NZ786122A - Pharmaceutical composition comprising empagliflozin and uses thereof - Google Patents

Abstract

The present invention relates to methods for preventing or treating acute or chronic heart failure and for reducing the risk of cardiovascular death, hospitalization for heart failure and other conditions in patients with preserved or reduced ejection fraction by administering empagliflozin to the patient.

Description

PHARMACEUTICAL ITION COMPRISING EMPAGLIFLOZIN AND USES THEREOF Cross Reference The t application is a onal of New Zealand patent application no. 744427, which was the national phase entry of , the entire specifications of which are incorporated herein by cross-reference.

Technical Field of the Invention The present invention relates to methods for treating c heart failure, for reducing the risk of vascular death, for ng the risk of hospitalization for heart failure, for reducing use mortality, for reducing the risk of all-cause hospitalization, for reducing the risk of new onset of atrial fibrillation and for improving health-related quality of life and/or the functional ty in a patient with chronic heart failure. The present invention also relates to methods for treating, preventing, protecting against, ng the risk of or delaying the occurrence of acute heart failure, including acute decompensated heart failure. Furthermore the present invention relates to methods for improving the renal function and for treating or preventing certain renal conditions and diseases in a patient with chronic heart failure. The present invention further relates to empagliflozin for use in methods for treating and/or preventing certain diseases or disorder or reducing the risk of or delaying the occurrence of certain diseases or disorders in a patient with chronic heart failure.

Background of the Invention Heart failure (HF) is a clinical syndrome caused by the inability of the heart to e adequate blood supply or by sustaining te blood supply at the expense of elevated left ventricular (LV) filling pressure. Patients with Heart e (HF) face a poor diagnosis, and about 50% of patients die from HF within 5 years. About 66% of patients with HF are non-diabetic patients. Total prevalence of HF worldwide was 26 million in 2013. In the US, more than 1 million HF hospitalizations occur every year. There is a considerable unmet need in HF. The overall goal for the treatment of HF is to prevent alization and mortality, control ms, and improve quality of life. There are two types of HF: HF with reduced (HFrEF) or preserved (HFpEF) Ejection Fraction, the latter representing 50% of total HF. Both HFrEF and HFpEF are associated with high ity and mortality. Current treatment options for HFrEF are mainly based on administration of beta-blockers, ACEi, ARBs, ARNi, MRAs and diuretics. Despite these options, outcomes remain suboptimal. There are at present no effective treatments indicated for HFpEF, with treatment focused on symptom ment and on comorbidities.

Therefore, there is an unmet l need for methods for treating chronic heart failure, in particular in patients with HFrEF or HFpEF, with a good efficacy, with regard to disease- modifying properties and with regard to reduction of risk of mortality or hospitalization while at the same time g an good safety profile. y of the Invention The present ion relates to a method for treating, preventing, protecting against or delaying the occurrence 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 cardiovascular death in a t with chronic heart failure comprising stering empagliflozin to the patient.

In addition the present invention relates to a method for reducing the risk of alization (first and recurrent) for heart failure in a patient with chronic heart failure comprising administering empagliflozin to the t.

Furthermore the present ion relates to a method for reducing all-cause mortality in a patient with chronic heart failure sing administering empagliflozin to the patient.

Furthermore the present invention relates to a method for reducing the risk of all-cause hospitalization in a patient with chronic heart failure comprising administering empagliflozin to the t.

The present invention also relates to a method for reducing the risk of new onset of atrial fibrillation in a patient with chronic heart failure comprising stering iflozin to the patient.

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

The present invention also relates to a method for preventing, slowing or reversing the progression to macroalbuminuria in a patient with chronic heart failure comprising administering empagliflozin to the patient.

The present invention also s to a method for improving the renal function or for renal protection in a t with chronic heart failure comprising administering empagliflozin to the patient.

The present invention also relates to a method for treating, ting, protecting against, reducing the risk of, delaying the occurrence of and/or delaying the progression of chronic kidney disease in a patient with chronic heart failure comprising administering empagliflozin to the patient.

The t invention also relates to a method for improving the health related y of life and/or the functional capacity in a patient with chronic heart failure sing administering empagliflozin to the patient.

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

The t invention further provides for empagliflozin or a pharmaceutical composition comprising empagliflozin optionally in combination with one or more other eutic nces for use in a method for treatment, prevention or risk reduction in any one of the diseases or conditions described herein.

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

In one ment, the present invention provides a method of treatment comprising: a) identifying 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 of treating chronic heart e in a patient comprising: a. determining the symptoms ing to the NYHA classification of the patient; b. identifying that the patient has chronic heart failure according to NYHA class I; c. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a t comprising: a. determining the symptoms according to the NYHA fication of the patient; b. identifying that the patient has chronic heart e ing to NYHA class II; c. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a. determining the symptoms according to the NYHA classification of the patient; b. identifying that the patient has chronic heart failure according to NYHA class III; c. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient sing: a. determining the symptoms according to the NYHA classification of the t; b. identifying that the patient has chronic heart failure according to NYHA class IV; c. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a. determining the ejection fraction of the patient; b. identifying that the t has an ejection fraction equal or smaller than 40%; c. stering empagliflozin to the t.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a. ining the symptoms according to the NYHA classification of the patient; b. determining the ejection fraction of the patient; c. identifying that the patient has chronic heart failure according to NYHA class I and has an ejection fraction equal or smaller than 40%; d. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating c heart failure in a patient comprising: a.determining the symptoms according to the NYHA classification of the patient; b.determining the ejection fraction of the patient; c. identifying that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection fraction equal or smaller than 40%; d.administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart e in a patient comprising: a. determining the symptoms according to the NYHA classification of the patient; b. determining the on fraction of the patient; C. identifying that the patient has chronic heart failure according to NYHA class I and has an ejection fraction greater than 40%, in particular r than 50%; d. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a t sing: a.determining the ms according to the NYHA classification of the t; b.determining the ejection fraction of the patient; 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%; nistering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a. determining the symptoms according to the NYHA classification of the patient; b. determining the ejection on of the patient; c. determining the BNP or NT-proBNP value of the t; d. identifying that the patient has c heart failure according to NYHA class I and has an ejection fraction equal or smaller than 40%, in particular r than 50%, and has an elevated BNP or NT—proBNP value; e. administering empagliflozin to the patient.

In one embodiment, the present invention provides a method of treating chronic heart failure in a patient comprising: a.determining the symptoms according to the NYHA classification of the patient; b.determining the ejection fraction of the patient; c. determining the BNP or NT-proBNP value of the patient; d.identifying that the patient has chronic heart failure according to NYHA class II, III or IV and has an ejection on equal or smaller than 40%, in particular greater than 50%, and has an elevated BNP or NT—proBNP value; nistering empagliflozin to the patient.

According to this embodiment an elevated BNP or NT—proBNP value is particularly a BNP value equal to or r than 150 pg/mL or a NT—proBNP value equal to or greater than 600 pg/mL. Furthermore according to this embodiment an ed BNP or NT-proBNP value is particularly a BNP value equal to or greater than 100 pg/mL or a NT-proBNP value equal to or greater than 400 pg/mL if the patient was hospitalized for heart failure within the last 9 months.

In the methods according to the present invention empagliflozin is optionally administered in combination with one or more other therapeutic substances to the patient.

Further aspects of the present invention become nt to the one skilled in the art by the description hereinbefore and in the following and by the es.

Definitions The term "active ingredient" of a pharmaceutical composition ing to the present invention means the SGLT2 inhibitor empagliflozin ing to the present invention. An "active ingredient" is also sometimes referred to herein as an e nce".

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

The term "overweight" is defined as the condition wherein the individual has a BMI greater than or 25 kg/m2 and less than 30 kg/mz. The terms "ovenNeight" and "pre-obese" are used interchangeably.

The terms "obesity" or "being obese" and the like are defined as the condition wherein the individual has a BMI equal to or greater than 30 kg/mz. According to a WHO definition the term obesity may be categorized as follows: the term "class I obesity" is the condition wherein the BMI is equal to or greater than 30 kg/m2 but lower than 35 kg/mz; the term "class II obesity" is the condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/mz; the term "class III obesity" is the ion wherein the BMI is equal to or greater than 40 kg/mz.

The indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary y, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity.

The term "visceral obesity" is defined as the condition wherein a waist-to-hip ratio of r than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for insulin resistance and the pment of pre—diabetes.

The term "abdominal obesity" is usually d as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients nal obesity may be defined as waist circumference Z 85 cm in men and Z 90 cm in women (see e.g. investigating committee for the sis of metabolic syndrome in Japan).

The term "euglycemia" is defined as the condition in which a subject has a g 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 the usual meaning as a medical term.

The term "hyperglycemia" is d as the ion 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 ng" has the usual meaning as a medical term.

The term "hypoglycemia" is defined as the condition in which a subject has a blood glucose concentration below the normal range, in particular below 70 mg/dL (3.89 mmol/L).

The term "postprandial hyperglycemia" is defined as the condition in which a t has a 2 hour postprandial blood glucose or serum glucose concentration r than 200 mg/dL (11.11 mmol/L).

The term "impaired fasting blood glucose" or "IFG" is d as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration in a range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL and less than 126 mg/dl (7.00 mmol/L). A subject with "normal fasting glucose" has a fasting glucose concentration smaller than 100 mgidl, i.e. smaller than 5.6 .

