A paper has just been published about the re-evaluation of the Minnesota Coronary Experiment, which was a very large double-blind randomized control study investigating whether replacing saturated fat with linoleic acid would reduce death from heart disease. The original premise for this study was that 1) randomized trials showed that linoleic acid reduces cholesterol, and 2) epidemiological studies showed a relationship between elevated cholesterol levels and increased risk of death due to heart disease. Therefore, their hypothesis was that replacing saturated fats with linoleic acid, which would lower cholesterol levels, should result in fewer deaths.
The study occurred during 1968-1973 and was conducted in nursing homes and mental institutions so that meals could be controlled. The participants and investigators were blinded to which arm they were randomized to, and meals were designed to look very similar. The standard institution diet was analyzed to determine the average fat content supplied prior to the study, which was approximately 18.5% calories as saturated fat and 3.8% as polyunsaturated fat. On average the intervention diet reduced saturated fat by 50% and increased linoleic acid by 280%. The control diet maintained the same amount of saturated fat, but because margarines and shortenings were used, the linoleic acid content actually increased from baseline from 3.4% to 4.7% of total calories. As expected, the intervention group experienced a drop in cholesterol level, with the size in drop being connected with adherence to the diet, which was tracked by missed meals. The control group also experienced a minor reduction in cholesterol. The reduction in death in the intervention group did not result in reduced deaths, however. In fact, mortality was higher in the intervention group. The authors write, “There was a 22% higher risk of death for each 30 mg/dL (0.78 mmol/L) reduction in serum cholesterol in covariate adjusted Cox regression models (hazard ratio 1.22, 95% confidence interval 1.14 to 1.32; P<0.001).” Autopsy data was collected for 295 deaths, and analysis of 149 cases (the other 146 cases are missing) showed that myocardial infarctions and atherosclerosis were higher in the intervention group. ” In this autopsy cohort, however, 41% (31/76) of participants in the intervention group had at least one myocardial infarct, whereas only 22% (16/73) of participants in the control group did (incidence rate ratio 1.90, 95% confidence interval 1.01 to 3.72; P=0.035). Also, participants in the intervention group did not have less coronary atherosclerosis or aortic atherosclerosis.” However, the authors caution that because not all of the original data was recovered, these findings should be interpreted cautiously.
The MCE study was not the only study to show that replacing saturated fat with linoleic acid increased risk of death for coronary disease and all causes. The investigators also reviewed the data from the Sidney Diet Heart Study (SDHS), which was originally conducted during 1966-1973. This study had the same results as the MCE. Both the MCE and the SDHS did not fully publish their results. Although a paper on the MCE was eventually published in 1989, the investigators reported that there was no difference between the groups, which as we can see, is not really true.
The authors of the current study conclude, “Available evidence from randomized controlled trials shows that replacement of saturated fat with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes. MCE findings add to growing evidence that incomplete publication has contributed to overestimation of benefits, and underestimation of potential risks, of replacing saturated fat with vegetable oils rich in linoleic acid.” Randomized controlled studies are considered to be the gold standard for testing scientific hypotheses. These were large and carefully designed studies that were investigating the causal effect of linoleic acid on heart disease. Their results should have made big news, especially considering they contradicted the traditional diet-heart hypothesis, which “predicts that the serum cholesterol lowering effects of replacing saturated fat with vegetable oil rich in linoleic acid will diminish deposition of cholesterol in the arterial wall, slow progression of atherosclerosis, reduce coronary heart disease events, and improve survival.” Why weren’t these studies published?
I think the current investigators make a great point about incomplete publication – for whatever reason. Without the full picture, how can we really build an accurate model? I understand that it might be disappointing as an investigator to have negative findings, especially if you are attached to the hypothesis (one of the original investigators was Ancel Keys); however, even “failed” experiments have much they can teach us. It makes me wonder about all of the past research that has been lost to time because the results contradicted the pet theories of the day.
There is so much more that can be said about this article, but I will leave it for now. Click here for a more in-depth look at the re-evaluation of the MCE study.
Reference:
Ramsden CE, Zamora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). Bmj. 2016:i1246. doi:10.1136/bmj.i1246.
