Composition, combination and combination therapy for treatment of type 2 diabetes mellitus

Abstract

The present invention relates to a composition, a combination, and a combination therapy for treating type 2 diabetes mellitus. The composition, combination, and combination therapy effectively reduce blood glucose level by administering 10 mg or 25 mg of empagliflozin to a patient with type 2 diabetes mellitus whose blood glucose level is not adequately controlled by a combination therapy of metformin and sitagliptin, and maintains the controlled blood glucose level for a long period of time with symptoms mostly confirmed to be moderate or lower, and most of the adverse drug reactions are known adverse reactions that have been previously reported in previous clinical trials of clinical trial drugs, and therefore, a new three-drug composition, a combination, and a combination therapy with ensured safety may be provided.

Description

COMPOSITION, COMBINATION AND COMBINATION THERAPY FOR TREATMENT OF TYPE 2 DIABETES MELLITUS

[0001] The present invention relates to a composition, a combination, and a combination therapy for treating type 2 diabetes mellitus.

[0002] Diabetes is a disease in which metabolic abnormalities, including hyperglycemia, persist due to insufficient insulin action, and the disease has a high possibility of vascular complications occurring chronically. Diabetes may be broadly divided into type 1 diabetes and type 2 diabetes. Among these, type 2 diabetes is a disease associated with both insulin resistance (i.e., a condition in which the responsiveness of cells or tissues to insulin is reduced compared to normal at a given insulin concentration) and insulin secretion disorders due to decreased pancreatic β-cell function. More than 85% of patients with diabetes have adult type 2 diabetes, and the prevalence of type 2 diabetes continues to increase due to modern people's westernized lifestyle and the increase of obesity.

[0003] According to the diabetes management guidelines of various countries, including Korea, reducing the risk of microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications is the main treatment goal for diabetes, and thorough blood glucose control is recommended as the most effective method of reducing the risk. In most patients, since it is difficult to reach the target level of glycated hemoglobin and maintain it for a long period of time only by improving lifestyle, it is required to use oral hypoglycemic drugs. In addition, since there is a correlation between the period of exposure to hyperglycemia and the occurrence of diabetic complications, active treatment with early drug administration is required to shorten the period of exposure to hyperglycemia (Korean Diabetes Association, Diabetes Treatment Guidelines, 2015). However, among patients with diabetes in Korea, only 23.3% of patients are able to control their blood glucose below the target level (HbA1c<6.5%) (Diabetes Fact Sheet in Korea 2016, Korean Diabetes Association), and therefore, continuous use of hypoglycemic drugs is required to increase the therapeutic effect.

[0004] Oral hypoglycemic drugs used for the treatment of diabetes may be divided into 1) insulin secretion stimulants (sulfonylureas, non-sulfonylureas), 2) biguanide-based drugs, 3) alpha-glucosidase inhibitors, 4) glitazone-based drugs, 5) dipeptidyl peptidase-4 (DPPIV) inhibitors, and 6) sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and the like, depending on the mechanism of action.

[0005] Metformin, one of the biguanide-based drugs, is a first-line drug recommended for use in oral drug monotherapy for patients with type 2 diabetes and is advantageous in view of cost-effectiveness. It is known that important mechanisms of metformin are to inhibit gluconeogenesis in the liver, increase glucose uptake in peripheral tissues, and activate adenosine monophosphate (AMP)-dependent protein kinase. However, metformin is also known to have side effects such as loss of appetite, abdominal distension, nausea, diarrhea, skin rash, and hives, and in most cases, these side effects are transient and often disappear after two to three weeks after taking the drug, but when diarrhea or severe abdominal distension does not disappear, it is recommended to discontinue use of the drug.

[0006] Sitagliptin, one of dipeptidyl peptidase-4 (DPPIV) inhibitors, is able to effectively control the decrease in the secretion glucagon-like peptide-1 (GLP-1) or the reduction of its action. DPPIV is an aminopeptidase present in various tissues, including the intestinal mucosa, and degrades GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). DPPIV inhibitors inhibit the DPPIV to increase the concentration of GLP-1, thereby stimulating insulin secretion and suppressing glucagon secretion. Here, due to the actions of GLP-1 to suppress appetite and delay gastric release, sitagliptin is widely used recently because the risk of hypoglycemia and weight gain is low.

[0007] Meanwhile, SGLT-2 inhibitor-based drugs, a type of drug that lowers blood glucose level by inhibiting the reabsorption of glucose in the kidneys, mainly act by inhibiting SGLT-2. SGLT-2 inhibitor-based drugs are able to normalize plasma glucose by increasing glucose excretion in the urine without significant gastrointestinal side effects, thereby improving insulin sensitivity and delaying the onset of diabetic complications. Therefore, SGLT-2 inhibitors are drawing attention as a preventive or therapeutic agent for diabetes, diabetes-related diseases, and diabetic complications. However, SGLT-2 inhibitor-based drugs may increase the risk of urinary tract infections and genital infections due to glucose excretion in the urine, and may cause a decrease in effective blood volume in the blood vessels and renal dysfunction, so caution should be taken when taking the drugs in the presence of factors that predispose to acute kidney damage.

[0008] Diabetes has a very complex etiology, and each antidiabetic drug has distinct advantages and disadvantages, and therefore, dual combination therapy using antidiabetic agents having different action mechanisms is frequently prescribed in clinical practice to exhibit simultaneous actions on multiple targets. Considering not only that combination therapy with drugs shortens the patient's exposure period to hyperglycemia but also that type 2 diabetes is caused by complex pathophysiology of beta cell dysfunction and insulin resistance, the combination therapy in the treatment of diabetes may have a positive effect on treatment continuation and blood glucose control.

[0009] However, when the target blood glucose level cannot be achieved despite dual combination therapy, additional combination with a new class of hypoglycemic agents may be considered. However, there has been no research to date regarding the therapeutic effects or side effects of empagliflozin, an SGLT-2 inhibitor-based drug, when administered together with a dual combination therapy of other classes.

[0010] [Related Art Documents]

[0011] [Patent Documents]

[0012] (Patent Document 1) Korean Patent Publication 10-2024-0028315

[0013] [Non-Patent Documents]

[0014] (Non-Patent Document 1) Diabetes Fact Sheet in Korea 2016, Korean Diabetes Association

[0015] An object of the present invention is to provide a triple composition, a combination, and a combination therapy for treating type 2 diabetes mellitus in a patient whose blood glucose level is not adequately controlled by combination therapy of metformin and sitagliptin.

