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Diabetic patients treated with GLP-1 receptor agonists (GLP-1RAs) had a significantly lower risk of developing glaucoma as compared with metformin, a large retrospective cohort study showed.

Patients treated with a GLP-1RA agonist had a 41-50% lower relative risk of developing primary open-angle glaucoma (POAG) after 1-3 years of follow-up. A similar protective advantage for GLP-1RAs versus metformin was evident for ocular hypertension and initiation of first-line therapy for POAG.

The findings highlight GLP-1RAs' potential benefits beyond glycemic control, reported Iqbal Ike K. Ahmed, MD, of the University of Utah in Salt Lake City, and co-authors in .

"Our findings reveal that the neuroprotective actions of [GLP-1RAs], including their anti-inflammatory, antioxidative properties, potentially IOP-lowering effects, may begin to confer benefits within the first 3 years of therapy," the authors stated. "These insights highlight the importance of incorporating GLP-1 receptor agonists into the clinical management of diabetic patients."

The results added to a growing volume of evidence that GLP-1RAs agonists -- such as semaglutide (Ozempic) and liraglutide (Victoza) -- afford glaucoma protection for patients with type 2 diabetes.

, Danish researchers reported that second-line GLP-1RA therapy reduced the risk of glaucoma in diabetic patients by 15-20% over 3 years as compared with other second-line therapies. Also this year, Taiwanese investigators reported a significant association between a and a reduced risk of glaucoma in patients with type 2 diabetes. showed a 44% reduction in the glaucoma hazard for patients exposed to a GLP-1RA versus no exposure.

From a mechanistic perspective, GLP-1RAs have demonstrated neuroprotective effects in clinical and preclinical studies of neurodegenerative disorders, Ahmed and co-authors noted in their discussion. The agents have been shown to reduce inflammation and oxidative stress, improve neuronal survival and function by activating signaling pathways to enhance cellular resistance and reduce apoptotic cell death, and mitigate inflammatory responses in the retina.

To compare the effects of GLP-1RAs and metformin on glaucoma risk, investigators queried the health research network. The analysis included data from 120 healthcare organizations in 17 countries. Propensity score matching (PSM) was used to balance covariates, including demographics, comorbidities, and medication use. The primary outcomes were the incidence of POAG, ocular hypertension, and the need for first-line treatments for glaucoma (including beta-blockers, prostaglandin analogs, brimonidine, brinzolamide, dorzolamide, netarsudil [Rocklatan, Rhopressa], and laser trabeculoplasty).

Outcomes were assessed after 1, 2, and 3 years of follow-up. After PSM, the study population comprised 61,998 patients at 1 year, 27,414 at 2 years, and 14,100 at 3 years.

As compared with metformin, use of GLP-1RAs was associated with a significantly reduced risk of POAG at all three follow-up periods:

• 1 year: Relative risk (RR) 0.59, 95% CI 0.39-0.88
• 2 years: RR 0.50, 95% CI 0.32-0.78
• 3 years: RR 0.59, 95% CI 0.37-0.94

A similar pattern emerged for the association between GLP-1RAs and ocular hypertension:

• 1 year: RR 0.44, 95% CI 0.31-0.62
• 2 years: RR 0.43, 95% CI 0.30-0.62
• 3 years: RR 0.51, 95% CI 0.34-0.75

Initiation of first-line therapy for glaucoma also occurred significantly less often with GLP-1RAs

• 1 year: RR 0.63, 95% CI 0.53-0.74
• 2 years: RR 0.71, 95% CI 0.59-0.85
• 3 years: RR 0.75, 95% CI 0.62-0.91

The authors acknowledged several limitations of the research: accuracy and reliability of the PSM model, in ability of a PSM model to take into account confounding by unmeasured variables, inaccuracies in coding of medical data, and racial/ethnic and socioeconomic inequities in GLP-1RA prescribing patterns.

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