title: Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes.
abstract: OBJECTIVE
  To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM).
  
  
  METHODS
  Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability.
  
  
  RESULTS
  In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride).
  
  
  CONCLUSIONS
  In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.
authors.affiliation: Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA.
authors.forename: N B
authors.initials: NB
authors.lastname: Amin
authors.affiliation: Aggarwal & Associates Ltd, Brampton, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine, University of Debrecen Medical and Health Science Centre, Nagyerdei krt, Hungary.
authors.forename: D
authors.initials: D
authors.lastname: Pall
authors.affiliation: Department of Medicine, University of Debrecen Medical and Health Science Centre, Nagyerdei krt, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Paragh
authors.affiliation: Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Denney
authors.affiliation: Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Le
authors.affiliation: Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Riggs
authors.affiliation: Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Calle
mesh_terms: D000368:Aged; D001572:Benzofurans / Q000008:administration & dosage*; 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; D004359:Drug Therapy, Combination / Q000379:methods; D005215:Fasting / Q000097:blood; D005260:Female; D005941:Glucokinase; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage*; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage; D013453:Sulfonylurea Compounds / Q000008:administration & dosage
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D011743:Pyrimidines; D000068900:Sitagliptin Phosphate; D013453:Sulfonylurea Compounds; C000598526:N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide; C517652:hemoglobin A1c protein, human; C057619:glimepiride
keywords: PF-04937319; glycaemic control; type 2 diabetes