## 1 Introduction  
Patients with diabetes who have increased renal glucose reabsorption capacity experience continuous rises in serum glucose levels [1]. SGLT2, a high-capacity and low-affinity glucose transporter, is responsible for nearly 90% of renal glucose reabsorption and is mainly expressed in the renal proximal tubule, where inhibitors of sodium-glucose cotransporter 2 (SGLT2) have therapeutic potential [1, 2, 3]. Polysaccharide-based drugs have shown high efficacy and specificity as novel therapeutic approaches [4, 5]. Among these polysaccharide drugs, \(\alpha\)-glucosidase inhibitors (e.g., voglibose, miglitol and acarbose) and SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, ettugliflozin, etc.) have a promising future as antidiabetic agents [5; 6]. Enavgolfiozin (DWP16001; IUPAC Name: 25,3R,4R,55,6R)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol; molecular weight (MW): 446.9 g/mol; LogP value: 2.65; pKa value: 12.57), a selective SGLT2 inhibitor, received market approval in Korea in 2022 [7; 8]. Enavgolfiozin has a comparable IC\({}_{50}\) value (0.8 \(\pm\) 0.3 nM) to other SGLT2 inhibitors such as dapagliflozin, empagliflozin, and ipragliflozin [7]. The solubility of enavgolfiozin is 2.5 mg/mL and it is predicted to be rapidly absorbed with an absorption fraction of 0.866 using a physiologically based pharmacokinetic modeling technique [8]. Similarly, oral bioavailability was 84.5-97.2% for mice and 56.3-62.1% for rats [9]. Absorbed enavgolfiozin is primarily metabolized by CYP3A4 and CYP2C19 to M1 (monohydroylation in the dihydrobenzofuran group) and M2 (monohydroylation in cyclopropyl group) [10]. After multiple administrations of enavgolfiozin (0.1-2 mg) for 14 days, M1 and M2 levels in the human plasma were reported to be 20-25% and 1-6%, respectively, of parent enavgolfiozin [11]. M3 and M4 were produced by the hydroxylation of M1 and M2 via CYP3A, and three glucuronide metabolites were identified in hepatocytes [10]. However, the pharmacological activities and plasma concentrations of these metabolites M1 and M2 have not yet been reported. A multicenter phase III trial revealed that patients with type 2 diabetes mellitus (T2 DM) taking 0.3 mg enavgolfiozin for 24 weeks successfully achieved hemoglobin A1c levels below 7.0% and exhibited significant reductions in fasting plasma glucose levels (\(-\)40.1 mg/dL), body weight (\(-\)2.5 kg), blood pressure, and low-density lipoprotein cholesterol levels [12]. In multiple administrations, plasma exposure of enavgolfiozin and urinary glucose excretion (UGE) over 24 h showed a clear pharmacokinetic and pharmacodynamic correlation in the dose range of 0.1-2.0 mg [11; 13]. Additionally, as a result of high and sustained kidney distribution [7], enavgolfiozin demonstrated long-lasting UGE up to 168 h and equivalent daily UGE compared with dapagliflozin 10 mg [11]. These results suggest the greater potency and long-lasting efficacy of enavgolfiozin compared to dapagliflozin, which may reflect the importance of kidney distribution of in the pharmacodynamics of these SGLT2 inhibitors. Although about 2 years have passed since its market approval, a meta-analysis of enavgolfiozin was performed using four clinical trials that included 684 T2 DM patients for clinical outcomes over 12-24 weeks of clinical use. As a result, enavgolfiozin is a well-tolerated and effective SGLT2 inhibitor for T2 DM and could be superior to dapagliflozin with regard to hemoglobin A1c levels below 7.0% over 6 months of clinical use [11; 14; 15; 16]. In addition to the antidiabetic effect of SGLT2 inhibitors, they have been reported to show beneficial effects on weight loss and cardio- and reno-protective effects in T2 DM patients [17; 18; 19].