A Controlled Clinical Trial of a Diet High in Unsaturated Fat in Preventing Complications of Atherosclerosis

This report describes a clinical trial, with domiciled male veterans, designed to determine whether a diet which lowers serum cholesterol concentration can prevent overt complications of coronary heart disease and other manifestations of atherosclerosis. Volunteers were allocated randomly to control and experimental groups. Participants numbered 422 in the control group and 424 in the experimental group. The two groups were indistinguishable at the outset of the study in almost all observations. These included age, racial characteristics, and religious affiliation; height, weight, and blood pressure; electrocardiographic findings; prevalence of pre-existing anginal syndrome, myocardial infarction, peripheral atherosclerosis, cerebral ischemia, or cerebral infarction; cardiac decompensation; utilization of relevant medications; serum cholesterol and serum total lipid levels; and prevalence of corneal arcus and xanthelasma. One significant difference between the groups in regard to a possibly influential characteristic was that they differed slightly in patterns of cigarette smoking habits. The control diet was similar to the regular institutional diet, which is a standard American diet. It provided, by analysis, 40.1% of calories as fat, having a mean iodine value of 53.5; cholesterol intake was 262 mg/1,000 calories (653 mg/day). The experimental diet provided 38.9% of calories as fat, with an iodine value of 102.4, and had a cholesterol content of 146 mg/1,000 calories (365 mg/day). Linoleic acid content of the two diets was 10% and 38% of total fatty acid, respectively. The experimental diet was prepared to simulate conventional food. Over-all adherence expressed as percentage of total possible meals taken, from introduction into the study to termination of the study, averaged 56% for the control subjects and 49% for the experimental group. The experimental diet induced a prompt drop in serum cholesterol level and sustained a difference between the experimental and control groups amounting to 12.7% of the starting level. It is estimated from published data that the change in saturation of dietary fat accounted for five-sixths of the diet-induced lowering of serum cholesterol in the experimental group, the remaining one-sixth having been due to decreased cholesterol intake. Mean linoleic acid concentration of adipose tissue was initially 10.9%. During the latter part of the trial, which lasted eight years for some subjects, linoleic acid concentration in adipose tissue approached an asymptotic level of 33.7% among good adherers. This variable was a good measure of adherence to the diet after five or more years (r=+0.71), but not earlier. Clinical follow-up was carried out on a double-blind basis. The number of men sustaining events in major categories, in the control and experimental groups, respectively, was: definite silent myocardial infarction, 4 and 9; definite overt myocardial infarction, 40 and 27; sudden death due to coronary heart disease, 27 and 18; definite cerebral infarction, 22 and 13. The difference in the primary end point of the study-sudden death or myocardial infarction -was not statistically significant. However, when these data were pooled with those for cerebral infarction and other secondary end points, the totals were 96 in the control group and 66 in the experimental group; P =0.01. Fatal atherosclerotic events numbered 70 in the control group and 48 in the experimental group; P <0.05. Life-table analysis in general confirmed these conclusions. For all primary and secondary end points combined, eight-year incidence rates were 47.7% and 31.3% for the control and experimental groups, respectively; P value for the difference between the two incidence curves was 0.02. Stratification of the data by age demonstrated that most of the prophylactic effect occurred in the younger half of the study population, less than 65.5 years old at the start of the study. Stratification by baseline serum cholesterol concentration revealed that most of the effect was encountered in men with starting levels above the median (233 mg/dl). Stratification on the basis of pre-existing atherosclerotic complications failed to yield consistent evidence that subjects without pre-existing complications responded differently to diet than did those with prior overt disease. Deaths due to nonatherosclerotic causes numbered 71 in the control group and 85 in the experimental group. Most of the difference occurred in the latter part of the study. Consideration of causes of death in this category suggested that this difference probably did not reflect a toxic effect of the experimental diet. Gross grading of the extent of atheromata in individuals who died and were autopsied failed to reveal significant differences between the two groups of subjects. The same was true of arterial total lipid and calcium concentrations. Relative abundance of major lipid fractions in coronary atheromata and circle of Willis appeared to be independent of diet. In general, most of the varieties of lesions just cited revealed increased concentrations of linoleic acid in triglyceride, cholesterol ester, and phosphatide among the experimental subjects. In individuals on the experimental diet who died after prolonged experience in the study and high adherence to the diet, arachidonic acid concentration in atheroma phosphatide was significantly depressed. A similar but less consistent decrease was observed in arachidonic acid in cholesterol ester and free fatty acid of atheromata. Observations of other investigators suggest that these changes were due to the effects of high α-tocopherol intake on the experimental diet.