Saturated Fat & the Risk of Heart Disease and Death. Results from randomised controlled trials
All About Saturated Fat Part 2:
What do we know from randomised controlled trials?
Reviews of the observational evidence suggest that there is no effect of saturated fat intake on mortality or the incidence of cardiovascular disease. However, these results have been criticised because many of the studies included adjusted for cholesterol or LDL-cholesterol which have associations with cardiovascular disease events. When non-adjusted models are used, there is often an association between saturated fat and cardiovascular events. However, observational studies suffer from severe confounding due to diet, lifestyle, and psychosocial factors that are difficult to adequately correct for and so, they should be viewed in concert with more reliable ‘gold standard’ data from randomised controlled trials.
So, what do the meta-analyses of randomised trials tell us?
Meta-analyses of randomised controlled trials
Mozaffarian et al., 2010 
Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A…
Dariush Mozaffarian, Renata Micha, Sarah Wallace Subject Areas For more information about PLOS Subject Areas, click…
In this review of 8 RCTs (n = 13,614), there was a 19% reduced risk of coronary events in those consuming higher polyunsaturated fat (average ~15% of calories) versus lower (5%). This equated to a 10% reduced coronary heart disease risk for each 5% energy of increased polyunsaturated fat. Meta-regression identified study duration as an independent determinant of risk reduction (p = 0.017), with studies of longer duration showing greater benefits.
In a commentary, Lee Hooper noted that the dose-relationship between PUFA and reduced cardiovascular risk lacked evidence and did not address the dose of omega-3 fatty acids making up the PUFA dietary component. He further stated that “Such a shift [in reducing SFA and replacing with PUFA] has already occurred since these trials were carried out, and further shifts may be unhelpful.” 
Fumiaki et al., 2016 (RCTs) 
Effects of Saturated Fat, Polyunsaturated Fat, Monounsaturated Fat, and Carbohydrate on…
Fumiaki Imamura, Renata Micha, Jason H. Y. Wu, Marcia C. de Oliveira Otto, Fadar O. Otite, Ajibola I. Abioye, Dariush…
This review looked at the effects of substitution of fats on cardiometabolic markers. Replacing 5% energy from carbohydrate with saturated fat had no significant effect on fasting glucose but lowered fasting insulin. Replacing carbohydrate with monounsaturated fat lowered HbA1c, 2-hour post-glucose-challenge insulin, and homeostasis model assessment for insulin resistance.
Replacing carbohydrate with polyunsaturated fat significantly lowered HbA1c and fasting insulin while replacing saturated fat with polyunsaturated significantly lowered glucose, HbA1c, C-peptide, and HOMA-IR. Polyunsaturated fat significantly improved insulin secretion capacity whether replacing carbohydrate, saturated or monounsaturated fat.
These results suggest that any substitution of fat for carbohydrate might be of use for improving glucose and insulin homeostasis and further that polyunsaturated fats offer specific benefits to glucose and insulin status.
Hamley, 2017 
The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart…
Background A cornerstone of conventional dietary advice is the recommendation to replace saturated fatty acids (SFA)…
This analysis sought to differentiate between ‘adequately’ controlled studies and those that weren’t. Clinical trials categorised as adequately controlled were those that most accurately tested the effects of replacing saturated fat with mostly omega 6 polyunsaturated fat, while the clinical trials categorised as inadequately controlled had too many dietary and/or non-dietary differences between the groups to be considered a valid test of replacing saturated with (mostly omega 6) polyunsaturated fats.
While the results from all trials suggest that replacing saturated fats with mostly omega 6 polyunsaturated fats would significantly reduce the risk of total coronary heart disease events by approximately 20%, it did not affect major events, heart disease mortality, or total mortality. Furthermore, the results from adequately controlled trials showed no effect for major coronary heart disease events, total events, heart disease mortality, or total mortality.
The authors concluded; “available evidence from adequately controlled randomised controlled trials suggest replacing SFA with mostly n-6 PUFA is unlikely to reduce CHD events, CHD mortality or total mortality” and that “benefits reported in earlier meta-analyses is due to the inclusion of inadequately controlled trials”.
Hooper et al., 2020 
The Cochrane Library publishes ‘gold-standard’ reviews of randomised controlled trials. In this review, Hooper and colleagues updated their previous review of 2015,6 finding broadly similar results, namely that there was no effect of saturated fat on all-cause mortality or cardiovascular mortality, and little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, but there was found a significant effect on cardiovascular events. Reducing saturated fat was associated with a 17% reduction in total cardiovascular events. However, there was no effect of reducing saturated fats on non‐fatal myocardial infarction and any effects on total (fatal or non‐fatal) myocardial infarction, stroke, and coronary heart disease events, either fatal or non-fatal, were unclear.
Overall, these results suggest that there is no risk from saturated fat for all-cause or cardiovascular disease mortality but there may be a reduction in cardiovascular events from a reduction in saturated fat. However, a 2019 paper by Simon Thornley and colleagues has suggested that the ‘random effects models’ used by Hooper and colleagues to pool their data, has the effect of biasing the results in favour of smaller trials where those disagree with larger.  This is counter to the idea that larger numbers are more likely to have greater relevance to populations (‘the law of large numbers’). The authors suggest that ‘inverse-variance heterogeneity’ analysis is more suitable because it widens confidence intervals, “yet retain[s] the favourable weights of the fixed effect method”. Using this method of statistical analysis, a pooled relative risk of 0.93, with a 95% confidence interval of 0.74 to 1.16 is produced suggesting a null effect of saturated fat on cardiovascular events. In this secondary analysis, the authors also mentioned that “Egger tests, funnel and Doi plots along with recently published suppressed trial results suggest that publication bias is present”.
Analysis of the randomised controlled trials shows that saturated fat in the diet is not associated with mortality outcomes. Higher intakes of saturated fat might be associated with increased risk of suffering a cardiovascular event, but recent analyses also cast doubt on this due to differences inadequate controlling and statistical methods used. Overall, the evidence is clear from randomised controlled trials that there is no appreciable risk of early death resulting from saturated fat and any increased risk of cardiovascular events is small (if it exists at all).
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 Medicine. 2010;7(3):e1000252.
2. Hooper L. Meta-analysis of RCTs finds that increasing consumption of polyunsaturated fat as a replacement for saturated fat reduces the risk of coronary heart disease. Evidence Based Medicine. 2010;15(4):108–9.
3. Imamura F, Micha R, Wu JHY, de Oliveira Otto MC, Otite FO, Abioye AI, 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.
4. Hamley S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutrition Journal. 2017;16(1):30.
5. Thornley S, Schofield G, Zinn C, Henderson G. How reliable is the statistical evidence for limiting saturated fat intake? A fresh look at the influential Hooper meta-analysis. Internal Medicine Journal. 2019;0(ja).
6. Hooper L, Martin N, Abdelhamid A, Davey Smith G. Reduction in saturated fat intake for cardiovascular disease. The Cochrane database of systematic reviews. 2015(6):Cd011737.