Association of Metformin With the Development of Age-Related Macular Degeneration
Authors: Domalpally Amitha , Whittier Samuel A. , Pan Qing , Dabelea Dana M. , Darwin Christine H. , Knowler William C. , Lee Christine G. , Luchsinger Jose A. , White Neil H. , Chew Emily Y. ,   Diabetes Prevention Program Research (DPPOS) Group, Bray George A. , Gadde Kishore M. , Culbert Iris W. , Arceneaux Jennifer , Chatellier Annie , Dragg Amber , Champagne Catherine M. , Duncan Crystal , Eberhardt Barbara , Greenway Frank , Guillory Fonda G. , Herbert April A. , Jeffirs Michael L. , Kennedy Betty M. , Levy Erma , Lockett Monica , Lovejoy Jennifer C. , Morris Laura H. , Melancon Lee E. , Ryan Donna H. , Sanford Deborah A. , Smith Kenneth G. , Smith Lisa L. , St.Amant Julia A. , Tulley Richard T. , Vicknair Paula C. , Williamson Donald , Zachwieja Jeffery J. , Polonsky Kenneth S. , Tobian Janet , Ehrmann David A. , Matulik Margaret J. , Temple Karla A. , Clark Bart , Czech Kirsten , DeSandre Catherine , Dotson Brittnie , Hilbrich Ruthanne , McNabb Wylie , Semenske Ann R. , Caro Jose F. , Furlong Kevin , Goldstein Barry J. , Watson Pamela G. , Smith Kellie A. , Mendoza Jewel , Simmons Marsha , Wildman Wendi , Liberoni Renee , Spandorfer John , Pepe Constance , Donahue Richard P. , Goldberg Ronald B. , Prineas Ronald , Calles Jeanette , Giannella Anna , Rowe Patricia , Sanguily Juliet , Cassanova-Romero Paul , Castillo-Florez Sumaya , Florez Hermes J. , Garg Rajesh , Kirby Lascelles , Lara Olga , Larreal Carmen , McLymont Valerie , Mendez Jadell , Perry Arlette , Saab Patrice , Veciana Bertha , Haffner Steven M. , Hazuda Helen P. , Montez Maria G. , Hattaway Kathy , Isaac Juan , Lorenzo Carlos , Martinez Arlene , Salazar Monica , Walker Tatiana , Hamman Richard F. , Nash Patricia V. , Steinke Sheila C. , Testaverde Lisa , Truong Jennifer , Anderson Denise R. , Ballonoff Larry B. , Bouffard Alexis , Bucca Brian , Calonge B. Ned , Delve Lynne , Farago Martha , Hill James O. , Hoyer Shelley R. , Jenkins Tonya , Jortberg Bonnie T. , Lenz Dione , Miller Marsha , Nilan Thomas , Perreault Leigh , Price David W. , Regensteiner Judith G. , Schroeder Emily B. , Seagle Helen , Smith Carissa M. , VanDorsten Brent , Horton Edward S. , Munshi Medha , Lawton Kathleen E. , Jackson Sharon D. , Poirier Catherine S. , Swift Kati , Arky Ronald A. , Bryant Marybeth , Burke Jacqueline P. , Caballero Enrique , Callaphan Karen M. , Fargnoli Barbara , Franklin Therese , Ganda Om P. , Guidi Ashley , Guido Mathew , Jacobsen Alan M. , Kula Lyn M. , Kocal Margaret , Lambert Lori , Ledbury Sarah , Malloy Maureen A. , Middelbeek Roeland J.W. , Nicosia Maryanne , Oldmixon Cathryn F. , Pan Jocelyn , Quitingon Marizel , Rainville Riley , Rubtchinsky Stacy , Seely Ellen W. , Sansoucy Jessica , Schweizer Dana , Simonson Donald , Smith Fannie , Solomon Caren G. , Spellman Jeanne , Warram James , Kahn Steven E. , Fattaleh Basma , Montgomery Brenda K. , Colegrove Celeste , Fujimoto Wilfred , Knopp Robert H. , Lipkin Edward W. , Marr Michelle , Morgan-Taggart Ivy , Murillo Anne , O’Neal Kayla , Trence Dace , Taylor Lonnese , Thomas April , Tsai Elaine C. , Dagogo-Jack Samuel , Kitabchi Abbas E. , Murphy Mary E. , Taylor Laura , Dolgoff Jennifer , Applegate William B. , Bryer-Ash Michael , Clark Debra , Frieson Sandra L. , Ibebuogu Uzoma , Imseis Raed , Lambeth Helen , Lichtermann Lynne C. , Oktaei Hooman , Ricks Harriet , Rutledge Lily M.K. , Sherman Amy R. , Smith Clara M. , Soberman Judith E. , Williams-Cleaves Beverly , Patel Avnisha , Nyenwe Ebenezer A. , Hampton Ethel Faye , Metzger Boyd E. , Molitch Mark E. , Johnson Mariana K. , Adelman Daphne T. , Behrends Catherine , Cook Michelle , Fitzgibbon Marian , Giles Mimi M. , Heard Deloris , Johnson Cheryl K.H. , Larsen Diane , Lowe Anne , Lyman Megan , McPherson David , Penn Samsam C. , Pitts Thomas , Reinhart Renee , Roston Susan , Schinleber Pamela A. , Wallia Amisha , Nathan David M. , McKitrick Charles , Turgeon Heather , Larkin Mary , Mugford Marielle , Abbott Kathy , Anderson Ellen , Bissett Laurie , Bondi Kristy , Cagliero Enrico , Florez Jose C. , Delahanty Linda , Goldman Valerie , Grassa Elaine , Gurry Lindsery , D’Anna Kali , Leandre Fernelle , Lou Peter , Poulos Alexandra , Raymond Elyse , Ripley Valerie , Stevens Christine , Tseng Beverly , Olefsky Jerrold M. , Barrett-Connor Elizabeth , Mudaliar Sunder , Araneta Maria Rosario , Carrion-Petersen Mary Lou , Vejvoda Karen , Bassiouni Sarah , Beltran Madeline , Claravall Lauren N. , Dowden Jonalle M. , Edelman Steven V. , Garimella Pranav , Henry Robert R. , Horne Javiva , Lamkin Marycie , Janesch Simona Szerdi , Leos Diana , Polonsky William , Ruiz Rosa , Smith Jean , Torio-Hurley Jennifer , Pi-Sunyer F. Xavier , Lee Jane E. , Hagamen Susan , Allison David B. , Agharanya Nnenna , Aronoff Nancy J. , Baldo Maria , Crandall Jill P. , Foo Sandra T. , Luchsinger Jose A. , Pal Carmen , Parkes Kathy , Pena Mary Beth , Rooney Ellen S. , Van Wye Gretchen E.H. , Viscovich Kristine A. , de Groot Mary , Marrero David G. , Mather Kieren J. , Prince Melvin J. , Kelly Susie M. , Jackson Marcia A. , McAtee Gina , Putenney Paula , Ackermann Ronald T. , Cantrell Carolyn M. , Dotson Yolanda F. , Fineberg Edwin S. , Fultz Megan , Guare John C. , Hadden Angela , Ignaut James M. , Kirkman Marion S. , Phillips Erin O’Kelly , Pinner Kisha L , Porter Beverly D. , Roach Paris J. , Rowland Nancy D. , Wheeler Madelyn L. , Aroda Vanita , Magee Michelle , Ratner Robert E. , Youssef Gretchen , Shapiro Sue , Andon Natalie , Bavido-Arrage Catherine , Boggs Geraldine , Bronsord Marjorie , Brown Ernestine , Love Burkott Holly , Cheatham Wayman W. , Cola Susan , Evans Cindy , Gibbs Peggy , Kellum Tracy , Leon Lilia , Lagarda Milvia , Levatan Claresa , Lindsay Milajurine , Nair Asha K. , Park Jean , Passaro Maureen , Silverman Angela , Uwaifo Gabriel , Wells-Thayer Debra , Wiggins Renee , Saad Mohammed F. , Watson Karol , Budget Maria , Jinagouda Sujata , Botrous Medhat , Sosa Anthony , Tadros Sameh , Akbar Khan , Conzues Claudia , Magpuri Perpetua , Ngo Kathy , Rassam Amer , Waters Debra , Xapthalamous Kathy , Santiago Julio V. , Brown Angela L. , Das Samia , Khare-Ranade Prajakta , Stich Tamara , Santiago Ana , Fisher Edwin , Hurt Emma , Jones Tracy , Kerr Michelle , Ryder Lucy , Wernimont Cormarie , Golden Sherita Hill , Saudek Christopher D. , Bradley Vanessa , Sullivan Emily , Whittington Tracy , Abbas Caroline , Allen Adrienne , Brancati Frederick L. , Cappelli Sharon , Clark Jeanne M. , Charleston Jeanne B. , Freel Janice , Horak Katherine , Greene Alicia , Jiggetts Dawn , Johnson Deloris , Joseph Hope , Loman Kimberly , Mathioudakis Nestoras , Mosley Henry , Reusing John , Rubin Richard R. , Samuels Alafia , Shields Thomas , Stephens Shawne , Stewart Kerry J. , Thomas LeeLana , Utsey Evonne , Williamson Paula , Schade David S. , Adams Karwyn S. , Canady Janene L. , Johannes Carolyn , Hemphill Claire , Hyde Penny , Atler Leslie F. , Boyle Patrick J. , Burge Mark R. , Chai Lisa , Colleran Kathleen , Fondino Ateka , Gonzales Ysela , Hernandez-McGinnis Doris A. , Katz Patricia , King Carolyn , Middendorf Julia , Rubinchik Sofya , Senter Willette , Crandall Jill , Shamoon Harry , Brown Janet O. , Trandafirescu Gilda , Powell Danielle , Adorno Elsie , Cox Liane , Duffy Helena , Engel Samuel , Friedler Allison , Goldstein Angela , Howard-Century Crystal J. , Lukin Jennifer , Kloiber Stacey , Longchamp Nadege , Martinez Helen , Pompi Dorothy , Scheindlin Jonathan , Violino Elissa , Walker Elizabeth A. , Wylie-Rosett Judith , Zimmerman Elise , Zonszein Joel , Orchard Trevor , Venditti Elizabeth , Wing Rena R. , Jeffries Susan , Koenning Gaye , Kramer M. Kaye , Smith Marie , Barr Susan , Benchoff Catherine , Boraz Miriam , Clifford Lisa , Culyba Rebecca , Frazier Marlene , Gilligan Ryan , Guimond Stephanie , Harrier Susan , Harris Louann , Kriska Andrea , Manjoo Qurashia , Mullen Monica , Noel Alicia , Otto Amy , Pettigrew Jessica , Rockette-Wagner Bonny , Rubinstein Debra , Semler Linda , Smith Cheryl F. , Weinzierl Valarie , Williams Katherine V. , Wilson Tara , Mau Marjorie K. , Baker-Ladao Narleen K. , Melish John S. , Arakaki Richard F. , Latimer Renee W. , Isonaga Mae K. , Beddow Ralph , Bermudez Nina E. , Dias Lorna , Inouye Jillian , Mikami Kathy , Mohideen Pharis , Odom Sharon K. , Perry Raynette U. , Yamamoto Robin E. , Anderson Harelda , Cooeyate Norman , Dodge Charlotte , Hoskin Mary A. , Percy Carol A. , Enote Alvera , Natewa Camille , Acton Kelly J. , Andre Vickie L. , Barber Rosalyn , Begay Shandiin , Bennett Peter H. , Benson Mary Beth , Bird Evelyn C. , Broussard Brenda A. , Bucca Brian C. , Chavez Marcella , Cook Sherron , Curtis Jeff , Dacawyma Tara , Doughty Matthew S. , Duncan Roberta , Edgerton Cyndy , Ghahate Jacqueline M. , Glass Justin , Glass Martia , Gohdes Dorothy , Grant Wendy , Hanson Robert L. , Horse Ellie , Ingraham Louise E. , Jackson Merry , Jay Priscilla , Kaskalla Roylen S. , Kavena Karen , Kessler David , Kobus Kathleen M. , Krakoff Jonathan , Kurland Jason , Manus Catherine , McCabe Cherie , Michaels