EA042969B1 - PHARMACEUTICAL COMPOSITION CONTAINING EMPAGLIFLOZIN AND ITS APPLICATIONS - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to methods for treating chronic heart failure, reducing the risk of death due to cardiovascular disease, reducing the risk of hospitalization due to heart failure, reducing mortality from any cause, reducing the risk of hospitalization for any reason, reducing the risk of new-onset atrial fibrillation, and improving quality of life, due to the state of health and / or functionality, in a patient with chronic heart failure. The present invention also relates to methods of treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute heart failure, including acute decompensated heart failure. In addition, the present invention relates to methods for improving kidney function and treating or preventing certain kidney conditions and diseases in a patient with chronic heart failure. The present invention further relates to empagliflozin for use in methods of treating and/or preventing certain diseases or disorders or reducing the risk or delaying the onset of certain diseases or disorders in a patient with chronic heart failure.

Prior Art

Heart failure (HF) is a clinical syndrome caused by the inability of the heart to provide sufficient blood supply or to maintain sufficient blood supply due to increased left ventricular (LV) filling pressure. Patients with heart failure (HF) face poor diagnosis and about 50% of patients die from HF within 5 years. About 66% of patients with HF are non-diabetic patients. The total worldwide distribution of HF was 26 million in 2013. In the US, more than 1 million HF-related hospital admissions occur each year. There is a significant unmet need for HF treatment. The ultimate goal of HF treatment is to prevent hospitalization and death, control symptoms, and improve quality of life. There are two types of HF: HF with reduced (HFrEF) or saved (HFpEF) ejection fraction, the HF type with saved ejection fraction is 50% of the total HF. Both HFrEF and HFpEF are associated with high morbidity and mortality. Current treatment options for HFrEF are based primarily on the administration of beta-blockers, ACEi, ARB, ARNi, MRA, and diuretics. Despite these possibilities, treatment outcomes remain suboptimal. Currently, there is no effective treatment for HFpEF, and treatment is focused on symptomatic therapy and comorbidities.

Therefore, there is an urgent medical need for methods of treating chronic heart failure, especially in patients with HFrEF or HFpEF, with good efficacy in relation to disease-modifying properties and in relation to reducing the risk of mortality or hospitalization, and at the same time, showing good security profile.

The essence of the invention

The present invention relates to a method for treating, preventing, protecting against or slowing the onset of chronic heart failure in a patient in need thereof, comprising administering empagliflozin to the patient.

The present invention also relates to a method for reducing the risk of death due to cardiovascular disease in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient.

Additionally, the present invention relates to a method for reducing the risk of hospitalization (first and second) due to heart failure in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient.

In addition, the present invention relates to a method of reducing mortality from any cause in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient.

In addition, the present invention relates to a method for reducing the risk of hospitalization for any reason in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient.

The present invention also relates to a method for reducing the risk of new onset atrial fibrillation in a patient with chronic heart failure, which comprises administering empagliflozin to the patient.

The present invention also relates to a method of treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute heart failure in a patient in need thereof, which comprises administering empagliflozin to the patient.

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 a patient with chronic heart failure, which comprises administering empagliflozin to the patient.

The present invention also relates to a method for preventing, slowing down or reversing

- 1 042969 progression of macroalbuminuria in a patient with chronic heart failure, including administration of empagliflozin to the patient.

The present invention also relates to a method for improving kidney function or protecting the kidneys in a patient with chronic heart failure, comprising administering empagliflozin to the patient.

The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of, slowing the onset and/or slowing the progression of chronic renal failure in a patient with chronic heart failure, which includes administering empagliflozin to the patient.

The present invention also relates to a method for improving health-related quality of life and/or functionality in a patient with chronic heart failure, which comprises administering empagliflozin to the patient.

The present invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin, optionally in combination with one or more other therapeutic agents, for use as a drug in any of the methods described herein.

The present invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin, optionally in combination with one or more other therapeutic agents, for use in a method of treating, preventing, or reducing the risk of any of the diseases or conditions described herein.

The present invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin, optionally in combination with one or more other therapeutic agents, for use in the preparation of a medicament for use in any of the methods described herein.

In one embodiment, the present invention provides a method of treatment comprising:

a) identification of a patient in need of treatment for chronic heart failure; and b) administering empagliflozin to said patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) identifying that the patient has chronic heart failure according to NYHA class I;

c) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) identifying that the patient has chronic heart failure according to NYHA class II;

c) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) identifying that the patient has chronic heart failure according to NYHA class III;

c) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) identifying that the patient has chronic heart failure according to NYHA class IV;

c) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of the patient's ejection fraction;

b) identifying that the patient has an ejection fraction equal to or less than 40%;

c) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) identifying that the patient has NYHA class I chronic heart failure and has an ejection fraction equal to or less than 40%;

d) administering empagliflozin to the patient.

- 2 042969

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) identifying that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection fraction equal to or less than 40%;

d) administering empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) identifying that the patient has NYHA class I chronic heart failure and has an ejection fraction greater than 40%, in particular greater than 50%;

d) administering empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) identifying that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection fraction greater than 40%, in particular greater than 50%;

d) administering empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) determination of BNP or NT-proBNP values in a patient;

d) identifying that the patient has NYHA class I chronic heart failure and has an ejection fraction equal to or less than 40%, in particular greater than 50%, and has an elevated BNP or NT-proBNP value;

e) administration of empagliflozin to the patient.

In one embodiment, the present invention provides a method for treating chronic heart failure in a patient, comprising:

a) determination of symptoms in accordance with the NYHA classification of the patient;

b) determination of the patient's ejection fraction;

c) determination of BNP or NT-proBNP values in a patient;

d) identification that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection fraction equal to or less than 40%, in particular greater than 50%, and has an elevated BNP or NT-proBNP value ;

e) administration of empagliflozin to the patient.

According to this embodiment, the elevated BNP or NT-proBNP value is specifically a BNP value equal to or greater than 150 pg/ml, or an NT-proBNP value equal to or greater than 600 pg/ml. Further, according to this embodiment, the elevated BNP or NT-proBNP value is specifically a BNP value equal to or greater than 100 pg/mL or an NT-proBNP value equal to or greater than 400 pg/mL. if the patient has been hospitalized for heart failure within the last 9 months. In the methods of the present invention, empagliflozin is optionally administered in combination with one or more other therapeutic agents to a patient.

Further aspects of the present invention become clear to a qualified person in the art on the basis of the description presented above and hereinafter in this application, and the following examples.

Definitions

The term active ingredient of a pharmaceutical composition according to the present invention means the SGLT2 inhibitor empagliflozin according to the present invention. The active ingredient is also sometimes referred to in this application as the active substance.

The term body mass index or BMI of a human patient is defined as weight in kilograms divided by the square of height in meters, such that BMI is in units of kg/m ² .

The term overweight is defined as the condition in which an individual has a BMI greater than either 25 kg/m ² and less than 30 kg/m ² . The terms overweight and preobesity are used interchangeably.

The terms obese or be obese and the like are defined as a condition in which an individual has a BMI equal to or greater than 30 kg/m ² . According to the WHO definition, the term obesity can be classified as follows: the term class I obesity represents

- 3 042969 is a condition in which BMI is equal to or greater than 30 kg/m ² but less than 35 kg/m ² ; the term obesity

Class II is a condition in which BMI is equal to or greater than 35 kg/m ² but less than kg/m ² ; the term class III obesity is a condition in which the BMI is equal to or greater than 40 kg/m ² .

Indicators of obesity include, but are not limited to, exogenous obesity, hyperinsulinemic obesity, hyperplasmic obesity, hyperphyseal obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity, visceral obesity. fattening, abdominal obesity.

The term visceral obesity is defined as a condition in which the waist-to-hip circumference ratio is greater than or equal to 1.0 in men and 0.8 in women. It determines the risk of insulin resistance and the development of prediabetes.

The term abdominal obesity is commonly defined as a condition in which the waist circumference is >40 inches or 102 cm in men and >35 inches or 94 cm in women. In relation to Japanese ethnicity or patients from Japan, abdominal obesity can be defined as waist circumference >85 cm in men and >90 cm in women (see, for example, Research Committee for the Diagnosis of Metabolic Syndrome in Japan).

The term euglycemia is defined as a condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L) . The word fasting has a common meaning as a medical term.

The term hyperglycemia is defined as a condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L). The word fasting has a common 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, specifically below 70 mg/dL (3.89 mmol/L).

The term postprandial hyperglycemia is defined as a condition in which a subject has a blood or serum glucose concentration greater than 200 mg/dL (11.11 mmol/L) 2 hours after a meal.

The term fasting glucose disorder or IFG is defined as a condition in which a subject has a fasting blood glucose concentration or a fasting serum glucose concentration in the range of 100 to 125 mg/dL (i.e., 5.6 to 6.9 mmol/L) especially greater than 110 mg/dl and less than 126 mg/dl (7.00 mmol/l). A subject with a normal glucose level has a fasting glucose concentration of less than 100 mg/dL, i.e., less than 5.6 mmol/L.

The term Impaired Glucose Tolerance or IGT is defined as a condition in which, 2 hours after a meal, a subject has a blood or serum glucose concentration greater than 140 mg/dL (7.78 mmol/L) and less than 200 mg /dl (11.11 mmol/l). Abnormal glucose tolerance, i.e. 2 hours after a meal, blood glucose concentration or serum glucose concentration can be measured as blood sugar in mg glucose per plasma 2 hours after ingestion of 75 g of glucose after a meal. A subject with normal glucose tolerance has a blood glucose concentration or serum glucose concentration less than 140 mg/dL (7.78 mmol/L) 2 hours after a meal.

The term hyperinsulinemia is defined as a condition in which an insulin resistant subject, with or without euglycemia, has a fasting or postprandial serum or plasma insulin concentration elevated above that of a normal, lean, non-insulin resistant individual with a waist-to-hip ratio. <1.0 (for men) or <0.8 (for women).

The terms insulin sensitization, improvement in insulin resistance, or reduction in insulin resistance are synonymous and are used interchangeably.

The term insulin resistance is defined as a condition in which circulating insulin levels are required in excess of the normal response to glucose loading to maintain a euglycemic state (Ford ES, et al. JAMA. (2002) 287:356-9). The method for determining insulin resistance is a euglycemic-hyperinsulinemic fixing test. The ratio of insulin to glucose is determined in the volume of the combined insulin-glucose infusion technique. Insulin resistance is defined if glucose absorption is below the 25th baseline percentile for the study population (WHO definition). Significantly less laborious than the fixative test are the so-called minimal models, in which, when performing an intravenous glucose tolerance test, the concentration of insulin and glucose in the blood is measured at fixed time intervals and insulin resistance is calculated from these values. Using this method, it is not possible to distinguish between hepatic and peripheral insulin resistance.

