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

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 4months with an optional 2-month extension. Patients (n=458) with HbA1c7.5-10% were randomized to AZD1656 20mg (n=40) or 40mg (n=52) fixed doses or 10-140mg (n=91) or 20-200mg (n=93) titrated doses, placebo (n=88) or glipizide 5-20mg titrated (n=94). Patients (n=72) with HbA1c>10 and <= 12% received open-label AZD1656 (20-200mg titrated). Primary outcome was placebo-corrected change in HbA1c from baseline to 4months of treatment. Results: Significant reductions in HbA1c from baseline to 4months were observed with blinded AZD1656 10-140 and 20-200mg 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 4months. Mean (s.d.) change in HbA1c for open-label AZD1656 (20-200mg) was -2.8 (1.19) % after 4months. AZD1656 was well tolerated, with less hypoglycaemia than glipizide. In the extension population, HbA1c was still reduced with AZD1656 versus placebo after 6months, 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 4months, although efficacy diminished over time.