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)

Authors

• Steven E Kahn
• Mark Tripputi
• John M Lachin
• Ashok Balasubramanyam
• Mary Ann Banerji
• Joshua Barzilay
• Robert M Cohen
• W Timothy Garvey
• Michaela R Gramzinski
• Neda Rasouli
• Mary Rhee
• Jesse C Seegmiller
• Vatsala Singh
• William I Sivitz
• Michael W Steffes
• Kristina Utzschneider
• Ralph A DeFronzo

Language

English

Publication Date

2-1-2026

Journal

Diabetes Care

DOI

10.2337/dc25-2186

PMID

41432725

PMCID

PMC12824799

PubMedCentral® Posted Date

12-23-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Glucagon, C-Peptide, Diabetes Mellitus, Type 2, Middle Aged, Male, Female, Hypoglycemic Agents, Sulfonylurea Compounds, Metformin, Aged, Blood Glucose, Liraglutide, Adult, Sitagliptin Phosphate, Insulin Glargine, Glycated Hemoglobin, Glucagon-Secreting Cells

Published Open-Access

yes

Recommended Citation

Kahn, Steven E; Tripputi, Mark; Lachin, John M; et al., "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)" (2026). Faculty, Staff and Students Publications. 6899.
https://digitalcommons.library.tmc.edu/baylor_docs/6899