Niacin (Vitamin B3)

What niacin is

Niacin is the umbrella term for nicotinic acid and nicotinamide. Both are precursors of NAD+, the coenzyme involved in energy production and repair in every cell; related NAD precursors are nicotinamide riboside and NMN. Your body also makes niacin from the amino acid tryptophan; 60 mg of tryptophan yields 1 mg of niacin equivalent.

For adults, 11 to 16 mg of niacin equivalents per day are recommended. According to the German National Nutrition Survey II, adults in Germany take in a median of 24.7 to 39.9 mg. In the BK-Score, human evidence stands at 8 out of 10 points. Well studied here mainly means: for the heart question, there is a clear answer from large trials.

How it works

In pharmacological amounts, nicotinic acid changes blood lipids: in AIM-HIGH, HDL rose from 35 to 42 mg/dl after 2 years, triglycerides fell from 164 to 122 mg/dl, LDL from 74 to 62 mg/dl. Lipoprotein(a) also falls. Typical is the flush, a feeling of heat with reddening of the skin, on which the EU upper limit of 10 mg of nicotinic acid per day is based.

Nicotinamide has a different profile: its upper limit is 900 mg per day. It has mainly been studied as an NAD precursor and for protecting UV-damaged skin. Better blood lipid values are a surrogate marker; whether fewer heart attacks follow from them had to be settled by the endpoint trials.

What the studies show

Coronary Drug Project: Canner 1986

The trial ran from 1966 to 1975 with 8,341 men aged 30 to 64 after a heart attack and compared five lipid-lowering drugs with placebo. Nicotinic acid reduced nonfatal reinfarctions, but did not reduce overall mortality during the trial. In the follow-up after an average of 15 years, almost 9 years after the end of the trial, mortality was 52.0 percent under nicotinic acid versus 58.2 percent under placebo, 11 percent lower.

AIM-HIGH 2011: on top of statins

The trial randomized 3,414 patients with cardiovascular disease and low LDL to extended-release nicotinic acid, 1,500 to 2,000 mg daily, or placebo, all additionally on simvastatin. HDL and triglycerides improved markedly. The primary endpoint occurred in 16.4 versus 16.2 percent (hazard ratio 1.02); the trial was stopped after an average of 3 years for lack of efficacy.

HPS2-THRIVE 2014: 25,673 patients

Extended-release nicotinic acid with laropiprant on top of statin therapy lowered LDL by 10 mg/dl and raised HDL by 6 mg/dl. Major vascular events occurred after a median of 3.9 years in 13.2 versus 13.7 percent (rate ratio 0.96; 0.90 to 1.03). On the other hand, there were more serious disturbances of diabetes control (+3.7 percentage points), new diabetes diagnoses (+1.3), serious infections (+1.4) and bleeding (+0.7).

Lipoprotein(a): Sahebkar 2016

Across 14 placebo-controlled trials with 9,013 participants, extended-release nicotinic acid lowered lipoprotein(a) by an average of 22.9 percent, similarly at less than and more than 2,000 mg daily. Whether this reduction prevents cardiac events was not part of the analysis.

Nicotinamide and skin cancer: ONTRAC 2015

In the double-blind phase 3 trial, 386 people with at least two non-melanoma skin cancers in the previous 5 years took 500 mg of nicotinamide twice daily or placebo for 12 months. New non-melanoma skin cancers occurred 23 percent less often (95 % interval 4 to 38), actinic keratoses 11 to 20 percent less often. There were no notable differences in side effects. After stopping, the benefit disappeared.

Breakdown products 2PY and 4PY: Ferrell 2024

In patient groups from the US and Europe, high blood levels of the niacin breakdown products 2PY and 4PY were associated with a higher risk of major cardiovascular events within 3 years (hazard ratios 1.64 to 2.02). A gene variant that raises both levels was linked to the inflammatory marker sVCAM-1. In mice, 4PY, but not 2PY, triggered vascular inflammation. These are observational and animal data, not proof that niacin from food or supplements causes cardiac events.

Where the data stop

• Heart protection under today’s therapy. On top of statins, AIM-HIGH and HPS2-THRIVE found no benefit; the finding from the time before statins cannot be transferred.
• Lipoprotein(a) lowering as a benefit. The reduction of just over a fifth has been measured; resulting protection against heart attacks has not.
• Flush as detoxification. The flush is a known side effect of nicotinic acid and the basis of its upper limit; there is no evidence in the sources reviewed for a detoxifying effect.
• Skin cancer protection for everyone. ONTRAC studied people with a history of several non-melanoma skin cancers; the effect lasted only while the substance was being taken.
• What 2PY and 4PY mean. The association with cardiac events has been observed, not proven; whether supplements raise the levels relevantly was not part of the study. More on this on the page about NMN.

Status, approval and legal

Nicotinic acid and nicotinamide may be added to foods and dietary supplements as a source of niacin, and inositol hexanicotinate additionally to dietary supplements. For dietary supplements, the BfR recommends maximum amounts of 4 mg of nicotinic acid and 160 mg of nicotinamide per recommended daily intake; above 16 mg of nicotinamide, the product should carry a note for pregnant women. The BfR values are recommendations, not legal requirements.

As a medicine, nicotinic acid was used against elevated blood lipids. The combination with laropiprant (Tredaptive, Pelzont, Trevaclyn) has no longer been available in the EU since 2013: after HPS2-THRIVE, the EMA concluded that the benefits no longer outweigh the risks, and the European Commission suspended the marketing authorizations on March 22, 2013.

For niacin as a vitamin, the EU has authorized health claims, including on energy metabolism, the nervous system and the reduction of tiredness.

Safety

The documented risks concern pharmacological amounts of nicotinic acid. Besides the flush, they include liver damage: in a randomized trial with gradually increasing doses up to 3,000 mg daily, 12 of 23 patients on extended-release nicotinic acid developed liver damage, none on immediate-release; there, 9 of 23 dropped out, most often because of vascular complaints such as the flush, fatigue and skin changes. In HPS2-THRIVE, more disturbances of diabetes control, infections and bleeding occurred.

With nicotinamide, ONTRAC found no notable differences in side effects at 1,000 mg daily over 12 months. For products with more than 16 mg of nicotinamide, the BfR recommends a note that pregnant women should not take them. In the BK-Score, safety stands at 8 out of 10 points; this axis measures how well safety has been studied, not how safe the substance is. This text is information and does not replace medical advice.

Sources

• Canner PL et al., J Am Coll Cardiol 1986 – Coronary Drug Project, 8,341 men after a heart attack, mortality after 15 years
• AIM-HIGH Investigators, N Engl J Med 2011 – 3,414 patients, extended-release nicotinic acid on top of simvastatin
• HPS2-THRIVE Collaborative Group, N Engl J Med 2014 – 25,673 patients, nicotinic acid with laropiprant on top of statins
• Sahebkar A et al., Metabolism 2016 – meta-analysis, 14 placebo-controlled trials, lipoprotein(a)
• Chen AC et al., N Engl J Med 2015 – ONTRAC, phase 3, 386 patients, nicotinamide and non-melanoma skin cancer
• McKenney JM et al., JAMA 1994 – randomized trial, 46 patients, extended-release versus immediate-release nicotinic acid
• Ferrell M et al., Nat Med 2024 – niacin breakdown products 2PY and 4PY and cardiovascular risk
• EMA 2013 – Tredaptive, Pelzont and Trevaclyn suspended across the EU (EMA/402540/2013)
• BfR – proposed maximum levels for niacin in foods including dietary supplements (2021, German)
• Regulation (EU) No 432/2012 – list of permitted health claims made on foods