Lipid-Heart Hypothesis

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What does the lipid-heart hypothesis mean?

The lipid-heart hypothesis refers to the prediction that when replacing saturated fat in the diet with vegetable oil rich in linoleic acid (polyunsaturated omega 6 fatty acids), it will lower the serum cholesterol which will diminish the deposition of the cholesterol wall, therefore slowing down the progression of atherosclerosis, and reduce the number cardiovascular events [1].

Evidence regarding the lipid-heart hypothesis

The lipid-heart hypothesis is supported by evidence from randomized controlled trials that shows that substituting saturated fats with linoleic fats lowers total serum cholesterol and low-density lipoprotein (LDL) and using observational evidence links total serum cholesterol to cardiovascular disease and deaths. Despite these relations, no randomized controlled trial has shown that substitution of saturated fat with linoleic fatty acids significantly lowers cardiovascular disease or deaths [1].

The Minnesota Coronary Experiment (MCE), a randomized controlled trial conducted in the years 1968 to 1973, was the largest trial of cholesterol-lowering interventions by substituting saturated fat with vegetable oil rich in linoleic fatty acids. The MCE was designed to evaluate the effects of increasing omega 6 polyunsaturated fat from corn oil in the place of saturated fat on primary and secondary prevention of cardiovascular events and deaths, and for reducing the degree of coronary, aortic, and cerebrovascular atherosclerosis, and the number of myocardial infarcts and strokes detected at autopsy [1].

The intervention group (replacement of saturated fat with linoleic fatty acids), showed a significant reduction in total serum cholesterol. The control diet, which increased dietary linoleic acid by 38% but did not alter saturated fat, produced a modest but significant reduction in serum cholesterol compared with baseline. But it showed no mortality benefit in the full MCE population [1].

The lipid-heart hypothesis predicts that participants with a greater reduction in serum cholesterol would have a lower risk of death. MCE participants with a greater reduction in serum cholesterol, however, had a higher rather than a lower risk of death. In a previous study, The Sydney Diet Heart Study, the intervention group had an increased risk of death from cardiovascular disease and all causes, despite a significant reduction in serum cholesterol. Although the MCE was successful in lowering serum cholesterol in all subgroups, there was no clinical benefit in any group [1].

The MCE intervention group did not have less atherosclerosis or fewer myocardial infarcts (heart attacks) at autopsy [1]. If high serum cholesterol causes atherosclerosis, people with high serum cholesterol should have more atherosclerosis than people with low serum cholesterol. In 1936, Landé and Sperry found that people with low serum cholesterol were just as atherosclerotic as people with high serum cholesterol [2]. The role of triglyceride-rich lipoproteins is increasingly considered as a direct driver of atherosclerosis in diabetic patients, even in those receiving the best standards of care, including the use of statins [3].

The MCE also did not show improved survival. The opposite was found. MCE participants who had a greater reduction in serum cholesterol had a higher, rather than lower, risk of death. Meta-analyses of randomized controlled trials that specifically tested substitution of saturated fat with vegetable oil rich in linoleic fatty acids showed no indication of clinical benefit. Thus, collective findings from randomized controlled trials do not provide support for the lipid-heart hypothesis that the serum cholesterol-lowering effects of substituting saturated fat with linoleic fatty acids will lower the risk of cardiovascular disease or death [1].


Results of a systematic review and meta-analysis of randomized controlled trials do not provide support for the lipid heart hypothesis.


  1. Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK & Frantz P. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment. BMJ 2016;353:i1246. Available from:
  2. Ravnskov U, de Lorgeril M, Diamond DM, Hama R, Hamazaki T, Hammarskjöld B, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature, Expert Review of Clinical Pharmacology. 2018;11(10):959-970. DOI:10.1080/17512433.2018.1519391
  3. Hermans MP, Valensi P. Elevated triglycerides and low high-density lipoprotein cholesterol level as marker of very high risk in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2018 Apr;25(2):118-129. DOI: 10.1097/MED.0000000000000398

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