[0016] In order to solve the above-described problem, the present invention discloses the following solutions.

[0017] In one aspect, the present invention discloses a pharmaceutical composition for treating a patient with type 2 diabetes mellitus who does not respond to a combination therapy of metformin and sitagliptin, the composition comprising: empagliflozin, metformin and sitagliptin, or pharmaceutically acceptable salts thereof as active ingredients.

[0018] In another aspect, the present invention discloses a method of controlling blood glucose or treating type 2 diabetes mellitus, the method comprising administering the pharmaceutical composition to a patient who does not respond to a combination therapy of metformin and sitagliptin.

[0019] In still another aspect, the present invention discloses a combination for treating or ameliorating type 2 diabetes mellitus, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin, the combination comprising: (i) a first agent comprising metformin or a pharmaceutically acceptable salt thereof; (ii) a second agent comprising sitagliptin or a pharmaceutically acceptable salt thereof, and (iii) a third agent comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0020] The novel combination therapy of the present invention can effectively reduce blood glucose level in a patient with type 2 diabetes mellitus whose blood glucose level is not adequately controlled by a combination therapy of metformin and sitagliptin, by administering 10 mg or 25 mg of empagliflozin, and maintain the controlled blood glucose level for a long period of time, thereby achieving clinically significant effects in a patient with type 2 diabetes mellitus.

[0021] The novel combination therapy of the present invention is mostly confirmed to be moderate or less severe in terms of safety, and most of the adverse drug reactions are known adverse reactions that have been previously reported in previous clinical trials of clinical trial drugs, and therefore, a new combination therapy with ensured safety can be provided.

[0022] The effects of the present invention are not limited to the above-mentioned effects, and various effects may be comprised within a range obvious to those skilled in the art from the contents that will be described below.

[0023] Hereinafter, the present specification will be described in more detail.

[0024] The present specification is described in more detail as follows. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present invention, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like.　In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention.　Therefore, the terms used in the present invention should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply the names of the terms.

[0025] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present invention pertains.　Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present invention.

[0026] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0027] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. In other words, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention may not be considered as being limited by the specific description described below.

[0028] Expressions such as "comprising" as used herein should be understood as open-ended terms implying the possibility of comprising other embodiments.

[0029] While researching and developing a composition, a combination, and a combination therapy effective for treating type 2 diabetes mellitus, the present inventors confirmed the efficacy and safety when empagliflozin was additionally administered to a patient with type 2 diabetes mellitus whose blood glucose level was not adequately controlled by a combination therapy of metformin and sitagliptin, thereby completing the present invention.

[0030] Hereinafter, the present invention will be described in detail.

[0031] The term metformin as used herein may refer to metformin or a pharmaceutically acceptable salt thereof. Accordingly, a pharmaceutical composition / combination / combination therapy comprising metformin may herein refer to a pharmaceutical composition / combination / combination therapy comprising metformin or a pharmaceutically acceptable salt thereof.

[0032] The term sitagliptin as used herein may refer to sitagliptin or a pharmaceutically acceptable salt thereof. Accordingly, a pharmaceutical composition / combination / combination therapy comprising sitagliptin may herein refer to a pharmaceutical composition / combination / combination therapy comprising sitagliptin or a pharmaceutically acceptable salt thereof.

[0033] The term empagliflozin as used herein may refer to empagliflozin or a pharmaceutically acceptable salt thereof. Accordingly, a pharmaceutical composition / combination / combination therapy comprising empagliflozin may herein refer to a pharmaceutical composition / combination / combination therapy comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0034] Pharmaceutical composition for treating a patient with type 2 diabetes mellitus who does not respond to a combination therapy with metformin and sitagliptin

[0035] To solve the above-described problem, the present invention discloses the following solutions.

[0036] In one aspect, the present invention discloses a pharmaceutical composition for treating a patient with type 2 diabetes mellitus who does not respond to a combination therapy of metformin and sitagliptin, the composition comprising empagliflozin, metformin, and sitagliptin, or pharmaceutically acceptable salts thereof, as active ingredients.

[0037] As one aspect to achieve the object, the present invention provides a pharmaceutical composition for treating type 2 diabetes mellitus, the composition comprising empagliflozin, metformin, and sitagliptin, or pharmaceutically acceptable salts thereof, as active ingredients.

[0038] The present invention relates to a pharmaceutical composition comprising a specific combination of combination drugs capable of achieving an efficient therapeutic effect when a plurality of antidiabetic agents having different action mechanisms are co-administered so as to simultaneously act on multiple targets to treat type 2 diabetes mellitus.

[0039] In order to clinically significantly treat type 2 diabetes mellitus, which has diverse and very complex etiologies, it is necessary to select antidiabetic drugs to be used in combination therapy and to establish a target patient group that may exhibit an optimal therapeutic effect according to such combination therapy. The selection of the patient group to be administered such combination drugs has the significance as a factor that allows the drugs to fully exhibit their efficacy, along with the target disease or drug efficacy for which the drug is used.

[0040] Specifically, the present invention provides a pharmaceutical composition for treating a patient with type 2 diabetes mellitus who does not respond to a combination therapy of metformin and sitagliptin, the composition comprising empagliflozin, metformin, and sitagliptin, or pharmaceutically acceptable salts thereof, as active ingredients.

[0041] The composition of the present invention comprises the following ingredients as active ingredients:

[0042] i) metformin or a pharmaceutically acceptable salt thereof;

[0043] ii) sitagliptin or a pharmaceutically acceptable salt thereof; and

[0044] iii) empagliflozin or a pharmaceutically acceptable salt thereof.

[0045] In the present invention, metformin is a biguanide-based drug and a compound represented by Chemical Formula 1 below.

[0046] [Chemical Formula 1]

[0047]

[0048] The metformin may be used in various forms of pharmaceutically acceptable salts, and according to one embodiment of the present invention, it may be metformin hydrochloride.

[0049] In the present invention, sitagliptin is a dipeptidyl peptidase-4 (DPPIV) inhibitor-based drug and a compound represented by Chemical Formula 2 below.

[0050] [Chemical Formula 2]

[0051]

[0052] The sitagliptin may be used in various forms of pharmaceutically acceptable salts, and according to one embodiment of the present invention, it may be sitagliptin phosphate hydrate.

