Pharmaceutical compositions containing empagliflozin and their use

Abstract

To provide methods for treating chronic heart failure, in particular in patients with HFrEF or HFpEF, with a good efficacy, with regard to disease modifying properties and with regard to reduction of risk of mortality or hospitalization while at the same time showing a good safety profile.SOLUTION: The present invention relates to methods for preventing or treating acute or chronic heart failure and for reducing the risk of cardiovascular death, hospitalization for heart failure and other conditions in patients with preserved or reduced ejection fraction by administering empagliflozin to the patient.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for treating chronic heart failure, reducing the risk of cardiovascular death, reducing the risk of hospitalization due to heart failure, reducing all-cause mortality, reducing the risk of all-cause hospitalization, reducing the risk of new onset of atrial fibrillation, and improving health-related quality of life and / or functional capacity in patients with chronic heart failure. The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, or delaying the occurrence of acute heart failure, including acute decompensated heart failure. Furthermore, the present invention relates to a method for improving renal function in patients with chronic heart failure and for treating or preventing certain renal symptoms and diseases. Furthermore, the present invention relates to empagliflozin for use in a method for treating and / or preventing or reducing the risk of or delaying the occurrence of certain diseases or disorders in patients with chronic heart failure.

Background Art

[0002] Heart failure (HF) is a clinical syndrome that occurs when the heart cannot provide adequate blood supply or sustains adequate blood supply at the expense of elevated left ventricular (LV) filling pressure. Patients with heart failure (HF) face inadequate diagnosis, and approximately 50% of patients die from HF within 5 years. Approximately 66% of HF patients are non-diabetic. The global prevalence of HF was 26 million in 2013. In the United States, more than one million HF hospitalizations occur annually. There are significant unmet needs in HF. The overall goal of HF treatment is to prevent hospitalization and death, control symptoms, and improve quality of life. There are two types of HF: heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), and the latter accounts for 50% of all HF cases. Both HFrEF and HFpEF are associated with high morbidity and mortality. Current treatment options for HFrEF are mainly based on the administration of beta-blockers, ACEi, ARBs, ARNi, MRAs, and diuretics. Despite these options, outcomes remain suboptimal. There is currently no effective treatment indicated for HFpEF that focuses on symptom management and comorbid conditions.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Therefore, there is an unmet medical need for a method that has good efficacy in terms of disease modification and reduction of the risk of death or hospitalization, and that exhibits a good safety profile, particularly in patients with HFrEF or HFpEF, while treating chronic heart failure.

Means for Solving the Problems

[0004] The present invention relates to a method for treating, preventing, protecting against, or delaying the onset of chronic heart failure in a patient, characterized by administering empagliflozin to a patient who needs it. The present invention also relates to a method for reducing the risk of cardiovascular death in a patient with chronic heart failure, characterized by administering empagliflozin to the patient. In addition, the present invention relates to a method for reducing the risk of hospitalization (first and recurrent) for heart failure in patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for reducing all-cause mortality in patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for reducing the risk of hospitalization for any cause in patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for reducing the risk of new onset of atrial fibrillation in patients with chronic heart failure, characterized by administering empagliflozin to the patient.

[0005] The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute heart failure in patients, characterized by administering empagliflozin to patients who require it. The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute decompensated heart failure (ADHF) in patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for preventing macroalbuminuria in patients with chronic heart failure, slowing its progression, or reversing it, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for improving renal function or protecting the kidneys in patients with chronic heart failure, characterized by administering empagliflozin to the patient. The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, delaying the onset and / or progression of chronic kidney disease in patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention relates to a method for improving the health-related quality of life and / or functional capacity of patients with chronic heart failure, characterized by administering empagliflozin to the patient. Furthermore, the present invention provides a pharmaceutical composition comprising empagliflozin for use as a drug in any one of the methods described herein, or in combination with one or more other therapeutic substances as necessary. Furthermore, the present invention provides a pharmaceutical composition comprising empagliflozin, or optionally in combination with one or more other therapeutic substances, for use in methods for treating, preventing or reducing the risk of any one of the diseases or symptoms described herein. Furthermore, the present invention provides a pharmaceutical composition comprising empagliflozin for use in the manufacture of a drug for use in any one of the methods described herein, or in combination with one or more other therapeutic substances as necessary.

[0006] In one embodiment, the present invention a) Identify patients who require treatment for chronic heart failure; and b) A method of treatment comprising administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient's symptoms according to the NYHA classification. b. Identify that the patient has NYHA class I chronic heart failure, c. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient's symptoms according to the NYHA classification. b. Identify that the patient has NYHA class II chronic heart failure, c. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient's symptoms according to the NYHA classification. b. Identify that the patient has NYHA class III chronic heart failure, c. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient's symptoms according to the NYHA classification. b. Identify that the patient has NYHA class IV chronic heart failure, c. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient.

[0007] In one embodiment, the present invention a. Measure the patient's ejection fraction, b. Identify that the patient has an ejection fraction of 40% or less, c. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Identify that the patient has NYHA class I chronic heart failure and an ejection fraction of 40% or less. d. To provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Identify that the patient has NYHA class II, III, or VI chronic heart failure and an ejection fraction of 40% or less. d. To provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Identify that the patient has NYHA class I chronic heart failure and has an ejection fraction greater than 40%, and especially greater than 50%, d. To provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient.

[0008] In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Identify that the patient has NYHA class II, III, or IV chronic heart failure and has an ejection fraction greater than 40%, particularly greater than 50%, d. To provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Measure the patient's BNP or NT-proBNP level. d. Identify that the patient has NYHA class I chronic heart failure, an ejection fraction of 40% or less, especially greater than 50%, and elevated BNP or NT-proBNP levels. e. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. In one embodiment, the present invention a. Measure the patient’s NYHA classification symptoms, b. Measure the patient's ejection fraction, c. Measure the patient's BNP or NT-proBNP level. d. Identify that the patient has NYHA class II, III, or IV chronic heart failure, has an ejection fraction of 40% or less, especially greater than 50%, and has elevated BNP or NT-proBNP levels. e. Provide a method for treating chronic heart failure in patients, including administering empagliflozin to the patient. According to this embodiment, the elevated BNP or NT-proBNP value is particularly a BNP value of 150 pg / mL or higher or an NT-proBNP value of 600 pg / mL or higher. Furthermore, according to this embodiment, if the patient has been hospitalized within the past nine months due to heart failure, the elevated BNP or NT-proBNP value is particularly a BNP value of 100 pg / mL or higher or an NT-proBNP value of 400 pg / mL or higher. In the method of the present invention, empagliflozin may be administered to a patient, if necessary, in combination with one or more other therapeutic substances. Further aspects of the present invention will be apparent to those skilled in the art from the foregoing and the following description and examples.

[0009] Definitions The term "active ingredient" of the pharmaceutical composition of the present invention means the SGLT2 inhibitor empagliflozin of the present invention. The "active ingredient" is also sometimes referred to herein as the "active substance". The term "body mass index" or "BMI" of a human patient is defined as the weight (in kilograms) divided by the square of the height (in meters), such that the BMI is kg / m 2 and has the unit of. The term "overweight" is defined as the condition in which an individual has a BMI of 25 kg / m 2 or more and less than 30 kg / m 2 The terms "overweight" and "pre-obesity" are used interchangeably. The term "obese" or "being obese" etc. is defined as the condition in which an individual has a BMI of 30 kg / m 2 or more. According to the WHO definition, the term obesity may be categorized as follows: The term "class I obesity" refers to the condition in which the BMI is 30 kg / m 2 or more but lower than 35 kg / m 2 The term "class II obesity" refers to the condition in which the BMI is 35 kg / m 2 or more but lower than 40 kg / m 2 The term "class III obesity" refers to the condition in which the BMI is 40 kg / m 2 or more. Indicated obesity includes, in particular, exogenous obesity, hyperinsulinic obesity, proliferative obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity. The term "visceral obesity" is defined as a condition in which the waist-to-hip ratio is measured as 1.0 or higher in men and 0.8 or higher in women. It identifies an increased risk of developing insulin resistance and prediabetes. The term “abdominal obesity” is typically defined as a waist circumference greater than 40 inches (102 cm) for men and greater than 35 inches (94 cm) for women. For Japanese people or Japanese patients, abdominal obesity may be defined as a waist circumference of 85 cm or more for men and 90 cm or more for women (see, for example, the Committee on the Diagnosis of Metabolic Disorders in Japan).

[0010] The term "normal blood glucose" is defined as a state in which a subject has a fasting blood glucose concentration that is greater than 70 mg / dL (3.89 millimoles / L) and less than 100 mg / dL (5.6 millimoles / L), which is within the normal range. The term "fasting" has its usual meaning as a medical term. The term "hyperglycemia" is defined as a condition in which a subject has a fasting blood glucose concentration greater than 100 mg / dL (5.6 millimoles / L), which is above the normal range. The term "fasting" has its usual meaning as a medical term. The term "hypoglycemia" is defined as a condition in which a subject has a blood glucose concentration below the normal range, particularly below 70 mg / dL (3.89 mmol / L). The term "postprandial hyperglycemia" is defined as a condition in which a subject has a blood glucose or serum glucose concentration greater than 200 mg / dL (11.11 millimoles / L) two hours after a meal.

[0011] The term “abnormal fasting blood glucose” or “IFG” is defined as a condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in the range of 100–125 mg / dl (i.e., 5.6–6.9 millimoles / l), particularly greater than 110 mg / dL and less than 126 mg / dL (7.00 millimoles / L). A subject with “normal fasting glucose” has a fasting glucose concentration less than 100 mg / dl, i.e., less than 5.6 millimoles / l. The term “impaired glucose tolerance,” or “IGT,” is defined as a condition in which a subject has a blood glucose or serum glucose concentration two hours postprandial that is greater than 140 mg / dL (7.78 mmol / L) and less than 200 mg / dL (11.11 mmol / L). Impaired glucose tolerance, i.e., blood glucose or serum glucose concentration two hours postprandial, can be measured as the blood glucose level, which is the number of mg of glucose per dL of plasma two hours after ingesting 75 g of glucose from a fasting state. A subject with “normal glucose tolerance” has a blood glucose or serum glucose concentration two hours postprandial that is less than 140 mg / dL (7.78 mmol / L). The term "hyperinsulinemia" is defined as a condition in which subjects with or without normal blood glucose levels, who are insulin-resistant, have higher-than-normal fasting or postprandial serum or plasma insulin concentrations, and lean individuals without insulin resistance have a waist-to-hip ratio of less than 1.0 (per male) or less than 0.8 (per female). The terms “insulin sensitization,” “improvement of insulin resistance,” and “decreased insulin resistance” are synonymous and can be used interchangeably.

