SAJDVD Volume 9, Issue 2

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Volume 9 Number 2June 2012

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

Reducing non-communicable diseases

Peri-operative management of patients with diabetes

Cardiovascular risk factors in hyperglycaemia

Exercise in type 1 diabetes

Combination therapy in hypertension

Analogue insulins

Diabetes management in 2012

Vitamin D: a magic bullet?

Exercise and peripheral arterial disease

Insulin usage in hospital

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Dyna Gliclazide SR 30 mg. Each modified release tablet contains 30 mg gliclazide. Reg. No.: S3 42/21.2/0249. For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority. 1. Crepaldi G and Fioretto P. Gliclazide modified release: Its place in the therapeutic armamentarium. Metabolism. 2000;49(10) supplement 2:21-25.2. McGavin JK, Perry CM and Goa KL. Gliclazide modified release. Drugs. 2002;62(9):1357-1364.3. Data on file.4. Department of Health website http://www.doh.gov.za – Accessed on 01/04/2012.5. http://en.wikipedia.org/wiki/hummingbird.

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THE SOUTH AFRICAN JOURNAL OF

Diabetes & vascular Disease

Corresponding EditorDr L LombarDNetcare, Kuilsrivier Hospital, Cape Town

Consulting EditorsProF J-C mbaNYaProF aJ brINKDr F maHomED

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, Johan-nesburg

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 9 NUMBER 2 • JUNE 2012www.diabetesjournal.co.za

CONTENTS Editorial

51 First global target to reduce non-communicable diseases by 25% by 2025L Lombard

Review

52 Peri-operative management of patients with diabetesG Hough

Research Articles

55 Cardiovascular morbidity: a comparative study on diabetes mellitus and hypertensionB Okeahialam, B Alonge, F Puepet, S Pam, M Balogun

61 Antibodies against oxidised LDL, and cardiovasular risk factors in individuals with hyperglycaemiaT Matsha, T Tjaronda, G Hon, A Esterhuyse, M Hassan, R Erasmsus

Reports

66 Does exercise improve or impair blood glucose control in type 1 diabetes?A Heilbrunn

70 Optimal combination therapy in hypertensionP Wagenaar

72 Achieving improved glucose control and quality of life with analogue insulins: A1chieve study in everyday clinical practiceJ Aalbers

75 Diabetes Expert Forum: Perspectives on diabetes management in 2012L Lombard

Assistant Editor: Special AssignmentsJULIa aaLbErSTEL: (021) 976-4378FAX: 086 610 3395e-mail: [email protected]

Development Editor: GLENDa HarDYCELL: 071 819 6425FAX: 086 610 3395e-mail: [email protected]

Production EditorSHaUNa GErmISHUIZENTEL: (021) 785-7178FAX: 086 628 1197e-mail: [email protected]

Editorial Assistant and CirculationELSabÉ bUrmEISTErTEL/FAX: (021) 976-8129e-mail: [email protected]

Production Co-ordinatorWENDY WEGENErTEL: (021) 976-4378e-mail: [email protected]

Content ManagermICHaEL mEaDoN (Design Connection)TEL: (021) 975-3785FAX: 0866 557 149e-mail: [email protected]

The South African Journal of Diabetes and Vascular Disease is published four times a year for Clinics Cardive Publishing (Pty) Ltd and printed by Tandym Print. 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/FAX: (021) 976-8129INT: 2721 976-8129

Full text articles available on:

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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.

Reports

77 47th SEMDSA congress 2012G Hardy

78 Vitamin D and human health: a magic bullet? G Hardy

81 Novo Nordisk incretin leadership summit, Cape TownP Wagenaar, G Hardy, J Aalbers

Patient Leaflet

87 Exercise after anticoagulation of deep-vein thrombosisS Nel

88 Exercise and peripheral arterial diseaseS Nel

Diabetes Educator’s Focus

89 Screening for peripheral arterial disease in people with diabetes

G van Rensburg

Hands On

92 Practical guidance on insulin usage in the hospital setting

A Kok

Drug Trends

98 Liraglutide launched in South AfricaJ Aalbers

100 Saxagliptin (Onglyza) launched in South AfricaJ Aalbers

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SA JOURNAL OF DIABETES & VASCULAR DISEASE EDITORIAL

VOLUME 9 NUMBER 2 • JUNE 2012 51

and reflect on the opportunity to improve outcomes for hospitalised hyperglycaemic patients.

Improved peri-operative care of diabetic patients could have very significant benefits for reaching these new WHA targets. A recent South African registry1 of outcomes in patients with myocardial infarction, admitted to South African hospitals, has shown that 23.9% of admitted patents were diabetic and the presence of diabetes was a major predictor of death in the first year.

Two research studies are published in this issue. A well-conducted Nigerian study compares the cardiovascular morbidity and mortality of African normotensive type 2 diabetes patients and hypertensive non-diabetic patients. The diabetic patients had more burden of cardiovascular risk factors than the non-diabetic hypertensives. Interestingly, the prevalence of microalbuminuria was similar in the normotensive diabetics to that of the hypertensive non-diabetics. Cardiovascular disease was found to account for most morbidity and mortality in the diabetic patients. Therefore diabetics should have regular and specialised cardiovascular care to minimise disabilities.

In the other research article, from the Cape Peninsula University of Technology and the University of Stellenbosch, the relationship between oxidised low-density lipoprotein (oxLDL) and the generation of auto-antibodies against oxLDL was investigated. The authors found that decreased levels of anti-oxLDL antibodies were associated with increased cardiovascular risk scores. The results partially support the role of these antibodies as an indirect assessment of oxidative stress.

In our Diabetes Educator’s Focus, Gerda van Rensburg, podiatrist, CDE, Houghton, notes that the presence of peripheral arterial disease (PAD) is an independent risk factor for increased mortality due to associated cardiovascular disease. Patients with PAD have the same relative risk for death from cardiovascular events as patients with a history of coronary and cerebrovascular disease. Early detection of PAD will enable early risk intervention and improve outcomes. Read this practical advice on screening for PAD.

South Africa has a lively conference and symposium programme. We report on a meeting in Marseilles, France, the incretin leadership summit held in South Africa with experts from Africa, India and the Middle East, and the 47th SEMDSA congress highlights.

We thank our contributors and the reviewers of research articles.

ReferenceShamroth C, ACCESS South Africa investigators. Management of acute coronary 1. syndrome in South Africa: insights from the ACCESS (Acute Coronary Events – a Multinational Survey of Current Management Strategies) registry. Advance publication Cardiovasc J Afr, 13 March 2012. DOI: 10.5830/CVJA-2012-017

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

S Afr J Diabetes Vasc Dis 2012; 9: 51.

Global targets for reducing death (and disability) from non-communicable diseases have been set for the first time by the 65th World Health Assembly (WHA), of which South

Africa is a prominent participatory member. This declaration will demand better care and treatment for patients with diabetes, heart disease, cancer and chronic respiratory disease, and prevention of the development of these conditions by advocating healthier lifestyle choices.

For the medical community in South Africa, this will pose significant challenges, particularly with regard to improving outcomes for diabetic patients. Fortunately there are new therapeutic agents available in South Africa to improve glucose control and overall health outcomes in diabetes. Recently announced SEMDSA guidelines for type 2 diabetes management are also a first as they represent truly national guidelines with the involvement of all stake holders, including Government, healthcare funders and the diabetes care team.

In this issue of the journal, we hope to promote better diabetes care. We present two expert reviews on peri-operative care of diabetic patients. The first is by Dr Gregory Hough, Port Elizabeth, which calls for a change in attitude to the level of care required to bring diabetic patients safely through surgery. Dr Hough reviews the subject and discusses general treatment principles and the use of hypoglycaemic agents in peri-operative care. He points to the vital roles of the endocrinologist and the diabetic patients themselves. He notes that ‘patients should be encouraged to participate in the management of their diabetes during this period’.

In a hands-on approach, Dr Adri Kok, specialist physician, Johannesburg, provides practical advice for specific in-hospital settings, such as non-critically ill patients experiencing hypoglycaemia, planning surgery on the diabetic patent, and care of the diabetic patient in the intensive care unit. While these two articles do have overlapping principles, they nonetheless complement one another

First global target to reduce non-communicable diseases by 25% by 2025LANDI LOMBARD

REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE

52 VOLUME 9 NUMBER 2 • JUNE 2012

Correspondence to: Dr Gregory Hough Specialist physician/endocrinologist/diabetologistGreenacres Hospital, Greenacres, Port ElizabethTel: +27 0(41) 363-5249Fax: 086 648 9407e-mail: [email protected]

S Afr J Diabetes Vasc Dis 2012; 9: 52–54

T his is an important but often neglected topic that is frequently poorly managed. Too often peri-operative care is left in the hands of nursing staff in the ward, following the anaesthetist’s

peri- and postoperative instructions. These instructions usually take the form of a crude generic sliding scale adapted to fit comfortably into the usual six-hourly patient monitoring that occurs in most wards. This form of care is wrong in every possible way and should be actively discouraged by everyone involved in patient care, from the nursing staff to the surgeon and anaesthetist, and even the attending physician, if involved.

‘Why bother with good glycaemic control; surely a few days of erratic or high sugar levels cannot do any real harm?’ This seems to be the pervasive attitude that has crept into much of routine medical care in the peri-operative period. A similar attitude prevailed, until a few years ago, with regard to the care needed to prevent venous thrombo-embolism in the peri-operative period. Through education and new guidelines, our attitudes and practices to prevent venous thrombo-embolism have changed dramatically. A similar change is now needed with regard to what is considered to be routine practice in the care of diabetes in the peri-operative period.

There is a large body of observational evidence linking in-hospital hyperglycaemia to poorer outcomes. There is also a growing body of evidence in the form of cohort studies and even some early randomised, controlled trials showing that intensive treatment of hyperglycaemia in hospital improves outcomes.1,2,3

The most famous study analysing tight glycaemic control in the peri-operative period was a single-centre study which reported a 42% reduction in ICU mortality.2 Recent multi-centre studies in both medical and surgical patients have failed to demonstrate the same benefits; in fact the outcomes in the intensive groups were slightly worse.4 However closer examination of the largest of these trials reveals that the difference between intensive and standard care was very small; blood sugar levels of 6.4 versus 8%. These trials do not suggest that intensive target glucose control is not important or causes harm but rather that the target chosen for tight control may have been a little too ambitiously low, with the resultant frequent hypoglycaemia contributing to the increase in adverse outcomes.

A recent meta-analysis of 26 trials5 assessed care of hospitalised diabetic patients, with intensive glucose control (glucose target 4.5–6 mmol/l) versus conventional control (glucose target 7.8–10 mmol/l). The relative risk (RR) of death was 0.93, favouring conventional control. About 50% of the trial participants reported hypoglycaemia, with a pooled RR of 6 for hypoglycaemia in the intensive-control group.

Peri-operative management of patients with diabetesGREGORY HOUGH

This suggests that the reason for the negative outcome of the trials of intensive treatment in hospitalised diabetics may be due to the inevitable increase in hypoglycaemia. This trend has also been seen in outpatient-care trials of intensive versus standard care in diabetics. The ADVANCE, ACCORD and VADT trials of intensive versus standard care in diabetics with a high risk of cardiovascular disease all showed an increase in mortality in the intensive-control groups. Subsequent meta-analyses have shown that in these groups, this incidence of hypoglycaemia was significantly higher than in the standard-care groups, suggesting this was the possible cause for the negative outcomes.

It may be reasonable therefore to say that hypoglycaemia should be avoided in these patients at the expense of tight glycaemic control. It seems that high-risk patients in both in- and out-patient settings are more vulnerable to the severe adverse outcomes of hypoglycaemia.

Interestingly, both the meta-analysis mentioned above,5 and randomised, controlled trials2,6,7 show that critically ill surgical patients may actually benefit from tighter glycaemic control, whereas critically ill medical patients do not. This may be a reflection of the pre-hospital health of surgical and medical patients where, by their very nature, surgical patients are likely to have had better pre-admission health status and therefore be better able to tolerate the inevitable hypoglycaemia associated with tight glycaemic control.

How do we incorporate this information into guidelines for peri-operative care of diabetics? See Tables 1 and 2 for definitions of hyper- and hypoglycaemia.

Where hyperglycaemia is discovered incidentally on routine testing of patients who have not previously been diagnosed with dysglycaemia or diabetes, these patients should be monitored and managed as if they were diabetic for the duration of the admission. Upon discharge, a formal plan for follow up of the impaired glucose metabolism should be made to assess if this was just a transient problem or one which will need further treatment and follow up.

Table 2. Hypoglycaemia.

Blood glucose (mmol/l)

Hypoglycaemia < 3.9

Mild to moderate hypoglycaemia 2.2–3.9

Severe hypoglycaemia < 2.2

Note: these are laboratory values. Finger-prick values should guide treatment but if there is doubt, confirm with a formal laboratory test.

Table 1. Hyperglycaemia.

Hyperglycaemia Diagnostic of diabetes

Fasting glucose level > 5.9 mmol/l > 7 mmol/l

Random glucose level > 7.8 mmol/l > 11.1 mmol/l

HbA1c level > 6% > 6.5%

Note: these are laboratory values. Finger-prick values should prompt a formal laboratory test.

SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW


Basal–bolus insulin regimenDiscontinue oral anti-diabetic drugs on admission • Calculate the starting total daily dose (TDD): •

– 0.4 U/kg/d for admission blood glucose between 7.8 and 11.1 mmol/l

– 0.5 U/kg/d × blood glucose between 11.2 and 22.2 mmol/l Half of TDD as insulin glargine (Lantus• ®) and half as rapid-acting analogueInsulin glargine once daily, at the same time of day • Rapid-acting insulin analogue three equally divided doses with meals• Supplemental insulin: •

– Give supplemental insulin (rapid-acting analogue) following the ‘sliding-scale’ protocol below for blood glucose 7.8 mmol/l.

– If a patient is able and expected to eat all, give supplemental insulin (rapid-acting analogue) before each meal and at bedtime following the ‘usual’ column.

– If a patient is not able to eat, give supplemental insulin (rapid-acting analogue) every six hours (6–12–6–12) following the ‘insulin sensitive’ column.

Table 3. An appropriate peri-operative insulin regime.9

Blood glucose (mmol/l)

Insulin sensitive (units)

Usual (units)

Insulin resistant (units)

> 7.8–10 2 4 6

10.1–12.2 4 6 8

12.3–14.4 6 8 10

14.5–16.7 8 10 12

16.8–19.4 10 12 14

19.5–22.2 12 14 16

> 22.2 14 16 18

Insulin adjustment: • – If the fasting or mean blood glucose during the day is 7.8 mmol/l

in the absence of hypoglycaemia, increase insulin glargine dose by 20% every day.

– If a patient develops hypoglycaemia (3.9 mmol/l), decrease glargine daily dose by 20%.

Blood glucose monitoring: • – Measure blood glucose level before each meal and at bedtime (or

every six hours if a patient is nil per os.

As hypoglycaemia has been linked to increased mortality in hospitalised patients, especially high-risk patients, mild to moderate hypoglycaemia should be identified and treated promptly to avoid progression to a more severe episode, with possible severe consequences.

General treatment principlesDiabetic patients admitted to hospital should be clearly identified as such and this identification should trigger a pre-specified set of standardised protocols. The identification of patients as diabetics should be clear to all members of the care group, from food, kitchen and dietetics staff to the ward and theatre nursing staff, and even to the surgeons and anaesthetists involved in the surgical procedure itself.

Protocols should be available to all staff and should be as clear and simple as possible. They should also be able to cater for all types of diabetics from the brittle type 1 patient to the type 2 patient normally controlled on diet alone.

Critically ill patientsEvidence, expert opinion and guidelines by most national and international endocrine and diabetes associations recommend the

use of insulin infusions in these patients, particularly in the intensive care unit (ICU) setting. Glucose targets should be 7.8–10 mmol/l in most patients, however less vulnerable and surgical patients may benefit from a slightly lower range of 6.1–10 mmol. The use of an intravenous infusion requires frequent glucose monitoring, not less than every two hours and preferably hourly, with adjustments made to the infusion rate depending on the glucose levels and trends.

Non-critically ill patientsAs randomised, controlled trials are lacking, guidelines in this group are based on clinical experience and judgement. Glucose targets in most patients controlled with insulin would be 7.8–10 mmol/l, providing these can be achieved with a low risk of hypoglycaemia. When glucose values frequently fall below 5.6 mmol/l, consideration should be given to modifying the treatment to avoid hypoglycaemia. When glucose values fall below 3.9 mmol/l, treatment must be modified to avoid more serious hypoglycaemic episodes.

In patients using insulin who have been stable prior to admission, in a tighter glycaemic range, lower limits may be acceptable in hospital and peri-operatively. Conversely, patients who are critically ill or in patient-care settings where frequent monitoring is not possible or feasible, less tight control may be acceptable.

Clinical judgement must be used when considering an acceptable range for patients where medications, nutritional status and severity of illness may influence what may be considered an acceptable glycaemic range.

Hypoglycaemic agents in peri-operative careInsulinThis is the treatment of choice in hospitalised patients and in the peri-operative management of diabetics (Table 3).8 Insulin should be given via insulin infusions in critically ill patients and in ICU care. Non-critically ill patients should be managed with subcutaneous insulin.

The method through which subcutaneous insulin is delivered is very important. A sliding-scale insulin regime (SSI) to control hyperglycaemia in hospitalised and peri-operative patients should never be used for more than a few hours. Prolonged use of sliding-scale insulin should be avoided for the following reasons:

It is ineffective in the majority of patients.• It increases the risk of both hyperglycaemia and hypoglycaemia.• A recent randomised trial in general surgical patients with type • 2 diabetes has shown that its use is associated with adverse outcomes.9

It is potentially extremely dangerous in type 1 diabetes patients.• 8

A safe and effective subcutaneous insulin regime should deliver basal insulin that should be given, even in the fasting patient, to maintain normal glucose metabolism and avoid ketogenesis. Timed prandial doses should be given with meals. Allowance should be made for corrective doses to be given both with meals and at other times, should there be a need for this. A number of recently published protocols guiding insulin use in a variety of circumstances can be adapted for particular circumstances and patients.

Other hypoglycaemic agentsThere are no safety data on the use of these agents in hospitalised and peri-operative care of patients. For this reason, as a general rule, these agents should be avoided and discontinued in the peri-operative period. Exceptions may be considered for patients who

REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE


are not particularly ill and are likely to be eating normally. These agents can be restarted prior to discharge once it is clear that the patient is recovering and will be ready for discharge soon.

Metformin: this should be discontinued in anticipation of • contra-indications to its use, which may be likely to arise in the peri-operative period. These include renal failure, unstable haemodynamics and the need for an imaging study, which will require contrast.Sulphonylureas: there are no safety data and the risk of prolonged • hypoglycaemia in unstable patients who may not be eating is significant. It should be discontinued and only re-initiated once it is clear that the patient is stable, eating normally and is nearly ready for discharge.Thiazolidinediones are no longer considered to be safe • hypoglycaemic agents, even in the outpatient setting and should be discontinued in the peri-operative period. Upon discharge, an alternative agent should be considered.DDP4 inhibitors: there are no safety data and they should be • discontinued. Particular care should be taken with vildagliptin with renal impairment. It should only be restarted once the patient is stable, eating normally, is almost ready for discharge and renal function has been determined to be normal.GLP1 analogues: there are no safety data and these should be • discontinued until the patient is stable, eating normally and nearing discharge.

Healthcare specialist’s roles in the peri-operative periodDiabetes management may be under the care of the patient’s general practitioner, a physician, an endocrinologist, the surgeon or the anaesthetist, depending on the circumstances and levels of experience. However, the use of appropriately trained specialists such as endocrinologists has been shown to reduce the length of stay, improve glycaemic control and improve outcomes.3 Where available, their involvement should be sought for management of all diabetics in the hospital setting and especially the peri-operative period.

The patient’s role in the peri-operative periodPatients who are fully conscious, well educated in diabetes care and have stable pre-operative glucose profiles should be encouraged to participate in the management of their diabetes in this period. Involvement may range from self monitoring of blood glucose and carbohydrate consumption to assuming full responsibility for their insulin treatment under the guidance of the healthcare team.

Planning dischargeThis is not as simple as just sending the patient home and telling him/her to restart the usual medication. There are some very important points which need to be considered and guidelines to be adhered to:

Care must be taken to be sure that the diabetic has stable • glycaemic control on treatment that can be continued safely at home.If the patient is newly diagnosed or there has been significant • change to the pre-admission treatment, care must be taken to ensure the patient understands the changes. This may not be appropriate for the surgeon to do and an endocrinologist consultation may be required.If required, consider:•

– dietician consultation to educate and plan the post-operative diet if significant changes are required.

– diabetic educator if newly diagnosed or significant changes to medication or complications of diabetes have been detected.

A discharge summary should be sent to the healthcare • professional usually responsible for the patient’s diabetes care.A follow-up appointment should be made with the healthcare • professional responsible for the diabetes care, to ensure glycaemic control remains stable and to ensure compliance and adherence to treatment, especially if significant changes have been made.

ConclusionThere are a number of important factors to be considered and guidelines that need to be in place to ensure optimal care of patients in the peri-operative period. This will result in optimal outcomes. Most important is identification of the patient as a diabetic, and then planning treatment of the diabetes in the peri-operative period.

Other than in exceptional circumstances, most anti-diabetic agents, except insulin, should be discontinued. For patients not on insulin already, an appropriate regime should be planned. The use of sliding-scale insulin regimes should never be used for longer than a few hours and ideally all patients should be started on an appropriate basal–bolus regime with allowance made for corrective doses if needed.

Glycaemic control should not be too tight in the majority of patients, with a range of 6.1–10 mmol/l considered most appropriate for most patients. Hypoglycaemia should be avoided as it appears that this is linked to increased mortality. Appropriately trained specialists such as endocrinologists should be involved whenever possible. Appropriate education and understanding should be ensured and careful follow up and monitoring arranged prior to discharge.

ReferencesClement S, Braithwaite SS, Magee MF, 1. et al. American Diabetes Association: Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004; 27: 553–591.Van den Berghe G, Wouters P, Weekers F, 2. et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: 1359–1367.Malmberg K, Norhammar A, Wedel H, Rydén L. Glycometabolic state at 3. admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAM) study. Circulation 1999; 99: 2626–2632.Finfer S, Chittock DR, Su SY, 4. et al. NICE-SUGAR study investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360: 1283–1297.Griesdale DE, de Sousa RJ, van Dam RM, 5. et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. Can Med Aassoc J 2009; 180: 821–827.Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in 6. critically ill adults: a meta-analysis. J Am Med Assoc 2008; 300: 933–944.Brunkhorst FM, Engel C, Bloos F, 7. et al. German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125–139.Moghissi ES, Korytkowski MT, DiNardo M, 8. et al. American Association of Clinical Endocrinologists: American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 2009; 32: 1119–1131.Umpierrez GE, Smiley D, Jacobs S, 9. et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Diabetes Care 2011; 34: 256–261.


SA JOURNAL OF DIABETES & VASCULAR DISEASE RESEARCH ARTICLE

Correspondence to: Basil OkeahialamUniversity of Jos, Jos, Nigeriae-mail: [email protected]

Benjamin AlongeNNPC Hospital, Kaduna, Nigeria

Fabian PuepetDepartment of Medicine, Jos University Teaching Hospital, Jos, Nigeria

Stephen PamDepartment of Radiology, Jos University Teaching Hospital, Jos, Nigeria

Michael BalogunDepartment of Medicine, Obafemi Awolowo University Teaching Hospital, Ile, Nigeria


AbstractBackground: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity and mortality. Although most diabetics die from cardiovascular causes, clinicians tend to pay more attention to blood sugar levels in their follow-up care. Since hypertension has been firmly established as a major risk factor for cardiovascular disease, we sought to compare cardiovascular risk factors in normotensive type 2 diabetes patients and hypertensive non-diabetics. This was to determine the level of cardiovascular morbidity in the diabetic patients, so as to make a case for control of other cardiovascular disease risk factors during follow up. No such study has been done so far in our immediate environment.Methods: There were three groups of age- and gender-matched subjects: 70 normotensive diabetics, 70 hypertensive non-diabetics and 71 normotensive non-diabetic controls. Each participant had a detailed clinical examination as well as assessment of levels of fasting plasma glucose and two hours postprandial glucose, as well as plasma lipid, uric acid and creatinine levels. Microalbuminuria was detected using freshly voided urine. All subjects underwent electrocardiography for left ventricular hypertrophy. Whereas 45 of the controls had echocardiography, all the hypertensive and diabetic patients underwent echocardiography. Risk factors such as alcohol abuse, cigarette smoking and physical inactivity were also documented.Results: The clinical characteristics resulting from significant alcohol consumption, cigarette smoking and physical inactivity were significantly higher in the diabetics than in the hypertensive subjects and normal individuals. The waist-to-hip ratio of the diabetics was significantly greater than that of the hypertensives. Dyslipidaemia and high low-density lipoprotein (LDL) cholesterol levels were more prevalent in the diabetics. Hyperuricaemia was more prevalent in the hypertensives, as was left ventricular

Cardiovascular morbidity: a comparative study on diabetes mellitus and hypertensionBASIL OKEAHIALAM, BENJAMIN ALONGE, FABIAN PUEPET, STEPHEN PAM, MICHAEL BALOGUN

hypertrophy (LVH), diagnosed electrocardiographically and echocardiographically. The prevalence of microalbuminuria was similar in the diabetic and hypertensive patients.Conclusion: The normotensive type 2 diabetes patients were burdened in most cases with cardiovascular risk factors surpassing those of the hypertensive non-diabetic subjects. Of particular note was diabetic dyslipidaemia, especially hypo-high-density lipoprotein (HDL) cholesterolaemia, hyper-LDL cholesterolaemia and hypertriglyceridaemia. The hypertensives, however, were significantly more burdened with LVH and hyperuricaemia. These results support the opinion that cardiovascular disease accounts for most morbidity and mortality in diabetics. Therefore, all diabetics should have regular and specialised cardiovascular care to minimise disabilities.

Keywords: cardiovascular risk factors, hypertension, dyslipidaemia, hyperuricaemia, left ventricular hypertrophy, microalbuminuria, type 2 diabetes mellitus

Submitted 3/10/2011, accepted 23/2/2012

Diabetes mellitus (DM) is a metabolic disorder of multiple aetiology, characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism, resulting from defects in insulin secretion, insulin action or both.1 Type 2 DM may range from primarily insulin resistance with relative insulin deficiency, to a predominantly secretory defect with or without insulin resistance.2 In Nigeria, the national prevalence of diabetes is estimated at 2.2%.3

According to data from the United Kingdom Prospective Diabetes study (UKPDS), cardiovascular disease (CVD) accounts for 80% of mortality in diabetic patients.4 Clinical and epidemiological studies in Africa have clearly demonstrated that diabetic persons are at increased risk for cardiovascular morbidity and mortality.5 Diabetic patients are likely to have established cardiovascular disease by the time their diabetes is diagnosed.6 Of the threat to health and life that besets the person with diabetes, CVD and peripheral vascular disease represent the heaviest burden.

In all societies, diabetes increases cardiovascular risk two-fold or more compared with the local non-diabetic population.7 In Africa, three out of four diabetic patients die from cardiovascular complications.8 Type 2 DM may be considered a vascular disease diagnosed by elevated blood, glucose levels.9 Atherosclerotic disease, and macrovascular disease and its complications account for more than half of the deaths in patients with type 2 DM.10 Patients with type 2 DM usually have many genetically interlinked risk factors for coronary atherosclerosis, such as hypertension, dyslipidaema, android obesity, hyperinsulinaemia with insulin resistance and haemorrheological abnormalities at the time of diagnosis of diabetes.6

Hypertension has been firmly established as a major risk factor for cardiovascular disease11 and is responsible for more deaths than any other risk factor for CVD.12 When combined with diabetes,


RESEARCH ARTICLE SA JOURNAL OF DIABETES & VASCULAR DISEASE

especially with the metabolic syndrome with hyperinsulinaemia and insulin resistance in the background, the CVD risk increases.13 This usually involves macro- and microvascular complications.14

Most individuals who will develop cardiovascular disease at some time in their lifetime are likely to first present to a health worker with elevated blood pressure. In most of the epidemiological surveys on CVD, hypertension is usually the commonest risk factor present.15 Since diabetics die largely from cardiovascular causes, they would therefore be burdened with many CVD risk factors. This study was designed to determine the rate of CVD risk factors present in normotensive diabetics compared with that of hypertensive non-diabetics, since hypertension is the major risk factor for CVD. The aim was to present a case for a paradigm shift in the management of type 2 diabetes patients.

MethodsThe study was conducted on 70 normotensive, type 2 DM patients, 70 hypertensive, non-diabetic patients and 71 non-diabetic, normotensive (normal) patients attending the out-patient diabetes clinic, cardiology clinic and general out-patient department of the Jos University Teaching Hospital between November 2005 and May 2006. The WHO consultation on the diagnosis and classification of DM criteria was used for diagnosis and classification of type 2 diabetes.16 Systemic hypertension was diagnosed based on the WHO/ISH writing group statement.17

A history was taken, with current age, age at diagnosis, gender, duration of disease and family history of DM or hypertension and drug history documented. Lifestyle assessment of alcohol consumption, quantity of cigarettes smoked and physical activity was also carried out. Significant alcohol consumption (SAC) was defined as three or more bottles of beer or three calabashes of local brew per day, cigarette smoking as any smoking in the past month, and physical inactivity (PI) as restricted to office work, house bound or unemployed, as prescribed by Levitt et al.18

Height and weight were recorded to the nearest cm and kg, respectively, as recommended by Dowse and Zimmet,19 and the body mass index (BMI) in kg/m2 was calculated. Waist and hip girths were measured (with a dressmaker’s tape) to the nearest cm, as detailed in the NIH guidelines,20 and the waist-to-hip ratio (WHR) was determined.

Fasting blood samples (10 ml) were drawn by venepuncture from each subject into fluoride oxalate tubes and sent to the chemical pathology laboratory of the hospital within two hours of collection. Plasma glucose was estimated by the glucose oxidase method, total and high-density lipoprotein (HDL) cholesterol using the enzymatic endpoint method, serum uric acid with the phosphotungstic acid method, and serum creatinine by Jaffe’s method. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedwald formula.21

LDL cholesterol (mmol/l) = HDL cholesterol – triglycerides 2.2

A dyslipidaemic subject was one with: TC > 5.2 mmol/l; LDL-C > 2.6 mmol/l; HDL-C < 0.9 mmol/l (male), < 1.1 mmol/l (female); TG > 1.7 mmol/l; TC/HDL-C > 4.1 mmol/l. (TC = total cholesterol, LDL-C = low-density lipoprotein cholesterol, HDL-C = high-density lipoprotein cholesterol and TG = triglycerides.)

Microalbuminuria was only assayed when clinical-grade proteinuria was absent, using the micral test method. Subjects who tested positive for nitrite on the urine dipstick test were excluded from the micral test.

