Enavogliflozin: A Comprehensive Pharmacological and Clinical Review

1. Introduction to Enavogliflozin

1.1. Overview of Enavogliflozin

Enavogliflozin is an orally administered, selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2).[1] It has been developed primarily for the management of type 2 diabetes mellitus (T2DM) and is also under investigation for its potential therapeutic applications in obesity, heart failure, diabetic retinopathy, and for cardioprotection.[1] The development of Enavogliflozin, particularly its efficacy at a notably low dosage of 0.3 mg, reflects a strategic approach by its developers to potentially offer advantages over existing therapies in the SGLT2 inhibitor class.[2] This low-dose efficacy, coupled with claims of being a "best-in-class" agent, suggests an aim to achieve a differentiated profile, possibly in terms of improved tolerability or cost-effectiveness, within a competitive therapeutic landscape. Pooled analyses demonstrating superior glucose-lowering effects compared to dapagliflozin in specific patient populations, such as those with mild renal impairment, at this low dose, lend support to this distinct positioning.[14]

The SGLT2 inhibitor class, to which Enavogliflozin belongs, constitutes a significant advancement in antidiabetic therapy. These agents operate via a mechanism independent of insulin, providing glycemic control alongside a range of other metabolic benefits, including potential cardiovascular and renal protection.[5] Enavogliflozin's emergence as a new entity within this class, particularly with its specific dosing and efficacy claims, necessitates a thorough evaluation of its comparative clinical performance.

1.2. Chemical Identity and Synonyms

Enavogliflozin is chemically identified by its International Union of Pure and Applied Chemistry (IUPAC) name: (2S,3R,4R,5S,6R)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol.[23] Throughout its development and in various publications, it has also been referred to by other names and development codes, including DWP16001 and GCC5694A.[1]

In South Korea, the monotherapy formulation of Enavogliflozin is marketed under the brand name Envlo®, while its fixed-dose combination with metformin is known as Envlomet® SR Tab..3

Key chemical identifiers include:

• CAS Number: 1415472-28-4 [1]
• Molecular Formula: C$_{24}$H$_{27}$ClO$_6$ [1]
• Molar Mass: 446.92 g·mol$^{-1}$ [1]

Standardization of these identifiers is essential for accurate scientific communication and database referencing.

1.3. Developers

Enavogliflozin was primarily developed by Daewoong Pharmaceutical Co., Ltd., a company based in South Korea.[1] GC Pharma is also cited as a developer in some sources.[1] Daewoong Pharmaceutical's central role in bringing Enavogliflozin through development to market, particularly as the first domestically developed SGLT2 inhibitor in South Korea, underscores a significant achievement in pharmaceutical innovation within the region.[26] This accomplishment reflects growing R&D capabilities and has paved the way for Daewoong's plans for international market expansion, with aims to introduce the drug in numerous countries.[32]

2. Pharmacological Profile

2.1. Drug Class

Enavogliflozin is classified as a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor.[1] According to the Anatomical Therapeutic Chemical (ATC) classification system, it is assigned the code A10BK09.[1] This classification situates Enavogliflozin within a group of antidiabetic medications characterized by a distinct mechanism of action and a known profile of class-specific therapeutic benefits and potential risks.

2.2. Mechanism of Action

The therapeutic effect of Enavogliflozin is derived from its selective inhibition of the SGLT2 protein, which is predominantly located in the S1 segment of the proximal renal tubules.[7] SGLT2 is the primary transporter responsible for the reabsorption of approximately 90% of the glucose filtered by the glomeruli back into the systemic circulation; SGLT1 contributes to a lesser extent to renal glucose reabsorption.[14]

By inhibiting SGLT2, Enavogliflozin effectively reduces the renal threshold for glucose reabsorption, thereby promoting the excretion of excess glucose in the urine (glucosuria).[4] A key characteristic of this mechanism is its independence from insulin secretion or action, which allows SGLT2 inhibitors like Enavogliflozin to be effective across various stages of T2DM, including in patients with impaired β-cell function or significant insulin resistance.[7]

Enavogliflozin exhibits a high degree of selectivity for SGLT2 over SGLT1. Studies have reported selectivity ratios exceeding 1000-fold (specifically, a 1,015-fold selectivity).[9] This high selectivity is a desirable attribute, as it aims to maximize the therapeutic effect on renal glucose handling while minimizing potential off-target effects associated with SGLT1 inhibition, such as gastrointestinal disturbances. The combination of high potency, allowing for efficacy at a low 0.3 mg dose, and this significant selectivity for SGLT2 are central to its pharmacological design. This profile theoretically offers a favorable efficacy-to-safety balance by achieving robust glucosuria and its associated metabolic benefits with a reduced likelihood of SGLT1-mediated adverse events. Clinical data demonstrating significant reductions in HbA$_{1c}$, body weight, and blood pressure at the 0.3 mg dose support the clinical relevance of this potency.[6]

2.3. Pharmacodynamics

The pharmacodynamic effects of Enavogliflozin extend beyond simple glucose reduction, encompassing a range of metabolic improvements.

• Glycemic Control: Enavogliflozin effectively lowers blood glucose levels, as evidenced by reductions in both glycated hemoglobin (HbA$_{1c})andfastingplasmaglucose(FPG).[4,5,6,7,9,10,11,12,13,14,15,16,18,19,20,22,24,30,31,32,33,34,35,36,37,38]Thisisadirectconsequenceofincreasedurinaryglucoseexcretion.∗∗∗WeightManagement:∗∗TreatmentwithEnavogliflozinisassociatedwithweightloss.[4,5,7,9,10,11,12,13,14,15,18,19,20,22,32,33,34,36,37,38]Thiseffectisattributedtothecaloriclossresultingfromglucosuriaandmayalsoinvolveincreasedlipolysis.∗∗∗BloodPressureReduction:∗∗Enavogliflozinleadstoreductionsinbothsystolicanddiastolicbloodpressure.[6,7,9,10,12,13,14,18,19,20,21,32,33,34,36,37,38]Thisisthoughttobemediatedbyosmoticdiuresisandnatriuresisinducedbythedrug.∗∗∗RenalEffects:∗∗Enavogliflozinhasthepotentialtoconferrenalprotectivebenefits,acharacteristicoftenobservedwithSGLT2inhibitors.Ithasbeenshowntoreducealbuminuriaandiscurrentlybeingevaluatedforbroadercardiorenaloutcomesinclinicalstudies.[6,9,10,12,14,15,18,19,20,21,34,37,38]Notably,apooledanalysisoftwoPhase3trialssuggestedthatEnavogliflozinprovidessuperiorglucose−loweringefficacycomparedtodapagliflozininT2DMpatientswithmildrenalimpairment(estimatedglomerularfiltrationrate60to<90mL/min/1.73m^2$).[14] This superior effect in mild renal impairment is attributed to Enavogliflozin's potent ability to promote urinary glucose excretion, maintaining its efficacy even as renal function begins to decline, a stage where dapagliflozin's efficacy was observed to lessen. This suggests a potentially wider applicability or more consistent performance of Enavogliflozin in the common scenario of T2DM coexisting with early-stage chronic kidney disease, possibly due to more efficient SGLT2 inhibition or a higher intrinsic activity that compensates for a reduced filtered glucose load. The reported higher urinary glucose excretion rate with Enavogliflozin compared to dapagliflozin supports this.[9]
• Insulin Resistance: Clinical studies, including the ENHANCE-M trial and pooled analyses, indicate that Enavogliflozin can lead to a significant decrease in insulin resistance, as measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).[7]
• Lipid Profile: Some clinical trial data suggest beneficial effects of Enavogliflozin on lipid profiles, such as improvements in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in monotherapy settings.[5] However, the ENHANCE-M trial did not find significant differences in lipid profiles when Enavogliflozin was compared to dapagliflozin as an add-on to metformin.[13]
• Cardiovascular Effects: As a class, SGLT2 inhibitors have demonstrated significant cardiovascular benefits. Enavogliflozin is currently under investigation for such outcomes in dedicated trials like the ENVELOP study.[5] Preclinical data also point towards potential for cardioprotection and improved cardiac function.[4]

The multifaceted pharmacodynamic effects of Enavogliflozin, including improvements in body weight, blood pressure, and potentially insulin resistance and lipid parameters, position it as a broader metabolic modulator rather than solely a glucose-lowering agent. This is highly relevant for the comprehensive management of T2DM, which is frequently associated with a constellation of cardiovascular risk factors. These pleiotropic benefits are critical for reducing the overall cardiovascular and renal risk burden in this patient population.

