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Role of Niacin in Current Clinical Practice: A Systematic Review

Published:October 25, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.07.038

      Abstract

      Background

      Niacin, a potent high-density lipoprotein cholesterol-raising drug, seems an attractive approach to reduce cardiac events in patients with or at risk of atherosclerotic cardiovascular disease. However, previous evidence for niacin has been challenged recently by negative outcomes in 2 large, randomized, controlled trials comparing niacin to placebo with background statin therapy. We studied the currently available evidence for the role of niacin treatment for reducing the risk of cardiovascular events in current practice.

      Methods

      A systematic review of randomized controlled trials in the MEDLINE, EMBASE, CINAHL, and Cochrane databases comparing niacin alone or combined with statin therapy was performed. We extracted trial level data, including basic characteristics and number of patients enrolled, duration of follow up, occurrence of adverse events, and cardiovascular-related outcomes. Random effects meta-analysis was conducted to estimate the risk ratio (RR) for individual trial endpoints.

      Results

      Thirteen trials (N = 35,206) were selected for final analysis. The mean follow-up duration was 32.8 months. Overall, niacin led to significant increases in serum high-density lipoprotein cholesterol levels from baseline trial enrolment by 21.4%, 9.31 (95% confidence interval [CI] 5.11-13.51) mg/dL. However, we did not observe any differences in all-cause mortality rates (RR 0.99; 95% CI 0.88-1.12) between niacin and control arms. Further, niacin treatment was associated with a trend toward lower risk of cardiovascular mortality (RR 0.91; 95% CI 0.81-1.02), coronary death (RR 0.93; 95% CI 0.78-1.10), nonfatal myocardial infarction (RR 0.85; 95% CI 0.73-1.0), revascularization (coronary and noncoronary) (RR 0.83; 95% CI 0.65-1.06), and stroke (RR 0.89; 95% CI 0.72-1.10), compared with control.

      Conclusion

      Niacin therapy does not lead to significant reductions in total or cause-specific mortality or recurrent cardiovascular events among persons with or at risk of atherosclerotic cardiovascular disease.

      Keywords

      Clinical Significance
      • Niacin therapy leads to a significant increase in high-density lipoprotein cholesterol levels.
      • Among patients with or at high-risk of atherosclerotic cardiovascular disease, niacin does not reduce mortality.
      • Treatment with niacin is not associated with significant reduction in recurrent cardiovascular events such as myocardial infarction, stroke, or revascularizations.
      • Niacin is associated with increased risk of new-onset or worsening diabetes or skin, gastrointestinal, and musculoskeletal adverse effects.
      Atherosclerotic cardiovascular disease (ASCVD) remains a huge burden on global health, despite decades of focused research and intervention.
      Executive summary: heart disease and stroke statistics-2015 update: a report from the American Heart Association.
      In large epidemiologic studies and subsequent analyses, low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels have been independently associated with an increased risk of cardiovascular disease (CVD).
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      Cholesterol and lipids in the risk of coronary artery disease—the Framingham Heart Study.
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      Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease.
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      The causal association of LDL-C with cardiovascular risk has been well validated in large, randomized, controlled trials.
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      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      In meta-analyses of patient-level data from statin trials, the Cholesterol Treatment Trialists' collaborators group observed a 5%-6% reduction in vascular events for every 10-mg/dL decrease in serum LDL-C levels.
      Cholesterol Treatment Trialist (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
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      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      On the basis of these and other findings, major international cardiology and lipid associations recommend statins as the first-line agent for managing dyslipidemia as a risk factor for ASCVD.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      • Jacobson T.A.
      • Ito M.K.
      • Maki K.C.
      • et al.
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—executive summary.
      However, withstanding significant interindividual variations in response seen with statin therapy,
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      guidelines recommend that the utilization of beneficial nonstatin drugs may be considered in patients with intolerance or less than anticipated response to statins.
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      Furthermore, there are accumulating data that despite aggressive LDL-C targeted therapy with high-intensity statins, residual cardiovascular burden persists.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
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      • et al.
      Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
      Several studies have shown an independent prognostic value of HDL-C levels with a strong inverse relation to HDL-C with incident major cardiac events, even among patients achieving very low levels of LDL-C with statin therapy.
      • Barter P.
      • Gotto A.M.
      • LaRosa J.C.
      • et al.
      HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
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      • Karas R.H.
      Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk.
      • Acharjee S.
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      • Hartigan P.M.
      • et al.
      Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post-hoc analysis from the COURAGE trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation).
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      • Yaari S.
      • Medalie J.H.
      Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: a 21-year follow-up of 8000 men.
      • Stampfer M.J.
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      • Hennekens C.H.
      A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction.
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      • Robins S.J.
      • Collins D.
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.
      Thus, targeting HDL-C has been proposed as a potential approach to mitigate a sizeable residual risk of CVD. In clinical use for the past several decades, niacin is one of the most effective agents currently available to increase serum levels of HDL-C.
      • Kamanna V.S.
      • Kashyap M.L.
      Mechanism of action of niacin.
      It exerts multiple other lipid-modulating effects, including decreases in total cholesterol (TC), LDL-C, triglycerides, and lipoprotein (a) levels. In addition, in prior studies niacin has been shown to significantly reduce cardiovascular events.
      The Coronary Drug Project Research Group
      Clofibrate and niacin in coronary heart disease.
      • Taylor A.J.
      • Sullenberger L.E.
      • Lee H.J.
      • Lee J.K.
      • Grace K.A.
      Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
      However, 2 recent clinical trials have demonstrated an increase in adverse events with no ischemic benefit (coronary events, stroke, or revascularization) with the addition of niacin to effective statin therapy.
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      A.I.M.-H.I.G.H. Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      Thus, in the present meta-analysis, we specifically investigated the cumulative evidence for the effects of niacin on different serum cholesterol fractions and several clinical endpoints.

