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Combination therapy of glucokinase activators and sodium-glucose cotransporter-2 inhibitors may exhibit potent glucose-lowering effects and improvement of β-cell function and insulin sensitivity in patients with type 2 diabetes mellitus, given their complementary mechanisms of action. However, the safety, pharmacokinetic interactions and pharmacodynamic effects of such combinations remain unexplored. To address this gap, we conduct an open-label, sequential phase I trial (ClinicalTrials.gov, NCT03790787) evaluating the dorzagliatin and the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with type 2 diabetes mellitus and obesity in the US. After strict screening against the inclusion/exclusion criteria, 16 participants are deemed eligible. Participants receive sequential treatments-empagliflozin alone, empagliflozin plus dorzagliatin, and dorzagliatin alone-five days for each regimen, followed by a comprehensive assessment of pharmacokinetic profiles and safety. The primary outcomes included GMR for C_max and AUC_0-24h of empagliflozin and dorzagliatin of pharmacokinetic parameters and the incidence of adverse events, abnormal vital signs, abnormal clinical laboratory findings, and 12-lead electrocardiogram abnormalities of safety profile. A total of 27 adverse events occurs in 9 participants (56.3%), the majority of which are mild, with the exception of one case of moderate constipation. No clinically significant findings or changes attributable to study drug treatment were found in clinical chemistry, hematology and urinary analyses, and observed in vital signs, 12-lead electrocardiogram and physical examination. The geomean ratio and their associated 90% confidence intervals for both maximum plasma concentration (empagliflozin: 98.43% (84.07%, 115.25%); dorzagliatin: 103.94% (90.45%, 119.44%)) and area under the concentration-time curve from 0 to 24 h (empagliflozin: 97.53% (94.35%, 100.82%); dorzagliatin: 99.65% (95.25%, 104.25%)) of empagliflozin and dorzagliatin fall entirely within the conventional bioequivalence range of 80.00% to 125.00%. No pharmacokinetic drug-drug interaction is observed, and the treatment exhibits a favorable safety profile with good overall tolerability.