:1365-71.

25. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.

26. Goldfine AB, Kaul S, Hiatt WR. Fibrates in the treatment of dyslipidemias – time for a reassessment. N Engl J Med 2011;365:481-4.

27. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-3.

28. Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open label, blinded endpoint analysis. Lancet 2007;369:1090-8.

29. Omacor Summary of Product Characteristics. http://www.medicines.org.uk/emc/medicine/10312 (Accessed 11 October 2011)

30. National Institute for Health and Clinical Excellence. NICE clinical guideline 48. Secondary prevention in primary and secondary care for patients following a myocardial infarction. London: NICE, 2007. http://www.nice.org.uk/nicemedia/live/11008/30493/30493.pdf (Accessed 8 March 2012)

Correct words and language assist weight-loss consultations

SAJDVD recommeded action Primary care professionals have an important role to play in motivating patients in weight loss. They need to use an individualised approach in discussing weight with their patients and to motivate weight loss. References1. Gray C, Hunt K, Lorimer K, et al. Words matter: a qualitative investigation

of which weight status terms are acceptable and motivate weight loss when used by health professionals. BMC Public Health 2011; 11: 513.

2. NICE obesity guideline.3. SIGN obesity guideline.

General practitioners’ choice of words may have a direct impact on patients’ weight loss, according to a recent UK

qualitative study.1 The study used 34 semi-structured face-to-face and telephone interviews to explore the acceptability of various weight-status terms and their effectiveness in motivating lifestyle changes. Interview transcripts were analysed using the systematic framework approach.

Although some men and younger people seem to appreciate a direct approach from healthcare professionals, others needed to be treated more sensitively. Many people favoured the term ‘overweight’ to describe their weight status although there were doubts about its effectiveness to motivate weight loss. The response to the term ‘obese’ was largely negative although responders recognised that it could be appropriate in a health consultation. The use of the word ‘fat’ was viewed by most interviewees, particularly women, as being too personal or judgemental.

However, other terms that were considered acceptable by clinicians included ‘high BMI’, ‘unhealthy BMI’ and ‘unhealthily high body weight’. These three terms were also considered professional and useful to motivate weight loss. Use of the terms ‘fat’ and ‘large’ were not generally considered motivational when used by a health professional and the word ‘obese’ should be used carefully by healthcare professionals with clear explanation of what this actually means to the individual. A popular suggestion

was to related weight status to health to motivate weight loss, and a number of responders felt it important to allow time for full discussion of the problem, including health implications and possible solutions.

NICE2 and SIGN3 have recently published comprehensive clinical guidelines for the assessment, treatment and support of patients who are overweight and obese. Current evidence suggests that the cost of excess weight and obesity to society is £15.8 billion per year and is forecast to rise to £49.9 billion by 2050.




Correspondence to: Dr Hilton KaplanClaremont, Cape Towne-mail: [email protected]


Painful diabetic peripheral neuropathyHILTON KAPLAN

Marchal de Calvi gave the first description of neuropathic pain in 1864. FW Pavy, a Guy’s Hospital physician and a pupil of Claude Bernard, the father of modern physiology,

described in 1885 the symptoms of diabetic polyneuropathy as ‘… of darting or lightening pains… Or there may be great pain… I have noticed that these pains may be worse at night’ and some patients ‘could not feel properly in their legs’ and that ‘these features may be accompanied by loss of the patellar reflexes.’

As insightful as this definition was, it did not entirely describe neuropathic pain in the full spectrum of presentation, and the definition of neuropathic pain presented researchers and clinicians with difficulties.1 However, the development and validation of clinical tools in the form of questionnaires has been of immense help in defining the condition and may be used in research as well as in the clinical setting. These tools are simple and easy to use.1

The Assessment Committee of the Neuropathic Pain Special Interest Group NeuPSIG defined neuropathic pain (2011) as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’. The International Association for the Study of Pain (IASP) definition is ‘pain initiated or caused by a primary lesion or dysfunction of the nervous system’.

The NeuPSIG definition is probably more accurate as it distinguishes neuropathic pain from pain caused by neuroplastic changes in the central nervous system (CNS) in response to strong nociceptive stimulation. The term ‘somatosensory’ is used rather than ‘nervous system’ to differentiate neuropathic pain from pain caused by lesions in other parts of the CNS.

Peripheral neuropathy and neuropathic pain are frequent complications of type 1 and 2 diabetes and have a similar frequency: approximately 54–59% in type 1 and 37–45% in type 2 diabetes. There is variability in the reported prevalence of neuropathy, ranging from 5–80%. This probably reflects differences in population groups studied or the diagnostic criteria used to diagnose neuropathy. Neuropathy is usually a late finding in type 1 diabetes, but is often an early finding in type 2 diabetes.

Neuropathy may also present with impaired glucose tolerance (IGT) (Figs 1, 2). There is an increased risk with longer duration of diabetes (Fig. 3) and also with poor glucose control.

The pathophysiological mechanisms underlying PNPD are complex and beyond the scope of this article, other than a brief outline. Hyperglycaemia activates several processes, resulting in metabolic pathways contributing to polyneuropathy. These include activation of protein kinase C beta, which in turn leads to altered expression of endothelial nitric oxide synthetase and vascular growth

factor (VEGF), increased flux through the polyol pathway, oxidative stress and damage caused by increased glycation of protein, and increase in advanced glycation end-products (AGES).

Hyperglycaemia is highly correlated with the development and progression of all neuropathies, including painful diabetic peripheral neuropathy (PDPN). The DCCT (Diabetes Control and Complications trial) showed that tight glycaemic control reduced the incidence of neuropathy by 60%.2 However, even in patients with excellent long-term control, the lifetime incidence of PDPN remains 20%. Strict glycaemic control is still the single most important prevention measure for neuropathy.

The most common type of neuropathy involves the feet or hands, in a glove or stocking pattern. The feet are much more commonly affected than the hands. Sensory symptoms predominate, but motor and autonomic dysfunctions often co-exist.

In the Rochester diabetes study,3 a cross-sectional survey and longitudinal follow up of diabetic neuropathy, 60.4% of patients

Figure 1. Prevalence of DPN by age and glucose tolerance status.

Figure 2. Prevalence of polyneuropathy and neuropathic pain. MONICA/KORA Augsburg surveys S2S3.



had neuropathy, 47.3% had distal neuropathy, and 31.7% had carpal tunnel syndrome. In other studies the prevalence of autonomic neuropathy was 16 to 75%.

Progression of the neuropathy usually presents as a change in sensation, followed by abnormal reflexes, then muscle weakness, pain, progressive debilitating symptoms, and finally nerve death. Diabetic peripheral neuropathy can affect any nerve and the clinical symptoms and signs depend on which nerve or nerves have been affected. The neuropathy can be focal, e.g. cranial nerve palsies or entrapment neuropathy; multifocal, e.g. polyradiculopathy and mononeuritis multiplex; or diffuse and symmetrical.

Sensory symptoms include parasthesias, hyperalgesia, allodynia, and a burning or lancinating pain. The pain is usually burning in nature and is worse at night. The pain typically persists for years, causing considerable disability for the patient. Loss of sensation or numbness and loss of proprioception often occurs and may eventually predominate. The signs of neuropathy include diminished vibratory perception, decreased knee and ankle reflexes, reduced sensation to hot and cold, diminished sensation to pinprick and loss of proprioception (Table 1).

Risk of painful neuropathy in diabetes (Table 2)Painful neuropathy is a common and often progressive compli-cation of diabetes. There are multiple patterns of sensory neuropathy, including sensory motor neuropathies and small-fibre neuropathies.

Between 10 and 25% (approximately 16%)4 of diabetic patients may experience painful neuropathy. In 10–20% of patients, the symptoms are severe enough to warrant treatment. It is frequently unreported in 12.5% of patients and untreated in 39% of patients.5

Pain may be mild and intermittent or severe and unremitting, resulting in diminished quality of life. Patients describe the pain as burning, scalding, lancinating, tingling or having electric shocks. Most frequently, the symptoms are restricted to the feet, but any nerve may be affected, including the legs, arms, hands and fingers. Patients may also experience allodynia or hypersensitivity of the skin.

Symptoms may become chronic and worsen over time, but in some patients, improvement and occasionally resolution occurs over a period of years. A decrease in pain may imply either a gradual recovery of nerve function or a worsening of the condition, with progressive nerve death.

Painful neuropathy is also associated with and complicated by sleep and mood disorders and these tend to aggravate the symptoms considerably. Depression unrelated to the pain itself and other causes of pain must be excluded.

There are significant social, psychological and financial stresses imposed on patients with chronic painful neuropathy. The financial burden is made even more acute by painful neuropathy being excluded from the list of prescribed minimum benefit (PMB) conditions guaranteed for automatic full reimbursement by medical aid societies, the cost not automatically being covered as a ‘chronic condition’.

Acute painful neuropathy may also be induced by rapid correction of serum glucose, and this is called treatment-induced diabetic neuropathy. In a report from Daby et al.,6 acute painful neuropathy developed two to four weeks after starting insulin in six patients, four of whom were long-standing diabetics and in whom the blood sugar was lowered from 15–33 mmol/l to 3.5–9 mmol/l. Symptoms gradually improved over time (three to eight months).

Gibbons and Freeman7 found that rapid glucose control occasionally brought on acute nerve pain. Rapid weight loss also did the same occasionally with no apparent cause. Improvement occurred after 18 months of glucose control. The authors of this article found that there was greater improvement in patients with type 1 diabetes than in those with type 2 diabetes.7

Pathophysiology of PDPNThe pathophysiological mechanisms underlying PDPN are complex and beyond the scope of this article other than a brief outline (Fig. 4).

The peripheral nerve is made up of different nerve types. Within the nerve, the small unmyelinated C fibres cluster towards the mid

Figure 3. Prevalence of DPN by duration of type 2 diabetes.

Table 1. Differential diagnosis.

The differential diagnosis of neuropathy includes:

• Diabetes (painful neuropathy) • Claudication • Morton’s neuroma• Osteoarthritis • Radiculopathy • Non-diabetic or inflammatory neuropathies • Charcot’s neuropathy • Plantar fasciitis • Tarsal tunnel syndrome• Fibromyalgia• Connective tissue diseases• Sarcoidosis• Vitamin B1 deficiency• Paraproteinaemia• HIV infection, neurotoxic drug exposure• Paraneoplastic syndrome• Coeliac disease

Table 2. Risk factors for developing diabetic neuropathy.

Long duration of diabetesPoor blood glucose controlPoor weight controlMale genderAge above 40 yearsHigh cholesterol levelHigh blood pressureAlcohol usageCigarette smokingTall statureInsulin use



area of the nerve bundle with the small, thin myelinated and large myelinated fibres on the periphery of the nerve bundle. Peripheral nerve fibres conducting impuses from the periphery conduct via large Aδ myelinated fibres travelling at 30–70 m/s and sub-serving touch, pressure and vibration. These fibres are considered to be nociceptors, but due to anatomical or neurochemical changes, these fibres may elicit pain signals.

Small myelinated Aδ fibres travelling at a speed of 5–30 m/s sub-serve pain in the form of pinprick and cold threshold. Small unmyelinated C fibres conduct slowly and can respond to heat, mechanical or chemical stimuli. Because they conduct so slowly, standard electrophysiological neuronal testing does not reveal damage to those Aδ and C fibres.

Depending on the neuron type, each group of neurons responds with slow, intermediate or rapid velocity to different stimuli and pain thresholds. Electrical signals (action potentials) are transmitted to the dorsal horn of the spinal cord, and then relayed via two primary ascending pathways, the spinothalamic and spinoparabrachial tracts, to the thalamus. The spinothalamic pathway projects into the thalamus and somatosensory cortex. The spinoparabrachial tract connects to the ventral medial nucleus of the hippocampus and the central nucleus of the amygdala.

