Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies

OBJECTIVE Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose, was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We assessed the efficacy (HbA 1c ) and safety (serum aminotransferases) of once-daily oral administration of LY2409021 in a double-blind, phase 2 study. Patients with an HbA 1c level of 6.5–10% (48–86 mmol/mol), who were naive to antidiabetic medications or were receiving metformin treatment were randomized to receive 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. RESULTS LY2409021 produced dose-dependent reductions in mean HbA 1c levels that were significantly different from placebo over the 12-week treatment period. After 12 weeks, the least squares mean change from baseline in HbA 1c level was −0.83% (−9.1 mmol/mol) at 10 mg, −0.65% (−7.1 mmol/mol) at 30 mg, and −0.66% (−7.2 mmol/mol) at 60 mg (all P 1c level, fasting glucose level was lowered with LY2409021 at doses associated with only modest increases in aminotransferase levels (the mean increase in alanine aminotransferase was ∼10 units/L). The incidence of hypoglycemia was minimal, and there were no differences between placebo and LY2409021 treatment groups in adverse event frequency. CONCLUSIONS Glucagon receptor antagonism with LY2409021 substantially lowers HbA 1c and serum glucose levels. Modest, reversible increases in aminotransferase levels were evident without elevated bilirubin or other signs or symptoms of liver injury. The efficacy, safety, and tolerability of LY2409021 in patients with type 2 diabetes support further clinical development.