The 1982 Multiple Risk Factor Intervention Trial (MRFIT) was a multimillion-dollar trial to test the effectiveness of a complex intervention in reducing heart disease mortality. The trial randomized 12,866 high-risk men aged 35 to 57 years old into two groups: a special intervention (SI) group that received “stepped-care treatment for hypertension, counseling for cigarette smoking, and dietary advice for lowering blood cholesterol levels”; and a usual care group that had access to “usual sources of health care in the community.” There was no reduction in overall mortality in the intervention group, despite reductions in blood pressure, blood cholesterol, and smoking rates. While the combinatorial nature of the trial makes it impossible to understand the impact of any specific piece of the intervention, the trial failed to demonstrate that a diet-based, cholesterol-reducing intervention could reduce overall mortality. Funded alongside the Lipid Research Clinics Coronary Primary Prevention Trial, MRFIT ostensibly was funded (≥$200 million) to provide insights into effective heart disease treatments but did not successfully deliver such insights.

In 1972 and 1973, a large National Heart, Lung, and Blood Institute grant funded the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) to substantiate the then-emerging understanding of modifiable heart disease risk factors (alongside the Multiple Risk Factor Intervention Trial, or MRFIT). The trial randomized subjects to either cholesterol-lowering cholestyramine or placebo for an average of 7.4 years and observed a significant associated reduction in heart disease morbidity and mortality. The trial became one of the most important pieces of evidence cited in support of the diet-heart hypothesis and was used to support the claim that a 1% reduction in cholesterol reduces coronary mortality by 2%. However, the effects of lowering cholesterol with cholestyramine cannot be extrapolated to the effects of lowering cholesterol by other means, such as diet.