Tried and True: Exploring Metformin’s Potential for Geographic Atrophy

Across the continuously evolving world of medicine, true breakthroughs remain rare, but when they happen, they can turn a light at the end of the tunnel into a beacon of hope. For patients battling the relentless advance of geographic atrophy (GA), a severe form of age-related macular degeneration (AMD), 2023 marked a game-changing moment as the US Food and Drug Administration (FDA) greenlit not one, but two revolutionary treatments: pegcetacoplan injection (SYFOVRE) and avacincaptad pegol (IZERVAY).^1,2

However, despite these agents achieving the first FDA approvals, they may not have marked the completion of the GA treatment journey. Although designed to halt the progression of GA, both pegcetacoplan and avacincaptad pegol fall short of preventing the disease or improving a patient’s visual acuity.

In expanding that search to fill an unmet need, recent evidence has implicated oral metformin in potentially delaying the onset of GA. Beyond its primary use as an anti-diabetic medication, metformin has been linked to anti-aging and neuroprotective properties.³

“As AMD is a disease of the retina, and if indeed, metformin has anti-aging properties, it can also affect macular degeneration,” Dimitra Skondra, MD, PhD, an associate professor of ophthalmology and visual science at The University of Chicago, told HCPLive.⁴ “That will be an attractive candidate because it’s a non-invasive way that can be used for a more preventive intervention before people go to the advanced stages and more targeted interventions are needed.”

Nearly 20 million people in the US are diagnosed with AMD, with approximately 1.5 million affected by late-stage neovascular (wet) AMD and GA forms.⁵ Intravitreal anti-vascular endothelial growth factor (VEGF) serves the standard of care role for retinal diseases, but close to 40% of treated patients still develop GA over time.

Approval of pegcetacoplan and avacincaptad pegol were the latest additions to the boom of new therapies the field of retina has experienced in recent decades. But, for generations, patients with GA were unable to be treated and experienced progressive vision loss impacting their quality of life.⁶

“There remain many unmet needs, even in GA. It is great to have these two proven therapies, but they only slow the disease down and slow it down modestly,” Srinivas Sadda, MD, professor of ophthalmology at the University of California, Los Angeles, and current president of the Association for Research in Vision and Ophthalmology (ARVO) told HCPLive.⁷ “There’s still a long way to go in stopping its progression and reversing or restoring vision.

Although the pathophysiologic mechanisms involved in the initiation and progression of GA remain mostly unknown, activation of the complement system and chronic local inflammation have been implicated in the pathogenesis of GA. Each agent targets a different complement pathway (C3 for pegcetacoplan and C5 for avacincaptad pegol), but efficacy is limited and the treatment burden of frequent injections remains high for both patients and clinicians.^8,9

“I think we do have a path to efficacy through the complement pathway, we’ve seen that with these two FDA-approved drugs,” Ashkan M. Abbey, MD, director of clinical research at Texas Retina Associates, told HCPLive.¹⁰ “The problem is the treatment burden and I think we need to find durability within the complement pathway.”

In the search for alternative agents to treat GA, metformin is an attractive candidate, not just for its well-tested nature in diabetes, but an impressive clinical data set for AMD.¹¹ Multiple observational studies have reported a protective effect of metformin against the likelihood of AMD development, including dry AMD.

However, these studies did not designate GA as its primary outcome, including the late-stage subtype within the broader characterization of any dry AMD. Citing an unmet need in the literature, an investigative team, led by Skondra, conducted a case-control study in the Merative MarketScan Commercial and Medicare Databases between January 2017 and December 2021.¹²

Patients aged ≥60 years with new-onset International Classification of Diseases (ICD) coding of GA were matched to controls without GA in the same year. A sample of 10,505 cases with GA and 10,502 matched controls without GA were identified —1149 (10.9%) and 1277 (12.2%), respectively, were exposed to metformin.

After performing multivariable regression analysis, adjusted for AMD risk factors and other anti-diabetic medications, metformin was shown to reduce the odds of new-onset ICD coding of GA by approximately 12%.

“I think we need to move the target of intervention [in GA] sooner, and metformin will be the perfect candidate for that,” Skondra said.⁴ “It can be applied in parts of the world that do not have access to very expensive drugs, but metformin is widely available and affordable, even without a prescription.”

These study data were particularly notable in that metformin’s protective effect against GA persisted and was more pronounced for patients without diabetes.¹² Among cases without diabetes, 29 cases (0.4%) and 63 (0.8%) controls were exposed to metformin – the analysis revealed a decrease of approximately 47% in new-onset ICD coding of GA.

“It seems that when you look at more specific subtypes, and you define your cohorts, the more homogenously, the signal becomes stronger,” Skondra added.⁴ “And that was very encouraging to see a possibly non-diabetic cohort for clinical application.”

