A growing body of nutritional science highlights the complex mechanisms and pleiotropic pathways of cardiometabolic effects of different foods. Among these, some of the most exciting advances are ...occurring in the area of flavonoids, bioactive phytochemicals found in plant foods; and in the area of dairy, including milk, yogurt, and cheese. Many of the relevant ingredients and mechanistic pathways are now being clarified, shedding new light on both the ingredients and the pathways for how diet influences health and well-being. Flavonoids, for example, have effects on skeletal muscle, adipocytes, liver, and pancreas, and myocardial, renal, and immune cells, for instance, related to 5'-monophosphate-activated protein kinase phosphorylation, endothelial NO synthase activation, and suppression of NF-κB (nuclear factor-κB) and TLR4 (toll-like receptor 4). Effects of dairy are similarly complex and may be mediated by specific amino acids, medium-chain and odd-chain saturated fats, unsaturated fats, branched-chain fats, natural
fats, probiotics, vitamin K1/K2, and calcium, as well as by processing such as fermentation and homogenization. These characteristics of dairy foods influence diverse pathways including related to mammalian target of rapamycin, silent information regulator transcript-1, angiotensin-converting enzyme, peroxisome proliferator-activated receptors, osteocalcin, matrix glutamate protein, hepatic de novo lipogenesis, hepatic and adipose fatty acid oxidation and inflammation, and gut microbiome interactions such as intestinal integrity and endotoxemia. The complexity of these emerging pathways and corresponding biological responses highlights the rapid advances in nutritional science and the continued need to generate robust empirical evidence on the mechanistic and clinical effects of specific foods.
Dietary guidelines recommend avoiding foods high in saturated fat. Yet, emerging evidence suggests cardiometabolic benefits of dairy products and dairy fat. Evidence on the role of butter, with high ...saturated dairy fat content, for total mortality, cardiovascular disease, and type 2 diabetes remains unclear. We aimed to systematically review and meta-analyze the association of butter consumption with all-cause mortality, cardiovascular disease, and diabetes in general populations.
We searched 9 databases from inception to May 2015 without restriction on setting, or language, using keywords related to butter consumption and cardiometabolic outcomes. Prospective cohorts or randomized clinical trials providing estimates of effects of butter intake on mortality, cardiovascular disease including coronary heart disease and stroke, or diabetes in adult populations were included. One investigator screened titles and abstracts; and two reviewed full-text articles independently in duplicate, and extracted study and participant characteristics, exposure and outcome definitions and assessment methods, analysis methods, and adjusted effects and associated uncertainty, all independently in duplicate. Study quality was evaluated by a modified Newcastle-Ottawa score. Random and fixed effects meta-analysis pooled findings, with heterogeneity assessed using the I2 statistic and publication bias by Egger's test and visual inspection of funnel plots. We identified 9 publications including 15 country-specific cohorts, together reporting on 636,151 unique participants with 6.5 million person-years of follow-up and including 28,271 total deaths, 9,783 cases of incident cardiovascular disease, and 23,954 cases of incident diabetes. No RCTs were identified. Butter consumption was weakly associated with all-cause mortality (N = 9 country-specific cohorts; per 14g(1 tablespoon)/day: RR = 1.01, 95%CI = 1.00, 1.03, P = 0.045); was not significantly associated with any cardiovascular disease (N = 4; RR = 1.00, 95%CI = 0.98, 1.02; P = 0.704), coronary heart disease (N = 3; RR = 0.99, 95%CI = 0.96, 1.03; P = 0.537), or stroke (N = 3; RR = 1.01, 95%CI = 0.98, 1.03; P = 0.737), and was inversely associated with incidence of diabetes (N = 11; RR = 0.96, 95%CI = 0.93, 0.99; P = 0.021). We did not identify evidence for heterogeneity nor publication bias.
This systematic review and meta-analysis suggests relatively small or neutral overall associations of butter with mortality, CVD, and diabetes. These findings do not support a need for major emphasis in dietary guidelines on either increasing or decreasing butter consumption, in comparison to other better established dietary priorities; while also highlighting the need for additional investigation of health and metabolic effects of butter and dairy fat.
Effects of major dietary macronutrients on glucose-insulin homeostasis remain controversial and may vary by the clinical measures examined. We aimed to assess how saturated fat (SFA), monounsaturated ...fat (MUFA), polyunsaturated fat (PUFA), and carbohydrate affect key metrics of glucose-insulin homeostasis.
