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
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Several recently published articles have concluded that associations between high cholesterol and premature death are lacking and advocate that current guidance advising low (<10%) saturated fat consumption should be revised(1-3). One such study by Ramsden et al., recovered 45 year-old data from the Minnesota Coronary Experiment (MCE), a randomized controlled trial performed in state mental hospitals and nursing homes in Minnesota, USA, and focused on reassessing the effect of a linoleic acid-rich diet on serum cholesterol and mortality(3). The authors reported that such a diet lowered total cholesterol, but did not reduce the risk of premature mortality, and might even have increased it.
However, to propagate a change in the current consensus, these claims should be based upon the valid and reliable evidence. Therefore we performed a critical appraisal of MCE consulting the methods and data provided in three publicly available descriptions of this trial: Ramsden et al., and Frantz et al., both peer-reviewed papers, and a thesis by Broste, on which the primary data in the analysis by Ramsden et al., were based(3-5).
We used the Cochrane risk of bias tool to assess the internal validity of data from the original MCE (Table 1)(6).
Several factors that weaken the validity of conclusions drawn from the MCE study were identified. Here we focus on the areas of most concern - discrepancies in data and selective outcome reporting, high attrition and poor generalisability.
Discrepancies in data and selective outcome reporting
The total number of MCE participants and event rates differed in each report of the same data: 9570 participants and 517 deaths in Ramsden et al., 9057 and 517 in Frantz et al. and 9570 and 477 in Broste’s thesis. The difference in event rates between intervention and control groups is driven by events occurring in those aged >65 years(4). We again observed a discrepancy in the numbers analysed for this age group: 626 participants were left after year 1 in Broste’s thesis, whilst only 595 are reported by Ramsden et al. These inconsistencies in participant and event rates cast doubt over the overall precision of data collection and their recovery.
Ramsden et al. focused on one statistically significant mortality association – with serum cholesterol concentrations. However, smoking, a higher BMI, and a higher diastolic blood pressure were each associated with a lower mortality risk in Broste’s thesis and also substantially contradict our current knowledge(4). As outcomes and statistical analysis methods in original MCE were not clearly pre-specified a priori, any subsequent statistical sub-analyses of MCE data should have been adjusted for multiple analysis inflation. This was not performed nor acknowledged in Ramsden et al., and the resultant observed associations could have arisen by chance.
Attrition bias
We had to turn to data in Broste’s original thesis to analyse the extent of attrition in each group(4). Firstly, more than 83% of participants are lost to follow-up from both study arms (4028 control, 3953 diet). All people lost to follow-up were excluded from further analysis and per protocol analysis was performed. Such analysis is likely to inflate estimated effect sizes(7).
Secondly, 21 more deaths were observed in the diet group (269 vs 248) and this difference is exclusively driven by a higher mortality rate in the >65 year old population (190/953 = 19.9%, 162/958 = 16.9% in the diet and control groups, respectively)(3, 5). We manually counted events from Kaplan-Meier curves for >65 year old participants remaining in study for >1 year (when mortality difference between diet and control groups becomes established). 27 patients in the control arm and 40 patients in the diet group died during year 1-2 period. However, during the same period 15 more control group participants are lost to follow-up without explanation (81 and 96). It is likely that some of these 15 participants could have actually died, as year 1-2 per protocol mortality rate in control group was 12% (27/225). Treating excessive control group’s attrition cases as deaths significantly alters the mortality rate estimates for >65 group and halves the relative risk reduction to 0.075.
Unfortunately none of the MCE reports provide data to ascertain if prognostic equivalence between both >65 groups has been maintained throughout follow-up, which significantly impairs the validity of any demonstrated effect(s)(8). Incidentally, equivalent compensation for evident higher attrition in the control group in the overall MCE population would actually demonstrate a higher mortality rate within the control group.
Generalisability of findings
Apart from highly selective study population (mental hospital inpatients), the dietary interventions present a major concern for the external validity from the MCE data. Current World Health Organisation dietary recommendations are that no more than 30% of daily calories come from fat(9). In MCE, the intervention and control diets, respectively, contained 38% and 39% of calories from fat. AMA recommends a daily intake of linoleic acid of between 5% and 10% of the energy content of the diet, with a note of caution for higher intakes (>11%) due to an observed association with increased lipid peroxidation(10, 11). The proportion of energy from linoleic acid in the MCE intervention arm was 13%. This was achieved by adding large quantities of liquid corn oil - practically the sole source of linoleic acid in MCE. Such a diet may be harmful for reasons unrelated to potential cholesterol mechanism and does not reflect current dietary recommendations either in terms of proportion of energy from linoleic acid or its consumption in the general population. Even if correct and correctly interpreted, calls for a change to dietary guidelines based on MCE data are remiss as recommendations do not reflect the diets offered to control group participants in the MCE study.
Summary
Well supported developments in our understanding of the interaction between dietary fat and human health are needed. However, data from the MCE suffer from multiple methodological shortcomings such as discrepant reporting, heavy attrition and poor generalisability. A detailed re-analysis empirically demonstrates that any claims to change our current understanding of the relationship between saturated fat intake and mortality are not fully supported by data from MCE.
Authors
Tumas Beinortas1*, Kamal R. Mahtani2, David Nunan2
1 St. James Hospital, Leeds Teaching Hospitals NHS Trust
2 Centre for Evidence Based Medicine, Department of Primary Care Health Sciences, University of Oxford
*Corresponding author:
Tumas Beinortas
St. James Hospital, Leeds Teaching Hospitals NHS Trust
tumasbeinortas@gmail.com
References
1. de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ (Clinical research ed). 2015;351:h3978.
2. Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, 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 (Clinical research ed). 2013;346:e8707.
3. Ramsden CE, Zamora D, Majchrzak-Hong S, Faurot KR, Broste SK, Frantz RP, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ (Clinical research ed). 2016;353:i1246.
4. Broste SK. Lifetable analysis of the Minnesota Coronary Survey: The University of Minnesota; 1981.
5. Frantz ID, Jr., Dawson EA, Ashman PL, Gatewood LC, Bartsch GE, Kuba K, et al. Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey. Arteriosclerosis (Dallas, Tex). 1989;9(1):129-35.
6. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2011;343:d5928.
7. Abraha I, Cherubini A, Cozzolino F, De Florio R, Luchetta ML, Rimland JM, et al. Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. BMJ (Clinical research ed). 2015;350:h2445.
8. Dumville JC, Torgerson DJ, Hewitt CE. Reporting attrition in randomised controlled trials. BMJ (Clinical research ed). 2006;332(7547):969-71.
9. World Health Organization. Healthy diet Factsheet. 2015.
10. Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009;119(6):902-7.
11. Food and Agriculture Organization of the United Nations. Fats and fatty acids in human nutrition: report of an expert consultation. FAO Food and Nutrition Paper 91. Rome: 2010.
Competing interests: No competing interests
Why the Minnesota Coronary Experiment matters
In our report of recovered documents and data from the Minnesota Coronary Experiment (MCE)[1]—we found that replacement of saturated fat (SFA) with vegetable oil rich in linoleic acid (LA) effectively lowered serum cholesterol, but did not translate to improved health outcomes. Paradoxically, MCE participants who had greater reduction in serum cholesterol had higher, rather than lower, risk of death. Moreover, in our systematic review and meta-analysis of randomized controlled trials (RCT) that specifically replaced SFA with vegetable oils rich in LA there was no indication of benefit. These findings were interpreted cautiously with an emphasis on limitations. The responses ranged from appreciative to dismissive. Now, after the dust has settled, we respond to some BMJ comments and provide additional context.
Dose matters
Comment: the MCE intervention “was never consumed by any appreciable number of Americans”-Walter Willett
The MCE intervention provided ≈13%E (%E) as LA[1]. According to NHANES, more than 13 million American adults currently consume ≥13%E as LA[2].
Comment: MCE results have “no relevance to current dietary recommendations”-Walter Willett
In 2016, the NutriCoDE group defined optimal LA intake as 12%E (±1.2)[3]—a range that overlaps with the MCE intervention. In 2009, the American Heart Association advised “at least 5 to 10%E” as LA[4].
Traditional and modern Mediterranean diets contain about 2%E as LA[5,6]. The average American currently consumes ≈7%E as LA[2,7]. These levels depend on widespread consumption of concentrated vegetable oils[7]. Individuals eating only minimally-processed whole foods (customary until about 100 years ago) would have consumed about 2-3%E as LA.
Thus, wide ranges of LA are currently advised and consumed; current intakes in non-Mediterranean populations are much higher than historic norms. A central question for current dietary recommendations is:
What is the optimal intake of LA?
• Should it be 2-3%E, consistent with all diets prior to industrial oil processing[7,8], and Mediterranean-style diets[5,6]?
• Or should it be closer to 7%E, average intake in the U.S.[2], and consistent with some current guidelines[4]?
• Or should it be closer to 12%E, recently defined as optimal for the entire world population[3]? To our knowledge, there is a lack of evidence supporting the safety or efficacy of 12%E as LA.
Other tissues and diseases matter
Biochemical consequences of high intake of LA extend far beyond lowering serum cholesterol and the cardiovascular system[9-11](reviewed in [1,20]). Emerging research shows that high LA intakes increase bioactive lipid mediators in many tissues ranging brain[12] to mammary tissue[13]. These non-cholesterol mediators are implicated in the pathogenesis of many diseases[1,9-11,14,15,20]. While more research is needed, there is a possibility for unintended harm. There is also very little biochemical or clinical data about the effects of high LA intakes in special populations, such as older adults, pregnant women, and young children. Since the effects of high LA diets are poorly understood and there is a possibility for harm, it is crucial to know if the proposed benefit of LA on cardiovascular health is supported by RCT evidence.
Randomization matters
In a detailed systematic review and meta-analysis of RCT that specifically replaced SFA with vegetable oils rich in LA, we found no indication of benefit. This is important because RCTs allow stronger causal inferences and are less susceptible to confounders than non-randomized studies. Findings were presented in the context of the surprising lack of causal RCT data on this topic, emphasizing key limitations. For the broader context needed to fully evaluate the results and limitations of our review and meta-analysis, please see our manuscript[1] and appendices http://www.bmj.com/content/bmj/suppl/2016/04/12/bmj.i1246.DC1/ramc027623...).
Below we summarize some of this published information in response to BMJ comments.
Comment: Our meta-analysis of RCTs “omitted the Finnish Mental Hospital trial, an important study”
-Bhupathiraju & Hu
The Finnish Mental Hospital Study (FMHS)16 was not suitable for inclusion because it was not an RCT (reviewed in[16,17]). The FMHS was also potentially confounded by unequal use of thioridazine (linked to electrocardiographic abnormalities and sudden death)[1,17].
