Niacin at 56 years of age--time for an early retirement?

A reduction in serum cholesterol with niacin therapy in humans was first described in 1955, when Altschul and colleagues reported, in a letter to the editor, the findings in 11 healthy medical students and 57 patients.1 Subsequent clinical studies showed multiple favorable effects of niacin therapy on lipid particles, including decreases in levels of low-density lipoprotein (LDL) cholesterol, triglycerides, small dense LDL cholesterol, very-low-density lipoprotein, lipoprotein(a), and apolipoprotein Β and increases in levels of high-density lipoprotein (HDL) cholesterol and selective lipoprotein A-1 particles.2 The mechanism of action of niacin is complex, involves several biochemical pathways, and is still not well defined.3 The current indications for niacin — reducing the risk of reinfarction, favorably altering lipid levels, and slowing the progression of atherosclerosis — are derived from three lines of evidence: the Coronary Drug Project (CDP),4 studies of combination therapy consisting of niacin and a second lipid-lowering agent, and evaluation of surrogate markers. From 1966 through 1969, the CDP enrolled 8341 men, 40 to 64 years of age, with a prior myocardial infarction to one of five lipid-modifying therapies. There was no significant difference between the men who were treated with niacin (1119 subjects) and those who received placebo (2789 subjects) in the primary end point of the rate of death from any cause (24.4% and 25.4%, respectively) over a minimum follow-up period of 5 years. However, the rates of myocardial infarction and of cerebrovascular events were significantly reduced with niacin — by 26% and 24%, respectively. It is worth noting, however, that 40 or more years ago, many therapies that have since been proved to reduce mortality or morbidity after myocardial infarction either were not routinely administered (e.g., aspirin and beta-blockers) or were not yet available (e.g., statins, inhibitors of the renin–angiotensin–aldosterone system, P2Y12 inhibitors, and implantable defibrillators). The second line of evidence, derived from studies of combined therapy consisting of niacin and a second lipid-lowering drug, do not inform us about the benefit of adding niacin alone to background therapy; for example, in the HDL-Atherosclerosis Treatment Study (ClinicalTrials.gov number, NCT00000553), was it simvastatin, simvastatin plus niacin, or niacin alone that was responsible for the observed clinical benefit?5 Finally, studies using surrogate markers (e.g., carotid intima–media thickness) remain controversial,6 since they have shown inconsistent results, even when proven lipid-modifying therapies that clearly reduce clinical end points have been evaluated by these means.7,8 Thus, a critical appraisal of the prior studies of niacin reveals three shaky pillars supporting its clinical efficacy and identifies a need for large, modern trials of clinical end points. The first of these is reported in this issue of the Journal.9 The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes trial (AIMHIGH, NCT00120289)9 was designed with 85% power to show a 25% reduction in the primary end point (a composite of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization), with the