We systematically searched multiple databases (PubMed, EMBASE, OVID, BIOSIS, Web-of-Knowledge, CAB, CINAHL, Cochrane Library, SIGLE, Faculty1000) for randomised controlled feeding trials published by 26 Nov 2015 that tested effects of macronutrient intake on blood glucose, insulin, HbA1c, insulin sensitivity, and insulin secretion in adults aged ≥18 years. We excluded trials with non-isocaloric comparisons and trials providing dietary advice or supplements rather than meals. Studies were reviewed and data extracted independently in duplicate. Among 6,124 abstracts, 102 trials, including 239 diet arms and 4,220 adults, met eligibility requirements. Using multiple-treatment meta-regression, we estimated dose-response effects of isocaloric replacements between SFA, MUFA, PUFA, and carbohydrate, adjusted for protein, trans fat, and dietary fibre. Replacing 5% energy from carbohydrate with SFA had no significant effect on fasting glucose (+0.02 mmol/L, 95% CI = -0.01, +0.04; n trials = 99), but lowered fasting insulin (-1.1 pmol/L; -1.7, -0.5; n = 90). Replacing carbohydrate with MUFA lowered HbA1c (-0.09%; -0.12, -0.05; n = 23), 2 h post-challenge insulin (-20.3 pmol/L; -32.2, -8.4; n = 11), and homeostasis model assessment for insulin resistance (HOMA-IR) (-2.4%; -4.6, -0.3; n = 30). Replacing carbohydrate with PUFA significantly lowered HbA1c (-0.11%; -0.17, -0.05) and fasting insulin (-1.6 pmol/L; -2.8, -0.4). Replacing SFA with PUFA significantly lowered glucose, HbA1c, C-peptide, and HOMA. Based on gold-standard acute insulin response in ten trials, PUFA significantly improved insulin secretion capacity (+0.5 pmol/L/min; 0.2, 0.8) whether replacing carbohydrate, SFA, or even MUFA. No significant effects of any macronutrient replacements were observed for 2 h post-challenge glucose or insulin sensitivity (minimal-model index). Limitations included a small number of trials for some outcomes and potential issues of blinding, compliance, generalisability, heterogeneity due to unmeasured factors, and publication bias.
This meta-analysis of randomised controlled feeding trials provides evidence that dietary macronutrients have diverse effects on glucose-insulin homeostasis. In comparison to carbohydrate, SFA, or MUFA, most consistent favourable effects were seen with PUFA, which was linked to improved glycaemia, insulin resistance, and insulin secretion capacity.
We reviewed available evidence for cardiovascular effects of n-3 polyunsaturated fatty acid (PUFA) consumption, focusing on long chain (seafood) n-3 PUFA, including their principal dietary sources, ...effects on physiological risk factors, potential molecular pathways and bioactive metabolites, effects on specific clinical endpoints, and existing dietary guidelines. Major dietary sources include fatty fish and other seafood. n-3 PUFA consumption lowers plasma triglycerides, resting heart rate, and blood pressure and might also improve myocardial filling and efficiency, lower inflammation, and improve vascular function. Experimental studies demonstrate direct anti-arrhythmic effects, which have been challenging to document in humans. n-3 PUFA affect a myriad of molecular pathways, including alteration of physical and chemical properties of cellular membranes, direct interaction with and modulation of membrane channels and proteins, regulation of gene expression via nuclear receptors and transcription factors, changes in eicosanoid profiles, and conversion of n-3 PUFA to bioactive metabolites. In prospective observational studies and adequately powered randomized clinical trials, benefits of n-3 PUFA seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on other cardiovascular outcomes are less-well-established, including conflicting evidence from observational studies and/or randomized trials for effects on nonfatal myocardial infarction, ischemic stroke, atrial fibrillation, recurrent ventricular arrhythmias, and heart failure. Research gaps include the relative importance of different physiological and molecular mechanisms, precise dose-responses of physiological and clinical effects, whether fish oil provides all the benefits of fish consumption, and clinical effects of plant-derived n-3 PUFA. Overall, current data provide strong concordant evidence that n-3 PUFA are bioactive compounds that reduce risk of cardiac death. National and international guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFA or at least 2 servings/week of oily fish.
