Impact of Insulin Sensitivity and β-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy

Abstract

Objective: To compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy.

Research design and methods: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of 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 outcome 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 greater 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 of 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 lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome.

Conclusions: 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 in comparison with the glimepiride and liraglutide groups.

Graphical abstract

Figure 1

Short-term (0–3 months) and long-term (slope of rise in HbA_1c after 3 months) mean HbA_1c change by baseline tertiles of insulin sensitivity (HOMA2-%S [A and D]) and β-cell function as reflected by CP responses (CPI [B and E] and total CP response [C and F]) with models adjusted for HOMA2-%S as a covariate. For each panel, each treatment group is depicted separately with a test for overall treatment heterogeneity noted (i.e., a test of the interaction between treatment group and the continuous insulin sensitivity or CP response measure). For those with overall significance, any significant pairwise comparisons (P < 0.05) of the association of the metabolic measure and short- or long-term HbA_1c change between treatment groups are denoted in the triangle with a bold black line between treatment groups: G, glimepiride (orange); L, liraglutide (blue); S, sitagliptin (red). Note, for D, there were no treatment group differences (all P > 0.05) and thus no pairwise comparisons were performed.

Figure 2

The association of baseline tertiles of insulin sensitivity (HOMA2-%S) and CP responses (CPI, total CP response) with time to reach primary outcome is depicted with Kaplan-Meier plots for each treatment group. For those variables with significant treatment group differences in this association, identified with a global Wald test from Cox regression analysis (models for CP indices adjusted for HOMA2-%S as a covariate), significant pairwise comparisons (P < 0.05) within each panel are denoted in the triangle with a bold black line between treatment groups: G, glimepiride (orange); L, liraglutide (blue); S, sitagliptin (red).