Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin

Diabetes Obes Metab. 2013 Aug;15(8):750-9. doi: 10.1111/dom.12088. Epub 2013 Mar 24.

Abstract

Aim: 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.

Conclusion: Addition of AZD1656 (individually titrated) to metformin gave significant improvements in glycaemic control up to 4 months, although efficacy diminished over time.

Keywords: dose-ranging; glucokinase activator; metformin; phase II; type 2 diabetes mellitus.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Azetidines / therapeutic use*
  • Blood Glucose / metabolism
  • Body Mass Index
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Enzyme Activation / drug effects
  • Enzyme Reactivators / therapeutic use*
  • Europe / epidemiology
  • Fasting
  • Female
  • Glucokinase / drug effects
  • Glucokinase / metabolism*
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Pyrazines / therapeutic use*
  • Time Factors
  • Treatment Outcome
  • Triglycerides / blood

Substances

  • AZD1656
  • Azetidines
  • Blood Glucose
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Enzyme Reactivators
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Pyrazines
  • Triglycerides
  • hemoglobin A1c protein, human
  • Metformin
  • Glucokinase