3. Pharmacokinetics (PK)

The pharmacokinetic profile of Enavogliflozin has been characterized through preclinical studies in animals and clinical trials in humans, including healthy volunteers and patients with T2DM.

3.1. Absorption

Enavogliflozin is rapidly absorbed following oral administration.7 In human subjects, the time to reach peak plasma concentration (T$_{max}$) is typically observed between 1 to 3 hours post-dose.7

Studies in animal models have indicated good oral bioavailability: 84.5–97.2% in mice and 56.3–62.1% in rats.6 Data on the absolute bioavailability in humans are not explicitly provided in the available information.

Regarding food effect, pharmacokinetic profiles and parameters in mice were not significantly different between fed and fasted states after a 1 mg/kg oral dose.6 Consistent with this, the recommended human dosage of 0.3 mg once daily can be administered regardless of mealtime, enhancing dosing convenience for patients.4

3.2. Distribution

Preclinical studies in mice have provided insights into the tissue distribution of Enavogliflozin. The drug exhibits the highest distribution in the kidneys, followed by the large intestine, stomach, small intestine, liver, heart, lungs, spleen, and testes. Notably, Enavogliflozin was not detected in the brain of mice in these studies.[6] The area under the curve (AUC) ratio of kidney to plasma in mice was notably high (e.g., 41.9 ± 7.7 following a 1 mg/kg oral dose), indicating preferential accumulation in the target organ.[35] This high and sustained distribution to the kidneys is considered a key factor for its pharmacodynamic activity, contributing to its potent and prolonged urinary glucose excretion.[6] Such targeted distribution to the site of action is favorable for efficacy and might also serve to minimize systemic exposure in non-target tissues, potentially reducing the risk of off-target side effects, although specific data on this latter aspect are limited.

3.3. Metabolism

Enavogliflozin undergoes metabolism, primarily in the liver. In vitro studies using human liver microsomes indicate that it is metabolized, generating metabolites designated as M1 ((2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-cyclopropylbenzyl)-2-hydroxy-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) and M2.24 In humans, after daily oral administration of Enavogliflozin (0.1 to 2.0 mg), the metabolic ratio of M1 (relative to parent drug exposure) was estimated to be between 0.20 and 0.25.24

Further in vitro investigations suggest that DWP16001 (Enavogliflozin) is predominantly metabolized by cytochrome P450 (CYP) enzymes, specifically CYP3A4 and CYP2C19, leading to the formation of active metabolites M1 and M2. Additionally, glucuronidation via UDP-glucuronosyltransferases (UGT), including UGT2B7, UGT1A4, and UGT1A9, is another metabolic pathway.22 Physiologically Based Pharmacokinetic (PBPK) models developed for Enavogliflozin have incorporated a non-linear formation of the M1 metabolite in the liver, suggesting that this metabolic pathway might be saturable at higher exposures or influenced by other factors.24 While systemic exposure is reported as dose-proportional in the therapeutic range of 0.1-2.0 mg 22, these underlying non-linear metabolic processes could become relevant in specific scenarios such as overdose or with co-administration of drugs affecting these CYP or UGT enzymes.

3.4. Excretion

The excretion pathways of Enavogliflozin and its metabolites have been studied in both humans and animal models. In humans, the fraction of unchanged Enavogliflozin excreted in urine appears to increase with single dose escalation (from 0.87% for a 0.2 mg dose to 1.67% for a 5.0 mg dose).24 PBPK modeling has incorporated non-linear urinary excretion for the parent drug, suggesting complex renal handling mechanisms.24

In contrast, animal studies in mice and rats indicate that biliary excretion is a more significant route for the parent drug. In mice, 72 hours after intravenous injection, fecal recovery of unchanged Enavogliflozin (39.3 ± 3.5%) was substantially higher than urinary recovery (6.6 ± 0.7%). Similar findings in rats (15.9 ± 5.9% fecal recovery, 0.7 ± 0.2% urinary recovery) also point to major biliary excretion.35 These species differences in primary elimination routes are important considerations when extrapolating preclinical data to human scenarios. While biliary excretion is prominent in rodents, human data emphasize urinary excretion of metabolites along with a smaller fraction of the parent drug.

3.5. Half-life and Dose Proportionality

Enavogliflozin is characterized by a long terminal elimination half-life in humans, ranging from 13 to 29 hours following both single and repeated oral administrations.7 This pharmacokinetic property supports a once-daily dosing regimen.

Systemic exposure to Enavogliflozin, as measured by AUC, has been shown to increase proportionally with the dose after repeated administrations in humans within the range of 0.1 mg to 2.0 mg.7 Dose-proportional pharmacokinetics were also observed in mice following intravenous and oral administration of doses at 0.3, 1, and 3 mg/kg.35 Furthermore, studies in mice did not show evidence of drug accumulation in plasma or major distributed tissues after repeated oral administration for up to 2 weeks.35

3.7. Summary of Key Pharmacokinetic Parameters of Enavogliflozin

A consolidated view of the key pharmacokinetic parameters for Enavogliflozin is presented in Table 1. This summary facilitates an understanding of its absorption, distribution, metabolism, and excretion characteristics, which are fundamental to its clinical application.

Parameter	Value (Healthy Volunteers/Patients, specify dose if context-specific)	Source(s)	Notes
T$_{max}$ (humans)	1–3 hours	24	Rapid absorption
Half-life (t$_{1/2}$, humans)	13–29 hours	24	Supports once-daily dosing
Dose Proportionality (humans)	Yes (0.1–2.0 mg, repeated admin, AUC)	24	Systemic exposure increases proportionally with dose in this range
Food Effect (humans)	Recommended dose (0.3 mg) regardless of mealtime	4	Based on clinical use; mouse data shows no significant food effect 6
Key Metabolites	M1, M2	22	M1 metabolic ratio (vs. parent) 0.20–0.25 in humans
Primary Metabolism Pathways	CYP3A4, CYP2C19, UGTs (UGT2B7, UGT1A4, UGT1A9)	22	In vitro data
Excretion (humans)	Urinary (parent drug % increases with dose); metabolites also in urine	24	Non-linear urinary excretion of parent drug
Excretion (mice/rats)	Predominantly Biliary	35	Highlights potential species differences
Kidney Distribution	High (animal models)	6	Consistent with renal site of action; sustained levels

4. Non-Clinical Studies

Non-clinical studies, encompassing in vitro experiments and animal models, have been instrumental in elucidating the pharmacological properties of Enavogliflozin and providing a rationale for its clinical development.

4.1. In Vitro Potency and Selectivity

In vitro assays have confirmed that Enavogliflozin (DWP16001) is a potent inhibitor of SGLT2, characterized by a low half-maximal inhibitory concentration (IC$_{50}$).[6] A reported IC$_{50}$ value is 0.8 ± 0.3 nM.[6] Furthermore, Enavogliflozin demonstrates exceptional selectivity for SGLT2 over the SGLT1 isoform, with selectivity ratios reported to be greater than 1000-fold, and more specifically as 1,015-fold.[9] This high potency and selectivity observed preclinically are desirable attributes, suggesting efficient target engagement with a reduced likelihood of off-target effects related to SGLT1 inhibition. This profile forms a strong basis for its therapeutic hypothesis and supports the aspiration for a "best-in-class" status.

4.2. Animal Model Efficacy

Enavogliflozin has been evaluated in various animal models, demonstrating efficacy beyond T2DM:

• Obesity: In a study involving naturally obese dogs, Enavogliflozin administration led to reductions in body weight, body fat percentage, and fat thickness, without adversely affecting food consumption.[1]
• Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis: Efficacy has been confirmed in a STAM mouse model of NASH and a thioacetamide (TAA)-induced mouse model of liver fibrosis.[25]
• Diabetic Retinopathy and Cardioprotection: The drug has been investigated for its potential therapeutic efficacy in these diabetes-related complications.[6]
• Vascular Function: Preclinical studies suggest that Enavogliflozin can improve vascular function. This is attributed to mechanisms including the reduction of reactive oxygen species, upregulation of endothelial nitric oxide synthase expression, and inhibition of inflammatory responses. Additionally, Enavogliflozin was found to decrease nanoplastic-induced premature endothelial senescence.[6]

These findings from animal models point towards a broad therapeutic potential for Enavogliflozin, extending beyond glycemic control to include benefits in obesity, liver diseases, and vascular health. Such pleiotropic effects are consistent with the expanding understanding of the SGLT2 inhibitor class and warrant further clinical investigation for these potential new indications.