Sara , Morgan Tina , Nashboo Yolanda , Nelson Julie A. , Poirier Steven , Polczynski Evette , Piromalli Christopher , Reidy Mike , Roumain Jeanine , Rowse Debra , Roy Robert J. , Sangster Sandra , Sewenemewa Janet , Smart Miranda , Spencer Chelsea , Tonemah Darryl , Williams Rachel , Wilson Charlton , Yazzie Michelle , Bain Raymond , Fowler Sarah , Temprosa Marinella , Larsen Michael D. , Brenneman Tina , Edelstein Sharon L. , Abebe Solome , Bamdad Julie , Barkalow Melanie , Bethepu Joel , Bezabeh Tsedenia , Bowers Anna , Butler Nicole , Callaghan Jackie , Carter Caitlin E. , Christophi Costas , Dwyer Gregory M. , Foulkes Mary , Gao Yuping , Gooding Robert , Gottlieb Adrienne , Grimes Kristina L. , Grover-Fairchild Nisha , Haffner Lori , Hoffman Heather , Jablonski Kathleen , Jones Steve , Jones Tara L. , Katz Richard , Kolinjivadi Preethy , Lachin John M. , Ma Yong , Mucik Pamela , Orlosky Robert , Reamer Susan , Rochon James , Sapozhnikova Alla , Sherif Hanna , Stimpson Charlotte , Hogan Tjaden Ashley , Walker-Murray Fredricka , Venditti Elizabeth M. , Kriska Andrea M. , Weinzierl Valerie , Marcovina Santica , Aldrich F. Alan , Harting Jessica , Albers John , Strylewicz Greg , Eastman R. , Fradkin Judith , Garfield Sanford , Lee Christine , Gregg Edward , Zhang Ping , O’Leary Dan , Evans Gregory , Budoff Matthew , Dailing Chris , Stamm Elizabeth , Schwartz Ann , Navy Caroline , Palermo Lisa , Rautaharju Pentti , Prineas Ronald J. , Alexander Teresa , Campbell Charles , Hall Sharon , Li Yabing , Mills Margaret , Pemberton Nancy , Rautaharju Farida , Zhang Zhuming , Soliman Elsayed Z. , Hu Julie , Hensley Susan , Keasler Lisa , Taylor Tonya , Blodi Barbara , Danis Ronald , Davis Matthew , Hubbard* Larry , Endres** Ryan , Elsas** Deborah , Johnson** Samantha , Myers** Dawn , Barrett Nancy , Baumhauer Heather , Benz Wendy , Cohn Holly , Corkery Ellie , Dohm Kristi , Gama Vonnie , Goulding Anne , Ewen Andy , Hurtenbach Cynthia , Lawrence Daniel , McDaniel Kyle , Pak Jeong , Reimers James , Shaw Ruth , Swift Maria , Vargo Pamela , Watson Sheila , Manly Jennifer , Mayer-Davis Elizabeth , Moran Robert R. , Ganiats Ted , David Kristin , Sarkin Andrew J. , Groessl Erik , Katzir Naomi , Chong Helen , Herman William H. , Brändle Michael , Brown Morton B. , Altshuler David , Billings Liana K. , Chen Ling , Harden Maegan , Knowler William C. , Pollin Toni I. , Shuldiner Alan R. , Franks Paul W. , Hivert Marie-France 
Published: December 2022

Importance

Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.

Objective

To investigate the association between metformin use and age-related macular degeneration (AMD).

Design, Setting, and Participants

The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.

Interventions

Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.

Main Outcomes and Measures

Prevalence of AMD in the treatment arms.

Results

Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).

Conclusions and Relevance

These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.