In addition, insulin resistance, insulin resistance patient response to treatment, insulin sensitivity, and hyperinsulinemia can be quantified by evaluating the Homeostatic Model for Assessing Insulin Resistance (HOMA-IR) scale, a reliable indicator of insulin resistance ( Katsuki A, et al Diabetes Care 2001;24:362-5). Further reference is made to methods for determining the HOMA insulin sensitivity index (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl, 1): A459 ) and the euglycemic clamp method. Additionally, plasma levels of adiponectin can be monitored as a potential surrogate for insulin sensitivity. The assessment of insulin resistance according to the homeostatic assessment model (HOMA)-IR scale is carried out according to the formula (Galvin P, et al. Diabet Med 1992;9:921-8):

HOMA-IR = [fasting serum insulin (μU/mL)] x [fasting plasma glucose concentration (mmol/L)/22.5]

Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purposes of the present invention, insulin resistance is defined as 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 determined by in vitro glucose and insulin testing.

As a rule, in normal clinical practice, other parameters are used to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, since elevated triglyceride levels correlate significantly with the presence of insulin resistance.

Individuals likely to be insulin resistant are those individuals who have two or more of the following: 1) overweight or obesity, 2) high blood pressure, 3) hyperlipidemia, 4) one or more first-degree relatives diagnosed with IGT or IFG or type 2 diabetes.

Patients with a predisposition to develop IGT or IFG or type 2 diabetes are those patients who are euglycemic with hyperinsulinemia and are, by definition, insulin resistant. The typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of prediabetes. Therefore, a situation may arise that in order to maintain glucose homeostasis, an individual needs 2-3 times the level of insulin compared to a healthy individual, and this does not lead to any clinical symptoms.

Prediabetes is a general term that refers to an intermediate stage between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus (T2DM), also referred to as intermediate hyperglycemia. Therefore, in one aspect of the present invention, an individual is diagnosed with prediabetes if the HbA1c is greater than or equal to 5.7% and less than 6.5%. According to another aspect of the present invention, prediabetes represents 3 groups of individuals, those with only impaired glucose tolerance (IGT), those with only impaired fasting glucose (IFG), or those with both IGT and IFG. IGT and IFG usually have distinct pathophysiological etiologies, however, a mixed state can also exist with characteristic features of both pathologies in patients. Therefore, in another aspect of the present invention, a patient diagnosed as having prediabetes is an individual diagnosed with IGT or diagnosed with IFG or diagnosed with both IGT and IFG. As defined by the American Diabetes Association (ADA) and in the context of an aspect of the present invention, a patient diagnosed as having prediabetes is an individual with

a) Fasting plasma glucose (FPG) <100 mg/dL [1 mg/dL = 0.05555 mmol/L] and 2-hour plasma glucose (PG) measured using a 75-g oral glucose tolerance test ( OGTT) between >140 mg/dl and <200 mg/dl (i.e. IGT); or

b) fasting plasma glucose (FPG) in the range of >100 mg/dl and <126 mg/dl and 2-hour plasma glucose (PG) measured using the 75-g oral glucose tolerance test (OGTT) <140 mg /dl (i.e. IFG); or

c) fasting plasma glucose (FPG) in the range of >100 mg/dl and <126 mg/dl and 2-hour plasma glucose (PG) measured using a 75-g oral glucose tolerance test (OGTT) in range >140 mg/dl and <200 mg/dl (i.e. both IGT and IFG).

Prediabetic patients are individuals who are predisposed to developing type 2 diabetes. Prediabetes expands the definition of IGT to include individuals with fasting glucose levels above the normal range of >100 mg/dl (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying prediabetes as a serious health condition is set out in a white paper entitled The Prevention or Delay of Type 2 Diabetes jointly issued by the American Diabetes Association and the National Institute of Diabetes, Digestive and Kidney Diseases (Diabetes Care 2002; 25:742- 749).

Methods for testing pancreatic beta cell function are similar to those described above for insulin sensitivity, hyperinsulinemia, or resistance.

- 5 042969 sti to insulin: Improvement in beta cell function can be measured, for example, by determining the HOMA index (homeostatic model score) for beta cell function, HOMA-B, (Matthews et al., Diabetologia 1985, 28: 412- 19), intact proinsulin to insulin ratios (Forst et al., Diabetes 2003, 52(Suppl, 1): A459), first and second phase insulin secretion after an oral glucose tolerance test or a food tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301), insulin/C-peptide secretion after an oral glucose tolerance test or a food tolerance test, or by using a hypoglycemic clamp study and/or minimal simulation after a frequently selected intravenous glucose tolerance test ( 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, in the presence of autoimmunity to pancreatic beta cells or insulin, fasting glucose levels or a serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). If a glucose tolerance test is performed, the blood sugar level of a diabetic will exceed 200 mg glucose per dl (11.1 mmol/l) of plasma 2 hours after ingestion of 75 g of fasting glucose, in the presence of autoimmunity to pancreatic beta cells or insulin. In the glucose tolerance test, 75 g of glucose is orally administered to the test patient after 10-12 hours on an empty stomach and the blood sugar level is recorded immediately after glucose ingestion and 1 and 2 hours after ingestion. The presence of autoimmunity on pancreatic beta cells can be observed by detecting circulating islet cell autoantibodies (diabetes mellitus type 1A), i.e. at least one of: GAD65 (glutamic acid decarboxylase-65), ICA (islet cell cytoplasm), IA- 2 (intracytoplasmic domain of tyrosine phosphatase-like protein IA-2), ZnT8 (zinc transporter-8) or anti-insulin; or other evidence of autoimmunity without the presence of typical circulating autoantibodies (type 1B diabetes, i.e. as detected by biopsy or imaging of the pancreas). Typically there is a genetic predisposition (eg HLA, INS VNTR and PTPN22), but this is not always the case.

The term type 2 diabetes mellitus or T2DM is defined as a condition in which a subject has fasting glucose levels or a serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). Measuring blood glucose values is a standard procedure in conventional medical analysis. If a glucose tolerance test is performed, the blood sugar level of a diabetic will exceed 200 mg glucose per dl (11.1 mmol/l) plasma 2 hours after ingestion of 75 g glucose on an empty stomach. In the glucose tolerance test, 75 g of glucose is orally administered to the test patient after 10-12 fasting periods and the blood sugar level is recorded immediately after glucose ingestion and 1 and 2 hours after ingestion. In a healthy subject, blood sugar after glucose ingestion will range from 60 to 110 mg per dl in plasma, less than 200 mg per dl at 1 hour after glucose ingestion, and less than 140 mg per dl at 2 hours. after 2 hours the value is in the range of 140 and 200 mg, this is referred to as abnormal glucose tolerance.

The term late stage type 2 diabetes includes patients with secondary drug failure, indications for insulin therapy, and progression of micro- and macrovascular complications, such as diabetic nephropathy, or coronary heart disease (CHD).

The term LADA (latent adult autoimmune diabetes) refers to patients who have a clinical diagnosis of type 2 diabetes but have been found to be autoimmune to pancreatic beta cells. Latent autoimmune adult diabetes (LADA) is also known as slowly progressive type 1 diabetes mellitus (T1DM), mild T1DM, non-insulin dependent type 1 DM, type ^1/2 DM, _double diabetes, or antibody-positive type 2 DM (T2DM). LADA is often undetected and, unlike T1DM, rarely or never present with significant weight loss and ketoacidosis due to rapid progression of β-cell damage.

The term HbA1c refers to the non-enzymatic glycation product of the B hemoglobin chain. This definition is known to a person skilled in the art. When monitoring diabetes treatment, the HbA1c value is extremely important. Since its production is significantly dependent on blood sugar levels and the life of red blood cells, HbA1c in the meaning of blood sugar memory refers to the average blood sugar level over the previous 4-6 weeks. Patients with diabetes whose HbA1c value is necessarily corrected by intensive diabetes management (i.e. <6.5% of total hemoglobin in the sample) are significantly better protected from diabetic microangiopathy. For example, metformin alone provides a mean improvement in HbA1c values in diabetics of the order of 1.0-1.5%. This decrease in HbA1c value is not sufficient for all diabetics to achieve the desired target range of <7% or <6.5% and preferably <6% HbA1c.

The term poor glycemic control or inadequate glycemic control within the scope of the present invention means a condition in which patients have HbA1c values above 6.5%, especially above 7.0%, even more preferably above 7.5%, especially above 8% .

Metabolic syndrome, also called syndrome X (when used in the context of a metabolic disorder), also called dysmetabolic syndrome, is a

- 6 042969 plex syndromes with the main characteristic of insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). In accordance with 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 if three or more of the following are present.

1. Abdominal obesity, defined as waist circumference >40 inches or 102 cm in men and >35 inches or 94 cm in women; or in relation to Japanese ethnicity or Japanese patients defined as waist circumference >85 cm in men and >90 cm in women.

2. Triglycerides: > 150 mg/dL.

3. HDL cholesterol < 40 mg/dl in men.

4. Blood pressure > 130/85 mm Hg. (SKD>130 or DKD>85).

5. Fasting glucose levels >100 mg/dl.

NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). Blood triglycerides and HDL cholesterol can also be determined using standard medical analysis methods and as described, for example, in Thomas L (Editor): Labor und Diagnose, TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to the commonly used definition, hypertension is diagnosed when the systolic blood pressure (SBP) is greater than 140 mmHg. and diastolic blood pressure (DBP) is greater than 90 mmHg. If the patient is suffering from the manifestations of diabetes, it is currently recommended that the systolic blood pressure be lowered to below 130 mmHg. and diastolic blood pressure was reduced below 80 mmHg.

The term empagliflozin refers to the SGLT2 inhibitor 1-chloro-4-(β-O-glycopyranos-1-yl)-2-[4((S)-tetrahydrofuran-3-yloxy)-benzene]-benzene of the formula as described, for example, in WO 2005/092877. Synthesis methods are described in the literature, for example WO 06/120208 and WO 2011/039108. In accordance with the present invention, the definition of empagliflozin is intended to also cover its hydrates, solvates and its polymorphs, and its prodrugs. A favorable crystalline form of empagliflozin is described in WO 2006/117359 and WO 2011/039107, which are hereby incorporated by reference in their entirety. This crystalline form has good solubility properties which allow good bioavailability of the SGLT2 inhibitor. In addition, the crystalline form is physico-chemically stable, and therefore provides good storage stability of the pharmaceutical composition. Preferred pharmaceutical compositions such as solid preparations for oral administration, eg tablets, are described in WO 2010/092126, which is hereby incorporated by reference in its entirety.

The terms "treat" and "treatment" include the therapeutic treatment of patients who already have said condition, especially overtly. The therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a specific indication, or etiotropic treatment to reverse or partially reverse indication conditions or to arrest or slow the progression of a disease. Thus, the compositions and methods according to the present invention can be used, for example, as a therapeutic treatment over a period of time, as well as chronic therapy.

The terms prophylactic treatment, prophylactic treatment and prevention are used interchangeably and cover the treatment of patients at risk of developing the condition described hereinbefore, thus reducing said risk.

The term tablet includes tablets without a coating and tablets with one or more coatings. In addition, the term tablet includes tablets having one, two, three or even more layers and tablets with a shell applied under pressure, where each of the above types of tablets can be without or with one or more shells. The term tablet also includes mini, dissolvable, chewable, effervescent and orally dispersible tablets.

