Hanna Bloomfield Rubins

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol

BACKGROUND Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.

Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Background—A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. Methods and Results—Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P =0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. Conclusions—In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Distribution of lipids in 8,500 men with coronary artery disease

In the present study we measured fasting lipid profiles in over 8,500 community-living men with coronary artery disease (CAD) to determine the distribution of lipid abnormalities in this population: 81% were white and 16% black; mean age 62.9 +/- 8 years; mean total cholesterol 214 +/- 41 mg/dl; low-density lipoprotein (LDL) cholesterol 140 +/- 37 mg/dl; high-density lipoprotein (HDL) cholesterol 39 +/- 11 mg/dl; and triglycerides 190 +/- 142 mg/dl. After adjusting for age, the only significant difference between blacks and whites was a higher HDL cholesterol in blacks (45 vs 38 mg/dl, p < 0.003). With use of cut points established by the National Cholesterol Education Program, 87% of subjects had high LDL cholesterol (> or = 100 mg/dl), 38% had low HDL cholesterol (< 35 mg/dl), and 33% had high triglycerides (> 200 mg/dl). We estimated that 42% of men with CAD would be definite candidates for cholesterol-lowering medication according to the National Cholesterol Education Program guidelines and that 41% of those in whom cholesterol-lowering medication would not be definitely indicated had low levels of HDL cholesterol. We conclude that (1) black men with CAD have substantially higher HDL cholesterol than white men, (2) almost 90% of male patients with CAD are candidates for dietary intervention and > 40% may need medications to lower LDL cholesterol, and (3) 40% of patients without a definite indication for cholesterol-lowering medications have low levels of HDL cholesterol.

Cholesteryl Ester Transfer Protein TaqI B2B2 Genotype Is Associated With Higher HDL Cholesterol Levels and Lower Risk of Coronary Heart Disease End Points in Men With HDL Deficiency Veterans Affairs HDL Cholesterol Intervention Trial

Objective—We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) Taq IB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. Methods and Results—We tested for associations between the CETP Taq IB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (≤40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (−27%, P <0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P <0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6±4.8 mg/dL), followed by B1B2 men (32.0±5.3 mg/dL), and, last, by B1B1 men (30.9±4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (−34%, P =0.006). CETP Taq IB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P =0.08). Conclusions—Our data demonstrate that in men with CHD and HDL deficiency, the CETP Taq I B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.

Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.

The veterans affairs high-density lipoprotein intervention trial: Baseline characteristics of normocholesterolemic men with coronary artery disease and low levels of high-density lipoprotein cholesterol

This report describes the baseline characteristics of the 2,531 patients with coronary artery disease enrolled in the Veterans Affairs Cooperative Studies Program High Density Lipoprotein Intervention Trial. The population is characterized by a large percentage of elderly patients, diabetic patients, and patients with the clinical characteristics of the insulin-resistance syndrome.

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.

Carotid Atherosclerosis in Men With Low Levels of HDL Cholesterol

BACKGROUND AND PURPOSE A low HDL cholesterol (HDL-C) frequently occurs in conjunction with a desirable LDL cholesterol (LDL-C) and is a risk factor for coronary heart disease (CHD). Additionally, the presence of carotid atherosclerosis is a strong and independent predictor of morbidity and mortality in patients with CHD. This article describes the prevalence and correlates of sonographically detected carotid atherosclerosis in men with low levels of HDL-C and CHD but without elevated levels of LDL-C or total cholesterol. METHODS High-resolution B-mode ultrasonography was used to quantify intima-media wall thickness (IMT) in the common and internal carotid arteries and at the carotid artery bifurcation in 202 randomly selected male veterans with CHD and low levels of HDL-C who are participating in the VA HDL Intervention Trial. Ultrasonographic measurement of carotid artery wall stiffness was determined in a subset of 94 of these individuals. RESULTS The mean maximum and single greatest carotid artery IMT measurements were 1.41 and 2.58 mm, respectively. The prevalence of ultrasound-detected carotid atherosclerosis as defined by a mean maximum IMT > or = 1.3 mm was 58.9% and by single maximum IMT > or = 1.5 mm was 87.1%. IMT was associated with increased age, lower extremity arterial disease, systolic blood pressure, and ultrasonographically measured carotid artery stiffness. CONCLUSIONS Men with low levels of HDL-C and CHD but without elevated LDL-C or total cholesterol have a very high prevalence of ultrasound-detected carotid artery atherosclerosis.

Importance of high-density lipoprotein cholesterol and triglyceride levels in coronary heart disease

Although the prognostic information and treatment approach for increases in low-density lipoprotein (LDL) cholesterol have been advanced significantly over the last 10 years (with continuing controversy over baseline trigger points for treatment and degree of required LDL-cholesterol lowering), the management of abnormal triglyceride (TG) or high-density lipoprotein (HDL) cholesterol values to achieve cardiovascular benefits remains poorly defined. The recently published Adult Treatment Panel (ATP) III guidelines, expertly crafted based on current evidence and economic considerations, provide second-tier strategies for increased TGs (200 mg/dl used as the trigger point and non-HDL cholesterol as a complex target) and suggest the use of therapeutic lifestyle changes and pharmaceutical agents when HDL cholesterol is 40 mg/dl. For today’s practice, we believe the current data support a more explicit and perhaps more aggressive set of guidelines for HDL cholesterol and TG therapy, as well as the common coexistence of both. Furthermore, studies that will augment our understanding of hypertriglyceridemic treatment must be initiated to allow for the presentation of improved strategic plans related to HDL cholesterol and TGs within ATP IV.

Target Levels for Low-Density Lipoprotein in Patients With Coronary Heart Disease

In Reply. —Dr Rubins takes the summary of the Adult Treatment Panel II report to task for being inadequately documented. The full report, which draws on a very large body of evidence in arriving at its recommendations and contains 640 references, was too lengthy to be published in JAMA but will be published elsewhere. 1 The summary could not have reflected the extensive documentation of the full report. Dr Rubins questions the target of a LDL cholesterol level of 100 mg/dL (2.6 mmol/L) or lower for patients with CHD. A lower target for LDL cholesterol was set for such patients because of the very high risk for recurrence of CHD events and because clinical trial evidence shows that cholesterol lowering significantly reduces recurrent CHD. More aggressive therapy for LDL lowering in secondary prevention than in primary prevention thus seems reasonable. The target of 100 mg/dL (2.6 mmol/L) or lower is