Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study | Geriatrics | JAMA Ophthalmology | JAMA Network
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Pennington  KL, DeAngelis  MM.  Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors.   Eye Vis (Lond). 2016;3:34. doi:10.1186/s40662-016-0063-5PubMedGoogle ScholarCrossref
Campbell  JM, Bellman  SM, Stephenson  MD, Lisy  K.  Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis.   Ageing Res Rev. 2017;40:31-44. doi:10.1016/j.arr.2017.08.003PubMedGoogle ScholarCrossref
UK Prospective Diabetes Study (UKPDS) Group.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).   Lancet. 1998;352(9131):854-865. doi:10.1016/S0140-6736(98)07037-8PubMedGoogle ScholarCrossref
Kooy  A, de Jager  J, Lehert  P,  et al.  Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus.   Arch Intern Med. 2009;169(6):616-625. doi:10.1001/archinternmed.2009.20PubMedGoogle ScholarCrossref
Bodmer  M, Meier  C, Krähenbühl  S, Jick  SS, Meier  CR.  Long-term metformin use is associated with decreased risk of breast cancer.   Diabetes Care. 2010;33(6):1304-1308. doi:10.2337/dc09-1791PubMedGoogle ScholarCrossref
Bosco  JL, Antonsen  S, Sørensen  HT, Pedersen  L, Lash  TL.  Metformin and incident breast cancer among diabetic women: a population-based case-control study in Denmark.   Cancer Epidemiol Biomarkers Prev. 2011;20(1):101-111. doi:10.1158/1055-9965.EPI-10-0817PubMedGoogle ScholarCrossref
Mazzone  PJ, Rai  H, Beukemann  M, Xu  M, Jain  A, Sasidhar  M.  The effect of metformin and thiazolidinedione use on lung cancer in diabetics.   BMC Cancer. 2012;12:410. doi:10.1186/1471-2407-12-410PubMedGoogle ScholarCrossref
Tseng  CH.  Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan.   Eur J Endocrinol. 2012;167(3):409-416. doi:10.1530/EJE-12-0369PubMedGoogle ScholarCrossref
Ng  TP, Feng  L, Yap  KB, Lee  TS, Tan  CH, Winblad  B.  Long-term metformin usage and cognitive function among older adults with diabetes.   J Alzheimers Dis. 2014;41(1):61-68. doi:10.3233/JAD-131901PubMedGoogle ScholarCrossref
Lin  HC, Stein  JD, Nan  B,  et al.  Association of geroprotective effects of metformin and risk of open-angle glaucoma in persons with diabetes mellitus.   JAMA Ophthalmol. 2015;133(8):915-923. doi:10.1001/jamaophthalmol.2015.1440PubMedGoogle ScholarCrossref
Saisho  Y.  Metformin and inflammation: its potential beyond glucose-lowering effect.   Endocr Metab Immune Disord Drug Targets. 2015;15(3):196-205. doi:10.2174/1871530315666150316124019PubMedGoogle ScholarCrossref
Martin-Montalvo  A, Mercken  EM, Mitchell  SJ,  et al.  Metformin improves healthspan and lifespan in mice.   Nat Commun. 2013;4:2192. doi:10.1038/ncomms3192PubMedGoogle ScholarCrossref
Barzilai  N, Crandall  JP, Kritchevsky  SB, Espeland  MA.  Metformin as a tool to target aging.   Cell Metab. 2016;23(6):1060-1065. doi:10.1016/j.cmet.2016.05.011PubMedGoogle ScholarCrossref
Brown  EE, Ball  JD, Chen  Z, Khurshid  GS, Prosperi  M, Ash  JD.  The common antidiabetic drug metformin reduces odds of developing age-related macular degeneration.   Invest Ophthalmol Vis Sci. 2019;60(5):1470-1477. doi:10.1167/iovs.18-26422PubMedGoogle ScholarCrossref
Park  SJ, Lee  JH, Woo  SJ,  et al; Epidemiologic Survey Committee of the Korean Ophthalmologic Society.  Age-related macular degeneration: prevalence and risk factors from Korean National Health and Nutrition Examination Survey, 2008 through 2011.   Ophthalmology. 2014;121(9):1756-1765. doi:10.1016/j.ophtha.2014.03.022PubMedGoogle ScholarCrossref
Chakravarthy  U, Wong  TY, Fletcher  A,  et al.  Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis.   BMC Ophthalmol. 2010;10:31. doi:10.1186/1471-2415-10-31PubMedGoogle ScholarCrossref
Chen  X, Rong  SS, Xu  Q,  et al.  Diabetes mellitus and risk of age-related macular degeneration: a systematic review and meta-analysis.   PLoS One. 2014;9(9):e108196. doi:10.1371/journal.pone.0108196PubMedGoogle Scholar
Velilla  S, García-Medina  JJ, García-Layana  A,  et al.  Smoking and age-related macular degeneration: review and update.   J Ophthalmol. 2013;2013:895147. doi:10.1155/2013/895147PubMedGoogle Scholar
Woo  SJ, Ahn  J, Morrison  MA,  et al.  Analysis of genetic and environmental risk factors and their interactions in korean patients with age-related macular degeneration.   PLoS One. 2015;10(7):e0132771. doi:10.1371/journal.pone.0132771PubMedGoogle Scholar
Hahn  P, Acquah  K, Cousins  SW, Lee  PP, Sloan  FA.  Ten-year incidence of age-related macular degeneration according to diabetic retinopathy classification among medicare beneficiaries.   Retina. 2013;33(5):911-919. doi:10.1097/IAE.0b013e3182831248PubMedGoogle ScholarCrossref
He  MS, Chang  FL, Lin  HZ, Wu  JL, Hsieh  TC, Lee  YC.  The association between diabetes and age-related macular degeneration among the elderly in taiwan.   Diabetes Care. 2018;41(10):2202-2211. doi:10.2337/dc18-0707PubMedGoogle ScholarCrossref
