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