The term "impaired glucose tolerance" or "IGT" is defined as the condition in which a subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg/dl (7.78 mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal glucose nce, i.e. the 2 hour postprandial blood glucose or serum glucose concentration can be measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75 g of glucose after a fast. A t with "normal e tolerance" has a 2 hour postprandial blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term "hyperinsulinemia" is defined as the condition in which a subject with insulin resistance, with or without euglycemia, has fasting or andial serum or plasma insulin tration elevated above that of , lean individuals without n resistance, having a waist-to-hip ratio < 1.0 (for men) or < 0.8 (for women).

The terms "insulin-sensitizing", "insulin resistance-improving" or "insulin resistance-lowering" are synonymous and used interchangeably.

The term "insulin resistance" is defined as a state in which circulating insulin levels in excess of the normal response to a e load are required to maintain the emic state (Ford ES, et al. JAMA. (2002) 287:356—9). A method of determining insulin resistance is the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined insulin-glucose infusion technique. There is found to be insulin resistance if the glucose absorption is below the 25th percentile of the background population investigated (WHO definition). Rather less laborious than the clamp test are so called minimal models in which, during an intravenous glucose tolerance test, the insulin and glucose concentrations in the blood are measured at fixed time intervals and from these the insulin resistance is ated. With this method, it is not le to distinguish between hepatic and peripheral n resistance.

Furthermore, insulin resistance, the response ofa t with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to insulin resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further nce is made to methods for the determination of the HOMA—index for insulin sensitivity (Matthews et al., Diabeto/ogia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forstetal., Diabetes 2003, 52(Suppl. 1): A459) and to an euglycemic clamp study. In on, plasma adiponectin levels can be monitored as a potential surrogate of insulin sensitivity. The estimate of insulin resistance by the homeostasis assessment model (HOMA)—|R score is calculated with the formula (Galvin P, etal'. Diabet Med 1992;9z921-8): HOMA-IR = [fasting serum insulin (uU/mL)] x [fasting plasma glucose(mmol/L)/22.5] Insulin resistance can be med in these individuals by ating the HOMA-IR score.

For the purpose of this ion, insulin resistance is defined as the 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 defined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as sed triglyceride levels correlate significantly with the presence of insulin resistance. duals likely to have insulin resistance are those who have two or more of the following attributes: 1) ight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1St degree relative with a diagnosis of IGT or IFG or type 2 diabetes.

Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those having euglycemia with hyperinsulinemia and are by definition, insulin resistant. A l patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may be that in order to maintain glucose homoeostasis a person needs 2-3 times as much insulin as a healthy person, without this ing in any al symptoms.

"Pre-diabetes" is a general term that refers to an intermediate stage between normal glucose nce (NGT) and overt type 2 diabetes mellitus (T2DM), also referred to as intermediate hyperglycaemia. Therefore in one aspect of the present invention iabetes" is diagnosed in an individual if HbA1c is more or equal to 5.7% and less than 6.5%.

According to another aspect of this invention "pre-diabetes" represents 3 groups of individuals, those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone or those with both IGT and IFG. IGT and IFG usually have distinct pathophysiologic etiologies, however also a mixed condition with features of both can exist in patients. Therefore in another aspect of the present invention a patient being diagnosed of having "pre-diabetes" is an individual with diagnosed IGT or diagnosed IFG or diagnosed with both IGT and IFG. Following the definition ing to the American es Association (ADA) and in the context an aspect of the t invention a patient being diagnosed of having "pre—diabetes" is an individual with: a) a g plasma glucose (FPG) concentration <100 mg/dL [1 mg/dL = 0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between 2140 mg/dL and <200 mg/dL (i.e., IGT); or b) a fasting plasma e (FPG) concentration between 2100 mg/dL and <126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); or c) a fasting plasma glucose (FPG) concentration between 2100 mg/dL and <126 mg/dL and a 2-hour plasma e (PG) concentration, measured by a 75-g oral glucose nce test (OGTT), ranging between 2140 mg/dL and <200 mg/dL (i.e., both IGT and IFG).

Patients with "pre-diabetes" are individuals being pre-disposed to the development of type 2 diabetes. Pre-diabetes extends the definition of IGT to include individuals with a fasting blood glucose within the high normal range 2 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and ive and Kidney es (Diabetes Care 2002; 25:742-749).

The s to investigate the function of pancreatic beta-cells are similar to the above s with regard to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement of beta-cell function can be measured for example by determining a HOMA- index stasis model assessment) for beta-cell function, HOMA—B, (Matthews et al., ologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1): A459), first and second phase insulin secretion after an oral e tolerance test or a meal tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301), the insulin/C-peptide secretion after an oral e tolerance test or a meal nce test, or by employing a hyperglycemic clamp study and/or l ng after a frequently sampled intravenous glucose tolerance test (Stumvoll et at, EurJ Clin Invest 2001, 31: 380-81).

The term "type 1 diabetes" is defined as the condition in which a subject has, in the presence of munity towards the pancreatic beta-cell or insulin, a fasting blood e or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of e have been taken on an empty stomach, in the presence of autoimmunity towards the pancreatic beta cell or insulin. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. The presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies ["type 1A diabetes mellitus"], i.e., at least one of: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm], lA—2 [intracytoplasmatic domain of the tyrosine phosphatase-like protein lA—2], ZnT8 [zinc-transporter-8] or anti—insulin; or other signs of autoimmunity without the presence of typical circulating autoantibodies [type 18 diabetes], i.e. as detected through pancreatic biopsy or g). Typically a genetic position is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.

The term "type 2 diabetes mellitus" or "T2DM" is d as the condition in which a subject has a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy t, the blood sugar level before taking the glucose will be n 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.

The term "late stage type 2 diabetes mellitus" includes patients with a secondary drug failure, indication for n therapy and progression to micro- and macrovascular complications e.g. diabetic nephropathy, or coronary heart disease (CH D).

The term "LADA" ("latent autoimmune diabetes of adults") refers to patients that have a clinical diagnosis of type 2 diabetes, but who are being detected to have autoimmunity towards the pancreatic beta cell. Latent mune diabetes of adults (LADA) is also known as slowly ssive type 1 diabetes mellitus (T1DM), "mild" T1 DM, non-insulin dependent type 1 DM, type 1 1/2 DM, double diabetes or dy positive type 2 DM (T2DM). LADA is often not clearly defined and, opposed to T1 DM, seldom or never presents with significant weight loss and idosis due to rapidly progressive B-cell failure.

The term "HbA1c" refers to the product of a non—enzymatic ion of the haemoglobin B chain. Its determination is well known to one skilled in the art. In monitoring the treatment of diabetes mellitus the HbA1c value is of exceptional importance. As its production depends essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the preceding 4-6 weeks. ic patients whose HbA1c value is consistently well adjusted by intensive diabetes treatment (i.e. < 6.5 % of the total haemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin on its own achieves an average improvement in the HbA1c value in the diabetic of the order of 1.0 — 1.5 %. This reduction of the HbA1C value is not sufficient in all diabetics to e the desired target range of <7% or < 6.5 % and preferably < 6 % HbA1c.

The term "insufficient glycemic control" or quate glycemic control" in the scope of the present invention means a condition wherein patients show HbA1c values above 6.5 %, in particular above 7.0 %, even more preferably above 7.5 %, ally above 8 %.

The "metabolic syndrome", also called "syndrome X" (when used in the context of a lic disorder), also called the "dysmetabolic syndrome" is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen DE, et al. Am J iol 2002;156:1070—7). ing to the ATP llllNCEP guidelines (Executive y 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 lll) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal y, defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients defined as waist circumference 2 85 cm in men and 2 90 cm in women; 2. Triglycerides: 2 150 mg/dL 3 HDL-cholesterol < 40 mg/dL in men 4. Blood pressure 2 130/85 mm Hg (SBP 2 130 or DBP 2 85) 5 Fasting blood glucose 2 100 mg/dL The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be ined by standard methods in medical analysis and are described for example in Thomas L (Editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used tion, hypertension is diagnosed if the systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a t is suffering from manifest diabetes it is currently recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and the diastolic blood pressure be lowered to below 80 mm Hg.

The term "empagliflozin" refers to the SGLT2 inhibitor 1-chloro(B-D-glucopyranosy|)- 2-[4-((S)—tetrahydrofuranyloxy)—benzyl]—benzene of the a as described for example in literature, for example WO 06/120208 and to be understood that the definition of empagliflozin also comprises its es, solvates and polymorphic forms thereof, and prodrugs f. An advantageous crystalline form of iflozin is described in incorporated herein in their entirety. This crystalline form possesses good solubility properties which enables a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition. Preferred pharmaceutical itions, such as solid formulations for oral administration, for example tablets, are described in which hereby is incorporated herein in its entirety.

The terms "treatment" and "treating" comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the ic indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for c therapy.

The terms "prophylactically treating , preventivally ng" and "preventing" are used interchangeably and comprise a ent of patients at risk to p a condition mentioned hereinbefore, thus reducing said risk.

The term "tablet" comprises tablets without a coating and tablets with one or more coatings.

Furthermore the "term" tablet comprises s having one, two, three or even more layers and press-coated tablets, wherein each of the mentioned types of tablets may be without or with one or more coatings. The term "tablet" also comprises mini, melt, chewable, effervescent and orally disintegrating tablets.

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

The term "chronic heart failure" or "CHF" is a synonym of congestive heart failure (CCF).

The extent of heart failure may be classified according to the New York Heart ation (NYHA) onal Classification and encompasses the NYHA classes |, II, III and IV.

Chronic heart failure may be distinguished ing to the y of the left ventricle to contract is affected (heart failure with reduced on fraction) or the heart's abiility to relax is affected (heart failure with preserved ejection fraction).

