Metformin should be considered in all patients with type 2 diabetes unless contra-indicated

November 2001 N P S National Prescribing Service Limited PPR fifteen Prescribing Practice Review PPR Managing type 2 diabetes For General Practice Key messages Metformin should be considered in all patients with type 2 diabetes unless contra-indicated Sulfonylureas are an alternative for patients in whom metformin is either contra-indicated (including those at risk of lactic acidosis) or not tolerated Combination metformin/sulfonylurea is recommended in patients whose blood glucose is controlled inadequately Tight control of blood pressure reduces the risks of microvascular and macrovascular diabetic complications All cardiovascular risk factors diabetes, hypertension, smoking, dyslipidaemia, a previous cardiovascular event need to be managed to optimally reduce the risk of diabetic complications How to manage type 2 diabetes Encourage the patient to adopt lifestyle/dietary measures Lifestyle/dietary measures need to be continued even when drug treatment is required Reduce excess weight through diet and exercise: avoid simple carbohydrates reduce fat intake, particularly saturated fat increase consumption of high-fibre foods increase physical activity, taking into account the presence of ischaemic heart disease or foot problems. For patient materials on healthy eating, visit the Heart Foundation website at http://www.heartfoundation.com.au/heart/index_fr.html Promote smoking cessation Quitting smoking needs to be a goal for anyone with diabetes, especially because of their high risk of experiencing a cardiovascular event. National Prescribing Service Limited ACN 082 034 393 An independent, Australian organisation for Quality Use of Medicines

Aim to improve blood glucose control Target blood glucose 1,2 Glucose control (as measured by HbA 1c ) progressively declines over time leading to diabetic complications, including mortality 3 5 Consider metformin for all patients with type 2 diabetes, irrespective of their weight, unless contra-indicated Fasting level 6 mmol/l Random level 4 7 mmol/l HbA 1c 7% Any improvement in HbA 1c reduces the incidence of complications, but the greatest benefit occurs in those with higher initial HbA 1c values. Drug therapy often needs to increase over time to maintain glycaemic control: 50% of patients will require more than one antidiabetic drug by 3 years after diagnosis, increasing to 75% by 9 years after diagnosis. 6 Significant benefits have been shown in microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (myocardial infarction, stroke, peripheral vascular disease) morbidity and mortality: in overweight individuals, 10 patients need to be treated with metformin for 10 years to prevent one diabetes-related endpoint; almost five times as many overweight patients (47) need to be treated with sulfonylureas or insulin for 10 years for the same outcome. 5 Other benefits of metformin: no significant weight gain no hypoglycaemia improved lipid profile (reduces LDL and total cholesterol, and triglycerides). 7 Risk of lactic acidosis, a rare but serious adverse effect of metformin, is increased by: doses > 2 g/day renal impairment (a creatinine clearance below 50 ml/min) 8 or any condition which can diminish renal function (e.g. dehydration, surgery) hepatic or cardiac impairment use in the elderly, particularly the very old (> 85 years). 8 Consider sulfonylureas for patients in whom metformin is contra-indicated or who are at risk of developing lactic acidosis Sulfonylureas and insulin have been shown to have similar efficacy in type 2 diabetes; both reduce the risk of microvascular complications while a strong trend showed possible macrovascular benefits: 4 in non-overweight people, 31 patients need to be treated for 10 years with sulfonylureas or insulin to prevent one diabetesrelated endpoint. Choose the sulfonylurea most suitable for the individual: the elderly are at greater risk of hypoglycaemia so short-acting sulfonylureas (gliclazide, glipizide) are preferred to longer-acting sulfonylureas (glibenclamide, glimepiride) avoid glibenclamide or glimepiride in those with renal impairment. When monotherapy is not enough If monotherapy does not provide adequate glycaemic control, a combination of metformin with a sulfonylurea is recommended. For details of this and the place in therapy of the new oral antidiabetic agents, see NPS News 17: Managing type 2 diabetes.

