Dual GLP-1R/GCGR Agonist SAR425899 Improves Beta-cell Function in Type 2 Diabetes.
SAR425899 is a novel dual glucagon-like peptide-1 receptor / glucagon receptor (GLP-1R/GCGR) agonist. A randomized, double-blind, placebo-controlled, 4-week phase 1 multiple-ascending-dose study (NCT02411825) in 36 overweight to obese subjects with type 2 diabetes mellitus receiving SAR425899 demonstrated decreased body weight with a safety profile comparable with GLP-1R agonists. Here we evaluate the change in insulin sensitivity, β-cell function and glucose absorption after 28 days treatment with high- and low-doses SAR425899 versus placebo. Subjects were randomized to receive daily subcutaneous administrations of low-dose SAR425899 (0.03, 0.06, 0.09 mg), high-dose SAR425899 (0.06, 0.12, 0.18 mg) or placebo for 28 days; dose escalation occurred after Days 7 and 14. Mixed meal tests were conducted before treatment (Day -1) and on Days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β-cell responsiveness, and glucose absorption. β-cell function from Day -1 to Day 28 increased by 163%, 95%, and 23%, respectively, with low-dose SAR425899, high-dose SAR425899, and placebo. Percent change in area under the curve for rate of meal glucose appearance between 0 and 120 min was -12%, -24%, and 29%, respectively. After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β-cell function, and slowing glucose absorption rate. This article is protected by copyright. All rights reserved.