Comment: “The Cochrane review of 15 well-designed randomized controlled trials concluded that reducing SFA reduces the risk of cardiovascular events by 17 percent)”-Liebman, Blackburn & Jacobson
The Cochrane review and meta-analysis of RCTs by Hooper et al18 was not specifically focused on replacing SFA with LA. As such, it included several trials that lowered total fat and SFA without increasing LA, and trials that provided large doses of omega-3 EPA+DHA.
In reply to the comment that “a previous meta-analysis, which included the MCE, found significant benefits of replacing SFA with polyunsaturated fats on both serum cholesterol and incidence of major cardiovascular events.” -Bhupathiraju & Hu
The cited meta-analysis by Mozaffarian et al[19] was not specifically focused on replacing SFA with LA. It included trials that provided large doses of EPA+DHA from seafood and cod liver oil, trials with minimal increases in LA, and trials with complex diet changes (e.g. sugar restriction, increase in soluble fiber). It also included the non-randomized FMHS, but not recently recovered RCT data from the Sydney Diet Heart Study (SDHS)[20]. Recovered SDHS data belatedly showed that replacement of SFA with vegetable oil rich in LA significantly increased the risk of death from coronary heart disease, despite lowering serum cholesterol.
Comment: MCE findings are not meaningful due to the “very short duration on the assigned diets”.-Walter Willett
The fact that “only about a quarter of randomized participants remained in the study for a year or longer” was emphasized as a key limitation in our manuscript[1]. Importantly, however, 2,355 MCE participants were exposed to MCE diets for ≥1 year. The original investigators emphasized this subsample, which alone is much larger than any other RCT testing the effects of replacing SFA with LA. There was no indication of benefit; and although we didn’t emphasize this in the manuscript, there was an unfavorable separation of the mortality curves after about one-year of corn oil exposure (see Fig. 5 in[1]). This separation was most evident in older adults (Fig. 1, below after references).
Conclusion
We stand by our conclusion that available RCT evidence does not provide support for the hypothesis that serum cholesterol-lowering effects of replacing SFA with vegetable oil rich in LA translate to lower risk of death from coronary heart disease or all causes.
References
1. 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;353:i1246. PubMed PMID: 27071971. Pubmed Central PMCID: 4836695.
2. U.S. Department of Agriculture, Agricultural Research Service. Nutrient Intakes from Food: Mean Amounts Consumed per Individual, by Gender and Age, What We Eat in America, National Health and Nutrition Examination Survey (NHANES 2011-2012). [Internet].
3. Wang Q, Afshin A, Yakoob MY, et al. Impact of Nonoptimal Intakes of Saturated, Polyunsaturated, and Trans Fat on Global Burdens of Coronary Heart Disease. J Am Heart Assoc. 2016 Jan;5(1). PubMed PMID: 26790695. Pubmed Central PMCID: 4859401.
4. Harris WS, Mozaffarian D, Rimm E, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009 Feb 17;119(6):902-7. PubMed PMID: 19171857. Epub 2009/01/28. eng.
5. Ferro-Luzzi A, Sette S. The Mediterranean Diet: an attempt to define its present and past composition. Eur J Clin Nutr. 1989;43 Suppl 2:13-29. PubMed PMID: 2689161.
6. Kushi LH, Lenart EB, Willett WC. Health implications of Mediterranean diets in light of contemporary knowledge. 2. Meat, wine, fats, and oils. Am J Clin Nutr. 1995 Jun;61(6 Suppl):1416S-27S. PubMed PMID: 7754997.
7. Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr. 2011 May;93(5):950-62. PubMed PMID: 21367944. Pubmed Central PMCID: 3076650.
8. Kuipers RS, Luxwolda MF, Dijck-Brouwer DA, et al. Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet. Br J Nutr. 2010 Dec;104(11):1666-87. PubMed PMID: 20860883. Epub 2010/09/24. eng.
9. Vangaveti V, Baune BT, Kennedy RL. Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis. Ther Adv Endocrinol Metab. 2010 Apr;1(2):51-60. PubMed PMID: 23148150. Pubmed Central PMCID: 3475286.
10. Ramsden CE, Ringel A, Majchrzak-Hong SF, et al. Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes? Mol Pain. 2016;12. PubMed PMID: 27030719.
11. Feldstein AE, Lopez R, Tamimi TA, et al. Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res. 2010 Oct;51(10):3046-54. PubMed PMID: 20631297. Pubmed Central PMCID: 2936759.
12. Taha AY, Hennebelle M, Yang J, et al. Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid. Prostaglandins Leukot Essent Fatty Acids. 2016;Forthcoming.
13. Johnson JA, Blackburn ML, Bull AW, Welsch CW, Watson JT. Separation and quantitation of linoleic acid oxidation products in mammary gland tissue from mice fed low- and high-fat diets. Lipids. 1997 Apr;32(4):369-75. PubMed PMID: 9113624.
14. Kirpich IA, Feng W, Wang Y, et al. Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol. Alcohol. 2013 May;47(3):257-64. PubMed PMID: 23453163. Pubmed Central PMCID: 3617059.
15. Liu H, Beier JI, Arteel GE, et al. Transient receptor potential vanilloid 1 gene deficiency ameliorates hepatic injury in a mouse model of chronic binge alcohol-induced alcoholic liver disease. Am J Pathol. 2015 Jan;185(1):43-54. PubMed PMID: 25447051. Pubmed Central PMCID: 4278357.
