Saturated Fat and Cardiometabolic Risk Factors, Coronary Heart Disease, Stroke, and Diabetes: a Fresh Look at the Evidence

Inflammation independently increases risk of CVD and diabetes [8, 9, 10, 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 [12]. 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) [12]. 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 [13]. 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 [14].

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 [15]. Other cross-sectional studies have been very small and/or not multivariable-adjusted [16]. 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, 20, 21, 22]. Overall, the limited and mixed evidence precludes strong conclusions about potential pro-inflammatory effects of SFA consumption.

Effects of dietary SFA on markers of vascular function including blood pressure, endothelial function, and arterial stiffness are similarly not well characterized [23]. 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 [24]. 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 [25].

SFA has been considered a risk factor for insulin resistance and diabetes mellitus [38], 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, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 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).

Table 2

Effects of saturated fatty acids on insulin resistance in human feeding trials

Study	Subjects	N	Duration	Design	Comparison	Outcomes and results	SFA replaced by
							PUFA	MUFA	TFA	CHO
Individuals Predisposed to Insulin Resistance
Christiansen et al. [42]	Obese (BMI 33.5 ± 1.2 kg/m2), type 2 diabetic, age 55 ± 3 years	Nine men; seven women	6 weeks	Cross-over	Three isocaloric diets: all 30%E fat, with 20%E from SFA, MUFA, or TFA	SFA versus MUFA: ↑ postprandial insulin by 78.9% and ↑ postprandial C-peptide by 41.8% (P < 0.05 for each) SFA versus TFA: no significant effects on postprandial insulin and C-peptide No significant effects on fasting insulin, fasting C-peptide, or fasting and postprandial glucose with any diet		↓	↔
Vessby et al. [43]	Moderately overweight (BMI 26.5 ± 3 kg/m2), age 48.5 ± 7.8 years	86 men, 76 women	3 months	Parallel	Two isocaloric diets: both ~37%E fat, with 17.6%E SFA, or 21.2%E MUFA; each group was further randomized to 3.6 g of either omega-3 fatty acids or olive oil	SFA versus MUFA: ↓ insulin sensitivity by 23.8% (P = 0.05), and ↑ insulin levels by 30.3% (P = 0.06) during a FSIGTT No significant effects on acute insulin response, or glucose levels during a FSIGTT with either diet		↓
Summers et al. [44]	Obese (BMI 37 ± 6 kg/m2), type 2 diabetic, age 53.7 ± 11 years	Eight men; nine women	5 weeks	Cross-over	Two diets: 42%E fat in SFA diet with 21%E from SFA, and 34%E fat in PUFA diet with 9%E from PUFA	SFA versus PUFA: ↓ insulin sensitivity by 20.3% (P = 0.02) during an euglycemic clamp No significant effects on fasting glucose insulin, or triglycerides with either diet	↓
Vega-Lopez et al. [45]	Hyperlipidemic (LDL-cholesterol ≥ 130 mg/dl), moderately overweight (BMI 26 ± 2.4 kg/m2), age 63.9 ± 5.7 years	Five men; ten women	5 weeks	Cross-over	Four isocaloric diets: all ~30%E fat, with 20%E from partially hydrogenated soybean (4.2%E TFA), soybean (12.5%E PUFA), palm (14.8%E SFA), or canola (15.4%E MUFA)	SFA versus PUFA, MUFA, or TFA: no significant effects on fasting insulin, fasting glucose, or HOMA	↔	↔	↔
Paniagua et al. [46]	Obese (BMI 32.6 ± 7.8 kg/m2), insulin resistant (as assessed by OGTT), age 62.3 ± 9.4 years	Four men; seven women	28 days	Cross-over	Three isocaloric diets: 38%E fat and 47%E CHO in the two high-fat diets, with 23%E from SFA or MUFA, and 20%E fat and 65%E CHO in the low-fat diet (the latter as a replacement of SFA)	SFA versus MUFA: ↑ HBA1c (P < 0.01), ↑ fasting glucose by 9.6% (P < 0.05), ↑ HOMA by 17.2% (P < 0.01), ↑ fasting proinsulin by 26.1% (P < 0.05), no significant effects on postprandial glucose, postprandial insulin, or postprandial GLP-1 SFA vs. CHO: ↑ HBA1c by 6.3% (P < 0.01), ↑ fasting glucose by 9.3% (P < 0.05), ↓ postprandial glucose by 51% (P < 0.05), ↓ postprandial insulin by 53% (P < 0.05), ↑ postprandial GLP-1 by 134.6% (P < 0.05), no significant effects on HOMA or fasting proinsulin No significant effects on fasting insulin or GLP-1, or the 60 min proinsulin:insulin ratio with any diet		↓		↓
