title: Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.
abstract: 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).
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Cristina B
authors.initials: CB
authors.lastname: Guzman
authors.affiliation: Eli Lilly Canada Inc, Toronto, Ontario, Canada.
authors.forename: Xiaotian M
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Arie
authors.initials: A
authors.lastname: Regev
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Sudha
authors.initials: S
authors.lastname: Shankar
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Parag
authors.initials: P
authors.lastname: Garhyan
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Sreekumar G
authors.identifier: 0000-0001-7385-4953
authors.initials: SG
authors.lastname: Pillai
authors.affiliation: Eli Lilly and Company, Neuilly-sur-Seine, France.
authors.forename: Christof
authors.initials: C
authors.lastname: Kazda
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hardy
mesh_terms: D000328:Adult; D000368:Aged; D001713:Biphenyl Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors
chemical_list: D001713:Biphenyl Compounds; D018027:Receptors, Glucagon; C000601762:adomeglivant
keywords: fatty liver; glucagon antagonist; randomized trial; type 2 diabetes