Type 2 diabetes
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.
- Blood pressure and cholesterol management are priorities
- Aspirin — doubtful benefit in primary prevention
- Individualise glycaemic targets
- What to add when metformin is not enough
- Case study 75: Intensifying glycaemic control
- News insert - Advantages and disadavantages of glucose-lowering drugs PLUS Abridged PBS listings
- HbA1c converter (% <—> SI units)
- More about the online Clinical e-Audit on type 2 diabetes
Reducing risk of cardiovascular events in people with type 2 diabetes requires concurrent management of lifestyle factors, blood pressure, lipids and blood glucose.1 Lifestyle improvement is the backbone of management; identifying people at high cardiovascular risk is a priority as drug treatment of blood pressure and cholesterol will substantially reduce their absolute risk.1,2 Glycaemic control should be individualised, taking into account duration of diabetes and other patient factors.3 In this issue of News, we focus on the role of drug treatments in reducing cardiovascular risk for people with type 2 diabetes.
Having type 2 diabetes more than doubles the risk of dying from cardiovascular causes.4,5 Tight glycaemic control (close to normal glycaemia) helps prevent long-term cardiovascular events in people newly diagnosed with type 2 diabetes.6 However, in the short term (3 to 5 years) it has a limited effect on cardiovascular outcomes7,8 — lowering blood pressure or low-density lipoprotein (LDL) cholesterol levels seems to be more effective (see Figure 1).8
Figure 1: Modelled effects of cholesterol, blood pressure and HbA1c lowering on major cardiovascular events.
(Data were compiled by Yudkin et al8 from meta-analyses.7,9,10 The number of events prevented for each intervention is based on the rate of events in the standard treatment arm of the meta-analysis of blood glucose lowering, with risk reductions applied to these data.7 Coronary events are fatal or non-fatal myocardial infarction or sudden death. Cardiovascular events are coronary events or stroke. Effect of blood glucose lowering on stroke was not significant.)
Manage according to cardiovascular risk
Assess absolute cardiovascular disease risk to determine how intensively to manage blood pressure, cholesterol and lifestyle factors.2 People at high cardiovascular risk (>15% risk of a cardiovascular event in the next 5 years) benefit from a statin and an antihypertensive, regardless of cholesterol level and blood pressure.2,10,11(This benefit is uncertain with antihypertensive drug therapy if BP < 110/70 mm Hg.10) The benefits are similar for people with and without diabetes.9,12 Start a statin and an antihypertensive together with lifestyle changes for any adult with diabetes if one or more of the following apply (these indicate that the person is at high cardiovascular risk):
- age over 60 years
- cardiovascular disease
- moderate or severe chronic kidney disease
- familial hypercholesterolaemia
- systolic blood pressure ≥ 180 mm Hg or diastolic blood pressure ≥ 110 mm Hg
- total cholesterol > 7.5 mmol/L.2
There are differences between guidelines and the Pharmaceutical Benefits Scheme (PBS) criteria for subsidy of lipid-modifying drugs; e.g. people with diabetes and total cholesterol ≥ 5.5 mmol/L qualify for subsidy after a 6-week trial of dietary therapy. The full PBS criteria can be found on their website.
For people with diabetes aged ≥ 45 years (≥ 35 years for Aboriginal and Torres Strait Islander peoples) without a known high-risk condition, assess cardiovascular risk using a risk tool (see nps.org.au/cvdrisktools for links).2
Start a statin and an antihypertensive in conjunction with lifestyle changes if the risk score – calculated risk of a cardiovascular event in the next 5 years – is high (>15%).2 These treatments should also be considered for certain groups at moderate cardiovascular risk (risk score of 10% to 15%):
- Aboriginal and Torres Strait Islander peoples
- populations where risk tools may underestimate risk (South Asian, Maori and Pacific Islanders, Middle Eastern)
- persistent blood pressure ≥ 160/100 mm Hg
- family history of a cardiovascular event at an early age.2
Trial lifestyle changes for 3–6 months for everyone else at moderate cardiovascular risk before considering drug treatment.2 Lifestyle changes should be the management focus for people at low cardiovascular risk (risk score < 10%), although an antihypertensive should be considered if blood pressure is persistently ≥ 160/100 mm Hg.2,13
Targets as guides
Lowering blood pressure reduces the risk of macrovascular and microvascular events in people with diabetes, regardless of the antihypertensive regimen.12,14,15 New guidelines recommend a target of 130/80 mm Hg for people with type 2 diabetes, including those with albuminuria.2,16 See NPS News 52 for information on choosing antihypertensives for people with diabetes.
