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Effect of Bempedoic Acid on atherogenic lipids and inflammation: A meta-analysis.
Masson, W, Lobo, M, Lavalle-Cobo, A, Molinero, G
Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis. 2021;(3):117-126
Abstract
BACKGROUND Bempedoic acid is a novel non-statin drug that was developed to treat hyperlipidemia in combination with other lipid-lowering drugs in those patients who need additional lipid lowering. OBJECTIVES (1) To investigate the lipid efficacy of bempedoic acid; (2) to analyze the anti-inflammatory effects of bempedoic acid estimated through high sensitivity C-reactive protein (hsCRP). METHODS We performed a meta-analysis including randomized trials of bempedoic acid therapy, reporting low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and hsCRP with a minimum of 4 weeks of follow-up. The primary endpoint was defined as the percentage change in lipids and hsCRP levels measured from baseline to follow-up, comparing groups of subjects on bempedoic acid versus placebo. RESULTS Seven eligible trials of bempedoic acid (3892 patients) were included. The bempedoic acid therapy was associated with a significant reduction in LDL-C levels [-20.3% (CI 95% -23.5 to -17.1)]; I2=43%]. Similarly, a significant percentage reduction in the apolipoprotein B levels [-14.3% (CI 95% -16.4 to -12.1)]; p<0.05; I2=46%], non-HDL-C levels [-15.5% (CI 95% -18.1 to -13.0)]; p<0.05; I2=53%] and hsCRP [-23.4% (CI 95% -32.6 to -14.2)]; p<0.05; I2=69%] was demonstrated with the bempedoic acid use. The sensitivity analysis showed that the results were robust. CONCLUSION Our data suggests that the use of bempedoic acid significantly reduces the levels of all atherogenic lipid markers, including LDL-C, non-HDL-C and apolipoprotein B. Furthermore, considering hsCRP levels, the drug produces an anti-inflammatory effect.
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Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis.
Trieu, K, Bhat, S, Dai, Z, Leander, K, Gigante, B, Qian, F, Korat, AVA, Sun, Q, Pan, XF, Laguzzi, F, et al
PLoS medicine. 2021;(9):e1003763
Abstract
BACKGROUND We aimed to investigate the association of serum pentadecanoic acid (15:0), a biomarker of dairy fat intake, with incident cardiovascular disease (CVD) and all-cause mortality in a Swedish cohort study. We also systematically reviewed studies of the association of dairy fat biomarkers (circulating or adipose tissue levels of 15:0, heptadecanoic acid [17:0], and trans-palmitoleic acid [t16:1n-7]) with CVD outcomes or all-cause mortality. METHODS AND FINDINGS We measured 15:0 in serum cholesterol esters at baseline in 4,150 Swedish adults (51% female, median age 60.5 years). During a median follow-up of 16.6 years, 578 incident CVD events and 676 deaths were identified using Swedish registers. In multivariable-adjusted models, higher 15:0 was associated with lower incident CVD risk in a linear dose-response manner (hazard ratio 0.75 per interquintile range; 95% confidence interval 0.61, 0.93, P = 0.009) and nonlinearly with all-cause mortality (P for nonlinearity = 0.03), with a nadir of mortality risk around median 15:0. In meta-analyses including our Swedish cohort and 17 cohort, case-cohort, or nested case-control studies, higher 15:0 and 17:0 but not t16:1n-7 were inversely associated with total CVD, with the relative risk of highest versus lowest tertile being 0.88 (0.78, 0.99), 0.86 (0.79, 0.93), and 1.01 (0.91, 1.12), respectively. Dairy fat biomarkers were not associated with all-cause mortality in meta-analyses, although there were ≤3 studies for each biomarker. Study limitations include the inability of the biomarkers to distinguish different types of dairy foods and that most studies in the meta-analyses (including our novel cohort study) only assessed biomarkers at baseline, which may increase the risk of misclassification of exposure levels. CONCLUSIONS In a meta-analysis of 18 observational studies including our new cohort study, higher levels of 15:0 and 17:0 were associated with lower CVD risk. Our findings support the need for clinical and experimental studies to elucidate the causality of these relationships and relevant biological mechanisms.
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Bempedoic Acid and Ezetimibe for the Treatment of Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Phase II/III trials.