      Methods

      Study Selection

      We performed a systematic literature search for studies testing niacin in comparison with a control agent in the MEDLINE, EMBASE, EBSCO, CINAHL, Web of Science, and Cochrane databases. The review was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      The PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Key words of interest were “niacin,” “nicotinic acid,” “HDL-C,” “cardiovascular,” and “randomized trial,” used in different combinations. The search period was restricted from January 1969 to October 30, 2015. The following criteria were applied for study inclusion: 1) randomized, controlled design with one treatment arm as niacin and the other arm as placebo or other lipid-lowering therapies; 2) median follow-up of at least 6 months; and 3) reporting change in lipid fractions or at least one clinical endpoint at follow-up.

      Data Extraction

      Two independent reviewers (A.S., A.G.) screened the titles and abstracts for relevance. Discrepancies between reviewers were discussed until consensus was reached. The manuscripts of selected titles/abstracts were reviewed for inclusion. Using our selection criteria, these 2 reviewers independently determined the articles to be included, and data from the relevant articles were extracted using predefined extraction forms. The data elements collected for each study were first author, year of publication, sample size in each study and in different treatment arms, treatment in interventional and control arms, duration of follow-up, baseline characteristics, baseline and final levels of LDL-C, HDL-C, and TC, adverse events, and clinical endpoints. Prespecified outcomes of interest were 1) all-cause mortality; 2) cardiovascular mortality (defined as death from coronary heart disease [acute myocardial infarction, sudden death, or ischemic heart failure event], ischemic stroke, or revascularization procedures); 3) coronary heart disease death; 4) myocardial infarction; 5) revascularization (including coronary and noncoronary [peripheral arterial or cerebrovascular] procedures); and 6) cerebrovascular accidents. In addition, data for the following adverse events of clinical significance with niacin were collected: 1) new-onset diabetes or worsening glucose tolerance in patients with pre-existing diabetes; 2) gastrointestinal side effects (abdominal pain, nausea, dyspepsia, diarrhea); 3) liver toxicity (transaminases >3 upper limits normal); 4) musculoskeletal events (myositis with creatine kinase elevation); and 5) skin flushing.

      Statistical Analysis

      Statistical analyses were performed according to the recommendations from the Cochrane Collaboration using Review Manager version 5.1 (2008; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). We conducted meta-analysis using the random-effects model of DerSimonian and Laird with inverse variance weighting. For each clinical endpoint, pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to assess the treatment effects of niacin compared with control/usual care. The pooled effect of niacin on different lipid fractions (TC, LDL-C, and HDL-C) was also estimated. Heterogeneity between studies was assessed using Cochrane's Q test and the I2 statistic, which denotes the percentage of total variation across studies that is a result of heterogeneity rather than chance. Heterogeneity was considered significant if the P value was <.05.

