Nicotinamide riboside improves gait in patients with peripheral arterial disease

Patients with peripheral arterial disease (PAD) who took nicotinamide riboside (NR) experienced significant improvements in their six-minute walk distance compared with a placebo, according to the authors of a study published in 2010. Nature Communications.¹

There are few effective treatments for PAD, which can cause severe walking problems. Researchers say PAD is caused by inadequate supply of nutrients and oxygen to lower limb skeletal muscles, which can lead to muscle fiber damage, inhibition of mitochondrial function, and increased oxidative stress in the legs.¹

NR is a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for mitochondrial respiration. Studies have shown that higher levels of NAD+ improve mitochondrial activity and skeletal muscle health. Zhang et al. found that oral NR supplementation in mice increased mitochondrial activity, enhanced limb muscle strength, and improved endurance during running. NR also enhanced muscle function and prevented muscle stem cell loss in mice.²

This study, combined with pilot studies showing increased NAD+ in human blood after a single dose of oral NR,³ The researchers in this study were guided to see if NR could improve the 6-minute walk distance in PAD patients compared to a placebo. Additionally, the researchers combined NR with resveratrol, a natural polyphenol that can increase the affinity for NAD+, to see if it could further enhance function in PAD patients.

The study included 90 randomly selected participants, with 89 completing the 6-month follow-up. Mean age was 71.2 years (SD: 9.1). The proportion of participants who were 75% or more adherent to taking the pills was 75% for NR, 52% for NR plus resveratrol, and 76% for placebo, the researchers wrote.¹

NR improved 6-minute walk distance by 17.6 meters (57.7 feet) (90% CI: +1.77, +∞, P = 0.08) improved at 6-month follow-up compared to placebo. However, the combination of NR and resveratrol did not significantly improve 6-minute walk distance at 6-month follow-up compared to placebo (+3.65 m). [90% CI: -11.2, +∞, P = 0.38]).¹

A post-hoc analysis of the study results showed that among those who were at least 75% adherent to the study medication, NR alone significantly improved 6-minute walk distance by 31.0 meters (101.7 feet), whereas NR plus resveratrol improved 6-minute walk distance by 26.9 meters (88.2 feet).¹

About the trial

Trial Name: Nicotinamide riboside with and without resveratrol improves function in peripheral arterial disease (NICE)

ClinicalTrials.gov Identifier: NCT03743636

sponsor: Northwestern University

Completion date: May 23, 2023

“This suggests that nicotinamide riboside may be able to help these patients,” senior author Christian Leeuwenberg, PhD, professor of physiology and gerontology at the University of Florida, said in a news release.^Four

According to the study authors, no randomized clinical trials have been conducted to date to demonstrate the benefits of NR on walking ability in humans.¹

Of note, the difference in improvement in 6-minute walk distance between the NR alone and NR + resveratrol groups was not statistically significant. Interestingly, the researchers observed lower adherence rates with the NR + resveratrol compared to the NR alone group.¹

Participants randomly assigned to receive the combination of NR and resveratrol also experienced higher rates of nausea and diarrhea, and the researchers noted that these two factors may be the reason why the NR and resveratrol group did not see significant improvements.¹

One of the study's major limitations, the researchers acknowledged, is the sample size: “We would like to conduct a larger follow-up study to validate our findings,” Lieuwenburg said, and he also hopes to test NR in a group of healthy older adults before making treatment recommendations for healthy individuals.^Four

References

1. McDermott MM, Martens CR, Domanchuk KJ, et al. Nicotinamide riboside for peripheral arterial disease: the NICE randomized clinical trial. NatCommon. 2024;15:5046. doi:10.1038/s41467-024-49092-5

2. Trammell S, Schmidt M, Weidemann B, et al. Nicotinamide riboside exhibits unique oral bioavailability in mice and humans. NatCommon2016;7:12948. doi:10.1038/ncomms12948

3. Zhang H, Ryu D, Wu Y, et al. “NAD+ supplementation improves mitochondrial and stem cell function and extends lifespan in mice.” Science2016;352(6292):1436-1443. doi:10.1126/science.aaf2693

4. EurekAlert! Over-the-Counter Supplement Improves Walking in Patients with Peripheral Arterial Disease. University of Florida. Press Release. Published June 18, 2024. Accessed June 24, 2024. https://www.eurekalert.org/news-releases/1048639