16. Turpeinen O, Karvonen MJ, Pekkarinen M, Miettinen M, Elosuo R, Paavilainen E. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. Int J Epidemiol. 1979 Jun;8(2):99-118. PubMed PMID: 393644. Epub 1979/06/01. eng.
17. Ramsden CE, Hibbeln JR, Majchrzak SF, Davis JM. n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials. Br J Nutr. 2010 Dec;104(11):1586-600. PubMed PMID: 21118617. Epub 2010/12/02. eng.
18. Hooper L, Martin N, Abdelhamid A, Davey Smith G. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015;6:CD011737. PubMed PMID: 26068959.
19. Mozaffarian D, Micha R, Wallace S. Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Plos Medicine. 2010 Mar;7(3):-. PubMed PMID: ISI:000276311600013. English.
20. 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. PubMed PMID: 23386268.
Fig 1. Risk of death from any cause by diet assignment in the prespecified subgroup of adults 65 and older (Broste Thesis1)
The unfavorable separation of the mortality curve for the corn oil group began approximately one-year after diet exposure.
Competing interests: No competing interests
The “International Expert Movement to improve dietary fat quality” (IEM) submits the following comments on “Re-evaluation of the Traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968- 1973)”
The topic of dietary fat intake is one of great interest and one of great confusion for consumers. A recent publication appears to be adding to that confusion. In the manuscript “Re-evaluation of the Traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968- 1973)” Ramsden et al reexamined data that is more than 40 years old. These data had not been previously used in the Minnesota Coronary Experiment (MCE), and by doing an updated meta-analysis, the authors attempted to determine if the original outcomes were in fact supported by current randomized controlled trials (RCTs). Unfortunately their conclusions are plagued with several limitations.
The Minnesota Coronary Experiment (MCE) had a more than 75% dropout rate after one year. This makes it difficult to determine real outcomes of diet change and disease due to the short study duration and the lack of statistical power to detect any effects of treatment on endpoints. Outcomes related to mortality were published in 1989 by Frantz, and were included in meta-analyses setting current dietary guidelines, but the original study did not report on associations between cholesterol and endpoints.1 In addition; the association between changes in blood cholesterol levels and death was observational, so the outcome, identical in both study diets, is really associative, not causal.
The overall dietary intake, along with trans fat intake, of subjects in the MCE was not assessed meaning that any study outcomes could be subject to other dietary factors, especially trans fat. Given the impact of trans fats on heart disease risk this failure to assess trans fat intakes makes the extrapolation of diet –outcome-relations of the MCE to current dietary patterns questionable. The MCE study also did not assess LDL cholesterol levels, weight loss, smoking status or presence of existing coronary disease – variables that can significantly affect outcomes - making any conclusion from the study open to question.
This new analysis also attempted to compare mortality outcomes from other RCT’s to the MCE and found 4 smaller RCT’s that studied replacement of saturated fats with linoleic rich vegetable oil. These studies did not all use mortality as an endpoint so comparing the outcomes of these trials was not reviewing comparable studies. In addition, because the MCE trial was the largest RCT in the meta-analysis conducted by Ramsden et al the MCE trial contributed the greatest weight to the results of the meta-analysis.
We note that many of the references used in this publication were out of date and/or not supportive of the statements that they were linked with. The current body of scientific evidence continues to support the importance of limiting saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, including but not limited to, the essential fatty acid linoleic acid.
The “2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines” 2 clearly reviewed the evidence supporting lowering saturated fats and choosing polyunsaturated fats instead as a means of lowering LDL-Cholesterol, thus reducing heart disease risk.
The 2015 US Dietary Guidelines Committee scientific report also addressed the topic of saturated fats and disease risk with a systematic review of both RCTs and observational studies and reported the following:
“Strong and consistent evidence from RCTs shows that replacing SFA with unsaturated fats, especially PUFA, significantly reduces total and LDL cholesterol.”
“Strong and consistent evidence from RCTs and statistical modeling in prospective cohort studies shows that replacing SFA with PUFA reduces the risk of CVD events and coronary mortality.”
“For every 1 percent of energy intake from SFA replaced with PUFA, incidence of CHD is reduced by 2 to 3 percent. However, reducing total fat (replacing total fat with overall
carbohydrates) does not lower CVD risk.” 3
Changing dietary habits is a challenging task for consumers. Studies that do not put their outcomes in context or do not draw conclusions that reflect a cause and effect outcome only contribute to the confusion. Ramsden et al have conducted a data analysis that can be viewed as adding to the body of evidence on the topic of fats and cardiovascular disease. However, the analysis does not provide evidence that indicates how to change dietary habits, and in our view only adds confusion to the topic of healthful fats.
1. Frantz, ID. Et al. Test of Effect of Lipid Lowering by Diet on Cardiovascular Risk. The Minnesota Coronary Survey. Atherosclerosis 1989; 9:129-135
2. Eckel, R. et al. AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S76-99.
doi: 10.1161/01.cir.0000437740.48606.d1. Epub 2013 Nov 12. 2013 .
3. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. http://health.gov/dietaryguidelines/2015-scientific-report/pdfs/scientif.... Accessed April 20. 2016
Authors (IEM committee members)
Helmut Heseker, Professor. MD, PhD Institute of Nutrition, Consumption and Health
Faculty of Natural Sciences University Paderborn. IUNS Council Member
BERTHOLD V. KOLETZKO, Professor of Paediatrics. MD PhD (Dr med Dr med habil)
Head Div. Metabolic Diseases & Nutritional Medicine, Univ. Munich Medical Centre, Munich, Germany.