      Results

      Study Characteristics

      The initial search identified a total of 1296 publications that were screened at the abstract level. Among these, 13 randomized clinical trials met the aforementioned inclusion criteria and were included in the final analysis (Figure 1). These studies included a total of 35,206 patients (with or at-risk of ASCVD), with 16,858 randomized to the niacin arm and 18,348 to the control arm. The mean duration of follow-up was 32.8 months (range, 6-74 months).
      Figure thumbnail gr1
      Figure 1The PRISMA flow chart for the trial selection process.
      Baseline characteristics of subjects and included studies are shown in Tables 1 and 2, respectively. Patients included in the final analysis had a mean age of 58 years, and 81% were male. Five studies used placebo as the control arm,
      The Coronary Drug Project Research Group
      Clofibrate and niacin in coronary heart disease.
      • Kane J.P.
      • Malloy M.J.
      • Ports T.A.
      • Phillips N.R.
      • Diehl J.C.
      • Havel R.J.
      Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.
      • Blankenhorn D.H.
      • Nessim S.A.
      • Johnson R.L.
      • Sanmarco M.E.
      • Azen S.P.
      • Cashin-Hemphill L.
      Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
      • Brown G.
      • Albers J.J.
      • Fisher L.D.
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      • Whitney E.J.
      • Krasuski R.A.
      • Personius B.E.
      • et al.
      A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events.
      whereas 8 studies used either a statin or ezetimibe or “conventional” treatment in the control arm.
      • Taylor A.J.
      • Sullenberger L.E.
      • Lee H.J.
      • Lee J.K.
      • Grace K.A.
      Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      A.I.M.-H.I.G.H. Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      • Carlson L.A.
      • Rosenhamer G.
      Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
      • Brown B.G.
      • Xue-Qiao Z.
      • Chait A.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      • Taylor A.J.
      • Villines T.C.
      • Stanek E.J.
      • et al.
      Extended-release niacin or ezetimibe and carotid intima-media thickness.
      • Guyton J.R.
      • Brown B.G.
      • Fazio S.
      • Polis A.
      • Tomassini J.E.
      • Tershakovec A.M.
      Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia.
      • Sang Z.C.
      • Wang F.
      • Zhou Q.
      • et al.
      Combined use of extended-release niacin and atorvastatin: safety and effects on lipid modification.
      Table 1Baseline Patient Characteristics in the Included Studies
      StudyNNiacin (n)Control (n)Follow-Up (mo)Age (y)Male (%)DM (%)HTN (%)BL LDL-C (mg/dl)Final LDL-C (mg/dl)BL HDL-C (mg/dl)Final HDL-C (mg/dl)
      CDP390811192789604410040NANANANANA
      CLAS188949424541000391719744.660.8
      STOCKHOLM5552792766060803NANANANANA
      USCF-SCOR724049264243NA152831724759
      FATS10048523047100NA361901293955
      HATS6733343653871649132753140
      ARBITER 21497871126791277587853947
      AFREGS1437172306392NA711261113447
      GUYTON6043912136575016641576550.566
      SANG10852561271613467106764963
      ARBITER 6-HALTS20897111146580358580.570.542.550.0
      AIM-HIGH3414171816963664853471746534.544.0
      HPS2-THRIVE25,67312,82812,83543658332NA64544450
      AFREGS = Armed Forces Regression Study; AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; ARBITER 2 = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; ARBITER 6-HALTS = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies; BL = baseline; CDP = Coronary Drug Project; CLAS = Cholesterol-Lowering Atherosclerosis Study; DM = diabetes mellitus; FATS = Familial Atherosclerosis Treatment Study; HATS = HDL-Atherosclerosis Treatment Study; HDL-C = high-density lipoprotein cholesterol; HPS2-THRIVE = Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events; HTN = hypertension; LDL-C = low-density lipoprotein cholesterol; UCSF-SCOR = University of California, San Francisco, Arteriosclerosis Specialized Center of Research.
      Table 2Baseline Characteristics of Included Studies
      StudyDesignIntervention ArmControl ArmInclusion CriteriaExclusion CriteriaPrimary Endpoint
      CDP (1975)Randomized, double-blind, multicenterNiacinLactose placebo1) History of documented MI before >3 mo;

      2) Age 30-64 y;

      3) Male gender
      1) NYHA >2;

      2) Not worsening of coronary disease or major illnesses
      All-cause mortality
      CLAS (1987)Randomized, double-blind, single centerNiacin + colestipolPlacebo1) Documented CAD with CABG >3 mo;

      2) Age 40-59 y;

      3) Male gender;

      4) Nonsmokers;

      5) Total cholesterol

      185-350 mg/dL
      1) Diabetes mellitus;

      2) Uncontrolled hypertension (diastolic blood pressure >115 mm Hg);

      3) Thyroid disease;

      4) Renal insufficiency;

      5) Fasting blood immunosuppressive levels >500 mg/dL;

      6) Congestive heart failure;

      7) Major arrhythmia;

      8) QRS width >0.12 s;

      9) Weight exceeding 1.5× ideal weight
      Angiographic evaluation of atherosclerosis
      STOCKHOLM (1988)Randomized, unblinded, single centerNiacin + clofibrateConventional treatment1) Consecutive survivors to myocardial infarction

      2) Age <70 y
      1) Insulin-dependent diabetes;

      2) Myocardial insufficiency, grade 4 NYHA;

      3) Diastolic blood pressure >120 mm Hg;

      4) Extreme hyperlipidemia requiring treatment;

      5) Kidney or liver failure;

      6) Malignant disease;

      7) Disabling diseases;

      8) Other complicating diseases;

      9) Psychosocial reasons
      Total plus ischemic heart disease mortality
      FATS (1990)Randomized, double-blind, multicenterNiacin + colestipolPlacebo + colestipol1) Documented CAD with >50% stenosis;

      2) Apo-B >125 mg/dL;

      3) Family history of CAD;

      4) Age <62 y
      1) Diabetes;

      2) Uncontrolled hypertension;

      3) Liver disease;

      4) Renal disease;