Following peripheral nerve injury, there are changes in the CNS that contribute to the manifestation of neuropathic pain. These changes have both a qualitative and quantitative impact on how and where the pain is perceived. It is likely that aberrant afferent activity is necessary for the initiation and maintenance of all aspects of neuropathic pain associated with injury to the peripheral nervous system.

Neuronal inflammation causes an increase in neurochemicals in adjacent tissue. Undamaged axons distal to the site of injury are broken down and reabsorbed by immune cells via a process termed Wallerian degeneration. Nerve growth factor is released near the undamaged nerve fibres and this may cause a release of tumour necrosis factor-α and expression of sodium channels, transient receptor potential vanilloid and adrenoceptors. Peripheral nerve lesions or axonal damage can trigger an increased sodium channel activity on C fibres.

Signal transduction is complex and involves different receptor potential ionic channel families, e.g. the transient receptor potential (TRP) family of ion channels, which provide the molecular basis for thermoregulation and mechanotransduction; members of the

epithelial Na channel (ENaC) superfamily; members of the two-pore potassium channel family; a low-voltage-gated Ca channel; and ionotropic purinergic receptors.

The electrical stimulus then travels along the peripheral nerve to the spinal cord. After the stimulus for pain has been transducted, the electrical signal is conducted to the spinal cord and transmitted to central nerves in the spinal dorsal horn. Here, signals can be modulated (amplified or inhibited).

The signal is then conducted further until it reaches the brain, where different brain regions process the signal (known as the pain matrix). Only when the brain has processed the signals received from the periphery does pain perception occur. The influence of emotional and cognitive input and feedback from different brain areas makes pain not only a perception but also an experience.

The dorsal horn acts as a first interface before pain signals are conducted to the brain. Transmission of signals from the peripheral afferent neurons to the brain is modulated by neuronal, glial and endocrine factors.

The inhibitory mechanisms in pain processing are referred to as the ‘gate control theory’. There is modulation of nociceptive information by inhibitory structures, including inhibitory inter-neurons, and descending structures from the brain at the level of the dorsal horn. Motivational affective and cognitive factors also influence pain modulation before pain is finally perceived and experienced.

Many different neurotransmitters and neuromodulators are involved in this gating process, including glutamate and substance P, which have a facilitatory effect on signal transmission. Glutamate is the most common facilitating agent. Substance P is released with high-frequency input for further amplification.

Glycine, γ-aminobutyric acid, endocannabinoids, endorphins, monoamines and neurosteroids exert (mainly) an inhibitory effect on pain transmission. As well as modulation by factors in the dorsal horn, descending inhibitory (and also facilitatory) pathways also play a part in nociceptive signal transmission. ‘Gating’ today is used as a term for all the processes involved in dorsal horn processing.

Within the brain there are specialised areas where pain is processed, modified and finally experienced. This complex neurophysiological process is beyond the scope of this article, but the main areas involved in this process are the thalamus, amygdala, hippocampus, prefrontal cortex, inferior cortex and anterior cingulate cortex. The thalamus is the main relay station for pain input before relaying this information on to the cortical and subcortical areas. The other areas are involved in complex processing of information between different parts of the brain, in memory of emotional reactions to pain, in processing affective aspects of sensory stimulation, in placing the painful experience into an emotionally relevant context, and in the affective and motor responses to pain.

While affective components of pain are thought to be mainly mediated by the medial thalamus, anterior cingulate cortex and anterior insula, sensory aspects are attributed to the lateral thalamus, primary and secondary somatosensory cortex, and posterior insula. Genetics, gender and individual differences influence whether or not a brain region is involved in pain processing.

The brain regions involved in processing pain depend on the type of pain experienced (extreme temperature, electrical shock, visceral). Distraction, anticipation, expectation and emotional states also affect pain processing. The attention and perception of pain occur in adjacent but separate sectors of the anterior cingulate cortex.

Figure 4. A simplified view of the PNS.



A key distinction between acute and chronic pain is that the brain regions involved in interpreting chronic pain states appear to be activated differentially, except in the thalamus. There is a difference in degree of activation of these regions.

Different descending pathways are available in the body. Cognitive and emotional information pathways go down via the peri-aqueductal gray, the rostral ventromedial medulla, and finally to the dorsal horn.

Pain is processed in inhibitory and facilitatory descending pathways. The inhibitory descending pathways work through the action of opioids, γ-aminobutyric acid, norepinephrine and serotonin and are activated when the organism’s attention is focused away from pain to a more serious and immediate threat.

The facilitatory descending pathways work with the transmitters glutamate, aspartate and serotonin. The system presumably starts working in circumstances where too much distraction away from the injury would result in potentially aggravating matters and result in the patient/person not caring enough about the present injury. Facilitating pain could be a physiological protection mechnism.

The intensity of the peripheral nociceptive stimulus is primarily related to the type, intensity and duration of peripheral input. The intensity of the nociceptive stimulus being transmitted to the brain depends on the integration in the dorsal horn. Here, facilitating, inhibiting, ascending and descending information is processed, and information is added or subtracted, resulting in some information being transmitted further on. The nociceptive stimulus is further modulated in the thalamus and various brain areas, where emotional and cognitive information are integrated.

Relationship of pain with depression and anxietyPain can lead to depression and anxiety. Both serotonin (5-HT) and norepinephrine (NE) have emerged as neurotransmitters that are thought to be involved in pain and depression. 5-HT and NE pathways are present in the cortical areas, such as the prefrontal cortex and the limbic system, areas that are involved in the modulation of mood and pain. 5-HT and NE neurotransmitters also have descending tracts from the brainstem that innervate the spinal cord and descending modulation of pain.

Anxiety and depression are often co-morbid factors co-existing with painful conditions and this may lead to sleep disturbances, which further aggravate the experience of pain. This leads to a vicious circle of pain → depression → anxiety → sleep disorder → further aggravation of pain, etc. This should be taken into account when deciding on an appropriate treatment regimen for pain.

Neuropathic pain is a type of maladaptive pain that can be the result of various types of pathophysiology, potentially emerging both peripherally and centrally. There is strong evidence implicating nerve ischaemia as the cause of diabetic peripheral neuropathy, with resulting reduced nerve perfusion and endoneural hypoxia. There are graded structural changes in nerve microvasculature, including basement membrane thickening, pericyte degeneration and endothelial cell perfusion. The vascular dysfunction in turn is driven by metabolic changes.

This pathophysiology of neuropathic pain may therefore involve diverse mechanisms. Different mechanisms may also be involved in different patients with the same symptoms.

Diagnosis and initial work up of patients with PDPNEvaluation of PDPN relies on taking a careful and detailed history,

performing a thorough physical examination, doing a psychosocial assessment, and then proceeding to establish a diagnosis, taking into account various screening tools. When establishing a clinical diagnosis, one must take into account the history of the pain, e.g. continuous or spontaneous, hyperalgesia or allodynia, and nocturnal exacerbation or not. Other causes of pain and depression should be excluded. The severity and frequency of the pain should be scored.

In screening, patients are asked whether the pain exhibits one or more of the following features: burning, painful cold, or electric shocks. Is pain associated in the same area with one or more of the following: tingling, pins and needles, numbness or itching? Is pain present in an area where physical examination reveals the following: numbness or decreased sensation, and does brushing over the painful area cause further pain?

It is sometimes difficult to make the correct diagnosis of painful neuropathy based on pain questionnaires and there is a difference in sensitivity from 67–85% and specificity of 74–90% between different questionnaires. It should be pointed out that screening tools relying on language descriptors have been validated in patients who have pain localised to only one part of the body. Their ability to discriminate between neuropathic and non-neuropathic pain is therefore reliable only when the pain is localised to a single specific area.

Screening tools should not be used for diagnostic purposes in patients with widespread pain. The presence of neuropathic symptoms in different areas of the body at some distance from each other does not have the same diagnostic value as the combination of these symptoms in a single painful area of the body.

Painful neuropathy screening tools fail to diagnose 10–20% of patients with clinician-diagnosed neuropathic pain. Screening tools are not suitable to assess the effects of therapy. An excellent review of this subject is dealt with by Bouhassira and Attal.1

Severity assessment: pain diary and scalesIn clinical trials, efficacy is often measured with numerical or categorical pain scales, e.g. the Likert four-hour average pain scores and the Brief pain inventory (BPI) (Fig. 5).

Average pain score: the Likert scale is an 11-point linear visual analogue pain scale ranging from 0 (no pain) to 10 (maximum pain) (Fig. 6). On examination it is imperative to assess the arterial pulses carefully to exclude peripheral arterial disease.

Figure 5. Severity assessment: pain diary and scales.



Altered reflexes, deformities, ulcers or slow-healing wounds should be excluded.

Foot examination should be carefully performed and the reflexes checked. Absent ankle reflexes may imply an early motor neuropathy.

Vibration sense is examined using a tuning fork and soft touch is examined using a 10-g Semmes Weinstein monofilament. The responses to pain, touch, pin prick, pressure, cold, heat, vibration and temporal summation must be checked and graded as normal, decreased or increased. The positive pain types are classified as hyperalgesic or allodynic and categorised in accordance with the dynamic or static character of the stimulus. Pain sensation is assessed using a sharp object (a pin) and temperature sensation using a cold probe.

A careful psychosocial history must be taken and the quality of life of the patient assessed. Depression, anxiety and sleep disorders must be excluded, and if present will direct the physician to adopt specific modes of treatment of the pain.

It is important to remember that although patients may experience considerable pain, the examination of the peripheral nervous system may be completely normal, although it is common to find some distal sensory loss. Likewise, tests such as nerve conduction studies and electromyography are typically normal in this condition.

Neurophysiological testing using nerve conduction testing and electromyography are frequently used in suspected disorders of the peripheral nervous system. Polyneuropathies and focal nerve lesions with only small-tier involvement can have normal nerve conduction velocity and electromyography despite significant nerve damage and neuropathic pain. Other modalities used in the diagnostic work

up include quantitive sensory testing, autonomic nerve testing and skin biopsy.4

Goals of neuropathic pain treatment8,9 Treatment of neuropathic pain must be individualised. The primary goal is the reduction of pain. If it is not possible to eliminate pain, as is often the case, treatment should focus on ameliorating the pain. Secondary goals include improvement in physical function, reduction in affective distress and improvement in quality of life. Achieving these goals is dependent on making an accurate diagnosis of any underlying aetiology.

The first step in the management of PDPN is to optimise glycaemic control. In the DCCT, strict control of the blood sugar not only decreased the incidence of neuropathy, but also slowed its progression by 57%.2

Concomitant chronic medical conditions and treatment of these conditions must be taken into account. Individual risks, such as history of previous drug abuse or suicide attempt must be considered. Cost of treatment should be discussed with the patient and must be affordable.

The drug regimen must be carefully planned with the patient and potential side effects addressed. Fears regarding possible negative outcomes and lack of efficacy of the treatment should be discussed.

Treatment recommendations are often given as tier I, II or III depending on evidence supported from three or more, two or one randomised clinical trial, respectively. Safety data, special considerations, co-morbid conditions, and cost are important considerations in choosing a particular drug.1,10-17

Choosing treatment options By understanding the site at which different drugs act, a regimen can be chosen that is complementary and where treatment is aimed at specific sites of pain control.18,19 Opioids are μ-receptor agonists and bind to μ-opioid receptors, to stop disinhibiton. Opioids used for neuropathic pain therapy include oxycodone and tramadol.

