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

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 HbA1c model, 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.