title: Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.
abstract: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM).
  
  
  
  Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured.
  
  
  
  PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated.
  
  
  
  PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kazierad
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bergman
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Tan
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Erion
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Somayaji
authors.affiliation: Pfizer, Cambridge, MA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Rolph
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005215:Fasting; D005260:Female; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000410:Alanine Transaminase; D000596:Amino Acids; D001219:Aspartate Aminotransferases; D001786:Blood Glucose; D002096:C-Peptide; D008078:Cholesterol, LDL; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011720:Pyrazoles; D018027:Receptors, Glucagon; D013453:Sulfonylurea Compounds; D015091:beta-Alanine; C000624434:PF-06291874; C517652:hemoglobin A1c protein, human
keywords: clinical trial; glucagon antagonist; pharmacodynamics; phase I-II study; randomized trial; type 2 diabetes