[0053] In the present invention, empagliflozin is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor-based drug and is a compound represented by Chemical Formula 3 below.

[0054] [Chemical Formula 3]

[0055]

[0056] The empagliflozin may be used in various forms of pharmaceutically acceptable salts.

[0057] The patient with type 2 diabetes mellitus to be treated in the present invention may be a patient who does not respond to a combination therapy, such as a patient whose blood glucose is not properly controlled by the combination therapy of metformin and sitagliptin, and specifically, a patient whose blood glucose is not controlled below a target level despite the combination therapy of metformin and sitagliptin for at least 10 weeks, and more specifically, a patient who has a glycated hemoglobin (HbA1c) value of 7.0% to 10%.

[0058] Patients who are to be treated using the pharmaceutical composition of the present invention may be patients who meet all of the following criteria.

[0059] 1) Male or female aged 19 to 85 years

[0060] 2) Patients with Type 2 diabetes mellitus

[0061] 3) Patients who have taken an oral hypoglycemic agent for at least 8 weeks and whose glycated hemoglobin (HbA1c) value is higher than or equal to 7.0% and lower than or equal to 10.0% as a result of a screening examination (however, when a triple combination therapy was performed before the screening examination, only patients whose glycated hemoglobin is higher than or equal to 6.5% and lower than or equal to 9.5% may participate)

[0062] 4) Patients whose body mass index (BMI) is higher than or equal to 18.5 kg / m2and lower than or equal to 40 kg / m2.

[0063] In addition, patients who are to be treated using the pharmaceutical composition of the present invention may be excluded when they meet one or more of the following criteria.

[0064] 1) Patients with type 1 diabetes or secondary diabetes

[0065] 2) Patients with severe complications of diabetes such as proliferative diabetic retinopathy

[0066] 3) Patients with acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, or patients with diabetic coma or precoma

[0067] 4) Patients with a history of hypersensitivity to SGLT2 inhibitors, biguanides, or DPP-4 inhibitors in the past

[0068] 5) Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

[0069] 6) Patients with severe infections or severe traumatic systemic disorders

[0070] 7) Patients with serious urinary tract infections, including urosepsis and pyelonephritis

[0071] 8) Patients with malnutrition, starvation, debility, pituitary insufficiency, or adrenal insufficiency

[0072] 9) Patients with a history of malignancy within five years prior to the screening visit (Visit 1) (however, appropriately treated basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial carcinoma, thyroid cancer, or malignancy considered cured are permitted)

[0073] 10) Patients with a history of acute myocardial infarction, cardiovascular collapse (shock), cerebral infarction, cerebral hemorrhage, transient ischemic attack, acute or unstable heart failure, or unstable angina within 24 weeks prior to the screening visit (Visit 1)

[0074] 11) Patients with pulmonary infarction, severe pulmonary dysfunction, or other risk factors for developing hypoxemia

[0075] 12) Patients with severe gastrointestinal disorders such as dehydration, diarrhea, or vomiting

[0076] 13) Patients with acute pancreatitis, including hemorrhagic or necrotizing pancreatitis

[0077] 14) Patients with a history of drug abuse or alcoholism within 12 weeks prior to the screening visit (Visit 1)

[0078] 15) Patients who have undergone insulin treatment for more than seven consecutive or non-consecutive days within 12 weeks prior to the screening visit (Visit 1)

[0079] 16) Patients receiving continuous SGLT2 inhibitor-based drug treatment for 8 weeks at the time of the screening visit (Visit 1)

[0080] 17) Patients receiving chronic (more than seven consecutive days) systemic corticosteroid treatment within 4 weeks prior to the screening visit (Visit 1)

[0081] 18) Patients taking anti-obesity treatment drugs within 12 weeks prior to the screening visit (Visit 1) or expected to require continuous administration during the clinical trial period, or patients who have undergone bariatric surgery within two years prior to the screening visit (Visit 1)

[0082] 19) Patients with the following abnormal laboratory test results

[0083] - Patients with a fasting blood glucose (FPG) level exceeding 270 mg / dL

[0084] - Patients with a triglyceride　(TG) level of 500 mg / dL or more

[0085] - Patients being treated for active liver disease, or patients with significant liver function abnormalities such as aspartate transaminase (AST) or alanine transaminase (ALT) exceeding three times the upper limit of the normal range, or total bilirubin exceeding two times the upper limit of the normal range, etc.

[0086] - Patients whose　thyroid-stimulating hormone (TSH) level is judged to be clinically significantly outside the normal range according to the investigator's judgment

[0087] 20) Patients with an estimated glomerular filtration rate (eGFR) of less than 45 mL / min / 1.73 m2or with an end-stage renal disease or patients undergoing dialysis

[0088] 21) Patients who have undergone a test requiring intravenous administration of radioactive iodine contrast material within 48 hours prior to the screening visit (Visit 1) or are scheduled to undergo such a test during the clinical trial

[0089] 22) Pregnant or potentially pregnant women or breast-feeding women or patients who do not agree to use an appropriate contraceptive method during the clinical trial

[0090] The pharmaceutical composition of the present invention may be administered to a patient with type 2 diabetes mellitus to appropriately control the patient's blood glucose level without side effects, and specifically, it can effectively reduce the glycated hemoglobin (HbA1c) value.

[0091] According to one embodiment of the present invention, the patient group administered the composition of the present invention exhibited a decrease in the average glycated hemoglobin (HbA1c) value after 24 weeks compared to the baseline, and this showed a significant difference even when compared to the patient group administered the empagliflozin placebo, confirming that the composition of the present invention has a clinically excellent effect in the treatment of a patient with type 2 diabetes mellitus, specifically, a patient with type 2 diabetes mellitus whose blood glucose level is not adequately controlled by a combination therapy of metformin and sitagliptin.

[0092] In addition, the pharmaceutical composition of the present invention can improve glycemic parameters by reducing the glycated hemoglobin (HbA1c) value of a patient with type 2 diabetes mellitus and reducing the FPG level.

[0093] According to one embodiment of the present invention, the patient group administered the composition of the present invention showed a decrease in the FPG level in the analysis of the change in glycemic parameters at week 24 compared to the baseline, indicating that the glycemic parameters were significantly improved. Through the results, it was confirmed that the composition of the present invention has a clinically excellent effect in the treatment of a patient with type 2 diabetes mellitus by controlling glycemic parameters.

