Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight
William I. Sivitz, Lawrence S. Phillips, Deborah J. Wexler, Stephen P. Fortmann, Anne Camp, Margaret Tiktin, Magalys Perez, Jacqueline Craig, Priscilla Hollander, Andrea Cherrington, Vanita R. Aroda, Meng H. Tan, Jonathan Krakoff, Neda Rasouli, Nicole M. Butera, Naji Younes, Jill P. Crandall, M. Diane McKee, Janet Brown-Friday, Entila Xhori, Keisha Ballentine-Cargill, Sally Duran, Jennifer Lukin, Stephanie Beringher, Susana Gonzalez de la torre, Lawrence S. Phillips, Elizabeth Burgess, Darin E. Olson, Mary K. Rhee, Peter W.F. 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, C. Wright, Priscilla Hollander, Erin Roe, Analyn Uy, Polly Burt, Lorie Estrada, Kris Chionh, Faramarz Ismail‐Beigi, Corinna Falck-Ytter, Laure Sayyed Kassem, A. K. 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, P. Kringas, Jéssica 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, J.B. Kimpel, Ronna P. Zimmer, Mary Furst, B.M. Satterwhite, Connie R. Thacker, Kathryn Evans Kreider, Kieren J. Mather, Amale Lteif, T. Hamilton, Nick C. Patel, G. Riera, Marcia Jackson, Vivian Pirics, D. Howard, Danielle Aguillar
Abstract
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 <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 < 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.