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).

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.