      5) Thyroid disease;

      6) Declined participation
      Change in severity of disease in proximal coronary arteries
      UCSF-SCOR (1990)Randomized, multicenterNiacin + colestipolPlacebo ± colestipol1) Documented coronary stenosis >10%;

      2) Heterozygous familial hypercholesterolemia with xanthomas, LDL >200 mg/dL

      3) Triglycerides <275 mg/dL;

      4) Age 18-72 y
      1) Previous CABG; PCI; multiple infarcts;

      2) Planned revascularization for unstable lesions;

      3) Systemic disease other than atherosclerosis or hypertension
      Mean change in percent area stenosis
      HATS (2001)Randomized, double-blind, single centerNiacin + simvastatinPlacebo1) Documented coronary disease with >3 stenosis of 30% or 1 stenosis 50%;

      2) HDL <35/40 mg/dL for male/female;

      3) LDL <145 mg/dL;

      4) TG <400 mg/dL;

      5) Age <63 y
      1) Previous CABG;

      2) Uncontrolled hypertension;

      3) Uncontrolled DM;

      4) Renal disease;

      5) Thyroid disease
      Mean change in percent stenosis of most severe coronary artery; time to first composite CVD event
      ARBITER 2 (2004)Randomized, double-blind, single centerNiacin ER + statinStatin1) Documented CAD;

      2) Age >30 y;

      3) Stable statin treatment;

      4) LDL <130 mg/dL;

      5) HDL <45 mg/dL
      1) Liver disease or transaminases >3 ULN;

      2) Known niacin intolerance
      Change in CIMT
      AFREGS (2005)Randomized, double-blind, single centerNiacin + gemfibrozilPlacebo1) Documented CAD with 1 angiographic stenosis 30%-80% or >80% with negative treadmill test;

      2) Age <76 y;

      3) LDL <160 mg/dL;

      4) HDL <45 mg/dL
      1) Unstable CAD or cardiovascular event within 6 mo;

      2) EF <40%;

      3) Uncontrolled hypertension;

      4) Diabetes;

      5) Cardiac immunosuppressive;

      6) Thyroid disease;

      7) Liver disease;

      8. Creatinine >2 mg/dL;

      9) Concomitant therapy with heparin, CCS, or immunosuppressive
      Change in global angiographic stenosis
      Guyton et al (2008)Randomized, multicenterNiacin + simvastatin + ezetimibeSimvastatin + ezetimibe1) Hyperlipidemia type Iia or Iib (LDL 130-190 mg/dL; triglycerides <500 mg/dL);

      2) Age 18-79 y
      1) Metabolic or clinical instability;

      2) Thyroid disease;

      3) Creatinine >2 mg/dL;

      4) CK >2× ULN;

      5) Transaminases >1.5× ULN
      NA
      SANG (2009)Randomized, single centerNiacin ER + atorvastatinAtorvastatin1) At least 50% stenosis of one coronary artery;

      2) High total cholesterol (>3.5 mmol/L)
      1) Serious hepatic or kidney diseases;

      2) Hemodynamic instability;

      3) Tumor with an expected survival time of less than 1 y;

      4) Known intolerance or allergy to niacin or statins;

      5) Administration of lipid-lowering drugs within the month before the inclusion
      NA
      ARBITER 6-HALTS (2009)Randomized, open-label, multicenterNiacin + any statinEzetimibe + any statin1) Documented CAD or CAD equivalent

      2) Statin therapy >3 mo;

      3) LDL <100 mg/dL;

      4) HDL <50/55 mg/dL for male/female);

      5) Age >30 y
      NAChange in CIMT
      AIM-HIGH (2011)Randomized, double-blind, multicenterNiacin + simvastatinSimvastatin1) Documented CAD or PAD or cerebrovascular disease;

      2) HDL <40/50 mg/dL male/female

      3) LDL <180 mg/dL without statin therapy or “adjusted” level in statin therapy

      4) Triglycerides <400 mg/dL;

      5) Age >45 y
      1) Acute coronary event within 4 wk;

      2) Coronary revascularization within 4 wk or planned;

      3) Stroke within 8 wk;

      4) Fasting glucose >180;

      5) EF <30%;

      6) AST/ALT >2 ULN;

      7) CKD (creatinine >2.5 mg/dL);

      8) Concomitant drugs with increased risk of hepatotoxicity or myopathy
      Composite of CVD events
      Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization (for >23 h) for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.
      HPS2-THRIVE (2013)Randomized, double-blind, multicenterNiacin ER+ larpopirant + simvastatinSimvastatin1) History of MI, stroke/TIA; PAD or DM with other symptoms of CAD;

      2) Age 50-80 y
      1) Cardiovascular event within 3 mo or planned revascularization;

      2) Liver disease or transaminase >1.5× ULN;

      3) Creatinine >2 mg/dL;

      4) Myositis or CK >3× ULN;

