Good Calories, Bad Calories

The critical question was whether prolonged exposure to an abnormally high triglyceride level increased the risk of atherosclerosis. If carbohydrate-induced lipemia was as common as Ahrens believed, “especially in the areas of the world distinguished by caloric abundance and obesity,” then it was important to know. If so, then having patients with high triglycerides eat less fat would only make the condition worse. By 1957, Ahrens was also warning about the dangers of oversimplifying the diet-heart science: maybe fat and cholesterol caused heart disease, or maybe it was the carbohydrates and triglycerides. “We know of no solid evidence on this point,” wrote Ahrens, “and until the question is further explored we question the wisdom of prescribing low-fat diets for the general population.”

The evidence that Ahrens was looking for came first from Margaret Albrink, who was then a young physician working with John Peters, chief of the metabolic division in the Department of Medicine at Yale University. Once again, the available technology drove the research. Peters was renowned in the medical community for his measurements of the chemical constituents of body fluids. For this purpose he had a device called an analytical centrifuge, a less sophisticated version of Gofman’s ultracentrifuge, which could quantify the triglyceride concentration of the blood. Peters’s lab also analyzed blood samples for New Haven Hospital (now Yale–New Haven Hospital), so Peters suggested to Albrink that they use the analytical centrifuge to measure the triglycerides in those blood samples and test the hypothesis that high triglycerides are associated with an increased risk of heart disease. Peters was a “contrarian,” Albrink says; he didn’t believe the cholesterol hypothesis. Nor did Evelyn Man, Peters’s longtime collaborator. Albrink also worked with Wister Meigs, a Yale professor of preventive medicine who also served as company physician for the nearby American Steel and Wire Company. Meigs had been recording cholesterol levels in the plant employees, along with their family history of heart disease, diabetes, and other ailments. By 1960, Albrink, Man, and Meigs (Peters died in 1955) were comparing triglyceride and cholesterol levels of heart-disease patients from New Haven Hospital with the levels among the healthy employees of American Steel and Wire. Elevated triglyceride levels, they concluded, were far more common in coronary-heart-disease patients than high cholesterol: only 5 percent of healthy young men had elevated triglycerides, compared with 38 percent of healthy middle-aged men and 82 percent of coronary patients.

In May 1961, just a few months after the American Heart Association publicly embraced Keys’s hypothesis, both Ahrens and Albrink presented their research at a meeting of the Association of American Physicians in Atlantic City, New Jersey. Both reported that elevated triglycerides were associated with an increased risk of heart disease, and that low-fat, high-carbohydrate diets raised triglycerides. The New York Times covered Ahrens’s talk—“Rockefeller Institute Report Challenges Belief that Fat Is Major Factor”—in a story buried deep in the paper. Ahrens’s data suggested that “dietary carbohydrate, not fat, is the thing to watch in guarding against [atherosclerosis and heart disease],” the Times reported, and this “came as something of a surprise to many of the scientists and physicians attending the meeting.” Albrink’s talk did not make the newspaper, but she later told a similar story about her presentation. “It just about brought the house down,” she recalled. “People were so angry; they said they didn’t believe it.” This remained the case for much of the next decade. Albrink continued to work out the connection between carbohydrates, triglycerides, and heart disease and would present her results at conferences, where she would inevitably be attacked by proponents of Keys’s hypothesis.

