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' conclusion
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.
Study context
- Population
- Adults ≥30 years with T2D taking 1,000–2,000 mg metformin daily, HbA1c 6.8%-8.5%subset of 5,047 randomized
- Participants
- 724 adults
- Comparison
- Insulin glargine U100 vs glimepiride vs liraglutide vs sitagliptin, added to metformin
- Primary endpoint
- Primary metabolic outcome (HbA1c ≥7.0%) in relation to α-cell function (fasting glucagon, GGI) and β-cell function (fasting C-peptide, CPI)
Methodological detailsmulticentre, subset analysis
- Multicentre
- Subset analysis
Primary result
As reported in the abstract
Association of α- and β-cell measures with primary metabolic outcome (HbA1c ≥7.0%)
- Baseline fasting glucagon and GGI not associated with primary metabolic outcome (2 df)
- P = 0.55
- Baseline β-cell measures associated with primary metabolic outcome (2 df)
- P = 0.04
- Changes in CPI associated with primary metabolic outcome, unadjusted for α-cell function
- P < 0.05
- Changes in CPI associated with primary metabolic outcome, adjusted for α-cell function
- P < 0.001
- Risk reduction of primary metabolic outcome per 1-SD increase in CPI
- 17%
Further findings
- No clear differential effects of the medications on glucagon responses
Original publication
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). Diabetes Care. Published 23 December 2025. doi:10.
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