Pharmaceutical composition comprising enagliflozin for preventing or treating nephropathy and / or diabetes

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating diabetes mellitus and / or nephropathy in a patient suffering from or at risk of developing diabetes mellitus and / or nephropathy, the pharmaceutical composition comprising enagliflozin as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating diabetes and / or nephropathy in a patient suffering from nephropathy and / or diabetes or at risk of suffering from nephropathy and / or diabetes, comprising enavogliflozin as an active ingredient. Background Art

[0002] Sodium glucose cotransporter 2 (SGLT-2) is a transporter that, together with sodium glucose cotransporter 1 (SGLT-1), is responsible for the reabsorption of excess blood glucose in the kidneys, with SGLT-2 playing a major role. Therefore, when SGLT-2 inhibitors block the SGLT-2 transporter, the amount of blood glucose excreted in the urine increases, ultimately lowering blood glucose levels and releasing calories from blood glucose, leading to weight loss.

[0003] Due to this action, one of the drugs developed as a SGLT-2 inhibitor useful as a therapeutic agent for type 2 diabetes is enagliflozin represented by the following Chemical Formula 1, which is disclosed in Korean Unexamined Patent Application Publication No. 2014-0022086 (Patent Document 1).

[0004] [Chemical formula 1]

[0005]

[0006] Compound name: (2S,3R,4R,5S,6R)-2-(7-chloro-6(4-cyclopropylbenzyl)-2,3-dihydrobenzofuran-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[0007] Enagagliflozin (DWP16001) is a drug currently in Phase 3 clinical trials. Phase 2 clinical trials have confirmed that in all groups receiving 0.1 mg, 0.3 mg and 0.5 mg of enagliflozin, enagliflozin has a statistically significant hypoglycemic effect compared with placebo.

[0008] It is estimated that at very low doses (i.e., 1 / 100 of the dose of similar drugs), enagliflozin has an excellent effect on urinary glucose secretion (glucose excreted in urine).

[0009] However, enagliflozin has not been reported to have a therapeutic effect on kidney disease or to be used to treat diabetes in patients with kidney disease or at risk of developing kidney disease. Summary of the invention

[0010] Technical issues

[0011] The present inventors administered enagliflozin to patients suffering from diabetes and / or kidney disease or at risk of suffering from diabetes and / or kidney disease to find a new method for treating patients, and confirmed that enagliflozin can prevent or treat kidney disease, thereby completing the present invention.

[0012] Therefore, the present invention aims to provide a pharmaceutical composition for preventing or treating nephropathy and / or diabetes in a patient suffering from or at risk of suffering from diabetes and / or nephropathy, which comprises enagliflozin as an active ingredient.

[0013] Technical Solution

[0014] The present invention provides a pharmaceutical composition for preventing or treating nephropathy and / or diabetes in a patient suffering from or at risk of suffering from diabetes and / or nephropathy, comprising enagliflozin as an active ingredient.

[0015] Hereinafter, the present invention will be described in detail.

[0016] The present invention provides the use of enagliflozin for preventing or treating kidney disease, a pharmaceutical composition for preventing or treating kidney disease, and a method for preventing or treating kidney disease, which comprises administering an effective amount of enagliflozin to a subject in need thereof.

[0017] In the present invention, the renal disease may be, but is not limited to, a disease selected from diabetic nephropathy, renal failure, chronic kidney disease, glomerulonephritis and proteinuria.

[0018] In one embodiment of the present invention, the pharmaceutical composition can be used to reduce the risk of sustained decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, death caused by cardiovascular disease, and kidney-related death in patients with chronic kidney disease.

[0019] In another embodiment of the present invention, the renal disease may be diabetic nephropathy.

[0020] In one embodiment, the pharmaceutical composition may be administered to a diabetic or pre-diabetic patient.

[0021] The pharmaceutical composition comprising enagliflozin can be used as a monotherapy or in combination therapy.

[0022] Enagagliflozin alone is sufficient to prevent or treat diabetes and / or nephropathy. However, for various purposes, therapeutic agents for diabetes or nephropathy are administered in combination, and since these therapeutic agents can exhibit complementary or synergistic effects when administered in combination, a pharmaceutical composition including Enagagliflozin can be administered in combination with another therapeutic agent for diabetes or nephropathy.

[0023] In one embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with metformin.

[0024] In another embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with a DPP4 inhibitor.

[0025] For example, the DPP4 inhibitor may be, but is not limited to, gemigliptin.

[0026] In another embodiment, the combination therapy can be administered in combination with two or more different drugs. For example, a pharmaceutical composition including enagliflozin can be administered in combination with metformin and a DPP4 inhibitor.

[0027] Alternatively, the pharmaceutical composition comprising enagliflozin may be administered in combination with a sulfonylurea-based insulin secretagogue.

[0028] In another embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with insulin.

[0029] The present invention also provides the use of enagliflozin for preventing or treating diabetes in patients with kidney disease, a pharmaceutical composition comprising enagliflozin for preventing or treating diabetes in patients with kidney disease, and a method for preventing or treating diabetes in patients with kidney disease, the method comprising administering an effective amount of enagliflozin to a subject in need thereof.

[0030] In the present invention, the renal disease may include a disease selected from diabetic nephropathy, renal failure, chronic kidney disease, glomerulonephritis and proteinuria, but the present invention is not limited thereto.

[0031] In another embodiment of the present invention, the renal disease may be diabetic nephropathy.

[0032] In one embodiment, the pharmaceutical composition may be administered to a diabetic or pre-diabetic patient.

[0033] The pharmaceutical composition including enagliflozin may be administered alone or in combination.

[0034] Enagagliflozin alone is sufficient to prevent or treat diabetes and / or nephropathy. However, for various purposes, therapeutic agents for diabetes or nephropathy are administered in combination, and since these therapeutic agents can exhibit complementary or synergistic effects when administered in combination, a pharmaceutical composition including Enagagliflozin can be administered in combination with another therapeutic agent for diabetes or nephropathy.

[0035] In one embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with metformin.

[0036] In another embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with a DPP4 inhibitor.

[0037] For example, the DPP4 inhibitor may be gemagliptin, but the present invention is not limited thereto.

[0038] In another embodiment, the combination therapy can be administered in combination with two or more different drugs. For example, a pharmaceutical composition comprising enagliflozin can be administered in combination with metformin and a DPP4 inhibitor.

[0039] Alternatively, the pharmaceutical composition comprising enagliflozin may be administered in combination with an insulin secretagogue of the sulfonylurea class.

[0040] In another embodiment, the pharmaceutical composition comprising enagliflozin may be administered in combination with insulin.

[0041] The term "prevention" used in the present specification refers to all effects of inhibiting or delaying the occurrence of renal disease and / or diabetes by administering the pharmaceutical composition according to the present invention.

[0042] The term "treatment" used in the present specification refers to improving or beneficially changing all effects involved in kidney disease and / or diabetes by administering the pharmaceutical composition according to the present invention.

[0043] The dosage of enagliflozin that can be used for preventing or treating diabetes and / or kidney disease in patients having diabetes and / or kidney disease or at risk of developing diabetes and / or kidney disease is not particularly limited and can be appropriately adjusted based on the severity of the patient's disease, weight, age, sex, and the presence or absence of other complications.

[0044] The clinician may appropriately adjust the duration of administration of enagliflozin based on the preventive or therapeutic effects of enagliflozin on patients with or at risk of developing diabetes and / or kidney disease.

[0045] In one embodiment of the present invention, the method of treatment may be to administer a pharmaceutical composition for preventing or treating diabetes and / or kidney disease in combination with metformin and / or gemagliptin.

[0046] The method for treating diabetes and / or kidney disease uses a pharmaceutical composition for preventing or treating diabetes and / or kidney disease, and thus any duplication between the two is omitted to avoid lengthy description in the specification.

[0047] The enagliflozin used as an active ingredient in the present invention can be synthesized by known relevant literature. In the present invention, enagliflozin can be crystalline or amorphous. For example, enagliflozin can be crystalline form A, B, C, D or E of enagliflozin, or amorphous enagliflozin, which has the following X-ray diffraction spectrum according to Korean unexamined patent application publication number 2017-0142904 or Korean patent application number 2022-0123673.

[0048] Form A: a crystal form having an X-ray diffraction (XRD) spectrum with a peak at a 2[θ] value selected from 6.2°±0.2°, 7.2°±0.2°, 8.8°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 22.5°±0.2° and 25.1°±0.2°.

[0049] Form B: a crystal form having an X-ray diffraction (XRD) spectrum with a peak at a 2[θ] value selected from 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2° and 23.5°±0.2°.

[0050] Form C: a crystal form having an X-ray diffraction (XRD) spectrum with a peak at a 2[θ] value selected from 5.6°±0.2°, 7.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 21.2°±0.2° and 21.9°±0.2°.

[0051] Form D: a crystal form having an X-ray diffraction (XRD) spectrum with a peak at a 2[θ] value selected from 5.5°±0.2°, 7.2°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.9°±0.2° and 21.1°±0.2°.

[0052] Form E: a crystalline form having an X-ray diffraction (XRD) spectrum with a peak at a 2[θ] value selected from 4.93°±0.2°, 6.12°±0.2°, 7.43°±0.2°, 8.89°±0.2°, 9.74°±0.2°, 14.79°±0.2°, 15.79°±0.2°, 16.11°±0.2°, 19.79°±0.2° and 22.83°±0.2.

[0053] Each of Forms A, B, C and D is identified by an X-ray diffraction spectrum having four or more, for example 4, 5, 6, 7, 8 or more peaks at given 2[θ] values.

[0054] The pharmaceutical composition including enagliflozin according to the present invention may have the composition of the pharmaceutical composition of PCT / KR2022 / 014640.

[0055] For example, the pharmaceutical composition of the present invention may be a pharmaceutical composition including the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, an excipient, a disintegrant, and a binder, and the average particle size of the compound of Chemical Formula 1 may be 15 μm or less.

[0056] In an exemplary embodiment of the present invention, the average particle size of enagliflozin may be 15 μm or less, preferably 10 μm or less.

[0057] When the average particle size of enagliflozin was greater than 15 μm, the 5-minute dissolution rate was very low, less than 40% of the total content of enagliflozin, and the 30-minute dissolution rate was also less than 80% thereof, indicating that the final dissolution rate was insufficient.

[0058] When it is necessary to micronize the drug particles, conventional grinders capable of micronizing the particles, such as a Z-grinder, a hammer mill, a ball mill, or a fluid energy grinder, can be used to pulverize the drug particles. In addition, the drug particle size can be divided by a size classification method, such as screening with a sieve or airflow classification. Methods for controlling the desired particle size are well known in the art (e.g., see [Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: HALieberman, L.Lachman, JB Schwartz (Chapter 3: SIZE REDUCTION)].

[0059] In the present specification, the particle size of the drug is expressed based on the particle size distribution such as D(X)=Y (wherein X and Y are positive numbers). D(X)=Y means that when the particle size distribution of the drug obtained by measuring the particle size of any drug in the preparation is expressed by a cumulative curve, the particle diameter at the point where the particle size becomes X% when accumulated in the order of decreasing particle size (% is calculated based on number, volume or weight) is Y. For example, D(10) represents the particle diameter at the point where the particle size becomes 10% when accumulated in the order of decreasing particle size, D(50) represents the particle diameter at the point where the particle size becomes 50% when accumulated in the order of decreasing particle size, and D(90) represents the particle diameter at the point where the particle size becomes 90% when accumulated in the order of decreasing particle size.

[0060] Whether the particle size distribution D(X) is based on the percentage of the total cumulative particles by number, volume or weight depends on the method used to measure the particle size distribution. The method of measuring the particle size distribution and the type of % associated therewith are known in the art. For example, when the particle size distribution is measured by the well-known laser diffraction method, the X value in D(X) represents the percentage calculated by the average volume. It is well known to those of ordinary skill in the art that the particle size distribution measurement results obtained by a particular method can be associated with the results obtained by other techniques based on the experience obtained by routine experiments. For example, laser diffraction is sensitive to the volume of particles and provides a volume average particle size, which is equivalent to the weight average particle size at a constant density.

[0061] In the present invention, the measurement of the particle size distribution of the drug particles can be carried out using commercially available equipment based on a laser diffraction / scattering method based on Mie theory. For example, the particle size distribution is measured using commercial equipment such as a Mastersizer laser diffraction device (Malvern Instruments). In this device, a helium-neon laser beam and a blue light emitting diode are applied to the particles, causing scattering, thereby generating a light scattering pattern on a detector. By interpreting the light scattering pattern according to Mie theory, the particle diameter distribution is obtained. The measurement method can be a dry method or a wet method.

[0062] For reference, in the examples of the present invention, the particle size of the drug was measured by volume average particle size using laser diffraction.

[0063] In one embodiment of the present invention, the compound of Chemical Formula 1 may be included in an amount of less than 1 part by weight relative to 100 parts by weight of the total pharmaceutical composition.

[0064] The appropriate daily dose of enagliflozin determined during clinical trials is 0.1 to 0.5 mg, and when the pharmaceutical composition is formulated into a unit dosage form, the content of the active ingredient in the pharmaceutical composition may be 0.1 to 0.5 mg.

[0065] The pharmaceutical composition according to the present invention includes pharmaceutically acceptable additives other than the compound of Chemical Formula 1 as an active ingredient.

[0066] The pharmaceutical composition of the present invention comprises an excipient, a disintegrant and a binder.

[0067] Examples of excipients include lactose (including hydrates), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose (e.g. Celphere TM ), silicified microcrystalline cellulose (e.g. Prosolv TM ), calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, sugar or a mixture thereof. In one embodiment of the present invention, the preferred excipient is microcrystalline cellulose.

[0068] Examples of disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate or low-substituted hydroxypropylcellulose. In one embodiment of the present invention, the preferred excipient is croscarmellose sodium.

[0069] Examples of binders include polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (eg hydroxypropylmethylcellulose) and mixtures thereof. In one embodiment of the present invention, the preferred binder is hydroxypropylcellulose.

[0070] Examples of additives include lubricants and colorants in addition to those listed above.

[0071] The lubricant can be stearic acid, stearates (e.g., magnesium stearate), light anhydrous silicic acid, talc, corn starch, carnauba wax, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, polyethylene glycol 4000 or 6000, isopropyl myristate, calcium hydrogen phosphate, or a mixture thereof.

[0072] In one embodiment of the present invention, 80 to 95 parts by weight of the excipient may be included relative to 100 parts by weight of the total pharmaceutical composition.

[0073] In one embodiment of the present invention, 2 to 8 parts by weight of disintegrants may be included relative to 100 parts by weight of the total pharmaceutical composition. When less than 2 parts by weight of disintegrants are included relative to 100 parts by weight of the total pharmaceutical composition, the initial disintegration capacity may be low, and thus the dissolution rate may be delayed, affecting the Cmax in vivo. In addition, when more than 8 parts by weight of disintegrants are included relative to 100 parts by weight of the total pharmaceutical composition, the overall flowability of the particles may decrease as the amount of disintegrants in the post-mixing part increases.

[0074] In one embodiment of the invention, relative to the total pharmaceutical composition of 100 weight parts, 3 to 10 weight parts of adhesive can be included. When the total pharmaceutical composition relative to 100 weight parts includes less than 3 weight parts of adhesive, it may be difficult to form and maintain suitable dry particles, due to the generation of fine particles and the maintenance of the uniform dispersion of the main component and the fluidity of the particles. In addition, when the total pharmaceutical composition relative to 100 weight parts includes more than 10 weight parts of adhesive, particles with strong binding strength are formed, which affects the solubility of the particles of initial disintegration in the dissolution process, and also affects the Cmax in vivo.

[0075] The pharmaceutical composition according to the present invention may be an immediate release formulation.

[0076] In one embodiment of the present invention, the dissolution rate of the pharmaceutical composition after 5 minutes may be 50% or more, preferably 60% or more of the total content of the active ingredient.

[0077] In one embodiment of the present invention, the dissolution rate of the pharmaceutical composition after 15 minutes may be 80% or more, preferably 80% or more, of the total content of the active ingredient.

[0078] In one embodiment of the present invention, the dissolution rate of the pharmaceutical composition after 30 minutes may be 85% or more, preferably 90% or more of the total content of the active ingredient.

[0079] When the drug is administered, the dissolution rate of the active ingredient in the pharmaceutical composition affects the maximum blood concentration (Cmax) and the blood concentration area under the blood concentration-time curve (AUC), that is, in order to obtain suitable Cmax and AUC, it is important to adjust the dissolution rate of the pharmaceutical composition. Since the Tmax of enagliflozin is 1-2 hours, it is considered that the absorption rate of the drug in the stomach is very important. According to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, the above dissolution rate is determined under the condition of dissolution solution 1.2. Refer to the following experimental examples for specific conditions.

[0080] The present invention also provides a pharmaceutical composition comprising a premixed granule and a granule mixture of a post-mixed portion, wherein the premixed granule comprises the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0081] During the study of the formulation of the compound of Chemical Formula 1, the present inventors confirmed that preparing granules and formulating them into tablets is advantageous in terms of drug content uniformity and dosage unit uniformity.

[0082] In the pharmaceutical composition, granules are prepared by mixing the premixed granules and the postmixed part.

[0083] The premixed granules may include the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof, an excipient, a binder, and a lubricant.

[0084] Additionally, the post-mixing part may include excipients, disintegrants, and lubricants.

[0085] The descriptions of the excipients, binder, disintegrant, and lubricant are the same as those described above and thus are omitted to avoid duplicate descriptions.

[0086] In one embodiment of the present invention, each of the premixed granules and the postmixed part may include an excipient. More specifically, each of the premixed granules and the postmixed part may include microcrystalline cellulose as an excipient.

[0087] According to the following examples, it was found that microcrystalline cellulose included in the premixed granules and the postmixed part affected the content uniformity of the drug according to the particle size and bulk density of the drug.

[0088] In one embodiment of the present invention, the particle size of microcrystalline cellulose in the premixed granules may be 130 μm or less, preferably 60 to 130 μm. The bulk density of microcrystalline cellulose in the premixed granules may be 0.26 to 0.33. When the particle size and bulk density of microcrystalline cellulose in the premixed granules are the same as the above conditions, a preparation with a low standard deviation (SD) of content uniformity can be obtained. When the particle size of microcrystalline cellulose in the premixed granules is 130 μm or less, the content uniformity of the premixed granules, the content uniformity of the final granules, and the preparation uniformity all show good levels, and the Carr's index value indicating the physical properties of the final granules is also good, confirming that the fluidity of the preparation is also excellent. On the other hand, when the particle size of microcrystalline cellulose in the premixed granules exceeds 130 μm, due to large variations, the content uniformity of the premixed granules and the content uniformity of the final granules are not suitable, and poor preparation uniformity is also found.

[0089] Meanwhile, the particle size of the microcrystalline cellulose in the post-mixing part may be 130 μm or more, preferably 130 to 250 μm. The bulk density of the excipient in the post-mixing part may be 0.28 to 0.37. When the particle size of the microcrystalline cellulose in the post-mixing part is less than 130 μm, the Carr index value indicating the physical properties of the final granules is not appropriate, and the granules have poor fluidity.

[0090] When comparing the microcrystalline cellulose in the premixed granules and the microcrystalline cellulose in the postmixed part, it is preferred that the particle size of the microcrystalline cellulose in the premixed granules is small, whereas it is preferred that the particle size of the microcrystalline cellulose in the postmixed part is relatively larger than that of the microcrystalline cellulose in the premixed granules.

[0091] According to the following examples, not only the particle sizes of microcrystalline cellulose in the premixed granules and the microcrystalline cellulose in the postmixed part, but also the weight ratio of the excipients in the premixed granules and the excipients in the postmixed part were confirmed to affect the content uniformity of the drug.

[0092] In one embodiment of the present invention, the weight ratio of the excipients in the premixed granules and the excipients in the post-mixing part may be 4: 1 to 1: 1. As the proportion of microcrystalline cellulose in the post-mixing part increases, the fluidity of the granules is improved, but the content variation increases, so it is found that it is preferable to adjust the weight ratio within a suitable range.

[0093] Meanwhile, in the pharmaceutical composition according to the present invention, the binder may be one or more selected from the group consisting of hydroxypropyl cellulose, povidone, copovidone and hypromellose.

[0094] In one embodiment of the present invention, the binder may be hydroxypropyl cellulose and have a weight average molecular weight of less than 200,000. When hydroxypropyl cellulose having a weight average molecular weight of 200,000 or more is used, the dissolution rates in 5 minutes and 30 minutes are low, which is not preferred in terms of bioavailability.

[0095] Meanwhile, the Carr's index of the granules is preferably 21 to 25, considering that the Carr's index is used as a measure of the fluidity of the preparation.

[0096] In the pharmaceutical composition of the present invention, the granules may be dry granules, but the present invention is not limited thereto. In another embodiment, the granules may be wet granules.