Prattichizzo  F, Giuliani  A, Mensà  E,  et al.  Pleiotropic effects of metformin: shaping the microbiome to manage type 2 diabetes and postpone ageing.   Ageing Res Rev. 2018;48:87-98. doi:10.1016/j.arr.2018.10.003PubMedGoogle ScholarCrossref
Vinolo  MA, Rodrigues  HG, Nachbar  RT, Curi  R.  Regulation of inflammation by short chain fatty acids.   Nutrients. 2011;3(10):858-876. doi:10.3390/nu3100858PubMedGoogle ScholarCrossref
Rinninella  E, Mele  MC, Merendino  N,  et al.  The role of diet, micronutrients and the gut microbiota in age-related macular degeneration: new perspectives from the gutretina axis.   Nutrients. 2018;10(11):E1677. doi:10.3390/nu10111677PubMedGoogle Scholar
Rena  G, Pearson  ER, Sakamoto  K.  Molecular mechanism of action of metformin: old or new insights?   Diabetologia. 2013;56(9):1898-1906. doi:10.1007/s00125-013-2991-0PubMedGoogle ScholarCrossref
Chin-Hsiao  T.  Metformin and the risk of dementia in type 2 diabetes patients.   Aging Dis. 2019;10(1):37-48. doi:10.14336/AD.2017.1202PubMedGoogle ScholarCrossref
Zheng  Z, Chen  H, Li  J,  et al.  Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin.   Diabetes. 2012;61(1):217-228. doi:10.2337/db11-0416PubMedGoogle ScholarCrossref
Muraleva  NA, Kozhevnikova  OS, Zhdankina  AA,  et al.  The mitochondria-targeted antioxidant SkQ1 restores αB-crystallin expression and protects against AMD-like retinopathy in OXYS rats.   Cell Cycle. 2014;13(22):3499-3505. doi:10.4161/15384101.2014.958393PubMedGoogle ScholarCrossref
Howell  JJ, Hellberg  K, Turner  M,  et al.  Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex.   Cell Metab. 2017;25(2):463-471. doi:10.1016/j.cmet.2016.12.009PubMedGoogle ScholarCrossref
Borrone  R, Saravia  M, Bar  D.  Age related maculopathy and diabetes.   Eur J Ophthalmol. 2008;18(6):949-954. doi:10.1177/112067210801800615PubMedGoogle ScholarCrossref
Srinivasan  S, Swaminathan  G, Kulothungan  V, Ganesan  S, Sharma  T, Raman  R.  Age-related macular degeneration in a South Indian population, with and without diabetes.   Eye (Lond). 2017;31(8):1176-1183. doi:10.1038/eye.2017.47PubMedGoogle ScholarCrossref
Wang  L, Ruan  X, Yang  P, Liu  H.  Comparison of three information sources for smoking information in electronic health records.   Cancer Inform. 2016;15:237-242. doi:10.4137/CIN.S40604PubMedGoogle Scholar
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    1 Comment for this article
    Metformin in Macular Degeneration.
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Thank you for your extensive study of metformin use and association with Macular Degeneration. The fact that you found that there was an inverse dose relationship with metformin use suggests to me that there is a confounding variable at play here. Also, that it is not metformin is not associated with MD reduction in people with diabetes supports this. Thus, the lower metformin doses are associated with milder diabetic disease, the higher metformin doses associated with more MD and worse diabetes, so, you are looking at not so much an inverse dose relationship (spurious) but an association between severity of diabetes and the development of MD. In my opinion, the current recommendations for the use of metformin should remain the same while the use of metformin for the prevention of MD and other complications of aging should be reserved for further study. Again, thank you. Gary Joseph Ordog, MD.
    Original Investigation
    January 21, 2021

    Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study

    Author Affiliations
    • 1Department of Ophthalmology and Visual Science, University of Chicago Medical Center, Chicago, Illinois
    • 2Center for Health and the Social Sciences, The University of Chicago, Chicago, Illinois
    • 3Department of Ophthalmology, New York University, New York
    JAMA Ophthalmol. 2021;139(3):302-309. doi:10.1001/jamaophthalmol.2020.6331
    Key Points

    Question  Is there an association between metformin use and the development of age-related macular degeneration (AMD)?

    Findings  In this large case-control study using a national database of patients, we found that metformin use was associated with decreased odds of developing AMD in a dose-dependent manner, with the greatest benefit at low to moderate dosages.

    Meaning  The use of metformin may protect against the development of AMD and lead to a novel therapeutic strategy for the prevention of this disease.


    Importance  Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD.

    Objective  To determine whether metformin use is associated with reduced odds of developing AMD.

    Design, Setting, and Participants  This case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020.

    Exposures  Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims.

    Main Outcomes and Measures  Risk of developing AMD.

    Results  A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]).

    Conclusion and Relevance  In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.