Association of metformin use with age-related macular degeneration risk
Medical hypothesis, discovery & innovation in optometry,
Vol. 4 No. 3 (2023),
3 October 2023
,
Page 129-134
https://doi.org/10.51329/mehdioptometry182
Abstract
Background: The association between metformin use and reduced age-related macular degeneration (AMD) risk has been explored. Studies have shown a positive association, no association, or ambiguous results. The aim of this narrative review is to compile these divergent findings, and thereby, better assess the potential of metformin use in reducing the AMD risk.Methods: Studies were extracted in two ways. First, a standard Google Scholar™ search was performed using the keywords “metformin” AND “macular degeneration” without language or time restrictions. The full texts of relevant articles identified in this search were retrieved and assessed, and articles of peer-reviewed original studies and meta-analyses were included. Second, the reference lists of the included articles were used to identify additional articles that satisfied the search algorithm and included in this review.
Results: Of the 12 studies included in this review, eight showed a positive correlation between metformin use and a reduced AMD risk, while one showed no association. Of the eight positive studies, seven were retrospective. Apart from the design, the studies were also diverse. The number of participants in each study ranged from over 300 to 30 million person-years. The study populations included those with type 2 diabetes mellitus, those with AMD, and those without either. The study locations were the United States, Europe, and Asia. The ambiguous or negative results from four studies could largely be rationalized based on the confounding factor of study design.
Conclusions: Most studies examined in this review demonstrated a positive association between metformin use and a reduced AMD risk. Studies not reporting such an association did not definitively demonstrate its absence. Overall, the studies reviewed herein support further clinical investigation of metformin as a prophylactic and potential treatment modality for AMD. Further randomized clinical trials with reasonably longer follow-up periods are necessary to determine the generalizability of the findings of studies reporting positive results.
Keywords:
- metformin hydrochloride
- type 2 diabetes mellitus
- age-related macular degeneration
- retinal pigment epithelium
- cell senescence
- dry AMD
- exudative AMD
- wet macular degeneration
- geographic atrophy
- macular degeneration
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17. Stewart JM (2019). ‘Metformin for the Minimization of Geographic Atrophy Progression in Patients With AMD (METforMIN)’. ClinicalTrials.gov Identifier: NCT02684578. Available at: https://clinicaltrials.gov/ct2/show/NCT02684578 (Accessed: July 01, 2023)
18. Blasiak J, Piechota M, Pawlowska E, Szatkowska M, Sikora E, Kaarniranta K. Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role? Oxid Med Cell Longev. 2017;2017:5293258. doi: 10.1155/2017/5293258 pmid: 29225722
19. Kozlowski MR. RPE cell senescence: a key contributor to age-related macular degeneration. Med Hypotheses. 2012;78(4):505-10. doi: 10.1016/j.mehy.2012.01.018 pmid: 22296808
20. Kozlowski MR, Grossman B, Kneeland A, Zemski S, Crandell A, Kozlowski RE. Inhibition of Retinal Pigment Epithelial Cell Senescence by Metformin: Implications for the Treatment of Macular Degeneration. Japanese Journal of Ophthalmology and Research. 2020;2(1):1-5. doi:10.31546/2732-4516.1005
21. Blitzer AL, Ham SA, Colby KA, Skondra D. Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study. JAMA Ophthalmol. 2021;139(3):302-309. doi: 10.1001/jamaophthalmol.2020.6331 pmid: 33475696
22. 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.18-26422 pmid: 30973575
