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, Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
W Timothy Garvey, Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
Alokananda Ghosh, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Erin J. Kazemi, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Heidi Krause-Steinrauf, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Andrew J. Ahmann, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health and Science University, Portland, OR.
Janet Brown-Friday, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
Sabina Casula, Endocrinology, Diabetes, and Metabolism, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL.
Andrea L. Cherrington, Divisions of Preventive and General Internal Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Tom A. Elasy, Vanderbilt University Medical Center, Nashville, TN.
Stephen P. Fortmann, Kaiser Permanente Center for Health Research, Portland, OR.
Jonathan A. Krakoff, Obesity and Diabetes Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.
Sunder Mudaliar, Veterans Affairs San Diego Healthcare System and Division of Endocrinology and Metabolism, University of California, San Diego School of Medicine, La Jolla, CA.
Margaret Tiktin, Louis Stokes Cleveland Veterans Affairs Medical Center and Case Western Reserve University, Cleveland, OH.
Naji Younes, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.

Document Type

Journal Article

Publication Date

4-23-2025

Journal

Diabetes care

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.

Department

Biostatistics and Bioinformatics

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