Retinopathy Outcomes With Empagliflozin Versus Placebo in the EMPA-REG OUTCOME Trial

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce cardiovascular (CV) events in CV outcome trials in patients with type 2 diabetes and CV disease. In BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), the SGLT2 inhibitor empagliflozin reduced the risk of 3-point major adverse CV events (3P-MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) by 14% versus placebo, driven primarily by a 38% reduction in the risk of CV death (1). Empagliflozin also reduced the risk of a prespecified microvascular outcome (composite of time to first initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident/worsening nephropathy) by 38% versus placebo, driven by a reduction in kidney outcomes (2). Similarly, in Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide reduced the risk of 3P-MACE versus placebo (hazard ratio [HR] 0.74 [95% CI 0.58, 0.95]; P < 0.001), but was associated with a 76% increase in the risk of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) (1.49 vs. 0.86 events/100 patient-years, respectively; HR 1.76 [95% CI 1.11, 2.78]; P = 0.02]) (3). The reason for the increased risk of retinopathy in SUSTAIN-6 is unknown but has been hypothesized to be a consequence of rapid glucose lowering (4). In Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), the GLP-1 RA liraglutide reduced the risk of 3P-MACE versus placebo …