The American Glaucoma Society (AGS) and the American Academy of Ophthalmology (AAO) have issued new guidelines regarding the use of nicotinamide supplementation as a neuroprotective agent for patients with open-angle glaucoma. AGS President Carla J. Siegfried, MD, highlighted the new guidelines, which were recently published in Ophthalmology Glaucoma, during remarks at the organization’s annual meeting in Washington, DC.

In recent years, interest has grown in identifying neuroprotective agents that can slow, and potentially repair, retinal ganglion cell damage caused by glaucoma.¹ Laboratory studies in mouse models have suggested that supplementation with nicotinamide, a form of vitamin B3, may improve mitochondrial function and protect retinal cells from damage.² In early human trials, patients taking high doses of nicotinamide (≥3 g/day) showed improvements in retinal function and visual field testing.^3,4 These findings have spurred a clinical trial in the United States led by Columbia University in New York City, as well as additional trials in the United Kingdom, Sweden, South Korea, and elsewhere, with a target enrollment of more than 1,300 participants.

However, safety concerns have emerged. Liver toxicity is a well-documented side effect of niacin (nicotinic acid), another form of vitamin B3, but nicotinamide has generally been considered safer. However, the daily nicotinamide dose used in glaucoma trials (3 g/day) is significantly higher than the recommended daily intake (20 mg/day). Dr. Siegfried said that Aakriti Garg Shukla, MD, MSc, and colleagues at Columbia University recently alerted the Society to 2 cases of drug-induced liver injury (DILI) in glaucoma neuroprotection trials. One case involved a 73-year-old woman in the United States who developed severe liver enzyme elevations and was hospitalized. Another case in Singapore involved a 69-year-old woman who experienced jaundice and gastrointestinal symptoms. Both patients recovered after discontinuing the supplement, but their cases underscore the risks associated with high-dose nicotinamide use.

“This is potentially a very serious issue for our patients and the public in regards to the use of nicotinamide, especially in higher doses,” said Dr. Siegfried on Saturday morning at the AGS meeting. “People may think that the supplements are completely harmless, but there can be very serious implications.”

Because nicotinamide is not approved as a glaucoma treatment and its safety remains unknown, Dr. Siegfried explained that AGS and AAO recommend the following guidelines regarding nicotinamide supplementation:

• Given the potential for drug-induced liver injury, nicotinamide should not be used at high doses (≥3 g/day) outside of clinical trials, during which liver function is closely monitored.
• If doses <3 g/day of nicotinamide are being considered, collaboration with the primary care physician (PCP) is necessary and frequent liver function testing should be performed.
• Patients should be advised of possible side effects of nicotinamide and urged to report them immediately to their PCP or emergency room. Patients enrolled in a clinical trial who exhibit symptoms should also report them to the study investigators.
• Patients with current or prior liver disease should not be offered nicotinamide supplementation.
• Although niacin is a form of vitamin B3, it is not interchangeable with nicotinamide. Niacin is not being tested as a neuroprotective agent in human glaucoma trials, and it is known to be hepatotoxic in high doses. The AGS and AAO strongly recommend against the use of niacin for glaucoma neuroprotection. GP

References

1. Downs JC, Fleischman D; 2020–2022 Research Committee of the American Glaucoma Society and the 2020–2022 Glaucoma Clinical Committee of the American Society of Cataract and Refractive Surgery. Unmet needs in the detection, diagnosis, monitoring, treatment, and understanding of primary open-angle glaucoma: a position statement of the American Glaucoma Society and the American Society of Cataract and Refractive Surgery. Ophthalmol Glaucoma. 2022;5(5):465-467. doi:10.1016/j.ogla.2022.02.008

2. Williams PA, Harder JM, Foxworth NE, et al. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science. 2017;355(6326):756-760. doi:10.1126/science.aal0092

3. De Moraes CG, John SWM, Williams PA, Blumberg DM, Cioffi GA, Liebmann JM. Nicotinamide and pyruvate for neuroenhancement in open-angle glaucoma: a phase 2 randomized clinical trial. JAMA Ophthalmol. 2022;140(1):11-18. doi:10.1001/jamaophthalmol.2021.4576

4. Hui F, Tang J, Williams PA, et al. Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: a crossover randomized clinical trial. Clin Exp Ophthalmol. 2020;48(7):903-914. doi:10.1111/ceo.13818