4.1 Epidemiology

Morbidity and mortality from cardiovascular disease (CVD) are two to five times higher in patients with diabetes compared with non-diabetics.^{152, 153, 154, 155, 156, 157, 158} Women with diabetes have been shown to have a higher relative risk of death from cardiovascular disease than men, although the absolute risk is lower.^{156, 159, 160} Diabetes is associated with excess mortality, even in areas with high background death rates from cardiovascular disease. This excess mortality is evident in all age groups, most pronounced in young people with type 1 diabetes, and exacerbated by socio-economic deprivation. The life expectancy of both men and women diagnosed as having type 2 diabetes at age 40 is reduced by eight years relative to people without diabetes.^{161, 162} There is an increased prevalence of cardiovascular disease in South Asian individuals with diabetes^{156, 157} although the United Kingdom Prospective Diabetes Study (UKPDS) reported no increase in the incidence of acute myocardial infarction compared to caucasian subjects.¹⁶³

4.2 Cardiovascular risk factors

Cigarette smoking

The prevalence of smoking is significantly higher among patients with diabetes than the non-diabetic population (33% vs 27%).¹⁶⁴

Smoking is an independent risk factor in people with diabetes^{165, 166, 167} and the excess risk attributable to smoking is more than additive.¹⁶⁸ Evidence level 2++

Dyslipidaemia

Dyslipidaemia is commonly present in patients with type 2 diabetes.¹⁶⁹ An increased concentration of low density lipoprotein (LDL) cholesterol or total cholesterol is an independent risk factor for cardiovascular morbidity and mortality.^{165, 167} Each 1 mmol/l reduction of LDL cholesterol represents a 36% reduction in risk of CVD disease. Evidence level 2++

Triglycerides are an independent marker of increased risk of cardiovascular disease in type 2 diabetes.¹⁷⁰ The ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (n=8,000) is addressing whether lowering serum triglyceride concentrations reduces CVD events in patients with diabetes with and without coronary heart disease. Evidence level 2+

Hypertension

Hypertension is positively related to risk of CVD death, with a progressive increase in risk with rising systolic pressures.^{165, 166, 167} Each 10 mm Hg reduction in systolic pressure is associated with a 15% (95% CI 12-18%) reduction in the risk of CVD death over 10 years.¹⁷¹ Evidence level 2++

Hyperglycaemia

Increasing glycaemia (measured as HbA1c) results in increased risk of CVD morbidity and mortality.¹⁶⁵ Each 1% reduction in HbA1c is associated with a 21% (95% CI 15-27%) reduction in the risk of diabetes-related death and specifically a 14% reduction for myocardial infarction (MI) over 10 years. No lower threshold can be demonstrated.¹⁷² Evidence level 2++

Other potential risk factors

No studies identifying obesity as an independent risk factor in established diabetes were identified. In addition to its role in identifying patients at risk of diabetic nephropathy (see Section 5), microalbuminuria is an independent marker associated with a doubling in cardiovascular risk.¹⁷³ There is insufficient evidence to determine whether reducing albumin excretion rate specifically reduces cardiovascular morbidity or mortality.

4.3 Primary prevention of coronary heart disease

4.3.1 LIFESTYLE MODIFICATION

Lifestyle modification as discussed in section 3 is recommended to reduce cardiovascular risk factors.

4.3.2 PHARMACOLOGICAL THERAPY

There have been many large randomised clinical trials that have evaluated pharmacological treatments in reducing cardiovascular disease. Until recently, most trials have not randomised a large proportion of people with type 1 and type 2 diabetes; whereas in clinical practice, cardiovascular disease is the principal cause of morbidity and mortality in people with diabetes.

Glucose lowering

In a substudy of the UKPDS, 1704 overweight patients (>120% ideal body weight) in the first fifteen centres who had fasting plasma glucose between 6.1 and 15.0 mmol/l were randomised to conventional (diet) therapy (24%), or to intensive treatment with either chlorpropamide (16%), glibenclamide (16%), insulin (24%) or metformin (20%). The patients assigned metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47%, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (95% CI 9-63%, p=0.017), and 36% for all-cause mortality (95% CI 9-55%, p=0.011). Among patients allocated intensive blood glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint, all-cause mortality, and stroke.¹⁷⁴ Evidence level 1+

Metformin should be considered as the first-line oral hypoglycaemic agent in patients with diabetes.

