Discussion
In this study, the amount of UGE showed maximum values of >
60 g/day in groups treated 1.0 mg or higher after a single dose. The
steady state daily UGE seemed to peak at > 50 g/day in the
groups treated with 0.5 mg or higher after multiple dosing. The UGE over
24 h seemed to be saturated at higher doses. This was considered to be
compensation for glucose reabsorption in the proximal tubule by the
SGLT1 receptor under normoglycemic conditions and by a decrease in renal
clearance [19,20].
In previous clinical studies of SGLT-2 inhibitors in healthy subjects,
the UGE after multiple doses was 33.8 g/day with canagliflozin 100 mg
and 35.5 g/day with dapagliflozin 10 mg [20,21]. The corresponding
values for canagliflozin 100 mg and dapagliflozin 10 mg after multiple
doses in T2DM patients both exceeded 70 g/day and were demonstrated to
show clinical efficacy [22,23]. Considering this relationship
between the results in healthy subjects and patients, DWP16001 doses
above 0.1 mg are expected to show clinical efficacy in T2DM patients.
Urine glucosuria induced by administration of DWP16001 lasted up to 168
h after a single dose. DWP16001 maintained a longer inhibition of SGLT2
than dapagliflozin and ipragliflozin in an in vitro test
[18]. In addition, DWP16001 showed a better kidney distribution and
longer elimination half-life than dapagliflozin and ipragliflozin at the
ICR mouse and these results could have accounted for the long duration
of UGE of DWP16001 [18]. Considering the elimination half-life and
the usage of most type2 DM treatments (daily medication), DWP16001 seems
to be desirable to be administered as a once daily therapy.
Additionally, it is expected that long-lasting UGE and
anti-hyperglycemic effect suppress glucose excursion to achieve
desirable treatment target even in T2DM patients with low medication
adherence.
The Cmax and AUCtau of DWP16001 after
multiple administrations showed dose-proportional increments in the
range of 0.1 mg to 2.0 mg. Meanwhile, the t1/2 and
Tmax were independent of the dose. A high-fat meal
delayed the absorption of DWP16001 and decreased Cmax,
but drug exposure was almost unaffected. The fraction of DWP16001
excreted in an unchanged form in the urine was less than 2.5%. This
finding is consistent with nonclinical data that show that DWP16001 is
extensively metabolized and mainly eliminated through a non-renal
pathway in humans [17]. SGLT2 inhibitors have controversial effects
on kidney injuries, but the PK characteristics of DWP16001 might be less
affected by renal impairment. Further clinical pharmacology studies in
subjects with decreased renal function will be needed to elucidate the
PK characteristics of DWP16001.
The possibility of DWP16001-related kidney damage is expected to be
relatively low considering the results obtained in healthy subjects.
There are positive reports that the long-term use of SGLT-2 inhibitors
decreases the burden on the glomerulus and shows a renoprotective effect
[25,26,27]. In contrast, there is a suspicion that long-term use of
SGLT2 inhibitors could lead to tubular injury depending on the mechanism
of action [28,29]. This has been observed through the elevation of
renal tubular markers in some previous studies [30,31]. Therefore,
the levels of NAG and B2M were monitored in this study throughout the
multiple dose period. After administration of 0.1 mg DWP16001, NAG
levels slightly increased at steady state compared to the baseline.
However, this tendency was not dose-related, and the values returned to
the respective baseline level during follow-up visits. B2M levels were
not statistically different at all doses, including those in the
placebo. Likewise, there was a similar pattern of the estimated GFR
between the baseline and post-dose.
DWP16001 was generally safe and well tolerated among all doses in this
study. The incidence of AEs after single and multiple doses of DWP16001
did not appear to be dose-related in either study. Genitourinary
infection is known to be a major adverse event following the use of
SGLT2 inhibitors [32], but only one subject in the 1.0 mg multiple
DWP16001 dose group suffered balanoposthitis; there were no other
occurrences of genitourinary infections. In addition, only a few
subjects experienced gastrointestinal adverse events, reflecting the
inhibition of SGLT1 in the GI tract. This can be explained by the
selective inhibitory effect of DWP16001 on SGLT2.