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Lipid-Lowering Agents in Older Individuals: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Ponce, OJ, Larrea-Mantilla, L, Hemmingsen, B, Serrano, V, Rodriguez-Gutierrez, R, Spencer-Bonilla, G, Alvarez-Villalobos, N, Benkhadra, K, Haddad, A, Gionfriddo, MR, et al
The Journal of clinical endocrinology and metabolism. 2019;(5):1585-1594
Abstract
BACKGROUND The efficacy of lipid-lowering agents on patient-important outcomes in older individuals is unclear. METHODS We included randomized trials that enrolled individuals aged 65 years or older and that included at least 1 year of follow-up.Pairs of reviewers selected and appraised the trials. RESULTS We included 23 trials that enrolled 60,194 elderly patients. For primary prevention, statins reduced the risk of coronary artery disease [CAD; relative risk (RR): 0.79, 95% CI: 0.68 to 0.91] and myocardial infarction (MI; RR: 0.45, 95% CI: 0.31 to 0.66) but not all-cause or cardiovascular mortality or stroke. These effects were imprecise in patients with diabetes, but there was no significant interaction between diabetes status and the intervention effect. For secondary prevention, statins reduced all-cause mortality (RR: 0.80, 95% CI: 0.73 to 0.89), cardiovascular mortality (RR: 0.68, 95% CI: 0.58 to 0.79), CAD (RR: 0.68, 95% CI: 0.61 to 0.77), MI (RR: 0.68, 95% CI: 0.59 to 0.79), and revascularization (RR: 0.68, 95% CI: 0.61 to 0.77). Intensive (vs less-intensive) statin therapy reduced the risk of CAD and heart failure. Niacin did not reduce the risk of revascularization, and fibrates did not reduce the risk of stroke, cardiovascular mortality, or CAD. CONCLUSION High-certainty evidence supports statin use for secondary prevention in older individuals. Evidence for primary prevention is less certain. Data in older individuals with diabetes are limited; however, no empirical evidence has shown a significant difference based on diabetes status.
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Assessment of the Role of Niacin in Managing Cardiovascular Disease Outcomes: A Systematic Review and Meta-analysis.
D'Andrea, E, Hey, SP, Ramirez, CL, Kesselheim, AS
JAMA network open. 2019;(4):e192224
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Abstract
IMPORTANCE Niacin remains a therapeutic option for patients with cardiovascular disease, but recent studies have called into question the effectiveness of other drugs that increase high-density lipoprotein cholesterol levels. OBJECTIVE To systematically review and evaluate the evidence supporting current US Food and Drug Administration-approved uses of niacin in cardiovascular disease prevention settings. DATA SOURCES MEDLINE, Embase, Cochrane Controlled Clinical Trial Register (Central), ClinicalTrials.gov, and TrialResults-center, from database inception to October 2017. STUDY SELECTION The systematic review included clinical trials involving niacin as a treatment for cardiovascular disease. The meta-analysis included randomized clinical trials reporting niacin's effect, as exposure, on at least 1 long-term cardiovascular disease outcome. DATA EXTRACTION AND SYNTHESIS Aggregate study-level data were extracted between November 2017 and January 2018 by 3 independent reviewers, and the analysis was performed in February 2018. Inverse-variance weighted methods were used to produce pooled risk ratios using random-effects models for between-study heterogeneity. Random effects-weighted metaregression analysis was used to assess the association of change in high-density lipoprotein cholesterol levels with the log risk ratio of the pooled results. MAIN OUTCOMES AND MEASURES Cardiovascular disease, coronary heart disease mortality, and other cardiovascular events, including acute coronary syndrome, fatal and nonfatal stroke, revascularization, and major adverse cardiac events. RESULTS Of 119 clinical trials, 17 documented niacin's effect on at least 1 cardiovascular disease outcome. The meta-analysis included 35 760 patients with histories of cardiovascular disease or dyslipidemia. Cumulative evidence found no preventive association of niacin with cardiovascular outcomes in secondary prevention. Stratified meta-analysis showed an association of niacin monotherapy with reduction of some cardiovascular events among patients without statin treatment (acute coronary syndrome: relative risk, 0.74; 95% CI, 0.58-0.96; stroke: relative risk, 0.74; 95% CI, 0.59-0.94; revascularization: relative risk, 0.51; 95% CI, 0.37-0.72). These results were mainly derived from 2 trials conducted in the 1970s and 1980s. CONCLUSIONS AND RELEVANCE Niacin may have some use in lipid control for secondary prevention as monotherapy, perhaps in patients intolerant to statins, but evidence is from older studies on a population potentially not representative of current-day patients.
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Definition of a tolerable upper intake level of niacin: a systematic review and meta-analysis of the dose-dependent effects of nicotinamide and nicotinic acid supplementation.
