Regardless of Drug Used, Weight Gain Worsens Type 2 Diabetes Outcomes: GRADE Study

These findings are from a detailed secondary analysis of the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) randomized controlled trial led by Dr. Deborah J. Wexler and colleagues from Massachusetts General Hospital and Harvard Medical School in Boston, MA. 

The study followed 4,980 adults with type 2 diabetes over five years to assess the relationship between weight changes and health outcomes. Participants, all of whom were already on metformin, were randomly assigned to receive one of four additional treatments: insulin glargine, glimepiride, liraglutide, or sitagliptin. The primary outcome was HbA1c levels of 7% or higher, with secondary outcomes including cardiovascular disease (CVD), kidney disease, neuropathy, and treatment satisfaction.

The study revealed the following findings:

• Liraglutide and sitagliptin were associated with average weight loss of −3.5 kg and −1.07 kg, respectively, during the first year.
• Glargine and glimepiride users experienced slight weight gains of 0.45 kg and 0.89 kg, respectively.
• Over time, there was a general trend toward weight stabilization or reduction across all medication groups.
• Each kilogram of weight gain was associated with a 5% increased risk of HbA1c rising above 7.5%, irrespective of the medication used.
• Weight gain in the first year was linked to a 3% increased risk per kilogram for cardiovascular and kidney events.
• These risk associations remained significant even after adjusting for age, sex, race, baseline HbA1c, and other clinical variables.
• Weight gain was found to reduce patient satisfaction with diabetes treatment.
• Baseline weight was associated with a higher likelihood of developing neuropathy, but weight gain during the study was not a contributing factor, possibly due to already high baseline rates of neuropathy.

The study emphasizes the critical role of weight management in optimizing outcomes for people with type 2 diabetes. While some medications are more prone to cause weight changes than others, the adverse impact of weight gain on blood sugar levels and organ health appears consistent across treatment options.

The authors noted that the highly motivated study population, combined with regular follow-up and lifestyle guidance, may limit generalizability to broader clinical settings. Nonetheless, the findings offer robust evidence for clinicians to emphasize weight control as a key strategy alongside pharmacologic treatment in managing type 2 diabetes.

Reference:

Deborah J. Wexler, W. Timothy Garvey, Alokananda Ghosh, Erin J. Kazemi, Heidi Krause-Steinrauf, Andrew J. Ahmann, Janet Brown-Friday, Sabina Casula, Andrea L. Cherrington, Tom A. Elasy, Stephen P. Fortmann, Jonathan A. Krakoff, Sunder Mudaliar, Margaret Tiktin, Naji Younes, GRADE Study Research Group; 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 20 May 2025; 48 (6): 935–944. https://doi.org/10.2337/dc24-2825