[0012] The term "insulin resistance" is defined as a condition in which circulating insulin levels exceeding the normal response to glucose loading are required to maintain normal blood glucose levels (Ford ES et al., JAMA. (2002) 287:356-9). The method for measuring insulin resistance is the euglycemic-hyperinsulinic blood clamp test. The insulin-to-glucose ratio is measured within the range of insulin-glucose infusion techniques. Insulin resistance is determined when glucose absorption is below 25% of the background population studied (WHO definition). A less labor-intensive method than the clamp test is the so-called minimal model, in which blood insulin and glucose concentrations are measured at regular time intervals during an intravenous glucose tolerance test, and insulin resistance is calculated from these values. This method cannot distinguish between hepatic insulin resistance and peripheral insulin resistance. Furthermore, insulin resistance, patient response to insulin resistance to treatment, insulin sensitivity, and hyperinsulinemia may be quantified by analyzing the Homeostasis Model Analysis (HOMA-IR) score and reliable indicators of insulin resistance (Katsuki A et al., Diabetes Care 2001; 24: 362-5). Additionally, methods for measuring the HOMA index for insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), the intact proinsulin to insulin ratio (Forst et al., Diabetes 2003, 52(Suppl.1): A459), and euglycemic clamp studies may be consulted. In addition, plasma adiponectin levels can be monitored as a potential surrogate for insulin sensitivity. Estimation of insulin resistance using the Homeostasis Model Analysis (HOMA)-IR score is calculated using the following formula (Galvin P et al., Diabet Med 1992; 9: 921-8). HOMA-IR = [Fasting serum insulin (μU / mL)] x [Fasting plasma glucose (millimoles / L) / 22.5] Insulin resistance can be confirmed by calculating the HOMA-IR score in these individuals. For the purposes of this invention, insulin resistance is suspected to be a clinical condition in which an individual has a HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal, as identified by the laboratory performing the glucose and insulin assays. In general, other parameters are used in daily clinical practice to analyze insulin resistance. For example, the patient's triglyceride concentration is preferably used because elevated triglyceride levels are significantly correlated with the presence of insulin resistance.

[0013] Individuals likely to have insulin resistance possess two or more of the following characteristics: 1) excessive body weight or obesity, 2) hypertension, 3) hyperlipidemia, and 4) one or more first-degree conditions associated with the diagnosis of IGT or IFG or type 2 diabetes. Patients predisposed to developing IGT, IFG, or type 2 diabetes have normal blood glucose levels along with high insulin levels and are, by definition, insulin resistant. Typical patients with insulin resistance are usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of prediabetes. Thus, to maintain glucose homeostasis, a person may require 2-3 times more insulin than a healthy person (without producing clinical symptoms). "Prediabetes" is a general term that describes an intermediate stage (also referred to as intermediate hyperglycemia) between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus (T2DM). Therefore, in one aspect of the present invention, "prediabetes" is diagnosed in an individual when HbA1c is 5.7% or higher and less than 6.5%. According to another aspect of the present invention, "prediabetes" corresponds to three groups of individuals: those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone, or those with both IGT and IFG. Although IGT and IFG usually have different pathophysiological etiologies, mixed symptoms exhibiting characteristics of both may be present in patients. Therefore, in another aspect of the present invention, a patient diagnosed with "prediabetes" is an individual with diagnosed IGT, or an individual with diagnosed IFG, or an individual diagnosed with both IGT and IFG. Patients diagnosed with “prediabetes” according to the definition of the American Diabetes Association (ADA) and, in the context of the present invention, are patients a) Fasting plasma glucose (FPG) concentration <100 mg / dL [1 mg / dL = 0.05555 millimoles / L] and plasma glucose (PG) concentration 2 hours later measured by a 75-g oral glucose tolerance test (OGTT) in the range of 140 mg / dL or greater and less than 200 mg / dL (i.e., IGT); or b) Fasting plasma glucose (FPG) concentration of 100 mg / dL or higher and less than 126 mg / dL, and plasma glucose (PG) concentration less than 140 mg / dL after 2 hours as measured by a 75-g oral glucose tolerance test (OGTT) (i.e., IFG); or c) Fasting plasma glucose (FPG) concentration of 100 mg / dL or higher and less than 126 mg / dL, and plasma glucose (PG) concentration 2 hours later measured by a 75-g oral glucose tolerance test (OGTT) in the range of 140 mg / dL or higher and less than 200 mg / dL (i.e., both IGT and IFG). This is an individual that possesses [this trait]. Patients with “prediabetes” are individuals considered to have a predisposition to developing type 2 diabetes. The definition of IGT is expanded to include individuals with high fasting blood glucose levels within the normal range (100 mg / dL or higher) (JB Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying prediabetes as a significant health threat is laid out in the Position Statement entitled “Prevention or Delay of Type 2 Diabetes” and in Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749), jointly published by the American Diabetes Association and the National Diabetes Association.

[0014] The method for examining the function of pancreatic beta cells is the same as the method described above for insulin sensitivity, hyperinsulinemia, or insulin resistance. Improvements in beta-cell function can be measured, for example, by the HOMA index (homeostasis model analysis) for beta-cell function, HOMA-B (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), insulin secretion in the first and second phases after oral glucose tolerance or food load tests (Stumvoll et al., Diabetes care 2000, 23:295-301), measuring insulin / C-peptide secretion after oral glucose tolerance or food load tests, or by using hyperglycemia clamp studies and / or minimal modeling after frequently sampled intravenous glucose tolerance tests (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81). The term "Type 1 diabetes" is defined as a condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg / dL (6.94 mmol / L) due to autoimmunity against pancreatic beta cells or in the presence of insulin. If a glucose tolerance test is performed, the blood glucose level in diabetes would be greater than 200 mg (11.1 mmol / L) of plasma per dL two hours after ingestion of 75 g of glucose on an empty stomach, due to autoimmunity against pancreatic beta cells or in the presence of insulin. In a glucose tolerance test, 75 g of glucose is orally administered to the patient being tested after 10-12 hours of fasting, and blood glucose levels are recorded immediately before glucose ingestion and one and two hours after ingestion. The presence of autoimmunity against pancreatic beta cells can be observed by the detection of circulating islet cell autoantibodies ["Type 1A diabetes mellitus"], namely GAD65 [glutamate decarboxylase-65], ICA [islet cell cytoplasm], IA-2 [cytoplasmic domain of tyrosine phosphatase-like protein IA-2], ZnT8 [zinc transporter-8], or anti-insulin; or by the detection of at least one other sign of autoimmunity [Type 1B diabetes mellitus] without the presence of typical circulating autoantibodies (i.e., as detected by pancreatic biopsy or imaging). Typically, a genetic predisposition is present (e.g., HLA, INS VNTR, and PTPN22), but this is not always the case.

[0015] The term “Type 2 Diabetes Mellitus” or “T2DM” is defined as a condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg / dL (6.94 mmol / L). Measuring blood glucose levels is a standard procedure in routine medical analysis. When a glucose tolerance test is performed, the blood glucose level of a diabetic would exceed 200 mg of glucose per dL (11.1 mmol / L) in plasma two hours after 75 g of glucose is ingested into an empty stomach. In a glucose tolerance test, 75 g of glucose is orally administered to the patient being tested after 10-12 hours of fasting, and blood glucose levels are recorded immediately before glucose intake and one and two hours after intake. In a healthy subject, the blood glucose level before glucose intake would be 60-110 mg per dL in plasma, less than 200 mg per dL one hour after glucose intake, and less than 140 mg per dL two hours after intake. If the value is between 140 and 200 mg after two hours, this is considered impaired glucose tolerance. The term “late type 2 diabetes mellitus” includes patients with secondary drug failure, instructions regarding insulin therapy, and progression to microvascular and macrovascular complications, such as diabetic nephropathy or coronary artery disease (CHD). The term “LADA” (Latent Autoimmune Diabetes in Adults) refers to patients who have a clinical diagnosis of type 2 diabetes but are found to have autoimmunity against pancreatic beta cells. Latent autoimmune diabetes in adults (LADA) is also known as gradually progressive type 1 diabetes mellitus (T1DM), “mild” T1DM, non-insulin-dependent type 1 DM, 1 1 / 2 DM, bidiabetes, or antibody-positive type 2 DM (T2DM). LADA is often not clearly defined and, unlike T1DM, rarely, or never, shows significant weight loss and ketoacidosis due to rapidly progressive β-cell deficiency.

[0016] The term “HbA1c” represents the product of non-enzymatic glycation of hemoglobin B chains. Its measurement is known to those skilled in the art. In monitoring the treatment of diabetes mellitus, HbA1c values ​​are of particular importance. Since its generation is substantially dependent on blood glucose levels and the lifespan of red blood cells, HbA1c in the sense of “blood glucose memory” reflects the average blood glucose level over the previous 4-6 weeks. Diabetic patients whose HbA1c values ​​are consistently well regulated by intensive diabetes treatment (i.e., less than 6.5% of total hemoglobin in the sample) are significantly better protected against diabetic microangiopathy. For example, metformin itself achieves an average improvement in HbA1c values ​​of the order of 1.0-1.5% in diabetes. This reduction in HbA1c values ​​is not sufficient to achieve the desired target range of less than 7% or less than 6.5%, preferably less than 6%, in all diabetes. Within the scope of this invention, the terms “insufficient blood glucose regulation” or “inappropriate blood glucose regulation” refer to a condition in which a patient exhibits an HbA1c value of 6.5%, particularly 7.0%, more preferably 7.5%, and particularly 8%. "Metabolic syndrome" (also referred to as "Syndrome X" (when used in the context of metabolic disorders) and "Metabolic disorder syndrome") is a complex syndrome characterized by insulin resistance as a fundamental feature (Laaksonen DE et al., Am J Epidemiol 2002;156:1070-7). According to the ATP III / NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), a diagnosis of metabolic syndrome is made when three or more of the following risk factors are present.

[0017] 1. Abdominal obesity defined as a waist circumference greater than 40 inches (102 cm) for men and greater than 35 inches (94 cm) for women, or, in the case of Japanese people or Japanese patients, a waist circumference of 85 cm or more for men and 90 cm or more for women; 2. Triglycerides of 150 mg / dL or higher 3. HDL cholesterol levels below 40 mg / dL in men 4. Blood pressure of 130 / 85 mm Hg or higher (SBP ≥ 130 or DBP ≥ 85) 5. Fasting blood glucose level of 110 mg / dL or higher The NCEP definition had been validated (Laaksonen DE et al., Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be measured by standard methods in medical analysis, as described, for example, in Thomas L (editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt / Main, 2000. According to commonly used definitions, hypertension is diagnosed when systolic blood pressure (SBP) exceeds 140 mm Hg and diastolic blood pressure (DBP) exceeds 90 mm Hg. If the patient has significant diabetes, it is currently recommended that systolic blood pressure be reduced to below 130 mm Hg and diastolic blood pressure to below 80 mm Hg. The term “empagliflozin” refers, for example, to the SGLT2 inhibitor 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]benzene, as described in WO 2005 / 092877.

