Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Abstract

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 ).

Fig. 1. DAWN study patient disposition.

DAWN study patient disposition flow diagram for the entire trial. Note that ten patients did not meet the inclusion and exclusion criteria but were included in the run-in period. In total, 767 patients were randomized, and 766 patients who took at least one dose of the study drug were included in the SS. The FAS included 751 patients who took at least one dose of the study drug and had at least one post-treatment measurement of the primary endpoint during the double-blind treatment period. Two patients did not meet the criteria for randomization but were randomized, one of whom was included in the FAS and the other was not, as this patient did not take at least one dose of the study drug.

Fig. 2. Primary and secondary efficacy endpoints.

a, The primary endpoint: LS mean changes in the HbA1c level from baseline to week 24 in patients who received either dorzagliatin and metformin or placebo and metformin. The ETD and corresponding 95% CI were estimated using, in the FAS, an MMRM without missing value imputation (dorzagliatin, n = 374; placebo, n = 374) (P < 0.0001). b, The mean HbA1c level recorded at each visit over 24 weeks in patients who received either dorzagliatin and metformin or placebo and metformin. c, The LS mean change in 2h-PPG levels from baseline. ETD and 95% CI were estimated in the FAS using an MMRM (dorzagliatin, n = 360; placebo, n = 355). d, The LS mean change in FPG from baseline. ETD and 95% CI were estimated in the FAS using an MMRM (dorzagliatin, n = 374; placebo, n = 374). e, The mean HbA1c levels measured at each visit over 52 weeks. The FAS comprised all randomized patients who took at least one dose of the study drug and had at least one post-treatment measurement of the primary endpoint during the double-blind treatment period. All statistical tests were two-sided at a significance level of 0.05, and no adjustments were made for multiplicity. Data in a, c and d are presented as LS mean ± s.e.; data in b and e are presented as mean ± s.e. Met: metformin.

Extended Data Fig. 1

DAWN study design.