      5) Treatment with other statin or simvastatin >40 mg/d
      Major vascular events
      Major coronary event (nonfatal myocardial infarction or death from coronary causes), stroke of any type, or coronary or noncoronary revascularization.
      For full trial names, see Table 1 footnote.
      ALT = alanine transaminase; AST = aspartate transaminase; CABG = coronary artery bypass graft; CAD = coronary artery disease; CCS = corticosteroids; CIMT = carotid intimal media thickness; CK = creatine kinase; CKD = chronic kidney disease; DM = diabetes mellitus; EF = ejection fraction; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; MI = myocardial infarction; NYHA = New York Heart Association; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention; TG = triglyceride; TIA = transient ischemic attack; ULN = upper limit of normal.
      Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization (for >23 h) for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.
      Major coronary event (nonfatal myocardial infarction or death from coronary causes), stroke of any type, or coronary or noncoronary revascularization.

      Clinical Outcomes

      Results of the clinical outcomes with niacin versus control are summarized in Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7 and Table 3. Among the 34,810 subjects in 11 studies, 2841 patients (8.2%) died from any cause (Figure 2). We failed to observe any differences in all-cause mortality rates (RR 0.99; 95% CI 0.88-1.12) between the niacin and control arms, and there was no significant heterogeneity between the included studies for this endpoint (I2 = 31.1%).
      Figure thumbnail gr2
      Figure 2Forest plot showing effect of niacin on risk of all-cause mortality. CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Figure thumbnail gr3
      Figure 3Forest plot showing effect of niacin on risk of cardiovascular (CV) mortality. CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Figure thumbnail gr4
      Figure 4Forest plot showing effect of niacin on coronary death. CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Figure thumbnail gr5
      Figure 5Forest plot showing effect of niacin on myocardial infarction (MI). CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Figure thumbnail gr6
      Figure 6Forest plot showing effect of niacin on revascularization rates. CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Figure thumbnail gr7
      Figure 7Forest plot showing effect of niacin on stroke. CI = confidence interval; RR = risk ratio. For full trial names, see footnote.
      Table 3Outcomes in Niacin Group Compared with Control
      OutcomeNiacin (n = 16,858)Control (n = 18,348)Risk ratio (95% confidence interval)PinteractionHeterogeneity (I2) (%)
      All-cause mortality1230/16,6671611/18,1430.99 (0.88-1.12).18031
      Cardiovascular mortality339/3880759/53560.91 (0.81-1.02).4280.1
      Coronary death590/15,947933/17,5960.93 (0.78- 1.10).08355
      Myocardial infarction660/16,296974/17,9550.85 (0.73-1.0).18828.9
      Revascularization987/14,9321101/14,9100.83 (0.65-1.06).09842
      Cerebrovascular events599/14,385818/16,0430.89 (0.72-1.10).19234.4
      Cardiovascular mortality was reported in 1095 patients (11.8%) among 9 trials involving 9236 patients (Figure 3). Four trials, including 33,543 subjects, reported coronary death as a separate endpoint in 1523 patients (4.5%) (Figure 4). Compared with the control arm, niacin did not result in a significant reduction in cardiovascular related mortality (RR 0.91; 95% CI 0.81-1.02) or coronary death (RR 0.93; 95% CI 0.78-1.10).
      Nine studies involving 34,251 patients reported the frequency of myocardial infarction (Figure 5). Among these, 1634 patients (4.8%) experienced this event. Niacin treatment was associated with a nonsignificant reduction in nonfatal myocardial infarction (RR 0.85; 95% CI 0.73-1.0). A total of 2088 patients (7%) underwent revascularization procedures among 29,842 patients across 8 studies (Figure 6). Niacin did not result in a significant risk reduction for revascularization (RR 0.83; 95% CI 0.65-1.06). Similarly, among 1417 cerebrovascular events (4.6%) in 30,428 patients, randomization to niacin did not affect this outcome (RR 0.89; 95% CI 0.72-1.10) (Figure 7). Finally, there was no significant heterogeneity between the included studies for each of the endpoints examined.

      Effects on Adverse Events

      Results for adverse events with niacin as compared with control are summarized in Figure 8, Figure 9, Figure 10, Figure 11, Figure 12. Among 4 studies reporting diabetes as an adverse event, patients assigned to niacin therapy were at significantly increased risk for this metabolic disorder compared with control (RR 1.44; 95% CI 1.31-1.59). Treatment with niacin was associated with a cumulative higher risk of gastrointestinal (RR 1.53; 95% CI 1.23-1.90) and musculoskeletal adverse events (RR 1.24; 95% CI 1.09-1.42), as compared with the respective control arms. Subjects receiving niacin therapy experienced a significantly higher risk of skin flushing (RR 18.59; 95% CI 2.52-137.29), whereas the risk of liver toxicity was not significantly elevated (RR 1.66; 95% CI 0.65-4.27) compared with those in the respective control groups.
      Figure thumbnail gr8
      Figure 8Forest plot showing effect of niacin on new-onset or worse control of pre-existing diabetes mellitus (DM). CI = confidence interval; M-H = Mantel-Haenszel. For full trial names, see footnote.
      Figure thumbnail gr9
      Figure 9Forest plot showing effect of niacin on gastrointestinal (GI) adverse events. CI = confidence interval; M-H = Mantel-Haenszel. For full trial names, see footnote.
      Figure thumbnail gr10
      Figure 10Forest plot showing effect of niacin on musculoskeletal adverse events. CI = confidence interval; M-H = Mantel-Haenszel. For full trial names, see footnote.
      Figure thumbnail gr11
      Figure 11Forest plot showing effect of niacin on skin flushing. CI = confidence interval; M-H = Mantel-Haenszel. For full trial names, see footnote.
      Figure thumbnail gr12
      Figure 12Forest plot showing effect of niacin on liver toxicity. CI = confidence interval; M-H = Mantel-Haenszel. For full trial names, see footnote.

      Effects on Serum Lipoproteins

      Overall, niacin therapy resulted in a nonsignificant decrease in serum levels of TC (0.39 [95% CI 0.20, 0.98]) and LDL-C (0.43 [95% CI 0.05, 0.91]). There was a significant increase in levels of HDL-C from baseline by 21.4%, 9.31 (95% CI 5.11, 13.51) mg/dL, (0.67 [95% CI 0.86, 0.47]) with niacin compared with the control group.

