Concomitant administration of lobeglitazone, empagliflozin, and metformin is expected to enhance blood glucose-lowering effects and improve medication compliance in patients with diabetes mellitus. In this study, we investigated the pharmacokinetic (PK) interactions and safety of lobeglitazone and co-administered empagliflozin and metformin, which are approved agents used in clinical settings. Two randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover clinical trials (parts 1 and 2) were conducted independently. In part 1, lobeglitazone monotherapy or lobeglitazone, empagliflozin, and metformin triple therapy was administered for 5 days. In part 2, empagliflozin and metformin dual therapy or the abovementioned triple therapy were administered for 5 days. Serial blood samples were collected up to 24 hours after the last dose in each period for PK evaluation.The primary PK parameters (AUC tau,ss , C max,ss ) of treatment regimens in each study part were calculated and compared. For lobeglitazone, the geometric mean ratios (GMRs) with 90% confidence intervals (CI) for triple therapy over monotherapy were 1.08 (1.03–1.14) for C max,ss and 0.98 (0.90–1.07) for AUC tau,ss . For empagliflozin, the GMRs and 90% CIs for triple therapy over dual therapy were 0.87 (0.78–0.97) for C max,ss and 0.97 (0.93–1.00) for AUC tau,ss.For metformin, the GMRs and 90% CIs for triple therapy over dual therapy were 1.06 (0.95– 1.17) for C max,ss and 1.04 (0.97–1.12) for AUCtau,ss . All reported adverse events were mild. The triple therapy consisting of lobeglitazone, empagliflozin, and metformin did not show any clinically relevant drug interactions in relation to the PKs and safety of each drug substance.