title: Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.
abstract: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes.
  
  
  
  This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers.
  
  
  
  At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P  < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P  < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P  < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P  < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P  < .05 vs placebo).
  
  
  
  Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.
authors.affiliation: Eli Lilly and Company, Neuilly-sur-Seine, France.
authors.forename: Christof M
authors.initials: CM
authors.lastname: Kazda
authors.affiliation: National Research Institute, Los Angeles, California.
authors.forename: Juan
authors.initials: J
authors.lastname: Frias
authors.affiliation: Eli Lilly and Company, Danforth, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Foga
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Cui
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Cristina B
authors.initials: CB
authors.lastname: Guzman
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: Cory
authors.initials: C
authors.lastname: Heilmann
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Jihui Anne
authors.initials: JA
authors.lastname: Yang
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hardy
mesh_terms: D000284:Administration, Oral; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000139:chemically induced*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D006949:Hyperlipidemias / Q000139:chemically induced / Q000150:complications; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; C517652:hemoglobin A1c protein, human; C000601762:adomeglivant
keywords: clinical trial; glucagon receptor antagonist; type 2 diabetes