Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study
Authors:   Diabetes Prevention Program Research Group, Nathan David M. , Knowler William C. , Edelstein Sharon , Crandall Jill P. , Dabelea Dana , Goldberg Ronald B. , Kahn Steven E. , Mather Kieren J. , Trandafirescu Gilda , Walker Elizabeth A. , Temprosa Marinella , Bray George A. , Gadde Kishore , Chatellier Annie , Arceneaux Jennifer , Dragg Amber , Duncan Crystal , Greenway Frank L. , Hsia Daniel , Levy Erma , Lockett Monica , Ryan Donna H. , Ehrmann David , Matulik Margaret J. , Czech Kirsten , DeSandre Catherine , Goldstein Barry J. , Furlong Kevin , Smith Kellie A. , Wildman Wendi , Pepe Constance , Calles Jeanette , Ojito Juliet , Castillo-Florez Sumaya , Giannella Anna , Lara Olga , Veciana Beth , Haffner Steven M. , Hazuda Helen P. , Montez Maria G. , Hattaway Kathy , Lorenzo Carlos , Martinez Arlene , Walker Tatiana , Hamman Richard F. , Testaverde Lisa , Anderson Denise , Bouffard Alexis , Jenkins Tonya , Lenz Dione , Perreault Leigh , Price David W. , Steinke Sheila C. , Horton Edward S. , Poirier Catherine S. , Swift Kati , Caballero Enrique , Fargnoli Barbara , Guidi Ashley , Guido Mathew , Jackson Sharon D. , Lambert Lori , Lawton Kathleen E. , Ledbury Sarah , Sansoucy Jessica , Spellman Jeanne , Montgomery Brenda K. , Fujimoto Wilfred , Knopp Robert H. , Lipkin Edward W. , Morgan-Taggart Ivy , Murillo Anne , Taylor Lonnese , Thomas April , Tsai Elaine C. , Trence Dace , Kitabchi Abbas E. , Dagogo-Jack Samuel , Murphy Mary E. , Taylor Laura , Dolgoff Jennifer , Clark Debra , Ibebuogu Uzoma , Lambeth Helen , Ricks Harriet , Rutledge Lily M.K. , Soberman Judith E. , Molitch Mark E. , Metzger Boyd E. , Johnson Mariana K. , Giles Mimi M. , Larsen Diane , Pen Samsam C. , Larkin Mary , McKitrick Charles , Turgeon Heather , Anderson Ellen , Bissett Laurie , Bondi Kristy , Cagliero Enrico , D’Anna Kali , Delahanty Linda , Florez Jose C. , Goldman Valerie , Lou Peter , Poulos Alexandra , Raymond Elyse , Stevens Christine , Tsent Beverly , Barrett-Connor Elizabeth , Carrion-Petersen Mary Lou , Claravall Lauren N. , Dowden Jonalle M. , Horne Javiva , Leos Diana , Mudaliar Sundar , Smith Jean , Szerdi Janisch Simona , Vejvoda Karen , Pi-Sunyer F. Xavier , Lee Jane E. , Foo Sandra T. , Hagamen Susan , Marrero David G. , Kelly Susie M. , Putenney Paula , Jackson Marcia A. , McAtee Gina , Ackermann Ronald T. , Cantrell Carolyn M. , Fineberg Edwin S. , Hadden Angela , Kirkman Mario S. , O’Kelly Phillips Erin , Roach Paris J. , Ratner Robert E. , Aroda Vanita , Shapiro Sue , Bavido-Arrage Catherine , Gibbs Peggy , Uwaifo Gabriel , Wiggins Renee , Saad Mohammed F. , Watson Karol , Botrous Medhat , Jinagouda Sujata , Budget Maria , Conzues Claudia , Magpuri Perpetua , Ngo Kathy , Xapthalamous Kathy , White Neil H. , Brown Angela L. , Das Samia , Khare-Ranade Prajakta , Stich Tamara , Santiago Ana , Wernimont Cormarie , Saudek Christopher D. , Hill Golden Sherita , Whittington Tracy , Brancati Frederick L. , Clark Jeanne M. , Greene Alicia , Jiggetts Dawn , Mosley Henry , Reusing John , Rubin Richard R. , Stephens Shawne , Utsey Evonne , Shade David S. , Adams Karwyn S. , Hemphill Claire , Hyde Penny , Canady Janene L. , Colleran Kathleen , Gonzeles Ysela , Hernandez-McGinnis Doris A. , King Carolyn , Crandall Jill , Brown Janet O. , Adorno Elsie , Duffy Helena , Goldstein Angela , Lukin Jennifer , Martinez Helen , Pompi Dorothy , Shamoon Harry , Scheindlin Jonathan , Wylie-Rosett Judith , Orchard Trevor , Kriska Andrea , Jeffries Susan , Kramer M. Kaye , Smith Marie , Benchoff Catherine , Guimond Stephanie , Pettigrew Jessica , Rubinstein Debra , Semler Linda , Venditti Elizabeth , Weinzierl Valarie , Arakaki Richard F. , Baker-Ladao Narleen K. , Isonaga Mae K. , Bermudez Nina E. , Mau Marjorie K. , Melish John S. , Yamamoto Robin E. , Cooeyate Norman , Enote Alvera , Hoskin Mary A. , Natewa Camille , Percy Carol A. , Acton Kelly J. , Andre Vickie L. , Barber Roz , Begay Shandiin , Bucca Brian C. , Cook Sherron , Curtis Jeff , Dodge Charlotte , Doughty Matthew S. , Kurland Jason , Glass Justin , Glass Martia , Hanson Roberta L. , Ingraham Louise E. , Kobus Kathleen M. , Krakoff Jonathan , Manus Catherine , McCabe Cherie , Michaels Sara , Morgan Tina , Nelson Julie A. , Piromalli Christopher , Roy Robert J. , Sangster Sandra , Smart Miranda , Tonemah Darryl P. , Williams Rachel , Wilson Charlton , Fowler Sarah , Larsen Michael , Brenneman Tina , Sherif Hanna , Abebe Solome , Bamdad Julie , Barkalow Melanie , Bethepu Joel , Bezebeh Tsedenia , Butler Nicole , Callaghan Jackie , Carter Caitlin E. , Christophi Costas , Dwyer Gregory M. , Foulkes Mary , Gao Yuping , Gooding Robert , Gottlieb Adrienne , Grover Nisha , Hoffman Heather , Hogan Ashley N. , Jablonski Kathleen , Katz Richard , Kolinjivadi Preethy , Lachin John M. , Ma Yong , Pan Qing , Reamer Susan , Sapozhnikova Alla , Venditti Elizabeth M. , Kriska Andrea M. , Semler Linda , Weinzierl Valerie , Marcovina Santica , Strylewicz Greg , Albers John , Fradkin Judith , Garfield Stanford , Lee Christine , Gregg Edward , Zhang Ping , Herman William H. , Brändle Michael , Brown Morton B. 
Published: March 2019

OBJECTIVE
We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).

RESEARCH DESIGN AND METHODS
During the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs).

RESULTS
During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD −4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD −1.03 cases/100 person-years with baseline HbA1c &lt;6.0% (42 mmol/mol) and −3.88 cases/100 person-years with 6.0–6.4% (P = 0.0001).

CONCLUSIONS
Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA1c and women with a history of GDM.