Electrocardiography was carried out on all patients using an AT two-plus, six-channel ECG machine (Schiller Switzerland) at 25 mm/s paper speed. A diagnosis of left ventricular hypertrophy (LVH) was based on Araoye’s criteria.22

An echocardiographic LVH diagnosis was derived from inter-ventricular septal thickness or left venticular posterior wall thickness > 12 mm in diastole using the Penn cube convention. This was confirmed by left ventricular mass (LVM), corrected for height.23 A SONOS 1500 ultrasound system (Hewlett Packard USA) with a 3.5-mHz transducer was used.

Statistical analysisThe results were analysed using the EPI INFO 2000 (version 1.1.2a) statistical software. Mean (± SD) was used to describe continuous variables and proportions for categorical data. The Student’s t-test was used to assess the significance between the means of two groups. The one-way analysis of variance was used to ascertain the significance between means of more than two groups. The Chi-square (χ2) test was used to determine the significance of the observed differences when comparing groups of subjects. Probability values < 0.05 were considered significant.

Results The mean ages (± SD) of the diabetics, hypertensives and controls were 51.2 (10.63), 49.8 (12.03) and 49.7 (11.02) years, respectively, F = 0.37, p = 0.69. The diabetics included 34 (48.6%) males and 36 (51.4%) females. The hypertensives consisted of 33 (47.1%) males and 37 (52.9%) females, while the normal controls were made up of 35 (49.3%) males and 36 (50.7%) females (p = 0.97, χ2 = 0.07).

The BMI and WC of the hypertensives were significantly greater than that of the other groups (p < 0.01, p < 0.01), whereas the WHR of the diabetics was significantly higher than that of the other groups (p < 0.01). All blood pressure indices were significantly higher in the hypertensive subjects (p < 0.01), whereas the heart rate (supine and standing) was significantly higher in the diabetics (p < 0.01, p < 0.05, respectively). See Table 1 for anthropometric and clinical characteristics of the study subjects.

Table 1. Anthropometric measurements and clinical characteristics of the study population.

ParametersDiabetics(n = 70)

Hypertensives(n = 70)

Control(n = 71)

BMI (kg/m2) 27.15 ± 4.35 29.16 ± 6.07* 24.16 ± 4.34

WC (cm) 93.51 ± 11.64 95.27 ± 14.10* 85.20 ± 10.25

HC (cm) 99.03 ± 9.60 103.9 ± 14.30* 94.92 ± 14.70

WHR 0.94 ± 0.06* 0.92 ± 0.08 0.89 ± 0.05

SBP (st) (mmHg) 123.6 ± 11.07 153.3 ± 19.99* 119.0 ± 12.19

SBP (sup) (mmHg) 129.11 ± 7.81 161.37 ± 20.00* 123.89 ± 9.72

DBP (st) (mmHg) 83.03 ± 5.00 102.97 ± 14.08* 82.38 ± 6.13

DBP (sup) mmHg 80.77 ± 5.28 100.20 ± 13.26* 76.56 ± 10.98

PP (mmHg) 48.3 ± 6.13 61.2 ± 14.34* 47.3 ± 13.28

HR (st) (beats/min) 90.03 ± 12.47* 85.31 ± 13.77 83.49 ± 13.11

HR (sup) (beats/min)

80.46 ± 10.77* 80.20 ± 13.71 71.52 ± 12.06

BMI, body mass index; WC, waist circumference; HC, hip circumference; WHR, waist–hip ratio; SBP (st), systolic blood pressure standing; SBP (sup), systolic blood pressure supine; DBP (st), diastolic blood pressure standing; DBP (sup), diastolic blood pressure supine; PP, pulse pressure; HR (st), heart rate standing; HR (sup), heart rate supine. Mean ± SD. *statistically significant difference.



All measures of dyslipidaemia were higher in the diabetics than in the hypertensive and normal control subjects, with the exception of HDL cholesterol, which was lowest in the diabetics compared with the other groups, and the total cholesterol, which was highest in the hypertensives. Uric acid levels were significantly higher in the hypertensives than in the diabetics and controls (p < 0.01). See Table 2 for biochemical parameters of the study population.

With the exception of the atherogenic index (AI) and LVH on ECG, all the cardiovascular risk factors were statistically more prevalent in the diabetics than in the normal controls. See Table 3 for the prevalence of CVD risk factors of the diabetic subjects and normal controls.

All the cardiovascular risk factors were statistically more prevalent

in the hypertensives than in the normal controls. See Table 4 for the prevalence of CVD risk factors of the hypertensive subjects and normal controls.

Significant alcohol consumption, cigarette smoking, physical activity, high LDL levels and dyslipidaemia were statistically more prevalent in the diabetic patients (p < 0.001). The prevalence of low HDL and high TG levels, and high WHR was higher in the diabetics, although it was not statistically significant. High atherogenic index, hyperuricaemia, LVH, and high BMI and WC were statistically more prevalent in the hypertensives (p < 0.05, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively). The diabetics and hypertensives showed no statistical difference in the prevalence of high total cholesterol and microalbuminuria levels (p = 1.00, p = 1.00, respectively) (Table 5).

Discussion The prevalence of significant alcohol consumption (8.6%) was significantly higher in the normotensive diabetics than in the hypertensive subjects and normal controls (p = 0.01, p < 0.001, respectively). This was lower than the prevalence of 17.24% reported by Omotoso et al.24 in their cohort. Alcohol consumption in any population is usually dependent on its availability and socio-cultural factors. Excessive alcohol consumption has been associated with diabetes in adult Africans.25

The prevalence of cigarette smoking (7.1%) was also significantly higher in the diabetic group (p < 0.001), as there were no cigarette smokers in the hypertensive and control groups. This prevalence agrees with the report by Omotoso et al.,24 but contrasts with a higher prevalence reported from Asian26 and Western population studies.7,27 Cigarette smoking is an independent and modifiable risk factor for type 2 diabetes.28

Table 2. Biochemical parameters of the study population.

ParametersDiabetics (n = 70)

Hypertensives(n = 70)

Control(n = 71)

TC (mmol/l) 5.09 ± 1.59 5.24 ± 1.05* 4.44 ± 1.02

HDL-C (mmol/l) 1.71 ± 0.78 2.15 ± 1.05 1.93 ± 0.82

LDL-C (mmol/l) 2.66 ± 1.48* 2.37 ± 1.63 2.01 ± 1.13

TG (mmol/l) 1.59 ± 0.87* 1.58 ± 1.12 1.10 ± 0.42

AI 3.52 ± 2.03 3.37 ± 2.72 3.10 ± 3.03

UA (umol/l) 256.63 ± 113.75 314.39 ± 110.43* 310.01 ± 81.77

Cr (umol/l) 96.26 ± 35.11 92.60 ± 30.61 98.07 ± 24.66

FPG (mmol/l) 7.93 ± 4.74* 3.94 ± 0.70 3.94 ± 0.80

2 HPP (mmol/l) 12.44 ± 5.60* 6.09 ± 1.73 5.51 ± 1.22

TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; TG, triglyceride; AI, atherogenic index (TC/HDLC); UA, uric acid; FPG, fasting plasma glucose; 2HPP, two hours postpran-dial glucose; Cr, creatinine. Mean ± SD. *Statistically significant difference.

Table 3. Prevalence of CVD risk factors of the diabetics and normal controls.

Index (CVD risk factors)

Diabeticsn (%)

Control n (%)

Odds ratio χ2

SAC 6 (8.6)* 0 (0) Undefined 89.86#

Cigarette smoking 5 (7.1)* 0 (0) Undefined 71.45#

PI 39 (55.7)* 23 (32.4) 1.62 110.14

BMI (kg/m2) 46 (65.7)* 27 (38.6) 3.05 147.15

WC (cm) 30 (42.9)* 15 (21.1) 2.818 109.20

WHR 51 (72.9)* 33 (46.5) 3.09 144.84

ECG LVH 4 (5.7) 3 (4.30) 1.35 1.78#

Echo LVH 10 (14.3)* 6 (8.5) 1.8 16.65

TC (mmol/l) 39 (55.7)* 21 (29.6) 2.99 139.25

HDL-C (mmol/l) 15 (21.9)* 7 (9.9) 2.48 50.09

LDL-C (mmol/l) 33 (47.0)* 22 (31.0) 1.97 53.80

TG (mmol/l) 26 (37.1)* 5 (7.0) 7.84 263.56

AI 13 (18.6) 11 (15.5) 1.25 3.40

Dyslipidaemia 58 (82.9)* 34 (47.9) 5.27 270.70

Microalbuminuria 19 (27.2)* 9 (12.7) 2.57 65.83

Hyperuricaemia (µmol/l) 6 (8.60)* 14 (19.7) 2.61 50.7

AI, atherogenic index (TC/HDL); SAC, significant alcohol consumption; BMI, body mass index; WC, waist circumference; WHR, waist-hip ratio; ECG LVH, electrocardiographically diagnosed LVH; Echo LVH, echocardiographi-cally diagnosed LVH; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; PI, physical inactivity. #Yates correction for continuity *Statistically significant difference.

Table 4. Prevalence of CVD risk factors in hypertensives and normal controls.


Hyperten-sives n (%)

Controln (%)

Odds ratio χ2

SAC 4 (5.70)* 0 (0) Undefined 56.63#

Cigarette smoking 0 (0) 0 (0) - -

PI 34 (48.6)* 23 (32.4) 1.97 54.45

BMI (kg/m2) 54 (74.3)* 27 (38.6) 4.60 259.21

WC (cm) 40 (57.1)* 15 (21.1) 4.98 272.13

WHR 49 (70)* 33 (46.5) 2.68 113.54

ECG LVH 48 (68.6)* 3 (4.3) 48.62 889.67#

Echo LVH 52 (74.3)* 6 (8.5) 31.92 892.33

TC (mmol/l) 39 (55.7)* 21 (29.6) 2.99 139.25

HDL-C (mmol/l) 13 (18.6)* 7 (9.9) 2.08 30.97

LDL-C (mmol/l) 28 (40.0)* 22 (31.0) 1.48 17.68

TG (mmol/l) 25 (35.7)* 5 (7.0) 7.38 245.27

Dyslipidaemia 52 (74.3)* 34 (47.9) 3.14 146.60

AI 16 (22.9)* 11 (15.5) 1.62 17.65

Microalbuminuria 19 (27.2)* 9 (12.7) 2.57 65.83

Hyperuricaemia (µmol/l) 19 (27.1)* 14 (19.7) 1.52 15.28

AI, atherogenic index (TC/HDL); SAC, significant alcohol consumption; BMI, body mass index; WC, waist circumference; WHR, waist hip ratio; ECGLVH, electrocardiographically doagnosed LVH; Echo LVH, echocardiographically diagnosed LVH; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; PI, physical inactivity.#Yates correction for continuity, *Statistically significant difference.



In the case of physical inactivity, the prevalence (55.7%) was significantly higher in the diabetics than in the hypertensives and controls (p < 0.001, p < 0.001). This agrees with other reports in the literature.7,29 Many investigations,30 including the Framingham Heart study,31,7 demonstrated that physical inactivity caused an increased risk for coronary heart disease.

In Africa, a higher prevalence of diabetes mellitus than of hypertension was reported among urban, sedentary office workers than in active, rural farmers.32 These lifestyle issues apply to hypertension as well. The explanation for the lower prevalence of hypertension in that study may derive from the fact that whereas clinicians actively recommend lifestyle modifications for hypertension in our environment, normotensive diabetics are counselled on diet only as a non-pharmacological aspect of their treatment.

In our study, BMI, WC and WHR were the indices of obesity. The diabetics and hypertensives were significantly more obese than the normal controls (BMI: p < 0.001, WC: p < 0.001, WHR: p < 0.001). Puepet et al.33 also found that BMI and WHR were significantly higher in the diabetics than the controls. Using BMI and WC, the hypertensives in our study were significantly more obese than the diabetics. However, more diabetics had higher WHR than the hypertensives.

Obesity is a major risk factor for CVD and this risk is said to be accentuated when obesity has a predominantly abdominal component.34 Obesity as a CVD risk factor in both the diabetics and hypertensives had insulin resistance as a common denominator. Using WHR, which is thought to be the most widely used measure of central adiposity,35 a prevalence of 72.9% was recorded for obesity in this study. This is in line with the study by Fadupin et al.36 in Ibadan, but somewhat higher than that in other reports both

locally37,38 and in Western populations,7,27 which used BMI as an index of obesity. However, using BMI, the prevalence of obesity in our study agreed with that of other reports.

In the Hoorn study, it was observed that WHR and not BMI was an independent predictor of the incidence of diabetes in 50- to 75-year-old individuals.39 It also correlated better than BMI with incidence of hypertension, and there was an inclination to use measures of central obesity and adiposity rather than BMI in determining risk.40

The prevalence of dyslipidaemia (LDL > 2.6 mmol/l, TC > 5.2 mmol/l, TG > 1.7 mmol/l, TC/HDL > 4.1 mmol/l, HDL < 0.9 mmol/l for males and < 1.1 mmol/l for females) was significantly higher in the diabetics (82.7%) than in the hypertensives and controls (p < 0.001, p < 0.001). This was higher than the reported prevalence in the Western population,7,24 perhaps because lower lipid values were used in our study (LDL-C > 2.6 mmol/l).

The observations in this study of significant elevation of total cholesterol, LDL cholesterol and triglyceride levels is supported by the work of Isezuo et al.,41 who also reported significantly greater dyslipidaemia in the diabetic and hypertensive patients than in the controls. The point of difference however was that HDL cholesterol levels were similar in all groups studied in their work. In our study HDL cholesterol levels were lowest in the diabetics, which is typically expected in diabetic dyslipidaemia:10,42 high LDL-C, high TC and low HDL-C levels.

Oxidation of lipoproteins is enhanced in the presence of hyperglycaemia and hypertriglyceridaemia.43 The latter is elevated in diabetes as a result of reduced lipoprotein lipase activity.44 The low HDL-C levels reported here are to be expected. Lipoproteins are glycated more readily in hyperglycaemic states. When HDL is glycated, its clearance is increased and serum levels become low.45

The observations in our study agreed with those of Puepet et al.,33 who observed significantly higher (p < 0.05) TC, LDL-C and TG levels in the diabetics than in the controls. However, the HDL-C levels were similar in all groups, including the hypertensives who also had higher TC, LDL-C and TG levels than the diabetics, although not significantly so. The low HDL-C levels observed in the diabetics in our study were supported by the work of Agboola-Abu et al.37 who, interestingly, recorded an improvement in low HDL-C levels with treatment.

The TC levels of the diabetics and hypertensives were significantly higher than those of the controls (p < 0.001). The prevalence of elevated TC levels was the same in the diabetics and hypertensives (p = 1.00). Studies such as Aduba et al.38 from Nigeria and Smellie et al.46 also reported high TC levels in diabetics. The findings of Adedeji and Onitiri47 were that TC levels in hypertensives did not differ significantly from those of normal controls.

Obeka48 argued that the liberal consumption of alcohol and intake of a highly thermogenic lipid diet may have been the reasons for the higher TC levels in the hypertensive subjects in Jos than reported elsewhere in the country. 49,50 Hypertension and diabetes are both associated with hyperinsulinaemia, in which there is disordered lipid metabolism.

The higher TC, LDL-C and TG levels observed in some reports with a hypertensive diabetic subgroup may have been related to worsening hyperinsulinaemic states that these two conditions combined confer on an individual. It was reported that individuals who will develop type 2 diabetes mellitus may have higher triglyceride and lower HDL cholesterol levels than individuals who will not develop type 2 diabetes,10 which is one fact our study revealed.

Table 5. Prevalence of CVD risk factors of diabetics and hypertensive patients.


Diabeticsn (%)

Hyperten-sives n (%)

Odds ratio χ2

SAC 6 (8.60)* 4 (5.70) 1.56 6.33#

Cigarette smoking 5 (7.10)* 0 (0.00) Undefined 71.55#

PI 39 (55.7)* 34 (48.6) 1.33 10.10

BMI > 25 kg/m2 46 (65.7) 52 (74.3)* 1.51 17.61

WC (cm) 30 (42.9) 40 (57.1)* 1.77 40.33

WHR 51 (72.9) 49 (70.0) 1.15 2.06

ECG LVH 4 (5.70) 48 (68.6)* 36.14 844.55#

Echo LVH 10 (14.3) 52 (74.3)* 17.33 729.28

TC (mmol/l) 39 (55.7) 39 (55.7) 1.00 0.00

HDL- C (mmol/l) 15 (21.4) 13 (18.6) 1.19 4.45

LDL-C (mmol/l) 33 (47.0)* 28 (40.0) 1.33 9.97

TG (mmol/l) 26 (37.1) 25 (35.7) 1.06 0.42

AI 13 (18.6) 16 (22.9)* 0.07 5.62

Dyslipidaemia 58 (82.9)* 52 (74.3) 1.68 21.9

Microalbuminuria 19 (27.2) 19 (27.2) 1.00 0.00

Hyperuricaemia (µmol/l) 6 (8.60) 19 (27.1)* 3.95 116.70

AI, atherogenic index ( TC/HDL); SAC, significant alcohol consumption; BMI, body mass index; WC, waist circumference; WHR, waist hip ratio; ECG LVH, electrocardiographically diagnosed LVH; Echo LVH, echocardiographically diagnosed LVH; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-den-sity lipoprotein cholesterol; TG, triglycerides; PI, physical inactivity. #Yates correction for continuity, *Statistically significant difference.



Hyperuricaemia was significantly more prevalent in the hypertensives than in the diabetics and the controls (p < 0.001, p < 0.001). Interestingly, the prevalence of hyperuricaemia was significantly higher in the control group than in the diabetics (p < 0.001). The higher prevalence of hyperuricaemia observed in the hypertensives (27.1%) may have been due to drugs such as thiazide diuretics, which are taken for the control of blood pressure, and these drugs increase serum uric acid as a metabolic consequence.

The prevalence of hyperuricaemia was 8.6% in the diabetics and 19.7% in the controls. It is believed that once diabetes develops, serum uric acid levels fall. This action is a function of glycosuria stimulating renal urate excretion. Therefore, serum concentrations of uric acid are elevated in insulin resistance but not necessarily in diabetes.51

Interestingly, in studies of type 2 diabetes, persistent hyper-uricaemia correlated with poor metabolic control, hyperfiltration and decreased risk of progression of renal disease.52 Hyperuricaemia is therefore thought to be more important in the development of insulin resistance than in the maintenance of the pre-diabetic state.

The prevalence of microalbuminuria was 27.2% in our study, having removed subjects with overt proteinuria. This observation is in line with that reported by Alebiosu et al.,53 who reported a prevalence of 25.3%, but contrasts with findings of other Nigerian investigators. Adedapo et al. in Ibadan54 reported a prevalence of 60% among diabetic patients and 30% among the controls. The contribution of background renal insult was highlighted as the probable reason for the high prevalence of microalbuminuria. Tranche et al.,27 working in a Western population, reported a prevalence of 34.7%.

Microalbuminuria has been related to insulin resistance and can occur prior to the onset of diabetes.55 The higher prevalence of microalbuminuria in these other reports may possibly be due to differences in age, duration of disease, the influence of blood pressure, which was removed in our study, and the prevalence of obesity in the study population. The prevalence of 27.2% recorded in our study was significantly higher than in the controls (p < 0.001) and the same as that observed for the hypertensives (p = 1.00)

The prevalence of echo-diagnosed LVH was significantly higher in the diabetics (14.3%) than in the controls (p < 0.001). This was higher than the prevalence of 4.76% reported by Tranche et al.27 in their cohort. The higher prevalence recorded in our study may be related to the known fact that blacks have an increased tendency to develop LVH.56 However it is unclear whether this is due to genetic or environmental factors. The observation of LVH in the normotensive diabetics and even in the controls was not surprising since it is known that LVH may precede hypertension.57.

It is not surprising that a prevalence of echo-diagnosed LVH of 74.3% was observed in the hypertensive group in our study, since LVH occurs as an early response to hypertension.58 LVH has been demonstrated among diabetic African patients and up to 50% of asymptomatic patients may present with these abnormalities.59,60. This was in contrast to the prevalence of 14.3% recorded in the normotensive diabetics in our study. There is a paucity of data on echo-diagnosed LVH among normotensive diabetics. However, Osuntokun et al.61 found that 11% of 556 diabetic Nigerian patients had an abnormal ECG, mainly LVH and strain pattern, associated with hypertension.

Electrocardiographic (ECG) diagnosis of LVH depends on the criteria used and there is a paucity of data on ECG-diagnosed LVH

in normotensive diabetics in both African and Western populations. Araoye et al.62 reported a prevalence of 70.5% using Sokolow-Lyon criteria in a study of 288 hypertensive Nigerians. ECG-diagnosed LVH was observed in 68.6% of the hypertensives and 5.7% of the diabetics. Huston et al.63 reported ECG-diagnosed LVH of 3–29%, based on different criteria, in a population of civil servants in Benin, Nigeria. The prevalence of ECG-diagnosed LVH was significantly higher (11–49%) among those with hypertension, which was 19% of the population.

There was no significant difference in mean serum creatinine levels between all three groups (Table 2). However, in the study of Puepet et al.,33 the mean serum creatinine level of the diabetics studied was significantly higher than that of the controls (p = 0.03). An interesting observation in this study was that mean serum creatinine level of the normal group was higher than that of the diabetics and hypertensives but not significantly so (p = 0.55). The reason for this could not readily be found but may have been a reflection of renal dysfunction in the population. In one study, individuals with normal blood pressure were found to have chronic kidney disease, albeit lower than those with atherosclerotic disease states.64

It has been shown that there is a strong correlation between serum creatinine levels and cardiovascular event rates. The hazards ratio for a patient with a serum creatinine level of 1.4 to 2.0 mg/dl was 40% higher than that of the normal controls, for the patient with microalbuminuria, 59% higher, and for the patient with both increased serum creatinine levels and microalbuminuria, 108% higher.65 The high cardiovascular risk conferred by minor renal dysfunction could perhaps be explained by the known endothelial cell dysfunction in incipient renal disease. However, creatinine is a notoriously insensitive reflection of glomerular filtration as it is strikingly influenced by muscle mass and other confounding factors.

ConclusionThis study found that apart from markers of left ventricular hypertrophy and hyperuricaemia, the diabetic patients equaled the hypertensive subjects with regard to cardiovascular disease morbidity. Interestingly, they were worse off with regard to significant alcohol use, cigarette smoking and physical inactivity. This calls for a paradigm shift in the management of diabetic patients. Lifestyle modification must be stressed for diabetics as much as for hypertensive patients. The diabetic patients’ prescribed diet would need to be adjusted since their lipid profiles were worse than the hypertensives, and regular cardiovascular evaluation should form part of their monitoring.

ReferencesReport of a WHO consultation. Definition, diagnosis and classification of diabetes 1. mellitus: World Health Organization publication 1999, Geneva, Switzerland. WHO/ NCD/NCS/99.2. Colman PG, Zimmet PZ, Welborn TA. New classification and criteria for diagnosis 2. of diabetes mellitus. Med J Afr 1999; 170: 375–378.The national expert committee on non-communicable diseases in Nigeria. Final 3. report of a national survey 1997; series 4: 64–96.American Diabetes Association (ADA) 59th scientific sessions, San Diego, 4. California, 1999.Adesanya CO. Diabetes and the heart.5. E Afr Med J 1977; 54: 417–420.Morrish NJ, Stevens LK, Head J, 6. et al. A prospective study of morbidity among middle-aged diabetic patients (the London cohort of the WHO multinational study of vascular disease in diabetes) 1: causes and death rates. Diabetologia 1990; 33: 538–540. Keen H, Clark C, Laakso M. Diabetes metabolism research and review. 7. Diabetes Metab Res Rev 1999; 15: 186–196.



Longo-Mbenza B. Diabetes mellitus and cardiovascular disease.8. Trop Cardiol 1995; 21: 44–46. Yki Jarvinen H. Management of type 2 diabetes and cardiovascular risk: lessons 9. from intervention trials. Drugs 2000; 60: 975–983.Treatment options for type 2 diabetes.10. Am Fam Phys Monog 2000; 1: 16–19.Kannel WB. Coronary risk factors: an overview. In: Willerson JT, Cohn JN, (eds). 11. Cardiovascular Medical. New York: Churchhill Livingstone, 1995: 1809–1828.Elliot WJ, Black HR. Hypertension. In: ND Wong, HR Black, JM Gardin (eds). 12. Preventive Cardiology. A Practical Approach. 2nd edn. New York: McGraw Hill, 2005: 149–182.El-Attat F, McFarlane SI, Sowers R. Diabetes, hypertension and cardiovascular 13. derangements. pathophysiology and management. Curr Hypertens Rep 2004; 6(3): 215–23. DOI: 10.1007/S11906-004-0072-y.American Diabetes Association. Treatment of hypertension in adults with diabetes.14. Diabetes Care 2003; 26(Supp 1): 580–582.Kannel WB. Risk stratification in hypertension: new insights from the Framingham 15. study. Am J Hypertens 2000; 13: 3S–10S.Alberti KGMM, Zimmet PZ. Definition diagnosis and classification of diabetes 16. mellitus and its complication part II. Diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation. Diabetes Med 1998; 15: 539–643. World Health Organization – International society of hypertension writing group. 17. International Society of Hypertension statement on management of hypertension. J Hum Hypertens 2008; 21: 1983–1992.Levitt NS, Katzerellenbagen JM, Bradshaw D, Hoffman MN, Bannici F. The 18. prevalence and identification of risk factors for NIDDM in urban Africans in Cape Town, South Africa. Diabetes Care 1993; 164: 601–607.Dowse GK, Zimmet P. A model protocol for diabetes and other non-communicable 19. diseases field study. World Health Stat Q 1992; 45: 360–372.National Institute of Health. National Heart Lung and Blood Institute Clinical 20. Guidelines on Identification, Evaluation and Treatment of Overweight and Obesity in Adults. The evidence report. Obes Res 1998; 6: 515–595. Friedewald WT, Levy RJ, Fredrickson DS. Estimation of the concentration of low 21. density lipoprotein-cholesterol in plasma, without use of the preparative ultra-centrifuge. Clin Chem 1972; 18; 499–502.Araoye MA. Left ventricular hypertrophy by eletrocardiography; A code system 22. applicable to negroes. Nig Post Grad Med J 1996; 3: 92–97.Katibi IA, Adenle AD. Comparison between various criteria for the diagnosis of left 23. ventricular hypertrophy and echocardiogram in adult hypertensive Nigerians. Nig Med Pract 2003; 43: 3–6.Omotoso ABO, Opadijo OG, Araoye MA. Diabetes mellitus and hypertension in 24. Nigerians: A review of 572 diabetic patients. Nig J Med 1999; 8: 108–111.Wicks ACB, Love RF, Jones JJ. Alcohol a cause of diabetes in Rhodesia.25. S Afr Med J 1974; 48: 1115–1117.Talat N, Aamir K, Chaudhry MA. Dyslipidaemia in type 2 diabetes mellitus patients 26. in a teaching hospital of Lahore, Pakistan. Pak J Med Sci 2003; 19: 283–286.Tranche S, Galgo A, Xavier M, 27. et al. Cardiovascular risk factor in type 2 diabetic patients: multifactorial intervention in primary care. Kidney Int 2005; 67: 55–62. Wannamethae SG, Sharper AG, Perry IJ. Smoking as a metabolic risk factor for type 28. 2 diabetes in middle-aged men. Diabetes Care 2001; 24: 1590–1595.Hays LM, Clark DO. Correlates of physical activity in a sample of older adults with 29. type 2 diabetes. Diabetes Care 1999; 22: 706–712.US Department of Health and Human Services. Physical activity and health: a report 30. of the surgeon general. Atlanta, Ga: Department of Health and Human Services, Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion, 1996.Kannel WB, Belanger A, D’Agostino R, Israel J. Physical activity and physical demand 31. on the job and risk of cardiovascular disease and death: the Framingham study. Am Heart J 1986; 112: 820–825.Fisch A, Pichard E, Prazuck T, Leblac H, Sidibe Y, Bruckes G. Prevalence and risk 32. factors of diabetes in rural region of Mali. Diabetologia 1987; 30: 859–862.Puepet FH, Agaba EI, Chuhwak EK. Some metabolic abnormalities in type 2 diabetic 33. patients in Jos, north central Nigeria. Nig J Med 2003; 12: 193–197.NHLBI Obesity Education Initiative Expert Panel. Clinical guidelines on identification 34. evaluation and treatment of overweight and obesity in adults: The Evidence Report. Bethesdar, Md: National Institute of Health. National Heart, Lung and Blood Institute, 1998.Folsom AR, Princess RJ, Kaye SA, Munger RG. Incidence of hypertension and stroke 35. in relation to body fat distribution and other risk factors in older women. Stroke 1990; 21: 701–706. Fadupin GT, Joseph EU, Keshinro OO. Prevalence of obesity among type 2 diabetics 36. in Nigeria; a case study of patients in Ibadan,Oyo state, Nigeria. Afr J Med Sci 2004; 33: 381–384. Agboola-Abu CF, Ohwovoriole AE, Akinlade RB. The effect of glycaemic control on the 37.

prevalence and pattern of dyslipidaemia in Nigeria patients with newly diagnosed non-insulin dependent diabetes mellitus. W Afr J Med 2000; 19: 27–33.Aduba O, Onwuamaeze I, Oli J, Udeozo K. Serum cholesterol and HDL cholesterol 38. in Nigerian diabetics. E Afr Med J 1984; 61: 35–39.De Vegt F, Dekker JM, Jager A. Relation of impaired fasting and post load glucose 39. with incidence of type 2 diabetes in Dutch population. The Hoorn Study. J Am Med Assoc 2001; 285: 2109–2113.40. Dalton M, Cameron AJ, Zimmet PZ,40. et al. Waist circumference, waist hip ratio and body mass index and their correlations with cardiovascular disease risk factors in Australian adults. J Int Med 2003; 254(6): 555–563.Isezuo SA, Badung SL, Omotoso ABO. Comparative analysis of lipid profiles 41. among patients with type 2 diabetes mellitus, hypertension and concurrent type 2 diabetes and hypertension: a review of metabolic syndrome. J Natl Med Assoc 2003; 95: 328–334.Olson DC. 42. Risk Factor for Cardiovascular Disease: Diagnosis and Management of Diabetes Mellitus. 2nd edn. New York: Raven, 1988; 239–248.Dinneen SF, Gestein HC. The association of microalbuminuria and mortality in 43. non insulin dependent diabetes mellitus. A systematic review of literature. Arch Intern Med 1997; 157: 1413–1418.Gugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic complications. 44. Diabetes Care 1996; 19: 257–267.Lyons T. Lipoprotein glycation and its metabolic consequences.45. Diabetes 1992; 41(S2): 67.Smellie WF, Sandler D, O’Donwell J, Mac Cuish AC. Screening and treatment for 46. hyperlipidaemia in Non-insulin dependent diabetes: A prospective assessment of 350 patients. Br J Clin Pract 1995; 49: 83–85.Adedeji OO, Onitiri AC. Plasma lipids in Nigerian hypertensives. 47. Afr J Med Sci 1990; 19: 281–284.Obeka NC. Serum uric acid profile among hypertensive patients in Jos. Part II. 48. Dissertation for FWACP 2005.Jarikre AE, Dim DC, Ajuluchukwu JNA. Plasma lipid levels in Nigerian hypertensives; 49. the gender factor. Nig Quart J Hosp Med 1996; 6: 293–298.Ukoh VA, Oforofuo IA. Plasma lipid profile in Nigerian normotensives, hypertensives 50. and patients with other acquired cardiac conditions. Nig Clin Rev 2004; 8: 7–12.Tuomilehto J. Plasma uric acid level and its association with diabetes mellitus and 51. some biological parameters in a biracial population of Fiji. Am J Epidemiol 1988; 127(2): 321–336.Bo S. Hypouricaemia and hyperuricaemia in type 2 diabetes: two different 52. phenotypes. Eur J Clin Invest 2001; 31: 318–332.Alebiosu CO, Odunsa BO. Metabolic syndrome in subjects with type 2 diabetes 53. mellitus. J Natl Med Assoc 2004; 96: 817–821.Adedapo KS, Abbiyesiku FM, Adedapo AA, Osotimehin BO. Microalbuminuria in 54. controlled type 2 diabetes mellitus patients. Afr J Med Sci 2001; 30: 323–326.Kolterman OG, Sackow M, Olefsky JM,55. et al. Mechanisms of insulin resistance in human obesity: Evidence for receptor and post receptor defects. J Clin Invest 1980; 65: 1272–1284.Grusin H. Peculiarities of the African electrocardiogram and the changes observed 56. in serial studies. Circulation 195; 9: 860–867.Schunkert H, Hense HW, Holmer SR,57. et al. Association between a deletion polymorphism of angiotensin converting enzyme gene and left ventricular hypertrophy. N Engl J Med 1994; 330: 1634–1638. Devereux RB, Lutes EM, Casale PN, 58. et al. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 1984; 4: 1222.Mbanya JC, Sobngwi E, Mbanya DNS, Ngu KB. Left ventricular hypertrophy and 59. systolic dysfunction in a diabetic population of Cameron. Diabetes Metab 2001; 27: 378–382.Babalola RO, Ajayi AA. A cross sectional study of echocardiographic indices, 60. treadmill exercise capacity and micro vascular complications in Nigerian patients with hypertension associated diabetes mellitus. Diabet Med 1992; 9: 899–903.Osuntokun BO, Akinkugbe FM, Francis TI. Diabetes mellitus in Nigeria: a study of 61. 832 patients W Afr J Med 1971; 20: 295–298. Araoye MA, Omotoso ABO, Opadijo OG. The orthogonal and 12-lead ECG in 62. adult Negroes with systemic hypertension; comparison with age-matched control. W Afr J Med 1998; 17: 157–164.Huston SL, Bunker CH, Ukoli FA. Electrocardiographic LVH by five criteria among 63. civil servants in Benin city, Nigeria, prevalence and correlates. Int J Cardiol 1999; 70: 1–14.Crews DC, Plantinga LC, Miller ER, 64. et al. Prevalence of chronic kidney disease in persons with undiagnosed or prehypertension in the United States. Hypertension 2010; 55: 1102–1109.Mann JF, Gerstein HC, Pogue J. Renal insufficiency as a predictor of cardiovascular 65. outcomes and the impact of ramipril: The HOPE randomised trial. Ann Intern Med 2001; 134: 629–636.



