Niacin
Nicotinic acid, niacin, the acid form of vitamin B3
Written by Aaron CuhaReviewed Sep 2026
Also known as: Nicotinic acid, Vitamin B3, Extended-release niacin, Niaspan
The only compound in the NAD pathway ever tested against hard cardiovascular outcomes, in 25,673 patients in HPS2-THRIVE and 3,414 in AIM-HIGH. It moved every lipid it was supposed to move and prevented no events in either trial, and HPS2-THRIVE found excess serious adverse events including infection and bleeding.
Overview
If you want to understand why a moving biomarker is not evidence, this is the compound to study. Nothing else in the longevity supplement world has been tested this thoroughly against outcomes that actually matter, and the answer came back twice.
Nicotinic acid raises HDL cholesterol, lowers triglycerides and lowers LDL cholesterol. It does this reliably and it has been known to do it since the 1950s. For decades that made it the standard answer to low HDL, on the reasoning that HDL is protective and raising it should therefore protect.
AIM-HIGH randomised 3,414 patients with established cardiovascular disease, all on simvastatin with ezetimibe as needed, to extended-release niacin at 1500 to 2000 mg daily or placebo. Niacin raised median HDL from 35 to 42 mg/dL, dropped triglycerides from 164 to 122 mg/dL and dropped LDL from 74 to 62 mg/dL. The trial was stopped after a mean of 3 years for lack of efficacy. The primary composite endpoint occurred in 16.4 percent on niacin and 16.2 percent on placebo.
HPS2-THRIVE was seven times larger. 25,673 adults with vascular disease, on statin-based therapy, randomised to 2 g of extended-release niacin with 40 mg of laropiprant, a prostaglandin antagonist added specifically to suppress flushing, or placebo, for a median of 3.9 years. LDL was 10 mg/dL lower and HDL 6 mg/dL higher on niacin. Major vascular events occurred in 13.2 percent on niacin and 13.7 percent on placebo, rate ratio 0.96, not significant.
And then the part that is usually left out. Niacin-laropiprant caused an absolute excess of serious disturbances in diabetes control of 3.7 percentage points, new diabetes diagnoses up 1.3 points, serious gastrointestinal events up 1.0 point, musculoskeletal up 0.7, skin up 0.3, and, unexpectedly, infection up 1.4 points and bleeding up 0.7 points. A drug that raises HDL beautifully, prevents nothing, and causes serious harm at scale is the single most instructive object in this entire field.
Mechanism of action
Nicotinic acid enters NAD synthesis through the Preiss-Handler pathway rather than the NAMPT salvage route, which is why it is a genuinely potent NAD booster and why a 2026 human study proposed that gut bacterial conversion of NR and NMN into nicotinic acid may be how those two expensive precursors work at all. Its lipid effects are separate and act mainly through inhibition of adipocyte lipolysis and hepatic diacylglycerol acyltransferase, reducing free fatty acid flux to the liver and VLDL output. The flush is a third, distinct mechanism: nicotinic acid activates the receptor GPR109A on immune cells in skin, releasing prostaglandins D2 and E2 that dilate cutaneous vessels. Mouse knockout work established each link in that chain. The laropiprant in HPS2-THRIVE was a prostaglandin D2 receptor antagonist added to block exactly this, which worked for the flush and did nothing for the outcomes.
Human evidence
By far the largest human evidence base of any compound in the NAD pathway, and it is overwhelmingly negative on the outcomes that matter. Roughly 29,000 randomised participants across two modern outcome trials, both null, one showing net harm.
- AIM-HIGH, n=3,414, mean 3 years, stopped early for futility: primary composite endpoint 16.4 percent on niacin versus 16.2 percent on placebo, hazard ratio 1.02.
- HPS2-THRIVE, n=25,673, median 3.9 years: major vascular events 13.2 percent versus 13.7 percent, rate ratio 0.96 (95 percent CI 0.90 to 1.03).
- HPS2-THRIVE harms: excess serious diabetes-control disturbances of 3.7 percentage points, new diabetes 1.3 points, infection 1.4 points, bleeding 0.7 points, all P at or below 0.003.
- The lipid changes in both trials were exactly as predicted. HDL up, triglycerides down, LDL down. The biomarker worked perfectly and the patients did not benefit.
- Coronary Drug Project 15-year follow-up, n=8,341 men, pre-statin era: 11 percent lower all-cause mortality, 52.0 versus 58.2 percent, P=0.0004, observed nearly 9 years after the drug was stopped.
