title: Glycemic Effect and Safety of a Systemic, Partial Glucokinase Activator, PF-04937319, in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin-A Randomized, Crossover, Active-Controlled Study.
abstract: Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic β cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily). The primary end point was day 14 weighted mean daily glucose (WMDG) change from period-specific baseline. Secondary end points included change from baseline in fasting plasma glucose, premeal C-peptide and insulin, and safety, including hypoglycemia frequency. Mean decrease from baseline in observed WMDG (mg/dL) was greater for PF-04937319 (split-dose, -31.24; once daily, -31.33) versus sitagliptin (-19.24). Using the integrated glucose red-cell HbA1cmodel, the observed WMDG effect with both PF-04937319 dosing regimens was projected to yield a clinically superior effect on mean glycated hemoglobin (HbA1c; split-dose, -0.88%; once daily, -0.94%) compared with sitagliptin (-0.63%). There was no difference in premeal C-peptide or insulin levels, and although the effect on WMDG with both PF-04937319 regimens was similar, the split-dose regimen appeared to offer some advantage in safety and tolerability.
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Denney
authors.affiliation: Clinical Trials of Texas, Inc, San Antonio, TX, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Denham
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Riggs
authors.affiliation: Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Neeta B
authors.initials: NB
authors.lastname: Amin
mesh_terms: D000328:Adult; D000368:Aged; D001572:Benzofurans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D023381:Endpoint Determination; D020536:Enzyme Activators / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005941:Glucokinase / Q000187:drug effects / Q000378:metabolism*; D006442:Glycated Hemoglobin; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate / Q000627:therapeutic use
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; D020536:Enzyme Activators; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011743:Pyrimidines; D000068900:Sitagliptin Phosphate; C000598526:N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide
keywords: PF-04937319; integrated glucose red-cell HbA1c model; partial glucokinase activator; type 2 diabetes mellitus; weighted mean daily glucose