INTRODUCTION
Dipeptidyl peptidase-4 (DPP-4) inhibitors inhibit DPP-4, increasing active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels. GLP-1 and GIP increase insulin concentrations in a glucose-dependent fashion by increasing the intracellular levels of cyclic adenosine , 5’-monophosphate (cAMP) and lowering glucagon concentrations. [1] Thereby, DPP-4 inhibitors lower blood glucose levels. Many clinical trials have proven that evogliptin, a DPP-4 inhibitor, lowers blood glucose, and it was approved in Korea in 2015. [2, 3] It is rapidly absorbed after oral administration and takes approximately 5 hours to reach maximal concentration (Tmax). [4] Evogliptin is mainly eliminated by non-renal routes, involving the human cytochrome P450 3A (CYP3A) enzyme. [5] Especially, 4(S)-hydroxyevogliptin (evogliptin M7) and 4(R)-hydroxyevogliptin (evogliptin M8) which are main metabolites of evogliptin are produced by CYP3A4 and CYP3A5. [6]
Glimepiride is a third-generation sulfonylurea that stimulates insulin release. Because the main cause of type 2 diabetes mellitus (T2DM) in Asians is a predominant insulin secretory defect, sulfonylureas may be an effective treatment option for Asian T2DM patients. Therefore, glimepiride has been used as an initial treatment for T2DM in many countries, including China and Japan. [7] It is rapidly absorbed after oral administration and reaches Tmax within 3 hours. [8] It is mainly eliminated by non-renal routes, involving the CYP2C9 which metabolites glimepiride to hydroxy-glimepiride (glimepiride M1), its main metabolite. [8]
Monotherapy with metformin is the recommended initial pharmacotherapy for T2DM; however, the therapeutic failure of monotherapy is approximately 45% in Korea. [9] Many T2DM treatment guidelines recommend combination therapy with drugs that have different action mechanisms, if monotherapy fails to achieve the glycemic target. [10, 11] Therefore, combination therapy with a DPP-4 inhibitor and sulfonylurea can be an effective T2DM treatment option. Glimepiride has not shown any pharmacokinetic (PK) interaction with some DPP-4 inhibitors, including vildagliptin, sitagliptin, and linagliptin. [12, 13], However its interaction with evogliptin remains unevaluated. Therefore, this study aimed at evaluating the PK and pharmacodynamic (PD) interactions between evogliptin and glimepiride.