Glucagon and insulin work in concert to achieve and maintain proper blood glucose levels. Glucagon, released by pancreatic alpha cells, prevents hypoglycemia, while insulin released by beta cells prevents hyperglycemia. Together they preserve a tight blood glucose concentration between 70-100 mg/dL fasting and 70-140 mg/dL after meals. In type 2 diabetes, glucagon production, release, and action are malfunctioning. Overproduction of glucagon leads to over-stimulation of gluconeogenesis and glycolysis, in turn exacerbating hyperglycemia of diabetes mellitus.
It is only natural to look for ways of lowering the synthesis, secretion, or effects of glucagon. In this phase-2 clinical trial, the researchers tested the ability of a glucagon receptor antagonist in lowering A1c in 166 patients with metformin-uncontrolled type 2 diabetes over 12 weeks. The glucagon receptor antagonist RVT-1502, at the high dose 15 mg per day, lowered A1c by 1.0% without severe hypoglycemia. Slight and mild elevation of aminotransferases and blood pressure were documented respectively.
Since study results are meaningfully positive, a follow-up phase-3 randomized clinical trial would be expected.
Phase 2 RCT
Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin.
In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n = 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.
Primary endpoint was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo.
Secondary endpoints included change from baseline in fasting plasma glucose (FPG) and safety assessments.
Over 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L (P < 0.001).
The proportions of subjects achieving an HbA1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg (P ≤ 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.
Glucagon receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies