Semaglutide, a glucagon-like peptide 1 receptor agonists (GLP-1 RA), has been reported to be associated with a reduction in the development of retinopathy with HbA1c reduction, although data is conflicting; some literature report transient paradoxical worsening of diabetic retinopathy in patients with type 2 diabetes mellitus (T2DM) prior to seeing benefits with glucose control in cohorts who had pre-existing diabetic retinopathy progression. The SUSTAIN-6 trial, which evaluated retinopathy as a secondary outcome measure with subcutaneous semaglutide therapy, reported a significantly increased risk of diabetic retinopathy in the semaglutide group versus placebo; however, this may be due to the lack of consideration for HbA1c limits or pre-existing diabetic retinopathy as patient exclusion criteria in SUSTAIN-6, and thus the inclusion of older patients with higher baseline HbA1c levels, longer duration of diabetes, and more advanced diabetic retinopathy at baseline may have influenced diabetic retinopathy progression and observation. In patients with no known pre-existing diabetic retinopathy at baseline who were treated with semaglutide, risk of diabetic retinopathy was low, and matched the event incidence of diabetic retinopathy in the placebo group. Further research is required to ascertain the extent of diabetic retinopathy risk with semaglutide therapy. [1], [2], [3]
A 2022 meta-analysis evaluated the association between semaglutide and the risk of retinopathy in patients with T2DM, assessing data from 23 randomized trials (N= 22,096 patients). Follow-up periods ranged from 15.9 to 104 weeks. In total, 730 cases of diabetic retinopathy events were identified, with 463 events from patients taking semaglutide and 267 in the control cohort. Pooled data from the trials did not find the semaglutide cohort to be at an increased risk of diabetic retinopathy events versus controls (risk ratio [RR] 1.14; 95% confidence interval [CI] 0.98 to 1.33), though patient aged ≥60 years and diabetes duration ≥10 years were independent risk factors for diabetic retinopathy when taking semaglutide. Additionally, a subgroup analysis found semaglutide to be associated with diabetic retinopathy when compared to placebo (RR 1.23; 95% CI 1.03 to 1.50). The investigators recommend paying additional attention when initiating semaglutide treatment in older patients or patients with longer duration of diabetes, but overall note that semaglutide is not suggested to be associated with an increased risk of retinopathy. Whether these findings correlate to new or underlying retinopathy is uncertain. [4]
Though not specific to semaglutide’s effects in specific, a 2022 systematic review and meta-analysis sought to evaluate the effect of GLP-1 RAs on diabetic retinopathy. Thirteen randomized trials were included, of which ten assessed the effects of semaglutide (4 injection, 6 oral). Overall, GLP-1 RAs were associated with worsening diabetic retinopathy despite reporting cardiovascular benefits (odds ratio [OR] 1.23; 95% CI 1.05 to 1.44), with a greater association between GLP-1 RAs and diabetic retinopathy in trials with follow-up durations past 52 weeks which used placebo as a comparator. Based on these findings, diabetic retinopathy may not be agent- or administration route-specific, though included studies varied in utilized comparators, T2DM durations, follow-up periods, and sample sizes. [5]