Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

Summary

Background

Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes.

Methods

We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events.

Findings

We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0–18) for major cardiovascular events (p=0·048) and a 13% RR reduction (7–19) for coronary events (p<0·0001), but had no benefit on stroke (−3%, −16 to 9; p=0·69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, −8 to 7; p=0·92), cardiovascular mortality (3%, −7 to 12; p=0·59), sudden death (11%, −6 to 26; p=0·19), or non-vascular mortality (−10%, −21 to 0·5; p=0·063). Fibrates reduced the risk of albuminuria progression by 14% (2–25; p=0·028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1·21, 0·91–1·61; p=0·19), although increases in serum creatinine concentrations were common (1·99, 1·46–2·70; p<0·0001).

Interpretation

Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia.

Funding

National Health and Medical Research Council of Australia.

Introduction

Cardiovascular disease is the leading cause of premature morbidity and mortality worldwide.¹ The past few decades have provided a clear understanding of the role that lipids have in the causation of vascular disease, including specific insights into the effects of lipid subfractions. Pharmacotherapy targeting LDL cholesterol has proved a particularly effective intervention strategy with statins2, 3 substantially reducing the risks of coronary heart disease, stroke, and mortality. However, a high residual risk of coronary and other cardiovascular events persists, drawing attention to the need for additional effective preventive therapies.

Therapies targeting the other main components of the lipid profile have had less effect. Although several studies have shown associations of HDL cholesterol and triglyceride concentrations with vascular risk,4, 5 interventions that increase HDL cholesterol or reduce triglyceride concentrations, or both, have not consistently shown benefit. Fibrates, agonists of the peroxisome proliferator receptors selective for the α receptors (PPAR), have been studied for more than 40 years6, 7, 8 and are clearly effective at raising HDL cholesterol, lowering triglyceride concentrations,⁹ and could also reduce LDL cholesterol and chylomicron remnants. However, their effects on vascular events remain uncertain. Additionally, concerns about the toxicity of early fibrates¹⁰ and the risk of rhabdomyolysis,¹¹ particularly when gemfibrozil was used in combination with statin therapy, have further restricted their uptake in clinical practice.

Several more large-scale trials of fibrate therapy have been completed in the past few years. Although some of these trials have suggested benefit, others have shown no effect, leading to uncertainty about the presence and magnitude of any cardiovascular protective effects and difficulties for clinicians in interpretation of the results. The ACCORD study¹² reported no overall benefit for fenofibrate, raising further questions about the usefulness of these agents. We aimed to synthesise the available clinical trial evidence and to improve definition of the likely effects of fibrate therapy on major clinical outcomes.