Lithander et al. [47]	Hyperlipidemic (LDL 3.0–5.0 mmol/L), moderately overweight (BMI 25.9 ± 4.2 kg/m2), age 39.7 ± 13.9 years	18 men	3 weeks	Cross-over	Two isocaloric diets, both 38%E fat: 18%E SFA, 10%E MUFA and 7%E PUFA in the high SFA:USFA diet, and 13%E SFA, 12%E MUFA and 8%E PUFA in the low SFA:USFA diet	SFA versus PUFA + MUFA: No significant effects on fasting adiponectin	↔	↔
Healthy individuals
Schwab et al. [48]	Healthy, normal weight (BMI 21.4 ± 0.5 kg/m2), age 23.9 ± 1.2 years	11 women	4 weeks	Cross-over	Two isocaloric diets: all ~38%E fat, with 5%E from lauric acid (12:0 SFA), or 11.4%E from palmitic acid (16:0 SFA)	12:0 SFA versus 16:0 SFA: no significant effects on insulin, glucose, acute insulin response, or insulin sensitivity index during a FSIGTT with either diet
Fasching et al. [49]	Healthy, normal weight (BMI 22.4 ± 1.8 kg/m2), age 26 ± 3.5 years	8 men	1 week	Cross-over	Four isocaloric diets: 54%E fat and 35%E CHO in the three high-fat diets with 31.5%E from SFA, 28%E from PUFA and 22%E from MUFA, and 25%E fat and 64%E CHO in the high CHO diet	SFA versus PUFA, MUFA, or CHO: no significant effects on insulin, glucose, acute insulin response, or insulin sensitivity index during a FSIGTT with any diet	↔	↔		↔
Louheranta et al. [50]	Healthy, normal weight (BMI 22.6 ± 0.6 kg/m2), age 22 ± 0.6 years	14 women	4 weeks	Cross-over	Two isocaloric diets: both ~38%E fat, with 18.5%E from SFA or MUFA	SFA versus MUFA: no significant effects on insulin, glucose, acute insulin response, or insulin sensitivity index during a FSIGTT with either diet		↔
Perez-Jimenez et al. [52]	Healthy, normal weight (BMI 22.87 ± 2.45 kg/m2), age 23.1 ± 1.8 years	30 men, 29 women	28 days	Cross-over	Baseline 28-day high SFA diet followed by Two randomized cross-over periods; all isocaloric diets: 38%E fat and 47%E CHO in the two high-fat diets, with 20%E from SFA or 22%E from MUFA, and 28%E fat and 57%E CHO in the low-fat diet (the latter as a replacement of SFA)	SFA versus MUFA: ↑ fasting insulin by 134%, ↑ fasting free fatty acids by 40.5%, ↑ mean steady-state plasma glucose by 21.9%, ↓ in vitro basal glucose uptake by 61.3%, and ↓ in vitro insulin-stimulated glucose uptake by 55.3% (P < 0.001 for each) SFA versus CHO: ↑ fasting insulin by 119.7%, ↑ fasting free fatty acids by 40.5%, ↑ mean steady-state plasma glucose by 29%, ↓ in vitro basal glucose uptake by 57.1% %, and ↓ in vitro insulin-stimulated glucose uptake by 55.9% (P < 0.001 for each) No significant effects on fasting glucose with any diet		↓		↓
Lovejoy et al. [51]	Healthy, normal weight (BMI 23.5 ± 0.5 kg/m2), age 28 ± 2 years	12 men; 13 women	4 weeks	Cross-over	Three isocaloric diets: all 30%E fat, with 9%E from elaidic acid (TFA), oleic acid (MUFA), or palmitic acid (SFA)	SFA versus MUFA or TFA: no significant effects on insulin, glucose, acute insulin response, or insulin sensitivity index during a FSIGTT with any diet		↔	↔

Direction of effect on biomarkers of insulin resistance (↑increased; ↓ decreased; ↔ no effect). If even one biomarker was affected, this was considered an effect; this might overestimate the effects of these dietary changes as often many other biomarkers were unaffected (detailed results are also provided)

BMI body mass index, CHO carbohydrate, FSIGTT frequently sampled intravenous glucose tolerance test, GLP-1 glucagon-like peptide-1, HBA1c glycosylated hemoglobin, HOMA homeostasis model assessment, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids, SFA saturated fatty acids, TFA trans fatty acids, USFA unsaturated fatty acids, %E percentage of total energy intake

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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, 54, 55, 56]. In contrast, three of four cohorts [54] 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 [57]. 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.