The terms pharmacopeia and pharmacopeia refer to standard pharmacopoeias such as USP 31-NF 26 through Second Supplement (United States Pharmacopeial Convention) or European Pharmacopoeia 6.3 (European Directorate for the Quality of Medicines and Health Care, 2000-2009 ).

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The term chronic heart failure or CHF is synonymous with congestive heart failure (CCF). The degree of heart failure can be classified according to the New York Heart Association (NYHA) functional classification and covers NYHA classes I, II, III, and IV. Chronic heart failure can differ according to damage to the contractility of the left ventricle (heart failure with reduced ejection fraction) or damage to the ability of the heart to relax (heart failure with preserved ejection fraction).

The term HFpEF refers to heart failure with preserved ejection fraction. HFpEF is sometimes also referred to as diastolic heart failure.

The term HFrEF refers to heart failure with reduced ejection fraction. HFrEF is sometimes also referred to as systolic heart failure.

The term LVEF refers to the left ventricular ejection fraction. The ejection fraction can be obtained using echocardiography, radionuclide ventriculography and angiography, preferably using echocardiography.

The term BNP refers to brain natriuretic peptide, also called B-type natriuretic peptide. BNP is used for screening and diagnosis of chronic heart failure. The value of BNP is determined in plasma or serum.

The term NT-proBNP refers to the brain's N-terminal prohormonal natriuretic peptide. NT-proBNP is used for screening and diagnosis of chronic heart failure. The value of NT-proBNP is determined in plasma or serum.

The term albuminuria is defined as a condition in which the amount of albumin in the urine is higher than normal. Albuminuria can be measured by urinary albumin excretion rate (AER) and/or urinary albumin to creatine ratio (ACR) (also referred to as UACR).

The categories of albuminuria in CKD are defined as follows.

ACR (approximate equivalent) Category AER (mg/24 hours) (mg/mmol) (mg/g) Quantities A1 < 30 < 3 < 30 Normal to slightly elevated A2 30-300 3-30 30-300 Moderately elevated AZ >300 >30 >300 Significantly increased

Category A1 represents the absence of albuminuria, category A2 represents microalbuminuria, category A3 represents macroalbuminuria. Category A1 progression usually leads to microalbuminuria (A2), but can also lead directly to macroalbuminuria (A3). Progression of microalbuminuria (A2) leads to macroalbuminuria (A3).

The term eGFR refers to the estimated glomerular filtration rate (GFR). GFR describes the rate of flow of filtered fluid through the kidneys. Estimated GFR can be calculated from serum creatinine values, for example, using the Collaboration in the Epidemiology of Chronic Kidney Disease (CKD-EPI) equation, the Cockcroft-Gault formula, or the Renal Disease Diet Modification (MDRD) formula, all of which are known. in this field of technology.

In accordance with one aspect of the present invention, the estimated glomerular filtration rate (eGFR) is obtained using the CKD-EPI equation based on serum creatinine values, age, sex and race:

GFR = 141 x min (S _cr /k, 1) ^α x max(S _cr /k, l)' ¹²⁰⁹ x 0.993 ^Age x 1.018 [if female] ^x 1.159 [if black] where

Scr is serum creatinine in mg/dL, k is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum the value of S _cr /k or 1, and max indicates the maximum value of S _cr /k or 1.

For the purposes of the present invention, the degree of renal failure in a patient is determined using the following estimated glomerular filtration rate (eGFR):

normal kidney function (CKD stage 1): eGFR > 90 ml/min/1.73 m ² ;

mild renal failure (CKD stage 2): eGFR >60 to <90 ml/min/1.73 m ² ;

moderate renal failure (CKD stage 3): eGFR >30 to <60 ml/min/1.73 m ² ;

severe renal failure (CKD stage 4): eGFR> 15 to <30 ml / min / 1.73 m ² ;

- 8 042969 decompensated renal failure (CKD stage 5): eGFR <15 ml/min/1.73 m ² .

According to the present invention, moderate renal insufficiency can be further divided into two sub-stages:

moderate renal failure A (CKD 3A): eGFR > 45 to <60 ml/min/1.73 m ² ;

moderate renal failure B (CKD 3B): eGFR> 30 to <45 ml / min / 1.73 m ² .

The term KCCQ refers to the Kansas City Cardiomyopathy Questionnaire. Health-related quality of life can be defined according to KCCQ or KCCQ12. The KCCQ-12 is an approved abbreviated version of the original 23-item KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire was designed to assess physical limitations, symptoms (frequency, severity, and change in trend), social limitations, self-efficacy, and quality of life in patients with HF.

The term MLHFQ refers to the Minnesota Quality of Life Questionnaire for Chronic Heart Failure. Quality of life, including for example, its physical, emotional, social and mental performance, can be determined in accordance with the MLHFQ.

Detailed description of the invention

In addition to improving glycemic control and weight loss due to urinary glucose excretion, empagliflozin exhibits a diuretic effect, reduces arterial stiffness and direct vascular effects (Cherney et al., Cardiovasc Diabetol. 2014; 13:28; Cherney et al., Circulation. 2014; 129:587-597). In the EMPA-REG OUTCOME™ study, empagliflozin was shown to reduce the risk of CV death, hospitalization for heart failure, and all-cause mortality in patients with type 2 diabetes mellitus at high CV risk (Zinman et al., N Engl J Med 2015;373:2117-2128). Treatment with empagliflozin has been found to reduce blood pressure without clinically significant changes in heart rate, thus improving heart rate pressure product (RPP), a surrogate marker of the heart's oxygen demand. In addition, empagliflozin was not found to be associated with clinically relevant reflex-mediated activation of the sympathetic nervous system, in contrast to the increase seen with diuretics. This may be because altered glucose and sodium gradients in the kidneys can generate a sympathetic-inhibitory afferent renal nerve signal. The lack of activation of the sympathetic nervous system may contribute to the favorable cardiovascular and renal profile of empagliflozin (heart-kidney relationship). Based on clinical and non-clinical studies, including mechanistic discussions such as the effect of empagliflozin on autonomic human cardiovascular regulation, the present application describes the use of empagliflozin for the treatment and prevention of certain diseases and conditions, especially chronic heart failure, acute heart failure and chronic renal failure.

The present invention relates to a method for treating chronic heart failure in a patient in need thereof, comprising administering empagliflozin to the patient. The present invention also relates to a method for reducing the risk of death due to cardiovascular disease in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient. The present invention further relates to a method for reducing the risk of hospitalization for heart failure in a patient with chronic heart failure, which comprises administering empagliflozin to the patient. The present invention also relates to a method for reducing the risk of death due to cardiovascular disease and hospitalization due to heart failure in a patient with chronic heart failure, which includes the introduction of empagliflozin to the patient. According to an embodiment of the present invention, the risk of hospitalization for heart failure is the risk of first hospitalization for heart failure. In accordance with another embodiment of the present invention, the risk of hospitalization due to heart failure is the risk of re-hospitalization due to heart failure. The present invention further relates to a method for reducing all-cause mortality in a patient with chronic heart failure, which comprises administering empagliflozin to the patient. In addition, the present invention relates to a method for reducing the risk of hospitalization for any reason in a patient with chronic heart failure, including the introduction of empagliflozin to the patient. In accordance with an embodiment of the present invention, the risk of hospitalization for any reason is the risk of a first hospitalization for any reason. In accordance with another embodiment of the present invention, the risk of hospitalization for any reason is the risk of re-hospitalization for any reason. The present invention also relates to a method for reducing the risk of new onset atrial fibrillation in a patient with chronic heart failure, which comprises administering empagliflozin to the patient.

The present invention also relates to a method for preventing, protecting against or slowing down

- 9 042969 occurrence of chronic heart failure in a patient who needs it, including the introduction of empagliflozin to the patient. In accordance with an embodiment of the present invention, there is provided a method for preventing worsening of chronic heart failure in a patient with NYHA class I chronic heart failure to NYHA class II, III, or IV chronic heart failure.

The present invention also relates to a method of treating, preventing, protecting against or slowing the onset of acute heart failure in a patient in need thereof, comprising administering empagliflozin to the patient, especially where the patient is a patient with chronic heart failure.

The present invention also relates to a method of treating, preventing, protecting against, reducing the risk of, or delaying the onset of acute decompensated heart failure (ADHF) in a patient with chronic heart failure in need, comprising administering empagliflozin to the patient.

In the methods of the present invention, the risk of a particular event, disease, or disorder is reduced compared to a patient who was administered a placebo under the background therapy treatment standards. In one embodiment, the risk is reduced by 15% or more. In one 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.

In accordance with one embodiment of the present invention, the patient is a NYHA class II, III, or IV chronic heart failure patient.

According to one aspect of this embodiment of the present invention, the patient is a NYHA class II or III chronic heart failure patient.

In accordance with another embodiment of the present invention, the patient is a NYHA class I chronic heart failure patient.

In accordance with one embodiment of the present invention, the patient is a chronic heart failure patient with 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 a variation of this embodiment, a chronic heart failure patient with preserved ejection fraction (HFpEF) exhibits an LVEF equal to or greater than 50%. According to another variation of this embodiment, the patient exhibits an LVEF in the range of 40% to 49%, also referred to as congestive heart failure with reduced mean ejection fraction (HFmrEF).

In accordance with another embodiment of the present invention, the patient is a chronic heart failure patient with reduced ejection fraction (HFrEF). For example, a patient with reduced ejection fraction exhibits an LVEF less than or equal to 40%, especially less than 40%.

Therefore, in accordance with an embodiment of the present invention, the invention provides a method for treating congestive heart failure with preserved ejection fraction (HFpEF) in a patient in need thereof, comprising administering empagliflozin to a patient, e.g., a patient with congestive heart failure according to the NYHA class I, II, III or IV. In accordance with one aspect of this embodiment, the degree of chronic heart failure in a patient with chronic heart failure according to NYHA class II, III or IV improves according to the NYHA classification. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

According to another embodiment, the present invention provides a method of treating chronic heart failure with reduced ejection fraction (HFrEF) in a patient in need thereof, comprising administering empagliflozin to a patient, e.g., a patient with NYHA class I chronic heart failure, II, III or IV. In accordance with one aspect of this embodiment, the degree of chronic heart failure in a patient with chronic heart failure according to NYHA class II, III or IV improves according to the NYHA classification. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of death due to cardiovascular disease in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, with preserved ejection fraction (HFpEF), comprising the administration of empagliflozin patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular

- 10,042,969 non-diabetic patients.

