This point cannot be unduly emphasized. An unfortunate lesson came in the summer of 2002, when physicians learned that the hormone-replacement therapy they had been prescribing to some six million postmenopausal women—either estrogen or a combination of estrogen and progestin—seemed to be doing more harm than good. The parallels to the dietary-fat controversy are worth pondering. Since 1942, when the FDA first approved hormone replacement therapy (HRT) for the treatment of hot flashes and night sweats, reams of observational studies comparing women who took hormone replacements with women who did not (just as dietary-fat studies compared populations that ate high-fat diets with populations that did not) reported that the therapy dramatically reduced the incidence of heart attacks. It was only in the 1990s that the National Institutes of Health launched a Women’s Health Initiative that included the first large-scale, double-blind, placebo-controlled trial of hormone-replacement therapy. Sixteen thousand healthy women were randomly assigned to take either hormone replacement or a placebo, and then followed for at least five years. Heart disease, breast cancer, stroke, and dementia were all more common in the women prescribed hormone replacement than in those on placebos.*11

The episode was an unfortunate lesson in what the epidemiologist David Sackett memorably called the “disastrous inadequacy of lesser evidence.” In an editorial published in August 2002, Sackett argued that the blame lay solely with those medical authorities who, for numerous reasons, including “a misguided attempt to do good, advocate ‘preventive’ maneuvers that have never been validated in rigorous randomized trials. Not only do they abuse their positions by advocating unproven ‘preventives,’ they also stifle dissent.”

From 1960 onward, those involved in the diet-heart controversy had intended to conduct precisely the kind of study that three decades later would reverse the common wisdom about the long-term benefits of hormone-replacement therapy. This was the enormous National Diet-Heart Study that Jeremiah Stamler in 1961 had predicted would take five or ten years of hard work to complete. In August 1962, the National Heart Institute awarded research grants to six investigators—including Stamler, Keys, and Ivan Frantz, Jr.—to explore the feasibility of inducing a hundred thousand Americans to change the fat content of their diet.*12 In 1968, the National Institutes of Health assembled a committee led by Pete Ahrens of Rockefeller University to review the evidence for and against the diet-heart hypothesis and recommend how to proceed. The committee published its conclusions in June 1969. Even though the American Heart Association had been recommending low-fat diets for almost a decade already, Ahrens and his colleagues reported, the salient points remained at issue. “The essential reason for conducting a study,” they noted, “is because it is not known whether dietary manipulation has any effect whatsoever on coronary heart disease.” And so they recommended that the government proceed with the trial, even though, Ahrens recalled, the committee members came to believe that any trial large enough and sufficiently well controlled to provide a reliable conclusion “would be so expensive and so impractical that it would never get done.”