Lipids and Lipoproteins
RCTs have established clear multiple effects of SFA consumption on circulating lipids and lipoproteins [5, 6]. Each of these effects varies depending on the comparison nutrient, i.e., the nutrient isocalorically replaced for SFA (Fig. 2). Compared with CHO, SFA intake raises TC and LDL-C, but also lowers triglycerides and raises high-density lipoprotein cholesterol (HDL-C). Given these conflicting directions of effects, effects on apolipoproteins or, even better, a more global risk marker such as the TC:HDL-C ratio may provide the best overall indication of potential effects on CHD risk. Compared with CHO, SFA intake has no significant effects on the TC:HDL-C ratio or ApoB levels, and raises ApoA1 levels. In contrast, consumption of PUFA or MUFA in place of SFA leads to lowering of TC, LDL-C, and ApoB; slight lowering (for PUFA) of HDL-C and ApoA1; little effect on triglycerides; and lowering of the TC:HDL-C ratio. Compared with trans fatty acids (TFA), SFA intake has minimal effects on LDL-C but raises HDL-C and lowers triglycerides and lipoprotein(a), with improvement in the TC:HDL-C ratio . Thus, consideration of which nutrient is being replaced is essential when considering lipid effects or designing dietary guidelines or policy measures related to SFA consumption. Overall, the changes in lipid and apolipoprotein levels predict minimal effects on CHD risk when CHO replaces SFA, benefits when PUFA or MUFA replace SFA, and harms when TFA replace SFA.
Effects of SFA consumption on serum lipids and lipoproteins further vary according to which specific SFA is consumed (Fig. 3) . With CHO consumption as the reference, lauric (12:0), myristic (14:0), and palmitic (16:0) acid raise TC and LDL-C, whereas stearic acid (18:0) does not. All SFA raise HDL-C, but HDL-raising effects are greater as chain-length decreases. Overall, the TC:HDL-C ratio is not significantly affected by myristic or palmitic acid consumption, is nonsignificantly decreased by stearic acid consumption, and is significantly decreased by lauric acid consumption (Fig. 3). These effects suggest little CHD benefit of replacing myristic, palmitic, or stearic acid with CHO, and potential harm of replacing lauric acid with CHO.
Inflammation independently increases risk of CVD and diabetes [8–11]. Compared with lipid effects, the influence of SFA consumption on inflammation is less well investigated, with mixed results. In a randomized cross-over trial, 20 healthy men consumed a high SFA (22%E SFA), a high MUFA (24%E MUFA), and a high CHO high PUFA (55%E CHO, 8%E PUFA) diet for 4 weeks . At the end of each intervention period, participants were given a fat-rich breakfast (60%E fat) with similar fat composition to that of each diet. Consumption of a butter-rich breakfast (35%E SFA) had no effect on postprandial plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 or monocyte chemoattractant protein (MCP)-1, compared with an olive oil-rich breakfast (36%E MUFA) or a walnut-rich breakfast (16%E PUFA) . In another cross-over trial of 50 healthy men, consumption of low-chain SFA (12:0–16:0) for 5 weeks (8%E) had no effect on fibrinogen, C-reactive protein (CRP), or IL-6 levels; similar consumption of stearic acid (18:0) increased plasma levels of fibrinogen, but not of CRP or IL-6, compared with CHO . Among hypercholesterolemic subjects (n = 18), a one-month diet with 16.7%E from SFA (butter), compared with 12.5%E from PUFA (soybean oil), resulted in a trend toward higher macrophage production of TNF-α, without effects on IL-6 .
Observational studies investigating associations between SFA intake and markers of inflammation are limited [15, 16]. Among 4,900 US adults, dietary SFA intake was not cross-sectionally associated with CRP levels, after adjusting for other risk factors and lifestyle behaviors . Other cross-sectional studies have been very small and/or not multivariable-adjusted . Observational studies of circulating (e.g., plasma) or tissue (e.g., adipose) SFA levels [17, 18] are helpful for investigating effects of metabolism but not of SFA consumption, as circulating and tissue SFA are poorly reflective of dietary SFA due to endogenous synthesis and regulation by lipolysis, lipogenesis, and beta-oxidation [19–22]. Overall, the limited and mixed evidence precludes strong conclusions about potential pro-inflammatory effects of SFA consumption.
Blood Pressure, Endothelial Function, and Arterial Stiffness
Effects of dietary SFA on markers of vascular function including blood pressure, endothelial function, and arterial stiffness are similarly not well characterized . A few observational studies have evaluated SFA intake and incidence of hypertension, with mixed results [24, 25]. Among 30,681 US men followed for 4 years, no significant associations were seen between SFA intake and incident hypertension, after adjusting for age, body mass index, and alcohol consumption . In contrast, among 11,342 US men in the MRFIT study, SFA intake was cross-sectionally positively associated with systolic and diastolic blood pressure, after adjusting for risk factors and lifestyle behaviors, although no adjustments were made for other dietary fats, CHO, or protein .