4.3. Animal Pharmacokinetics and Tissue Distribution

Pharmacokinetic studies in animals have revealed key characteristics of Enavogliflozin (detailed in Section 3). These include dose-proportional pharmacokinetics in mice and rats 35, high oral bioavailability in these species (84.5–97.2% in mice, 56.3–62.1% in rats) 6, and predominantly biliary excretion in both mice and rats.35

A significant finding is the high distribution of Enavogliflozin to the kidneys, its primary site of action, with slow elimination from this organ. Substantial distribution was also observed in the liver, stomach, and intestines. Conversely, the drug was not detected in the brain of mice.6 Repeated oral administration in mice did not lead to accumulation in plasma or major tissues.35 The combination of high in vitro potency, selectivity for SGLT2, and significant kidney distribution in animal models provides a robust preclinical foundation for Enavogliflozin's efficacy. This profile supports the drug's design principles and its potential to achieve therapeutic goals in human subjects.

5. Clinical Development and Efficacy

The clinical development program for Enavogliflozin has encompassed Phase 1 studies in healthy volunteers and extensive Phase 3 trials in patients with T2DM, evaluating its efficacy and safety as monotherapy and in various combination regimens.

5.1. Phase 1 Clinical Trials

Phase 1 studies are crucial for establishing the initial safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of a new drug in humans. For Enavogliflozin (DWP16001), these trials were primarily conducted in healthy subjects.[7]

Key findings from these early human studies include:

• Pharmacokinetics: Enavogliflozin demonstrated rapid absorption, with T$_{max}$ occurring between 1.0 to 3.0 hours post-administration.[7] It exhibited a long elimination half-life of 13 to 29 hours, supporting the potential for once-daily dosing.[7] Systemic exposure, measured by AUC, increased proportionally with multiple dose administrations in the range of 0.1 mg to 2.0 mg.[7] The metabolic ratio of the M1 metabolite was estimated to be between 0.20 and 0.25 after daily oral doses of 0.1 mg to 2.0 mg.[24] Data from these Phase 1 trials (e.g., NCT03364985) were utilized in the development of PBPK models.[24]
• Pharmacodynamics: A dose-dependent increase in urinary glucose excretion (UGE) was observed after single doses. Following multiple doses in the 0.3 mg to 2.0 mg range, steady-state UGE was approximately 50–60 g/day.[7]
• Safety and Tolerability: Enavogliflozin was well-tolerated in healthy volunteers, with single oral doses up to 5.0 mg and multiple oral doses up to 2.0 mg demonstrating good tolerability.[7]

These Phase 1 results were foundational, confirming the desired pharmacodynamic effect (glucosuria), establishing a PK profile amenable to convenient dosing, and demonstrating acceptable safety in humans, thereby supporting progression to later-phase clinical trials.

5.2. Phase 3 Clinical Trials

The Phase 3 program for Enavogliflozin has been extensive, primarily focusing on Korean patients with T2DM. These trials have assessed Enavogliflozin at a consistent dosage of 0.3 mg once daily, both as monotherapy and in combination with other standard antidiabetic agents like metformin and gemigliptin. Many of these studies were 24 weeks in duration, with some incorporating longer-term extension periods, and often used dapagliflozin 10 mg as an active comparator.[5]

5.2.1. Monotherapy (ENHANCE-A Study)

The ENHANCE-A study was a multicenter, randomized, double-blind, placebo-controlled, therapeutic confirmatory trial involving 160 T2DM patients whose condition was inadequately controlled by diet and exercise alone.15 The primary endpoint was the change in HbA$_{1c}$ from baseline at 24 weeks.

Results demonstrated a statistically significant reduction in HbA$_{1c}$ with Enavogliflozin 0.3 mg compared to placebo, with a reported difference of approximately 0.99%p to 1%.15 Furthermore, Enavogliflozin monotherapy led to significant improvements in secondary endpoints, including body weight, systolic and diastolic blood pressure, and lipid parameters (LDL-C, HDL-C) when compared to placebo.32

A 52-week extension of this study confirmed that Enavogliflozin 0.3 mg monotherapy provided sustained long-term glycemic control and remained safe and well-tolerated. Significant body weight reduction was maintained at week 52, with decreases of 3.5 kg in the group continuing Enavogliflozin and 3.8 kg in the group that switched from placebo to Enavogliflozin.15 The ENHANCE-A study thus established the efficacy and safety of Enavogliflozin as a standalone therapeutic option for T2DM, offering benefits that extend beyond mere glycemic improvement.

5.2.2. Combination Therapy with Metformin (ENHANCE-M Study)

The ENHANCE-M study (NCT04634500) was a multicenter, randomized, double-blind trial that compared Enavogliflozin 0.3 mg with dapagliflozin 10 mg, both as add-on therapy to metformin, in approximately 200 T2DM patients with inadequate glycemic control on metformin monotherapy.[7] The primary endpoint was to demonstrate the non-inferiority of Enavogliflozin to dapagliflozin in terms of HbA$_{1c}$ change from baseline at 24 weeks, with a pre-specified non-inferiority margin of 0.35%.[7]

At 24 weeks, Enavogliflozin 0.3 mg plus metformin was found to be non-inferior to dapagliflozin 10 mg plus metformin [7]:

• The adjusted mean change in HbA$_{1c}$ was –0.80% for the Enavogliflozin group versus –0.75% for the dapagliflozin group (difference: –0.04%; 95% CI, –0.21% to 0.12%).
• The proportion of patients achieving an HbA$_{1c}$ level below 7.0% was 61% in the Enavogliflozin group and 62% in the dapagliflozin group.
• FPG reduction was –32.53 mg/dL with Enavogliflozin versus –29.14 mg/dL with dapagliflozin.
• Enavogliflozin led to a significantly greater increase in the urine glucose-creatinine ratio (UGCR) (60.48 vs. 44.94, P<0.0001) and a significantly greater decrease in HOMA-IR (–1.85 vs. –1.31, P=0.0041) compared to dapagliflozin.
• Beneficial effects on body weight (–3.77 kg vs. –3.58 kg) and blood pressure (systolic/diastolic changes: –5.93/–5.41 mmHg vs. –6.57/–4.26 mmHg) were comparable between the two groups.

The 52-week open-label extension of the ENHANCE-M study, where all patients received Enavogliflozin plus metformin, showed that Enavogliflozin was well-tolerated and provided continuous glycemic control. HbA$_{1c}$ reductions were sustained at approximately -0.85% in the group that continued Enavogliflozin and -0.81% in the group that switched from dapagliflozin. The significant increase in UGCR was also maintained.[35] This study is pivotal as metformin is the cornerstone of T2DM therapy. Demonstrating non-inferiority to an established SGLT2 inhibitor like dapagliflozin, along with potentially advantageous effects on UGCR and HOMA-IR, supports Enavogliflozin's role as an effective add-on treatment.

5.2.3. Triple Combination Therapy (ENHANCE-D Study: Enavogliflozin + Metformin + Gemigliptin)

The ENHANCE-D study evaluated Enavogliflozin 0.3 mg as part of a triple therapy regimen. This multicenter, double-blind, randomized, active-controlled trial involved approximately 270 T2DM patients whose blood glucose was inadequately controlled with a combination of metformin and gemigliptin (a DPP-4 inhibitor). Enavogliflozin was compared against dapagliflozin 10 mg, both added to the existing metformin and gemigliptin background therapy.[15] The primary endpoint was the change in HbA$_{1c}$ from baseline to week 24.

Results at 24 weeks indicated that Enavogliflozin 0.3 mg, when added to metformin and gemigliptin, was non-inferior to dapagliflozin 10 mg added to the same dual therapy [15]:

• The reduction in HbA$_{1c}$ was -0.92% for the Enavogliflozin group versus -0.86% for the dapagliflozin group (difference: -0.06%; 95% CI: -0.19 to 0.06).
• Changes in FPG were not significantly different between the groups.[34]
• The increase in UGCR was significantly greater with Enavogliflozin (60.2 g/g vs. 43.5 g/g, P < 0.0001).[34] This study demonstrates Enavogliflozin's efficacy within a triple-drug regimen, a common therapeutic approach for patients with more advanced T2DM who require multiple agents to achieve adequate glycemic control.

