Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial

Abstract

Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD+, is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [-4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

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“…Potential adverse effects of blocking drugs include interference with innate immunity for SARM1 and axon growth effects for MYCBP2/PHR1, but mouse data suggest that with careful targeting and/or timing, these risks could be largely avoided. Other points for intervention in the pathway include MAPK inhibition [ 210 ] and supplementation with NAD precursors such as nicotinamide [ 211 ], nicotinamide riboside [ 212 ] or nicotinic acid riboside.…”

Dietary Intervention in Glaucoma

“…16 Nicotinamide has been evaluated as a dietary supplement in patients with glaucoma. 17 Administration of nicotinamide up to 3 g/day prevented dysregulation of key metabolic pathways, loss of internal mitochondrial structure and size, and RGC loss. 18,19 However, the long-term effects of niacin administration are unknown.…”

Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma

“…In a recent study, a significantly lower concentration of nicotinamide (the amide form of vitamin B3) was reported in a cohort of POAG individuals as compared to controls [ 49 ]. In a crossover, double-masked, randomized clinical trial (57 participants with glaucoma), oral nicotinamide supplementation leads to an early improvement in inner retinal function, which is measured as photopic negative response, in glaucoma patients under IOP-lowering medications [ 50 ].…”