Selective serotonin–norepinephrine re-uptake inhibitors (SNRIs) aid in neuropathic pain therapy as they inhibit the re-uptake of serotonin and help increase the levels of serotonin available. Duloxetine is approved for treatment of diabetic peripheral neuropathic pain.

Tricyclic antidepressants (TCAs), including amitriptyline, work like SNRIs, blocking the re-uptake of serotonin. Additionally, TCAs serve as sodium channel blockers, which may aid in neuropathic pain treatment.

Alpha-2 δ-ligands, including pregabalin and gabapentin, are calcium channel blockers used in neuropathic pain therapy. These help decrease levels of neurotransmitter involved in central sensitisation.

Older sodium channel blockers (anticonvulsants and anesthetics) aid in modulating the release of excitatory amino acids, including glutamate, and can be used in neuropathic pain therapy. Vanilloid receptors sense extreme heat and can be activated by capsaicin to reduce neuropathic pain.

The choices for individual patients must take into account patient factors such as co-morbidities, other medication taken by the patient, goals of treatment, adverse-event profiles of agents, drug interactions, and cost and availability of the drugs. The choice of first-tier agents used to treat pain is based on positive results

Figure 6. The Likert pain scale.



from two or more randomised clinical trials and includes duloxetine, pregabalin, oxycodone CR, TCAs, amitryptiline and venlafaxine.

The expert panel of the American Academy of Neurology, the American Association of Neuromuscular and Electro-diagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation based their recommendations on three class I and five class II studies and recommended amitryptiline, and venlafaxine and duloxetine in lessening the pain of PDPN.4 Venlafaxine and duloxetine also improved quality of life of patients. Venlafaxine was superior to placebo when added to gabapentin. Only pregabalin was recommended as a level A treatment.5

There is insufficient evidence for the efficacy of desipramine, imipramine, fluoxetine, or the combination of nortryptiline and fluphenazine for the treatment of PDPN. SSRIs at this time should be considered as third-line treatment. Topical therapies used early on may be effective in some patients.

Most randomised, controlled trials have shown that drugs generally have similar efficacy. Level A evidence in support of their use includes tricyclic antidepressants, pregabalin, gabapentin, tramadol, opioids, duloxitine, venlafaxine, topical lidocaine and capsacin patches.

Combination therapy appears useful with tricyclic antidepressants (gabapentin) and opiods (level A) but there are too few large-scale comparative studies to compare the efficacy of these drugs. Future trials will no doubt take into account co-morbidities, quality of life, symptoms and signs using standardised tools, and attempt to better define profiles that are effective when using specific drug treatments.

Other options that have been tried and are under investigation include:

Aldose reductase inhibitors: there have been many trials and • clinical attempts using this drug in the treatment of painful neuropathy, but just as many failures, either because of toxicity or lack of response to treatment. Epelrestat prevents progression of peripheral neuropathy. Its • action is related to a reduction in the progression of advanced glycation end-products.VEGF-gene transfer is experimental treatment at this stage but • may show promise in the future.

Tricyclic antidepressantsSee Fig. 7 for their mode of action.

NE + 5HT re-uptake inhibitor • Block Na• + channelsBlock cholinergic, histaminergic and • α-adrenergic receptors.

Tricyclic antidepressants have the following adverse side effects: cardiovascular-orthostatic hypotension and cardiac arrhythmias, and drowsiness. They are also antagonists at the α1-adrenergic receptors, and anticholinergic and antihistaminic.

Tricyclic antidepressants should be used with caution in patients with glaucoma, prostatic hypertrophy, cardiac conduction problems, and a history of seizures.

Patients lacking cytochrome P450 2D6 isoenzyme activity are prone to the adverse effects of tricyclic antidepressants (and venlafaxine) and have a weaker analgesic response to tramadol. In my experience, drowsiness may be severe and persist well into the following day.

For this reason, amitryptiline should be taken in the evening and not before bedtime in order to limit this side effect. Starting with 10 mg/day and increasing the dose gradually every few

days, to the therapeutic maximally tolerated effective dose is advisable. In my view, the maximum dose that should be used is 75 mg/day, although some authors have suggested a dose as high as 150 mg/day. Alternatives to amitriptyline include imipramine and venlafaxine.

ECG screening is recommended in adults over 40 years of age. Careful follow up of blood pressure (supine and erect) and heart rate should also be carried out.

AnticonvulsantsGabapentin binds to the regulatory unit of neuronal calcium channels and blocks excessive excitability in the ascending pathways. The therapeutic dose is 600 mg twice daily.

Pregabalin binds to an alpha-2D subunit of voltage-gated Ca2+

channels, affects Ca

2+ influx at the presynaptic terminals in hyper-

excited neurons, and reduces release of excitatory neurotransmitters. The effective dose is 75–300 mg bid. It is effective in 23–26% of cases (50% reduction in pain) and is more effective than oxycodone in reducing pain.

Sodium channel antagonists Mexilitene is a third-line agent and its potency is equal to morphine, gabapentin and amitriptyline for neuropathic pain. Side effects include drowsiness, fatigue, nausea and dizziness.

Lacosamide16 is an investigational drug for epilepsy and neuro-pathic pain. It slowly inactivates voltage-gated sodium channels and interacts with the collapsin response-mediator protein-2. It has not been shown to be any better than placebo. These agents are not recommended for the treatment of PDPN.

OpioidsOpioids act as agonists at µ, k and δ-opioid receptors. They inhibit ascending transmission, activate descending inhibitory pathways

Figure 7. Tricyclic antidepressants: mode of action.



and alter limbic system activity. There are significant risks using this class of drug, including over-sedation, respiratory depression, confusion and cognitive slowing.

Tramadol is a 5-HT releasing agent with widespread receptor antagonist action in the CNS (antagonism to centrally acting µ-opioid receptors, and to 5-HT, NMDA, nicotinic and M1 and M3 receptors). It is also a weak inhibitor of 5-HT and noradrenaline re-uptake.

The effective therapeutic dose varies widely from patient to patient and the lowest possible dose for relieving pain should be used: 200–400 mg two to three times a day. Adverse side effects include nausea and vomiting, dizziness, constipation, headache, somnolence, excitability, pruritis, urinary retention, dependency and potential abuse. Overdose on treatment is also a concern.

In a long-term tramadol–paracetamol trial, treatment-emergent adverse side effects were transient and mild to moderate in severity, with nausea recorded in 215 patients, dizziness in 16%, somnolence in 16%, headache in 15% and constipation in 14% (Janssen Pharmaceutical). In my experience, the side-effect profile of tramadol is excellent if used at a low (but effective) dose and treatment is carefully monitored.

Patients lacking cytochrome P450 2D6 isoenzyme activity have a weaker analgesic response to tramadol.

Selective serotonin–norepinephrine re-uptake inhibitors: These agents act by inhibiting 5-HT and noradrenaline re-uptake. Drugs in this class include duloxetine and venlafaxine. The dose of duloxetine is 60–120 mg/day and venlafaxine 75–225 mg/day. Side effects include gastrointestinal symptoms: nausea, vomiting, diarrhoea and constipation; pressor effects; weight gain with venlafaxine; sexual dysfunction; and discontinuation reactions.

There have been many trials comparing duloxetine to placebo.20-22 In most of these studies there was very little advantage using duloxetine over the placebo group, i.e. the efficacy of the two groups was about the same.

The duloxetine studies however did estimate a clinically important difference on the scale by relating it to global assessments of change in multiple studies of chronic pain. The clinical data derived from these studies are difficult to interpret however because the clinical importance of change from the baseline is not easy to assess on the Likert scale, and there are no data-driven estimates for clinically important differences in pain-intensity scales used for chronic pain studies. The duloxetine studies however did estimate a clinically important difference on the scale by relating it to global assessments of change in multiple studies of chronic pain.

In a poster presentation at the 25th American Pain Society Annual Scientific Meeting in San Antonio, Texas, in May 2006,22 Raskin showed data that supported the notion that duloxetine was significantly better than placebo in reducing neuropathic pain in diabetes at one week. It maintained the improvement throughout the trial.

Duloxetine’s half-life is about 12 hours (in plasma) and is highly

protein bound (> 90%). Once-daily dosing suggests that the therapeutic effects may persist after the drug is cleared and the brain concentration may differ from the plasma concentration. There is no need for dose adjustment based on age, gender and/or smoking. No specific laboratory tests are recommended prior to the use of the drug, although duloxetine should ordinarily not be prescribed to patients with substantial alcohol use or patients with any hepatic insufficiency. Duloxetine does not affect HbA1c level, has no significant long-term effect on blood pressure, has minimal long-term effect on weight and has no increased risk of suicidal ideation.

Transient receptor-potential vanilloid receptor-1 (TRPV):16,23

Capsaicin TRPV 1 is a non-selective cation channel abundantly expressed in the C fibres. Modulating the TRPV 1 may be a therapeutic option in PDPN. Capsaicin can desensitise TRPV 1 channels and relieve pain. It is the most widely studied drug in this class in PDPN. Its use is limited to topical application due to a narrow therapeutic index and side effects following systemic administration. Because TRPV 1 causes an excitatory response prior to desensitisation, it results in unwanted side effects and non-compliance with the treatment. Antagonists of TRPV 1 may be useful, but further trials are needed.11,13,16

In a small trial using capsaicin, 22 patients with chronic severe PDPN were randomised to 0.075% topical capsaicin or placebo for eight weeks.14 The results showed a reduction in pain intensity: 16 vs 4.1%; pain relief: 44.65 vs 23.25%; and a complete cure in 50% of the cohort.

The analgesic is applied topically three to four times a day. The major side effect is burning and reddening of the skin, which may be intolerable to some patients. Long-term use may cause degeneration of epidermal and dermal autonomic nerve fibres.24-27

Alpha-lipoic acid13,14 may be beneficial in reducing pain in PDPN. One class I and two class II studies showed benefit, but pain was not the pre-defined endpoint in these studies. The effect of the size of pain reduction was 20–24% and superior to placebo.14

Less commonly used or research optionsTNF-alpha is one of a group of pro-inflammatory cytokines mediating hyperalgesia in a diverse range of inflammatory and neuropathic conditions. It is up-regulated following nerve injury. Cytokine inhibitors and anti-inflammatory cytokines have an analgesic effect. In painful neuropathy as opposed to non-painful neuropathy, TNF-alpha and inerleukin-2 levels are increased.

TNF-alpha levels are higher in the serum of diabetic patients and have been implicated in the aetiology of micro- and macro-angiopathy. Hypertriglyceridaemia associated with small-fibre neuropathy induces increased TNF-alpha production. Administration of insulin and anti-oxidant therapy results in a reduction of TNF-alpha and improvement of neuropathy. Antibodies to TNF-alpha cause reduction in pain and allodynia. TNF-alpha causes up-regulation of COX-2, PGE2, IL6 and CGRP and is involved in the regulation of nerve growth factor.

Protein kinase-C inhibitors (PCK): There is a well-established link between PKC activation and endoneural ischaemia and neuropathy. One of the drugs in this class is ruboxistaurin. However in one trial where the drug was compared to a placebo group, there was no difference in the primary endpoint, although the neuropathy symptom score may have improved.

Actovegin28,29 is a deproteinised haemoderivative produced from calf’s blood by ultrafiltration. It stimulates oxygen absorption and utilisation, and cellular energy metabolism. Actovegin exerts an insulin-like effect: it stimulates glucose transport, pyruvate dehydrogenase and glucose oxidation. It may improve hypoxia and decrease nerve ischaemia.

