A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events

18 January 2005 | Volume 142 Issue 2 | Pages 95-104

Background: The high-density lipoprotein (HDL) cholesterol level is a strong predictor of cardiovascular events in epidemiologic studies. Until recently, it has been less extensively studied as a therapeutic target.

Objective: To assess the angiographic and clinical effects of a pharmacologic strategy to increase HDL cholesterol levels.

Design: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1996.

Setting: Outpatient specialty clinic of a large U.S. military medical center.

Participants: 143 military retirees younger than 76 years of age with low HDL cholesterol levels and angiographically evident coronary disease.

Intervention: Gemfibrozil, niacin, and cholestyramine or corresponding placebos, with aggressive dietary and lifestyle intervention at baseline.

Measurements: Change from baseline to 30 months and a composite measure of clinical events that included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death, and cardiovascular procedures.

Results: At baseline, mean (±SD) lipid values were as follows: total cholesterol, 5.1 ± 0.8 mmol/L (196 ± 31 mg/dL); low-density lipoprotein (LDL) cholesterol, 3.3 ± 0.7 mmol/L (128 ± 27 mg/dL); and HDL cholesterol, 0.9 ± 0.2 mmol/L (34 ± 6 mg/dL). Compared with placebo, the pharmacologically treated group experienced a 20% (95% CI, 14.8% to 24.3%) decrease in total cholesterol level, a 36% (CI, 28.4% to 43.5%) increase in HDL cholesterol level, a 26% (CI, 19.1% to 33.7%) decrease in LDL cholesterol level, and a 50% (CI, 40.5% to 59.2%) reduction in triglyceride levels. Focal coronary stenosis increased by 1.4% in the placebo group but decreased by 0.8% in the drug group (difference, –2.2 percentage points [CI, –4.2 to –0.1 percentage points]). A composite cardiovascular event end point was reached in 26% of patients in the placebo group and 13% of those in the drug group (difference, 13.7 percentage points [CI, 0.9 to 26.5 percentage points]). Side effects, particularly flushing and gastrointestinal intolerance, were more common in the drug group but rarely led to withdrawal from the study.

Limitations: The study was small and used a composite clinical outcome. Whether improvements in angiographic findings were due to reductions in LDL cholesterol or increases in HDL cholesterol was not established. Flushing may have led to inadvertent unblinding in patients who were randomly assigned to active study drugs.

Conclusions: A combination regimen aimed at increasing HDL cholesterol levels improves cholesterol profiles, helps prevent angiographic progression of coronary stenosis, and may prevent cardiovascular events in some people who exercise regularly and eat low-fat diets.

Editors' Notes Context Most trials that address lipid management focus on reducing low-density lipoprotein (LDL) cholesterol levels rather than increasing high-density lipoprotein (HDL) cholesterol levels. Contribution In this double-blind trial, 143 military retirees with low HDL cholesterol levels and coronary artery disease were randomly assigned to placebo or aggressive HDL cholesterol–increasing therapy with gemfibrozil, niacin, and cholestyramine for 30 months. All participants received diet and exercise counseling. Compared with the placebo group, the treated group had a 20% decrease in total cholesterol level; a 36% increase in HDL cholesterol level; less focal coronary stenosis; fewer total cardiovascular events; and more flushing, skin rashes, and abdominal symptoms. Cautions The small trial had limited ability to assess clinical outcomes. –The Editors

 

Author and Article Information

From Heart and Vascular Institute of San Antonio, San Antonio, Texas, Wilford Hall Medical Center, Lackland Air Force Base, and University of Texas School of Public Health, Houston, Texas; Cardiology Consultants, Grant Pass, Oregon; Northwestern University, Chicago, Illinois; University of Washington School of Medicine, Seattle, Washington; and Weill Medical College of Cornell University, New York, New York.

Disclaimer: The opinions expressed in this article are those of the authors, not the U.S. Air Force.

Acknowledgments: The authors thank Jennifer Palmer for her assistance with editing the manuscript.

Grant Support: By an unrestricted grant from the Parke Davis Branch of Pfizer Pharmaceuticals.

Potential Financial Conflicts of Interest: Consultancies: R.A. Krasuski (Pfizer Pharmaceuticals), A.M. Gotto Jr. (Pfizer Pharmaceuticals); Honoraria: R.A. Krasuski (Pfizer Pharmaceuticals), A.M. Gotto Jr. (Pfizer Pharmaceuticals, Kos Pharmaceuticals); Grants received: R.A. Krasuski (Pfizer Pharmaceuticals).

Requests for Single Reprints: Richard A. Krasuski, MD, U.S. Air Force Medical Center, 759 MSGS/MCCC, 2200 Bergquist Drive, Suite 1, Wilford Hall Medical Center, Lackland Air Force Base, TX; e-mail, Richard.krasuski{at}lackland.af.mil.

Current Author Addresses: Dr. Whitney: Heart and Vascular Institute of Texas, 1933 NE Loop 410, San Antonio, TX 78217.

Drs. Krasuski, Maranian, and Kolasa: 759 MSGS/MCCC, 2200 Bergquist Drive, Suite 1, Wilford Hall Medical Center, Lackland Air Force Base, TX 78236-5300.

Dr. Personius: Cardiology Consultants, 520 SW Ramsey Avenue, Suite 101, Grants Pass, OR 97526.

Dr. Michalek: University of Texas School of Public Health, 5323 Harry Hines Boulevard, V8.112M, Dallas, TX 75390-9128.

Dr. Monick: Department of Medicine, Northwestern University—The Feinberg School of Medicine, 251 East Huron Street, Galter Pavilion, Suite 3-150, Chicago, IL 60611.

Dr. Brown: Box 356422, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195-6422.

Dr. Gotto: Joan and Samuel Weill College of Medicine, Cornell University, 1300 New York Avenue, Box 5, New York, NY 10021.

Author Contributions: Conception and design: E.J. Whitney, B.G. Brown.

Analysis and interpretation of the data: E.J. Whitney, R.A. Krasuski, B.E. Personius, A.M. Maranian, M.W. Kolasa, E. Monick, B.G. Brown.

Drafting of the article: E.J. Whitney, R.A. Krasuski, B.E. Personius.

Critical revision of the article for important intellectual content: E.J. Whitney, R.A. Krasuski, B.E. Personius, A.M. Maranian, E. Monick, B.G. Brown, A.M. Gotto Jr.

Final approval of the article: E.J. Whitney, R.A. Krasuski, B.G. Brown, A.M. Gotto Jr.

Provision of study materials or patients: E.J. Whitney.

Statistical expertise: E.J. Whitney, R.A. Krasuski, J.E. Michalek.

Obtaining of funding: E.J. Whitney.

Administrative, technical, or logistic support: E.J. Whitney, R.A. Krasuski, A.M. Maranian.

Collection and assembly of data: E.J. Whitney, R.A. Krasuski, A.M. Maranian, M.W. Kolasa, E. Monick.

Read all Rapid Responses

HDL Elevation and Plaque Burden

Stephen J Nicholls

Annals Online, 20 Jan 2005 [Full text]

Biochemical sequelae when increasing HDL levels

Viliam Lustig, et al.

Annals Online, 16 Feb 2005 [Full text]

The Authors Respond

Richard A. Krasuski, et al.

Annals Online, 21 Mar 2005 [Full text]