Over-the-counter supplement touted for improving walking distance in PAD

Nicotinamide riboside supplements show a signal of benefit for helping patients with lower extremity peripheral arterial disease (PAD) walk more, according to a group of US-based investigators.

In a preliminary, double-blind randomized clinical trial, a total of 90 patients (mean age 71.2 years, 46.7 percent female, 47.8 percent Black) were randomly assigned to receive placebo (n=29) or nicotinamide riboside alone (two 250-mg pills twice daily, n=28) or with resveratrol (one 125-mg pill daily, n=33) for 6 months.

At the end of the intervention, the primary endpoint of 6-minute walking distance increased by 7.0 m in the nicotinamide riboside alone group and decreased by 10.6 m in the placebo group (between-group difference, 17.6, 90 percent confidence interval [CI], 1.8 to ∞; p=0.08). The nicotinamide riboside plus resveratrol group also showed a decrease of 6.9 m (between-group difference vs placebo, 3.7, 90 percent CI, −11.2 to ∞; p=0.38). [Nat Commun 2024;15:5046]

“This is a signal that nicotinamide riboside could help these patients,” said senior study author Prof Christiaan Leeuwenburgh from the University of Florida in Gainesville, Florida, US.

While the magnitude of improvement in 6-min walking distance at 6 months was greater in the nicotinamide riboside alone group than in the nicotinamide riboside plus resveratrol group, the difference between them was not statistically significant, as Leeuwenburgh pointed out. This difference in effectiveness, however, might be explained by adherence to the treatment, he added.

Notably, 75 percent of patients in the nicotinamide riboside alone group took ≥75 percent of the study pills, whereas only 52 percent of those in the nicotinamide riboside plus resveratrol group did so. In this subset of patients who took at least 75 percent of the study pills, the 6-min walking distance increased by 31.0 m with nicotinamide riboside alone and by 26.9 m with the addition of resveratrol when compared with placebo.

Secondary outcomes such as 6-min walking distance at 3 months significantly increased with nicotinamide riboside alone (between-group difference, 22.4 m, 90 percent CI, 7.3 to ∞; p=0.029) and nicotinamide riboside plus resveratrol (between-group difference, 20.6 m, 90 percent CI, 6.3 to ∞; p=0.034) relative to placebo. Moreover, the nicotinamide riboside alone group showed numerical improvements in 6-month peak treadmill walking time compared with the placebo group (between-group difference, 2.1 min, 90 percent CI, 0.24 to ∞; p=0.08). 

In terms of safety, the nicotinamide riboside plus resveratrol group had higher rates of diarrhoea (54.6 percent vs 39.3 percent in the nicotinamide riboside alone group and 27.6 percent in the placebo group) and nausea or emesis (36.4 percent vs 14.3 percent and 24.1 percent, respectively). One patient who received placebo experienced chest pain during the 6-min walking distance test at the 3-month follow-up and later underwent coronary artery bypass grafting. No other serious adverse events were reported.

Available as an over-the counter supplement, nicotinamide riboside is a precursor to NAD+, which has been shown to play a role in increased sirtuin1 expression and improved skeletal muscle health, mitochondrial activity, and nitric-oxide-mediated endothelial function. [Cell Rep 2019;28:1717-1728; Aging Cell 2016;15:522-530; Science 2016;352:1436-1443]

In an exploratory analysis, Leeuwenburgh and colleagues found that patients in the nicotinamide riboside alone group had increased gastrocnemius muscle satellite cell abundance compared with those in the placebo group (between-group difference, 11.14 satellite cells/100 fibres; p=0.06).