[0018] [ka]

[0019] Methods of synthesis are described in the literature, e.g., WO 06 / 120208 and WO 2011 / 039108. According to the present invention, the definition of empagliflozin should also be understood to include its hydrate, solvate and polymorphs thereof, as well as their prodrugs. Advantageous crystalline forms of empagliflozin are described in WO 2006 / 117359 and WO 2011 / 039107, which are incorporated herein by reference. This crystalline form has good solubility, enabling good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physicochemically stable, thus providing good shelf-life stability for the pharmaceutical composition. Preferred pharmaceutical compositions, e.g., solid formulations for oral administration, e.g., tablets, are described in WO 2010 / 092126, which are incorporated herein by reference. The terms “treatment” and “treating” include, in a particularly prominent form, treatment measures for patients who have already developed the aforementioned symptoms. Treatment measures may be symptomatic measures to alleviate the symptoms of a particular indication, or causal measures to reverse or partially reverse the symptoms of a particular indication, or to stop or delay the progression of the disease. Thus, the compositions and methods of the present invention can be used, for example, not only as treatment measures over a period of time, but also for chronic treatment. The terms “preventive measures,” “preventive measures,” and “prevention” are used interchangeably and include measures taken for patients at risk of developing the aforementioned symptoms, thus mitigating the risk.

[0020] The term “tablet” includes tablets without coatings and tablets with one or more coatings. Furthermore, the term “tablet” includes tablets having one, two, three or more layers and press-coated tablets, in which case each of the aforementioned types of tablets may be without a coating or may have one or more coatings. The term “tablet” also includes minitablets, dissolvable tablets, chewable tablets, effervescent tablets and orally disintegrating tablets. The term “pharmacopoeia” refers to a standard pharmacopoeia, such as “USP 31-NF 26 ~ Second Supplement” (United States Pharmacopoeia Convention) or “European Pharmacopoeia 6.3” (European Council on Quality of Healthcare, 2000–2009). The terms “chronic heart failure” or “CHF” are synonymous with congestive heart failure (CCF). The degree of heart failure may be classified according to the New York Heart Association (NYHA) functional classification, including NYHA classes I, II, III, and IV. Chronic heart failure may be distinguished according to whether the left ventricle's ability to contract is affected (heart failure with reduced ejection fraction) or whether the heart's ability to relax is affected (heart failure with preserved ejection fraction). The term "HFpEF" refers to heart failure with preserved ejection fraction. HFpEF is often also referred to as "diastolic heart failure." The term "HFrEF" refers to heart failure with reduced ejection fraction. HFrEF is often also referred to as "systolic heart failure." The term "LVEF" represents the left ventricular ejection fraction. Ejection rate may be obtained by ultrasound cardiac dynamics, radionuclide ventricular angiography, and angiography, preferably by ultrasound cardiac dynamics. The term "BNP" refers to brain sodium excretion-increasing peptide, also known as type B sodium excretion-increasing peptide. BNP is used for screening and diagnosis of chronic heart failure. BNP levels are measured in blood plasma or serum. The term “NT-proBNP” refers to the N-terminus of a prohormone peptide that increases brain sodium excretion. NT-proBNP is used for screening and diagnosis of chronic heart failure. NT-proBNP levels are measured in blood plasma or serum. The term "albuminuria" is defined as a condition in which there is more albumin in the urine than normal. Albuminuria can be measured by the albumin excretion rate (AER) and / or the albumin-to-creatine ratio (ACR) (also referred to as UACR) in urine. Albuminuria categories in CKD are defined as follows:

[0021] [Table 1]

[0022] Category A1 reflects the absence of albuminuria, Category A2 reflects microalbuminuria, and Category A3 reflects macroalbuminuria. Progression of Category A1 usually leads to microalbuminuria (A2), but may also directly lead to macroalbuminuria (A3). Progression of microalbuminuria (A2) leads to macroalbuminuria (A3). The term “eGFR” represents the estimated glomerular filtration rate (GFR). GFR describes the flow rate of filtered fluid in the kidney. Estimated GFR can be calculated based on serum creatinine levels using, for example, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, the Cockcroft-Gault formula, or the Modification of Diet in Renal Disease (MDRD) formula (all of which are well known in the industry). According to aspects of the present invention, the estimated glomerular filtration rate (eGFR) is derived from serum creatinine levels, age, sex, and race based on the following CKD-EPI formula. GFR = 141 × min (S cr / κ, 1) α × max (S cr / κ, 1) -1.209 × 0.993 Age × 1.018 [for women] × 1.159 [for Black people] During the ceremony, Scr is serum creatinine (mg / dL), κ is 0.7 for females and 0.9 for males. α is -0.329 for females and -0.411 for males. min is S cr / κ represents the minimum of 1, and max is S cr / κ indicates the maximum value of 1.

[0023] For the purposes of this invention, the degree of renal impairment in a patient is determined by the following estimated glomerular filtration rate (GFR): Normal kidney function (CKD Stage 1): eGFR ≥ 90 mL / min / 1.73 m² 2 Mild renal impairment (CKD stage 2): eGFR ≥ 60 to < 90 mL / min / 1.73 m² 2 Moderate renal impairment (CKD stage 3): eGFR ≥ 30 to < 60 mL / min / 1.73 m² 2 Severe kidney impairment (CKD stage 4): eGFR ≥ 15 to < 30 mL / min / 1.73 m² 2 Renal failure (CKD stage 5): eGFR <15 mL / min / 1.73 m 2 According to the present invention, moderate kidney damage can be further divided into two substages: Moderate renal impairment (CKD 3A): eGFR ≥ 45 to < 60 mL / min / 1.73 m² 2 Moderate B kidney impairment (CKD 3B): eGFR ≥ 30 to < 45 mL / min / 1.73 m² 2 The term “KCCQ” refers to the Kansas City Cardiomyopathy Questionnaire. Health-related quality of life can be measured according to the KCCQ or KCCQ-12. The KCCQ-12 is an activated, shortened version of the original 23-item KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire is designed to assess physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self-efficacy, and quality of life in patients with HF. The term “MLHFQ” refers to Minnesota Living with Heart Failure Questionnaire. For example, quality of life, including its physical, emotional, social, and mental dimensions, can be measured according to the MLHFQ. [Modes for carrying out the invention]

[0024] In addition to improving weight loss through blood glucose regulation and increased urinary glucose excretion, empagliflozin exhibits diuretic effects, reduced arteriosclerosis, and direct vascular effects (Cherney et al., Cardiovasc Diabetol. 2014;13:28; Cherney et al., Circulation. 2014;129:587-597). EMPA-REG OUTCOME TM In studies, empagliflozin has been shown to reduce the risk of cardiovascular death, hospitalization for heart failure, and overall mortality in patients with type 2 diabetes mellitus and high cardiovascular risk (Zinman et al., N Engl J Med. 2015;373:2117-2128). Treatment with empagliflozin was observed to lower blood pressure without clinically relevant changes in heart rate, thus improving the product of heart rate and blood pressure (RPP), a surrogate marker of cardiac oxygen demand. Furthermore, empagliflozin was found not to be associated with clinically relevant reflex-mediated sympathetic activation, in contrast to the increases observed with diuretics. It can be hypothesized that altered glucose and sodium gradients within the kidney may generate sympathetic inhibitory afferent renal nerve signals. The lack of sympathetic activation may contribute to the beneficial cardiovascular and renal profiles (cardiorenal axis) of empagliflozin. Based on mechanistic considerations, such as clinical and nonclinical studies including the effects of empagliflozin on autonomous cardiovascular regulation in humans, the use of empagliflozin in the treatment and prevention of certain diseases and conditions, particularly chronic heart failure, acute heart failure, and chronic kidney disease, will be described first and second. The present invention relates to a method for treating chronic heart failure in patients, comprising administering empagliflozin to patients in need. The present invention also relates to a method for reducing the risk of cardiovascular death in patients with chronic heart failure, comprising administering empagliflozin to patients. Furthermore, the present invention relates to a method for reducing the risk of hospitalization for heart failure in patients with chronic heart failure, comprising administering empagliflozin to patients. The present invention also relates to a method for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure, comprising administering empagliflozin to patients. According to an embodiment of the present invention, the risk of hospitalization for heart failure is the risk of initial hospitalization for heart failure. According to another embodiment of the present invention, the risk of hospitalization for heart failure is the risk of recurrent hospitalization for heart failure. Furthermore, the present invention relates to a method for reducing all-cause mortality in patients with chronic heart failure, comprising administering empagliflozin to patients. Furthermore, the present invention relates to a method for reducing the risk of all-cause hospitalization in patients with chronic heart failure, comprising administering empagliflozin to patients. According to an embodiment of the present invention, the risk of all-cause hospitalization is the risk of initial all-cause hospitalization. According to another embodiment of the present invention, the risk of all-cause hospitalization is the risk of recurrent all-cause hospitalization. The present invention also relates to a method for reducing the risk of new onset of atrial fibrillation in patients with chronic heart failure, comprising administering empagliflozin to the patient.

[0025] The present invention also relates to a method for preventing, protecting against, or delaying the onset of chronic heart failure in patients, comprising administering empagliflozin to patients in need. According to embodiments of the present invention, a method is provided for preventing the worsening of chronic heart failure in patients with NYHA class I chronic heart failure to NYHA class II, III, or IV chronic heart failure. Furthermore, the present invention relates to a method for treating, preventing, protecting against, or delaying the onset of acute heart failure in a patient, particularly a patient with chronic heart failure, comprising administering empagliflozin to the patient in need. The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute decompensated heart failure (ADHF) in patients with chronic heart failure, comprising administering empagliflozin to patients who require it. In the method of the present invention, the risk of a certain event, disease, or disability is reduced compared to a patient who has been given a placebo in a care-background medical setting. In one embodiment, the risk is reduced by 15% or more. In another embodiment, the risk is reduced by 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 25% or more, or 30% or more. According to one embodiment of the present invention, the patient is a patient with NYHA class II, III, or IV chronic heart failure. According to this embodiment of the present invention, the patient is a patient with NYHA class II or III chronic heart failure. According to another embodiment of the present invention, the patient is a patient with NYHA class I chronic heart failure.

