Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Abstract

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 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 from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was −1.07% (−1.19%, −0.95%) in the dorzagliatin group and −0.50% (−0.68%, −0.32%) in the placebo group (estimated treatment difference, −0.57%; 95% confidence interval: −0.79%, −0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats

“…TTP399 is currently investigated as an add-on therapy in type 1 diabetes, with positive effects seen on HbA1c lowering along with reduced hypoglycemia without increasing the risk of ketosis ( 70 ). Presently, dorzagliatin is, to our knowledge, the only GKA still in active clinical development for the treatment of patients with T2D, and phase 3 clinical trial testing has recently been completed ( 71 , 72 ). Dorzagliatin appears to show both maintained efficacy and good safety profile during the entire 52-week treatment period, with no occurrence of drug-related serious adverse events or severe hypoglycemia ( 71 , 72 ).…”

“…Presently, dorzagliatin is, to our knowledge, the only GKA still in active clinical development for the treatment of patients with T2D, and phase 3 clinical trial testing has recently been completed ( 71 , 72 ). Dorzagliatin appears to show both maintained efficacy and good safety profile during the entire 52-week treatment period, with no occurrence of drug-related serious adverse events or severe hypoglycemia ( 71 , 72 ). Additional studies would be needed to elucidate the differences in efficacy and safety between dorzagliatin and previously developed GKAs ( 73 ).…”

Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis

“…Hypoglycemia has been associated with an increased risk of cardiovascular events [34] via a number of potential mechanisms [35]. In 52-week trials of the dual-acting GKA dorzagliatin in drug-naïve and metformin treated Chinese patients with type 2 diabetes versus placebo, the reported incidence of clinically significant hypoglycaemia (< 3.0 mmol/L) was low (0.3% and 0.8% respectively) with no severe hypoglycaemic events [8,36]. Overstimulation of hepatic GK may lead to hypertriglyceridemia [37,38], which could increase the risk of CVDs.…”

“…Several GKAs have shown promising glucose-lowering effect in patients with type 2 diabetes. For example, dorzagliatin, a dual pancreatic and hepatic allosteric GKA lowered HbA 1c by 1.07% (95% confidence interval [CI] − 1.19 to − 0.95) at a dose of 75 mg twice daily versus placebo which reduced HbA 1c by -0.50% (95% CI -0.68 to -0.32) during a 24-week of double-blind treatment in 463 drug-naive patients with type 2 diabetes in a phase 3 study [8]. Meanwhile, a liver-selective GKA, TTP-339, produced a placebo-subtracted 0.9% (95% CI − 1.5 to − 0.3%) reduction in HbA 1c over 6 months in 42 patients with type 2 diabetes at a dose of 800 mg once daily [9].…”

Dorzagliatin improves glucose-stimulated GLP-1 secretion in T2D and is synergistic with sitagliptin in glycemic control

“…Dorzagliatin is an orally active glucokinase activator (GKA) which acts on glucokinase (GK) in the pancreas and liver for the treatment of T2D. [12][13][14][15] Here we report its role in the regulation of GLP-1 release in response to oral glucose challenge in obese T2D subjects either alone or in combination with sitagliptin, a DDP-4 inhibitor, suggesting a triple acting role of dorzagliatin in regulation of glucose homeostasis.…”