Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)

Abstract

Objective: To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic review and meta-analysis.

Design: The MCE (1968-73) is a double blind randomized controlled trial designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduces coronary heart disease and death by lowering serum cholesterol. Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators. Further, a systematic review and meta-analyses of randomized controlled trials that lowered serum cholesterol by providing vegetable oil rich in linoleic acid in place of saturated fat without confounding by concomitant interventions was conducted.

Setting: One nursing home and six state mental hospitals in Minnesota, United States.

Participants: Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants exposed to the study diets for a year or more; 149 completed autopsy files.

Interventions: Serum cholesterol lowering diet that replaced saturated fat with linoleic acid (from corn oil and corn oil polyunsaturated margarine). Control diet was high in saturated fat from animal fats, common margarines, and shortenings.

Main outcome measures: Death from all causes; association between changes in serum cholesterol and death; and coronary atherosclerosis and myocardial infarcts detected at autopsy.

Results: The intervention group had significant reduction in serum cholesterol compared with controls (mean change from baseline -13.8%v-1.0%; P<0.001). Kaplan Meier graphs showed no mortality benefit for the intervention group in the full randomized cohort or for any prespecified subgroup. 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). There was no evidence of benefit in the intervention group for coronary atherosclerosis or myocardial infarcts. Systematic review identified five randomized controlled trials for inclusion (n=10,808). In meta-analyses, these cholesterol lowering interventions showed no evidence of benefit on mortality from coronary heart disease (1.13, 0.83 to 1.54) or all cause mortality (1.07, 0.90 to 1.27).

Conclusions: Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet 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. Findings from the Minnesota Coronary Experiment add to growing evidence that incomplete publication has contributed to overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.

Fig 1 Traditional diet-heart hypothesis. Solid line indicates that causal relation has been established by randomized controlled trials (A); dashed lines indicate that no causal relation has been established (B and C). A=randomized controlled trials show that replacement of saturated fat with vegetable oils rich in linoleic acid lowers serum total cholesterol and LDL; B=intermediate endpoints related to serum cholesterol are robustly associated with risk of coronary heart disease events and deaths in observational studies; C= randomized controlled trials have tested whether replacement of saturated fat with linoleic acid reduces coronary heart disease events or deaths; none have shown significant benefit

Fig 2 MCE total population and recovered cohorts (517 total deaths reported in 1989 publication by Frantz and colleagues15)

Fig 3 Linoleic acid and saturated fat compositions of MCE control and intervention group diets. Values in figure are based on chemical analysis of study foods. Intervention group reduced saturated fat intake by about 50% and increased linoleic acid intake by >280%. Control group maintained high saturated fat intake but increased linoleic acid intake by about 38%. Based on Keys equation, these diet changes are predicted to lower cholesterol in both groups (table 2)

Fig 4 MCE flow diagram. *16 825 participants completed MCE form No 011 (tape 4 data, appendix part 1); †Broste thesis reports that 9570 participants were randomized and that 147 dropped out prior to diet exposure, 1975 abstract and 1989 manuscript reported that 9449 and 9057 participants were randomized, respectively; ‡longitudinal serum cholesterol data recovered for 2355/2403 randomized participants exposed to diet for one year or more (tape 2 data, appendix part 1); ¶autopsy files with aortic and coronary atherosclerosis and infarct data recovered for 149/295 completed autopsies

Fig 5 Risk of death from any cause by diet assignment in full MCE cohort and prespecified subgroups (Kaplan Meier life table graphs of cumulative mortality). Graphical depiction of cumulative mortality in full MCE cohort (n=9423) and prespecified subgroups in 1981 Broste thesis showed no indication of benefit and suggested possibility of unfavorable effects of serum cholesterol lowering intervention among participants aged ≥65. Patient level data needed to repeat this analysis were not recovered

Fig 6 Death from any cause and change in serum cholesterol in cohort that received diets for one year or more (n=2355). Panels indicate relations between change in serum cholesterol and number of participants, number of deaths, percent of deaths, and probability of death among intervention, control, and combined groups. Change in serum cholesterol calculated with average of measurements before and after randomization for each individual. Last row represents logistic model for death as function of average change in cholesterol, adjusted for age at baseline. Likelihood ratio test used to test effect modification by diet group (P=0.67)

Fig 7 Meta-analysis for mortality from coronary heart disease in trials testing replacement of saturated fat with vegetable oils rich in linoleic acid. Main analysis: trials provided replacement foods (vegetable oils) and were not confounded by any concomitant interventions. Sensitivity analysis: includes trials that provided advice only and/or were confounded by addition of n-3 EPA and DHA. Risk ratios were used as estimates of hazard ratios in MCE, RCOT, LA Vet, and MRC-Soy. MCE=Minnesota Coronary Experiment; SDHS=Sydney Diet Heart Study; RCOT=Rose Corn Oil Trial; LA Vet=Los Angeles Veterans Trial; MRC-Soy=Medical Research Council Soy Oil Trial; DART=Diet and Re-infarction Trial; ODHS=Oslo Diet Heart Study; STARS=St. Thomas Atherosclerosis Regression Study; LA=linoleic acid; SFA=saturated fat; ALA=α linolenic acid; EPA=eicosapentaenoate; DHA=docosahexaenoate

Fig 8 Linoleic acid content of MCE diets compared with current and historical intakes in US in 2011-12 (NHANES, adults aged ≥20). Nutritional adequacy defined as lowest amount of dietary linoleic acid required to prevent deficiency symptoms. Pre-agricultural diets modeled from fatty acid compositions of hunter-gatherer diets. Pre-industrial US diets calculated from US Department of Agriculture economic disappearance data

Fig 9 Potential unanticipated consequences of high linoleic acid intake. A=increased consumption of vegetable oils rich in linoleic acid alters non-cholesterol lipid mediators, including hydroperoxy- and hydroxy-octadecadienoic acids, eicosanoids, and endocannabinoids; B=hydroperoxy- and hydroxy-octadecadienoic acids have been linked to coronary heart disease pathogenesis via mechanisms independent of traditional diet-heart hypothesis; non-cholesterol lipid mediators can also contribute to development of other common conditions including chronic pain and steatohepatitis

Fig 10 Diet-heart timeline: key research and policy events. SDHS=Sydney Diet heart Study; MCE=Minnesota Coronary Experiment; AHA=American Heart Association; LA=linoleic acid