[0026] According to one embodiment of the present invention, the patient is a patient with chronic heart failure and preserved ejection fraction (HFpEF). For example, a patient with preserved ejection fraction exhibits an LVEF greater than 40%, or even greater than 50%. According to another embodiment, a patient with chronic heart failure and preserved ejection fraction (HFpEF) exhibits an LVEF of 50% or more. According to another embodiment, the patient exhibits chronic heart failure with an LVEF in the range of 40% to 49%, and a so-called moderate range of reduced ejection fraction (HFmrEF). According to another embodiment of the present invention, the patient is a patient with chronic heart failure and reduced ejection fraction (HFrEF). For example, a patient with reduced ejection fraction has an LVEF of 40% or less, and in particular less than 40%. Therefore, according to embodiments of the present invention, the present invention provides a method for treating chronic heart failure with preserved ejection fraction (HFpEF) in patients, for example, in patients with chronic heart failure of NYHA class I, II, III, or IV, comprising administering empagliflozin to patients requiring it. According to aspects of this embodiment, the degree of chronic heart failure in patients with chronic heart failure of NYHA class II, III, or IV is improved according to the NYHA classification. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients.

[0027] According to another embodiment, the present invention provides a method for treating chronic heart failure with reduced ejection fraction (HFrEF) in patients requiring empagliflozin, for example, in patients with chronic heart failure of NYHA class I, II, III, or IV. According to aspects of this embodiment, the degree of chronic heart failure in patients with chronic heart failure of NYHA class II, III, or IV is improved according to the NYHA classification. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients. According to one embodiment, the present invention provides a method for reducing the risk of cardiovascular death in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients. According to another embodiment, the present invention provides a method for reducing the risk of cardiovascular death in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of hospitalization for heart failure in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the risk of initial hospitalization for heart failure is reduced. According to another aspect of this embodiment, the risk of readmission for heart failure is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to another embodiment, the present invention provides a method for reducing the risk of hospitalization for heart failure in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to a part of this embodiment, the patient has NYHA class I chronic heart failure. According to a part of this embodiment, the risk of first hospitalization for heart failure is reduced. According to another part of this embodiment, the risk of readmission for heart failure is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients.

[0028] According to embodiments, the present invention provides a method for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to another embodiment, the present invention provides a method for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing all-cause mortality in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients.

[0029] According to embodiments, the present invention provides a method for reducing all-cause mortality in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of hospitalization for any cause in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, a patient having NYHA class I chronic heart failure. According to another aspect of this embodiment, the risk of initial hospitalization for any cause is reduced. According to another aspect of this embodiment, the risk of hospitalization for any cause of recurrence is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to another embodiment, the present invention provides a method for reducing the risk of hospitalization for any cause in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to an aspect of this embodiment, the risk of initial hospitalization for any cause is reduced. According to another aspect of this embodiment, the risk of recurrent hospitalization for any cause is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients.

[0030] According to embodiments, the present invention provides a method for reducing the risk of new onset of atrial fibrillation in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, in patients with NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to another embodiment, the present invention provides a method for reducing the risk of new onset of atrial fibrillation in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to embodiments, the present invention provides a method for improving health-related quality of life and / or functional capacity, particularly exercise capacity, in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, health-related quality of life is measured by questionnaires, for example, KCCQ or KCCQ-12. According to another aspect of this embodiment, health-related quality of life or exercise capacity is measured by a walking test, for example, a 6-minute walking test, or maximal oxygen uptake (VO2max). Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients.

[0031] According to embodiments, the present invention provides a method for improving health-related quality of life and / or functional capacity, particularly exercise capacity, in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, health-related quality of life is measured by questionnaires, for example, KCCQ or KCCQ-12. According to another aspect of this embodiment, health-related quality of life or exercise capacity is measured by a walking test, for example, a 6-minute walking test, or maximal oxygen uptake (VO2max). Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to embodiments, the present invention provides a method for treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute decompensated heart failure (ADHF) in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to another embodiment, the present invention provides a method for treating, preventing, protecting against, reducing the risk thereof, or delaying the onset thereof of acute decompensated heart failure (ADHF) in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), and for reducing the risk of new onset of atrial fibrillation, comprising administering empagliflozin to the patient. According to this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients.

[0032] According to embodiments, the present invention provides a method for reducing the risk of developing new type 2 diabetes mellitus in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of the present invention, the patient is a non-diabetic patient. According to another aspect of the present invention, the patient is a prediabetic patient. According to embodiments, the present invention provides a method for reducing the risk of developing new-onset type 2 diabetes mellitus in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of the present invention, the patient is a non-diabetic patient. According to another aspect of the present invention, the patient is a prediabetic patient. According to embodiments, the present invention provides a method for reducing the risk of myocardial infarction in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the risk of non-fatal myocardial infarction is reduced. According to aspects of this embodiment, the risk of fatal myocardial infarction is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of myocardial infarction in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the risk of non-fatal myocardial infarction is reduced. According to aspects of this embodiment, the risk of fatal myocardial infarction is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients.

[0033] According to embodiments, the present invention provides a method for reducing the risk of stroke in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the risk of non-fatal stroke is reduced. According to aspects of this embodiment, the risk of fatal stroke is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of stroke in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the risk of non-fatal stroke is reduced. According to aspects of this embodiment, the risk of fatal stroke is reduced. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (so-called 3-point MACE) in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of any of the following (so-called 3-point MACE) in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF): cardiovascular death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal myocardial infarction (excluding asymptomatic myocardial infarction), and non-fatal stroke (so-called 3-point MACE). According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for reducing the risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (so-called 3-point MACE) in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients.

[0034] According to embodiments, the present invention provides a method for reducing the risk of any of the following (so-called 3-point MACE) in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF): fatal stroke (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal myocardial infarction (excluding asymptomatic myocardial infarction), and non-fatal stroke (so-called 3-point MACE). According to aspects of this embodiment, the patient has NYHA class I chronic heart failure. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and in particular non-diabetic patients. According to embodiments, the present invention provides a method for preventing macroalbuminuria and delaying or reversing its progression in patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, a patient having NYHA class I chronic heart failure. According to aspects of this embodiment, the progression from microalbuminuria to macroalbuminuria is prevented, delayed, or reversed. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to embodiments, the present invention provides a method for preventing macroalbuminuria, delaying or reversing its progression, in patients with chronic heart failure, for example, in patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, in patients with NYHA class I chronic heart failure. According to aspects of this embodiment, the progression from microalbuminuria to macroalbuminuria is prevented, delayed, or reversed. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, and especially non-diabetic patients.

[0035] According to embodiments, the present invention provides a method for improving renal function or protecting the kidneys of patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the patient has mild, moderate, or severe renal impairment. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to aspects of this embodiment, improvement in renal function or kidney protection is a delay in the decline of eGFR, for example, a delay in the progressive decline of eGFR or a delay in the spontaneous progressive decline of eGFR. According to another aspect of this embodiment, improvement in renal function or kidney protection is diagnosed by an improvement in eGFR. According to embodiments, the present invention provides a method for improving renal function or protecting the kidneys of patients with chronic heart failure, for example, patients with NYHA class II, III, or IV chronic heart failure with reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. According to aspects of this embodiment, the patient has mild, moderate, or severe renal impairment. Patients in this embodiment are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. According to aspects of this embodiment, improvement in renal function or kidney protection is a delay in the decline of eGFR, for example, a delay in the progressive decline of eGFR or a delay in the spontaneous progressive decline of eGFR. According to aspects of this embodiment, improvement in renal function or kidney protection is diagnosed by an improvement in eGFR.

[0036] According to embodiments, the present invention provides a method for treating, preventing, protecting against, mitigating the risk of, delaying the onset and / or progression of chronic kidney disease in a patient diagnosed with chronic heart failure, comprising administering empagliflozin to the patient. In particular, this embodiment relates to a method for treating and / or delaying the progression of chronic kidney disease in a patient diagnosed with chronic heart failure, comprising administering empagliflozin to the patient. According to another aspect of this embodiment, the patient is a patient with stage 2 chronic kidney disease. According to another aspect of this embodiment, the patient is a patient with stage 3 chronic kidney disease, including stage 3a and / or 3b. According to yet another aspect of this embodiment, the patient is a patient with stage 4 chronic kidney disease. According to another aspect of this embodiment, the patient is a patient with stage 3 or stage 4 chronic kidney disease, including stage 3a and / or 3b, and with preserved ejection fraction (HFpEF), for example, NYHA class I, II, III, or IV chronic heart failure. According to another aspect of this embodiment, the patient is a patient with chronic heart failure of, for example, NYHA class I, II, III, or IV, having stage 3a and / or 3b chronic kidney disease and reduced ejection fraction (HFrEF). Patients of this embodiment, including various aspects of this embodiment, are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. In another embodiment, the present invention provides a method for treating, preventing, protecting against, reducing the risk of, delaying the onset and / or slowing the progression of chronic kidney disease in a patient who has not been diagnosed with chronic heart failure, comprising administering empagliflozin to a patient (in this case, a patient with pipism diabetic). In particular, this embodiment relates to a method for treating and / or slowing the progression of chronic kidney disease in a patient. In a part of this embodiment, the patient is a patient with stage 3 chronic kidney disease, including stages 3a and / or 3b. In another part of this embodiment, the patient is a patient with stage 4 chronic kidney disease.

[0037] In one embodiment, the present invention - New occurrence of albuminuria, - Progression from nonalbuminuria to microalbuminuria or macroalbuminuria. -45 mL / min / 1.73m 2 The following doubling of serum creatinine levels associated with eGFR (based on dietary changes in the mesenteric disease (MDRD) formula): - Sustained decrease of 30%, 40%, 50%, or 57% or more in eGFR (CKD-EPI), especially a sustained decrease of 40% or more in eGFR (CKD-EPI), -30 mL / min / 1.73 m 2 For patients with the above baseline eGFR, the flow rate is 15 mL / min / 1.73 m². 2 Sustained eGFR (CKD-EPI) less than -30 mL / min / 1.73 m 2 For patients with a baseline eGFR of less than 10 mL / min / 1.73 m 2 Sustained eGFR (CKD-EPI) less than - The need for continuous kidney replacement therapy, - The need for chronic dialysis treatment, —The need to receive a kidney transplant, - Death due to kidney disease, or - A sustained decrease of 40% or more in eGFR (CKD-EPI) or 30 mL / min / 1.73 m 2 For patients with the above baseline eGFR, the flow rate is 15 mL / min / 1.73 m². 2 Sustained eGFR (CKD-EPI) less than, and 30 mL / min / 1.73 m 2 For patients with a baseline eGFR of less than 10 mL / min / 1.73 m 2 Sustained eGFR (CKD-EPI) less than A combination of, or - A sustained decrease of 40% or more in eGFR (CKD-EPI) or 30 mL / min / 1.73 m 2 For patients with the above baseline eGFR, the flow rate is 15 mL / min / 1.73 m². 2Sustained eGFR (CKD-EPI) less than 30 mL / min / 1.73 m 2 For patients with a baseline eGFR of less than 10 mL / min / 1.73 m 2 Sustained eGFR (CKD-EPI) less than The need for chronic dialysis treatment, and I need a kidney transplant. compound To provide methods for treating, preventing, protecting against, or delaying the occurrence of these conditions.

