Diabetes and lipid lowering: where are we?
Authors: John P D Reckless
Journal: BMJ (2006)

Premature morbidity and mortality is substantially due to cardiovascular disease, with tobacco use, hypertension, and abnormal lipids being the main modifiable causal factors. Glycaemia is directly related to cardiovascular risk,1 and in people with diabetes the risk of cardiovascular disease approaches that in non-diabetic people with previous myocardial infarction.2,3

Because most people with type 2 diabetes have an absolute risk of cardiovascular disease of 20% or more over 10 years, guidelines suggest active intervention to reduce risk factors in patients with diabetes, including statin therapy to reduce the serum concentration of low density lipoprotein cholesterol (LDL-C) to < 2 mmol/l.3 In this week's BMJ Costa and colleagues report a meta-analysis of trials of lipid lowering drug therapy for primary and secondary coronary heart disease prevention in patients with and without diabetes.4

Review by the National Institute for Health and Clinical Excellence (NICE) of the role of statins in preventing cardiovascular disease has endorsed the routine use of statins in people with an absolute risk of 3 20% over 10 years as effective and cost effective (especially with the use of generic statins).5 Recent large randomised trials of treatment with statins, such as the heart protection study,6 have extended the evidence base over a wide range of populations. A prospective meta-analysis of more than 90 000 patients in cholesterol lowering trials showed that for a 1 mmol/l reduction in serum low density lipoprotein (LDL) cholesterol there is a 21% (95% confidence interval 0.77% to 0.81%) reduction in cardiovascular events and similarly in stroke of 21% (0.73% to 0.85%).7 These associations are largely independent of baseline cholesterol and demographic factors, while the larger the reduction in LDL cholesterol, the greater the risk reduction.

Although previous trials did not include large numbers of patients with diabetes, the many thousands of patients in the heart protection study (HPS)6 and the collaborative atorvastatin diabetes study (CARDS) trials8 have now provided further evidence that lowering LDL cholesterol is beneficial for people with diabetes. The data from the heart protection study show little heterogeneity in the reduction in cardiovascular risk in the presence or absence of diabetes. But do people with diabetes respond to lipid lowering therapy better, equally, or less well than those with normal glucose handling?

In their meta-analysis (p 1115), Costa and colleagues identified 581 relevant studies up to April 2004.4 Of these, 12 were randomised placebo controlled trials (six primary prevention, eight secondary prevention) which fulfilled the criteria of having > 500 patients per group treated for three years in whom cardiovascular outcome data for diabetes and nondiabetes subgroups could be identified separately. What did the meta-analysis find? In both primary and secondary prevention of major coronary events there were highly significant and similar relative risk reductions of 21% (diabetes) and 23% (non-diabetes), in the presence of similar lipid changes. In the analyses of secondary prevention the absolute risk was three times higher than in those for primary prevention.

Are there any difficulties with this study? This meta-analysis looked at lipid lowering drugs in general and not just statins (the agents of first choice to achieve target LDL cholesterol concentrations). Two studies used the fibrate gemfibrozil, which is less well tolerated and has more potential side effects than other agents,3 but their omission would not materially affect the overall results. Some data came from unplanned analyses of subgroups of participants with diabetes. Unfortunately, the analyses of secondary prevention excluded data from the heart protection study because there was no separate information for groups with diabetes. Data were insufficient to examine individual drugs or doses. Finally, no data from the CARDS study were included because this study was a randomised trial between placebo and the standard active drug in type 2 diabetes without a concurrent non-diabetes group.8

Where are we now, and what does this meta-analysis add to our knowledge? Statins are clearly a highly effective treatment for primary and secondary prevention of cardiovascular disease, yielding similar relative risk reductions in patients with and without diabetes. Absolute risk is higher in patients needing secondary prevention and in patients with diabetes.

All patients with type 2 diabetes should be considered for, and the vast majority should receive, statin treatment if their serum concentration of LDL cholesterol is ≥ 2 mmol/l. The situation is much less clear for treatment with fibrates. Fibrates will probably remain mainly second line agents after the LDL target is achieved, and—despite the finding of only moderate benefits in the fenofibrate intervention and event lowering in diabetes (FIELD) study9—fenofibrate is the agent of choice rather than gemfibrozil.

The study by Costa and colleagues does not contribute to the relative lack of information about patients with type 1 diabetes, because few such patients have been included in the many statin trials (apart from moderate numbers in the heart protection study), but responses among such patients would probably be similar. People with type 1 diabetes have substantial macrovascular risk, related to age and duration of diabetes. Statin therapy is indicated for those aged 40 and over, and also for adults under 40 who have microvascular complications, hypertension, sustained poor glycaemic control, metabolic syndrome, or an adverse family history.3 Statins should be avoided, however, among women from the planning of conception to the end of breast feeding.

In statins we now have highly effective treatments to prevent cardiovascular disease in people with diabetes, and as clinicians we need to ensure that this treatment is widely used along with other effective strategies. Nevertheless, even with statin therapy, 70% of cardiovascular events still occur.