Definition of a tolerable upper intake level of niacin: a systematic review and meta-analysis of the dose-dependent effects of nicotinamide and nicotinic acid supplementation

Context: Nicotinic acid and nicotinamide are soluble compounds of the vitamin B group, widely used to regulate the lipid profile in hyperlipidemic individuals. Higher doses of nicotinic acid are associated with adverse effects, especially flushing. A unique tolerable upper intake level (UL) of nicotinic acid has not been defined. Objective: This meta-analysis aims to evaluate adverse effects and their incidence after supplementation with different doses of nicotinic acid and nicotinamide, comparing results with current ULs in Europe and the United States. Data Sources: PubMed was searched for articles providing detailed information about nicotinic acid or nicotinamide supplementation and related outcomes. Study Selection: A total of 2670 citations were selected for screening. Two primary outcomes were considered: occurrence of adverse effects following nicotinic acid or nicotinamide supplementation, and dose at which adverse effects occurred. Data extraction: Details on study population, type and duration of treatment, dosage of vitamins, association with lipid-influencing drugs, length of follow-up, and incidence and type of adverse events were extracted. Results: After screening, 47 articles involving 11 741 individuals were included. Meta-analysis was based on estimation of benchmark doses for the probability of adverse effects after supplementation. In individuals with dyslipidemia or cardiovascular disease, nicotinic acid monotherapy seems to be protective against any adverse effects considered, as adverse events occurred at doses above those used with other treatments. In healthy individuals treated with nicotinic acid alone, major adverse effects occurred at doses below 1000 mg/d. Conclusions: Results may indicate a high degree of conservativeness in the UL of nicotinic acid, fixed at 35 mg/d in United States and 10 mg/d in Europe. Reconsideration of the UL of nicotinic acid for nutritional supplements, possibly differentiating between ULs in healthy and unhealthy individuals, may be warranted.