Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight
Authors: Sivitz William I. , Phillips Lawrence S. , Wexler Deborah J. , Fortmann Stephen P. , Camp Anne W. , Tiktin Margaret , Perez Magalys , Craig Jacqueline , Hollander Priscilla A. , Cherrington Andrea , Aroda Vanita R. , Tan Meng Hee , Krakoff Jonathan , Rasouli Neda , Butera Nicole M. , Younes Naji ,   GRADE Research Group, Crandall Jill P. , Diane McKee Melissa , Brown-Friday Janet , Xhori Entila , Ballentine-Cargill Keisha , Duran Sally , Lukin Jennifer , Beringher Stephanie , Gonzalez de la torre Susana , Phillips Lawrence , Burgess Elizabeth , Olson Darin , Rhee Mary , Wilson Peter , Stephanie Raines Tasha , Costello Julie , Gullett Chona , Maher-Albertelli Maxine , Morehead Folayan , Mungara Radhika , Person Saranjit , Savoye Louise , Sibymon Mabil , Tanukonda Sridhar , Ann White Carol , Holloway Leah , Adams Cynthia , Ross April , Balasubramanyam Ashok , Gonzalez Erica , Wright Charlyne , Hollander Priscilla , Roe Erin , Uy Analyn , Burt Polly , Estrada Lorie , Chionh Kris , Ismail-Beigi Faramarz , Falck-Ytter Corinna , Sayyed Kassem Laure , Sood Ajay , Tiktin Margaret , Cramer Bethany , Iacoboni Jacalyn , Kononets Maria V. , Kulow Tanya , Newman Cynthia , Stancil Katherine A. , Sanders Cristina , Tucker Lisa , Werner Amanda , Krol Adrienne , McPhee Gloria , Patel Christine , Colosimo Linda , Goland Robin , Pring James , Kringas Patricia , Tejada Jessica , Hausheer Camille , Schneier Harvey , Gumpel Kelly , Kirpitch Amanda , Green Jennifer B. , AbouAssi Hiba , Chatterjee Ranee , Feinglos Mark N. , English Jones Jennifer , Khan Shubi A. , Kimpel Jeanne B. , Zimmer Ronna P. , Furst Mary , Satterwhite Barbara M. , Thacker Connie R. , Evans Kreider Kathryn , Mather Kieren J. , Lteif Amale , Hamilton Tonya , Patel Nick , Riera Gabriela , Jackson Marcia , Pirics Vivian , Howard Devin , Aguillar Danielle , Hurt Sloan , Bergenstal Richard , Carlson Anders , Martens Thomas , Johnson Mary , Hill Renae , Hyatt Jamie , Jensen Connie , Madden Marcia , Martin Dianna , Willis Holly , Konerza Wanda , Passi Rebecca , Kleeberger Kathleen , Fortmann Stephen , Herson Michael , Mularski Karen , Glauber Harry , Prihoda James , Ash Britt , Carlson Christina , Anne Ramey Phyllis , Schield Emily , Torgrimson-Ojerio Britta , Arnold Kathy , Kauffman Bryan , Panos Elease , Sahnow Samantha , Bays Kristi , Cook Jennifer , Gluth Jennifer , Sasaki Debra , Schell Katrina , Criscola Jennifer , Friason Camille , Jones Suzi , Nazarov Sergey , Barzilay Joshua , Rassouli Negah , Puttnam Rachel , Curtis Michelle , Stokes Kia , Hollis Bonita , Sanders-Jones Cynthia , Nelson Roslin , El-Haqq Zakiah , Kolli Abby , Tran Tu , Wexler Deborah , Mary Larkin , Meigs James , Dushkin Amy , Rocchio Gianna , Chambers Brittany , Yepes Mike , Steiner Barbara , Dulin Hilary , Cayford Melody , DeManbey Andrea , Gurry Lindsey , Hillard Mallory , Martin Kimberly , Stevens Christine , Thangthaeng Nopporn , Kochis Raquel , Raymond Elyse , Ripley Valerie , Park Jean , Aroda Vanita , Ghazi Adline , Loveland Amy , Hurtado Maria , Kuhn Alexander , Mofor Florence , Florez Hermes J. , Valencia Willy Marcos , Marks Jennifer , Oropesa-Gonzalez Lisset , Riccio Veliz Ana K. , Nieto-Martinez Ramfis , Gutt Miriam , Ahmann Andrew , Aby-Daniel Diana , Joarder Farahnaz , Morimoto Victoria , Sprague Carol , Yamashita Daisuke , Cady Nancy , Kirchhoff Patricia , Rivera-Eschright Nadia , Adducci Joseph , Gomez Brianna M. , Goncharova Alina , Hox Sophia H. , Petrovitch Helen , Matwichyna Michael , Jenkins Victoria , Bermudez Nina O. , Ishii Renée R. , Hsia Daniel S. , Cefalu William T. , Greenway Frank L. , Waguespack Celeste , King Erin , Haynes Natalie , Thomassie Amy , Bourgeois Brandi , Hazlett Claire , Henry Robert , Mudaliar Sunder , Boeder Schafer , Pettus Jeremy , Diaz Elsa , DeLue Catherine , Castro Erick , Hernandez Sylvia , Krakoff Jonathan , Curtis Jeffrey M. , Killean Tina , Joshevama Erica , Diaz Enrique , Martin Denelle , Karshner Tracey , Albu Jeanine , Pi-Sunyer F. Xavier , Frances Sylvaine , Maggio Carol , Ellis Emily , Bastawrose Joseph , Gong Xiuqun , Ann Banerji Mary , August Phyllis , Lorber Daniel , Brown Necole M. , Josephson Debra H. , Thomas Lorraine L. , Tsovian Mari , Cherian Ajini , Jacobson Marlo H. , Mishko Motria M. , Kirkman M. Sue , Bergamo Katherine , Buse John B. , Dostou Jean , Young Laura , Goley April , Kerr Jeffrey , Largay Joseph F. , Guarda Sonia , Cuffee Juanita , Culmer Dawn , Fraser Rachael , Almeida Hope , Coffer Samantha , Debnam Elizabeth , Kiker Lauren , Morton Sarah , Josey Kim , Fuller Gail , Garvey W. Timothy , Cherrington Andrea , Golson Dana , Griffith Olivia , Catherine Robertson Mary , Agne April , McCullars Steve , Cohen Robert M. , Craig Jacqueline , Kersey Kimberly , Rogge M. Colleen , Wilson Carla , Burton Kathryn , Lipp Sonia , Vonder Meulen Mary Beth , Rasouli Neda , Schroeder Emily , Steiner Stephanie , Baker Chelsea , Underkofler Chantal , Douglass Sara , Sivitz William , Cline Erin , Knosp Laura , McConnell Jennifer , Lowe Tamara , Herman William H. , Pop-Busui Rodica , Tan Meng H. , Martin Catherine , Waltje Andrea , Goodhall Lynn , Eggleston Rebecca , Kuo Shihchen , Bule Stephanie , Kessler Nancy , LaSalle Elizabeth , Seaquist Elizabeth R. , Bantle Anne , Kumar Anjali , Redmon Bruce , Bantle John , Harindhanavudhi Tasma , Coe Mary , Mech Michael , Taddese Abdisa , Lesne Lesia , Smith Shannon , Desouza Cyrus , Kuechenmeister Lisa , Shivaswamy Vijay , Laura Morales Ana , Rodriguez Maria Grace , Seipel Kris , Alfred Alissa , Eggert Jenna , Lord Grace , Taylor William , Tillson Renee , Schade David S. , Adolphe Allen , Burge Mark , Duran-Valdez Elizabeth , Martinez Janae , McGinnis Doris Hernandez , Pucchetti Benjamin , Scripsick Elizabeth , DeFronzo Ralph A. , Cersosimo Eugenio , Abdul-Ghani Muhammad , Triplitt Curtis , Verastiqui Hector , Irene Garza Rosa , Wright Kathryn , Puckett Curtiss , Raskin Philip , Rhee Chanhaeng , Abraham Soma , Fan Jordan Lin , Sao Serey , Morton Luisa , Smith Oralenda , Osornio Walker Laura , Schnurr-Breen Laura , Ayala Rosa , Brian Kraymer Robert , Sturgess Daytheon , Utzschneider Kristina M. , Kahn Steven E. , Alarcon-Casas Wright Lorena , Boyko Edward J. , Tsai Elaine C. , Trence Dace L. , Fattaleh Basma N. , Montgomery Brenda K. , Atkinson Karen M. , Concepcion Tessa , Kozedub Alexandra , Moak Cameron , Rhothisen Samantha , Elasy Tom A. , Martin Stephanie , Shackelford Laura , Goidel Rita , Hinkle Nina , Lipps Hogan Janie , Lovell Cynthia , Myers Janet , McGill Janet B. , Salam Maamoun , Kissel Sarah , Schweiger Toni , Recklein Carol , Tamborlane William , Gatcomb Patricia , Camp Anne , Gulanski Barbara , Inzucchi Silvio , Pham Kim , Alguard