The effect of dietary fats on cardiometabolic diseases, including cardiovascular diseases and type 2 diabetes mellitus, has generated tremendous interest. Many earlier investigations focused on total ...fat and conventional fat classes (such as saturated and unsaturated fats) and their influence on a limited number of risk factors. However, dietary fats comprise heterogeneous molecules with diverse structures, and growing research in the past two decades supports correspondingly complex health effects of individual dietary fats. Moreover, health effects of dietary fats might be modified by additional factors, such as accompanying nutrients and food-processing methods, emphasizing the importance of the food sources. Accordingly, the rapidly increasing scientific findings on dietary fats and cardiometabolic diseases have generated debate among scientists, caused confusion for the general public and present challenges for translation into dietary advice and policies. This Review summarizes the evidence on the effects of different dietary fats and their food sources on cell function and on risk factors and clinical events of cardiometabolic diseases. The aim is not to provide an exhaustive review but rather to focus on the most important evidence from randomized controlled trials and prospective cohort studies and to highlight current areas of controversy and the most relevant future research directions for understanding how to improve the prevention and management of cardiometabolic diseases through optimization of dietary fat intake.
Cardiovascular disease (CVD) is the leading global cause of death, accounting for 17.3 million deaths per year. Preventive treatment that reduces CVD by even a small percentage can substantially ...reduce, nationally and globally, the number of people who develop CVD and the costs of caring for them. This American Heart Association presidential advisory on dietary fats and CVD reviews and discusses the scientific evidence, including the most recent studies, on the effects of dietary saturated fat intake and its replacement by other types of fats and carbohydrates on CVD. In summary, randomized controlled trials that lowered intake of dietary saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by ≈30%, similar to the reduction achieved by statin treatment. Prospective observational studies in many populations showed that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other major causes of death and all-cause mortality. In contrast, replacement of saturated fat with mostly refined carbohydrates and sugars is not associated with lower rates of CVD and did not reduce CVD in clinical trials. Replacement of saturated with unsaturated fats lowers low-density lipoprotein cholesterol, a cause of atherosclerosis, linking biological evidence with incidence of CVD in populations and in clinical trials. Taking into consideration the totality of the scientific evidence, satisfying rigorous criteria for causality, we conclude strongly that lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, will lower the incidence of CVD. This recommended shift from saturated to unsaturated fats should occur simultaneously in an overall healthful dietary pattern such as DASH (Dietary Approaches to Stop Hypertension) or the Mediterranean diet as emphasized by the 2013 American Heart Association/American College of Cardiology lifestyle guidelines and the 2015 to 2020 Dietary Guidelines for Americans.
Considerable research supports cardiovascular benefits of consuming omega-3 PUFA, also known as (n-3) PUFA, from fish or fish oil. Whether individual long-chain (n-3) PUFA have shared or ...complementary effects is not well established. We reviewed evidence for dietary and endogenous sources and cardiovascular effects on biologic pathways, physiologic risk factors, and clinical endpoints of EPA 20:5(n-3), docosapentaenoic acid DPA, 22:5(n-3), and DHA 22:6(n-3). DHA requires direct dietary consumption, with little synthesis from or retroconversion to DPA or EPA. Whereas EPA is also largely derived from direct consumption, EPA can also be synthesized in small amounts from plant (n-3) precursors, especially stearidonic acid. In contrast, DPA appears principally derived from endogenous elongation from EPA, and DPA can also undergo retroconversion back to EPA. In experimental and animal models, both EPA and DHA modulate several relevant biologic pathways, with evidence for some differential benefits. In humans, both fatty acids lower TG levels and, based on more limited studies, favorably affect cardiac diastolic filling, arterial compliance, and some metrics of inflammation and oxidative stress. All three (n-3) PUFA reduce ex vivo platelet aggregation and DHA also modestly increases LDL and HDL particle size; the clinical relevance of such findings is uncertain. Combined EPA+DHA or DPA+DHA levels are associated with lower risk of fatal cardiac events and DHA with lower risk of atrial fibrillation, suggesting direct or indirect benefits of DHA for cardiac arrhythmias (although not excluding similar benefits of EPA or DPA). Conversely, EPA and DPA, but not DHA, are associated with lower risk of nonfatal cardiovascular endpoints in some studies, and purified EPA reduced risk of nonfatal coronary syndromes in one large clinical trial. Overall, for many cardiovascular pathways and outcomes, identified studies of individual (n-3) PUFA were relatively limited, especially for DPA. Nonetheless, the present evidence suggests that EPA and DHA have both shared and complementary benefits. Based on current evidence, increasing consumption of either would be advantageous compared to little or no consumption. Focusing on their combined consumption remains most prudent given the potential for complementary effects and the existing more robust literature on cardiovascular benefits of their combined consumption as fish or fish oil for cardiovascular benefits.
Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over ...theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.
Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.
High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.
In patients with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to reduce glucose concentrations, blood pressure, and weight, but to increase LDL cholesterol and the ...incidence of urogenital infections. Protection against cardiovascular events has also been reported, as have possible increased risks of adverse outcomes such as ketoacidosis and bone fracture. We aimed to establish the effects of SGLT2 inhibitors on cardiovascular events, death, and safety outcomes in adults with type 2 diabetes, both overall and separately for individual drugs.