A trial using 20 intravenous infusions of actovegin 2 000 mg/day followed by 1 800 mg/day per os for 140 days was safe and effective in improving neuropathic symptoms, vibration perception threshold (VPT), sensory nerve function and mental health in type 2 diabetes patients with symptomatic polyneuropathy.29 Decreasing



the neuropathic symptom score by one point was thought to be significant. Ongoing trials are needed to establish whether this form of treatment might have relevance in treating PDPN.

Modulation of peripheral excitability by blocking excitatory spinal neuroglia, or increasing spinal inhibition by enhancing monoaminergic activity is of importance in the processes of neural sensitisation.30

Biological approaches include the use of antibodies, siRNA and gene therapy.30

Non-pharmacological options14

Electrical spinal cord stimulation, which is expensive and • invasive.Transcutaneous electrical nerve stimulation (TENS) has been • used for mild to moderate pain. One class I study reported that percutaneous electrical nerve stimulation (PENS) reduced pain in PNDN by 42% on the visual analogue scale compared with placebo, and also improved sleep. However, a class II study reported no effect with the treatment.14 One class III study showed that the addition of electrotherapy to amitryptiline was more beneficial than using amitryptiline on its own. It is recommended as a level B treatment for PNDN.Magnetic field therapy was not shown to be better than placebo • and should not be used to treat PNDN.Low-intensity laser therapy (LILT) has not been shown to be any • better than treating with a placebo.Reiki therapy did not show any benefit in treating PNDN.• Monochromatic near-infrared treatment (MIRE) was not • addressed by the American Academy of Neurology, the American Association of Neuromuscular and Electro-diagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.Opsite dressings showed limited evidence and are not recom-• mended.Acupuncture, yoga and exercise, e.g. tai chi, are probably no • better than a placebo in treating PNDN, although the use of acupuncture is perhaps more controversial. Acupuncture was developed in Chinese medicine in the 5th century BC and brought to Europe in the 17th century. It is inexpensive, painless, and the procedure has no side effects. Its efficacy is supported by a number of small clinical trials. It works by stimulating A-d and C afferent fibres in muscles, which activate the spinal cord, midbrain and hypothalamus, leading to release of endorphins in the peripheral circulation and CSF (cerebrospinal fluid) and inducing analgesia via encephalins, which block neuropathic pain.

Treatment options in clinical practiceTaking into account the availability of pharmaceutical agents that can be used to treat PDPN in South Africa and the cost involved in treating this condition, bearing in mind that PDPN is not reimbursed as a prescribed medical benefits condition and that for most patients the cost of treatment may be a financial burden, the following is a practical approach to the treatment of PDPN.

The treatment regimen takes into account ADA31 and NICE17 guidelines. The recommendations take into account the evidence-based guidelines advocated by the American Academy of Neurology, the American Association of Neuromuscular and Electro-diagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

Pregabalin represents level A treatment, but is relatively • expensive. Gabapentin, sodium valproate, venlafaxine, duloxetine, ami-• tryptiline, dextromethorphan, morphine sulphate, tramadol, oxycodone, capsaicin, isosorbide dinitrate spray and PENS are all recommended as level B treatment. Oxcarbazepine, lamotrogine, lacosamide, clonidine, petoxy-• fylline, mexiletene, magnetic field treatment, low-intensity laser treatment and Reiki therapy are not recommended.

Bearing in mind the cost of pregabalin, either duloxetine, or amitriptyline should be considered first-line treatment, especially if there is concomitant depression or a sleep disturbance. The starting dose of duloxetine is 60 mg/day and the maximum dose 120 mg/day. The starting dose of amitriptyline is 10 mg/day and the maximum dose 75 mg/day. If there is any drug intolerance, the duloxetine can be changed to amitriptyline or vice versa. If affordable, alphalipoic acid 200 mg tid could be added as an anti-oxidant supplement.

Most cases of PDPN will require multimodal therapy with agents from two or more classes of drugs. The patient should be carefully followed up with regular appointments every few weeks, and re-evaluated by the doctor after six weeks in the clinic. Careful attention should be given to tight blood sugar control unless there are clinical reasons to the contrary. It should be stressed that improvement will not occur unless blood sugar control is improved. However, too rapid, tight control of the blood sugar may paradoxically worsen the pain.

If the pain continues and is not relieved by the above regimen, then either pregabalin 75–150 mg/day in two divided doses or gabapentin 600 mg tid should be added to either amitriptyline or duloxetine. If this protocol is ineffective or if the patient’s general health deteriorates due to severe ongoing pain, or if daily activities are severely affected by the pain, then referral to a specialist pain clinic is advisable.

The third line of therapy includes the addition of oral tramadol 200–1 200 mg/day in two or three divided doses, added to either amitriptyline with or without pregabalin or gabapentin. The use of tramadol with duloxetine should be used with caution (relative contraindication) as the combination may result in a serotonergic-like syndrome. Lidocaine patches can also be used, as can capsaicin cream, lightly applied to the affected area (the use of capsaicin for long-term use is not advisable as it may cause unacceptable irritation of the skin).

The next line of treatment for ongoing pain is the addition of oxycodone or morphine. A specialist pain centre only should administer this treatment. If pain is ongoing, it may also be worthwhile referring the patient for acupuncture.

ConclusionPainful diabetic peripheral neuropathy is a relatively common complication of diabetes, occurring most typically in the setting of older patients with chronic poor glycaemic control and peripheral vascular disease. The pain may be mild and easily managed with simple analgesia, a small dose of a tricyclic antidepressant or an SSNRI drug, or severe and incapacitating, requiring more complicated drug regimens to control the pain.

It is an important cause of sleep disturbance and poor quality of life in diabetic patients and the cost of treatment is often a long-term financial burden when multiple drug-therapy regimens are



used. It is imperative to treat all risk factors associated with the neuropathy and glycaemic control should be gradually optimised. Care should be taken to evaluate and treat depression and sleep disorders.

In the future it is hoped that PDPN will be added to the list of PMB conditions and reimbursed in full and without prejudice by medical aids and medical insurance funders. PDPN should be recognised as a potentially serious, debilitating chronic condition, a common cause of morbidity in diabetic patients and a difficult therapeutic challenge for doctors.

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• Erin L St Onge and Shannon a Miller. Pain associated with Diabetic Peripheral Neuropathy. Jefferson University Continuing Education Credit. Feb 2008

• Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 16 Mar 2011; CD007938.

• Haanpää ML, Gourlay GK, Kent JL, et al. Treatment considerations for patients with neuropathic pain and other medical comorbidities. Mayo Clin Proc 2010; 85(3) Suppl: S15–S25.

• Fink E, Oaklander AL. Small fiber neuropathy: answering the burning questions. Sci Aging Knowl Environ 2006; 2006(6): 7.

• Bouhassira D, Attal N. Diagnosis and assessment of neuropathic pain: The saga of clinical tools. Pain 2011; 152: S74–S83.

• A new definition of neuropathic pain. Pain 2011; 152: 2204–2205• Harriot A, Gold MS. Contribution of primary afferent channels to neuropathic

pain. Curr Pain Headache Rep 2009; 13(3): 197–207.• Stillman M. Clinical approach to patients with neuropathic pain. Cleveland Clin J

Med 2006; 73(8): 726–736. • Ziegler D, Rathman W, Dickhaus T. Neuropathic pain in diabetes, prediabetes and

normal glucose tolerance: the MOICA/KORA Augsburg Surveys S2 and S3. Pain Med 2009; 10(2): 393–400.


SA JOURNAL OF DIABETES & VASCULAR DISEASE

Patients as Partners

HELPING PATIENTS ON INSULIN TOTRAVEL SAFELY


Sandra WaddinghamDiabetes Co-ordinator North Lancs PCT

Sandra Waddingham is the Diabetes Coor-dinator for North Lancashire PCT, following extensive experience as a practice nurse and an MSc in diabetes care from Warwick University. She led the implementation of the NSF for diabetes, including developing a tier 2 intermediate clinic service and a patient education programme and improving the involvement of service users in the develop-ment of diabetes services. She currently leads the diabetes team in delivering the X-pert patient education programme.

People with diabetes need to plan carefully

for holidays, especially if they are treated

with insulin. Although much of the advice

will be the same as for the general population, these

patients are more vulnerable and will need to take

particular care in looking after themselves to avoid

any ill health while away from home.

GOING ABROAD

Holiday injections and malaria prophylaxis are ex-

actly the same for people with diabetes as for eve-

ryone else. However, advice regarding safe food and

water for some destinations, using bottled water and

avoiding ice cubes is very important to avoid sick-

ness and diarrhoea while away from home. People

with diabetes will struggle to maintain stable blood

glucose levels if vomiting and diarrhoea occur. Pre-

ventive measures therefore should be emphasised,

pointing out the particular risks to people with diabe-

tes and especially in those taking insulin.

PREVENTING DEEP VEIN THROMBOSIS (DVT)

Diabetes sufferers are at a higher risk than the gen-

eral population of developing a deep vein throm-

bosis (DVT). Advice about how to improve circula-

tion, avoiding alcohol and drinking plenty of water

should be given. Long-haul flights increase the risk

of DVT, especially if little or no exercise is attempted.

People who remain immobile during long coach

trips are also at risk, although there is usually more

opportunity for periodic exercise as most coaches

stop at services every few hours.

Most people with diabetes will already be taking

aspirin. If not, consideration should be given to tak-

ing this, especially if travel arrangements will mean

long periods of inactivity. The usual dose of 75 mg

should be maintained – an increase in dose would

not be appropriate.

MEDICINES AND EQUIPMENTAn adequate supply of regular medication, including

insulin and essential equipment such as glucom-

eters and test strips, should be taken to comfortably

cover the whole of the trip. These should to be car-

ried in hand luggage in case they are needed during

the journey and because the luggage hold is likely to

freeze, which could damage some medicines, with

insulin being particularly vulnerable. There is also

Originally in: Prim Care Nursing 2012; 30–32


SA JOURNAL OF DIABETES & VASCULAR DISEASE PATIENTS AS PARTNERS

a small risk of suitcases going astray; therefore these essential items

should be kept close at hand.

Patients should be advised to check with airlines before their journey

regarding travelling with medicines and equipment in hand luggage, par-

ticularly as airlines have tightened up procedures in recent years. People

with diabetes using insulin generally need a letter from their GP to be able

to take insulin pens and needles onto an aircraft.

GLYCAEMIC CONTROL ON HOLIDAYMost people away from home change their lifestyle temporarily. Eating

habits may change to allow one or two more treats than usual, and ca-

tering arrangements are likely to be different. Levels of activity may also

be different away from home – some people will be more active, and

some less so; therefore people with diabetes should consider these is-

sues in relation to their glycaemic control. Insulin or oral hypoglycaemic

agents might need some adjustment to compensate, and patients will

need to be advised accordingly. Even a change in the weather can make

a difference. Insulin is absorbed faster in hot weather, which could lead

to unexpected hypoglycaemia, and patients need to be aware that their

insulin dose should be reduced as necessary.

ADJUSTMENTS FOR DIFFERENT TIME ZONESPatients might need help in adjusting the times of insulin injections to fit

in with the time difference of their holiday destination compared to home.

This should be carefully planned in advance to ensure the patient fully

understands what to do, and when. Changes might need to begin a few

days before travelling to ensure an efficient and gentle transition to the

new time zone.

BASAL-BOLUS ALTERATIONSShort- or rapid-acting insulin injections are fairly straightforward to

manage, as they act quickly when food is eaten, so, generally speak-

ing, no food means no insulin. More frequent blood glucose testing will

be needed to prevent hypoglycaemia. Long-acting in-

sulin analogues are designed to be taken at roughly

the same time each day, within a two-hour window.