The term "HFpEF" refers to heart failure with preserved ejection fraction. HFpEF is mes also referred to as "Diastolic Heart Failure".

The term "HFrEF" refers to heart failure with d 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 may be obtained by echocardiography, radionuclide ventriculography and angiography, preferably by echocardiography.

The term "BNP" refers to the brain natriuretic peptide, also called B-type natriuretic peptide.

BNP is used for screening and diagnosis for c heart failure. The BNP value is determined in the blood plasma or serum.

The term "NT-proBNP" refers to the inal of the prohormone brain natriuretic peptide.

NT-proBNP is used for screening and diagnosis for chronic heart failure. The NT-proBNP value is determined in the blood plasma or serum.

The term "albuminuria" is defined as a condition wherein more than the normal amount of albumin is present in the urine. Albuminuria can be determined by the albumin excretion rate (AER) and/or the n-to-creatine ratio (ACR) in the urine (also refered to as UACR).

Albuminuria categories in CKD are defined as follows: ‘ ACR (approximate equivalent) Category AER (mg/24 hours) ‘ (mg/mmol) (mg/g) Terms A1 < 30 < 3 < 30 Normal to mildly increased A2 30-300 ‘ 3-30 30-300 Moderately increased A3 >300 ‘ >30 >300 Severely increased Category A1 reflects no albuminuria, category A2 reflects lbuminuria, ry A3 reflects macroalbuminuria. The progression of category A‘I y leads to microalbuminuria (A2) but may also directly result in macroalbuminuria (A3). ssion of microalbuminuria (A2) results in macroalbuminuria (A3).

The term "eGFR" refers to the estimated glomerular filtration rate (GFR). The GFR describes the flow rate of filtered fluid through the kidney. The estimated GFR may be calculated based on serum nine values e.g. using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in Renal e (MDRD) formula, which are all known in the art.

According to an aspect of this invention the estimated glomerular filtration rate (eGFR) is derived from serum creatinine values, age sex and race based on the CKD-EPI equation: GFR = 141 x min (scr /K, 1)" x max(s,,/K, 1)"~209 x 0.993Age x 1.018 [if female] x 1.159 [if black] where: Scr is serum nine in mg/dL, K is 0.7 for females and 0.9 for males, 01 is -0.329 for females and -O.411 for males, min tes the minimum of Scr/K or 1, and max indicates the maximum of Scr /K or 1.

For the purpose of the present invention, the degree of renal impairment in a patient is defined by the following estimated ular filtration rate (eGFR): Normal renal function (CKD stage 1): eGFR Z 90 mL/min/1.73 m2 Mild renal impairment (CKD stage 2): eGFR 260 to <90 /1.73 m2 Moderate renal impairment (CKD stage 3): eGFR 230 to <60 mL/min/1.73 m2 Severe renal impairment (CKD stage 4): eGFR 215 to <30 mL/min/1.73 m2 Kidney failure (CKD stage 5): eGFR <15 mL/min/1.73 m2 According to the present invention moderate renal ment can be further d into two sub-stages: Moderate A renal impairment (CKD 3A): eGFR 245 to <60 mL/min/1.73 m2 Moderate B renal impairment (CKD 3B): eGFR 230 to <45 mL/min/1.73 m2 The term "KCCQ" refers to Kansas City Cardiomyopathy Questionnaire. The health related quality of life may be measured according to KCCQ or KCCQ-12. KCCQ-12 is a validated short n of the original 23—item KCCQ (Kansas City Cardiomyopathy Questionnaire).

This self-administered questionnaire is ed to evaluate physical limitations, symptoms (frequency, severity, and s over time), social limitations, self-efficacy, and quality of life in patients with HF.

The term "MLHFQ" refers to Minnesota Living With Heart Failure Questionnaire. The quality of life, including for example its physical, emotional, social and mental dimensions, may be ed according to MLH FQ.

Detailed Description of the Invention Beyond an improvement of glycemic control and weight loss due to an increase in urinary glucose excretion, iflozin shows a ic effect, d arterial stiffness and direct vascular effects (Cherney et al., Cardiovasc Diabetoi. 2014;13:28; Cherney et al., Circulation. 2014;129:587-597). In the EMPA—REG OUTCOMETM study it was trated that empagliflozin d the risk of cardiovascular death, hospitalization for heart failure and l mortality in patients with type 2 diabetes mellitus and high vascular risk (Zinman et al., N Engl J Med. 2015;373:2117—2128). It was observed that treatment with empagliflozin leads to blood pressure reductions t clinically relevant changes of the heart rate, thus improving rate re product (RPP), a surrogate marker of cardiac oxygen demand. Furthermore empagliflozin was found of not being associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics. It may be assumed that altered glucose and sodium gradients within the kidney may generate a sympathoinhibitory afferent renal nerve signal. The lack of sympathetic activation may contribute to a beneficial cardiovascular and renal profile of empagliflozin orenal axis). Based on al and non-clinical studies including mechanistic considerations, such as the effect of empagliflozin on human autonomic cardiovascular regulation, the use of empagliflozin in the treatment and prevention of certain diseases and conditions, in particular in chronic heart failure, acute heart failure and chronic kidney disease, is described hereinbefore and hereinafter.

The present invention relates to a method for treating chronic heart failure in a patient in need thereof comprising stering empagliflozin to the patient. The present invention also relates to a method for reducing the risk of cardiovascular death in a patient with chronic heart failure comprising administering 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 comprising administering empagliflozin to the patient. The present invention also relates to a method for reducing the risk of cardiovascular death and alization for heart failure in a patient with chronic heart failure comprising administering empagliflozin to the patient. According to an embodiment of this invention the risk of hospitalization for heart failure is the risk of first hospitalization for heart e. According to another embodiment of this ion the risk of hospitalization for heart failure is the risk of recurrent hospitalization for heart failure. The present invention further relates to a method for reducing use mortality in a patient with chronic heart failure comprising administering iflozin to the patient. Furthermore the t invention relates to a method for reducing the risk of all-cause hospitalization in a patient with chronic heart failure comprising administering empagliflozin to the t. According to an embodiment of this invention the risk of all-cause hospitalization is the risk of first all-cause hospitalization.

According to another embodiment of this invention the risk of all-cause hospitalization is the risk of recurrent all—cause hospitalization. The present invention also relates to a method for reducing the risk of new onset of atrial fibrillation in a patient with chronic heart failure comprising stering empagliflozin to the patient.

The present invention also relates to a method for preventing, protecting against or delaying the occurrence of chronic heart failure in a patient in need thereof comprising administering empagliflozin to the t. According to an embodiment of this invention a method for preventing a worsening of chronic heart failure in a patient with chronic heart failure of NYHA class I to chronic heart failure of NYHA class II, III or IV is provided.

The present invention also relates to a method for treating, preventing, protecting against or delaying the occurrence of acute heart failure in a patient in need thereof comprising administering iflozin to the patient, in ular wherein the patient is a patient with chronic heart failure.

The present invention also relates to a method for treating, preventing, protecting against, reducing the risk of or delaying the ence of acute decompensated heart failure (ADH F) in a patient with c heart failure in need thereof comprising administering empagliflozin to the t.

In the methods according to the present invention the risk of a certain event, e or disorder is reduced when compared to a t administered with a placebo on rd of care background medication. In one embodiment, the risk is reduced by 15% or more. In one embodiment, the risk is reduced by 16% or more, by 17% or more, by 18% or more, by 19% or more, by 20% or more, by 25% or more or by 30% or more.

According to one ment of this invention the patient is a patient with c heart failure according to NYHA class II, III or IV. ing to an aspect of this embodiment of this invention the patient is a patient with chronic heart failure according to NYHA class II or III.

According to another embodiment of this invention the patient is a patient with chronic heart failure according to NYHA class I.

According to one embodiment of this invention the patient is a t with chronic heart failure and preserved ejection fraction (HFpEF). For example the patient with preserved ejection on shows a LVEF greater than 40% or even greater than 50%. According to a variant of this embodiment the patient with chronic heart failure and preserved ejection on (HFpEF) shows a LVEF equal to or greater than 50%. According to another variant of this embodiment the patient shows a LVEF in a range from 40 % to 49%, also called chronic heart failure with mid-range reduced ejection fraction (HFmrEF).

According to r embodiment of this invention the patient is a patient with chronic heart failure and reduced ejection fraction (HFrEF). For example the patient with reduced ejection on shows a LVEF of smaller or equal than 40%, in particular smaller than 40%.

Therefore according to an embodiment of this invention the invention provides a method for treating chronic heart failure with preserved on fraction (HFpEF) in a patient in need thereof comprising administering empagliflozin to the patient, for example in a patient with chronic heart failure according to NYHA class I, II, III or IV. According to an aspect of this embodiment the extent of chronic heart failure in a t with chronic heart failure ing to NYHA class II, III or IV is improved according to the NYHA classification. The t ing to this embodiment is for example a non-diabetic patient, a patient with pre- diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic t.

According to another embodiment this invention provides a method for treating chronic heart failure with reduced on fraction (HFrEF) in a patient in need thereof comprising administering empagliflozin to the patient, for e in a patient with chronic heart failure according to NYHA class I, II, III or IV. According to an aspect of this embodiment the extent of chronic heart failure in a patient with chronic heart failure according to NYHA class II, III or IV is improved ing to the NYHA classification. The patient according to this embodiment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 es mellitus, in particular a abetic patient.

