In a case-control substudy of the Veterans Affairs High-Density Lipoprotein Intervention Trial, therapy with gemfibrozil was shown to reduce the total number of low-density lipoprotein (LDL) particles, especially small, more oxidizable LDL particles, which was associated with a reduced risk of coronary heart disease (CHD) events. Gemfibrozil also increased small-sized high-density lipoprotein particle numbers, which also correlated with a decrease in CHD events. Notably, these changes in particle numbers were not associated with significant changes in lipoprotein cholesterol concentrations, which current guidelines have made the principal target of lipid therapy.
Readers wishing to see the tables for this paper should consult the printed version.
The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) was a placebo-controlled, secondary prevention trial conducted from 1991 to 1998 to determine if raising a low high-density lipoprotein (HDL) cholesterol level with the fibrate gemfibrozil (Lopid) would decrease coronary heart disease (CHD) events.1 VA-HIT not only showed that myocardial infarction (MI) and CHD mortality could be significantly reduced with fibrate therapy, but a recent study showed that these events could be reduced without lowering low-density lipoprotein (LDL) cholesterol and with achieving only a very modest (6%) increase in HDL cholesterol.1 Although triglycerides were substantially reduced by gemfibrozil in VA-HIT, the decrease in triglycerides did not predict a reduction in CHD events and, indeed, the cumulative changes in all major plasma lipid fractions were found to account for only a small percentage of the benefit of drug therapy in this trial.2
How, then, might one explain the favorable clinical response to gemfibrozil in the absence of any substantial changes in either LDL cholesterol or HDL cholesterol? It is possible that gemfibrozil, as a peroxisome proliferator-activated receptor-alpha (PPARa) agent, may have a variety of favorable effects on vascular function that are not directly mediated through changes in plasma lipids. Fibrates, as well as other PPARa agents, have been reported to reduce insulin resistance, decrease proinflammatory cytokines, decrease procoagulant activity, and upregulate several key receptors that mediate cholesterol transport,3,4 which might occur without necessarily changing plasma cholesterol concentrations. It is also possible that a drug such as gemfibrozil might modify the “atherogenicity” of lipoproteins without producing major alterations in the cholesterol content of these lipoproteins by changing the number or size of lipoprotein particles.
Individuals with dyslipidemia that is characterized by a low HDL cholesterol level and an increased triglyceride level are known to have an increase in small-sized LDL particles.5 Although the LDL cholesterol level may not be increased in these individuals, the number of LDL particles is usually increased, as reflected by an increased concentration of apolipoprotein (apo) B. Studies have indicated that a preponderance of small LDL particles, even in the absence of elevated LDL cholesterol concentrations, may correlate with an increased CHD risk.6 Although similar data regarding HDL cholesterol are less clear than for LDL cholesterol, it seems that, like LDL cholesterol, both the number and size of HDL particles might also influence CHD risk independent of the cholesterol content of HDL.
Subjects and methods
In a recently published case-control substudy from VA-HIT, LDL and HDL particle numbers and size were determined by nuclear magnetic resonance (NMR) spectroscopy at baseline and after 7 months of therapy.7 The NMR method used for this analysis has been previously described 8 and has been used in several epidemiologic studies to show, in particular, that high LDL particle counts, independent of LDL cholesterol concentrations, predict an increase in cardiovascular events.9-11 In VA-HIT, this NMR analysis was undertaken not only to determine if LDL and HDL particle numbers predicted new events, but to determine whether therapy with gemfibrozil favorably changed particle concentrations and whether these changes with gemfibrozil might predict a reduction in MI and CHD death (the primary end point of VA-HIT).
As shown in Table 1, gemfibrozil reduced total LDL particle numbers, secondary to a decrease in the number of small-sized LDL particles, while increasing the number of large-sized LDL particles. The drug also produced an increase in HDL particles, essentially restricted to an increase in the number of small-sized HDL particles. As Table 1 also shows, these changes in particle numbers with therapy could hardly be predicted by the relatively small change in either LDL cholesterol or HDL cholesterol levels or by changes in the average size of LDL or HDL particles.
This VA-HIT analysis further showed that changes in both LDL and HDL particle numbers predicted significant changes in CHD events (Table 2). In this subset of VA-HIT subjects, the odds of experiencing a CHD event were not significantly related to incremental changes in LDL cholesterol, HDL cholesterol, triglyceride, or apoB levels. However, in contrast, an increase in LDL particle numbers, particularly small-sized particles, significantly predicted an increase in CHD events, whereas an increase in small-sized HDL particles predicted a significant decrease in events. Notably, changes in LDL or HDL size alone failed to significantly predict a change in events.
Finally, this study addressed the possibility that the commonly used total cholesterol/HDL cholesterol ratio or the apoB/apoA1 ratio might be as good an estimate of CHD risk as LDL and HDL particle numbers. However, over a quartile range of values in this VA-HIT population, CHD events were not predicted by either the total cholesterol/HDL cholesterol ratio ( value for trend, .27) or the apoB/apoA1 ratio ( value for trend, .37), whereas the ratio of LDL particles/HDL particles was strongly predictive of events ( value for trend, .009). A plot of these results shows a steeper gradient over a quartile range of values for the relation of particles to CHD events than for the relation of either the cholesterol or apo ratios to CHD events (
The results of an analysis of plasma LDL and HDL particles in VA-HIT showed that although therapy with gemfibrozil did not appreciably change either plasma LDL cholesterol or HDL cholesterol concentrations, it produced substantial changes in the numbers of LDL and HDL particles. Gemfibrozil reduced total LDL particle numbers, especially small, more oxidizable LDL particles, changes that were associated with a reduced risk of a CHD event. Gemfibrozil increased small HDL particle numbers as well, which was also associated with a reduction in CHD events. In contrast to an increase in LDL particles, an increase in HDL particles may be protective by enhancing the capacity of HDL to efflux and transport tissue cholesterol to the liver for excretion from the body.
The results of this analysis appear to stand in sharp contrast to current lipid guidelines, which have made LDL cholesterol reduction the principal target of lipid therapy. If nothing else, these VA-HIT results should provide impetus for reappraising the notion that LDL cholesterol lowering in patients with both low LDL cholesterol and low HDL cholesterol levels is necessary for CHD reduction.
The results of our study showed that although gemfibrozil did not significantly alter LDL cholesterol and HDL cholesterol levels, it increased LDL particle size and lowered the number of LDL particles, while raising the number of HDL particles and small subclass HDL particles. These changes predicted a decrease in CHD events.