In accordance with another embodiment, the present invention provides a method for reducing the risk of death due to cardiovascular disease in a patient with chronic heart failure, for example, in accordance with the NYHA class II, III or IV, reduced ejection fraction (HFrEF), including the introduction empagliflozin to a patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of hospitalization due to heart failure in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient . In accordance with one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of first hospitalization due to heart failure is reduced. According to another aspect of this embodiment, the risk of rehospitalization due to heart failure is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

According to another embodiment, the present invention provides a method for reducing the risk of hospitalization due to heart failure in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin patient. In accordance with one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of first hospitalization due to heart failure is reduced. According to another aspect of this embodiment, the risk of rehospitalization due to heart failure is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of death due to cardiovascular disease and hospitalization due to heart failure in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, with preserved ejection fraction (HFpEF), which involves the administration of empagliflozin to a patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with another embodiment, the present invention provides a method for reducing the risk of death due to cardiovascular disease and hospitalization due to heart failure in a patient with chronic heart failure, for example, in accordance with NYHA class II, III or IV, with a reduced fraction release (HFrEF), which involves administering empagliflozin to a patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with an embodiment, the present invention provides a method for reducing all-cause mortality in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

According to an embodiment, the present invention provides a method of reducing all-cause mortality in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

According to an embodiment, the present invention provides a method for reducing

- 11 042969 the risk of hospitalization for any reason in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, with preserved ejection fraction (HFpEF), including the administration of empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with another aspect of this embodiment, the risk of a first hospitalization for any reason is reduced. In accordance with another aspect of this embodiment, the risk of repeated hospitalization for any reason is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with another embodiment, the present invention provides a method for reducing the risk of hospitalization for any reason in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of a first hospitalization for any reason is reduced. In accordance with another aspect of this embodiment, the risk of repeated hospitalization for any reason is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

According to an embodiment, the present invention provides a method for reducing the risk of new onset atrial fibrillation in a patient with chronic heart failure, e.g., according to NYHA class II, III, or IV, with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with another embodiment, the present invention provides a method for reducing the risk of new onset atrial fibrillation in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for improving health-related quality of life and/or functional capacity, especially exercise capacity, in a patient with chronic heart failure, e.g., according to NYHA Class II, III, or IV , with preserved ejection fraction (HFpEF), which involves the administration of empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. In accordance with one aspect of this embodiment, health-related quality of life is determined using a questionnaire such as, for example, KCCQ or KCCQ-12. According to another aspect of this embodiment, health-related quality of life or exercise capacity is determined by a walking test, such as a 6-minute walking test, or by maximum oxygen uptake (VO ₂ max). The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for improving health-related quality of life and/or functional capacity, especially exercise capacity in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), which involves administering empagliflozin to the patient. For example, the patient has NYHA class I chronic heart failure. In accordance with one aspect of this embodiment, health-related quality of life is determined using a questionnaire such as, for example, KCCQ or KCCQ-12. According to another aspect of this embodiment, health-related quality of life or exercise capacity is determined by a walking test, such as a 6-minute walking test, or by maximum oxygen uptake (VO2max). The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, 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 a patient with chronic heart failure, for example, in accordance with NYHA Class II, III or IV, with preserved ejection fraction (HFpEF), involving the administration of empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with another embodiment, 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) by reducing the risk of new onset atrial fibrillation in a patient with chronic heart failure, for example, in accordance with the NYHA class II, III, or IV, reduced ejection fraction (HFrEF), which involves administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

According to an embodiment, the present invention provides a method for reducing the risk of new onset type 2 diabetes mellitus in a patient with chronic heart failure, e.g., according to NYHA class II, III, or IV, with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient . For example, the patient has NYHA class I chronic heart failure. In accordance with one aspect of the present invention, the patient is a non-diabetic patient. In accordance with another aspect of the present invention, the patient is a patient with prediabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of new onset type 2 diabetes mellitus in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient . For example, the patient has NYHA class I chronic heart failure. In accordance with one aspect of the present invention, the patient is a non-diabetic patient. In accordance with another aspect of the present invention, the patient is a patient with prediabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of myocardial infarction in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of non-fatal myocardial infarction is reduced. According to one aspect of this embodiment, the risk of fatal myocardial infarction is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of myocardial infarction in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of non-fatal myocardial infarction is reduced. According to one aspect of this embodiment, the risk of fatal myocardial infarction is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of stroke in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of non-fatal myocardial stroke is reduced. According to one aspect of this embodiment, the risk of fatal myocardial stroke is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of stroke in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the risk of non-fatal myocardial stroke is reduced. According to one aspect of this embodiment, the risk of fatal myocardial stroke is reduced. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for reducing the risk of any death due to cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke (so-called 3-point MACE) in a patient with chronic heart failure, for example, in accordance with NYHA class II, III or IV, with preserved ejection fraction (HFpEF), involving the administration of empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of any death due to cardiovascular disease (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal myocardial infarction (excluding silent myocardial infarction), non-fatal stroke (so-called 3-point MACE ) in a patient with chronic heart failure, e.g., according to NYHA class II, III, or IV, with preserved ejection fraction (HFpEF), which involves administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of any death due to cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke (so-called 3-point MACE) in a patient with chronic heart failure, for example, in accordance with NYHA class II, III or IV, reduced ejection fraction (HFrEF), which involves administering empagliflozin to the patient. According to one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is, for example, a non-diabetic patient, a patient with prediabetes, or a patient with type 2 diabetes mellitus, in particular patient without diabetes.

In accordance with an embodiment, the present invention provides a method for reducing the risk of any death due to cardiovascular disease (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal myocardial infarction (excluding silent myocardial infarction), non-fatal stroke (so-called 3-point MACE ) in a patient with chronic heart failure, for example, according to NYHA class II, III, or IV, reduced ejection fraction (HFrEF), which involves administering empagliflozin to the patient. In accordance with one aspect of this embodiment, the patient has chronic heart failure according to NYHA class I.

The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

According to an embodiment, the present invention provides a method for preventing, slowing or reversing the progression of macroalbuminuria in a patient with chronic heart failure, e.g., according to NYHA class II, III or IV, with preserved ejection fraction (HFpEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. According to one aspect of this embodiment, progression from microalbuminuria to macroalbuminuria is prevented, retarded, or regressed. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for preventing, slowing or reversing the progression of macroalbuminuria in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. According to one aspect of this embodiment, progression from microalbuminuria to macroalbuminuria is prevented, retarded, or regressed. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with an embodiment, the present invention provides a method for improving kidney function or protecting the kidneys in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, with preserved ejection fraction (HFpEF), comprising

- 14 042969 administration of empagliflozin to a patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the patient has minor, moderate, or severe renal insufficiency. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient. According to one aspect of this embodiment, the improvement in kidney function or protection of the kidneys is a slowdown in the decline of eGFR, for example, it is a slowdown in the progressive decline in eGFR or a slowdown in the natural progressive decline in eGFR. According to another aspect of this embodiment, an improvement in kidney function or kidney protection is diagnosed according to an improvement in eGFR.

In accordance with an embodiment, the present invention provides a method for improving kidney function or protecting the kidneys in a patient with chronic heart failure, for example, according to NYHA class II, III or IV, reduced ejection fraction (HFrEF), comprising administering empagliflozin to the patient. For example, the patient has chronic heart failure according to NYHA class I. In accordance with one aspect of this embodiment, the patient has minor, moderate, or severe renal insufficiency. The patient according to this embodiment is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient. According to one aspect of this embodiment, the improvement in kidney function or protection of the kidneys is a slowdown in the decline of eGFR, for example, it is a slowdown in the progressive decline in eGFR or a slowdown in the natural progressive decline in eGFR. According to one aspect of this embodiment, an improvement in kidney function or kidney protection is diagnosed according to an improvement in eGFR.

According to an embodiment, the present invention provides a method for treating, preventing, protecting against, reducing risk, slowing the onset and/or slowing the progression of chronic renal failure 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 slowing the progression of chronic renal failure in a patient diagnosed with chronic heart failure, comprising administering empagliflozin to the patient. In accordance with another aspect of this embodiment, the patient is a patient with chronic kidney disease in stage 2. According to one aspect of this embodiment, the patient is a patient with chronic kidney disease in stage 3, including stages 3a and/or 3b. In accordance with another aspect of this embodiment, the patient is a patient with chronic kidney disease in stage 4. In accordance with one aspect of this embodiment, the patient is a patient with chronic kidney disease in stage 3, including stage 3a and/or 3b, or stage 4 and with chronic heart failure, for example, according to NYHA class I, II, III or IV, with preserved ejection fraction (HFpEF). In accordance with another aspect of this embodiment, the patient is a patient with chronic renal failure in stage 2. In accordance with another aspect of this embodiment, the patient is a patient with chronic renal failure in stage 3, including stage 3a and/or 3b, or stage 4 and with chronic heart failure, for example, according to NYHA class I, II, III or IV, reduced ejection fraction (HFrEF). The patient according to this embodiment, including various aspects of this embodiment, is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In accordance with another embodiment, the present invention provides a method for treating, preventing, protecting against, reducing risk, slowing the onset and/or slowing the progression of chronic renal failure in a patient with undiagnosed chronic heart failure, comprising administering empagliflozin to a patient, where the patient is a patient without diabetes. In particular, this embodiment relates to a method for treating and/or slowing the progression of chronic renal failure in a patient. According to one aspect of this embodiment, the patient is a chronic renal failure patient in stage 3, including stages 3a and/or 3b. In accordance with another aspect of this embodiment, the patient is a patient with stage 4 chronic renal failure.

In one embodiment, the present invention provides a method for treating, preventing, protecting against, or slowing the onset of:

new onset albuminuria, progression from albuminuria-free to micro- or macroalbuminuria, doubling of serum creatinine, accompanied by an eGFR (based on the Renal Disease Diet Modification Formula (MDRD)) <45 ml/min/1.73 ^m2 ,

- 15 042969 prolonged decrease of >30%, >40%, >50% or >57% of eGFR (CKD-EPI), especially prolonged decrease of >40% of eGFR (CKD-EPI), prolonged eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1.73 ^m2 , long-term eGFR (CKD-EPI) <10 ml/min/1.73 ^m2 for patients with eGFR <30 ml/min/1.73 m ² at baseline, need for continuous renal replacement therapy, need for chronic dialysis, need for a kidney transplant, death due to kidney disease, or a >40% long-term decrease in eGFR (CKD- EPI) or long-term eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1.73 ^m2 , and long-term eGFR (CKD-EPI) <10 ml /min/1.73 m ² for patients with a baseline eGFR value <30 ml/min/1.73 m ² , or a complex of long-term reduction by >40% eGFR (CKD-EPI) or long-term eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1.73 ^m2 , long-term eGFR (CKD-EPI) <10 ml/min/1.73 ^m2 for patients with baseline eGFR <30 ml/min/1.73 m ² , the need for chronic dialysis treatment and the need for a kidney transplant in a patient diagnosed with chronic heart failure, where this method includes the introduction of empagliflozin to the patient. In accordance with one aspect of this embodiment, the patient is a chronic heart failure patient, for example, according to NYHA class I, II, III, or IV, with preserved ejection fraction (HFpEF). According to another aspect of this embodiment, the patient is a chronic heart failure patient, for example, according to NYHA class I, II, III, or IV, with reduced ejection fraction (HFrEF). The patient according to this embodiment, including various aspects of this embodiment, is, for example, a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient, especially a non-diabetic patient.

In the methods of the present invention, empagliflozin is optionally administered in combination with one or more other therapeutic agents to a patient.