5.2.4. Pooled Analyses of Phase 3 Trials

Pooled analyses of data from Phase 3 trials have provided further insights, particularly regarding Enavogliflozin's efficacy in specific patient subgroups. One such analysis combined data from two 24-week Phase 3 trials, involving a total of 470 patients (235 on Enavogliflozin 0.3 mg/day, 235 on dapagliflozin 10 mg/day). This analysis specifically assessed efficacy and safety based on baseline kidney function, categorizing patients into those with mildly reduced eGFR (60 to <90 mL/min/1.73 m$^2$) and those with normal eGFR (≥90 mL/min/1.73 m$^2$).[14]

Key findings from this pooled analysis focusing on renal function include:

• In patients with mildly reduced eGFR: Enavogliflozin demonstrated a significantly greater reduction in adjusted mean HbA$_{1c}$ (–0.94% vs. –0.77%, P=0.0196) and FPG at week 24 compared to dapagliflozin.
• Enavogliflozin exhibited potent blood glucose-lowering effects irrespective of baseline renal function, whereas the efficacy of dapagliflozin was observed to decrease significantly as renal function declined.
• A higher UGE rate was observed with Enavogliflozin in both eGFR groups.
• Enavogliflozin treatment led to a significant decrease in HOMA-IR.
• No significant differences in blood pressure or weight loss were noted between the Enavogliflozin and dapagliflozin groups in this specific pooled analysis.

Results presented at the American Diabetes Association (ADA) conference in 2024, from a pooled analysis of Phase 3 trials focusing on Enavogliflozin combined with metformin, further highlighted superior blood glucose-lowering effects for Enavogliflozin compared to dapagliflozin in T2DM patients with mild renal impairment. Over 24 weeks, Enavogliflozin reduced HbA$_{1c}$ by 0.94%, compared to 0.77% with dapagliflozin, and also showed enhanced UGE and improved insulin resistance.16

These pooled analyses are important as they offer greater statistical power for subgroup examinations. The consistent observation that Enavogliflozin may provide superior or at least well-maintained glycemic control in patients with mild renal impairment, when compared to dapagliflozin, represents a potentially significant clinical distinction. This could be attributed to its higher intrinsic potency or more efficient interaction with SGLT2 transporters, leading to greater UGE for a given level of GFR, as supported by the consistently higher UGCR values observed with Enavogliflozin. This characteristic could make it a preferred SGLT2 inhibitor for patients in the early stages of diabetic kidney disease.

5.3. Cardiorenal Outcome Studies

The ENVELOP (Enavogliflozin to Evaluate Cardiorenal Outcomes in Patients with Type 2 Diabetes) study is a significant ongoing trial designed to assess the long-term cardiovascular and renal effects of Enavogliflozin.[9]

• Design: This is an investigator-initiated, multicenter, randomized, pragmatic, open-label, active-controlled, non-inferiority trial.
• Participants: The study enrolls adults (aged ≥19 years) with T2DM who have a history of, or are at high risk for, cardiovascular disease.
• Intervention: Enavogliflozin is being compared against other SGLT2 inhibitors with established cardiorenal benefits, specifically dapagliflozin or empagliflozin, in addition to standard of care.
• Primary Objective: To evaluate the effect of Enavogliflozin on major cardiovascular and renal outcomes.
• Primary Endpoint: The primary endpoint is the time to the first occurrence of a composite of major adverse cardiovascular events (MACE) or renal events. MACE includes non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure, coronary or peripheral revascularization, and death from any cause. Renal events include a sustained decline in eGFR of ≥40% from baseline to <60 mL/min/1.73 m$^2$, onset of end-stage kidney disease (defined as dialysis for ≥28 days, kidney transplantation, or an eGFR of <15 mL/min/1.73 m$^2$), or renal death.[10]

The results of the ENVELOP study are crucial. While Enavogliflozin has demonstrated efficacy in glycemic control and improvement of metabolic parameters, establishing its non-inferiority or superiority in terms of hard cardiorenal outcomes is essential for its competitive positioning against other SGLT2 inhibitors that have already proven such benefits. A positive outcome from ENVELOP would solidify Enavogliflozin's role in comprehensive T2DM management, particularly given the strong emphasis on cardiovascular and renal risk reduction in current treatment guidelines.

The consistent efficacy of Enavogliflozin 0.3 mg across monotherapy, dual therapy with metformin, and triple therapy with metformin and a DPP-4 inhibitor underscores its versatility in T2DM management. This adaptability is valuable for a progressive condition that often requires treatment intensification over time. The non-inferiority to dapagliflozin in combination settings provides assurance of its comparable efficacy to an established SGLT2 inhibitor, allowing clinicians to integrate Enavogliflozin at various points in T2DM treatment algorithms. Furthermore, the consistent findings of weight loss, blood pressure reduction, and improvements in HOMA-IR and some lipid parameters highlight the broader metabolic benefits of Enavogliflozin, aligning with the goals of comprehensive T2DM care aimed at mitigating associated cardiovascular risk factors.

5.5. Overview of Major Phase 3 Clinical Trial Efficacy Results for Enavogliflozin

Table 2 summarizes the key efficacy findings from the pivotal Phase 3 clinical trials of Enavogliflozin.

Trial Name (Study ID if available)	Patient Population	Intervention Arms	Duration	Primary Efficacy Endpoint	Key Result for Primary Endpoint (Enavogliflozin vs. Control/Comparator)	Select Key Secondary Endpoint Results (e.g., FPG, Weight, BP change)	Source(s)
ENHANCE-A	T2DM, inadequately controlled by diet/exercise	Enavogliflozin 0.3mg vs. Placebo	24 weeks	Δ HbA$_{1c}$ from baseline	Approx. -0.99%p to -1% vs. Placebo (P<0.001)	Significant ↓ Weight, BP, LDL-C; ↑ HDL-C vs. Placebo	22
ENHANCE-M (NCT04634500)	T2DM, inadequately controlled on Metformin	Enavogliflozin 0.3mg + Metformin vs. Dapagliflozin 10mg + Metformin	24 weeks	Non-inferiority in Δ HbA$_{1c}$	Non-inferior: -0.80% vs. -0.75% (Difference: -0.04%, 95% CI –0.21 to 0.12)	Significant ↑ UGCR, Significant ↓ HOMA-IR; Comparable ↓ Weight, BP	7
ENHANCE-M Extension	T2DM, on Metformin (continued from ENHANCE-M)	All patients on Enavogliflozin 0.3mg + Metformin	52 weeks	Sustained Δ HbA$_{1c}$	Maintained HbA$_{1c}$ reduction (approx. -0.81% to -0.85% from original baseline)	Sustained UGCR increase	35
ENHANCE-D	T2DM, inadequately controlled on Metformin + Gemigliptin	Enavogliflozin 0.3mg + Met/Gemi vs. Dapagliflozin 10mg + Met/Gemi	24 weeks	Non-inferiority in Δ HbA$_{1c}$	Non-inferior: -0.92% vs. -0.86% (Difference: -0.06%, 95% CI -0.19 to 0.06)	Significant ↑ UGCR; Comparable FPG, Weight, BP changes	15
Pooled Analysis (Renal Function)	T2DM, varied baseline renal function	Enavogliflozin 0.3mg vs. Dapagliflozin 10mg (both typically with Metformin background)	24 weeks	Δ HbA$_{1c}$ in eGFR subgroups	Mildly reduced eGFR: -0.94% (Ena) vs. -0.77% (Dapa) (P=0.0196, Enavogliflozin superior)	Enavogliflozin: potent effect regardless of eGFR; Dapagliflozin: efficacy ↓ with eGFR ↓; Higher UGE with Enavogliflozin	14

6. Safety and Tolerability Profile

The safety and tolerability of Enavogliflozin have been evaluated throughout its clinical development program, from Phase 1 studies in healthy individuals to extensive Phase 3 trials in patients with T2DM.

6.1. Overall Safety Assessment

Enavogliflozin has been generally reported as well-tolerated in clinical trials, whether administered as monotherapy or in combination with other antidiabetic agents like metformin and gemigliptin.[4] The majority of treatment-emergent adverse events (TEAEs) observed were of mild to moderate intensity.[7] Importantly, in the triple combination therapy trial (Enavogliflozin, metformin, and gemigliptin), no unexpected adverse drug reactions (ADRs) or significant drug-drug interactions were identified.[29] The overall safety profile of Enavogliflozin appears consistent with the known characteristics of the SGLT2 inhibitor class.[13] This predictability is an advantage for clinicians, though it also implies that class-specific warnings and precautions are applicable.

6.2. Common Adverse Events (AEs) and Adverse Drug Reactions (ADRs)

While comprehensive, itemized lists of all common AEs with precise incidences are not consistently available across all provided sources, the general tolerability has been a consistent theme.

