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Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial
S J Robins1, D Collins, J T Wittes
1Department of Medicine, Boston University School of Medicine, 88 E Newton St, Boston, MA 02118, USA. sjrobins@bu.edu
Insights
Gemfibrozil significantly reduced coronary heart disease (CHD) events in men with low high-density lipoprotein cholesterol (HDL-C). While increased HDL-C levels contributed, they only partially explained gemfibrozil's overall benefit.
Area of Science:
- Cardiovascular Medicine
- Clinical Lipidology
- Pharmacological Intervention
Background:
- Low high-density lipoprotein cholesterol (HDL-C) is a significant risk factor for coronary heart disease (CHD).
- The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) previously showed gemfibrozil reduced CHD events in patients with low HDL-C.
Purpose of the Study:
- To ascertain if the observed reduction in major CHD events with gemfibrozil in VA-HIT was attributable to alterations in key plasma lipid levels.
- To investigate the relationship between lipid changes and CHD event reduction.
Main Methods:
- A multicenter, randomized, double-blind, placebo-controlled trial involving 2531 men with a history of CHD and low HDL-C.
- Participants received either gemfibrozil (1200 mg/d) or a placebo.
- The primary outcome measure was the combined incidence of nonfatal myocardial infarction and CHD death, analyzed in relation to baseline and on-treatment lipid levels.
Main Results:
- Elevated HDL-C concentrations demonstrated an inverse relationship with CHD events.
- Gemfibrozil treatment led to an 11% reduction in CHD events for every 5-mg/dL increase in HDL-C (P =.02).
- The beneficial effect of gemfibrozil extended beyond the changes in HDL-C, particularly in higher HDL-C quintiles during treatment; neither triglyceride nor LDL-C levels predicted CHD events.
Conclusions:
- Achieved HDL-C concentrations with gemfibrozil therapy were associated with a significant decrease in CHD events among patients with initially low HDL-C.
- The observed increase in HDL-C levels accounted for only a portion of the overall cardioprotective effect of gemfibrozil.
Context:
A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C.
Objective:
To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels.
Design:
Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998.
Setting:
The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites.
Participants:
A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]).
Intervention:
Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267).
Main Outcome Measure:
Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death.
Results:
Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events.
Conclusions:
Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.
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