Evidence Trace, complete trial record

In plain terms

In plain terms: Niacin (extended-release, for lipids) has been tested in human trials aimed at the relevant outcome and did not show benefit at the doses and durations studied. The animal research may be encouraging, but it has not yet translated to humans in these trials.

Niacin (extended-release, for lipids)

D Not shown: no human trial shows benefit

Route 2 — tested in humans; benefit not shown

Category Supplements

Evidence Two large randomized outcome trials, no benefit (D Route 2)

Reviewed July 2026

PMIDs 25014686 · 22085343 · 28616955 · 31447131 · 3782631

The endpoint this grade is based on: Hard clinical endpoint (mortality, major event), Tested at scale on top of statins. Extended-release niacin alone (AIM-HIGH) and extended-release niacin with laropiprant (HPS2-THRIVE) did not reduce vascular events; the laropiprant combination increased serious adverse events.

The evidence as the record states it

Evidence record

PMID 25014686 PMID 22085343 PMID 28616955 PMID 31447131 PMID 3782631

Boden et al., AIM-HIGH (NEJM, 2011; PMID 22085343): 3,414 patients with established cardiovascular disease on simvastatin, extended-release niacin 1,500 to 2,000 mg/day alone against placebo; stopped after 3 years for lack of efficacy, primary events 16.4 against 16.2 percent (hazard ratio 1.02) despite higher HDL and lower triglycerides; funded by the National Heart, Lung, and Blood Institute and Abbott, the product's maker. Landray et al., HPS2-THRIVE (NEJM, 2014; PMID 25014686): 25,673 adults with vascular disease on statin-based therapy after a run-in that excluded people who could not tolerate niacin, 2 g extended-release niacin with 40 mg laropiprant in one pill against placebo for a median of 3.9 years; major vascular events 13.2 against 13.7 percent, not significant; serious adverse events increased; funded by Merck, the combination's maker, with the trial run by Oxford. Haynes et al. (Clin Ther, 2019; PMID 31447131): the HPS2-THRIVE adverse-effect report; new-onset diabetes hazard ratio 1.32, with excess disturbances of diabetes control, bleeding, infection and gastrointestinal events; the pill combined two drugs, so the harms cannot be assigned to niacin alone. Schandelmaier et al. (Cochrane, 2017; PMID 28616955): 23 trials, 39,195 people, median dose 2 g/day; no reduction in overall mortality (RR 1.05, high quality), cardiovascular mortality, myocardial infarction or stroke, and more discontinuations for side effects. Canner et al. (J Am Coll Cardiol, 1986; PMID 3782631): the Coronary Drug Project, immediate-release niacin alone in men with prior infarction before statins existed; fewer nonfatal reinfarctions and 11 percent lower 15-year mortality, the reason this record excludes immediate-release preparations rather than grading them. D Route 2: tested, no benefit; harm signal in the combination trial.

PMID 25014686 PMID 22085343 PMID 28616955 PMID 31447131 PMID 3782631

Trials showing no benefit

Trial 1

PMID 22085343

Endpoint: Composite of coronary death, myocardial infarction, ischemic stroke, acute coronary syndrome hospitalization or revascularization
Population: 3,414 adults with established cardiovascular disease on simvastatin, extended-release niacin 1,500 to 2,000 mg/day alone, mean 3 years

No benefit shown

High. Stopped early for lack of efficacy; hazard ratio 1.02 (95% CI 0.87 to 1.21) despite HDL raised and triglycerides lowered. Funded by NHLBI and Abbott, the product's maker.

Trial 2

PMID 25014686

Endpoint: Major vascular events (nonfatal myocardial infarction, coronary death, stroke or arterial revascularization)
Population: 25,673 adults with atherosclerotic vascular disease on statin-based therapy, 2 g extended-release niacin with 40 mg laropiprant, median 3.9 years

No benefit shown

High. Events 13.2 against 13.7 percent, not significant. Serious adverse events increased (new-onset diabetes HR 1.32, bleeding, infection, gastrointestinal), a harm signal that belongs to the niacin-laropiprant combination and cannot be assigned to niacin alone.

Why Grade D Route 2 and not Grade C

Grade D Route 2 applies when a compound has been tested in humans and benefit was not shown. Niacin (extended-release, for lipids) has been tested in 2 human trials on endpoints relevant to the claim being evaluated, and the primary endpoint was not met.

A randomized, placebo-controlled trial pre-specifying a meaningful clinical or functional endpoint and demonstrating statistically significant benefit would move this to Grade C or higher, depending on effect size, population size, and whether it is independently replicated.

What this grade covers and what it does not

Grade D on Route 2: tested, no benefit. Two large randomized trials on top of statin therapy found none. AIM-HIGH (Boden et al., 2011; PMID 22085343) gave extended-release niacin alone to 3,414 patients and was stopped early for futility, hazard ratio 1.02; it is the clean test of this record's product. HPS2-THRIVE (Landray et al., 2014; PMID 25014686) gave 2 g extended-release niacin combined with 40 mg laropiprant, a flushing blocker, to 25,673 adults for a median of 3.9 years; major vascular events were not reduced and serious adverse events rose (new-onset diabetes, disturbed diabetes control, bleeding, infection, gastrointestinal, musculoskeletal and skin events; Haynes et al., 2019; PMID 31447131). Because that pill combined two drugs, the excess harm cannot be assigned to niacin alone, which is why the record reads no benefit with a harm signal rather than harm found. The Cochrane review of 23 trials (PMID 28616955) found no reduction in death, heart attack or stroke and more discontinuations for side effects. This is the clearest case on the site of a surrogate moving while the outcome did not: niacin does to the lipid panel what it is advertised to do, and the events it was meant to prevent did not fall. HPS2-THRIVE standardized background therapy in a run-in that excluded people who could not tolerate niacin, so adverse effects in ordinary use are likely higher than the trial recorded. WHAT THIS GRADE DOES NOT COVER: this letter grades extended-release niacin added on top of a statin for cardiovascular event prevention. It does not grade niacin as a vitamin, where deficiency is a defined clinical condition with its own treatment. It does not grade immediate-release niacin alone before statins existed, where the Coronary Drug Project (PMID 3782631) found fewer reinfarctions and lower long-term mortality in men with prior infarction. And it does not grade nicotinamide or nicotinamide riboside, which are different molecules carrying their own records and their own letters.

What would move this grade

A randomized, placebo-controlled trial pre-specifying a clinical aging endpoint and demonstrating statistically significant benefit on that primary endpoint would be sufficient to move this to Grade C or higher, depending on effect size and population.

How to track whether this is working No validated human outcome to track. Surrogate lipid changes are not the outcome.