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Randomized Controlled Trial
. 2025 Jun 1;48(6):935-944.
doi: 10.2337/dc24-2825.

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

Deborah J Wexler  1 , W Timothy Garvey  2 , Alokananda Ghosh  3 , Erin J Kazemi  3 , Heidi Krause-Steinrauf  3 , Andrew J Ahmann  4 , Janet Brown-Friday  5 , Sabina Casula  6 , Andrea L Cherrington  7 , Tom A Elasy  8 , Stephen P Fortmann  9   10 , Jonathan A Krakoff  11 , Sunder Mudaliar  12 , Margaret Tiktin  13 , Naji Younes  3 ; GRADE Study Research Group
Collaborators, Affiliations
Randomized Controlled Trial

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

Deborah J Wexler et al. Diabetes Care. .

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.

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Conflict of interest statement

Duality of Interest. D.J.W. reports participation on data monitoring committees for Novo Nordisk A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW) and Semaglutide Cardiovascular Outcomes Trial (SOUL) trials outside the submitted work. W.T.G. reports receiving consulting fees for membership on advisory boards for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Allurion, Carmot/Roche, and Merck; payments for participation on data safety monitoring board in phase 3 trials for Boehringer-Ingelheim and Eli Lilly; honoraria for invited lectureships at universities: Brown University, Auburn University, Wayne State, University of Illinois, Mt Sinai, Cleveland Clinic, and University of Miami; membership (unpaid) on Lancet Commission on Obesity; and publicly traded stock with Eli Lilly, Pfizer, Novartis, Merck, Ionis, and Bristol-Myers Squibb (each <$20,000 in value and managed independently by an investment firm), outside the submitted work. A.J.A. reports participation on a scientific advisory board for Medtronic Diabetes insulin pumps outside the submitted work. J.B.F. reports membership (unpaid) for the American Diabetes Association National Board outside the submitted work. S.P.F. reports research contracts from Pfizer paid to the institution for vaccine studies outside the submitted work. S.M. reports speakers bureau payment from AstraZeneca Pharmaceuticals outside the submitted work. All authors affirm that authorship is merited based on the ICMJE authorship criteria. No other potential conflicts of interest relevant to this article were reported.

References

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