Correspondence to: Tandi Matsha Timothy Tjaronda, Gloudina Hon, Adriaan EsterhuyseDepartment of Biomedical Sciences, Faculty of Health and Wellness Science, Cape Peninsula University of Technology, Bellville, Cape TownTel: + 27 (0)21 959 6366Fax: +27 (0)21 959 6760e-mail: [email protected]

Mogamat Hassan Department of Nursing and Radiography, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Cape Town

Rajiv ErasmusDivision of Chemical Pathology, Faculty of Health Sciences, University of Stellenbosch, Cape Town

S Afr J Diabetes Vasc Dis 2012; 9: 61–65.

AbstractBackground: Hyperglycaemia is strongly associated with increased oxidative stress, and the oxidation of low-density lipoprotein (LDL) is suggested to play a significant role in the pathogenesis of the macrovascular complications observed in diabetic patients. We investigated the relationship between auto-antibodies against oxidised low-density lipoprotein (oxLDL), high-sensitivity C-reactive protein (hs-CRP) and cardiovascular profile in individuals with hyperglycaemia.Methods: Antibodies against oxLDL and hs-CRP were measured in 97 hyperglycaemic and 79 normoglycaemic individuals. Gender-specific prediction for cardiovascular disease (CVD) risk was calculated using the 30-year CVD interactive risk calculator.Results: Anti-oxLDL antibodies were significantly lower in hyperglycaemic individuals (p = 0.02). Significant correlations were observed between levels of anti-oxLDL and hs-CRP (r = –0.16; 0.03), HbA1c (r = –0.22; p = 0.003), triglycerides (r = –0.15; p = 0.04), serum cotinine (r = –0.15; p = 0.047), and fasting blood glucose (r = –0.22; p = 0.003). The predictors of anti-oxLDL antibodies after multiple stepwise linear regression were levels of post two-hour blood glucose, serum cotinine, total cholesterol, triglycerides, and age and waist circumference; the last showing a positive association.Conclusion: Anti-oxLDL antibodies were reduced in subjects with hyperglycaemia and these low levels were associated with an increased cardiovascular disease risk score.

Keywords: oxidised LDL, antibodies, hyperglycaemia, cardiovascular diseases, C-reactive protein

Submitted 6/4/2011, accepted 23/2/2012

IntroductionDiabetes mellitus (DM), particularly type 2 diabetes is highly associated with atherosclerosis and therefore cardiovascular disease (CVD). Mortality from CVD is two- to four-fold higher in those with diabetes.1 The link between diabetes and atherosclerosis is possibly due to the association of hyperglycaemia with oxidative stress.2

One of the key processes in the initiation of atherosclerosis is the oxidation of low-density lipoprotein (LDL). Oxidised LDL (oxLDL) promotes monocyte adhesion to injured or inflamed epithelium, migration into the artery wall and differentiation into macrophages, which take up oxLDL, leading to macrophage foam cell formation and subsequent atherosclerosis.3 The binding of oxLDL to macrophages is enhanced by C-reactive protein (CRP) via Fcy receptors.4 Furthermore, CRP has been shown to form complexes with oxLDL at physiological calcium concentrations and such complexes have been detected in DM patients with atherosclerosis.5

The identification of CRP within early atherosclerotic lesions in human coronary arteries provides a link that CRP is probably directly involved in the intra-plaque inflammatory process.6 Therefore CRP has been proposed as a good biomarker for atherosclerotic inflammation and among apparently healthy men and women, plasma levels of CRP above 3 µg/ml are associated with future major cardiovascular events.7,8

Oxidised LDL is immunogenic, consequently antibodies against OxLDL are generated and these antibodies have been shown to be present in children,9 healthy adults, and patients with CVD10 and DM.11 However, there is controversy regarding the role of these circulating antibodies in humans. In animal models, IgM anti-oxLDL natural antibodies were shown to block the binding and degradation of oxLDL by macrophages in vitro, suggesting a protective role of these antibodies.12,13 By contrast, IgG anti-oxLDL/beta2GPI antibodies were shown to enhance macrophage uptake of oxLDL in vitro, promoting the atherogenic process.14

In humans, high titres of IgG anti-oxLDL antibodies have been reported in children compared to adults, and these have been suggested to modulate the antigen and thus protect against atherosclerosis.9 Conversely, elevated anti-oxLDL antibodies have been shown in atherosclerotic lesions, linking them to a pathogenic role in CVD.15 Similarly in diabetes, controversial results have been reported.11,16,17

The aim of the present study was to investigate the relationship between auto-antibodies against oxLDL, hs-CRP levels and cardiovascular profile in individuals with hyperglycaemia, and ascertain whether the levels of auto-antibodies against oxLDL were reduced in hyperglycaemic individuals with a high prevalence of diabetes.

MethodsThe study was approved by the Cape Peninsula University of Technology, Faculty of Health and Wellness Sciences ethics

Antibodies against oxidised LDL, and cardiovascular risk factors in individuals with hyperglycaemiaTANDI MATSHA, TIMOTHY TJARONDA, GLOUDINA HON, ADRIAAN ESTERHUYSE, MOGAMAT HASSAN, RAJIV ERASMUS



committee, and was conducted according to the code of ethics of the World Medical Association (Declaration of Helsinki). All participants provided written informed consent after all the procedures had been fully explained in the language of their choice.

In an epidemiological study aimed at establishing a cohort that could be followed up for insulin resistance and its sequel in a mixed-ancestry population of South Africa,18 a total of 956 subjects participated. They comprised 642 random subjects between the ages 35 and 65 years, and 304 voluntary subjects, age range 16 to 95 years. From the database containing the 642 randomly selected subjects, a total of 176 (hyperglycaemic and normoglycaemic) individuals between 31 and 65 years of age were randomly selected for this study.

Anthropometric measurements (body weight and height, waist and hip circumference, waist-hip ratio and skinfold thickness measurements) were performed on all subjects as described in Matsha et al.18 Body mass index (BMI) was calculated as weight per square metre (kg/m2). Three readings were taken for blood pressure, and waist and hip circumferences. Blood pressure measurements were performed according to WHO guidelines.19

All participants except the self-reported diabetic subjects, confirmed by either medical card record or drugs in use, underwent a 75-g oral glucose tolerance test (OGTT) as prescribed by the WHO. Fasting blood glucose levels were determined in all participants, including self-reported diabetic subjects. Categories of glucose tolerance were defined, applying the 1998 WHO criteria.20

Blood samples were transported in an ice box daily for processing at the Metropolis private pathology laboratory (Century City, Cape Town). Plasma glucose level was measured by the enzymatic hexokinase method (Cobas 6000, Roche Diagnostics). Glycosylated haemoglobin (HbA1c) was assessed using turbidimetric inhibition immunoassay (Cobas 6000, Roche Diagnostics). Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels were estimated by enzymatic colorimetric methods (Cobas 6000, Roche Diagnostics). Low-density lipoprotein cholesterol (LDL-C) was calculated using Friedwald’s formula.

CRP was measured with a high-sensitivity CRP assay, based on the highly sensitive near infrared particle immunoassay rate methodology (Immage® Immunochemistry System; Beckman Coulter), with a lower limit of detection of 0.2 mg/l. Participants with CRP concentrations < 0.2 mg/l had a value assigned to them of 0.2 mg/l. To determine serum antibodies against oxLDL we used the OLAB IgG anti-oxidised LDL ELISA kit (Biomedica Medizinprodukte GmbH and Co KG), as per manufacturer’s instructions, on serum that had been stored at –80°C.

Serum cotinine was measured by chemiluminescent assay (Immulite 1000, Siemens). According to the manufacturer, the normal range on 50 subjects was 263 mU/ml (median) and the intra-assay and inter-assay co-efficient of variations were respectively, 3.6–4.3% and 4–8.2%. Urine microalbumin was measured by an immunoturbidimetric assay (Cobas 6000, Roche Diagnostics).

Gender-specific prediction for CVD risk was calculated using the 30-year CVD interactive risk calculator.21 The calculator uses standard CVD risk factors (male gender, age, systolic blood pressure, antihypertensive treatment, diabetes mellitus, smoking, total and HDL cholesterol) to predict two outcomes: full CVD risk (hard CVD or coronary insufficiency, angina pectoris, transient ischaemic attack, intermittent claudication or congestive heart failure) and hard CVD risk (coronary death, myocardial infarction, fatal or non-fatal stroke).

Statistical analysisStatistical analysis of the data was performed using STATISTICA (STATISTICA 9, StatSoft Inc 1984–2009). The continuous variables are presented as medians with 95% confidence interval. The Mann-Whitney U-test was used for independent data. Kruskal-Wallis ANOVA was used to study anti-oxLDL antibody differences between the individual glycaemic states (normal, impaired glucose tolerance, impaired fasting glucose, undiagnosed diabetes and self-reported diabetes).

The relationship between anti-oxLDL antibodies, hs-CRP level and CVD risk factors was studied by means of Spearman’s rank correlation coefficient and multiple stepwise linear regression analysis. The dependent variable, anti-oxLDL antibodies was log transformed prior to the regression analysis. Independent variables contained in the model were: age, BMI, waist–hip ratio or waist and hip circumferences, systolic and diastolic blood pressures, and hs-CRP, HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, urine microalbumin, serum cotinine, fasting blood glucose and two-hour post blood glucose levels.

Table 1. Characteristics of the 176 participants according to glycaemic state.

Normal (n = 79)

Hyperglycaemic(n = 97) p-value

Males, n (%) 32 (40.5) 31 (32.0)

Age (years) 47 (46, 50) 53 (50, 53) 0.006

BMI (kg/m2) 24.3 (24.7, 27.5)

32.2 (31.4, 34.1) < 0.0001

Waist circumference (cm)

87 (86, 93) 103 (101, 106) < 0.0001

Hip circumference (cm)

101 (101, 106) 111 (111, 117) < 0.0001

WHR 0.87 (0.85, 0.88)

0.91 (0.90, 0.93) 0.0007

SBP (mmHg) 105 (114, 122) 112 (121, 127) 0.02

DBP (mmHg) 75 (72, 78) 75 (74, 78) 0.92

FBG (mmol/l) 5.0 (4.9, 5.2) 6.6 (7.6, 9.0) < 0.0001

Post BG (mmol/l) 5.7 (5.6, 6.0) 8.8 (9.4, 11.7) < 0.0001

HbA1c (%) 5.6 (5.5, 5.7) 6.3 (6.7, 7.4) < 0.0001

TC (mmol/l) 5.5 (5.2, 5.7) 5.6 (5.3, 5.8) 0.45

TG (mmol/l) 1.1 (1.2, 1.5) 1.5 (1.5, 1.8) < 0.001

HDL-C (mmol/l) 1.2 (1.2, 1.4) 1.1 (1.1, 1.2) 0.03

LDL-C (mmol/l) 3.3 (3.3, 3.7) 3.6 (3.5, 3.9) 0.28

Urine microalbumin (mg/l)

2.9 (5.2, 8.2) 4.6 (7.9, 14.6) 0.09

GGT (IU/l) 23 (27, 36) 31 (34, 43) 0.005

Serum cotinine (ng/ml)

346 (120, 206) 174 (75, 142) 0.06

Hs-CRP (mg/l) 3.7 (3.9, 6.3) 6.6 (6.7, 9.5) 0.001

Anti-oxLDL (mU/ml) 1699 (1842, 2670)

1119 (1551, 2328)

0.02

Full CVD (%) 29 (29, 39) 47 (41, 52) 0.001

Hard CVD (%) 16 (18, 28) 29 (28, 39) 0.002

BMI, body mass index; WHR, waist–hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; Post BG, two-hour post blood glucose; TC, total cholesterol; TG, triglycerides; HDL-C, high- density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Full CVD, hard CVD or coronary insufficiency, angina pectoris, transient ischaemic attack, intermittent claudication or congestive heart failure; Hard CVD, coronary death, myocardial infarction, fatal or non-fatal stroke. Results are expressed as median (95% confidence interval).



Table 2. Correlation between anti-OXLDL antibodies and cardiovascular disease biomarkers.

Spearman R p-value

Age (years) –0.14 0.07

BMI (kg/m2) –0.12 0.12

Waist circumference (cm) –0.12 0.10

Hip circumference (cm) –0.10 0.20

WHR –0.03 0.70

SBP (mmHg) –0.002 0.95

DBP (mmHg) 0.03 0.66

FBG (mmol/l) –0.22 0.003

Post BG (mmol/l) –0.22 0.006

HbA1c (%) –0.22 0.003

TC (mmol/l) –0.13 0.08

TG (mmol/l) –0.15 0.04

HDL-C (mmol/l) –0.01 0.90

LDL-C (mmol/l) –0.11 0.15

Urine microalbumin (mg/l) –0.02 0.71

Serum cotinine (ng/ml) –0.15 0.047

Hs-CRP (mg/l) –0.16 0.03

Full CVD (%) –0.010 0.908

Hard CVD (%) –0.03 0.768

BMI, body mass index; WHR, waist-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; Post BG, two-hour post blood glucose; TC, total cholesterol; TG, triglycerides; HDL-C, high- density lipoprotein cholesterol; LDL-C, low-density lipoprotein choles-terol; Full CVD, hard CVD or coronary insufficiency, angina pectoris, tran-sient ischaemic attack, intermittent claudication or congestive heart failure; Hard CVD, coronary death, myocardial infarction, fatal or non-fatal stroke. Results are expressed as median (95% confidence interval).

Fig. 1. Box plot representing anti-oxLDL antibody levels in normal subjects, and those with normoglycaemia (n = 79), impaired fasting glucose (IFG) (n = 14), impaired glucose tolerance (IGT) (n = 29), undiagnosed diabetes (DM) (n = 29), known DM (n = 25), and self-reported diabetes. Undiagnosed diabetes was sig-nificantly lower (p = 0.01) compared to normal subjects using Kruskal-Wallis ANOVA.

ResultsThe study group consisted of 176 subjects of whom 114 (64.7%) were females and 63 (35.3%) were males. The subjects were categorised into those with hyperglycaemia [29 undiagnosed DM, 25 known DM, 14 impaired fasting glucose (IFG) and 29 impaired glucose tolerance (IGT)] and 79 normoglycaemia (normal), and their characteristics are presented as medians (95% confidence interval) in Table 1.

By selection, glycated haemoglobin (HbA1c), fasting plasma glucose and two-hour post 75-g glucose load blood glucose were significantly higher in the hyperglycaemic group. Obesity indices, BMI, waist–hip ratio, waist and hip circumferences and increased CVD risk scores were significantly more prevalent in hyperglycaemic individuals. However, tobacco exposure as assessed by serum cotinine was more common in the normoglycaemic subjects. Anti-oxLDL antibodies and HDL cholesterol levels were significantly lower in the hyperglycaemic individuals.

Anti-oxLDL antibodies were further investigated according to the individual glycaemic states (normal, IGT, IFG, undiagnosed diabetes and self-reported diabetes) using ANOVA, and were found to be lowest in individuals with undiagnosed diabetes (Fig. 1). Anti-oxLDL antibodies presented significant negative correlations with hs-CRP, fasting blood glucose, post two-hour glucose, HbA1c, triglycerides and serum cotinine (Table 2). Furthermore, when correlations were done on each study group, total cholesterol correlated negatively with anti-oxLDL antibodies in normoglycaemic subjects (r = –0.2883; p = 0.0100).

Multiple stepwise linear regression including anti-oxLDL antibodies as the dependent variable showed that post two-hour glucose, triglycerides and serum cotinine levels remained independently associated with anti-oxLDL antibodies. Other contributors to anti-oxLDL antibodies were total cholesterol, age and waist–hip ratio; the last showed a positive association with anti-oxLDL antibodies (Table 3).

DiscussionThe inflammatory nature of atherosclerosis is well established. Key to this is the oxidation of LDL, resulting in the formation of immune complexes and the production of antibodies against oxLDL.3 It is well recognised that diabetes mellitus increases the risk of developing cardiovascular diseases, and oxidation of LDL is suggested to play a significant role in the pathogenesis of the macrovascular complications observed in diabetic patients.2

Antibodies against oxidised LDL have been detected in healthy and diseased individuals,9-11 however their role in disease

Table 3. Variables that contribute to anti-oxLDL antibodies after multiple linear stepwise regression.

Variable β Adjusted β p-value

Post BG (mmol/l) –0.255 –0.023 0.003

Serum creatinine (ng/ml) –0.246 –0.0005 0.003

TC (mmol/l) –0.109 –0.034 0.245

TG (mmol/l) –0.144 –0.078 0.114

WHR 0.151 0.598 0.09

Age (years) –0.096 –0.004 0.270

Post BG, two-hour post blood glucose; TC, total cholesterol; TG, triglycerides; WHR, waist–hip ratio. Adjusted R2 = 0.1198.



is poorly understood. In the present study we found IgG anti-oxLDL antibodies to be low in individuals with hyperglycaemia, especially in those with undiagnosed diabetes, perhaps due to the unmanaged glycaemic state. Furthermore, after the multiple stepwise linear regression analysis, two-hour post blood glucose showed a negative association with anti-oxLDL antibodies.

Although there are several reports on the levels of anti-oxLDL antibodies in patients with diabetes, there is considerable inconsistency in reports from several investigators. In a longitudinal study, Garrido-Sánchez et al.17 demonstrated that low levels of anti-oxLDL antibodies in subjects with normal glucose tolerance, impaired fasting glucose or impaired glucose tolerance were a significant predictor of onset of type 2 diabetes. Furthermore, another report had previously shown a distinct fall of these antibodies after the age of 35 years,22 and increasing age is strongly associated with the development of type 2 diabetes. By contrast, other studies have found higher,11,23 or comparable levels of anti-oxLDL antibodies in both type 1 and type 2 diabetes.24-26

Anti-oxidised LDL antibodies have been found in patients with advanced atherosclerotic lesions,27 however, their role in atherosclerosis is also controversial. Salonen et al.15 reported high levels of auto-antibodies to malonyldialdehyde-LDL particles in subjects with carotid atherosclerosis, but the Framingham Offspring study failed to show a relationship between baseline levels of IgG anti-oxLDL antibodies and the development of CVD or coronary heart disease.28 Furthermore, another study found an inverse relationship between antibody levels and carotid intima–media thickness after adjusting for several CVD risk factors such as age, blood pressure, BMI and lipid levels.29

We also observed a negative association with cardiovascular disease risk factors, as shown by the inverse association between anti-oxLDL antibodies and several markers of cardiovascular disease. After multiple stepwise linear regression, an increase in levels of total cholesterol and triglycerides and age was associated with a reduction in the levels of anti-oxLDL antibodies.

Standard CVD risk factors such as male gender, age, obesity, high blood pressure, diabetes mellitus, and total and HDL cholesterol levels are well established and have been used in the CVD interactive risk calculator.21 We also used the CVD risk calculator and found that, in keeping with the strong link between hyperglycaemia and CVD risk, the CVD risk scores were significantly higher in subjects with hyperglycaemia. Furthermore, HbA1c and hs-CRP levels correlated negatively with anti-oxLDL antibodies. Similarly, Santos and co-workers30 showed a negative correlation between anti-oxLDL antibodies and hs-CRP levels, and an inverse association after performing a multiple linear regression analysis.

CRP and HbA1c have recently gained popularity in the assessment of cardiovascular disease risk. However, the range of CRP levels associated with vascular risk is way below the reference range used to assess inflammation, and high sensitivity assays were developed to measure CRP levels associated with CVD risk.31 Recent prospective studies have shown that elevated HbA1c levels are associated with risk of CVD and death.32 This association has recently been extended to non-diabetic subjects, where non-diabetic adults with HbA1c levels of 6.0% or higher were found to be at an increased risk of developing CVD and diabetes mellitus.32

It has been suggested that measurement of level of antibodies against oxLDL may serve as an index of in vivo LDL oxidation, however this remains to be elucidated. While lipoprotein oxidation was not measured in the present study, serum cotinine levels, which are a reliable marker of tobacco exposure,33 demonstrated

an inverse association with anti-oxLDL antibody levels. Cigarette smoking exposes an individual to a variety of highly oxidant gases and free radicals, and is believed to add to the toxic accumulation of reactive oxygen species (ROS) in the diabetic subject.34

Therefore our results partially support the role of these antibodies as an indirect assessment of oxidation, whereby lower antibody levels may indicate increased oxidative stress with a consequent increase in LDL oxidation. It is however pertinent to mention that waist circumference was retained after multiple stepwise linear regression analysis and showed a positive association with anti-oxLDL antibody levels. Although obesity is defined by body mass index, it is central obesity as measured by the waist circumference that is strongly associated with metabolic abnormalities.

Adipose tissue expresses inflammatory cytokines, interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a), which are a source of oxidative stress.35 A relationship between abdominal fat and enhanced lipid peroxidation has been demonstrated by the direct proportional elevation of oxidative stress biomarkers, particularly oxidised LDL (OxLDL) and waist circumference.36

The discrepancy between the role of antibodies against oxidised LDL reported in this study and that in other studies could be due to the heterogeneous effect of these antibodies. Human IgG antibodies have different subclasses, including IgA, IgG1, IgG2 and IgG3.37 While IgG2 is the dominant subclass to respond to epitopes containing phospholipids, it is the IgG3 subclass that is more pathogenic as it fixes complement better and binds Fc receptors more ardently.38

The major limitation in this study was the measurement of total IgG anti-oxLDL antibodies, as quantification of the specific antibody subclasses may elucidate the role and usefulness of these antibodies in various disease states. Another limitation was the inclusion of only one ethnic group, the mixed-ancestry population of South Africa, with a reportedly high incidence of diabetes. 39 These anti-oxLDL antibodies have been shown to differ in south Asian individuals with an increased risk of atherosclerosis compared to whites.40

ConclusionOur findings demonstrated that anti-oxLDL antibody levels were reduced in subjects with hyperglycaemia and that these low levels were associated with an increased cardiovascular disease risk score. However, these findings should be corroborated by further studies, taking into account the different subclasses of human IgG anti-oxLDL antibodies, as well as different ethnic groups. Furthermore, future studies should compare individuals with cardiovascular disease but with normal glucose tolerance to individuals with coronary artery disease and abnormal glucose tolerance, in order to determine whether reduced anti-oxLDL levels are a risk factor for cardiovascular diseases. AcknowledgementsThis research was supported by a grant from the University Research Fund of the Cape Peninsula University of Technology, South Africa. The grant was used solely for funding the project. We thank the Bellville South community for participating in this study.

ReferencesGu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in 1. a national cohort of the US population, 1971-1993. Diabetes Care 1998; 21: 1138–1145.Ceriello A, Quagliaro L, Catone B, 2. et al. Role of hyperglycemia in nitrotyrosine postprandial generation. Diabetes Care 2002; 25:1439–1443.



Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. 3. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci USA 1984; 81: 3883–3887.Van Tits L, de Graaf J, Toenhake H, van Heerde W, Stalenhoef A. 4. C-reactive protein and annexin A5 bind to distinct sites of negatively charged phospholipids present in oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 2005; 25: 717–722. Tabuchi M, Inoue K, Usui-Kataoka H, Kobayashi K, Teramoto M, Takasugi K, 5. et al. The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis. J Lipid Res 2007; 48: 768–781. Torzewski J, Torzewski M, Bowyer DE, Fröhlich M, Koenig W, Waltenberger J, 6. et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 1998; 18: 1386–1392.Rifai N, Ridker PM. High sensitivity CPR protein: A novel and promising marker of 7. coronary heart disease. Clin Chem 2001; 47: 403–411.Koenig W, Sund M, Fröhlich M, Fischer HG, Löwel H, Döring A, 8. et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999; 99: 237–242.Iughetti L, Volta C, Maggi E, Palladini G, Perugini C, Bellomo G, Bernasconi S. 9. Circulating antibodies recognizing oxidatively modified low-density lipoprotein in children. Pediatr Res 1999; 45: 94–99.Virella G, Virella I, Leman RB, Pryor MB, Lopes-Virella MF. 10. Anti-oxidized low-density lipoprotein antibodies in patients with coronary heart disease and normal healthy volunteers. Int J Clin Lab Res 1993; 23: 95–101.Bellomo G, Maggi E, Poli M, Agosta FG, Bollati P, Finardi G. 11. Autoantibodies against oxidatively modified low-density lipoproteins in NIDDM. Diabetes 1995; 44: 60–66.Shaw PX, Hörkkö S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, Witztum 12. JL. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest 2000; 105: 1731–1740.Hörkkö S, Bird DA, Miller E, Itabe H, Leitinger N, Subbanagounder G, 13. et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest 1999; 103: 117–128.Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. 14. Involvement of beta 2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol 1997; 107: 569–573.Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssönen 15. K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883–887.Mironova MA, Klein RL, Virella GT, Lopes-Virella MF. 16. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with type 2 diabetes. Diabetes 2000; 49: 1033–1041.1Garrido-Sánchez L, Cardona F, García-Fuentes E, Rojo-Martínez G, Gómez-17. Zumaquero JM, Picón MJ, et al. Anti-oxidized low-density lipoprotein antibody levels are associated with the development of type 2 diabetes mellitus. Eur J Clin Invest 2008; 38: 615–621.Matsha TE, Hassan MS, Kidd M, Erasmus RT. The 30-year cardiovascular risk profile 18. of South Africans with diagnosed diabetes, undiagnosed diabetes, pre-diabetes or normoglycaemia. The Bellville, South Africa pilot study. Cardiovasc J Afr 2012; 23(1): 5–11.World Health Organization (WHO). International Society of Hypertension Guidelines 19. for the Management of Hypertension. J Hypertens 1999; 17: 151–183.Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus 20. and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553.Pencina MJ, D’Agostino RB Sr, Larson MG, Massaro JM, Vasan RS. Predicting the 21. 30-year risk of cardiovascular disease: the framingham heart study. Circulation 2009; 119: 3078–3084.Tinahones F22. J, Gómez-Zumaquero JM, Garrido-Sánchez L, García-Fuentes E, Rojo-Martínez G, Esteva I, et al. Influence of age and sex on levels of anti-oxidized LDL antibodies and anti-LDL immune complexes in the general population. J Lipid Res 2005; 46: 452–457.Festa A, Kopp HP, Schernthaner G, Menzel EJ. Autoantibodies to oxidized 23. low density lipoproteins in IDDM are inversely related to metabolic control and microvascular complications. Diabetologia 1998; 41: 350–356.Uusitupa MIJ, Niskanen L, Luoma J, Vilja P, Mercuri M, Rauramaa R, Yla-Hertualla S. 24. Autoantibodies against oxidized LDL do not predict atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996; 16: 1236–1242.

