Reducing risk in type 2 diabetes (Prescribing Practice Review)

Published in MedicineWise News

Date published: About this date

Clinical content may change after this date. This information is not intended as a substitute for medical advice from a qualified health professional. Health professionals should rely on their own expertise and enquiries when providing medical advice or treatment.

Key messages

  • Encourage intensive lifestyle change to slow progression to diabetes and prevent complications
  • Assess and manage overall cardiovascular risk early
  • Metformin remains the drug of choice in type 2 diabetes, especially in overweight people
    • Consider glitazones only when a combination of metformin and a sulfonylurea is not suitable or fails to maintain glycaemic control
  • Consider insulin early when blood glucose control fails with maximal oral therapy
Encourage lifestyle change to reduce risk of developing diabetes and cardiovascular disease

Healthy eating, regular physical activity and weight loss can reduce the relative risk of progressing to diabetes by more than 50% in overweight people with impaired glucose regulation.[1,2] Lifestyle changes can also reduce cardiovascular risk by reducing blood pressure, assisting with weight loss and improving lipid profile and are an important part of the ongoing management of diabetes.

Anyone with risk factors for diabetes but blood glucose measurements not diagnostic of diabetes is a candidate for intensive lifestyle changes to delay progression to diabetes. See Diabetes Management in General Practice 2004/5[3] for information about which patients should be tested for diabetes. The SNAP (Smoking, Nutrition, Alcohol, Physical Activity) Guide provides practical advice and information about sources of support for general practitioners working with patients on lifestyle change.[4]

Assess and manage overall cardiovascular risk

Assess cardiovascular risk

Assessing overall cardiovascular risk allows treatment to be directed at those at highest risk who are likely to receive the greatest benefit. Risk stratification may also be a useful tool for discussing the benefits of lifestyle changes in reducing overall risk with patients. Use a tool such as the National Heart Foundation of Australia's Cardiovascular Risk Chart.[5]

Manage all modifiable risk factors

No single factor predicts cardiovascular risk in people with diabetes so attention must be given to all modifiable risk factors. Long-term intervention involving a number of risk factors (including hypertension, dyslipidaemia, hyperglycaemia, microalbuminuria and lifestyle) can significantly reduce the risk of macro- and microvascular disease.[6,7]

An incentive payment (through the Practice Incentives Program [PIP]) is available for completion of the minimum annual cycle of care for people with diabetes, using the Medicare Benefits Schedule (MBS) item numbers for this purpose. The annual cycle of care includes (but is not limited to) attention to glycaemic control, cardiovascular risk factors and complications of diabetes such as eye damage, renal disease and foot problems.

Aim for tight blood pressure control—any move towards target is likely to be beneficial

Tight blood pressure control substantially reduces the risk of diabetic complications and appears to be more effective than tight blood glucose control in reducing the risk of both macro- and microvascular disease.[8,9]

The systolic blood pressure target in diabetes is < 130 mmHg. Guidelines variously give diastolic targets of < 80 mmHg[10,11] or < 85 mmHg.[12,13] People with proteinuria > 1 g/day should aim for a target of < 125/75 mmHg.

Evidence for blood pressure targets in diabetes includes:

  • A subgroup analysis of diabetic patients in the Hypertension Optimal Treatment (HOT) study, which found that a diastolic blood pressure target of 80 mmHg reduced the risk of major cardiovascular events compared to a target of 90 mmHg (11.9 vs 24.4 events per 1000 patient-years) and the risk of cardiovascular mortality compared to a target of 85 mmHg (3.7 vs 11.2 events per 1000 patient-years).[14]
  • The United Kingdom Prospective Diabetes Study (UKPDS), in which treating to a target of 150/85 mmHg compared to treating to a target of 180/105 mmHg was associated with a lower risk of complications (50.9 vs 67.4 events per 1000 patient-years) and deaths (13.7 vs 20.3 events per 1000 patient-years) related to diabetes.[8]
Consider co-existing conditions

When choosing an antihypertensive drug for a person with diabetes, consider whether there are any co-existing conditions apart from diabetes that favour the use of a particular class. For example, ACE inhibitors and/or beta-blockers are appropriate for people with diabetes after myocardial infarction.