[0094] Therefore, the pharmaceutical composition of the present invention can exhibit an effective therapeutic effect in the treatment of type 2 diabetes mellitus by exhibiting an effect of not only improving glucose metabolism indices but also ameliorating lipids related to dyslipidemia accompanying diabetes.

[0095] In the present invention, treatment means all actions that beneficially change, such as amelioration, alleviation, improvement, or suppression, of symptoms of a patient with type 2 diabetes mellitus by administration of the composition. Specifically, the treatment may be an effective reduction in blood glucose level in a patient with type 2 diabetes mellitus, for example, a significant reduction in glycated hemoglobin (HbA1c), and specifically it may mean a statistically significant reduction between the group administered the composition of the present invention and the baseline and empagliflozin placebo administration groups.

[0096] The dose of the pharmaceutical composition according to the present invention may comprise a pharmaceutically effective amount, that is, an amount sufficient to treat type 2 diabetes mellitus with a reasonable benefit / risk ratio applicable to medical prevention or treatment and may be appropriately adjusted by the number of administrations, period, and the like. Specifically, the dose of the pharmaceutical composition according to the present invention means an amount that is effective for treating a patient with type 2 diabetes mellitus, particularly a patient with type 2 diabetes mellitus who does not respond to combination therapy of metformin and sitagliptin, and provides a desired outcome or objective or subjective benefit to the subject.

[0097] According to one embodiment of the present invention, metformin may be administered as metformin hydrochloride at a dose of 500 to 2,000 mg / day, specifically 1,000 to 2,000 mg / day.

[0098] According to one embodiment of the present invention, sitagliptin may be administered as sitagliptin at a dose of 25 to 100 mg / day, specifically 100 mg / day.

[0099] According to one embodiment of the present invention, empagliflozin may be administered as empagliflozin at a dose of 10 to 25 mg / day, specifically 10 mg / day or 25 mg / day.

[0100] The composition of the present invention may be administered once a day or in several divided doses within the daily dose range of each effective ingredient, specifically once or twice a day, more specifically once a day.

[0101] The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient, or diluent in addition to the effective ingredient. The carrier, excipient, and diluent may comprise lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oils, but are not limited thereto.

[0102] The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powder, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. Specifically, when formulated, it may be prepared using diluents or excipients such as fillers, weighting agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used.

[0103] Solid preparations for oral administration comprise tablets, pills, powder, granules, capsules, and the like, but are not limited thereto. These solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration comprise suspensions, oral solutions, emulsions, syrups, and the like. In addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be added.

[0104] Formulations for parenteral administration may comprise sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may comprise propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, Witepsol, Macrogol, Tween 61, cacao oil, laurel oil, glycerogelatin, or the like may be used.

[0105] The administration method of the composition of the present invention may be orally or parenterally administered depending on the intended method, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like. Specifically, the composition of the present invention may be administered orally.

[0106] The administration period of the pharmaceutical composition according to the present invention may be appropriately selected by those skilled in the art depending on the degree of amelioration of the disease, the activity of the drug, the age, weight, health, sex of the patient, the sensitivity of the patient to the drug, and the like, and according to one embodiment of the present invention, it may be 12 to 24 weeks, but is not limited thereto.

[0107] The composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the treatment of type 2 diabetes mellitus.

[0108] Blood glucose control method or method of treating type 2 diabetes mellitus

[0109] In addition, as another aspect for achieving the object, the present invention provides a method of controlling blood glucose or a method of treating type 2 diabetes mellitus, the method comprising a step of administering the pharmaceutical composition to a patient who does not respond to a combination therapy of metformin and sitagliptin.

[0110] In the present invention, the term "blood glucose control" means all actions of changing the blood glucose level in a subject to a normal value by administering the pharmaceutical composition of the present invention.

[0111] In the present invention, the term "treatment" means partially or completely alleviating, ameliorating, alleviating, inhibiting, or delaying the onset of type 2 diabetes mellitus, reducing the severity, or reducing the occurrence of one or more symptoms or characteristics.

[0112] A combination for the treatment or amelioration of type 2 diabetes mellitus, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin

[0113] As still another aspect for achieving the object, the present invention provides a combination for treating or ameliorating type 2 diabetes mellitus, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin, the combination comprising: (i) a first agent comprising metformin or a pharmaceutically acceptable salt thereof; (ii) a second agent comprising sitagliptin or a pharmaceutically acceptable salt thereof, and (iii) a third agent comprising empagliflozin or a pharmaceutically acceptable salt thereof.

[0114] In the present invention, the term "combination" refers to a combination in the sense of a combination of two or more active substances in a formulation and a combination in the sense of individual formulations of active substances administered at a specified interval from each other in treatment. Therefore, the term "combination" when described in connection with the present invention, comprises the clinical realization of co-administration of two or more therapeutically effective compounds.

[0115] In the combination of the present invention, a first agent, a second agent, and / or a third agent may each be administered parenterally or orally, and specifically they may be administered orally.

[0116] In the present invention, the terms "first", "second", and "third" do not specifically indicate a particular order but are simply intended to indicate that the meanings of the terms described below are different from each other.

[0117] In the combination of the present invention, a first agent, a second agent, and a third agent may be administered simultaneously, sequentially, or separately.

[0118] The combination of the present invention may be a combination preparation comprising a first agent, a second agent, and a third agent, specifically, an orally administered combination preparation.

[0119] All matters mentioned in the compositions, combinations, and treatment methods of the present invention are equally applicable unless they are contradictory.

[0120] Hereinafter, the present invention will be described in detail based on examples, comparative examples, and experimental examples. However, the following examples, comparative examples, and experimental examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0121] Example 1. Phase 3 clinical trial design and analytical method

[0122] 1.1 Test method

[0123] This clinical trial is a multicenter, randomized, double-blind, parallel, placebo-controlled phase 3 clinical trial to compare the efficacy and safety of additional combination administration of empagliflozin (10 mg or 25 mg) in patients with type 2 diabetes mellitus whose blood glucose levels are not adequately controlled by a combination therapy with metformin and sitagliptin.

[0124] This clinical trial consisted of screening, a run-in period, and a treatment period. During the treatment period, the subjects underwent evaluations and tests planned for each visit: Visit 3 (day 0), Visit 4 (week 4), Visit 5 (week 12), and Visit 6 (week 24).

[0125] The clinical trial was conducted with only subjects who gave written consent to participate in the clinical trial according to the following criteria.