- Nicotinic acid is a potent NAD precursor through the Preiss-Handler pathway, and a 2026 human study proposed that it may be the actual route by which NR and NMN raise systemic NAD.
What this does not tell you: AIM-HIGH and HPS2-THRIVE both tested niacin added on top of effective statin therapy, so they answer the question of whether niacin adds anything to modern treatment, and the answer is no. They do not test niacin as a standalone lipid drug in an untreated patient, which is no longer a realistic clinical scenario anyway. The HPS2-THRIVE harms were seen with the niacin-laropiprant combination, and laropiprant cannot be fully excluded as a contributor, although the pattern of harms is consistent with known niacin effects on glucose control. The 4PY work is observational and does not establish that taking niacin causes events.
Reading the research record
This is the worked example the rest of the NAD pathway should be read against.
Niacin raises HDL. HDL is inversely associated with cardiovascular risk in every observational dataset ever collected. Raising HDL therefore ought to reduce risk, and for three decades that inference was treated as close enough to established that niacin sat in guidelines on the strength of it. Two large randomised trials then tested the inference directly, and both found that the lipid changes happened exactly as predicted and the events did not change at all. The larger trial found that patients were actively harmed.
Every compound on this pathway is currently sold on the same shape of inference. Blood NAD falls with age, blood NAD is associated with health, therefore raising blood NAD should help. That inference has never been tested against a hard clinical endpoint for any NAD precursor, and the one time an analogous inference in this exact vitamin family was tested at scale, it failed twice and produced net harm once.
The 4PY finding adds a further wrinkle. The terminal breakdown products of excess niacin were associated with increased cardiovascular events and with a vascular inflammation marker, with genetic support for the link. That is not proof that supplemental niacin causes events, but it is a specific, testable proposal that more of this vitamin than the body needs is not neutral.
Three claim types get collapsed into one in almost all consumer writing about this pathway, and keeping them apart is most of the work. A biomarker claim is that a compound raises blood NAD. That is easy to demonstrate and for several of these compounds it is simply true. A surrogate claim is that it moves something sitting between a biomarker and a symptom, such as arterial stiffness or an acylcarnitine profile. A clinical claim is that a person walks further, remembers more, gets fewer cancers or lives longer. A compound can be firmly established at the first level and have nothing at all at the third, and that is the actual position of most of the NAD pathway. There is no published human trial of any NAD precursor with a hard clinical endpoint that reported a benefit, with one exception on this list, and that exception is nicotinamide in skin cancer, which works through DNA repair in sun-damaged skin rather than through anything to do with ageing.
The evidence, charted
Fig. 1 · evidence composition
5of 6 citations (83%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 6 distinct years, 1986 to 2024, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Approved
UK
Not approved
AU
Prescription
CA
Prescription
Approved in 1 of 4, prescription route in 2, not approved in 1. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2011
Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy
AIM-HIGH, NCT00120289. 3,414 patients with established atherosclerotic cardiovascular disease and LDL below 70 mg/dL, randomised to extended-release niacin 1500 to 2000 mg daily (n=1718) or placebo (n=1696), all on simvastatin plus ezetimibe as needed. Stopped after a mean of 3 years for lack of efficacy. Niacin raised median HDL from 35 to 42 mg/dL, lowered triglycerides from 164 to 122 mg/dL and lowered LDL from 74 to 62 mg/dL. The primary composite endpoint occurred in 282 niacin patients (16.4 percent) and 274 placebo patients (16.2 percent), hazard ratio 1.02 (95 percent CI 0.87 to 1.21, P=0.79). Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories.
New England Journal of Medicine - Human2014
Effects of extended-release niacin with laropiprant in high-risk patients
HPS2-THRIVE, NCT00461630. 25,673 adults with vascular disease on statin-based therapy randomised to 2 g extended-release niacin with 40 mg laropiprant or placebo for a median of 3.9 years. LDL was 10 mg/dL lower and HDL 6 mg/dL higher on treatment. Major vascular events occurred in 13.2 percent versus 13.7 percent, rate ratio 0.96 (95 percent CI 0.90 to 1.03, P=0.29). Treatment caused absolute excesses in serious disturbances of diabetes control (3.7 percentage points, P<0.001), new diabetes diagnoses (1.3 points, P<0.001), serious gastrointestinal events (1.0 point), musculoskeletal events (0.7 point), skin events (0.3 point), and unexpectedly infection (1.4 points) and bleeding (0.7 points). Funded by Merck and others.
