Changes in HbA1c with Optimization of Metformin Dosage in the GRADE Cohort
Authors: SIVITZ WILLIAM , PHILLIPS LAWRENCE S. , FORTMANN STEPHEN P. , WEXLER DEBORAH J. , CAMP ANNE W. , TIKTIN MARGARET , PEREZ MAGALYS , CRAIG JACQUELINE E. , HOLLANDER PRISCILLA , CHERRINGTON ANDREA , ARODA VANITA R. , TAN MENG , KRAKOFF JONATHAN , RASOULI NEDA , YOUNES NAJI ,   GRADE RESEARCH GROUP
Published: June 2018

Delay in maximizing metformin (MET) therapy is a common problem - attributed to “clinical inertia” - which might be reduced if there were better understanding of the impact of increasing MET in persons already on MET at submaximal dosage. We determined the effect of optimizing MET dosage on glycemic control in GRADE study participants. We examined the HbA1c of 6767 participants before and after a run-in period, during which MET dosage was adjusted to 2000 mg daily, or a maximally tolerated lower dose. The run-in was 6-14 weeks for participants taking MET at a dose other than 2000 mg/day, or &gt;4 weeks if on 2000 mg/day at entry. To be eligible, participants had to have type 2 diabetes &lt;10 years and HbA1c &gt;6.8% while taking &gt;500 mg of MET daily and no other glucose-lowering drug. Participants also received diet and exercise counseling. Increases in MET dosing during run-in were associated with a progressive fall in HbA1c (p&lt;0.001). The mean decrease in HbA1c was 0.5 ± 1.1% (SD) in participants whose MET was increased by &lt;500 mg/day, 0.5 ± 0.9% for an increase of 500-999 mg/day, and 0.7 ± 1% for an increase of &gt;1000 mg/day. There was also a mean HbA1c decrease of 0.4 ± 0.9% if MET dosage was kept at 2000 mg/day (n=3472), and a mean HbA1c decrease of 0.2 ± 0.7% if the daily dose was decreased (from a mean of 2213 to 1612 mg/day, n=187) - possibly reflecting better adherence to medications and/or lifestyle recommendations. In subjects whose MET dosage was increased (n=3108), the decrease in HbA1c was inversely and strongly correlated with the initial HbA1c at entry (p&lt;0.001, r=-0.53).
Conclusions: Maximizing MET dosage can improve glycemic control in persons with type 2 diabetes who have HbA1c values above 6.7% while taking less than 2000 mg of MET daily, and maximizing MET dosage produces a larger fall in HbA1c if the initial HbA1c is higher. Moreover, a decrease in MET dosage did not increase HbA1c. These findings support health policies aimed to improve and optimize use of metformin among persons with type 2 diabetes whose glycemic control is suboptimal.

Disclosure
W. Sivitz: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc.. S.P. Fortmann: None. D.J. Wexler: None. A.W. Camp: None. M. Tiktin: None. M. Perez: None. J.E. Craig: None. P. Hollander: Advisory Panel; Self; Novo Nordisk Inc., Eli Lilly and Company, Merck & Co., Inc. A. Cherrington: Advisory Panel; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc. V.R. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck & Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. M. Tan: Other Relationship; Self; Eli Lilly and Company. J. Krakoff: None. N. Rasouli: Consultant; Self; AstraZeneca, Intarcia Therapeutics, Inc.. N. Younes: None. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.