Korpinen E, Groop P-H, Akerblom HK, Vaarala O. Immune response to glycatedand 25. oxidized LDL in IDDM patients with and without renal disease. Diabetes Care 1997; 20: 1168–1171.Mironova M, Virella G, Virella-Lowell I, Lopes-Virella MF. Anti-modified LDL 26. antibodies and LDL-containing immune complexes in IDDM patients and healthy controls. Clin Immunol Immunopathol 1997; 85: 73–82.Inoue T, Uchida T, Kamishirado H, Takayanagi K, Hayashi T, Morooka S. Clinical 27. significance of antibody against oxidized low density lipoprotein in patients with atherosclerotic coronary artery disease. J Am Coll Cardiol 2001; 37: 775–779.Wilson PW, Ben-Yehuda O, McNamara J, Massaro J, Witztum J, Reaven PD. 28. Autoantibodies to oxidized LDL and cardiovascular risk: the Framingham Offspring Study. Atherosclerosis 2006; 189: 364–368. Fukumoto M, Shoji T, Emoto M, Kawagishi T, Okuno Y, Nishizawa Y. 29. Antibodies against oxidized LDL and carotid artery intima-media thickness in a healthy population. Arterioscler Thromb Vasc Biol 2000; 20: 703–707.Santos AO, Fonseca FA, Fischer SM, Monteiro CM, Brandão SA, Póvoa RM,30. et al. High circulating autoantibodies against human oxidized low-density lipoprotein are related to stable and lower titers to unstable clinical situation. Clin Chim Acta 2009; 406: 113–118. Ridker PM. C-reactive protein: eighty years from discovery to emergence as a 31. major risk marker for cardiovascular disease. Clin Chem 2009; 55: 209–215.Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, 32. et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010; 362: 800–811.Shepperd C33. J, Eldridge AC, Mariner DC, McEwan M, Errington G, Dixon M. A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure. Regul Toxicol Pharmacol 2009; 55: 97–109.Benowitz NL. Cigarette smoking & cardiovascular disease pathophysiology and 34. complications for treatment. Prog Cardiovasc Dis 2003; 46: 91–111.Higdon J V, Frei B. 2003. Obesity and oxidative stress. 35. Arterioscler,Thromb Vasc Biol 23: 365–367.Weinbrenner T, Schroder H, Escurriol V, Fito M, Elosua R, Vila J, 36. et al. Circulating oxidised LDL is associated with increased waist circumference independent of body mass index in men and woman. Am Soc Clin Nutr 2006; 83: 30–35.337. Wu R, Shoenfeld Y, Sherer Y, Patnaik M, Matsuura E, Gilburd B, et al. Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations – possible immunomodulation of atherosclerosis. Autoimmunity 2003; 36: 91–97.Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. 38. J Allergy Clin Immunol 2010; 125: S41–52. Levitt NS, Katzenellenbogen JM, Bradshaw D, Hoffman MN, Bonnici F. 39. The prevalence and identification of risk factors for NIDDM in urban Africans in Cape Town, South Africa. Diabetes Care 1993; 16: 601–607.Miller MA, Strazzullo P, Karanam S, Cappuccio FP. 40. Ethnic variation in levels of circulating IgG autoantibodies to oxidised low-density lipoprotein. Atherosclerosis 2009; 203: 126–136.

It's theshell that

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REPORT SA JOURNAL OF DIABETES & VASCULAR DISEASE

Correspondence to: Andrew HeilbrunnBiokinetics Department, Centre for Diabetes and Endocrinology, Houghton, Johannesburge-mail: [email protected]


Does exercise improve or impair blood glucose control in type 1 diabetes?ANDREW HEILBRUNN

Over the last four decades, large landmark studies such as the Harvard study and the Cooper Centre Longitudinal Study (CCLS) clearly demonstrated that regular physical activity

reduces the risk of coronary heart disease, stroke, osteoporosis, and colon and breast cancer in the general population.1-3 There is also evidence that physical activity reduces obesity, osteoarthritis, lower back pain and clinical depression.4

With regard to type 2 diabetes, randomised, controlled trials have demonstrated that physical activity can delay the progression of impaired glucose tolerance to type 2 diabetes when combined with dietary changes.5 In patients with established type 2 diabetes, regular physical activity significantly improves glycaemic control, reduces cardiovascular risk factors and may reduce chronic medication dosages.6

Cardiovascular diseaseIncidence of cardiovascular disease and mortality are increased in both type 1 and type 2 diabetes and cardiovascular disease remains the most common cause of death.7 With respect to type 1 diabetes, the Pittsburgh IDDM Morbidity and Mortality study demonstrated that at 25 years’ duration of diabetes, men who had participated in team sports during high school were three times less likely to report macrovascular disease and had mortality rates three times lower than those who did not.8 A cohort study of patients with type 1 diabetes found that the seven-year mortality was 50% lower in those reporting more than 2 000 kcal of weekly exercise (equivalent of ≥ seven hours of brisk walking per week) compared to those reporting less than 1 000 kcal of physical activity per week.9

How much exercise is necessary to bring about physiological adaptations to decrease cardiovascular disease and increase longevity?Findings from the Harvard study suggest 75 minutes of physical activity per day. The CCLS findings suggest 30 to 60 minutes of physical activity per day, at a moderate intensity.1,2

In light of the above benefits, diabetes associations strongly support the role for physical activity in the management of diabetes. For type 2 diabetes, the latest American Diabetes Association (ADA) and Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines recommend a minimum of

150 minutes’ exercise per week, combining moderate-intensity aerobic exercise and strength/resistance training.10

Many of the guidelines applicable to patients with type 1 diabetes are based on understandings gained from small cohort studies on individuals with type 1 diabetes, people without diabetes or people with type 2 diabetes.9 One could postulate that the type 2 diabetes guidelines would be suitable for the population with type 1 diabetes; however, the few randomised, controlled trials reported for type 1 diabetes have not shown the same glycaemic benefits.

In the absence of comprehensive exercise guidelines for type 1 diabetes patients, a large segment of primarily young patients with type 1 diabetes participate in marathons, high-intensity ball sports and body building. Some may challenge themselves with recreational climbing and diving. However, a large percentage of these patients do not understand the complex relationship that exists between exercise and their diabetes. Once again, this raises the question; Does regular exercise improve or impair blood glucose control in type 1 diabetes?

Exercise physiologyExercise physiology and in particular, that of fuel sources and delivery, is critical to understanding the challenges faced by individuals with type 1 diabetes. Exercise increases both oxygen demands (which are met by the cardio-pulmonary system) and fuel demands (met by the neuro-endocrine system).11

Autonomic and endocrine regulationIn the non-diabetic person, insulin levels decrease with the onset of exercise; this allows for an increase in counter-regulatory hormones, in particular glucagon. This response leads to hepatic glucose production, and the subsequent increase in blood glucose is balanced by glucose uptake into the muscles. Due to this precise neuro-endocrine regulation, blood glucose levels remain stable under most exercise conditions.12,13

In type 1 diabetes, the pancreas cannot regulate insulin levels in response to exercise and there may be impaired glucose counter-regulation, making normal fuel regulation nearly impossible.12,13 Therefore, the patient with type 1 diabetes is at risk of becoming hypoglycaemic or hyperglycaemic, dependant largely on the levels of circulating insulin and the duration and intensity of the exercise.11

Duration and intensity of exerciseExercises performed at a low-moderate intensity, (40–80% of one’s heart rate maximum) for a long period of time, such as jogging, cycling and long-distance walking, may cause more hypoglycaemia than higher-intensity exercise. This acute complication is because this mode of exercise circulates exogenous insulin more efficiently and the counter-regulatory response may be blunted.11

High-intensity exercise such as sprinting or playing squash may cause hyperglycaemia due to an excessive adrenal response. This phenomenon may lead to ‘hepatic dumping’, which results in large amounts of glucose entering the circulation. Due to this adrenal


SA JOURNAL OF DIABETES & VASCULAR DISEASE REPORT

response, blood glucose levels may remain elevated for several hours post exercise.11

Research over the last five years has suggested that intermittent-type activities such as basketball, hockey and football, where periods of high-intensity sprints are interspersed with periods of moderate-intensity jogging, may have a more favourable blood glucose response during and after exercise. In theory, the adrenal response to the high-intensity sprints may prevent the hypoglycaemic effect of the moderate-intensity jogging.11

Improved insulin sensitivityNumerous mechanisms may explain why exercise may improve insulin sensitivity, including increased muscle blood flow (capillary blood flow in particular), increased insulin binding by muscle receptors and increased insulin-regulating glucose transporters. However, the primary theory and benefit of exercise occurs during the 12 to 24 hours post exercise, during which time glycogen is replenished.

During the course of exercise, liver and muscle glycogen stores are utilised as an energy source. Post exercise, the liver and muscle cells draw glucose from the blood to replenish the stores utilised during exercise. This process requires little insulin and is enzyme initiated. When the glycogen stores are low, glycogen synthase levels increase, resulting in glucose uptake from the circulation.

Regular trainingRegular, sustained exercise or training has a different overall effect on blood glucose compared with a single exercise session. The literature suggests that patients with type 1 diabetes should exercise daily or at least on alternate days to improve and then maintain their insulin sensitivity. Insulin sensitivity is enhanced with regular exercise/training due to enhanced insulin-mediated glucose disposal throughout the whole body. Furthermore, muscle levels of GLUT 4 and the activity of glycogen synthase increase significantly with training. However, with cessation of regular activity, insulin sensitivity is rapidly lost within days.14

Pharmacokinetics of insulinFactors influencing insulin actionThe type of insulin injected, in particular the time of peak action, influences absorption of insulin. Furthermore, the circulatory effects of certain types of exercise may influence the absorption of insulin. Endurance-type activities may increase total body circulation, while resistance exercise may attract blood flow primarily to the exercising muscle group. Because of these circulatory differences, hypoglycaemic episodes increase with endurance-type activities.13

The muscle mass or number of muscle fibres recruited during swimming may be higher than cycling because one is exercising both upper and lower limbs. This also increases the frequency of hypoglycaemia. Jogging may also lead to more hypoglycaemia than cycling due to the increased recruitment of muscle fibres with weight-bearing exercise.13

Ambient temperatureA warm environment may lead to more vasodilatation and better absorption and circulation of insulin. Exercise in a warm environment also increases the stress on the cardiovascular system and thus increases energy expenditure. This combination may lead to more hypoglycaemia.13

A cold environment at rest may lead to vasoconstriction and

lower levels of circulating insulin. However, when exercising in a cold environment, such as swimming, there may be increased glucose uptake to heat the muscles and this may lead to more hypoglycaemia.11

Injection site and injection depthOne should always try to exercise the muscles distal to the injection site. A cyclist should inject in the abdomen as opposed to the leg.13 In addition, the latest research on insulin needles suggests that shorter 4- and 5-mm needles may be just as effective as 8- to 12-mm needles. Their use may prevent deeper intramuscular injections and lower the frequency of hypoglycaemia.

Hydration levels and smokingIf a person is well hydrated, he/she may absorb more insulin and circulate it more efficiently. Smoking decreases capillary blood flow and consequently absorption.

If we combine the blood glucose effects related to duration and intensity of exercise with the lack of neuro-endocrine precision found in type 1 diabetes, and add the variability of insulin and the various factors influencing insulin action mentioned above, it is difficult to ascertain how exercise could reliably benefit blood glucose control. To compound this problem, one of the primary factors preventing good glycaemic control may be hypoglycaemia or the threat of hypoglycaemia.

HypoglycaemiaFear of hypoglycaemia is the primary factor affecting the attitude of patients towards exercise. According to Rabasa-Lohret, those individuals who best understood how insulin functioned in their body were shown to be less fearful of physical activity and hypoglycaemia. Furthermore, those individuals with the greatest fear of physical activity had the poorest control of their diabetes.15

In McMahon’s euglycaemic clamp studies in 2007, patients performing endurance-type activities at 16:30 had a biphasic need for glucose infusion.16 Glucose infusion was required during the 45 minutes of exercise and for 45 minutes post exercise. Further glucose infusion was required seven to 11 hours post exercise, which equated to a potential hypoglycaemic episode between 02:00 and 04:00. Dealing with glucose requirements during activity is not too difficult. However, dealing with late hypoglycaemia, occurring in the late evening and early morning has always been a challenge.16

According to Riddel, exercise late in the day may lead to nocturnal hypoglycaemia, which may be unnoticed during sleep in the majority of individuals.12 The incidence of hypoglycaemia may be as high as 26% in adolescents and children on the night of exercise. This may be due to a child or adolescent’s inadequate glycogen-replenishment strategies, low glycogen-storage capacity and blunted counter-regulatory responses overnight.

Strategies to prevent hypoglycaemiaThe literature suggests that while taking multiple daily injections, the most favourable times to exercise are in the pre-prandial periods before breakfast and before dinner. The reason for this suggestion is that the active patient is less likely to become hypoglycaemic at these times due to increased insulin resistance.17 Tansey et al. explained that performing low/moderate-intensity endurance-type exercise postprandially resulted in an 86% chance of developing hypoglycaemia if the patient’s glucose level was below 7.0 mmol/l before the start of the exercise.18



The risk of hypoglycaemia can be managed by increasing carbohydrate (CHO) intake before, during and after exercise. The amount of carbohydrate consumed is dependent on the type and dosage of insulin injected, specifically the time of peak action, body mass of the exercising person and energy expenditure of the exercise. Riddel recommends 1.0 g CHO/kg/hour. This can be ingested in the form of a 6–8% glucose drink, such as Energade

(6.6 g/100 ml) and Powerade (5.6 g/100 ml).12

Insulin dosage reductionIn order to reduce hypoglycaemia, Rabasa-Lohret suggested that one could reduce the insulin dosage in accordance with the intensity of the exercise.19 He suggested reducing the pre-meal dosage by 25% when exercising at a low intensity, a 50% reduction when exercising at a moderate intensity and up to 75% reduction when exercising at a high intensity. Some people find, however, that lowering their pre-meal insulin dose may cause an initial rise in their blood glucose, which impairs their performance.19

Grimm found it was more important to supplement with carbohydrates than to lower the insulin dosage to prevent hypoglycaemia. His study indicated that the intensity and duration of exercise would determine the patient’s carbohydrate intake and insulin adjustments. He suggested 15–100 g of carbohydrate per hour during exercise, if the exercise is performed at the time of the peak effect of insulin action. Furthermore, daily insulin dosages should be decreased by 20–30% if exercising for one hour or more (Table 1).20

Sprinting to prevent hypoglycaemia during and after exerciseGuelfi revealed a novel approach to preventing hypoglycaemia during moderate-intensity exercise.21 She suggested going for four-second maximal sprints every two minutes in the middle of a moderate-intensity workout to simulate the activity patterns of intermittent sport. This high-intensity activity increases adrenal hormone levels, which leads to less hypoglycaemia both during and for several hours after exercise.21

Post-exercise snacks and insulin adjustments to prevent post-exercise hypoglycaemiaThe key to good glycaemic control is strategic carbohydrate replenishment and insulin lowering post exercise. If one has exercised at a moderate to high intensity for more than 45 minutes, it is imperative to take the necessary snacks before going to bed and/or to decrease one’s insulin dosage strategically at each meal and at bedtime over the next 24 hours.

Glycogen-replenishment drinks and low-dose insulin post exercise may speed up liver and muscle glycogen replenishment in athletes with diabetes who exercise for more than two hours daily. Endurance athletes may require a combination of 0.8 g/kg carbohydrate and 0.4 g/kg protein in their replenishment drinks. This combination is known to hasten glycogen replenishment, creating an essential substrate that can convert to glucose when the blood glucose levels drop too low.22

Previous hypoglycaemic episodes and moderate-intensity exercise may lead to more hypoglycaemiaStudies have shown a blunted counter-regulatory response to hypoglycaemia following low/moderate-intensity exercise. Furthermore, hypoglycaemia prior to exercise, even in the sedentary state, attenuates the counter-regulatory response to exercise. In other words, hypoglycaemia begets hypoglycaemia.23 Some researchers suggest increasing one’s blood glucose levels and avoiding hypoglycaemia for two weeks prior to an endurance event in order to prevent hypoglycaemia during the event.

Exercise, sleep and unchanged insulin may lead to nocturnal hypoglycaemiaIf a person with diabetes exercises for more than 45 minutes, he/she will utilise the majority of the muscle and liver glycogen stores and is thus more likely to develop hypoglycaemia over the next 24 hours. Sleep may decrease one’s autonomic nervous system responses to hypoglycaemia. If a patient does not reduce his/her insulin dosage and take an appropriate bedtime snack, he/she has a good chance of developing nocturnal hypoglycaemia.

Is insulin pump therapy the answer to hypoglycaemia?Insulin pump therapy may provide a solution to hypoglycaemia for a number of reasons:

In most cases, patients infuse 20% less insulin when using a • pump versus multiple daily injections.The depot of insulin remains in the pump and only small • amounts of insulin are infused under the skin and circulate.Pump users can adjust their insulin dosages in fractions, which • makes insulin adjustments far more accurate.An insulin pump can be disconnected during exercise and basal • rates can be reduced for an appropriate period before exercise to lower circulating insulin levels during exercise.Pump users can decrease their basal rates of insulin replacement • at critical times during the night and early morning to reduce the incidence of nocturnal hypoglycaemia.

HyperglycaemiaHyperglycaemia may be common in exercises such as squash or high-intensity spinning or resistance training, due to an excessive counter-regulatory hormonal response. In the non-diabetic, circulating counter-regulatory hormones decrease rapidly post exercise and insulin levels increase, allowing for rapid glycogen replenishment and therefore a rapid decrease in glucose levels.

Most patients with type 1 diabetes choose to exercise during the tail effect of their insulin action, or they will decrease their insulin dosage to avoid hypoglycaemia. Therefore, post-exercise insulin levels may be low. With high post-exercise circulating counter-regulatory hormones and low insulin levels in the patient with type 1 diabetes, the patient’s blood glucose levels may remain high

Intensity/ duration

Length of exercise < 20 min 20–60 min > 60 min

< 60% of maxi-mal heart rate

0 g 15 g 30 g/h

60–75% of maxi-mal heart rate

15 g 30 g 75 g/h↓ insulin dosage 20%

> 75% of maxi-mal heart rate

30 g 75 g↓ insulin dosage

0–20%

100 g/h↓ insulin dosage 30%

Adapted from Grimm et al., Diabetes Metab 2004: 30: 465–470.

Table 1. Extra carbohydrate and insulin adjustments (depending on duration and intensity) to prevent hypoglycaemia in patients with type 1 diabetes engaging in physical activity.



for a number of hours post exercise. Competition days and extra carbohydrates will exacerbate the problem. One to two units of insulin prior to exercise and/or after exercise may counteract this hyperglycaemic effect.24

ConclusionExercise has been proven to improve physical fitness and strength, reduce cardiovascular risk factors and improve well-being in type 1 diabetes patients. Regular physical activity or training significantly reduces insulin dosages and may improve glycaemic control.4 One would then assume that patients with diabetes would remain active. Yet findings indicate that patients with type 1 diabetes, much like the general public, are not completely comfortable with exercise. One of the primary reasons for this is the fear of hypoglycaemia.15

However, in Herbst’s 2006 cross-sectional multi-centre analysis of 19 143 children and adolescents with type 1 diabetes, the frequency of activity had a significant influence on glycaemic control without increasing the risk of severe hypoglycaemia. Furthermore, patients who exercised on a regular basis planned their insulin and carbohydrate adjustments more efficiently than patients exercising sporadically, hence the lower incidence of hypoglycaemia.25 In Bernadini’s 2004 study, it was observed that children participating in more than 360 minutes of competitive sport a week had significantly better glycaemic control than those children exercising less than 60 minutes per day.26

Cardio-respiratory, metabolic and perceptual effort may also be altered in type 1 diabetes patients and this may impair exercise performance. In persons with type 1 diabetes, improvement of HbA1c levels with exercise has not been firmly established. The lack of evidence of improvement in HbA1c levels with exercise may be related to a tendency to over-reduce insulin dosages and consume excessive amounts of carbohydrates in an effort to avoid hypoglycaemia. The few randomised, controlled trials conducted have been small, of short duration and have not provided guidance on the intensity, duration or type (endurance/resistance) of physical activity that will provide the greatest benefit.12

The management of diabetes and exercise therefore requires consideration of the complex interactions, which makes a single generic formula inappropriate.13 Numerous exercise and diabetes guidelines and books are available for reference. Our physiological understanding can help guide individuals, but it cannot replace the importance of individuals monitoring their own blood glucose responses to a particular exercise.11 Where appropriate, referral to an exercise specialist such as a biokineticist, who has training in and understanding of the complexities of such cases, is likely to be of great value.

Until we have further long-duration, prospective data, assessing large cohorts of people with type 1 diabetes in different modes of exercise and controlling for factors such as diet and adjustment of insulin dosages, we need to encourage regular activity for the additional health-related benefits.

Patients with type 1 diabetes who exercise regularly report that they feel better, sleep better, have more energy and are more self-disciplined. Ideally, patients should be exercising daily, or on alternate days, to maximise insulin sensitivity. Patients who exercise on a regular basis plan their insulin and carbohydrate adjustments more efficiently than patients exercising sporadically. This would aid in the prevention and management of hypoglycaemia and hyperglycaemia, and essentially should lead to better blood glucose control.

ReferencesPaffenbarger RS, Hyde RT, Wing AL, Min Lee I, Jung DL, Kampert JB. The 1. association of changes in physical-activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993: 328: 538–545.Farrell SW, Kampert JB, Kohl HW III, Barlow CE, Macera CA, Paffenbarger RS Jr, 2. et al. Influences of cardiorespiratory fitness levels and other predictors on cardiovascular disease mortality in men. Med Sci Sports Exercise 1998: 30(6): 899–905.Wei M, Gibbons LW, Kampert JB, Milton Z, Nichaman MD, Blair SN. Low 3. cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Int Med 2000: 132(8): 605–611. Chimen M, Kennedy A, Nirantharakumar K, Pang T, Andrews R, Narendran. What 4. are the health benefits of physical activity in type 1 diabetes mellitus? A literature review. Diabetolgia 2012: 55: 542–551. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman 5. AT, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374(9702): 1677–1686.Thomas D, Elliot EJ, Naughton GA. Exercise for type 2 diabetes. Cochrane 6. Database Syst Rev 2006, Issue 3 Art. No.: CD002968. Doi: 10.1002/14651858.CD002968.pub 2.Soedamah-Muthu SS, Fuller JH, Mulnier HE, Raleigh VS Lawrenson RA, Colhoun 7. HM. All-cause mortality rates in patients with type 1 diabetes compared with a non-diabetic population from the UK general practice research database, 1992–1999. Diabetologia 2006: 49: 660–666.La Porte RE, Dorman JS, Tajima N, 8. et al. Pittsburgh Insulin-dependent Diabetes Mellitus and Mortality Study: physical activity and diabetic complications. Pediatrics 1986: 78: 1027–1033.Moy CS, Songer TJ, La Porte RE, Dorman JS, Kriska AM, Orchard TJ, 9. et al. Insulin-dependent diabetes mellitus, physical activity, and death. Am J Epidemiol 1993: 137(1): 74–81.Sigal RJ, Kenny G, OH P, Perkins B, Plotnikoff RC, Prud’homme D, Riddel MC. 10. Physical activity and diabetes. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008: 32(Suppl 1): S37–S39.Perry E, Gallen IW. Guidelines on the current best practice for the management of 11. type 1 diabetes, sport and exercise. Pract Diabetes Int 2009: 26(3): 116–123.Riddel, MC, Iscoe KE. Physical activity, sport, and pediatric diabetes. 12. Pediatric Diabetes 2006: 7: 60–70.Robertson K, Adolfsson P, Riddell MC, Scheiner G, Hanas R. Exercise in children 13. and adolescents with diabetes. Pediatric Diabetes 2009: 10(Suppl 12): 154–168.Youngren JF. Exercise and the regulation of blood glucose. Diabetes manager 14. 2011. pbworks.com/w/page/176178.Brazeau A, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity 15. among patients with type 1 diabetes. Diabetes Care 2008: 31(11): 2108–2109.McMahon SK, Ferreira LD, Ratnam N, Davey RJ, Youngs LM, Davis EA, 16. et al. Glucose requirements to maintain euglycaemia after moderate-intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab 2007: 92(3): 963–968.Ruegemer17. JJ, Squires RW, Marsh HM, et al. Differences between pre-breakfast and late afternoon glycemic responses to exercise in IDDM patients. Diabetes Care 1990: 13: 104–110. Tansey MJ, Tsalikian E, Beck RW, Mauras N, Buckingham BA, Weinzimer SA, 18. et al. The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care 2006; 29(1): 20–25. Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson J. Guidelines for premeal insulin 19. dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (Ultralente-Lispro). Diabetes Care 2001; 24(4): 625–630.Grimm JJ, Ybarra J, Berne C Muchnick S, Golay A. A new table for prevention of 20. hypoglycemia during physical activity in type 1 diabetic patients. Diabetes Metab 2004: 30: 465–470.McMahon SK, Ferreira LD, Ratnam N, Davey R, Youngs LM, Davis EA, 21. et al. Glucose requirements to maintain euglycemia after moderate-intensity afternoon exercise in adolescents with type 1 diabetes are increased in a biphasic manner. J Clin Endocrinol Metab 2007: 92(3): 963–968.Berardi JM, Noreen EE, Lemon PW. Recovery from a cycling time trial is enhanced 22. with carbohydrate-protein supplementation vs. isoenergetic carbohydrate supple-mentation. J Int Soc Sports Nutr 2008: 24(5): 24. Galassatti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN. Effect of 23. antecedent hypoglycemia on counter-regulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes 2003: 52: 1761–1769. Lumb A, Gallen IW. Insulin dose adjustment and exercise in type 1 diabetes. What 24. do we tell the patient? Br J Diabetes Vasc Dis 2009: 9: 273–277.Herbst A, Bachran R, Kapellen T, Holl R. Effects of regular physical activity on 25. control of glycemia in pediatric patients with type 1 diabetes mellitus; for the DPV Science Initiative. Arch Pediatr Adolesc Med 2006; 160: 573–577.Bernardini A, Vanelli M, Chiari G, Lovane B, Gelmetti C, Vitale R, Erricoet K. 26. Adherence to physical activity in young people with type 1 diabetes.2004. Acta BioMedica Ateneo Parmense 2004; 75(3): 153–157.



Optimal combination therapy in hypertension

Prof Neil Poulter

Throughout the world, hypertension is the single biggest contributor to death – killing via cardiovascular disease. It’s therefore

imperative to treat it, and to get that treatment right. Professor Neil Poulter, professor of Preventive Cardiovascular Medicine, Imperial College London, UK, expressed this view during his recent visit to South Africa as a guest of Servier Laboratories.

In 2000, there were approximately one billion hypertensives worldwide and it is projected that the number will rise to 1.56 billion by 2025. ‘The problem will continue to get worse’, said Prof Poulter. ‘As populations develop, people age, adopt unhealthy dietary habits, exercise less and drink more, which lead to increased weight and predispose to high blood pressure. Controlling blood pressure with medication is one of the most cost-effective ways of reducing the premature, and largely preventable, cardiovascular morbidity and mortality that results from this.’

There are more data on hypertension than in any other area of medicine, according to Prof Poulter, and yet the various guidelines on the subject are not in agreement. ‘Monotherapy is usually inadequate, but whether you start with two drugs or move from monotherapy to combination therapy, what should you use? The 2007 ESH/ESC guidelines recommend starting with thiazide diuretics, even though the data do not support their use. The recommendation should be simply for diuretics.’ The 2009 guidelines streamlined matters by recommending one of the following:

angiotensin converting enzyme inhibitor (ACEI) plus diuretic• angiotensin receptor blocker (ARB) plus diuretic• calcium channel blocker (CCB) plus diuretic• ACEI plus CCB• ARB plus CCB.•

The first two and the last two are known colloquially in the UK as ‘A+D’ and ‘A+C’ strategies.

Reviewing the various A+D trials (LIFE, VALUE, PROGRESS, HYVET and ADVANCE), Prof Poulter noted that more than one trial had shown a benefit for this type of combination with regard to stroke and coronary risk reduction. Both HYVET and ADVANCE trials also showed benefits in respect of all-cause mortality, something not often improved in hypertension trials.

Turning to A+C studies, and the ASCOT trial in particular, Prof Poulter observed that the combination of amlodipine and perindopril had shown superiority over a beta-blocker–thiazide diuretic combination in terms of all-cause mortality. The trial was therefore stopped early. ‘ACE inhibitors appear to have benefits beyond blood pressure when it comes to coronary protection, and CCBs appear to have benefits beyond blood pressure in relation to stroke prevention. So the combination of an ACE inhibitor and a CCB, as in ASCOT, might be expected to generate extra benefits in both. Every cardiovascular risk factor apart from heart rate

was positively impacted on, and statistically highly significantly so by amlodipine–perindopril.’

The latest novel finding to emerge from the ASCOT trial was the role of blood pressure variability in predicting patients’ stroke and coronary heart disease (CHD) outcomes. ‘Does it matter more than average blood pressure? Yes. How much blood pressure varied was the most important factor. Nothing predicted both stroke and CHD risk better than long-term blood pressure variability, i.e. over several years’, said Prof Poulter.

The discovery may well lead to what he describes as a ‘sea change’ in how blood pressure should be perceived. ‘We now know that intermittent

hypertension is more dangerous than constant hypertension, and this has significant implications for how blood pressure should be monitored, measured and treated. Mean blood pressure has a minimal association with stroke and CHD outcomes, while visit-to-visit variability is a powerful predictor of both.’ Perindopril-amlodipine was shown to be superior to a beta-blocker-thiazide diuretic in controlling blood pressure variability.

More recently, the ACCOMPLISH trial evaluated a single-pill ACEI–CCB combination versus ACEI–low-dose thiazide. The primary endpoint, a composite of cardiovascular events and cardiovascular death, favoured the A+C combination. Yet the ACEI–thiazide combination is probably the most commonly used combination of antihypertensive worldwide.

In the context of the ASCOT and ACCOMPLISH trials, the NICE 2011 guidelines now recommend the following. As a first step, in patients under 55 years, start with an A. In patients over 55 years and/or of African/Caribbean descent, start with a C. The second step is to combine them. Because this combination is believed to be the best, it is now central to the guidelines, which no longer advocate the use of thiazide diuretics.

Summarising the evidence for diuretics in hypertension trials, Prof Poulter said that the diuretic of choice is not a thiazide. ‘There is no evidence of benefit from low-dose thiazides and they were shown to be inferior to other options in both ASCOT and ACCOMPLISH trials. There is, however, some good evidence for higher-dose non-thiazide diuretics such as chlorthalidone and indapamide.’

Turning his attention to what not to combine, he cited the findings of the ONTARGET trial in which an ACEI-ARB combination was shown to have no benefits in respect of cardiovascular events. His feeling was that there was a disconnect between the benefits of preventing proteinuria versus cardiovascular events.

Having established the superiority of A+C in general, and perindopril-amlodipine specifically, Prof Poulter concluded that despite unaccountable resistance to fixed-dose combination pills in the UK, this was the way to go. ‘Compliance has been shown to be 21% better with fixed-dose combinations, which makes a single pill a no-brainer. If it can be done at no extra cost, why not?’

PETER WAGENAAR

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Improving glucose control and quality of life for type 2 diabetes patients demands clinical acumen and the timely introduction of or switching to analogue insulin therapies. The A1chieve

study was an observational study across four continents (Asia, Africa, Latin America and Europe), to assess insulin usage in clinical practice, particularly evaluating effectiveness in terms of HbA1c

, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels, and patient quality of life.