      Discussion

      Our results showed that the addition of niacin to statin therapy was associated with a significant increase in serum levels of HDL-C and nonsignificant decreases in TC and LDL-C compared with placebo. However, niacin therapy did not lead to significant reductions in all-cause mortality, cardiovascular-related mortality, myocardial infarction, revascularization, or stroke among patients with established or at-high risk of ASCVD.
      Despite the widespread use of statins as first-line therapy, patients with established ASCVD remain at increased risk for adverse cardiovascular events.
      Cholesterol Treatment Trialist (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      In the Framingham study cohort, an inverse relation between serum levels of HDL-C and cardiovascular events was observed.
      • Gordon T.
      • Castelli W.P.
      • Hjortland M.C.
      • Kannel W.B.
      • Dawber T.R.
      High-density lipoprotein as a protective factor against coronary heart disease: the Framingham Study.
      This was further supported by evidence from various clinical studies, which reported an improvement in both surrogate markers of atherosclerosis and the frequency of cardiovascular events with niacin, one of the most effective HDL-C–raising drugs.
      The Coronary Drug Project Research Group
      Clofibrate and niacin in coronary heart disease.
      • Taylor A.J.
      • Sullenberger L.E.
      • Lee H.J.
      • Lee J.K.
      • Grace K.A.
      Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
      • Taylor A.J.
      • Villines T.C.
      • Stanek E.J.
      • et al.
      Extended-release niacin or ezetimibe and carotid intima-media thickness.
      However, in the “statin era,” an independent relation of HDL-C with decreased cardiovascular risk has been difficult to demonstrate.
      • Ray K.K.
      • Cannon C.P.
      • Cairns R.
      • Morrow D.A.
      • Ridker P.M.
      • Braunwald E.
      Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: results from PROVE IT-TIMI 22.
      • Ridker P.M.
      • Genest J.
      • Boekholdt S.M.
      • et al.
      HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial.
      Two large clinical trials, AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) and HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events), testing niacin in addition to background statin therapy, failed to show any reduction in cardiovascular events.
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      A.I.M.-H.I.G.H. Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      To our knowledge the present meta-analysis is the largest to date, comprising 13 trials and including 35,206 patients with or at-risk of ASCVD. Because of heterogeneity in the definition and classification of the primary endpoint among the various trials included, we undertook pooling of individual endpoints to detect meaningful differences in outcomes. Our results showed no significant effect on several important clinical outcomes with the addition of niacin therapy. The Coronary drug project (1975), a 6-year prospective trial randomizing patients with established coronary artery disease to either niacin or placebo, showed lower incidence of myocardial infarction among patients on niacin.
      The Coronary Drug Project Research Group
      Clofibrate and niacin in coronary heart disease.
      Furthermore, the 15-year follow-up of the Coronary drug project trial demonstrated that niacin was associated with benefits on long-term survival despite discontinuation after 5 years, thereby suggesting an alteration of ischemic risk.
      • Canner P.L.
      • Berge K.G.
      • Wenger N.K.
      • et al.
      Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
      Subsequent randomized controlled trials were not adequately powered to detect significant differences in individual endpoints.
      • Blankenhorn D.H.
      • Nessim S.A.
      • Johnson R.L.
      • Sanmarco M.E.
      • Azen S.P.
      • Cashin-Hemphill L.
      Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
      • Brown G.
      • Albers J.J.
      • Fisher L.D.
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      • Carlson L.A.
      • Rosenhamer G.
      Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
      With the advent of widespread statin use, the AIM-HIGH and HPS2-THRIVE trials investigated the strategy of niacin in patients already receiving effective statin therapy.
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      A.I.M.-H.I.G.H. Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      The AIM-HIGH study, which enrolled patients with stable CHD with low levels of mean baseline LDL-C (74 mg/dL) and HDL-C (35 mg/dL) on statin treatment, found no significant decrease in cardiovascular events with niacin-statin combination despite a significant increase in HDL-C levels, as compared with the statin-only group.
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      A.I.M.-H.I.G.H. Investigators
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      In the multicenter HPS2-THRIVE study, which randomized more than 25,000 patients with stable cardiovascular disease receiving effective lipid-lowering therapy to niacin plus statin combination therapy or statins only over a mean follow-up of 3.6 years, the combination therapy with extended-release niacin and statin failed to significantly reduce the risk of major vascular events.
      • Landray M.J.
      • Haynes R.
      • Hopewell J.C.
      • et al.
      HPS2-THRIVE Collaborative Group
      Effects of extended-release niacin with laropiprant in high-risk patients.
      Our results are in contrast to the findings from previous meta-analyses that evaluated the role of niacin therapy.
      • Duggal J.K.
      • Singh M.
      • Attri N.
      • et al.
      Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease.
      • Bruckert E.
      • Labreuche J.
      • Amarenco P.
      Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis.
      However, these analyses included trials which predated the era of optimal statin therapy and did not include the AIM-HIGH and HPS2-THRIVE studies. A recently conducted meta-analysis of 39 clinical trials involving several HDL-C–directed therapies (niacin, fibrates, cholesteryl ester transfer protein inhibitors) demonstrated results consistent with our study.
      • Keene D.
      • Price C.
      • Shun-Shin M.J.
      • Francis D.P.
      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.
      Additionally, 2 randomized trials that investigated the effects of niacin therapy in combination with statin therapy were not included in their analysis, thereby failing to study the cumulative evidence available.
      • Brown B.G.
      • Xue-Qiao Z.
      • Chait A.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      • Taylor A.J.
      • Villines T.C.
      • Stanek E.J.
      • et al.
      Extended-release niacin or ezetimibe and carotid intima-media thickness.
      Further, in addition to the larger sample size of our meta-analysis, we attempted to include all the cardiovascular endpoints available in different studies, to broaden the interpretation of these studies, whereas the endpoints of cardiovascular mortality and revascularization have not been evaluated in previous meta-analyses.
      • Keene D.
      • Price C.
      • Shun-Shin M.J.
      • Francis D.P.
      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.
      • Lavigne P.M.
      • Karas R.H.
      The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
      The present analysis is also unique in reporting the safety profile of niacin with respect to different adverse events. Consistent with prior evidence, we found significant increases in the niacin arm, compared with control, on the risks of skin, gastrointestinal, diabetes, and musculoskeletal adverse events. Most importantly, our study coincides with the recent withdrawal of approval by the US Food and Drug Administration for combination use of extended-release niacin with statin therapy based on results from the AIM-HIGH and HPS2-THRIVE trials.
