SYR-472, a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial

Background In patients with type 2 diabetes, improving adherence to medication is important in order to maintain favourable glycaemic control during long-term treatment and, thus, prevent the onset or aggravation of complications. SYR-472 is a novel once-weekly oral DPP-4 inhibitor for type 2 diabetes, which could be a treatment option when clinicians seek to improve medication adherence by reducing the number of required administrations. In this study, we assessed the efficacy and safety of SYR-472 in patients with type 2 diabetes. Methods In this phase 2, multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging study, we included Japanese patients with inadequately controlled type 2 diabetes despite diet and exercise treatment. Patients were randomly assigned (allocation ratio 1:1:1:1:1:1) to receive either placebo or SYR-472 at five different doses (12.5 mg, 25 mg, 50 mg, 100 mg, or 200 mg). Randomisation was done with a permuted block schedule. All investigators and patients were unaware of the treatment assignment. Treatment drug was given orally once weekly for 12 weeks. The primary efficacy variable was the change in HbA(1c) concentration from baseline to the end of treatment. This study has been registered at the Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information: Japic CTI-090899. Findings 322 patients were randomly assigned to receive placebo (55 patients) or SYR-472 at 12.5 mg (54 patients), 25 mg (52 patients), 50 mg (51 patients), 100 mg (55 patients) or 200 mg (55 patients). The least square (LS) mean change in HbA(1c) concentration from baseline was 0 35% (SE 0.068; -20 mmol/mol) for the placebo group, -0.37% (0.068; -28 mmol/mol) for the 12.5 mg group, -0.32% (0.070; -27 mmol/mol) for the 25 mg group, -0.42% (0.070; -28 mmol/mol) for the 50 mg group, -0.54% (0.068; -29 mmol/mol) for the 100 mg group, and -0.55% (0.069; -30 mmol/mol) for the 200 mg group. In general, HbA(1c) concentration decreased in a dose-dependent manner (trend test using contrast coefficients p<0.0001) and the reduction was significantly greater for all SYR-472 doses (p<0.0001 for each group) than for placebo. The incidence of treatment-emergent adverse events in each SYR-472 group was similar to that in the placebo group. The most common adverse event was nasopharyngitis in all groups. No episodes of hypoglycaemia defined by investigator occurred with any treatment during the study. Interpretation Once-weekly SYR-472 treatment produced clinically and statistically significant improvements in glycaemic control in patients with type 2 diabetes. It was well tolerated and might be a new treatment option for patients with this disease.