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(unpublished in-house data).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.