A focus on developing countries An important aim was to remedy the deficit of data on the efficacy and safety of insulin analogues in routine clinical care in less well-resourced or newly developed countries. The baseline data from the 66 000 patients recruited in A1chieve1 shows the depth of the unmet clinical need in diabetes management in everyday practice. Overall baseline HbA1c control was poor, at 9.5 ± 1.8%.

Diabetes duration among insulin-naïve patients was 6.6 years, while prior insulin users had a diabetes history of 10.8 years. There were slightly more men than women; 55% were male. Prior oral glucose therapy included metformin, sulfonylureas and thiazolidinediones.

Baseline HbA1c level was similar in all regions, whether prior insulin treated or not, with the Latin American region showing the highest (9.9%), and South Asia the lowest (9.3%) levels.

Achieving improved glucose control and quality of life with analogue insulinsA1chieve study in everyday clinical practice

JULIA AALBERS

Insulin-experienced people were somewhat older than the insulin-naïve cohort (55.6 vs 53.2 years) and had a higher body mass index (BMI).

Study designIn the study of six months’ duration, clinicians were not subjected to defined study-related criteria and were free to use any insulin or treatment, but patients inclued in this study were started on Novomix® 30, NovoRapid® and Levemir® as local practice dictated. This is important as it reflects daily clinical practice unrelated to clinical trial definitions. The final results from A1chieve were unveiled at the International Diabetes Federation (IDF) Watch diabetes congress in Dubai, 4–8 December 2011.

Improved blood glucose control Blood glucose control improved markedly between baseline and six months in both the insulin-naïve and prior insulin-user groups on therapy with analogue insulins. After six months, the percentage of patients with an HbA1c level below 7% increased dramatically from 4 to 32%. Reduction of use of oral glucose-lowering drugs was evident in both insulin-naïve and -experienced regimens. In-depth analysis of insulin usage and control highlighted interesting data pertinent to everyday practice.1

Fig. 1. Baseline and week 24 mean HbA1c level (%) in those patients adding insulin aspart to a basal insulin.

Fig. 2. Baseline and week 24 mean FPG (mmol/l) and PPG levels (mmol/l) in those patients adding insulin aspart to a basal insulin.




Addition of insulin aspart (NovoRapid) to basal therapyAs fasting plasma glucose levels increase, mealtime insulin secretion is progressively impaired and clinicians add a quick-acting insulin to improve control. In this evaluation of the addition of insulin aspart to basal analogue insulin (Levemir®), HbA1c level improved, with a mean reduction of 2.3% over the six months (Fig. 1), as did the FPG and PPG levels (Fig. 2).2

Switching from basal insulin glargine to detemir (Levemir®)In a sub-group2 of almost 1 000 patients who were switched from insulin glargine to detemir to improve glycaemic control, mean overall HbA1c level was significantly reduced by 1.3% at six months, while insulin dosage increased from 0.35 to 0.42 U/kg/day (Fig. 3). Hypoglycaemia was reduced on insulin detemir and quality of life improved (Fig. 4).

Switching to Novomix (BIAsp 30) from premixed human insulin3

This large group (6 326) of patients in the A1chieve study, who started and completed the six-month study on biphasic insulin aspart, showed a 1.7% reduction in HbA1c level over the six

Fig. 4. Change in HRQoL from baseline to final visit shown as mean EQ-5D questionnaire and VAS score.

Fig. 5. Change in HbA1c after 24 weeks of treatment with BIAsp 30 ± OGLDs in people previously receiving BHI 30 therapy.

Fig. 3. Insulin dose change (U/kg) pre-study, baseline and 24 week (final visit).



Fig. 6. Change in FPG (A) and post-breakfast PPG (B) levels after 24 weeks of treatment with BIAsp 30 ± OGLDs in people previously receiving BHI 30 therapy.

Fig. 7. Change in total, major, nocturnal and minor hypoglycaemia after 24 weeks of treatment with BIAsp 30 ± OGLDs.

A

B

months (Fig. 5), compared to their baseline treatment on premixed human insulin. Mean FPG and PPG levels were also significantly reduced (Fig. 6), and importantly, reported rates of hypoglycaemia were significantly lower at six months, compared with baseline (Fig. 7).

Improvement in quality of lifeThis extensive quality-of-life evaluation using the validated EQ-5D

questionnaire in the total cohort of 66 726 patients included in the A1chieve study provides positive re-enforcement for both clinicians and patients who have differing but important concerns regarding insulin usage in type 2 diabetes patients. Overall, the quality of life of patients starting insulin with, or switching to insulin detemir, insulin aspart or biphasic insulin aspart 30 experienced significantly increased improvements across all five component health dimensions.

ReferencesHome P, Naggar NE, Khamseh M, Gonzalez-Galvez G, Shen C, 1. et al. An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: the A1chieve study. Diabetes Res Clin Pract 2011; 94(3): 352–363.Hussein Z, Shah S, Gonzalez-Galvez G, Latif Z, Home P, 2. et al. Effect of adding insulin aspart to basal insulin in clinical practice: results from the global A1chieve observational study. Presentation from IDF 2011.Litwak L, Haddad J, Su Yen G, Chakkarwar P, Baik SH. Improved glycaemic 3. control after transferring basal insulin from glargine to detemir in type 2 diabetes: subgroup analyses of A1chieve. Presentation from IDF 2011.Hasan MI, Yuxiu L, Naggar NE, Khamseh ME, 4. et al. Safety and efficacy of biphasic insulin aspart in people with type 2 diabetes switched from premixed human insulin: results from A1chieve study. Presentation from IDF 2011.


SA JOURNAL OF DIABETES & VASCULAR DISEASE CONFERENCE REPORT

I was recently privileged to attend the Diabetes Expert Forum in Marseilles on

11 and 12 May 2012. This was a two-day conference with world-class international speakers, sponsored by Lilly.

Initiation and use of insulin in type 2 diabetesThe first speaker was Prof Dario Giugliano, from Naples University, Italy. He discussed when and how to initiate insulin in type 2 diabetes. Data show that 26% of diabetics in the USA are on insulin and about 30% of those in Italy. He also presented data suggesting about 40% of type 2 diabetes patients can reach target on basal insulin, according to a recent meta-analysis. However, if the HbA1c level is more than 9%, it is unlikely that HbA1c control will be achieved with basal insulin alone.

He gave a few pointers as to which patients should be started on insulin, including patients who fail to control their diabetes on two drugs, those who are more than 1% above target on two drugs, and symptomatic patients. He also discussed the new idea of a patient-centred approach for diabetes care and said the 4-S principle was important: Safe, Successful, Simple and Sensible initiation of insulin and basal insulin. He also mentioned new GLP-1 analogues, including dulaglutide, which will be available in the future.

GLP-1 receptor agonists in type 2 diabetesDr Guillaume Charpentier from Paris gave a talk on the use of GLP-1 receptor agonists in type 2 diabetes. According to studies, about 45–50% of patients can reach target on GLP-1 analogues, which is comparable to basal insulin use. These drugs are clearly more potent than DPP-4 inhibitors, and liraglutide has been shown to be more effective than exenatide (bd) in general control and weight loss. However, extended-release exenatide has been shown to be superior to liraglutide in terms of glucose control, although the difference is quite small. Currently in South Africa, only liraglutide (Victoza) and twice-daily exenatide (Byetta) are available.

It is difficult to predict a response to GLP-1 analogues. Recent data showed that

Diabetes Expert Forum Perspectives on diabetes management in 2012

people with longstanding diabetes often responded well to GLP-1 analogues and this should not be an exclusion criterion. It has also been shown that exenatide can be combined with insulin glargine as a very effective combination.

Dr Charpentier also discussed a recent article by Zinman in Diabetes, Obesity and Metabolism (2012), which gives criteria for good diabetes care. These criteria combined a goal of HbA1c level less than 7%, no weight gain and no hypoglycaemia. Liraglutide use could achieve this goal in up to 40% of cases, while exenatide (bd) could achieve this in 25% of cases. Both are more effective than any other diabetic agents available.

Treatment of the elderly diabeticAn interesting talk by Prof Isabelle Bourdel-Marchasson, from Bordeaux University in France, was given on treatment considerations in the elderly diabetic patient. She discussed the definition of frail patients and what constitutes frailty; and concluded that gait speed is a good measure. Many patients older than 75 years are diabetics. There is a clearly documented increased mortality rate in diabetics and one must specifically try to avoid hypoglycaemia, more often seen in elderly patients with dementia, which can lead to other complications.

The relative risk of dementia in diabetes is increased 2.3-fold. Risk of vascular dementia increases as much as three-fold in diabetic patients on treatment. These very frail patients are also more likely to develop hyperosmolar comas. Different goals must be set for these frail patients, who should have an HbA1c target level of 7.5–8%. In patients who are dependent, the goal should be 7.5–8.5% HbA1c.

Specific preference must be given to medicine that does not cause hypoglycaemia; metformin and DPP-4 inhibitors are the first choices, after which other options need consideration. Only low-risk sulfonylureas should be considered and renal function should always be kept in mind.

Safety considerations and drug interactions of new diabetes agentsProf Andre Scheen from Belgium gave a talk on safety considerations and drug

interactions of new diabetic drug classes. Common drugs such as purbac, flagyl and fluconazole all have a potentiating effect on sulfonylureas. This should be kept in mind, because combined use will increase the risk of hypoglycaemia.

In terms of DPP-4 inhibitors, he discussed the fact that they showed very low side-effect profiles in all the studies. Nasal congestion was seen initially but not confirmed in meta-analyses. Infections due to defects in T cells were seen initially but also not confirmed by follow-up meta-analyses. The risk of pancreatitis is still being investigated and currently there are only case reports. The increased risk of pancreatitis and pancreatic cancer will be closely watched in the future.

There is also the suggestion that these drugs might have cardiovascular benefits. On-going outcome trials are already in progress.

The new SGLT-2 inhibitor dapagliflozin and others of this class were also discussed. These agents are not yet registered in this country and will take quite a while to reach our shores. Increased glucosuria, caused by SGLT-2 inhibitors, tends to cause weight loss, but also an increase in genital and urinary tract infections. The response of these drugs is independent of the duration of diabetes and will give a predictable result in longstanding diabetics. The mode of action is not dependant on beta-cell function.

Diabetes and cancerProf Martin Buysschaert from Belgium discussed diabetes and cancer, showing data on the increased risk of cancer in diabetes, particularly cancers of the liver, biliary tract, pancreas, colon, kidneys and breast. The mechanisms of oncogenesis were discussed, including hyperglycaemia. The higher the HbA1c level, the greater the risk was for cancer. With an HbA1c level of 6%, no clear increased risk could be shown, whereas an HbA1c of 10% represented a two-fold increased risk of cancer.

Other mechanisms of oncogenesis included hyperinsulinaemia and increased IGF-1 levels. He also discussed the possibility of so-called ‘intruders’, among which were many of the drugs used by diabetics that might increase the risk of cancer, including the new DPP-4 inhibitors and GLP-1 analogues.

CONFERENCE REPORT SA JOURNAL OF DIABETES & VASCULAR DISEASE

Beta-cell death and the mitochondrial permeability transition poreDr Sandrine Lablanche was awarded the Lilly Award (2012) for Best Research and Lecture. Her very interesting presentation concerned the involvement of the mitochondrial per-

meability transition pore (PTP) and pancreatic beta-cell death.

She presented fascinating research on the issue of pancreatic beta-cell death on transplant, with 30% beta-cell loss at the time of transplantation. It appears that the mitochondrial PTP plays an important role in this. This mitochondrial PTP also seems to be involved in glucose toxicity. Opening of the pore is increased by calcium, radical oxygen species and adenine, and inhibited by cyclosporin and metformin, even in the presence of high glucose concentrations.

Ischaemia and reperfusion tend to increase the opening of the mitochondrial PTP, leading to beta-cell death. It has been shown in animal studies of isolated beta-

cells that pre-treatment with metformin and cyclosporin could prevent ischaemic reperfusion damage to the beta-cells. Other factors that may affect pore opening include N-acetyl-cysteine (prevents opening) and oxidative stress.

Current research is investigating improving the survival of beta-cells in transplantation for type 1 diabetes patients. Consideration will be given for research to investigate pre-treatment with metformin or cyclosporin in improving beta-cell survival. Further research is clearly necessary in this very interesting area of beta-cell transplant and improving survival of the transplanted cells.

Landi Lombard

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Parking was at a premium during the recent SEMDSA congress hosted in Cape Town.

Balmy autumn weather and spectacular Atlantic views marginally compensated for the trudge up a steep incline. However, the congress itself proved to be most worthwhile. Many interesting local studies were presented. Two topics appeared to dominate the chit chat during tea times: evidence that has emerged on the use of incretin-based therapies in the treatment of diabetes, and the role that vitamin D plays in the general health of humans.

Incretin-based therapies The incretins are among the many hormones responsible for glucose homeostasis. Incretins, including glucagon-like peptide-1 (GLP-1), are released by intestinal entero-endocrine cells in response to a meal. GLP-1 elicits glucose-dependent insulin secretion; suppresses glucagon secretion, appetite and food intake; slows gastric emptying, and stimulates beta-cell proliferation in pre-clinical models. Circulating GLP-1 is short-lived, 80% is degraded within two minutes by the enzyme dipeptidyl peptidase-4 (DPP-4).

GLP-1 secretion is diminished in patients with type 2 diabetes mellitus (T2DM); how-ever its insulinotropic activity is maintained, resulting in the targeting of this hormone for diabetic therapy. Incretin agents include GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists produce effects similar to native GLP-1 and are resistant to degrada-tion by DPP-4. DPP-4 inhibitors inactivate the enzyme responsible for GLP-1 degradation. Exenatide, a synthetic formulation on exend-in-4, has similar effects to native GLP-1.1

Undoubtedly the highlight of the meeting, a lunchtime professorial debate between the eminent opinion leaders David Nathan (MGH Diabetes Centre, Harvard Medical School, Boston, USA) and Edward Gale (Diabetes and Metabolism Unit, University of Bristol, UK) provided an excellent platform to summarise currently known advantages and disadvantages of incretin therapy. I am uncertain as to how the decision was made (who made it up that steep hill the fastest?), but David Nathan was in the position of defending the integrity of incretin therapy whereas Edward Gale raised some of the concerns surrounding these agents. In introducing these speakers, it was stated that even though they will fight vociferously to

47th SEMDSA congress 2012get their points across, it doesn’t necessarily mean that they agree with everything they say.

In support of incretin therapy, Prof Nathan explored value judgements on available data. Among the main points under consideration was that of an increased body mass index (BMI) indicating an increased risk for the development of diabetes. Those with a BMI > 35 kg/m2 face a hundred times greater risk of T2DM. Obesity and other lifestyle considerations (falling activity levels) are contributing to the current global diabetes pandemic.

The undesirability of therapeutic weight gain with some anti-diabetic agents may also increase cardiovascular disease risk. Another consideration is that of the microvascular complications of diabetes. Glycaemic status has a significant effect on microvascular complications; risk reduction has been equated to a lowered HbA1c level.

Referring to the LEAD studies, Prof Nathan noted that liraglutide was superior to comparators in HbA1c level reduction. He added that GLP-1 agonists have the value-add of weight loss; no hypoglycaemia (unless in combination with other agents); and the cardiovascular benefits of decreased systolic blood pressure, decreased triglycerides and being high-density lipoprotein (HDL) and low-density lipoprotein (LDL) neutral.

The GLP-1 agonists also display anti-inflammatory effects and improvement of beta-cell function. He added that it has not yet been demonstrated in humans that GLP-1 analogues improve beta-cell mass. In the concluding statements of his argument, Prof Nathan raised the question of how to weight composite outcomes in trials for clinical importance or effect.

Prof Gale’s turn at the podium began with an amusing anecdote from his student days. He referred to the wise words of one of his own mentors; that there are three phases in the use of any new pharmaceutical agent: ‘the best thing since sliced bread’, ‘I wouldn’t use it on my dog’, and finally, ‘it is appropriate for use in certain sub-populations’.

With any new agent, problems emerge over time. He stated that all diabetes agents are equally effective for HbA1c level reduction. In terms of incretin therapy, we are ‘optimism rich and data poor’.

Generally, there is insufficient outcome data for DPP-4 inhibitors, with a significantly

more expensive cost to be factored in. A cost comparison made revealed a ratio of 35 metformin to one liraglutide for equivalent treatment costs. In dealing with the advantages espoused by Prof Nathan, Prof Gale questioned whether the weight loss observed with GLP-1 agonists could be sustained over the long term. He also mentioned adverse events, quoting a 20% discontinuation within three months, with 7% of patients immediately unable to tolerate GLP-1 agonists.

He examined the side effects of pancreatitis, renal failure and anaphylaxis. GLP-1 receptors are profusely expressed in pancreatic exocrine ducts and there is evidence that GLP-1 has a proliferative effect on the duct cells, resulting in a thickening of the lining. Low-grade inflammation occurs, which could result in sub-clinical pancreatitis, although there are currently no data on pancreatic enzyme levels in humans. Prof Gale also raised the issue of a highly significant excess of pancreatitis with the use of exenatide and sitagliptin. This is consistently reported within the class of GLP-1 agonists, but not with other anti-diabetic agents.

Another consideration was that of beta-cell mass. Proliferation of beta-cells in humans decreases as they age, therefore we can’t increase beta-cell mass, according to Prof Gale. His final concerns were increased risk of pancreatic cancer and fluid depletion syndromes with the use of GLP-1 agonists.

Two other interesting presentations exam-ined the potentially cardioprotective effects of GLP-1 agonists and DPP-4 inhibitors.

DPP-4 inhibition is cardioprotective and improves glucose homeostasis in obese, insulin-resistant rats

B Huisamen, University of Stellenbosch Faculty of Health Sciences, Department Biomedical Sciences, Division Medical Physiology, Cape Town

Currently, therapy based on GLP-1 is one of the most promising for type 2 diabetes. Because of the rapid degradation of GLP-1 by DPP-4, a two-pronged pharmaceutical attack has been developed with the use of GLP-1 analogues and DPP-4 inhibitors. Research has focused on the use of DPP-4 inhibitors to raise attenuated levels of GLP-1 observed in type 2 diabetes.



There is still a dearth of evidence on the cardiovascular effects of incretin therapy. Research has found cardioprotective out-comes in rats, which is most effective when GLP-1 is accompanied by a DPP-4 inhibi-tor. Also observed was increased functional recovery of hearts in reperfusion after an ischaemic event.

In this study, Dr Huisamen and colleagues tested whether treatment with a DPP-4 inhibitor of obese, pre-diabetic rats with car-diovascular pathology was cardioprotective. Diet-induced obesity (animal feed supple-mented with sucrose and condensed milk) was effected in Wistar rats over a period of 12 weeks, resulting in visceral obesity, increased intraperitoneal fat levels and sig-nificantly lower levels of GLP-1, exhibiting insulin resistance. These animals had higher blood glucose levels, dyslipidaemia and signs of oxidative stress.

Following the initial 12-week period, half of each of the control-fed and obesi-ty-induced rats were treated orally for four weeks with vildagliptin (DPP-4 inhibitor) 10 mg/kg/day in jelly blocks, in conjunc-tion with the obesity-inducing diet. Upon sacrifice, blood was collected and the body weight and intraperitoneal fat weight was recorded. Pancreases were also harvested. Isolated hearts were perfused and the kinase profile was determined in the reperfusion phase. Ventricular myocytes were prepared to determine insulin sensitivity.

Results indicated increased GLP-1 meas-urement, a reduction in plasma insulin levels and enhanced beta-cells (compared to base-line beta-:alpha-cell ratio) upon treatment. Dr Huisamen stated that similar to clinical experience, vildagliptin therapy was found to have no effect on weight and amount of intraperitoneal fat, and insulin and non-fasting glucose levels.

The area of infarct, as opposed to area of infarct risk, was found to be larger in

the more obese animals. Those animals with DPP-4 treatment had smaller infarcts. The kinase pathway profile (associated with cardioprotection) was used to measure car-dioprotective effects. An increase in protein kinase B levels and significantly reduced phosphorylation of protein kinase B in obese rats was found to be partially restored by the use of DPP-4 inhibitors. Cardiomyocytes did not show insulin sensitisation.

In summary, Dr Huisamen indicated that vildagliptin therapy in obese, insulin-resist-ant rat models was found to be cardiopro-tective and alleviated insulin resistance.

Raising the bar: liraglutide (GLP-1 analogues) and composite endpoints MAK Omar, Centre for Diabetes and Endocrinology, Overport, Durban

Mortality in T2DM is most commonly a result of cardiovascular disease. Obesity, dyslipidaemia and hypertension co-exist in up to 90% of T2DM patients. These are all poorly controlled risk factors for cardi-ovascular disease, with less than 10% of diabetics having good control of all these factors. However, optimal control with existing treatments is counterbalanced by the common side effects of weight gain and increased hypoglycaemic events. Hypogly-caemia is a very important risk factor of cardiovascular disease.

Historically, the unmet needs of ideal diabetes therapy include the issues of weight gain, hypoglycaemia and increased cardiovascular events. Prof Omar went on to elaborate how the GLP-1 analogue, liraglutide, can be effective in meeting the needs of diabetes therapy, with a resultant effect on cardiovascular risk factors.

Prof Omar referred to results of the LEAD MT programme that compared liraglutide as monotherapy and as combination therapy

with other agents (metformin, glimepiride, rosiglitazone, insulin glargine and exenatide). Liraglutide was shown to be the most effec-tive at achieving the goal of improving HbA1c levels (78%) and weight loss. Liraglutide was also found to have a modest effect on hypertension, and in terms of dyslipidaemia, there was a 10% reduction in total choles-terol and an 18–20% reduction in LDL cho-lesterol.

Two composite endpoints were exam-ined. The first target group endpoint was an HbA1c level < 7.0%, with no weight gain and no confirmed hypoglycaemic episode. The second target group endpoint differed only in the third criterion, a systolic blood pressure (SBP) < 130 mmHg.

Meta-analysis revealed that of those study subjects taking liraglutide therapy, 40% managed to achieve all three of the first endpoints and 25% achieved all three of the second endpoints. Two-thirds of liraglutide patients achieved the HbA1c target and 70% achieved the no weight-gain target. The target SBP < 130 mmHg was achieved by 60% of the liraglutide patients. Liraglutide was also found to have a more favourable side-effects ratio than the comparator agents in the LEAD study.

Prof Omar then pondered the question of whether the above-established benefits of liraglutide therapy favourably influence cardiovascular events. Quite simply, there is no answer yet. He referred to a number of on-going intervention trials, with results pending in 2015–2018, and concluded by saying, ‘We are living in very exciting times…’

Glenda HardyCampbell, RK. Clarifying the role of incretin-based 1. therapies in the treatment of type 2 diabetes mellitus. Clin Therapeut 2011; 33(5); 511–527.Takiishi T, 2. et al. Vitamin D and diabetes. Endocrinol Metab Clin N Am 2010; 39: 419–446.

Vitamin D is a secosteroid generated by the skin under the influence of ultraviolet light. Rather than a true vitamin, vitamin D is a prohormone. Normal human diets are

Vitamin D and human health: a magic bullet?

Roger Bouillon, professor of Medicine, Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit, Leuven, Belgium

usually poor in vitamin D, with fatty fish being one of the few food sources rich in vitamin D.

Regardless of the source of vitamin D, it needs to be hydroxylated twice before becoming biologically active. This occurs in the liver and the kidney. Vitamin D and its metabolites are bound to a carrier protein (vitamin D-binding proteins: DBP) in the circulation. Vitamin D receptors (VDRs) are found in almost all nucleated cells present in a range of tissues, with the highest VDR

concentrations being in the epithelial cells of the gut.

The vitamin D endocrine system is essen-tial for calcium and bone homeostasis. A large number of genes exert direct and indi-rect control of vitamin D receptor expres-sion. Every tissue transports calcium, with vitamin D required for calcium homeostasis. In the absence of a functional VDR or cyto-chrome P27B1 (CYP27B1), severely rachitic bone occurs. Historically, ricketts was a fre-quent cause of death. Enzymes and proteins

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essential for the action of vitamin D are also present in tissues not related to bone and calcium metabolism, such as the immune system. There is much evidence of non-classi-cal targets, particularly an endocrine focus.

Tissue-specific deletions of VDR have now better defined the role of vitamin D in different tissues, with multiple implications for humans. Research in mice with a calbindin deletion found that in the absence of VDRs in the intestinal endothelium, excess osteoid tissue is produced. At only 20% of normal VDR levels in the intestine, calcium homeostasis in the gut normalises, with normal bone and growth plates resulting. However, when there is a total knockout of VDR in the gut, a massive loss of bone results with an excess of osteoid tissue.

Deletion of VDR in the growth plate affects kidney function. An increase in sodium and phosphorous transport occurs, as well as increased serum phosphate. Levels of fibroblast growth factor are also affected. The effects of VDR knockout in osteoblasts differ depending on diet. With normal calcium levels in the diet, calcium and phosphorous transport remains normal, as does the bone. In a low-calcium diet however, impaired bone mineralisation is observed in the knockout mice with osteoblast VDR deletion.

The native immune system is activated by the vitamin D endocrine system. Immune system VDR knockout in mice has vary-ing effects. The acquired immune system is damped down by receptor knockout, whereas the natural immune system regulated by mac-

rophages is stimulated, with monocyte activa-tion inducing the production of defensins.

Vitamin D deficiency can also affect the survival of T cells. Individuals with low levels of vitamin D are observed to have more infections. A low VDR expression increases the risk of Mycobacterium tuberculosis (MTB) and other respiratory infections. Patients with active MTB are found to have reduced levels, and those who are HIV positive have very low levels of vitamin D. Evidence has emerged that vitamin D supplementation improves chronic obstructive pulmonary disorder. Vitamin D or VDR deficiency leads to increased sensitivity to autoimmune diseases, such as inflammatory bowel disease or autoimmune diabetes.

Vitamin D deficiency in early life has a legacy effect in later life. Early life vitamin D deficiency in mice doubles the diabetes risk and Dr Bouillon postulated that a reduction in incidence of type 1 diabetes mellitus of 70% could be achieved with vitamin D supplementation in the first year of life. An observational study has also reported a doubling of risk of multiple sclerosis with decreased vitamin D levels.

An increased incidence of cancer has been observed in mice with VDR knockout in the intestinal mucosa, breast and prostate. While there was no spontaneous increase in cancer in these mice, they were more prone to oncogen-, chemocarcinogen- and ultraviolet B-induced tumours. Observational data from the NHANES III study found an increased risk of colon cancer with low levels of vitamin D.

In terms of cardiovascular disease, VDR knockout mice displayed higher renin hyper-tension, increased cardiac hypertrophy and increased thrombosis. Observational reports associated increased risk of cardiovascular events with decreasing levels of vitamin D in humans. Cardiovascular mortality is increased in those with vitamin D levels < 10–15 ng/mol, however, interventional studies have shown no effect on myocardial infarction and stroke.

Vitamin D deficiency is associated with the metabolic syndrome. Vitamin D supple-mentation has been associated with resolving maturation problems (weakness) in skeletal muscle. The elderly also benefit from supple-mentation, with a decreased risk of falls.

Undoubtedly, vitamin D deficiency is associated with increased mortality rates. Supplementation could decrease mortality rates by as much as 8%.

What is the optimal supplementation level? One-third of the world’s population falls below the threshold level of 25 ng/mol. Dr Bouillon recommends 20 ng/mol as an ideal supplementation level. Faced with the question of possible harm in supplementation doses > 90 ng/mol, he referred to a trial where an increase in falls and fractures were observed with vitamin D levels maintained at > 90 ng/mol. His final response, ‘more is not better’.

G Hardy

Source: Presentation at 2012 SEMDSA congress, Cape Town, South Africa

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References:1. Nauck M, et al; for the LEAD-2 Study Group. Effi cacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination with Metformin, in Type 2 Diabetes. The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care. 2009;32(1):84-90. 2. Gallwitz B, et al. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64(2):267-276. 3. Garber A, et al; on behalf of the LEAD-3 (Mono) Study Group. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes, Obes Metab. 2011; 13: 348-356. 4. Chang AM, et al. The GLP-1 Derivative NN2211 Restores ß-cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose. Diabetes. 2003;52:1786-1791.

Proprietary Name: Victoza®. Scheduling Status: S4 Composition: Liraglutide 6 mg/ml. Indications: As an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus. Registration Number: 43/21.13/0781. For full prescribing information refer to package insert approved by the medicines regulatory authority.

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Reductions in HbA1C1-3

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Improvements in beta-cell function4



A faculty of top local and international opinion leaders were unanimous at the

incretin leadership summit hosted by Novo Nordisk in Cape Town on 5 May 2012. The incretin-based therapies represent a major advance on what was previously available for the treatment and management of type 2 diabetes and are revolutionising the way the condition is viewed.

GLP-1 and the beta-cellIslet cell dysfunction: an underlying defect in the pathophysiology of type 2 diabetes

Juris Meier, head: Division of Diabetology and GI Endocrinology, St Josef-Hospital, Ruhr-Universitat, Bochum, Germany

Over the past 10 to 15 years, there has been a shift

away from the focus on insulin resistance as the major cause of type 2 diabetes, with increasing recognition of the role of beta-cell mass and function. ‘We now look at many polymorphisms, few of which are found in adipose tissue, bone or the liver. The majority of the genes associated with type 2 diabetes are in the pancreas, making it primarily a pancreatic disease’, said Prof Meier.

On average, patients with type 2 diabetes have 65% less beta-cells than non-diabetics, a finding that has been replicated often and in many different populations, irrespective of whether the individuals in question were lean or obese. Prof Meier therefore feels that there is an important relationship between beta-cells and glycaemic control and that a normal beta-cell mass is required for glucose homeostasis.

Autopsy studies have shown that those with type 2 diabetes experience an increased rate of beta-cell apoptosis.1 ‘We have no clear answers yet as to why this is the case, but there are many factors associated with it. In chronic hyperglycaemia, the higher the glucose concentrations, the higher the rate of apoptosis, which means that hyperglycaemia per se accelerates the loss of beta-cells.’

‘Islet amyloid deposits, which are seldom seen in non-diabetics, are also a likely cause of the apoptosis; they are the result of IAPP, a beta-cytotoxic factor secreted with insulin. Other factors implicated include high con-centrations of free fatty acids, endoplasmatic

Novo Nordisk incretin leadership summit, Cape Townreticulum stress and autoimmune factors.’ He suggested that there might also be treatment-related factors involved over and above these endogenous ones.

‘The consequences of all of this include loss of first-phase insulin secretion, 85% of which is lost in type 2 diabetes patients. Loss of insulin pulsatility leads to peripheral insulin resistance. The clinical implications thereof are deficits in alpha- and beta-cell function in the postprandial context, along with disturbances in glucagon secretion. The normal glucose-induced decline in glucagon is almost absent in type 2 diabetes, leading to postprandial hyperglycaemia.’

Prof Meier cited an animal study, which showed a link between the reduction in insulin secretion, increased glucagon secretion and beta-cell loss.2 ‘Reduction in beta-cell mass in pigs was associated with high fasting glucagon levels, an almost identical picture to that seen in humans.’