Bhagavathula, AS, Al Matrooshi, NO, Clark, CCT, Rahmani, J
Clinical drug investigation. 2021;(1):19-28
Abstract
UNLABELLED BACKGROUND AND OBJECTIVE A limited number of trials have evaluated the efficacy of a fixed-dose combination of bempedoic acid and ezetimibe for the treatment of hypercholesterolemia. The aim of this meta-analysis of existing studies was to evaluate the efficacy and safety of fixed-dose bempedoic acid and ezetimibe combination therapy for the treatment of hypercholesterolemia. METHODS A systematic literature search was conducted to identify randomized controlled trials (RCTs) comparing bempedoic acid and ezetimibe, versus placebo or ezetimibe alone, to 30 August 2020. A meta-analysis was conducted to investigate the efficacy of bempedoic acid and ezetimibe on lipid parameters and highly sensitive C-reactive protein (hsCRP) levels in patients with hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Mean differences (MDs) or relative risk (RR) with their corresponding 95% confidence intervals (CIs), using random-effects models, were used to provide pooled estimates. RESULTS A total of three phase II and III RCTs, comprising 388 patients, of whom 49.2% were treated with bempedoic acid and ezetimibe, and 197 controls, were identified. The duration of treatment was 12 weeks. Bempedoic acid and ezetimibe significantly reduced low-density lipoprotein cholesterol (MD - 29.14%, 95% CI - 39.52 to - 18.76; p < .001), total cholesterol (MD - 15.78%, 95% CI - 20.84 to - 10.72; p = 0.01), non-high-density lipoprotein cholesterol (MD - 18.36%, 95% CI - 24.60 to - 12.12; p = 0.01), and hsCRP levels (MD - 30.48%, 95% CI - 44.69 to - 16.28; p = 0.04). No significant effects on triglycerides (MD - 8.35%, 95% CI - 16.08 to - 0.63; p = 0.72) and improvement in high-density lipoprotein cholesterol (MD 1.63%, 95% CI - 4.03 to 7.28; p = 0.92) were observed with the fixed-dose combination therapy. Regarding safety, bempedoic acid and ezetimibe combination was associated with a non-significant increased risk of drug-related adverse events (RR 1.61, 95% CI 0.86-2.35) and overall adverse events (RR 1.16. 95% CI 0.97-1.35); however, the incidence of discontinuation of therapy (RR 0.75, 95% CI 0.35-1.49) was lower. CONCLUSION This review found bempedoic acid and ezetimibe significantly lowered lipid parameters, attenuated hsCRP levels, and had an acceptable safety profile for the treatment of hypercholesterolemia and ASCVD.
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The Effects of Irvingia gabonensis Seed Extract Supplementation on Anthropometric and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.
Lee, J, Chung, M, Fu, Z, Choi, J, Lee, HJ
Journal of the American College of Nutrition. 2020;(5):388-396
Abstract
Background: It has been hypothesized that Irvingia gabonensis can promote weight loss by increasing fatty acid breakdown and inhibiting fatty acid synthesis.Objective: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Irvingia gabonensis seed extract supplementation on weight-related health outcomes.Methods: Literature searches were conducted in 4 databases from January 2018 to identify randomized controlled trials (RCTs) investigating the effects of Irvingia gabonensis seed extract supplementation on anthropometric measures and cardiovascular biomarkers. Two investigators independently performed abstract screenings, full-text screenings, data extraction, and risk of bias (ROB) assessments. Random effects meta-analyses were performed when 3 or more RCTs reported the same outcome.Results: Five RCTs met the eligibility criteria for this systematic review. Four of the 5 RCTs were rated as having a high ROB, and only one RCT was rated as having a low ROB. Random-effects meta-analysis of the 5 RCTs showed that a significant decrease in body weight, body fat, and waist circumference was observed in relation to Irvingia gabonensis seed extract supplementation. However, the only one low-ROB trial did not have significantly different outcomes. Meta-analysis also showed beneficial effects of Irvingia gabonensis seed extract supplementation on total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides. Only the low-ROB trial showed a trend of increasing HDL-cholesterol levels (net percent change = 11.61%; 95% confidence interval (CI: -6.12%, 29.34%) and decreasing triglyceride levels (net percent change = -29%; 95% CI: -76%, 19%). The reported adverse events were minor in these 5 RCTs.Conclusions: Overall efficacy of Irvingia gabonensis seed extract supplementation on weight loss seems positive but is limited due to poor methodological quality and the insufficient reporting of the clinical trials. Further high quality RCTs are needed to determine the effectiveness of Irvingia gabonensis seed extract supplement on the weight-related health outcomes.
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Efficacy and safety of bempedoic acid alone or combining with other lipid-lowering therapies in hypercholesterolemic patients: a meta-analysis of randomized controlled trials.
Zhao, X, Ma, X, Luo, X, Shi, Z, Deng, Z, Jin, Y, Xiao, Z, Tan, L, Liu, P, Jiang, S, et al
BMC pharmacology & toxicology. 2020;(1):86
Abstract
BACKGROUND Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients. METHODS Randomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid. RESULTS A total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), - 18.37, 95% CI, - 20.16 to - 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), - 18.89, 95% CI, - 29.66 to - 8.13, I2 = 87%). But the difference in efficacy between bempedoic acid and ezetimibe was not obvious. Meta-regression analysis showed the treatment duration was a source of heterogeneity (adj R2 = 16.92, 95% CI, 0.04 to 0.72). Furthermore, the background therapy of statin before screening decreased the efficacy of bempedoic acid. In addition, bempedoic acid also resulted in a significant reduction in TC, non-HDL-C, ApoB and hsCRP level. The OR of muscle-related AEs by the combination of bempedoic acid and statin was 1.29 (95% CI, 1.00 to 1.67, I2 = 0) when compared with statin alone. CONCLUSION This study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.