ACE inhibitors, betablockers and low-dose thiazides are suitable first-line antihypertensives

ACE inhibitors, low-dose thiazides and beta-blockers reduce cardiovascular morbidity and mortality in people with diabetes and hypertension.[8,15–18] They can be considered first-line choices for people with diabetes who do not have an indication for a particular antihypertensive drug class. Calcium-channel blockers should be reserved for second-line use: some trials have suggested a higher rate of major vascular events with dihydropyridine calcium-channel blockers (such as amlodipine) than with ACE inhibitors in people with diabetes.[19,20] Most people will require more than one antihypertensive drug to reach target.

Use an ACE inhibitor or angiotensin II receptor antagonist in those with microalbuminuria or proteinuria

ACE inhibitors and angiotensin II receptor antagonists slow the progression of renal disease in diabetes[21] and many guidelines recommend that either class be used first-line for diabetes with microalbuminuria or proteinuria.[3,10–12] ACE inhibitors have been shown to reduce the risk of cardiovascular events and death in people with diabetes.[15] Comparable evidence for angiotensin II receptor antagonists is not yet available.

Consider overall cardiovascular risk when contemplating lipid-modifying therapy or low-dose aspirin

Optimising glycaemic control and making lifestyle changes can improve the lipid profile; lipid-modifying therapy may be required if these measures are insufficient. People with diabetes and other cardiovascular risk factors benefit from lipidmodifying drug therapy even when lipid levels are not markedly elevated.[22,23]

In people with diabetes who have no other cardiovascular risk factors, aspirin’s gastrointestinal adverse effects may outweigh its benefits.[13] Calculate overall cardiovascular risk to determine whether potential benefits are likely to outweigh possible harms.

Achieving blood glucose control

Tight blood glucose control reduces the risk of microvascular and probably macrovascular complications

Intensive glycaemic control* has been shown to reduce the relative risk of microvascular complications by 25% compared with diet alone.[9]

A reduction in the risk of macrovascular events (myocardial infarction but not stroke) associated with blood glucose lowering alone has only been seen with metformin in overweight patients.[24] However, there is evidence of a relationship between glycaemia and macrovascular risk.[25] Multiple risk factor management including glycaemic control has also been shown to substantially reduce the risk of macrovascular events in people with diabetes and microalbuminuria.[6]

Consider metformin first in type 2 diabetes

Although the evidence for the effect of metformin on diabetes-related complications comes from a study in which only overweight patients were treated first-line with metformin (because this was the practice at the time), it is considered a suitable choice for non-overweight patients as well because:

  • it is the only antidiabetic drug shown to reduce the risk of diabetes-related death and all-cause mortality[24]
  • unlike sulfonylureas, it does not cause weight gain
  • unlike sulfonylureas, it does not cause hypoglycaemia when used alone.

A sulfonylurea could be considered when metformin is contra-indicated or not tolerated, or in non-overweight people.[13]

* Using insulin or a sulfonylurea, treating to a target fasting plasma glucose level of less than 6 mmol/L.

Consider insulin early

Considerations for starting insulin

Maintaining tight glucose control is critical for preventing diabetic complications so starting insulin treatment should not be delayed. There is no agreed HbA1c threshold for starting insulin once maximal tolerated doses of oral agents fail to maintain glycaemic control. The decision to start insulin will likely depend on factors such as co-existing conditions, the patient’s life expectancy and his or her ability to manage insulin therapy. For example, initiation of insulin might be considered at a lower HbA1c threshold in a younger patient (who has a greater lifetime risk of complications) than in an older patient who is asymptomatic and has no microvascular complications.[26]

A simple approach to starting insulin — add a single bedtime dose of insulin to existing oral therapy 
When starting insulin, adding a single bedtime dose of intermediate-acting insulin to continuing oral therapy has a number of practical advantages over ceasing oral therapy[26,27]:

  • only one injection is needed per day and can be given at home, which is simpler and more convenient for the patient
  • a lower dose of insulin is required for comparable glycaemic control
  • glycaemic control improves from the initiation of insulin, rather than risking a deterioration of glycaemic control when oral drugs are ceased.

A suggested schedule is 10 units of isophane insulin just before bed.[3,26] Starting with a slightly lower dose may be appropriate for people who are particularly concerned about hypoglycaemia; a higher dose may be required for those with hyperglycaemic symptoms.[26] Once insulin is started, the dose can be gradually adjusted according to blood glucose levels. For more details, see NPS News 39: Reducing risk in type 2 diabetes.

