Weight Gain Was Associated With Worsening Glycemia and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes Independent of Diabetes Medication in the GRADE Randomized Controlled Trial

Diabetes Care. 2025 Jun 1;48(6):935-944. doi: 10.2337/dc24-2825.

Abstract

Objective: Weight gain with glucose-lowering medications may interfere with effective type 2 diabetes (T2D) management. We evaluated weight change and the effect of weight gain on outcomes over 5 years on four diabetes medications.

Research design and methods: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) randomized trial compared the addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin in participants with T2D. We report weight change and hazard ratio (HR) per kilogram of weight change for HbA1c >7.5%; cardiovascular disease (CVD), kidney disease, and neuropathy outcomes; and diabetes treatment satisfaction.

Results: Participants (n = 4,980) were 57 ± 10 years, 44% non-White, with HbA1c 7.5% ± 0.5%, and BMI 34.3 ± 6.8 kg/m2. Mean (95% CI) weight change (kg) during the first year was -3.5 (-3.8,-3.2) with liraglutide,-1.07 (-1.4,-0.78) with sitagliptin, 0.45 (0.16, 0.74) with glargine, and 0.89 (0.60, 1.2) with glimepiride (P < 0.0001). Thereafter, weight decreased in all groups. Weight gain within the first 6 months was associated with increased risk of HbA1c >7.5%, with modest differences by treatment, and with subsequent CVD (HR 1.03 [95% CI 1.005, 1.06]). Weight gain at 1 year was associated with increased risk of HbA1c >7.5% (HR 1.05 [1.04, 1.07]) and kidney disease (HR 1.03 [1.01, 1.06]). Baseline weight, but not weight gain, was associated with new-onset neuropathy. Weight gain was associated with lower diabetes treatment satisfaction.

Conclusions: Liraglutide and sitagliptin were associated with initial weight loss and glargine and glimepiride with slight weight gain, followed by weight loss in metformin-treated T2D. Weight gain was associated with worsening glycemia and increased risk of cardiovascular and kidney outcomes largely independent of treatment.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / etiology
  • Cardiovascular Diseases* / physiopathology
  • Diabetes Mellitus, Type 2* / blood
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / physiopathology
  • Female
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemic Agents* / therapeutic use
  • Insulin Glargine / therapeutic use
  • Liraglutide / therapeutic use
  • Male
  • Metformin / therapeutic use
  • Middle Aged
  • Sitagliptin Phosphate / therapeutic use
  • Sulfonylurea Compounds / therapeutic use
  • Weight Gain* / drug effects
  • Weight Gain* / physiology

Substances

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