Historical Events

Lipid Research Clinic Coronary Primary Prevention Trial (LRC) results are released.

$150 million Lipid Research Clinic Coronary Primary Prevention Trial (LRC)

The LRC Trial Puts an End to Debate

The last word on the debate over the diet-heart hypothesis came from the NHLBI in the early 1980s. Remember that two trials had been planned a decade earlier, when the institute decided against spending a billion dollars on a single, definitive full-scale trial of the prudent diet. One of these two smaller trials was MRFIT, the experiment run by Stamler using the “kitchen sink” model that had such a disappointing outcome. The other trial was the $150 million Lipid Research Clinic Coronary Primary Prevention Trial (LRC), the largest-ever experiment to test the idea that lowering one’s cholesterol could protect against heart disease. MRFIT was a huge

disappointment for the diet-heart hypothesis, so everyone was waiting for the LRC results, hoping they’d be better.

LRC was led by Basil Rifkind, chief of NHLBI’s Lipid Metabolism Branch, together with Daniel Steinberg, a cholesterol specialist at the University of California, San Diego. They screened nearly half a million middle-aged men and found 3,800 with levels of cholesterol high enough (265 mg/dL or above) to be considered likely to have a heart attack soon; these men were divided into two groups. Both received counseling to eat a cholesterol-lowering diet, with fewer eggs, leaner meat, and lower-fat dairy than the national average. The treatment group was also given a cholesterol-lowering drug called cholestyramine, while the controls received a placebo.


It’s important to understand that this trial did not test diet. Both groups in the study were advised to eat the same low-fat fare. Therefore, diet was not a variable tested in the trial; only the drug cholestyramine was tested in this design. The reason for not testing different diets, the investigators explained to critics, was that the NHLBI could not, in good conscience, deprive any high-risk man of a cholesterol-lowering diet—even though one of the trial’s original goals was to test whether such a diet could protect against heart disease in the first place. It was a Kafkaesque circle of reasoning. Keys’s hypothesis had evidently managed to sail over the normal hurdles of scientific proof such that the mere act of testing the diet was now considered unethical.


Despite this omission of diet as a variable in the trial, the LRC results, when they came out in 1984, were nevertheless hailed as a triumph for the diet-heart hypothesis. Part of that hypothesis dealt with the importance of lowering total cholesterol to prevent plaque buildup, and the drug did cause cholesterol to drop more in the treatment group compared to the controls. The treatment group also had slightly fewer heart attacks, and fewer of those that did occur were fatal.XVI


As we have come to expect, however, these results seem promising only until we look a little more closely at the data. The difference in heart attacks, for instance, was relatively small and turned out not to be statistically significant according to the statistical test that the authors had originally chosen to use. At the end of the study, investigators took the unorthodox and controversial step of retroactively selecting a more lenient test by which their results could be called statistically significant.XVII They also decided to report their data on LDL-cholesterol as percentage changes, which skewed the results and obscured the relatively small changes in absolute numbers. Even with this statistical sleight of hand, however, there was still the problem that while the treatment had reduced coronary deaths, it had not, curiously enough, improved total mortality hardly at all; sixty-eight men in the treatment group had died from all causes compared to seventy-one of the controls, a mere 0.2 percent difference.

All-cause mortality was always the pitfall of cholesterol-lowering trials. Bizarrely but consistently, men whose cholesterol had gone down were found to die at significantly higher rates from suicides, accidents, and homicides. Rifkind thought the results were a fluke, yet this strange finding had shown up before in trials that reduced saturated fat, such as the Helsinki Heart Study. In fact, a metanalysis of six cholesterol-lowering trials found that the chance of dying from suicide or violence was twice as high in the treatment groups as it was in the control groups, and the authors posited that the diet might cause depression. (Researchers have subsequently suggested that cholesterol depletion in the brain may lead to impaired functioning of seratonin receptors.) Other cholesterol-lowering studies where diet had been the only intervention consistently found higher rates of cancer and gallstones in the experimental group, which is why the NHLBI itself had held that series of workshops on the problem only a few years earlier. In addition, populations found to have very low cholesterol, such as the Japanese, suffer from higher rates of strokes and cerebral hemorrhage compared to groups whose average cholesterol is higher.

A number of biostatisticians felt strongly that the LRC leaders should account for the trial’s “fluke” findings. “Any statistician would turn in his badge if he couldn’t find an excuse for such an outcome,” said Paul Meier, one of the most influential biostatisticians of his generation. Nor could NHLBI administrator Salim Yusuf dismiss the LRC findings so easily. “I can’t fully explain it and it worries the hell out of me,” he told Science at the time.

Yet Rifkind and Steinberg did not attempt to account for these problems; they announced that the trial had been a resounding success in showing the health benefits of reducing cholesterol. Moreover, they did not merely conclude that cholysteramine prevented heart attacks; they came to the further conclusion that cholesterol-lowering changes in the diet must also reduce heart attacks—even though diet itself had not been tested. The assumption that reducing cholesterol with a drug must equal reducing cholesterol with diet represented a leap of faith and it was a questionable one. It led the biostatistician Richard A. Kronmal to write in the Journal of the American Medical Association that while it was tempting to assume that a low-fat, prudent diet would result in a reduction in heart attacks similar to what the drug had produced, the results of the trial “do not provide evidence to support this conclusion.” Kronmal was concerned that Rifkind and colleagues had pushed the data to such an extent that it seemed more like “advocacy than science.” The biostatistician Paul Meier commented that to call the results “conclusive” would constitute “a substantial misuse of the term.”

Despite these criticisms, however, Rifkind told Time magazine, “It is now indisputable that lowering cholesterol with diet and drugs can actually cut the risk of developing heart disease and having a heart attack.” Steinberg triumphantly declared LRC to be the “keystone in the arch” of the diet-heart hypothesis. Rifkind and Steinberg also assumed that their findings, based on extremely high-risk middle-aged men, “could and should be extended to other age groups and women,” as well as low-risk men, based on the commonly held assumption that the fight against heart disease could never start too soon.

Their study results were hailed as definitive in part because experts so badly wanted them to be. The NHLBI had spent $250 million on two trials, each among the most expensive studies in the history of nutrition. This investment by the government virtually demanded that the trials lead to conclusive recommendations. Decades had gone by with supporters of the diet-heart hypothesis waiting for a “definitive” trial, and this pent-up demand put pressure on experts to overlook the study’s problematic numbers and alarming side effects. According to the optimistic view of LRC taken by its lead investigators, the public could now be advised to lower their cholesterol by cutting back on saturated fat, or by taking a drug, or both.

LRC was therefore far from just the latest study on the stack. This trial, that did not even test diet at all, turned out to be one of the most influential studies of all time because its findings were subsequently used by the NHLBI to set up an entire bureaucracy devoted solely to lowering the serum cholesterol of every “high risk” person in America. Part of this effort involved telling people to cut back on dietary fat, especially saturated fat. And the effort came to encompass every man, woman, and child in the nation.


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