Hyperlipidaemia in diabetes

Hyperlipidaemia is common in type 2 diabetes and contributes significantly to the incidence of coronary heart disease. The dyslipidaemic profile includes a high total triglyceride and a low HDL cholesterol. The concentrations of LDL cholesterol show less specific changes in diabetics, but when elevated, are an important contributor to the risk of coronary heart disease. Patients with diabetes should be screened for hyperlipidaemia and other vascular risk factors. Lifestyle measures such as weight loss, regular exercise and dietary vigilance with optimisation of glycaemic control are important. Treatment with HMG CoA reductase inhibitors or fibrates may be indicated.

Atherosclerosis and its complications are a major cause of mortality and morbidity among patients with type 2 diabetes. This increased risk of cardiovascular complications has many causes including dyslipidaemia*, hypertension and smoking. Hyperglycaemia and hyperinsulinaemia may also contribute. Epidemiological evidence shows that there is a strong link between altered lipoproteins and the risk of coronary heart disease (CHD) in diabetes.¹ There is a relationship between the incidence of CHD and the concentrations of total triglycerides and low density lipoprotein (LDL) cholesterol. There is an inverse relationship between CHD and high density lipoprotein (HDL) cholesterol.

Most studies show that patients with type 2 diabetes have more triglyceride and less HDL cholesterol (in particular, a lower HDL2 subfraction) than non-diabetics.^2,3 These lipid abnormalities are also seen in non-diabetic individuals with increased obesity (in particular, an android or `upper body' fat distribution with increased visceral fat), hypertension and insulin resistance, hence leading to the recognition of the `metabolic syndrome' or `syndrome X'. Although the dyslipidaemia in diabetics appears to be greater, the non-diabetic people with the `metabolic syndrome' are also at an increased risk of CHD.

While LDL cholesterol concentrations are usually similar in diabetic and non-diabetic populations, qualitative changes have been described. LDL particles have been shown to be smaller and denser in diabetics, which may enhance their atherogenicity.⁴ In non-diabetic populations, small dense LDL particles and apolipoprotein B (a component of LDL) have been shown to be independent risk factors for CHD.

In type 1 diabetics, raised triglycerides (especially very low density lipoprotein particles) are commonly seen when there is poor glycaemic control. In well-controlled patients, the overall lipid profile is often `normal', although there is evidence for an increase in small dense LDL and intermediate density lipoprotein. These findings explain in part why type 1 diabetics also have an excess of cardiovascular complications.

There is a lack of clinical studies of dyslipidaemia in type 1 diabetics. The approach should be broadly similar to that for type 2 diabetes, but glycaemic control may be more important for patients with type 1 diabetes.

HMG CoA reductase inhibitors (statins)

There are good secondary prevention data from randomised controlled trials showing that statins are highly effective in reducing the incidence of coronary events in diabetics with a previous history of CHD. The benefit seen in the diabetic subgroup of the Scandinavian Simvastatin Survival Study (4S) was reported to be greater (55% reduction in CHD events) than in non-diabetics (32% reduction).⁵ In the Cholesterol and Recurrent Events (CARE) study of pravastatin, there was a similar reduction in CHD events in both diabetics (25%) and non-diabetics (23%).⁶

While there are no data yet available on the use of these drugs in the primary prevention of CHD in diabetes, it seems probable that there would be a similar relative benefit in treating the patient's hyperlipidaemia.

Fibrates

The data for fibrates have been mixed. The Helsinki Heart Study showed that, in diabetic men without evidence of CHD (i.e. primary prevention), gemfibrozil may reduce the incidence of coronary events over 5 years. Although a 60% reduction in CHD incidence was seen, the number of diabetic patients was low and the reduction was not statistically significant.⁷

There is currently no evidence to show that, when fibrates are used for secondary prevention, correction of hypertriglyceridaemia and low HDL cholesterol will reduce the rate of CHD events. The question of the importance of treating this form of dyslipidaemia may be resolved by other trials currently in progress (e.g. the FIELD trial of bezafibrate).

The fasting lipid profile should include the concentrations of total cholesterol and triglyceride, together with the HDL cholesterol fraction and calculated LDL cholesterol. Currently, routine measurements of LDL particle size or other subfractions are not available.

It is important to consider and exclude other factors that may alter the lipid profile. These include hypothyroidism, alcohol consumption, renal disease and hereditary hyperlipidaemic syndromes.

Detailed and specific reviews of the management of hyperlipidaemia in diabetics have been written.^8,9 The management of dyslipidaemia encompasses both lifestyle and pharmacological measures. Patients with multiple risk factors need more intensive treatment (see `Sheffield tables for primary prevention of coronary heart disease - an alternative approach' ). The factors that should be considered in every patient include:

• Diet. The amount of total fat, particularly saturated fat, should be limited in tandem with the general recommendations of a diabetic diet.
• Weight control. Even a 10% weight reduction may be associated with significant metabolic benefits (reduction in triglyceride, elevation of HDL cholesterol and improvement in insulin sensitivity).
• Regular exercise. Exercise improves insulin sensitivity and the lipid profile (HDL rises), and enhances weight loss. The exercise should be individualised and appropriate to the person's cardiovascular status and fitness.
• Monitoring other vascular risk factors. Blood pressure should be controlled and people should stop smoking.
• Optimising glycaemic control. Some improvement in the lipid levels (especially hypertriglyceridaemia) often follow stabilisation of glycaemic control, but many patients with type 2 diabetes will show a sustained high triglyceride low HDL pattern. There do not appear to be any lipid profile differences when using sulphonylureas, metformin or insulin.

If the lipid profile remains suboptimal after 3 months of lifestyle measures and attempted glycaemic control, drug treatment is indicated. The Pharmaceutical Benefits Scheme provides practical guidelines (see Table 1).

• Statins. All statins have a dose-dependent effect on lowering total cholesterol and LDL cholesterol as well as moderate triglyceride lowering effects. They are recommended for patients with predominant raised LDL cholesterol.
• Fibrates (gemfibrozil). Reduce hypertriglyceridaemia and are associated with improvement of HDL cholesterol. A 3-6 month trial is recommended as there may be a transient rise in the LDL cholesterol concentrations.
• Oestrogen replacement in postmenopausal women. Hypercholesterolaemia and HDL cholesterol may improve, but triglycerides may worsen.
• Fish oils (omega-3 fatty acids). May be used as second-line agents in treating hypertriglyceridaemia.
• Bile acid binding resins. These are often unpalatable and can raise triglyceride levels. They are less useful in diabetes.
• Nicotinic acid. Although a potent lipid modifying agent, it is poorly tolerated and can increase insulin resistance. It is also less useful in diabetes.

Guidelines have been published by the Australian Diabetes Association.⁸ In addition, the American Diabetes Association recently advocated a target LDL cholesterol of 2.6 mmol/L in patients with known cardiovascular disease. In those without existing cardiovascular complications, a target LDL cholesterol of 3.4 mmol/L was recommended.⁹ The Australian Diabetes Society recommends targets of HDL cholesterol >1.0 mmol/L and triglycerides <2.0 mmol/L.⁸

The commonest cause of mortality in diabetics is CHD. There is a strong direct relationship between the dyslipidaemia seen in diabetics and the increased risk of CHD. Correction of the dyslipidaemia has been shown to reduce this risk substantially. The high frequency of atherosclerotic vascular disease in patients with diabetes justifies vigorous primary and secondary prevention, including the use of lipid lowering drugs. Multiple risk factors are an indication for more aggressive treatment.