Fast track — ArticlesEffects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis
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.
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Data sources, search strategy, and selection criteria
We did a systematic review of the published work according to the PRISMA statement for the conduct of meta-analyses of intervention studies. Relevant studies were identified by searching the following data sources: Medline via Ovid (from 1950 to March, 2010), Embase (from 1966 to March, 2010), and the Cochrane Library database (Cochrane Central Register of Controlled Trials; no date restriction), with relevant text words and medical subject headings that included all spellings of “fibrate”,
Results
The literature search yielded 1555 articles, of which 27 were reviewed in full text (figure 1). Of these studies, 18 randomised controlled trials met the inclusion criteria.6, 8, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 These trials included a total of 45 058 patients, in whom 2870 major cardiovascular events were reported from five studies,12, 16, 17, 18, 25 3880 deaths from 15 studies,6, 8, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 4552 coronary events from
Discussion
This large quantitative review, including more than 45 000 individuals with a broad range of baseline characteristics, suggests that therapy with fibrates could reduce the risk of major cardiovascular events, mainly as a consequence of a favourable effect on the risk of coronary events. The findings contrast with the results of some of the individual trials that have reported no benefit.12, 16
The magnitude of the proportional risk reduction is more modest than that achieved with other vascular
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