However, these results contrasted with the Phase 2 METforMIN randomized clinical trial, wherein metformin demonstrated no reduction in GA progression and no change in the decline of best-corrected visual acuity (BCVA).¹³ These data did show a lower decline in low-luminance visual acuity (LLVA) approaching statistical significance (P = .006), suggesting metformin’s potential protective effect against photoreceptor degeneration.

Investigators at the University of California, San Francisco called for further placebo-controlled, randomized studies to determine the role of metformin for AMD, particularly in the earlier stages of the disease.¹³

“The evidence is there, but we cannot be sure it actually works until we do a prospective clinical trial to see if the people that take metformin develop less advanced AMD, either GA or wet AMD or both,” Skondra noted.⁴

As intravitreal anti-VEGF agents have become the standard of care for retinal disease over the past two decades, further FDA approvals and availability have personalized treatments for individual patients.¹⁴ Now, clinical trial programs in ophthalmology are evaluating the effect of sustained-release drugs, such as an ocular implant delivering an anti-VEGF drug, or gene therapy, intending to provide a one-time injection to resolve the symptoms of a retinal disease.

“We’re privileged to be in the space across retina, where the previous 5 years have seen more innovation and more medicines brought to market than the 10 years before that,” Deepak Sambhara, MD, told HCPLive.¹⁵ “As far as therapeutic scope, we're in a golden age of retina.”

These novel programs may tackle an unmet treatment need, which by targeting AMD early, clinicians can prevent the disease from advancing into later-stage forms, including GA. The only thing standing in the way is time, for these clinical programs to mature, and discover a preventive or restorative effect for vision affected by the retinal disease.

“We’re hopefully going to get there eventually, maybe with extended-release agents or gene therapy,” Abbey added.¹⁰ “I think it is a worthy pursuit to continue looking at the complement pathway, but also continue to look at these other things.”

Still, in Skondra’s view, metformin could already slot into the treatment armamentarium as an early-stage treatment, working to delay the progression to GA in a non-invasive matter.⁴ Given this promising evidence base, Skondra urged the need for a prospective clinical trial before wider implementation of metformin for GA.

“[Metformin’s] almost the perfect candidate for a non-invasive strategy to target patients when they’re earlier in the disease stage,” Skondra said.⁴ “It’s safe, affordable, and may help delay the process until they go to advanced stages of wet AMD or GA in particular.”

References

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2. _{Kunzmann K. FDA approves Avacincaptad Pegol for geographic atrophy. HCP Live. August 5, 2023. Accessed August 28, 2024. https://www.hcplive.com/view/fda-approves-avacincaptad-pegol-geographic-atrophy.}
3. _{Isop LM, Neculau AE, Necula RD, Kakucs C, Moga MA, Dima L. Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders. Pharmaceuticals (Basel). 2023;16(12):1714. Published 2023 Dec 11. doi:10.3390/ph16121714}
4. _{Iapoce C. Dimitra Skondra, MD, Phd: Protective effect of metformin in geographic atrophy. HCP Live. May 31, 2024. Accessed August 28, 2024. https://www.hcplive.com/view/dimitra-skondra-md-phd-protective-effect-metformin-geographic-atrophy.}
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6. _{Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-1761. doi:10.1016/j.ophtha.2016.03.045}
7. _{Iapoce C. ARVO President Srinivas R. Sadda, MD, Visualizes Ophthalmology's Future. May 13, 2024. Accessed August 28, 2024. https://www.hcplive.com/view/fda-approves-pegcetacoplan-injection-geographic-atrophy.}
8. _{Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology. 2020;127(2):186-195. doi:10.1016/j.ophtha.2019.07.011}
9. _{Jaffe GJ, Westby K, Csaky KG, et al. C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2021;128(4):576-586. doi:10.1016/j.ophtha.2020.08.027}
10. _{Iapoce C. Ashkan M. Abbey, MD: 3-Year Efficacy of Pegcetacoplan for Geographic Atrophy. May 6, 2024. Accessed August 28, 2024. https://www.hcplive.com/view/ashkan-abbey-md-3-year-efficacy-pegcetacoplan-geographic-atrophy}
11. _{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}
12. _{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}
13. _{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}
14. _{Matonti F, Korobelnik JF, Dot C, et al. Comparative Effectiveness of Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Managing Neovascular Age-Related Macular Degeneration: A Meta-Analysis. J Clin Med. 2022;11(7):1834. Published 2022 Mar 25. doi:10.3390/jcm11071834}
15. _{Iapoce C. Deepak Sambhara, MD: Impact of CRT on Aflibercept 8 mg Outcomes in DME. HCP Live. May 28, 2024. Accessed August 28, 2024. https://www.hcplive.com/view/deepak-sambhara-md-impact-crt-aflibercept-8-mg-outcomes-dme}