Fast track — ArticlesEffects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial
Introduction
The prevalence of type 2 diabetes mellitus is rapidly increasing worldwide. Rates of coronary heart disease at any given age are three–four-fold higher in patients with type 2 diabetes than in those without, and the risk of coronary heart disease is higher across all levels of cholesterol.1, 2 The high rates of pre-hospital, in-hospital, and subsequent mortality after myocardial infarction reduce life expectancy by an average of 5–10 years.3, 4 Hence, type 2 diabetes contributes to the overall burden of premature morbidity and mortality from coronary heart disease to a greater extent than expected by its prevalence in the community.
Although total-cholesterol and LDL-cholesterol concentrations for age and sex in those with diabetes are usually similar to or lower than those in non-diabetic populations,5 their lipid patterns differ. First, LDL-cholesterol particles are smaller and denser in individuals with diabetes than in those without diabetes,6 so that similar LDL-cholesterol levels mask a higher number of LDL particles. Second, people with diabetes generally have lower HDL-cholesterol and higher triglyceride concentrations,7, 8 which are associated with an increased risk of cardiovascular disease.9, 10
This pattern of dyslipidaemia typical of type 2 diabetes can be corrected with fibrates. Although the effects of fenofibrate on lipid fractions can vary with the population under study, a fall of 15% or more in total cholesterol and LDL cholesterol has often been reported.11 In parallel, an increase in HDL cholesterol of 10–15% is expected, together with substantial reductions in plasma triglycerides of about 30%.11 Many doctors therefore believe that fibrates are a logical drug treatment for diabetic dyslipidaemia.
The Helsinki Heart Study12 tested long-term fibrate (gemfibrozil) use in men with hypercholesterolaemia without previous coronary disease. Fibrates lowered coronary events more in people with diabetes than in others in a post-hoc analysis, though the difference was not separately significant.13 The overall reduction in coronary events was greater than would have been expected on the basis of lowering of LDL cholesterol alone. More recently, several other studies have reported beneficial effects of fibrates in individuals with diabetes or metabolic syndrome. First, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention trial (VA-HIT)14 reported that gemfibrozil reduced recurrent events in patients with coronary heart disease and low HDL-cholesterol concentrations, with greater relative benefits seen in those with diabetes or insulin resistance than in those without. Second, the findings of the Bezafibrate Infarct Prevention (BIP) trial15 showed greater cardiovascular disease event reductions in those with metabolic syndrome. These reports were also post-hoc analyses. In the Saint Mary's Ealing Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) study16 of 150 patients with diabetes without previous cardiovascular disease, there was a significant reduction in ischaemic events, including electrocardiographic changes. In the Diabetes Atherosclerosis Intervention Study (DAIS)17 of 418 individuals with diabetes and angiographically documented coronary disease, established coronary atherosclerosis progressed less in those assigned fenofibrate than in those assigned matching placebo over 3 years; there were also fewer clinical events with treatment, but this finding was not significant and the study was not designed to examine clinical outcomes.
Thus, despite its potentially important role in reducing cardiovascular risk in the setting of diabetes, no large clinical-endpoint trials of fibrate therapy specifically in people with diabetes have been done. We therefore designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effects on coronary morbidity and mortality of long-term treatment with fenofibrate to raise HDL-cholesterol concentrations and lower triglyceride levels in patients with type 2 diabetes and total blood cholesterol concentrations of less than 6·5 mmol/L.
Section snippets
Patients
A detailed description of the design of the FIELD study—a double-blind, placebo-controlled trial done in 63 centres in Australia, New Zealand, and Finland—has been published.18 In brief, patients with type 2 diabetes diagnosed according to WHO criteria1 and aged 50–75 years were randomly allocated between February, 1998, and November, 2000, to once-daily micronised fenofibrate 200 mg (Laboratoires Fournier, Dijon, France) or matching placebo capsules. Patients were recruited from hospital
Results
Figure 1 shows the trial profile. In the three countries, 14 247 patients were registered, of whom 4900 were randomised to placebo and 4895 to fenofibrate. Women comprised 37% (n=3657) of the sample, 40% (n=3955) were aged 65 years or older at screening, and 22% (n=2131) had previous cardiovascular disease. The two treatment groups were well matched for baseline characteristics, including use of cardiovascular and glucose-lowering therapies (table 1). 5820 patients (59%) met the prespecified
Discussion
This large and scientifically rigorous study provided mixed results on the effects of fenofibrate in individuals with type 2 diabetes. Our findings indicate that fenofibrate did not significantly reduce the risk of the primary trial outcome of major coronary events. However, fenofibrate did reduce the risk of total cardiovascular disease events, particularly through the prevention of non-fatal myocardial infarctions and coronary revascularisations. Further, fenofibrate significantly reduced
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