GLP-1RAs may increase ischemic optic neuropathy risk

1. In this target trial emulation, glucagon-like peptide-1 receptor agonist (GLP-1RA) use was associated with a small increase in the risk of ischemic optic neuropathy (ION) among adults with type 2 diabetes (T2D).

2. The increased risk of ION associated with GLP-1RA use was most pronounced among patients aged 50 years or older, men, and those with pre-existing eye disease.

Evidence Rating Level: 2 (Good)

Study Rundown: Non-arteritic anterior ischemic optic neuropathy (NAION), caused by reduced blood flow to the optic nerve, is the most common form of ischemic optic neuropathy (ION) and the second-leading cause of blindness in middle-aged and older adults. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial cardiovascular, renal, and metabolic benefits in type 2 diabetes (T2D), their association with NAION remains uncertain. This target trial emulation evaluated whether GLP-1RAs were associated with ION, which served as a proxy for NAION because no NAION-specific diagnostic codes were available. GLP-1RA use was associated with a modestly higher incidence of ION than sodium-glucose cotransporter-2 inhibitors (SGLT-2is) or dipeptidyl peptidase-4 inhibitors (DPP4is), including after adjustment for age and sex. Findings were generally consistent across baseline diabetes treatments, although metformin users had slightly more ION cases than SGLT-2i or DPP4i users. Most ION cases among GLP-1RA users occurred in patients aged 50 years or older and in men, both of whom experienced more events than comparable SGLT-2i or DPP4i users. Risk was also higher among patients with pre-existing eye disease. Among individuals using medications for weight loss, 14 ION cases occurred with GLP-1RAs compared with none among users of bupropion-naltrexone or phentermine-topiramate. Although limited by the lack of NAION-specific diagnostic codes and potential residual confounding, the findings suggest GLP-1RAs may modestly increase the risk of ION while underscoring the need to balance this potential risk against their established cardiometabolic benefits.

Click to read this study in AIM

Relevant Reading: Once-weekly semaglutide doubles the five-year risk of nonarteritic anterior ischemic optic neuropathy in a Danish cohort of 424,152 persons with type 2 diabetes

In-Depth [prospective cohort]: This target trial emulation evaluated the association between GLP-1RA use and risk of ION. Adults with T2D initiating a new glucose-lowering therapy between January 2017 and December 2022 were identified using the Merative MarketScan Commercial Claims and Encounters database. Patients were excluded if they had prior NAION or other ION, previous use of GLP-1RAs, SGLT2is, or DPP4is, or contraindications to study medications. The primary outcome was 18-month risk of ION (used as a proxy for NAION) per 10,000 patients and corresponding risk differences (RDs). The study included 161,489 GLP-1RA initiators, 122,114 SGLT2i initiators, and 86,047 DPP4i initiators. GLP-1RA users were generally younger, more often female, and more likely to have obesity and prior insulin use. During median follow-up of 424 days, 81 ION cases occurred among GLP-1RA users compared with 48 cases among SGLT2i users (median follow-up, 438 days), corresponding to an 18-month risk of 8.5 versus 5.5 cases per 10,000 patients (RD, 3.0; 95% [confidence interval] CI, 0.4-5.7). Compared with DPP4i users (33 cases; median follow-up, 477 days), the 18-month risk was 7.8 versus 4.2 per 10,000 patients (RD, 3.6; 95% CI, 1.1-6.1). Age- and sex-adjusted analyses produced similar results. Subgroup analyses showed larger RDs among patients receiving two or more diabetes medications, adults aged 50-65 years (5.3 and 5.4 per 10,000 vs SGLT2is and DPP4is, respectively), men (6.0 and 4.9 per 10,000), and those with pre-existing eye disease (3.8 and 8.6 per 10,000). Most ION cases among GLP-1RA users occurred in patients aged ≥50 years (85.2%) and men (70.3%), despite women comprising 55% of the GLP-1RA cohort. Among 65,708 patients using GLP-1RAs for weight loss, 14 ION cases occurred, whereas no cases were observed among users of bupropion-naltrexone or phentermine-topiramate. Overall, GLP-1RA use was associated with a small increase in ION risk among patients with T2D.

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