Elsevier

The Lancet

Volume 366, Issue 9500, 26 November–2 December 2005, Pages 1849-1861
The Lancet

Fast track — Articles
Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial

https://doi.org/10.1016/S0140-6736(05)67667-2Get rights and content

Summary

Background

Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.

Methods

We did a multinational, randomised controlled trial with 9795 participants aged 50–75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3·0–6·5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4·0 or more or plasma triglyceride of 1·0–5·0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481).

Findings

Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0·0001) commenced other lipid treatments, predominantly statins. 5·9% (n=288) of patients on placebo and 5·2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0·89, 95% CI 0·75–1·05; p=0·16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0·76, 0·62–0·94; p=0·010) and a non-significant increase in coronary heart disease mortality (1·19, 0·90–1·57; p=0·22). Total cardiovascular disease events were significantly reduced from 13·9% to 12·5% (0·89, 0·80–0·99; p=0·035). This finding included a 21% reduction in coronary revascularisation (0·79, 0·68–0·93; p=0·003). Total mortality was 6·6% in the placebo group and 7·3% in the fenofibrate group (p=0·18). Fenofibrate was associated with less albuminuria progression (p=0·002), and less retinopathy needing laser treatment (5·2% vs 3·6%, p=0·0003). There was a slight increase in pancreatitis (0·5% vs 0·8%, p=0·031) and pulmonary embolism (0·7% vs 1·1%, p=0·022), but no other significant adverse effects.

Interpretation

Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.

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

References (35)

  • WilsonPWF et al.

    Lipids, glucose intolerance and vascular disease: The Framingham Study

    Monogr Atheroscler

    (1985)
  • MR Taskinen

    Diabetic dyslipidaemia: from basic research to clinical practice

    Diabetologia

    (2003)
  • A Fontbonne et al.

    Hypertriglyceridemia as a risk factor for coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes

    Diabetologia

    (1989)
  • G Assmann et al.

    Triglycerides and atherosclerosis; results from the Prospective Cardiovascular Munster Study

    Arterioscler Rev

    (1991)
  • GM Keating et al.

    Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia

    Drugs

    (2002)
  • MH Frick et al.

    Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia—safety treatment, changes in risk factors, and incidence of coronary heart disease

    N Engl J Med

    (1987)
  • P Koskinen et al.

    Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study

    Diabetes Care

    (1992)
  • Cited by (2850)

    • Cardiac maturation

      2024, Journal of Molecular and Cellular Cardiology
    • The role of statins in diabetic retinopathy

      2024, Trends in Cardiovascular Medicine
    View all citing articles on Scopus

    Investigators listed at end of report

    View full text