Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study

Objective: Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin.

Research Design And Methods: In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes ( = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments.

Results: Over 12 weeks, RVT-1502 significantly reduced HbA relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups ( < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L ( < 0.001). The proportions of subjects achieving an HbA <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg ( ≤ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502-associated mild increases in blood pressure were not dose related or consistent across time.

Conclusions: Glucagon receptor antagonism with RVT-1502 significantly lowers HbA and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849).