Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) vs Simvastatin) (N = ∼18,000) (25) is evaluating the role of further LDL-C reduction and modest HDL-C increases with ezetimibe/simvastatin versus simvastatin alone in patients with acute coronary syndromes. J Manag Care Pharm. "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" Cannon C.P., Giugliano R.P., Blazing M.A.et al. Barter P., Gotto A.M., LaRosa J.C.et al. 15. : A meta-analysis of 41 randomized trials", "Effects of combination lipid therapy in type 2 diabetes mellitus", "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis", "OMEGA, a randomized, placebo-controlled trial to test the effects of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction". The SANDS (Stop Atherosclerosis in Native Diabetics Study) compared the effects of aggressive LDL-C–lowering strategy (target LDL-C goal <70 mg/dl) with those of a standard-treated group (LDL-C goal <100 mg/dl) (26). Circulation2009; 120: S376. Foam cell accumulation in the carotid arteries, the principal pathological feature of an increased cIMT, is likely the main component that is capable of regression; direct comparisons of cIMT and magnetic resonance imaging–measured regression in the context of statins are not available. Brown G., Albers J.J., Fisher L.D.et al. Low HDL-C levels may be simply a marker of risk, given its association with metabolic syndrome and insulin resistance, and not a causal factor. Clipboard, Search History, and several other advanced features are temporarily unavailable. It remains unknown whether more aggressive LDL-C reduction with a more potent statin would be more effective than adding a second lipid-modifying agent to a less potent statin or lower statin dose. 17. Designed for a power to detect a 25% reduction in the primary outcome, anticipating 800 events was perhaps optimistic. The full mechanism of action of niacin is still unclear (1,2). Of the participants, 25% and 20% in the niacin and placebo arms, respectively, discontinued the study drug (p < 0.001). HATS also showed a reduction in the progression of coronary stenosis with the niacin-simvastatin combination compared with placebo (Table 1). . Taylor A.J., Villines T.C., Stanek E.J.et al. J Am Coll Cardiol2010; 55: 2721. The standard-treated group showed an increase in cIMT. . Metabolic risk factors and vascular disease were highly prevalent (34% diabetes, 71% hypertension, 81% metabolic syndrome, and 92% coronary disease). . 20. Villines T.C., Stanek E.J., Devine P.J.et al. Nine years after termination of the Coronary Drug Project, niacin still conferred an 11% reduction in all-cause mortality compared with placebo (p = 0.0004) (5). Like the HALTS trial, there was a differential dropout related to side effects. "The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3" The baseline mean LDL-C in AIM-HIGH was lower than in the HALTS and Oxford studies, which may partially explain the lack of benefit for additional niacin therapy. Canner P.L., Berge K.G., Wenger N.K.et al. In contrast, the OMEGA (Effect of Omega 3-Fatty Acids on the Reduction of Sudden Cardiac Death After Myocardial Infarction) study failed to show any additional CVD benefit at 1 year of omega-3 fatty acids when combined with modern guideline-adjusted therapy after myocardial infarction (24). Improving HDL-C function will be the focus of new therapies (2), particularly through enhancing reverse cholesterol transport but perhaps also through HDL-C's proposed antithrombotic, antioxidant, and anti-inflammatory properties. 7. Abdel-Maksoud M, Sazonov V, Gutkin SW, Hokanson JE. LDL-C remains the primary target of lipid therapy with non–HDL-C as the secondary target. "Effects of combination lipid therapy in type 2 diabetes mellitus" Unfortunately, the published studies to date do not provide a definitive answer as to which of these therapies >should be chosen when LDL-C and non–HDL-C goals cannot be reached despite maximally tolerated statin therapy. The results of AIM-HIGH should not necessarily be extrapolated to other patient populations such as those with LDL-C >100 mg/dl for whom there still might be a role for niacin. Glob Heart. © 2020 American College of Cardiology Foundation. and Sullenberger L.E. . 6. However, surrogate markers of atherosclerosis from various vascular beds (coronary artery calcium, cIMT, ankle-brachial index) are only modestly correlated with each other, and coronary artery calcium is more strongly predictive of CHD events than cIMT (16). Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. : Taylor A.J., Sullenberger L.E., Lee H.J., Lee J.K. and Grace K.A. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. . Lipoprotein subfraction analysis should be performed in larger studies utilizing niacin in … Niacin-tolerant participants (N = 3,414) were then randomized to ERN (at 1,500 to 2,000 mg/day) or placebo (which contained a 50-mg dose of immediate-release niacin to help ensure blinding). The Oxford Niaspan study (10) was a smaller (N = 71) RCT of modified-release niacin (target 2,000 mg/day) versus placebo added to baseline statin therapy on the primary endpoint of change in common carotid artery wall area by magnetic resonance imaging at 1 year. There are other therapeutic agents under investigation targeting HDL-C (2). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the standard of care for the management of dyslipidemia. 2016 Mar;11(1):97-107. doi: 10.1016/j.gheart.2015.12.014. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis. This does not necessarily mean that niacin lacks a role in lipid-modifying therapy. : . "Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study" J Am Coll Cardiol2008; 52: 2198. . Arch Intern Med2008; 168: 1333. "Effects of high dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo controlled, magnetic resonance imaging study" Am Heart J2008; 156: 826. . In an exploratory analysis, increasing niacin exposure resulted in a further reduction in cIMT, whereas increased cumulative ezetimibe exposure was associated with cIMT progression (13). Taylor A.J., Sullenberger L.E., Lee H.J., Lee J.K. and Grace K.A. J Cardiovasc Pharmacol. "Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndrome" Association between uric acid and brachial-ankle pulse wave velocity: secondary analysis of data from a cross-sectional study. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. The Coronary Drug Project was a pre-statin era secondary prevention trial that randomized 1,119 subjects to clofibrate or niacin. With only 556 events, the study may have been underpowered to see a difference between the groups. There is an ongoing substudy of AIM-HIGH with the primary outcome of change in mean plaque lipid composition assessed by carotid magnetic resonance imaging, which may shed light on the apparent discordance between surrogate endpoints using imaging and clinical events.