medwireNews: People with type 2 diabetes who have suboptimal glycemic control on metformin alone may benefit from add-on treatment with the dual-acting glucokinase activator dorzagliatin, report the DAWN investigators.
Discussing the rationale for their trial, Li Chen (Hua Medicine Ltd., Shanghai, China) and co-authors explain that dorzagliatin monotherapy has previously been shown to improve glycemic control in treatment-naïve people with type 2 diabetes who participated in the SEED trial.
“Given that dorzagliatin acts by improving glucose sensitivity and β-cell function, its combination with metformin has the potential to offer synergistic benefits,” they write in Nature Medicine.
In the phase 3 DAWN study, 767 participants (mean age 54.5 years, 62% men) from 73 centers in China with glycated hemoglobin (HbA1c) levels of 7.5–10.0% (58–86 mmol/mol) despite stable treatment with metformin were randomly assigned to receive add-on treatment with oral dorzagliatin 75 mg twice daily or placebo alongside continued treatment with metformin 1500 mg/day. The average baseline HbA1c was 8.3% (67 mmol/mol) in both groups.
Chen and team found that the least squares mean improvement in HbA1c levels was significantly greater among participants given dorzagliatin compared with placebo, at 1.02% versus 0.36%. They say that improvements in the dorzagliatin arm “started at week 4 and were maintained compared to the placebo group until the end of the 24-week treatment period.”
After week 24, people in the placebo group switched over to the glucokinase activator, and all participants received open-label dorzagliatin for an additional 28 weeks. Those originally assigned to dorzagliatin experienced sustained reductions in HbA1c, with average levels of 7.19% (55 mmol/mol) at week 24 and 7.41% (57 mmol/mol) at week 52, while those originally assigned to placebo experienced improvement from 7.90% to 7.31% (63 to 56 mmol/mol) over this period.
In all, adverse events (AEs) occurred in 78% of participants in the dorzagliatin arm and 72% of those in the placebo arm from baseline to week 24, with treatment-related AEs reported in 14% and 9%, respectively. Chen et al say that the majority of events “were mild and resolved while on treatment.” They also note that there was “no excess occurrence of drug-related [serious AEs] or severe hypoglycemia in the dorzagliatin and metformin group.”
The DAWN investigators caution that their study “was designed for registration in China and was conducted in only one country,” and that their findings “might not be generalizable to broader patient populations” than those included in the study.
“The efficacy and safety outcomes of combination treatments involving dorzagliatin with multiple anti-diabetic drugs need to be evaluated in future international multi-center clinical trials,” they conclude.
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