Type 2 diabetes

Published in MedicineWise News

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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.

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.

Blood pressure and cholesterol management are priorities

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

Modelled effects of cholesterol, blood pressure and HbA1c lowering on major cardiovascular events

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
  • microalbuminuria
  • 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

Aspirin — doubtful benefit in primary prevention

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

Given current evidence, new NVDPA guidelines do not recommend routine use of low-dose aspirin for people without known cardiovascular disease, including people with diabetes.2

Individualise glycaemic targets

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

Box 1: Some recommended HbA1c targetsA for people with type 2 diabetes3
Clinical condition HbA1c mmol/mol (%)
Diabetes of short duration and no clinical cardiovascular disease
  • requiring lifestyle modification with or without metformin
  • requiring any glucose-lowering drugs other than metformin or insulin
  • requiring insulin

  • ≤ 42 (≤ 6.0)A
  • ≤ 48 (≤ 6.5)A
  • ≤ 53 (≤ 7.0)A
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)
A. HbA1c targets must be balanced against the risk of severe hypoglycaemia, especially among older people.
B. In an older adult long duration might be considered to be > 10 to 20 years, but for a person who develops type 2 diabetes at a young age it may be considerably longer.

What to add when metformin is not enough

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

Expert reviewers

Dr Joey Kaye, Head of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, WA

Dr Pat Phillips, Endocrinologist, Queen Elizabeth Specialist Centre, SA

Reviewers

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.

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