By the early 1970s, Albrink’s interpretation of the evidence had been confirmed independently, first by Peter Kuo of the University of Pennsylvania, then by Lars Carlson of the Karolinska Institute in Stockholm, and by the future Nobel laureate Joseph Goldstein and his colleagues from the University of Washington. All three reported that high triglycerides were considerably more common in heart-disease victims than was high cholesterol. In 1967, Kuo reported in The Journal of the American Medical Association that he had studied 286 atherosclerosis patients, of whom 246 had been referred to him by physicians who thought their patients had the genetic form of high cholesterol. This turned out to be the case for fewer than 10 percent. The other 90 percent had carbohydrate-induced lipemia, and, for most of these patients, their sensitivity to carbohydrates had elevated both their triglyceride levels and their cholesterol. When Kuo put his patients on a sugar-free diet, he reported, with only five to six hundred calories of starches a day, both their triglyceride levels and their cholesterol lowered. Two months later, JAMA published an editorial in response to Kuo’s article, suggesting that the “almost embarrassingly high number of researchers [who had] boarded the ‘cholesterol bandwagon’” had done a disservice to the field. “This fervent embrace of cholesterol to the exclusion of other biochemical alterations resulted in a narrow scope of study,” the editorial said. “Fortunately, other fruitful approaches have been made possible in the past few years by identification of the fundamental role of such factors as triglycerides and carbohydrate metabolism in atherogenesis.”

By then, however, the science had already become secondary to more practical issues. Despite JAMA’s optimism that a new era was dawning, it was no longer a question of whether it was cholesterol or triglycerides that caused atherosclerosis and heart disease, whether saturated fat or carbohydrates were to blame, but which of the two hypotheses dominated the research. Here Keys’s hypothesis had precedence. A generation of clinical investigators—the “cholesterol bandwagon”—had gathered an enormous amount of data, however ambiguous, on cholesterol levels and heart disease; only Albrink, Kuo, and a handful of other researchers had studied triglycerides. Only Gofman had studied the VLDL particles that transport triglycerides through the circulation.

Moreover, measuring triglycerides was still much more difficult than measuring cholesterol, and so only the rare laboratory had the facilities to do it. The National Institutes of Health, which was effectively the only source of funding for this research in the United States, had already committed its resources to three enormous studies—the Framingham Heart Study, Keys’s Seven Countries Study, and the pilot programs of the National Diet-Heart Study. These studies would measure only cholesterol and so test only Keys’s hypothesis. No consideration was given to any alternative hypothesis. By 1961, Keys and his collaborators in the Seven Countries Study had measured cholesterol in over ten thousand men. By 1963, they had completed the exams on another eighteen hundred men. Even had it been technically possible to include triglycerides in the measurements, or to return to the original locales and retest for triglycerides, the cost would have been astronomical. The result, as we’ve seen, was considered a resounding victory for Keys’s fat-cholesterol hypothesis.

The research that would finally lead to a large-scale test of the carbohydrate/ triglyceride/heart-disease hypothesis emerged from the National Institutes of Health in early 1967. This was a collaboration between Donald Fredrickson and Robert Levy, who would become directors of the National Institutes of Health and the National Heart, Lung, and Blood Institute respectively, and Robert Lees, then of Rockefeller University. It was published in a fifty-page, five-part series in The New England Journal of Medicine. First Fredrickson, Levy, and Lees proposed a simplified classification of lipoproteins (perhaps an oversimplification, they acknowledged), which divided the lipoproteins in the bloodstream into four categories: LDL, which typically carried most of the cholesterol; VLDL, which carried most of the triglycerides; the high-density lipoproteins, HDL; and chylomicrons, which carry dietary fat from the intestine to the fat tissue. Then they proposed a classification scheme for disorders of lipoprotein metabolism, each delineated by a roman numeral, that included both those of abnormally high amounts of LDL cholesterol, which they suggested might be ameliorated by low-fat diets, as well as those characterized by abnormally high triglycerides carried in VLDL, which would be ameliorated by low- carbohydrate diets.

Four of the five lipoprotein disorders described in this series were characterized by abnormally elevated levels of triglycerides in the very low-density lipoproteins. For this reason, Fredrickson, Levy, and Lees also warned against the dangers of advocating low-fat diets for all patients, because these diets increased carbohydrate consumption and so would elevate triglycerides and VLDL even further. By far the most common of the five lipoprotein disorders was the one designated Type IV, characterized by elevated VLDL triglycerides—“sometimes considered synonymous with ‘carbohydrate-induced hyperlipemia,’” they wrote—and it had to be treated with a low-carbohydrate diet. “Patients with this syndrome,” Lees later wrote, “form a sizable fraction of the population