Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Dariush Mozaffarian, MD DrPH

It has been noted by some comments that, in our investigation “Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials,”1 the cross-over intervention design for the two clusters in the Finnish Mental Hospital study (1959-1971) was not randomized. One hospital started with the control diet and the other with the intervention diet for 6 years, and then these diets were reversed for another 6 years. Thus, over the 12 year intervention, each hospital served as its own control, with each hospital receiving each diet in alternating order.

Because this trial was conceived and designed in the 1950s, before current standardized designs and reporting were widely accepted for randomized cross-over trials, we considered this equivalent to a cluster-randomized cross-over trial in our meta-analysis. While the method for determining which hospital started with which diet was not described, both hospitals received both interventions, in differing order over time.

As we noted in the Discussion of our manuscript:

“Many of the identified randomized trials in our meta-analysis had important design limitations (Table 1). For example, some trials provided all or most meals, increasing compliance but perhaps limiting generalizability to effects of dietary recommendations alone; whereas other trials relied only on dietary advice, increasing generalizability to dietary recommendations but likely underestimating efficacy due to noncompliance. Several of these trials were not double-blind, raising the possibility of differential classification of endpoints by the investigators that could overestimate benefits of the intervention. One trial used a cluster-randomization cross-over design that intervened on sites rather than individuals; and two trials used open enrollment that allowed participants to both drop-in and drop-out during the trial. The methods for estimating and reporting PUFA and SFA consumption in each trial varied, which could cause errors in our estimation of the quantitative benefit per %E replacement.”

It is reasonable that one could disagree with our description of “cluster-randomization,” and describe this as a “cluster-quasi-experimental intervention” instead. Given the nature of this trial and its time period of implementation, this was our best interpretation.

Due to the design limitations of several of the trials, we performed several secondary analyses excluding studies based on different design characteristics. Combining all trials, the pooled RR for CHD events was 0.81 (95% CI=0.70-0.95, p=0.008). As we reported in the manuscript: “Excluding the Finnish mental hospital trial (2 reports) that used a cluster-randomization design, the overall pooled RR was 0.87 (95% CI=0.76-1.00, p=0.05).” None of these subgroup analyses were significantly different from the main pooled result, as demonstrated by the 95% CIs in each subgroup analysis including the value of the main pooled RR estimate of 0.81.

As we concluded in our Discussion:

“Given these limitations of each individual trial, the quantitative pooled risk estimate should be interpreted with some caution. Nevertheless, this is the best current worldwide evidence from
RCTs for effects on CHD events of replacing SFA with PUFA, and, as discussed above, the pooled risk estimate from this meta-analysis (10% lower risk per 5%E greater PUFA) is well within the range of estimated benefits from randomized controlled feeding trials of changes in lipid levels (9% lower risk per 5%E greater PUFA) and prospective observational studies of clinical CHD events (13% lower risk per 5%E greater PUFA). The consistency of the findings across these different lines of evidence provides substantial confidence in both the qualitative benefits and also a fairly narrow range of quantitative uncertainty.”

Since the publication of our meta-analysis in 2010, multiple additional studies have further supported cardiometabolic benefits of PUFA consumption. Notably, these studies suggest that benefits are largely related to increased PUFA consumption, rather than decreased SFA consmption per se. For example, a meta-analysis of prospective cohort studies demonstrated that total dietary PUFA is associated with lower risk of clinical events in cohort studies whether replacing total SFA or total carbohydrate.2 A meta-analysis of 102 randomized controlled feeding trials demonstrated that dietary PUFA produces multiple beneficial effects on glycemic control, including lowering of fasting glucose, HbA1C, and insulin resistance and improving pancreatic beta cell function as measured by gold-standard insulin secretion capacity.3 Of note, glycemic benefits are seen whether PUFA replaces carbohydrate, SFA, or even MUFA.3 And, a pooling of new, harmonized, individual-level analysis including 39,740 individuals from 20 prospective cohort studies across ten nations demonstrated that objective blood or tissue biomarkers of linoleic acid (the predominant dietary PUFA) are associated with 35% lower risk of diabetes (per interquintile range, RR=0.65, 95% CI=0.60–0.72, p<0.0001).4

In sum, the overall evidence confirms cardiometabolic benefits of PUFA consumption, including based on evidence from controlled feeding studies of blood lipids, controlled feeding studies of glucose-insulin homeostasis, prospective cohort studies of estimated dietary PUFA and clinical outcomes, prospective cohort studies of objective PUFA biomarkers and clinical outcomes, and controlled clinical trials of PUFA consumption and clinical outcomes.




1. 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(3):e1000252.
2. Farvid MS, Ding M, Pan A, et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation 2014;130(18):1568-78. doi: 10.1161/circulationaha.114.010236 [published Online First: 2014/08/28]
3. Imamura F, Micha R, Wu JH, et al. Effects of Saturated Fat, Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on Glucose-Insulin Homeostasis: A Systematic Review and Meta-analysis of Randomised Controlled Feeding Trials. PLoS medicine 2016;13(7):e1002087. doi: 10.1371/journal.pmed.1002087 [published Online First: 2016/07/21]
4. Wu JHY, Marklund M, Imamura F, et al. Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies. Lancet Diabetes Endocrinol 2017;5(12):965-74. doi: 10.1016/S2213-8587(17)30307-8 [published Online First: 2017/10/17]