[0038] In patients diagnosed with chronic heart failure, the method includes administering empagliflozin to the patient. According to this embodiment, the patient is a patient with chronic heart failure of, for example, NYHA class I, II, III, or IV with preserved ejection fraction (HFpEF). According to another embodiment, the patient is a patient with chronic heart failure of, for example, NYHA class I, II, III, or IV with reduced ejection fraction (HFrEF). Patients of this embodiment, including various aspects of this embodiment, are, for example, non-diabetic patients, pre-diabetic patients, or patients with type 2 diabetes mellitus, particularly non-diabetic patients. In the method of the present invention, empagliflozin may be administered to the patient in combination with one or more other therapeutic substances as necessary. According to one embodiment of the method described earlier and later, the patient is a patient with elevated BNP or elevated plasma NT-proBNP. For example, the patient has elevated BNP of 75 pg / mL or higher (NT-proBNP ≥ 300 pg / mL), 100 pg / mL or higher (NT-proBNP ≥ 400 pg / mL), 150 pg / mL or higher (NT-proBNP ≥ 600 pg / mL), or 225 pg / mL or higher (NT-proBNP ≥ 900 pg / mL). According to another embodiment of the method described earlier and later, the patient is a patient who has been hospitalized for heart failure within the past nine months, in particular a patient who has been hospitalized for heart failure within the past nine months and has elevated BNP or NT-proBNP.

[0039] According to embodiments of the methods described earlier and later, the patient is a patient with a reduced ejection fraction (HFrEF) and elevated NT-proBNP of ≥36% to ≤40% for patients without atrial fibrillation, or ≥2500 pg / ml for patients with atrial fibrillation. According to embodiments of the methods described earlier and later, the patient is a patient with a reduced ejection fraction (HFrEF) and elevated NT-proBNP of ≥31% to ≤35% for patients without atrial fibrillation, or ≥1000 pg / ml for patients with atrial fibrillation. According to embodiments of the methods described earlier and later, the patient is a patient with reduced ejection fraction (HFrEF) and elevated NT-proBNP of ≥600 pg / ml for patients without ejection fraction EF ≤30% or ≥1200 pg / ml for patients with atrial fibrillation. According to one embodiment of the method described earlier and later, the patient is a patient with normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment. According to this embodiment, the patient is 20 mL / min / 1.73 m 2 It has the above eGFR. According to one embodiment of the method described earlier and later, the patient is a patient with normal renal function, mild renal impairment, or moderate renal impairment. According to this embodiment, the patient is 30 mL / min / 1.73 m 2 It has eGFR. According to another embodiment of the method described earlier and later, the patient is a patient with normal renal function, mild renal impairment, or moderate CKD 3A. According to this embodiment, the patient is 45 mL / min / 1.73 m 2 It has the above eGFR.

[0040] According to another embodiment of the method described earlier and later, the patient is a patient with normal renal function or mild renal impairment. According to this embodiment, the patient is 60 mL / min / 1.73 m2 It has the above eGFR. According to another embodiment of the method described earlier and later, the patient is a patient with moderate A renal impairment (CKD 3A). According to this embodiment, the patient is 45 mL / min / 1.73 m 2 The above and 60 mL / min / 1.73 m 2 It has a lower eGFR. According to another embodiment of the method described earlier and later, the patient is a patient with moderate B renal impairment (CKD 3B). According to this embodiment, the patient is 30 mL / min / 1.73 m 2 The above and 45 mL / min / 1.73 m 2 It has a lower eGFR. According to embodiments of the methods described earlier and later, the patient is a non-diabetic patient, a prediabetic patient, a patient with type 2 diabetes mellitus, or a patient with type 1 diabetes mellitus. According to another embodiment of the method described earlier and later, the patient is a non-diabetic patient, a prediabetic patient, or a patient with type 2 diabetes mellitus. According to another embodiment of the method described earlier and later, the patient is a patient with prediabetes. According to this embodiment, the patient has an HbA1c of 5.7% or higher and less than 6.5%. According to another embodiment of the method described earlier and later, the patient is either a prediabetic or non-diabetic patient. In this aspect of the embodiment, the patient has an HbA1c of less than 6.5%. According to another embodiment of the method described earlier and later, the patient is a non-diabetic patient. According to this embodiment, the patient has an HbA1c of less than 5.7%. In another context, non-diabetic patients do not exhibit impaired glucose tolerance (IGT), meaning they have normal glucose tolerance. For example, their blood glucose or plasma glucose (PG) concentration two hours after a meal is less than 140 mg / dI (7.78 millimoles / L). In another context, non-diabetic patients do not exhibit abnormal fasting blood glucose (IFG), meaning they have normal fasting glucose levels. For example, their fasting plasma glucose (FPG) concentration is less than 100 mg / dl, i.e., less than 5.6 millimoles / l.

[0041] In particular, non-diabetic patients do not exhibit abnormal fasting blood glucose (IFG) and impaired glucose tolerance (IGT), meaning they have normal glucose tolerance. For example, their fasting plasma glucose (FPG) concentration is less than 100 mg / dl, i.e., less than 5.6 mmol / l, and their blood glucose or plasma glucose (PG) concentration 2 hours postprandial is less than 140 mg / dl (7.78 mmol / L). According to embodiments of the methods described earlier and later, empagliflozin is administered to a patient in doses ranging from 1 mg to 25 mg per day, for example, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, or 25 mg per day. The administration of empagliflozin may occur once or twice daily, more preferably once daily. For example, the dose for a daily administration is 10 mg or 25 mg. The preferred route of administration is oral. According to a particular aspect of the present invention, empagliflozin is administered to the patient at a dose of 10 mg per day. According to another special aspect of the present invention, empagliflozin is administered to the patient at a dose of 25 mg per day. It is preferable that empagliflozin be administered to the patient once daily.

[0042] In one embodiment, patients within the meaning of the present invention may include patients with chronic heart failure who have not already been treated with drugs for the treatment of chronic heart failure (heart failure drug-naive patients). Thus, in embodiments, the therapeutic agents described herein may be used in heart failure drug-naive patients. In another embodiment, patients within the meaning of the present invention may include patients with chronic heart failure and prediabetes or type 2 diabetes mellitus (T2DM) who are not already being treated with antidiabetic drugs (T2DM drug-naive patients). Thus, in this embodiment, the therapeutic agents described herein may be used in T2DM drug-naive patients. Furthermore, the method of the present invention is particularly suitable for the treatment of patients with chronic heart failure and insulin dependence, i.e., patients who are treated with insulin or insulin derivatives or insulin substitutes or formulations containing insulin or insulin derivatives or these substitutes, or who are otherwise treated or who will require treatment with such substances. These patients include patients with type 2 diabetes and patients with type 1 diabetes. Furthermore, it is found that administration of the pharmaceutical composition of the present invention does not cause or causes a low risk of hypoglycemia. Therefore, the treatment or prevention of hypoglycemia of the present invention is also advantageously possible in these patients who show or have an increased risk of hypoglycemia. Administration of empagliflozin causes excess blood glucose to be excreted in the patient's urine based on its SGLT2 inhibitory activity, resulting in no weight gain or even a weight loss in the patient. Therefore, the method of the present invention is favorably suited to these patients with chronic heart failure diagnosed with overweight and obesity, particularly one or more of the following conditions selected from the group consisting of Class I obesity, Class II obesity, Class III obesity, visceral obesity, and abdominal obesity. In addition, the method of the present invention is favorably suited to these patients for whom weight gain is contraindicated. Where the present invention relates to patients requiring treatment or prevention, it primarily concerns the treatment and prevention of humans, but the pharmaceutical composition may also be used in veterinary medicine for mammals. Within the scope of the present invention, adult patients are preferably humans aged 18 years or older. Also within the scope of the present invention, patients are adolescent humans, i.e., humans aged 10 to 17 years, preferably 13 to 17 years. According to embodiments of the present invention, empagliflozin is administered to a patient in combination with one or more other therapeutic substances. The combined administration may be simultaneous, separate, or sequential. In one aspect of this embodiment of the present invention, one or more other therapeutic substances are selected from active substances indicated for the treatment of chronic heart failure, antidiabetic substances, active substances that lower total cholesterol, LDL cholesterol, non-HDL cholesterol and / or Lp(a) levels in the blood, active substances that raise HDL cholesterol levels in the blood, active substances that lower blood pressure, active substances indicated for the treatment of atherosclerosis or obesity, antiplatelet substances, anticoagulants, and vascular endothelial protectants.

[0043] In one embodiment, the active substance indicated for the treatment of chronic heart failure is selected from angiotensin receptor blockers (ARBs), angiotensin invertase (ACE) inhibitors, angiotensin receptor neprilysin inhibitors (ARNi), beta-blockers, aldosterone antagonists (MRAs), digoxin, ivabradine, and diuretics. In one embodiment, the antidiabetic substance is selected from metformin, sulfonylurea, nateglinide, repaglinide, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs, and DPP-4 inhibitors. In one embodiment, a patient receives usual care, which includes medical treatment and / or devices prescribed for a patient with heart failure, e.g., chronic or acute heart failure. In one aspect, a patient diagnosed with HFrEF in particular has or receives a device selected from the group consisting of ICDs (implantable electrocardiographs / defibrillators) and CRTs (cardiac resynchronization therapy), e.g., CRT-P (cardiac resynchronization pacemaker) and CRT-D (cardiac resynchronization therapy combining a pacemaker and a defibrillator). In one embodiment, the patient receives standard medical care prescribed for patients with chronic heart failure. In one aspect of this embodiment, empagliflozin is administered to the patient in combination with one or more active substances prescribed for the treatment of chronic heart failure. For example, empagliflozin is administered in combination with one or more active substances selected from the group consisting of angiotensin receptor blockers (ARBs), angiotensin-inverting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists, diuretics, angiotensin receptor neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists, and ivabradine. According to this aspect of the embodiment, the patient is, for example, a non-diabetic or pre-diabetic patient. In one aspect of this embodiment, the number, dosage, and / or regimen of the drugs used to treat chronic heart failure are reduced in the patient, while empagliflozin administration continues. For example, the dosage of one or more diuretics administered to the patient may be reduced, while empagliflozin administration continues.