Michele , Lessard Katarzyna , Perez Magalys , Magenheimer Elizabeth , Montoza Abmaridel , Nathan David M. , Lachin John , Buse John B. , Kahn Steven E. , Krause-Steinrauf Heidi , Larkin Mary , Tiktin Margaret , Wexler Deborah , Burch Henry B. , Linder Barbara , Bremer Andrew , Lachin John , Krause-Steinrauf Heidi , Younes Naji , Backman Michael , Bebu Ionut , Buys C. J. , Fagan Murphy Anna , Gao Yuping , Gramzinski Michaela , Hall Stephanie , Legowski Elizabeth , Arey Alyssa , Bethepu Joel , Lund Claire , Mangat Dhaliwal Pam , McGee Paula , Mesimer Emily , Ngo Lisa , Steffes Michael , Seegmiller Jesse , Saenger Amy , Arends Valerie , Gabrielson Deanna , Conner Todd , Warren Stuart , Day Jolene , Scrymgeour Alexandra , Soliman Elsayed Z. , Zhang Zhu-Ming , Campbell Charles , Hu Julie , Keasler Lisa , Hensley Susan , Li Yabing , Herman William , Martin Catherine , Waltje Andrea , Kuo Shihchen , Mihalcea Rada , Perez-Rosas Veronica , Prosser Lisa , Resnicow Kenneth , Ye Wen , Shao Hui , Zhang Ping , Luchsinger Jose , Sanchez Danurys , Burch Henry B. , Bremer Andrew , Linder Barbara , Fradkin Judith , Groessl Erik , Chong Helen , Hillery Naomi , Abdouch Ivan , Brantley Paula , Broyles Frances E. , Canaris Gay , Copeland Paul , Craine Jeri J. , Fein Warren L. , Lee Melissa S. , Meiners Rebecca , Meiners Vaughn , O’Neal Hollis , Park James E. , Sledge Edward , Steppel-Resnick Jeanne , Turchin Alexander , Brooks-Worrell Barbara , Hampe Christiane S. , Newgard Christopher B. , Palmer Jerry P. , Shojaie Ali , Higgins John , Fischer Lawrence , Golden Sherita , Gonzalez Jeffery , Naik Aanand , Walker Elizabeth , Doner Lotenberg Lynne , Gallivan Joanne M. , Lim Joanne , Tuncer Diane M. , Behringer-Massera Stephanie 
Published: March 2020

OBJECTIVE
We evaluated the effect of optimizing metformin dosing on glycemia and body weight in type 2 diabetes.

RESEARCH DESIGN AND METHODS
This was a prespecified analysis of 6,823 participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) taking metformin as the sole glucose-lowering drug who completed a 4- to 14-week (mean ± SD 7.9 ± 2.4) run-in in which metformin was adjusted to 2,000 mg/day or a maximally tolerated lower dose. Participants had type 2 diabetes for &lt;10 years and an HbA1c ≥6.8% (51 mmol/mol) while taking ≥500 mg of metformin/day. Participants also received diet and exercise counseling. The primary outcome was the change in HbA1c during run-in.

RESULTS
Adjusted for duration of run-in, the mean ± SD change in HbA1c was −0.65 ± 0.02% (−7.1 ± 0.2 mmol/mol) when the dose was increased by ≥1,000 mg/day, −0.48 ± 0.02% (−5.2 ± 0.2 mmol/mol) when the dose was unchanged, and −0.23 ± 0.07% (−2.5 ± 0.8 mmol/mol) when the dose was decreased (n = 2,169, 3,548, and 192, respectively). Higher HbA1c at entry predicted greater reduction in HbA1c (P &lt; 0.001) in univariate and multivariate analyses. Weight loss adjusted for duration of run-in averaged 0.91 ± 0.05 kg in participants who increased metformin by ≥1,000 mg/day (n = 1,894).

CONCLUSIONS
Optimizing metformin to 2,000 mg/day or a maximally tolerated lower dose combined with emphasis on medication adherence and lifestyle can improve glycemia in type 2 diabetes and HbA1c values ≥6.8% (51 mmol/mol). These findings may help guide efforts to optimize metformin therapy among persons with type 2 diabetes and suboptimal glycemic control.