Targeting Cholesterol Treatment toward Increasing High-Density Lipoprotein Levels

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The summary below is from the full report titled "A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events." It is in the 18 January 2005 issue of Annals of Internal Medicine (volume 142, pages 95-104). The authors are E.J. Whitney, R.A. Krasuski, B.E. Personius, J.E. Michalek, A.M. Maranian, M.W. Kolasa, E. Monick, B.G. Brown, and A.M. Gotto Jr.

What is the problem and what is known about it so far?

Cholesterol and triglycerides are fatty substances known as lipids. They travel through the bloodstream in the form of lipid–protein packages called lipoproteins. There are several types of lipoproteins, including low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs). Low-density lipoproteins carry more cholesterol than do HDLs and deposit the cholesterol around the body. High levels of total and LDL cholesterol increase the risk for heart attacks and arterial disease. In contrast, low rather than high levels of HDL increase the risk for arterial disease. Several studies show that "antilipid" drugs that primarily reduce LDL cholesterol levels can decrease the risk for arterial disease. However, some antilipid drugs primarily increase HDL cholesterol levels. Few studies have tested whether these drugs decrease the risk for arterial disease among people with low HDL cholesterol levels.

Why did the researchers do this particular study?

To see whether aggressive drug therapy aimed at increasing HDL cholesterol levels reverses progression of coronary artery disease and prevents coronary events.

Who was studied?

143 military retirees with low HDL cholesterol levels (<40 mg/dL) and known coronary artery disease. None had diabetes or kidney disease or had recently had a heart attack, stroke, heart failure, or heart procedure (such as bypass surgery). All had LDL cholesterol levels less than 160 mg/dL.

How was the study done?

Each retiree had a heart catheterization that showed coronary artery stenosis. All received low-fat diet counseling from a dietitian, exercise guidance from an exercise specialist, and smoking cessation advice. They were then randomly assigned to aggressive HDL level–increasing therapy with gemfibrozil, niacin, and cholestyramine or matching dummy pills (placebos) for 30 months. Drug doses were adjusted regularly, and niacin and cholestyramine were added at month 3 and month 6, respectively. Neither the retirees nor their doctors knew who received drug therapy or placebos.

What did the researchers find?

All retirees lost weight. Compared with those taking placebos, retirees treated with drugs had a 20% decrease in total cholesterol level, 26% decrease in LDL cholesterol level, 50% decrease in triglyceride level, and 36% increase in HDL cholesterol level. Coronary lesions regressed with drug therapy and progressed without drug therapy. Retirees receiving drug therapy had fewer total cardiovascular events, such as hospitalizations for chest pain and bypass procedures, than did those taking placebos. They also had more flushing, skin rashes, and abdominal pain.

What were the limitations of the study?

The trial was small and lasted only 30 months. It had limited ability to test whether the drug treatment prevented heart attacks and deaths. Drug treatment beneficially affected levels of all types of lipids. We do not know whether the increases in HDL levels, the decreases in other lipid levels, or both led to the changes in arterial disease.

What are the implications of the study?

Aggressive drug therapy aimed at increasing HDL cholesterol levels improves lipid levels, reverses coronary stenosis, and might prevent some cardiovascular events in some people who exercise regularly and eat low-fat diets.