Specific data from the 52-week ENHANCE-M extension study (Enavogliflozin plus metformin) offer some details 35:

• In the maintenance group (patients who continued on Enavogliflozin for the full 52 weeks), ADRs were reported in two patients (2.44%). These ADRs were cystitis and vaginal infection.
• In the switch group (patients who switched from dapagliflozin to Enavogliflozin for the 28-week extension), an ADR of hypoglycemia was reported in one patient (1.30%).
• All reported ADRs in this extension study were described as mild in severity.

A protocol for a real-world observational study of Enavogliflozin (Envlo®) and its metformin combination (Envlomet®) includes plans for monitoring ADRs and specific events of interest, which will provide further data from a broader patient population.[4]

6.3. Serious Adverse Events (SAEs)

Phase 3 clinical trials of Enavogliflozin have generally not indicated a significant increase in the occurrence of serious adverse events (SAEs).[9] In the 24-week ENHANCE-M trial, three SAEs were reported: one case of mechanical ileus in the Enavogliflozin group, and one case of benign prostatic hyperplasia (BPH) and one case of prostate cancer in the dapagliflozin group. None of these SAEs were assessed by the investigators as being related to the study drug.[7] The low incidence of drug-related SAEs is a positive safety indicator.

6.4. Adverse Events of Special Interest (AESI) for SGLT2 Inhibitors

Given Enavogliflozin's class, particular attention is paid to adverse events known to be associated with SGLT2 inhibition.

• Hypoglycemia: The risk of hypoglycemia with SGLT2 inhibitors is generally low when used as monotherapy or in combination with metformin, due to their insulin-independent mechanism of action.
• In the 24-week ENHANCE-M trial, no episodes of hypoglycemia were recorded in the Enavogliflozin group, while one episode occurred in the dapagliflozin group.[7]
• In the 52-week ENHANCE-M extension study, one case of hypoglycemia (1.30%) was reported in the group that had switched from dapagliflozin to Enavogliflozin.[35]
• The low intrinsic risk of hypoglycemia with Enavogliflozin, particularly in monotherapy or metformin combination, is a key safety advantage. However, ongoing vigilance is necessary, especially if co-administered with insulin or insulin secretagogues, or if patient risk factors change.
• Urinary Tract Infections (UTIs): Glucosuria induced by SGLT2 inhibitors can increase the risk of UTIs.[35]
• In the 24-week ENHANCE-M trial, UTI rates were low, with a single case of cystitis observed in the Enavogliflozin group and one case in the dapagliflozin group.[7]
• In the 52-week ENHANCE-M extension, cystitis was reported as an ADR in the maintenance group (contributing to the 2.44% overall ADR rate).[35]
• Genital Mycotic Infections (GMIs): SGLT2 inhibitors are associated with an increased risk of GMIs, reported to be approximately 2–3 times higher than placebo (around 8–10% vs. 3–5%) in some studies of the class.[40] These infections usually respond to standard antifungal treatments. Poor genital hygiene and a prior history of GMIs are known risk factors.[40]
• In the 52-week ENHANCE-M extension, vaginal infection was reported as an ADR in the maintenance group (also contributing to the 2.44% ADR rate).[35]
• Polyuria and Pollakiuria: These can occur due to the osmotic diuretic effect of SGLT2 inhibitors.
• In the 24-week ENHANCE-M trial, one case of pollakiuria was reported in the dapagliflozin group, with no cases in the Enavogliflozin group.[7]
• Diabetic Ketoacidosis (DKA): While not specifically mentioned in the context of Enavogliflozin in the provided documents, DKA is a known rare but serious AESI for the SGLT2 inhibitor class.

The planned real-world observational study will specifically monitor for hypoglycemia, UTIs, genital infections, polyuria, and polydipsia, which will be crucial for understanding the incidence of these AESIs in a broader clinical setting.[4] This proactive monitoring reflects an understanding that controlled trial environments may not fully capture the safety profile in diverse, real-world patient populations and is essential for confirming the long-term risk-benefit balance.

6.5. Drug-Drug Interactions (DDIs)

The potential for drug-drug interactions is an important consideration for any new therapeutic agent, especially in T2DM where polypharmacy is common.

• Specific pharmacokinetic and pharmacodynamic interaction studies have been conducted for Enavogliflozin (DWP16001) with metformin and with phentermine in healthy subjects.[1]
• In the Phase 3 triple combination therapy trial (Enavogliflozin + metformin + gemigliptin), no unexpected drug-drug interactions were noted, which is a positive finding for its use in multi-drug regimens.[29]

6.7. Summary of Common/Key Adverse Events Reported in Enavogliflozin Clinical Trials

Table 3 provides a summary of common and key adverse events reported in selected Enavogliflozin clinical trials, based on the available information.

Adverse Event Category	Specific Event(s)	Trial(s) Noted / Population	Incidence/Details for Enavogliflozin Group(s)	Incidence/Details for Comparator/Control Group(s)	Source(s)
Overall TEAEs	Any TEAE	ENHANCE-M (24 wk)	24% (mostly mild)	22% (Dapagliflozin, mostly mild)	7
Adverse Drug Reactions (ADRs)	Any ADR	ENHANCE-M (24 wk)	1.0%	7.1% (Dapagliflozin) (P=0.0341)	3
	Cystitis, Vaginal infection	ENHANCE-M Ext. (52 wk, Maintenance group)	2.44% (2 patients)	N/A	35
Hypoglycemia	Hypoglycemia	ENHANCE-M (24 wk)	0 cases	1 case (Dapagliflozin)	7
	Hypoglycemia	ENHANCE-M Ext. (52 wk, Switch group from Dapa)	1.30% (1 patient)	N/A	35
Urinary Tract Infections	Cystitis	ENHANCE-M (24 wk)	1 case	1 case (Dapagliflozin)	7
	Cystitis	ENHANCE-M Ext. (52 wk, Maintenance group, part of ADRs)	Part of 2.44% ADR rate	N/A	35
Genital Mycotic Infections	Vaginal infection	ENHANCE-M Ext. (52 wk, Maintenance group, part of ADRs)	Part of 2.44% ADR rate	N/A	35
Polyuria/Pollakiuria	Pollakiuria	ENHANCE-M (24 wk)	0 cases	1 case (Dapagliflozin)	7
Serious Adverse Events (SAEs)	Mechanical Ileus	ENHANCE-M (24 wk, Enavogliflozin group, not drug-related)	1 case	BPH (1), Prostate Cancer (1) (Dapagliflozin group, not drug-related)	7

7. Regulatory Status and Market Access

The regulatory journey of Enavogliflozin reflects its progression from a novel investigational drug to a marketed product in select regions.

7.1. Approvals

• South Korea (Ministry of Food and Drug Safety - MFDS):
• Envlo® Tablet (Enavogliflozin 0.3 mg monotherapy): Received approval on November 30, 2022 (alternatively cited as December 1, 2022).[4] It was launched in South Korea in May 2023, with health insurance coverage established.[25] This approval marked Enavogliflozin as South Korea's 36th domestically developed novel drug and the first SGLT2 inhibitor developed within the country.[26]
• Envlomet® SR Tab. 0.3/1000mg (Enavogliflozin/Metformin Hydrochloride sustained-release): This fixed-dose combination product received MFDS approval on June 13, 2023, with a planned launch in the second half of 2023.[17] The rapid approval of this combination product, shortly after the monotherapy launch, indicates a strategy to quickly expand treatment options for patients.
• Ecuador: Enavogliflozin has also received regulatory approval in Ecuador.[1]

The initial approval in its country of origin, South Korea, followed by approvals in other markets like Ecuador, signifies the commencement of Enavogliflozin's global market presence. Daewoong Pharmaceutical's strategy to market the first domestically developed SGLT2 inhibitor in Korea is a notable achievement and provides a foundation for broader international commercialization.

7.2. Applications for Approval (Pending)

Daewoong Pharmaceutical has actively pursued market authorization in other countries. Applications for the approval of Enavogliflozin have been submitted and are reportedly pending in several Latin American countries, including Brazil, Mexico, Peru, and Colombia.[1] This focus on Latin American markets suggests a targeted international expansion strategy.