According to one embodiment of the methods as previously and hereinafter described herein, the patient is a patient with elevated plasma BNP or elevated plasma NTproBNP. For example, the patient has an elevated BNP equal to or greater than 75 pg/mL (NTproBNP>300 pg/mL) or equal to or greater than 100 pg/mL (NT-proBNP>400 pg/mL) or equal to or greater than 150 pg/mL. ml (NT-proBNP>600 pg/ml) or equal to or greater than 225 pg/ml (NT-proBNP>900 pg/ml).

According to another embodiment of the methods as previously and hereinafter described herein, the patient is a patient who has been hospitalized for heart failure within the past 9 months, specifically hospitalized for heart failure within the past 9 months. and has elevated BNP or NT-proBNP.

According to an embodiment of the methods as previously and hereinafter described herein, the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF >36% to >40% and elevated NT-proBNP >2500 pg/mL for patients without atrial fibrillation or >5000 pg/ml for patients with atrial fibrillation.

According to an embodiment of the methods as previously and hereinafter described herein, the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF >31% to <35% and elevated NT-proBNP >1000 pg/mL for patients without atrial fibrillation, or >2000 pg/mL for patients with atrial fibrillation.

According to an embodiment of the methods as previously and hereinafter described herein, the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF <30% and elevated NT-proBNP >600 pg/mL for patients without atrial fibrillation , or >1200 pg/mL for patients with atrial fibrillation.

In accordance with one embodiment of the methods as described hereinbefore and hereinafter, the patient is a patient with normal renal function or with mild renal insufficiency or with moderate or severe renal insufficiency. In accordance with this embodiment, the patient has an eGFR equal to or greater than 20 ml/min/1.73 m ² .

In accordance with one embodiment of the methods as previously and hereinafter described herein, the patient is a patient with normal renal function or with mild or moderate renal impairment. According to this embodiment, the patient has an eGFR equal to or greater than 30 ml/min/1.73 m ² .

According to another embodiment of the methods as previously and hereinafter described herein, the patient is a patient with normal renal function or with mild or moderate renal impairment A (CKD 3A). In accordance with this embodiment, the patient has an eGFR equal to or greater than 45 ml/min/1.73 m ² .

In accordance with another embodiment of the methods as described hereinbefore and hereinafter, the patient is a patient with normal renal function or with mild renal insufficiency. In accordance with this embodiment, the patient has an eGFR equal to or greater than 60 ml/min/1.73 m ² .

According to another embodiment of the methods as previously and hereinafter described herein, the patient is a patient with moderate renal impairment A (CKD 3A). In accordance with this embodiment, the patient has an eGFR equal to or greater than 45 and lower than 60 ml/min/1.73 m ² .

In accordance with another embodiment of the methods as described hereinbefore and hereinafter, the patient is a patient with moderate renal insufficiency B (CKD 3B). In accordance with this embodiment, the patient has an eGFR equal to or greater than 30 and less than 45 ml/min/1.73 m ² .

According to an embodiment of the methods as previously and hereinafter described herein, the patient is a non-diabetic patient, a pre-diabetic patient, a type 2 diabetic patient, or a type 1 diabetic patient.

According to another embodiment of the methods as previously and hereinafter described herein, the patient is a non-diabetic patient, a pre-diabetic patient, or a type 2 diabetic patient.

In accordance with another embodiment of the methods as described hereinbefore and hereinafter, the patient is a patient with prediabetes. In accordance with one aspect of this embodiment, the patient has an HbA1c greater than or equal to 5.7% and less than 6.5%.

In accordance with another embodiment of the methods as described hereinbefore and hereinafter, the patient is a patient with prediabetes or a patient without diabetes. In accordance with one aspect of this embodiment, the patient has an HbA1c of less than 6.5%.

In accordance with another embodiment of the methods as described hereinbefore and hereinafter, the patient is a non-diabetic patient. In accordance with one aspect of this embodiment, the patient has an HbA1c of less than 5.7%.

According to another aspect, the non-diabetic patient does not exhibit impaired glucose tolerance (IGT), ie the patient exhibits normal glucose tolerance. For example, a glucose level 2 hours after a meal or a plasma glucose (PG) concentration is less than 140 mg/dL (7.78 mmol/L).

In another aspect, the non-diabetic patient does not exhibit impaired fasting blood glycemia (IFG), ie the patient exhibits normal fasting blood glucose. For example, fasting plasma glucose (FPG) is less than 100 mg/dL, i.e., less than 5.6 mmol/L.

In particular, a non-diabetic patient does not exhibit impaired fasting blood glycemia (IFG) and does not exhibit impaired glucose tolerance (IGT), that is, the patient exhibits normal glucose tolerance and a normal glucose tolerance. For example, fasting plasma glucose (FPG) is less than 100 mg/dL, i.e., less than 5.6 mmol/L, and the glucose level 2 hours after a meal or plasma glucose concentration (PG) is less than 140 mg/dL (7.78 mmol/L).

According to an embodiment of the methods as described herein, empagliflozin is previously and subsequently administered at a dose ranging from 1 to 25 mg per day, e.g., at a dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg or 25 mg per day to the patient. The administration of empagliflozin may be once or twice daily, most preferably once daily. For example, the dose for administration once a day is 10 mg or 25 mg. The preferred route of administration is oral administration.

According to a preferred aspect of the present invention, empagliflozin is administered at a dose of 10 mg per day to a patient.

In accordance with another preferred aspect of the present invention, empagliflozin is administered at a dose of 25 mg per day to the patient.

Preferably empagliflozin is administered orally to the patient once a day.

In one embodiment, patients in the context of the present invention may include patients with chronic heart failure who have not previously been treated with a drug for the treatment of chronic heart failure (patients who have not previously taken a drug for heart failure). Thus, in an embodiment, the therapies described herein can be used for patients who have not previously taken a drug for heart failure.

- 17 042969

In another embodiment, patients in the context of the present invention may include patients with chronic heart failure and prediabetes or type 2 diabetes mellitus (T2DM) who have not previously received treatment with an antidiabetic agent (patients who have not previously taken a T2DM drug) . Thus, in an embodiment, the therapies described herein can be used for patients who have not previously taken a T2DM drug.

In addition, the methods according to the present invention are particularly suitable for the treatment of patients with chronic heart failure and insulin dependence, i.e. patients who are or will otherwise be treated or in need of treatment with insulin or an insulin derivative or an insulin substitute or a preparation containing insulin or its derivative or substitute. These patients include type 2 diabetic patients and type 1 diabetic patients.

In addition, administration of the pharmaceutical composition according to the present invention may be found to result in no or low risk of hypoglycemia. Therefore, treatment or prophylaxis according to the present invention may also advantageously be possible in those patients who exhibit or have an increased risk of hypoglycemia.

By administering empagliflozin, excess blood glucose is excreted through the patient's urine based on SGLT2 inhibitory activity, so that weight gain or even weight loss of the patient may not be obtained. Therefore, the methods of the present invention are advantageously useful in those patients with chronic heart failure who have been diagnosed with one or more conditions selected from the group consisting of overweight and obesity, especially class I obesity, class II obesity, III obesity. class, visceral obesity and abdominal obesity. Additionally, the method in accordance with the present invention is beneficial for those patients who are contraindicated in weight gain.

If the present invention relates to patients in need of treatment or prevention, it relates mainly to treatment and prevention in humans, but the pharmaceutical composition can also be used, respectively, in mammalian veterinary medicine. Within the scope of the present invention, adult patients are preferably 18 years of age or older. Also within the scope of the present invention, patients are adolescents, that is, people between the ages of 10 and 17, preferably between the ages of 13 and 17.

According to an embodiment of the present invention, empagliflozin is administered in combination with one or more other therapeutic agents to a patient. 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 that are indicated for the treatment of chronic heart failure, antidiabetic substances, active substances that reduce total cholesterol, LDL cholesterol, non-HDL cholesterol and/or LP (a) in the blood, active substances that increase the level of HDL cholesterol in the blood, active substances that lower blood pressure, active substances that are indicated for the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants, and agents that protect the vascular endothelium.

In one embodiment, the active substances that are indicated for the treatment of chronic heart failure are selected from angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, angiotensin-neprilysin receptor inhibitors (ARNi), beta-blockers, aldosterone antagonists ( MRA), digoxin, ivabradine and diuretics.

In one embodiment, the anti-diabetic agents are 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, the patient is receiving standard care that includes a drug and/or devices indicated for patients with heart failure, such as chronic or acute heart failure. In one aspect, a patient, especially one diagnosed with HFrEF, has or is receiving a device selected from the group of ICD (implantable cardioverter defibrillator) and CRT (cardiac resynchronization therapy), such as CRT-P (CRT pacemaker) and CRT-D (CRT combination pacemaker and defibrillator).

In one embodiment, the patient is receiving a standard drug intended for patients with chronic heart failure. In one aspect of this embodiment, empagliflozin is administered to a patient in combination with one or more active agents that are indicated 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 converting enzyme (ACE) inhibitors, beta blockers, aldosterone antagonists, diuretics, angiotensin receptor neprilysin inhibitor (ARNi ), mineralocorticoid receptor antagonists and ivabradine. According to this aspect of the embodiment, the patient is, for example, a non-diabetic patient or a pre-diabetic patient.

- 18 042969

In one aspect of this embodiment, the amount, dosage and/or regimen of said congestive heart failure drugs is reduced in said patient while administration of empagliflozin is continued. For example, one can reduce the dose of one or more diuretics administered to a patient while continuing to administer empagliflozin.

Examples of angiotensin II receptor blockers (ARBs) are telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan; the dosage(s) of some of these drugs are, for example, as follows:

Candesartan (Atacand) 4 mg, 8 mg, 16 mg, or 32 mg cilexetil candesartan;

Eprosartan (Teveten) 400 mg or 600 mg;

Irbesartan (Avapro) 75 mg, 150 mg, or 300 mg irbesartan;

Losartan (Cozaar), 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 each of telmisartan and hydrochlorothiazide;

Telmisartan/amlodipine (Twynsta) 40 mg/5 mg, 40 mg/10 mg, 80 mg/5 mg, and 80 mg/10 mg each of telmisartan and amlodipine;

Valsartan (Diovan) 40mg, 80mg, 160mg, or 320mg valsartan.

Examples of angiotensin converting enzyme (ACE) inhibitors are benazepril, captopril, ramipril, lisinopril, moexipril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; the dosage(s) of some of these drugs are, for example, as indicated below:

Benazepril (Lotensin) 5 mg, 10 mg, 20 mg, and 40 mg oral;

Captopril (Capoten) 12.5 mg, 25 mg, 50 mg, and 100 mg scored tablets for oral administration;

Enalapril (Vazotec) 2.5 mg, 5 mg, 10 mg and 20 mg tablets for oral administration;

Fosinopril (Monopril), for oral administration as 10 mg, 20 mg and 40 mg tablets;

Lisinopril (Prinivil, Zestril) 5 mg, 10 mg, and 20 mg oral tablets;

Moexipril (Univasc), 7.5 mg and 15 mg for oral administration;

Perindopril (Aceon) 2mg, 4mg and 8mg oral dosages;

Quinapril (Accupril) 5 mg, 10 mg, 20 mg, or 40 mg quinapril for oral administration;

Ramipril (Altace) 1.25 mg, 2.5 mg, 5 mg, 10 mg;

Trandolapril (Mavic) 1 mg, 2 mg, or 4 mg trandolapril for oral administration.

