Early worsening of diabetic retinopathy in individuals with type 2 diabetes treated with tirzepatide: a real-world cohort study

Abstract Aims/hypothesis Early worsening of diabetic retinopathy (EWDR) has been described during treatment with glucagon-like peptide-1 receptor agonists including subcutaneous semaglutide. Whether EWDR occurs after initiating treatment with the potent glucagon-like peptide 1 / gastric inhibitory polypeptide receptor agonist tirzepatide is unknown. Methods In this retrospective cohort study using real-world clinical data, we matched 3435 tirzepatide-exposed (≥180 days treatment) individuals with type 2 diabetes 1:1 with 3434 tirzepatide-unexposed individuals for sex, diabetes duration, retinopathy status, HbA1c, number of retinal screening episodes and use of glucose-lowering medications. New-onset diabetic retinopathy and retinopathy progression were explored using conditional logistic regression. Results Individuals included in the study had tight baseline glycaemic control (mean HbA1c 56.1 ± 15.8 mmol/mol [7.28 ± 1.43%]). New-onset proliferative diabetic retinopathy (PDR) (grade R3M0, R3M1) occurred in 1.1% of tirzepatide-exposed (n=33) and 0.5% of tirzepatide-unexposed (n=17) individuals. Tirzepatide was significantly associated with new-onset PDR in multivariate analysis after adjustment for established risk factors (OR 2.15 [95% CI 1.24, 3.74], p<0.01). However, tirzepatide was also associated with reduced odds of new onset of retinopathy (OR 0.73 [95% CI 0.62, 0.86], p<0.001) in individuals without diabetic retinopathy (R0M0) at initiation in multivariate analysis, and was not significantly associated with retinopathy progression in individuals with mild non-proliferative diabetic retinopathy (NPDR, grade R1M0 or R1M1). Conclusions/interpretation Tirzepatide therapy resulted in significantly increased odds of incident PDR, particularly in individuals with mild NPDR with maculopathy (grade R1M1), or moderate-to-severe NPDR with or without maculopathy (grade R2M0, R2M1). The increase in odds of progression would justify specialist ophthalmologist referral by Early Treatment Diabetic Retinopathy Study (ETDRS) criteria. Graphical Abstract