      Our study demonstrated no improvement in clinical outcomes despite a significant increase in serum HDL-C levels with niacin therapy. This lack of clinical benefit could have several potential explanations. First, major weightage in our analysis was provided by the AIM-HIGH and HPS2-THRIVE trials, which recruited patients with highly optimized statin-based therapy maintaining below goal LDL-C levels (<70 mg/dL), which is not universally seen in clinical practice.
      • de Lemos J.A.
      • Blazing M.A.
      • Wiviott S.D.
      • et al.
      Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
      • Puri R.
      • Nissen S.E.
      • Shao M.
      • et al.
      The beneficial effects of raising high-density lipoprotein cholesterol depends upon achieved levels of low-density lipoprotein cholesterol during statin therapy: implications for coronary atheroma progression and cardiovascular events.
      This is in contrast with the trials conducted before effective LDL-C–reducing drugs were available.
      • Blankenhorn D.H.
      • Nessim S.A.
      • Johnson R.L.
      • Sanmarco M.E.
      • Azen S.P.
      • Cashin-Hemphill L.
      Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
      • Brown B.G.
      • Xue-Qiao Z.
      • Chait A.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      Furthermore, other trials investigating the role of niacin in combination with statins among patients with low serum levels of HDL-C studied surrogate endpoints and had a low number of clinical events.
      • Taylor A.J.
      • Sullenberger L.E.
      • Lee H.J.
      • Lee J.K.
      • Grace K.A.
      Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.
      • Taylor A.J.
      • Villines T.C.
      • Stanek E.J.
      • et al.
      Extended-release niacin or ezetimibe and carotid intima-media thickness.
      Second, with an evolving understanding of HDL composition and function, it is being increasingly realized that HDL-C's role and clinical effects may extend far beyond simply the concentration levels, and is more related to HDL particle number (HDL-P) and function.
      • Mora S.
      • Glynn R.J.
      • Ridker P.M.
      High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy.
      • Otvos J.D.
      • Collins D.
      • Freedman D.S.
      • et al.
      Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.
      As seen in the AIM-HIGH trial, combination of niacin-statin therapy may not lead to a significant increase in HDL-P and thus cholesterol efflux, thereby explaining the negative results.
      • Khera A.V.
      • Patel P.J.
      • Reilly M.P.
      • Rader D.J.
      The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality.
      Further, in a population-based cohort of subjects free from ASCVD, cholesterol efflux activity was inversely associated with incident cardiovascular events over a long-term follow-up of approximately 9 years.
      • Rohatgi A.
      • Khera A.
      • Berry J.D.
      • et al.
      HDL cholesterol efflux capacity and incident cardiovascular events.
      Indeed, the efficacy of niacin on the atheroprotective cholesterol efflux pathway is less certain owing to conflicting results in different studies.
      • El Khoury P.
      • Waldmann E.
      • Huby T.
      • et al.
      Extended-release niacin/laropiprant improves overall efficacy of postprandial reverse cholesterol transport.
      • Ronsein G.E.
      • Hutchins P.M.
      • Isquith D.
      • et al.
      Niacin therapy increases high-density lipoprotein particles and total cholesterol efflux capacity but not ABCA1-specific cholesterol efflux in statin-treated subjects.
      Third, niacin raises HDL-C through induction of apolipoprotein A-I (apoA-I) synthesis, a major constituent of the HDL molecule.
      • Kane J.P.
      • Malloy M.J.
      • Ports T.A.
      • Phillips N.R.
      • Diehl J.C.
      • Havel R.J.
      Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.
      In a meta-analysis of statin trials evaluating association of HDL-C and apoA-I with major adverse cardiovascular events in patients reaching LDL-C <70 mg/dL, a reduced incidence of cardiovascular events was seen only with apoA-I increase, but not HDL-C.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Hovingh G.K.
      • et al.
      Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.
      Finally, although the effect of niacin in raising HDL-C is well known, it is unclear whether the observed reductions in cardiovascular events in previous studies were related solely to its favorable effect on the patient's lipid profile. In a meta-regression analysis of 11 niacin trials, Lavigne et al
      • Lavigne P.M.
      • Karas R.H.
      The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
      failed to demonstrate an association of serum levels of HDL-C with a reduction in cardiovascular events. This finding could be due to an independent antiatherogenic effect of niacin through its anti-inflammatory and antioxidant properties.
      • Digby J.E.
      • McNeill E.
      • Dyar O.J.
      • Lam V.
      • Greaves D.R.
      • Choudhury R.P.
      Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin.
      Our analysis suggesting a lack of clinical benefit with niacin is in agreement with studies involving other HDL-raising drugs.
      • Bots M.L.
      • Visseren F.L.
      • Evans G.W.
      • et al.
      Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • et al.
      ACCORD Study Group
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      Recently published trials investigating fibrates and cholesteryl ester transfer protein inhibitors have added to a growing consensus against the hypothesis that HDL-C–raising therapies would be atheroprotective.
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • et al.
      ACCORD Study Group
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      Notably, among statin-treated patients, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) and dal-OUTCOMES (Study of the Effect of Dalcetrapib on Atherosclerotic Disease in Patients with Coronary Artery Disease) trials failed to show any reduction in recurrent cardiovascular events, with the addition of fenofibrate and dalcetrapib, respectively.
      • Ginsberg H.N.
      • Elam M.B.
      • Lovato L.C.
      • et al.
      ACCORD Study Group
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      The major strength of the present analysis is individual pooling of important clinical outcomes from available randomized controlled trials comparing niacin with a control agent. In addition, we evaluated the cumulative adverse effect profile associated with niacin treatment. Our results did not show any benefit in terms of all-cause mortality or other cardiovascular events, while suggesting increased risk of several adverse events, with niacin therapy. Our study has several limitations. The dosages and comparators varied across the studies included, and we were not able to estimate the effect of niacin monotherapy. Although clinical outcomes were adjudicated in individual trials, standardized adjudication was not possible across all included randomized controlled trials included in the present analysis.

      Conclusion

      Niacin therapy does not lead to a significant reduction in total or cause-specific mortality or recurrent cardiovascular events, despite an improvement in serum HDL-C levels. Additional research is indicated to better understand HDL subfractions and their association with cardiovascular outcomes with targeted therapies, to increase only those subfractions associated with better cardiovascular outcomes.

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      Linked Article

      • Concerning Niacin in Current Clinical Practice
        The American Journal of MedicineVol. 130Issue 8
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          In their systematic review of the role of niacin in clinical practice, Garg et al1 found that niacin therapy does not reduce all-cause mortality, cardiovascular mortality, or adverse cardiovascular events. Garg et al1 included niacin studies with and without a statin as part of the intervention.
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