So, by pushing the injection on an hour or taking it

an hour sooner than usual, and continuing to alter the

time gradually over the few days preceding the trip,

the injection can be moved to fit in with the expected

holiday time zone.

ALTERING AN INSULIN MIXInsulin mixes are made up of intermediate-acting insu-

lin lasting about 16 hours and a short- or rapid-acting

insulin, which acts on the meal about to be eaten.

Moving the timing of these injections will depend on the patient’s itiner-

ary and should be considered accordingly. Alterations can probably be

left until the day of travel and, as long as it is remembered that the

intermediate insulin lasts for 16 hours, then changes can be thought

through logically.

A patient can safely have a snack to prevent hypoglycaemia and move

an injection forward as long as it is not more than 16 hours since the last

one, and, of course, the later injection needs to correspond with a meal.

For example, a patient taking a night-time flight could have their morning

injection with breakfast as usual, and lunch as normal, then a snack late

afternoon, delaying the second injection until the next meal, later in the

evening, perhaps at the airport before the flight.

DRIVING AND INSULINThe risk of hypoglycaemia while driving has to be taken very seriously. By

law, people with diabetes must inform the Driver and Vehicle Licensing

Agency (DVLA) in certain circumstances. Fortunately, medical conditions

account for a relatively small percentage of road traffic accidents.

Going on holiday: points to remember

• Consider necessary holiday vaccinations and malaria prophylaxis well in advance.

• Follow safe food and water advice. • Take enough medication to cover the trip. • Take any necessary equipment, glucometer, etc. • Consider aspirin therapy, as appropriate. • Ensure travel insurance is adequate, and take your European Health.

Insurance Card (EHIC) if appropriate. The EHIC (formally known as the E111) entitles most UK residents to reciprocal healthcare when temporarily visiting a country in the European Union.

• Pack snacks, as appropriate, for the journey.• Follow DVT prevention advice. • Consider the effect of changes in diet and exercise levels on diabetes

control.• Plan changes to insulin regimens in advance to fit in with different time

zones.


PATIENTS AS PARTNERS SA JOURNAL OF DIABETES & VASCULAR DISEASE

HYPOGLYCAEMIA AND DRIVINGThe main concern is the consequences of hypoglycaemia on driving abil-

ity. Low blood glucose severely impairs cognitive function, affecting driv-

ing capability and road safety. The impact of diabetes on driving should

be discussed regularly with patients, perhaps as part of the annual review

process. Patients need to know that suffering a hypoglycaemic attack at

the wheel is not only extremely dangerous but the courts are unlikely to

be sympathetic if they are involved in an incident, and a custodial sen-

tence could well be the result. Patients have to take responsibility to keep

themselves and other road users safe, although healthcare professionals

also have a duty to make patients aware of the facts.

WHAT TO DO IF HYPOGLYCAEMIA OCCURSAccidents occur when drivers ignore the warning signs of hypoglycaemia

and continue to drive. Patients need to stop the car as soon as safely pos-

sible, and in a suitable location. The keys should be removed from the igni-

tion and the driver needs to move out of the driver’s seat. They should take

fast-acting glucose, in the form of glucose tablets (three tablets are usually

sufficient), or a glucose drink, for example, 100 ml of Lucozade original.

Glucose taken orally will act faster than products containing sucrose,

fructose, lactose or other forms of sweeteners, as it will be absorbed

much quicker. This should be followed up with a meal or substantial

snack before resuming driving. As it takes about 45 minutes for the brain

to fully recover from hypoglycaemia, driving should not be resumed until

45 minutes after the blood glucose has returned to normal.

HYPOGLYCAEMIA AWARENESSMake sure that patients are aware of their particular signs of hypogly-

caemia and warn them most people experience symptoms at blood glu-

Advice to drivers using insulin

• Test blood glucose before driving, even before a short journey

• Have a snack before driving if blood glucose is below 5 mmol/l

• Retest every two hours if driving long distances

• Keep a supply of glucose tablets or Lucozade in the car

• Glucometers and strips should be carried in the car

• Don’t ignore early warning signs of hypoglycaemia

• Take particular care during treatment changes, changes in lifestyle,

exercise, travel or pregnancy

• Do not drive if diabetes is unstable and hypoglycaemia is likely

• Regular snacks and meals should be taken on long journeys. Always

avoid alcohol

• Wearing an identification bracelet for diabetes, or other alert, is

advisable.

cose levels of around 4 mmol/l. Some patients lose their warning signs

if glucose levels are allowed to drop below 4 mmol/l on a regular basis,

and may be unaware this is happening. If symptoms are experienced at

glucose levels as low as 2 or 3 mmol/l, then the risk is that deterioration

could be rapid and sudden, which would be much more likely to end in

disaster on the road. The DVLA will withhold a driver’s licence if there is

impaired awareness of hypoglycaemia. A driver is obliged to inform the

DVLA if this happens, or if they suffer hypoglycaemia requiring assistance

either at the wheel or otherwise.

INFORMING THE DVLAPeople using insulin must inform the DVLA, including women with gesta-

tional diabetes treated with insulin. Any deterioration in eyesight, whether

involving field of vision, laser treatment for retinopathy or any other rea-

sons that might affect a patient’s vision, should also be reported. Any

other complications of diabetes should be reported to the DVLA. This

does not necessarily mean that a licence will be refused, but the details

might be considered more closely and the DVLA may liaise with the prac-

tice for further details.

LORRY AND BUS DRIVERSDrivers treated with insulin holding a licence for group 2 vehicles will no

longer be able to drive these vehicles. Group 2 vehicles include heavy

goods vehicles and passenger carrying vehicles, in other words, large

lorries and buses. This has huge implications for lorry and bus drivers and

does, understandably, deter them from using insulin.

NON-INSULIN-TREATED DIABETES AND THE DVLADiabetes managed by diet alone or tablets needs to be reported to

the DVLA only if relevant complications occur, for example, if retino-

pathy develops or hypoglycaemia is experienced. People using exena-

tide and gliptins in combination with a sulphonylurea are included in

this group.


SA JOURNAL OF DIABETES & VASCULAR DISEASE PATIENTS AS PARTNERS

SUMMING UPEducating patients about their diabetes is a continuous and ongoing

process. People generally worry less about aspects of their health if they

know what to expect, how to deal with it and when to ask questions. If

people with diabetes understand why they put on weight with insulin they

can be proactive and take preventive action. Likewise, understanding the

effect of exercise on blood glucose levels is important for anyone with

diabetes, not just for those using insulin.

Driving with diabetes has legal implications, and it is essential that peo-

ple realise the dangers and know how to keep safe on the roads. Illness is

a nuisance at the best of times and is a bigger nuisance when combined

with diabetes, especially if patients are unaware of what to expect and how

to deal with the unexpectedly high blood glucose levels that can result.

Practice nurses are well placed to support and help patients through these

aspects of their care. Continuous education and reinforcing important mes-

sages means patients learn to self-care effectively, promoting their well-

being, reducing the incidence of complications and keeping them safe.

www.diabetes.org.uk•Shaw K. Safe driving with diabetes: risks, reality and responsibilities. •Practical Diabetes International Sept 2008 vol 25 no7.Dept of Transport, For Medical Practitioners. At a glance guide to the cur-•rent medical standards of fitness to drive. Drivers Medical Group. DVLA. Swansea. Sept 2008 www.dvla.gov.uk/medical aspxMacKinnon • M. Diabetes Care in General Practice. A Practical Guide to Integrated Care. Fourth ed. London: Class, 2002.Sonksen P, Fox C, Judd S. • Diabetes at your Fingertips. Fifth ed. London: Class 2003.Barnett AH.• Insulin Made Easy. Revised ed. London: Medical Education Partnership, 2004.Krentz AJ, Bailey CJ. Type 2 • Diabetes in Practice. London: RSM, 2001.Williams G, Pickup JC. Handbook of Diabetes. Third ed. Oxford: Blackwell •2004.Waugh A, Grant A. • Ross and Wilson Anatomy and Physiology in Health and Illness. Ninth ed. London: Churchill Livingstone 2001.www.ehic.org.uk•

MORE INFORMATION

DIABETES NEWS

Changing dietary habits and consequent nutritional deficiencies are having a

significant impact on the health status of individuals living with chronic heart failure (CHF) in Soweto. These were the findings of a study published in January 2013.1

The earlier Heart of Soweto study was undertaken to document the increase in cardiovascular disease among recently urbanised Africans in Soweto. Further to this, nutritionist Sandra Pretorius of the Soweto Cardiovascular Research Unit, University of the Witwatersrand, Johannesburg, undertook that study specifically to assess the nutritional aspect of this worrying phenomenon.2

Her conclusion was that patients suffering from CHF in Soweto might be in the early stages of the ‘nutrition transition’ and that while they continue to eat some of the more ‘traditional’ carbohydrate foods, their food choices are increasingly being affected by urbanisation. Where the traditional rural

Diabetes newsChanging dietary habits and associated nutritional deficiencies impact on urban African patients living with heart failure in Soweto

diet is low in fat and high in unrefined carbohydrates, vegetables and fruit, urban diets are being supplemented by highly refined carbohydrate sources, with individuals now consuming only around one piece of fruit and one vegetable serving per day.

‘Urbanisation has brought increased access to a wider range of food choices, but many of these are the wrong choices’, she told the SAJDVD in a recent interview. ‘Fast foods and convenience foods, which usually have high fat, trans fats and salt content, are not only easily available but also more affordable, so people are consuming more of them. An increasingly sedentary lifestyle exacerbates the problem.’

Pretorius feels strongly that it’s not enough simply to document these trends. Steps need to be taken to arrest them. Specific dietary recommendations, which are culturally sensitive and economically viable for the prevention and management

of CHF in this population group, as well as targeted intervention programmes, need to be developed and implemented. She is currently working on making these a reality.

Her concerns go beyond CHF, however, to embrace diseases of lifestyle in general and the risk factors for these. The findings are sobering. In a survey of 1 311 patients attending primary health clinics in Soweto, Stewart et al. found a high prevalence of obesity; 42–47% in women and 11% in men. There was a similarly high prevalence of hypertension of approximately 33%.2

Pretorius, together with Prof Karen Sliwa and the Soweto Cardiovascular Research team, has been instrumental in organising awareness days in Soweto to make the public more conscious of the dangers associated with obesity and hypertension. ‘There is still a lot of ignorance among the public, especially when it comes to obesity,’ she says.


DIABETES NEWS SA JOURNAL OF DIABETES & VASCULAR DISEASE

The current global attention directed at non-communicable diseases (NCDs)

is being driven at the highest levels, with the World Health Assembly adopting the important new global target of a 25% reduction in preventable NCD deaths by 2025 (the 25 by 25 goal). South Africa, and indeed sub-Saharan Africa, is currently a melting pot of confounding factors affecting both risk and prevalence of chronic diseases of lifestyle, now reaching epidemic proportions in the developing world. Addressing social and economic inequalities among disadvantaged groups, regulation of the food, drink, alcohol and tobacco industries, and learning from the lessons of the HIV and TB epidemics are all vital to tackling NCDs on a national and international level.

Further confounding factors in the diag-nosis and medical management of NCDs need to be considered in that sometimes profound differences in risk factors are evi-dent based on ethnicity and gender. Many guidelines developed by North American and European bodies are not necessar-ily appropriate for use in the developing world. South African publications in the international literature consider some of these concerns.

Urban black women at greater risk of chronic heart failure with a younger age of onsetChanging dietary habits and consequent nutritional deficiencies are having a significant impact on the health status of individuals living with chronic heart failure (CHF) in Soweto (see interview with Dr Pretorius, p 36). Interesting findings of Dr Pretorius’ study can be seen in the demographic profile of the Sowetan

population living with heart failure.1 Contrary to European findings, in an

urban cohort of black Africans, more women present with CHF than men. Furthermore, the mean age of onset for women is lower than for men in the Soweto study, as well as occurring at a younger age (5–10 years) than in European counterparts.