Randomized controlled feeding trials ranging in duration from 3 weeks to 6 months have demonstrated mixed results of SFA intake compared with MUFA, PUFA, TFA, or CHO on measures of blood pressure, endothelial dysfunction, and/or arterial stiffness  (Table 1). Among nine trials assessing blood pressure, seven observed no differences between the different diets [26–34]. These trials evaluated a range of SFA consumption levels and replacement nutrients (Table 1). Improvements in BP were seen in two of five RCTs including a comparison to MUFA, one of five RCTs including a comparison to PUFA, and zero of four RCTs including a comparison to CHO. Among four trials assessing indices of endothelial function, three observed differences in brachial artery flow-mediated dilatation (FMD) between the different diets [31, 35–37]. Improvements in endothelial function were seen in two of three RCTs including a comparison to MUFA, one RCT including a comparison to PUFA, and one of three RCTs including a comparison to CHO; endothelial function was worsened in one RCT replacing SFA with TFA. In two trials evaluating arterial stiffness as assessed by pulse wave velocity (PWV) [31, 37], no effects of reducing SFA consumption were seen, including two RCTs including a comparison to MUFA, one RCT including a comparison to PUFA, and two RCTs including a comparison to CHO. Thus, evidence for effects of SFA consumption on vascular function is mixed, with no clear pattern based on underlying population characteristics, SFA consumption levels, or the comparison nutrient, and with most studies suggesting no effects.
Insulin Resistance and Diabetes
SFA has been considered a risk factor for insulin resistance and diabetes mellitus , but review of the current evidence indicates surprisingly equivocal findings. SFA consumption inconsistently affects insulin resistance in controlled trials (Table 2) and has not been associated with incident diabetes in prospective cohort studies (Fig. 4) [39–52]. Among generally healthy individuals, most RCTs show no differences in markers of glucose-insulin homeostasis comparing different intakes of SFA versus MUFA, PUFA, or CHO. Findings are more mixed among individuals having or predisposed to insulin resistance. In these individuals, improvements in markers of glucose-insulin homeostasis were seen in three of five RCTs including a comparison to MUFA, one of three RCTs including a comparison to PUFA, and one RCT including a comparison to CHO. Among all these trials, the great majority were short-term (up to several weeks) and surprisingly small (<20 subjects). The two largest trials (n = 162, n = 59) found SFA to worsen several indices of glucose-insulin homeostasis in comparison to MUFA (two trials) or CHO (one trial).
Significant additional insight into effects of dietary fats on glucose-insulin homeostasis can be gained from long-term studies evaluating actual onset of diabetes. Among four large prospective cohort studies, none found independent associations between consumption of either SFA (Fig. 4) or MUFA and onset of diabetes [53–56]. In contrast, three of four cohorts  observed lower incidence of diabetes with greater consumption of PUFA and/or vegetable fat [53, 55, 56]. In the large Women’s Health Initiative trial (n = 45,887), SFA intake was reduced in the intervention group from 12.7 to 9.5%E over 8 years as part of overall total fat reduction, largely replaced with CHO . In this large RCT, this significant reduction in SFA consumption had no effect on fasting glucose, fasting insulin, homeostasis model assessment (HOMA) insulin resistance, or incident diabetes (RR = 0.95, 95% CI = 0.90–1.03).
Thus, some evidence from short-term RCTs suggests that SFA consumption in place of MUFA may worsen glucose-insulin homeostasis, especially among individuals predisposed to insulin resistance. However, several long-term observational studies and one large RCT suggest no effect of SFA consumption on onset of diabetes. Further confirmatory results of either harm or no effect in additional appropriately powered studies are needed given the present inconsistency of effects across all studies.
Weight Gain and Adiposity
The role of total dietary fat in obesity has been widely studied due to its high energy content (9 kcal/g) and subsequent potential for weight gain [58–60]. Based on RCTs of weight loss with balanced-intensity interventions (i.e., all individuals receiving similar guidance and follow-up, with only the specific dietary advice varying) and prospective observational studies of weight gain, the %E from total fat does not have strong effects on adiposity compared with overall quality and quantity of foods consumed. Evidence for independent effects of specific dietary fats such as SFA on weight gain or adiposity are much more limited. In two large prospective cohort studies, increases in SFA consumption were associated with very small increases in abdominal circumference  or body weight during 8–9 years follow-up  compared with CHO, after adjusting for other risk factors and lifestyle and dietary behaviors.