CONNIE DIEKMAN, MEd, RD, CSSD, LD, FAND
Director of University Nutrition at Washington University in St. Louis, Missouri.
GERARD HORNSTRA, PhD Med
Professor Em. of Experimental Nutrition, Maastricht University, Maastricht, The Netherlands
JOYCE NETTLETON, DSc; Specialist in seafood nutrition and science communication.
Dr Joyce Nettleton has an independent consulting practice, ScienceVoice Consulting, in Denver, CO.
Competing interests: No competing interests
There may still be a confounding variable in this study. In 1978, a researcher on aflatoxins in grains told me that the USDA or FDA (been a long time) was allowing farmers in places like Georgia where mold in corn is not unusual to sell corn heavily contaminated with aflatoxin that was unfit for animal feed, even diluted, to be used for corn oil extraction for human consumption. The idea was that the proteins and aflatoxin from mold in the corn was separated out in the oil extraction. The researcher went on to tell me that at that time the assays used for aflatoxin did not work in a high oil sample, so obviously you would not find it: a catch-22. That no protein would remain in extracted oil would put in question why people who eat food cooked in peanut oil would or could have anaphylaxis or death (the son of a friend of mine died from eating a donut in an Amsterdam bar cooked in peanut oil). Is it possible for low levels of these toxins to produce enough inflammation over time to produce the results in a high corn oil diet?
Competing interests: No competing interests
This review on 'LA' rich foods was a little disappointing. Corn and corn oil have been shown to contribute to heart disease, especially when fed to cows that are raised for human consumption. The research paper is using a blanket statement of all LA rich foods, not specifically corn or fried foods. I believe labeling and categorizing corn oil in the same group as flax is incorrect and it is also incorrect to imply that fried and fresh is the same. While my nutrition background tells me that many other LA rich foods are high in antoxidants and that corn is not, which might have something to do with it, blanketing corn oil as a representative of all other LA foods, especially when used for frying is bad science. Research studies will show a higher correlation of heart disease when comparing 'LA' rich corn oil to flax oil among others. I am not sure if that makes a difference in your position, but I thought it might help to shed light on the problems/issues instead of spreading misinformation (I had to dig to find the details).
Competing interests: No competing interests
The response to this newly disclosed evidence and new meta-analysis by those still promoting the replacement of saturated fat with polyunsaturated vegetable oil seems to be, that while the incidence of obesity and diabetes have increased because the population is not, overall, following the dietary guidelines, heart disease mortality has dropped because the population has, overall, followed the dietary guidelines.
But, as Anthony Colpo has pointed out in his recent rapid response, the incidence of coronary disease has stayed much the same, and the drop in mortality is mainly due to improvements in treatment.[1] Macrovascular disease attributable to diabetes, as measured by the rate of amputations, has increased exponentially in the interim; Professor Tim Noakes has recently drawn attention to the similarities between these pathologies. It cannot be said that our arteries are healthier than they have ever been.[2]
In the Framingham study, which may be the longest running and most extensive observational test of the lipid hypothesis, higher levels of LDL cholesterol were predictive of significant reductions in the risk of type 2 diabetes.[3] This is consistent with biomarker studies showing that a higher serum level of saturated fatty acids found in ruminant fats is associated with a large reduction in type 2 diabetes risk, and also consistent with the recent meta-analysis of observational studies showing that higher vs lower consumption of ruminant trans fats was associated with reduced type 2 diabetes risk.[4]
Are there indications that a higher intake of linoleic acid from oils and spreads may be harmful in specific conditions? Non-alcoholic liver disease (NAFLD) is predictive of, and plausibly causational in, both type 2 diabetes and cardiovascular disease. Two recent studies have showed the successful treatment of NAFLD with diet. In one, GGT, HbA1c and BMI were all reduced by a very low-carbohydrate dietary approach in which polyunsaturated vegetable oils were replaced with fat from dairy and olive oil.[5] In the other, biomarkers of omega 6 metabolism were found to be elevated. Sugar was restricted to under 10% of energy and linoleic acid was restricted to below 4% of energy, resolving NAFLD over a 6 month period.[6] In Poland, where this study took place, the recommended upper limit for linoleic acid intake is 3% of energy, showing that not all authorities are in agreement with the American epidemiologists; in particular, the lipid biochemists consulted by European government bodies tend to have different opinions on this matter.
Chronic hepatitis C virus (HCV) infection is associated with a reduction in cholesterol, but this confers no benefit in terms of cardiovascular disease. Linoleic acid lowers cholesterol by upregulating the LDL receptor; HCV circulates in association with triglyceride-rich lipoproteins and infects hepatocytes via the LDL receptor complex. In a study of a population with chronic HCV infection, a higher intake of polyunsaturated fat was associated with an increased incidence of steatosis, but a higher intake of saturated and monounsaturated fat was not.[7]
Professor Brunner in his response drew a comparison between statins and linoleic acid, but this comparison may not be safe. Statins lower cholesterol by HMG-CoA reductase inhibition and may be effective in the secondary prevention of heart attacks because they stabilize arterial plaques.[8] However, arterial plaques with a higher content of linoleic acid are less stable than plaques with a high content of saturated fatty acids.[9] Rather than inhibiting HMG-CoA reductase, linoleic acid increases its activity, as 22% of the carbon from linoleic acid is converted to cholesterol in the liver, despite LA also increasing the liver’s uptake of cholesterol via LDL receptor upregulation.[10]
It has long been known, through multiple animal experiments with highly significant and consistent results, that polyunsaturated fats are essential for the progression of alcoholic liver disease, which can be prevented by feeding a diet sufficiently low in polyunsaturated fat and high in saturated fats, which have separate protective effects via multiple mechanisms.[11] A potentially life-saving treatment in humans has never been trialed because of concerns about cardiovascular safety which may have been unfounded. Meanwhile our citizens, still drinking much more heavily than public health experts would like, are likely today to fill their stomachs with food laden with polyunsaturated vegetable oils.