1. Pretorius S. The impact of dietary habits and nutritional deficiencies in urban African patients living with heart failure in Soweto, South Africa – A review. Endocrin Metab Immune Disord Drug Targets 2013: 13 (1). Jan 15 [Epub ahead of print].

Population-specific cut-off points proposed for diagnosis of the metabolic syndrome in South Africa Nigel Crowther and Shane Norris of the Witwatersrand University’s Departments of Chemical Pathology and Paediatrics ques-tion the appropriateness of the European guidelines used for the diagnosis of the metabolic syndrome in sub-Saharan African women. Their study measured the preva-lence of obesity and related metabolic disor-ders in an urban population of black women to determine the appropriate waist cut-off point for diagnosing metabolic syndrome.1

Of 1 251 African females from the Birth to Twenty cohort in Soweto, prevalence of obesity, T2D and the metabolic syndrome were 50.1, 14.3 and 42.1%, respectively. The appropriate waist cut-off point was found to be 91.5 cm (currently recommended levels are 80.0 cm) and was similar to the cut-off points obtained for detecting increased risk of insulin resistance (89.0 cm), dyscglycaemia (88.4 cm), hypertension (90.1 cm), hypo-high-density lipoproteinaemia (87.6 cm) and hyper-low-density lipoproteinaemia (90.5 cm). The similar waist cut-off points identified for the detection of the individual

components of the metabolic syndrome and related cardiovascular risk factors demonstrates that the risk for different metabolic diseases increases at the same level of abdominal adiposity, suggesting a common aetiological pathway.

Salome Kruger and colleagues from the Centre of Excellence for Nutrition at the North West University’s Potchefstroom campus propose a cut-off point of waist-to-height ratio (WHtR) of 0.41 for metabolic risk in African township adolescents.2 It has previously been proposed that a WHtR > 0.5 be the cut-off point for abdominal obesity in both genders and all ages. To date it is unknown if this cut-off point is appropriate for previously undernourished adolescents.

Assessment of the cut-off value of WHtR associated with increased metabolic risk was performed in 178 black South African adolescents aged between 14 and 18 years. The WHtR cut-off points ranged from 0.40 to 0.41, with best diagnostic value at 0.41.

A WHtR of 0.40 had 80% sensitivity and 38.5% specificity to classify fasting blood glucose > 5.6 mmol/l. A WHtR of 0.41 had 64% sensitivity and 58.5% specificity for a HOMA-IR > 3.4; 55% sensitivity and 55.6% specificity for a high-sensitivity C-reactive protein level > 1 mg/l; and a 64% sensitivity and 50.2% specificity for a blood pressure higher than the age-, gender-, and height-specific 90th percentiles.

1. Crowther NJ and Norris SA. The current waist circumference cut point used for the diagnosis of metabolic syndrome in sub-Saharan African women is not appropriate. PLOS ONE 2012; 7(11): e48883.

2. Kruger HS, Faber M, Schutte AE, Ellis SM. A proposed cutoff point of waist-to-height ratio for metabolic risk in African township adolescents. Nutrition 2013; 29(3): 502–507.

South African studies in the international literature: considerations of ethnicity and gender in chronic diseases of lifestyle

‘Various misperceptions need to be corrected. Not only is the notion widespread that obesity is not a problem, but the myth persists that it is actually desirable. For many recently urbanised people, gaining weight is a sign that they can now afford to eat better than before and that they are able to feed their children foods that they themselves were denied in childhood. In

addition, not being thin is often interpreted as evidence that an individual is not HIV positive. We have a lot of work ahead of us if we are to successfully address the increasing incidence in this population of diseases of lifestyle and the risk factors for them’, she concluded.

P Wagenaar

1. Pretorius S. The impact of dietary habits and nutritional deficiencies in urban African patients living with heart failure in Soweto, South Africa – A review. Endocrin Metab Immune Disord Drug Targets 2013; 13 (1). Jan 15 [Epub ahead of print].

2. Stewart S, Carrington MJ, Pretorius S, Ogah OS, Blauwet L, Antras-Ferry J, Sliwa K. Elevated risk factors but low burden of heart disease in urban African primary care patients: A fundamental role for primary prevention. Int J Cardiol 2012; 158(2): 205–210. doi:10.1016/j.ijcard.2011.01.022. Epub 2011 Feb 24.


SA JOURNAL OF DIABETES & VASCULAR DISEASE DIABETES NEWS

Ethnic variations in the role of adipose tissue on insulin resistance in womenCompared to their white counterparts, urban black women experience a disproportionately higher prevalence of type 2 diabetes (T2D), as well as higher levels of the major risk factors of obesity and insulin resistance. Numerous mechanisms have been postulated as to what underlies the increased risk of T2D. Julia Goedecke from the UCT/MRC Research Unit for Exercise Science and Sport Medicine, SAMRC and colleagues from the Department of Human Biology and Department of Medicine at UCT have published a review on the role of adipose tissue in insulin resistance in women of African ancestry.1

Centralisation of body fat, specifically increased visceral adipose tissue (VAT), is historically one of the major determinants of insulin resistance; whereas peripheral subcutaneous adipose tissue (VAT) has been shown to be ‘protective’ in predominantly white populations. However, numerous studies indicate that at the same level of body mass index (BMI) or waist circumference, black women are more insulin resistant than their white counterparts in spite of having less VAT and hepatic steatosis.

In white women, VAT is the most significant determinant of insulin sensitivity, whereas in black women this is more closely associated with abdominal SAT. Gluteal SAT is negatively correlated with insulin sensitivity in black but not white women. The larger SAT adipocyte size in black women is associated with a reduced adipogenic capacity and a higher expression of inflammatory genes

compared with their white counterparts. Questions raised include whether

adipose tissue hypertrophy in black women is associated with increased hypoxia and/or oxidative stress in SAT and consequently insulin resistance.

1. Goedecke JH, Levitt NS, Evans J, Ellman N, Hume DJ, Kotze L, et al. The role of adipose tissue in insulin resistance in women of African ancestry. J Obesity 2013, Article ID 952916. http://dx.doi.org/10.1155/2013/952916.

Geographic variation of hypertension in South AfricaA study arising out of the Division of Health Sciences, University of Warwick Medical School, Coventry, UK, examines the geographic variation of hypertension in South Africa.1 Analysis of the South African Demographic and Health Survey of 13 596 individuals older than 15 years mapped the geographic distribution of hypertension at the provincial level, accounting for individual risk factors.

Overall prevalence of hypertension (blood pressure ≥ 140/90 mmHg or self-reported diagnosis or on medication) was 30.4%. Higher prevalence of hypertension was sig-nificantly associated with current smoking, current drinking, self-reported sleep pro-blems and the presence of cardiovascular comorbidities such as T2D.

The North West, Free State and North-ern Cape provinces had the highest preva-lence of hypertension, with the lowest levels found in Limpopo. These geographic varia-tions suggest the potential role of socio-economic, nutritional and environmental

factors beyond individual-level risk factors in the development of hypertension.

1. Kandal NB, Tigbe W, Manda SO, Stranges S. Geographic variation of hypertension in sub-Saharan Africa: a case study of South Africa. Am J

Hypertens 2012; 26(3): 382–391.

NCD risk factors in a high HIV-prevalence rural settingAbraham Malaza of the Africa Centre for Health and Population Studies, University of KwaZulu-Natal, and colleagues examined adult hypertension and obesity in a high HIV-prevalence rural area.1 The prevalence of obesity in women was 6.5 times higher than in men, whereas prevalence of hypertension was 1.4 times higher than in men.

Obesity was a bigger risk factor for hypertension in men and overweight was a risk factor for men only. The BMI of men and women on antiretroviral treatment (ART) was lower than that of their HIV-negative counterparts.

The negative association of ART with BMI could be attributed to late presenta-tion and initiation of individuals on ART and the associated weight loss with advanced HIV disease progression. It is also possible that HIV-infected persons are more in con-tact with healthcare services, so they may be more susceptible to adopting nutrition-related advice.

1. Malaza A, Mossong J, Barnighausen T, Newell ML. Hypertension and Obesity in Adults Living in a High HIV Prevalence Rural Area in South Africa. PLOS

ONE 2012; 7(10): e47761.

G Hardy

SCHEDULING STATUS: S3 PROPRIETARY NAME AND DOSAGE FORM: LANTUS® solution for injection. COMPOSITION: Each ml of the solution for injection contains 3.64 mg of the active ingredient insulin glargine, corresponding to 100 U human insulin, 2.7mg of the preservative metacresol and 0.0626mg of zinc chloride as stabiliser. 10ml vial contains 0.02mg polysorbate 20 as additional stabiliser. REGISTRATION NUMBER: 34/21.1/0248. NAME AND BUSINESS ADDRESS OF THE APPLICANT: sanofi -aventis south africa (pty) ltd, 2 Bond Street, Midrand, 1685. Tel: 011 256 3700. Reg. No. 1996/10381/07.

61627 Lantus CVJ Africa.indd 1 2013/03/06 12:04 PM

SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS


Sanofi hosted their annual specialist diabetes meeting in Cape Town in

November 2012. Pieter Taljaard of Sanofi opened the meeting with a brief address, raising the concern that the number of diabetes patients in South Africa is increasing annually by 18 000. Sanofi are committed to treatment and innovation in the management of types 1 and 2 diabetes in both the public and private sectors.

It is increasingly accepted that the long-term outcomes of chronic illness are significantly improved when healthcare is managed with a team approach. The patient is integral to the team, with healthcare workers providing the support system that caters to the patient’s specific circumstances. Guidelines should serve to assist the clinician in tailoring a suitable response that considers the unique combination of circumstances any patient may have. Individualisation of patient care is paramount, not only in terms of pharmaceutical therapies but also in the allied field of psychosocial support, which encourages lifestyle alterations and therapeutic adherence.

Examining the players implicated in the pathogenesis of type 2 diabetes (T2DM), De Fronzo’s ‘ominous octet’ was often referred to during the Sanofi meeting.1 The implications of De Fronzo’s review for T2DM therapy are that treatment will require multiple combinations of agents to correct multiple pathophysiological defects, based on known pathogenic abnormalities in the individual rather than simple reduction in HbA1c levels. Treatment must also be started early in the natural history of T2DM if β-cell failure is to be prevented (Fig. 1).

1. De Fronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 589: 774–795.

Treating type 2 diabetes in 2012: choices based on factsProf Larry Distiller, endocrinologist, CDE, Houghton

Previous estimates and projections on the global prevalence of T2DM have had

to be revisited due to the obesity-driven exponential increase in diabetes. The latest figures indicate more than 880 million people will have diabetes by 2025, approximately one in every 10 people on the planet.

Meeting the challenges of diabetes treatment is confounded by many factors. South Africa currently represents the third most obese population in the world, with an increase in body mass index (BMI) of 5 to 8 kg/m2 over the last two decades. Healthcare workers are weighed down by the evidence, the treatment guidelines of various authorities rarely reach consensus, and protocols are becoming increasingly more complex in light of the multiple new therapeutic agents available for diabetes management.

Moreover, patient-centred care that is respectful of and responsive to the needs and values of the patient shows improved clinical outcomes. The doctor no longer dictates the therapeutic options but negotiates the route with the patient. When profiling the patient with diabetes, the doctor needs to ascertain the attitudes of the individual and what motivates him/her, the risks of hypoglycaemia

Figure 1

SANOFI diabetes specialist weekend 2012, Cape TownDrug trends

DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE


and other adverse events, the duration of diabetes and life expectancy, and the presence of microvascular disease, cardiovascular disease and other co-morbidities. Targets for HbA1c levels will differ accordingly.

