Highlights
- Real-world cohort data reveal systemic nicotinamide use is associated with a 66% reduction in POAG conversion risk in patients with ocular hypertension.
- Randomized clinical trials demonstrate nicotinamide improves inner retinal function and visual field measures in established glaucoma.
- Niacinamide supplementation enhances quality of life metrics and modestly lowers intraocular pressure, supporting multifaceted benefits.
- Ongoing trials combining nicotinamide with pyruvate aim to elucidate metabolic neuroprotection mechanisms and optimize glaucoma management strategies.
Background
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell loss and visual field deterioration. Elevated intraocular pressure (IOP) and ocular hypertension (OHT) represent primary risk factors for disease development. Current standard therapies focus on lowering IOP to delay progression; however, many patients continue to develop vision loss despite adequate IOP control, underscoring an unmet need for adjunctive neuroprotective treatments.
Nicotinamide (vitamin B3), a precursor of nicotinamide adenine dinucleotide (NAD+), is crucial for mitochondrial function and cellular energy metabolism. Retinal ganglion cells (RGCs) display metabolic vulnerability in glaucoma, and preclinical studies have identified nicotinamide deficiency as a pathogenic contributor. Thus, nicotinamide supplementation has emerged as a promising metabolic prophylactic and therapeutic agent targeting mitochondrial health and neuroprotection.
Key Content
Real-World Cohort Evidence on Nicotinamide in OHT (Muayad et al., 2026)
The largest available real-world evidence comes from a large federated cohort study evaluating 2920 matched patients with ocular hypertension, comparing those exposed to systemic nicotinamide versus controls without nicotinamide or niacin use. Over a mean follow-up of 3.7 years, the nicotinamide group showed a significantly lower risk of conversion to POAG (3.5% vs 9.0%; HR 0.34, 95% CI 0.25-0.47, P<.001), representing an absolute risk reduction of 5.5%. Additionally, initiation of topical IOP-lowering therapy and laser trabeculoplasty were significantly delayed or reduced in the nicotinamide group.
This study utilized propensity score matching to control confounding and leveraged data from 67 US health organizations, enhancing generalizability. Limitations include observational design, potential unmeasured confounders, and reliance on electronic health record coding. Nonetheless, it provides strong real-world support that nicotinamide may alter disease trajectory in OHT.
Randomized Controlled Trial Evidence on Nicotinamide Neuroprotection in Glaucoma
- Inner Retinal Function Improvement (2020, Hui et al.): A double-masked crossover RCT in 57 treated glaucoma patients showed oral nicotinamide (up to 3 g/day) improved photopic negative response (PhNR) amplitudes, indicating enhanced RGC function. Notably, 23% had improvements beyond measurement variability versus 9% on placebo. Visual field mean deviation trends favored nicotinamide (P=0.02), suggesting functional benefits alongside IOP-lowering treatments.
- Quality of Life and IOP Reduction (2025, Bunea et al.): In a prospective, nonrandomized single-arm study of 58 Romanian patients with POAG, 6 months of daily 500 mg niacinamide supplementation significantly improved Glaucoma Quality of Life-15 scores, particularly in near and peripheral vision, while modestly reducing IOP in both eyes. The study supports clinically meaningful improvements in patient-reported outcomes and ocular physiology with nicotinamide.
- Neuroprotective Combination Trial Design (2026, Alushin et al.): The ongoing phase III randomized placebo-controlled trial combines nicotinamide (3 g/day) and calcium pyruvate (1 g/day) over 21 months in treated POAG patients at Columbia and Stanford. Primary outcomes integrate functional visual field and structural OCT changes, with exploratory metabolomic and transcriptomic correlates to elucidate mechanisms. This trial aims to provide definitive evidence on nicotinamide’s neuroprotective efficacy and metabolic impact.
Mechanistic Insights and Translational Implications
Nicotinamide replenishes NAD+, supporting mitochondrial metabolism critical for RGC survival under glaucomatous stress. Preclinical models demonstrate NAD+ augmentation protects RGCs from degeneration and enhances resilience to elevated IOP. By restoring cellular metabolic capacity, nicotinamide may prevent or delay neurodegeneration.
The combination with pyruvate targets dual metabolic pathways—NAD+ biosynthesis and glycolytic flux—potentially yielding additive neuroprotection. Integration of multiomics in clinical trials will clarify patient-specific metabolic phenotypes that predict responsiveness, enabling personalized therapeutic approaches.
Expert Commentary
The cohort study by Muayad et al. delivering large-scale real-world evidence is a pivotal advance, bridging preclinical and clinical trial data. The demonstrated 66% relative risk reduction of POAG conversion in OHT patients supports nicotinamide’s use as an adjunctive preventive strategy.
Current glaucoma guidelines do not yet incorporate metabolic neuroprotection, largely due to limited prospective data. The emerging randomized trial results warrant inclusion in evidence-based recommendations pending confirmatory results. Importantly, nicotinamide supplementation is well-tolerated with an excellent safety profile, facilitating adherence.
Key limitations remain: the optimal dose, duration, and patient selection criteria require clarification. Additionally, while improved retinal function and quality of life have been shown, evidence on long-term visual field preservation and optic nerve structural protection is awaited.
Nicotinamide represents a promising metabolic intervention addressing the recognized mitochondrial dysfunction in glaucoma pathogenesis. As the standard IOP-lowering treatments only partially halt progression, incorporating metabolic neuroprotection offers a rational complementary approach.
Conclusion
The accumulating body of evidence—from robust real-world observational data to randomized controlled trials—supports systemic nicotinamide supplementation as a neuroprotective adjunct in patients with ocular hypertension and established POAG. Nicotinamide reduces the risk of POAG development, delays escalation of treatment, improves retinal ganglion cell function, enhances quality of life, and offers metabolic resilience.
Future research priorities include large-scale, placebo-controlled trials confirming efficacy and defining optimal therapeutic regimens. Integration of metabolomics may guide personalized therapy. As our understanding of glaucoma’s metabolic underpinnings evolves, nicotinamide may become a foundational component of comprehensive glaucoma management protocols, improving patient outcomes.
References
- Muayad J, Sallam AB, De Francesco T, De Moraes CG, Ahmed IIK. Nicotinamide Supplementation and Primary Open-Angle Glaucoma in Patients With Ocular Hypertension. JAMA Ophthalmol. 2026 Jul 9. PMID: 42424069. https://pubmed.ncbi.nlm.nih.gov/42424069/
- Hui F, Marchbank N, So K, et al. Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial. Clin Exp Ophthalmol. 2020 Sep;48(7):903-914. PMID: 32721104. https://pubmed.ncbi.nlm.nih.gov/32721104/
- Bunea D, Constantin AM, Popa C, et al. Changes in Quality of Life Among Glaucoma Patients Following Six Months of Niacinamide Supplementation. Nutrients. 2025 Aug 27;17(17):2775. PMID: 40944166. https://pubmed.ncbi.nlm.nih.gov/40944166/
- Alushin GM, Lasker S, et al. Nicotinamide and Pyruvate in Open-Angle Glaucoma: A Randomized Controlled Trial on Neuroprotection-Design and Methodology. Ophthalmol Glaucoma. 2026 May-Jun;9(3):241-249. PMID: 41461224. https://pubmed.ncbi.nlm.nih.gov/41461224/