[0097] In the present invention, the pharmaceutical composition may have a dosage form for oral administration, such as a tablet or a capsule. In one embodiment of the present invention, the pharmaceutical composition may have a tablet formulation.

[0098] In an exemplary embodiment, the pharmaceutical composition may include 0.3 to 0.5 mg of the compound of Chemical Formula 1.

[0099] The pharmaceutical composition according to the present invention can be orally administered once a day, but the present invention is not limited thereto.

[0100] Beneficial Effects

[0101] The pharmaceutical composition of the present invention comprising enagliflozin as an active ingredient can be used to prevent or treat renal disease, or prevent or treat diabetes in patients with renal disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1 The results of HbA1c measurements at weeks 6, 12, 18, and 24 after 24 weeks of enagliflozin or enagliflozin placebo monotherapy in patients with type 2 diabetes are shown. The test group was administered enagliflozin at a dose of 0.3 mg once a day for 24 weeks, and the control group was administered enagliflozin placebo once a day for 24 weeks. The bar graph represents the mean of each variable, and the error bar represents the standard deviation (SD). A p value of less than 0.05 was considered statistically significant.

[0103] Figure 2The results of HbA1c measurements at weeks 6, 12, 18 and 24 are shown after 24 weeks of administration of enagliflozin or dapagliflozin in patients with type 2 diabetes who have insufficient glycemic control using metformin. The test group was administered 0.3 mg of enagliflozin or 10 mg of dapagliflozin placebo, and the control group was administered 0.3 mg of enagliflozin placebo or 10 mg of dapagliflozin once a day for 24 weeks. Here, the dose of metformin was the same as before. The bar graph represents the mean of each variable, and the error bar represents the standard deviation (SD). A p value of less than 0.05 is considered statistically significant.

[0104] Figure 3 The results of HbA1c measurements at weeks 6, 12, 18, and 24 were shown after 24 weeks of administration of enagliflozin or dapagliflozin in patients with type 2 diabetes who were not adequately controlled with metformin and gemagliptin. The experimental group was administered 0.3 mg of enagliflozin or 10 mg of dapagliflozin placebo, and the control group was administered 0.3 mg of enagliflozin placebo or 10 mg of dapagliflozin once a day for 24 weeks. Here, the doses of metformin and gemagliptin were the same as before. The bar graph represents the mean of each variable, and the error bar represents the standard deviation (SD). A p value of less than 0.05 was considered statistically significant.

[0105] Figure 4 It is a graph showing the UACR change rate at week 24 by administration of placebo in proteinuric patients (baseline UACR is 30 to 3500 g / kg). At week 24, based on the baseline value, enagliflozin monotherapy, enagliflozin and metformin combination therapy, and enagliflozin, metformin and gemagliptin combination therapy all showed a significant reduction in the UACR change rate compared to the control group.

[0106] Figure 5 It is a graph showing changes in urinary glucose excretion after administration of 0.5 mg of enagliflozin in patients satisfying eGFR≥90, 60≤eGFR<90, 30≤eGFR<60, or 15≤eGFR<30.

[0107] Figure 6 It is a graph showing the change in eGFR after administration of 0.5 mg of enagliflozin in patients satisfying eGFR≥90, 60≤eGFR<90, 30≤eGFR<60, or 15≤eGFR<30.

[0108] Figure 7It is a graph showing the measurement results of urine albumin concentration at 4, 8 and 12 weeks after administration of a test material to SD rats treated with streptozotocin.

[0109] Figure 8 It is a graph showing the measurement results of GS score and TA score at week 12 after administration of a test material to SD rats treated with streptozotocin. DETAILED DESCRIPTION

[0110] Hereinafter, one or more exemplary embodiments will be described in more detail with reference to examples. However, these examples are intended to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.

[0111] [Example]

[0112] Example 1: Single administration of enagliflozin to patients with type 2 diabetes

[0113] 1. Research process

[0114] When the subject voluntarily agrees in writing to participate in this clinical trial, a screening test will be performed. Patients with type 2 diabetes who have inadequate glycemic control (7% ≤ HbA1c ≤ 10%) at the first follow-up (screening) are eligible to participate in the trial, and patients with type 2 diabetes who are taking hypoglycemic drugs at the time of screening are eligible to participate in the trial after a wash-out period of at least 8 weeks (56 days) before screening. However, when the administration of hypoglycemic drugs is discontinued before the first follow-up (screening) of the clinical trial, a wash-out period of at least 8 weeks (including a drug-free period) is required, and during this period, a stable diet and exercise plan is followed. For patients who have not received treatment Patients were screened without a separate washout period, and the criterion for treatment-naive patients was defined as those who had not used glucose-lowering medications within 24 weeks before the date of written consent.

[0115] Subjects who met the inclusion / exclusion criteria [1] were administered a placebo of the clinical trial drug in a single-blind (subject-unaware) state during a 2-week run-in period. At the second follow-up (randomization), subjects who met the final inclusion / exclusion criteria and whose medication compliance rate with placebo during the run-in period was 70% to 130% were centrally randomized in a 1:1 ratio to the test group (enagliflozin 0.3 mg) or the control group (placebo). In this article, the subjects were divided into two groups according to whether they had used hypoglycemic drugs (drug-free) within 24 weeks before obtaining written informed consent (drug-free) or not. Randomly assigned subjects were stratified according to the HbA1c value (<8% or ≥8%) measured in the central laboratory at the first follow-up (screening) visit and were administered the assigned group of clinical trial drugs for 24 weeks.

[0116] The randomly assigned subjects took one tablet of clinical trial drug corresponding to each administration group every day, and then visited the testing institution for efficacy and safety evaluation at weeks 6, 12, 18, and 24 during the 24-week administration period. In addition, they were instructed to maintain regular exercise and dietary control from 8 weeks before screening without changing their daily life patterns during the clinical trial.

[0117] The results are shown in Table 1-20 and Figure 1 shown.

[0118] [1] [Inclusion criteria]

[0119] Inclusion criteria before follow-up (pre-screening) or first follow-up (screening)

[0120] 1. Adults aged 19 to 80 years old as of the date of written consent

[0121] 2. Those with HbA1c*≤7%≤10% at the first follow-up (screening) and diagnosed with type 2 diabetes at least 8 weeks before the first follow-up

[0122] (For subjects who took hypoglycemic drugs within 8 weeks before the first follow-up (screening), the test results of the testing agency must be 6.5% ≤ HbA1c ≤ 10% before the follow-up (screening), and the test results at the first follow-up (screening) after the drug washout period must be 7% ≤ HbA1c* ≤ 10%.)

[0123] *Test results from either the testing house or the central testing laboratory are available. The final decision is made based on the central laboratory results, but before the central laboratory results are confirmed for the import process, if the test results from the testing house are suitable, the import can proceed.

[0124] 3. Those who meet FPG < 270 mg / dL before follow-up (before screening) and at the first follow-up (screening)

[0125] 4. BMI was 20 to 45 kg / m before follow-up (before screening) and at the first follow-up (screening) 2 People

[0126] 5. Those who have been on a stable diet and exercise program for at least 8 weeks before the first follow-up (screening)

[0127] 6. After listening to the explanation of the purpose, methods and effects of this clinical trial, the person who voluntarily decides to participate and gives written consent

[0128] Inclusion criteria for the second follow-up (randomization)

[0129] 1. According to the test results of the first follow-up (screening), people with HbA1c 7% ≤ HbA1c ≤ 10%

[0130] 2. Those with a confirmed run-in placebo compliance rate of 70 to 130% at the second follow-up (randomization)

[0131] [Exclusion criteria]

[0132] Exclusion criteria before follow-up (pre-screening) or at the first follow-up (screening)

[0133] 1. Those who have a history of illness or allergy to drugs and ingredients (including the clinical trial drugs in this test or any similar drugs) (for example, those who have a history of allergy to SGLT2 inhibitor drugs, etc.)

[0134] 2. Those with the following medical history or surgery / treatment history

[0135] Have a history of medically significant renal disease: renal vascular occlusive disease, nephrectomy, renal transplantation, etc.

[0136] History of major gastrointestinal surgery: total gastrectomy, total colectomy, small bowel resection, gastrointestinal anastomosis, gastrointestinal diversion, etc.

[0137] History of acute pancreatitis or pancreatic surgery

[0138] History of bariatric surgery within the past 2 years

[0139] Diabetic ketoacidosis, diabetic coma, or prodromal coma within the past year

[0140] Urinary tract infection or genital infection within the past year

[0141] Alcohol or drug abuse in the past year

[0142] Acute coronary syndrome, unstable angina, myocardial infarction requiring hospitalization, stroke, transient ischemic attack, or cardiac arrhythmia within the past 24 weeks

[0143] (However, those who have been ill for more than 24 weeks and are currently cured or in stable condition are allowed to participate.)

[0144] People who have had a history of major surgery that caused electrolyte imbalance within the past 12 weeks, or who plan to have major surgery within 12 weeks after the end of the clinical trial

[0145] 3. People with the following diseases or symptoms

[0146] Types of diabetes other than type 2 diabetes (type 1 diabetes, secondary diabetes, or congenital renal diabetes)

[0147] Symptoms of incontinence, anuria, oliguria, and urinary retention that are not controlled by medication due to stress incontinence, neurogenic bladder, and benign prostatic hyperplasia

[0148] Severe complications of diabetes (proliferative diabetic retinopathy, grade 4 or higher kidney disease (nephropathy), or severe diabetic neuropathy)

[0149] Chronic conditions that require ongoing use of diuretics (oral, injectable, or inhaled), systemic steroids, or immunosuppressants

[0150] Serious infection (eg, requiring continued antibiotics or immunotherapy), clinically significant major trauma

[0151] Unstable mental illness whose symptoms are not controlled by medication

[0152] Severe gastrointestinal diseases: active ulcers, gastrointestinal / rectal bleeding, active inflammatory bowel syndrome, patients with biliary obstruction, active gastritis that cannot be controlled by drugs, etc.

[0153] Uncontrolled hypertension (SBP>180 mmHg or DBP>110 mmHg)

[0154] Patients with moderate to severe renal disease (eGFR < 60 mL / min / 1.73 m2)

[0155] Patients with severe liver impairment who fall into one of the following categories:

[0156] -AST or ALT > three times the upper limit of normal

[0157] -Total bilirubin > twice the upper limit of normal

[0158] - Hepatitis or liver failure

[0159] Patients with severe hypertriglyceridemia (triglycerides >500 mg / dL)

[0160] Acquired Immune Deficiency Syndrome

[0161] Severe heart failure (NYHA class III-IV)

[0162] People who need treatment for dehydration due to persistent diarrhea or vomiting, or who are at risk of fluid depletion

[0163] 4. Patients who have used other clinical trial drugs / medical devices in the past 4 weeks (However, if the investigator believes that these studies are unlikely to affect the efficacy and safety of the trial, such as observational or retrospective studies, recruitment is allowed.)

[0164] 5. Patients with a history of malignant tumors in the past 5 years

[0165] However, patients with adequately controlled basal cell carcinoma, squamous cell carcinoma, or cervical intraepithelial carcinoma were allowed to participate.

[0166] However, if there has been no recurrence for more than 5 years after complete cure (time such as complete removal of the tumor by surgery or completion of chemotherapy), participation is possible.

[0167] 6. Pregnant or breastfeeding women or women who do not agree to use appropriate contraceptive measures during clinical trials

[0168] * Appropriate contraceptive measures for the subject or his / her partner: one of the following should be agreed:

[0169] ① One of the sterilization surgeries (vasectomy, etc.), intrauterine device (copper ring, hormone-containing intrauterine system),

[0170] ② A combination of non-oral hormonal contraceptives or spermicides and a barrier method, or

[0171] ③ Combination of cervical cap or diaphragm and male condom

[0172] 7. Persons deemed by the investigator to be ineligible for this clinical trial

[0173] Exclusion criteria for the first follow-up (screening)

[0174] 1. Those who have a history of taking the following drugs or are expected to need to take the following drugs continuously during clinical trials

[0175] Use of systemic steroids (more than 30 mg prednisolone per day) within the past 2 weeks

[0176] Diabetes medications in the past 8 weeks

[0177] Patients whose dose of any medication has been changed due to thyroid dysfunction in the past 6 weeks (combination therapy is allowed when the dose is stable before participating in the clinical trial; dose reduction is allowed when stable.)

[0178] Taking weight loss medications within the past 12 weeks

[0179] 2. Experimental results

[0180] Description of experimental results

[0181] 1) Change in HbA1c at Week 24 after administration of clinical trial drug compared to the second follow-up (randomization)

[0182] The primary efficacy endpoint of this clinical trial was "change in HbA1c from baseline (second follow-up) at week 24 after taking the clinical trial drug". After analysis of covariance (ANCOVA) using baseline values ​​and stratification factors (taking hypoglycemic drugs within 24 weeks before obtaining written consent, HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, the least squares mean (LS mean (SE)) of the change in HbA1c was -0.88 (0.10)% p in the test group and 0.11 (0.11)% p in the control group, and the between-group difference (LS mean difference (95% CI)) was -0.99 (-1.24, -0.74)% p, showing a statistically significant difference, indicating the superiority of the test group over the control group (p<0.0001).

[0183] As a result of confirming the trend of HbA1c change over time after administration of the clinical trial drug, the HbA1c level decreased over time in the test group, but first decreased and then increased in the control group.

[0184] [Table 1]

[0185]

[0186] 2) Changes in HbA1c at each time point of 6, 12, and 18 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0187] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in HbA1c change (LS mean difference (95% CI)) were 0.52 (-0.65, -0.39)% p at week 6, -0.71 (-0.89, -0.54)% p at week 12, and -0.79 (-1.00, -0.58)% p at week 18, and the between-group differences at all time points were statistically significant (p<0.0001).

[0188] [Table 2]

[0189] Change from baseline in HbA1c at weeks 6, 12, and 18—LOCF (full analysis set)

[0190]

[0191]

[0192]

[0193] 3) Changes in FPG at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0194] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in FPG changes (LS mean difference (95% CI)) were -26.91 (-33.19, -20.63) mg / dL at week 6, -32.26 (-39.69, -24.82) mg / dL at week 12, -33.40 (-41.59, -25.22) mg / dL at week 18, and -40.08 (-49.39, -30.77) mg / dL at week 24, and the between-group differences at all time points were statistically significant (p<0.0001).

[0195] [Table 3]

[0196] Change from baseline in FPG at weeks 6, 12, 18, and 24—LOCF (full analysis set)

[0197]

[0198]

[0199]

[0200]

[0201] 4) The proportion of subjects achieving HbA1c < 7% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0202] After logistic regression analysis adjusted for stratification factors, the results showed that compared with the control group, the odds ratio (95% CI) of achieving HbA1c < 7% in the test group was 6.55 (2.92, 14.70) at week 6, 6.53 (3.11, 13.70) at week 12, 4.85 (2.34, 10.07) at week 18, and 9.08 (4.27, 19.31) at week 24, and the differences between the groups at all time points were statistically significant (p < 0.0001).

[0203] [Table 4]

[0204] Proportion of subjects achieving HbA1c target <7% at Weeks 6, 12, 18, and 24 - LOCF (Full Analysis Set)

[0205]

[0206]

[0207] 5) The proportion of subjects achieving HbA1c < 6.5% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0208] After logistic regression analysis adjusted for stratification factors, the results showed that compared with the control group, the odds ratio (95% CI) of achieving HbA1c < 6.5% in the test group was 3.29 (1.00, 10.83) at week 6, 7.58 (2.43, 23.65) at week 12, 5.58 (2.09, 14.90) at week 18, and 12.10 (3.90, 37.53) at week 24. The differences between the groups at all time points were statistically significant (p = 0.0498 at week 6, p = 0.0005 at week 12, p = 0.0006 at week 18, and p < 0.0001 at week 24).

[0209] [Table 5]

[0210] Proportion of subjects achieving HbA1c target <6.5% at Weeks 6, 12, 18, and 24 - LOCF (Full Analysis Set)

[0211]

[0212]

[0213] 6) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0214] After logistic regression analysis adjusted for stratification factors, the results showed that the odds ratio (95% CI) of achieving treatment response in the test group was 12.84 (5.76, 28.63) at week 6, 14.77 (6.57, 33.17) at week 12, 7.45 (3.48, 15.95) at week 18, and 12.98 (5.78, 29.15) at week 24, compared with the control group. The differences between the groups at all time points were statistically significant (p<0.0001).

[0215] [Table 6]

[0216] Proportion of Subjects Achieving a Therapeutic Glycemic Response at Weeks 6, 12, 18, and 24—LOCF (Full Analysis Set)

[0217]

[0218]

[0219] 7) Changes in fasting C-peptide (FAS) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0220] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences (LS mean difference (95% CI)) in the change in fasting C-peptide between the control and test groups were -0.11 (-0.17, -0.06) ng / dL at week 6, -0.12 (-0.18, -0.06) ng / dL at week 12, -0.11 (-0.16, -0.05) ng / dL at week 18, and -0.13 (-0.18, -0.07) ng / dL at week 24, and the differences between all time points were statistically significant.

[0221] [Table 7]

[0222] Change from baseline in fasting C-peptide at weeks 6, 12, 18, and 24—LOCF (full analysis set)

[0223]

[0224]

[0225]

[0226]

[0227] 8) Changes in body weight (FAS) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0228] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in weight change (LS mean difference (95% CI)) were -1.45 (-1.93, -0.97) kg at week 6, -1.66 (-2.35, -0.96) kg at week 12, -2.37 (-3.14, -1.60) kg at week 18, and -2.47 (-3.30, -1.63) kg at week 24, and the between-group differences at all time points were statistically significant.

[0229] [Table 8]

[0230] Change in Body Weight from Baseline at Weeks 6, 12, 18, and 24—LOCF (Full Analysis Set)

[0231]

[0232]

[0233]

[0234]

[0235] 9) Changes in fasting lipid concentrations (triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0236] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in total cholesterol changes (LS mean difference (95% CI)) were 1.95 (-4.54, 8.43) mg / dL at week 6, -4.04 (-11.86, 3.77) mg / dL at week 12, -0.99 (-8.33, 6.34) mg / dL at week 18, and -6.40 (-14.63, 1.83) mg / dL at week 24, showing no statistically significant differences at any time point.

[0237] [Table 9]

[0238] Changes from Baseline in Fasting Lipid Parameters at Weeks 6, 12, 18, and 24—LOCF (Modified Full Analysis Set 1) [Total Cholesterol]

[0239]

[0240]

[0241]

[0242] 10) Changes in fasting lipid concentration (LDL-C) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0243] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in LDL-C changes (LS mean difference (95% CI)) were 0.64 (-5.12, 6.41) mg / dL at week 6, -6.00 (-12.58, 0.57) mg / dL at week 12, -2.35 (-8.59, 3.89) mg / dL at week 18, and -6.91 (-13.54, -0.28) mg / dL at week 24, showing statistically significant differences at week 24.

[0244] [Table 10]

[0245] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 - LOCF (modified full analysis set 1) [LDL-C]

[0246]

[0247]

[0248]

[0249] 11) Changes in fasting lipid concentration (HDL-C) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0250] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in HDL-C changes (LS mean difference (95% CI)) were 1.89 (0.15, 3.64) mg / dL at week 6, 2.36 (0.11, 4.62) mg / dL at week 12, 2.69 (0.64, 4.74) mg / dL at week 18, and 4.05 (1.71, 6.38) mg / dL at week 24, and the between-group differences were statistically significant at all time points.

[0251] [Table 11]

[0252] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 - LOCF (modified full analysis set 1) [HDL-C]

[0253]

[0254]

[0255]

[0256] 12) Changes in fasting lipid concentrations (triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0257] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in triglyceride changes (LS mean difference (95% CI)) were -17.69 (-34.78, -0.60) mg / dL at week 6, -10.37 (-28.69, 7.95) mg / dL at week 12, -17.74 (-39.45, 3.98) mg / dL at week 18, and -28.56 (-54.04, -3.07) mg / dL at week 24, showing statistically significant differences at weeks 6 and 24.

[0258] [Table 12]

[0259] Changes from Baseline in Fasting Lipid Parameters at Weeks 6, 12, 18, and 24—LOCF (Modified Full Analysis Set 1) [Triglycerides]

[0260]

[0261]

[0262]

[0263] 13) Changes in systolic blood pressure at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0264] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in systolic BP change (LS mean difference (95% CI)) were -4.07 (-6.90, -1.23) mmHg at week 6, -3.06 (-6.21, 0.09) mmHg at week 12, -3.36 (-6.62, -0.10) mmHg at week 18, and -5.75 (-9.39, -2.11) mmHg at week 24, and the between-group differences were statistically significant at all time points except week 12.

[0265] [Table 13]

[0266] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 - LOCF (modified full analysis set 2) [Systolic blood pressure]

[0267]

[0268]

[0269]

[0270]

[0271] 14) Changes in diastolic blood pressure at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0272] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in diastolic BP change (LS mean difference (95% CI)) were -2.43 (-4.65, -0.22) mmHg at week 6, -2.33 (-4.53, -0.14) mmHg at week 12, -1.90 (-3.98, 0.18) mmHg at week 18, and -3.12 (-5.46, -0.77) mmHg at week 24, and the between-group differences were statistically significant at all time points except week 18.