According to an embodiment this invention provides a method for reducing the risk of cardiovascular death in a patient with c heart failure, for example according to NYHA class II, III or IV, with preserved ejection on (HFpEF) comprising administering empagliflozin to the patient. According to an 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 pre-diabetes or a t with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to another ment this invention provides a method for reducing the risk of cardiovascular death in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced ejection fraction ) comprising administering empagliflozin to the patient. According to an aspect of this ment the patient has chronic heart failure according to NYHA class I. The patient according to this ment is for example a non-diabetic patient, a patient with pre-diabetes or a t with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of hospitalization for heart failure in a patient with chronic heart e, for example ing to NYHA class II, III or IV, with ved on fraction (HFpEF) comprising administering empagliflozin to the patient. According to an aspect of this embodiment the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk of first hospitalization for heart failure is reduced. According to another aspect of this embodiment the risk of re- hospitalization for heart failure is reduced. The patient according to this ment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to r embodiment this invention provides a method for reducing the risk of hospitalization for heart e in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced ejection fraction (HFrEF) comprising administering empagliflozin to the patient. According to an aspect of this embodiment the t has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk of first hospitalization for heart failure is reduced. According to another aspect of this embodiment the risk of re- hospitalization for heart failure is reduced. The patient according to this embodiment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 es mellitus, in particular a non-diabetic patient.

According to an embodiment this ion provides a method for reducing the risk of cardiovascular death and hospitalization for 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. According to an 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 pre- diabetes or a patient with type 2 diabetes mellitus, in ular a non-diabetic patient.

According to another ment this invention es a method for reducing the risk of cardiovascular death and hospitalization for heart failure in a patient with c heart failure, for example according to NYHA class II, III or IV, with reduced ejection fraction (HFrEF) comprising administering empagliflozin to the patient. According to an aspect of this embodiment the patient has chronic heart failure according to NYHA class I. The t according to this ment is for example a non—diabetic patient, a patient with pre- es or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this ion es 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. ing to an 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 pre-diabetes or a patient with type 2 diabetes us, in ular a non-diabetic patient.

According to an embodiment this 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 reduced ejection fraction (HFrEF) comprising administering iflozin to the patient. According to an 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 pre—diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of all- cause hospitalization in a patient with chronic heart failure, for example ing to NYHA class II, III or IV, with ved ejection fraction (HFpEF) sing administering empagliflozin to the patient. For example the patient has chronic heart failure according to NYHA class I. According to another aspect of this embodiment the risk of first all-cause hospitalization is d. ing to another aspect of this embodiment the risk of recurrent all-cause hospitalization is reduced. The patient according to this embodiment is for example a non-diabetic patient, a patient with pre—diabetes or a patient with type 2 es mellitus, in particular a non-diabetic t.

According to another embodiment this invention provides a method for reducing the risk of all-cause hospitalization in a patient with chronic heart failure, for e according to NYHA class II, III or IV, with d ejection fraction (H FrEF) comprising administering empagliflozin to the patient. For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk of first all-cause hospitalization is reduced. According to another aspect of this embodiment the risk of recurrent all-cause hospitalization is reduced. The patient according to this embodiment is for example a abetic patient, a patient with abetes or a patient with type 2 diabetes us, in particular a non-diabetic patient.

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

According to another embodiment this invention provides a method for reducing the risk of new onset of atrial fibrillation in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced on fraction (HFrEF) comprising administering empagliflozin to the patient. For example the t has chronic heart failure according to NYHA class I. The patient according to this embodiment is for e a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient. ing to an embodiment this invention provides a method for improving the health related quality of life and/or the functional capacity, in particular the exercise capacity, 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.

For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the health related quality of life is measured by a questionnaire such as for example KCCQ or KCCQ-12. ing to another aspect of this embodiment the health related quality of life or exercise ty is measured by a walk test, for example a 6 s walk test, or by the maximum oxygen uptake (VOzmax). The patient according to this embodiment is for example a non-diabetic patient, a t with pre-diabetes or a patient with type 2 diabetes mellitus, in ular a non—diabetic patient.

According to an embodiment this ion provides a method for improving the health related quality of life and/or the functional capacity, in particular the exercise capacity in a patient with c heart failure, for example according to NYHA class II, III or IV, with reduced on fraction (HFrEF) comprising administering empagliflozin to the patient. For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the health related y of life ed by a questionnaire such as for example KCCQ or KCCQ-12. According to another aspect of this embodiment the health related quality of life or exercise capacity is measured by a walk test, for example a 6 s walk test, or by the maximum oxygen uptake (VOzmax). The patient according to this embodiment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this invention es a method for treating, preventing, protecting against, reducing the risk of or delaying the occurrence of acute decompensated heart failure (ADHF) in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with preserved ejection fraction ) comprising administering empagliflozin to the patient. According to an aspect of this embodiment the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is for e a abetic patient, a patient with pre-diabetes or a patient with type 2 diabetes us, in particular a non—diabetic patient.

According to another embodiment this ion provides a method for treating, preventing, protecting against, reducing the risk of or ng the occurrence of acute decompensated heart failure (ADHF) reducing the risk of new onset of atrial fibrillation in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced ejection on (HFrEF) comprising stering empagliflozin to the patient. According to an aspect of this ment 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 pre-diabetes or a patient with type 2 diabetes mellitus, in ular a non-diabetic patient.

According to an embodiment this invention provides a method for ng the risk of new onset of type 2 diabetes mellitus in a patient with chronic heart failure, for e 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 an aspect of this invention the patient is a non-diabetic patient.

According to another aspect of this invention the patient is a patient with pre-diabetes.

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

According to another aspect of this invention the patient is a patient with pre-diabetes.

According to an embodiment this 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, with preserved ejection fraction (HFpEF) sing administering empagliflozin to the patient. For e the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk on non-fatal myocardial infarction is reduced. ing to an aspect of this embodiment the risk on fatal myocardial infarction is reduced. The patient ing to this embodiment is for example a non-diabetic patient, a t with pre-diabetes or a patient with type 2 diabetes us, in particular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of myocardial infarction in a patient with c heart failure, for e according to NYHA class II, III or IV, with d ejection fraction (HFrEF) comprising stering empagliflozin to the patient. For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk on non-fatal myocardial infarction is d. According to an aspect of this embodiment the risk on fatal myocardial infarction is reduced. The patient according to this embodiment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in ular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of stroke in a patient with c heart failure, for e according to NYHA class II, III or IV, with preserved on fraction (HFpEF) comprising administering empagliflozin to the t.

For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the risk on non-fatal stroke is reduced. According to an aspect of this embodiment the risk on fatal stroke is reduced. The patient according to this embodiment is for e a non—diabetic patient, a t with pre—diabetes or a patient with type 2 diabetes mellitus, in particular a non—diabetic patient.

According to an embodiment this 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, with 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 an aspect of this embodiment the risk on non-fatal stroke is reduced. According to an aspect of this embodiment the risk on fatal stroke is reduced. The t according to this embodiment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient. ing to an embodiment this invention provides a method for reducing the risk of any of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (the so-called t MACE) in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with ved on fraction (HFpEF) sing administering empagliflozin to the patient. According to an aspect of this embodiment the patient has chronic heart failure according to NYHA class I. The patient according to this embodiment is for e a non- diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of any of cardiovascular death ding fatal stroke, fatal myocardial infarction and sudden death), non-fatal dial infarction (excluding silent dial infarction), non-fatal stroke (the so-called 3-point MACE) in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with preserved ejection on (HFpEF) comprising administering empagliflozin to the patient. According to an aspect of this ment 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 pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an ment this invention provides a method for ng the risk of any of cardiovascular death, non-fatal myocardial infarction, tal stroke (the so-called 3-point MACE) in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced ejection fraction (HFrEF) comprising administering empagliflozin to the patient. According to an 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- ic patient, a t with pre—diabetes or a patient with type 2 diabetes mellitus, in ular a non-diabetic patient.

According to an embodiment this invention provides a method for reducing the risk of any of cardiovascular death (including fatal stroke, fatal dial infarction and sudden death), non-fatal myocardial infarction (excluding silent myocardial infarction), non-fatal stroke (the so-called 3-point MACE) in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with reduced ejection fraction (HFrEF) comprising administering iflozin to the patient. According to an aspect of this embodiment the patient has chronic heart failure according to NYHA class I. The patient ing to this ment is for example a non-diabetic t, a t with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an ment this invention provides a method for preventing, slowing or reversing the progression to macroalbuminuria in a patient with chronic heart failure, for example according to NYHA class II, III or IV, with preserved ejection fraction (H FpEF) comprising administering empagliflozin to the patient. For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the progression from microalbuminuria to macroalbuminuria is prevented, slowed or reversed.

The patient according to this ment is for example a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient.

According to an embodiment this invention provides a method for preventing, slowing or ing the progression to macroalbuminuria in a patient with chronic heart failure, for example ing to NYHA class II, III or IV, with reduced ejection fraction (HFrEF) comprising administering empagliflozin to the patient. For e the patient has chronic heart failure according to NYHA class I. According to an aspect of this embodiment the ssion from microalbuminuria to macroalbuminuria is prevented, slowed or reversed.

The patient according to this embodiment is for e a non-diabetic patient, a patient with pre-diabetes or a patient with type 2 es mellitus, in particular a non-diabetic patient.

According to an ment this invention provides a method for ing the renal function or for renal protection 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. For example the patient has chronic heart failure according to NYHA class I. According to an aspect of this ment the patient has mild,moderate or severe renal impairment. The patient according to this embodiment is for example a non- diabetic patient, a patient with pre—diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient. According to an aspect of this embodiment the improvement of the renal function or the renal protection is a slowing of a decline in eGFR, for example a slowing of a progressive decline in eGFR or a slowing of a natural progressive decline in eGFR. According to another aspect of this embodiment the improvement of the renal function or the renal protection is diagnosed by an improvement of the eGFR.

