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Sustained High-Intensity Lipophilic Statin Use and Risk of Age-Related Macular Degeneration: A Target Trial Emulation
Maria Anna Bantounou1, Maria Emfietzoglou1, Tiarnán D L Keenan2
1Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Objective:
To evaluate whether sustained high-intensity lipophilic statin exposure is associated with reduced risk of incident nonexudative age-related macular degeneration (AMD) and progression from nonexudative to exudative AMD.
Design:
Target trial emulation retrospective cohort study.
Participants:
Data were obtained from the Mass General Brigham database (2005-2025). For incident nonexudative AMD, hypertensive adults ≥55 years old were included if they were treated or untreated with high-intensity lipophilic statins (atorvastatin 40-80 mg or simvastatin 40-80 mg) within 2 years following the hypertension date. For progression to exudative AMD, adults ≥55 years old with hypertension and nonexudative AMD were included if they were treated or untreated within 1 year before the nonexudative AMD date.
Methods:
Sustained exposure was defined as ≥80% cumulative exposure during the exposure window. Exposed and unexposed individuals were propensity-score matched 1:1 on demographics, diabetes, obesity, healthcare utilization, calendar time. Subdistribution hazard ratios (sHR) accounting for the competing risk of death and inverse probability of censoring weighting (IPCW) hazard ratios (HR) were estimated for exposed vs. unexposed, adjusting for cardiovascular and chronic kidney disease. Sensitivity analyses included: positive-control (cataract), negative-control [posterior vitreous detachment (PVD)], any statin vs no exposure.
Main Outcome Measures:
Incident clinically documented nonexudative AMD and progression to exudative AMD.
Results:
Over 2.8±1.8 years, 68/8,633 participants (0.79%) in the high-intensity lipophilic statin-exposed cohort and 88/8,633 (1.02%) in the unexposed cohort developed nonexudative AMD (sHR=0.53, 95%-CI, 0.38-0.74; P=0.0002; IPCW HR=0.53, 95%-CI, 0.37-0.76; P=0.0005). In the progression cohort, over 2.1±1.6 years, 66/1,082 high-intensity lipophilic statin-exposed participants (6.10%) and 85/1,082 unexposed participants (7.86%) progressed to exudative AMD (sHR=0.62, 95%-CI, 0.45-0.87; P=0.006; IPCW HR=0.61, 95%-CI, 0.43-0.87; P=0.006). Any statin use was not associated with AMD. For cataract, the sHR was 1.18 (95%-CI, 1.03-1.34; P=0.015), and the IPCW HR was 1.20 (95%-CI, 1.05-1.38; P=0.007). For PVD, the sHR was 1.00 (95%-CI, 0.81-1.22; P=0.96), and the IPCW HR was 1.00 (95%-CI, 0.81-1.24; P=0.99).
Conclusions:
High-intensity lipophilic statin exposure was associated with lower clinically documented nonexudative AMD and progression to exudative AMD risk, whereas any statin exposure was not. These findings support regimen-specific statin effects on AMD risk. Confirmation in prospective studies and randomized trials with retinal outcomes is needed.