Antihypertensive therapy

Blood pressure (BP) lowering in people with diabetes reduces the risk of macrovascular and microvascular disease.^{171, 172, 175} Evidence level 1+

Hypertension in people with diabetes should be treated aggressively with lifestyle modification and drug therapy.

The lowering of blood pressure to 80 mm Hg diastolic is of benefit in people with diabetes. In the Hpertension Optimal Treatment (HOT) study, the lowest incidence of major cardiovascular events in all patients occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg and further reduction below this blood pressure was safe in patients with diabetes. There was a 51% reduction in major cardiovascular events in the BP target group =<80 mm Hg compared with target group =<90 mm Hg (p =0.005).¹⁷⁶ Evidence level 1++

Target diastolic blood pressure in people with diabetes is =< 80 mm Hg.

In the HOT study, although diastolic BP was accurately measured, systolic BP was consistently underestimated. The reported achieved systolic BP of 139.7 mm Hg in patients with a diastolic target of =<80 mm Hg is likely to have been closer to 146 mm Hg.¹⁷⁷ In the UKPDS, the achieved systolic BP of 144 mm Hg in patients allocated to 'tight control' was observed when aiming for a systolic BP of <150 mm Hg. In an epidemiological analysis, lowest risk was observed in those with a systolic BP <120 mm Hg.¹⁷¹

The British Hypertension Society recommends a target systolic BP of 140 mm Hg in non-diabetic and diabetic subjects. Evidence level 4

Target systolic blood pressure in people with diabetes is <140 mm Hg.

Thiazides, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are all effective in lowering blood pressure and reducing the risk of cardiovascular events.^{178, 179} ACE inhibitors should be considered as first line therapy in patients with microalbuminuria due to their additional benefit on renal function (see section 5.5.2). Evidence level 1++

Angiotensin II receptor blockers are useful alternative antihypertensive agents in patients with ACE inhibitor-induced cough or rash. They have similar renal benefits in patients with microalbuminuria¹⁸⁰, but they have not yet been shown to decrease cardiovascular events. Evidence level 1++

Aspirin therapy

There remains uncertainty about the role of aspirin in primary prevention. In the HOT study low dose aspirin further reduced cardiovascular risk in well-controlled hypertensive patients with diabetes,¹⁷⁶ but its use must be balanced against the risk of bleeding.

This balance of benefit over risk increases with the absolute risk of MI, which can be estimated from, for example, the Joint British Guidelines.¹⁸¹ (See the SIGN guideline on lipids and the primary prevention of coronary heart disease (SIGN40)).¹¹³ The use of aspirin and other antiplatelet agents in primary prophylaxis of myocardial infarction in high risk patients is discussed in the SIGN guideline on antithrombotic therapy.¹⁸² Evidence level 1+

Aspirin (75 mg) should be considered for all patients who have diabetes and well controlled hypertension whose risk of a coronary event is estimated to be >20% over 10 years.

Lipid lowering

Treatment with lipid lowering drugs reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease. Lipid lowering for the primary prevention of coronary heart disease is discussed in SIGN 40, which includes the following recommendations:¹¹³ Evidence level 4

As for non-diabetics, lipid lowering drug therapy should be considered for primary prevention in patients with type 2 diabetes without evidence of nephropathy when the 10 year risk of a major coronary event is >=30% using the Joint British Chart.

Current assessment methods may underestimate risk in patients with type 1 diabetes and in patients with type 2 diabetes and nephropathy. Lipid lowering drug therapy should be considered at a lower risk threshold in these individuals.

4.4 Management of the patient with diabetes and new or established vascular disease

Myocardial infarction is a common cause of death in people with diabetes. The principles of management are as for patients without diabetes (see the SIGN guideline on secondary prevention of coronary heart disease following myocardial infarction (SIGN 41))¹⁸³. However, the case fatality from myocardial infarction is double that of the non-diabetic population.¹⁸⁴ Patients with diabetes more often present with a painless or 'silent' MI, which leads to a delay in admission to hospital.

4.4.1 USE OF INSULIN

A prospective randomised controlled study of intensive insulin treatment on long term survival after MI in patients with diabetes showed a reduction in mortality at one year. Insulin-glucose-potassium infusion for at least 24 hours, followed by four times daily insulin treatment for at least three months, was shown to improve long term survival, with an absolute reduction in mortality of 11%.¹⁸⁵ Evidence level 1++

It is not clear which element of treatment led to this improvement in survival and a further study is due for completion by 2003 to determine whether the reduction in mortality is caused by the infusion, the subcutaneous insulin treatment, or both.

