Improved postprandial glucose metabolism in type 2 diabetes by the dual glucagon-like peptide-1/glucagon receptor agonist SAR425899 in comparison with liraglutide

Abstract

Aim: To gain further insights into the efficacy of SAR425899, a dual glucagon-like peptide-1/glucagon receptor agonist, by providing direct comparison with the glucagon-like peptide-1 receptor agonist, liraglutide, in terms of key outcomes of glucose metabolism.

Research design and methods: Seventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once-daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods.

Results: From BSL to EOT (median [25th, 75th] percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% [21%, 74%]), while secretion enhanced both in SAR425899 (125% [63%, 228%]) and liraglutide (73% [43%, 147%]). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% [58%, 440%] and 36% [21%, 197%]), basal beta-cell responsiveness (67% [34%, 112%] and 40% [16%, 59%]), and above-basal beta-cell responsiveness (139% [64%, 261%] and 69% [-15%, 120%]). A significant delay in glucose absorption was highlighted in SAR425899 (37% [52%,18%]).

Conclusions: SAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in beta-cell function was shown by SAR425899 than liraglutide.

Trial registration: ClinicalTrials.gov NCT02973321.

Keywords: beta-cell function; disposition index; dual agonist; glucagon; glucagon-like peptide-1; insulin sensitivity; liraglutide; mixed meal tolerance test; oral minimal model.

FIGURE 1

Mean ± standard error (SE) time courses of (A) plasma glucose, (B) insulin and (C) C‐peptide measured at day ‐1 (baseline [BSL], dashed line and white squares), and after 26 weeks (end of treatment [EOT], continuous line and black circles) of placebo (PBO), SAR425899 at 0.12 mg (SAR 0.12 mg), SAR425899 at 0.16 mg (SAR 0.16 mg), SAR425899 at 0.20 mg (SAR 0.20 mg) and liraglutide at 1.80 mg (Lira 1.80 mg) administration

FIGURE 2

Mean ± standard error (SE) of Homeostasis Model Assessment (HOMA2) indices of insulin action (HOMA2 %S, panel A) and beta‐cell responsivity (HOMA2 %B, panel B), as well as Oral Minimal Model (OMM) indices of insulin sensitivity (SI, panel C), fractional glucose absorption 2 hours after meal ingestion (AUC(Ra0‐120), panel D), overall above basal and basal β‐cell responsiveness (Φtot, and Φb, panels E and F, respectively), disposition index (DI, panel G), together with body weight (BW, panel H) and HbA1c (panel I). Indices were calculated at day ‐1 (baseline [BSL], white bars) and after 26 weeks (end of treatment [EOT], black bars) of placebo (PBO), all SAR425899 dose regimens (SAR 0.12, 0.16 and 0.20 mg) and liraglutide (Lira) administration. Comparison between BSL vs. EOT was performed using paired T‐test, for normally distributed variables, and Wilcoxon Signed‐Rank test otherwise (P‐value <.05 was considered statistically significant). Of note, the number of subjects (N) may change among outcomes due to missing/unreliable samples limiting model outcome estimation

FIGURE 3

Percent deviation between BSL vs. EOT values, that is (EOT – BSL)/BSL, of Homeostasis Model Assessment (HOMA2) index of insulin action (HOMA2 %S, panel A) and beta‐cell responsivity (HOMA2 %B, panel B), as well as Oral Minimal Model (OMM) indices of insulin sensitivity (SI, panel C), fractional glucose absorption 2 hours after meal ingestion (AUC(Ra0‐120), panel D), overall above basal and basal β‐cell responsiveness (Φtot, and Φb, panels E and F, respectively), disposition index (DI, panel G), together with body weight (BW, panel H) and HbA1c (panel I). Indices were calculated for placebo (PBO, white with dots), all SAR425899 dose regimens (SAR 0.12, 0.16 and 0.20 mg, white with lines) and liraglutide (Lira, black with dots) cohorts. Comparison between cohorts was performed by one‐way analysis of variance (ANOVA) followed by post‐hoc analysis using Tukey‐Kramer correction for multiple comparisons, for normally distributed variables, and Kruskall‐Wallis test followed by post‐hoc analysis using Dunn‐Sidak correction for multiple comparisons otherwise (P‐value<.05 was considered statistically significant). Of note, the number of subjects (N) may change among outcomes due to missing/unreliable samples limiting model outcome estimation

FIGURE 4

Mean ± standard error (SE) time courses of estimated meal glucose rate of appearance (Ra) at day ‐1 (baseline [BSL]) and after 26 weeks (end of treatment [EOT]) for placebo (PBO, left panel), SAR425899 (SAR, middle panel) and liraglutide (Lira, right panel) cohorts. Ra is assumed to be completely absorbed within 6 hours after meal ingestion. Of note, the number of subjects (N) may change among outcomes due to missing/unreliable samples limiting model parameter estimation