Re: 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. Blackburn,
Thank you for your insightful comments.
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.
Thank you for your interest in our paper, and we appreciate the opportunity to respond.
Russell J de Souza
Sonia S Anand
1. de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, Uleryk E, Budylowski P, Schunemann H, Beyene J, Anand SS. 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;91:497-499
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;92:458-459; author reply 459
4. Jakobsen MU, O'Reilly EJ, Heitmann BL, Pereira MA, Balter K, Fraser GE, Goldbourt U, Hallmans G, Knekt P, Liu S, Pietinen P, Spiegelman D, Stevens J, Virtamo J, Willett WC, Ascherio A. Major types of dietary fat and risk of coronary heart disease: A pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89:1425-1432
Competing interests: This study was funded by WHO, which defrayed costs associated with preparing the draft manuscript, including information specialist and technical support and article retrieval costs. This systematic review was presented by RJdeS at the 5th Nutrition Guidelines Advisory Group (NUGAG) meeting in Hangzhou, China (4-7 March, 2013), the 6th NUGAG meeting in Copenhagen, Denmark (21-24 Oct, 2013), and the 7th NUGAG meeting in Geneva, Switzerland (9-12 Sept, 2014). WHO covered travel and accommodation costs for RJdeS to attend these meetings. The research questions for the review were discussed and developed by the WHO Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health and the protocol was agreed by the WHO NUGAG Subgroup on Diet and Health; however, neither WHO nor the WHO NUGAG Subgroup on Diet and Health had any role in data collection or analysis. Drs. Beyene and Anand declare no competing interests.