title: Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin.
abstract: OBJECTIVE
  To investigate the effect of glucokinase activator AZD1656 on glycated haemoglobin (HbA1c) as an add-on to metformin in patients with type 2 diabetes.
  
  
  METHODS
  This randomized, double-blind, placebo-controlled study (NCT01020123) was conducted over 4 months with an optional 2-month extension. Patients (n = 458) with HbA1c 7.5-10% were randomized to AZD1656 20 mg (n = 40) or 40 mg (n = 52) fixed doses or 10-140 mg (n = 91) or 20-200 mg (n = 93) titrated doses, placebo (n = 88) or glipizide 5-20 mg titrated (n = 94). Patients (n = 72) with HbA1c >10 and ≤12% received open-label AZD1656 (20-200 mg titrated). Primary outcome was placebo-corrected change in HbA1c from baseline to 4 months of treatment.
  
  
  RESULTS
  Significant reductions in HbA1c from baseline to 4 months were observed with blinded AZD1656 10-140 and 20-200 mg versus placebo [mean (95% CI) changes: -0.80 (-1.14; -0.46) and -0.81 (-1.14; -0.47) %, respectively), with similar reductions observed with glipizide. A higher percentage of patients on AZD1656 than on placebo achieved HbA1c ≤7.0 or ≤6.5 % after 4 months. Mean (s.d.) change in HbA1c for open-label AZD1656 (20-200 mg) was -2.8 (1.19) % after 4 months. AZD1656 was well tolerated, with less hypoglycaemia than glipizide. In the extension population, HbA1c was still reduced with AZD1656 versus placebo after 6 months, but the effect of AZD1656 on glucose control was not sustained over time.
  
  
  CONCLUSIONS
  Addition of AZD1656 (individually titrated) to metformin gave significant improvements in glycaemic control up to 4 months, although efficacy diminished over time.
authors: Department of Obesity and Endocrinology, University Hospital Aintree, Liverpool, UK. J.P.H.Wilding@liverpool.ac.uk
authors: J P H
authors: JP
authors: Wilding
authors: M
authors: M
authors: Leonsson-Zachrisson
authors: C
authors: C
authors: Wessman
authors: E
authors: E
authors: Johnsson
mesh_terms: D000704:Analysis of Variance; D001384:Azetidines / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D004793:Enzyme Reactivators / Q000627:therapeutic use*; D005060:Europe / Q000453:epidemiology; D005215:Fasting; D005260:Female; D005941:Glucokinase / Q000187:drug effects / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D011719:Pyrazines / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
chemical_list: D001384:Azetidines; D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004793:Enzyme Reactivators; D005941:Glucokinase; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D011719:Pyrazines; D014280:Triglycerides; C576407:AZD1656; C517652:hemoglobin A1c protein, human
keywords: dose-ranging; glucokinase activator; metformin; phase II; type 2 diabetes mellitus