[0044] Examples of angiotensin II receptor blockers (ARBs) include telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan, and eprosartan, and some dosages of these drugs are shown below, for example: Candesartan (Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil • Eprosartan (tebeten), 400 mg or 600 mg Irbesartan (Avapro), 75 mg, 150 mg, or 300 mg. • Losartan (Kozar), 25 mg, 50 mg, or 100 mg of losartan potassium • Telmisartan (Micardis), 40 mg or 80 mg • Telmisartan (Micardis HCT), 40 mg / 12.5 mg, 80 mg / 12.5 mg, and 80 mg / 25 mg, respectively, containing telmisartan and hydrochlorothiazide. • Telmisartan / amlodipine (Twinsta), 40 mg / 5 mg, 40 mg / 10 mg, 80 mg / 5 mg, and 80 mg / 10 mg, respectively. Valsartan (Diovan), 40 mg, 80 mg, 160 mg, or 320 mg. Examples of angiotensin-inverting enzyme (ACE) inhibitors include benazepril, captopril, ramipril, lisinopril, moexipril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril, and trandolapril, some of which are shown below, for example: Benazepril (rotensin), administered orally in doses of 5 mg, 10 mg, 20 mg, and 40 mg. Captopril (Capoten), available as 12.5 mg, 25 mg, 50 mg, and 100 mg tablets for oral administration. • Enalapril (Vasotec), tablets for oral administration in doses of 2.5 mg, 5 mg, 10 mg, and 20 mg. • Fosinopril (Monopril), administered orally as 10 mg, 20 mg, and 40 mg tablets. • Lisinopril (Plinivir, Zestril), 5 mg, 10 mg, and 20 mg tablets for oral administration • Moexipril (Univasc), 7.5 mg and 15 mg orally • Perindopril (Aceon), administered orally in concentrations of 2 mg, 4 mg, and 8 mg. • Quinapril (Acpril), administered orally in doses of 5 mg, 10 mg, 20 mg, or 40 mg. Ramipril (Artes), 1.25 mg, 2.5 mg, 5 mg, 10 mg • Trandolapril (Maviq), 1 mg, 2 mg, or 4 mg for oral administration.

[0045] Examples of beta-blockers include acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nevivolol, propranolol, timolol, and carvedilol, and some doses of these drugs are shown below, for example: • Acebutrol (Sectral), acebutrol hydrochloride in 200 or 400 mg doses. • Atenolol (tenormin), 25 mg, 50 mg, and 100 mg oral tablets Betaxolol (Kerlon), 10 mg and 20 mg oral tablets. Bisoprolol / hydrochlorothiazide (Diac), 2.5 / 6 mg, 5 / 6.25 mg, 10 / 6.25 mg • Bisoprolol (Zebeta), 5 mg and 10 mg oral tablets • Metoprolol (Lopressor, Toprol XL), 50 mg and 100 mg oral tablets and 5 mL ampoules for intravenous administration. • Propranolol (Inderal), 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg oral tablets Timolol (Brocadren), timolol maleate for oral administration in doses of 5 mg, 10 mg, or 20 mg. Examples of aldosterone antagonists include spironolactone, eprene, canrenone, and fineronone, and some dosages of these drugs are shown below, for example: • Spironolactone (e.g., Aldactone), 25 mg or 50 mg once daily or every other day. • Eplenone (e.g., Insupra), 25 mg or 50 mg once daily.

[0046] Examples of diuretics include bumetanide, hydrochlorothiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, xipamide, indapamide, furosemide, pyretanide, torasemide, spironolactone, eplerenone, amiloride, and triamterene. These drugs include thiazide diuretics, e.g., chlorthalidone, HCT; loop diuretics, e.g., furosemide, torasemide; or potassium sparing diuretics, e.g., eplerenone; or combinations thereof. Some doses of these drugs are shown below, for example: • Amyloride (Midamol), 5 mg of anhydrous amyloride HCl • Bumetanide (Bumex) is available as incised tablets for oral administration, in 0.5 mg (light green), 1 mg (yellow), and 2 mg (peach) doses. Chlorothiazide (diuryl) • Chlorthalidon (Higroton) • Furosemide (Lasix) • Hydrochlorothiazide (Esidolic, Hydrodiuryl) • Indapamide (Rozol) and spironolactone (Aldactone) • Eplenone (insula).

[0047] An example of an angiotensin receptor neprilysin inhibitor (ARNi) is the combination of valsartan and sacubitril (Entresto). Cardiac pacemaker I f An example of current suppression is ivabradine (procoralan, corlanol). Examples of calcium channel blockers include amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lasidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, garopamil, and diltiazem. Examples of drugs that lower blood pressure include angiotensin II receptor blockers (ARBs), angiotensin-inverting enzyme (ACE) inhibitors, beta-blockers, diuretics, and calcium channel blockers. In another aspect of this embodiment, the patient is a patient with type 2 diabetes mellitus, and empagliflozin is administered to the patient in combination with one or more active substances indicated for the treatment of chronic heart failure, and in combination with one or more antidiabetic substances. Examples of antidiabetic substances include metformin, sulfonylurea, nateglinide, repaglinide, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs, and DPP-4 inhibitors. Examples of these include metformin and DPP-IV inhibitors, e.g., sitagliptin, saxagliptin, and linagliptin. Examples of active substances indicated for the treatment of chronic heart failure include angiotensin receptor blockers (ARBs), angiotensin-inverting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists, and diuretics.

[0048] Therefore, according to one aspect of the method of the present invention, empagliflozin is administered to the patient in combination with linagliptin. Patients in this aspect are particularly those with type 2 diabetes mellitus. Preferred doses are, for example, 10 mg of empagliflozin once daily and 5 mg of linagliptin once daily. Therefore, according to one aspect of the method of the present invention, empagliflozin is administered to the patient in combination with metformin hydrochloride. Patients in this aspect are particularly those with type 2 diabetes mellitus. Preferred doses are, for example, 10 mg of empagliflozin once daily or 5 mg of empagliflozin twice daily and 500 mg, 850 mg, or 1000 mg of metformin hydrochloride twice daily. In one aspect of this embodiment, the number, dose, and / or regimen of the drugs used to treat chronic heart failure are reduced in the patient, while empagliflozin administration continues. In another aspect of this embodiment, the number, dose, and / or regimen of the drugs used to treat type 2 diabetes mellitus are reduced in the patient, while empagliflozin administration continues. In yet another aspect of this embodiment, the number, dose, and / or regimen of the drugs used to treat type 2 diabetes mellitus and the drugs used to treat chronic heart failure are reduced in the patient, while empagliflozin administration continues. In this context, empagliflozin is administered in combination with metformin, or in combination with linagliptin, or in combination with metformin and linagliptin, in combination with one or more active substances selected from the group consisting of angiotensin receptor blockers (ARBs), angiotensin invertase (ACE) inhibitors, beta-blockers, aldosterone antagonists, diuretics, angiotensin receptor neprilysin inhibitors (ARNis), mineralocorticoid receptor antagonists, and ivabradine. Examples of the active substances in the above group, including their drug concentrations, administration schemes, and formulations, are known to those skilled in the art. In the context of the present invention, the term metformin includes metformin hydrochloride in the form of an immediate-release formulation, an extended-release formulation, or a delayed-release formulation. The dose of metformin hydrochloride administered to a patient is particularly 500 mg to 2000 mg per day, for example, 750 mg, 1000 mg, 1500 mg, and 2000 mg per day. Empagliflozin and metformin may be administered separately in two different dosage forms, or combined in one dosage form. A combined dosage form of empagliflozin and metformin as an immediate-release formulation is described in WO 2011 / 039337, known, for example, as SYNJARDI®. Combined dosage forms of empagliflozin and metformin in which empagliflozin is part of an immediate-release formulation and metformin is part of a long-release formulation are described in WO 2012 / 120040 and WO 2013 / 131967.

[0049] The preferred dose of linagliptin administered to patients is 5 mg per day. Empagliflozin and linagliptin may be administered separately in two different dosage forms, or combined in one dosage form. A combined dosage form of empagliflozin and linagliptin is described in WO 2010 / 092124 and is known, for example, as GLYXAMBI®. Within the scope of this invention, it should be understood that the combinations, compositions, or combined administrations of the present invention may aim for simultaneous, sequential, or separate administration of the active ingredients. In this context, “combination” or “combined” within the meaning of the present invention may include, but is not limited to, limited forms, multi-drug forms and non-multi-drug (e.g., free) forms (including kits) and uses, such as simultaneous, sequential or separate use of components. The combined administration of the present invention may occur by administering the active ingredients together, for example, by administering them simultaneously in a single formulation or dosage form, or in two separate formulations or dosage forms. Alternatively, the administration may occur by administering the active ingredients sequentially, for example, in two separate formulations or dosage forms consecutively. For the combination therapy of the present invention, the active ingredients may be administered separately (meaning they are formulated separately) or together (meaning they are formulated in the same formulation or in the same dosage form). Therefore, the administration of one element of the combination of the present invention may be before, simultaneously with, or after the administration of the other elements of the combination.

[0050] Unless otherwise specified, combination therapy may refer to first-line therapy, second-line therapy, or third-line therapy, or initial or combined therapy or replacement therapy. The methods of the present invention are particularly suitable for the long-term treatment or prevention of diseases and / or symptoms described earlier and later. The term “long-term” as used earlier and later refers to the treatment or administration of a patient over a period of time longer than 12 weeks, preferably longer than 25 weeks, and more preferably longer than 1 year. The pharmaceutical composition comprising empagliflozin of the present invention can be formulated for oral or parenteral (including intramuscular, subcutaneous, and intravenous) administration in liquid or solid form or in a form suitable for administration by inhalation or gas injection. Oral administration is preferred. The pharmaceutical composition can be formulated in the form of tablets, granules, fine particles, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dried syrups, chewable tablets, lozenges, effervescent tablets, drops, suspensions, rapidly dissolving tablets, orally rapidly dispersible tablets, etc. The pharmaceutical composition and dosage form preferably contain one or more pharmaceutically acceptable carriers that are compatible with the other components of the formulation and are “acceptable” in the sense that they are not harmful to the recipient. Examples of pharmaceutically acceptable carriers are known to those skilled in the art. The pharmaceutical compositions and methods of the present invention exhibit advantageous effects in the treatment and prevention of the diseases and symptoms described above. These advantageous effects may be observed, for example, in terms of efficacy, dosage concentration, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer side effects, convenience, and compliance. Methods for producing empagliflozin are known to those skilled in the art. Advantageously, the compounds of the present invention can be prepared using synthetic methods described in the literature, including the previously cited patent applications. Preferred production methods are described in WO 2006 / 120208 and WO 2007 / 031548. With respect to empagliflozin, an advantageous crystalline form is described in international patent application WO 2006 / 117359 (which is incorporated herein by reference). Further embodiments, features, and advantages of the present invention may become apparent from the following examples. The following examples can be used, by analogy, to illustrate the principles of the present invention, but are not intended to limit the invention. [Examples]

[0051] Example 1: Treatment of patients with chronic heart failure and HFrEF The long-term effects of empagliflozin treatment on cardiovascular death, hospitalization for heart failure, and other parameters in a reasonable population of patients with chronic heart failure and reduced ejection fraction are investigated as follows: Patients with chronic heart failure and NYHA II, III, or IV symptoms, reduced ejection fraction (LVEF ≤40%), and elevated BNP (or elevated NT-proBNP) (e.g., as specified below) are treated with empagliflozin (or, if necessary, in combination with one or more other active substances, e.g., those described herein) for an extended period (e.g., approximately 20–38 months for each patient) and compared to patients treated with placebo in a usual care background. Empagliflozin is administered orally once daily (e.g., 10 mg daily). Patients include non-diabetic patients, patients with prediabetes, and patients with type 2 diabetes mellitus. Prediabetes is diagnosed when HbA1c is 5.7% or higher and less than 6.5%. If HbA1c is less than 5.7%, the individual is considered non-diabetic. The patient has a LVEF of 40% or less.