In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and websites of US, European, and Japanese regulatory authorities from Jan 1, 1950, to Sept 30, 2015, for data from prospective randomised controlled trials assessing the effects of SGLT2 treatment compared with controls. We excluded duplicate reports, trials of compound drugs, trials that lasted 7 days or fewer, trials that did not report on outcomes of interest, and articles that presented pooled trial data for which the individual trials could not be identified. We extracted data in duplicate using a standardised approach. The primary outcome was major adverse cardiovascular events. Secondary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, admission to hospital for unstable angina, heart failure, and all-cause mortality. We estimated summary relative risks with fixed-effects meta-analysis, with the I(2) statistic used to estimate heterogeneity of results beyond chance.
The analyses included data from six regulatory submissions (37 525 participants) and 57 published trials (33 385 participants), which provided data for seven different SGLT2 inhibitors. SGLT2 inhibitors protected against the risk of major adverse cardiovascular events (relative risk 0·84 95% CI 0·75-0·95; p=0·006), cardiovascular death (0·63 0·51-0·77; p<0·0001), heart failure (0·65 0·50-0·85; p=0·002), and death from any cause (0·71 0·61-0·83; p<0·0001). No clear effect was apparent for non-fatal myocardial infarction (0·88 0·72-1·07; p=0·18) or angina (0·95 0·73-1·23; p=0·70), but we noted an adverse effect for non-fatal stroke (1·30 1·00-1·68; p=0·049). We noted no clear evidence that the individual drugs had different effects on cardiovascular outcomes or death (all I(2)<43%). Safety analyses showed consistent increased risks of genital infections (regulatory submissions 4·75 4·00-5·63; scientific reports 2·88 2·48-3·34), but findings for some safety outcomes varied depending on whether anlayses were based on data extracted from regulatory submissions or trials reported in the scientific literature.
These data suggest net protection of SGLT2 inhibitors against cardiovascular outcomes and death. The efficacy results were driven by findings for empagliflozin (the only SGLT2 inhibitor for which data from a dedicated long-term cardiovascular safety trial have been reported), although results for the other drugs in the class were not clearly different. Adverse events were more difficult to quantify than was efficacy, with the effects of individual drugs in the class seeming to differ for some safety outcomes. Results from ongoing studies will be crucial to substantiate these findings across the drug class, but the available data provide a strong rationale to expect benefit from use of SGLT2 inhibitors in patients with type 2 diabetes at high risk of cardiovascular events.
National Health and Medical Research Council of Australia.
Background: Clinical hypomagnesemia and experimental restriction of dietary magnesium increase cardiac arrhythmias. However, whether or not circulating or dietary magnesium at usual concentrations or ...intakes influences the risk of cardiovascular disease (CVD), including fatal ischemic heart disease (IHD), is unclear.Objective: We performed a systematic review and meta-analysis to investigate prospective associations of circulating and dietary magnesium with incidence of CVD, IHD, and fatal IHD.Design: Multiple literature databases were systematically searched without language restriction through May 2012. Inclusion decisions and data extraction were performed in duplicate. Linear dose-response associations were assessed by using random-effects meta-regression. Potential nonlinear associations were evaluated by using restricted cubic splines.Results: Of 2303 articles, 16 studies met the eligibility criteria; these studies comprised 313,041 individuals and 11,995 CVD, 7534 IHD, and 2686 fatal IHD events. Circulating magnesium (per 0.2 mmol/L increment) was associated with a 30% lower risk of CVD (RR: 0.70; 95% CI: 0.56, 0.88 per 0.2 mmol/L) and trends toward lower risks of IHD (RR: 0.83; 95% CI: 0.75, 1.05) and fatal IHD (RR: 0.61; 95% CI: 0.37, 1.00). Dietary magnesium (per 200-mg/d increment) was not significantly associated with CVD (RR: 0.89; 95% CI: 0.75, 1.05) but was associated with a 22% lower risk of IHD (RR: 0.78; 95% CI: 0.67, 0.92). The association of dietary magnesium with fatal IHD was nonlinear (P < 0.001), with an inverse association observed up to a threshold of ∼250 mg/d (RR: 0.73; 95% CI: 0.62, 0.86), compared with lower intakes.Conclusion: Circulating and dietary magnesium are inversely associated with CVD risk, which supports the need for clinical trials to evaluate the potential role of magnesium in the prevention of CVD and IHD.
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