Nicotinamide Riboside Improves Walking in Patients With Peripheral Artery Disease

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Compared to placebo, nicotinamide riboside significantly improved the 6-minute walking capabilities in patients with decreased endurance and muscle function due to peripheral artery disease.

Individuals with peripheral artery disease (PAD) who took nicotinamide riboside (NR) meaningfully improved their 6-minute walking distance compared to placebo, according to the authors of a study published in Nature Communications.1

PAD - Peripheral Artery Disease written on sticky note isolated on wooden table.

Image credit: syahrir | stock.adobe.com

Few effective treatments are available for PAD, which can cause severe walking disability. In PAD, there is insufficient nutrient and oxygen delivery to the lower extremity skeletal muscles, which can cause damaged muscle fibers, inhibit mitochondria function, and increase oxidative stress on the legs, according to the investigators.1

NR is a precursor to nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for mitochondrial respiration. Studies have indicated that a greater abundance of NAD+ can improve mitochondrial activity and skeletal muscle health. Zhang et al found that, in mice, oral NR increased mitochondrial activity and improved limb strength, as well as enhanced endurance while running. NR also enhanced muscle function and protected mice from the loss of muscle stem cells.2

This research, along with literature from a pilot study (indicating increased NAD+ in human blood in an individual after 1 dose of oral NR),3 guided the investigators of the current study as they sought to determine whether NR could improve the 6-minute walking distance of patients with PAD compared to placebo. Additionally, the investigators examined resveratrol, which is a naturally occurring polyphenol that could increase affinity for NAD+, in conjunction with NR to see if it would induce additional functioning in patients with PAD.

There were 90 randomized participants involved in the study, and 89 participants that completed 6-month follow-up. The mean age was 71.2 years (SD: 9.1). The proportions of individuals with at least 75% adherence to pills were 75% for NR, 52% for NR plus resveratrol, and 76% for placebo, the investigators wrote.1

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

Among those with at least 75% adherence to the study pills, NR alone significantly improved 6-minute walking distance by 31.0 meters (101.7 feet), while NR plus resveratrol improved 6-minute walking distance by 26.9 meters (88.2 feet), according to post-hoc analyses of the study results.1

About the Trial

Trial Name: Nicotinamide Riboside With and Without Resveratrol to Improve Functioning in Peripheral Artery Disease (NICE)

ClinicalTrials.gov Identifier: NCT03743636

Sponsor: Northwestern University

Completion Date: May 23, 2023

“This is a signal that nicotinamide riboside could help these patients,” said senior author Christiaan Leeuwenburgh, PhD, professor of physiology and aging at the University of Florida, in a news release.4

According to the study authors, there have been no previously conducted randomized clinical trials that demonstrated the benefits of NR on walking performance in any human population.1

Notably, the difference in improvement of 6-minute walking distance between the NR alone group compared to the NR plus resveratrol group was not statistically significant. Interestingly, the investigators observed poorer adherence to NR plus resveratrol compared to NR alone.1

Individuals randomized to NR plus resveratrol also noted higher rates of nausea and diarrhea. The investigators noted these 2 factors as potential reasons why there was no significant improvement in the NR plus resveratrol group.1

One major limitation of the study that the investigators acknowledged was its sample size. “We are hoping to conduct a larger follow-up trial to verify our findings,” Leeuwenburgh said, who also hopes to test NR in a group of healthy older adults before any treatment recommendations are made for healthy individuals.4

References
  1. McDermott MM, Martens CR, Domanchuk KJ, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun. 2024;15:5046. doi:10.1038/s41467-024-49092-5
  2. Trammell S, Schmidt M, Weidemann B, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948. doi:10.1038/ncomms12948
  3. Zhang H, Ryu D, Wu Y, et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-1443. doi:10.1126/science.aaf2693
  4. EurekAlert! Over-the-counter supplement improves walking for peripheral artery disease patients. University of Florida. Press release. Released June 18, 2024. Accessed June 24, 2024. https://www.eurekalert.org/news-releases/1048639
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