(Comments on Ramsden et al. in the British Medical Journal)
Our expert examines a recent paper (1) based on 1960’s data that challenges current guidelines on the benefits of replacing saturated fat with polyunsaturated fat.
In the 1968, the Minnesota Coronary Experiment (MCE) set out to test the traditional “diet-heart” hypothesis, which predicts that replacing saturated fat with vegetable oils rich in linoleic acid (the primary n-6 polyunsaturated fatty acid in our diet) reduces coronary heart disease (heart attacks) by lowering serum cholesterol. Though the initial results of the trial reported no reduction in mortality as a result of a linoleic-acid enriched diet (2), the experiment had serious limitations, largely beyond the control of the investigators.
50 years later, we have a much better picture of the many pathways that connect diet with heart disease, including the importance of including n-3 polyunsaturated fatty acids (absent from the MCE intervention diet) along with n-6 polyunsaturated fatty acids. Current dietary recommendations that emphasize replacing saturated fat with polyunsaturated fat (including both n-3 and n-6) are backed by multiple lines of evidence, and the 60 percent decline in coronary heart disease mortality in the US since the 1960’s underlines the importance of this guidance (3).
However a recent paper (1) is attempting to challenge current guidance by re-examining MCE data, claiming an “overestimation of the benefits of replacing saturated fat with vegetable oils rich in linoleic acid.” We sat down with Nutrition Department Chair Dr. Walter Willett, to help clear up this new controversy surrounding dietary fat, taking a closer look at the study design of the original MCE trial, what actually happened in conducting the trial, and how the 1960’s data stack up to today’s research.
Does this trial conducted over 50 years ago have any relevance to our current guidelines on dietary fat? How does this reevaluation of data fit in with newer findings about the connection between diet and heart disease?
This is an interesting historical footnote that has no relevance to current dietary recommendations. We have known for many years that the classical diet-heart hypothesis is incomplete, including that we have recognized the importance of including n-3 fatty acids as well as n-6 fatty acids, the roles of different cholesterol fractions, and the many other pathways that connect diet with heart disease.
The MCE’s intervention diet replaced saturated fat with linoleic acid from corn oil. How was that accomplished and how does this swap align with current or past recommendations?
The diet used in the MCE was never consumed by any appreciable number of Americans and the level of linoleic acid was well above the range recommended by the American Heart Association or any other group. To reach these levels, investigators created fake meat, cheese, and milk by removing as much of other types of fat as possible, replacing these with corn oil. Whatever small amounts of n-3 fatty acids were present would have been largely removed. It’s also important to note that investigators created a special corn oil margarine that was lower in trans fat than the standard margarine, but we now know that the most dangerous types of trans fat (18:2 trans isomers) are likely to be higher in these lightly hydrogenated products than in the more heavily hydrogenated forms (4).
Randomized controlled trials, used in the MCE, are often referred to the “gold standard” when it comes to studying dietary intervention and disease. How important a role does study duration play when looking at the long term of effects of diet on risk of heart disease? How did the MCE’s study design stack up?
The most serious problem with the MCE is the very short duration, as this trial was the victim of the deinstitutionalization of mental health hospitals that occurred in the 60’s and 70’s. The original authors had determined that nearly 10,000 participants needed to be followed for at least three years to detect a likely benefit, and enrolled 9423 women and men aged 20 to 97. Researchers identified patients hospitalized with mental illness as a good population to study because they were a “captive audience” who would be available for investigation over many years. However, largely because of patients being discharged, they lost nearly 75 percent of their participants within the first year. From this report, it seems that only about half of the remaining patients stayed a full three years, which is still a short time to study the effects of diet on atherosclerosis. The study was clearly a failure for reasons beyond the control of the investigators, and it adds very minimal information, if any, about the long-term effects of diet on risk of heart disease.
In this recent BMJ paper, Ramsden et al. recovered previously unpublished data from the MCE to put its findings in context with existing diet-heart trials through systematic review and meta-analysis. What does this reevaluation add to the MCE’s original conclusions?
The main results of the MCE were published by Frantz et al. (2) in 1989 with all of the aforementioned limitations, and no differences were reported between the treatment and control groups for cardiovascular events, cardiovascular deaths, or total mortality. The report of “recovered” data by Ramsden et al. (1) in BMJ adds no new data regarding these conclusions. The causes of death in the BMJ paper are not known, which makes evaluation of total mortality in non-randomized analysis relating degree of cholesterol reduction to death particularly uninformative. A small amount of new but incomplete data on autopsies were included, however the average follow up to autopsy was less than one year from baseline, making it unlikely that any benefit on gross autopsy findings for atherosclerosis would be seen.
Ramsden et al. include a meta-analysis of previously published data examining mortality from coronary heart disease. In addition to major limitations of the MCE and other diet-heart studies included in the meta-analysis, the statistical power was low for cardiovascular mortality and the confidence interval includes a potentially important benefit. Very importantly, the authors failed to mention that they earlier reported a benefit for incidence of coronary heart disease in a meta-analysis of randomized trials in which saturated fat was replaced by vegetable oils high in linoleic acid with a small amount of n-3 polyunsaturated fatty acids, usually as soybean oil (5). This finding is consistent with other summaries of published evidence and current dietary recommendations for replacing saturated fat with oils high in polyunsaturated fats. Notably, n-3 fatty acids can be obtained from seafood as well as plant oils, but seafood intake was likely to be low in Minnesota during the time when the MCE was conducted.
What would you say to those doubting the established guidelines surrounding the health benefits of replacing saturated fat with polyunsaturated fats as a result of this report? With this in mind, where should the research on dietary fats go next?
The bottom line is that this report adds no useful new information and is irrelevant to current dietary recommendations that emphasize replacing saturated fat with polyunsaturated fat, including sources of both n-3 and n-6 fatty acids. Many lines of evidence support this conclusion, including beneficial effects on blood lipids (6), summaries of prospective cohort studies (7), and randomized trials (8)—including the meta-analysis previously published by the authors in Ramsden et al. (5). Notably, since the 1960’s, the US diet has changed in this way; intake of linoleic acid has approximately doubled, and this has corresponded to a greater than 60 percent decline in coronary heart disease mortality (3). Although multiple factors have contributed to this decline, none of the other factors can explain this huge improvement in health, and the replacement of saturated fat with polyunsaturated fat (both n-6 and n-3 fatty acids) is almost certainly a major, probably most important, factor. Reversing these changes would almost certainly result in great harm.
Although we have a high level of evidence that the direction of current dietary recommendations will be beneficial, more research is desirable to determine optimal intakes of different types and sources of dietary fat and their effects on various health outcomes.
- Ramsden CE, Zamaora 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;352:i1246.
- Frantz ID Jr., Dawson EA, Ashman PL, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis, 1989;9:129-35.
- Willett, W. (2013). Nutritional epidemiology, Third Edition. Oxford: Oxford University Press.
- Sun Q, Ma J, Campos H, et al. A prospective study of trans fatty acids in erythrocytes and risk of coronary heart disease. Circulation 2007 Apr 10;115(14):1858-65.
- Ramsden CE, Zamora D, Leelarthaepin B, et al. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ, 2013;346:e8707.
- Mensink, R.P., et al., Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr, 2003. 77(5): p. 1146-55.
- Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation, 2014;130:1568-78.
- Dietary Guidelines Advisory Committee. Report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2015, to the Secretary of Agriculture and the Secretary of Health and Human Services: U.S. Department of Agriculture, Agricultural Research Service, Washington D.C.; 2015. Available from: http://health.gov/dietaryguidelines/2015-scientific-report/