Glucokinase activation could be back in play for type 2 diabetes
medwireNews: Phase II study findings indicate that the dual-acting glucokinase activator dorzagliatin has a sustained effect on glucose levels in patients with type 2 diabetes, without the adverse events previously associated with the medication class.
The research is published in The Lancet Diabetes & Endocrinology, along with a commentary from André Scheen (Academic Hospital of Liège, Belgium), who stresses that “[t]he reason for the difference in safety profiles between dorzagliatin and previously investigated glucokinase activators withdrawn for safety reasons needs to be investigated.”
Previous glucokinase activators were withdrawn from development primarily because of liver steatosis, hypertriglyceridemia, and systemic hypertension, he says, adding: “These side-effects are particularly unwanted in patients with type 2 diabetes who are already prone to such complications.”
None of these outcomes occurred at a frequency of at least 5% in any of the five treatment groups in the current trial. The most common adverse events were upper respiratory tract infection and hyperuricemia.
Adverse events that were thought to be drug-related occurred in 9% and 12% of patients taking dorzagliatin at a dose of 75 and 100 mg once daily, respectively, and in a corresponding 12% and 6% of those taking 50 and 75 mg doses twice daily, as well as in 2% of the placebo group.
During 12 weeks of treatment of the 258 patients there was just one drug-related adverse event that led to discontinuation – eyelid edema, in a patient taking dorzagliatin at a dose of 50 mg twice daily.
Confirmed hypoglycemia occurred in 4–6% of the active treatment groups, but not in any patient taking placebo. However, Li Chen (Hua Medicine, Shanghai, China) and study co-authors note that most of these episodes were transient and occurred during the first 8 weeks of treatment. There were no episodes of severe hypoglycemia.
These figures, which compare favorably with results of other modern glucose-lowering drugs, build hope for the use of dorzagliatin in future.
The patients were all Chinese and had early-stage type 2 diabetes. Around 40% were drug-naïve and their average glycated hemoglobin (HbA1c) levels were about 8.5% (69 mmol/mol). During treatment, these fell by 0.35% in the placebo group, but by 0.39% and 0.65% in patients taking dorzagliatin at a dose of 75 and 100 mg once daily, respectively, and by a corresponding 0.79% and 1.12% in those taking 50 and 75 mg twice daily. The reductions were significantly greater than that in the placebo group for all but the lowest dorzagliatin dose.
Dorzagliatin did not have a significant effect on fasting plasma glucose, but all doses significantly reduced 2-hour postprandial glucose, which Scheen says is “consistent with a potentiation of glucose-induced insulin secretion,” one of the main actions of glucokinase inhibitors, along with boosting glucose uptake and glycogen synthesis by the liver.
HbA1c declined throughout the treatment period and did not appear to have plateaued at 12 weeks, at least in patients taking the twice-daily doses, which Scheen notes “is in contrast with the transient glucose-lowering effects reported with previous glucokinase activators.”
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