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.