There is an inverse relationship between insulin and glucagon, with the former driving down the latter. ‘This inverse interaction is lost in type 2 diabetes, leading to a failure to suppress glucagon’, said Prof Meier.

Both insulin resistance and impaired insulin secretion increase the risk of type 2 diabetes, and the major factor driving resistance is obesity. Obese individuals need more than three times as much insulin to maintain normoglycaemia as normal-weight individuals. Those with a body mass index (BMI) > 30 kg/m2 have a 15% greater risk of developing diabetes.

‘But if these are the causes of diabetes, then all obese individuals should develop the condition; yet 85% don’t. The differentiator is that those who don’t have a healthy pancreas develop diabetes, which leads to the conclusion that obesity, insulin resistance and impaired insulin secretion are important co-factors increasing diabetes risk, but are not themselves the underlying causes.’

Turning to the question of whether loss of beta-cell mass or function is the key issue, Prof Meier argued that both are important, as one goes along with the other. ‘If beta-cells are the key problem where insulin impairment in diabetes is concerned, we should be able to restore normal function by normalising beta-cell mass and function. We’ve shown this by transplanting a healthy pancreas into a previously diabetic patient. After two years, glucose values were normal,

evidence that healthy beta-cell mass and function can overcome insulin resistance.’

Summarising, Prof Meier observed that deficits in beta-cell mass can lead to stress and impaired function, allied to disturbances in alpha-cell function and insulin action. Beta-cell mass and function are closely related. ‘Restoration of beta-cell mass can normalise hyperglycaemia’, he concluded.

Targeting beta cells: the rationale for GLP-1 use in type 2 diabetes

Wolfgang E Schmidt, chair and professor of Internal Medicine and director of the Department of Medicine, St Josef-Hospital, Ruhr-Universitat, Bochum, Germany

The UKPDS showed that type 2 diabetes is associated with a progressive decline in beta-cells and by the time they are diagnosed, most patients will already have lost 50% of their beta-cells. Prof Schmidt underscored that stopping that decline is a challenge, but that glucagon-like peptide 1 (GLP-1), an incretin whose role in diabetes is increasingly being recognised, could help to achieve some currently unmet treatment goals. The so-called ‘incretin effect’ is severely impaired in type 2 diabetes patients, which suggests that if the ‘something missing’ is reconstituted, the condition could be positively impacted on.

‘The progressive loss of beta-cells starts early in the disease process, during the pre-clinical phase’, he said. ‘Even those who have only impaired fasting glucose levels experience beta-cell loss, and this loss is the basis for the deterioration in glucose control seen in so many studies. Different drugs have differing effects on beta-cell apoptosis. Incretin therapy now gives us the opportunity to intervene by targeting an aspect of islet cell dysfunction that other drugs don’t, namely the alpha-cell dysfunction/hyperactivity that causes hyperglucagonaemia.’

GLP-1 and 2 were discovered in 1983 and the former’s role in stimulating insulin secretion was identified in 1985. ‘It’s a player in the pathophysiology of diabetes as well as a promising candidate for therapy’, observed Prof Schmidt. ‘It normalises glucose levels in poorly controlled type 2 diabetes without inducing hyperglucagonaemia. Beta-cells are



Mahomed AK Omar, specialist physician/endocrinologist/diabetologist, Parklands Medical Centre, and honorary professor, Department of Diabetes

and Endocrinology, University of KwaZulu-Natal, Durban.

resensitised to glucose, elevated glucagon levels are reduced, and because GLP-1 is glucose dependent, its effects taper off as glucose levels normalise, therefore also minimising the risk of hypoglycaemic episodes.

Because higher doses of GLP-1 improve the insulin response in type 2 diabetes, elevating GLP-1 levels is the basis for the therapeutic concept behind the use of GLP-1 analogues. One such analogue, liraglutide, has been shown to improve both phases of insulin secretion. Its restoration of beta-cell sensitivity is an immediate effect, and it also works in a chronic setting, improving metabolic control, with positive effects on glycaemia, weight loss, insulin secretion and insulin sensitivity.

‘Liraglutide improves two markers of beta-cell function, HOMA-B and the pro-insulin/insulin ratio’, said Prof Schmidt. ‘Animal and in vitro studies have shown that it promotes beta-cell survival, stimulating proliferation and inhibiting apoptosis and, as a consequence, increasing mass.’ He added the rider that while the evidence for proliferation is currently indirect, it is hoped that long-running clinical studies will, in time, confirm this.

Liraglutide’s induction of weight loss, as seen in the LEAD studies,3-8 is a key advantage of the treatment. More than 75% of patients on liraglutide lost weight, with one-quarter losing an average of 7.7 kg. ‘Data from LEAD also support its being used as early as possible to preserve beta-cell mass and function, with greatest effectiveness seen in those with early-stage type 2 diabetes who still had a relatively high beta-cell mass.’

In conclusion, Prof Schmidt reiterated that targeting islet cell dysfunction resulted in preservation of beta-cell function and mass, with restoration of insulin pulsatility, normalisation of excessive glucagon secre-tion and normalisation of excessive hepatic glucose output. ‘GLP-1 therapy is a promis-ing option to help achieve this.’

Incretin-based therapies in type 2 diabetes: the clinical evidenceAre all incretin-based therapies created equal?

There are two types of incretin therapy, namely GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, each with differing modes of action and hence differing efficacy and safety profiles. Prof Omar began by pointing out that endogenous GLP-1 is degraded by DPP-4 and rendered inactive within two minutes. ‘This means we need to prolong the activity of GLP-1 to achieve metabolic effects. We can either inhibit DPP-4 to lengthen GLP-1’s action, or we can use a GLP-1 analogue that acts in the same way as GLP-1, but is not degraded by DPP-4.’ GLP-1 analogues are given subcutaneously. DPP-4 inhibitors are oral medications.

Liraglutide is a once-daily GLP-1 analogue with a 97% amino acid sequence similarity to human GLP-1. Its half-life has been prolonged to 13 hours. By contrast, the other GLP-1 analogue, exenatide, has only a 53% sequence homology compared to native GLP-1. It too is resistant to DPP-4 and has a longer half-life, though not as long as liraglutide’s. It is also available in an extended-release delivery system, exenatide ER, which is administered once a week (not available in South Africa).

Turning to pharmacodynamics, Prof Omar said that the concentration of active liraglutide is significantly higher than the GLP-1 concentration achievable with a DPP-4 inhibitor. This is significant in that small levels have only modest effects and higher levels are necessary to increase satiety and reduce weight.

The clinical advantages of liraglutide have been demonstrated in head-to-head trials. The 1860 LIRA-DDP-4 trial compared liraglutide to the DPP-4 inhibitor, sitagliptin.9 There was a significant drop in HbA1c levels in the liraglutide group, but only a modest benefit in the sitagliptin-treated patients. Sixty per cent of those on liraglutide achieved their target HbA1c level of < 7%, compared with only a quarter of those taking sitagliptin.’

When it came to body weight, liraglutide produced a 3- to 3.6-kg loss, where the drop with sitagliptin was only 1 kg. When it came to side effects, both agents were associated with some minor episodes of hypoglycaemia, while there was also some transient nausea with liraglutide’, Prof Omar noted.

Patient satisfaction rates were higher with liraglutide. After a year, some sitagliptin patients were switched to liraglutide; they experienced improvements in HbA1c level as well as additional weight loss. ‘It is impressive that patients rated treatment satisfaction higher with an injectable therapy that cased

mild gastrointestinal (GI) symptoms than an oral therapy with fewer GI symptoms.’

In the DURATION-2 study, which compared exenatide once weekly to sitagliptin or pioglitazone, superior HbA1c levels were achieved with exenatide ER.10 Sixty per cent of patients reached target on exenatide ER compared with only 30% on sitagliptin. ‘As expected, weight loss was also better with exenatide’, observed Prof Omar. ‘Side-effect profiles were similar, with no major hypoglycaemic episodes and only a low frequency of minor hypoglycaemia.’

So if the GLP-1 analogues are superior to the DPP-4 inhibitors, how do they compare against each other? In LEAD-6, exenatide was compared to liraglutide, with HbA1c level as the primary endpoint.8 Liraglutide had a significantly greater effect in lowering HbA1c levels than exenatide. Those switched from the latter to the former at 26 weeks experienced further improvement. Weight loss was similar with both agents.

Where side effects were concerned, there was transient nausea with liraglutide, but the rates of nausea were higher with exenatide and persisted for longer. ‘Antibody formation was also much greater with exenatide, because of its only having a 53% homology with human GLP-1, compared with liraglutide’s 97%’, said Prof Omar. ‘This is significant because these antibodies may blunt exenatide’s effectiveness.’

DURATION-1 compared exenatide twice daily to exenatide ER.11 The latter was associated with a significantly greater drop in HbA1c levels, with many more exenatide ER-treated patients attaining the target of < 7%. Those switched to the ER formula-tion after 52 weeks experienced further improvements in HbA1c levels, suggesting that exenatide ER is more efficacious than exenatide twice daily. Exenatide ER also had a superior side-effect profile.

DURATION-6 compared exenatide ER to liraglutide.12 Liraglutide performed better, with 60% of patients reaching their HbA1c target level of < 7%, compared with 52%. Weight-loss results were also better with liraglutide. When it came to side effects, liraglutide was associated with higher rates of nausea and vomiting, while injection site reactions were more common with exenatide ER (published at present as an abstract only).

‘In conclusion, there is evidence that HbA1c lowering is better with GLP-1 analogues than with DPP-4 inhibitors, and that of the former, liraglutide is superior to both exenatide formulations’, said Prof Omar. GLP-1 analogues, liraglutide in particular, also



Adri Kok, specialist physician, Union Hospital, Gauteng. CEO of Faculty of Consulting Physicians of South Africa, chairperson of the Medical Advisory and Ethics Committee of Netcare, and a director of

the South African Private Practitioners Forum

performed better in respect of weight loss. Exenatide ER, however, was superior overall in terms of side effects. Patient satisfaction was higher with the injectable GLP-1 agents than with the oral DPP-4 inhibitors.

Incretin-based therapies: focus on clinical effectiveness

Jeffrey Wing, chief physician, professor of Medicine and clinical head, Department of Medicine, Charlotte Maxeke Johannesburg Hospital

Dr Wing pointed out that there were very consistent messages coming through with regard to the clinical effectiveness of incretin therapies. ‘Vildagliptin produces very little hypoglycaemia and is associated with little or no weight gain, except when combined with sulphonylureas. There are convincing data that exenatide lowers blood glucose, whether used as monotherapy or in combination with other agents. There is impressive weight loss and little or no hypoglycaemia, except when it is used together with sulphonylureas.

‘The LEAD studies send the same mes-sage about liraglutide. It produces impressive reductions in HbA1c levels in various combina-tions, with similarly impressive weight loss and little or no hypoglycaemia except, once again, when it is combined with sulphonylureas.’

Looking at the composite endpoints of HbA1c lowering, weight loss and minimis-ing of hypoglycaemia, Dr Wing assigned the following grades to the various drugs avail-able. Both the thiazolidinediones (TZD) and sulphonylureas failed to impress, with scores of 15 and 33%, respectively. Exenatide was awarded a 72% pass, while liraglutide achieved a 78% pass for achieving compos-ite endpoints.

‘To date, no other class of agent has achieved this level and incretin therapies, whether oral or injectable, perform much better than what we have. High-dose liraglutide will be leading the way.’ He added that it seemed almost greedy to want more, but that liraglutide 1.8 mg also reduced a secondary risk factor, namely systolic blood pressure.

‘The era of the incretins has arrived, and the new guidelines will reflect this’, Dr Wing concluded. ‘Diabetes is a progressive condition and the incretins may well be able to modify the disease process before overt type 2 diabetes manifests, delaying beta-cell failure and providing long-term durability by preserving beta-cell function.’

Early use of incretin-based therapies in type 2 diabetes treatment: clinical benefits

Type 2 diabetes (T2DM) has traditionally been managed algorithmically. Following a T2DM diagnosis, initial interventions are diet and lifestyle modifications. The natural disease progression of T2DM implies that glycaemic control will continue to deteriorate over time and once required, oral therapy (usually metformin first) is prescribed. The dose of metformin is gradually uptitrated as the disease worsens, and when the maximal dose no longer maintains glycaemic control, a second oral agent may be added; with more than half of patients ultimately requiring insulin therapy.

Dr Adri Kok, specialist physician at Union Hospital (Alberton), expressed her views that an algorithmic approach to the management of T2DM is ‘reactive’ and may lead to unacceptable delays in treatment intensification, leaving patients exposed to long periods of hyperglycaemia. Dr Kok expressed particular concern about those patients who are diagnosed late, as is often the case in South Africa.

In patients with an HbA1c level > 9%, the recommendation is to implement the early use of insulin therapy combined with oral agents to control initial hyperglycaemia within two weeks. Thereafter, the insulin can be withdrawn and other therapies considered. Dr Kok emphasised that it is of particular importance that pathophysiology, over and above HbA1c levels, needs to be addressed.

To provide better glycaemic control and improve treatment outcomes, Dr Kok recommends the implementation of a more pro-active approach than those suggested by historical guidelines. The most recent AACE/ACE guidelines include multiple options for first-line monotherapy, including incretin-based therapy. The incretins are among the many hormones responsible for glucose homeostasis.

Incretins, including glucagon-like pep-tide-1 (GLP-1), are released by intestinal enteroendocrine cells in response to a meal. GLP-1 elicits glucose-dependent insulin secretion; suppresses glucagon secretion, appetite and food intake; slows gastric emptying and stimulates beta-cell prolifera-tion in pre-clinical models. Circulating GLP-1 is short lived; 80% is degraded within two minutes by the enzyme dipeptidyl pepti-dase-4 (DPP-4).

GLP-1 secretion is diminished in patients with T2DM; however its insulinotropic activity is maintained, resulting in the targeting of this hormone for diabetic therapy. Incretin agents include GLP-1 receptor agonists and

There are many challenges and contradictions to be overcome where diabetes is concerned, and we want to have our cake and eat it, with access to therapeutic options that are safe, effective, cheap and free of side effects. This was the view expressed by Dr Wing.

The first challenge is the numbers. ‘There has been a 98% increase in the number of diabetics in Africa,13 and South Africa has a strikingly high prevalence. According to the NHLS database, glucose control is poor in patients treated in the public sector, and based on the Ampath/Lancet databases, the private sector is not doing any better. Rising rates of obesity, especially in urban women, are a further clinical challenge, as one can’t address glucose control without also looking at obesity.’

Where contradictions are concerned, normalising HbA1c levels has not yielded the risk reductions expected. ‘It was thought that normalisation of HbA1c levels would lead to better cardiovascular outcomes, yet in the ACCORD trial, intensive glucose lowering led to increased mortality rates, possibly as a result of increased hypoglycaemia and highly significant weight gain’, said Dr Wing.

So obesity needs to be addressed. Treatment should not aggravate weight gain, and weight loss would be a bonus. HbA1c levels need to be lowered to < 7%, and with no hypoglycaemia. Looking at current drug options, Dr Wing underscored that metformin is associated with cardiac protection. ‘So you would need a very good reason not to start with metformin.

‘As far as the thiazolidinediones (TZD) are concerned, rosiglitazone is bad, pioglitazone less so. The sulphonylureas do not yield car-dioprotection and most do badly relative to metformin, with the exception of gliclazide. So there is a real need for new therapies that lower glucose levels without weight gain and hypoglycaemia, while providing the bonus of cardiovascular protection.’



DPP-4 inhibitors. GLP-1 receptor agonists produce effects similar to native GLP-1 and are resistant to degradation by DPP-4. DPP-4 inhibitors inactivate the enzyme responsible for GLP-1 degradation. Exenatide, a synthetic formulation on exendin-4, has similar effects to native GLP-1.

Concerns surrounding conventional oral diabetic therapies include risk of hypogly-caemia; however, the glucose-dependant action of incretin-based therapies provides good glycaemic control with a low risk of hypoglycaemia. The incretin agents are also associated with weight neutrality, or even weight loss, whereas most conventional therapies are associated with weight gain. Also promising are findings that incretin-based therapy may have beneficial effects on beta-cell function, potentially slowing progression of diabetic disease.

Dr Kok commented on her practical clinical experience, which included a significant number of patients who were put on liraglutide therapy through compassionate-use approval from the South African Medicines Control Council (MCC) prior to recent regulatory approval of liraglutide in South Africa. In her experience, she had patients losing up to 38 kg of weight while achieving excellent glycaemic control.

Dr Kok went on to more closely examine the indications for incretin-based therapy, specifically the GLP-1 receptor agonists. There is a body of evidence supporting the use of GLP-1s across the continuum of disease progression, both as monotherapy and in combination with a number of other agents.

Dr Kok advises an early combination approach for early management of glucose levels that can then be maintained. She noted that as yet, it is not known for how long beta-cell failure will be delayed with early use of GLP-1s.

‘Such information should emerge with the GRADE study (Glycaemia Reduction Approaches in Diabetes), a cohort of 7 500 recently diagnosed type 2 diabetes patients. The metabolic effects of five different agents in combination with metformin are being compared; as well as the benefits of early combination therapy versus sequential therapy in drug-naïve patients’, Dr Kok said.

Usage trials of exenatide and liraglutide were then presented. Monotherapy trials of exenatide at doses of 5 and 10 µg yielded good results. Compared to placebo, there was a distinct improvement in HbA1c levels, with the higher dose shown to be more effective in reaching target HbA1c levels of < 7.0%.

An exenatide ER trial showed the best change in HbA1c level, with 49% of patients achieving HbA1c levels of < 6.5%, and 63% achieving HbA1c < 7.0%. In an exenatide monotherapy trial, an average weight loss of 3 kg was evident in patients. ‘However, a number of patients lost significantly more weight, with those on the higher dose (10 µg) losing the most weight’, Dr Kok stressed.

Also of note was evidence of beta-cell protection, particularly as loss of beta-cell mass prior to diagnosis is estimated to be as much as 70%. In these trials, exenatide was used as monotherapy or in combination with metformin, sulfonylureas (SFUs) and thiazolidinediones (TZDs). Exenatide can be safely used with insulin.14

The LEAD-3 trial compared monotherapy with liraglutide (1.2 and 1.8 mg) against glimepiride (sulfonylurea) monotherapy. It was found that the 1.8-mg liraglutide dose proved most effective in HbA1c level change from baseline, with 42% achieving target of < 6.5% and 51% achieving target of < 7.0%, while 27.8% of glimepiride-treated patients reached an HbA1c level of < 7%.

The use of liraglutide also showed a 2.8-kg weight benefit over glimepiride, as well as significant benefits in reducing hypoglycaemic events. A trial comparing liraglutide and metformin therapy to therapy with both agents and added insulin detemir showed that the greater the beta-cell mass (as assessed by baseline HbA1c level) at initiation of liraglutide, the better the treatment outcomes, most likely due to greater beta-cell protection.

In summary, Dr Kok noted that liraglutide can be used as monotherapy or in combination with metformin, a sulphonylurea or a TZD. The concurrent use of liraglutide with insulin is still under investigation.

SourceDr Adri Kok, Johannesburg. Early treatment prevents loss of glycaemic control and beta-cell function.Campbell, RK. Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus. Clin Therapeut 2011; 33(5); 511–527.

Incretin-based therapies in clinical practice

Research. He is principal investigator on a number of international phase II, III and IV trials.

Key challenges to be addressed as T2DM progresses are a decline in beta-cell function and beta-cell mass, a deterioration in glycaemic control and an increase in cardiovascular disease. Data from the ACCORD, ADVANCE, UKPDS and VADT trials have indicated that delayed treatment of T2DM can increase the risk of cardiovascular mortality.

Anti-diabetic agents themselves may contribute to the development of cardiovascular disease. As early as the 1970s, the UGDP study indicated adverse cardiovascular outcome with the use of early sulfonylureas (tolbutamide). Newer agents within the sulfonylurea family may have varying and reduced degrees of adverse cardiovascular outcome.

The availability of incretin-based therapies addresses some of the concerns surrounding progression and treatment of T2DM. Dr Kumar summarised clinical trial data on the safety and efficacy of these therapies, showing successfully improved glycaemic control with a low risk of hypoglycaemia and the added benefit of being weight neutral (DPP-4 inhibitors) or resulting in weight loss (GLP-1 receptor agonists).

Evidence of preservation of beta-cell function also emerged. ‘There is limited information on the cardiovascular actions of incretin-based therapy. Short-term studies in human subjects demonstrate modest, yet beneficial action on cardiac function in patients with ischaemic heart disease. These agents also decrease blood pressure and have been shown to reduce inflammation in pre-clinical studies’, Prof Kumar noted.

The early advocation of incretin-based therapy in the AACE/ACE (American Association of Clnical Endocrinologists/American college of Endocrinology) algorithm underscores the need for those agents to be in our armamentarium – Prof Kumar, Patna, India

Dr Ajay Kumar, consultant physician and diabetologist. Director of the Diabetes Care and Research Centre in Patna, India. He also holds a position at the University

of Newcastle, Australia and is a committee member of the Indian Council of Medical

Although impressed with the very prom-ising results of clinical trials, Dr Kumar did emphasise that the true potential of any ther-apy cannot be fully determined until it has been extensively used in clinical practice, and that costs, particularly in developing econo-mies such as India, are a limiting factor.

Recent findings from the Association of British Clinical Diabetologists (ABCD) suggest that the GLP-1 receptor agonists



exenatide and liraglutide have been widely used in clinical practice in the UK since 2008 and 2009, respectively.15 Improvements in glycaemic control and body weight in the clinical setting correlate with that observed in the trial setting.

With experience from his own practice, Dr Kumar commented that incretin therapies were superior to insulin, sulfonylureas and thiazides for weight advantage and avoidance of hypoglycaemia. With an excellent safety and tolerability profile (nausea usually settles within a week), incretin therapy has high acceptability in patients.

Furthermore, Dr Kumar finds incretin therapy suitable for use in the patient failing metformin; and has noted efficacy in combination with almost all other oral anti-diabetic agents (as well as insulin) at different stages of the natural history of disease progression. Cost as a limiting factor was the only disadvantage highlighted, with Dr Kumar postulating that he expects this to also be a disadvantage for use in South Africa.

SourceUssher JR, Drucker DJ. Cardiovascular Biology of the Incretin System. Endocrine Rev 2012; 33: 187–215.

Incretins in combination with insulinThe rationale for using incretin mimetics with insulin was discussed by Prof Mahomed Omar (South Africa) and Dr Ajay Kumar (India) with reference to relevant studies.

Adding incretins to insulin-treated patients ‘At the outset, this approach should seek to mitigate the problems associated with increasing insulin dosages such as weight gain, hypoglycaemia and complications of high insulin dose therapy’, Prof Omar said. He addressed firstly, the addition of DPP-4 inbhibitors, vildagliptin and sitagliptin to type 2 diabetes patients who are poorly controlled on insulin.16,17

‘The reductions in HbA1c levels were modest, about 0.59%, but were sustained over a year, when these agents were added to patients on insulin, with or without metformin. Experience with hypoglycaemia was mixed, with vildagliptin reducing

hypoglycaemic events and sitagliptin increasing these events, perhaps due to the latter study design, which tried to improve overall glucose control. The weight reduction effect was neutral in both studies’, Prof Omar pointed out.

Turning to the incretin mimetics, Prof Omar cited a proof-of-concept study where the addition of exenatide to patients on insulin glargine resulted in a greater decrease in HbA1c level (a reduction of 1.9%), a low hypoglycaemic event rate and weight loss of 1 to 2 kg in the exenatide arm.18

In a further study of exenatide, which was given to patients with diabetes of long duration (10 years) and an expected low level of residual beta-cell function, who were already on insulin, metformin and pioglitazone, exenatide (bd) resulted in improved glucose control accompanied by a very significant reduction in insulin (glargine) dose.19 ‘The adverse GI events with incretin mimetics were as expected but did improve over time’, Prof Omar noted.

A newer concept: patients already on liraglutide who are then given added insulin In a well-conducted study over a year,20

the addition of insulin detemir to a group of patients on metformin and liraglutide, who were not yet at target HbA1c level, was contrasted with the larger primary group, which had reached optimal control on these two agents (61% of the 988 patients), and to a control group within the poorer-controlled arm without insulin. The patients receiving insulin were told to self-titrate, and in this well-controlled therapy reached the recommended range of 35–40 U/day of insulin detemir.

Importantly, the addition of insulin detemir resulted in a further drop of 0.5% in HbA1c level and patients did not gain weight. The rate of hypoglycaemia was very low at 0.23 in these insulin-treated patients. ‘If you contrast this to the Treat-To-Target study, where a rate of three to 3.5 episodes/patient year was seen, this strategy was very successful’, Prof Omar noted.

‘In conclusion, it is better to put patients onto a GLP-1 agonist before using insulin than using the reverse strategy’, Dr Ajay Kumar.

There have been no studies as yet using incretin-based therapies in children/adolescents under the age of 18 years and clinicians should wait for these studies before treating this category of patient – Prof Juris Meier

Incretins and pancreatitis

Dr Adri Kok and Prof Juris Meier

This session scrutinised the evidence related to the increased prevalence of acute pancreatitis in type 2 diabetes patients, acknowledging that these patients have a three-fold higher risk of developing pancreatitis (4.5 cases per 1 000 patient years). ‘We know that the exocrine pancreas is also affected in diabetic patients, with increased fibrosis occuring in both type 1 and type 2 diabetes’, Dr Adri Kok noted.

Prof Meier presented the animal studies on incretins and the risk of pancreatitis, noting the difficulty of extrapolating these findings to humans.

Following the published analysis of the Adverse Event Reports (AERS) as reported to the FDA,21 the EASD has recently published their expert comment on their website http://www.easd.org/easd/index.php/easd-statements. Their evaluation indicates that at this juncture the AERS evaluation cannot be considered as robust data on which to base clinical decisions.

Dr Kok concluded that physicians should not over-interpret this matter, but should be cautious. In summary, Prof Ascott-Evans noted that there is no major signal of concern about either incretin mimetics or DDP-4 inhibitors and the causation of pancreatitis.

Practical advice

Adding liraglutide therapy to a sulpho-nylurea (SU) plus metformin therapy, clinicians can halve the SU dose and then monitor glucose levels to decrease the risk of hypoglycaemia.

When adding liraglutide to insulin-treated patients, one can pragmatically reduce the insulin units by 20–25%, and then monitor – Dr Mahomed AK Omar

‘There is no value in doing HOMA tests prior to using these incretin-based therapies, as they have been shown to be effective across the diabetes spectrum – Prof Juris Meier



Hypoglycaemic events mark vulnerability

Prof Brian Frier, honorary professor of diabetes at the University of Edinburgh, affiliated to the BHF Centre for Cardiovascular Science.

and not correlated to low glucose levels’, Prof Freir warned.

Hypoglycaemia provokes profound haemodynamic changes through sympatho-adrenal activation, resulting in the profuse secretion of catecholamines.24 This can provoke ECG-abnormalities; prolongation of the QT interval, and abnormalities in AV conduction (due also to a fall in plasma potassium), which are associated with a risk of life-threatening cardiac arrhythmias.

Hypoglycaemic events adversely affect quality of life and ‘having events, increases the fear of having further events’. Dr Frier said. The rate of hypoglycaemic events induced by incretin-based therapies is trivial, as these drugs promote glucose-dependent insulin secretion’, Prof Frier concluded.

Peter Wagenaar, Glenda Hardy, Julia Aalbers

ReferencesButler AE, Janson J, Bonner-Weir S, 1. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52(1): 102–110.Meier JJ, Kjems LL, Veldhuis JJ, 2. et al. Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis. Diabetes 2006; 55(4): 1051–1056.Buse JB, Rosenstock J, Sesti G, 3. et al. Liraglutide once a day versus exentatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374(9683): 39–47.Garber A, Henry R, Ratner R, Garcia-Hernandez PA, 4. Rodriguez-Pattzi H, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase II, double-blind, parallel-treatment trial. Lancet 2009; 373(9662): 473–481.Marre M, Shaw J, Brandle M, Bebakar WM, 5. Kamaruddin NA, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabetes Med 2009; 26(3): 268–278.Nauck MA, Frid A, Hermansen K, Shah NS, 6. et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32(1): 84–90.Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic 7. N, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 2009; 52(10): 2046–2055.Zinman B, Gerich J, Buse JB, Lewing A, Schwartz S, 8. et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32(7): 1224–1230.

Pratley R, Nauck M, Bailey T, 9. et al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel group, open-label trial. Int J Clin Pract 2011; 65(4): 397–407.Bergenstal RM, Wysham C, Macconell L, 10. et al. Efficacy and safety of exentatide once-weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet 2010; 9739: 431–439.Buse JB, Drucker DJ, Taylor KL. Duration-1: exenatide 11. once weekly products sustained glycaemic control and wigth loss over 52 weeks Diabetes Care 2010; 33(6): 1255–1261.Buse JB, Nauck MA, Forst T, Sheu WHH, Hoogwerf 12. BJ, et al. Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study. Diabetologia 2011; 54(suppl 1): 538. EASD 2011 congress abstract: oral presentation.Hall V, Thomson RW, Henriksen O, Lohse N. Diabetes 13. in sub-Saharan Africa 1999–2011: Epidemiology and public health implications. A systematic review. BMC Public Health 2011; 15(11): 564.Levin P, Wei W, Wang L, 14. et al. Combination therapy with insulin glargine and exenatide: real world outcomes in patients with type 2 diabetes. Curr Med Res Opin 2012; 28(3): 439–446.Thong KY, Jose B, Sukumar N, Cull ML, 15. et al. Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit. Diabetes Obes Metab 2011; 13(8): 703–710.Vilsboll T, Rosenstock Y, Yki-Jarvinen H, 16. et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010; 12(2): 167–177. Bain SC, De Vries JH, Rodbard HW. Adding insulin 17. detemir (IDet) to liraglutide and metformin improves glycaemic control with sustained weight reduction and low hypoglycaemia rate: 52-week results. Abstract, EASD Congress, 2011.Arnolds S, Dellweg S, Clair J, 18. et al. Further improvement in post prandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care 2010; 33(7): 1509–1515.Bus JB, Bergenstol RM, Glass LC, 19. et al. Use of twice daily exenatide in Basal Insulin-treated patients with type 2 diabetes: a randomised controlled trial. Arch Intern Med 2011; 154(2): 103–112.Fonseca V, Baron M, Shao Q, Dejager S., 20. et al. Sustained efficacy and reduced hypoglycaemia during one year of treatment with vildagliptin added to insulin in patients with type 2 diabetes. Horm Metab Res 2008; 40(6): 427–430.Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler 21. PC. et al. Pancreatitis, pancreatic and thyroid cancer with GLP-1-based therapies. Gastroenterology 2011; 141(1): 150–156.UK Hypoglycaemia Study Group Diabetologia. 22. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 2007; 50(6): 1140–1147.McAulay V, Deary IJ, Frier BM. Symptoms of 23. hypoglyacamia in people with diabetes. Diabet Med 2001; 18(9): 690-705.Frier BM, Schernthaner G, Heller SR. Hypoglycaemia 24. and cardiovascular risks. Diabetes Care 2001; 34: 5132–137.

