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

Dear Dr. Ornish,

Thank you for your insightful comments.

First, in response to the comment about adjustment in observational studies—as we note in our discussion1, we agree that the validity of using “most-adjusted” models, which account both for potential confounders and causal intermediates is debatable2, 3. In the studies we meta-analyzed, several investigator groups adjusted for other risk factors for the health outcomes (such as body-mass-index, family history, and smoking), as well as changes in risk factors on the causal pathway between diet and disease, such as serum lipids and blood pressure. These adjustments certainly attenuate the observed relationships between SFA and the outcomes. To allow readers to ascertain the impact of these adjustments on the interpretability of the pooled risks, in our supplementary materials and GRADE tables, we present both models.

Models adjusted for potential confounders and intermediate variables underestimate associations because of over-controlling for the effect of causal intermediates; unadjusted models overestimate associations, because estimates reflect other determinants of the health outcomes. Notably, in our study those in the highest categories of saturated fat intakes tended to exercise less, smoke more, and eat less fibre. So whether the stronger associations between saturated fat and the health outcomes in the unadjusted models more fully reflect the independent contribution of saturated fat is debatable. We would posit that the least adjusted models reflect the contribution to risk of several unhealthy behaviours which tend to travel together (higher saturated fat diets, smoking, physical inactivity, and lower fibre intake).

To assess the potential impact of over-adjustment, we assessed “intermediately-adjusted models”, i.e. those that adjusted for the most-relevant confounders (smoking, age, sex, and total energy), but not potential causal intermediates (blood pressure or anti-hypertensive medications, serum lipids or lipid-lowering medications) for associations between saturated fat and cardiovascular outcomes, for which we had a reasonable number of studies. In these sensitivity analyses, the adjusted RR for saturated fat and CHD mortality is 1.21 (95% CI: 0.93 to 1.58 in 8 studies); for total CHD is 1.05 (95% CI: 0.93 to 1.19 in 11 studies) and for ischemic stroke is 0.87 (95% CI: 0.76 to 1.00 in 2 studies), which would not meaningfully change our conclusions based on the fully-adjusted models. This demonstrates that the overall results of our synthesis are robust and are not substantially affected by different approaches to covariate adjustment. They are also consistent with the pooled analysis of 11 American and European cohort studies that show that replacement of saturated fat by carbohydrate was not associated with decreased risk of CHD4.

Second, we fully agree with you that the choice of replacement nutrient is important, and we have tried to make this point in several different ways in our paper (in the abstract as well as extensive discussion). Our approach to our study was to address two questions sequentially—first what is the impact of higher saturated fat on the health outcomes? This was the primary question we sought to answer, as developed in conjunction with the World Health Organization. However we recognize that simply giving advice on “eating less” saturated fat is not useful unless some alternative nutrient recommendation is made—and this is precisely how we interpret our main “null” association. We thus proceeded to provide context for this “null” association in our discussion and supplementary material, which considers replacement nutrients. We elected not to conduct a meta-analysis to answer these questions because the available observational evidence for replacement nutrients is sparse, yet remains important. We thus discussed both observational4, 5 and interventional6, 7 studies, to provide a more complete and accurate picture of the evidence base.

Third, we agree that there may be some important differences in the associations across sources of saturated fats—indeed this may contribute to the overall heterogeneity of our findings for saturated fat. Our mandate, was to address total saturated fats primarily; and then to examine the evidence for specific types. In our supplementary material, we have reviewed the evidence for specific sources of saturated fats, which may be found in Appendix 3 for dairy fats (15:0 and 17:0; generally neutral), myristic acid (14:0; generally neutral), palmitic acid (16:0; generally neutral); stearic acid (18:0; generally neutral). However, we would interpret these findings with some caution because of the small number of studies contributing to these analyses. Further, individual saturated fatty acids may share many common food sources, which is challenging for food-based nutrition guidelines. We also summarize here the results of individual studies of exchanging sources of saturated fat for one another8, 9. More work is needed to understand the roles of different saturated fats on health, and more importantly, how to craft public health messages surrounding them.

Finally, we would also draw attention to the fact that using the GRADE rating scale, which takes into account the limitations of the available evidence, we rated our certainty in the null association between saturated fats and the outcomes as overall, “very low”. This means that our estimate of association is very uncertain, in light of the many limitations of the included studies—including those which you have raised. Furthermore, our meta-analysis is observational, and thus cannot infer causality. We fully acknowledge that future work, and other lines of evidence (i.e. randomized controlled trials of replacement nutrients) have an important impact on how we interpret the associations between saturated fat and mortality, CHD/CVD, and type 2 diabetes, and this body of evidence should not be ignored. Thank you for your interest in our paper, and we appreciate the opportunity to respond.

Sincerely,

Russell de Souza
Joseph Beyene
Sonia Anand

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 2015;351:h3978.
2. Stamler J. Diet-heart: a problematic revisit. Am J Clin Nutr 2010;91:497-9.
3. Scarborough P, Rayner M, van Dis I, Norum K. Meta-analysis of effect of saturated fat intake on cardiovascular disease: overadjustment obscures true associations. Am J Clin Nutr 2010;92:458-9; author reply 59.
4. Jakobsen MU, O'Reilly EJ, Heitmann BL, Pereira MA, Balter K, Fraser GE, et al. Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr 2009;89:1425-32.
5. Farvid MS, Ding M, Pan A, Sun Q, Chiuve SE, Steffen LM, 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.
6. 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 Med 2010;7:e1000252.
7. Hooper L, Martin N, Abdelhamid A, Davey Smith G. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev 2015;6:CD011737.
8. Hu FB, Stampfer MJ, Manson JE, Ascherio A, Colditz GA, Speizer FE, et al. Dietary saturated fats and their food sources in relation to the risk of coronary heart disease in women. Am J Clin Nutr 1999;70:1001-8.
9. de Oliveira Otto MC, Mozaffarian D, Kromhout D, Bertoni AG, Sibley CT, Jacobs DR, Jr., et al. Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr 2012;96:397-404.