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 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.