[0052] Patients with elevated BNP (or elevated NT-proBNP) are identified as having one of the following: - Elevated BNP ≥ 150 pg / mL or NT-proBNP ≥ 600 pg / mL; or - If the patient has been hospitalized for heart failure within the past 9 months, elevated BNP ≥ 100 pg / mL or NT-proBNP ≥ 400 pg / mL. Patients with reduced ejection fraction may be included according to at least one of the following evidence of heart failure: If the ejection fraction (EF) is between 36% and 40%, elevated NT-proBNP should be 2500 pg / ml or higher in patients without atrial fibrillation, or 5000 pg / ml or higher in patients with atrial fibrillation. If the ejection fraction (EF) is between 31% and 35%, elevated NT-proBNP should be ≥1000 pg / ml in patients without atrial fibrillation, or ≥2000 pg / ml in patients with atrial fibrillation. If the ejection fraction (EF) is 30% or less, elevated NT-proBNP should be 600 pg / ml or higher in patients without atrial fibrillation, or 1200 pg / ml or higher in patients with atrial fibrillation. The study is event-driven, and all randomized patients will remain in the trial until a specific number of patients experiencing a primary endpoint event are reached. The number of confirmed and declared primary endpoint events will be continuously monitored throughout the study. Patients with cardiovascular risk factors should be treated in accordance with usual care, which includes, for example, treatment with or without cardiac device therapy including ICDs, CRT-Ds, or CRT-Ps, and with therapeutic agents selected from diuretics, ARNi, ACE inhibitors, ARBs, statins, aspirin, beta-blockers, mineralocorticoid antagonists, or ivabradine. Patients in the study will follow the following criteria: - Ages 18 and above - Diagnosis of heart failure (HF). Identifying HF for inclusion in this study is a left ventricular ejection fraction (LVEF) of 40% or less (per local reading) (ideally obtained by echocardiography, but radionuclide ventricleography and angiography are acceptable). Ejection fraction values ​​should preferably be obtained before randomization and within 6 months after myocardial infarction (MI) or other event affecting ejection fraction. —One or more symptoms of heart failure (HF) (NYHA Class II-IV) - At least one of the following: elevated NT-proBNP ≥ 600 pg / mL and / or elevated NT-proBNP ≥ 400 pg / mL if the patient has been hospitalized for heart failure within the past 9 months. - Background therapy for heart failure if necessary - In the case of antidiabetic background -Body mass index (BMI) < 45 kg / m 2 -eGFR ≥ 20 mL / min / 1.73 m 2 Alternatively, eGFR ≥ 30 mL / min / 1.73 m² 2

[0053] The time to cardiovascular death or hospitalization due to heart failure is measured in patients with heart failure and reduced ejection fraction (according to the criteria described above) treated with empagliflozin (e.g., 10 mg once daily) compared to a placebo. Measure one or more of the following events: - Time until first hospitalization for heart failure - eGFR (CKD-EPI) slope of change from baseline Time to the first occurrence of sustained reduction of -40% eGFR (CKD-EPI) or more -Baseline eGFR ≥30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 Time until the first occurrence -Baseline eGFR <30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 Time until the first occurrence - Sustained reduction of 40% or more in eGFR (CKD-EPI) or Baseline eGFR ≥30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 , baseline eGFR <30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 The combined time until the first occurrence - Sustained reduction of 40% or more in eGFR (CKD-EPI) or Baseline eGFR ≥30 mL / min / 1.73 m 2In patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 , and baseline eGFR <30 mL / min / 1.73 m 2 For patients requiring chronic dialysis treatment or kidney transplantation, a sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 The combined time to the first occurrence - time to cardiovascular death. - Time to death from any cause - Health-related quality of life (e.g., as measured by KCCQ or KCCQ-12) - Time to the onset of new type 2 diabetes mellitus in non-diabetic patients

[0054] - Time until readmission for heart failure - Changes in NYHA classification - Time to hospitalization for any cause, including initial and / or recurrent cases - Time to the onset of atrial fibrillation - Time to non-fatal or fatal myocardial infarction - Time to non-fatal or fatal stroke - Time to cardiovascular death or combined myocardial infarction - Time to cardiovascular death or stroke (complex condition) - Time to cardiovascular death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal myocardial infarction, or non-fatal stroke (so-called 3-point MACE). - Changes in eGFR - Progression to macroalbuminuria (defined as albumin / creatinine ratio (ACR) ≥ 300 mg / g) - Time until chronic dialysis treatment is required - Time until kidney transplant is needed - A combination of decreased eGFR, kidney replacement therapy, or renal death. - A combination of decreased eGFR, kidney replacement therapy, renal death, or cardiovascular death. - A combination of eGFR reduction, kidney replacement therapy, renal death, or death from any cause.

[0055] Example 2: Treatment of patients with chronic heart failure and HFpEF The long-term effects of empagliflozin treatment on cardiovascular death or hospitalization and other parameters for heart failure in a reasonable population of patients with chronic heart failure and preserved ejection fraction are investigated as follows: Patients with chronic heart failure and NYHA II, III, or IV symptoms and preserved ejection fraction (greater than 40% or greater than 50% LVEF) are treated with empagliflozin (in combination, if necessary, with one or more other active substances, e.g., those described herein) for an extended period (e.g., approximately 20–38 months for each patient) and compared to patients treated with placebo in a usual care background. Empagliflozin is administered orally once daily (e.g., 10 mg daily). Patients include non-diabetic patients, patients with prediabetes, and patients with type 2 diabetes mellitus. Prediabetes is diagnosed when HbA1c is 5.7% or higher and less than 6.5%. If HbA1c is less than 5.7%, the individual is considered non-diabetic. Patients have a LVEF greater than 40%, and especially greater than 50%.

[0056] The patient includes individuals who have been hospitalized for heart failure within the past nine months and / or have elevated BNP ≥ 75 pg / mL or NT-proBNP ≥ 300 pg / mL (for patients without atrial fibrillation (AF)) or elevated BNP > 225 pg / mL or NT-proBNP > 900 pg / mL (for patients with atrial fibrillation (AF)). The study is event-driven, and all randomized patients will remain in the trial until a specific number of patients experiencing a primary endpoint event are reached. The number of confirmed and declared primary endpoint events will be continuously monitored throughout the study. Patients with cardiovascular risk factors should be treated according to usual care, which includes symptomatic treatment as well as treatment of cardiovascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia. Patients in the study will follow the following criteria: - Ages 18 and above - Diagnosis of heart failure (HF). Identifying HF for inclusion in this study is a left ventricular ejection fraction (LVEF) greater than 40% (per local reading) (ideally obtained by echocardiography, but radionuclide ventricleography and angiography are acceptable). Ejection fraction values ​​should preferably be obtained before randomization and within 6 months after myocardial infarction (MI) or other event affecting ejection fraction. —One or more symptoms of heart failure (HF) (NYHA Class II-IV) - Structural heart disease recorded by echocardiography (left atrial enlargement or left ventricular hypertrophy) - At least one of the following: Hospitalization for heart failure and / or elevated NT-proBNP (>300 pg / mL for patients without atrial fibrillation (AF) or >900 pg / mL for patients with atrial fibrillation (AF)) within the past 9 months. - Background therapy for heart failure if necessary - In the case of antidiabetic background -Body mass index (BMI) < 45 kg / m 2 -eGFR ≥ 20 mL / min / 1.73 m 2 Alternatively, eGFR ≥ 30 mL / min / 1.73 m² 2

[0057] The time to cardiovascular death or hospitalization due to heart failure is measured in patients with heart failure and preserved ejection fraction (according to the criteria described above) treated with empagliflozin (e.g., 10 mg once daily) compared to a placebo. Measure one or more of the following events: - Time until first hospitalization for heart failure - eGFR (CKD-EPI) slope of change from baseline Time to the first occurrence of sustained reduction of -40% eGFR (CKD-EPI) or more -Baseline eGFR ≥30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 Time until the first occurrence -Baseline eGFR <30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 Time until the first occurrence - Sustained reduction of 40% or more in eGFR (CKD-EPI) or Baseline eGFR ≥30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 , baseline eGFR <30 mL / min / 1.73 m 2 For patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 The combined time until the first occurrence - Sustained reduction of 40% or more in eGFR (CKD-EPI) or Baseline eGFR ≥30 mL / min / 1.73 m 2 In patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 , baseline eGFR <30 mL / min / 1.73 m 2 In patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <10 mL / min / 1.73m² 2 The combined time until the first occurrence - Sustained reduction of 40% or more in eGFR (CKD-EPI) or Baseline eGFR ≥30 mL / min / 1.73 m 2 In patients with chronic kidney disease (CKD-EPI), sustained eGFR (CKD-EPI) <15 mL / min / 1.73 m² 2 , baseline eGFR <30 mL / min / 1.73 m 2 For patients requiring chronic dialysis treatment or kidney transplantation, a sustained eGFR (CKD-EPI) <10 mL / min / 1.73 m² 2 The combined time until the first occurrence - Time to cardiovascular death - Time to death from any cause - Health-related quality of life (e.g., as measured by KCCQ or KCCQ-12) - Time to the onset of new type 2 diabetes mellitus in non-diabetic patients

[0058] - Time until readmission for heart failure - Changes in NYHA classification - Time to hospitalization for any cause, including initial and / or recurrent cases - Time to the onset of atrial fibrillation - Time to non-fatal or fatal myocardial infarction - Time to non-fatal or fatal stroke - Cardiovascular death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal myocardial infarction (excluding asymptomatic myocardial infarction), non-fatal stroke (so-called 3-point MACE) - Changes in eGFR - Progression to macroalbuminuria (defined as albumin / creatinine ratio (ACR) ≥ 300 mg / g) - Time until chronic dialysis treatment is required - Time until kidney transplant is needed - A combination of decreased eGFR, kidney replacement therapy, or renal death. - A combination of decreased eGFR, kidney replacement therapy, renal death, or cardiovascular death. - A combination of eGFR reduction, kidney replacement therapy, renal death, or death from any cause. Health-related quality of life can be measured according to the KCCQ or KCCQ-12. The KCCQ-12 is an activated, shortened version of the original 23-item KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-management questionnaire is designed to assess physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self-efficacy, and quality of life in patients with HF.