Examples of beta-blockers are acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, propranolol, timolol and carvedilol; the dosage(s) of some of these drugs are, for example, as indicated below:

Acebutolol (Sektral), 200 or 400 mg of acebutolol as the hydrochloride salt;

Atenolol (Tenormin), 25, 50 and 100 mg tablets for oral administration;

Betaxolol (Kerlon), 10-mg and 20-mg oral tablets;

Bisoprolol/hydrochlorothiazide (Ziak) 2.5/6mg, 5/6.25mg, 10/6.25mg;

Bisoprolol (Zebeta), 5 and 10 mg tablets for oral administration;

Metoprolol (Lopressol, Toprol XL), 50- and 100-mg tablets for oral administration and in 5-ml ampoules for intravenous administration;

Propranolol (Inderal) 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg oral tablets;

Timolol (Blokadren) 5 mg, 10 mg, or 20 mg timolol maleate for oral administration.

Examples of aldosterone antagonists are spironolactone, eplerenone, canrenone and fineronone; the dosage(s) of some of these drugs are, for example, as indicated below:

spironolactone (eg, Aldactone), 25 or 50 mg once daily or every other day;

eplerenone (eg, Inspra), 25 or 50 mg once daily.

Examples of diuretics are bumetanide, hydrochlorothiazide, chlorthalidone, chlorthiazide, hydrochlorothiazide, xipamide, indapamide, furosemide, pyretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; for example, these drugs are thiazide diuretics, eg chlorthalidone, HCT, loop diuretics, eg furosemide, torasemide, or potassium-sparing diuretics, eg eplerenone, or a combination thereof; the dosage(s) of some of these drugs are, for example, as indicated below:

Amiloride (Midamore), 5 mg anhydrous amiloride HCl;

Bumetanide (Bumex), available as scored tablets, 0.5 mg (light green), 1 mg (yellow), and 2 mg (peach) for oral administration;

Chlorthiazide (Diuril);

Chlortalidone (Hygroton);

Furosemide (Lasix);

Hydro-chlorothiazide (Ezidrix, Gilrodiuril);

Indapamide (Lozol) and Spironolactone (Aldactone);

- 19 042969

Eplerenone (Inspra).

An example of an angiotensin receptor-neprilysin inhibitor (ARNi) is the combination of valsartan and sacubitril (Entresto).

An example of If inhibition of pacemaker current is ivabradine (Procoralan, Corlanol).

Examples of calcium channel blockers are amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lencapipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem.

Examples of drugs that lower blood pressure include angiotensin II receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, beta-blockers, diuretics, and calcium channel blockers.

In another aspect of this embodiment, the patient is a type 2 diabetic patient and empagliflozin is administered to the patient in combination with one or more active agents that are indicated for the treatment of chronic heart failure and in combination with one or more antidiabetic agents.

Antidiabetic agents include metformin, sulfonylurea, nateglinide, repaglinide, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogs, GLP-1 and GLP1 analogs, and DPP-4 inhibitors. Examples are metformin and DPPIV inhibitors such as sitagliptin, saxagliptin and linagliptin. Active agents that are indicated for the treatment of chronic heart failure include angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists and diuretics.

Therefore, in accordance with one aspect of the methods of the present invention, empagliflozin is administered in combination with linagliptin to a patient. The patient in accordance with this aspect is, in particular, a patient with type 2 diabetes. Preferred doses are, for example, empagliflozin 10 mg once daily and linagliptin 5 mg once daily.

Therefore, according to another aspect of the methods of the present invention, empagliflozin is administered in combination with metformin hydrochloride to a patient. The patient in accordance with this aspect is, in particular, a patient with type 2 diabetes. Preferred doses are, for example, 10 mg empagliflozin once daily or 5 mg empagliflozin twice daily and 500 mg, 850 mg or 1000 mg metformin hydrochloride twice daily.

In one aspect of this embodiment, the amount, dosage and/or regimen of said congestive heart failure drugs is reduced in said patient while administration of empagliflozin is continued. In another aspect of this embodiment, the amount, dosage and/or regimen of said type 2 diabetes mellitus drugs is reduced in said patient while administration of empagliflozin is continued. In still another aspect of this embodiment, the amounts, dosages and/or regimens of said type 2 diabetes mellitus drugs and said chronic heart failure drugs are reduced in said patient while administration of empagliflozin is continued.

According to an example of this aspect, empagliflozin is administered in combination with one or more active substances selected from the group consisting of angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists, diuretics, receptor inhibitor angiotensin-neprilysin (ARNi), mineralocorticoid receptor antagonists and ivabradine in combination with metformin or in combination with linagliptin or in combination with metformin and linagliptin.

Examples of the active substances in the above groups are known to those skilled in the art, including their dosages, administration schedules, and formulations.

In the context of the present invention, the term metformin includes metformin hydrochloride in the form of an immediate release, sustained or sustained release formulation. The doses of metformin hydrochloride that are administered to the patient are in particular 500 mg to 2000 mg per day, for example 750 mg, 1000 mg, 1500 and 2000 mg per day.

Empagliflozin and metformin may be administered separately in two different dosage forms or combined in one dosage form. Combination dosage forms of empagliflozin and metformin as fast release preparations are described in WO 2011/039337 and are known, for example, as SYNJARDI®. Combination dosage forms of empagliflozin and metformin, where empagliflozin is part of a fast release formulation and metformin is part of a sustained release formulation, are described in WO 2012/120040 and WO 2013/131967.

The preferred dose of linagliptin for administration to a patient is 5 mg per day.

Empagliflozin and linagliptin may be administered separately in two different dosage forms or combined in one dosage form. Combination dosage forms of empagliflozin and linagliptin are described in WO 2010/092124 and are known, for example, as GLYXAMBI®.

The present invention contemplates that the combinations, compositions or administration in combinations according to the present invention may encompass the simultaneous, sequential or separate administration of the active components or ingredients.

In the present context, combination or combined within the scope of the present invention may include, but are not limited to, fixed and non-fixed (e.g., free) forms (including kits) and uses such as, for example, simultaneous, sequential or separate use of components or ingredients. .

The combination administration according to the present invention can be carried out by administering the active components or ingredients together, such as, for example, by administering them simultaneously in one single or two separate preparations or dosage forms. Alternatively, administration may be by administering the active ingredients or ingredients sequentially, such as, for example, sequentially in two separate preparations or dosage forms.

For combination therapy according to the present invention, the active components or ingredients can be administered separately (which implies that they are prepared separately) or prepared together (which implies that they are prepared in the same preparation or in the same dosage form). Therefore, the administration of one element of the combination according to the present invention can be carried out before, simultaneously with, or after the administration of another element of the combination.

Unless specifically stated otherwise, combination therapy may refer to first line, second line or third line therapy, or initial or additional combination therapy or replacement therapy.

Methods in accordance with the present invention are particularly suitable for the long-term treatment or prevention of diseases and/or conditions, as described hereinafter and hereinafter. The term long-term, as used hereinafter and hereinafter, indicates treatment or administration to a patient for a period of time greater than 12 weeks, preferably greater than 25 weeks, even more preferably greater than 1 year.

A pharmaceutical composition containing empagliflozin according to the invention may 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 insufflation. Oral administration is preferred. The pharmaceutical composition may be in the form of tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, lozenges, effervescent tablets, drops, suspensions, instant tablets, oral fast dispersible tablets, etc. The pharmaceutical composition and dosage forms preferably contain one or more pharmaceutically acceptable carriers, which must be acceptable in terms of compatibility with other ingredients of the drug and not harmful to its recipient. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

Pharmaceutical compositions and methods in accordance with the present invention exhibit beneficial effects for the treatment and prevention of those diseases and conditions that are described in this application earlier. Beneficial effects can be observed, for example, with respect to efficacy, effective dose, frequency of dosing, pharmacodynamic properties, pharmacokinetic properties, fewer side effects, convenience, comfort, and so on.

Methods for the preparation of empagliflozin are known to those skilled in the art. Advantageously, the compounds of the present invention can be prepared using synthetic methods as described in the literature, including the patent applications cited earlier in this application. Preferred preparation methods are described in WO 2006/120208 and WO 2007/031548. With respect to empagliflozin, a favorable crystalline form is described in international patent application WO 2006/117359, which is thus incorporated herein by reference in its entirety.

Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples may serve to illustrate, by way of example, the principles of the invention without limiting it.

Examples

Example 1 Treatment of Patients with Chronic Heart Failure and HfrEF.

The prospective effect on cardiovascular mortality or hospitalization due to heart failure and other parameters of treatment with empagliflozin in a relevant population of patients with chronic heart failure and reduced ejection fraction was investigated as follows.

Patients with chronic heart failure and symptoms consistent with NYHA II, III, or IV and decreased ejection fraction (LVEF less than or equal to 40%) and elevated BNP (or elevated NT-proBNP), for example, as described below, were treated for long-term (eg, over a period of approximately 20 to 38 months for each patient) with empagliflozin (optionally in combination with one or more other active

- 21 042969 substances, for example, such as those described in this application) and compared with patients who received treatment using placebo according to the standards of treatment of background therapy.

Empagliflozin is administered orally once a day (eg, 10 mg/day). Patients include non-diabetic patients, pre-diabetic patients, and type 2 diabetic patients. Prediabetes is diagnosed if HbA1c is greater than or equal to 5.7% and less than 6.5%. An individual is a non-diabetic patient if the HbA1c is less than 5.7%. Patients have an LVEF less than or equal to 40%.

Patients with elevated BNP (or elevated NT-proBNP) are defined as those who have one of the following:

elevated BNP >150 pg/ml, or NT-proBNP > 600 pg/ml; or if patients have 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 in accordance with at least one of the following manifestations of heart failure.

If the ejection fraction EF is >36% to <40%, then the elevated NT-proBNP will be >2500 pg/mL for patients without atrial fibrillation, or >5000 pg/mL for patients with atrial fibrillation.

If the ejection fraction EF is >31% to <35%, then the elevated NT-proBNP will be >1000 pg/mL for patients without atrial fibrillation, or >2000 pg/mL for patients with atrial fibrillation.

If the ejection fraction EF is <30%, then the elevated NT-proBNP will be >600 pg/mL for patients without atrial fibrillation, or >1200 pg/mL for patients with atrial fibrillation.

The study is event-based and all randomized patients remained in the study until a defined number of patients with events meeting the primary endpoint was reached. The number of reported confirmed events corresponding to the primary endpoint will be continuously monitored during the study.

Patients with cardiovascular risk factors were treated according to standards of care, which include, for example, treatment with therapeutic agents selected from diuretics, ARNi, ACEi, ARB, statins, aspirin, beta-blockers, a mineralocorticoid antagonist, or ivabradine, with a device for cardiac therapy or without it, including ICD, CRT-D or CRT-P.

