title: A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.
abstract: OBJECTIVE
  The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM.
  
  
  METHODS
  After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28.
  
  
  RESULTS
  Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia.
  
  
  CONCLUSIONS
  PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM.
authors.affiliation: Pfizer Inc., Cambridge, MA, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Bergman
authors.affiliation: Pfizer Inc., Cambridge, MA, USA.
authors.forename: Beesan
authors.initials: B
authors.lastname: Tan
authors.affiliation: Pfizer Inc., Cambridge, MA, USA.
authors.forename: Veena R
authors.initials: VR
authors.lastname: Somayaji
authors.affiliation: Pfizer Inc., Cambridge, MA, USA.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Calle
authors.affiliation: Pfizer Inc., Cambridge, MA, USA. Electronic address: david.j.kazierad@pfizer.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kazierad
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D014481:United States
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon
keywords: Glucagon receptor antagonist; PF-06291874; Pharmacodynamics; Pharmacokinetics; Phase 2 study; Type 2 diabetes mellitus