[0059] Example 3: Treatment of patients with chronic heart failure and HFrEF The effects of empagliflozin treatment on functional capacity and other parameters in a reasonable population of patients with chronic heart failure and reduced ejection fraction and frailty are investigated as follows: Patients with chronic heart failure and NYHA II, III, or IV symptoms, reduced ejection fraction (LVEF ≤40%), elevated BNP (or elevated NT-proBNP) (e.g., as specified below), and frailty are treated with empagliflozin (or, if necessary, in combination with one or more other active substances, e.g., those described herein) over a period of time (e.g., about 12 weeks for each patient) and compared to patients treated with placebo in a usual care background. Empagliflozin is administered orally once daily (e.g., 10 mg daily). Patients include non-diabetic patients, patients with prediabetes, and patients with type 2 diabetes mellitus. Prediabetes is diagnosed when HbA1c is 5.7% or higher and less than 6.5%. If HbA1c is less than 5.7%, the individual is considered non-diabetic. The patient has a LVEF of 40% or less.

[0060] Patients with elevated BNP (or elevated NT-proBNP) are identified as having one of the following: - Elevated BNP ≥ 150 pg / mL or NT-proBNP ≥ 600 pg / mL; or - If the patient has been hospitalized for heart failure within the past 9 months, elevated BNP ≥ 100 pg / mL or NT-proBNP ≥ 400 pg / mL. Patients with reduced ejection fraction may be included according to at least one of the following evidence of heart failure: If the ejection fraction (EF) is between 36% and 40%, elevated NT-proBNP should be 2500 pg / ml or higher in patients without atrial fibrillation, or 5000 pg / ml or higher in patients with atrial fibrillation. If the ejection fraction (EF) is between 31% and 35%, elevated NT-proBNP should be ≥1000 pg / ml in patients without atrial fibrillation, or ≥2000 pg / ml in patients with atrial fibrillation. If the ejection fraction (EF) is 30% or less, elevated NT-proBNP should be 600 pg / ml or higher in patients without atrial fibrillation, or 1200 pg / ml or higher in patients with atrial fibrillation. Frail patients are included in the study, for example, if they complete a 6-minute walking test by walking less than 350 meters. At the end of the study period for each patient, functional capacity, particularly motor capacity, such as a 6-minute walk test, and further clinical parameters (e.g., the following) will be examined. Patients with cardiovascular risk factors should be treated in accordance with usual care, which includes, for example, treatment with or without cardiac device therapy including ICDs, CRT-Ds, or CRT-Ps, and with therapeutic agents selected from diuretics, ARNi, ACE inhibitors, ARBs, statins, aspirin, beta-blockers, mineralocorticoid antagonists, or ivabradine. Patients in the study will follow the following criteria: - Ages 18 and above - Diagnosis of heart failure (HF). Identifying HF for inclusion in this study is a left ventricular ejection fraction (LVEF) of 40% or less (per local reading) (ideally obtained by echocardiography, but radionuclide ventricleography and angiography are acceptable). Ejection fraction values ​​should preferably be obtained before randomization and within 6 months after myocardial infarction (MI) or other event affecting ejection fraction. —One or more symptoms of heart failure (HF) (NYHA Class II-IV) - At least one of the following: elevated NT-proBNP ≥ 600 pg / mL and / or elevated NT-proBNP ≥ 400 pg / mL if the patient has been hospitalized for heart failure within the past 9 months. -For example, frailty, which can be measured by a 6-minute walking test in which the patient walks a distance of less than 350 meters. - Background therapy for heart failure if necessary - In the case of antidiabetic background -Body mass index (BMI) < 45 kg / m 2 -eGFR ≥ 20 mL / min / 1.73 m 2 Alternatively, eGFR ≥ 30 mL / min / 1.73 m² 2

[0061] At a specified time interval, e.g., at the end of 12 weeks, functional capacity, in particular exercise capacity, e.g., a 6-minute walk test, is measured in patients with heart failure and reduced ejection fraction (according to the criteria described above) treated with empagliflozin (e.g., 10 mg once daily) or placebo. Measure one or more of the following events: - Changes in NYHA classification - Health-related quality of life (e.g., measured by KCCQ or KCCQ-12, MLHFQ, fatigue score, depression score, anxiety score, and overall assessment score) - Changes from baseline biomarkers, e.g., NT-proBNP - Time until first hospitalization for heart failure - The time until readmission for heart failure.

[0062] Example 4: Treatment of patients with chronic heart failure and HFpEF The effects of empagliflozin treatment on functional capacity and other parameters in a reasonable population of patients with chronic heart failure and preserved ejection fraction and frailty are investigated as follows: Patients with chronic heart failure and NYHA II, III, or IV symptoms, preserved ejection fraction (LVEF greater than 40% or greater than 50%), and frailty are treated with empagliflozin (or, if necessary, in combination with one or more other active substances, e.g., those described herein) over a period of time (e.g., about 12 weeks for each patient) and compared to patients treated with placebo in a usual care background. Empagliflozin is administered orally once daily (e.g., 10 mg daily). Patients include non-diabetic patients, patients with prediabetes, and patients with type 2 diabetes mellitus. Prediabetes is diagnosed when HbA1c is 5.7% or higher and less than 6.5%. If HbA1c is less than 5.7%, the individual is considered non-diabetic. Patients have a LVEF greater than 40%, and especially greater than 50%.

[0063] The patient includes individuals who have been hospitalized for heart failure within the past nine months and / or have elevated BNP ≥ 75 pg / mL or NT-proBNP ≥ 300 pg / mL (for patients without atrial fibrillation (AF)) or elevated BNP > 225 pg / mL or NT-proBNP > 900 pg / mL (for patients with atrial fibrillation (AF)). Frail patients are included in the study, for example, if they complete a 6-minute walking test by walking less than 350 meters. At the end of the study period for each patient, functional capacity, particularly motor capacity, such as a 6-minute walk test, and further clinical parameters (e.g., the following) will be examined. Patients with cardiovascular risk factors should be treated according to usual care, which includes symptomatic treatment as well as treatment of cardiovascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia. Patients in the study will follow the following criteria: - Ages 18 and above - Diagnosis of heart failure (HF). Identifying HF for inclusion in this study is a left ventricular ejection fraction (LVEF) greater than 40% (per local reading) (ideally obtained by echocardiography, but radionuclide ventricleography and angiography are acceptable). Ejection fraction values ​​should preferably be obtained before randomization and within 6 months after myocardial infarction (MI) or other event affecting ejection fraction. —One or more symptoms of heart failure (HF) (NYHA Class II-IV) - Structural heart disease recorded by echocardiography (left atrial enlargement or left ventricular hypertrophy) - At least one of the following: hospitalization for heart failure and / or elevated NT-proBNP (>300 pg / mL for patients without atrial fibrillation (AF) or >900 pg / mL for patients with atrial fibrillation (AF)) within the past 9 months. -For example, frailty, which can be measured by a 6-minute walking test in which the patient walks a distance of less than 350 meters. - Background therapy for heart failure if necessary - In the case of anti-diabetic background -Body mass index (BMI) < 45 kg / m 2 -eGFR ≥ 20 mL / min / 1.73 m 2 Alternatively, eGFR ≥ 30 mL / min / 1.73 m² 2

[0064] At a specified time interval, e.g., at the end of 12 weeks, functional capacity, in particular exercise capacity, e.g., a 6-minute walk test, is measured in patients with heart failure and preserved ejection fraction (according to the criteria described above) treated with empagliflozin (e.g., 10 mg once daily) or placebo. Measure one or more of the following events: - Changes in NYHA classification - Health-related quality of life (e.g., as measured by KCCQ or KCCQ-12, MLHFQ, fatigue score, depression score, anxiety score, and overall assessment score) - Changes from baseline biomarkers, e.g., NT-proBNP - Time until first hospitalization for heart failure - The time until readmission for heart failure.

[0065] Examples of pharmaceutical compositions and dosage forms The following examples of solid pharmaceutical compositions and dosage forms for oral administration can be used to further illustrate the present invention, but are not limited to the examples. Further examples of compositions and dosage forms for oral administration are described in WO 2010 / 092126. The term “active substance” refers to empagliflozin of the present invention, in particular its crystalline form as described in WO 2006 / 117359 and WO 2011 / 039107. Tablets containing the active substance empagliflozin in doses of 2.5 mg, 5 mg, 10 mg, or 25 mg. The amount of the active ingredient is indicated in mg per film-coated tablet.

[0066] [Table 2]

[0067] Details relating to the manufacture of the tablets, the active pharmaceutical ingredient, the excipients and the film coating system are described in WO 2010 / 092126, in particular in Examples 5 and 6 (which are incorporated herein by reference).

Claims

1. A pharmaceutical composition comprising empagliflozin for treating chronic heart failure in a patient, wherein the patient has moderate or severe renal impairment.

2. The pharmaceutical composition according to claim 1, wherein the patient is a non-diabetic patient.

3. The pharmaceutical composition according to claim 1 or 2, which reduces the risk of cardiovascular death in patients.

4. The pharmaceutical composition according to claim 1 or 2, which reduces the risk of hospitalization for heart failure in patients.

5. The pharmaceutical composition according to claim 4, wherein the risk of hospitalization for heart failure is the risk of first hospitalization for heart failure.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the risk of chronic kidney disease in a patient is reduced or the progression of chronic kidney disease is delayed.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient is a patient with NYHA class II, III, or IV chronic heart failure.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the patient exhibits a LVEF greater than 40%.

9. A pharmaceutical composition according to any one of claims 1 to 7, wherein the patient exhibits a LVEF of 40% or less.

10. The patient was receiving 20 mL / min / 1.73 m² 2 The above and 60 mL / min / 1.73 m 2 A pharmaceutical composition according to any one of claims 1 to 9, having an eGFR of less than .

11. The patient was receiving 20 mL / min / 1.73 m² 2 The above and 45 mL / min / 1.73 m 2 A pharmaceutical composition according to any one of claims 1 to 9, having an eGFR of less than .

12. The patient was receiving 30 mL / min / 1.73 m² 2 The above and 45 mL / min / 1.73 m 2 A pharmaceutical composition according to any one of claims 1 to 9, having an eGFR of less than .

13. A pharmaceutical composition according to any one of claims 1 to 12 for administering empagliflozin to a patient in a dose ranging from 1 mg to 25 mg per day, particularly 10 mg.

14. A pharmaceutical composition according to any one of claims 1 to 13, for administering empagliflozin to a patient in combination with one or more other therapeutic substances.

15. The pharmaceutical composition according to claim 14, wherein one or more other therapeutic substances are selected from the group consisting of active substances indicated for the treatment of chronic heart failure, antidiabetic substances, active substances that lower total cholesterol, LDL cholesterol, non-HDL cholesterol and / or Lp(a) levels in the blood, active substances that raise HDL cholesterol levels in the blood, active substances that lower blood pressure, active substances indicated for the treatment of atherosclerosis or obesity, antiplatelet substances, anticoagulants, and vascular endothelial protectants.

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