23. Chen YY, Shen YC, Lai YJ, Wang CY, Lin KH, Feng SC, et al. Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes. J Ophthalmol. 2019;2019:1649156. doi: 10.1155/2019/1649156 pmid: 31781371
24. Jiang J, Chen Y, Zhang H, Yuan W, Zhao T, Wang N, et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: a retrospective study. BMJ Open. 2022;12(4):e054420. doi: 10.1136/bmjopen-2021-054420 pmid: 35473747
25. Starr MR, Dalvin LA, AbouChehade JE, Damento GM, Garcia M, Shah SM, et al. Incidence of metformin use in patients with age-related macular degeneration versus normal controls: A population-based study in Olmsted County, Minnesota. Eye (Lond). 2023;37(9):1861-1865. doi: 10.1038/s41433-022-02245-6 pmid: 36151313
26. Stewart JM, Lamy R, Wu F, Keenan JD. Relationship between Oral Metformin Use and Age-Related Macular Degeneration. Ophthalmol Retina. 2020;4(11):1118-1119. doi: 10.1016/j.oret.2020.06.003 pmid: 32525055
27. Tseng CH. The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin. Pharmaceuticals (Basel). 2023;16(2):224. doi: 10.3390/ph16020224 pmid: 37259372
28. Vergroesen JE, Thee EF, Ahmadizar F, van Duijn CM, Stricker BH, Kavousi M, et al. Association of Diabetes Medication With Open-Angle Glaucoma, Age-Related Macular Degeneration, and Cataract in the Rotterdam Study. JAMA Ophthalmol. 2022;140(7):674-681. doi: 10.1001/jamaophthalmol.2022.1435 pmid: 35587864
29. Lee H, Jeon HL, Park SJ, Shin JY. Effect of Statins, Metformin, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers on Age-Related Macular Degeneration. Yonsei Med J. 2019;60(7):679-686. doi: 10.3349/ymj.2019.60.7.679 pmid: 31250582
30. Domalpally A, Whittier SA, Pan Q, Dabelea DM, Darwin CH, Knowler WC, et al; Diabetes Prevention Program Research (DPPOS) Group. Association of Metformin With the Development of Age-Related Macular Degeneration. JAMA Ophthalmol. 2023;141(2):140-147. doi: 10.1001/jamaophthalmol.2022.5567 pmid: 36547967
31. Gokhale KM, Adderley NJ, Subramanian A, Lee WH, Han D, Coker J, et al. Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study. Br J Ophthalmol. 2023;107(7):980-986. doi: 10.1136/bjophthalmol-2021-319641 pmid: 35115301
32. Eton EA, Wubben TJ, Besirli CG, Hua P, McGeehan B, VanderBeek BL. Association of metformin and development of dry age-related macular degeneration in a U.S. insurance claims database. Eur J Ophthalmol. 2022;32(1):417-423. doi: 10.1177/1120672121997288 pmid: 33607930
33. Anisimov VN, Semenchenko AV, Yashin AI. Insulin and longevity: antidiabetic biguanides as geroprotectors. Biogerontology. 2003;4(5):297-307. doi: 10.1023/a:1026299318315 pmid: 14618027
34. Cao F, Wu K, Zhu YZ, Bao ZW. Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging. Front Endocrinol (Lausanne). 2021;12:731273. doi: 10.3389/fendo.2021.731273 pmid: 34489872
35. Madonna R, Doria V, Minnucci I, Pucci A, Pierdomenico DS, De Caterina R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J Cell Mol Med. 2020;24(21):12331-12340. doi: 10.1111/jcmm.15699 pmid: 32940423
36. Fang J, Yang J, Wu X, Zhang G, Li T, Wang X, et al. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell. 2018;17(4):e12765. doi: 10.1111/acel.12765 pmid: 29659168
37. Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012;5(4):536-43. doi: 10.1158/1940-6207.CAPR-11-0536 pmid: 22262811
38. Mao Z, Liu W, Huang Y, Sun T, Bao K, Feng J, et al. Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species. Acta Pharm Sin B. 2022;12(2):665-677. doi: 10.1016/j.apsb.2021.08.007 pmid: 35256938
39. Chen L, Bi B, Zeng J, Zhou Y, Yang P, Guo Y, et al. Rosiglitazone ameliorates senescence-like phenotypes in a cellular photoaging model. J Dermatol Sci. 2015;77(3):173-81. doi: 10.1016/j.jdermsci.2015.01.007 pmid: 25703056