Patients in the study meet the following criteria.

Age over 18 years old.

Diagnosed heart failure (HF). The definition of HF for inclusion in a study is a left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are also acceptable) less than or equal to 40% (per reading). The value of the ejection fraction is preferably obtained within 6 months before randomization and after any myocardial infarction (MI) or other event that will affect the ejection fraction.

Symptom(s) of heart failure (HF) (NYHA class II-IV).

At least one of the following: elevated NT-proBNP >600 pg/ml and/or, if the patient has been hospitalized for heart failure within the past 9 months, elevated NT-proBNP >400 pg/ml.

Background therapy in connection with heart failure, if necessary.

Antidiabetic background therapy, if needed.

Body mass index (BMI) < 45 kg/m ² .

eGFR > 20 ml/min/1.73 m ² or eGFR > 30 ml/min/1.73 m ² .

Time to death due to cardiovascular disease or hospitalization due to heart failure was determined in patients with heart failure with reduced ejection fraction (according to the criteria described earlier in this application) treated with empagliflozin (for example, 10 mg once per day) to the placebo group.

One or more of the following criteria were determined.

Time to first hospitalization for heart failure.

eGFR (CKD-EPI) slope changes from baseline.

Time to first manifestation of a sustained >40% decrease in eGFR (CKD-EPI).

Time to first manifestation of sustained eGFR (CKD-EPI) <15 ml/min/1.73 m ² for patients with baseline eGFR >30 ml/min/1.73 m ² .

Time to first manifestation of sustained eGFR (CKD-EPI) <10 ml/min/1.73 m ² for patients with baseline eGFR <30 ml/min/1.73 m ² .

Cumulative time to first manifestation of a sustained >40% decrease in eGFR (CKD-EPI) or

- 22 042969 long-term eGFR (CKD-EPI) <15 ml/min/1.73 m ² for patients with baseline eGFR >30 ml/min/1.73 m ² , long-term eGFR (CKD-EPI) <10 ml/ min/1.73 m ² for patients with baseline eGFR <30 ml/min/1.73 m ² .

Cumulative time to first manifestation of a sustained >40% decrease in eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1, 73 m ² , and continuous eGFR (CKD-EPI) <10 ml/min/1.73 m ² for patients with baseline eGFR <30 ml/min/1.73 m ² , or needing chronic dialysis treatment or needing to receive kidney transplant - time to death due to cardiovascular disease;

time to death for any reason;

health-related quality of life (eg, as measured by the KCCQ or KCCQ-12);

time to first onset type 2 diabetes in non-diabetic patients;

time to re-hospitalization due to heart failure;

change in NYHA classification;

time to hospitalization for any reason, including the first and / or recurrent;

time to first developed atrial fibrillation;

time to non-lethal or fatal myocardial infarction;

time to nonfatal or fatal stroke;

time to composite death due to cardiovascular disease or myocardial infarction;

time to composite death due to cardiovascular disease or stroke;

time to any death due to cardiovascular disease (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal myocardial infarction, non-fatal stroke (so-called 3-point MACE);

change in eGFR;

progression to macroalbuminuria (defined as albumin/creatinine ratio (ACR) >300 mg/g);

time to need for chronic dialysis treatment;

the time until the need for a kidney transplant;

a constellation of eGFR reduction, renal replacement therapy, or renal death;

a combination of eGFR reduction, renal replacement therapy, renal death, or death due to cardiovascular disease;

constellation of eGFR reduction, renal replacement therapy, renal death, or death from any cause.

Example 2 Treatment of Patients with Chronic Heart Failure and HfpEF.

The prospective effect on cardiovascular mortality or hospitalization for heart failure and other treatment parameters with empagliflozin in a relevant population of patients with chronic heart failure and preserved ejection fraction was investigated as follows.

Patients with chronic heart failure and symptoms consistent with NYHA II, III, or IV and preserved ejection fraction (LVEF greater than 40% or greater than 50%) were treated for a long time (for example, for a time interval ranging from about 20 up to 38 months for each patient) using empagliflozin (optionally in combination with one or more other active substances, such as those described in this application) and compared with patients who received treatment with placebo according to the standards of treatment of background therapy .

Empagliflozin is administered orally once a day (eg, 10 mg/day). Patients include non-diabetic patients, pre-diabetic patients, and type 2 diabetic patients. Prediabetes is diagnosed if HbA1c is greater than or equal to 5.7% and less than 6.5%. An individual is a non-diabetic patient if the HbA1c is less than 5.7%. Patients have an LVEF greater than 40%, in particular greater than 50%.

Patients include individuals who have been hospitalized for heart failure within the past 9 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-based and all randomized patients remained in the study until a defined number of patients with events meeting the primary endpoint was reached. The number of reported confirmed events corresponding to the primary endpoint will be continuously monitored during the study.

- 23 042969

Patients with cardiovascular risk factors were treated according to the standard of care, which includes symptomatic treatment and treatment of cardiovascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia.

Patients in the study meet the following criteria.

Age over 18 years old.

Diagnosed heart failure (HF). The definition of HF to be included in the study is left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) >40% (per reading). The value of the ejection fraction is preferably obtained within 6 months before randomization and after any myocardial infarction (MI) or other event that will affect the ejection fraction.

Symptom(s) of heart failure (HF) (NYHA class II-IV).

Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.

At least one of the following: hospitalization for heart failure within the past 9 months and/or elevated NT-proBNP (>300 pg/mL in patients without atrial fibrillation (AF) or >900 pg/mL in patients with fibrillation atrial (AF)).

Background therapy in connection with heart failure, if necessary.

Antidiabetic background therapy, if needed.

Body mass index (BMI) <45 kg/m ² .

eGFR>20 ml/min/1.73 ^m2 or eGFR>30 ml/min/1.73 ^m2 .

Time to death due to cardiovascular disease or hospitalization due to heart failure was determined in patients with heart failure with preserved ejection fraction (according to the criteria described earlier in this application) treated with empagliflozin (for example, 10 mg once per day) to the placebo group.

One or more of the following criteria were determined.

Time to first hospitalization for heart failure.

eGFR (CKD-EPI) slope changes from baseline.

Time to first manifestation of a sustained >40% decrease in eGFR (CKD-EPI).

Time to first manifestation of sustained eGFR (CKD-EPI) <15 ml/min/1.73 m ² for patients with baseline eGFR >30 ml/min/1.73 m ² .

Time to first manifestation of sustained eGFR (CKD-EPI) <10 ml/min/1.73 m ² for patients with baseline eGFR <30 ml/min/1.73 m ² .

Cumulative time to first manifestation of >40% sustained decrease in eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1, 73 m ² , continuous eGFR (CKD-EPI) <10 ml/min/1.73 m ² for patients with baseline eGFR <30 ml/min/1.73 m ² .

Cumulative time to first manifestation of >40% sustained decrease in eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1, 73 m ² , continuous eGFR (CKD-EPI) <10 ml/min/1.73 m ² for patients with baseline eGFR < 30 ml/min/1.73 m ² , or need for chronic dialysis or need for renal transplant.

Time to death due to cardiovascular disease;

time to death for any reason;

health-related quality of life (eg, as measured by the KCCQ or KCCQ-12);

time to first onset type 2 diabetes in non-diabetic patients;

time to re-hospitalization due to heart failure;

change in NYHA classification;

time to hospitalization for any reason, including the first and / or recurrent;

time to first developed atrial fibrillation;

time to non-lethal or fatal myocardial infarction;

time to nonfatal or fatal stroke;

time to any death due to cardiovascular disease (including fatal stroke, fatal myocardial infarction and sudden death);

non-lethal myocardial infarction (excluding asymptomatic myocardial infarction), non-lethal stroke (the so-called 3-point MACE);

change in eGFR;

progression to macroalbuminuria (defined as albumin/creatinine ratio

- 24 042969 (ACR) >300 mg/g);

time to need for chronic dialysis treatment;

the time until the need for a kidney transplant;

a constellation of eGFR reduction, renal replacement therapy, or renal death;

a combination of eGFR reduction, renal replacement therapy, renal death, or death due to cardiovascular disease;

constellation of eGFR reduction, renal replacement therapy, renal death, or death from any cause.

Health-related quality of life can be defined according to the KCCQ or KCCQ-12. The KCCQ-12 is an approved 23-item shortened version of the original KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire was designed to assess physical limitations, symptoms (frequency, severity, and changes in dynamics), social limitations, self-efficacy, and quality of life in patients with HF.

Example 3 Treatment of Assisted Patients with Chronic Heart Failure and HfrEF.

The effect of treatment with empagliflozin on function and other parameters in a relevant patient population with chronic heart failure and reduced ejection fraction and infirmity was investigated as follows.

Patients with chronic heart failure and symptoms consistent with NYHA II, III, or IV and reduced ejection fraction (LVEF less than or equal to 40%) and elevated BNP (or elevated NT-proBNP), such as as described below, and with infirmity treated over a period of time (eg, approximately 12 weeks for each patient) with empagliflozin (optionally in combination with one or more other active agents, such as those described herein, for example) and compared with patients who were treated with placebo according to the standard treatment of background therapy.

Empagliflozin is administered orally once a day (eg, 10 mg/day). Patients include non-diabetic patients, pre-diabetic patients, and type 2 diabetic patients. Prediabetes is diagnosed if HbA1c is greater than or equal to 5.7% and less than 6.5%. An individual is a non-diabetic patient if the HbA1c is less than 5.7%. Patients have an LVEF less than or equal to 40%.

Patients with elevated BNP (or elevated NT-proBNP) are defined as those who have one of the following:

elevated BNP >150 pg/mL, or NT-proBNP >600 pg/mL; or if patients have 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 in accordance with at least one of the following manifestations of heart failure.

If the ejection fraction EF is >36% to <40%, then the elevated NT-proBNP will be >2500 pg/mL for patients without atrial fibrillation, or >5000 pg/mL for patients with atrial fibrillation.

If the ejection fraction EF is >31% to <35%, then the elevated NT-proBNP will be >1000 pg/mL for patients without atrial fibrillation, or >2000 pg/mL for patients with atrial fibrillation.

If the ejection fraction EF is <30%, then the elevated NT-proBNP will be >600 pg/mL for patients without atrial fibrillation, or >1200 pg/mL for patients with atrial fibrillation.

An infirm patient was included in the study if, for example, the patient walked less than 350 m during a 6-minute walking test.

After the end of the study period, functional ability was examined for each patient, in particular exercise capacity, eg, the 6-minute walking test, and additional clinical parameters, eg, as indicated below.

Patients with cardiovascular risk factors were treated according to standards of care, which include, for example, treatment with therapeutic agents selected from diuretics, ARNi, ACEi, ARB, statins, aspirin, beta-blockers, a mineralocorticoid antagonist, or ivabradine, with a device for cardiac therapy or without it, including ICD, CRT-D or CRT-P.

Patients in the study meet the following criteria.

Age over 18 years.