[0273] [Table 14]

[0274] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 - LOCF (revised full analysis set 2) [diastolic blood pressure]

[0275]

[0276]

[0277]

[0278]

[0279] 15) Changes in beta-cell function measured by HOMA-β at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0280] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in HOMA-β changes (LS mean difference (95% CI)) were 3.30 (-3.49, 10.09) at week 6, 12.09 (-0.52, 24.70) at week 12, 22.40 (-7.93, 52.73) at week 18, and 5.88 (-2.31, 14.06) at week 24, showing no statistically significant differences between the groups at any time point.

[0281] [Table 15]

[0282] Change from baseline in beta-cell function at weeks 6, 12, 18, and 24 - LOCF (full analysis set) [HOMA-β]

[0283]

[0284]

[0285]

[0286]

[0287] 16) Changes in insulin resistance measured by HOMA-IR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the 2nd follow-up (randomization)

[0288] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in HOMA-IR change (LS mean difference (95% CI)) were -1.81 (-2.73, -0.89) at week 6, -1.72 (-2.32, -1.13) at week 12, -1.49 (-2.01, -0.96) at week 18, and -1.94 (-2.52, -1.37) at week 24, and the between-group differences were statistically significant at all time points.

[0289] [Table 16]

[0290] Change from baseline in insulin resistance at weeks 6, 12, 18, and 24 - LOCF (full analysis set) [HOMA-IR]

[0291]

[0292]

[0293]

[0294]

[0295] 17) Changes in renal function-related indices measured by UACR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0296] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in UACR change (LS mean difference (95% CI)) were 7.96 (-19.51, 35.43) g / kg at week 6, -15.16 (-53.39, 23.06) g / kg at week 12, -13.39 (-37.46, 10.68) g / kg at week 18, and -13.92 (-41.03, 13.19) g / kg at week 24, showing no statistically significant differences between the groups at any time point.

[0297] [Table 17]

[0298] Changes from Baseline in Renal Function Parameters at Weeks 6, 12, 18, and 24—LOCF (Full Analysis Set) [UACR]

[0299]

[0300]

[0301]

[0302]

[0303] 18) Changes in renal function-related indices measured by UGCR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0304] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in UGCR changes (LS mean difference (95% CI)) were 52.97 (46.70, 59.25) mg / mg at week 6, 51.21 (45.41, 57.00) mg / mg at week 12, 47.66 (42.32, 53.01) mg / mg at week 18, and 47.36 (42.25, 52.48) mg / mg at week 24, and the between-group differences at all time points were statistically significant.

[0305] [Table 18]

[0306] Change from baseline in renal function parameters at weeks 6, 12, 18, and 24 - LOCF (full analysis set) [UGCR]

[0307]

[0308]

[0309]

[0310] 19) Changes in obesity-related indices measured by adiponectin at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0311] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in adiponectin changes (LS mean difference (95% CI)) were 0.26 (-0.72, 1.24) μg / mL at week 6, 0.67 (-0.50, 1.83) μg / mL at week 12, 1.04 (0.04, 2.05) μg / mL at week 18, and 0.98 (-0.05, 2.00) μg / mL at week 24, showing statistically significant differences between the groups at week 18.

[0312] [Table 19]

[0313] Change from Baseline in Adiposity Parameters at Weeks 6, 12, 18, and 24 - LOCF (Full Analysis Set) [Adiponectin]

[0314]

[0315]

[0316]

[0317] 20) Changes in obesity-related indices measured by leptin at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0318] After ANCOVA using baseline values ​​and stratification factors as covariates, the between-group differences in leptin changes (LS mean difference (95% CI)) were -2.89 (-4.30, -1.47) ng / mL at week 6, -3.17 (-4.66, -1.68) ng / mL at week 12, -2.36 (-3.58, -1.14) ng / mL at week 18, and -2.99 (-4.30, -1.68) ng / mL at week 24, and the between-group differences were statistically significant at all time points.

[0319] [Table 20]

[0320] Change from Baseline in Adiposity Parameters at Weeks 6, 12, 18, and 24 - LOCF (Full Analysis Set) [Leptin]

[0321]

[0322]

[0323]

[0324] 3. Conclusion

[0325] As a result of the efficacy evaluation, the test group was shown to be superior to the control group in terms of the change in HbA1c from baseline (2nd follow-up) at week 24 after the administration of the clinical trial drug, which is the primary efficacy endpoint. In addition, after the administration of the clinical trial drug, the items showing statistically significant differences in the test group at all time points from baseline compared with the control group were the items of the secondary endpoints, as well as the changes in fasting C-peptide, body weight, fasting HDL-C, HOMA-IR, UGCR, and leptin in the exploratory endpoints. In addition, among the exploratory endpoints, the changes in LDL-C (at week 24), triglycerides (at weeks 6 and 12), systolic blood pressure (at weeks 6, 18, and 24), diastolic blood pressure (at weeks 6, 12, and 24), and adiponectin (at week 18) in the test group showed statistically significant differences compared with the control group at certain time points.

[0326] To summarize the results of the efficacy evaluation, the HbA1c and FPG evaluations confirmed that after administration, Enagagliflozin had a blood sugar control effect, and the proportion of subjects reaching HbA1c <7% or HbA1c <6.5% (which is the treatment target recommended by the diabetes treatment guidelines) was also statistically significant, indicating that Enagagliflozin has the potential to become an effective treatment for diabetes as a monotherapy. In addition, some of the items in the exploratory evaluation were statistically significant, indicating that it had an indirect improvement effect on insulin resistance and obesity-related indicators.

[0327] In the safety evaluation results, there was no statistically significant difference in the incidence of adverse events or adverse drug reactions, serious adverse events or serious adverse drug reactions, or adverse events that must be carefully monitored compared with the control group, and there were no adverse events or adverse drug reactions that led to discontinuation of the clinical trial drug, and no adverse events or adverse drug reactions that led to death. Except for "periodontitis", "bone marrow suppression" and "skin ulcers", all adverse drug reactions (PTs) that occurred in this clinical trial were previously reported for the investigational drug enagliflozin and similar drugs, among which "pyelonephritis" and "skin ulcers" were adverse events that occurred in the control group but not in the test group.

[0328] Based on the above, the efficacy and safety of enagliflozin monotherapy in patients with type 2 diabetes were confirmed, thereby determining that enagliflozin can be used as an effective therapeutic agent for monotherapy of diabetes.

[0329] Example 2: Combination administration of enagliflozin and metformin to patients with type 2 diabetes

[0330] 1. Research process

[0331] Patients with type 2 diabetes mellitus who, despite having received metformin at a constant dose (≥ 1000 mg / day) for at least 8 weeks before the first follow-up (screening), have inadequate glycemic control (7% < HbA1c ≤ 10.5% at screening) may participate in the trial. Patients with type 2 diabetes mellitus who are taking metformin and other hypoglycemic agents at the time of screening may participate in the trial after a washout period of at least 8 weeks (56 days), including discontinuation of hypoglycemic agents other than metformin.

[0332] During the 2-week lead-in period, a placebo of the clinical trial drug was administered to subjects meeting the inclusion / exclusion criteria under single-blind (subjects were unaware) conditions while continuing metformin treatment. At the second follow-up (randomization), subjects meeting the final inclusion / exclusion criteria and having a compliance of 70% to 130% with the placebo and metformin during the lead-in period were randomly assigned to the test group (empagliflozin 0.3 mg) or the control group (dapagliflozin 10 mg) at a ratio of 1:1. Randomized subjects in each treatment group took two tablets of the clinical trial drug daily and were then institutionally followed up at weeks 6, 12, 18, and 24 during the 24-week treatment period for efficacy and safety evaluations.

[0333] [Inclusion Criteria]

[0334] Inclusion criteria before follow-up (pre-screening) or at the first follow-up (screening)

[0335] 1. Patients with type 2 diabetes mellitus aged 19 to 80 years as of the date of obtaining written consent

[0336] 2. Patients who have received monotherapy with fixed-dose metformin (≥ 1,000 mg / day) for at least 8 weeks before the first follow-up (screening) and have 7% ≤ HbA1c* ≤ 10.5% at the first follow-up (screening)

[0337] (Subjects taking fixed-dose metformin (≥ 1,000 mg / day) and other hypoglycemic agents must have 6.5% ≤ HbA1c ≤ 10% before follow-up (before screening) and 7% ≤ HbA1c* ≤ 10.5% at the first follow-up (screening) after the washout period.)

[0338] (*Results from the testing institution or central laboratory are available. The final decision is made based on the results of the central laboratory, but before confirmation of the lead-in period results from the central laboratory, if the results from the testing institution are appropriate, the lead-in period is allowed to continue.)

[0339] 3. Patients with FPG < 270 mg / dL before follow-up (before screening) and at the first follow-up (screening)

[0340] 4. Patients with a BMI of 20 to 45 kg / m 2 at the time of follow-up (before screening) and at the first follow-up (screening)

[0341] 5. After listening to the explanation of the purpose, methods and effects of this clinical trial, the person who voluntarily decides to participate and gives written consent

[0342] Inclusion criteria for the second follow-up (randomization)

[0343] 1. Patients with HbA1c ≤ 7% ≤ 10.5% tested in the central laboratory at the first follow-up (screening)

[0344] 2. Patients who demonstrated compliance of 70% to 130% with placebo and metformin during the run-in period at the second follow-up (randomization)

[0345] [Exclusion criteria]

[0346] Exclusion criteria before follow-up (pre-screening) or at the first follow-up (screening)

[0347] 1. Those who have a history of medical history or hypersensitivity to drug ingredients including the clinical trial drugs in this trial, metformin, or any other drugs of the same class (for example, those with a history of allergy to biguanides and SGLT2 inhibitors, etc.)

[0348] 2. Those with the following medical history or surgery / treatment history

[0349] Medically significant history of renal disease: renal vascular occlusive disease, nephrectomy, renal transplantation, etc.

[0350] History of major gastrointestinal surgery: total gastrectomy, total colectomy, small bowel resection, gastrointestinal anastomosis, gastrointestinal bypass, etc.

[0351] History of acute pancreatitis or pancreatic surgery

[0352] History of bariatric surgery within the past 2 years

[0353] Diabetic ketoacidosis, diabetic coma, or prodromal coma within the past year

[0354] Urinary tract infection or genital infection within the past year

[0355] Alcohol or drug abuse in the past year

[0356] Acute coronary syndrome, unstable angina, myocardial infarction requiring hospitalization, stroke, transient ischemic attack, or cardiac arrhythmia within the past 24 weeks

[0357] (However, those who had the disease before 24 weeks and are currently cured or in stable condition can participate)

[0358] People who have had a history of major surgery that caused electrolyte imbalance within the past 12 weeks, or who plan to have major surgery within 12 weeks after the end of the clinical trial

[0359] Lactic acidosis or a history of lactic acidosis

[0360] 3. People with the following diseases or symptoms

[0361] Types of diabetes other than type 2 diabetes (type 1 diabetes, secondary diabetes, or congenital renal diabetes)

[0362] Symptoms of incontinence, anuria, oliguria, and urinary retention that are not controlled by medication due to stress incontinence, neurogenic bladder, and benign prostatic hyperplasia

[0363] Severe complications of diabetes (proliferative diabetic retinopathy, grade 4 or higher kidney disease, or severe diabetic neuropathy)

[0364] Chronic conditions that require ongoing use of diuretics (oral, injectable, or inhaled), systemic steroids, or immunosuppressants

[0365] Pituitary insufficiency or adrenal insufficiency

[0366] Serious infection (eg, requiring continued antibiotics or immunotherapy), clinically significant major trauma

[0367] Unstable mental illness whose symptoms are not controlled by medication

[0368] Severe gastrointestinal diseases: active ulcers, gastrointestinal / rectal bleeding, active inflammatory bowel syndrome, patients with biliary obstruction, active gastritis that cannot be controlled by drugs, etc.

[0369] Uncontrolled hypertension (SBP>180 mmHg or DBP>110 mmHg)

[0370] Patients with moderate to severe renal disease (eGFR < 60 mL / min / 1.73 m 2 )

[0371] Patients with severe liver impairment who fall into one of the following categories:

[0372] -AST or ALT > three times the upper limit of normal

[0373] -Total bilirubin > twice the upper limit of normal

[0374] - Hepatitis or liver failure

[0375] Patients with severe hypertriglyceridemia (triglycerides >500 mg / dL)

[0376] Acquired Immune Deficiency Syndrome

[0377] Severe heart failure (NYHA class III / IV)

[0378] Patients with pulmonary infarction, severe pulmonary dysfunction, and others who are susceptible to hypoxemia

[0379] People who need treatment for dehydration due to persistent diarrhea or vomiting, or who are at risk of fluid depletion

[0380] People with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

[0381] 4. Patients who have used other clinical trial drugs / medical devices in the past 4 weeks (However, recruitment is allowed if the investigator believes that it is unlikely to affect the effectiveness and safety of the study, such as observational or retrospective studies.)

[0382] 5. Patients with a history of malignant tumors in the past 5 years

[0383] -However, patients with adequately controlled basal cell carcinoma, squamous cell carcinoma, or cervical intraepithelial carcinoma were allowed to participate.

[0384] - However, participation is only possible if there has been no recurrence for more than 5 years after complete cure (complete removal of the tumor by surgery or completion of chemotherapy, etc.)

[0385] 6. Pregnant or breastfeeding women or women who do not agree to use appropriate contraceptive measures during clinical trials

[0386] Appropriate contraceptive method for the subject or his / her partner: should agree to one of the following:

[0387] ① One of the following: sterilization surgery (vasectomy, etc.), intrauterine device (copper ring, hormone-containing intrauterine system),

[0388] ② A combination of non-oral hormonal contraceptives or spermicides and a barrier method, or

[0389] ③ Combination of cervical cap or diaphragm and male condom

[0390] 7. Persons deemed by the investigator to be ineligible for this clinical trial

[0391] Exclusion criteria for the first follow-up (screening)

[0392] 1.1. Patients who have a history of taking the following drugs or are expected to need to take the following drugs continuously during clinical trials have used systemic steroids (more than 30 mg prednisolone per day) in the past 2 weeks

[0393] Patients whose dose of any medication has been changed due to thyroid dysfunction in the past 6 weeks (combination medication is allowed when the dose is stable before participating in the clinical trial; dose reduction is allowed when stable)

[0394] Diabetes medications other than metformin in the past 8 weeks

[0395] Weight loss medications taken in the past 12 weeks

[0396] Validation variables

[0397] [Primary efficacy endpoint]

[0398] 1. Change in HbA1c at Week 24 after administration of clinical trial drug compared to the second follow-up (randomization)

[0399] [Secondary efficacy endpoints]

[0400] 1. Change in HbA1c at each time point of 6, 12, and 18 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0401] 2. Changes in FPG at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0402] 3. The proportion of subjects achieving HbA1c < 7% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0403] 4. The proportion of subjects achieving HbA1c < 6.5% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0404] 5. Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0405] [Exploratory endpoint]

[0406] 1. Change in fasting C-peptide at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0407] 2. Changes in body weight at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0408] 3. Changes in fasting lipid concentrations (total cholesterol, LDL-C, HDL-C, and triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0409] 4. Changes in systolic or diastolic blood pressure at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0410] 5. Changes in β-cell function and insulin resistance as measured by HOMA-β and HOMA-IR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the 2nd follow-up (randomization)

[0411] 6. Changes in renal function-related indices (UACR, UGCR) measured by UACR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0412] 7. Changes in obesity-related indicators (adiponectin, leptin) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared with the second follow-up (randomization)

[0413] 1. Experimental results

[0414] 1.1.1.1. Primary efficacy endpoint

[0415] 1) Change in HbA1c at Week 24 after administration of clinical trial drug compared to the second follow-up (randomization)

[0416] Table 21 shows the summary results of the change in HbA1c in the PPS at Week 24 after taking the clinical trial drug, which was the primary efficacy endpoint in this clinical trial.

[0417] The results of analysis of covariance (ANCOVA) of PPS showed that with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the wash-out period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, the least squares means (LS mean (SE)) of the HbA1c changes compared with baseline at week 24 after administration of the clinical trial drug were -0.80 (0.06)% p in the test group (enagliflozin, 0.3 mg) and -0.75 (0.06)% p in the control group (dapagliflozin, 10 mg), and the between-group difference (LS mean difference (95% CI)) was -0.04 (-0.21, 0.12)% p. The upper limit of the 95% confidence interval of [test group-control group] is 0.12%p, which is less than the non-inferiority margin of 0.35, indicating that the test group is not inferior to the control group.

[0418] The change (SD) in HbA1c between the administration groups was -0.78 (0.73) %p in the test group and -0.71 (0.76) %p in the control group, and there was a statistically significant difference between the two groups (p<0.0001).

[0419] [Table 21]

[0420] Change from baseline in HbA1c at week 24 (per protocol)

[0421]

[0422]

[0423] SD = standard deviation, Min = minimum, Max = maximum, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error, UCI = upper confidence interval. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0424] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0425] Note: Baseline is Visit 2 (Randomization).

[0426] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0427] At each evaluation time point after administration of the clinical trial drug, changes in HbA1c in the PPS relative to baseline (second follow-up) were examined, and the results showed that both groups showed a trend of decreasing or maintaining over time.

[0428] Secondary Efficacy End Points

[0429] 1) Changes in HbA1c at each time point at 6, 12, and 18 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0430] Table 22 presents summary results of the change from baseline in HbA1c in the PPS at Weeks 6, 12, and 18 after administration of the clinical trial drug.

[0431] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means of the changes in HbA1c from baseline at different time points after the administration of the clinical trial drugs were calculated using the baseline value and the stratification factors (i.e., the conventional regimen of hypoglycemic drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any hypoglycemic drugs except metformin) and the HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. (LS mean (SE)) At week 6, the test group (enagliflozin, 0.3 mg) was -0.68 (0.04)% p, and the control group (dapagliflozin, 10 mg) was -0.63 (0.04)% p; at week 12, the test group was -0.83 (0.06)% p, and the control group was -0.79 (0.05)% p; at week 18, the test group was -0.74 (0.06)% p, and the control group was -0.70 (0.06)% p. The inter-group differences (LS mean difference / test group - control group (95% CI)) were -0.05 (-0.16, 0.06)% p at week 6, -0.03 (-0.17, 0.11)% p at week 12, and -0.05 (-0.21, 0.11)% p at week 18, indicating that no statistically significant differences were observed between the groups at any time point (p = 0.3806 at week 6, p = 0.6604 at week 12, and p = 0.5606 at week 18).

[0432] The changes in HbA1c over time (SD) were -0.62 (0.39)% p in the test group and -0.58 (0.51)% p in the control group at week 6, -0.77 (0.55)% p in the test group and -0.74 (0.69)% p in the control group at week 12, and -0.71 (0.67)% p in the test group and -0.66 (0.76)% p in the control group at week 18, indicating that the differences between the groups were statistically significant (p<0.0001) at all time points and in all administration groups.

[0433] [Table 22]

[0434] Change from baseline in HbA1c at weeks 6, 12, and 18 (per protocol)

[0435]

[0436]

[0437]

[0438] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0439] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0440] Note: Baseline is Visit 2 (Randomization).

[0441] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0442] 2) Changes in FPG at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0443] Table 23 shows the summary results of the change from baseline in FPG in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0444] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least squares means (LS means (SE)) of the changes in FPG from baseline at different time points after the administration of the clinical trial drugs were -28.0 for the test group (enagliflozin, 0.3 mg) at week 6, with the baseline value and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the wash-out period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. 7 (2.14) mg / dL, and the control group (dapagliflozin, 10 mg) was -23.81 (2.23) mg / dL. At week 12, the test group was -29.70 (1.96) mg / dL, and the control group was -30.11 (2.03) mg / dL. At week 18, the test group was -33.44 (1.60) mg / dL, and the control group was -31.13 (1.63) mg / dL. At week 24, the test group was -32.53 (1.76) mg / dL, and the control group was -29.14 (1.82) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -4.27 (-10.08, 1.55) mg / dL at week 6, 0.42 (-4.90, 5.74) mg / dL at week 12, -2.31 (-6.62, 2.00) mg / dL at week 18, and -3.38 (-8.15, 1.39) mg / dL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.1491 at week 6, p = 0.8765 at week 12, p = 0.2911 at week 18, and p = 0.1633 at week 24).

[0445] The FPG changes (SD) over time were -26.91 (22.00) mg / dL in the test group and -24.90 (28.02) mg / dL in the control group at week 6, -27.74 (24.23) mg / dL in the test group and -31.89 (31.22) mg / dL in the control group at week 12, -31.78 (23.46) mg / dL in the test group and -32.55 (26.20) mg / dL in the control group at week 18, and -31.77 (23.03) mg / dL in the test group and -31.42 (30.03) mg / dL in the control group at week 24, indicating that the differences between the groups were statistically significant (p<0.0001) at all time points and in all administration groups.

