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.