Differential Longitudinal Effects of Glucose-Lowering Medications on Glucagon and C-peptide Responses in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Steven E. Kahn, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
Mark Tripputi, The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Bethesda, MD.
John M. Lachin, The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Bethesda, MD.
Ashok Balasubramanyam, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX.
Mary Ann Banerji, Division of Endocrinology and Department of Medicine, State University of New York Downstate Medical Center, Kings County Hospital, Brooklyn, NY.
Joshua Barzilay, Department of Endocrinology, Kaiser Permanente of Georgia, Duluth, GA.
Robert M. Cohen, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH.
W Timothy Garvey, Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, AL.
Michaela R. Gramzinski, The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Bethesda, MD.
Neda Rasouli, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO.
Mary Rhee, Atlanta VA Medical Center, Decatur, GA.
Jesse C. Seegmiller, Department of Laboratory Medicine and Pathology, Advanced Research and Diagnostic Laboratory, University of Minnesota, Minneapolis, MN.
Vatsala Singh, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO.
William I. Sivitz, Department of Internal Medicine, University of Iowa, Iowa City, IA.
Michael W. Steffes, Department of Laboratory Medicine and Pathology, Advanced Research and Diagnostic Laboratory, University of Minnesota, Minneapolis, MN.
Kristina Utzschneider, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
Ralph A. DeFronzo, Diabetes Division, University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, TX.

Document Type

Journal Article

Publication Date

12-23-2025

Journal

Diabetes care

DOI

10.2337/dc25-2186

Abstract

OBJECTIVE: To determine the longitudinal effects on α-cell function of four classes of glucose-lowering agents added to metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin. In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]). Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined. RESULTS: Baseline fasting glucagon and GGI were not associated with the primary metabolic outcome (2 df; P = 0.55), whereas the β-cell measures were (2 df; P = 0.04). Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function. A 1-SD increase in CPI was associated with a 17% reduction in the risk of the primary metabolic outcome. There were no clear differential effects of the medications on glucagon responses. CONCLUSIONS: There were different patterns of effects of the four glucose-lowering medications on the α-cell, with no relationship of α-cell function with worsening glycemia. Thus, in treating type 2 diabetes, for choice of medication(s) the focus should primarily be on their impact on β-cell function.

Department

Biostatistics and Bioinformatics

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