When some experts say saturated fat is still harmful, they often refer to observational or feeding studies concerning the fat in muffins, pizzas, frankfurters, milkshakes, and other processed foods that are also sources of refined carbohydrates, for example in “dietary pattern” type analyses. When other experts say saturated fat is not harmful, they refer to studies directly concerning cheese and milk, steak and coconut. Are these really conflicting opinions?
Dietary saturated fat is in the position of someone wrongly accused and convicted on mistaken and falsified evidence in the middle of a moral panic. In such cases, although better evidence becomes available, other suspects appear, and cooler heads prevail, acquittal is always a slow and painful process.
Meanwhile, the accused is unable to make whatever contribution to society they have always been capable of.
[1] http://www.bmj.com/content/353/bmj.i1246/rr-13
[2] http://www.thenoakesfoundation.org/news/blog/the-low-fat-diet-does-not-p...
[3] Andersson C, Lyass A, Larson MG, Robins SJ, Vasan RS. Low-density-lipoprotein cholesterol concentrations and risk of incident diabetes: epidemiological and genetic insights from the Framingham Heart Study. Diabetologia. 2015 Dec;58(12):2774-80. doi: 10.1007/s00125-015-3762-x. Epub 2015 Sep 26
[4] de Souza, RJ, Mente, A, Maroleanu et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978
[5] Unwin DJ, Cuthbertson DJ, Feinman R, Sprung VS. A pilot study to explore the role of a low-carbohydrate intervention to improve GGT levels and HbA1c. Diabesity in Practice. 2015;4:102–8.
[6] Maciejewska D, Ossowski P, Drozd A, et al. Metabolites of arachidonic acid in early stages of non-alcoholic fatty liver disease – a pilot study. Prostaglandins Other Lipid Mediat. 2015;121(B):184-9.
[7] Loguercio C, Federico A, Masarone M et al. The impact of diet on liver fibrosis and on response to interferon therapy in patients with HCV-related chronic hepatitis. Am J Gastroenterol. 2008 Dec;103(12):3159-66. doi: 10.1111/j.1572-0241.2008.02159.x. Epub 2008 Sep 11.
[8] http://www.acc.org/latest-in-cardiology/articles/2016/04/14/09/58/impact...
[9] Felton CV, Crook D, Davies MJ, Oliver MF. Dietary polyunsaturated fatty acids and composition of human aortic plaques. Lancet. 1994 Oct 29;344(8931):1195-6.
[10] Cunnane SC. Problems with essential fatty acids: time for a new paradigm? Prog Lipid Res. 2003 Nov;42(6):544-68.
[11] Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ. Dietary Saturated Fatty Acids Reverse Inflammatory and Fibrotic Changes in Rat Liver Despite Continued Ethanol Administration. JPET November 1, 2001 vol. 299 no. 2 638-644.
Competing interests: No competing interests
Ramsden et al’s intriguing findings from this famous experiment raises a fundamental question in cardiovascular disease prevention and treatment. The institutionally-imposed change in dietary fat quality produced lowering of serum cholesterol, but paradoxically the greater the reduction in serum cholesterol the greater was the excess in all-cause mortality. The authors recognise the challenge to explain this paradox. To state the obvious, statins are a triumph of allopathic medicine and cholesterol-lowering is the mode of action.(1) Could it be then that controlling one’s blood lipids using polyunsaturated oils as part of a healthy diet increases rather than reduces coronary risk?
An analysis in the Whitehall II cohort identified dietary patterns specifically linked to serum total and HDL-cholesterol and serum triglycerides, and then related these diets to future risk of myocardial infarction or coronary death.(2) The dietary patterns linked to an adverse blood lipid profile were associated with increased coronary risk over the 15 years of follow-up, after controlling for demographic and behavioural variables. Reported average intake of polyunsaturated margarine differed by a factor of almost 3 across quartiles of dietary pattern scores (healthy versus unhealthy: 14.4 and 5.4 g/d). Intakes of other sources of polyunsaturated fats likely varied in a similar manner. So, the paradoxical findings in the Minnesota Coronary Experiment (MCE) in the 1960s were not replicated in Whitehall II around the millennium.
We would like to suggest there may have been a ‘period effect’ at work in the MCE. The table of characteristics of the MCE cohort does not report the prevalence of smoking, but it is likely to have been almost universal at the time of the study. Those who smoked the most, and those who were sickest as a result of their habit, are likely to have experienced the largest decline in cholesterol. This mechanism is a form of reverse causation, and it might explain the paradox in question.
(1) Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005 October 8;366(9493):1267-78.
(2) McNaughton SA, Mishra GD, Brunner EJ. Food patterns associated with blood lipids are predictive of coronary heart disease: the Whitehall II study. Br J Nutr 2009 August;102(4):619-24.