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Circulating Very-Long-Chain Saturated Fatty Acids Were Inversely Associated with Cardiovascular Health: A Prospective Cohort Study and Meta-Analysis.
Liu, M, Zuo, LS, Sun, TY, Wu, YY, Liu, YP, Zeng, FF, Chen, YM
Nutrients. 2020;(9)
Abstract
Saturated fatty acids with different chain lengths have different biological activities, but little is known about very-long-chain saturated fatty acids (VLCSFAs). This study investigated the associations between the circulating VLCSFAs and cardiovascular health. This community-based cohort study included 2198 adults without carotid artery plaques (CAPs) at baseline. The percentage of baseline erythrocyte VLCSFA (arachidic acid (C20:0), behenic acid (C22:0), and lignoceric acid (C24:0)) was measured by gas chromatography. The presence of CAPs was determined at baseline and every 3 years thereafter by ultrasound examination. A meta-analysis was conducted to summarize the pooled associations between circulating VLCSFAs and the risk of cardiovascular diseases (CVDs). During a median of 7.2 years of follow-up, 573 women (35.1%) and 281 men (49.6%) were identified as CAP incident cases. VLCSFAs were inversely related with CAP risk in women (all p-trend <0.05) but not in men. Multivariate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of CAPs for the highest (vs. lowest) quartile were 0.80 (0.63-1.01) for C20:0, 0.71 (0.56-0.89) for C22:0, 0.75 (0.59-0.94) for C24:0, and 0.69 (0.55-0.87) for total VLCSFAs in women. The pooled HRs (95% CIs) of CVDs for the highest (vs. lowest) circulating VLCSFAs from seven studies including 8592 participants and 3172 CVD events were 0.67 (0.57-0.79) for C20:0, 0.66 (0.48-0.90) for C22:0, and 0.57 (0.42-0.79) for C24:0, respectively. Our findings suggested that circulating VLCSFAs were inversely associated with cardiovascular health.
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Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia: Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Di Minno, A, Lupoli, R, Calcaterra, I, Poggio, P, Forte, F, Spadarella, G, Ambrosino, P, Iannuzzo, G, Di Minno, MND
Journal of the American Heart Association. 2020;(15):e016262
Abstract
Background Bempedoic acid (BA) is a novel lipid-lowering drug. We performed a systematic review and meta-analysis on efficacy and safety of BA compared with standard treatment in patients with hypercholesterolemia. Methods and Results Studies were systematically searched in the PubMed, Web of Science, Scopus, and EMBASE databases. Efficacy outcome was represented by percentage changes (mean difference [MD] with pertinent 95% CIs) in total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, and hs-CRP (high-sensitivity C-reactive protein) in BA patients and controls. Seven studies were included (2767 BA-treated patients and 1469 controls), showing a more significant reduction in low-density lipoprotein cholesterol (MD, -17.5%; 95% CI, -22.9% to -12.0%), total cholesterol (MD, -10.9%; 95% CI, -13.3% to -8.5%), non-high-density lipoprotein cholesterol (MD, -12.3%; 95% CI, -15.3% to -9.20%), apolipoprotein B (MD, -10.6%; 95% CI, -13.2% to -8.02%), and hs-CRP (MD, -13.2%; 95% CI, -16.7% to -9.79%) in BA-treated patients compared with controls. Results were confirmed when separately analyzing studies on patients with high cardiovascular risk, studies on statin-intolerant patients, and studies on patients with hypercholesterolemia on maximally tolerated lipid-lowering therapy. BA-treated subjects reported a higher rate of treatment discontinuation caused by adverse effects, of gout flare, and of increase in uric acid compared with controls. On the other hand, BA-treated patients showed a lower incidence of new-onset diabetes mellitus than controls. Conclusions BA is associated with a significant reduction in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP compared with standard treatment. Documented efficacy is accompanied by an acceptable safety profile.
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Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia.