40. Kalur A, Muste J, Valentim CC, Iyer A, Singh RP. Novel mitochondrial therapies for the treatment of age-related macular degeneration. Ann. Eye Sci. 2021;6:21-7. doi: 10.21037/aes-21-7
2. Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, et al. Metformin: a review of its potential indications. Drug Des Devel Ther. 2017;11:2421-2429. doi: 10.2147/DDDT.S141675 pmid: 28860713
3. Chen S, Gan D, Lin S, Zhong Y, Chen M, Zou X, et al. Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms. Theranostics. 2022;12(6):2722-2740. doi: 10.7150/thno.71360 pmid: 35401820
4. Lv Z, Guo Y. Metformin and Its Benefits for Various Diseases. Front Endocrinol (Lausanne). 2020;11:191. doi: 10.3389/fendo.2020.00191 pmid: 32425881
5. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-1585. doi: 10.1007/s00125-017-4342-z pmid: 28776086
6. ?mieszek A, Str?k Z, Kornicka K, Grzesiak J, Weiss C, Marycz K. Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels-An Ex Vivo Study. Int J Mol Sci. 2017;18(4):872. doi: 10.3390/ijms18040872 pmid: 28425952
7. Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-?B activation. Aging Cell. 2013;12(3):489-98. doi: 10.1111/acel.12075 pmid: 23521863
8. Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis. 2016;7(10):e2441. doi: 10.1038/cddis.2016.334 pmid: 27787519
9. Zhang C, Chen M, Zhou N, Qi Y. Metformin Prevents H?O?-Induced Senescence in Human Lens Epithelial B3 Cells. Med Sci Monit Basic Res. 2020;26:e923391. doi: 10.12659/MSMBR.923391 pmid: 32336745
10. Molnar Z, Millward AB, Tse W, Demaine AG. p21(WAF1/CIP1) Expression is Differentially Regulated by Metformin and Rapamycin. Int J Chronic Dis. 2014;2014:327640. doi: 10.1155/2014/327640 pmid: 26464852
11. Karnewar S, Neeli PK, Panuganti D, Kotagiri S, Mallappa S, Jain N, et al. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt A):1115-1128. doi: 10.1016/j.bbadis.2018.01.018 pmid: 29366775
12. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192(4):547-56. doi: 10.1083/jcb.201009094 pmid: 21321098
13. Burton DG. Cellular senescence, ageing and disease. Age (Dordr). 2009;31(1):1-9. doi: 10.1007/s11357-008-9075-y pmid: 19234764
14. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24(22):2463-79. doi: 10.1101/gad.1971610 pmid: 21078816
15. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482-96. doi: 10.1038/nrm3823 pmid: 24954210
16. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705. doi: 10.1146/annurev-physiol-030212-183653 pmid: 23140366
17. Stewart JM (2019). ‘Metformin for the Minimization of Geographic Atrophy Progression in Patients With AMD (METforMIN)’. ClinicalTrials.gov Identifier: NCT02684578. Available at: https://clinicaltrials.gov/ct2/show/NCT02684578 (Accessed: July 01, 2023)
18. Blasiak J, Piechota M, Pawlowska E, Szatkowska M, Sikora E, Kaarniranta K. Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role? Oxid Med Cell Longev. 2017;2017:5293258. doi: 10.1155/2017/5293258 pmid: 29225722
19. Kozlowski MR. RPE cell senescence: a key contributor to age-related macular degeneration. Med Hypotheses. 2012;78(4):505-10. doi: 10.1016/j.mehy.2012.01.018 pmid: 22296808
20. Kozlowski MR, Grossman B, Kneeland A, Zemski S, Crandell A, Kozlowski RE. Inhibition of Retinal Pigment Epithelial Cell Senescence by Metformin: Implications for the Treatment of Macular Degeneration. Japanese Journal of Ophthalmology and Research. 2020;2(1):1-5. doi:10.31546/2732-4516.1005
21. Blitzer AL, Ham SA, Colby KA, Skondra D. Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study. JAMA Ophthalmol. 2021;139(3):302-309. doi: 10.1001/jamaophthalmol.2020.6331 pmid: 33475696
22. 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.18-26422 pmid: 30973575
23. Chen YY, Shen YC, Lai YJ, Wang CY, Lin KH, Feng SC, et al. Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes. J Ophthalmol. 2019;2019:1649156. doi: 10.1155/2019/1649156 pmid: 31781371