Competing interests: No competing interests
Diet -heart hypothesis which suggest the intake of larger amounts of linoleic acid(LA) may promote or help reduce cadiovascular events. Soyabean oil is prescribed as a good source of LA and recommended its intake for a good cardiovascular health. Diet is one of the many components that go to harm or exert its beneficial effects on cardiovascular health. It has multiple factors like life-style (obesity, sedentary or active), type of personality, hypertension, family history, dyslipidemia and diabetes. If one has to promote the well-being of a cardiovascular patients- it has to be holistic approach. Diet is one of the factors that may help alleviate the condition,. When one promotes the intake of LA - it has to be remembered that it will generate free radicals that will harm the cardiac health. One has to therefore remember that along with LA intake anitoxidant intake must be increased to counter the harmful effects of free radicals generated from poly unsaturated fatty acids. There is no single panacea for maintaining cardiovascular health. It may be true that diet-heart hypothesis which promotes greater intake of omega-6 fatty acids may be true . It has to be balanced by holistic approach to nullify other risk factors related to cardiac health,
Competing interests: No competing interests
Rather than applaud the efforts of Ramsden et al, Walter Willett dismisses their paper as largely useless and “irrelevant”. He writes:
"We have known for many years that the classical diet-heart is incomplete, including recognition of the importance of both N-3 fatty acids and N-6 dietary fatty acids..."
As history shows, the initial focus of dietary CHD recommendations was increased consumption of oils rich in the omega-6 fatty acid linoleic acid (LA). This polyunsaturated fatty acid was widely touted as beneficial due to its cholesterol-lowering effects. Widespread awareness of the benefits of n-3 fatty acids, specifically those from fish, did not occur until much later.
While Willett would have us believe soybean oil is a lifesaver, NIH researchers have linked America’s steadily worsening omega-6:omega-3 ratio over the last century to its embrace of this oil, the main constituent of which is LA. Estimated per capita consumption of soybean oil increased over 1000-fold from 1909 to 1999; as a result, the ratio of LA to ALA increased from 6.4 in 1909 to 10.0 in 1999. The researchers concluded this increased consumption of LA has likely decreased human tissue concentrations of the all-important n-3 fatty acids EPA and DHA[2].
Willett goes on to claim replacement of saturated fat with polyunsaturated fat “is almost certainly” a major factor, if not the primary factor, behind a decline in CHD mortality that began in the 1960s.
To accept this assertion, we need to accept that a worsening n-6:n-3 ratio is somehow good for coronary health. We also need to ignore the lack of decline in non-fatal CHD, because while CHD mortality did indeed decrease after the 1960s, total age-adjusted incidence of CHD did not[3-6]. If increased LA intake and decreased saturate intake were effective in preventing CHD, then they would surely have lowered both fatal and nonfatal CHD.
The real reason people continued to have just as many heart attacks but survived more of them is because of significant advances in extending the lives of CHD patients (including more emergency medical services, coronary-care units, anti-clotting drugs, etc) are far more coherent explanations for the decline in CHD deaths than consumption of LA.
In RCTs, the dietary fat changes recommended by Willett have been wholly ineffective in reducing CHD and overall mortality, as Ramsden et al note. Willett, however, protests that Ramsden et al "fail to mention that they earlier reported a benefit for incidence of coronary heart disease in a meta-analysis of randomized trials of trials in which saturated fat was replaced by a vegetable oils high in linoleic acid with a small amount of N-3 fatty acids, usually as soybean oil." [sic]
What Ramsden et al actually wrote in the meta-analysis to which Willett refers was "... pooled analysis of the four randomized controlled trials that increased n-3 PUFAs alongside n-6 LA showed reduced cardiovascular mortality."[8]
What a pooled statistical analysis of heterogeneous trials shows and what an intervention actually does is not the same thing. Let’s take a look at those four trials and see what actually transpired:
-In the Oslo Diet-Heart Study, the experimental group did indeed experience lower CHD incidence and cardiovascular mortality. But the control group was disadvantaged by more subjects aged 60 or older, more overweight men and, by the end of the study, almost twice as many heavy smokers[9,10].
These factors alone could easily explain the CHD outcomes. As for diet, replacement of animal fats with soy oil was only one of several dietary interventions employed. The intervention group was also instructed to increase fruit, vegetable and nut intake, and to eliminate consumption of trans fat-rich margarines. The diet group were also liberally supplied with sardines canned in cod liver oil. Unlike soya oil, sardines and cod liver are rich in long-chain omega-3 fatty acids; when tested in isolation, LC n-3 fatty acids have a far more impressive track record in CHD and mortality reduction than plant-based n-3s.
-In the MRC trial, coronary and overall mortality were the same in the soy oil and control groups[11].
-STARS also involved numerous dietary interventions: More fruits, vegetables and starchy complex carbohydrate foods, reduced consumption of processed foods (including "cookies, pastry, cakes"). While the dietary guidelines given to the patients called for "strictly limiting" intake of meat, fish and dairy products, dietary records showed 3-fold higher DHA intake among intervention subjects. DHA can only be obtained from animal foods, so either the dietary records were wrong (in which case we have to doubt the remainder of the recorded intakes) or the intervention group ate more n-3-rich animal foods such as fish.
Also of key importance is the intervention group maintained lower caloric intake and as result lost weight (-2.9 kg), while weight did not change in the control group (+0.3 kg)[12,13].