The effect of statins on cardiovascular risk depends on the extent of LDL-cholesterol lowering.17 Some statins have a greater effect on LDL cholesterol than others, but no statin is a clear winner in reducing cardiovascular events.18
Start people with diabetes on a statin with a cholesterol-lowering effect equivalent to simvastatin 40 mg19 and treat to an LDL cholesterol target < 2 mmol/L.1,2 See NPS News 71 for the relative effects of statins on cholesterol levels.
Treat blood pressure and cholesterol targets as a guide, not goals that everyone must achieve.2 For individuals who are close to target, assess whether the drug-related risks of intensifying drug therapy are worth the small added benefit.2
Benefits of statins outweigh effects on glycaemic control
Although statins have been linked to worsened glycaemic control and a small increase in diabetes onset, for people at high cardiovascular risk the benefits of statin therapy outweigh the harms.20,21
For example, for every 255 people at high cardiovascular risk without diabetes, statin treatment for 4 years results in 5.4 fewer major coronary events and 1 extra case of diabetes.20,21
The benefits of low-dose aspirin clearly offset the harms for people with diabetes who already have cardiovascular disease. Prescribe low-dose aspirin 75–150 mg daily for all adults with known cardiovascular disease unless there are contraindications.17,22
The balance of benefits and harms for people without cardiovascular disease is less favourable — for every 1000 people treated with low-dose aspirin for 2 years, there are 6 fewer serious vascular events and 3 extra major extracranial bleeds per year.23 Data in people with diabetes are limited and evidence of a benefit from low-dose aspirin is weak.24-26
Tight glycaemic control (close to normal glycaemia) is desirable for people recently diagnosed with diabetes, as it prevents long-term diabetes-related complications.6 However, the benefits of tight glycaemic control on cardiovascular outcomes are small in the short term and do not outweigh the risks for people with long-standing diabetes.7,8,27,28 For every 1000 people with type 2 diabetes who have tight glucose control instead of less tight control over 5 years (average HbA1c difference of 0.9% between tight and less-tight glucose control) there are about 7 fewer coronary events (including fatal and non-fatal MI and sudden death) and 47 extra episodes of severe hypoglycaemia.7,8
Consider patient factors
Use a target HbA1c ≤ 53 mmol/mol (≤ 7%) for most people with type 2 diabetes (see Box 1).3,29 In the UKPDS study, there was a reduced risk of microvascular complications over 10 years associated with achieving HbA1c around 53 mmol/mol (7%) compared with HbA1c around 63 mmol/mol (7.9%).30 (Note: HbA1c levels are now reported in SI units of millimoles of HbA1c per mole of total haemoglobin [mmol/mol].31) (See the NPS online HbA1c unit converter.)