[0126] 1) Patients who took metformin (D150) 1000 mg or more per day and sitagliptin (D759) 100 mg per day stably for at least eight weeks without any change in the dose (total daily dose) entered the run-in period without undergoing a stabilization period.

[0127] Patients who did not fall under this category entered the run-in period after being orally administered metformin (D150) 1000 mg or more per day and sitagliptin (D759) 100 mg per day for at least 8 weeks without any change in the dose (total daily dose). At this time, no other hypoglycemic agents were administered.

[0128] Patients corresponding to the following items were included:

[0129] ① Patients taking metformin≥1000 mg / day and sitagliptin 100 mg but the duration of treatment did not meet the criteria (minimum 10 weeks)

[0130] ② Patients taking other oral hypoglycemic agents, alone or in combination, other than metformin≥1000 mg / day and sitagliptin 100 mg

[0131] After the end of the two-week single-blind run-in period, subjects whose re-examined glycated hemoglobin (HbA1c) values were 7.0% or more and 10.0% or less were randomly allocated to either an empagliflozin administration group (groups I and II) or a placebo administration group, while maintaining the existing metformin and sitagliptin administration doses in the open state and stratifying the subjects by the following criteria: (① glycated hemoglobin (HbA1c) test results of 8.5% or less or 8.5% or more, ② eGFR results of 45 or more but less than 60, 60 or more but less than 90, or 90 or more (mL / min / 1.73 m2)). The clinical trial drug was administered while maintaining the double-blind treatment for a total of 24 weeks of the treatment period.

[0132] Among the subjects who completed the 24-week treatment period, the clinical trial was conducted for up to 24 weeks, excluding those who met the discontinuation and dropout criteria.

[0133] 1.2 Clinical trial drugs

[0134] - Test drug 1: empagliflozin 10 mg -> Test Group I (Administration of combination drugs and test trial drug 1)

[0135] - Test drug 2: empagliflozin 25 mg -> Test Group II (Administration of combination drugs and test drug 2)

[0136] - Control Drug: empagliflozin placebo -> Control group (Administration of combination drugs and control drug)

[0137] - Combination drugs: metformin hydrochloride (≥1,000 mg) and sitagliptin 100 mg (128.5 mg as sitagliptin phosphate hydrate)

[0138] 1.3 Endpoints

[0139] 1.3.1 Efficacy endpoints

[0140] Primary efficacy endpoints

[0141] - Change in glycated hemoglobin (HbA1c) at week 24 compared to baseline

[0142] Evaluation of the superiority of Test Group I (empagliflozin 10 mg) compared to the control group (empagliflozin placebo) and evaluation of the superiority of Test Group II (empagliflozin 25 mg) compared to the control group (empagliflozin placebo)

[0143] Secondary efficacy endpoints

[0144] - Change in glycated hemoglobin (HbA1c) from baseline at week 12

[0145] - Change in FPG level from baseline at week 12 / week 24

[0146] - Proportion of subjects with HbA1c values less than 6.5% at week 24

[0147] - Proportion of subjects with HbA1c values less than 7.0% at week 24

[0148] 1.3.2 Safety endpoints

[0149] - Adverse events (AE), adverse drug reactions (ADR), serious adverse events (SAE), and serious adverse drug reactions (SADR)

[0150] 1.4 Number of subjects

[0151] ◆ Target number of subjects: 165 (55 per group, considering a dropout rate of 15%)

[0152] ◆ Number of screening subjects: 230

[0153] ◆ Number of enrolled subjects: 172

[0154] ◆ Number of completed subjects

[0155] - Treatment period (weeks 0 to 24): 162

[0156] 1.5 Selection of subjects

[0157] 1.5.1 Inclusion criteria

[0158] ◆ Visit 1 (screening): Time of Screening Examination

[0159] 1) Male or female aged 19 to 85 years

[0160] 2) Patients with type 2 diabetes mellitus

[0161] 3) Patients who have taken oral hypoglycemic agents for at least 8 weeks and whose HbA1c value is 7.0% to 10.0% as a result of the screening examination (however, when 3-drug combination therapy was conducted before the screening examination, only patients with glycated hemoglobin of 6.5% or more and 9.5% or less were allowed to participate)

[0162] 4) Patients with BMI of 18.5 kg / m2or more and 40 kg / m2or less

[0163] 5) Patients who voluntarily decided to participate in this clinical trial and gave written consent

[0164] ◆ Visit 2-1 before entering the treatment period

[0165] 6) Patients whose glycated hemoglobin (HbA1c) value measured after the end of the run-in period is 7.0% or more and 10.0% or less

[0166] 1.5.2 Exclusion criteria

[0167] ◆Visit 1 (screening): Time of Screening Examination

[0168] 1) Patients with type 1 diabetes or secondary diabetes

[0169] 2) Patients with severe complications of diabetes such as proliferative diabetic retinopathy

[0170] 3) Patients with acute or chronic metabolic acidosis including lactic acidosis or diabetic ketoacidosis, or diabetic coma or precoma

[0171] 4) Patients with a history of hypersensitivity to SGLT2 inhibitors, biguanides, or DPP-4 inhibitors in the past

[0172] 5) Patients with genetic problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

[0173] 6) Patients with severe infections or severe traumatic systemic disorders

[0174] 7) Patients with serious urinary tract infections, including urosepsis and pyelonephritis

[0175] 8) Patients with malnutrition, starvation, debility, pituitary insufficiency, or adrenal insufficiency

[0176] 9) Patients with a history of malignancy within five years prior to the screening visit (Visit 1) (however, appropriately treated basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial carcinoma, thyroid cancer, or malignancy considered cured are permitted)

[0177] 10) Patients with a history of acute myocardial infarction, cardiovascular collapse (shock), cerebral infarction, cerebral hemorrhage, transient ischemic attack, acute or unstable heart failure, or unstable angina within 24 weeks prior to the screening visit (Visit 1)

[0178] 11) Patients with pulmonary infarction, severe pulmonary dysfunction, or other risk factors for developing hypoxemia

[0179] 12) Patients with severe gastrointestinal disorders such as dehydration, diarrhea, or vomiting

[0180] 13) Patients with acute pancreatitis, including hemorrhagic or necrotizing pancreatitis

[0181] 14) Patients with a history of drug abuse or alcoholism within 12 weeks prior to the screening visit (Visit 1)