According to an embodiment this invention provides a method for improving the renal on or for renal protection in a t with chronic heart failure, for example according to NYHA class II, III or IV, with 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 an aspect of this embodiment the patient has mild, moderate or severe renal impairment. The patient according to this embodiment is for example a non- ic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non-diabetic patient. According to an aspect of this embodiment the ement of the renal function or the renal protection is a g of a decline in eGFR, for e a slowing of a progressive decline in eGFR or a slowing of a natural progressive decline in eGFR. According to an aspect of this embodiment the improvement of the renal function or the renal protection is diagnosed by an improvement of the eGFR.

According to an embodiment this invention provides a method for treating, ting, protecting t, reducing the risk of, delaying the ence of and/or ng the progression of c kidney disease in a patient diagnosed with chronic heart failure comprising administering empagliflozin to the patient. In particular this embodiment relates to a method for treating and/or delaying the progression of chronic kidney disease in a patient diagnosed with chronic heart failure comprising administering empagliflozin to the patient. .

According to another aspect of this embodiment the patient is a patient with stage 2 chronic kidney disease. According to an aspect of this embodiment the patient is a patient with stage 3, including stage 3a and/or 3b, chronic kidney disease. According to another aspect of this ment the patient is a patient with stage 4 chronic kidney disease. ing to an aspect of this embodimemt the patient is a patient with stage 3, including stage 3a and/or 3b, or stage 4 chronic kidney e and with chronic heart failure, for example according to NYHA class I, II, III or IV, with ved ejection fraction (HFpEF). According to another aspect of this ment the patient is a patient with stage 2 chronic kidney disease.

According to another aspect of this embodiment the patient is a patient with stage 3, including stage 3a and/or 3b, or stage 4 c kidney disease and with chronic heart failure, for example according to NYHA class I, II, III or IV, with d ejection fraction (HFrEF). The t according to this embodiment, including the various aspects of this embodiment, is for example a non—diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non—diabetic patient.

According to another embodiment this invention provides a method for ng, preventing, protecting against, reducing the risk of, delaying the occurrence of and/or delaying the progression of chronic kidney e in a patient not diagnosed with chronic heart failure comprising administering empagliflozin to the patient n the patient is a non-diabetic patient. In particular this embodiment relates to a method for treating and/or delaying the progression of chronic kidney disease in the t. According to an aspect of this embodiment the patient is a patient with stage 3, including stage 3a and/or 3b, chronic kidney disease. According to another aspect of this embodiment the patient is a patient with stage 4 chronic kidney disease.

In one embodiment, the present invention provides a method of treating, preventing, protecting against or ng the occurrence of: - new onset of albuminuria, - progression from no albuminuria to micro- or macroalbuminuria, - ng of serum creatinine level accompanied by an eGFR (based on modification of diet in renal disease (MDRD) formula) S45 lemin/1.73m2, - sustained reduction of 230%, 240%, 250% or 257% eGFR (CKD-EPI), in particular ned reduction of 240% eGFR (CKD-EPI), - ned eGFR (CKD-EPI) <15 mL/min/1.73 m2 for patients with baseline eGFR 230 mL/min/1.73 m2, - sustained eGFR (CKD-EPI) <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, - need for continuous renal replacement therapy, — need for chronic dialysis treatment, — need for receiving a renal transplant, — death due to renal disease, or - composite of sustained reduction of 240% eGFR (CKD-EPI) or sustained eGFR (CKD—EPI) <15 mL/mini1.73 m2 for patients with ne eGFR 230 mL/min/1.73 m2, and sustained eGFR PI) <10 mL/minl1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, or - composite of sustained reduction of 240% eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 mL/min/1.73 m2 for ts with baseline eGFR 230 mL/min/1.73 m2, sustained eGFR (CKD-EPI) <10 /1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, need for chronic dialysis treatment, and need for receiving a renal transplant. in a patient diagnosed with chronic heart failure, said method comprising administering empagliflozin to the patient. According to an aspect of this embodimemt the patient is a patient with chronic heart failure, for example ing to NYHA class I, II, III or IV, with preserved ejection fraction (HFpEF). According to another aspect of this embodiment the patient is a patient with chronic heart failure, for example according to NYHA class I, II, III or IV, with reduced ejection fraction (H FrEF). The t according to this embodiment, including the various aspects of this embodiment, is for example a non—diabetic patient, a patient with pre-diabetes or a patient with type 2 diabetes mellitus, in particular a non- diabetic patient.

In the methods according to the present ion empagliflozin is ally stered in combination with one or more other therapeutic substances to the patient.

According to one embodiment of the s as described hereinbefore and hereinafter the patient is a patient with an elevated BNP or an elevated plasma BNP. For example the patient has an elevated BNP of equal to or greater than 75 pg/mL (NT-proBNP 2 300 pg/mL) or equal to or greater than 100 pg/mL (NT-proBNP 2 400 pg/mL) or equal to or greater than 150 pg/mL (NT-proBNP 2 600 pg/mL) or equal to or greater than 225 pg/mL (NT-proBNP 2 900 pg/mL).

According to another embodiment of the methods as described hereinbefore and after the patient is a patient who was hospitalized for heart failure within the last 9 months, in particular hospitalized for heart failure within the last 9 months and has an elevated BNP or NT-proBNP.

According to an embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with reduced ejection fraction (HFrEF) and an ejection fraction EF 236% to 540% and an elevated NT-proBNP 22500 pg/ml for patients without atrial fibrillation, or 25000 pg/ml for patients with atrial fibrillation.

According to an embodiment of the methods as described hereinbefore and hereinafter the patient is a t with reduced ejection fraction (HFrEF) and an ejection fraction EF 231% to 535% and an elevated BNP 21000 pg/ml for patients without atrial fibrillation, or 22000 pg/ml for patients with atrial fibrillation.

According to an ment of the methods as described hereinbefore and hereinafter the t is a patient with reduced ejection fraction (HFrEF) and an ejection fraction EF 530% and an elevated NT-proBNP 2600 pg/ml for patients t atrial fibrillation, or 21200 pg/ml for patients with atrial fibrillation. ing to one embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with normal renal on or with mild renal impairment or with moderate renal or severe renal impairment. According to this ment the t has an eGFR equal to or greater than 20 mL/min/1.73 m2.

According to one embodiment of the s as described hereinbefore and hereinafter the patient is a patient with normal renal function or with mild renal impairment or with moderate renal impairment. According to this embodiment the patient has an eGFR equal to or greater than 30 mL/min/1.73 m2.

According to another embodiment of the s as described hereinbefore and hereinafter the t is a patient with normal renal function or with mild renal impairment or with moderate A renal impairment (CKD 3A). According to this embodiment the patient has an eGFR equal to or greater than 45 mL/min/1.73 m2.

According to another embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with normal renal function or with mild renal impairment. According to this ment the patient has an eGFR equal to or greater than 60 mL/min/1.73 m2 . ing to another embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with moderate A renal impairment (CKD 3A). According to this embodiment the patient has an eGFR equal to or greater than 45 and lower than 60 mL/min/1.73 m2. ing to another embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with moderate B renal impairment (CKD 38). According to this embodiment the patient has an eGFR equal to or greater than 30 and lower than 45 mL/min/1.73 m2. ing to an embodiment of the methods as described hereinbefore and hereinafter the patient is a non-diabetic patient, a patient with pre—diabetes, a patient with type 2 diabetes mellitus or a patient with type 1 diabetes mellitus.

According to r embodiment of the s as described hereinbefore and hereinafter the patient is a non-diabetic t, a patient with pre—diabetes or a patient with type 2 diabetes mellitus.

According to another embodiment of the methods as described hereinbefore and hereinafter the patient is a patient with abetes. According to an aspect of this embodiment the patient has a HbAtc more or equal to 5.7% and less than 6.5%.

According to another embodiment of the methods as described hereinbefore and hereinafter the patient is a t with pre—diabetes or a non—diabetic patient. According to an aspect of this embodiment the patient has a HbA1c less than 6.5%.

According to another ment of the methods as described hereinbefore and hereinafter the patient is a non-diabetic patient. According to an aspect of this embodiment the patient has a HbA1c less than 5.7%.

According to another aspect the non-diabetic patient does not show an impaired e tolerance (IGT), i.e. the patient shows a normal glucose tolerance. For example the 2 hour andial blood glucose or plasma glucose (PG) concentration is smaller than 140 mg/dl (7.78 mmol/L). ing to another aspect the non-diabetic patient does not show an impaired fasting blood glucose (IFG), i.e. the patient shows a normal g glucose. For example the fasting plasma glucose concentration (FPG) is r than 100 mg/dl, i.e. r than 5.6 mmol/l.

In particular the non-diabetic patient does not show an impaired fasting blood glucose (IFG) and does not show an impaired glucose tolerance (IGT), i.e. the patient shows a normal glucose tolerance and a normal glucose tolerance. For example the fasting plasma glucose concentration (FPG) is smaller than 100 mg/dl, i.e. smaller than 5.6 , and the 2 hour postprandial blood glucose or plasma glucose (PG) concentration is smaller than 140 mg/dl (7.78 mmol/L).

According to an embodiment of the methods as described hereinbefore and hereinafter empagliflozin is administered at a dose in a range from 1 to 25 mg per day, for example 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 occur one or two times a day, most preferably once a day. For example a dose for once daily administration is 10 mg or 25 mg. The preferred route of administration is oral administration.