Lifestyle intervention is effective; however the willpower required for lifestyle changes is often short lived. Because of this, many protocols recommend initiation of first-line therapy (usually metformin as monotherapy) on diagnosis of diabetes. This is based largely on the United Kingdom Prospective Diabetes Study (UKPDS) sub-group analysis of 342 obese patients reflecting an improved relative risk of myocardial infarction, all-cause mortality and diabetes-related deaths and end-points with earlier metformin initiation.

The side effects of metformin include gastrointestinal disturbances, vitamin B12 deficiency, and in rare cases (1:100 000) lactic acidosis. In the context of renal impairment, dose reduction or cessation of the drug is indicated.

Prof Distiller added that sulphonylureas (SU) have a small but significant benefit in terms of heart disease, although this risk–benefit in conjunction with insulin use remains uncertain. Although relatively cheap, SU have the disadvantage of increased hypoglycaemic events and weight gain. Use of glibenclamide is no longer recommended due to the risk of hypoglycaemia and the International Diabetes Federation (IDF) recommends slow-release gliclazide as the SU of choice. Prof Distiller recommended glimepiride as another reasonable alternative.

Acarbose has seen limited use in South Africa. Its cost versus its relatively weak blood glucose-lowering effect and unpleasant gastrointestinal side effects have not made it popular in this region. In terms of the thiazolidinediones, rosiglitazone has been withdrawn due to fears of increased risk of cardiovascular disease. Pioglitazone has been withdrawn from French and German markets and has a ‘black-box warning’ in the USA due to concerns surrounding increased risk of fractures and bladder cancer.

Incretin-based therapies are relatively recent additions to the treatment options available for T2DM. The dipeptidyl peptidase (DPP-4) inhibitors are all equivalent in reducing HbA1c levels (0.5–1%). They have the advantage of no hypoglycaemia, and possibly, preservation of β-cell function. The glucagon-like peptide-1 (GLP-1) agonists exhibit a 0.8 to 1.5% reduction in HbA1c level, promote weight loss and demonstrate a reduced risk of hypoglycaemia. GLP-1 agonists may also reduce cardiovascular

risk, and early outcome studies indicate preservation of β-cell function and possibly β-cell regeneration.

Within the GLP-1 class, liraglutide has slight advantages over exenatide, which requires twice-daily dosing, whereas liraglutide has the benefits of once-daily dosing and slightly greater reductions in HbA1c level and body weight. Prof Distiller did question whether the benefits of small weight loss (average of 3 kg) and a slightly reduced risk of hypoglycaemia were sufficient to justify the relative cost of the use of these agents.

Insulin therapy is a vital tool in the management of T2DM, especially with the inevitable decline in β-cell function seen with the condition. All other therapies targeting insulin deficiency rely on the presence of functioning β-cells. Weight gain associated with insulin use is mostly due to achieving better glycaemic control, resulting in decreased glycosuria, as well as increased fat storage. The earlier insulin is used, the less weight gain is evident, although insulin resistance remains an issue. It is for this reason that metformin therapy is maintained.

A dose of intermediate- or long-acting insulin at bedtime to provide basal supplementation of insulin is appropriate for early initiation in the patient with some β-cell function, and may be effective for months or years. As β-cell loss progresses, boluses of short- or rapid-acting insulin prior to meals will also be required (the so-called incremental basal-plus or full basal-bolus approaches). The patient should be prepared to expect insulin therapy as inevitable at some stage of the management of his/her diabetes.

Talking about bariatric surgery, Prof Distiller pointed out that this does not represent a cure for diabetes and is not free of complications. Bariatric surgery is most effective in recently diagnosed T2DM and can be considered in those where lifestyle interventions (nutrition and activity levels) have not been effective. There is, however, an 80% redevelopment of diabetes post-surgery.

In summary, Prof Distiller concluded that doctors should be using guidelines to facilitate decision making and that these recommendations should never replace clinical judgment. Lifestyle modification is highly effective and is the essential foundation for drug therapy. There is no best therapeutic algorithm, with each of the diabetes agents having their own merits. No

drug will work as well without appropriate behavioural modification.

Dyslipidaemia in diabetes = LDL-C lowering + X (?)Dr Dirk Blom, head of Lipidology, Groote Schuur Hospital Lipid Unit, Cape Heart Centre, UCT

Dr Blom began by emphasising that atherosclerosis appears to be an almost inevitable complication of long-standing T2DM. Atherosclerosis manifests clinically with cardiovascular events and it is therefore not surprising that 50 to 75% of deaths in those with T2DM are secondary to cardiovascular disease. Atherosclerosis in T2DM is often diffuse with a higher plaque burden, smaller arteries and inadequate compensatory heart remodelling. Very high rates of peripheral vascular disease are also observed in patients with diabetes. Dr Blom added that the younger the patient when diagnosed with diabetes, the greater the number of life years lost, predominantly due to vascular disease.

The pathogenesis of vascular disease is complex, with manifold interactions between factors such as dyslipidaemia, hypergly-caemia and insulin resistance, hypertension, inflammation, oxidation and smoking. Two major mechanisms in the pathogenesis of atherosclerosis are endothelial dysfunction or the response-to-injury reaction, and sub-endothelial retention and accumulation of lipids, leading to what is often called the response-to-retention reaction. Thinking of T2DM as a vascular disorder with increased glucose levels rather than as a pure disorder of glucose metabolism helps to focus attention on the fact that treatment of T2DM involves much more than just controlling glucose levels.

Dr Blom is of the opinion that targeting dyslipidaemia in T2DM is a highly effective and worthwhile intervention. Lipids should be considered the ‘low-hanging fruit’ in the management of T2DM, as it is often easier to control lipids well than, for instance, achieve tight glycaemic control.

In terms of low-density lipoprotein (LDL) cholesterol, lower is better (LDL-C < 1.8 mmol/l; apoB < 0.80 g/l). LDL and remnant lipoproteins are the two most atherogenic lipoproteins and are central to the pathogenesis of atherosclerosis. The CARDS study enrolled patients with T2DM with one added vascular risk factor who were free of



clinically overt cardiovascular disease. The results showed an unequivocal decrease in cardiovascular events with the administration of atorvastatin over placebo.

Dr Blom used these data and those from a meta-analysis of all major statin trials to substantiate an across-the-board statin strategy for T2DM, even in the absence of cardiovascular disease or increased LDL cholesterol levels. He further stated, ‘Statins reduce almost all cardiovascular outcomes except haemorrhagic stroke and are the number one workhorse in LDL cholesterol lowering.’ Other LDL cholesterol-lowering agents include ezetimibe, which combines well with statins.

Bile acid sequestrants are not frequently used in South Africa but are interesting agents to consider in those with T2DM, as they have been shown to not only reduced LDL cholesterol but can also improve glycaemic control. Unfortunately cholestyramine is poorly tolerated due to frequent gastrointestinal side effects. Colesevelam is better tolerated but is not available in South Africa. Colesevelam has more extensive data on glycaemic control than cholestyramine and reduces HbA1c levels by approximately 0.5%.

Aggressive management of LDL cholesterol unfortunately does not prevent all cardiovascular events. This residual risk is a major target of on-going research and therapeutic efforts. More aggressive management of dyslipidaemia may be one way to reduce residual risk. Dr Blom considered two potential management strategies. The first is to focus harder on LDL cholesterol lowering, as current interventions are often too little, too late. Earlier and more aggressive statin therapy could bring substantial benefits.

The second strategy is often referred to as comprehensive lipid management. This strategy targets other components of the atherogenic lipid phenotype, such as elevated triglycerides, low high-density (HDL) cholesterol and the presence of small, dense LDL particles.

Of the agents used in comprehensive lipid management, Dr Blom discussed fibrates and niacin, as well as some agents still in development. Data from trials of fibrate monotherapy indicate that fibrates reduce cardiovascular event rates in patients with atherogenic dyslipidaemia, but are not efficacious in high vascular-risk patient without atherogenic dyslipidaemia. Sub-group analysis of the ACCORD trial, which enrolled T2DM patients with particularly high vascular risk, indicated some benefit

from adding fenofibrate to simvastatin for patients with marked dyslipidaemia, defined as triglycerides > 2.30 mmol/l and HDL < 0.88 mmol/l.

The AIM-HIGH study, examining the efficacy of niacin in atherosclerotic dyslipidaemia, was abandoned as it was seen as futile, with no improved cardiovascular outcomes evident from adding niacin as a second agent to statins. Results from the larger HPSII-THRIVE trial are pending.

In summary, Dr Blom recommended early, aggressive statin therapy. In the case of severe hypertriglyceridaemia (> 10 mmol/l) a fibrate is often required to prevent pancreatitis. There is no benefit from adding fibrates to statins in patients with T2DM who do not have marked dyslipidaemia, as defined in the ACCORD study. Dr Blom also warned against therapeutic inertia, as several surveys show that many patients remain on their initial statin dose despite not reaching their LDL cholesterol targets.

Portions of portions: the diet debacleDr Wayne May, endocrinologist, Cape Town

From as early as the 17th century, individuals with type 1 diabetes (T1DM) have been placed on low-carbohydrate diets to better manage their health. Diet, despite being the oldest tool in the health arsenal, remains a controversial issue and the debate around low-carbohydrate diets is currently of particular interest in South Africa, with much discussion being generated in the practice of medicine and in the social media.

Low-carbohydrate diets can be stratified according to daily carbohydrate intake. A ketogenic diet is defined as carbohydrate intake of less than 50 g daily, whereas a non-ketogenic diet may be defined as low in carbohydrates (50–130 g daily) or moderate (130–225 g daily).

Low-fat diets became popularised in the 1950s with the hypothesis that fat is the cause of heart disease, after associations were made between dietary fat and heart disease mortality. By 1986, a blood cholesterol level above 200 mg/dl was treated as a disease. Despite being a molecule that is essential throughout the body, many epidemiological studies have indicated that as levels of cholesterol and saturated fat increase, the risk of coronary death over 10 years also increases.

Migrational studies of Japanese immigrants to the USA have shown increased risk of

heart disease accompanying the change to a Western diet, however no consistent evidence exists. Some dietary-intervention studies have indicated that interventional lowering of cholesterol and saturated fats in the diet is associated with a decreased risk of heart disease. In terms of the patient with diabetes, UKPDS data rates cholesterol as the strongest predictor for heart disease. The CARD study indicates that statin therapy alone can reduce the risk of heart disease in the patient with diabetes.

Dr May went on to compare benefits of low-carbohydrate and low-fat diets for the patient with diabetes. Obesity reviews indicate that in terms of weight loss, low-carbohydrate diets show better results in the short term (at six months), but within a year, weight loss will be equivalent in both low-carbohydrate and low-fat diets. Low-carbohydrate diets have the advantage of raising HDL cholesterol levels; however, at both six and 12 months, low-fat diets had the advantage in terms of LDL cholesterol levels.

Trials on the dietary prevention of diabetes have indicated that a diet low in fat and saturated fats, and high in fibre (Mediterranean diet) will delay the progression to diabetes. Why this is the case remains in the realm of speculation, although weight loss could be the predominant driving factor. Similarly, pharmaceutical agents that decrease fat intake show a delay in progression to diabetes, with associated cardiovascular benefits.

A study by Shai and colleagues1 comparing low-carbohydrate, low-fat, and Mediterranean diets indicated that the Mediterranean diet was best for fasting sugar levels. At 24 months, weight loss was superior in the low-carbohydrate and Mediterranean dietary arms.

