IMPORTANCE: Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking. OBJECTIVE: To determine whether nicotinamide use results in an increase of MACE. DESIGN, SETTING, AND PARTICIPANTS: This study used retrospective electronic health record data of 2 patient cohorts, the Vanderbilt University Medical Center (VUMC) and Million Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared with the risk of MACE in unexposed patients. In the VUMC cohort, patients were either exposed to nicotinamide based on keyword entry for nicotinamide or niacinamide and manual review of medical records or were unexposed but had documented recommendation for use. In the MVP cohort, those exposed to nicotinamide were matched via propensity scores to those who were not exposed. Data were collected from January 1989 to February 2024, and data were analyzed from March to December 2024. EXPOSURES: The primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide on medical record review. The primary exposure for the MVP cohort was medication entry for nicotinamide or niacinamide. MAIN OUTCOMES AND MEASURES: The primary outcome was development of MACE based on a validated phenotype. RESULTS: Of 13 108 included patients, 11 926 (91.0%) were male, and the mean (SD) age was 66.8 (11.5) years. In the VUMC cohort, 1228 patients were exposed to nicotinamide and 253 were unexposed
in the MVP cohort, 4063 were exposed and 7564 were not. A total of 5291 had exposure to nicotinamide. Neither cohort had significant differences in mean age, sex, race, or ethnicity between the nicotinamide exposed and unexposed groups. There was no difference in the cumulative incidence of MACE after nicotinamide exposure in either the VUMC cohort or MVP cohorts. In adjusted cause-specific models stratified by history of prior MACE, there was no significant association between nicotinamide exposure and the primary outcome of MACE in either the VUMC cohort (no prior MACE: hazard ratio [HR], 2.02
95% CI, 0.81-5.05
prior MACE: HR, 0.46
95% CI, 0.22-0.95) or MVP cohort (no prior MACE: HR, 1.07
95% CI, 0.75-1.17
prior MACE: HR, 1.04
95% CI, 0.53-2.06). CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of 13 108 adults from 2 different patient populations, there was no increased risk of MACE in patients with nicotinamide exposure.