Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)BMJ 2016; 353 doi: https://doi.org/10.1136/bmj.i1246 (Published 12 April 2016) Cite this as: BMJ 2016;353:i1246
- Christopher E Ramsden, medical investigator1 2,
- Daisy Zamora, epidemiologist3,
- Sharon Majchrzak-Hong, research chemist1,
- Keturah R Faurot, epidemiologist2,
- Steven K Broste, retired statistician4,
- Robert P Frantz, professor of medicine5,
- John M Davis, professor of psychiatry3 6,
- Amit Ringel, guest researcher1,
- Chirayath M Suchindran, senior biostatistician7,
- Joseph R Hibbeln, senior clinical investigator1
- 1Section on Nutritional Neurosciences, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- 2Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina, Chapel Hill, NC, USA
- 3Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
- 4Medtronic, Minneapolis, MN, USA
- 5Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
- 6Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA
- 7Department of Biostatistics, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA
- Correspondence to: C E Ramsden
- Accepted 19 February 2016
Objective To examine the traditional diet-heart hypothesis through recovery and analysis of previously unpublished data from the Minnesota Coronary Experiment (MCE) and to put findings in the context of existing diet-heart randomized controlled trials through a systematic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 Recovered MCE unpublished documents and raw data were analyzed according to hypotheses prespecified by original investigators.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Participants Unpublished documents with completed analyses for the randomized cohort of 9423 women and men aged 20-97; longitudinal data on serum cholesterol for the 2355 participants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.
We thank the original MCE team of researchers for their contributions, including Ivan Frantz (principal investigator), Ancel Keys (co-principal investigator), Patricia Ashman (senior nutritionist and administrative assistant), Gerald Lee (physician assistant), Paul Lober (pathologist), Lael Gatewood (statistician), Sandra Knapp (statistical clerk), the staff of the seven Minnesota hospitals, and all the patients who participated in the study.
We also thank the following people for their contribution to the present manuscript: John Svee (data conversion resource, Westminster, CO, US) for the conversion of 9-track tape data and greenbar data to modern spreadsheet format; Toni Calzone for expertise in optical character recognition and magnetic tape data recovery; Bradley Kuennen and Mathew Schuler (Iowa State University Special Collections Department), Rachael Davis (E G Miner Library), National Library of Medicine staff, and Margo Denke for efforts searching for study data and materials; Alan Hoofring (Intramural NIH Medical Arts Design Section) for expertise in medical art; Sarah Strandjord for general research assistance; Denisse Zamora for expertise in graphic design; and Mark S Horowitz for expertise in statistical programming and technical writing.
Contributors: CER and DZ contributed as co-first authors. CER designed and directed the project; located, managed, and validated the recovered data and materials; performed literature review; and was the main writer of the manuscript. DZ conducted the statistical analyses and was a main writer of the manuscript. SFMH located, managed and validated the recovered data, and assisted in the literature review and in writing and revising the manuscript. KRF conducted the systematic review and meta-analyses, in collaboration with SFMH, CER, DZ, JMD, and CMS. SKB wrote the 1981 master’s thesis, provided insights into trial design, data analyses and incomplete publication, and contributed to the writing and revision of the manuscript. RPF located recovered data, wrote the tribute to Ivan Frantz and the MCE research team (in appendix), and revised the manuscript. JMD, CMS, and KRF contributed to the statistical analysis, interpretation of study results, and the writing and revision of the manuscript. AR validated the recovered data and revised the manuscript. JRH directed the project and contributed to writing and revision of the manuscript. All authors contributed to analyses or interpretation of results and to the intellectual content of the manuscript. CER is guarantor.
Funding: The MCE was funded by the US Public Health Service and the National Heart Institute through the R01 mechanism (grant HE09686). The intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, and the University of North Carolina Program on Integrative Medicine (National Institutes of Health grant T-32 AT003378) supported data recovery and evaluation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US Public Health Service.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: The MCE was approved by the clinical research committee of the University of Minnesota and by each of the seven collaborating hospitals.
Data sharing: Dataset requests should be sent to the corresponding author. Data sharing consent was not obtained, but the presented data are anonymized and risk of identification is low. Please contact D Zamora atfor questions about statistical code.
Transparency: The manuscript’s guarantor affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the present data recovery and analysis have been omitted; and that any discrepancies from the study as planned have been explained.
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