Changes in HDL and LDL particle subclasses with gemfibrozil predict coronary events

New data from the Veterans Affairs HDL Trial (VA-HIT)1 show that fibrate therapy produces favourable changes in the lipoprotein profile of patients, which may help to explain the reduction in coronary heart disease (CHD) events and CHD mortality previously reported in this trial.2,3

A cohort of 364 men with a new CHD event (nonfatal myocardial infarction or CHD death) during a median 5.1 year follow-up and 697 age-matched controls were included in this prospective nested case-control study. Using nuclear magnetic resonance spectroscopy, researchers measured levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses and mean particle sizes in plasma at baseline and after 7 months of treatment with gemofibrozil or placebo.

Treatment with gemfibrozil led to a 5% decrease in the concentration of total LDL particles (LDL-P). This was caused by a 20% decrease in the number of small LDL particles, partially offset by a 36% increase in the number of large LDL particles (p<0.0001 for each analysis). As a result of these changes, average LDL particle size increased significantly from 20.4 to 20.9 nm (p<0.0001). Although gemfibrozil treatment raised HDL cholesterol levels by only 6%, there was also a 10% increase in the concentration of total HDL particles (HDL-P). This was largely due to a 21% increase in numbers of small, relatively cholesterol-poor HDL particles (p<0.0001), which offset reductions in large and medium-sized HDL subclass particles. Both baseline and on-trial concentrations of LDL-P and HDL-P were strong, independent predictors of a new CHD event. The small, HDL-P subclass (HDL3), which represented the majority of total HDL-P in subjects), was also a significant predictor of CHD endpoints. Mean LDL and HDL particle sizes were not associated with CHD events.

The authors concluded that favourable changes in LDL and HDL particle subclass distributions, which occur independently of changes in the cholesterol content of these lipoproteins, may help to explain the beneficial treatment outcomes observed in VA-HIT. Increases in the small HDL subclass accounted for the increase in HDL cholesterol with gemfibrozil. It was suggested that higher numbers of these HDL particles might promote greater cholesterol efflux and protect LDL from oxidative changes.

References

1. Otvos JD, Collins D, Freedman DS et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favourably changed by gemfibrozil therapy in the Veterans Affairs High-density Lipoprotein Intervention Trial. Circulation 2006;113:1556-63.

2. Rubins HB, Robins SJ, Collins D et al. Gemfibrozil or the secondary prevention of coronary heart dosease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8.

3. Robins SJ, Collins D, Wittes JT et al. Realtion of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91.

Commentary

The results of large scale clinical trials have shown that the ability of fibrates to reduce cardiovascular risk by decreasing triglyceride levels and raising HDL cholesterol is variable. In the VA-HIT study, the increase in HDL cholesterol that accompanied treatment with gemfibrozil was inversely related to the incidence of CHD. However, as this increase in HDL cholesterol accounted for only approximately 20% of the reduction in events, it would seem that gemfibrozil has beneficial effects beyond raising HDL cholesterol levels. In this paper, the researchers have endeavoured to determine the underlying mechanism of this additional benefit by using NMR spectroscopy to investigate changes in LDL and HDL particle concentrations. They concluded that changes in particle concentrations accounted for at least part of the increased benefit that was observed in the study. It is, however, worth viewing these conclusions with a degree of caution. Firstly, the concentration of apolipoprotein B, which is regarded as a direct measure of LDL particle numbers, was not predictive of cardiovascular events, while measuring LDL particle number by NMR was. Similarly, it is difficult to reconcile the fact that the change in HDL particle concentration as determined by NMR was superior to a direct measure of HDL cholesterol for predicting risk. Finally, these observations still do not fully explain the mechanism whereby gemfibrozil reduces cardiovascular risk.