A glitazone is a third-line choice

Where monotherapy with metformin (or a sulfonylurea) is insufficient, the combination of first choice is metformin plus a sulfonylurea. A glitazone can be considered as part of this combination when either metformin or a sulfonylurea is contra-indicated or not tolerated, or when combination therapy with metformin and a sulfonylurea fails. When deciding whether to add a glitazone or initiate insulin, consider:

  • The evidence for each drug in preventing diabetic complications. Insulin has been shown to reduce the risk of diabetic complications9, whereas the effect of glitazones (alone or in combination with existing therapies) on diabetesrelated morbidity and mortality is yet to be defined.
  • The safety profile of each drug. The long-term safety profile of insulin is better defined than that of the glitazones. Insulin may be more likely to cause hypoglycaemia; however, evidence quantifying the risk of hypoglycaemia with combinations that include either insulin or a glitazone is currently limited and suggests no difference in the occurrence of symptomatic hypoglycaemia (although a higher rate of hypoglycaemia with insulin, based on blood glucose measures, has been observed).[28,29]
  • The likelihood of achieving glycaemic control with oral therapy. When added to metformin, a sulfonylurea, or insulin, a glitazone reduces HbA1c levels by approximately a further 0.5–1.5%. Greater reductions in HbA1c are seen in patients who have poorer glycaemic control (HbA1c ³ 9% before treatment) than patients with better control (HbA1c < 9% before treatment).[30]
  • Co-morbidities that may limit the use of one drug (for example, glitazones are contra-indicated in moderate to severe heart failure).
  • Patient preference and ability or willingness to inject insulin.

More information about the glitazones is available in NPS RADAR.

† Rosiglitazone, but not pioglitazone, is TGA-approved and PBS-listed for use in combination with metformin plus a sulfonylurea.

Expert reviewer

Professor George Jerums
Director, Endocrine Unit, Austin Hospital, Heidelberg, Vic


  1. Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393–403.
  2. Tuomilehto J, et al. N Engl J Med 2001;344:1343–50.
  3. Diabetes management in general practice 2004/5, 10th edition. Diabetes Australia; 2004.
  4. SNAP: a population health guide to behavioural risk factors in general practice. South Melbourne: Royal Australian College of General Practitioners National Standing Committee–Quality Care; 2004.
  5. New Zealand Guidelines Group. The assessment and management of cardiovascular risk, accessed 7 March 2005.
  6. Gaede P, et al. N Engl J Med 2003;348:383–93.
  7. Gaede P, et al. Lancet 1999;353:617–22.
  8. UK Prospective Diabetes Study Group. (UKPDS 38). BMJ 1998;317:703–13.
  9. UK Prospective Diabetes Study Group. (UKPDS 33). Lancet 1998;352:837–53.
  10. Australian Centre for Diabetes Strategies. National evidence-based guidelines for management of type 2 diabetes mellitus. Part 4: blood pressure control. National Health and Medical Research Council; 2004.
  11. Therapeutic Guidelines: Endocrinology. Version 3, 2004.
  12. National Heart Foundation of Australia. Hypertension management guide for doctors 2004, accessed 7 March 2004.
  13. Australian Medicines Handbook 2004.
  14. Hansson L, et al. Lancet 1998;351:1755–62.
  15. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet 2000;355:253–9.
  16. Curb J, et al. JAMA 1996;276:1886–92.
  17. Lindholm L, et al. J Hypertens 2000;18:1671–5.
  18. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2002;288:2981–97.
  19. Tatti P, et al. Diabetes Care 1998;21:597–603.
  20. Estacio R, et al. Diabetes Care 2000;23(Suppl 2):B54–64.
  21. Strippoli GFM, et al. BMJ 2004;329:828.
  22. Heart Protection Study Collaborative Group. Lancet 2003;361:2005–16.
  23. Colhoun HM, et al. Lancet 2004;364:685–96.
  24. UK Prospective Diabetes Study Group. (UKPDS 34). Lancet 1998;352:854–65.
  25. Stratton I, et al. BMJ 2000;321:405–12.
  26. Wong J, Yue D. Aust Prescr 2004;27:93–6.
  27. Goudswaard AN, et al. Cochrane Database Syst Reviews 2004;(4):CD003418.pub2.
  28. Aljabri K, et al. Am J Med 2004;116:230–5.
  29. Schwartz S, et al. Diabetes Care 2003;26:2238–43.
  30. Diamant M, Heine RJ. Drugs 2003;63:1373–405.