[0446] [Table 23]

[0447] Changes from baseline in FPG at weeks 6, 12, 18, and 24 (per protocol)

[0448]

[0449]

[0450]

[0451]

[0452] FPG = fasting plasma glucose, SD = standard deviation, Min = minimum, Max = maximum, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0453] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0454] Note: Baseline is Visit 2 (Randomization).

[0455] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0456] 3) The proportion of subjects achieving HbA1c < 7% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0457] Table 24 shows the summary results of the proportion of subjects achieving HbA1c < 7% in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0458] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering medication except metformin), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed an odds ratio (95% CI) of achieving HbA1c <7% in the test group (enagaliflozin, 0.3 mg) compared with the control group (dapagliflozin, 10 mg). CI) at different time points were: 1.06 (0.54, 2.09) at week 6, 1.21 (0.63, 2.34) at week 12, 1.29 (0.67, 2.46) at week 18, and 0.97 (0.52, 1.83) at week 24, indicating that there were no statistically significant differences between the groups at all time points (p = 0.8592 at week 6, p = 0.5678 at week 12, p = 0.4413 at week 18, and p = 0.9366 at week 24).

[0459] Over time, the proportion of subjects achieving HbA1c < 7% was 53.68% (51 / 95) in the test group and 51.69% (46 / 89) in the control group at week 6, 68.09% (64 / 94) in the test group and 63.64% (56 / 88) in the control group at week 12, 62.64% (57 / 91) in the test group and 57.47% (50 / 87) in the control group at week 18, and 61.05% (58 / 95) in the test group and 62.22% (56 / 90) in the control group at week 24.

[0460] [Table 24]

[0461] Proportion of subjects achieving HbA1c target <7% at Weeks 6, 12, 18, and 24 (Per Protocol)

[0462]

[0463]

[0464] Proportion = number of subjects with HbA1c below 7% at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] Test the difference between DWP16001 and dapagliflozin (logistic regression model with treatment group as factor and stratification factors (regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0465] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0466] 4) The proportion of subjects achieving HbA1c < 6.5% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0467] Table 25 shows the summary results of the proportion of subjects achieving HbA1c < 6.5% in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0468] Logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering medication except metformin), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed an odds ratio (95% CI) of achieving HbA1c < 6.5% in the test group (enanagliflozin, 0.3 mg) compared with the control group (dapagliflozin, 10 mg). CI) at different time points were: 0.83 (0.35, 1.97) at week 6, 0.51 (0.24, 1.09) at week 12, 0.31 (0.13, 0.72) at week 18, and 0.40 (0.19, 0.86) at week 24, indicating that there were statistically significant differences between the groups at weeks 18 and 24 (p = 0.6733 at week 6, p = 0.0819 at week 12, p = 0.0068 at week 18, and p = 0.0188 at week 24).

[0469] At each time point, the proportion of subjects achieving HbA1c < 6.5% was 12.63% (12 / 95) in the test group and 14.61% (13 / 89) in the control group at week 6, 15.96% (15 / 94) in the test group and 26.14% (23 / 88) in the control group at week 12, 9.89% (9 / 91) in the test group and 25.29% (22 / 87) in the control group at week 18, and 13.68% (13 / 95) in the test group and 27.78% (25 / 90) in the control group at week 24.

[0470] [Table 25]

[0471] Proportion of subjects achieving HbA1c target <6.5% at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0472]

[0473]

[0474] Proportion = number of subjects with HbA1c below 7% at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] Test the difference between DWP16001 and dapagliflozin (logistic regression model with treatment group as factor and stratification factors (regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0475] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0476] 5) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0477] Table 26 shows the summary results of the proportion of subjects achieving a treatment response in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0478] Logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering medication except metformin), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed that the odds ratio (95% CI) of achieving a treatment response in the test group (enagaliflozin, 0.3 mg) was significantly higher than that in the control group (dapagliflozin, 10 mg). CI) at different time points were: 0.98 (0.47, 2.02) at week 6, 2.04 (0.89, 4.66) at week 12, 1.58 (0.76, 3.28) at week 18, and 1.30 (0.63, 2.68) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.9484 at week 6, p = 0.0917 at week 12, p = 0.2197 at week 18, and p = 0.4776 at week 24).

[0479] Over time, the proportion of subjects achieving treatment response was 78.95% (75 / 95) in the test group and 79.78% (71 / 89) in the control group at week 6, 88.30% (83 / 94) in the test group and 79.55% (70 / 88) in the control group at week 12, 80.22% (73 / 91) in the test group and 73.56% (64 / 87) in the control group at week 18, and 78.95% (75 / 95) in the test group and 75.56% (68 / 90) in the control group at week 24.

[0480] [Table 26]

[0481] Proportion of Subjects Achieving a Therapeutic Glycemic Response at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0482]

[0483]

[0484]

[0485] Proportion = number of subjects achieving a therapeutic glycemic response at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] Test the difference between DWP16001 and dapagliflozin (logistic regression model with treatment group as a factor and stratification factors (regimen [monotherapy or combination therapy] and HbA1c level [<8% or ≥8%] at the first follow-up [screening]) as covariates).

[0486] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0487] Exploratory End Points

[0488] 1) Changes in fasting C-peptide at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0489] Table 27 shows the summary results of the change from baseline in fasting C-peptide in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0490] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in fasting C-peptide from baseline at different time points after the administration of the clinical trial drug were -0.1% for the test group (enagliflozin, 0.3 mg) at week 6, with the baseline value and stratification factors (i.e., conventional regimen of antidiabetic drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any antidiabetic drugs other than metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 12, the test group was -0.08 (0.02) ng / mL, and the control group was -0.09 (0.02) ng / mL. At week 18, the test group was -0.07 (0.18) ng / mL, and the control group was -0.06 (0.19) ng / mL. At week 24, the test group was -0.10 (0.16) ng / mL, and the control group was -0.04 (0.26) ng / mL. The between-group differences (LS mean difference / test group - control group (95% CI)) were 0.00 (-0.05, 0.04) ng / mL at week 6, 0.01 (-0.05, 0.06) ng / mL at week 12, -0.02 (-0.07, 0.03) ng / mL at week 18, and -0.06 (-0.12, 0.00) ng / mL at week 24. Only at week 24 did the between-group differences show statistically significant differences (p = 0.9601 at week 6, p = 0.8086 at week 12, p = 0.3689 at week 18, and p = 0.0355 at week 24).

[0491] The changes (SD) of fasting C-peptide over time were: at week 6, the test group was -0.06 (0.19) ng / mL, and the control group was -0.07 (0.18) ng / mL; at week 12, the test group was -0.07 (0.21) ng / mL, and the control group was -0.08 (0.18) ng / mL; at week 18, the test group was -0.07 (0.18), and the control group was -0.06 (0.19); at week 24, the test group was -0.10 (0.16) ng / mL, and the control group was -0.04 (0.26) ng / mL, showing statistically significant inter-group differences at all time points and all administration groups (p=0.0001 in the test group and the control group at week 6, p<0.0001 in the test group and the control group at week 12, p=0.0002 in the test group and p=0.0003 in the control group at week 18, p<0.0001 in the test group and p=0.0016 in the control group at week 24).

[0492] [Table 27]

[0493] Change from baseline in fasting C-peptide at weeks 6, 12, 18, and 24 (per protocol)

[0494]

[0495]

[0496]

[0497]

[0498] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0499] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0500] Note: Baseline is Visit 2 (Randomization).

[0501] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0502] 2) Changes in body weight at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0503] Table 28 shows the summary results of the change from baseline in body weight in the PPS at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0504] Results of the analysis of covariance (ANCOVA) for the PPS showed that the least square means (LS means (SE)) of the changes in body weight from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enager) and At week 12, the test group was -2.81 (0.23) kg, and the control group was -2.63 (0.23) kg. At week 18, the test group was -3.14 (0.26) kg, and the control group was -3.16 (0.26) kg. At week 24, the test group was -3.77 (0.33) kg, and the control group was -3.58 (0.34) kg. The between-group differences (LS mean difference / test group - control group (95% CI)) were 0.04 (-0.51, 0.59) kg at week 6, -0.19 (-0.81, 0.44) kg at week 12, 0.02 (-0.68, 0.71) kg at week 18, and -0.18 (-1.08, 0.71) kg at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.8846 at week 6, p = 0.5548 at week 12, p = 0.9590 at week 18, and p = 0.6840 at week 24).

[0505] The changes in body weight (SD) over time were -1.56 (2.30) kg in the test group and -1.60 (1.25) kg in the control group at week 6, -2.78 (2.48) kg in the test group and -2.61 (1.66) kg in the control group at week 12, -3.17 (2.68) kg in the test group and -3.19 (1.93) kg in the control group at week 18, and -3.78 (3.77) kg in the test group and -3.60 (2.14) kg in the control group at week 24, indicating that the differences between the groups were statistically significant (p<0.0001) at all time points and in all administration groups.

[0506] [Table 28]

[0507] Change in Body Weight from Baseline at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0508]

[0509]

[0510]

[0511]

[0512] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0513] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0514] Note: Baseline is Visit 2 (Randomization).

[0515] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0516] 3) Changes in fasting lipid concentrations (total cholesterol, LDL-C, HDL-C, and triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0517] ①Total cholesterol

[0518] Table 29 shows summary results for change from baseline in total cholesterol in the modified per-protocol set 1 (mPPS1) at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0519] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least squares means (LS means (SE)) of the changes in total cholesterol from baseline at different time points after administration of the clinical trial drugs were compared with the baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 At week 12, the test group was 7.26 (1.98) mg / dL and the control group was 4.25 (2.04) mg / dL. At week 18, the test group was 7.80 (2.16) mg / dL and the control group was 9.57 (2.20) mg / dL. At week 24, the test group was 9.13 (2.22) mg / dL and the control group was 6.74 (2.30) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -2.10 (-8.16, 3.95) mg / dL at week 6, 3.01 (-2.45, 8.46) mg / dL at week 12, -1.77 (-7.69, 4.15) mg / dL at week 18, and 2.40 (-3.74, 8.53) mg / dL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.4940 at week 6, p = 0.2784 at week 12, p = 0.5560 at week 18, and p = 0.4422 at week 24).

[0520] The changes in total cholesterol (SD) over time were: at week 6, the test group was 4.34 (17.75) mg / dL and the control group was 7.71 (22.44) mg / dL; at week 12, the test group was 5.74 (18.70) mg / dL and the control group was 5.47 (18.88) mg / dL; at week 18, the test group was 6.23 (16.54) mg / dL and the control group was 10.18 (22.74) mg / dL; at week 24, the test group was 7.99 (20.78) mg / dL and the control group was 8.85 (21.77) mg / dL; at week 5 ) mg / dL, and the control group was 9.15 (22.59) mg / dL, showing statistically significant inter-group differences at all time points and all administration groups (at week 6, p=0.0371 in the test group and p=0.0027 in the control group, at week 12, p=0.0010 in the test group and p=0.0003 in the control group, at week 18, p=0.0007 in the test group and p<0.0001 in the control group, at week 24, p<0.0001 in both the test group and the control group).

[0521] [Table 29]

[0522] Changes from Baseline in Fasting Lipid Parameters at Weeks 6, 12, 18, and 24 (Modified Per-Protocol Set 1) [Total Cholesterol]

[0523]

[0524]

[0525]

[0526] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0527] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0528] Note: Baseline is Visit 2 (Randomization).

[0529] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0530] ②LDL-C

[0531] Table 30 shows the summary results of the change from baseline in LDL-C in mPPS1 at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0532] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least squares means (LS means (SE)) of the changes in LDL-C from baseline at different time points after administration of the clinical trial drugs were compared with the baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 At week 12, the test group was 1.86 (1.68) mg / dL, and the control group was 0.56 (1.73) mg / dL. At week 18, the test group was 1.42 (1.86) mg / dL, and the control group was 2.58 (1.89) mg / dL. At week 24, the test group was 1.64 (1.92) mg / dL, and the control group was 0.93 (1.98) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -4.29 (-9.49, 0.90) mg / dL at week 6, 1.30 (-3.31, 5.92) mg / dL at week 12, -1.15 (-6.22, 3.91) mg / dL at week 18, and 0.71 (-4.56, 5.99) mg / dL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.1045 at week 6, p = 0.5783 at week 12, p = 0.6536 at week 18, and p = 0.7898 at week 24).

[0533] The changes in LDL-C over time (SD) were: at week 6, the test group was -0.67 (15.12) mg / dL, and the control group was 4.87 (19.92) mg / dL; at week 12, the test group was 0.78 (16.26) mg / dL, and the control group was 1.33 (16.02) mg / dL; at week 18, the test group was 0.50 (14.20) mg / dL, and the control group was 3.27 (20.01) mg / dL; at week 24, the test group was 0.88 (17.04) mg / dL. g / dL in the test group and 2.68 (20.64) mg / dL in the control group. Only in the 6th week did the control group show a statistically significant difference between the groups (at the 6th week, p=0.3026 in the test group and p=0.0469 in the control group, at the 12th week, p=0.5116 in the test group and p=0.1260 in the control group, at the 18th week, p=0.9665 in the test group and p=0.0798 in the control group, at the 24th week, p=0.2948 in the test group and p=0.1171 in the control group).

[0534] [Table 30]

[0535] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [LDL-C]

[0536]

[0537]

[0538]

[0539]

[0540] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0541] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0542] Note: Baseline is Visit 2 (Randomization).

[0543] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0544] ③HDL-C

[0545] Table 31 shows the summary results of the change from baseline in HDL-C in mPPS1 at Weeks 6, 1, 2, 18, and 24 after administration of clinical trial drug.

[0546] The results of analysis of covariance (ANCOVA) for mPPS1 showed that the baseline value and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) were used as covariates. The least squares means (LS means (SE)) of the changes in HDL-C from baseline at different time points after the administration of the clinical trial drugs were significantly different at week 6. At week 12, the test group was 2.31 (0.60) mg / dL, and the control group was 2.25 (0.62) mg / dL. At week 18, the test group was 2.46 (0.66) mg / dL, and the control group was 3.08 (0.67) mg / dL. At week 24, the test group was 3.06 (0.64) mg / dL, and the control group was 3.19 (0.66) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -0.49 (-2.10, 1.12) mg / dL at week 6, 0.06 (-1.59, 1.72) mg / dL at week 12, -0.62 (-2.42, 1.19) mg / dL at week 18, and -0.14 (-1.90, 1.63) mg / dL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.5500 at week 6, p = 0.9405 at week 12, p = 0.4996 at week 18, and p = 0.8788 at week 24).

[0547] The changes in HDL-C over time (SD) were: at week 6, the test group was 1.18 (5.14) mg / dL, and the control group was 1.94 (5.62) mg / dL; at week 12, the test group was 2.08 (5.60) mg / dL, and the control group was 2.65 (5.61) mg / dL; at week 18, the test group was 1.89 (6.20) mg / dL, and the control group was 3.17 (5.82) mg / dL; at week 24, the test group was 2.75 (6.70) mg / dL, The control group was 3.55 (5.30) mg / dL, showing statistically significant inter-group differences at all time points and all administration groups (at week 6, p=0.0290 in the test group and p=0.0037 in the control group, at week 12, p=0.0006 in the test group and p<0.0001 in the control group, at week 18, p=0.0054 in the test group and p<0.0001 in the control group, at week 24, p=0.0001 in the test group and p<0.0001 in the control group).

[0548] [Table 31]

[0549] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [HDL-C]

[0550]

[0551]

[0552]

[0553] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0554] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0555] Note: Baseline is Visit 2 (Randomization).

[0556] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0557] ④Triglycerides

[0558] Table 32 shows the summary results of the change from baseline in triglycerides in mPPS1 at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0559] The results of analysis of covariance (ANCOVA) for mPPS1 showed that the least squares means (LS means (SE)) of the changes in triglycerides from baseline at different time points after the administration of the clinical trial drugs were as follows: baseline value and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) were used as covariates. At week 6, the test group (enagliflozin, 0.3 mg) was At week 12, the test group was -7.53 (4.80) mg / dL, and the control group was -10.10 (4.92) mg / dL. At week 18, the test group was -4.99 (5.99) mg / dL, and the control group was 1.88 (6.04) mg / dL. At week 24, the test group was -5.07 (5.14) mg / dL, and the control group was -6.70 (5.28) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were 18.76 (-0.01, 37.53) mg / dL at week 6, 2.57 (-10.49, 15.62) mg / dL at week 12, -6.87 (-23.09, 9.34) mg / dL at week 18, and 1.63 (-12.36, 15.63) mg / dL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.0501 at week 6, p = 0.6984 at week 12, p = 0.4038 at week 18, and p = 0.8181 at week 24).

[0560] The changes in triglycerides (SD) over time were: at week 6, the test group was 9.49 (73.63) mg / dL, and the control group was -11.86 (54.93) mg / dL; at week 12, the test group was -5.00 (57.85) mg / dL, and the control group was -14.35 (70.12) mg / dL; at week 18, the test group was -2.70 (78.86) mg / dL, and the control group was -4.10 (62.62) mg / dL; at week 24, the test group was -2.47 (76.88) mg / dL / dL, and the control group was -10.64 (52.51) mg / dL, and no statistically significant between-group differences were shown at any time point or in any administration group (at week 6, p = 0.8181 in the test group and p = 0.1343 in the control group, at week 12, p = 0.7179 in the test group and p = 0.0965 in the control group, at week 18, p = 0.9181 in the test group and p = 0.3730 in the control group, at week 24, p = 0.7295 in the test group and p = 0.0749 in the control group).

[0561] [Table 32]

[0562] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [Triglycerides]

[0563]

[0564]

[0565]

[0566]

[0567] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0568] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0569] Note: Baseline is Visit 2 (Randomization).

[0570] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0571] 4) Changes in systolic or diastolic blood pressure at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0572] ① Systolic blood pressure (SBP)

[0573] Table 33 shows summary results for the change from baseline in systolic blood pressure in the modified per-protocol set 2 (mPPS2) at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0574] Results of analysis of covariance (ANCOVA) for mPPS2 showed that the least squares means (LS means (SE)) of the changes in systolic blood pressure from baseline at different time points after administration of the clinical trial drug were compared with the baseline value and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 At week 12, the test group was -5.86 (1.04) mmHg, and the control group was -6.12 (1.07) mmHg. At week 18, the test group was -6.69 (1.12) mmHg, and the control group was -5.97 (1.15) mmHg. At week 24, the test group was -5.93 (1.01) mmHg, and the control group was -6.57 (1.04) mmHg. The between-group differences (LS mean difference / test group-control group (95% CI)) were -0.58 (-3.40, 2.23) mmHg at week 6, 0.26 (-2.59, 3.10) mmHg at week 12, -0.72 (-3.78, 2.34) mmHg at week 18, and 0.63 (-2.13, 3.39) mmHg at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.6824 at week 6, p = 0.8582 at week 12, p = 0.6433 at week 18, and p = 0.6512 at week 24).

[0575] The changes in systolic blood pressure (SD) over time were: at week 6, the test group was -3.28 (9.34) mmHg, and the control group was -1.98 (11.14) mmHg; at week 12, the test group was -6.42 (9.73) mmHg, and the control group was -5.86 (11.46) mmHg; at week 18, the test group was -7.04 (10.51) mmHg, and the control group was -5.43 (12.97) mmHg; at week 24, the test group was -6.34 (9.75) mmHg mmHg, and the control group was -6.03 (12.13) mmHg, showing statistically significant inter-group differences at all time points and in all administration groups except the control group at week 6 (p=0.0010 in the test group and p=0.1035 in the control group at week 6, p<0.0001 in the test group and the control group at week 12, p<0.0001 in the test group and p=0.0002 in the control group at week 18, and p<0.0001 in the test group and the control group at week 24).

[0576] [Table 33]

[0577] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 (modified per-protocol set 2) [Systolic blood pressure]

[0578]

[0579]

[0580]

[0581]

[0582] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0583] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0584] Note: Baseline is Visit 2 (Randomization).

[0585] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0586] ② Diastolic blood pressure

[0587] Table 34 shows summary results for the change from baseline in diastolic blood pressure in the modified per-protocol set 2 (mPPS2) at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0588] Results of analysis of covariance (ANCOVA) for mPPS2 showed that the least squares means (LS means (SE)) of the changes in diastolic blood pressure from baseline at different time points after administration of the clinical trial drugs were compared with the baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 At week 12, the test group was -4.19 (0.79) mmHg and the control group was -4.35 (0.81) mmHg. At week 18, the test group was -4.80 (0.78) mmHg and the control group was -4.10 (0.81) mmHg. At week 24, the test group was -5.41 (0.65) mmHg and the control group was -4.26 (0.67) mmHg. The between-group differences (LS mean difference / test group-control group (95% CI)) were -1.28 (-3.18, 0.63) mmHg at week 6, 0.16 (-2.00, 2.32) mmHg at week 12, -0.70 (-2.85, 1.45) mmHg at week 18, and -1.15 (-2.94, 0.63) mmHg at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.1879 at week 6, p = 0.8819 at week 12, p = 0.5201 at week 18, and p = 0.2044 at week 24).