‘Hypoglycaemia is a marker of a patient’s vulnerability to a wide spectrum of cardio-vascular, cerebrovascular and musculo-skeletal events. It is not a transient event, as commonly perceived. There are longer-term effects on cardiac function, platelets, the inflammatory response and overall endothe-lial function’.

Expressing this view, Prof Brian Frier, University of Edinburgh, drew on his clinical insights gained from a research career focused on the pathophysiology of hypoglycaemia. While hypoglycaemia is more common in type 1 diabetes patients, type 2 diabetes patients on insulin experience on average one severe event per month.

‘In the definitive UK Hypoglycaemia study,22 we were surprised to see in a real-world setting that hypoglycaemia in type 2 diabetes patients treated with sulphonylureas was higher than we thought, at a rate of 7% per year. Hypoglycaemic events also increased over time in type 2 diabetes patients on insulin but remained less frequent than in type 1 diabetes patients.’

This study used patients’ self-reporting and biochemical episodes of less than 2.2 mmol/l on continuous glucose monitoring to determine events over nine to 12 months in UK secondary care diabetes centres. Insights from continuous glucose monitoring has shown that the majority of hypoglycaemic events occur at night, and in the younger patient, do not appear to impair cognitive function, although, the next day, subjective well being is affected. ‘These nocturnal events may, however, contribute to the development of impaired awareness of hypoglycaemia’, Dr Frier noted.

Age affects hypoglycaemic awareness, with younger patients being able to tolerate lower glucose levels without cognitive dysfunction, while older patients, over the age of 65 years have less time for corrective action and generally experience wider cognitive dysfunction, including visual disturbances, inco-ordination and impaired balance.23 ‘These symptoms could be perceived by the attending physician as a transient ischaemic attack or early dementia

SA JOURNAL OF DIABETES & VASCULAR DISEASE


Keep and Copy Series

EXERCISE AFTER ANTICOAGULATION OF DEEP-VEIN THROMBOSIS


In the past, strict bed rest for seven to 10 days

was advised on being diagnosed with deep-vein

thrombosis (DVT). The assumption was that any

movement may dislodge a blood clot, causing a pul-

monary embolism (PE). However, recent evidence

shows that there is no higher risk of this occurring in

appropriately treated patients who are mobile than in

those on bed rest. Early mobilisation (taking a daily

walk) may also reduce symptoms and speed up re-

covery.

HOW DO I START?

Exercise patterns after anticoagulation of DVT may

vary, depending on your condition. Consult your

treating physician on when to start. This could be as

soon as the second day after the start of your treat-

ment. You should always exercise under supervision

for the first few days; therefore ask a friend or family

member to accompany you. Use compression stock-

ings to help reduce pain and swelling before, during

and after exercise.

HOW MUCH SHOULD I DO?It is advisable to move around as much as possible.

Studies show that an average daily walking distance

of 0.6 to 12 km has been associated with improve-

ments in pain and swelling and no increased risk of

PE, when compared to bed rest.

ATHLETES AND PEOPLE FOLLOWING A REGULAR EXERCISE ROUTINE There are no official guidelines on when to return to

high-intensity exercise, but it seems appropriate to re-

frain from these types of activities for the first 10 to 14

days after an acute DVT or PE. To limit deconditioning

during this period of relative inactivity, strength training

of the trunk and unaffected limbs may be done. Activ-

ity may then be increased between weeks two and

four, with a return to pre-clot activity by week four.

Being on anticoagulation medication increases

the risk of bleeding. Contact sports should therefore

be avoided while on treatment. Runners, cyclists or

triathletes may continue their sport but should adapt

their activities to avoid trauma.

Stephan NelStephan Nel Fisioterapeute/ Physiotherapists Tel: 021 900 6244/6414 Fax: 021 900 6773e-mail: [email protected]



Week Time (min) Mon Tue Wed Thu Fri Sat Sun Distance

(m)

1 5

2 10

3 15

4 20

5 25

6 30

7 30

8 30

9 30

10 30

11 30

12 30

Table 1. Example of an exercise chart.

Peripheral arterial disease (PAD) can make walking and other

physical activities painful and challenging. Regular aerobic ac-

tivities aim to improve circulation to the leg muscles and can

reduce the pain caused by PAD. Walking is, therefore, the best exercise

for people with PAD as it may also reduce cardiovascular risk factors.

HOW TO STARTIt is important to concentrate on the duration of the exercise and not •

the distance you have walked. Begin with a five- to 15-minute walk.

Your pace will vary depending on your leg pain. Try to walk until the •

pain slows you down, then walk slower or stop until the pain sub-

sides. Repeat this cycle for the whole exercise period.

Try to exercise at least three days per week, but preferably more. •

After one week you can increase the time period of exercise by five

minutes and repeat this every week until you can do 30 minutes or

more. If time limits you; for example, you have only 30 minutes per

day to exercise, you can still improve weekly by trying to increase the

distance covered in 30 minutes.

Make this part of your daily routine over the long term. Do not stop •

exercising when you reach 30 minutes.

You may replace walking with other aerobic exercise such as cycling •

or swimming.

PRECAUTIONSCardiovascular disease often accompanies PAD. Stop and contact •

your doctor if you experience chest pain, severe shortness of breath

and/or nausea during exercise.

Refrain from exercising in extremely hot or humid weather or in the •

midday sun.

Your symptoms may feel worse in cold weather.•

Use an exercise chart to keep track of your progress. Tick the box for

every day that you completed the allocated time per week. Try to increase

your time every week. In the example below (Table 1) you will start with a

five-minute walk every day of the week. The progression is five minutes

per week up to 30 minutes after six weeks.

From week seven to 12, try to increase the distance that you cover in the 30

minutes every week. After 12 weeks, a regular 30-minute walk should be part

of your daily life. If your baseline activity level is more than a five-minute walk,

start with a longer time period, for example 15 minutes, and progress in the

same way over the first six weeks before you start increasing the distance.

Keep and Copy Series

EXERCISE AND PERIPHERAL ARTERIAL DISEASE



Diabetes Educator’s Focus

SCREENING FOR PERIPHERAL ARTERIAL DISEASE IN PEOPLE WITH DIABETES


Peripheral arterial disease (PAD) in people

with diabetes is due to the artheroscle-

rotic process affecting the medium-sized

arteries of the legs. The arteries that are commonly

involved in patients with diabetes are the peroneal,

tibial and profunda femoris arteries.

The diagnosis of PAD remains somewhat prob-

lematic at the primary-care level but is essential, as

PAD in people with diabetes is associated with high

morbidity and mortality rates from cardiovascular

disease. Early detection of PAD, risk modification and

referral for foot care, and surgical intervention when

appropriate, may improve outcome.

Diabetic foot disease is a multi-factorial condition

with sensori-motorneuropathy being the principle

factor involved in the development of ulceration of

the foot. PAD is one factor leading to the most dev-

astating outcome of diabetic foot disease – amputa-

tion.1 PAD was found to be more common in patients

with diabetes who had had a major amputation and

among those undergoing re-amputation. In people

with a major amputation and critical leg ischaemia,

Bodily and Burgess found the re-amputation rate to

their contralateral leg to be 36% after two years.2

People with diabetes are at high risk for PAD but the

true incidence and prevalence is not certain in this pop-

ulation because of different methods used to diagnose

PAD. Diagnostic criteria used in several studies vary

from using one or more of the following: deficit of pedal

pulses, symptoms of intermittent claudication, ankle–

brachial pressure index (ABPI) of < 0.9, presence of foot

ulcer, and history of lower extremity amputation.

Two studies reporting on the prevalence of PAD

among people with type 1 and 2 diabetes mellitus

had different results. Welborn et al.3 showed an iden-

tical prevalence of 38% in patients with type 1 and

2 diabetes, using intermittent claudication and pulse

Gerda van RensburgPodiatrist, Centre for Diabetes, Houghton, Johannesburge-mail: [email protected]

deficit as diagnostic criteria. Walters et al.4 found that

patients with type 2 diabetes had a higher prevalence

(23.5%) than those with type 1 diabetes (8.7%), us-

ing ABPI < 0.9 as diagnostic criterion.

PAD AND CARDIOVASCULAR DISEASEThe presence of PAD is an independent risk factor for

increased mortality, due to associated cardiovascular

disease (CVD).5 Patients with PAD have the same rela-

tive risk of death from cardiovascular events as pa-

tients with a history of coronary and cerebrovascular

disease. Mortality is higher among those with critical

leg ischaemia (annual mortality of 25%). The lower the

ABPI, the greater the risk of cardiovascular events.6

Early detection of PAD is important for risk modifi-

cation, which reduces the progression and improves

the outcome. Guidelines recommend that all patients

diagnosed with PAD should have a full cardiovas-

cular risk assessment.7 The PARTNERS progam8

demonstrated that patients with PAD were less in-

tensively treated than patients with CVD. This survey

showed that patients with PAD received lower rates

of antiplatelet and hypertension therapy compared to

patients with documented CVD.

PRESENTATION OF PAD AND DIABETESPAD in diabetes can be asymptomatic, influencing

the diagnosis thereof. Jude et al. found that many

patients with PAD and diabetes did not experience

symptoms of intermittent claudication of the calf

muscles because of the presence of peripheral neu-

ropathy.9 The high level of inactivity of many of these

patients may also affect diagnosis. PAD may there-

fore be asymptomatic until an advanced stage, when

patients present with critical ischaemic changes in

the feet. Poorer functional ability among people with

diabetes and PAD compared to those with only PAD

has been reported by Dolan.10


EDUCATOR’S FOCUS SA JOURNAL OF DIABETES & VASCULAR DISEASE

PAD presents at an earlier age in people with diabetes, and the proc-

ess is more rapid than in the non-diabetic population.9 This is noted in

the proposed protocol for the evaluation of patients in whom PAD is sus-

pected (Fig. 1). Patients are at increased risk for PAD if their age is above

50 years and they are diabetic or smokers, compared to 70 years old in

those without diabetes.8

DIAGNOSIS OF PAD Clinical practice guidelines on preventative management of the diabetic

foot, such as the American Diabetes Association (ADA) position state-

ment on foot care, the Scottish Intercollegiate Guideline Network (SIGN),

the National Institute for Clinical Excellence (NICE), and the International

Working Group on the Diabetic Foot (IWGDF), recommend an annual foot

assessment to identify those at risk for ulceration11-14 (Table 1). Screening

the feet for PAD should start with taking a history of age, cardiovascular

risks, symptoms of intermittent claudication, skin integrity, colour, pres-

ence of ulcers, hair growth and temperature.

The pedal pulses should be examined: absence of both pedal pulses,

dorsalis pedis and posterior tibial pulse, may be associated with PAD

and should be investigated further (Fig. 2). The ABPI is indicated in all

patients suspected of PAD. The ADA guidelines recommend that an

ABPI be performed in patients with diabetes who are older than 50

years and patients under 50 years who have other risks factors such as

smoking, hypertension, hyperlipidaemia, or duration of diabetes more

than 10 years.

Patients with significant symptoms and signs of PAD should be re-

ferred immediately for further vascular assessment. Risk-factor modifica-

tion should be introduced early to improve outcome.

INTERMITTENT CLAUDICATIONThe classical symptom of intermittent claudication is muscle discomfort

in the lower leg, brought on by exercise and relieved within 10 minutes

by rest.15 The location of the pain is determined by the level of stenosis

and is most commonly in the calf. This may be the only clear primary

symptom in patients with PAD.

Questionnaires have been developed and used to diagnose symptoms

Table 1. Risk stratification system (SIGN 2010).

Low risk No risk factors, e.g. loss of protective sensation, no signs of PAD and no other signs of risk factors

Moderate risk One risk factor present, e.g. loss of protective sensa-tion, or signs of PAD without callus formation or deformity

High risk Previous ulceration or amputation or more than one risk factor present, e.g. loss of protective sensation or signs of PAD with callus or deformity

Fig. 1. Proposed protocol for the diagnosis of PAD in patients with diabetes mellitus (Hiatt15).

ABPI measurement

Assess other causes of leg symp-toms

Normal results: no PAD

Post-exercise ABPI measurement

Refer vascular unit: TPI measurementDuplex ultra- sonography

Abnor-mal results

PAD

Normal post-exercise ABPI

Decreased post- exercise ABPI

Patient history and physical examination

Age 50 to 69 years and smoking or diabetes

Leg pain with exertion and reduced physical functioning

Abnormal results on vascular examination of leg

Coronary, carotid, renal arterial disease

ABPI > 1.4 ABPI < 0.9ABPI = 0.91–1.4

Fig. 2. Location of pedal pulses.


SA JOURNAL OF DIABETES & VASCULAR DISEASE EDUCATOR’S FOCUS

of PAD but with varying levels of sensitivity.16 A planned verbal inquiry will

yield critical information. The differential diagnosis is tabled in the TASC2

guidelines.14

PEDAL PULSESThe presence of foot pulses does not exclude PAD and patients present-

ing with the classic history of intermittent claudication should be inves-

tigated further. Various recording systems are used to record the pulse

intensity. For screening purposes, the least confusing system should be

used and pulse intensity should be recorded as absent or present.

ANKLE-BRACHIAL PRESSURE INDEX The ABPI is a reliable test in the absence of vascular calcification. A

resting cut-off point of 0.9 (95% sensitivity) is used in detecting angio-

gram-positive disease, with 99% specificity in identifying healthy sub-

jects. Symptoms of intermittent claudication are usually experienced at

a level between 0.6 and 0.9 and critical ischaemia is associated with an

ABPI of less than 0.5.

A high ABPI above 1.5 may be misleadingly in patients with vascular

calcification, as found in diabetes and advanced renal failure. For this

reason the toe pressure can be measured, as much less calcification is

found in the toe arteries. The toe pressure test is not recommended for

screening or at the primary-care level.

ABPI > 1.3 indicates medial calcification resulting in incompressible •

arteries.

ABPI is normally > 1.0. •

ABPI < 0.9 indicates some arterial disease. •

ABPI > 0.5 and < 0.9 can be associated with claudication and •

if symptoms warrant it, a patient should be referred for further

assessment.

ABPI < 0.5 indicates severe arterial disease and may be associated •

with gangrene, ischaemic ulceration or rest pain and warrants urgent

referral for a vascular opinion.

Other modalities used to diagnose PAD are post-exercise ABPI, tread-

mill testing, pulse oximetry and near-infrared spectroscopy.

CLASSIFICATION OF PADThe Rutherford classification is similar to the Fountaine classification and

can be used as a clinical means to describe peripheral arterial disease

(Table 2). They are useful for standardised communication among prac-

titioners.14

CONCLUSIONBecause of the effect of PAD on the lower extremities and its associa-

tion with elevated risk of cardiovascular and cerebrovascular events

in people with diabetes, its early detection is essential. Initiation

of a screening protocol in patients at high risk, such as those with

diabetes, by taking a thorough history, recording deficit pulses and

performing an ankle–brachial pressure index test may improve the

diagnosis, enable early risk intervention and improve the outcome in

patients with PAD.

ReferencesAdler AI, Boyko EJ, Ahroni JH, Smith DG. Lower extremity amputation in 1. diabetes. The independent effects of peripheral vascular disease, sensory neuropathy and foot ulcers. Diabetes Care 1999; 22(7): 1029–1035.Bodily K, Burgess BM. Contralateral limb and patient survival after amputation. 2. J Am Surg 1983; 280–282.Welborn TA, Knuiman M, McCann V, Stanton K, Constable IJ. Clinical 3. macrovascular disease in Caucasoid diabetic subjects: logistic regression analysis of risk variables. Diabetologia 1984; 27: 568–573.Walters DP, Gathing W, Mulke MA, Hill RD. The prevalence, detection, and 4. epidemiology correlates of peripheral disease: a comparison of diabetes and non-diabetic subjects in an English community. Diab Med 1992; 9: 710–715.American Diabetes Association. Peripheral arterial disease. 5. Diabetes Care 2003; 26: 3333–3341. Dormandy JA, Heeck L, Vig S. The fate of patients with critical ischemia. 6. Semin Vasc Surg 1999; 12: 142–147.SIGN Scottish Intercollegiate Guidelines Network. Diagnosis and management 7. of peripheral arterial disease. October 2006; www.sign.ac.uk.Hirch AT, Hiatt WR. PAD awareness, risk, and treatment: new resources for 8. survival – the USA PARTNERS program. Vasc Med 2001; 6: 9–12.Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in 9. diabetic and non-diabeic patients: a comparison of severity and outcome. Diabetes Care 2001; 24: 1433–1437.Dolan NC, Liu K, Criqui MH, Greenland P, Guralnik JM, Chan C, 10. et al. Peripheral artery disease, diabetes, and reduced lower extremity functioning. Diabetes Care 2002; 25: 113–120.SIGN Scottish Intercollegiate Guideline Network. Management of Diabetes 11. National Clinical Guideline. March 2010. www.sign.ac.uk. National Institute for Clinical Excellence. Type 2 diabetes prevention and 12. management of foot problems. January 2004. www.nice.org.uk. International Working Group on the Diabetic Foot. International Consensus 13. www.iwgdf.org.TASCII. Inter-Society Consensus for the Management of PAD. 14. www.tasc-2-pad.org. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. 15. N Engl J Med 2001; 344: 1608–1621.Dormandy J, Heeck l, Vig S. Intermittent claudication: a condition with 16. underrated risks. Semin Vasc Surg 1999; 12: 96–108.

Table 2. Comparison of two systems of classification of PAD.

Rutherford’s categories of PADFountaine stage classification

of PAD

Grade CategoryClinical description Stage Clinical findings

0 0 Asymptomatic I Asymptomatic, decreased pulses, ABPI < 0.9

I 1 Mild claudication

II Intermittent clau-dication

I 2 Moderate claudication

III Daily rest pain

I 3 Severe claudi-cation

IV Focal tissue necrosis

II 4 Ischaemic rest pain

II 5 Minor tissue loss

III 6 Major tissue loss



Hands on

PRACTICAL GUIDANCE ON INSULIN USAGE IN THE HOSPITAL SETTING


Adri KokSpecialist physician, Union Hospital, Gauteng, CEO of Faculty of Consulting Physicians of South Africa, chairperson of the Medical Advisory and Ethics Committee of Netcare, and a director of the South African Private Practitioners’ Forum e-mail: [email protected]

INTRODUCTIONIn recent years, there has been much debate and

controversy about the correct use of insulin in the

hospital setting. There is little debate however on

the impaired glucose metabolism present in the

majority of critically ill patients, often aggravated by

parenteral feeding, infections, inotrope support and/

or pre-existent diabetes.

Insulin resistance is common and even a single

elevated blood glucose level has been associated

with adverse outcomes. Intensive insulin therapy has

been shown to reduce mortality and morbidity, with-

out the risk of hypoglycaemia, if it is done safely by

informed, educated nursing staff. It has also been

shown to be cost-effective.

The correct target level of glucose which can be

achieved safely has been the discussion point for

some years and the new American Diabetes Asso-

ciation (ADA) practice guidelines recommend a safe

level of 7.8–10 mmol/l but not to exceed a threshold

of 10 mmol/l in selected patients (consensus state-

ment of ADA/AACE 2012) in the intensive care unit

setting.1 There are other situations where hyper-

glycaemia in the in-patient setting may significantly

affect the outcome of the illness. Many patients may

be diagnosed as being new-onset diabetics during a

hospital admission for another reason.

An understanding of factors affecting the indi-

vidual patient must be considered when a protocol

is developed. The nursing staff must understand

clearly defined goals for blood glucose levels, have

clear action points to avoid hypoglycaemia and must

be educated on how anti-diabetic medication works

and what the pitfalls of treatment are.

All patients with diabetes admitted for whatever

reason must have their diabetic status prominently

identified in the patient file and be automatically

monitored at mealtimes, with a record of glucose lev-

els available to all members of the healthcare team.

Specific issues will be discussed in depth below.

MONITORING

The usual bedside glucometer readings are adequate

in the non-critically ill patient. If there is any doubt,

a laboratory glucose test can be done to confirm an

abnormal result, especially if a patient has never been

diagnosed with diabetes before. If a random level is

elevated, a fasting laboratory glucose test should be

done to confirm the diagnosis at a time when there

are no confounding factors present that could influ-

ence the glucose level, e.g. infection, trauma, sur-

gery. This is usually done in an out-patient setting six

to eight weeks following discharge from hospital.

In the intensive care unit (ICU), continuous glucose-

monitoring devices are used by some but are costly. In

South African ICUs, glucometer readings may be used

but it is preferred to use glucose levels on the arterial

blood gas analysis to determine action points.

If a patient is shocked with poor peripheral per-

fusion, an arterial line will facilitate accurate deter-

mination of glucose levels, as poor capillary filling

will affect the accuracy of finger-prick glucose levels.

Capillary blood may overestimate actual blood glu-

cose levels and if strict targets are set, it may result

in hypoglycaemia. These limitations must be consid-

ered when organising a hospital insulin protocol.

New glucometers are able to compensate for

changes in haematocrit level, they can adjust for

reducing agents such as vitamin C and acetami-

nophen, require only a small amount of capillary

blood, and provide a rapid glucose level, often within

six seconds, thus saving on nursing time.


SA JOURNAL OF DIABETES & VASCULAR DISEASE HANDS ON

PATHOPHySIOLOGy OF ‘STRESS’ HyPERGLyCAEMIA2,3

At the 2012 International Symposium on Intensive Care and Emergency

Medicine (ISICEM) meeting in Brussels, Krinsley made some important

observations. Diabetic patients respond differently from non-diabetics.

They will have higher HbA1c levels on admission and will tolerate higher

glucose levels in the acute setting without adverse effect. The aim then

is to avoid tight control (< 6.1 mmol/l) in the patient with diabetes in the

in-patient setting.

A better determinant of mortality is the glucose variability or ‘lability’,

i.e. swinging from high to low to high over the in-patient period. This

has been shown to be independently associated with an increased mor-

tality. Hypoglycaemic events are associated with a 2.5-times increased

mortality rate. Hypo- and hyperglycaemic episodes are associated with a

4.8-times increased mortality rate, but with glucose variability, there is a

six-fold increased mortality rate associated with the difference between

the highest and lowest glucose levels.

To avoid this glucose lability, high-concentration glucose infusions

(50%) should be avoided and a more stable caloric intake should be

maintained. Possibly consider using a basal insulin as ‘background’

therapy in a stable patient, with associated lower short-acting insulin

dosage requirements. Increase the frequency of measurements and

rather use smaller dosages of short-acting insulin at one time to avoid

wide fluctuations in glucose levels.

In the presence of a stress response, as most ICU patients will experi-

ence, hyperglycaemia results from gluconeogenesis and glycogenolysis

when stress hormones such as cortisol, adrenaline, glucagon and growth

hormone are released. Hyperglycaemia directly affects the mitochondrial

function of cells in the liver, kidneys and lungs. Compensatory responses

in the cells (autophagy) are impaired and circulatory glucose can cause

direct cellular damage.

Hyperglycaemia is also pro-inflammatory with the release of

NF-kβ and interleukins. A reduction in endothelial nitric oxide

will affect vasoconstriction and alter organ perfusion. There is an

activation of the coagulation pathway with a risk of thrombosis and

it adversely affects the efficacy of neutrophil activation in the presence

of sepsis.4

Hyperglycaemia in hospital can occur due to previously diagnosed

diabetes, previously undiagnosed diabetes or iatrogenic hyperglycaemia

(fasting sugar level ≥ 7 mmol/l; random glucose level ≥ 11.1 mmol/l),

which will revert to normoglycaemia post discharge. Stress, decompen-

sation of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus

(T2DM) or other types of diabetes, e.g. gestational diabetes, causes such

as withholding of diabetic medication, such as pre-operatively, or the

administration of drugs such as glucocorticoids or vasopressors, may all

precipitate hyperglycaemia.

SPECIFIC IN-HOSPITAL SETTINGSDiabetic and non-diabetic non-critically ill patients No evidence exists for specific targets for glucose control in non-critically

ill patients. A safe level would be fasting levels of < 7.8 mmol/l. Post-meal

levels should be maintained below 10 mmol/l. Patient safety is crucial.

Clear guidelines are needed to detect and treat hypoglycaemic events.

If a previously diagnosed diabetic patient is admitted, a baseline

HbA1c level will give an indication of the adequacy of his/her control.

(Patients who are going for surgery will be discussed separately.) In

most instances the patient could continue his/her out-patient treat-

ment and supplementary insulin can be given before meals to avoid

excessive glucose excursions.

A simple supplementary scale using subcutaneous short-acting insulin

analogues is effective, safe and easy to administer (Table 1). The short-

acting insulin analogues are preferred as they act quickly, can be admin-

istered immediately pre-meal, which is crucial in the hospital setting, and

do not have a lag response, with less risk of hypoglycaemia.

If no insulin is to be given, monitor for hypoglycaemia if the glucose

levels are below 3.9 mmol/l. There are differing opinions as to what the

safe lower limit of glucose must be. It is prudent to use 3.9 mmol/l in our

setting, as recommended by the ADA.

If the patient is not a known diabetic, glucose levels should be moni-

tored in any setting where hyperglycaemia may occur, which could affect

the outcome of the hospitalisation and illness. Examples include glucocor-

ticoid therapy, enteral or parenteral nutrition and immune suppressives.

Persistent hyperglycaemia must be treated to the same targets as those

with pre-existent diabetes until the precipitating event has resolved.

It is crucial not to miss follow up of patients with persistent, unexplained

hyperglycaemia as out-patients once the acute event has resolved, as

they may be newly diagnosed or previously undiagnosed diabetics. There

must be a planned follow up within six weeks of discharge, when a fast-

ing glucose test and possibly an HbA1c assay should be performed. If the

HbA1c level is > 6.5%, it may be diagnostic of diabetes mellitus.

Table 1. Protocol example of supplementary subcutaneous insulin pre-meal (NovoRapid/Humalog/Apidra).

Glucose level (mmol/l)

Insulin-resistant patient e.g.

obese (units)Normal (units)

Insulin-sensitive patient e.g.

elderly (units)

< 3.9 Monitor for hypoglycaemia,

no insulin

Monitor for hypoglycaemia,

no insulin

Monitor for hypoglycaemia,

no insulin

4–5.9 2 0 0

6–7.9 4 2 0

8–9.9 6 4 2

10–11.1 8 6 4

12–13.9 10 8 6

> 14 12 10 8


HANDS ON SA JOURNAL OF DIABETES & VASCULAR DISEASE

If blood glucose levels are persistently below 5.9 mmol/l, the adjust-

ment insulin dosages must be reduced to avoid possible hypoglycaemia.

The in-patient setting is aimed at avoiding excessive hyperglycaemia

and not to achieve ideal diabetic control. Hypoglycaemia is defined as

a glucose level ≤ 3.9 mmol/l and will require specific instructions and

modification of the supplementary insulin protocol.

If the glucose level remains low, intravenous glucose must be given to

maintain safe levels until the cause of the hypoglycaemia has been elimi-

nated. If blood glucose levels remain above 14 mmol/l, an incremental

increase in insulin dosages can be planned, usually by two units at a

time, to avoid excessive hyperglycaemia, while at the same time, basal

insulin should be considered.

Timing of glucose testsThe use of sliding scales and the testing of glucose six hourly have both

become obsolete practices.5 Pre-meal testing in hospital provides safe

adjustments of glucose levels, and with the availability of short-acting

insulin analogues, insulin can be administered at the time of the meal,

thus avoiding delays and the risk of hypoglycaemia. The ‘supplementary’

short-acting insulin doses are added to basal insulin or even oral

anti-diabetic agents as appropriate and provide a rational and safe

physiological adjustment of insulin requirements.

Planned surgery in the previously diabetic patient The use of insulin and glucose infusion is recommended for the following:

type 1 diabetes patients•

insulin-treated type 2 diabetes patients•

poorly controlled type 2 diabetes patients•

if they are undergoing general anaesthesia, irrespective of the length of

the proposed anaesthesia and surgery.

The intravenous infusion of insulin provides a predictable, easily adjusted

and easily monitored effect on glucose levels. Subcutaneous administration

of insulin is unpredictable in the surgical patient. Minor procedures such as

endoscopy and procedures done under light sedation would not warrant in-

travenous insulin and glucose infusions, as patients will have a limited period

where they are at risk of transient hyperglycaemia, they will commence eat-

ing early, and can return to their normal treatment without complications.

It is preferable to use separate infusions for glucose and insulin to

enable independent adjustments as required (Table 2). Potassium levels

must also be carefully monitored to avoid hypokalaemia. It is necessary to

do hourly capillary blood glucose measurements to allow adjustments.

Patients undergoing coronary artery bypass graft surgery or surgery

requiring cardiopulmonary bypass may require higher doses of insulin to

achieve adequate glycaemic control during surgery and post-operatively.

In this situation, tighter glucose control has been shown to improve car-

diovascular morbidity and mortality and post-operative outcome in diabetic

patients. 6-9 Treatment goals in these patients should be 5.6–6.9 mmol/l but

with the same safeguards against hypoglycaemia as mentioned above.

Diabetes management for diabetic patients during minor surgical proceduresThe following protocol is advised (Table 3). If breakfast is allowed on the

day of the procedure, the normal morning dose of insulin, or oral agents

as used by the patient, can still be given. Then measure glucose levels

before and after the procedure and use supplemental insulin/protocol if

the glucose levels exceed 13.9 mmol/l.

The patient in the ICUThe ICU presents very specific challenges to the treating physician. It is in

this setting that the benefits of glycaemic control have best been studied

in various clinical situations. As discussed above, glucose variability is the

- Discontinue all subcutaneous insulin once the glucose–insulin infusion is commenced.

- Measure capillary blood hourly.- Infuse 5% dextrose–water in an infusion pump, preferably.- Infuse a solution of 200 IU rapid-acting insulin (NovoRapid/Humalog/

Apidra) in 200 ml NaCl to achieve 1 IU/1 ml. This can be used as a pig-gyback infusion to the dextrose infusion.

- Adjust the infusion/hourly glucose levels per suggested protocol.

Blood glucose Insulin infusion 5% dextrose–water(mmol/l) (ml/hour) (units/hour) (ml/hour)< 3.9 0.5 0.5 1503.9–5.6 1 1 1255.7–8.0 2 2 100 8.1–10 4 4 50 10.1–12 6 6 012.2–14 8 8 0≥ 14.1 10 10 0

If the patient is at risk of fluid overload, the insulin can be mixed in a more concentrated solution, e.g. 400 IU/200 ml = 2 IU/ml. The infusion of dextrose can be done via a central line and 50% dextrose can be used to limit the volume required.

Table 2. Example of insulin–glucose infusion for peri-operative periods.