Monitor blood glucose The GP: Measure glycated haemoglobin (HbA 1c ) levels 8,9 HbA 1c is a subfraction of haemoglobin that binds glucose. When blood glucose is persistently high, the percentage that binds to haemoglobin increases. HbA 1c reflects blood glucose control over the preceding 1 2 months whereas random blood sampling is a snapshot in time. Measure: at least twice a year in patients who are meeting treatment goals and who have stable glycaemic control 3-monthly in patients whose therapy has changed or who are not meeting glycaemic goals. Note: HbA 1c results vary between laboratories so the same laboratory should be used for repeated testing. The patient: Self monitoring 1,2,8 Take into account the patient s age, need for ideal control and motivation when considering self monitoring. Blood glucose monitoring is more accurate than urine testing and is preferred. The optimal frequency of testing in type 2 diabetes is unknown: testing at different times of the day, 1 2 days a week is suggested the patient should test more frequently when control is likely to be poor (e.g. during illness, after changes in therapy) or when using insulin. Control hypertension Target blood pressure Without proteinuria With proteinuria (1 g/day) < 130/85 mmhg < 125/75 mmhg Managing blood pressure reduces the complications of type 2 diabetes Tight blood pressure control (mean blood pressure over 9 years 144/82 mmhg vs 154/87 mmhg in the less tight control group) has been shown to reduce the risks of microvascular and macrovascular diabetic complications. 10 More than one antihypertensive agent may be needed to maintain blood pressure at target levels by nine years over 60% of patients required at least two antihypertensive drugs to maintain tight control of blood pressure and 29% needed three or more agents. 10 Use ACE inhibitors, beta-blockers, or thiazide diuretics as first-line therapy for hypertension in type 2 diabetes There is no conclusive evidence supporting one antihypertensive drug class over another. The evidence available is derived mainly from post hoc subgroup analyses of patients with diabetes from larger trials not focused on diabetes. Emphasis is given to trials investigating effects on cardiovascular morbidity and mortality. ACE inhibitors have the largest volume of evidence supporting their efficacy in reducing non-fatal and fatal diabetic complications. 11 16 ACE inhibitors reduce urinary albumin excretion in normotensive diabetic patients with microalbuminuria. 12,17 Beta-blockers were as effective as ACE inhibitors in reducing the incidence of diabetic cardiovascular complications. 11 Thiazide diuretics are first-line therapy in mild to moderate hypertension and have proven efficacy in older patients with diabetes. 18

Calcium-channel blockers are not recommended as first-line agents in diabetes Calcium-channel blockers (e.g. amlodipine, felodipine, nifedipine) have conflicting evidence, with some trials showing benefits on cardiovascular outcomes 19,20 while other studies have found an increased risk of myocardial infarction, stroke, and death with calcium-channel blockers. 14,15 Note that calcium-channel blockers are generally not used in patients who have had a myocardial infarction. More evidence is required to support the use of angiotensin II receptor antagonists in diabetes Angiotensin II receptor antagonists have, to date, mainly been shown to lower blood pressure and reduce urinary albumin excretion in diabetes; evidence relating to their effect on diabetic morbidity and mortality is emerging. Manage dyslipidaemia Target 2,21 Cholesterol HDL-cholesterol LDL-cholesterol Triglycerides < 5.0 mmol/l 1 mmol/l < 3 mmol/l < 2 mmol/l Diabetes has been classified a coronary heart disease risk equivalent, that is, providing the same level of risk as if the patient has had a prior CHD event 22 Behavioural modification and diet are first-line therapy High triglycerides and low HDL-cholesterol is the most common dyslipidaemia of diabetes. Lipid lowering reduces the incidence of cardiovascular events in people with a history of coronary heart disease (CHD) but no trials have been conducted specifically in diabetic subjects. Measure fasting lipids (preferably without a tourniquet) every 1 2 years if normal or every 3 6 months if either abnormal or on lipid-lowering therapy. 8,23,24 Weight loss, increased physical activity and improved blood glucose control will improve the lipid profile. Assess after a 3 6 months trial. Drug therapy 24 Evidence for secondary prevention with lipid-lowering drugs in diabetes has only been derived from subgroup analyses from the parent trials with small numbers of diabetic people although this evidence is not conclusive, lipid-lowering drugs reduced the number of CHD events in people with diabetes. 25 28 Where hypercholesterolaemia is predominant, use an HMG-CoA reductase inhibitor (statin). Where hypertriglyceridaemia is predominant, use a fibrate (such as gemfibrozil). With mixed hyperlipidaemia, use either a high-dose statin or statin + gemfibrozil. In mixed hyperlipidaemia, combining a fibrate with a statin can cause muscle damage with subsequent rhabdomyolysis specialist advice is recommended.

