Effects of the Novel Dual GLP-1R/GCGR Agonist SAR425899 on Postprandial Glucose Metabolism in Overweight/Obese Subjects with Type 2 Diabetes

SAR425899 (SAR) is a novel dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist. A randomized, double-blind, phase I multiple-ascending-dose study (NCT02411825) in 27 overweight/obese subjects with type 2 diabetes receiving SAR demonstrated decreased body weight with a safety profile comparable with GLP-1R agonists. Here, we report additional analyses of the effect of SAR on key processes in glucose metabolism. Subjects were randomized to receive daily subcutaneous administrations of low-dose SAR (30, 60, 90 µg) or high-dose SAR (60, 120, 180 µg) 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 glucose absorption, insulin sensitivity, and β-cell responsiveness. Percent change in area under the curve for rate of meal glucose appearance between 0 and 120 min from Day −1 to Day 28 was −14% and −19% with low- and high-dose SAR, respectively. Change in insulin sensitivity was 104% and 262%, respectively. Change in β-cell function was 127% and 145%, respectively (Table). After 28 days of treatment, SAR improved postprandial glucose control by significantly reducing glucose absorption rate, increasing insulin sensitivity, and enhancing β-cell function.