[0589] The diastolic blood pressure changes (SD) over time were: at week 6, the test group was -2.80 (6.99) mmHg, and the control group was -1.10 (7.02) mmHg; at week 12, the test group was -4.33 (7.69) mmHg, and the control group was -4.06 (8.78) mmHg; at week 18, the test group was -5.05 (6.71) mmHg, and the control group was -3.94 (9.82) mmHg; at week 24, the test group was -5.40 (5.94) mmHg Hg, and the control group was -3.87 (7.93) mmHg, showing statistically significant inter-group differences at all time points and in all administration groups except the control group at week 6 (p = 0.0002 in the test group and p = 0.2694 in the control group at week 6, p < 0.0001 in the test group and the control group at week 12, p < 0.0001 in the test group and p = 0.0004 in the control group at week 18, and p < 0.0001 in the test group and the control group at week 24).

[0590] [Table 34]

[0591] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 (modified per-protocol set 2) [diastolic blood pressure]

[0592]

[0593]

[0594]

[0595] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0596] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0597] Note: Baseline is Visit 2 (Randomization).

[0598] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0599] 5) Changes in β-cell function and insulin resistance as measured by HOMA-β and HOMA-IR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the 2nd follow-up (randomization)

[0600] ①β-cell function measured by HOMA-β

[0601] Table 35 shows the summary results of the change from baseline in HOMA-β in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0602] Results of the analysis of covariance (ANCOVA) for the PPS showed that the least square means (LS means (SE)) of the changes in HOMA-β from baseline at different time points after the administration of the clinical trial drugs were 1.04 ± 1.03, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 mg) was 7.22 (5.44), and the control group (dapagliflozin, 10 mg) was -1.79 (5.59); at week 12, the test group was 5.57 (3.08), and the control group was 8.75 (3.15); at week 18, the test group was 10.97 (3.06), and the control group was 13.49 (3.08); at week 24, the test group was 6.94 (3.17), and the control group was 11.93 (3.25). The between-group differences (LS mean difference / test group-control group (95% CI)) were 9.01 (-5.78, 23.80) at week 6, -3.17 (-11.52, 5.17) at week 12, -2.53 (-10.76, 5.71) at week 18, and -4.99 (-13.60, 3.62) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.2307 at week 6, p = 0.4542 at week 12, p = 0.5459 at week 18, and p = 0.2545 at week 24).

[0603] The changes (SD) of HOMA-β over time were as follows: at week 6, the test group was 5.87 (22.04) and the control group was -2.83 (69.39); at week 12, the test group was 5.59 (26.08) and the control group was 8.97 (32.68); at week 18, the test group was 10.63 (28.28) and the control group was 13.46 (27.25); at week 24, the test group was 6.80 (28.34) and the control group was 12.23 (3 1.72), showing statistically significant inter-group differences in all time points and all administration groups except the control group at week 6 (p<0.0001 in the test group and p=0.1818 in the control group at week 6, p=0.0003 in the test group and p=0.0027 in the control group at week 12, p<0.0001 in the test group and control group at week 18, and p=0.0069 in the test group and p=0.0002 in the control group at week 24).

[0604] [Table 35]

[0605] Change from baseline in beta-cell function at weeks 6, 12, 18, and 24 (per protocol) [HOMA-β]

[0606]

[0607]

[0608]

[0609]

[0610] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0611] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0612] Note: Baseline is Visit 2 (Randomization).

[0613] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0614] ② Detecting insulin resistance through HOMA-IR

[0615] Table 36 shows the summary results of the change from baseline in HOMA-IR in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0616] The results of analysis of covariance (ANCOVA) of PPS showed that the least square means (LS means (SE)) of the changes in HOMA-IR from baseline at different time points after the administration of the clinical trial drugs were significantly different in the first follow-up (screening) with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the wash-out period of any glucose-lowering drugs except metformin) and HbA1c level (<8% or ≥8%) at the first follow-up (screening) as covariates. At 6 weeks, the test group (enagliflozin, 0.3 mg) was -1.47 (0.14), and the control group (dapagliflozin, 10 mg) was -1.31 (0.15); at 12 weeks, the test group was -1.58 (0.17) and the control group was -1.60 (0.17); at 18 weeks, the test group was -1.79 (0.11) and the control group was -1.47 (0.12); at 24 weeks, the test group was -1.85 (0.13) and the control group was -1.31 (0.14). The between-group differences (LS mean difference / test group-control group (95% CI)) were -0.16 (-0.55, 0.22) at week 6, 0.02 (-0.43, 0.47) at week 12, -0.32 (-0.63, -0.01) at week 18, and -0.53 (-0.90, -0.17) at week 24, indicating that there were statistically significant differences between the groups only at weeks 18 and 24 (p = 0.4053 at week 6, p = 0.9442 at week 12, p = 0.0420 at week 18, and p = 0.0041 at week 24).

[0617] The changes in HOMA-IR over time (SD) were -1.35 (3.16) in the test group and -1.46 (1.88) in the control group at week 6, -1.36 (3.30) in the test group and -1.74 (2.16) in the control group at week 12, -1.58 (3.10) in the test group and -1.61 (2.09) in the control group at week 18, and -1.69 (2.98) in the test group and -1.47 (2.30) in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups (p<0.0001).

[0618] [Table 36]

[0619] Change from baseline in insulin resistance at weeks 6, 12, 18, and 24 (per-protocol) [HOMA-IR]

[0620]

[0621]

[0622]

[0623] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0624] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0625] Note: Baseline is Visit 2 (Randomization).

[0626] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0627] 6) Changes in renal function-related indicators (UACR, UGCR) at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared with the second follow-up (randomization)

[0628] ①UACR

[0629] Table 37 shows the summary results of the change from baseline in UACR in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0630] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in UACR from baseline at different time points after the administration of the clinical trial drugs were as follows: baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) were used as covariates. At week 6, the test group (enagliflozin, 0.3 mg) was -12.75 (10.48) g / kg, and the control group (dapagliflozin, 10 mg) was 8.13 (10.88) g / kg. At week 12, the test group was -21.65 (7.38) g / kg, and the control group was -3.38 (7.57) g / kg. At week 18, the test group was -23.05 (5.06) g / kg, and the control group was -12.95 (5.11) g / kg. At week 24, the test group was -24.29 (3.38) g / kg, and the control group was -17.37 (3.48) g / kg. The inter-group differences (LS mean difference / test group-control group (95% CI)) were -20.88 (-49.57, 7.82) at week 6, -18.27 (-38.36, 1.82) at week 12, -10.10 (-23.81, 3.61) at week 18, and -6.93 (-16.14, 2.29) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.1528 at week 6, p = 0.0744 at week 12, p = 0.1479 at week 18, and p = 0.1399 at week 24).

[0631] The changes in UACR over time (SD) were as follows: at week 6, the test group was -11.44 (123.47) g / kg, and the control group was 4.49 (84.95) g / kg; at week 12, the test group was -18.55 (130.70) g / kg, and the control group was -8.38 (40.82) g / kg; at week 18, the test group was -17.48 (143.19) g / kg, and the control group was -20.54 (102.64) g / kg; at week 24, the test group was -18.27 (144.42) g / kg, and the control group was -25. .76 (128.93) g / kg, showing statistically significant inter-group differences in all time points and all administration groups except the test group and control group at week 6 and the test group at week 18 (p = 0.7353 in the test group and p = 0.7282 in the control group at week 6, p = 0.0070 in the test group and p = 0.0090 in the control group at week 12, p = 0.0656 in the test group and p = 0.0067 in the control group at week 18, p = 0.0270 in the test group and p = 0.0013 in the control group at week 24).

[0632] [Table 37]

[0633] Changes from baseline in renal function parameters at weeks 6, 12, 18, and 24 (per protocol) [UACR]

[0634]

[0635]

[0636]

[0637]

[0638] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0639] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0640] Note: Baseline is Visit 2 (Randomization).

[0641] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0642] ②UGCR

[0643] Table 38 shows the summary results of the change from baseline in UGCR in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0644] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in UGCR from baseline at different time points after the administration of the clinical trial drugs were 6 for the test group (enagliflozin, 0.3 mg) at week 6, with the baseline value and stratification factors (i.e., the usual regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. 5.72 (2.70) mg / mg, and the control group (dapagliflozin, 10 mg) was 50.10 (2.80) mg / mg. At week 12, the test group was 64.70 (2.58) mg / mg, and the control group was 45.14 (2.66) mg / mg. At week 18, the test group was 60.97 (2.13) mg / mg, and the control group was 42.72 (2.15) mg / mg. At week 24, the test group was 60.48 (2.12) mg / mg, and the control group was 44.94 (2.18) mg / mg. The between-group differences (LS mean difference / test group-control group (95% CI)) were 15.62 (8.25, 23.00) mg / mg at week 6, 19.57 (12.55, 26.58) mg / mg at week 12, 18.25 (12.50, 24.00) mg / mg at week 18, and 15.54 (9.77, 21.31) mg / mg at week 24, indicating that the between-group differences were statistically significant at all time points (p<0.0001).

[0645] The changes (SD) of UGCR over time were 63.13 (24.93) mg / mg in the test group and 47.54 (26.73) mg / mg in the control group at week 6, 63.04 (24.63) mg / mg in the test group and 43.59 (23.33) mg / mg in the control group at week 12, 59.41 (19.10) mg / mg in the test group and 41.06 (21.79) mg / mg in the control group at week 18, and 58.90 (20.59) mg / mg in the test group and 43.01 (20.50) mg / mg in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points (p<0.0001).

[0646] [Table 38]

[0647] Changes from baseline in renal function parameters at weeks 6, 12, 18, and 24 (per protocol) [UGCR]

[0648]

[0649]

[0650]

[0651]

[0652] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0653] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0654] Note: Baseline is Visit 2 (Randomization).

[0655] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0656] 7) Changes in obesity-related indicators (adiponectin, leptin) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0657] ① Adiponectin

[0658] Table 39 shows the summary results of the change from baseline in adiponectin in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0659] Results of the analysis of covariance (ANCOVA) for the PPS showed that the least square means (LS means (SE)) of the changes in adiponectin from baseline at different time points after administration of the clinical trial drugs were compared using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 m g) was 0.92 (0.28) ng / mL, and the control group (dapagliflozin, 10 mg) was 0.80 (0.29) ng / mL. At week 12, the test group was 0.84 (0.27) ng / mL, and the control group was 1.02 (0.27) ng / mL. At week 18, the test group was 1.33 (0.28) ng / mL, and the control group was 1.29 (0.29) ng / mL. At week 24, the test group was 1.67 (0.31) ng / mL, and the control group was 1.69 (0.32) ng / mL. The between-group differences (LS mean difference / test group-control group (95% CI)) were 0.13 (-0.65, 0.90) ng / mL at week 6, -0.19 (-0.91, 0.54) ng / mL at week 12, 0.04 (-0.74, 0.81) ng / mL at week 18, and -0.02 (-0.87, 0.84) ng / mL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.7474 at week 6, p = 0.6107 at week 12, p = 0.9266 at week 18, and p = 0.9688 at week 24).

[0660] The changes (SD) of adiponectin over time were: at week 6, the test group was 0.84 (3.17) ng / mL and the control group was 0.77 (2.20) ng / mL; at week 12, the test group was 0.90 (2.61) ng / mL and the control group was 1.08 (2.33) ng / mL; at week 18, the test group was 1.26 (2.49) ng / mL and the control group was 1.28 (2.77) ng / mL; at week 24, the test group was 1.72 (3.03) ng / mL and the control group was 1.72 (2.78) ng / mL, showing statistically significant inter-group differences at all time points and all administration groups (p=0.0010 in the test group and p=0.0007 in the control group at week 6, and p<0.0001 in the test group and control group at weeks 12, 18 and 24).

[0661] [Table 39]

[0662] Changes from baseline in adiposity parameters at weeks 6, 12, 18, and 24 (per protocol) [Adiponectin]

[0663]

[0664]

[0665]

[0666] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0667] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0668] Note: Baseline is Visit 2 (Randomization).

[0669] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0670] ② Leptin

[0671] Table 40 shows the summary results of the change from baseline in leptin in the PPS at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0672] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in leptin from baseline at different time points after the administration of the clinical trial drugs, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, were -2 in the test group (enagliflozin, 0.3 mg) at week 6. .43 (0.46) ng / mL, and the control group (dapagliflozin, 10 mg) was -1.62 (0.47) ng / mL. At week 12, the test group was -2.64 (0.49) ng / mL, and the control group was -2.70 (0.51) ng / mL. At week 18, the test group was -2.49 (0.52) ng / mL, and the control group was -1.23 (0.53) ng / mL. At week 24, the test group was -2.40 (0.51) ng / mL, and the control group was -1.28 (0.53) ng / mL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -0.81 (-2.05, 0.44) ng / mL at week 6, 0.07 (-1.28, 1.41) ng / mL at week 12, -1.26 (-2.68, 0.16) ng / mL at week 18, and -1.12 (-2.51, 0.27) ng / mL at week 24, indicating that there was no statistically significant between-group difference at any time point (p = 0.2035 at week 6, p = 0.9233 at week 12, p = 0.0825 at week 18, and p = 0.1151 at week 24).

[0673] The changes in leptin over time (SD) were -2.54 (4.67) ng / mL in the test group and -1.61 (4.75) ng / mL in the control group at week 6, -2.73 (4.67) ng / mL in the test group and -2.70 (5.87) ng / mL in the control group at week 12, -2.50 (4.99) ng / mL in the test group and -1.20 (5.47) ng / mL in the control group at week 18, and -2.53 (4.17) ng / mL in the test group and -1.31 (6.08) ng / mL in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups (p<0.0001).

[0674] [Table 40]

[0675] Changes from baseline in adiposity parameters at weeks 6, 12, 18, and 24 (per protocol) [Leptin]

[0676]

[0677]

[0678]

[0679]

[0680] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0681] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [monotherapy or combination therapy] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0682] Note: Baseline is Visit 2 (Randomization).

[0683] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0684] 3. Conclusion

[0685] As a result of efficacy evaluation, the upper limit of the 95% confidence interval of the inter-group difference (LS mean difference / test group-control group) in the change from baseline in HbA1c (which is the primary efficacy endpoint) at week 24 after administration of the clinical trial drug was 0.12% p, which was less than the non-inferiority margin of 0.35, proving that the test group was not inferior to the control group. In addition, most secondary and exploratory endpoints, including FPG, showed similar results between the test group and the control group.

[0686] In the safety evaluation results, there was no statistically significant difference in the incidence of adverse events or serious adverse events between the test group and the control group. There was a significant between-group difference in the incidence of serious adverse drug reactions, but the incidence was higher in the control group (1 case in the test group and 7 cases in the control group). In addition, the incidence of serious adverse events and adverse events that require careful monitoring (hypoglycemia, urinary tract infection, genital infection, polyuria, and urgency) in the test group tended to be lower than that in the control group, although there was no significant difference in the incidence. All adverse drug reactions that occurred were adverse events previously reported in SGLT2 inhibitor-based drugs. However, in this clinical trial, an adverse event (PT name: prostate cancer) occurred in the control group, leading to discontinuation of the clinical trial drug, but it has been confirmed that this was not related to the clinical trial drug. In addition, there were no serious adverse drug reactions, adverse drug reactions that led to discontinuation of clinical trial drugs, adverse events leading to death, or adverse drug reactions. Except for one adverse event related to vital signs (PT name: hypertension), there were no clinically significant findings in other safety evaluation items.

[0687] Based on the above, the efficacy and safety of enagliflozin were confirmed in combination treatment with metformin in patients with type 2 diabetes who had poor glycemic control on metformin, indicating that enagliflozin is an effective diabetes treatment drug when administered in combination with metformin.

[0688] Example 3: Combination treatment with enagliflozin, metformin and gemagliptin in patients with type 2 diabetes

[0689] 1. Research process

[0690] 1) When metformin (≥1,000 mg / day) was administered at a constant dose for at least 8 weeks before the follow-up (before screening)

[0691] : During the 8-week stabilization period, metformin (≥1000 mg / day) and gemagliptin (50 mg / day) were administered in combination.

[0692] 2) When metformin (<1,000 mg / day) and oral hypoglycemic drugs were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening)

[0693] : During a dose-escalation period of up to 4 weeks, metformin was increased to at least 1000 mg / day, followed by an 8-week stabilization period with combination therapy of metformin (≥1000 mg / day) and gemagliptin (50 mg / day), in addition to a washout period of oral hypoglycemic agents.

[0694] 3) When metformin (≥1,000 mg / day) and oral hypoglycemic drugs (except gemagliptin) were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening)

[0695] : Metformin (≥1000 mg / day) and gemigliptin (50 mg / day) were co-administered during an 8-week stabilization period, with a washout period for another oral hypoglycemic agent administered in combination with metformin.

[0696] 4) When metformin (≥1,000 mg / day) and gemigliptin (50 mg / day) were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening)

[0697] : There is no separate stabilization period, and the period before follow-up (before screening) is the first follow-up (screening).

[0698] In each case, patients with type 2 diabetes who were screened and showed inadequate glycemic control at the first follow-up (screening) visit were enrolled in the clinical trial.

[0699] [Introduction period]

[0700] Subjects who met the inclusion / exclusion criteria continued to receive metformin and gemagliptin, and also received placebo of the clinical trial drug in a single-blind (unknown to the subject) state during a 2-week run-in period. Subjects who met the final inclusion / exclusion criteria and whose compliance with placebo, metformin, and gemagliptin during the run-in period was 70% to 130%, respectively, were randomized at the second follow-up (randomization).

[0701] [Treatment period]

[0702] At the second follow-up, the subjects were centrally randomized in a 1:1 ratio to one of the test group (enagliflozin, 0.3 mg) and the control group (dapagliflozin, 10 mg). In this article, the randomly assigned subjects were stratified according to the administration of conventional hypoglycemic drugs (before washing out another hypoglycemic drug) within 24 weeks before obtaining written informed consent (administered in combination with two or fewer drugs (one or two drugs) or three or more drugs), and the HbA1c value (<8% or ≥8%) at the first follow-up (screening) measured in the central laboratory.

[0703] The randomly assigned subjects took two tablets of the clinical trial drug corresponding to each administration group every day, and then went to the institution for efficacy and safety evaluation at weeks 6, 12, 18, and 24 during the 24-week administration period. In addition, during the clinical trial, they were instructed to exercise regularly and control their diet without changing their daily living patterns.

[0704] [Inclusion criteria]

[0705] Inclusion criteria before follow-up (pre-screening) or first follow-up (screening)

[0706] 1. Patients with type 2 diabetes aged 19 to 80 years old as of the date of written consent

[0707] 2. Patients whose HbA1c before follow-up (before screening) was confirmed as follows:

[0708] 1) When metformin (≥1,000 mg / day) was administered at a constant dose for at least 8 weeks before follow-up (before screening): 7.5% ≤ HbA1c ≤ 11%

[0709] 2) When metformin (<1,000 mg / day) and oral hypoglycemic drugs were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening): 7.5% ≤ HbA1c ≤ 11%

[0710] 3) When metformin (≥1,000 mg / day) and oral hypoglycemic drugs (except gemagliptin) were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening): 7% ≤ HbA1c ≤ 11%

[0711] 4) 7% ≤ HbA1c ≤ 11% when metformin (≥ 1,000 mg / day) and gemigliptin (50 mg / day) were administered in combination at a constant dose for at least 8 weeks before follow-up (before screening)

[0712] 3. HbA1c 7% ≤ HbA1c* ≤ 11% at the first follow-up (screening)

[0713] (*Results from either the testing facility or the central laboratory are available. The final decision is made based on the central laboratory results, but until the central laboratory results are confirmed for import, the import is allowed to proceed if the testing facility results are appropriate.)

[0714] 4. Patients with FPG < 270 mg / dL before follow-up (before screening) and at the first follow-up (screening)

[0715] 5. BMI was 20 to 45 kg / m before follow-up (before screening) and at the first follow-up (screening) 2 Patients

[0716] 6. After listening to the explanation of the purpose, methods and effects of this clinical trial, the person who voluntarily decides to participate and gives written consent

[0717] Inclusion criteria for the second follow-up (randomization)

[0718] 1. Patients with HbA1c ≤ 7% ≤ 10.5% tested in the central laboratory at the first follow-up (screening)

[0719] 2. Patients who demonstrated compliance of 70% to 130% with placebo and metformin during the run-in period at the second follow-up (randomization)

[0720] [Exclusion criteria]

[0721] Exclusion criteria before follow-up (pre-screening) or first follow-up (screening)

[0722] 1. Those who have a history of or hypersensitivity to drug ingredients including the clinical trial drugs in this trial or any other drugs of the same class (e.g., a history of allergy to biguanides, DPP-4 inhibitors, and SGLT2 inhibitors).

