Impact of insulin sensitivity and β-cell function over time on glycemic outcomes in the GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness) Study: differential treatment effects of dual therapy.

Objective: Compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. Design and Methods: GRADE Study participants were randomized to glimepiride (n=1254), liraglutide (n=1262), or sitagliptin (n=1268) added to baseline metformin and followed for 5.0±1.3 years with HbA1c quarterly and OGTTs at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA2-%S) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary: HbA1c≥7% (53 mmol/mol) and secondary outcome: HbA1c>7.5% (58 mmol/mol)) and examined differential treatment responses. Results: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a larger initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test heterogeneity p=0.009 HOMA2-%S; p=0.018 early CP; p=0.001 total CP) and risk of primary outcome (p=0.005 HOMA2-%S; p=0.11 early CP; p=0.025 total CP), but lower impact on HbA1c rise (p=0.175 HOMA2-%S; p=0.006 early CP; p<0.001 total CP) compared to glimepiride and liraglutide. There were no differential treatment effects on secondary outcome. Conclusion: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response compared to glimepiride and liraglutide.