The World Health Organization (WHO) recently published a report called Saturated fat and trans-fat intakes and their replacement with other macronutrients (found here).
This analysis was conducted "to inform World Health Organization (WHO) recommendations for intakes of SFA [saturated fats] and TFA [trans-fats]."
Based on their analysis, the authors concluded:
Consideration of the totality of evidence available from prospective observational studies provides convincing evidence that replacing SFA and TFA with other macronutrients may reduce risk of mortality and CHD.
Of course, the statement that replacing saturated fat with other macronutrients "may" reduce risk is one that expresses uncertainty. And for good reason.
If we examine the data, we will also see that replacing saturated fat with other macronutrients "may not" reduce risk.
To illustrate, let us look at their various analyses.
Saturated Fat and Total Mortality
The WHO report states:
Higher reported intakes of SFA were associated with increased risk of premature mortality when compared with lower intakes.
But an association alone does not prove anything.
To determine whether there might be a causal effect, we also need to consider the strength of association, consistency of association, dose-response, and so on (1).
For strength of association, the finding was very weak:
(Image: Only small epidemiological biases are needed to explain away an average relative risk increase of 8%. Note also the confidence interval, which includes weaker associations or no association at all)
For consistency of association, there was unexplained inconsistency (I2 = 90%). Studies reported estimates clearly below 1 (benefit), relatively close to 1 (neutral), and clearly above 1 (harm).
Nor was there any evidence of a dose-response relationship: 
In fact, the authors used the GRADE approach to evaluate the certainty of evidence, which considers strength, consistency, and dose-response (among others).
For all categories, the certainty of evidence was rated as "low" or "very low," meaning there is little confidence in the estimates. The true effect may be substantially different.
Thus, the epidemiological evidence is perfectly compatible with the idea that lowering saturated fat intake "may not" reduce mortality (2-9).
Other Endpoints
The WHO review also looked at cardiovascular disease and diabetes, but there were no robust associations between saturated fat, animal fat, or dairy fat and any of these endpoints.
Just as with total mortality, the certainty of evidence was "very low" or "low."
Furthermore, the WHO report only included studies up to October 2020. At this time of writing, twelve more cohorts have been published showing no evidence of an association between saturated fat and cardiovascular outcomes (2,5-15).
The Malmo and HUSK cohorts, for instance, suggested that saturated fat was actually associated with a reduced risk of cardiovascular events (10,11).
(Image: Cardiovascular event analysis when newer cohorts are added)
And a few cohorts even provided splines showing no dose-response relationships, consistent with the WHO report:
Thus, there are no convincing associations between saturated fat and cardiovascular outcomes.
Replacement Models
The WHO review asserts that replacing saturated fat with other macronutrients may reduce the risk of mortality and CHD.
In epidemiological studies, however, no one replaces saturated fat with anything. It is fantasy, as the WHO report admits:
Substitution analyses are based on statistical modelling of the data available from prospective observational studies; they are not the same as experimental data where intakes are changed.
But even if we assume the validity of this approach, the certainty of evidence for almost all replacement models was "low" or "very low."
And the results are more inconsistent than often portrayed.
For example, the WHO claimed a beneficial association for "replacing" saturated fat with polyunsaturated fat, but I found several other reports suggesting otherwise (7,11,13,16-19).
Some of these inconsistencies were highlighted in a 2021 paper by Gaeini and colleagues, stating (13):
The results of previous studies regarding the effect of substitution dietary fats on CVD risk are conflicting and not conclusive. Similar to our findings, some previous studies suggested that replacing total SFA with carbohydrate, MUFA and PUFA had no beneficial effects on CVD risk, while some others suggested a higher risk of CVD for replacing total SFA with total carbohydrate, MUFA, PUFA or animal protein.
There are also strong indications of residual confounding bias in some "replacement" cohorts.
The Zhuang cohort, for instance, claimed associations between saturated fat and non-cardiovascular outcomes (respiratory disease, infections, injuries/accidents, etc.). And these associations were as great or greater in magnitude than the association between saturated fat and cardiovascular mortality (20).
But associations for these non-cardiovascular outcomes are what we expect from confounders like pollution, smoking, occupation, and other socioeconomic factors (21,22). If we were to believe the results, we would have to believe that minor increases in saturated fat cause injuries and accidents.