[0723] 2. Those with the following medical history or surgery / treatment history

[0724] Medically significant history of renal disease: renal vascular occlusive disease, nephrectomy, renal transplantation, etc.

[0725] History of major gastrointestinal surgery: total gastrectomy, total colectomy, small bowel resection, gastrointestinal anastomosis, gastrointestinal bypass, etc.

[0726] History of acute pancreatitis or pancreatic surgery

[0727] History of bariatric surgery within the past 2 years

[0728] Diabetic ketoacidosis, diabetic coma, or prodromal coma within the past year

[0729] Recurrent urinary tract infections or genital infections requiring treatment within the past year

[0730] Alcohol or drug abuse in the past year

[0731] Acute coronary syndrome, unstable angina, myocardial infarction requiring hospitalization, stroke, transient ischemic attack, or cardiac arrhythmia within the past 24 weeks

[0732] (However, those who had the disease before 24 weeks and are currently cured or in stable condition can participate)

[0733] People who have had a history of major surgery that caused electrolyte imbalance within the past 12 weeks, or who plan to have major surgery within 12 weeks after the end of the clinical trial

[0734] People with lactic acidosis or a history of lactic acidosis

[0735] People with a history of Stevens-Johnson syndrome

[0736] 3. People with the following diseases or symptoms

[0737] Types of diabetes other than type 2 diabetes (type 1 diabetes, secondary diabetes, or congenital renal diabetes)

[0738] Symptoms of incontinence, anuria, oliguria, and urinary retention that are not controlled by medication due to stress incontinence, neurogenic bladder, and benign prostatic hyperplasia

[0739] Severe complications of diabetes (proliferative diabetic retinopathy, grade 4 or higher kidney disease, or severe diabetic neuropathy)

[0740] Chronic conditions that require ongoing use of diuretics (oral, injectable, or inhaled), systemic steroids, or immunosuppressants

[0741] Pituitary insufficiency or adrenal insufficiency

[0742] Serious infection (eg, requiring continued antibiotics or immunotherapy), clinically significant major trauma

[0743] Unstable mental illness whose symptoms are not controlled by medication

[0744] Severe gastrointestinal diseases: active ulcers, gastrointestinal / rectal bleeding, active inflammatory bowel syndrome, patients with biliary obstruction, active gastritis that cannot be controlled by drugs, etc.

[0745] Uncontrolled hypertension (SBP>180 mmHg or DBP>110 mmHg)

[0746] Patients with moderate to severe renal disease (eGFR < 60 mL / min / 1.73 m 2 )

[0747] Patients with severe liver impairment who fall into one of the following categories:

[0748] -AST or ALT > three times the upper limit of normal

[0749] -Total bilirubin > twice the upper limit of normal

[0750] - Hepatitis or liver failure

[0751] Patients with severe hypertriglyceridemia (triglycerides >500 mg / dL)

[0752] Acquired Immune Deficiency Syndrome

[0753] Severe heart failure (NYHA class II to IV)

[0754] Patients with pulmonary infarction, severe pulmonary dysfunction, and others who are susceptible to hypoxemia

[0755] People who need treatment for dehydration due to persistent diarrhea or vomiting, or who are at risk of fluid depletion

[0756] People with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

[0757] 4. Patients who have used other clinical trial drugs / medical devices in the past 4 weeks (however, recruitment is allowed if the investigator believes that it is unlikely to affect the effectiveness and safety of the study, such as observational or retrospective studies)

[0758] 5. Patients with a history of malignant tumors in the past 5 years

[0759] -However, patients with adequately controlled basal cell carcinoma, squamous cell carcinoma, or cervical intraepithelial carcinoma were allowed to participate.

[0760] - However, if there is no recurrence for more than 5 years after complete cure (complete removal of the tumor by surgery or completion of chemotherapy, etc.), you can participate. )

[0761] 6. Pregnant or breastfeeding women or women who do not agree to use appropriate contraceptive measures during clinical trials

[0762] Appropriate contraceptive method for the subject or his / her partner: should agree to one of the following:

[0763] ① One of the following: sterilization surgery (vasectomy, etc.), intrauterine device (copper ring, hormone-containing intrauterine system),

[0764] ② A combination of non-oral hormonal contraceptives or spermicides and a barrier method, or

[0765] ③ Combination of cervical cap or diaphragm and male condom

[0766] 7. Persons deemed by the investigator to be ineligible for this clinical trial

[0767] Exclusion criteria for the first follow-up (screening)

[0768] 1.1. Patients who have a history of taking the following drugs or are expected to need to take the following drugs continuously during clinical trials have used systemic steroids (more than 30 mg prednisolone per day) in the past 2 weeks

[0769] Patients whose dose of any medication has been changed due to thyroid dysfunction in the past 6 weeks (combination therapy is allowed when the dose is stable before participating in the clinical trial; dose reduction is allowed when stable)

[0770] Diabetes medications other than metformin in the past 8 weeks

[0771] Weight loss medications taken in the past 12 weeks

[0772] Patients who are expected to require continuous administration of oral hypoglycemic agents, excluding clinical trial drugs, concomitant medications (metformin and gemigliptin), and rescue medications during clinical trials

[0773] Primary Efficacy End Point

[0774] 1) Change in HbA1c at Week 24 after administration of clinical trial drug compared to the second follow-up (randomization)

[0775] Secondary Efficacy End Points

[0776] 1) Changes in HbA1c at each time point at 6, 12, and 18 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0777] 2) Changes in FPG at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0778] 3) The proportion of subjects achieving HbA1c < 7% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0779] 4) The proportion of subjects achieving HbA1c < 6.5% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0780] 5) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0781] 6) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.7% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0782] 7) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 1% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0783] Exploratory End Points

[0784] 1) Changes in fasting C-peptide at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0785] 2) Changes in body weight at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0786] 3) Changes in fasting lipid concentrations (total cholesterol, LDL-C, HDL-C, and triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0787] 4) Changes in systolic or diastolic blood pressure at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0788] 5) Changes in β-cell function and insulin resistance as measured by HOMA-β and HOMA-IR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the 2nd follow-up (randomization)

[0789] 6) Changes in renal function-related indices (UACR, UGCR) measured by UACR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0790] 7) Changes in obesity-related indicators (adiponectin, leptin) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0791] 8) Proportion of subjects receiving rescue medication at each time point of 6, 12, 18, and 24 weeks after administration of clinical trial drug

[0792] 2. Experimental results

[0793] Primary Efficacy End Point

[0794] 1) Change in HbA1c at Week 24 after administration of clinical trial drug compared to the second follow-up (randomization)

[0795] Table 41 shows the summary results of the change in HbA1c in the PPS at Week 24 after taking the clinical trial drug, which was the primary efficacy endpoint in this clinical trial.

[0796] The results of analysis of covariance (ANCOVA) of PPS showed that with baseline values ​​and stratification factors (i.e., conventional regimen of hypoglycemic drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the wash-out period of another hypoglycemic drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, the least squares mean (LS mean (SE)) of the change in HbA1c compared with baseline at week 24 after administration of the clinical trial drug was -0.92 (0.05)% p in the test group (enagliflozin, 0.3 mg) and -0.86 (0.05)% p in the control group (dapagliflozin, 10 mg), and the between-group difference (LS mean difference (95% CI)) was -0.06 (-0.19, 0.06)% p. The upper limit of the 95% confidence interval of [test group-control group] is 0.12%p, which is less than the non-inferiority margin of 0.35, indicating that the test group is not inferior to the control group.

[0797] The change (SD) of HbA1c between the administration groups was -0.93 (0.70) %p in the test group and -0.89 (0.65) %p in the control group, and there was a statistically significant difference between the two groups (p<0.0001).

[0798] [Table 41]

[0799] Change from baseline in HbA1c at week 24 (per protocol)

[0800]

[0801] SD = standard deviation, Min = minimum, Max = maximum, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error, UCI = upper confidence interval. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0802] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0803] Note: Baseline is Visit 2 (Randomization).

[0804] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0805] Secondary Efficacy End Points

[0806] 1) Changes in HbA1c at Weeks 6, 12, and 18 after administration of the clinical trial drug compared to the second follow-up (randomization)

[0807] Table 42 lists the summary results of the change from baseline in HbA1c in PPS at Weeks 6, 12, and 18 of the clinical trial.

[0808] The results of analysis of covariance (ANCOVA) of PPS showed that the changes in HbA1c from baseline at different time points after administration of the clinical trial drugs were evaluated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the wash-out period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. The least squares mean (LS mean (SE)) was -0.73 (0.03)% p for the test group (enagliflozin, 0.3 mg) and -0.70 (0.03)% p for the control group (dapagliflozin, 10 mg) at week 6; at week 12, it was -0.87 (0.04)% p for the test group and -0.83 (0.04)% p for the control group; at week 18, it was -0.83 (0.05)% p for the test group and -0.75 (0.04)% p for the control group. The between-group differences (LS mean difference (95% CI)) were -0.03 (-0.11, 0.06)% p at week 6, -0.04 (-0.15, 0.06)% p at week 12, and -0.07 (-0.19, 0.04)% p at week 18, indicating that there were no statistically significant between-group differences at any time point (p = 0.5606 at week 6, p = 0.4085 at week 12, and p = 0.1951 at week 18).

[0809] The changes in HbA1c (SD) over time were -0.74 (0.46)% p for the test group and -0.72 (0.41)% p for the control group at week 6, -0.89 (0.62)% p for the test group and -0.87 (0.57)% p for the control group at week 12, and -0.84 (0.69)% p for the test group and -0.79 (0.61)% p for the control group at week 18, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0810] [Table 42]

[0811] Change from baseline in HbA1c at weeks 6, 12, and 18 (per protocol)

[0812]

[0813]

[0814]

[0815] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0816] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0817] Note: Baseline is Visit 2 (Randomization).

[0818] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0819] 2) Changes in FPG at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0820] Table 43 shows the summary results of the change from baseline in FPG in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0821] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least squares means (LS means (SE)) of the changes in FPG from baseline at different time points after the administration of the clinical trial drugs, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the wash-out period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, were -25.9 for the test group (enagliflozin, 0.3 mg) at week 6. 6 (1.42) mg / dL, and the control group (dapagliflozin, 10 mg) was -22.71 (1.39) mg / dL. At week 12, the test group was -27.17 (1.54) mg / dL, and the control group was -24.42 (1.50) mg / dL. At week 18, the test group was -27.77 (1.63) mg / dL, and the control group was -23.55 (1.59) mg / dL. At week 24, the test group was -27.21 (1.81) mg / dL, and the control group was -23.72 (1.78) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -3.24 (-6.84, 0.36) mg / dL at week 6, -2.75 (-6.64, 1.14) mg / dL at week 12, -4.22 (-8.33, -0.11) mg / dL at week 18, and -3.49 (-8.08, 1.10) mg / dL at week 24, showing statistically significant differences between the groups at week 18 (p=0.0773 at week 6, p=0.1651 at week 12, p=0.0444 at week 18, and p=0.1354 at week 24).

[0822] The FPG changes (SD) over time were -25.72 (21.79) mg / dL in the test group and -22.87 (23.96) mg / dL in the control group at week 6, -27.47 (22.64) mg / dL in the test group and -25.28 (27.86) mg / dL in the control group at week 12, -28.00 (26.03) mg / dL in the test group and -24.80 (27.29) mg / dL in the control group at week 18, and -26.31 (25.46) mg / dL in the test group and -23.70 (29.86) mg / dL in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0823] [Table 43]

[0824] Changes from baseline in FPG at weeks 6, 12, 18, and 24 (per protocol)

[0825]

[0826]

[0827]

[0828]

[0829] FPG = fasting plasma glucose, SD = standard deviation, Min = minimum, Max = maximum, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0830] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0831] Note: Baseline is Visit 2 (Randomization).

[0832] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0833] 3) The proportion of subjects achieving HbA1c < 7% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0834] Table 44 shows the summary results of the proportion of subjects achieving HbA1c <7% in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0835] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering medication), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed that the odds ratio (95% CI) of achieving HbA1c <7% in the test group (enanagliflozin, 0.3 mg) was significantly higher than that in the control group (dapagliflozin, 10 mg). CI) at different time points were: 1.22 (0.66, 2.25) at week 6, 1.20 (0.66, 2.19) at week 12, 1.36 (0.78, 2.38) at week 18, and 1.17 (0.66, 2.09) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.5326 at week 6, p = 0.5560 at week 12, p = 0.2743 at week 18, and p = 0.5862 at week 24).

[0836] Over time, the proportion of subjects achieving HbA1c < 7% was 56.03% (65 / 116) in the test group and 51.64% (63 / 122) in the control group at week 6, 67.52% (79 / 117) in the test group and 63.41% (78 / 123) in the control group at week 12, 63.25% (74 / 117) in the test group and 56.10% (69 / 123) in the control group at week 18, and 66.39% (79 / 119) in the test group and 62.60% (77 / 123) in the control group at week 24.

[0837] [Table 44]

[0838] Proportion of subjects achieving HbA1c target <7% at Weeks 6, 12, 18, and 24 (Per Protocol)

[0839]

[0840]

[0841] Proportion = number of subjects with HbA1c less than 7% at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] The difference between DWP16001 and dapagliflozin was tested (logistic regression model with treatment group as factor and stratification factors (regimen ['double and / or less combination' or 'triple and / or more combination'] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0842] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0843] 4) The proportion of subjects achieving HbA1c < 6.5% at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0844] Table 45 shows the summary results of the proportion of subjects achieving HbA1c < 6.5% in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0845] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering medication), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed an odds ratio (95% CI) of achieving HbA1c < 6.5% in the test group (enogliflozin, 0.3 mg) compared with the control group (dapagliflozin, 10 mg). CI) at different time points were: 0.65 (0.30, 1.41) at week 6, 1.44 (0.74, 2.80) at week 12, 1.20 (0.56, 2.58) at week 18, and 1.27 (0.66, 2.46) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.2729 at week 6, p = 0.2784 at week 12, p = 0.6372 at week 18, and p = 0.4729 at week 24).

[0846] The proportion of subjects achieving HbA1c < 6.5% was 11.21% (13 / 116) in the test group and 15.57% (19 / 122) in the control group at week 6, 23.08% (27 / 117) in the test group and 17.07% (21 / 123) in the control group at week 12, 14.53% (17 / 117) in the test group and 12.20% (15 / 123) in the control group at week 18, and 21.01% (25 / 119) in the test group and 17.07% (21 / 123) in the control group at week 24.

[0847] [Table 45]

[0848] Proportion of subjects achieving HbA1c target <6.5% at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0849]

[0850]

[0851]

[0852] Proportion = number of subjects with HbA1c below 6.5% at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] The difference between DWP16001 and dapagliflozin was tested (logistic regression model with treatment group as factor and stratification factors (regimen ['double and / or less combination' or 'triple and / or more combination'] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0853] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0854] 5) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0855] Table 46 lists the summary results of the proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug.

[0856] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering medication), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed that the odds ratio (95% CI) of achieving HbA1c <7% in the test group (enanagliflozin, 0.3 mg) was significantly higher than that in the control group (dapagliflozin, 10 mg). CI) at different time points were: 1.52 (0.74, 3.13) at week 6, 1.09 (0.47, 2.55) at week 12, 1.02 (0.52, 2.02) at week 18, and 1.15 (0.55, 2.40) at week 24, indicating that there was no statistically significant difference between the groups at any time point (p = 0.2571 at week 6, p = 0.8399 at week 12, p = 0.9545 at week 18, and p = 0.7187 at week 24).

[0857] Over time, the proportion of subjects achieving treatment response was 87.07% (101 / 116) in the test group and 81.97% (100 / 122) in the control group at week 6, 89.74% (105 / 117) in the test group and 89.43% (110 / 123) in the control group at week 12, 82.91% (97 / 117) in the test group and 82.93% (102 / 123) in the control group at week 18, and 86.55% (103 / 119) in the test group and 85.37% (105 / 123) in the control group at week 24.

[0858] [Table 46]

[0859] Proportion of Subjects Achieving Therapeutic Glycemic Response 1 at Weeks 6, 12, 18, and 24 (Per-Protocol Set)

[0860]

[0861]

[0862] Proportion = number of subjects achieving therapeutic glycemic response 1 at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] The difference between DWP16001 and dapagliflozin was tested (logistic regression model with treatment group as factor and stratification factors (regimen ['double and / or less combination' or 'triple and / or more combination'] and HbA1c level at visit 1 [screening] [<8% or ≥8%]) as covariates).

[0863] Note: Therapeutic glycemic response 1 = change in HbA1c since the second follow-up [randomization] [HbA1c at the second follow-up - HbA1c at each evaluation time point] > 0.5% at each evaluation time point or HbA1c < 7%.

[0864] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0865] 6) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.7% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0866] Table 47 lists the summary results of the proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 0.5% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug.

[0867] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering medication), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed that the odds ratio (95% CI) of achieving a treatment response in the test group (enagaliflozin, 0.3 mg) was 2.4% (95% CI, 2.3% to 3.7%) compared with the control group (dapagliflozin, 10 mg). CI) at each time point were: 1.16 (0.62, 2.15) at week 6, 1.30 (0.65, 2.60) at week 12, 1.09 (0.60, 2.00) at week 18, and 0.98 (0.51, 1.91) at week 24, indicating that there were no statistically significant differences between the groups at any time point (p = 0.6458 at week 6, p = 0.4581 at week 12, p = 0.7760 at week 18, and p = 0.9633 at week 24).

[0868] Over time, the proportion of subjects achieving treatment response was 78.45% (91 / 116) in the test group and 76.23% (93 / 122) in the control group at week 6, 85.47% (100 / 117) in the test group and 82.11% (101 / 123) in the control group at week 12, 77.78% (91 / 117) in the test group and 76.42% (94 / 123) in the control group at week 18, and 81.51% (97 / 119) in the test group and 82.11% (101 / 123) in the control group at week 24.

[0869] [Table 47]

[0870] Proportion of Subjects Achieving Therapeutic Glycemic Response 2 at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0871]

[0872]

[0873] Proportion = number of subjects achieving therapeutic glycemic response 2 at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] The difference between DWP16001 and dapagliflozin was tested (logistic regression model with treatment group as factor and stratification factors (regimen ['double and / or less combination' or 'triple and / or more combination'] and HbA1c level at visit 1 [screening] [<8% or ≥8%]) as covariates).

[0874] Note: Therapeutic glycemic response 2 = change in HbA1c since the second follow-up [randomization] [HbA1c at the second follow-up - HbA1c at each evaluation time point] > 0.7% at each evaluation time point or HbA1c < 7%.

[0875] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0876] 7) Proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) > 1% or HbA1c < 7%) at each time point of 6, 12, 18 and 24 weeks after administration of the clinical trial drug

[0877] Table 48 lists the proportion of subjects who achieved treatment response (HbA1c change at each evaluation time point compared to the second follow-up (randomization) (HbA1c at the second follow-up - HbA1c at each evaluation time point) >1% or HbA1c <7%) at 6, 12, 18 and 24 weeks after administration of the clinical trial drug.

[0878] In the PPS, logistic regression analysis adjusted for stratification factors (i.e., usual regimen of glucose-lowering medication (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering medication), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) showed that the odds ratio (95% CI) of achieving a treatment response in the test group (enagaliflozin, 0.3 mg) was 2.4% (95% CI, 2.3% to 3.7%) compared with the control group (dapagliflozin, 10 mg). CI) at each time point were: 1.38 (0.78, 2.43) at week 6, 1.31 (0.71, 2.42) at week 12, 1.22 (0.68, 2.17) at week 18, and 1.22 (0.67, 2.25) at week 24, indicating that there were no statistically significant differences between the groups at any time point (p = 0.2640 at week 6, p = 0.3950 at week 12, p = 0.5063 at week 18, and p = 0.5130 at week 24).

[0879] Over time, the proportion of subjects achieving treatment response was 70.69% (82 / 116) in the test group and 63.93% (78 / 122) in the control group at week 6, 78.63% (92 / 117) in the test group and 73.98% (91 / 123) in the control group at week 12, 74.36% (87 / 117) in the test group and 70.73% (87 / 123) in the control group at week 18, and 78.15% (93 / 119) in the test group and 74.80% (92 / 123) in the control group at week 24.

[0880] [Table 48]

[0881] Proportion of Subjects Achieving Therapeutic Glycemic Response 3 at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0882]

[0883]

[0884] Proportion = number of subjects achieving therapeutic glycemic response 3 at week n / number of subjects with available data in the efficacy analysis set at week n*100, n=6, 12, 18, 24. [1] The difference between DWP16001 and dapagliflozin was tested (logistic regression model with treatment group as factor and stratification factors (regimen ['double and / or less combination' or 'triple and / or more combination'] and HbA1c level at visit 1 [screening] [<8% or ≥8%]) as covariates).

