Glaucoma Neuroprotection: Still Searching for the Right Notes

Clinical Report: Glaucoma Neuroprotection: Still Searching for the Right Notes

Overview

At AAO 2026 Glaucoma Subspecialty Day, Derek S. Welsbie, MD, reviewed nicotinamide and GLP-1 receptor agonists as potential approaches to optic-nerve neuroprotection. He described promising preclinical and observational signals but emphasized that evidence for preventing or slowing glaucoma progression remains insufficient, with safety questions unresolved.

Background

Glaucoma involves progressive retinal ganglion cell loss, and neuroprotective strategies aim to preserve these cells through mechanisms beyond intraocular pressure reduction. The related literature describes interest in targeting ganglion cells, axons, and vascular support, while the current guideline context identifies IOP reduction as the established disease-modifying approach. Nicotinamide is being studied as an NAD precursor, whereas GLP-1 receptor agonists have been investigated for possible effects on neuroinflammation and glaucoma risk. The clinical relevance of these approaches remains uncertain because available findings include short-term functional measures and observational associations rather than established evidence of slowed progression.

Data Highlights

Approach or evidence	Reported finding	Limitation or concern
Nicotinamide	Preclinical studies reported increased NAD levels and prevention of glaucomatous damage in mice; early human studies reported functional signals, including PhNR changes.	PhNR and individual Humphrey 24-2 test locations are variable measures; short-term functional changes do not establish slower progression.
Nicotinamide plus pyruvate	A short-term study reported improvement at more visual-field locations than placebo.	Individual visual-field locations are subject to considerable measurement variability.
Nicotinamide riboside	A prospective Hong Kong trial found no protective effect against glaucoma progression.	Potentially worse outcomes were reported among older participants.
GLP-1 receptor agonists	Retrospective studies reported lower glaucoma rates among patients with diabetes receiving these agents; a Danish registry analysis associated longer treatment duration with greater apparent protection. Studies in weight-management users also reported reduced glaucoma and ocular-hypertension rates.	Observational studies cannot establish causality or show protection against progression in established glaucoma.
Safety and evidence status	High-dose nicotinamide has been associated with hepatotoxicity; GLP-1 receptor agonists have been associated with rare NAION.	Welsbie called for randomized controlled trials to assess efficacy and safety.

Key Findings

Preclinical work described in the presentation found declining NAD levels in experimental glaucoma and reported that nicotinamide supplementation increased NAD and prevented glaucomatous damage in mice.
Early human nicotinamide studies reported functional signals, including PhNR improvement, but Welsbie cautioned that PhNR is highly variable and that the observed changes may not represent a meaningful treatment effect.
A short-term nicotinamide-plus-pyruvate study reported improvement at more visual-field locations than placebo; the speaker noted that individual Humphrey 24-2 locations are also subject to substantial measurement variability.
A prospective Hong Kong trial of nicotinamide riboside found no protective effect against glaucoma progression, with potentially worse outcomes among older participants.
Retrospective studies associated GLP-1 receptor agonist use with lower glaucoma rates, including a Danish registry analysis in which longer treatment duration was associated with greater apparent protection; these studies do not establish causality or progression benefit.
Welsbie identified high-dose nicotinamide hepatotoxicity and a reported association between GLP-1 receptor agonists and rare NAION as safety considerations, and said randomized controlled trials are needed for both approaches.

Clinical Implications

The presentation does not support routine recommendation of nicotinamide or GLP-1 receptor agonists specifically for glaucoma neuroprotection: Welsbie said he does not routinely recommend either while awaiting stronger trial evidence. The supplied guideline context identifies IOP reduction as the proven disease-modifying strategy and describes IOP-independent neuroprotection as unconfirmed in clinical practice.

Conclusion

Nicotinamide and GLP-1 receptor agonists remain investigational neuroprotective approaches, with encouraging signals but unresolved efficacy and safety questions. Welsbie emphasized the need for randomized controlled trials to determine whether either can prevent glaucoma or slow its progression.