Unfortunately, large cohorts such as Zhuang et al. tend to influence the results of meta-analyses, but are not necessarily valid (23):
Bigger studies are not necessarily better. Large numbers provide greater precision, but not greater validity. Very large studies commonly give precisely wrong answers, ie, high reproducibility but poor validity because of selection bias and inadequate control of confounding.
In support of this, we should note that actual replacement of saturated fat with polyunsaturated fat has already been tested in dietary trials, and the results do not support a benefit.
To quote Ramsden and colleagues (24):
Available evidence from randomized controlled trials shows that replacement of saturated fat in the diet with linoleic acid effectively lowers serum cholesterol but does not support the hypothesis that this translates to a lower risk of death from coronary heart disease or all causes.
(Image: Taken from reference 24)
Tissue Measurements
According to the WHO report:
We examined both dietary intakes and the fatty acid composition of relevant tissue and blood lipids as an objective biomarker of intake, because tissue and blood fatty acids are mainly derived from dietary fatty acids.
But the paper cited in support of this statement showed inconsistent and generally weak associations between saturated fat intakes and tissue/blood measurements (25).
One author of the WHO, in fact, was involved in a study showing no association between dietary saturated fatty acids and plasma saturated fatty acids (26).
Even some of the very studies included in their meta-analysis expressed caution in interpreting tissue/blood measurements as a reflection of dietary intake.
In the EPIC cohort, the researchers stated (27):
Plasma phospholipid SFAs might be indicative of both dietary and metabolic influences, affected by interplay of complex exogenous and genetic factors, which we were unable to tease out. This raises caution against inferring dietary consumption on the basis of measurements of SFAs that are not exclusively exogenously derived.
And from the Cardiovascular Health Study (28):
Several determinants influence the levels of these FAs in the body. Direct sources of 16:0 and 18:1n-9 are abundant in the diet, but dietary intakes of these FAs appear to be poorly correlated with circulating levels.
The unreliability of using tissue/blood measurements for (most) dietary saturated fatty acids has also been discussed in many other reports (29-31).
Not surprisingly, the recent INTERLIPID study found very weak to nonexistent correlations between dietary saturated fatty acids and blood levels but stronger and more consistent correlations for fatty acids like EPA and DHA (32).
Additionally, estimates of dietary intake and tissue measurements on disease outcomes can contradict one another.
In the WHO report, tissue measurement of palmitic acid was associated with diabetes while myristic acid was not. But in a meta-analysis of dietary intake, palmitic acid was not associated with diabetes while myristic acid (and lauric acid) was associated with a reduced risk (33).
Likewise, the WHI Observational Study found an association between plasma phospholipid saturated fatty acids (correlated with alcohol intake) and coronary events (34). But in the WHI randomized trial, there was no evidence of benefit for a diet lower in saturated fat (35).
Point is: Tissue/blood measurements of saturated fatty acids are not validated markers of dietary saturated fatty acids in epidemiological cohorts.
Conclusions
Contrary to what the WHO claims, their own review does not provide convincing evidence for replacing saturated fat with other macronutrients.
Interestingly, when discussing the limitations of the review, the authors state:
The GRADE assessment that some of the associations were based on “low quality” evidence may also be considered a weakness.
But the GRADE assessment is a strength of the review, not a weakness. The fact that the quality of evidence is graded as "low" simply illustrates the weaknesses of the epidemiological evidence against saturated fat.
And the authors should have taken it a step further to emphasize that causation was not established, just as the WHO PUFA review admitted (36):
Observational studies cannot provide causal evidence of an effect of PUFA [or SFA] on the development of health outcomes addressed, they can only describe associations.
Thus, a proper reading of the WHO report can only lead to one conclusion: We still have no support for lowering saturated fat intake.
References
1) Weed, D. L., & Alexander, D. D. (2022). The Erosion of Causal Inference in Systematic Reviews in Epidemiology. Medical Research Archives, 10(10).
2) Sadeghi, M., Simani, M., Mohammadifard, N., Talaei, M., Roohafza, H., Hassannejad, R., & Sarrafzadegan, N. (2021). Longitudinal association of dietary fat intake with cardiovascular events in a prospective cohort study in Eastern Mediterranean region. International Journal of Food Sciences and Nutrition, 72(8), 1095-1104.