7.3. Status with Major Regulatory Agencies

• Food and Drug Administration (FDA - USA): As of the latest available information, Enavogliflozin has not yet received approval from the U.S. FDA.[42]
• European Medicines Agency (EMA - Europe): Similarly, Enavogliflozin is not yet approved by the EMA. While some sources mention it is under the registration process in Europe, it is not currently listed among the SGLT2 inhibitors authorized for use in the European Union.[42]

Securing approvals from major regulatory bodies such as the FDA and EMA is a critical step for achieving widespread global market access and often influences regulatory decisions in other parts of the world. The current status indicates that Enavogliflozin's journey in these key markets is still ongoing. Daewoong Pharmaceutical has expressed ambitions to enter 10 major export markets by 2025 and expand to 50 countries by 2030, aiming for significant sales targets, which implies active efforts towards these major approvals.[32]

8. Combination Products

Recognizing the importance of combination therapy in managing T2DM, Daewoong Pharmaceutical has developed and secured approval for fixed-dose combination (FDC) products involving Enavogliflozin.

8.1. Envlomet® SR Tab. (Enavogliflozin/Metformin)

Envlomet® SR Tab. is a sustained-release FDC tablet combining Enavogliflozin 0.3 mg with metformin hydrochloride 1000 mg.17 Metformin is the universally recommended first-line pharmacological treatment for T2DM. The combination of an SGLT2 inhibitor like Enavogliflozin with metformin offers complementary mechanisms of action for blood glucose control.

Envlomet® SR Tab. was approved by the South Korean MFDS on June 13, 2023, as an adjuvant to diet and exercise therapies to improve glycemic control in patients with T2DM for whom the combination of Enavogliflozin and metformin is appropriate.17 The development of this FDC aims to improve patient convenience and adherence by reducing pill burden, a common challenge in chronic disease management.26 The Korean market for SGLT2 inhibitor and metformin combinations is estimated to be substantial, indicating a significant commercial opportunity for Envlomet®.26

8.2. Future Combination Developments

Daewoong Pharmaceutical is also pursuing further combination therapies. The company is reportedly developing a three-drug FDC product that combines Enavogliflozin, metformin, and a dipeptidyl peptidase-4 (DPP-4) inhibitor.[26] The specific DPP-4 inhibitor mentioned in this context for which Daewoong has received approval for a three-drug combination is gemigliptin.[26] Phase 3 clinical trials (ENHANCE-D) have already evaluated the efficacy and safety of Enavogliflozin added to a background of metformin and gemigliptin, demonstrating non-inferiority to dapagliflozin in this setting.[15] This suggests a strong clinical basis for developing such a triple FDC.

The strategy to develop multiple FDCs, such as Envlomet® and potentially a triple combination, reflects an understanding of the progressive nature of T2DM and the frequent need for multi-agent therapy to achieve and maintain glycemic targets. Offering FDCs can simplify treatment regimens, potentially enhance patient adherence, and provide clinicians with convenient options for intensifying therapy. This approach aligns with current diabetes management guidelines that advocate for individualized treatment, often involving combinations of drugs with different mechanisms of action.

9. Comparative Assessment (vs. other SGLT2 inhibitors, particularly Dapagliflozin)

Clinical trials for Enavogliflozin have frequently used dapagliflozin, an established SGLT2 inhibitor, as an active comparator. This allows for a direct assessment of Enavogliflozin's relative efficacy and safety.

9.1. Efficacy Comparisons

• Glycemic Control (HbA$_{1c}$ and FPG):
• In the ENHANCE-M study (add-on to metformin), Enavogliflozin 0.3 mg was non-inferior to dapagliflozin 10 mg in reducing HbA$_{1c}$ at 24 weeks (adjusted mean change: –0.80% vs. –0.75%).[7] FPG reductions were also comparable (–32.53 mg/dL vs. –29.14 mg/dL).
• In the ENHANCE-D study (add-on to metformin + gemigliptin), Enavogliflozin 0.3 mg was non-inferior to dapagliflozin 10 mg for HbA$_{1c}$ reduction at 24 weeks (–0.92% vs. –0.86%).[3] FPG changes were not significantly different.
• Renal Function Subgroups: A key differentiating factor emerged from pooled analyses. In patients with T2DM and mildly reduced eGFR (60 to <90 mL/min/1.73 m$^2$), Enavogliflozin 0.3 mg demonstrated significantly greater reductions in HbA$_{1c}$ (–0.94% vs. –0.77%, P=0.0196) and FPG compared to dapagliflozin 10 mg at 24 weeks.[14] Enavogliflozin maintained potent blood glucose-lowering effects regardless of renal function status within the studied range, whereas dapagliflozin's efficacy was observed to diminish with decreasing renal function.[14] This apparent advantage for Enavogliflozin in patients with early renal impairment is a notable finding.
• Urinary Glucose Excretion (UGE/UGCR): Enavogliflozin consistently demonstrated a significantly greater increase in UGE or UGCR compared to dapagliflozin in both the ENHANCE-M and ENHANCE-D trials, as well as in pooled analyses across different renal function subgroups.[7] This more potent glucosuric effect may underpin its robust glycemic lowering, particularly in populations where comparator efficacy might be reduced.
• Insulin Resistance (HOMA-IR): The ENHANCE-M study and pooled analyses indicated a significantly greater decrease in HOMA-IR with Enavogliflozin compared to dapagliflozin, suggesting a more pronounced effect on improving insulin sensitivity.[7]
• Body Weight and Blood Pressure: Effects on body weight reduction and blood pressure lowering were generally comparable between Enavogliflozin and dapagliflozin in head-to-head trials.[7]

9.2. Safety Comparisons

The overall incidence of TEAEs was similar between Enavogliflozin and dapagliflozin groups in comparative trials like ENHANCE-M (24% vs. 22%) and ENHANCE-D (21.64% vs. 23.53%).[7] Most events were mild.

• Adverse Drug Reactions (ADRs): In the ENHANCE-M trial, ADRs were reported less frequently in the Enavogliflozin group (1.0%) compared to the dapagliflozin group (7.1%, P=0.0341).[7]
• Specific AESIs:
• Hypoglycemia: Incidence was low and comparable, with one episode in the dapagliflozin group and none in the Enavogliflozin group in the 24-week ENHANCE-M study.[7]
• UTIs: Low rates and similar between groups (e.g., one case of cystitis in each group in ENHANCE-M).[7]
• GMIs: Specific comparative rates for GMIs in these head-to-head trials are not detailed in the snippets, but the overall safety profile was similar.
• Pooled analyses also reported that adverse events were similar between Enavogliflozin and dapagliflozin groups.[14]

9.3. Pharmacokinetic/Pharmacodynamic Differences

• Potency and Kidney Distribution: Enavogliflozin is characterized by its efficacy at a low 0.3 mg dose. Preclinical data and clinical observations of higher UGE suggest a potent SGLT2 inhibitory effect.[6] The high and sustained kidney distribution observed in animal models for Enavogliflozin might contribute to its potent and long-lasting UGE.[6] A study comparing Enavogliflozin 0.3 mg and dapagliflozin 10 mg in healthy adults indicated higher post-treatment UGE with Enavogliflozin.[14] This difference in glucosuric potency could explain the observed superior glycemic efficacy in patients with mild renal impairment.
• Selectivity: Enavogliflozin is reported to have exceptional selectivity for SGLT2 over SGLT1 (1,015-fold).[9] While dapagliflozin is also selective, the degree of selectivity can differ between agents and might influence profiles, although direct comparative selectivity data against dapagliflozin is not explicitly stated in terms of fold-difference in the provided snippets.

The comparative data, particularly from pooled analyses focusing on renal function, suggest that while Enavogliflozin 0.3 mg offers comparable overall glycemic control, weight, and blood pressure benefits to dapagliflozin 10 mg in the general T2DM population, it may hold an advantage in patients with mild renal impairment. This potential for more consistent efficacy as kidney function begins to decline, possibly linked to its more potent effect on UGE, could be a key differentiator if borne out in broader clinical practice and further studies. The ongoing ENVELOP trial, comparing Enavogliflozin against dapagliflozin or empagliflozin for cardiorenal outcomes, will be critical in further defining its place relative to these established SGLT2 inhibitors.[9]

10. Future Directions and Unmet Needs

The development and initial market introduction of Enavogliflozin represent significant progress, yet ongoing research and future investigations will be crucial in fully defining its therapeutic role and addressing remaining questions.