Select a lower HbA1c target (≤ 48 mmol/mol [≤ 6.5%]) for people recently diagnosed with type 2 diabetes who do not have cardiovascular disease and who are not using insulin.3 People managed with lifestyle interventions with or without metformin monotherapy can be treated to an even lower HbA1c target, as they are not at risk of hypoglycaemia (see Box 1).3 In the UKPDS study, metformin but not insulin or a sulfonylurea reduced the risk of myocardial infarction and death at 10 years among people newly diagnosed with diabetes.32,33 At 20 years, 10 years after the trial ended, risk reductions in macrovascular events emerged for people started on a sulfonylurea or insulin and continued for those started on metformin.6
Use the general HbA1c target ≤ 53 mmol/mol (≤ 7%) for people with long-standing diabetes, cardiovascular disease or other co-morbidities.3,29,34 These patients do not benefit from aggressive glucose lowering, which increases the risk of severe hypoglycaemia and may increase their risk of death.7,35
In the ACCORD study, involving people with long-standing diabetes, tight glucose control (HbA1c ≤ 42 mmol/mol [≤ 6.0%]) compared withless tight control (HbA1c 53 mmol/mol to 63 mmol/mol [7.0% to 7.9%]) resulted in 10 extra deaths per 1000 people over 3.5 years.35
People with a history of severe hypoglycaemia may require higher targets (see Box 1). Severe hypoglycaemia is associated with increased morbidity and mortality, and outweighs the benefit of tight glucose control.3
|Clinical condition||HbA1c mmol/mol (%)|
Diabetes of short duration and no clinical cardiovascular disease
|General target||≤ 53 (≤ 7.0)|
|Diabetes of longer duration or clinical cardiovascular disease (any therapy)B||≤ 53 (≤ 7.0)|
|Recurrent severe hypoglycaemia or hypoglycaemia unawareness (any therapy)||≤ 64 (≤ 8.0)|
Metformin remains the drug of first choice for people with type 2 diabetes who have inadequate glycaemic control after 3 months of making lifestyle changes.1,36 Among people with diabetes who are overweight metformin monotherapy reduces the risk of diabetic complications and mortality, is weight neutral, has a low risk of hypoglycaemia and improves lipid levels.32,37,38
Sulfonylurea and then insulin
Type 2 diabetes is progressive and most people will require additional glucose-lowering therapy.32
If the HbA1c target is not met despite 3–6 months of the maximal tolerated dose of metformin, exclude adherence problems before adding a second drug.29,39 Adding a sulfonylurea is the preferred option, unless there are contraindications.1,29,40,41
Sulfonylureas reduce microvascular complications33 and are as effective in lowering HbA1c as any of the newer oral hypoglycaemic drugs, either as monotherapy or when combined with metformin.38,42 A sulfonylurea is also the preferred alternative if metformin is contraindicated or not tolerated.1,19,29
Insulin is the preferred drug for people with inadequate glycaemic control despite taking maximally tolerated doses of metformin and a sulfonylurea.39,41 It is highly effective at lowering HbA1c39, reduces microvascular complications33 and has a well established safety profile. Basal isophane insulin can be initiated as a night-time dose, while oral glucose-lowering drugs are continued.1 Metformin combined with insulin reduces HbA1c, weight gain, and insulin dose.43
See the RACGP’s Diabetes Management in General Practice: Guidelines for Type 2 Diabetes for a guide to starting insulin for people with type 2 diabetes.
Long-term outcomes unknown for newer drugs
There are a number of options other than insulin for people who require dual therapy to control hyperglycaemia but who cannot tolerate either metformin or a sulfonylurea (Box 2 - links to a pdf). All improve glycaemic control, but none has been shown to reduce microvascular or macrovascular outcomes when used as monotherapy or in combination with metformin or a sulfonylurea.38,39 No combination using a newer glucose-lowering drug is superior in both safety and HbA1c reduction to any other.38
Choice should be based on patient factors such as the patient’s HbA1c level, hypoglycaemic risk and the importance of weight gain.39 The lack of long-term safety data for DPP-4 inhibitors and GLP-1 receptor agonists should also be considered.42
Pioglitazone, exenatide, and acarbose are alternatives to insulin for triple therapy when metformin and a sulfonylurea fail to control blood glucose (Box 3 - links to a pdf). A meta-analysis found that these third-line agents had a similar effect on glycaemic control, but had different effects on weight gain and risk of hypoglycaemia.44
Dr Joey Kaye, Head of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, WA
Dr Pat Phillips, Endocrinologist, Queen Elizabeth Specialist Centre, SA
Dr John Dowden, Editor, Australian Prescriber
Dr Graham Emblen, GP, Toowoomba
Dr Oliver Frank, GP, Hillcrest, South Australia
Dr Sarah Gani, GP and Medical Educator, Blacktown
Benafsha Khariwala, Managing Editor, Journal of Pharmacy Practice and Research
A/Prof Jennifer Martin, Head PA-Southside Clinical School
Deborah Norton, QUM Pharmacist, West Vic DGP
Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers.
