Fibrate meta-analysis: relevance of targeting non-LDL lipids

Fibrates, which raise HDL cholesterol and lower triglycerides, can reduce the risk of major cardiovascular events mainly by prevention of coronary events, according to a meta-analysis of 18 trials. These data suggest a potential role for fibrates in reducing cardiovascular risk especially in people with mixed dyslipidemia as in type 2 diabetes.

Jun M, Foote C, Lv J et al. Effects of fibrates on cardiovascular outcomes: a systemic review and meta-analysis. Lancet. Published on-line, May 11 2010.

Lowering of LDL cholesterol levels is the cornerstone of interventions to prevent cardiovascular disease. However, even with optimal statin therapy, only 30-40% of events are prevented.1,2  This underlines an important, unmet clinical need for additional therapy to reduce this high residual cardiovascular risk.

Increasing attention has focused on treatments that target non-LDL lipids, specifically low HDL cholesterol and elevated triglycerides. Fibrates, peroxisome proliferator-activated receptor (PPAR)alpha agonists, are effective against both of these parameters, as well as lowering LDL cholesterol and chylomicron remnants. However, results from outcomes studies have been less than conclusive.

To resolve this uncertainty, researchers from the George Institute for International Health, University of Sydney, Sydney, Australia undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. Literature searches over the period 1950-March 2010, identified 18 trials in 45,058 subjects eligible for inclusion in this meta-analysis. Treatments assessed in these trials were clofibrate (n=7), bezafibrate (n=4), fenofibrate (n=3), gemfibrozil (n=3) and etofibrate (n=1). The two most recent large trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study3 and the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid4 study evaluated the effects of fenofibrate in type 2 diabetes patients.

The analysis was based on 2870 major cardiovascular events, 4552 coronary events and 3880 deaths. Treatment with a fibrate was associated with a 10% (95% CI 0-18%) relative reduction in risk for major cardiovascular events (p=0.048), and a 13% (95% CI 7-19%) relative reduction in risk for major coronary events (p<0.0001). There was no statistically significant effect on stroke, all-cause mortality, cardiovascular mortality or sudden death.

The researchers showed a significant relation between baseline triglycerides and reported risk reductions in coronary events. Subgroup analyses showed that there was greater reduction in coronary events in trials with higher mean baseline triglycerides (p=0.03). There was, however, no apparent heterogeneity of effect in trials with different mean baseline levels of HDL cholesterol (p=0.47).

Additionally, on-treatment lipid levels were shown to be important. Univariate meta-regression showed that each 0.1 mmol/L (8.85 mg/dL) difference in triglycerides produced a significant 0.95 (95% CI 0.90-0.99) proportional change in the risk ratio (p=0.026). (Table 1). The effect was not, however, significant for HDL cholesterol.

Individual trials have shown significant treatment effects according to baseline lipid concentrations, with greater reduction in risk in individuals with mixed dyslipidemia, i.e., low plasma levels of HDL cholesterol and elevated triglycerides. In the FIELD study, individuals with the combination of both low HDL cholesterol (<1.0 mmol/L or 40 mg/dL in men and <1.29 mmol/L or 50 mg/dL in women) and elevated triglycerides (≥2.3 mmol/L or 204 mg/dL) at baseline derived the greatest benefit from fenofibrate treatment with a 27% reduction in cardiovascular risk (p=0.005) compared with 11% overall (p=0.16).5 Similarly, a pre-defined analysis of the ACCORD Lipid trial suggested additional benefit in individuals with baseline lipid levels in the lower tertile for HDL cholesterol (≤0.90 mmol/L or 34 mg/dL) and higher tertile for triglycerides (≥2.3 mmol/L or 204 mg/dL), with 31% reduction in risk for cardiovascular events compared with 8% overall with the combination of fenofibrate plus simvastatin.4

Analysis based on studies with fenofibrate (FIELD3, ACCORD-Lipid4 and the Diabetes Atherosclerosis Intervention Study6) also showed that treatment significantly reduced the risk of albuminuria progression by 14% (95% CI 2-25%, p=0.028).

In their conclusions, the authors said that fibrates might have a role in preventing cardiovascular disease in high-risk individuals. ‘A proportional risk reduction of 10-15% would translate into a worthwhile absolute risk reduction and plausible number needed to treat.’ As analyses suggested that the magnitude of benefit with fibrate therapy might be dependent on both baseline and on-treatment lipid levels, treatment might be especially relevant in individuals with mixed dyslipidemia, low HDL cholesterol and elevated triglycerides, typically associated with type 2 diabetes or metabolic syndrome.


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