According to a particular aspect of the t invention empagliflozin is stered at a dose of 10 mg per day to the patient.

According to another particular aspect of the t invention empagliflozin is administered at a dose of 25 mg per day to the patient.

Preferably empagliflozin is administered orally to the patient once daily.

In one embodiment, patients within the meaning of this invention may include patients with chronic heart failure who have not previously been treated with a drug to treat chronic heart failure (heart-failure-drug-nai've patients). Thus, in an embodiment, the therapies described herein may be used in heart-failure-drug-nai've patients.

In another embodiment, ts within the meaning of this invention may e patients with chronic heart failure and with pre—diabetes or with type 2 diabetes mellitus (T2DM) who have not previously been treated with an abetic drug drug-na'ive patients). Thus, in an embodiment, the therapies described herein may be used in T2DM-drug-nai‘ve patients.

Furthermore, the methods according to this ion are particularly suitable in the treatment of patients with chronic heart failure and with insulin dependency, i.e. in ts who are treated or otherwise would be treated or need treatment with an n or a derivative of insulin or a substitute of insulin or a formulation comprising an insulin or a derivative or substitute thereof. These patients include patients with diabetes type 2 and patients with diabetes type 1.

Furthermore, it can be found that the administration of a pharmaceutical composition according to this invention s in no risk or in a low risk of hypoglycemia. ore, a treatment or prophylaxis according to this invention is also advantageously possible in those patients showing or having an increased risk for hypoglycemia.

By the administration of empagliflozin excessive blood glucose is excreted through the urine of the patient based on the SGLT2 inhibiting activity, so that no gain in weight or even a reduction in body weight of the patient may result. Therefore, the methods according to this invention are advantageously suitable in those patients with chronic heart failure who are diagnosed of one or more of the conditions selected from the group consisting of ovenNeight and obesity, in particular class I y, class II obesity, class III obesity, visceral obesity and abdominal obesity. In addition a method according to this invention is advantageously suitable in those patients in which a weight increase is indicated.

When this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and tion in humans, but the pharmaceutical composition may also be used accordingly in veterinary medicine in mammals. In the scope of this ion adult patients are preferably humans of the age of 18 years or older. Also in the scope of this invention, patients are adolescent humans, i.e. humans of age 10 to 17 years, preferably of age 13 to 17 years.

According to an embodiment of the present invention empagliflozin is administered in combination with one or more other therapeutic nces to the patient. The combined administration may be simultaneously, separately or sequentially.

In one aspect of this embodiment of the present invention, the one or more other therapeutic nces are selected from active substances that are indicated in the treatment of chronic heart failure, antidiabetic nces, active substances that lower the total cholesterol, LDL- cholesterol, Non-HDL-cholesterol and/or Lp(a) level in the blood, active substances that raise the HDL-cholesterol level in the blood, active substances that lower blood pressure, active substances that are indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulant agents, and vascular endothelial protective agents.

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

In one embodiment, the antidiabetic nces are selected from metformin, sulphonylureas, nateglinide, repaglinide, PPAR—gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues and DPP-4 inhibitors.

In one embodiment the patient es rd of care, which includes medication and/or devices indicated for patients with heart failure, such as chronic or acute heart failure. In one aspect the t, in particular sed with HFrEF, has or receives a device ed from the group of ICD (implantable cardioverter defibrillator) and CRT (cardiac hronization therapy), such as CRT—P (CRT pacemaker) and CRT-D (CRT combination of pacemaker and defibrillator).

In one embodiment the patient receives standard of care medication indicated for patients with chronic heart e. In one aspect of this embodiment empagliflozin is administered to the patient in combination with one or more active substances that are indicated in the treatment of chronic heart failure. For example iflozin is adminstered in combination with one or more active substances selected from the group consisting of angiotensin receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists, diuretics, angiotensin receptor-neprilysin inhibitor , lcorticoid receptor nists and ivabradine. According to this aspect of the embodiment the patient is for example a non-diabetic patient or a patient with pre-diabetes.

In one aspect of this embodiment, the number, dosage and/or regimen of said medications to treat chronic heart failure is reduced in said patient, while the administration of empagliflozin is continued. For example the dose of one or more diuretics administered to the patient may be reduced, while the stration of empagliflozin is continued. es of angiotensin II receptor blockers (ARBs) are telmisartan, artan, valsartan, Iosartan, irbesartan, olmesartan, azilsartan and eprosartan; the dosage(s) of some of these medications are for example shown below: Candesartan (Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil Eprosartan (Teveten), 400 mg or 600 mg |rbesartan (Avapro), 75 mg, 150mg, or 300 mg of irbesartan. an (Cozaar), 25 mg, 50 mg or 100 mg of Iosartan 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) , 40 mg, 80 mg, 160 mg or 320 mg of tan Examples of Angiotensin-Converting Enzyme (ACE) inhibitors are benazepril, captopril, ramipril, lisinopril, Moexipril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; the (s) of some of these tions are for example shown below: Benazepril (Lotensin), 5 mg, 10 mg, 20 mg, and 40 mg for oral administration Captopril (Capoten), 12.5 mg, 25 mg, 50 mg, and 100 mg as scored s for oral administration Enalapril (Vasotec), 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 s for oral administration Moexipril (Univasc), 7.5 mg and 15 mg for oral administration Perindopril (Aceon), 2 mg, 4 mg and 8 mg strengths for oral administration Quinapril (Accupril), 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration . Ramipril (Altace), 1.25 mg, 2.5 mg, 5, mg, 10 mg . lapril (Mavik) 1 mg, 2 mg, or4 mg of trandolapril for oral stration Examples of beta-blockers are olol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, propranolol, timolol and carvedilol; the (s) of some of these medications are for example shown below: . Acebutolol (Sectral), 200 or 400 mg of acebutolol as the hydrochloride salt . Atenolol (Tenormin), 25, 50 and 100 mg tablets for oral stration . Betaxolol (Kerlone), 10-mg and 20-mg tablets for oral administration o Bisoprolol/hydrochlorothiazide (Ziac), 2.5/6 mg, 5/6.25 mg, 10/6.25 mg . Bisoprolol (Zebeta), 5 and 10 mg tablets for oral administration . Metoprolol (Lopressor, Toprol XL), 50— and 100—mg s for oral administration and in 5-mL ampuls for intravenous administration . Propranolol (Inderal), 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral stration . Timolol dren), 5 mg, 10 mg or 20 mg timolol maleate for oral administration.

Examples of aldosterone antagonists are spironolactone, eplerenone, one and fineronone; the dosage(s) of some of these medications are for example shown below: . spironolactone (e.g. Aldactone), 25 or 50 mg once daily or every second day, . eplerenone (e.g. lnspra), 25 or 50 mg once daily.

Examples of diuretics are bumetanide, hydrochlorothiazide, chlortalidon, chlorothiazide, hydrochlorothiazide, de, indapamide, mide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; for example these medications are thiazide diuretics, e.g. chlorthalidone, HCT, loop diuretics, e.g. furosemide, torasemide or potassium-sparing diuretics, e.g. eplerenone, or combination thereof; the dosage(s) of some of these medications are for example shown below: o Amiloride (Midamor), 5 mg of ous amiloride HCI . Bumetanide (Bumex), available as scored tablets, 0.5 mg (light green), 1 mg (yellow) and 2 mg (peach) for oral administration . Chlorothiazide(Diuril), . Chlorthalidone(Hygroton) . Furosemide (Lasix) . Hydro-chlorothiazide (Esidrix, Hydrodiuril) . lndapamide (Lozol) and Spironolactone (Aldactone) . Eplerenone (Inspra) An example of an angiotensin receptor-neprilysin inhibitor (ARM) is a combination of valsartan and sacubitril (Entresto).

An example of inhibition of the cardiac pacemaker If current is ivabradine (Procoralan, Examples of m channel blockers are amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, ipidine, manidipine, isradipine, ipine, mil, gallopamil and diltiazem. es of medications 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 patient with type 2 diabetes mellitus and empagliflozin is administered to the patient in combination with one or more active substances that are indicated in the treatment of chronic heart failure and in combination with one or more antidiabetic substances. The abetic substances include metformin, sulphonylureas, nateglinide, repaglinide, PPAR—gamma agonists, glucosidase inhibitors, insulin and n analogues, GLP-1 and GLP-1 analogues and DPP-4 inhibitors.

Examples thereof are metformin and DPPIV inhibitors, such as sitagliptin, saxaglitpin and linagliptin. The active substances that are ted in the ent of chronic heart failure include angiotensin or blockers (ARB), ensin-converting enzyme (ACE) inhibitors, beta-blockers, aldosterone antagonists and diuretics.

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

Therefore according to another aspect of the methods ing to this invention empagliflozin is administered in combination with metformin hydrochloride to the patient. The patient according to this aspect is in particular a patient with type 2 diabetes mellitus.

Preferred doses are for example 10 mg empagliflozin once daily or 5 mg iflozin twice daily and 500 mg, 850 mg or 1000 mg metformin hydrochloride twice daily.

In one aspect of this embodiment, the number, dosage and/or regimen of said medications to treat chronic heart failure is reduced in said patient, while the administration of iflozin is continued. In another aspect of this embodiment, the number, dosage and/or regimen of said medications to treat type 2 diabetes mellitus is reduced in said patient, while the administration of empagliflozin is continued. In yet another aspect of this embodiment, the s, dosages and/or regimens of said medications to treat type 2 diabetes mellitus and of said medications to treat chronic heart failure are reduced in said patient, while the administration of empagliflozin is ued.