New England Journal of Medicine - Human2013
HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment
The design and tolerability paper, published a year before the main result. It documents the pre-randomisation run-in used to exclude people who could not tolerate extended-release niacin, which means the main trial population was already enriched for tolerance and the adverse event excess reported later occurred despite that enrichment. Also reports the pre-specified muscle and liver outcomes and the reasons participants stopped study treatment.
European Heart Journal - Human1986
Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin
The historical result that kept niacin in the guidelines for thirty years, and it is weaker than its reputation. In the Coronary Drug Project, 8,341 men aged 30 to 64 with a previous myocardial infarction were treated between 1966 and 1975. Niacin modestly reduced definite non-fatal recurrent myocardial infarction but did not reduce total mortality during the trial. At a mean follow-up of 15 years, nearly 9 years after the drug was stopped, all-cause mortality was 52.0 percent on niacin versus 58.2 percent on placebo, 11 percent lower, P=0.0004. This is a post-trial observational mortality difference in a pre-statin population, not a result obtained on top of modern therapy, and both AIM-HIGH and HPS2-THRIVE tested niacin on top of modern therapy and found nothing.
Journal of the American College of Cardiology - Animal2005
GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing
Mouse knockout work establishing the flush mechanism. Mice lacking PUMA-G, the mouse orthologue of human GPR109A, did not flush in response to nicotinic acid. Flushing was also abolished in mice lacking cyclooxygenase type 1 and reduced in mice lacking prostaglandin D2 and E2 receptors, and transplanting wild-type bone marrow into PUMA-G-deficient mice restored the flush, locating the receptor on immune cells in skin.
Journal of Clinical Investigation - Human2024
A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk
Observational metabolomics rather than a trial, and it proposes a mechanism for why more niacin might be actively unhelpful. In a discovery cohort of 1,162 stable cardiac patients and validation cohorts of 2,331 US and 832 European patients, serum levels of the terminal metabolites of excess niacin, 2PY and 4PY, were associated with increased 3-year risk of major adverse cardiovascular events: for 4PY, adjusted hazard ratios of 1.89 (95 percent CI 1.26 to 2.84) and 1.99 (1.26 to 3.14). A genetic variant associated with both metabolites was also associated with soluble VCAM-1 in a meta-analysis of about 106,000 people. This is association plus a mechanistic hypothesis, not causal proof in humans.
Nature Medicine
Frequently asked questions
Did niacin fail, or did the trials fail?
The trials were large, well conducted and independently and industry funded respectively, and they agreed. AIM-HIGH randomised 3,414 patients and stopped for futility. HPS2-THRIVE randomised 25,673 and ran for a median of 3.9 years. Both showed the expected lipid changes and neither showed a reduction in events. The most common defence, that the placebo arm in AIM-HIGH contained a small amount of niacin to mask flushing, does not explain HPS2-THRIVE, which was seven times larger and used a true placebo.
Is niacin dangerous?
In HPS2-THRIVE, extended-release niacin with laropiprant caused an absolute excess of serious adverse events: disturbances of diabetes control up 3.7 percentage points, new diabetes diagnoses up 1.3 points, serious infection up 1.4 points and bleeding up 0.7 points. Those are absolute excesses over placebo in a population already screened for tolerance during a run-in phase. Separately, high-dose nicotinic acid has a long-recognised association with liver enzyme elevation and with worsened glucose control. This is not a benign vitamin at gram doses.
Why does niacin cause flushing and can I avoid it?
Nicotinic acid activates GPR109A on immune cells in the skin, which release prostaglandins D2 and E2 and dilate the cutaneous vessels. Mouse knockout work confirmed each step. Flush-free products either use the amide form nicotinamide, which does not activate the receptor and also does not have the lipid effects, or extended-release formulations, which slow absorption. HPS2-THRIVE blocked the flush pharmacologically with laropiprant and still found no benefit, so avoiding the flush is a comfort question rather than an efficacy question.
Is niacin a better NAD booster than NMN or NR?
Mechanistically it enters NAD synthesis through the Preiss-Handler pathway and is a potent NAD precursor, and a 2026 human study went further and proposed that gut bacteria convert NR and NMN into nicotinic acid, which would make the cheap acid the actual active route for the expensive precursors. That is an unresolved hypothesis rather than settled fact. What is settled is that being a potent NAD booster did not translate into any outcome benefit across roughly 29,000 randomised patients.
Should I take niacin for longevity?
There is no trial evidence that it extends life or healthspan in anyone, there are two large trials showing it does not prevent cardiovascular events on top of a statin, and one of them showed net harm including excess infection, bleeding and new diabetes. Doses at or above the amount needed to correct a deficiency should be a medical decision.