Metformin May Prevent Geographic Atrophy Onset, Independent of Diabetes Status

Dimitra Skondra, MD, PhD

Credit: University of Chicago

Metformin, a common anti-diabetic drug, may be a promising, alternative treatment to prevent the development of geographic atrophy (GA), a late-stage form of age-related macular degeneration (AMD).¹

A recent case-control study demonstrated an association between metformin and a decrease in new-onset International Classification of Diseases (ICD) coding of GA after controlling for other AMD risk factors, with a persistent association in patients without diabetes.

“Given the findings from this study, metformin’s ease of use, and the shortcomings of current therapeutics for GA, metformin may hold promise as an alternative agent that can be repurposed for preventing GA,” wrote the investigative team, led by Dimitra Skondra, MD, PhD, department of ophthalmology and visual science, University of Chicago.

The late-stage forms of AMD are separated into the neovascular form, defined by choroidal neovascularization (CNV), and GA, characterized by progressive and irreversible photoreceptor and retinal pigment epithelium (RPE) loss. Approximately 40% of patients who progress to GA later develop blindness—recent approvals from the US Food and Drug Administration (FDA) have marked the first two treatments for GA, pegcetacoplan and avacincaptad pegol.^2,3

However, these treatments only slow the progression of the disease and do not prevent its onset or improve visual acuity. Recent evidence has linked metformin with a reduced likelihood of AMD development, but the conclusions were limited.⁴ No observational study between metformin and AMD development has dictated GA as its primary outcome.

Skondra and colleagues conducted a case-control study, using the Merative MarketScan Commercial and Medicare databases, to investigate the association between metformin and GA.¹ The study identified patients aged ≥60 years with new-onset ICD coding of GA between January 2017 and December 2021.

Each GA case was matched with propensity scores estimated by age, region, Charlson Comorbidity Index (CCI), and hypertension to a control of the same year. Controls matched the same inclusion criteria but did not have a GA diagnosis. Exposures, defined as antidiabetic medications, required an outpatient prescription drug claim in the year before and including the index visit date.

Conditional multivariable logistic regression tested the association between metformin use and new-onset ICD coding of GA after adjusting for AMD risk factors. Statistical analysis on metformin use and GA was repeated in patients without diabetes.

The full sample identified 10,505 cases with new-onset coding of GA, with a mean age of 82.1 years and consisting of 63% female patients. Investigators matched these cases with 10,502 controls without GA, with a mean age of 82.1 years and consisting of 57% female patients.

Among the population, 2894 (27.6%) cases and 2935 (28%) controls were diagnosed with diabetes, with 1149 (10.9%) GA cases and 1277 (12.2%) controls exposed to metformin. Multivariable regression, adjusted for AMD and other anti-diabetic medications, revealed metformin reduced the likelihood of new-onset coding of GA by 12% (95% CI, 0.79–0.99).

For the sample of patients without diabetes, investigators identified 7611 cases with GA and 7608 matched controls without GA. Only 0.4% of GA cases and 0.8% of controls were exposed to metformin. In multivariable regression analysis, metformin decreased the odds of developing new-onset coding of GA by 47% (95% CI, 0.33 – 0.83).

These results contrasted with the recent phase 2 METforMIN trial, wherein metformin exhibited no reduction in GA progression and no change in the decline of best-corrected visual acuity.⁵ However, this trial reported a lower decline in low-luminance visual acuity with metformin treatment, which approached statistical significance (P = .006), suggesting its potential protective effect against photoreceptor degeneration.

“As more recent administrative data become available, additional studies are needed to confirm the associations identified herein and to motivate a clinical trial,” Skondra and colleagues wrote.¹

References

1. _{Moir J, Hyman MJ, Gonnah R, Flores A, Hariprasad SM, Skondra D. The Association Between Metformin Use and New-Onset ICD Coding of Geographic Atrophy. Invest Ophthalmol Vis Sci. 2024;65(3):23. doi:10.1167/iovs.65.3.23}
2. _{Iapoce C. FDA approves Pegcetacoplan Injection for geographic atrophy. HCP Live. February 17, 2023. Accessed March 19, 2024. https://www.hcplive.com/view/fda-approves-pegcetacoplan-injection-geographic-atrophy.}
3. _{Kunzmann K. FDA approves Avacincaptad Pegol for geographic atrophy. HCP Live. August 5, 2023. Accessed March 19, 2024. https://www.hcplive.com/view/fda-approves-avacincaptad-pegol-geographic-atrophy.}
4. _{Aggarwal S, Moir J, Hyman MJ, et al. Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes. JAMA Ophthalmol. 2024;142(1):53-57. doi:10.1001/jamaophthalmol.2023.5478}
5. _{Iapoce C. Oral metformin exhibits no reduction in geographic atrophy progression. HCP Live. February 2, 2024. Accessed March 18, 2024. https://www.hcplive.com/view/oral-metformin-exhibits-no-reduction-geographic-atrophy-progression.}