On the day of the procedure if the patient is nil per os:– Withhold the morning dose of insulin/oral agents.– Measure capillary blood pre-operatively and at two to four hours.– Give short-acting insulin (NovoRapid, Humalog, Apidra) subcutaneously

as follows:

Blood glucose NovoRapid/Humalog/Apidra (mmol/l) (units)

< 5.6 05.7–11.1 4 11.2–13.9 6 14–16.7 8 ≥ 16.8 10

Post-operatively give the usual insulin/oral agent.

Table 3. Example of insulin supplementary scale for minor surgical procedurers.


SA JOURNAL OF DIABETES & VASCULAR DISEASE HANDS ON

Table 4. Tight glycaemic control for all patients in the ICU.

Date Time Adult insulin infusion protocol 1. Discontinue all previous insulin orders (including sliding scale), and all other insulin protocols. 2. Run IV of: • Normal saline 0.9% to run at _____ml/h. Use only if patient is eating or on TPN, IVF or enteral feed. • Dextrose 5% in water to run at _____ ml/h. • Dextrose 5% in water and normal saline 0.45% to run at _____ ml/h. 3. Insulin drip: rapid-acting insulin 100 units/100 ml 0.9% normal saline. Deliver via infusion device, prime the tubing when initiating, and must be changed every 24 hours. There is no need to use glass bottles for the insulin. 4. Titrate insulin infusion to blood glucose goal of: (select one) regular control: 6.1–8 mmol/l (recommended for most patients). OR tight control (limited to ICU/CCU): 5.6–6.1 mmol/l mg/dl (recommended for unstable, critically ill patients, e.g. cardiothoracic surgery, receiving glucorticoids or vasopressors, or known diabetics on more than 80 units of insulin daily as an outpatient). May transfer to floor once patient is stabilised, requiring less Accuchecks. 5. Begin initial insulin infusion with: (select one) • Algorithm 1 (recommended for most patients). OR • Algorithm 2 (recommended for unstable, critically ill patients, e.g. cardiothoracic surgery, receiving glucorticoids or vasopressors or known diabetics on more than 80 units of insulin daily as an outpatient). Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 4

Blood glucose Insulin Blood glucose Insulin Blood glucose Insulin Blood glucose Insulin (mmol/l) (units/h) (mmol/l) (units/h) (mmol/l) (units/h) (mmol/l) (units/h) < 6 off < 6 off < 6 off < 6 off 6.1–7.9 1 6.1–7.9 1 6.1–7.9 2 6.1–7.9 4 8–9.9 2 8–9.9 2 8–9.9 4 8–9.9 6 10–11.9 4 10–11.9 4 10–11.9 6 10–11.9 8 12–13.9 6 12–13.9 6 12–13.9 8 12–13.9 10 14–15.9 8 14–154.9 8 14–15.9 10 14–15.9 12 > 16– < 360 10 > 16– < 360 10 > 16– < 360 12 > 16– < 360 14 6. When starting insulin infusion, begin with hourly capillary blood glucose until ordered goal is obtained. If possible use arterial sample. • If patient not at goal and blood glucose does not change (decrease) at least 4 mmol/l within one hour, move to next higher algorithm and notify ordering physician. • For blood glucose that is not at goal after four consecutive hours, contact the ordering physician; look for cause and adjust treatment, e.g. parenteral nutrition. 7. Once goal is achieved and maintained for four consecutive hours, monitor blood glucose as follows: Regular control: monitor glucose levels every four hours, given blood glucose is at goal and the patient is clinically stable. Any change in orders for diet, IV rate or composition or the patient becomes clinically unstable; begin again at number 6 above, unless ordered differently by the doctor. OR Tight control: monitor glucose levels every two hours. Note: critically ill patients may require hourly monitoring for other reasons even if they have stable blood glucose (e.g. vasopressor titration). 8. Notify the ordering physician promptly of: • Any blood glucose changes up or down greater than 6 mmol/l or any blood glucose level greater than 16 mmol/l that is persistent. • Whenever patient moves from one algorithm to another or the infusion is restarted. • When the patient has received IV insulin infusion for three days. 9. Any time blood glucose is between 5.6 and 6.1 mmol/l, stop insulin infusion and begin repeating glucoes levels every 30 minutes. • Once blood glucose is greater than 6.1 mmol/l × two samples, restart same algorithm and begin again at number 8 above. • For a blood glucose less than 6.1 mmol/l within four hours after resuming the same algorithm, move to next lower algorithm and begin again at step number 6 above. • For patient already on algorithm 1, contact ordering physician for further orders. 10. Blood glucose less than 5.6 mmol/l • Stop insulin infusion. • For awake patient – check if glucose required. • For patient that is NOT awake – give dextrose 50% 50 ml (1 ampule) IV push/central line preferably. • Recheck blood glucose Accucheck every 30 minutes. For blood glucose less than 5.6 mmol/l and patient awake, repeat dextrose 50% 25 ml (½ ampule) or for patient not awake repeat dextrose 50% 50 ml (1 ampule) IVP. • Once blood glucose is greater than 6.1 mmol/l × two; restart insulin infusion, move to next lower algorithm and begin again at step number 6 above. • For patient already on algorithm 1, contact ordering physician for further orders. • Notify the ordering physician after each dosing of dextrose 50% given and when algorithm restarted.

Adjustment for meals and/or tube feedings: Once the patient is consuming 50% or more of his/her last two meals (other than clear liquids) and/or is receiving bolus tube feelings: • Increase the insulin infusion rate two steps within the same algorithm for one hour and recheck blood glucose. • Adjust insulin infusion within same algorithm according to blood glucose level. • Repeat blood glucose in one hour. • For blood glucose between 6.1 and 8 mmol/l, turn insulin infusion off and go back to step number 9. If less than 5.6 mmol/l, go back to step number 10.

TPN, total parenteral nutrition; CCU, coronary care unit; ICU, intensive care unit; IV, intravenous infusion; IVF, intravenous fluids.


HANDS ON SA JOURNAL OF DIABETES & VASCULAR DISEASE

most important factor to impact on mortality, and hypoglycaemia must be

guarded against at all times.

It is noticeable in the various studies done in the ICUs internationally

that in the units where protocols were not algorithm or computer-driven,

the rate of hypoglycaemic events was very low and insulin use was ra-

tional, based on individual decisions for a specific clinical situation. An

example of an algorithm that can form the basis of decision making in an

individual patient is seen in Table 4.

CONCLUSIONGlucose control in the in-hospital patient requires dedication, an under-

standing of the targets of treatment, the need for close monitoring, and

rational decision making. The physician must understand the goal of the

intervention, the individual patient and his/her specific requirements, as

well as the post-discharge follow up of the patient.

All glucose levels are important and cannot be ignored. They must be

interpreted in the context of the individual patient and require appropriate

action to be taken. The suggested protocols and algorithms are to be used

with insight and adjusted to the individual unit. Education of the staff is cru-

cial and the limitations of each example must be explained and monitored

until the treating physician is satisfied the staff can implement them safely.

References American Diabetes Association 1. Clin Pract Recommendations 2012; 35(Suppl 1): 44–47.Capes SE, Hunt D, Malmberg K, 2. et al. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000; 355: 773–778.Amrein K, Ellmerer M, Hovorka R, 3. et al. Hospital glucose control: safe and reliable glycaemic control using enhanced model predictive control algorithm in medical ICU patients. Diabetes, Tech Therapeut 2010; 12(5): 405–412.Brunkhorst FM, Engel C, Bloos F, 4. et al. Intensive insulin therapy and Pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 10(358): 125–139.Distiller L. The infamous sliding scale: the myth persists. 5. Specialist Forum 2011: 26–30.Blaha J, Kopecky P, Matias M, 6. et al. Comparison of three protocols for tight glycemic control in cardiac surgery patients. Diabetes Care 2009; 32: 757–761.Lazaar HL, Chipkin SR, Fitzgerald CA, 7. et al. Tight control in the diabetic coronary artery bypass graft patients improves peri-operative outcomes and decreases recurrent ischemic events. Circulation 2004; 109(12): 1497–1502Ingels C, Debaveye Y, Milants I, 8. et al. Strict blood glucose control with insulin during intensive care after cardiac surgery:impact on 4 year survival, dependency on medical case and quality of life. Eur Heart J 2006; 27: 2716–2729.Malesker MA, Foral PA, McPhillips AC,9. et al. An efficiency evaluation of protocols for tight glycemic control in intensive care units. Am J Crit Care 2007; 16: 589–598.

Additional readingBartnik M, Ryden L, Ferrari R, • et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe : The Euro Heart Survey on diabetes and the heart. Eur Heart J 2004; 25: 1880–1890. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin •infusions reduces the risk of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thoracic Surg 1999; 67(20): 352–362.Goyal A, Mahaffey KW, Garg J, • et al. Prognostic significance of the change in glucose levels in the first 24 hours after acute myocardial infarction: results from the CARDINAL study. Eur Heart J 2006; 27: 1289–1297. Griesdale DE, de Souza RJ, Van Dam RM, • et al. Intensive insulin therapy and mortality among critically ill patients: a mota-analysis including NICE-SUGAR study data. Can Med Assoc J 2009; 180: 821–827.Hu D -Y, Pan C-Y, Yu J -M, China Heart Survey Group. The relationship between •coronary artery disease and abnormal glucose regulation in China: The China Heart Survey. Eur Heart J 2006; 27: 2573–2579.Krinsley JS, Grover A. Severe hypoglycaemia in critically ill patients: risk factors and •outcomes. Crit Care Med 2007: 35; 2262–2267.Krinsley JS. Effect of intensive glucose management protocol on the mortality of •critically ill adult patients. Mayo Clin Proc 2004: 79(8): 992–1000.Kosiborod M, Rathore SS, Inzucchi SE, • et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction : implications for patients with and without recognized diabetes. Circulation 2005; 111: 3078–3086.Malmberg K. Prospective randomized study of intensive insulin treatment on long •term survival after acute myocardial infarction in patients with diabetes mellitus. Br Med J 1997; 314: 1512–1515.Malmberg K, Norhammer A, Wedel H, Ryder l. Glycometabolic state at admission: •Important risk marker of mortality in conventionally treated patients with DM and acute myocardial infarction. DIGAMI study. Circulation 1999; 99: 2626–2632.Malmberg K, Ryden L, Wedel H, • et al. DIGAMI-2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction. Euro Heart J 2005; 26: 650–661.Mellbin LG, Malmberg K, Norhammer A, • et al. Prognostic implications of glucose lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the DIGAMI-2 study. Diabetologia 26 Feb 2011, published online.Nerenberg KA, Goyal A, Xavier D, • et al. Piloting a novel algorithm for glucose control in the coronary care unit. Diabetes Care 2012; 35: 19–24. NICE –SUGAR Study Investigators. Intensive versus conventional glucose control in •critically ill patients. N Engl J Med 2009: 360(13); 1283–1297. Umpierrez GE, Isaacs SD, Yu X, • et al. Hyperglycaemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87(3): 978–982.Umpierrez GE, Smiley D, Jacobs S, • et al. Randomised study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery. (RABBIT 2 surgery). Diabetes Care 2011; 34: 256–261.Van den Berghe G, Wouters P, Weekers F, • et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345(19): 1359–1367.Van den Berghe G, Wouters PJ, Kesteloot K, Hilleman DE. Analysis of health care •resource utilization with intensive insulin therapy in critically ill patients. Crit Care Med 2006; 34(3): 612–616.Wiener RS, Wiener DC, Larson KJ. Benefits and risks of tight glucose control in •critically ill adults. A meta-analysis. J Am Med Assoc 2008; 300: 933–944.Zerr KJ, Furnary AP, Grunkemeier GL, • et al. Glucose control lowers the risk of wound infection in Diabetics after open heart operations. Ann Thorac Surg 1997; 63: 356–361.

Congratulations to Dr Bert Evans and Celeste van Zyl on winning the March book giveaway of Fast Food For Sustained Energy by Gabi Steenkamp. If you would like to purchase a copy, visit your local book store.

Trusted, Simple, Safe

1

Reference:1. IMS MIDAS WorldWide Data - June 2010

Proprietary Name: Levemir®. Scheduling Status: S3 Composition: Insulin detemir 100 units /ml. Indication: Treatment of insulin requiring patients with diabetes mellitus.Registration Number:38/21.1/0084. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Proprietary Name: NovoMix® 30. Scheduling Status: S3 Composition: soluble insulin aspart/protamine crystallised insulin aspart 100 units/ml in the ratio of 30/70. Indication: Treatment of insulinrequiring patients with diabetes mellitus. Registration Number: 35/21.1/0031. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Proprietary Name: NovoRapid®. Scheduling Status: S3 Composition: 100 units insulin aspart/ml. Indication: Treatment of insulin requiring patients with diabetes mellitus.Registration Number: 34/21.1/0160. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. PO Box 783155, Sandton, 2146. Tel: (011) 202 0500 Fax: (011) 807 7989 www.novonordisk.co.za NN/DUO/3582/08/10/ver2

DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE


Drug TrendsLiraglutide launched in South Africa

The exciting promise of liraglutide (Victoza) in the treatment of type 2 diabetes rests

on three pillars. These are enhanced beta-cell functioning and good glycaemic control without weight gain or hypoglycaemic consequences.

The first two pillars of glycaemic control are in place, with extensive studies showing that more patients reach their target HbA1c levels on liraglutide treatment without weight gain or induced hypoglycaemia, than with any other diabetic agents.1-5 ‘The third pillar, inhibition of beta-cell apoptosis and preserved beta-cell functioning, has been shown in animal studies and in isolated human pancreatic islet cells’,6 Prof Juris Meier of St Josef Hospital and Ruhr University, Bochum, Germany explained at the liraglutide symposium held in Johannesburg recently.

The symposium was arranged by Novo Nordisk and included medical specialist Prof Juris Meier, South African physician, Dr Adri Kok, and psychologist Liane Lurie, with added insights from a patient perspective to complement the clinical views.

Type 2 diabetes patients typically have a loss of 50% of beta-cell functioning, with reduced insulin production and deficient glucagon suppression, which aggravates optimal blood glucose control. ‘Over time, with treatment using oral antidiabetic agents including metformin, various sulphonylureas, and agents such as pioglitazone, the beta-cell situation of patients continues to deteriorate and these agents offer very little protection from beta-cell loss’, Prof Meier noted. ‘There is even some evidence from laboratory studies that agents used in the treatment of diabetes, such as glibenclamide, also cause an increase in beta-cell apoptosis and beta-cell destruction’,7 he added.

The most significant unmet need in type 2 diabetes management is that the majority of patients do not reach their glycaemic targets of an HbA1c level less than 7%. Even as recently as a few years ago, with all the improvements in diabetes care, 43% of patients were not at target.8 The reason for poor control is fear of hypoglycaemia and actual hypoglycaemic events as treatment is intensified from oral agents to insulin.

‘In the ACCORD study,9 a higher mortality

rate was seen in patients who experienced severe hypoglycaemic events; in fact there was a two-and-a-half-fold increase in mortality in these patients’, Prof Meier noted. ‘We need to avoid hypoglycaemia in our strategic choices of treatment for our patients’, he stressed.

Weight gain is an ongoing problem in type 2 diabetes. In the UKPDS study of patients treated for 12 years, there was an average weight gain of some 8 kg. Even in recent studies such as the ADOPT study, patients gained up to 4.8 kg in five years of diabetes treatment.

Liraglutide as a GLP-1 mimetic offers the unique feature of enhanced insulin production and release from the pancreatic beta-cells only in the presence of hyperglycaemia, thereby ensuring that hypoglycaemia does not occur. Liraglutide also stimulates the delta-cells, leading to somatostatin release and glucagon suppression.

‘While early use of liraglutide in the management of type 2 diabetes is advocated, the agent is effective across all levels of remaining beta-cell function, perhaps also due to its glucagon action’, Prof Meier noted. This has been shown in a meta-analysis presented by Prof Meier at the most recent EASD meeting held in Paris last year.10

Liraglutide is easy to administer sub-cutaneously using an injectable pen, in a starter dose of 0.6 mg, with the majority of patients (80%) requiring a 1.2-mg dose daily. A larger dose of 1.8 mg is also available. Side effects are nausea and gastrointestinal disturbances.

Physicians are advised to withdraw the drug in the event of acute pancreatitis in a patient taking liraglutide. ‘There are however no significant additional risks of pancreatitis with this drug’, Prof Meier noted. C-cell hyperplasia was noted in animal studies but ongoing post-marketing evaluation of the marker calcitonin has not shown any concern with regard to this cancer, which in addition, is extremely rare in humans.

South African expert view on the new agentThe launch of Novo Nordisk’s GLP-1 analogue liraglutide (Victoza) marks a new direction in the treatment of type 2 diabetes

for South African clinicians in that if offers both patients and doctors a drug that helps meet their expectations of what a treatment should deliver.

Speaking at the launch on 28 February, Dr Adri Kok, a Johannesburg-based specialist physician in private practice who, over the past year, has treated 17 patients specially motivated under section 21, described liraglutide as ‘a product that can really make a difference to a patient, a magnificent alternative to what is currently available. We’re not just talking about theoretical scientific results’, she says. ‘Liraglutide works in patients.’

A key differentiator is that patients on liraglutide lose weight. This is not the case with other diabetes treatments, which tend to be weight neutral or actively promote weight gain. Dr Kok underscores, however, that liraglutide is not a weight-loss treatment, but a treatment for diabetes that has this as an added benefit. ‘One of the most important characteristics of liraglutide is that it has a central nervous system effect, increasing satiety while also slowing the passage of food through the gut, allowing the patient to feel fuller for longer.’

Only one of Dr Kok’s patients has discontinued liraglutide because he experienced nausea and vomiting. The other 16 have done ‘phenomenally’ on the treatment. Not only have they experienced weight loss ranging from 10 to 35 kg, but improved control of their diabetes as assessed by HbA1c levels. ‘And these benefits have been maintained over six to 12 months, without the tapering off in efficacy so often seen with other agents’, continues Dr Kok.

‘Liraglutide is well tolerated, easy to administer and titrate, and there are no adverse reactions at the injection site. In addition, it has benefits in respect of beta-cell protection and no risk of hypoglycaemia unless combined with another agent such as a sulphonylurea, which carries the risk of hypoglycaemia.’

Because of funding restrictions, doctors will need to motivate for particular patients to be prescribed liraglutide. Dr Kok feels it is especially advisable in patients with a body mass index above 30 kg/m2, in whom

New agent supports weight-loss efforts and improves glucose control without hypoglycaemia

SA JOURNAL OF DIABETES & VASCULAR DISEASE DRUG TRENDS


other treatments can be problematic. ‘In an ideal world, I’d love to be able use it earlier in the disease process, before patients become insulin dependent’, she observes. ‘Its beta-cell-protective qualities would make it especially valuable in these patients, helping to prevent the development of downstream complications. If it were more affordable, I would introduce it second only to metformin.’

Psychological processes in diabetes and its interventionsA diagnosis of type 2 diabetes requires a complete lifestyle overhaul that can leave a patient feeling overwhelmed. ‘Diabetes is a balancing act’, says Liane Lurie, clinical psychologist, Norwood, Johannesburg.

‘It’s natural for patients to feel confused and angry at the time of diagnosis, the impact of which can be devastating and exhausting. Doctors often intimate that had a patient taken more of a central role in their own care, this could have been prevented. We need to preserve the health of the body without destroying the mind.’

When faced with such life-changing news, patients typically go through the process described by psychiatrist Elisabeth Kubler-Ross as the five stages of grief:

denial• anger• bargaining and guilt• depression• acceptance.•

With enough information and support, the patient will reach stage five and realise that ‘it’s going to be OK. While the situation can’t be changed, it can be managed.’

Lurie underscores that the role of the physician/therapist/educator is critical to the acceptance process and should never be underrated. ‘Patients fight a diabetes diagnosis on many psychological levels, resisting the dietary and lifestyle changes that are the cornerstone of treatment. They are distressed by the weight gain that comes with many pharmacological treatments and resent being perceived by others as a “sick person”. Should they require insulin, there is often fear associated with the need to inject oneself, and the possibility of hypoglycaemic episodes.’

While one might expect patients to take an active and central interest in their healthcare for its own sake, in reality this is often not the case, according to Lurie. ‘Patients

usually need instrumental motivation that allows them to see how the health benefits can enhance other aspects of their lives. Many factors come into play here, including social support, stress, genetic loading and patient willingness and readiness to make the required changes. Each patient must therefore be treated as an individual, not as a number and not simply with a prescription pad.’

Even if the healthcare professional avoids lecturing and provides a therapeutic regimen that produces tangible results, change may remain elusive. ‘We can provide all the necessary information, but insight does not always lead to change.’

Psychological barriersLurie elaborates on these barriers as follows. ‘Some patients may not acknowledge the need to change, while others see the required changes as insurmountable. Still others buy into the myth of invincibility. Diabetes does not fade; it requires constant attention to diet and exercise, compliance with medication, and self-monitoring, a process that can take months or years to perfect.’

Patients need to embrace three key beliefs if they’re to accomplish this process:

Susceptibility: they need to accept that • they are not invulnerable.Severity: they need to understand that • they will pay a high price if they fail to take control of their diabetes.Benefits: they will reap the rewards, and • psychological enhancers can help them achieve these.

Psychological enhancersThe presence of support: social isola-• tion is a risk for morbidity and mortal-ity. A support network can provide care and motivation, while acting as a buffer against feelings of hopelessness.Seeing the need for and value of • change: once a patient is ready, he/she feels motivated to set realistic, feasible goals as he/she realises that the benefits of change far outweigh the current situ-ation, with increased well-being affect-ing other areas of his/her life.Instant gratification: healthcare profes-• sionals need to highlight the immediate, concrete rewards of adherence to treat-ment.

The ultimate goal of all medical inter-ventions should be to restore physical and

psychological balance. ‘We are holistic beings and treatment needs to address us on a bio-psycho-social level. This is essential to ensure better outcomes. Diabetes treatments must improve patients’ quality of life as well as their disease, so they experience the tangible benefits of improved glucose control in the form of reduced complications and feeling better,’ concludes Lurie. ‘Counselling is vital to helping patients cope with the identity shift that goes with the change from being healthy to having a chronic illness, and support needs to be ongoing if compliance with treatment regimens is to be achieved.’

Julia Aalbers

Marre M, Shaw J, Brandle M, Bebakar WM, 1. et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic in weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabetes Med 2009; 26(3): 268–278. Nauck M, Frid A, Hermansen K, Shah NS, 2. et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: The LEAD-2 study. Diabetes Care 2009; 32(1): 84–90. Epub 2008 Oct 17.Garber A, Henry R, Ratner R, 3. et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 20097; 373(9662): 473–481. Epub 2008 Sep 24.Russel-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic 4. N, Antic S, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomized controlled trial. Diabetologia 2009; 52(10): 2046–2055. Epub 2009 Aug 14.Zinman B, Gerich J, Buse JB, Lewin A, 5. et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009; 32(7): 1224–1230. Epub 2009 Mar 16. Farilla L, 6. et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003; 144: 5149–5158.Maedler K, Carr RD, Zuelig RA, 7. et al. Sulfonylurea induced beta-cell apoptosis in cultural human islets. J Clin Endocrinol Metab 2005; 90(1):502-6. Epub 2004 Oct 13.Courie CC, Rust KF, Ford ES, 8. et al. Full accounting of diabetes and pre-diabetes in the US population in 1988-1994 and 2005-2006. Diabetes Care 2009; 32(2): 287–294.Zoungas S, Woodward M. Diabetes: Insights from 9. the extended follow-up of the ACCORD trial. Nat Rev Cardiol 2011; 8(6): 308–310.Meier J. Abstract presented at EASD Congress 10. 2011.

DRUG TRENDS SA JOURNAL OF DIABETES & VASCULAR DISEASE


Drug TrendsSaxagliptin (Onglyza) launched in South Africa

The DPP-4 inhibitor saxagliptin was launched recently at a series of clini-

cal meetings in South Africa, arranged by Astra Zeneca and Bristol Myers Squibb. This incretin-enhancing agent is recommended for early use with lifestyle therapy in type 2 diabetes patients who are also on met-formin and other anti-diabetic agents, to help regain glucose control.

Dr Wayne May, endocrinologist and CDE practitioner based in Cape Town pointed out that clinicians need to tell their patients that diabetes is a chronic condition which progresses over time and that current treat-ment cannot halt this progression. Lifestyle modification is the cornerstone of therapy, but as lifestyle efforts (weight loss, exercise) diminish, the need for more complex regi-mens is inevitable.

‘What patients fear at this juncture is hypoglycaemia, which even though adju-dicated as mild, not severe, hypoglycae-mia is experienced as feelings of extreme confusion, anxiety, irritability and sweaty discomfort. Hypoglycaemia also reduces a patient’s satisfaction with their diabetes therapy and interferes with overall compli-ance.’

Weight gain is also a major concern for patients. Although metformin as first-level treatment for type 2 diabetes does not cause weight gain, most subsequent therapies do. In the UKPDS study series, patients gained up to 8 kg in 12 years, while in the ADOPT trial, average weight gain was 4.8 kg in five years.1,2

‘Sulphonylureas and insulin are the worst offenders with regard to weight gain’, Dr May noted. ‘In order to reduce overall car-diovascular risk, we also need to hit out on all fronts: lowering cholesterol and blood pres-sure, and keeping glucose levels to target.’

Supporting this approach, Dr Stephan Jacob from the Institute for Cardio- Metabolic Prevention and Therapy, University of Tubingen, Germany, noted that lowering blood pressure and cholesterol levels reduces the risk of cardivascular events to a greater degree than achieving lower HbA1c levels.

‘In my view, this is because, in the diabe-tes world, we set out primarily to beat HbA1c, particularly after the disappointing results of the UKPDS study on macrovascular compli-

cations, presented in 1999 at the EASD in Barcelona. In the UKPDS, metformin therapy was the only winner, and after UKPDS, we thought that we should reach for lower HbA1c levels to obtain macrovascular ben-efits’, he said.

More than 25 000 patients participated in the ACCORD, VADT and ADVANCE studies,3-5 in which near-normal glycaemic control should be achieved, targeting HbA1c levels of lower than 6.5 to 7%. However, ACCORD needed to be stopped early due to an increased mortality of 22% in the inten-sive glucose-control arm.

One important side effect of intensified therapy was seen more frequently: weight gain and hypoglycaemia. This was a sur-prise, as when these trials were planned, the importance of hypoglycaemic events was not considered to be so relevant.

‘In fact, the analysis following the VADT study of the factors most predictive of future cardiovascular death showed that the occur-rence of a severe hypoglyacaemic event was a better predictor of mortality than a prior myocardial infarction or other vascular event’, Dr Jacob stressed. In the ADVANCE study, severe hypoglycaemia was also asso-ciated with a greater risk of both micro- and macrovascular events.

‘In addition, in the older patient (mean age 65 years), it has been shown that risk of dementia was correlated with episodes of hypoglycaemia. The greater attributable risk of dementia was 2.39% per year in individ-uals with a history of hypoglycaemia, com-pared to those without hypoglycaemia’.6

‘We need to change our paradigm of treatment and follow the physiological route of better glucose control without hypogly-caemia and weight gain, and not use the reactive approach of intensifying therapy only when the HbA1c level deteriorates’, Dr Jacobs recommended.

‘Referring to the newer agents, the best agent to add to metformin is either a DPP-4 inhibitor or a GLP-1 agonist, which do not adversely affect cardio-metabolic risk by enhancing weight gain or inducing hypogly-caemic episodes’, Dr Jacob pointed out.

Saxagliptin usage7 has been shown to have a very low rate of hypoglycaemia, similar to placebo, when added to metformin

and other agents, and with no significant weight gain. ‘Treatment with saxagliptin when extrapolated over the long term does much better than the sulphonylureas’, Dr Jacob said.

‘The evaluation of cardiovascular safety with saxagliptin8 is very reassuring as there is no evidence that it increases cardiovascular risk when used as monotherapy or in com-bination with other agents. In fact, a long-term outcome study is currently underway, the SAVOR-TIMI 53 trial, which is 18 months into execution and the results should be available in 2015’, Dr Jacob pointed out.Patients who will benefit most from saxagliptin use are newly diagnosed patients with type 2 diabetes who are compliant with lifestyle changes. Also, all patients who should never have a hypoglycaemic event are ideal candidates for saxagliptin, such as truck and regular motor car drivers, elderly patients and those who have already had a myocardial infarction.

Julia Aalbers

UKPDS. Intensive blood glucose control with 1. sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) UK Prospective Diabetes Study. Lancet 1998; 352(9131): 837–853.Viberti G, Kahn SE, Greene DA,2. et al. A diabetes outcome progression trial (ADOPT) Diabetes Care 2002; 25(10): 1737–1743.Punthakee Z, Miller ME, Launer LJ, 3. et al. Poor cognitive function and risk of severe hypoglycaemia in type 2 diabetes – post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care 2012 Feb 28.VADT investigators. Glucose control and vascular 4. complications in veterans with type 2 diabetes. N Engl J Med 2009; 360(2): 129–39.Van Dieren S, Szemichow S, Chalmers J. Weight 5. changes and their predictors amongst 11 1104 patients with type 2 diabetes in the ADVANCE trial. Diabetes Obes Metab 2012 Jan 9. Doi 10.111/j 1463-1326 201201556.Whitmer RA, Karter AJ,6. et al. Hypoglycaemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. J Am Med Assoc 2009; 301(15): 1562–1572.Goke B, Gallwitz B, Eriksson J,7. et al. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone – a 52-week randomised controlled trial. Int J Clin Prac 2010; 64(12): 1619–1631.Cobble ME, Frederich R, 8. et al. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc Diabetol 2012; 16: 11–16.

For your patients with type 2 diabetes on monotherapy

when HbA1c levels begin to rise above 7 %1,2,3

References: 1. DeFronzo RA, et al. Diabetes Care 2009;32:1649–55. 2. Chacra AR, et al. Int J Clin Pract 2009;63(9):1395–406. 3. Hollander P, et al. J Clin Endocrinol Metab 2009;94(12):4810–9.

S3 ONGLYZA® 2.5 (Tablet). Each ONGLYZA® 2.5 tablet contains saxagliptin hydrochloride equivalent to 2.5 mg saxagliptin free base. S3 ONGLYZA® 5 (Tablet). Each ONGLYZA® 5 tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin free base. PHARMACOLOGICAL CLASSIFICATION: A.21.2 Oral hypoglycaemics. Reg. No. ONGLYZA® 2.5 : 43/21.2/0608. Reg. No. ONGLYZA® 5 : 43/21.2/0609. Ref: Reg. No. ONGLYZA® - EPI (28/07/11). ONGLYZA® is a registered trademark of Bristol-Myers Squibb. For full details relating to any information mentioned above please refer to the package insert. Bristol-Myers Squibb (Pty) Limited. Reg. No. 1956/001115/07. 47 van Buuren Road, Bedfordview, 2008, South Africa. Tel: (011) 456 6400. Fax: (011) 4566579/80. www.Bms.com. Date compiled: December 2011

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