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, 59, 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 [61] or body weight during 8–9 years follow-up [62] compared with CHO, after adjusting for other risk factors and lifestyle and dietary behaviors.

Most individual prospective cohort studies have not observed an independent relationship between SFA consumption and incident CHD [63, 64, 65, 66, 67]. The relatively small number of published studies, among the many available international cohorts, also raises concern for potential publication bias (i.e., additional unreported null studies). Two recent systematic reviews and meta-analyses, the first including 9 cohorts (11 estimates) evaluating 160,673 individuals [64], and the second including 16 cohorts among 214,182 individuals [68], found no significant association between SFA intake and CHD risk. Comparing the highest to the lowest category of consumption, the pooled RRs in these two meta-analyses were 1.06 (95% CI = 0.96–1.15) and 1.07 (95% CI = 0.96–1.19), respectively. These meta-analyses suggest no overall effect of SFA consumption on CHD events. However, these studies were unable to separately evaluate whether consuming SFA might have different effects on CHD events depending on the nutrient replaced, as would be suggested by differing effects of SFA, depending on the comparison nutrient, on blood lipids and apolipoproteins (Fig. 2).

The best observational evidence to-date of this question is a recent pooled analysis of individual-level data from 11 prospective cohort studies across three continents, including 344,696 individuals with 5,249 CHD events over 4–10 years of follow-up [69]. In fully multivariable-adjusted analyses, SFA consumption was associated with higher CHD risk only in comparison to PUFA. In other words, only consumption of PUFA in place of SFA was associated with lower CHD risk, whereas in fact consumption of CHO or MUFA in place of SFA was associated with higher CHD risk or trends toward higher CHD risk (Fig. 5). These associations were similar when analyses were restricted to CHD deaths only, and were not different in subgroups stratified by either sex or age.

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Eight RCTs have investigated the effects of consuming PUFA (either total or linoleic acid, LA) in place of SFA on CHD events [70, 71, 72, 73, 74, 75, 76, 77]. Most of these trials individually found no significant effects. A recent meta-analysis of these RCTs, including a total of 13,614 participants with 1,042 CHD events, found that CHD risk was lowered by 10% for each 5%E greater PUFA intake replacing SFA [78] (Fig. 5). Many of these trials have important limitations, including for example not being double-blind; incompletely assessing compliance; randomizing sites rather than individuals and having open enrollment and drop-out; and/or including vegetable oils that contained omega-3 PUFA of plant origin that may provide cardiovascular benefits unrelated to decreased SFA intake. Nonetheless, the overall findings from these RCTs of CHD endpoints are consistent with the results from prospective cohorts (Fig. 5).

One large RCT has tested the effect of reducing SFA consumption, replaced largely with CHO, on CHD events. As described, the Women’s Health Initiative trial randomized 46,558 women to lower total fat consumption, that included lowering of SFA consumption by ~3%E over 8 years, and largely replaced with CHO. Even though this was an unbalanced intervention (i.e., the intervention group received extensive dietary counseling, whereas the control group received usual care) that would generally bias toward risk-reduction in the intervention group, there were no significant effects on either incident CHD (RR = 0.93, 95%CI = 0.83–1.05) or total CVD (RR = 0.96, 95%CI = 0.89–1.03) [79]. This absence of benefit for substituting SFA with CHO is consistent with expected effects based on lipid changes (TC:HDL ratio) or observed relationships in prospective cohort studies (Fig. 5).

Among five prospective cohort studies evaluating SFA consumption and incidence of stroke, one of three found SFA to be associated with lower risk of ischemic stroke [80, 81, 82], and one of three found SFA to be associated with lower risk of hemorrhagic stroke [80, 83, 84]. Four prospective cohorts have also observed protective associations between animal protein intake, that is often consumed together with SFA, and risk of hemorrhagic stroke [85]. A recent systematic review and meta-analysis of eight prospective cohorts also found that SFA consumption was associated with trends toward lower risk of stroke: comparing the highest to the lowest category of SFA intake, the RR was 0.81 (95% CI = 0.62–1.05) [68]. In the Women’s Health Initiative trial, reduction in SFA consumption did not have a significant effect on incident stroke over 8 years (RR = 1.02, 95% CI = 0.90–1.17) [79]. Thus, overall, SFA consumption does not appear to increase the risk of stroke, and in fact some studies suggest a protective effect. Further investigation of these effects, including independence from potential benefits of animal protein intake, is warranted.