However, adherence to a low-carbohydrate diet over the long term is difficult, with a six-year follow up indicating equivalency to low-fat diets in terms of weight loss. Low-carbohydrate diets were also found to exhibit a short-term benefit in HbA1c levels, although this was lost over time, with equivalent levels with low-fat diets at 12 months. No diet has currently shown any benefit in terms of macro- and microvascular reduction or promoting a longer life.

Few data exist for low-carbohydrate diets in T1DM. Existing studies show improved HbA1c levels, reduction in hypoglycaemic episodes and a lowering of insulin-replacement requirements. Improved HbA1c level has also been noted in low-carbohydrate diets in the young; however, there are no data on



the effects of such a diet on growth and induction of puberty.

The American Diabetes Association currently recommends that macronutrient dietary portions be individualised to the patient’s circumstances and are to be formulated by a registered dietician. Locally, SEMDSA recommends a diet consisting of < 35% fat, 45 to 60% carbohydrate and 15 to 20% protein; and for weight loss, a low-fat, low-carbohydrate or Mediterranean diet.

1. Shai et al. N Engl J Med 2008; 359: 229≠241.

Diabetes in the elderlyDr Stan Landau, physician, CDE, Houghton

Developing countries are bearing the lion’s share of new-onset T2DM in the elderly. The elderly, along with the rest of the population, are progressively tending towards obesity. In South Africa, 8% of the population is represented by people over the age of 60 years, and of the population aged 65 years and older, one in five individuals has T2DM.

Dr Landau referred to De Fronzo’s ominous octet of pathogenic mechanisms in T2DM and questioned which of these were

of primary consideration in the elderly. As an example, incretin effects alter with ageing. The elderly with T2DM have greater levels of GLP-1 secretion that are poorly functional, and the activity of DPP-4 is exceptionally reduced. DPP-4 inhibition may therefore be inappropriate in this setting.

With increased insulin resistance and decreased insulin secretion, renal glucose thresholds are elevated, resulting in insidious and vague symptoms that are further com-pounded by the presence of co-morbidities. Data from the United Kingdom indicates that of the elderly population with T2DM, 16% are blind or have visual impairment and 25% have foot ulceration. Dr Landau advised that annual T2DM screening for people over 70 years of age is invaluable, particularly in those who are asymptomatic.

Dr Landau continued with a number of considerations in the treatment of T2DM in the elderly. He raised the point that blood pressure measurements in the elderly are more accurate when the patient is standing. Patients should be assessed for impaired cognitive function and also according to the Geriatric Depression scale. The elderly patient should be screened for osteoporosis, have a vascular risk assess-ment and be examined for sarcopaenia. The

frail, sick patient requires less aggressive T2DM therapeutic intervention as long-term cardio-vascular outcomes are not a priority.

Thiazolidinediones are to be avoided because of the threat of bone fractures and falls; and glibenclamide is also inappropriate for use in the elderly. Metformin is safe and there are a number of insulin options. Hypoglycaemic events are common with insulin use and this is often due to erratic nutrition/feeding patterns. Of the DPP-4 inhibitors, vildagliptin is most appropriate in those older than 70 years, although these patients are more likely to encounter side effects and severe adverse events. Data on GLP-1 liraglutide indicate dose efficacy in patients older than 65 years, and no contra-indications exist at this time.

When educating the elderly patient with diabetes, age-related factors such as poor eyesight and hearing, cognitive impairment, depression, limited mobility and access to healthcare services, and self-administration and monitoring of therapy in arthritic patients, need to be considered. It is important to set appropriate, individualised targets.

Glenda Hardy



Table 1. Antihyperglycaemic agents used in type 2 diabetes: sulphonylureas.

Class Drug (brand name)Effect on HbA1c level Therapeutic considerations Disadvantages

Insulin secretagogues

Sulphonylureas Glibenclamide (Daonil®, Euglucon®, generic) Gliclazide (Diamicron®, Diamicron MR 60 mg, generic) Glimepiride (Amaryl®, generic) Glipizide (Minidiab®)

Generally well tolerated. Proven reduction in microvascular endpoints (UKPDS and ADVANCE studies); reduction in cardio-vascular events and mortality in the long term (UKPDS post-trial monitoring). Relatively rapid glucose-lowering response; useful in the patient with symptomatic hyperglycaemia. Consider using other classes of antihyperglycaemic agents in patients at high risk of hypoglycaemia (e.g. the elderly, with renal and hepatic failure). If a sulphonylurea must be used in such individuals, gliclazide modified release is associated with the lowest inci-dence of hypoglycaemia. Glimepiride and glipizide are associated with less hypogly-caemia than glibenclamide.

Hypoglycaemia relatively common, but variable. Can cause severe hypoglycae-mia, including episodes necessitating hospital admission and causing death (particularly glibenclamide, and particu-larly when renal function is impaired). Causes weight gain (2–5 kg); worst with glibenclamide. May blunt myocardial ischaemic preconditioning (particularly glibenclamide). Renal impairment: glib-enclamide contraindicated if eGFR < 60 ml/min/1.73 m2; glimepiride and glipiz-ide dose may need to be reduced

Second-generation sulphonylureas: gliclazide modified release (60 mg) reviewed in clinical practice for type 2 diabetes

The modern use of sulphonylureas (SU) in the management of type 2 diabetes

focuses on second-generation agents with a lower risk of hypoglycaemia and weight gain than older agents. This is particularly important as the recently available oral incretin mimetics offer modest HbA1c level reduction with minimal or no hypoglycaemic events and are either weight neutral or may result in weight loss.

The comprehensive 2012 South African Guidelines for the Management of Type 2 Diabetes,1 compiled with the involvement of clinicians, academic endocrinologists and funders such as the Council of Medi-cal Schemes and the Department of Health, were published recently and stress lifestyle modification, education and multi-discipli-nary care. These guidelines advocate the use of sulphonylureas at steps 1, 2 and 3 in combination with other oral antidiabetic agents and insulin. At step 1, metformin is the preferred therapy, with sulphonylureas, DPP-4 inhibitors and acabose as alternative therapies for special circumstances.

In their clinical review, the experts compiling the South African Guidelines summarised the role of the insulin secre-tagogues and the therapeutic considera-tions for their use on the basis of evidence from long-term use in the UKPDS and the ADVANCE trials (Table 1).

Review of gliclazide MRIn terms of the three above-mentioned dis-

Fig. 1. Micro- and macrovascular events in the ADVANCE study.

advantages of sulphonylureas: hypoglycae-mia, weight gain and use in renally impaired patients, the evidence for gliclazide MR places it outside these general limitations.

Hypoglycaemia and gliclazide MRThe ADVANCE study used gliclazide modi-fied release with metformin as the basis of oral therapy for the intensive arm of this important large study in type 2 diabetes patients. At the end of the study, 90% of patients were on Diamicron MR 60 mg, with 70% receiving a daily dosage of 120 mg (2 tablets); 40% of patients were also on insulin to intensify their treatment and

reach the targeted HbA1c level of less than 7%, and preferably below 6.5%.2

The ADVANCE study achieved a 12% reduction in cardiovascular death in the intensive arm, showing a trend to benefit. This is reassuring as there is no increase in cardiovascular risk. The microvascular outcomes were significant, with major benefits for the kidney (Fig. 1).

In the intensive arm of ADVANCE, hypoglycaemia was much lower than in the intensive arms of either the ACCORD or the VADT trials. In the 5 571 patients treated in the intensive arm for a mean period of 4.9 years, only 150 hypoglycaemic events



occurred. This was despite the fact that more than 80% of patients reached an HbA1c level of less than 7%.

This lower rate of hypoglycaemia on a gliclazide-based therapy may partially be due to the fact that in experimental animal studies, the newer sulphonylureas’ stimulatory action on insulin release is related to glucose levels, with a lowered stimulatory effect occurring on beta-cells of the pancreas when glucose levels drop.3

Weight gain and gliclazide MR useIn the ADVANCE trial there was no weight gain seen in the patients with gliclazide MR 60 mg on intensive therapy, a very important and relevant clinical observation (Fig. 2).

Renally impaired patients and gliclazideIn the ADVANCE trial, gliclazide MR 60 mg– based therapy showed an overall renal-protective effect and in the intensively treated arm there was a 65% reduction in

Fig. 2. Weight gain at the end of the follow-up peroid.

end-stage renal disease.4 Currently, there is no need to do renal function testing when putting patients on gliclazide MR 60 mg therapy.

With regard to patient compliance, the availability of the Diamicron MR 60 mg dose, which will halve the number of tablets taken, will undoubtedly find favour with patients and enhance overall compliance and the clinical benefits that come along with this.

References1. The SEMDSA Guidelines 2012.2. Patel A, MacMahon S et al.; the ADVANCE

collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560–2572.

3. Gregorio F, Ambrosi F, Cristallini S, et al. Therapeutic concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic α- and β-cell function. Diabetes Res Clin Pract 1992; 18(3): 197–206.

4. Perkovic V, et al. Kidney international advance online publication. 9 Jan 2013. Doi: 10.1038/ki.2012.401.

Weight training lowers risk of type 2 diabetes

Risk reduction of type 2 diabetes with exercise

Exercise type Risk reduction in type 2 diabetes

> 150 min/week weight training 34% (95% CI: 7–54%)

> 150 min/week aerobic training 52% (95% CI: 45–58%)

> 150 min/week combined training 59% (95% CI: 39–73%)

SAJDVD recommended actionFor patients unwilling or unable to perform aerobic exercise, weight training may be valuable in reducing the risk of developing type 2 diabetes. Adding weight training to aerobic exercise appears to give further protection and should be encouraged in all at-risk patients. Reference1. Grøntved A, Rimm E, Willett W, et al. A prospective study of weight training

and risk of type 2 diabetes mellitus in men. Arch Intern Med Published online August 6, 2012. doi:10.1001/archinternmed.2012.3138.

Men involved in weight training for more than 150 minutes a week have a 34% lower risk of type 2 diabetes than

those doing no exercise. Although regular physical exercise is the cornerstone of diabetes prevention and management, the role of weight training has not been previously studied in detail.

The on-going prospective Health Professionals Follow-up study evaluates the risk of developing diabetes in 32 000 healthcare professionals aged 40–75 years.1 For each 60 minutes of weight training per week, the risk decreased by 13% (95% CI, 6–19%, p < 0.001).

The study also confirmed that men doing aerobic exercise for more than 150 minutes a week had a 52% lower risk of type 2 diabetes than those doing no exercise. However, the combination

of the two forms of exercise was associated with an even greater benefit, with a 59% reduction in type 2 diabetes risk in those engaged in both aerobic exercise and weight training for more than 150 minutes per week.


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For full prescribing information, refer to package insert approved by medicines regulatory authority. DIAMICRON® MR 60 mg Tablets. Gliclazide 60 mg. Reg. No. 43/21.2/0957. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: SERVIER LABORATORIES SOUTH AFRICA (Pty) Ltd. Reg. No. 72/14307/07. Building Number 4, Country Club Estate, 21 Woodlands Drive, Woodmead 2191. PO Box 930, Rivonia 2128, Republic of South Africa. Tel: +27 (0) 861 700 900. Fax: +27(0)11 525 3401. References: 1. The ADVANCE Collaborative Group. N Engl J Med. 2008; 358: 2560-2572 2. SEMDSA Guidelines 2012 3. Al Sifri S et al. Int J Clin Pract. 2011;11 :1132-1140 8. 4. Aravind SR et al. Curr Med Res Opin. 2012;28:1-8. 5.Perkovic V et al. Kidney Int. 2013 Jan 9. Epub ahead of print.

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