Patients with diabetes should be considered for intensive insulin treatment following acute MI.

4.4.2 THROMBOLYSIS

Thrombolytic therapy has been shown to reduce mortality after acute MI in subjects with diabetes by up to 42%, with no increase in risk of bleeding or stroke. It should not be withheld due to concern about retinal haemorrhage in patients with retinopathy, and the indications and contraindications for thrombolysis in patients with diabetes are the same as in non-diabetic subjects.¹⁸⁶ Evidence level 1+

Patients with diabetes should be given thrombolytic therapy following myocardial infarction.

4.4.3 PRIMARY CORONARY ANGIOPLASTY FOR ACUTE MI

Subgroup analysis has shown that primary angioplasty is similarly successful in patients with and without diabetes, and may be more effective than thrombolytic therapy in subjects with diabetes either with or without acute myocardial infarction.^{187, 188} Evidence level 2+

Patients with diabetes should be considered for primary angioplasty for acute myocardial infarction.

4.4.4 BETA-BLOCKERS

Diabetes is not a contraindication to use of beta-blockers, which reduce mortality, sudden cardiac death and re-infarction when given after acute myocardial infarction.¹⁸⁹ Evidence level 1++

Beta blocker therapy should be considered for all patients following myocardial infarction.

4.4.5 ANTIPLATELET THERAPY

Meta-analysis of platelet inhibitor therapy has demonstrated a 31% reduction in non-fatal re-infarction, a 42% reduction in non-fatal stroke and a 13% reduction in cardiovascular mortality.¹⁹⁰ Evidence level 1++

Aspirin (75 mg per day) should be given routinely and continued long term in patients with diabetes and coronary heart disease.

Substudy analysis of a large RCT has demonstrated that addition of clopidogrel to aspirin over 3-12 months may reduce the risk of fatal or non-fatal myocardial infarction or stroke by 20% in patients with a past history of coronary heart disease presenting with acute coronary syndromes (i.e without electrocardiographic ST elevation). This risk reduction is associated with an additional risk of bleeding.¹⁹¹ Evidence level 1++

Addition of clopidogrel 75 mg daily to usual aspirin therapy should be considered for patients with diabetes and a past history of coronary heart disease presenting with acute coronary syndromes. *

* The grade of recommendation has been adjusted due to derivation from a substudy analysis

4.4.6 ACE INHIBITORS

A meta-analysis of nearly 100,000 patients receiving therapy with an ACE inhibitor within 36 hours of acute MI and continued for at least four weeks, confirmed that ACE inhibitors reduce mortality. Most of the benefits appeared to occur during the first few days, when mortality was highest; and patients at higher risk appeared to benefit to a greater absolute extent.¹⁹² Evidence level 1++, 1+

Three large trials (the AIRE, SAVE and TRACE studies) have shown consistent reductions in mortality when ACE inhibitor therapy is given to people after acute MI with clinical evidence of heart failure or a reduced ejection fraction.^{193, 194, 195} Evidence level 1++, 1+

In the large SOLVD study, the absolute risk reduction for mortality in patients with diabetes with chronic heart failure was 4.5% over a mean follow-up of 4.5 years. The much smaller CONSENSUS-1 study showed more dramatic reductions in mortality.^{196, 197} Evidence level 1++, 1+

The HOPE study, a large, multi-national RCT, showed benefit of ramipril in 3,577 people with diabetes. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Ramipril lowered the risk of the combined primary outcome by 25%, myocardial infarction by 22% , stroke by 33%, cardiovascular death by 37%, and total mortality by 24% After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (95% CI 12-36%, p=0.0004).¹⁹⁸ Evidence level 1++, 1+

ACE inhibitor therapy should be given to patients with diabetes who fall into any of the following categories:

following MI with or without left ventricular dysfunction heart failure due to left ventricular systolic dysfunction

aged >55 years and who either smoke, have total cholesterol >5.2 mmol/l, HDL cholesterol =<0.9 mmol/l, microalbuminuria or hypertension.

In post MI patients with left ventricular dysfunction, ACE inhibitor therapy should be considered within 48 hours of the onset of symptoms.

In the presence of significant bilateral renal artery stenosis, ACE inhibitor therapy is associated with acute renal failure and should not be used.

