The cholesterol story in brief: lessons from the past


The early cholesterol studies provide a cautionary reminder about assuming a benefit to homocysteine reduction before clear evidence is available. In 1987, the National Heart, Lung, and Blood Institute, began to promote cholesterol testing for all adults, despite the fact that previous large-scale trials were marked by failure to prove that lowering cholesterol prolonged life.

1950s and 1960s
The first evidence that high blood levels of cholesterol were associated with an increased risk of heart attack came from the Framingham Heart Study. Over 5,000 healthy men and women living in Framingham, Massachusetts agreed to participate in a landmark observational study that led to the current information on how to prevent heart disease. High blood levels of cholesterol, along with smoking, obesity, sedentary lifestyle, and hypertension, emerged as a major risk factor for young and middle-aged men. Those with high cholesterol were three to four times more likely to have a heart attack, chest pains, or die suddenly, compared to men with low cholesterol. For women, high cholesterol generally did not increase the risk of heart disease.

Identifying a risk factor is important, but proving that a change in the risk factor will lower the death rate from heart attacks is an entirely different matter. This was demonstrated by the failure of the Multiple Risk Factor Intervention Trial (MR.FIT), sponsored by the National Heart, Lung, and Blood Institute. This ten-year, $115 million research project followed over 12,866 middle-aged healthy but high-risk men who were randomly assigned to one of two groups. The Special Intervention Group received intensive instruction on smoking cessation, reducing consumption of dietary cholesterol and saturated fats, the need for regular physical activity, and blood pressure reduction. The other half of the participants formed the Usual Care Group who received no encouragement to change their risk factors. At ten years, there was no difference between the two groups in overall death rate or in the heart disease death rate.

1970s and 1980s
The first drug trial to test the efficacy of cholesterol reduction involved cholestyramine which lowered blood cholesterol by interfering with digestion. This $142 million trial, sponsored by the National Heart, Lung, and Blood Institute, included 3,810 healthy male participants with extremely high levels of blood cholesterol. Seven years into the study, the cholestyramine-treated men had cholesterol levels that were only 6.7% lower than the placebo-treated men.

The World Health Organization conducted a trial in three European countries in which half the male participants are given another cholesterol-lowering drug called clofibrate and half given a placebo. All had elevated cholesterol levels but no heart disease. At five years, there was no difference between the two groups in the number of fatal heart attacks, though there were significantly fewer non-fatal heart attacks in the clofibrate-treated group. More disturbing, there were more deaths in the drug-treated group. Researchers could not identify for certain why the all-cause mortality rate was higher for the men taking clofibrate.

Thomas J. Moore creates waves in the nations cardiology community with his book Heart Failure. He showed how physicians at the National Heart, Lung and Blood Institute, the early proponents of cholesterol reduction, were selective about the research that formed their treatment guidelines, ignoring the 20-plus studies that failed to show cholesterol reduction has any effect on heart disease mortality.

A study conducted in Scotland finally proves that lowering cholesterol in healthy but high-risk men will reduce the rate of heart disease. Until this one, all the previous drug trials had failed to show a benefit to cholesterol reduction. The Scottish trial involved a new class of cholesterol-lowering drug called statins. Half of the 6,000 middle-aged Scottish men were given pravastatin (brand name: Pravachol) and the other half a placebo. Unlike the older drugs, Pravachol did not produce a higher rate of noncardiac mortality. The Scottish study lasted only five years. There was a 3.2% death rate among the men on Pravachol and a 4.1% death rate among the men on the placebo. This study was funded by Bristol-Myers Squibb, which produces Pravachol.

The Air Force/Texas Coronary Atherosclerosis Prevention Study becomes the first to prove that healthy men and women with normal or borderline levels of cholesterol can benefit from cholesterol-lowering drugs. The participants were randomly assigned to receive either a placebo or another statin drug, lovastatin (brand name: Mevacor). At five years, the overall death rate was the same for both groups, but there was a one-third reduction in first heart attack in the lovastatin-treated study participants. The heart attack rate in the placebo group was 5.4% and in the lovastatin-treated group it was 3.5%. This study was funded by Merck, which produces Mevacor.

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