Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight

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.

Trial registration: ClinicalTrials.gov NCT01794143.

© 2020 by the American Diabetes Association.

Figures

Figure 1

Dose-dependent effects of metformin on glycemia and body weight. Changes with 95% CIs in HbA1c (A) and body weight (B) by magnitude of metformin dose change during run-in. Numerical mean values are listed within the bars. Actual mean ± SD dose changes for reduced, unchanged, and <500, 500–999, and ≥1,000 mg/day, respectively, were −602 ± 245, 0 ± 0, 295 ± 22, 503 ± 28, and 1,084 ± 183 in A and −608 ± 250, 0 ± 0, 296 ± 20, 504 ± 29, and 1,080 ± 180 in B. C: Bars representing binary variable based on whether HbA1c (A1c) had improved by 0.3% (3.3 mmol/mol) or better (−0.3% is the median change); P < 0.001 by χ2 test. D: Proportion of participants with an HbA1c <7% (53 mmol/mol) before and after the run-in. The data in A and B are based on a regression model with HbA1c change or weight change as the response and the category of metformin change as a predictor, adjusted for duration of run-in. The estimates and error bars are from the least squares means for metformin change and their 95% CIs. The P values are calculated from contrasts between the least squares means and are adjusted for multiple comparisons using a Dunnett adjustment. HbA1c values in percentage units can be converted to millimoles per mole using the NGSP HbA1c converter at https://www.ngsp.org/convert1.asp.