Minto, C, Vecchio, MG, Lamprecht, M, Gregori, D
Nutrition reviews. 2017;(6):471-490
Abstract
CONTEXT Nicotinic acid and nicotinamide are soluble compounds of the vitamin B group, widely used to regulate the lipid profile in hyperlipidemic individuals. Higher doses of nicotinic acid are associated with adverse effects, especially flushing. A unique tolerable upper intake level (UL) of nicotinic acid has not been defined. OBJECTIVE This meta-analysis aims to evaluate adverse effects and their incidence after supplementation with different doses of nicotinic acid and nicotinamide, comparing results with current ULs in Europe and the United States. DATA SOURCES PubMed was searched for articles providing detailed information about nicotinic acid or nicotinamide supplementation and related outcomes. STUDY SELECTION A total of 2670 citations were selected for screening. Two primary outcomes were considered: occurrence of adverse effects following nicotinic acid or nicotinamide supplementation, and dose at which adverse effects occurred. DATA EXTRACTION Details on study population, type and duration of treatment, dosage of vitamins, association with lipid-influencing drugs, length of follow-up, and incidence and type of adverse events were extracted. RESULTS After screening, 47 articles involving 11 741 individuals were included. Meta-analysis was based on estimation of benchmark doses for the probability of adverse effects after supplementation. In individuals with dyslipidemia or cardiovascular disease, nicotinic acid monotherapy seems to be protective against any adverse effects considered, as adverse events occurred at doses above those used with other treatments. In healthy individuals treated with nicotinic acid alone, major adverse effects occurred at doses below 1000 mg/d. CONCLUSIONS Results may indicate a high degree of conservativeness in the UL of nicotinic acid, fixed at 35 mg/d in United States and 10 mg/d in Europe. Reconsideration of the UL of nicotinic acid for nutritional supplements, possibly differentiating between ULs in healthy and unhealthy individuals, may be warranted.
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Niacin is still beneficial. Implications from an updated meta-regression analysis.
Siniawski, D, Santos-Gallego, CG, Badimon, JJ, Masson, WM
Acta cardiologica. 2016;(4):463-72
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Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials.
Goldie, C, Taylor, AJ, Nguyen, P, McCoy, C, Zhao, XQ, Preiss, D
Heart (British Cardiac Society). 2016;(3):198-203
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OBJECTIVE Previous studies have suggested that niacin treatment raises glucose levels in patients with diabetes and may increase the risk of developing diabetes. We undertook a meta-analysis of published and unpublished data from randomised trials to confirm whether an association exists between niacin and new-onset diabetes. METHODS We searched Medline, EMBASE and the Cochrane Central Register of Controlled Trials, from 1975 to 2014, for randomised controlled trials of niacin primarily designed to assess its effects on cardiovascular endpoints and cardiovascular surrogate markers. We included trials with ≥50 non-diabetic participants and average follow-up of ≥24 weeks. Published data were tabulated and unpublished data sought from investigators. We calculated risk ratios (RR) for new-onset diabetes with random-effects meta-analysis. Heterogeneity between trials was assessed using the I(2) statistic. RESULTS In 11 trials with 26 340 non-diabetic participants, 1371 (725/13 121 assigned niacin; 646/13 219 assigned control) were diagnosed with diabetes during a weighted mean follow-up of 3.6 years. Niacin therapy was associated with a RR of 1.34 (95% CIs 1.21 to 1.49) for new-onset diabetes, with limited heterogeneity between trials (I(2)=0.0%, p=0.87). This equates to one additional case of diabetes per 43 (95% CI 30 to 70) initially non-diabetic individuals who are treated with niacin for 5 years. Results were consistent regardless of whether participants received background statin therapy (p for interaction=0.88) or combined therapy with laropiprant (p for interaction=0.52). CONCLUSIONS Niacin therapy is associated with a moderately increased risk of developing diabetes regardless of background statin or combination laropiprant therapy.
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Effect of niacin on lipids and glucose in patients with type 2 diabetes: A meta-analysis of randomized, controlled clinical trials.
Ding, Y, Li, Y, Wen, A
Clinical nutrition (Edinburgh, Scotland). 2015;(5):838-44
Abstract
BACKGROUND & AIMS This study aims to conduct a meta-analysis to evaluate the effects of niacin on serum lipids and glucose in patients with type 2 diabetes mellitus (T2DM). METHODS A comprehensive literature search in Medline, Scopus, AMED, Cochrane and Clinical trial registry databases was performed to identify randomized controlled trials investigating the effect of niacin on serum HDL cholesterol (HDL-c), LDL cholesterol (LDL-c), triglycerides (TG) and fasting plasma glucose (FPG). Pooled effects were measured by weighted mean difference (WMD) using fixed-effects or random-effects models. Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Inter-study heterogeneity was assessed and quantified. RESULTS The estimated pooled mean changes (95% confidence interval) with niacin were 0.27 (95% CI: 0.24 to 0.30; P < 0.001) mmol/L for HDL-c, -0.250 (95% CI: -0.47 to -0.03; P < 0.05) mmol/L for LDL-c and -0.39 (95% CI: -0.43 to -0.34; P < 0.001) mmol/L for TG compared with controls. There was a significant heterogeneity for the impact of niacin on LDL-c and FPG. Subgroup analyses revealed a significant increase in FPG 0.085 (95% CI: 0.029 to 0.141; P < 0.05) mmol/L compared with controls in patients with long term treatment. Our analysis also showed the absence of publication bias and any dose-response relations between niacin and effect size. CONCLUSIONS Analysis of the results showed that niacin alone or in combination significantly improved lipid abnormalities in patients with TDM, but requires monitoring of glucose in long term treatment.