[0182] 15) Patients who have undergone insulin treatment for more than 7seven consecutive or non-consecutive days within 12 weeks prior to the screening visit (Visit 1)

[0183] 16) Patients receiving continuous SGLT2 inhibitor-based drug treatment for 8 weeks at the time of the screening visit (Visit 1)

[0184] 17) Patients receiving chronic (more than seven consecutive days) systemic corticosteroid treatment within 4 weeks prior to the screening visit (Visit 1)

[0185] 18 Patients taking anti-obesity treatment drugs within 12 weeks prior to the screening visit (Visit 1) or expected to require continuous administration during the clinical trial period, or patients who have undergone bariatric surgery within two years prior to the screening visit (Visit 1)

[0186] 19) Patients with the following abnormal laboratory test results

[0187] - Patients with an FPG level exceeding 270 mg / dL

[0188] - Patients with a TG level of 500 mg / dL or more

[0189] - Patients being treated for active liver disease, or patients with significant liver function abnormalities such as AST or ALT exceeding three times the upper limit of the normal range, or total bilirubin exceeding two times the upper limit of the normal range, etc.

[0190] - Patients whose　TSH level is judged to be clinically significantly outside the normal range according to the investigator's judgment

[0191] 20) Patients with an eGFR of less than 45 mL / min / 1.73 m2or with an end-stage renal disease or patients undergoing dialysis

[0192] 21) Patients who have undergone a test requiring intravenous administration of radioactive iodine contrast material within 48 hours prior to the screening visit (Visit 1) or are scheduled to undergo such a test during the clinical trial

[0193] 22) Pregnant or potentially pregnant women or breast-feeding women or patients who do not agree to use an appropriate contraceptive method during the clinical trial

[0194] 23) Patients who have taken other clinical trial drugs within 4 weeks prior to the screening visit (Visit 1)

[0195] 24) Other patients who are unable to participate in this clinical trial according to the investigator's judgment

[0196] 1.6 Statistical analysis methods

[0197] 1.6.1 Analysis of efficacy endpoints

[0198] 1.6.1.1 Primary efficacy evaluation

[0199] The primary outcome of this clinical trial was to evaluate the change in glycated hemoglobin (HbA1c) after 24 weeks compared to the baseline to confirm the superiority of empagliflozin combination therapy (Test Groups I and II). Descriptive statistics for baseline, 24-week glycated hemoglobin (HbA1c) values, and change after 24 weeks were presented for each administration group, and the significance of the differences between the groups was confirmed through an analysis of covariance (ANCOVA) considering the stratification condition of glycated hemoglobin (HbA1c) at baseline (HbA1c ≤ 8.5% or HbA1c > 8.5%) and treatment group as factors.

[0200] 1.6.1.2 Secondary efficacy evaluation

[0201] Descriptive statistics were presented for the changes in glycated hemoglobin (HbA1c) from the baseline after 12 weeks and 24 weeks by administration group, and the changes in FPG from the baseline after 12 weeks and 24 weeks by administration group. The groups were compared through ANCOVA considering the stratification condition of glycated hemoglobin (HbA1c) at baseline (HbA1c ≤ 8.5% or HbA1c > 8.5%) and treatment group as factors. In addition, the number and proportion (%) of subjects with glycated hemoglobin (HbA1c) values less than 6.5% and 7.0% at week 24 were presented.

[0202] 1.6.2 Analysis of safety endpoints

[0203] 1.6.2.1 AEs

[0204] AEs were encoded using MedDRA version 25.0. Based on the time of onset, AEs were classified into AEs that occurred before administration of the clinical trial drug and AEs that occurred after administration of the clinical trial drug. For AEs that occurred after administration of the clinical trial drug, the number of subjects and the incidence rate (%) were presented by administration group according to the system-organ class (SOC) and preferred term (PT), and the groups were compared using Pearson's chi-square test or Fisher's exact test according to the expected frequency. AEs were analyzed by classifying them into SAEs, ADRs, and SADRs, and when necessary, they were presented in the data listing according to the number of subjects with an AE.

[0205] Example 2. Results of treatment period analysis

[0206] 2.1 Results of efficacy evaluation

[0207] 2.1.1 Primary efficacy endpoint: Change in glycated hemoglobin (HbA1c) at week 24 compared to baseline

[0208] 2.1.1.1 Superiority evaluation of Test Group I (empagliflozin 10 mg) compared to the control group (empagliflozin placebo)

[0209] The results of analyzing the change in the average glycated hemoglobin (HbA1c) after 24 weeks compared to the baseline are shown in Table 1. Referring to Table 1, Test Group I exhibited a statistically significant decrease in the glycated hemoglobin (HbA1c) value compared to the control group (difference between groups: -0.74 (±0.15)%, p<0.0001), demonstrating that the blood glucose-lowering effect in Test Group I was superior to the control group, and a similar trend was confirmed in the per protocol set (PPS) analysis results.

[0210] 2.1.1.2 Superiority evaluation of Test Group II (empagliflozin 25 mg) compared to the control group (empagliflozin placebo)

[0211] The results of analyzing the change in the average glycated hemoglobin (HbA1c) after 24 weeks compared to the baseline are shown in Table 1. Referring to Table 1, Test Group II exhibited a statistically significant decrease in the glycated hemoglobin (HbA1c) value compared to the control group (difference between groups: -0.76 (±0.15)%, p<0.0001), demonstrating that the blood glucose-lowering effect in Test Group II was superior to the control group, and a similar trend was confirmed in the PPS analysis results.

[0212] VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in HbA1c (%) after 24 weeksTest Group I57-0.93 (0.23)-0.74 (0.15)[-1.04, -0.44]<0.0001Control group560.19 (0.23)VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in HbA1c (%) after 24 weeksTest Group II58-0.95 (0.23)-0.76 (0.15)[-1.07, -0.46]<0.0001Control group560.19 (0.23)

[0213] (In Table 1 above, * indicates the 95% confidence interval for the least square (LS)-mean difference between the administration groups, and ** indicates the ANCOVA results for the LS-mean comparison between the administration groups (Covariate: stratification factors (HbA1c, eGFR)).)

