Dopamine-Enhancing Therapies and Risk of Neovascular AMD Conversion: A Target Trial Emulation.

Abstract

Age-related macular degeneration (AMD) is a leading cause of central vision loss worldwide. Emerging evidence suggests that targeting dopaminergic pathways may influence AMD progression. This study evaluates whether levodopa ± carbidopa or dopamine receptor D2 (DRD2) agonists are associated with reduced risk of conversion to neovascular AMD (nAMD). Population-based clinical cohort study. Adults aged ≥18 years diagnosed with non-nAMD between May 2005 and May 2025, within the TriNetX US Collaborative Network, a federated electronic health record database spanning 69 healthcare organizations. This retrospective cohort study emulated four distinct target trials comparing new users of (1) levodopa (± carbidopa) or (2) DRD2 agonists (pramipexole, ropinirole, bromocriptine, rotigotine, or cabergoline) to new users of two comparators (pantoprazole or gabapentin). Patients with prior nAMD or prescriptions of other dopamine-enhancing agents (eg, selegiline, rasagiline, tolcapone) were excluded. Each exposure group was independently matched to comparators using 1:1 propensity score matching for selected demographics, social factors, comorbidities, and AMD stage. The primary outcome was 3-year risk of conversion from non-nAMD to nAMD. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. An α level of 0.05 was used to determine statistical significance. Patients prescribed levodopa ± carbidopa had a reduced 3-year risk of conversion to nAMD relative to their matched counterparts prescribed pantoprazole (levodopa n = 1312, control n = 1312; HR 0.67; 95% CI, 0.45-0.98) and gabapentin (levodopa n = 1675, control n = 1675; HR 0.69; 95% CI, 0.50-0.95). No significant difference was observed in 3-year risk of conversion to nAMD between DRD2 agonists use relative to pantoprazole (DRD2 n = 1603, control n = 1603; HR 0.81; 95% CI, 0.58-1.13) or gabapentin (DRD2 n = 2779, control n = 2779; HR 0.92; 95% CI, 0.72-1.19). In this cohort study, levodopa ± carbidopa use was associated with lower 3-year risk of conversion to nAMD in two independent matched comparisons, whereas DRD2 agonists were not associated with significant differences in risk. These findings suggest dopaminergic signaling may influence AMD progression and warrant further prospective investigation.