Given the numerous potential confounders (weight loss, reduced processed food intake, higher animal n-3 intake) intake, it again constitutes poor science to pronounce an increase in the polyunsaturated:saturate ratio as the reason for beneficial mortality outcomes.
- The LA Veterans Administration Study observed reduced CHD deaths among those eating the polyunsaturated-rich diet. However, a significant increase in cancer deaths among the intervention group entirely negated the reduction in CHD mortality[14].
When autopsies were performed on deceased subjects the researchers found little difference in degree of atherosclerosis between the two groups. If anything, those in the soybean oil diet group, despite having lower serum cholesterol levels, had slightly more plaque build-up in the aorta[15].
There were more non-smokers in the intervention group and a significantly higher number of heavy smokers among the controls. Research has shown arteries of smokers are far more susceptible to undergo blood-stopping spasm, even when coronary angiography findings are normal[16]. This could easily explain the lower incidence of CHD among the intervention group.
Cancer incidence, in contrast, was highest in the intervention group. In animal studies, linoleate-rich oils consistently increase tumour incidence and growth[17].
The RCT evidence does not support, and in fact flatly refutes, Willett's assertion that linoleate-rich oils like soy impart heart-healthy, life-extending benefits.
References
1. Page IH, et al. Dietary fat and its relation to heart attacks and strokes. Circulation, 1961; 23:133-136.
2. Blasbalg TL, et al. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. American Journal of Clinical Nutrition. First published ahead of print March 2, 2011 as doi: 10.3945/ajcn.110.006643.
3. Rosamond WD, et al. Trends in incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994. New England Journal of Medicine,1998; 339: 861-867.
4. Center for Disease Control. Hospitalization Rates for Ischemic Heart Disease - United States, 1970-1986. MMWR Weekly, Apr 28, 1989; 38 (16); 275-276, 281-284.
5. Lampe FC, et al. Trends in rates of different forms of diagnosed coronary heart disease, 1978 to 2000: prospective, population-based study of British men. BMJ, 2005; 330: 1046.
6. Sytkowski PA, et al. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Study. New England Journal of Medicine, 1990; 322: 1635-1641.
7. Ramsden CE, 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.
8. Leren P. The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction. A controlled clinical trial. Acta Medica Scandanavica Supplement, 1966; 466: 1-92.
9. Leren P. The Oslo Diet-Heart Study: Eleven Year Report. Circulation, Nov 1970; Vol. 42: 935-942.
10. Medical Research Council. Controlled trial of soya-bean oil in myocardial infarction. Lancet, 1968; 2: 693-699.
11. Watts GF, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet, 1992; 339: 563-569.
12. Watts GF, et al. Dietary fatty acids and progression of coronary artery disease in men. American Journal of Clinical Nutrition, 1996; 64: 202-209.
13. Dayton S, et al. Controlled trial of a diet high in unsaturated fat for prevention of atherosclerotic complications. Lancet, 1968; 2: 1060-1062.
14. Dayton S, et al. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation, 1969; 40 (Suppl. II): 1-63.
15. Nitenberg A, et al. Acetylcholine-induced coronary vasoconstriction in young, heavy smokers with normal coronary arteriographic findings. American Journal of Medicine, 1993; 95: 71–77.
16. Ip C, et al. Requirement of essential fatty acid for mammary tumorigenesis in the rat. Cancer Research, 1985; Vol. 45, Issue 5: 1997-2001.
Competing interests: No competing interests
Re: Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)
While the results of the RCTs clearly show that reducing serum cholesterol does not affect mortality, it is noteworthy that all of the RCTs cited by Ramsden et al. [1] were relatively short term, and many were conducted on middle-aged people, in whom we would expect to see significant atherosclerosis anyway.
In 1996, Uusitalo and coworkers [2] reported an interesting experiment in Mauritius. Because of concerns about the high rate of CHD, the government of Mauritius decided in 1987 to change the composition of the cooking oil produced by the one (government owned) factory in the country, from one based on palm oil (and hence high in saturated fatty acids) to one based on soy bean oil, and therefore high in poly-unsaturated fatty acids. Five years later (1992) there was the expected significant reduction in mean serum cholesterol, but no mention of CHD mortality. The WHO Noncommunicable Disease Country profile for Mauritius in 2014 [3] shows a significant fall in CHD mortality starting in 2003 and continuing to 2012 (the last year for which the data were available). Overall from 2003 to 2012 there was a 32% reduction in CHD mortality among men and 40% among women.
The 16 year time lag between the start of the intervention and the beginning of the decrease in CHD mortality can be explained. During the early years, older people with significant atherosclerosis, and therefore already at risk of death, did not benefit from the dietary change – it was too late for them. It was only as younger people, who had been exposed to the improved oil from early adulthood, reached middle age that there was evidence of benefit; they had accumulated less atherosclerotic plaque throughout their lives.
This highlights a key problem in research on the effects of diet on health – if we want to see survival and improved health into our 8th or 9th decade, we are looking at long-term (life-long) experiments. Obviously these cannot be RCTs or other intervention trials.
References
1) Ramsden CE et al. 2016. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data form the Minnesota Coronary Experiment (1968-73). BMJ 353: i246. http: //dx.doi.org/bmj.i1246
2) Uusitalo U et al. 1996. Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 313: 1044-6.
3) WHO 2014. Noncommunicable Diseases (NCD) Country profiles. www.who.int/nmh/countries/mus_en.pdf
Competing interests: No competing interests