Diagnosed heart failure (HF). The definition of HF for inclusion in a study is a left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) less than or equal to 40% (per reading). The ejection fraction value is preferably obtained within 6 months prior to randomization and after any myocardial infarction (MI) or other event that will affect the ejection fraction.

Symptom(s) of heart failure (HF) (NYHA class II-IV).

At least one of the following: elevated NT-proBNP >600 pg/ml and/or, if the patient has been hospitalized for heart failure within the past 9 months, elevated NT-proBNP >400 pg/ml.

Frailty, for example, as determined by a 6-minute walking test in which the patient walked less than 350 m.

Background therapy in connection with heart failure, if necessary.

Antidiabetic background therapy, if needed.

Body mass index (BMI) < 45 kg/m ² .

eGFR >20 ml/min/1.73 m ² or eGFR > 30 ml/min/1.73 m ² .

After a specified period of time e.g. 12 weeks, functional capacity, in particular exercise capacity, e.g. 6 minute walking test, was determined in heart failure patients with reduced ejection fraction (according to the criteria described in previously herein) treated with empagliflozin (eg, 10 mg once daily) or placebo.

One or more of the following criteria were determined:

change in NYHA classification;

health-related quality of life (eg, as measured by KCCQ or KCCQ-12, MLHFQ, fatigue score, depression score, anxiety score, cumulative score);

change from baseline biomarkers, eg NT-proBNP;

time to first hospitalization for heart failure;

time to re-hospitalization due to heart failure.

Example 4 Treatment of Patients Requiring Assistance with Chronic Heart Failure and HFpEF.

The effect of treatment with empagliflozin on function and other parameters in a relevant population of patients with chronic heart failure and preserved ejection fraction and frailty was investigated as follows.

Patients with chronic heart failure and symptoms consistent with NYHA II, III, or IV and preserved ejection fraction (LVEF greater than 40% or greater than 50%) and infirmity were treated for a period of time (eg, approximately 12 weeks for each patient) using empagliflozin (optionally in combination with one or more other active substances, such as those described in this application) and compared with patients who received placebo treatment according to the background therapy treatment standards.

Empagliflozin is administered orally once a day (eg, 10 mg/day). Patients include non-diabetic patients, pre-diabetic patients, and type 2 diabetic patients. Prediabetes is diagnosed if HbA1c is greater than or equal to 5.7% and less than 6.5%. An individual is a non-diabetic patient if the HbA1c is less than 5.7%. Patients have an LVEF greater than 40%, in particular greater than 50%.

Patients include individuals who have been hospitalized for heart failure within the past 9 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)).

A patient with infirmity was included in the study if, for example, during a 6-minute walking test, the patient walked a distance of less than 350 m.

After the end of the study period, functional ability was examined for each patient, in particular exercise capacity, eg, the 6-minute walking test, and additional clinical parameters, eg, as indicated below.

Patients with cardiovascular risk factors were treated according to the standard of care, which includes symptomatic treatment, and treatment of cardiovascular risk factors including hypertension, diabetes mellitus, and dyslipidemia.

Patients in the study meet the following criteria.

Age over 18

Diagnosed heart failure (HF). The definition of HF to be included in the study is left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) >40% (per reading). The value of the ejection fraction is preferably obtained within 6 months before randomization and after any myocardial infarction (MI) or other event that will affect the ejection fraction.

- 26 042969

Symptom(s) of heart failure (HF) (NYHA class II-IV

Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.

At least one of the following: hospitalization for heart failure within the past 9 months and/or elevated NT-proBNP (>300 pg/mL in patients without atrial fibrillation (AF) or >900 pg/mL in patients with fibrillation atrial (AF)).

Frailty, for example, as determined by a 6-minute walking test in which the patient walked less than 350 m.

Background therapy in connection with heart failure, if necessary.

Antidiabetic background therapy, if needed.

Body mass index (BMI) <45 kg/m ² .

eGFR > 20 ml/min/1.73 ^m2 or eGFR >30 ml/min/1.73 ^m2 .

After a certain period of time, e.g. 12 weeks, functional capacity, in particular exercise capacity, e.g. 6-minute walking test, was determined in patients with heart failure with preserved ejection fraction (according to the criteria described in previously herein) treated with empagliflozin (eg, 10 mg once daily) or placebo.

One or more of the following criteria were determined:

change in NYHA classification;

health-related quality of life (eg, as measured by KCCQ or KCCQ-12, MLHFQ, fatigue score, depression score, anxiety score, cumulative score);

change from baseline biomarkers, eg NT-proBNP;

time to first hospitalization for heart failure;

time to re-hospitalization due to heart failure.

An example of a pharmaceutical composition and dosage form.

The following example of solid pharmaceutical compositions and oral dosage forms serves as a more complete illustration of the present invention without limiting its scope to a specific example. Further examples of compositions and dosage forms for oral administration are described in WO 2010/092126. The term active substance means empagliflozin according to the present invention, in particular its crystalline form as described in WO 2006/117359 and WO 2011/039107.

Tablets containing 2.5 mg, 5 mg, 10 mg or 25 mg of the active substance empagliflozin. The amount of ingredients is presented in mg per film-coated tablet.

Active substance 2.5 mg/tablet 5 mg/tablet 10 mg/tablet 25 mg/tablet Wet granulation empagliflozin 2.5000 5,000 10.00 25.00 Lactose monohydrate 40.6250 81.250 162.50 113.00 Microcrystalline cellulose 12.5000 25,000 50.00 40.00 Hydroxypropylcellulose 1.8750 3,750 7.50 6.00 Croscarmellose sodium 1.2500 2,500 5.00 4.00 Purified water q.s. q.s. q.s. q.s. Dry additives Microcrystalline cellulose 3.1250 6.250 12.50 10.00 colloidal silicon dioxide 0.3125 0.625 1.25 1.00 magnesium stearate 0.3125 0.625 1.25 1.00 Common core 62.5000 125,000 250.00 200.00 Film coating Film coating system 2.5000 4,000 7.00 6.00 Purified water q.s. q.s. q.s. q.s. Total 65,000 129,000 257.00 206.00

Details regarding the preparation of tablets, the active pharmaceutical ingredient, excipients and the film coating system are described in WO 2010/092126, in particular in examples 5 and 6, which is hereby incorporated by reference in its entirety.

Claims (18)

1. The use of empagliflozin in a method for the treatment of chronic heart failure to reduce the risk of death due to cardiovascular disease or to reduce the risk of hospitalization due to heart failure in a non-diabetic patient with chronic heart failure, comprising administration of empagliflozin at a dose of 10 mg per day to the patient. 2. Use according to claim 1, wherein the risk of hospitalization for heart failure is the risk of first hospitalization for heart failure. 3. Use according to claim 1 or 2, wherein the patient is a NYHA class II, III, or IV chronic heart failure patient. 4. Use according to claim 1, 2 or 3, wherein the patient is a chronic heart failure patient with reduced ejection fraction. 5. The use of claim 4, wherein the reduced ejection fraction patient exhibits a left ventricular ejection fraction (LVEF) less than or equal to 40%. 6. Use according to claim 1, 2 or 3, wherein the patient is a chronic heart failure patient with preserved ejection fraction. 7. The use of claim 6 wherein the patient with preserved ejection fraction exhibits a left ventricular ejection fraction (LVEF) greater than 40%. 8. The use of claim 6 wherein the patient with preserved ejection fraction exhibits a left ventricular ejection fraction (LVEF) greater than 50%. 9. Use according to one or more of the preceding claims, wherein the patient is a patient with elevated B-type natriuretic peptide (BNP) or elevated plasma N-terminal brain prohormonal natriuretic peptide (NT-proBNP). 10. Use according to claim 9, wherein the patient has an elevated BNP equal to or greater than 75 pg/ml or NT-proBNP >300 pg/ml. 11. Use according to claim 9, wherein the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF >36% to <40% and elevated NT-proBNP >2500 pg/mL for patients without atrial fibrillation, or > 5000 pg/mL for patients with atrial fibrillation, or the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF >31% to <35% and elevated NT-proBNP >1000 pg/mL for patients without atrial fibrillation, or >2000 pg/mL for patients with atrial fibrillation, or the patient is a patient with reduced ejection fraction (HFrEF) and ejection fraction EF <30% and elevated NT-proBNP >600 pg/mL for patients without atrial fibrillation, or >1200 pg /ml for patients with atrial fibrillation. 12. Use according to one or more of claims 1 to 11, wherein the patient is a patient with prediabetes, type 1 diabetes mellitus or type 2 diabetes mellitus. 13. Use according to one or more of claims 1 to 11, wherein the patient is a non-diabetic patient. 14. Use according to one or more of claims 1 to 13, wherein the patient has an eGFR equal to or greater than 20 ml/min/1.73 m ² , or an eGFR equal to or greater than 30 ml/min/1.73 m ² . 15. Use according to one or more of the preceding claims, wherein mortality from any cause or risk of hospitalization from any cause is reduced. 16. The use according to one or more of the preceding claims, in which the occurrence of: first-onset albuminuria, progression from albuminuria-free to micro- or macroalbuminuria, doubling of serum creatinine levels, which is accompanied by eGFR (based on the Renal Disease Diet Modification Formula (MDRD) )) <45 ml/min/1.73 m ² , sustained >30%, >40%, >50%, or >57% eGFR (CKD-EPI), especially >40% sustained eGFR (CKD -EPI), long-term eGFR (CKD-EPI) <15 ml/min/1.73 ^m2 for patients with baseline eGFR >30 ml/min/1.73 ^m2 , long-term eGFR (CKD-EPI) <10 ml /min/1.73 m for patients with baseline eGFR <30 ml/min/1.73 m ² , need for continuous renal replacement therapy, need for chronic dialysis, need for a kidney transplant, death due to kidney disease, or complex sustained >40% decrease in eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 ml/min/1.73 m ² for patients at baseline - 28 042969 eGFR >30 ml/min/1.73 ^m2 , and long-term eGFR (CKD-EPI) <10 ml/min/1.73 ^m2 for patients with baseline eGFR <30 ml/min/1.73 m ² , or a complex of prolonged decrease by > 40% eGFR (CKD-EPI) or prolonged eGFR (CKD-EPI) <15 ml / min / 1.73 m ² for patients with an initial value of eGFR > 30 ml / min / 1, 73 ^m2 , continuous eGFR (CKD-EPI) <10 ml/min/1.73 ^m2 for patients with baseline eGFR <30 ml/min/1.73 ^m2 , need for chronic dialysis, need for kidney transplant prevented, protected from, or slowed down. 17. Use according to one or more of claims 1 to 16 wherein empagliflozin is administered in combination with one or more other therapeutic agents to a patient. 18. Use according to claim 17 wherein one or more other therapeutic agents are selected from the group consisting of active agents which are indicated for the treatment of chronic heart failure, anti-diabetic agents, active agents which lower total cholesterol, LDL cholesterol, non- HDL and/or Lp(a) in the blood, active substances that increase the level of HDL cholesterol in the blood, active substances that lower blood pressure, active substances that are indicated for the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants and protective agents vascular endothelium.