[0885] Note: Therapeutic glycemic response 3 = change in HbA1c since the second follow-up [randomization] [HbA1c at the second follow-up - HbA1c at each evaluation time point] > 1% at each evaluation time point or HbA1c < 7%.

[0886] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0887] Exploratory End Points

[0888] 1) Changes in fasting C-peptide at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0889] Table 49 shows the summary results of the change from baseline in fasting C-peptide in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[0890] The results of analysis of covariance (ANCOVA) of PPS showed that the least square means (LS means (SE)) of the changes in fasting C-peptide from baseline at different time points after the administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the wash-out period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (enagliflozin, At week 12, the test group was -0.09 (0.02) ng / mL, and the control group was -0.07 (0.02) ng / mL. At week 18, the test group was -0.08 (0.02) ng / mL, and the control group was -0.06 (0.02) ng / mL. At week 24, the test group was -0.09 (0.02) ng / mL, and the control group was -0.08 (0.02) ng / mL. The between-group differences (LS mean difference (95% CI)) were -0.01 (-0.06, 0.04) ng / mL at week 6, -0.02 (-0.06, 0.03) ng / mL at week 12, -0.02 (-0.07, 0.03) ng / mL at week 18, and -0.01 (-0.05, 0.03) ng / mL at week 24, indicating that there were no statistically significant between-group differences at any time point.

[0891] The changes in fasting C-peptide (SD) over time were -0.06 (0.21) ng / mL in the test group and -0.04 (0.15) ng / mL in the control group at week 6, -0.09 (0.20) ng / mL in the test group and -0.06 (0.19) ng / mL in the control group at week 12, -0.09 (0.22) ng / mL in the test group and -0.06 (0.18) ng / mL in the control group at week 18, and -0.09 (0.18) ng / mL in the test group and -0.07 (0.19) ng / mL in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0892] [Table 49]

[0893] Change from baseline in fasting C-peptide at weeks 6, 12, 18, and 24 (per protocol)

[0894]

[0895]

[0896]

[0897]

[0898] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0899] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0900] Note: Baseline is Visit 2 (Randomization).

[0901] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0902] 2) Changes in body weight at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0903] Table 50 shows the summary results of the change from baseline in body weight in the PPS at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0904] The results of analysis of covariance (ANCOVA) of PPS showed that the least square means (LS means (SE)) of the changes in body weight from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the wash-out period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. The test group (enagliflozin, 0.3 mg) was -1.92 (0.17) kg, and the control group (dapagliflozin, 10 mg) was -1.80 (0.16) kg. At week 12, the test group was -2.72 (0.20) kg, and the control group was -2.71 (0.19) kg. At week 18, the test group was -3.16 (0.24) kg, and the control group was -3.01 (0.23) kg. At week 24, the test group was -3.15 (0.23) kg, and the control group was -3.01 (0.22) kg. The between-group differences (LS mean difference (95% CI)) were -0.13 (-0.55, 0.30) kg at week 6, -0.01 (-0.51, 0.49) kg at week 12, -0.15 (-0.76, 0.46) kg at week 18, and -0.15 (-0.73, 0.44) kg at week 24, indicating that there were no statistically significant between-group differences at any time point.

[0905] The changes in body weight (SD) over time were -1.87 (1.98) kg for the test group and -1.68 (1.41) kg for the control group at week 6, -2.65 (2.23) kg for the test group and -2.58 (1.79) kg for the control group at week 12, -3.10 (2.94) kg for the test group and -2.84 (1.94) kg for the control group at week 18, and -3.09 (2.72) kg for the test group and -2.83 (2.02) kg for the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0906] [Table 50]

[0907] Change in Body Weight from Baseline at Weeks 6, 12, 18, and 24 (Per-Protocol)

[0908]

[0909]

[0910]

[0911] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0912] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0913] Note: Baseline is Visit 2 (Randomization).

[0914] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0915] 3) Changes in fasting lipid concentrations (total cholesterol, LDL-C, HDL-C, and triglycerides) at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0916] ①Total cholesterol

[0917] Table 51 shows summary results for change from baseline in total cholesterol in the modified per-protocol set 1 (mPPS1) at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0918] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least square means (LS means (SE)) of the changes in total cholesterol from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (according to The serum levels of the test group and the control group were 5.07 (1.97) mg / dL at week 12 and 5.40 (1.98) mg / dL at week 18, respectively. The serum levels of the test group and the control group were 3.66 (1.88) mg / dL at week 24 and 4.48 (2.07) mg / dL at week 24. The serum levels of the test group and the control group were 5.57 (2.03) mg / dL at week 24. The between-group differences (LS mean difference (95% CI)) were 2.45 (-2.63, 7.53) mg / dL at week 6, 1.40 (-3.85, 6.64) mg / dL at week 12, 0.61 (-4.36, 5.58) mg / dL at week 18, and -1.09 (-6.43, 4.25) mg / dL at week 24, indicating that there were no statistically significant between-group differences at any time point.

[0919] The changes in total cholesterol (SD) over time were 4.65 (19.51) mg / dL in the test group and 1.55 (19.56) mg / dL in the control group at week 6, 7.79 (20.63) mg / dL in the test group and 4.61 (20.98) mg / dL in the control group at week 12, 5.06 (19.64) mg / dL in the test group and 2.51 (20.37) mg / dL in the control group at week 18, and 5.59 (17.04) mg / dL in the test group and 4.69 (25.08) mg / dL in the control group at week 24, indicating that the inter-group differences were statistically significant at all time points and in all administration groups except for the control group at weeks 6 and 18.

[0920] [Table 51]

[0921] Changes from Baseline in Fasting Lipid Parameters at Weeks 6, 12, 18, and 24 (Modified Per-Protocol Set 1) [Total Cholesterol]

[0922]

[0923]

[0924]

[0925]

[0926] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0927] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0928] Note: Baseline is Visit 2 (Randomization).

[0929] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0930] ②LDL-C

[0931] Table 52 shows the summary results of the change from baseline in LDL-C in mPPS1 at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0932] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least square means (LS means (SE)) of the changes in LDL-C from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (in combination with two or fewer drugs (one or two drugs) or three or more drugs) administered within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (according to The serum levels of the test group (napagliflozin, 0.3 mg) and the control group (dapagliflozin, 10 mg) were 2.49 (1.81) mg / dL, and 1.91 (1.78) mg / dL, at week 12, the test group was 2.95 (1.79) mg / dL and the control group was 2.71 (1.75) mg / dL, at week 18, the test group was 0.29 (1.63) mg / dL and the control group was 1.38 (1.59) mg / dL, at week 24, the test group was 0.85 (1.89) mg / dL and the control group was 3.12 (1.85) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were 0.57 (-4.10, 5.24) mg / dL at week 6, 0.24 (-4.37, 4.85) mg / dL at week 12, -1.10 (-5.28, 3.08) mg / dL at week 18, and -2.27 (-7.13, 2.59) mg / dL at week 24, indicating that there was no statistically significant difference between the groups at any time point.

[0933] The changes in LDL-C over time (SD) were 2.42 (16.77) mg / dL in the test group and 1.40 (19.16) mg / dL in the control group at week 6, 3.76 (15.91) mg / dL in the test group and 2.45 (20.28) mg / dL in the control group at week 12, 0.94 (14.64) mg / dL in the test group and 0.93 (18.49) mg / dL in the control group at week 18, and 1.75 (14.83) mg / dL in the test group and 2.72 (23.25) mg / dL in the control group at week 24, indicating that the between-group differences were statistically significant only in the test group at week 12.

[0934] [Table 52]

[0935] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [LDL-C]

[0936]

[0937]

[0938]

[0939] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0940] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0941] Note: Baseline is Visit 2 (Randomization).

[0942] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0943] ③HDL-C

[0944] Table 53 shows the summary results of the change from baseline in HDL-C in mPPS1 at Weeks 6, 12, 18, and 24 following administration of clinical trial drug.

[0945] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least square means (LS means (SE)) of the changes in HDL-C from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (according to The serum levels of the test group and the control group were 3.18 (0.62) mg / dL and 2.84 (0.60) mg / dL, respectively. At week 12, the serum levels of the test group and the control group were 3.82 (0.64) mg / dL and 3.42 (0.62) mg / dL, respectively. At week 24, the serum levels of the test group and the control group were 4.32 (0.71) mg / dL and 4.40 (0.69) mg / dL, respectively. The between-group differences (LS mean difference / test group-control group (95% CI)) were 0.83 (-0.63, 2.29) mg / dL at week 6, 0.34 (-1.25, 1.92) mg / dL at week 12, 0.40 (-1.23, 2.02) mg / dL at week 18, and -0.08 (-1.90, 1.73) mg / dL at week 24, indicating that there was no statistically significant difference between the groups at any time point.

[0946] The changes in HDL-C over time were 1.90 (5.34) mg / dL in the test group and 0.94 (6.05) mg / dL in the control group at week 6, 3.17 (6.08) mg / dL in the test group and 2.65 (6.41) mg / dL in the control group at week 12, 4.09 (6.15) mg / dL in the test group and 3.57 (6.53) mg / dL in the control group at week 18, and 4.53 (6.90) mg / dL in the test group and 4.44 (7.34) mg / dL in the control group at week 24, indicating that the differences between the groups at all time points and in all administration groups were statistically significant except for the control group at week 6.

[0947] [Table 53]

[0948] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [HDL-C]

[0949]

[0950]

[0951]

[0952]

[0953] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0954] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0955] Note: Baseline is Visit 2 (Randomization).

[0956] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0957] ④Triglycerides

[0958] Table 54 shows the summary results of the change from baseline in triglycerides in mPPS1 at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0959] Results of analysis of covariance (ANCOVA) for mPPS1 showed that the least square means (LS means (SE)) of the changes in triglycerides from baseline at different time points after administration of the clinical trial drugs were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (enagliflozin, 0 .3mg) was -6.85 (4.47) mg / dL, and the control group (dapagliflozin, 10 mg) was -5.39 (4.38) mg / dL. At week 12, the test group was -3.23 (5.25) mg / dL, and the control group was -12.02 (5.12) mg / dL. At week 18, the test group was -11.64 (4.46) mg / dL, and the control group was -12.39 (4.34) mg / dL. At week 24, the test group was -8.22 (4.01) mg / dL, and the control group was -8.78 (3.94) mg / dL. The between-group differences (LS mean difference / test group-control group (95% CI)) were -1.46 (-12.95, 10.03) mg / dL at week 6, 8.79 (-4.68, 22.27) mg / dL at week 12, 0.75 (-10.66, 12.16) mg / dL at week 18, and 0.56 (-9.75, 10.87) mg / dL at week 24, indicating that there was no statistically significant difference between the groups at any time point.

[0960] The changes in triglycerides (SD) over time were -4.37 (40.21) mg / dL in the test group and -10.00 (72.87) mg / dL in the control group at week 6, 0.59 (51.73) mg / dL in the test group and -16.03 (81.60) mg / dL in the control group at week 12, -9.60 (49.20) mg / dL in the test group and -17.31 (70.25) mg / dL in the control group at week 18, and -6.05 (42.91) mg / dL in the test group and -13.81 (71.91) mg / dL in the control group at week 24, indicating that the differences between the groups at all time points and in all administration groups were statistically significant except for the test group and control group at week 18.

[0961] [Table 54]

[0962] Changes from baseline in fasting lipid parameters at weeks 6, 12, 18, and 24 (modified per-protocol set 1) [Triglycerides]

[0963]

[0964]

[0965]

[0966] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0967] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0968] Note: Baseline is Visit 2 (Randomization).

[0969] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0970] 4) Changes in systolic or diastolic blood pressure at each time point at 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[0971] ① Systolic blood pressure (SBP)

[0972] Table 55 shows summary results for the change from baseline in systolic blood pressure in the modified per-protocol set 2 (mPPS2) at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[0973] Results of analysis of covariance (ANCOVA) for mPPS2 showed that the least square means (LS means (SE)) of the changes in systolic blood pressure from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug) and HbA1c level at the first follow-up (screening) (<8% or ≥8%) as covariates. At week 6, the test group (enagliflozin, 0.3 mg) It was -2.76 (0.90) mmHg, and the control group (dapagliflozin, 10 mg) was -3.49 (0.87) mmHg. At week 12, the test group was -6.43 (0.88) mmHg, and the control group was -5.06 (0.85) mmHg. At week 18, the test group was -6.82 (0.92) mmHg, and the control group was -5.16 (0.88) mmHg. At week 24, the test group was -4.49 (0.96) mmHg, and the control group was -4.27 (0.93) mmHg. The between-group differences (LS mean difference / test group-control group (95% CI)) were 0.73 (-1.56, 3.02) mmHg at week 6, -1.37 (-3.62, 0.88) mmHg at week 12, -1.66 (-4.00, 0.68) mmHg at week 18, and -0.22 (-2.67, 2.23) mmHg at week 24, indicating that there was no statistically significant difference between the groups at any time point.

[0974] The changes in systolic blood pressure (SD) over time were -3.67 (9.93) mmHg in the test group and -3.23 (8.88) mmHg in the control group at week 6, -7.10 (9.09) mmHg in the test group and -4.43 (9.82) mmHg in the control group at week 12, -7.37 (9.35) mmHg in the test group and -4.63 (10.16) mmHg in the control group at week 18, and -5.20 (9.81) mmHg in the test group and -3.74 (10.73) mmHg in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0975] [Table 55]

[0976] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 (modified per-protocol set 2) [Systolic blood pressure]

[0977]

[0978]

[0979]

[0980]

[0981] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0982] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0983] Note: Baseline is Visit 2 (Randomization).

[0984] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0985] ② Diastolic blood pressure

[0986] Table 56 shows the summary results of the change from baseline in diastolic blood pressure in mPPS2 at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[0987] Results of analysis of covariance (ANCOVA) for mPPS2 showed that the least square means (LS means (SE)) of the changes in diastolic blood pressure from baseline at different time points after administration of the clinical trial drug were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. At week 6, the test group (enagliflozin, 0.3 mg) It was -2.04 (0.70) mmHg, and the control group (dapagliflozin, 10 mg) was -1.88 (0.67) mmHg. At week 12, the test group was -4.30 (0.69) mmHg, and the control group was -2.26 (0.66) mmHg. At week 18, the test group was -3.41 (0.71) mmHg, and the control group was -2.42 (0.68) mmHg. At week 24, the test group was -2.55 (0.72) mmHg, and the control group was -1.89 (0.70) mmHg. The between-group differences (LS mean difference / test group-control group (95% CI)) were -0.16 (-1.94, 1.62) mmHg at week 6, -2.04 (-3.81, -0.28) mmHg at week 12, -0.99 (-2.80, 0.82) mmHg at week 18, and -0.66 (-2.50, 1.19) mmHg at week 24, showing statistically significant differences between the groups only at week 12.

[0988] The changes in diastolic blood pressure (SD) over time were -2.76 (8.36) mmHg in the test group and -1.57 (6.64) mmHg in the control group at week 6, -5.07 (7.87) mmHg in the test group and -1.88 (7.29) mmHg in the control group at week 12, -4.03 (7.86) mmHg in the test group and -2.12 (7.17) mmHg in the control group at week 18, and -3.19 (7.31) mmHg in the test group and -1.60 (7.95) mmHg in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[0989] [Table 56]

[0990] Change from baseline in blood pressure at weeks 6, 12, 18, and 24 (modified per-protocol set 2) [diastolic blood pressure]

[0991]

[0992]

[0993]

[0994]

[0995] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[0996] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[0997] Note: Baseline is Visit 2 (Randomization).

[0998] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[0999] 5) Changes in β-cell function and insulin resistance as measured by HOMA-β and HOMA-IR at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the 2nd follow-up (randomization)

[1000] ①β-cell function measured by HOMA-β

[1001] Table 57 shows the summary results of the change from baseline in HOMA-β in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[1002] The results of analysis of covariance (ANCOVA) of PPS showed that the least squares means of the changes in HOMA-β from baseline at different time points after the administration of the clinical trial drugs were calculated using baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or more drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the wash-out period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. The LS mean (SE) was 8.13 (3.08) for the test group (enagliflozin, 0.3 mg) and 3.20 (3.04) for the control group (dapagliflozin, 10 mg) at week 6; 7.78 (1.94) for the test group and 5.23 (1.90) for the control group at week 12; 5.97 (2.27) for the test group and 4.49 (2.22) for the control group at week 18; and 1.09 (4.79) for the test group and 5.78 (4.72) for the control group at week 24. The between-group differences (LS mean difference (95% CI)) were 4.93 (-2.95, 12.82) at week 6, 2.55 (-2.42, 7.51) at week 12, 1.48 (-4.31, 7.26) at week 18, and -4.69 (-16.95, 7.56) at week 24, indicating that there were no statistically significant between-group differences at any time point.

[1003] The changes in HOMA-β over time (SD) were 8.74 (39.40) in the test group and 4.48 (21.23) in the control group at week 6, 6.71 (20.59) in the test group and 4.70 (20.22) in the control group at week 12, 6.09 (25.33) in the test group and 5.32 (21.88) in the control group at week 18, and 2.57 (63.77) in the test group and 7.95 (26.82) in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[1004] [Table 57]

[1005] Change from baseline in beta-cell function at weeks 6, 12, 18, and 24 (per protocol) [HOMA-β]

[1006]

[1007]

[1008]

[1009]

[1010] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1011] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1012] Note: Baseline is Visit 2 (Randomization).

[1013] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1014] ② Detecting insulin resistance through HOMA-IR

[1015] Table 58 shows the summary results of the change from baseline in HOMA-IR in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[1016] The results of analysis of covariance (ANCOVA) of PPS showed that the least square means (LS means) of the changes in HOMA-IR from baseline at different time points after the administration of the clinical trial drugs were calculated with the baseline value and stratification factors (i.e., conventional regimen of glucose-lowering drugs (administered in combination with two or fewer drugs (one or two drugs) or three or more drugs) within 24 weeks before obtaining written consent (i.e., before the washout period of another glucose-lowering drug), HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates. (SE)) At week 6, the test group (enagliflozin, 0.3 mg) was -0.94 (0.15) and the control group (dapagliflozin, 10 mg) was -0.99 (0.14); at week 12, the test group was -1.11 (0.10) and the control group was -1.05 (0.10); at week 18, the test group was -1.14 (0.11) and the control group was -1.01 (0.11); at week 24, the test group was -1.09 (0.11) and the control group was -0.93 (0.11). The between-group differences (LS mean difference (95% CI)) were 0.05 (-0.32, 0.42) at week 6, -0.06 (-0.33, 0.20) at week 12, -0.13 (-0.41, 0.15) at week 18, and -0.16 (-0.44, 0.13) at week 24, indicating that there were no statistically significant between-group differences at any time point.

[1017] The changes (SD) of HOMA-IR over time were -0.90 (1.94) in the test group and -0.92 (1.49) in the control group at week 6, -1.16 (1.54) in the test group and -1.06 (1.70) in the control group at week 12, -1.16 (1.71) in the test group and -1.00 (1.58) in the control group at week 18, and -1.07 (1.52) in the test group and -0.88 (1.72) in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[1018] [Table 58]

[1019] Change from baseline in insulin resistance at weeks 6, 12, 18, and 24 (per-protocol) [HOMA-IR]

[1020]

[1021]

[1022]

[1023]

[1024] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1025] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1026] Note: Baseline is Visit 2 (Randomization).

[1027] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1028] 6) Changes in renal function-related indicators (UACR, UGCR) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[1029] ①UACR

[1030] Table 59 shows the summary results of the change from baseline in UACR in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drug.

[1031] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in UACR from baseline at different time points after the administration of the clinical trial drugs were as follows: baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) were used as covariates. At week 6, the test group (enagliflozin, 0.3 mg) was -8.76 (3.43) g / kg, and the control group (dapagliflozin, 10 mg) was -14.85 (3.36) g / kg. At week 12, the test group was -15.12 (4.60) g / kg, and the control group was -11.76 (4.47) g / kg. At week 18, the test group was -11.08 (3.89) g / kg, and the control group was -8.90 (3.79) g / kg. At week 24, the test group was -15.34 (3.93) g / kg, and the control group was -16.13 (3.84) g / kg. The between-group differences (LS mean difference / test group-control group (95% CI)) were 6.09 (-2.68, 14.87) g / kg at week 6, -3.35 (-15.10, 8.39) g / kg at week 12, -2.18 (-12.10, 7.73) g / kg at week 18, and 0.79 (-9.26, 10.84) g / kg at week 24, indicating that there was no statistically significant difference between the groups at any time point.

[1032] The changes (SD) in UACR over time were -11.43 (89.49) g / kg in the test group and -7.25 (52.04) g / kg in the control group at week 6, -18.62 (103.10) g / kg in the test group and -7.42 (53.04) g / kg in the control group at week 12, -12.07 (46.16) g / kg in the test group and -8.84 (63.74) g / kg in the control group at week 18, and -19.52 (108.55) g / kg in the test group and -11.12 (70.82) g / kg in the control group at week 24, indicating that the inter-group differences in the test group at weeks 12, 18, and 24 were statistically significant.

