Introduction
Type 2 diabetes mellitus (T2DM) is a major chronic metabolic disorder.
Over 463 million people were diagnosed with T2DM in 2019 and the
prevalence of T2DM has been increasing steadily worldwide [1]. T2DM
is characterized by insulin insensitivity, resistance, and secretion
defects caused by pancreatic beta cell dysfunction [2]. Metformin is
the preferred initial pharmacologic agent for the treatment of
T2DM[3,4]. However, sulfonylureas, thiazolidinedione, DPP-4
inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors are
prescribed as add-on drugs when target HbA1c levels are not achieved
with metformin therapy [5,6]. Among these, SGLT-2 inhibitor is
recommended in T2DM accompanied by cardiovascular disease such as heart
failure [7].
Sodium glucose cotransporters (SGLT) are of two types. SGLT-1 is
distributed throughout organs such as the intestine and kidneys and has
low capacity and high affinity. SGLT-2 is primarily present in the
kidneys and has a relatively high capacity and low affinity. Under
normal physiological conditions, both transporters reabsorb glucose in
the renal proximal tubule (<180 g/day), but the glucose uptake
of SGLT-2 is over 97% in the renal proximal tubule [8,9]. When
SGLT-2 is dysfunctional—as a result of mutations in the SLC5A2
gene—the renal capacity for absorbing glucose decreases to the
residual capacity of SGLT-1 (80 g/day) [10].
SGLT-2 inhibitors are considered potential strategies for T2DM treatment
because of the following advantages: (1) the mechanism of action of
SGLT-2 inhibitors is independent of insulin [11]; (2) SGLT-2
inhibitors lower the risk of cardiovascular disease—a major
complication of T2DM [12,13]; (3) SGLT-2 inhibitors protect kidney
function by decreasing glomerular filtration rate (GFR) reversibly and
preserving GFR in the long-term in patients with T2DM [14]; (4)
SGLT-2 inhibitors promote weight loss, which lowers the risk of
complications related to T2DM and can compensate for the weight gain
that is a side effect of insulin and sulfonylureas [15].
Canagliflozin (Invokana®), dapagliflozin
(Farxiga®), empagliflozin
(Jardiance®), and ertugliflozin
(SteglatroTM) have recently been approved by the US
FDA and EMA for the treatment of T2DM [16].
DWP16001 is a novel SGLT-2 selective inhibitor under clinical
development. In an in vitro study, DWP16001 selectively inhibited
SGLT2 and showed high potency for SGLT2 inhibition—more than 1000
times that of SGLT1. DWP16001 is mainly metabolized by CYP3A4 and
CYP2C19 into active metabolites M1 and M2 or via glucuronidation by
UGT2B7, UGT1A4, and UGT1A9 [17]. The inhibitory potency of these
metabolites for SGLT-2 was 10 times weaker than that of parent molecule.
[18].
The purpose of this study was to evaluate the safety, pharmacokinetics
(PKs), and pharmacodynamics (PDs) of DWP16001 after single and multiple
doses in healthy Korean subjects.