- Diabetes Australia. Diabetes management in general practice: guidelines for type 2 diabetes. 17th edition 2011/12. Diabetes Australia, RACGP, 2011. (accessed 22 June 2012).
- National Vascular Disease Prevention Alliance. Guidelines for the management of absolute cardiovascular disease risk. 2012. (accessed 22 June 2012).
- Cheung NW, Conn JJ, d'Emden MC, et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191:339–44.
- Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation 2007;116:151–7.
- Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 2006;332:73–8.
- Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.
- Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288–98.
- Yudkin JS, Richter B, Gale EA. Intensified glucose lowering in type 2 diabetes: time for a reappraisal. Diabetologia 2010;53:2079–85.
- Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117–25.
- Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.
- Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005;165:1410–9.
- Guide to management of hypertension 2008: Updated December 2010. Canberra: National Heart Foundation of Australia, 2010. (accessed 10 May 2012).
- UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703–13.
- UKPDS Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317:713–20.
- Chronic kidney disease management in general practice. Melbourne: Kidney Health Australia, 2012. (accessed 8 June 2012).
- Therapeutic guidelines: cardiovascular, version 5. Melbourne: Therapeutic Guidelines Ltd, 2008.
- Statins for the prevention of cardiovascular events in patients at increased risk of developing cardiovascular disease or those with established cardiovascular disease. Technology Appraisal 94. London: National Institute for Health and Clinical Excellence, 2006. (accessed 13 September 2010).
- National Collaborating Centre for Chronic Conditions. Type 2 diabetes: the management of type 2 diabetes. London: National Institute for Health and Clinical Excellence; 2009. (NICE clinical guideline 87). (accessed 22 June 2012).
- US Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. US Food and Drug Administration, 2012. (accessed 03 April 2012).
- Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–42.
- Reducing risk in heart disease: an expert guide to clinical practice for secondary prevention of coronary heart disease. Canberrra: National Heart Foundation of Australia, 2012. (accessed 26 May 2012).
- Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60.
- De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009;339:b4531.
- Calvin AD, Aggarwal NR, Murad MH, et al. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes. Diabetes Care 2009;32:2300–6.
- Younis N, Williams S, Ammori B, et al. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert opinion on pharmacotherapy 2010;11:1459–66.
- Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011;343:d4169.
- Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 2011;343:d6898.
- Colagiuri S, Dickinson S, Girgis S, et al. National Evidence Based Guideline for Blood Glucose Control in Type 2 Diabetes. Diabetes Australia and the NHMRC, Canberra 2009. (accessed 22 June 2012).
- UKPDS Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.
- Jones GR, Barker G, Goodall I, et al. Change of HbA1c reporting to the new SI units. Med J Aust 2011;195:45–6.
- UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65.
- UKPDS Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837–53.
- Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009;32:187–92.
- Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–59.
- Australian medicines handbook. Adelaide: Australian Medicines Handbook Ltd, 2012.
- Saenz A, Fernandez-Esteban I, Mataix A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev;(3):CD002966.
- Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Annals Intern Med 2011;154:602–13.
- Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009;52:17–30.
- National Collaborating Centre for Chronic Conditions. Type 2 diabetes: the management of type 2 diabetes. London: National Institute for Health and Clinical Excellence; 2009. (NICE clinical guideline 87).
- Therapeutic guidelines: endocrinology. version 4 ed. Melbourne: Therapeutic Guidelines Ltd, 2009.
- Karagiannis T, Paschos P, Paletas K, et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369.
- Hemmingsen B, Christensen LL, Wetterslev J, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ 2012;344:e1771.
- Canadian Agency for Drugs and Technologies in Health. Clinical Review: Third-Line Therapy for Patients with Type 2 Diabetes Inadequately Controlled with Metformin and a Sulfonylurea. CADTH, 2010. (accessed 22 June 2012).