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Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients.
Keene, D, Price, C, Shun-Shin, MJ, Francis, DP
BMJ (Clinical research ed.). 2014;:g4379
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OBJECTIVE To investigate the effects on cardiovascular outcomes of drug interventions that increase high density lipoprotein levels. DESIGN Meta-analysis. STUDIES REVIEWED Therapeutic benefit of niacin, fibrates, and cholesteryl ester transfer protein (CETP) inhibitors on cardiovascular events (all cause mortality, coronary heart disease mortality, non-fatal myocardial infarction, and stroke). RESULTS 117,411 patients were randomised in a total of 39 trials. All interventions increased the levels of high density lipoprotein cholesterol. No significant effect was seen on all cause mortality for niacin (odds ratio 1.03, 95% confidence interval 0.92 to 1.15, P=0.59), fibrates (0.98, 0.89 to 1.08, P=0.66), or CETP inhibitors (1.16, 0.93 to 1.44, P=0.19); on coronary heart disease mortality for niacin (0.93, 0.76 to 1.12, P=0.44), fibrates (0.92, 0.81 to 1.04, P=0.19), or CETP inhibitors (1.00, 0.80 to 1.24, P=0.99); or on stroke outcomes for niacin (0.96, 0.75 to 1.22, P=0.72), fibrates (1.01, 0.90 to 1.13, P=0.84), or CETP inhibitors (1.14, 0.90 to 1.45, P=0.29). In studies with patients not receiving statins (before the statin era), niacin was associated with a significant reduction in non-fatal myocardial infarction (0.69, 0.56 to 0.85, P=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect (0.96, 0.85 to 1.09, P=0.52). A significant difference was seen between these subgroups (P=0.007). A similar trend relating to non-fatal myocardial infarction was seen with fibrates: without statin treatment (0.78, 0.71 to 0.86, P<0.001) and with all or some patients taking statins (0.83, 0.69 to 1.01, P=0.07); P=0.58 for difference. CONCLUSIONS Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.
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Effect of niacin on endothelial function: a systematic review and meta-analysis of randomized controlled trials.
Sahebkar, A
Vascular medicine (London, England). 2014;(1):54-66
Abstract
Endothelial dysfunction is an independent predictor of incident atherosclerotic cardiovascular disease (ACVD). Niacin possesses high-density lipoprotein (HDL)-elevating, antioxidant and anti-inflammatory properties, all potentially contributing to the amelioration of endothelial function. However, controversies exist among trials reporting the effects of niacin on endothelium-dependent flow-mediated dilation (FMD) as a reliable surrogate of endothelial function. The objective of this study was to assess the effect of niacin on brachial artery FMD using a meta-analysis of available evidence. MEDLINE and Scopus databases were searched for randomized controlled trials investigating the impact of niacin therapy on brachial artery FMD. Meta-analysis of eligible studies was conducted using a random-effects model. Pooled effects were measured by weighted mean difference (WMD) and 95% confidence intervals (CIs). Quality assessment, and subgroup, meta-regression and sensitivity analyses were conducted using standard methods. Among 596 citations, 19 full-text articles were read and seven were found to be eligible for inclusion. Eligible studies involved 441 subjects comprising 228 in the niacin and 213 in the control groups. Niacin therapy significantly improved FMD (WMD: 1.98%; 95% CI: 0.91-3.05%; p = 0.0003) and this effect was robust in the sensitivity analysis. The effect size was greater in the subgroup of studies administering higher doses of niacin (≥ 2000 mg/day) as well as those studies administering niacin for primary prevention of ACVD. Meta-regression indicated no association between niacin-induced changes in FMD and changes in plasma HDL-cholesterol, low-density lipoprotein-cholesterol or triglycerides. None of the included studies could find any significant effect of niacin on nitroglycerin-mediated dilation. In conclusion, treatment with niacin improves endothelial function.
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Through the looking-glass of conventional meta-regression: an alternative approach based on fractional polynomials to a meta-analysis of niacin.
Takagi, H, Umemoto, T
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2013;(6):e23-5
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The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
Lavigne, PM, Karas, RH
Journal of the American College of Cardiology. 2013;(4):440-446
Abstract
OBJECTIVES This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial. BACKGROUND Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy. METHODS Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events. RESULTS Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes. CONCLUSIONS The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.