24. Jiang J, Chen Y, Zhang H, Yuan W, Zhao T, Wang N, et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: a retrospective study. BMJ Open. 2022;12(4):e054420. doi: 10.1136/bmjopen-2021-054420 pmid: 35473747
25. Starr MR, Dalvin LA, AbouChehade JE, Damento GM, Garcia M, Shah SM, et al. Incidence of metformin use in patients with age-related macular degeneration versus normal controls: A population-based study in Olmsted County, Minnesota. Eye (Lond). 2023;37(9):1861-1865. doi: 10.1038/s41433-022-02245-6 pmid: 36151313
26. Stewart JM, Lamy R, Wu F, Keenan JD. Relationship between Oral Metformin Use and Age-Related Macular Degeneration. Ophthalmol Retina. 2020;4(11):1118-1119. doi: 10.1016/j.oret.2020.06.003 pmid: 32525055
27. Tseng CH. The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin. Pharmaceuticals (Basel). 2023;16(2):224. doi: 10.3390/ph16020224 pmid: 37259372
28. Vergroesen JE, Thee EF, Ahmadizar F, van Duijn CM, Stricker BH, Kavousi M, et al. Association of Diabetes Medication With Open-Angle Glaucoma, Age-Related Macular Degeneration, and Cataract in the Rotterdam Study. JAMA Ophthalmol. 2022;140(7):674-681. doi: 10.1001/jamaophthalmol.2022.1435 pmid: 35587864
29. Lee H, Jeon HL, Park SJ, Shin JY. Effect of Statins, Metformin, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers on Age-Related Macular Degeneration. Yonsei Med J. 2019;60(7):679-686. doi: 10.3349/ymj.2019.60.7.679 pmid: 31250582
30. Domalpally A, Whittier SA, Pan Q, Dabelea DM, Darwin CH, Knowler WC, et al; Diabetes Prevention Program Research (DPPOS) Group. Association of Metformin With the Development of Age-Related Macular Degeneration. JAMA Ophthalmol. 2023;141(2):140-147. doi: 10.1001/jamaophthalmol.2022.5567 pmid: 36547967
31. Gokhale KM, Adderley NJ, Subramanian A, Lee WH, Han D, Coker J, et al. Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study. Br J Ophthalmol. 2023;107(7):980-986. doi: 10.1136/bjophthalmol-2021-319641 pmid: 35115301
32. Eton EA, Wubben TJ, Besirli CG, Hua P, McGeehan B, VanderBeek BL. Association of metformin and development of dry age-related macular degeneration in a U.S. insurance claims database. Eur J Ophthalmol. 2022;32(1):417-423. doi: 10.1177/1120672121997288 pmid: 33607930
33. Anisimov VN, Semenchenko AV, Yashin AI. Insulin and longevity: antidiabetic biguanides as geroprotectors. Biogerontology. 2003;4(5):297-307. doi: 10.1023/a:1026299318315 pmid: 14618027
34. Cao F, Wu K, Zhu YZ, Bao ZW. Roles and Mechanisms of Dipeptidyl Peptidase 4 Inhibitors in Vascular Aging. Front Endocrinol (Lausanne). 2021;12:731273. doi: 10.3389/fendo.2021.731273 pmid: 34489872
35. Madonna R, Doria V, Minnucci I, Pucci A, Pierdomenico DS, De Caterina R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J Cell Mol Med. 2020;24(21):12331-12340. doi: 10.1111/jcmm.15699 pmid: 32940423
36. Fang J, Yang J, Wu X, Zhang G, Li T, Wang X, et al. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell. 2018;17(4):e12765. doi: 10.1111/acel.12765 pmid: 29659168
37. Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila). 2012;5(4):536-43. doi: 10.1158/1940-6207.CAPR-11-0536 pmid: 22262811
38. Mao Z, Liu W, Huang Y, Sun T, Bao K, Feng J, et al. Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species. Acta Pharm Sin B. 2022;12(2):665-677. doi: 10.1016/j.apsb.2021.08.007 pmid: 35256938
39. Chen L, Bi B, Zeng J, Zhou Y, Yang P, Guo Y, et al. Rosiglitazone ameliorates senescence-like phenotypes in a cellular photoaging model. J Dermatol Sci. 2015;77(3):173-81. doi: 10.1016/j.jdermsci.2015.01.007 pmid: 25703056
40. Kalur A, Muste J, Valentim CC, Iyer A, Singh RP. Novel mitochondrial therapies for the treatment of age-related macular degeneration. Ann. Eye Sci. 2021;6:21-7. doi: 10.21037/aes-21-7
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