3) Van Blarigan, E. L., Ma, C., Ou, F. S., Bainter, T. M., Venook, A. P., Ng, K., ... & Meyerhardt, J. A. (2023). Dietary fat in relation to all‐cause mortality and cancer progression and death among people with metastatic colorectal cancer: Data from CALGB 80405 (Alliance)/SWOG 80405. International Journal of Cancer, 152(2), 123-136.
4) Taha, H. M., Rozek, L. S., Chen, X., Li, Z., Zarins, K. R., Slade, A. N., ... & Arthur, A. E. (2022). Risk of Disease Recurrence and Mortality Varies by Type of Fat Consumed before Cancer Treatment in a Longitudinal Cohort of Head and Neck Squamous Cell Carcinoma Patients. The Journal of Nutrition, 152(5), 1298-1305.
5) Gribbin, S., Enticott, J., Hodge, A. M., Moran, L., Thong, E., Joham, A., & Zaman, S. (2022). Association of carbohydrate and saturated fat intake with cardiovascular disease and mortality in Australian women. Heart, 108(12), 932-939.
6) Jessri, M., Hennessey, D., Eddeen, A. B., Bennett, C., Zhang, Z., Yang, Q., ... & Manuel, D. (2022). Sodium, added sugar and saturated fat intake in relation to mortality and cardiovascular disease events in adults: Canadian National Nutrition Survey linked with vital statistics and health administrative databases. British Journal of Nutrition, 1-33.
7) Yang, T., Yi, J., He, Y., Zhang, J., Li, X., Ke, S., ... & Liu, L. (2022). Associations of Dietary Fats with All-Cause Mortality and Cardiovascular Disease Mortality among Patients with Cardiometabolic Disease. Nutrients, 14(17), 3608.
8) Yiannakou, I., Yuan, M., Zhou, X., Singer, M. R., & Moore, L. L. Saturated and Unsaturated Dietary Fats and Cardiometabolic Risk in the Framingham Offspring Study. Available at SSRN 4198093.
9) McKenzie, B. L., Harris, K., Peters, S. A., Webster, J., & Woodward, M. (2022). The association of energy and macronutrient intake with all-cause mortality, cardiovascular disease and dementia: findings from 120 963 women and men in the UK Biobank. British Journal of Nutrition, 127(12), 1858-1867.
10) Acosta, S., Johansson, A., & Drake, I. (2021). Diet and lifestyle factors and risk of atherosclerotic cardiovascular disease—A prospective cohort study. Nutrients, 13(11), 3822.
11) Haugsgjerd, T. R., Egeland, G. M., Nygård, O. K., Igland, J., Sulo, G., Lysne, V., ... & Tell, G. S. (2022). Intake of carbohydrates and SFA and risk of CHD in middle-age adults: the Hordaland Health Study (HUSK). Public Health Nutrition, 25(3), 634-648.
12) Yao, X., Xu, X., Wang, S., & Xia, D. (2021). Associations of dietary fat intake with mortality from all causes, cardiovascular disease, and cancer: A prospective study. Frontiers in Nutrition, 8, 701430.
13) Gaeini, Z., Mirmiran, P., Bahadoran, Z., Aghayan, M., & Azizi, F. (2021). The association between dietary fats and the incidence risk of cardiovascular outcomes: Tehran Lipid and Glucose Study. Nutrition & Metabolism, 18(1), 1-11
14) Wang, Y., Fang, Y., Witting, P. K., Charchar, F. J., Sobey, C. G., Drummond, G. R., & Golledge, J. (2023). Dietary fatty acids and mortality risk from heart disease in US adults: an analysis based on NHANES. Scientific Reports, 13(1), 1614.
15) Lim, C. G., Tai, E. S., & van Dam, R. M. (2022). Replacing dietary carbohydrates and refined grains with different alternatives and risk of cardiovascular diseases in a multi-ethnic Asian population. The American Journal of Clinical Nutrition, 115(3), 854-863.
16) Ho, F. K., Gray, S. R., Welsh, P., Petermann-Rocha, F., Foster, H., Waddell, H., ... & Mathers, J. C. (2020). Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants. Bmj, 368.
17) Yamagishi K, Iso H, Yatsuya H, et al. Dietary intake of saturated fatty acids and mortality from cardiovascular disease in Japanese: the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study. Am. J. Clin. Nutr. 2010;92(4):759–765.
