DISCUSSIONS
According to T2DM treatment guidelines, combinations of DPP-4 inhibitors and sulfonylureas are recommended due to their different action mechanisms. Nevertheless, clinical use of the evogliptin and sulfonylurea combination is limited, as the significant drug-drug interactions between evogliptin and sulfonylureas, including glimepiride, remain unevaluated. In this respect, this study is meaningful, as it explored the PK and PD interactions between evogliptin and sulfonylurea in humans.
In general, for drug-drug interaction studies, it is recommended to evaluate PK interaction at steady-state, as it is most similar to actual clinical settings and the maximum effect as a perpetrator is shown at steady-state. Therefore, investigational drugs are multiply administered (4 or 5 times) for their half-lives to reach the steady-state. However, a single dose of glimepiride was adopted in this study because a single dosing of glimepiride can be considered to have reached steady state considering its short half-life (1.2-1.5 hours). Similar to this study, previous PK interaction studies of glimepiride adopted a single-dose regimen of glimepiride. [8, 14, 15].
This study revealed that evogliptin and glimepiride have no significant PK interactions with each other. As previously mentioned, evogliptin is mainly metabolized by CYP3A, whereas glimepiride may be a CYP3A4 inhibitor, given that it increased the plasma concentration of sildenafil, mainly metabolized by CYP3A4 in rats. [5, 16], Additionally, it is believed that there is no significant change in PK properties of glimepiride, mainly metabolized by CYP2C9, as evogliptin does not induce nor inhibit CYP enzymes (unpublished in-house data). This study actually revealed that the PK properties of glimepiride are not altered by evogliptin. In addition, evogliptin and glimepiride did not affect the formation of each major metabolite.
As expected, the combination therapy showed additive glycemic control compared to evogliptin or glimepiride monotherapy. However, the degree of the additive effect in this study is smaller than expected. The difference may be caused by differences in glycemic homeostasis in healthy subjects and T2DM patients; unlike in patients, GLP-1 does not augment insulin-mediated glucose uptake in young healthy subjects with euglycemia. [17]
Although DPP-4 inhibitors increase postprandial insulin secretion, insulin secretion in healthy subjects decreased after evogliptin monotherapy. [18, 19] This phenomenon difference in patients’ results was already observed in previous healthy volunteer studies. [3, 20, 21], Although there are no reported clinical studies about the mechanism, it is suggested to have resulted from the difference between healthy volunteers and T2DM patients, including blood glucagon level. [22] Therefore, a further study can be considered to evaluate the PD interactions in T2DM patients.