Nicotinamide Exposure Did Not Raise Major Cardiovascular Event Risk in Two Cohorts
Concern around nicotinamide has grown because metabolite signals have raised the possibility of cardiovascular harm, especially in older adults already living with substantial vascular risk. This retrospective analysis brings the question back to the bedside with two large real-world cohorts and a single clinical endpoint: major adverse cardiovascular events, or MACE.
The bottom line is direct. Across 13,108 adults drawn from Vanderbilt University Medical Center and the Million Veteran Program, nicotinamide exposure was not associated with an increased risk of MACE.
Large Real-World Cohorts, Same Clinical Question
Investigators used electronic health record data from two separate populations collected over a long interval, from January 1989 through February 2024, with analysis conducted from March to December 2024. The dual-cohort structure matters because it tested the same safety concern in two different clinical environments: one anchored in manual review and documented recommendation patterns at Vanderbilt, the other in a propensity-matched veteran cohort.
The overall study population was older and predominantly male. Among the 13,108 included patients, 11,926 were men, representing 91.0% of the sample, and the mean age was 66.8 years. In the Vanderbilt cohort, 1,228 patients had confirmed nicotinamide exposure and 253 were unexposed. In the Million Veteran Program cohort, 4,063 were exposed and 7,564 were not.
Exposure classification differed slightly between cohorts, but the clinical objective remained the same: determine whether nicotinamide use tracks with a higher incidence of MACE. The primary outcome relied on a validated phenotype, giving the analysis a clinically grounded endpoint rather than a loosely defined administrative signal.
No Signal for Higher MACE in Either Population
The event curves did not separate in a way that suggested excess harm from nicotinamide. Neither cohort showed a significant difference in cumulative incidence of MACE between exposed and unexposed patients.
In adjusted cause-specific models stratified by prior cardiovascular history, the estimated risks remained statistically non-significant in the key comparisons. In the Vanderbilt cohort, among patients with no prior MACE, the hazard ratio was 2.02 with a 95% CI of 0.81 to 5.05; among those with prior MACE, the hazard ratio was 0.46 with a 95% CI of 0.22 to 0.95. In the Million Veteran Program cohort, the hazard ratio was 1.07 with a 95% CI of 0.75 to 1.17 in patients without prior MACE and 1.04 with a 95% CI of 0.53 to 2.06 in those with prior MACE.
One sentence captures the clinical significance: there was no increased risk signal that would justify treating nicotinamide as a cardiovascular hazard on the basis of these data.
What the Biology Had Raised — and What the Data Do Not Support
The concern behind this study came from metabolite biology, not from a known clinical toxicity pattern. Nicotinamide sits within the broader niacin-related metabolic pathway, and metabolomic associations can generate legitimate concern when a compound appears linked to vascular risk. In practice, though, biomarker signals do not automatically translate into patient-level harm.
This study tested that gap between mechanism and outcomes. If nicotinamide were truly provoking clinically meaningful vascular injury, a signal would be expected to emerge in older, comorbid populations with substantial background cardiovascular risk. Instead, the adjusted analyses did not show a reproducible excess in MACE after exposure. The data are especially relevant because nicotinamide is widely used in dermatologic practice, often in patients taking it chronically and often without much discussion of cardiovascular safety.
The stratified results deserve careful reading. The Vanderbilt subgroup with prior MACE showed a hazard ratio below 1, while the no-prior-MACE subgroup showed a wide confidence interval that crossed 1.0. Those estimates are not a signal of protective effect; they are a reminder that smaller subgroup analyses can be unstable, especially when event counts are limited. The more consistent finding is the absence of a harmful association across both cohorts and both exposure histories.
Practical Meaning for Dermatology and Primary Care
For clinicians prescribing nicotinamide, these findings are reassuring. The study directly addresses a safety concern that could have altered prescribing behavior, especially for patients using nicotinamide for dermatologic indications or supplement-based prevention strategies. Based on these data, nicotinamide exposure alone should not be presumed to increase MACE risk.
Still, the study does not turn nicotinamide into a cardiovascular therapy, and it does not erase the usual need to manage baseline risk factors. Patients enrolled in the cohorts were older, predominantly male, and drawn from real-world clinical systems; their cardiovascular risk profiles likely reflected the complexity of routine practice. The analysis also remains retrospective, so residual confounding, exposure misclassification, and differences in how nicotinamide was recorded can never be fully eliminated.
Even so, the clinical message is useful because it is anchored in outcome data rather than speculation. In a setting where metabolite studies had raised concern, two distinct cohorts failed to show an increase in MACE after nicotinamide exposure.
The Remaining Boundary Conditions Around This Safety Signal
This study answers one question and leaves several others open. It does not define whether very long-term use, higher doses, or specific high-risk subgroups behave differently. It also does not settle whether nicotinamide metabolites might have other biologic effects that fall outside the MACE endpoint.
What it does establish is narrower and more actionable: among 13,108 adults in two retrospective cohorts, nicotinamide exposure was not associated with increased major cardiovascular event risk. For a drug often used quietly and repeatedly in outpatient care, that absence of harm carries practical weight, even as the retrospective design limits causal certainty.