[1033] [Table 59]

[1034] Changes from baseline in renal function parameters at weeks 6, 12, 18, and 24 (per protocol) [UACR]

[1035]

[1036]

[1037]

[1038]

[1039] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1040] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1041] Note: Baseline is Visit 2 (Randomization).

[1042] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1043] ②UGCR

[1044] Table 60 shows the summary results of the change from baseline in UGCR in the PPS at Weeks 6, 12, 18, and 24 after administration of clinical trial drugs.

[1045] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in UGCR from baseline at different time points after the administration of the clinical trial drugs, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, were 5.5% and 7.3% for the test group (enagliflozin, 0.3 mg) at week 6. 8.10 (2.18) mg / mg, and the control group (dapagliflozin, 10 mg) was 45.75 (2.14) mg / mg. At week 12, the test group was 58.21 (2.07) mg / mg, and the control group was 44.84 (2.02) mg / mg. At week 18, the test group was 58.74 (2.33) mg / mg, and the control group was 45.40 (2.27) mg / mg. At week 24, the test group was 60.22 (2.31) mg / mg, and the control group was 43.51 (2.26) mg / mg. The between-group differences (LS mean difference / test group-control group (95% CI)) were 12.35 (6.76, 17.94) mg / mg at week 6, 13.37 (8.06, 18.67) mg / mg at week 12, 13.34 (7.40, 19.27) mg / mg at week 18, and 16.71 (10.79, 22.63) mg / mg at week 24, indicating that the between-group differences were statistically significant at all time points.

[1046] The changes (SD) of UGCR over time were 56.38 (24.08) mg / mg in the test group and 43.58 (21.16) mg / mg in the control group at week 6, 57.00 (22.19) mg / mg in the test group and 43.19 (20.18) mg / mg in the control group at week 12, 57.23 (24.63) mg / mg in the test group and 43.29 (23.42) mg / mg in the control group at week 18, and 59.39 (24.52) mg / mg in the test group and 42.31 (22.51) mg / mg in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups.

[1047] [Table 60]

[1048] Changes from baseline in renal function parameters at weeks 6, 12, 18, and 24 (per protocol) [UGCR]

[1049]

[1050]

[1051]

[1052]

[1053] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1054] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1055] Note: Baseline is Visit 2 (Randomization).

[1056] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1057] 7) Changes in obesity-related indicators (adiponectin, leptin) at each time point of 6, 12, 18, and 24 weeks after administration of the clinical trial drug compared to the second follow-up (randomization)

[1058] ① Adiponectin

[1059] Table 61 shows the summary results of the change from baseline in adiponectin in the PPS at Weeks 6, 12, 18, and 24 after administration of the clinical trial drug.

[1060] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least squares means (LS means (SE)) of the changes in adiponectin from baseline at different time points after the administration of the clinical trial drugs, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the wash-out period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, were -0.10 for the test group (enagliflozin, 0.3 mg) at week 6. (0.34) μg / mL, the control group (dapagliflozin, 10 mg) was 0.37 (0.33) μg / mL, at week 12, the test group was 0.89 (0.34) μg / mL, the control group was 0.70 (0.33) μg / mL, at week 18, the test group was 0.78 (0.33) μg / mL, the control group was 0.36 (0.32) μg / mL, at week 24, the test group was 1.42 (0.35) μg / mL, the control group was 0.92 (0.35) μg / mL, the difference between the groups (LS mean difference (95% CI CI)) were -0.47 (-1.33, 0.39) μg / mL at week 6, 0.19 (-0.68, 1.06) μg / mL at week 12, 0.42 (-0.41, 1.25) μg / mL at week 18, and 0.49 (-0.42, 1.40) μg / mL at week 24, indicating that there were no statistically significant differences between the groups at any time point.

[1061] The changes (SD) of adiponectin over time were -0.08 (4.03) μg / mL in the test group and 0.31 (4.15) μg / mL in the control group at week 6, 0.88 (4.15) μg / mL in the test group and 0.63 (3.45) μg / mL in the control group at week 12, 0.80 (4.50) μg / mL in the test group and 0.30 (3.21) μg / mL in the control group at week 18, and 1.39 (4.63) μg / mL in the test group and 0.84 (3.23) μg / mL in the control group at week 24. At all time points except week 6, the differences between the groups at all administration times showed statistical significance.

[1062] [Table 61]

[1063] Changes from baseline in adiposity parameters at weeks 6, 12, 18, and 24 (per protocol) [Adiponectin]

[1064]

[1065]

[1066]

[1067]

[1068] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1069] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1070] Note: Baseline is Visit 2 (Randomization).

[1071] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1072] ② Leptin

[1073] Table 62 shows the summary results of the change from baseline in leptin in the PPS at Weeks 6, 12, 18, and 24 following administration of the clinical trial drug.

[1074] The results of the analysis of covariance (ANCOVA) of the PPS showed that the least square means (LS means (SE)) of the changes in leptin from baseline at different time points after the administration of the clinical trial drugs, with baseline values ​​and stratification factors (i.e., conventional regimen of glucose-lowering drugs (monotherapy or combination therapy) within 24 weeks before obtaining written consent (i.e., before the washout period of any glucose-lowering drugs except metformin) and HbA1c level at the first follow-up (screening) (<8% or ≥8%)) as covariates, were -1 for the test group (enagliflozin, 0.3 mg) at week 6. .83 (0.45) ng / mL, and the control group (dapagliflozin, 10 mg) was -2.03 (0.45) ng / mL. At week 12, the test group was -1.97 (0.48) ng / mL, and the control group was -1.69 (0.47) ng / mL. At week 18, the test group was -1.46 (0.52) ng / mL, and the control group was -1.06 (0.51) ng / mL. At week 24, the test group was -1.46 (0.52) ng / mL, and the control group was -0.57 (0.51) ng / mL. The between-group differences (LS mean difference (95% CI)) were 0.20 (-0.96, 1.36) ng / mL at week 6, -0.28 (-1.51, 0.94) ng / mL at week 12, -0.40 (-1.74, 0.94) ng / mL at week 18, and -0.89 (-2.21, 0.43) ng / mL at week 24, indicating that there were no statistically significant between-group differences at any time point.

[1075] The changes in leptin over time (SD) were -1.75 (5.38) ng / mL in the test group and -2.04 (6.20) ng / mL in the control group at week 6, -1.96 (5.27) ng / mL in the test group and -1.82 (6.56) ng / mL in the control group at week 12, -1.63 (5.66) ng / mL in the test group and -1.36 (6.68) ng / mL in the control group at week 18, and -1.52 (4.96) ng / mL in the test group and -0.74 (6.26) ng / mL in the control group at week 24, indicating that the differences between the groups were statistically significant at all time points and in all administration groups except for the control group at week 24.

[1076] [Table 62]

[1077] Changes from baseline in adiposity parameters at weeks 6, 12, 18, and 24 (per protocol) [Leptin]

[1078]

[1079]

[1080]

[1081] SD = standard deviation, Min = minimum value, Max = maximum value, ANCOVA = analysis of covariance, LS mean = least squares mean, SE = standard error. [1] Test within treatment group (paired t test (t) or Wilcoxon signed rank test (w)).

[1082] [2] The difference between DWP16001 and dapagliflozin was tested (ANCOVA with treatment group as the factor and baseline value and stratification factors (treatment regimen [‘dual and / or less combination’ or ‘triple and / or more combination’] and HbA1c level at the first follow-up [screening] [<8% or ≥8%]) as covariates).

[1083] Note: Baseline is Visit 2 (Randomization).

[1084] Data sources: Listing 16.2.3:1, Listing 16.2.6:1.

[1085] 8) Proportion of subjects receiving rescue medication at each time point of 6, 12, 18, and 24 weeks after administration of clinical trial drug

[1086] In the case of rescue medication, HbA1c values ​​measured after the start of rescue medication were processed by data interpolation according to the Statistical Analysis Plan (SAP) 12.2 of this study. Because the HbA1c values ​​at Week 24 were excluded from the PPS analysis set by data interpolation, no subjects took rescue medication at any time point in the PPS results.

[1087] In the FAS results, at week 24, in the control group (dapagliflozin, 10 mg), the proportion of subjects who received rescue drugs after the administration of clinical trial drugs was 0.74% (1 / 135). Subjects who received rescue drugs (27S036) began to use rescue drugs after 18 weeks of follow-up, and continued to take the drugs until the end of the clinical trial. At other time points, there was no such situation. As the logistic regression results corrected by stratification factors (the conventional regimen of hypoglycemic drugs (single or combination) within 24 weeks before obtaining written consent (before the washout period of another hypoglycemic drug), HbA1c levels at the first follow-up (screening) (<8% or ≥8%)), compared with the control group, in the test group (enagliflozin, 0.3 mg), the odds ratio (95% CI) of the rescue drug administered at week 24 was 0.36 (0.02, 5.14), showing no statistically significant difference between the groups (p = 0.4497).

[1088] (*When rescue medication was administered from Week 18 to the day before Week 24, data from Week 24 will be presented.)

[1089] 3. Conclusion

[1090] This clinical trial aims to demonstrate that the therapeutic effect of enagliflozin is non-inferior to dapagliflozin in patients with type 2 diabetes who have poor glycemic control on metformin and gemigliptin, and to evaluate its safety.

[1091] As a result of efficacy evaluation, the intergroup difference (LS mean difference (95% CI)) in the change of HbA1c from baseline (which is the primary efficacy endpoint) at week 24 after taking the clinical trial drug was -0.06 (-0.19, 0.06)% p, and the upper limit of the 95% confidence interval of [test group-control group] was 0.06% p, which was less than the non-inferiority margin of 0.35, proving that the test group was not inferior to the control group. In addition, most secondary and exploratory endpoints, including FPG, showed similar results between the test group and the control group.

[1092] In the results of the safety evaluation, there was no statistically significant difference between the incidence of adverse events or adverse drug reactions, or adverse events and adverse drug reactions that require careful monitoring and serious adverse events, and there were no serious adverse drug reactions, adverse events or adverse drug reactions that led to discontinuation of the clinical trial drug, or adverse events and adverse drug reactions that led to death. Except for "somnolence" and "eye discomfort", all adverse drug reactions (PTs) that occurred in the clinical trial were previously reported adverse events of the trial drug enagliflozin and similar drugs. Among them, "eye discomfort" is an adverse event that occurred in the control group but not the test group. In other safety evaluation items, all adverse events reported due to abnormal laboratory tests, vital signs and electrocardiogram results were confirmed to have no causal relationship with the clinical trial drug. In addition, some statistically significant changes were observed in laboratory tests, vital signs and physical examinations, but none of them were clinically significant. There were no other clinically significant findings. When summarizing the results of the safety evaluation, no special safety-related issues were found in the test group compared with the control group.

[1093] Based on the above, the efficacy and safety of enagliflozin were confirmed in patients with type 2 diabetes who had inadequate glycemic control using metformin and gemigliptin, and enagliflozin was considered to be an effective drug for the treatment of diabetes.

[1094] Example 4: Analysis of subgroups of patients with renal disease in Examples 1 to 3

[1095] Among the patient groups receiving the test drugs of Examples 1 to 3 and the control drug, a group of proteinuric patients (baseline UACR of 30 to 3500 g / kg) was additionally analyzed.

[1096] For the patients in Example 1, the subgroup with a baseline UACR of 30-3500 g / kg was classified as the proteinuria patient group.

[1097] [Table 63]

[1098] Proportion of subjects with baseline UACR (full analysis set)

[1099]

[1100] Note: The denominator of the percentages is the number of subjects in each group.

[1101] [1] Test for differences between treatment groups (chi-square test (c) or Fisher's exact test (f)).

[1102] In Example 1, in the proteinuria patient group (baseline UACR of 30 to 3500 g / kg), changes in UACR at week 24 according to administration of the test drug and the control drug (placebo) were as follows.

[1103] [Table 64]

[1104] Percent change from baseline in UACR at week 24 (full analysis set) [baseline UACR 30-3500 g / kg]

[1105]

[1106]

[1107] SD = standard deviation, Min = minimum value, Max = maximum value.

[1108] [1] Test of changes within treatment groups (paired t-test (t) or Wilcoxon signed-rank test (w)).

[1109] [2] Test of the percentage change between DWP16001 and placebo (two-sample t-test (t) or Wilcoxon rank-sum test (w)).

[1110] For the patients in Example 2, the subgroup with a baseline UACR of 30-3500 g / kg was classified as the proteinuria patient group.

[1111] [Table 65]

[1112] Proportion of subjects with baseline UACR (per protocol)

[1113]

[1114]

[1115] In Example 2, in the proteinuria patient group (baseline UACR of 30 to 3500 g / kg), changes in UACR at week 24 according to the administration of the test drug and the control drug (dapagliflozin) were as follows.

[1116] [Table 66]

[1117] Percent change from baseline in UACR at week 24 (per protocol) [baseline UACR 30-3500 g / kg]

[1118]

[1119]

[1120] Similarly, for the patients in Example 3, the subgroup with a baseline UACR of 30-3500 g / kg was classified as the proteinuria patient group.

[1121] [Table 67]

[1122] Proportion of subjects with baseline UACR (per protocol set)

[1123]

[1124] In Example 3, in the proteinuria patient group (baseline UACR of 30 to 3500 g / kg), changes in UACR at week 24 according to the administration of the test drug and the control drug (dapagliflozin) were as follows.

[1125] [Table 68]

[1126] Percent change from baseline in UACR at week 24 (per protocol) [baseline UACR 30-3500 g / kg]

[1127]

[1128]

[1129] In summary, if Figure 4As shown, as a result of confirming the changes in renal function-related indicators detected by UACR at week 24, when enagliflozin was administered alone, UACR at week 24 was reduced by 46.06% compared with baseline, and in the dual combination treatment of metformin and the triple combination treatment of metformin and gemagliptin, the UACR changes at week 24 were reduced by an average of 47.35% and 36.03% compared with baseline, respectively.

[1130] In dual combination therapy with metformin and triple combination therapy with metformin and gemagliptin, the reduction in UACR was lower in the group receiving enagliflozin compared with the group receiving the SGLT2 inhibitor dapagliflozin (as control).

[1131] Furthermore, when the two studies were combined and analyzed, it was confirmed that the change in UACR was reduced by 20.72% in the patient group administered with enagliflozin compared with the patient group administered with dapagliflozin.

[1132] Example 5: Safety related to renal function

[1133] In the Phase 3 clinical trials of Examples 1 to 3, changes in eGFR, which is a safety index related to renal function, were confirmed. As a result, as can be seen from the table below, no significant changes in eGFR were found due to administration of the test drug, confirming the safety of the test drug.

[1134] [Table 69]

[1135]

[1136]

[1137] Example 6: Phase 1 clinical trial in patients with type 2 diabetes and impaired renal function

[1138] In addition, a Phase 1 clinical trial was conducted to confirm the therapeutic effect of enagliflozin on diabetic nephropathy.

[1139] The subjects were divided into the following four groups according to the eGFR values, and urinary glucose excretion (UGE) and eGFR were evaluated according to the administration of 0.5 mg of enagliflozin as a test drug (Phase 1 and 3: repeated administration (1 week), Phase 2 and 4: single administration).

[1140] Stage 1: eGFR ≥ 90 (n = 6)

[1141] Stage 2: 60 ≤ eGFR < 90 (n = 7)

[1142] Stage 3: 30 ≤ eGFR < 60 (n = 4)

[1143] Stage 4: 15 ≤ eGFR < 30 (n = 5)

[1144] like Figure 5 As shown, as a result of confirming urinary glucose excretion (UGE) at week 1 and week 7 after administration of the test drug, it was confirmed that urinary glucose excretion increased after administration of the test drug in all renal function groups, but the efficacy tended to decrease in the group with poor renal function.

[1145] In addition, if Figure 6 As shown, as a result of confirming the change in eGFR after administration of the trial drug, a decrease in eGFR was confirmed in the patient group of 30≤eGFR<60, and these patients tended to recover their eGFR after drug discontinuation.

[1146] Therefore, the therapeutic effect of enagliflozin on diabetic nephropathy can be confirmed.

[1147] Example 7: Non-clinical trial related to kidney disease

[1148] Additional nonclinical trials were conducted to confirm the nephropathy-related effects of enagliflozin.

[1149] SD rats treated with streptozotocin exhibited hyperglycemia, renal dysfunction (proteinuria), and morphological abnormalities (glomerular mesangial expansion). Therefore, 60 mg / kg of streptozotocin was intravenously administered to SD rats and used as an animal model of diabetic nephropathy.

[1150] As shown in Table 70, SD rats were divided into 8 groups and orally administered the test material once a day for 12 weeks.

[1151] [Table 70]

[1152]

[1153]

[1154] ①G5: The difference in efficacy can be determined by administration Same dose Dapa (G6) and Empa (G7) to solve

[1155] ②G6: converted to adult dosage, approximately equivalent to 10 mg, CKD Allowable Dose

[1156] ③G7: converted to adult dosage, approximately equivalent to 10 mg, Diabetes Permitted Dose

[1157] ④G8: Losartan has been shown to reduce proteinuria in patients with diabetic nephropathy and has indications

[1158] (ARBs and ACEi are used as first-line treatment.)

[1159] As a result of the experiment, Figure 7 As shown, when urine albumin concentration was measured at 4, 8 and 12 weeks after administration, a dose-dependent reduction in proteinuria was observed in the group administered with enagliflozin. In addition, when enagliflozin was compared with the same dose group (1 mg / kg) of different SGLT2 inhibitors, enagliflozin showed the most excellent effect in reducing proteinuria.

[1160] At the 12th week of administration, the GS score used as a measure of glomerular sclerosis and the TA score used as a measure of tubular atrophy were measured. As a result, as shown in Table 8, in all enagliflozin administration groups, a trend of a decrease in the GS score (a significant decrease in the 0.3 mg / kg administration group) and a significant dose-dependent decrease in tubular atrophy were observed.

[1161] The fact that Enagaliflozin has an effect of improving glomerulosclerosis that is not found in other SGLT2 inhibitor drugs confirms the excellent pharmacological effect of Enagaliflozin on kidney disease. Enagaliflozin also showed improvement in tubular atrophy, indicating that it has an excellent effect of preventing and treating kidney disease at a relatively low dose compared with other drugs.

Claims

1. A pharmaceutical composition for preventing or treating kidney disease, comprising enagliflozin.

2. The pharmaceutical composition according to claim 1, wherein the renal disease comprises a disease selected from the group consisting of diabetic nephropathy, renal failure, chronic kidney disease, glomerulonephritis and proteinuria.

3. The pharmaceutical composition according to claim 1, which is used to reduce the risk of a sustained decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, death caused by cardiovascular disease, and kidney-related death in patients with chronic kidney disease. The pharmaceutical composition according to claim 1 , wherein the renal disease is diabetic nephropathy.

5. The pharmaceutical composition according to claim 1, which is used for administration to a diabetic or prediabetic patient.

6. The pharmaceutical composition according to any one of claims 1 to 5 for use in monotherapy.

7. The pharmaceutical composition according to any one of claims 1 to 5, for use in combination therapy with metformin.

8. The pharmaceutical composition according to any one of claims 1 to 5, for use in combination therapy with a DPP4 inhibitor.

9. The pharmaceutical composition according to claim 8, wherein the DPP4 inhibitor is gemagliptin.

10. The pharmaceutical composition according to any one of claims 1 to 5 for use in combination therapy with metformin and a DPP4 inhibitor.

11. The pharmaceutical composition according to any one of claims 1 to 5 for use in combination therapy with a sulfonylurea-based insulin secretagogue.

12. The pharmaceutical composition according to any one of claims 1 to 5 for use in combination therapy with insulin.

13. A pharmaceutical composition for preventing or treating diabetes in patients with kidney disease, comprising enagliflozin.

14. The pharmaceutical composition according to claim 13, wherein the renal disease comprises a disease selected from the group consisting of diabetic nephropathy, renal failure, chronic kidney disease, glomerulonephritis and proteinuria.

15. The pharmaceutical composition according to claim 13, wherein the renal disease is diabetic nephropathy.

16. The pharmaceutical composition according to any one of claims 13 to 15 for use in monotherapy.

17. The pharmaceutical composition according to any one of claims 13 to 15 for use in combination therapy with metformin.

18. The pharmaceutical composition according to any one of claims 13 to 15 for use in combination therapy with a DPP4 inhibitor.

19. The pharmaceutical composition according to claim 18, wherein the DPP4 inhibitor is gemagliptin.

20. The pharmaceutical composition according to any one of claims 13 to 15 for use in combination therapy with metformin and a DPP4 inhibitor.

21. The pharmaceutical composition according to any one of claims 13 to 15 for use in combination therapy with a sulfonylurea-based insulin secretagogue.

22. A pharmaceutical composition according to any one of claims 13 to 15 for use in combination therapy with insulin.

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