Dipeptidyl Peptidase-4 Inhibitors Lower POAG, NTG Risk in Diabetes Patients

In previous studies, DPP4i have demonstrated potential neuroprotective effects independent of glycemic control, which may have contributed to the reduced risk of glaucoma observed in this study. This chart from the study shows a significantly lower cumulative incidence of POAG in DPP4i vs. non-DPP4i users. Photo: Lu Y-A, et al. Ophthalmol Sci. May 8, 2025. Click image to enlarge. As the number of type 2 diabetes patients rises, so does the increased risk of glaucoma for these individuals. While metformin and, more recently, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are therapeutics to help reduce blood sugar, another medication may offer additional benefits—dipeptidyl peptidase-4 inhibitors (DPP4i). In a recent study, researchers investigated the association between DPP4i and the risk of primary open-angle glaucoma and normal-tension glaucoma in diabetes patients; they found patients on this drug had a significantly lower risk compared to users of first-generation diabetes medication, such as metformin, among others. The findings were published earlier this Wednesday in Ophthalmology Science.A total of 582,710 type 2 diabetes patients treated with either DPP4i or non-DPP4i meds (control group) were analyzed between 2008 and 2021. Subgroup analysis assessed the consistency of this association across various demographic and clinical subgroups and the risk reduction was more pronounced with increasing age and among patients with or without diabetic-related complications, including diabetic retinopathy, diabetic kidney disease and diabetic neuropathy.Previous studies that focused on incretin-related mechanisms found that the beneficial effects associated with DPP4i on neurodegenerative diseases are likely multifactorial, encompassing both incretin-dependent and incretin-independent pathways.“For example, in a rat model of cisplatin-induced neurotoxicity, DPP4i (vildagliptin) significantly increased levels of AMP-activated protein kinase, protein kinase B and cAMP response element-binding protein—key components of the incretin signaling pathway—thereby alleviating neuroinflammation and cognitive decline,” the researchers wrote in their paper on the work.There were similar results in another study that showed the use of DPP4i (sitagliptin) elevated central nervous system incretin levels in a rodent model of PD, reducing inflammatory markers in the brain.“These findings underscore the complex interplay of pathways in modulating inflammation as well as promoting neuroregeneration, which may contribute to the observed association between DPP4i use and glaucoma,” the authors explained in their article.DPP4i drugs exhibit both direct and indirect antioxidant effects by reducing reactive oxygen species production and disrupting the feedback loop through inhibition of advanced glycation end-products and their receptor interactions, the authors wrote. In a previous study with diabetic animal models, DPP4i (linagliptin) significantly decreased reactive oxygen species and methylglyoxal levels, and it also preserved cell numbers in the ganglion cell layer, maintaining levels comparable to non-diabetic controls.“These antioxidative properties, combined with their ability to remodel ocular connective tissue, may explain the associations observed in our study,” the authors wrote in their paper. “This suggests that DPP4i may mitigate some of the oxidative toxicity as well as structural changes associated with glaucoma progression.”Lastly, DPP4i agents also demonstrated efficacy in reducing glutamate concentrations and preserving glutamate-aspartate transporter levels in diabetic models. “For instance, topical DPP4i (saxagliptin and sitagliptin) treatment significantly reduced retinal glutamate levels to those comparable with controls and prevented glutamate-aspartate transporter downregulation in diabetic rat model, highlighting its potential neuroprotective effects independent of glycemic control,” the authors explained in their article. “These mechanisms may contribute to the reduced risk of glaucoma observed among DPP4i users in our study.”Overall, these findings suggest that DPP4i drugs may offer benefits beyond glycemic control, possibly influencing optic nerve health through multiple mechanisms. Further research is needed to explore the underlying mechanisms and their implications for glaucoma prevention and management, the authors concluded.Click here for the journal source. Lu Y-A, Tien P-T, Cheng Y-D, et al. Association of dipeptidyl peptidase-4 inhibitors with glaucoma risk in patients with type 2 diabetes: a nationwide cohort study. Ophthalmol Sci. May 8, 2025. [Epub ahead of print.]