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 Drs. Freeman and Esselstyn Jr.,

Thank you for your insightful commentary.

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, we present both models in our supplementary materials and GRADE tables.

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, the linear association reported in the Seven Countries’ Study for saturated fat and mortality is striking, and represents an important contribution to the study of fat and mortality. However, it bears noting that this model regressed average cohort values for saturated fat on age-adjusted all-cause mortality rates5. Such an ecological association must be interpreted with caution as it is hypothesis-generating at best, and does not imply causality. Because the unit of analysis in this regression model was the cohort (n=16), the investigators could only adjust for a limited number of confounding variables (vitamin C and smoking). For example, the confounding effects of socioeconomic status and occupation, physical activity, total energy, or family history could not be considered due to the sparseness of data. Further, the representativeness of the dietary data (which represented a fraction of the entire country-specific cohorts) may have been suboptimal.

Finally, the cited study of the efficacy of large dietary changes to reverse CAD is impressive. However, the results likely reflect more than the effect of simply reducing saturated fat. It is important to note that many diets which are naturally low in saturated fat—such as plant-based diets, contain several foods that are highly nutritious and generally regarded as cardioprotective, and avoid highly refined carbohydrates and trans fats. Therefore, when adopting such diets, people do more than just eliminate foods higher in saturated fat. For example, in the cited study6, involving participants who voluntarily asked for counseling on plant-based nutrition (i.e. a self-selected and highly-motivated group), some cardioprotective components were increased (whole plant foods such as whole grains, legumes, lentils, flaxseed, and fruit), others were decreased (dairy, nuts, plant oils, fish), and less healthful foods were reduced (meat, sugary drinks, excess salt, and caffeine). This study did not include a control group, which presents a challenge for establishing causality and ascribing the benefits solely to dietary changes. In Dr. Ornish’s study7, the combination of intensive dietary changes (very low fat, plant-based nutrition) and stress management yielded remarkable results. The magnitude of the response to comprehensive diet and lifestyle changes in both of these studies serve to underscore the importance of considering more than a single nutrient--a “whole diet” and lifestyle approach is likely to be the most impactful path to optimal health.

Sincerely,

Russell de Souza
Sonia Anand
Joseph Beyene

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. Kromhout D, Bloemberg B, Feskens E, Menotti A, Nissinen A. Saturated fat, vitamin C and smoking predict long-term population all-cause mortality rates in the Seven Countries Study. Int J Epidemiol 2000;29:260-5.
6. Esselstyn CB, Jr., Gendy G, Doyle J, Golubic M, Roizen MF. A way to reverse CAD? J Fam Pract 2014;63:356-64b.
7. Ornish D, Scherwitz LW, Doody RS, Kesten D, McLanahan SM, Brown SE, et al. Effects of stress management training and dietary changes in treating ischemic heart disease. JAMA 1983;249:54-9.