[0214] 2.1.2 Secondary efficacy endpoints

[0215] 2.1.2.1 Change in glycated hemoglobin (HbA1c) after 12 weeks compared to the baseline

[0216] The results of analyzing the change in average glycated hemoglobin (HbA1c) after 12 weeks compared to the baseline are shown in Table 2. Referring to Table 2, Test Group I exhibited a statistically significant decrease in the glycated hemoglobin (HbA1c) value compared to the control group (difference between groups: -0.84(±0.15)%, p<0.0001). In addition, Test Group II also exhibited a statistically significant decrease in the HbA1c value compared to the control group (difference between groups: -0.85(±0.15)%, p<0.0001). Both Test Groups I and II showed high blood glucose-lowering effects compared to the control group, and a similar trend was confirmed in the PPS analysis results.

[0217] VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in HbA1c (%) after 12 weeksTest Group I57-0.99 (0.22)-0.84 (0.15)[-1.13, -0.54]<0.0001Control group560.15 (0.22)VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in HbA1c (%) after 12 weeksTest Group II58-0.97 (0.22)-0.85 (0.15)[-1.14, -0.56]<0.0001Control group560.12 (0.22)

[0218] (In Table 2 above, * indicates the 95% confidence interval for the LS-mean difference between the administration groups, and ** indicates the ANCOVA results for the LS-mean comparison between the administration groups (Covariate: stratification factors (HbA1c, eGFR)).)

[0219] 2.1.2.2 Changes in FPG level after 12 / 24 weeks compared to the baseline

[0220] The results of analyzing the average changes in FPG after 12 / 24 weeks compared to the baseline are shown in Table 3. Referring to Table 3, FPG in Test Group I was statistically significantly reduced at all time points compared to the control group (differences between groups at each time point: -34.58(±5.14) mg / dL, -32.25(±4.62) mg / dL, all p<0.0001). In addition, FPG in Test Group II was also statistically significantly reduced at all time points compared to the control group (differences between groups at each time point: -33.04(±5.34) mg / dL, -32.56(±4.78) mg / dL, all p<0.0001). Both Test Group I and Test Group II showed a high FPG-reducing effect compared to the control group, and a similar trend was confirmed in the PPS analysis results.

[0221] VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in FPG after 12 weeks (mg / dL)Test Group I57-36.11 (7.79)-34.58 (5.14)[-44.77, -24.39]<0.0001Control group56-1.53 (7.79)Change in FPG after 24 weeks (mg / dL)Test Group I57-33.37 (7.00)32.25 (4.62)[-41.40, -23.10]<0.0001Control group56-1.12 (7.00)VariableAdministration groupnLS-Mean Change (SE)LS-Mean Diff (SE)[95% CI]*P-value**Change in FPG after 12 weeks (mg / dL)Test Group II58-29.46 (8.22)-33.04 (5.34)[-43.62, -22.45]<0.0001Control group563.57 (8.25)Change in FPG after 24 weeks (mg / dL)Test Group II5835.99 (7.35)-32.56 (4.78)[-42.03, -23.09]<0.0001Control group56-3.44 (7.38)

[0222] (In Table 3 above, * indicates the 95% confidence interval for the LS-mean difference between the administration groups, and ** indicates the ANCOVA results for the LS-mean comparison between the administration groups (Covariate: baseline, stratification factors (HbA1c, eGFR)).)

[0223] 2.1.2.3 Proportion of subjects with HbA1c values of less than 6.5% or less than 7.0% at week 24

[0224] Table 4 shows the results of analyzing the proportion of subjects with HbA1c values of less than 6.5% at week 24, and the results of analyzing the proportion of subjects with HbA1c values of less than 7.0% at week 24 are shown in Table 5.

[0225] 2.1.2.3.1 Proportion of subjects with HbA1c values of less than 6.5% at week 24

[0226] Referring to Table 4, the proportion was 21.05% (12 / 57) in Test Group I and 3.57% in the control group (2 / 56), indicating that the proportion was statistically significantly higher in the Test Group I than in the control group (p=0.0052). In addition, the proportion was 17.24% (10 / 58) in Test Group II, which was also statistically significantly higher than that in the control group (p=0.0174), and a similar trend was confirmed in the PPS analysis results.

[0227] VariableTest Group I (n=57)Control group (n=56)P-value* / **n (%)n (%)HbA1c less than 6.5%12 (21.05)2 (3.57)0.0052HbA1c more than or equal to 6.5%45 (78.95)54 (96.43)VariableTest Group II (n=58)Control group (n=56)P-value* / **n (%)n (%)HbA1c less than 6.5%10 (17.24)2 (3.57)0.0174HbA1c more than or equal to 6.5%48 (82.76)54 (96.43)

[0228] (In Table 4 above, * indicates the Cochran Mantel Haenszel Test (Covariate: stratification factors (HbA1c and eGFR)) for comparison between administration groups, and ** indicates the criterion of less than 6.5% of glycated hemoglobin (HbA1c).)

[0229] 2.1.2.3.2 Proportion of subjects with HbA1c values of less than 7.0% at week 24

[0230] Referring to Table 5, as a result of analyzing the proportion of subjects whose glycated hemoglobin (HbA1c) values at week 24 were less than 7.0%, the proportion was 47.37% (27 / 57) in Test Group I and 21.43% (12 / 56) in the control group, indicating that the proportion was statistically significantly higher in the Test Group I than in the control group (p=0.0040). In addition, the proportion was 43.10% (25 / 58) in Test Group II, which was also statistically significantly higher than that in the control group (p=0.0143), and a similar trend was confirmed in the PPS analysis results.

[0231] VariableTest Group I (n=57)Control group (n=56)P-value* / **n (%)n (%)HbA1c less than 7.0%27 (47.37)12 (21.43)0.0040HbA1c more than or equal to 7.0%30 (52.63)44 (78.57)VariableTest Group II (n=58)Control group (n=56)P-value* / **n (%)n (%)HbA1c less than 7.0%25 (43.10)12 (21.43)0.0143HbA1c more than or equal to 7.0%33 (56.90)44 (78.57)

[0232] (In Table 5 above, * indicates the Cochran Mantel Haenszel Test (Covariate: stratification factors (HbA1c and eGFR)) for comparison between administration groups, and ** indicates the criterion of less than 7.0% of glycated hemoglobin (HbA1c).)

[0233] 2.2 Safety evaluation results

[0234] The results for AEs, ADRs, SAEs, and SADRs are shown in Table 6.

[0235] 2.2.1 AEs

[0236] Referring to Table 6, 56 AEs were reported in 38 out of 171 patients (22.22%) in the Safety Analysis Set during the treatment period of this clinical trial. Specifically, 15 AEs were reported in 11 patients (19.30%) in Test Group I, 18 AEs in 12 patients (20.69%) in Test Group II, and 23 AEs in 15 patients (26.79%) in the control group. There was no statistically significant difference in the incidence of AEs between the administration groups (p=0.5959).

