Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

Aims: To evaluate whether treatment with LY2409021, a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D). Methods: Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c). Results: A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P <.001) and placebo (4.44%; P <.001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagliptin (6.8 U/L; P =.039) and vs placebo (10.7 U/L; P <.001). No patients had concomitant elevations in bilirubin levels. LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference -0.77%; P <.001) but not sitagliptin (-0.20%; P =.383). Similar results were observed for fasting plasma glucose. LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9 mm Hg; P =.030) and vs placebo (4.3 mm Hg; P =.029), as well as significant increases in body weight and total cholesterol. All effects of LY2409021 were reversible. Conclusion: In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.