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

Diabetes Care. 2020 May;43(5):940-947. doi: 10.2337/dc19-1769. Epub 2020 Mar 5.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism
  • Body Weight / drug effects*
  • Calibration
  • Comparative Effectiveness Research
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Glycated Hemoglobin A / analysis
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Insulin / administration & dosage
  • Insulin / adverse effects
  • Insulin / analogs & derivatives
  • Liraglutide / administration & dosage
  • Liraglutide / adverse effects
  • Male
  • Maximum Tolerated Dose
  • Metformin / administration & dosage*
  • Metformin / adverse effects
  • Middle Aged
  • Sitagliptin Phosphate / administration & dosage
  • Sitagliptin Phosphate / adverse effects
  • Sulfonylurea Compounds / administration & dosage
  • Sulfonylurea Compounds / adverse effects
  • Weight Loss / drug effects
  • Weight Loss / physiology

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Sulfonylurea Compounds
  • glimepiride
  • Liraglutide
  • Metformin
  • Sitagliptin Phosphate

Associated data

  • ClinicalTrials.gov/NCT01794143