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).

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

“…Overstimulation of hepatic GK may lead to hypertriglyceridemia [37,38], which could increase the risk of CVDs. In phase 3 trials of dorzagliatin among metformin-treated T2D patients, hypertriglyceridemia related to the study drug was higher in the intervention group versus placebo (2 vs. 0.5%) [36]. Overall, the potential adverse effects of GKA on hypoglycemia and lipids may depend on the degree and balance of pancreatic and hepatic GK activation.…”

“…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.…”

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 ).…”

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.…”