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

Examples of active substances in the above described groups are known to the one skilled in the art, including their dose strengths, administration schemes and formulations.

In the context of this invention the term metformin comprises min hydrochloride in the form of an immediate release, extended or slow release formulation. Doses of metformin hydrochloride administered to the patient are particularly 500 mg to 2000 mg per day, for example 750 mg, 1000 mg, 1500 and 2000 mg per day.

Empagliflozin and metformin may be adminstered separately in two different dosage forms or combined in one dosage form. Combined dosage forms of empagliflozin and metformin as immediate release formulations are bed in example as SYNJARD|®. Combined dosage forms of empagliflozin and metformin wherein empagliflozin is part of an immediate release formulation and metformin is part of an ed release formulation are bed in A preferred dose of linagliptin administered to the patient is 5 mg per day.

Empagliflozin and Iinagliptin may be adminstered separately in two different dosage forms or combined in one dosage form. ed dosage forms of empagliflozin and Iinagliptin are described in Within this invention it is to be understood that the combinations, compositions or administrations in combination according to this invention may envisage the simultaneous, sequential or separate administration of the active components or ingredients.

In this context, "combination" or "combined" within the meaning of this invention may include, without being limited, fixed and non-fixed (e.g. free) forms (including kits) and uses, such as e.g. the simultaneous, tial or separate use of the components or ingredients.

The combined administration of this invention may take place by administering the active ents or ingredients er, such as e.g. by administering them simultaneously in one single or in two separate formulations or dosage forms. Alternatively, the administration may take place by administering the active components or ingredients sequentially, such as e.g. successively in two separate formulations or dosage forms.

For the combination therapy of this invention the active components or ingredients may be administered separately (which implies that they are formulated tely) or formulated altogether (which implies that they are ated in the same preparation or in the same dosage form). Hence, the administration of one element of the combination of the t invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination.

Unless othenNise noted, combination therapy may refer to first line, second line or third line therapy, or initial or add-on combination therapy or replacement therapy.

The methods ing to this ion are ularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as described hereinbefore and hereinafter. The term "long term" as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

The ceutical composition comprising empagliflozin according to the invention may be formulated for oral or parenteral (including intramuscular, sub-cutaneous 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 formulated in the form of tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, le tablets, troches, effervescent tablets, drops, suspension, fast dissolving tablets, oral ispersing tablets, etc.. The pharmaceutical ition and the dosage forms ably comprises one or more pharmaceutical able carriers which must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the ent thereof. Examples of pharmaceutically acceptable carriers are known to the one skilled in the art.

The ceutical compositions and methods according to this invention show ageous effects in the treatment and prevention of those es and conditions as described before. Advantageous effects may be seen for example with respect to efficacy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer e effects, convenience, compliance, etc..

Methods for the manufacture of empagliflozin are known to the one skilled in the art.

Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore.

Preferred methods of manufacture are described in the 2007/031548. With regard to empagliflozin an advantageous crystalline form is bed in the international patent application its entirety.

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

Examples Example 1: Treatment of ts with c heart failure and HFrEF The longterm impact on cardiovascular death or hospitalization for heart failure and other parameters of treatment with empagliflozin in a relevant population of patients with chronic heart failure and reduced ejection fraction is investigated as follows: Patients with chronic heart failure and symptoms according to NYHA II, III or IV and a reduced ejection fraction (LVEF r or equal than 40%) and an elevated BNP (or elevated NT-proBNP), e.g. as defined below, are treated over a long term (e.g. for between approximately 20 to 38 months for each patient) with empagliflozin (optionally in ation with one or more other active substances, e.g. such as those described herein) and compared with patients who have been d with a o on standard of care background medication.

Empagliflozin is administered orally once daily (for example 10 mg/daily). Patients include non-diabetic patients, patients with pre-diabetes and patients with type 2 diabetes mellitus.Pre-diabetes is diagnosed if HbA1c is more 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 a LVEF smaller or equal than 40%.

Patients with an elevated BNP (or elevated BNP) are defined as having one of the following: - an ed BNP 2150 pg/mL or NT-proBNP 2 600 pg/mL; or - if patients were hospitalized for heart failure within the last 9 months, an elevated BNP 2100 pg/mL or NT-proBNP 2 400 pg/mL.

Patients with reduced ejection fraction may be included according to at least one of the following evidence of heart failure: If the ejection fraction EF is 236% to S40% then the elevated NT-proBNP shall be 22500 pg/ml for patients t atrial fibrillation, or 25000 pg/ml for patients with atrial fibrillation.

If the ejection fraction EF is 231% to 335% then the elevated BNP shall be 21000 pg/ml for patients without atrial fibrillation, or 22000 pg/ml for patients with atrial fibrillation.

If the ejection fraction EF is 530% then the ed NT-proBNP shall be 2600 pg/ml for patients without atrial fibrillation, or 21200 pg/ml for patients with atrial fibrillation.

The study is driven and all randomised ts will remain in the trial until the defined number of patients with primary endpoint events has been reached. The number of confirmed adjudicated primary endpoint events will be continuously monitored during the study.

The patients with cardiovascular risk factors are d according to standard of care, which includes for example treatment with therapeutic agents selected from diuretics, ARNi, ACEi, ARB, s, aspirin, beta-blockers, mineral corticoid antagonist or ivabradine,with or without cardiac device therapy including ICD, CRT-D or CRT-P. ts in the study follow the following criteria: - age above 18 years - Diagnosis of heart failure (HF). Definition of HF for inclusion in the study is left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, gh radionuclide ventriculography and angiography are acceptable) smaller or equal than 40 % (per local reading). The ejection fraction value is preferably obtained within 6 months prior to randomization and after any Myocardial Infarction (Ml) or other event that would affect the ejection fraction.

- Symptom(s) of heart failure (HF) (NYHA class ll—IV) - At least one of the following: an elevated NT—proBNP 2 600 pg/mL and/or if the patient was hospitalized for heart failure within the last 9 months an elevated NT-proBNP 2 400 pg/mL.

- Background therapy for heart failure if needed - Antidiabetic background if needed - Body Mass Index (BMI) < 45 kg/m2 - eGFR 2 20 /1.73 m2 or eGFR 2 30 mL/min/1.73 m2 The time to cardiovascular death or hospitalisation for heart failure is ined in patients with heart e with reduced ejection on (according to the criteria as described hereinbefore) treated with empagliflozin (e.g. 10 mg once daily) to placebo.

One or more of the following events are determined: - time to first hospitalisation for heart failure - eGFR (CKD-EPI) slope of change from baseline - Time to first occurrence of sustained reduction of 240% eGFR (CKD-EPI) - Time to first occurrence of sustained eGFR (CKD-EPI) <15 mL/min/1.73 m2 for patients with baseline eGFR 230 mL/min/1.73 m2 - Time to first occurrence of sustained eGFR (CKD—EPI) <10 mL/min/1.73 m2 for patients with ne eGFR <30 mL/min/1.73 m2 - Composite of time to first nce of sustained reduction of 240% eGFR PI) or sustained eGFR (CKD-EPI) <15 mL/minl1.73 m2 for patients with baseline eGFR 230 mL/min/1.73 m2, sustained eGFR (CKD-EPI) <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, - Composite of time to first occurence of sustained reduction of 240% eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 mL/min/1.73 m2 for patients with ne eGFR 230 mL/min/1.73 m2, and sustained eGFR PI) <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, or need for chronic dialysis ent or need for ing a renal transplant- time to cardiovascular death - time to all-cause mortality - health related quality of life (for example as measured by KCCQ or KCCQ-12) - time to new onset of type 2 diabetes mellitus in non-diabetic patients - time to re—hospitalisation for heart failure - change in NYHA classification - time to all-cause hospitalisation, including first and/or recurrent, - time to new onset of atrial fibrillation - time to non-fatal or fatal myocardial infarction - time to non-fatal or fatal stroke - time to composite of cardiovascular death or myocardial infarction - time to composite of cardiovascular death or stroke - time to any of vascular death ding fatal stroke, fatal myocardial infarction and sudden death), non-fatal myocardial infarction, non-fatal stroke (the so-called 3-point MACE) - change in eGFR - progression to lbuminuria (defined as albumin/creatinine ratio (ACR) 2 300 mg/g) - time to need for chronic dialysis treatment - time to need for receiving a renal transplant - composite of eGFR reduction, renal replacement y or renal death - composite of eGFR reduction, renal replacement therapy, renal death or cardiovascular death - composite of eGFR reduction, renal replacement therapy, renal death or all-cause mortality.

Example 2: Treatment of patients with chronic heart failure and HFpEF The longterm impact on cardiovascular death or hospitalization for heart failure and other parameters of treatment with empagliflozin in a relevant population of patients with chronic heart failure and preserved on fraction is investigated as follows: Patients with chronic heart failure and symptoms ing to NYHA II, III or IV and a preserved ejection fraction (LVEF greater than 40% or r than 50%) are treated over a long term (e.g. for n approximately 20 to 38 months for each patient) with empagliflozin (optionally in combination with one or more other active substances, e.g. such as those described herein) and compared with patients who have been treated with a placebo on standard of care background medication.

Empagliflozin is administered orally once daily (for example 10 mg/daily). Patients include non-diabetic patients, patients with pre—diabetes and patients with type 2 diabetes mellitus.Pre-diabetes is diagnosed if HbA1c is more 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 a LVEF r than 40%, in ular greater than 50%.

