title: Combining the G-protein-coupled receptor 40 agonist fasiglifam with sitagliptin improves glycaemic control in patients with type 2 diabetes with or without metformin: A randomized, 12-week trial.
abstract: To evaluate the efficacy and safety of fasiglifam, an orally active G-protein-coupled receptor 40 agonist, in combination with the dipeptidyl peptidase-4 inhibitor sitagliptin, in patients with type 2 diabetes inadequately controlled with diet/exercise (± metformin).
  
  
  
  In this randomized, double-blind, phase II study, 368 patients received once-daily placebo, sitagliptin 100 mg, fasiglifam 25 or 50 mg, or the combination of sitagliptin 100 mg plus fasiglifam 25 or 50 mg. The primary endpoint was change from baseline glycated haemoglobin (HbA1c) at 12 weeks; a key secondary endpoint was change in fasting plasma glucose (FPG).
  
  
  
  The fasiglifam 25 and 50 mg combination regimens produced significantly greater HbA1c reductions than sitagliptin (treatment differences of -0.45% and -0.61%; P < .01, respectively) or respective doses of fasiglifam monotherapy (-0.43% and -0.48%; P < .01) and significantly greater FPG reductions than sitagliptin (-1.1 mmol/L for both combination regimens; P < .01). Improved glycaemic control occurred by week 1 for FPG and week 4 for HbA1c in all groups. Hypoglycaemia rates were low (≤3.3%) and similar across treatments. Liver enzymes >3 × upper limit of normal occurred in four patients (fasiglifam 25 mg, n = 1; fasiglifam 50 mg, n = 2; 1 fasiglifam/sitagliptin 50/100 mg, n = 1).
  
  
  
  Combination of fasiglifam and sitagliptin provided significant additional effects on glycaemic control, with hypoglycaemia rates similar to placebo with or without metformin. This study provides supportive clinical evidence for the complementary mechanism of actions of this GPR40 agonist and DPP-4 inhibitor.
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, Illinois.
authors.forename: Xuejun V
authors.initials: XV
authors.lastname: Peng
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, Illinois.
authors.forename: John F
authors.identifier: 0000-0002-9408-1889
authors.initials: JF
authors.lastname: Marcinak
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, Illinois.
authors.forename: Marsha G
authors.initials: MG
authors.lastname: Raanan
authors.affiliation: Takeda Development Center Americas, Inc., Deerfield, Illinois.
authors.forename: Charlie
authors.initials: C
authors.lastname: Cao
mesh_terms: D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006455:Hemoglobins, Abnormal / Q000032:analysis; D006801:Humans; D006943:Hyperglycemia; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D054795:Incretins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D000068900:Sitagliptin Phosphate / Q000009:adverse effects / Q000627:therapeutic use*; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014481:United States / Q000453:epidemiology
chemical_list: D001572:Benzofurans; D054873:Dipeptidyl-Peptidase IV Inhibitors; C473034:FFAR1 protein, human; D006455:Hemoglobins, Abnormal; D007004:Hypoglycemic Agents; D054795:Incretins; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; C465352:hemoglobin A2-Monreale; D008687:Metformin; D000068900:Sitagliptin Phosphate
keywords: antidiabetic drug; glycaemic control; insulin secretagogue; phase I-II study; randomized trial; type 2 diabetes