Conclusions from the VA-HIT study.

A 1999 was a milestone for high-density lipoprotein (HDL) cholesterol research. First proposed as a risk factor for coronary heart disease (CHD) in the 1950s, it was not until 1975, when Miller and Miller1 published an influential article detailing how HDL might be involved in reverse cholesterol transport, that HDL began to attract substantial attention. In the next 25 years epidemiologic data from prospective studies established low HDL cholesterol as a major independent risk factor for CHD.2 Nevertheless, the mechanisms by which HDL might prevent atherosclerotic disease remained poorly defined and no major clinical trials focusing on HDL had been reported. In August 1999, Nature Genetics published 3 articles showing that the ATP–binding-cassette transporter 1 gene product (ABC-1) mediates cholesterol movement out of the cell into the lipidpoor apolipoprotein A-I particles, creating nascent HDL.3 The identification of a genetic mechanism for the efflux of cholesterol from human cells into HDL particles provides strong support for the reverse cholesterol transport hypothesis. This finding also builds on the discovery, just a few years earlier, of the SR-BI receptor, which is probably involved at the other end of reverse cholesterol transport, mediating the selective uptake of HDL cholesterol in the liver.4 A few days after the ABC-1 articles appeared, the results of the first major clinical trial specifically focusing on the treatment of low HDL cholesterol were published.5 This trial (the Department of Veterans Affairs HDL Intervention Trial [VA-HIT]) showed for the first time that lipid treatment, which had no effect on lowdensity lipoprotein (LDL) cholesterol levels but which raised HDL cholesterol and lowered triglycerides, could substantially reduce major cardiac events. VA-HIT was a multicenter, randomized clinical trial that tested the hypothesis that lipid therapy aimed primarily at raising HDL cholesterol and lowering triglycerides would reduce major cardiac events in patients with established CHD whose major lipid abnormality was a low level of HDL cholesterol. Patients were eligible for the trial if they were men with documented CHD, an HDL cholesterol #40 mg/dl, and an LDL cholesterol #140 mg/dl: 2,531 subjects were randomized to either gemfibrozil (1,200 mg/day) or placebo and were followed for an average of 5 years. The average lipids at baseline were total cholesterol 175 mg/dl, HDL cholesterol 32 mg/dl, LDL cholesterol 111 mg/dl, and triglycerides 160 mg/dl. The mean age was 64 years and the mean body mass index was 29. Systemic hypertension was present in 57% and diabetes mellitus in 25%. Compared with those assigned placebo, patients receiving gemfibrozil had an increase in HDL cholesterol by 6%, a reduction in triglycerides by 31%, and no change in LDL cholesterol. There was a 22% relative risk reduction in the primary end point of time to first nonfatal myocardial infarction or CHD death (95% confidence interval 7 to 35, p 5 0.006). There was also a significant reduction in cerebrovascular events. The drug was well tolerated and safe. What are the implications of this trial for clinicians? The immediate implication is that there is now a therapeutic option for CHD patients who have low HDL cholesterol and low-risk LDL cholesterol. Until now there have been no clinical trial data to guide therapeutic decisions for this population, which comprises about 20% to 25% of all CHD patients.6 For patients whose LDL cholesterol is ,100 mg/dl and whose HDL cholesterol is low, the decision to treat with gemfibrozil based on the results of this trial is straightforward. However, for patients with borderline low LDL cholesterol, i.e., between 100 and 130 mg/dl, the decision is more complicated. Although national guidelines acknowledge that the decision to administer cholesterol-lowering drugs (i.e., statins) to CHD patients with LDL cholesterol between 100 and 130 mg/dl is optional, the commonly accepted interpretation seems to be that statins should be given to all CHD patients with an LDL cholesterol .100 mg/dl.7,8 The authors of the guidelines have been careful to state that this approach is optional because there are no clinical trial data to support statin use in patients with baseline LDL cholesterol ,130 mg/dl. Indeed, recent subgroup analyses from large scale statin trials suggest that patients with LDL cholesterol ,125 to 130 mg/dl do not achieve a reduction in cardiovascular events with statin therapy.9 In the combined data from the Cholesterol and Recurrent Events and the Long-term Intervention with Pravastatin in Ischemic Disease studies, pravastatin was not associated with a reduction in risk of CHD death and nonfatal myocardial infarction (relative risk 0.97, 95% confidence interval 0.8 to 1.2) in the large subgroup of patients who had an LDL cholesterol ,125 mg/dl at baseline.10 This is in contrast to the highly significant 22% reduction in those same end points reported in the VA-HIT. Although there are trials now underway that will better define the role of statins in patients with LDL cholesterol ,130 mg/dl,11 currently the evidence for treating CHD patients with low LDL cholesterol From the Center for Chronic Disease Outcomes Research, VA Medical Center, Minneapolis, Minnesota; and the Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. Manuscript received February 29, 2000; revised manuscript received and accepted March 16, 2000. Address for reprints: Hanna B. Rubins, MD, MPH, Section of General Internal Medicine (111O), VA Medical Center, Minneapolis, Minnesota 55417. E-mail: bloom013@tc.umn.edu.