Banach, M, Duell, PB, Gotto, AM, Laufs, U, Leiter, LA, Mancini, GBJ, Ray, KK, Flaim, J, Ye, Z, Catapano, AL
JAMA cardiology. 2020;(10):1124-1135
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Abstract
IMPORTANCE Additional lipid-lowering therapy options are needed for patients who cannot achieve sufficient decreases in low-density lipoprotein cholesterol (LDL-C) levels using statins alone or for those who are statin intolerant. OBJECTIVE To conduct a pooled analysis of phase 3 randomized clinical trials of bempedoic acid vs placebo. DESIGN, SETTING, AND PARTICIPANTS This analysis pooled data from 4 double-blind, placebo-controlled randomized clinical trials conducted from 2016 to 2018. Patients were enrolled in North America and Europe. Eligibility criteria included hypercholesterolemia while receiving stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia and statin intolerance. INTERVENTIONS Patients were randomized 2:1 to bempedoic acid, 180 mg (n = 2425), or placebo (n = 1198) once daily for 12 to 52 weeks. MAIN OUTCOMES AND MEASURES Primary efficacy end point was percentage change from baseline in LDL-C level at week 12 in the intention-to-treat population. Patients were parsed into 2 groups according to enrollment criteria: (1) patients with hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or with heterozygous familial hypercholesterolemia (HeFH) or with both and receiving statins and (2) patients with hypercholesterolemia who were statin intolerant receiving maximally tolerated statins. RESULTS In this analysis of 3623 patients, the overall mean (SD) patient age was 65.5 (9.2) years (similar in both pools). Among patients with ASCVD or HeFH or both, the mean (SD) baseline LDL-C level was 107.6 (32.7) mg/dL. At week 12, the LDL-C level percentage change from baseline was -16.0% with bempedoic acid vs 1.8% with placebo (difference, -17.8%; 95% CI, -19.5% to -16.0%; P < .001). Patients with statin intolerance had a mean (SD) baseline LDL-C level of 144.4 (38.8) mg/dL. The percentage changes in LDL-C levels at week 12 were -23.0% in the bempedoic acid group and 1.5% in the placebo group (difference, -24.5%; 95% CI, -27.8% to -21.1%; P < .001). The decrease in LDL-C levels with bempedoic acid was sustained during long-term follow-up in both pools (patients with ASCVD or HeFH or both receiving a maximally tolerated statin, difference of -12.7% at week 52; patients with statin intolerance, difference of -22.2% at week 24). Decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid vs placebo. Treatment-emergent adverse events associated more frequently with bempedoic acid than with placebo included increased blood uric acid level (2.1% vs 0.5%), gout (1.4% vs 0.4%), decreased glomerular filtration rate (0.7% vs <0.1%), and increased levels of hepatic enzymes (2.8% vs 1.3%). CONCLUSIONS AND RELEVANCE Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels vs placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT02666664, NCT02991118, NCT03001076, and NCT02988115.
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Reduction in saturated fat intake for cardiovascular disease.
Hooper, L, Martin, N, Jimoh, OF, Kirk, C, Foster, E, Abdelhamid, AS
The Cochrane database of systematic reviews. 2020;(8):CD011737
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Abstract
BACKGROUND Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. OBJECTIVES To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. SEARCH METHODS We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. SELECTION CRITERIA Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. DATA COLLECTION AND ANALYSIS Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. MAIN RESULTS We included 15 randomised controlled trials (RCTs) (16 comparisons, 56,675 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.70 to 0.98, 12 trials, 53,758 participants of whom 8% had a cardiovascular event, I² = 67%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 53. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. AUTHORS' CONCLUSIONS The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.
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Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies.
Zhu, Y, Bo, Y, Liu, Y
Lipids in health and disease. 2019;(1):91
Abstract
BACKGROUND Several epidemiological studies have investigated the association between dietary fat intake and cardiovascular disease. However, dietary recommendations based on systematic review and meta-analysis might be more credible. METHODS AND RESULTS Pubmed, Embase and Cochrane library were searched up to July 1st 2018 for cohort studies reporting associations of dietary fat intake and risk of CVDs. By comparing the highest vs. the lowest categories of fat or fatty acids intake, we found that higher dietary trans fatty acids (TFA) intake was associated with increased risk of CVDs [RR:1.14(1.08-1.21)]. However, no association was observed between total fat, monounsaturated fatty acids (MUFA), saturated fatty acids (SFA), and polyunsaturated fatty acids (PUFA), and risk of CVDs. Subgroup analysis found a cardio-protective effect of PUFA in the studies that has been followed up more than 10 years [0.95(0.91-0.99), I2 = 62.4%]. Dose-response analysis suggested that the risk of CVDs increased 16% [1.16 (1.07-1.25), Plinearity = 0.033] for an increment of 2% energy/day of TFA intake. CONCLUSIONS This current meta-analysis of cohort studies suggested that total fat, SFA, MUFA, and PUFA intake were not associated with the risk of cardiovascular disease. However, we found that higher TFA intake is associated with greater risk of CVDs in a dose-response fashion. Furthermore, the subgroup analysis found a cardio-protective effect of PUFA in studies followed up for more than 10 years.