Oral Metformin Exhibits No Reduction in Geographic Atrophy Progression

Jay M. Stewart, MD

Credit: University of California, San Francisco

New trial results do not support oral metformin for reducing the progression of geographic atrophy (GA) or its effects on change in best-corrected visual acuity (BCVA) or low luminance visual acuity (LLVA).¹

The METformin for the MINimization of Geographic Atrophy Progression (METforMIN) parallel-group, randomized phase 2 clinical trial enrolled nondiabetic individuals aged ≥55 years with GA across 12 study centers to receive daily 2000 mg oral metformin or observation for 18 months.

“The results of the clinical trial do not support the use of oral metformin having effects on reducing GA progression or change in BCVA or LLVA between participants treated with metformin and those not receiving metformin despite relatively high self-reported adherence in the metformin group,” wrote the investigative team, led by Jay M. Stewart, MD, department of ophthalmology, University of California, San Francisco.

An advanced stage of neovascular age-related macular degeneration (nAMD), GA affects more than 5 million patients globally, although the exact mechanisms for progression remain unclear. Recently, the US Food and Drug Administration (FDA) approved two complement inhibitors, intravitreal pegcetacoplan (C3 inhibitor)² and avacincaptad pegol (C5 inhibitor)³, for slowing GA progression based on pivotal phase 3 trials.

Metformin, an antihyperglycemic oral medication for treating diabetes, has been theorized to reduce GA progression through multiple biological pathways.⁴ Retrospective data have signaled associations between metformin use and decreased AMD risk, but there are few randomized data on metformin’s effect on AMD.

In the METforMIN trial, participants assigned to the metformin group took a dose of 500 mg oral metformin once daily for the first week, 500 mg twice daily for the second week, and 1000 mg twice daily until 18 months.¹ All participants had a total GA area between 1.25 and 17.5 mm2 and were evaluated at baseline and every six months with a complete ophthalmic examination.

The prespecified primary efficacy endpoint was the annualized growth rate of the square root-transformed GA area (mm/year) in the study eye, measured using fundus autofluorescence (FAF) images. Secondary outcomes contained the annualized change in BCVA (letters/year), annualized change in LLVA (letters/year), and adverse events among patients treated with metformin.

A total of 93 participants were screened between October 2016 and August 2021, and 66 were enrolled in the METforMIN trial. Of the enrolled population, 34 participants (57 eyes) were randomized to observation and 32 participants (53 eyes) to oral metformin. Stewart and colleagues noted that 11 participants per group did not contribute follow-up data, with reasons for withdrawal including the inability to tolerate side effects, which affected 6 participants in the metformin group.

Upon analysis, the mean ± standard error annualized enlargement rate of square root transformed GA area from baseline to 18 months was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference, 0.07 mm/year; 95% CI, –0.05 to 0.18 mm/year; P = .26).

Both BCVA and LLVA declined throughout the study among both metformin and observation groups. The mean ± standard error decline in BCVA was –4.8 ± 1.7 letters/year in the observation group and –3.4 ± 1.1 letters/year in the treatment group (risk difference, 1.2 [95% CI, –5.1 to 2.7]; P = .56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (risk difference, 6.5 [95% CI, -0.1 to 13.2]; P = .06).

Stewart and colleagues noted the trial found an acceptable safety profile of metformin when used by this nondiabetic population, but overall, the data detected no difference in GA progression between metformin-treated and observation groups.

“It is possible that the AMD treated in this trial was too advanced to respond to therapy, and that treatment would need to be started earlier in the disease process, including AMD patients who either do not have GA or those with GA < 1.25 mm2,” investigators wrote.

References

1. _{Shen LL, Keenan JD, Chahal N, et al. METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial. Ophthalmol Sci. 2023;4(3):100440. Published 2023 Dec 4. doi:10.1016/j.xops.2023.100440}
2. _{Iapoce C. FDA approves Pegcetacoplan Injection for geographic atrophy. HCP Live. February 17, 2023. Accessed February 4, 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 February 4, 2024. https://www.hcplive.com/view/fda-approves-avacincaptad-pegol-geographic-atrophy.}
4. _{Blitzer A.L., Ham S.A., Colby K.A., Skondra D. Association of metformin use with age-related macular degeneration: a case-control study. JAMA Ophthalmol. 2021;139:302–309}