[0237] 2.2.2 ADRs

[0238] Referring to Table 6, 11 ADRs were reported in 8 out of 171 patients (4.68%) in the Safety Analysis set. Specifically, 5 ADRs were reported in 4 patients (7.02%) in Test Group I, 5 ADRs in 3 patients (5.17%) in Test Group II, and 1 ADRs in 1 patient (1.79%) in the control group. There was no statistically significant difference in the incidence rate between the administration groups (p=0.4915). Most of the reported ADRs were known ADRs that had been previously reported in previous clinical trials of clinical trial drugs.

[0239] 2.2.3 SAEs

[0240] Referring to Table 6, 6 SAEs were reported in 5 out of 171 patients (2.92%) in the Safety Analysis set. Specifically, 2 SAEs were reported in 2 patients (3.51%) in Test Group I, 3 SAEs in 2 patients (3.45%) in Test Group II, and 1 SAE in 1 patient (1.79%) in the control group. There was no statistically significant difference in the incidence rate between the administration groups (p=1.0000). All reported SAEs were evaluated as 'unlikely related' or 'unrelated' in terms of causality with the clinical trial drug, and most of them were confirmed to have recovered / resolved or were in the process of recovering / resolving.

[0241] 2.2.4 SADRs

[0242] Referring to Table 6, no SADR occurred among the 171 people in the Safety Analysis Set (0 SADR occurred).

[0243] Evaluation itemTest Group I (n=57)Test Group II (n=58)Control Group (n=56)Total (n=171)p-value*n (%) [No. of events / reactions]n (%) [No. of events / reactions]n (%) [No. of events / reactions]n (%) [No. of events / reactions]AE11 (19.30)

[0015] 12 (20.69)

[0018] 15 (26.79)

[0023] 38 (22.22)

[0056] 0.5959CADR4 (7.02) [5]3 (5.17) [5]1 (1.79) [1]8 (4.68)

[0011] 0.4915FSAE2 (3.51) [2]2 (3.45) [3]1 (1.79) [1]5 (2.92) [6]1.0000FSADR-----

[0244] (In Table 6 above, * indicates the test results for comparison between administration groups (Chi-square test (C) or Fisher's exact test (F)).)

[0245] 2.3 Conclusion of treatment period evaluation

[0246] In the clinical trial during the treatment period, as a result of confirming the change in glycated hemoglobin (HbA1c) at week 24 compared to the baseline, which was the primary efficacy endpoint for Test Groups I and II and the control group, it was confirmed that the glycated hemoglobin (HbA1c)-reducing effect of Test Groups I and II was superior to that of the control group.

[0247] In addition, in the case of the secondary efficacy evaluation results, as a result of confirming the change in glycated hemoglobin (HbA1c) in Test Groups I and II after 24 weeks compared to the baseline, it was found that the glycated hemoglobin (HbA1c)-reducing effect was superior in Test Groups I and II to the control group, and that the FPG was statistically significantly improved after 12 / 24 weeks compared to the baseline. In addition, the proportion of subjects who achieved a glycated hemoglobin (HbA1c) value of less than 6.5% or less than 7.0% at week 24 was statistically significantly higher in Test Groups I and II compared to the control group.

[0248] During the treatment period, 56 AEs occurred in 38 out of 171 patients (22.22%) in the Safety Analysis Set, and 11 ADRs were reported in 8 patients (4.68%). In addition, 6 SAEs occurred in 5 patients (2.92%), and 0 SADRs were reported in the test groups. Most of the AEs that occurred were mild or moderate, and most of the ADRs were known adverse reactions that had been previously reported in previous clinical trials of the clinical trial drugs, and no other notable safety issues were identified.

[0249] Through these results, it was confirmed that empagliflozin 10 mg / 25 mg can effectively control blood glucose level and maintain the controlled blood glucose for a long period of time in a patient with type 2 diabetes whose blood glucose is not adequately controlled through a combination therapy of metformin and sitagliptin. In addition, in terms of safety, most of the AEs that occurred were confirmed to be moderate or lower, and most of the ADRs were known adverse reactions that had been reported in previous clinical trials of clinical trial drugs, and no notable safety issues were identified. Therefore, the present invention provides an effective combination therapy for the treatment of type 2 diabetes mellitus, comprising empagliflozin, sitagliptin, and metformin.

[0250] While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1.A pharmaceutical composition for treating a patient with type 2 diabetes mellitus who does not respond to a combination therapy of metformin and sitagliptin, wherein the composition comprising: empagliflozin, metformin and sitagliptin, or pharmaceutically acceptable salts thereof as active ingredients.2.The pharmaceutical composition according to claim 1, wherein the metformin is metformin hydrochloride.3.The pharmaceutical composition according to claim 1, wherein the sitagliptin is sitagliptin phosphate hydrate.4.The pharmaceutical composition according to claim 1, wherein the patient has a glycated hemoglobin (HbA1c) value of 7.0% to 10% with a combination therapy of metformin and sitagliptin for at least 10 weeks prior to administration of the composition.5.The pharmaceutical composition according to claims 1 to 3, wherein the composition reduces the HbA1c value.6.The pharmaceutical composition according to claims 1 to 3, wherein the composition exhibits a glycemic parameter improvement effect of reducing fasting plasma glucose (FPG).7.The pharmaceutical composition according to claim 2, wherein the metformin is administered at 1,000 mg / day or more.8.The pharmaceutical composition according to claim 3, wherein the sitagliptin is administered at 100 mg / day.9.The pharmaceutical composition according to claim 1, wherein the empagliflozin is administered at 10 or 25 mg / day.10.The pharmaceutical composition according to claim 1, wherein the composition is administered orally once a day.11.A combination for treating or ameliorating type 2 diabetes mellitus, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin, wherein the combination comprising:(i) a first agent comprising metformin or a pharmaceutically acceptable salt thereof;(ii) a second agent comprising sitagliptin or a pharmaceutically acceptable salt thereof, and(iii) a third agent comprising empagliflozin or a pharmaceutically acceptable salt thereof.12.The combination according to claim 11, wherein each of the agents is administered simultaneously, sequentially, or separately.13.The combination according to claim 11, wherein the combination is an orally administered combination preparation.

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