Which patients with type 2 diabetes should be offered aspirin? There is insufficient evidence to define precisely which people with diabetes should receive aspirin prophylactically Aspirin has proven efficacy in the secondary prevention of CHD and stroke in people with diabetes. 19 However, there is little evidence to support routine primary prevention with aspirin in diabetes: a study in individuals without previous myocardial infarction or cerebrovascular disease found that aspirin did not significantly affect cardiovascular mortality or the risk of stroke during the 5-year follow-up period. 29 Whether aspirin should be offered to all patients with type 2 diabetes or only those at higher risk of adverse cardiovascular events remains contentious. In people without contraindications to aspirin use, a dose of 75 325 mg/day has been recommended as prophylaxis against cardiovascular events 1,30 An increased risk of haemorrhage with long-term aspirin use is a concern: in the HOT study, major fatal and non-fatal bleeds were almost twice as common in the aspirin group as in the placebo group, with gastrointestinal bleeds the most common (57%). 19 More than one antihypertensive drug is often required to achieve satisfactory blood pressure control. In patients where an ACE inhibitor is used with a thiazide diuretic, the use of NSAIDs (including aspirin) can have a triple whammy deleterious effect on renal function. References: 1. Writing Group for Therapeutic Guidelines: Endocrinology. Therapeutic Guidelines: Endocrinology 2nd ed. Melbourne: Therapeutic Guidelines Limited; 2001 2. Holmwood C et al. Diabetes management in general practice. Canberra: National Capital Printing; 2000 3. Stratton IM et al. (UKPDS 35). BMJ 2000;321:405 12 4. UKPDS Group. (UKPDS 33). Lancet 1998;352:837 53 5. UKPDS Group. (UKPDS 34). Lancet 1998;352:854 65 6. Turner RC et al. (UKPDS 49). JAMA 1999;281:2005 12 7. DeFronzo RA. Ann Intern Med 1999;131:281 303 8. Australian Medicines Handbook 2000 9. American Diabetes Association. Diabetes Care 2001;24 (Suppl 1):S33 S43 10. UKPDS Group. (UKPDS 38). BMJ 1998;317:703 13 11. UKPDS Group. (UKPDS 39). BMJ 1998;317:713 20 12. HOPE Study Investigators. Lancet 2000;355:253 9 13. Hansson L et al. Lancet 1999;353:611 16 14. Estacio RO et al. N Engl J Med 1998;338:645 52 15. Tatti P et al. Diabetes Care 1998;21:597 603 16. Pahor M et al. Diabetes Care 2000;23:888 92 17. Lovell HG. Angiotensin converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria. In: The Cochrane Library, Issue 2, 2001. Oxford: Update Software 18. Curb J et al. JAMA 1996;276:1886 92 19. Hansson L et al. Lancet 1998;351:1755 62 20. Tuomilehto J et al. N Engl J Med 1999;340:677 84 21. National Heart Foundation of Australia. Guide for the use of lipidlowering drugs in adults. http://www.heartfoundation.com.au/prof/index_fr.html (accessed 27 July 2001) 22. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA 2001;285:2486 97 23. NSW Health Department. The principles of care and guidelines for the clinical management of diabetes mellitus. Sydney: NSW Health Department; 1996 24. American Diabetes Association. Diabetes Care 2001;24 (Suppl 1):S58 S61 25. Pyörälä K et al. Diabetes Care 1997;20:614 20 26. Sacks FM et al. N Engl J Med 1996;335:1001 9 27. The LIPID Study Group. N Engl J Med 1998;339:1349 57 28. Rubins HB et al. N Engl J Med 1999;341:410 18 29. Steering Committee of the Physicians Health Study Research Group. N Engl J Med 1989;321:129 35 30. American Diabetes Association. Diabetes Care 2001;24 (Suppl 1):S62 S63