10.1. Ongoing Research

• ENVELOP Study: The "Enavogliflozin to evaluate cardiorenal outcomes in patients with type 2 diabetes" (ENVELOP) study is a major ongoing investigator-initiated, multicenter, randomized, pragmatic, open-label, active-controlled, non-inferiority trial.[9] Its primary objective is to assess the effect of Enavogliflozin on a composite of major adverse cardiovascular and renal events in T2DM patients with, or at risk of, cardiovascular disease, comparing it directly to dapagliflozin or empagliflozin. The results of this trial will be pivotal in establishing whether Enavogliflozin shares the well-documented cardiorenal protective benefits of other leading SGLT2 inhibitors.
• Real-World Evidence Studies: A large-scale, prospective, multicenter, non-interventional observational study is planned or underway to evaluate the effectiveness (particularly for weight loss) and safety of Enavogliflozin (Envlo®) and its metformin combination (Envlomet® SR) in real-world clinical settings in Korea over 24 weeks.[4] This study will also explore effects on cardiac function and metabolic risk factors in overweight or obese T2DM patients. Such studies are vital for confirming clinical trial findings in broader, more diverse patient populations and for identifying any new or rare safety signals or benefits not apparent in controlled trials.
• Phase 3 Trial for Heart Failure: AdisInsight reports a Phase 3 trial planned by Daewoong Pharmaceutical for Enavogliflozin in heart failure, set to start in December 2023 (NCT06141980).[3] This aligns with the known benefits of the SGLT2 inhibitor class in heart failure, irrespective of diabetes status.

10.2. Potential for Expanded Indications

Beyond its current approval for T2DM, Enavogliflozin is being investigated or shows preclinical promise for several other indications:

• Obesity: Positive results in naturally obese dogs and planned real-world evidence studies focusing on weight loss suggest potential as an anti-obesity agent.[1]
• Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis: Preclinical efficacy has been demonstrated in mouse models of NASH and liver fibrosis.[25]
• Diabetic Retinopathy and Cardioprotection: These are areas of investigation for expanded therapeutic efficacy.[6]
• Veterinary Use: The compound is noted as an asset targeting multiple indications for both human and veterinary use.[25]

The exploration of these additional indications is logical, given the interconnected nature of metabolic diseases and the pleiotropic effects observed with SGLT2 inhibitors. Success in these areas could significantly broaden Enavogliflozin's therapeutic utility.

10.3. Unanswered Questions and Areas for Further Research

Despite the promising data, several areas warrant further investigation:

• Long-term Cardiorenal Outcomes: The ENVELOP study is designed to address this, but long-term follow-up beyond this trial will also be important.
• Efficacy and Safety in Diverse Populations: While initial trials focused on Korean patients, data in other ethnic groups and specific patient populations (e.g., elderly, varying degrees of renal/hepatic impairment beyond mild) will be needed for global adoption. The planned study NCT06141980 targets adults and the elderly for T2DM, which will contribute to this.[3]
• Mechanisms of Superiority in Mild Renal Impairment: Further research into why Enavogliflozin appears more effective than dapagliflozin in patients with mild renal impairment could elucidate finer points of SGLT2 inhibitor pharmacology and kidney physiology.
• Comparative Efficacy against Newer SGLT2 Inhibitors: While dapagliflozin is a common comparator, comparisons with other SGLT2 inhibitors in various settings could further define Enavogliflozin's profile.
• Head-to-Head Safety Comparisons: More detailed head-to-head comparisons of specific adverse event rates (e.g., GMIs, UTIs, DKA risk) against other SGLT2 inhibitors in large trials would be beneficial.
• Pharmacogenomics: Investigating whether genetic polymorphisms influence Enavogliflozin's efficacy or safety.
• Pediatric Use: Currently, the focus is on adult populations; the potential for pediatric use in T2DM (a growing concern) remains to be explored.

10.4. Implications for Future Development

The trajectory of Enavogliflozin's development highlights a strategic focus on differentiating within an established drug class. The emphasis on low-dose efficacy and potential advantages in specific subgroups like those with mild renal impairment suggests a nuanced approach to market positioning. If the ENVELOP trial confirms robust cardiorenal benefits comparable to or better than existing agents, Enavogliflozin could become a significant global player. Furthermore, successful development for expanded indications like heart failure or NASH would substantially increase its therapeutic and commercial value. The ongoing collection of real-world data will be essential for building confidence among prescribers and for uncovering the full spectrum of its performance in routine clinical care.

11. Conclusion

Enavogliflozin (DWP16001, Envlo®) is a novel, potent, and selective SGLT2 inhibitor developed by Daewoong Pharmaceutical, approved in South Korea and other countries for the treatment of type 2 diabetes mellitus. Its primary mechanism involves the inhibition of glucose reabsorption in the renal proximal tubules, leading to increased urinary glucose excretion and consequently, reductions in blood glucose levels, body weight, and blood pressure.

Clinical development, including extensive Phase 3 trials (ENHANCE-A, ENHANCE-M, ENHANCE-D), has demonstrated that Enavogliflozin 0.3 mg once daily is effective in improving glycemic control, both as monotherapy and as an add-on to metformin and/or gemigliptin. Comparative studies have shown its non-inferiority to dapagliflozin 10 mg in terms of HbA$_{1c}$ reduction. A notable finding from pooled analyses is the potentially superior glucose-lowering efficacy of Enavogliflozin in patients with T2DM and mild renal impairment compared to dapagliflozin, an observation attributed to its potent induction of urinary glucose excretion that appears less affected by early declines in kidney function. Enavogliflozin also shows beneficial effects on insulin resistance (HOMA-IR).

The pharmacokinetic profile of Enavogliflozin is characterized by rapid absorption, a long elimination half-life supporting once-daily dosing, and dose-proportional exposure in the therapeutic range. It is metabolized by CYP and UGT enzymes and exhibits high distribution to the kidneys, its target organ.

The safety and tolerability profile of Enavogliflozin is generally consistent with the SGLT2 inhibitor class, with most adverse events being mild to moderate. Common class-related adverse events such as genital mycotic infections and urinary tract infections have been reported at low rates in the available trial data, and the risk of hypoglycemia is low when not used with insulin or insulin secretagogues.

Ongoing research, particularly the ENVELOP cardiorenal outcome trial and real-world evidence studies, will be critical in fully establishing Enavogliflozin's long-term benefits and its comparative effectiveness and safety against other established SGLT2 inhibitors. Preclinical data and planned clinical trials also suggest potential for expanded indications in areas such as heart failure, obesity, and NASH.

In summary, Enavogliflozin represents a valuable addition to the SGLT2 inhibitor class, offering effective glycemic control and metabolic benefits at a low dose. Its potential for maintained efficacy in mild renal impairment may offer a distinct advantage in a significant subset of T2DM patients. The comprehensive data from ongoing and future studies will further delineate its role in the evolving landscape of diabetes and metabolic disease management.

