The DAWN study of dorzagliatin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, phase 3 trial

Abstract Metformin is the first-line therapy for the treatment of type 2 diabetes (T2D) through mechanism of reduction in hepatic glucose production and fasting plasma glucose. Dorzagliatin is a novel glucokinase activator (GKA) that improves glucose and insulin sensitivity which significantly reduces post meal plasma glucose. Combination of dorzagliatin with metformin would offer benefits through the synergy of two mechanisms. In this randomized, double-blind, placebo-controlled phase 3 trial (NCT03141073), the efficacy and safety of dorzagliatin add-on to metformin in T2D patients were assessed. Eligible T2D patients (n=767) were randomly assigned in a 1:1 ratio to dorzagliatin group or placebo group add-on to metformin (1500 mg/day) for a 24-week double-blind treatment, then followed by a 28-week open-label treatment with dorzagliatin in all patients. The primary efficacy endpoint was the change from baseline in the glycated hemoglobin(HbA1c) level at week 24 and the safety was assessed throughout the trial. At week 24, the HbA1c was reduced from baseline in dorzagliatin group, superior to placebo (-1.02% vs. -0.36%; ETD, -0.66%; 95% CI, -0.79 to -0.53; P<0.0001), with the effects sustained through 52 weeks. The 2-hour postprandial glucose (2hPPG) was significantly decreased in dorzagliatin group over placebo (-98.10 mg/dl vs. -53.46 mg/dl, P<0.0001), and the homeostasis model assessment 2-β (HOMA2-β) and homeostasis model assessment 2-IR (HOMA 2-IR) were significantly improved at week 24 over placebo. The incidence of adverse events (AEs) was similar between the two groups during the 24 weeks. The hypoglycemia occurred in 4 (1.0%) out of 382 patients in dorzagliatin group during the 52 weeks. No severe hypoglycemia events were reported. In T2D patients with inadequate glycemic control by metformin alone, dorzagliatin demonstrated fast onset and sustained glycemic control with a good safety and tolerability profile for 52 weeks.