18) Bajracharya, R., Katzke, V., Mukama, T., & Kaaks, R. (2023). Effect of Iso-Caloric Substitution of Animal Protein for Other Macro Nutrients on Risk of Overall, Cardiovascular and Cancer Mortality: Prospective Evaluation in EPIC-Heidelberg Cohort and Systematic Review. Nutrients, 15(3), 794.
19) Steur, M., Johnson, L., Sharp, S. J., Imamura, F., Sluijs, I., Key, T. J., ... & Forouhi, N. G. (2021). Dietary Fatty Acids, Macronutrient Substitutions, Food Sources and Incidence of Coronary Heart Disease: Findings From the EPIC‐CVD Case‐Cohort Study Across Nine European Countries. Journal of the American Heart Association, 10(23), e019814.
20) Zhuang, P., Zhang, Y., He, W., Chen, X., Chen, J., He, L., ... & Jiao, J. (2019). Dietary fats in relation to total and cause-specific mortality in a prospective cohort of 521 120 individuals with 16 years of follow-up. Circulation research, 124(5), 757-768.
21) Blanchard, T. (2022). Specificity of association in epidemiology. Synthese, 200(6), 482.
22) Sainani, K. (2011). The limitations of statistical adjustment. PM&R, 3(9), 868-872.
23) Grimes, D. A., & Schulz, K. F. (2012). False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstetrics & Gynecology, 120(4), 920-927.
24) Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., ... & Hibbeln, J. R. (2016). Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73). bmj, 353.
25) Hodson, L., Skeaff, C. M., & Fielding, B. A. (2008). Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Progress in lipid research, 47(5), 348-380.
26) Parry, S. A., Rosqvist, F., Peters, S., Young, R. K., Cornfield, T., Dyson, P., & Hodson, L. (2021). The influence of nutritional state on the fatty acid composition of circulating lipid fractions: implications for their use as biomarkers of dietary fat intake. Upsala Journal of Medical Sciences, 126.
27) Forouhi, N. G., Koulman, A., Sharp, S. J., Imamura, F., Kröger, J., Schulze, M. B., ... & Wareham, N. J. (2014). Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. The lancet Diabetes & endocrinology, 2(10), 810-818.
28) Lai, H. T., de Oliveira Otto, M. C., Lee, Y., Wu, J. H., Song, X., King, I. B., ... & Mozaffarian, D. (2019). Serial plasma phospholipid fatty acids in the de novo lipogenesis pathway and total mortality, cause‐specific mortality, and cardiovascular diseases in the cardiovascular health study. Journal of the American Heart Association, 8(22), e012881.
29) Marchioni, D. M., de Oliveira, M. F., Carioca, A. A. F., Miranda, A. A. M., Carvalho, A. M., Oki, E., ... & Fisberg, R. M. (2019). Plasma fatty acids: biomarkers of dietary intake?. Nutrition, 59, 77-82.
30) Hyde, P. N., Sapper, T. N., Crabtree, C. D., LaFountain, R. A., Bowling, M. L., Buga, A., ... & Volek, J. S. (2019). Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI insight, 4(12).
31) Murru, E., Manca, C., Carta, G., & Banni, S. (2022). Impact of dietary palmitic acid on lipid metabolism. Frontiers in Nutrition, 9.
32) Miyagawa, N., Sekikawa, A., Miura, K., Evans, R. W., Okuda, N., Fujiyoshi, A., ... & Ueshima, H. (2022). Circulating plasma phospholipid fatty acid levels as a biomarker of habitual dietary fat intake: The INTERMAP/INTERLIPID Study. Journal of Clinical Lipidology.
33) Gaeini, Z., Bahadoran, Z., & Mirmiran, P. (2022). Saturated Fatty Acid Intake and Risk of Type 2 Diabetes: An Updated Systematic Review and Dose–Response Meta-Analysis of Cohort Studies. Advances in Nutrition, 13(6), 2125-2135.
34) Liu, Q., Matthan, N. R., Manson, J. E., Howard, B. V., Tinker, L. F., Neuhouser, M. L., ... & Eaton, C. B. (2019). Plasma phospholipid fatty acids and coronary heart disease risk: A matched case-control study within the Women’s Health Initiative Observational study. Nutrients, 11(7), 1672.
35) Howard, B. V., Van Horn, L., Hsia, J., Manson, J. E., Stefanick, M. L., Wassertheil-Smoller, S., ... & Kotchen, J. M. (2006). Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. Jama, 295(6), 655-666.