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.