4.4.7 LIPID LOWERING

The most common type of dyslipidaemia in type 2 diabetes is the combination of elevated triglycerides, low high density lipoprotein (HDL) and small, dense LDL.¹⁹⁹ The current evidence of benefit with lipid lowering drugs is derived from sub-group analysis of studies that were selected without primary reference to diabetes.

The Scandinavian Simvastatin Study (4S) included 204 patients with diabetes out of a total of 4,444 subjects. It demonstrated that cholesterol-lowering therapy was highly effective with significant reductions in cardiovascular deaths, cardiovascular events, and the need for revascularisation procedures. These effects appeared more marked in patients with diabetes than those without diabetes (risk reduction 55% vs 32%). The threshold for initiating treatment with a statin was total cholesterol of >5.0mmol/l and/or a LDL cholesterol >3.0 mmol/l on diet.²⁰⁰ The Cholesterol and Recurrent Events study (CARE), like 4S, demonstrated a statistically significant reduction in coronary events in patients with diabetes treated with pravastatin although the magnitude of the effect in this North American study was less than that in 4S.^{201, 202} The Long Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed a trend to reduction in recurrent coronary events, but the numbers (782 patients with diabetes) were insufficient to demonstrate statistical significance.²⁰³ Evidence level 1+

If total cholesterol is >5.0 mmol/l, statin therapy to reduce cholesterol should be initiated and titrated as necessary to reduce total cholesterol to <5.0 mmol/l.

The effectiveness of gemfibrozil in the secondary prevention of coronary events in men with coronary disease and 'low HDL dyslipidaemia' has been examined in the VA-HIT study, which showed a significant reduction in coronary events in men with diabetes under the age of 74 over a mean follow up period of 5.1 years.²⁰⁴ Evidence level 1+

In patients with established CVD who are not receiving statin therapy and whose total cholesterol is <5.0 mmol/l and HDL cholesterol <1.0 mmol/l, gemfibrozil should be intiated.

4.4.8 CORONARY REVASCULARISATION

Patients with diabetes are at increased risk of complications during revascularisation procedures. There is an increased risk of mortality following both coronary bypass surgery and angioplasty; and there a substantially increased risk of re-stenosis following angioplasty in diabetic patients, partly ameliorated by the use of coronary stents. Much of this increased risk is due to confounding associations, e.g. female sex, diffuse coronary disease, impaired left ventricular function and renal impairment, rather than the diabetic state itself. Indications for coronary angiography in patients with diabetes with symptomatic coronary disease are similar to those in non-diabetics, recognising the increased risk associated with revascularisation procedures.

Recommendations on revascularisation in the general population are given in SIGN guideline 32 on coronary revascularisation in the management of stable angina pectoris (SIGN 32).²⁰⁵

The BARI trial²⁰⁶ suggested that amongst patients with diabetes coronary atery bypass grafting (CABG) using internal mammary arteries was associated with a better survival rate than percutaneous transluminal coronary angioplasty (PTCA) although this trial was conducted before the advent of the routine use of stenting. However, the more recent EAST trial showed similar conclusions.²⁰⁷ The American College of Cardiology / American Heart Association Task Force recommend CABG over PTCA in patients with multivessel disease.²⁰⁸ Evidence level 1+, 4

For patients with diabetes and multivessel disease, CABG with use of the internal mammary arteries is preferred over PTCA.

Stenting improves the outcome after angioplasty.²⁰⁹ Platelet glycoprotein IIb/IIIa receptor antagonists (e.g. abciximab) also reduce mortality after angioplasty with or without stenting in patients with diabetes.^{210, 211, 212, 213} Evidence level 1++

Patients with diabetes undergoing angioplasty should be treated with stents where feasible, and receive adjunctive therapy with a platelet glycoprotein IIb/IIIa receptor antagonist.

4.5 Management of acute stroke

The incidence of stroke in patients with diabetes is high, and the mortality following stroke is increased compared to non-diabetic patients. The clinical presentation is similar to that in non-diabetic subjects.²¹⁴ There is little evidence specific to people with diabetes. Management of stroke is similar to that in non-diabetic subjects. Rehydration and intravenous insulin may also be required. Evidence level 4

4.6 Peripheral arterial disease

The most common complications of peripheral arterial disease are lower limb ischaemia, gangrene and amputation (see section 7).