title: Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.
abstract: 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.
  
  
  
  The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks.
  
  
  
  LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was -0.83% (10 mg), -0.65% (30 mg), and -0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was -0.45% (2.5 mg), -0.78% (10 mg, P < 0.05), -0.92% (20 mg, P < 0.05), and -0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo.
  
  
  
  In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.
authors.affiliation: Eli Lilly and Company, Suresnes, France kazda_christof@lilly.com.
authors.forename: Christof M
authors.initials: CM
authors.lastname: Kazda
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, Singapore.
authors.forename: Ronan P
authors.initials: RP
authors.lastname: Kelly
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Parag
authors.initials: P
authors.lastname: Garhyan
authors.affiliation: inVentiv Health Clinical, Clarksville, MD.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Shi
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Chay Ngee
authors.initials: CN
authors.lastname: Lim
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Haoda
authors.initials: H
authors.lastname: Fu
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: David E
authors.initials: DE
authors.lastname: Watson
authors.affiliation: National Research Institute, Los Angeles, CA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lewin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: William H
authors.initials: WH
authors.lastname: Landschulz
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Deeg
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: David E
authors.initials: DE
authors.lastname: Moller
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
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*; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis / Q000378:metabolism; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D000637:Transaminases / Q000097:blood; D055815:Young Adult
chemical_list: D001713:Biphenyl Compounds; D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D000637:Transaminases; C517652:hemoglobin A1c protein, human; C000601762:adomeglivant