Works cited

1. Enavogliflozin - Wikipedia, accessed June 9, 2025, https://en.wikipedia.org/wiki/Enavogliflozin
2. Enavogliflozin | CAS NO.:1415472-28-4 - GlpBio, accessed June 9, 2025, https://www.glpbio.com/enavogliflozin.html
3. Enavogliflozin - Daewoong - AdisInsight - Springer, accessed June 9, 2025, https://adisinsight.springer.com/drugs/800050860
4. (PDF) An anonymized, de-identified registry study protocol to determine the effectiveness and safety of weight loss with enavogliflozin in patients with type 2 diabetes mellitus - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/388277237_An_anonymized_de-identified_registry_study_protocol_to_determine_the_effectiveness_and_safety_of_weight_loss_with_enavogliflozin_in_patients_with_type_2_diabetes_mellitus
5. An anonymized, de-identified registry study protocol to determine the effectiveness and safety of weight loss with enavogliflozin in patients with type 2 diabetes mellitus | PLOS One, accessed June 9, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0315603
6. Pharmacokinetics and Tissue Distribution of Enavogliflozin in Mice Using a Validated Liquid Chromatography–Tandem Mass Spectrometry Method - MDPI, accessed June 9, 2025, https://www.mdpi.com/2076-3417/15/3/1445
7. Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus: A 24-Week, Double-Blind, Randomized Trial - Diabetes & Metabolism Journal, accessed June 9, 2025, https://www.e-dmj.org/journal/view.php?doi=10.4093%2Fdmj.2022.0315
8. (PDF) Pharmacokinetics and Tissue Distribution of Enavogliflozin in Mice Using a Validated Liquid Chromatography–Tandem Mass Spectrometry Method - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/388581075_Pharmacokinetics_and_Tissue_Distribution_of_Enavogliflozin_in_Mice_Using_a_Validated_Liquid_Chromatography-Tandem_Mass_Spectrometry_Method
9. Study Design and Protocol for a Randomized Controlled Trial of Enavogliflozin to Evaluate Cardiorenal Outcomes in Type 2 Diabetes (ENVELOP), accessed June 9, 2025, https://www.e-dmj.org/journal/view.php?number=2912
10. Study Design and Protocol for a Randomized Controlled Trial of Enavogliflozin to Evaluate Cardiorenal Outcomes in Type 2 Diabetes (ENVELOP) - PMC, accessed June 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11960196/
11. An anonymized, de-identified registry study protocol to determine the effectiveness and safety of weight loss with enavogliflozin in patients with type 2 diabetes mellitus - PLOS, accessed June 9, 2025, https://journals.plos.org/plosone/article/file?type=printable&id=10.1371/journal.pone.0315603
12. Study Design and Protocol for a Randomized Controlled Trial of Enavogliflozin to Evaluate Cardiorenal Outcomes in Type 2 - Diabetes & Metabolism Journal, accessed June 9, 2025, https://www.e-dmj.org/upload/pdf/dmj-2024-0238.pdf
13. Efficacy and Safety of Enavogliflozin versus Dapagliflozin as Add-on ..., accessed June 9, 2025, https://www.e-dmj.org/journal/view.php?number=2724
14. Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials - PMC - PubMed Central, accessed June 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10870449/
15. Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/369133860_Efficacy_and_safety_of_enavogliflozin_versus_dapagliflozin_added_to_metformin_plus_gemigliptin_treatment_in_patients_with_type_2_diabetes_a_double-blind_randomized_comparator-active_study_ENHANCE-D_st
16. Daewoong Presents Enavogliflozin's Phase 3 Pooled Analysis Results at 84th ADA Conference - PR Newswire, accessed June 9, 2025, https://www.prnewswire.com/news-releases/daewoong-presents-enavogliflozins-phase-3-pooled-analysis-results-at-84th-ada-conference-302176658.html
17. Korea approves SGLT2i + metformin combination drug Envlomet for diabetes treatment, accessed June 9, 2025, https://www.biospectrumasia.com/news/51/22748/korea-approves-sglt2i-metformin-combination-drug-envlomet-for-diabetes-treatment.html
18. Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials - PubMed, accessed June 9, 2025, https://pubmed.ncbi.nlm.nih.gov/38360626/
19. 940-P: Efficacy and Safety of Enavogliflozin vs. Dapagliflozin as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Based on Renal Function—A Pooled Analysis of Two Randomized Controlled Trials, accessed June 9, 2025, https://diabetesjournals.org/diabetes/article/73/Supplement_1/940-P/155008/940-P-Efficacy-and-Safety-of-Enavogliflozin-vs
20. (PDF) Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/378238853_Efficacy_and_safety_of_enavogliflozin_vs_dapagliflozin_as_add-on_therapy_in_patients_with_type_2_diabetes_mellitus_based_on_renal_function_a_pooled_analysis_of_two_randomized_controlled_trials
21. SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits - Oxford Academic, accessed June 9, 2025, https://academic.oup.com/cardiovascres/article/120/5/443/7624376
22. (PDF) Dose‐dependent glucosuria of DWP16001, a novel selective ..., accessed June 9, 2025, https://www.researchgate.net/publication/359844343_Dose-dependent_glucosuria_of_DWP16001_a_novel_selective_sodium-glucose_cotransporter-2_inhibitor_in_healthy_subjects
23. Enavogliflozin | C24H27ClO6 | CID 71076840 - PubChem, accessed June 9, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Enavogliflozin
24. Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans, accessed June 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10058973/
25. ENVLO® | Daewoong Pharmaceutical Co.,Ltd - CPHI Online, accessed June 9, 2025, https://www.cphi-online.com/envlo-prod1278676.html
26. Daewoong wins license for SGLT2i+metformin combo Envlomet - KBR, accessed June 9, 2025, https://www.koreabiomed.com/news/articleView.html?idxno=21332
27. Daewoong Pharmaceutical has obtained approval for SGLT2i + metformin combination drug Envlomet - PR Newswire, accessed June 9, 2025, https://www.prnewswire.com/in/news-releases/daewoong-pharmaceutical-has-obtained-approval-for-sglt2i--metformin-combination-drug-envlomet-301880411.html
28. journals.plos.org, accessed June 9, 2025, https://journals.plos.org/plosone/article/file?id=info%3Adoi/10.1371/journal.pone.0315603.s004&type=supplementary
29. Daewoong Pharmaceutical Announces Successful Phase 3 Topline Results for New Antidiabetic Drug's Triple Combination Therapy - BioSpace, accessed June 9, 2025, https://www.biospace.com/daewoong-pharmaceutical-announces-successful-phase-3-topline-results-for-new-antidiabetic-drug-s-triple-combination-therapy
30. Daewoong Pharmaceutical Released Positive Phase 3 Topline Results for New Antidiabetic Drug - BioSpace, accessed June 9, 2025, https://www.biospace.com/daewoong-pharmaceutical-released-positive-phase-3-topline-results-for-new-antidiabetic-drug
31. Daewoong Pharmaceutical Announces Successful Phase 3 Topline Results for New Antidiabetic Drug's Triple Combination Therapy - PR Newswire, accessed June 9, 2025, https://www.prnewswire.com/news-releases/daewoong-pharmaceutical-announces-successful-phase-3-topline-results-for-new-antidiabetic-drugs-triple-combination-therapy-301490372.html
32. Daewoong Pharmaceutical Presents Phase 3 Clinical Trial Results of New Diabetes Treatment 'Enavogliflozin' and Roadmap to Enter 50 Countries by 2030, accessed June 9, 2025, https://enmobile.prnasia.com/releases/apac/daewoong-pharmaceutical-presents-phase-3-clinical-trial-results-of-new-diabetes-treatment-enavogliflozin-and-roadmap-to-enter-50-countries-by-2030-381475.shtml
33. Daewoong Pharmaceutical Presents Phase 3 Clinical Trial Results of New Diabetes Treatment 'Enavogliflozin' and Roadmap to Enter 50 Countries by 2030, accessed June 9, 2025, https://www.prnewswire.com/ae/news-releases/daewoong-pharmaceutical-presents-phase-3-clinical-trial-results-of-new-diabetes-treatment-enavogliflozin-and-roadmap-to-enter-50-countries-by-2030-301664432.html
34. Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study - PubMed, accessed June 9, 2025, https://pubmed.ncbi.nlm.nih.gov/36906135/
35. A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study - ResearchGate, accessed June 9, 2025, https://www.researchgate.net/publication/378828934_A_52-week_efficacy_and_safety_study_of_enavogliflozin_versus_dapagliflozin_as_an_add-on_to_metformin_in_patients_with_type_2_diabetes_mellitus_ENHANCE-M_extension_study
36. www.researchgate.net, accessed June 9, 2025, https://www.researchgate.net/publication/369023987_Efficacy_and_safety_of_enavogliflozin_a_novel_SGLT2_inhibitor_in_Korean_people_with_type_2_diabetes_a_24-week_multicentre_randomised_double-blind_placebo-controlled_phase_III_trial#:~:text=Conclusions%3A%20Monotherapy%20with%20enavogliflozin%200.3,blood%20pressure%2C%20and%20lipid%20profile.
37. accessed January 1, 1970, https.pmc.ncbi.nlm.nih.gov/articles/PMC10058973/
38. synapse.patsnap.com, accessed June 9, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-enavogliflozin#:~:text=To%20summarize%2C%20Enavogliflozin%20operates%20by,may%20offer%20renal%20protective%20benefits.
39. What is Enavogliflozin used for? - Patsnap Synapse, accessed June 9, 2025, https://synapse.patsnap.com/article/what-is-enavogliflozin-used-for
40. High Prevalence of Genital Mycotic Infections with Sodium-glucose Co-transporter 2 Inhibitors among Indian Patients with Type 2 Diabetes, accessed June 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6446664/
41. Korea approves Daewoong Pharmaceutical's diabetes drug - KED Global, accessed June 9, 2025, https://www.kedglobal.com/bio-pharma/newsView/ked202212020003
42. An Overview of New Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Diabetes Mellitus | Nieczyporuk | Journal of Endocrinology and Metabolism, accessed June 9, 2025, https://jofem.org/index.php/jofem/article/view/942/284284710
43. SGLT2 inhibitors - referral | European Medicines Agency (EMA), accessed June 9, 2025, https://www.ema.europa.eu/en/medicines/human/referrals/sglt2-inhibitors