Early dietary interventions sought to demonstrate a beneficial effect of reducing saturated fat on CVD events or mortality, and while some [
28,
58,
105], though not all [
38,
69], of these studies resulted in reduced CVD risk, it is important to note that these diets replaced saturated fat with polyunsaturated fat. Clinical trials in which replacement of saturated fat occurs in the context of reduced total fat and increased carbohydrate have generally not been associated with improvements in CVD [
14,
23]. Recently, the Women’s Health Initiative showed no benefit on CVD of reducing total fat from 37% to 29% in a cohort of 48,000 post-menopausal women [
45]. In the Women’s Health Initiative, saturated fat was reduced from 12.4 to 9.5%, polyunsaturated fat was reduced by 1.5% and dietary carbohydrate was increased by ~8%. A number of large prospective epidemiological studies have not shown a relationship of saturated fat with CVD [
8,
46,
47]. In the Nurses’ Health Study, polyunsaturated fats and
trans fats from industrial sources were identified as being inversely and positively, respectively, associated with increased CHD risk [
46,
80]. Notably, the polyunsaturated fat:saturated fat (P:S) ratio appeared to be strongly and inversely associated with CHD risk, such that P:S ratios ≥0.49 were associated with decreased CHD events[
8]. This finding is in line with the data from the clinical trials cited above in which the benefit of reducing saturated fat occurred in the context of diets that were high in polyunsaturated fat [
28,
58,
105]. There are also several studies, which have cited inverse associations of dietary saturated fat with CVD. In particular, a handful of studies [
40,
51,
52], though not all [
43], have suggested that saturated fat intake is associated with decreased risk of ischemic or hemorrhagic stroke. In a study in post-menopausal women, saturated fat was associated with decreased progression of coronary atherosclerosis and dietary carbohydrate was associated with increased progression of the disease [
72]. Overall, the data from clinical trials and epidemiology do not support an independent role for saturated fat in the determination of CVD risk. The P:S ratio in the diet appears to be the factor most strongly associated with reduced risk. The main effect of saturated fat intake on CVD risk is thought to be mediated by elevation of LDL-C [
66]. Numerous animal and cellular studies have shown that saturated fat raises LDL-C, in part via suppressing LDL receptor activity. Replacement of saturated fat with polyunsaturated fat has been shown to reduce LDL-C [
44]. Further, the ability of saturated fat to raise LDL-C may depend on a polyunsaturated fat content below a threshold level (~5% of energy) [
114]. Dietary carbohydrate can also modulate the effect of saturated fat on lipid and lipoprotein profiles. Dietary carbohydrate increases plasma triglyceride concentrations, reduces HDL-C and increases concentrations of small, dense LDL—the subclass of LDL that is considered to be more atherogenic—by increasing hepatic triglycerides, which drives the secretion of large, triglyceride-enriched particles [
57]. Replacement of saturated fat with carbohydrate results in reductions in both total cholesterol and HDL-C, with no effects on the ratio of total cholesterol to HDL-C [
67]. Recently, it was demonstrated that in the context of lower carbohydrate diets (26% of total energy), lower versus higher levels of dietary saturated fat had no effect on small, dense LDL concentrations [
56]. However, the higher concentrations of saturated fat were associated with increases in larger LDL particles, thereby resulting in no change in plasma levels of LDL-C, in contrast to the reductions observed with the lower carbohydrate, low-saturated fat diet. Saturated fat may also influence CVD risk through lipid-independent mechanisms, including effects on lowering insulin sensitivity [
26,
89,
107], increasing thrombosis [
13], increasing inflammatory markers [
13,
16], compromising vascular function [
77] and raising blood pressure [
86]. However, the evidence relating saturated fat and the aforementioned risk factors remains inconclusive and will require further investigation. In the next section, the effects of dairy foods on non-lipid CVD risk are discussed.