Patients include individuals who were hospitalized for heart failure within the last 9 months and/or have an elevated BNP 2 75 pg/mL or NT—proBNP 2 300 pg/mL (for patients not with atrial fibrillation (AF)) or an ed BNP > 225 pg/mL or NT-proBNP > 900 pg/mL (for patients with atrial fibrillation (AF)).

The study is event-driven and all randomised patients will remain in the trial until the defined number of patients with primary nt events has been reached. The number of confirmed cated primary endpoint events will be continuously monitored during the study.

The patients with cardiovascular risk s are d according to standard of care, which includes symptomatic treatment, and treatment of cardiovascular risk factors including hypertension, diabetes mellitus, and dyslipidemia.

Patients in the study follow the following criteria: - age above 18 years - Diagnosis of heart failure (HF). Definition of HF for inclusion in the study is left ventricular ejection fraction (LVEF) ly obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) > 40 % (per local reading). The ejection fraction value is preferably ed within 6 months prior to randomization and after any Myocardial Infarction (Ml) or other event that would affect the ejection fraction.

- Symptom(s) of heart failure (HF) (NYHA class ||—|V) - Structural heart e (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram - At least one of the following: A heart failure hospitalization within the last 9 months and/or an elevated NT-proBNP (> 300 pg/mL for patients not with atrial fibrillation (AF) or > 900 pg/mL for patients with atrial fibrillation (AF)).

- Background therapy for heart e if needed - abetic background if needed - Body Mass Index (BMI) < 45 kg/m2 - eGFR 2 20 mL/min/1.73 m2 or eGFR 230 mL/min/1.73 m2 The time to cardiovascular death or hospitalisation for heart failure is determined in patients with heart failure with preserved ejection fraction (according to the criteria as bed hereinbefore) treated with empagliflozin (eg. 10 mg once daily) to placebo.

One or more of the following events are determined: - time to first hospitalisation for heart failure - eGFR (CKD-EPI) slope of change from baseline - Time to first occurrence of sustained reduction of 240% eGFR (CKD-EPI) - Time to first occurrence of sustained eGFR (CKD—EPI) <15 mL/min/1.73 m2 for patients with baseline eGFR 230 /1.73 m2 - Time to first occurrence of sustained eGFR PI) <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2 - Composite of time to first occurence of sustained reduction of 240% eGFR (CKD-EPI) or ned eGFR (CKD-EPI) <15 mL/min/1.73 m2 for ts with baseline eGFR 230 mL/min/1.73 m2, ned eGFR (CKD—EPI) <10 mL/min/1.73 m2 for patients with ne eGFR <30 mL/min/1.73 m2, - Composite of time to first occurence of sustained reduction of 240% eGFR (CKD-EPI) or sustained eGFR (CKD-EPI) <15 mL/min/1.73 m2 for ts with baseline eGFR 230 mL/min/1.73 m2, sustained eGFR (CKD—EPI) <10 mL/min/1.73 m2 for patients with baseline eGFR <30 mL/min/1.73 m2, or need for chronic dialysis treatment or need for receiving a renal transplant - time to vascular death - time to all-cause mortality - health related quality of life (for example as measured by KCCQ or KCCQ-12) - time to new onset of type 2 diabetes mellitus in non—diabetic patients - time to re-hospitalisation for heart failure - change in NYHA classification - time to all-cause hospitalisation, including first and/or recurrent, - time to new onset of atrial lation - time to non-fatal or fatal myocardial infarction - time to non-fatal or fatal stroke - time to any of cardiovascular death (including fatal stroke, fatal dial infarction and sudden death), non-fatal myocardial infarction (excluding silent myocardial infarction), non- fatal stroke (the so-called 3-point MACE) - change in eGFR - progression to macroalbuminuria (defined as albumin/creatinine ratio (ACR) 2 300 mg/g) - time to need for c dialysis treatment - time to need for receiving a renal transplant - composite of eGFR ion, renal replacement therapy or renal death - composite of eGFR reduction, renal replacement therapy, renal death or cardiovascular death - ite of eGFR reduction, renal replacement therapy, renal death or all-cause mortality The health related quality of life may be measured according to KCCQ or KCCQ-12. KCCQ- 12 is a validated short version of the original m KCCQ (Kansas City Cardiomyopathy Questionnaire). This self-administered questionnaire is designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self- efficacy, and quality of life in patients with HF.

Example 3: Treatment of frail patients with chronic heart failure and HFrEF The impact of a treatment with empagliflozin on the functional capacity and other parameters in a relevant population of patients with chronic heart failure and reduced ejection fraction and frailty is igated as follows: Patients with chronic heart failure and symptoms according to NYHA II, III or IV and a d ejection fraction (LVEF r or equal than 40%) and an elevated BNP (or elevated NT-proBNP), e.g. as defined below, and with frailty are d over a period of time (e.g. for approximately 12 weeks for each patient) with empagliflozin (optionally in combination with one or more other active substances, e.g. such as those described herein) and compared with patients who have been treated with a placebo on standard of care ound medication.

Empagliflozin is administered orally once daily (for example 10 mg/daily). Patients include non-diabetic ts, ts with pre-diabetes and patients with type 2 diabetes mellitus.

Pre-diabetes is diagnosed if HbAtc is more 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 a LVEF smaller or equal than 40%.

Patients with an elevated BNP (or elevated NT—proBNP) are defined as having one of the following: - an elevated BNP 2150 pg/mL or NT-proBNP 2 600 pg/mL; or - if patients were hospitalized for heart failure within the last 9 months, an ed BNP 2100 pg/mL or NT—proBNP 2 400 ngmL. ts with reduced ejection fraction may be included according to at least one of the following evidence of heart failure: If the ejection fraction EF is 236% to 540% then the elevated NT-proBNP shall be 22500 pg/ml for patients without atrial fibrillation, or 25000 pg/ml for patients with atrial fibrillation.

If the ejection fraction EF is 231% to 535% then the elevated NT-proBNP shall be 21000 pg/ml for patients without atrial fibrillation, or 22000 pg/ml for patients with atrial fibrillation.

If the ejection fraction EF is 530% then the elevated BNP shall be 2600 pg/ml for patients without atrial fibrillation, or 21200 pg/ml for patients with atrial fibrillation.

A patient with frailty is included in the study, if for example in 6 minutes walking test the patient manages a distance of less than 350 meters.

At the end of the study period for each patient the functional ty, in particular the se capacity, for example a 6 minutes walking test, and further clinical parameters, for example as below, are investigated.

The ts with cardiovascular risk factors are treated according to standard of care, which includes for example treatment with therapeutic agents selected from diuretics, ARNi, ACEi, ARB, statins, aspirin, lockers, mineral corticoid antagonist or ivabradine,with or without cardiac device y including ICD, CRT—D or CRT-P.

Patients in the study follow the following criteria: - age above 18 years - Diagnosis of heart failure (HF). Definition of HF for inclusion in the study is left cular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) smaller or equal than 40 % (per local reading). The ejection on value is preferably obtained within 6 months prior to randomization and after any dial Infarction (Ml) or other event that would affect the ejection fraction.

- Symptom(s) of heart failure (HF) (NYHA class ll-IV) - At least one of the following: an ed NT-proBNP 2 600 pg/mL and/or if the patient was hospitalized for heart failure within the last 9 months an elevated NT-proBNP 2 400 pg/mL. - frailty, for e determined via a 6 minutes walking test in which the patient manages a distance of less than 350 meters.

- Background therapy for heart failure if needed - abetic background if needed - Body Mass Index (BMI) < 45 kg/m2 - eGFR 2 20 mL/min/1.73 m2 or eGFR 2 30 mL/min/1.73 m2 At the end of a defined period of time, e.g. 12 weeks, the onal capacity, in particular the exercise capacity, for e a 6 s walking test, is determined in the patients with heart failure with reduced ejection fraction (according to the criteria as described before) treated with empagliflozin (e.g. 10 mg once daily) or placebo.

One or more of the following events are determined: - change in NYHA classification - health related quality of life (for example as measured by KCCQ or KCCQ-12, MLHFQ, fatique score, depression score, anxiety score, global assessment score) - change from baseline biomarkes, e.g. NT—proBNP - time to first hospitalisation for heart failure - time to re-hospitalisation for heart failure.

Example 4: Treatment of frail patients with chronic heart failure and HFpEF The impact of a treatment with empagliflozin on the functional capacity and other parameters in a relevant population of patients with chronic heart failure and preserved ejection fraction and y is investigated as follows: Patients with c heart e and ms according to NYHA II, III or IV and a preserved ejection on (LVEF greater than 40% or greater than 50%) and with frailty are treated over a period of time (e.g. for approximately 12 weeks for each t) with empagliflozin (optionally in ation with one or more other active substances, e.g. such as those described herein) and compared with patients who have been treated with a placebo on standard of care background medication.

Empagliflozin is administered orally once daily (for example 10 mg/daily). Patients include non-diabetic patients, patients with pre-diabetes and patients with type 2 diabetes mellitus.

Pre-diabetes is diagnosed if HbAtc is more 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 a LVEF greater than 40%, in particular greater than 50%.

Patients include individuals who were hospitalized for heart failure within the last 9 months and/or have an elevated BNP 2 75 pg/mL or BNP 2 300 pg/mL (for patients not with atrial fibrillation (AF)) or an elevated BNP > 225 pg/mL or NT-proBNP > 900 pg/mL (for patients with atrial fibrillation (AF)).

A patient with frailty is included in the study, if for example in 6 minutes walking test the patient manages a distance of less than 350 meters.

At the end of the study period for each patient the functional capacity, in particular the exercise capacity, for example a 6 minutes walking test, and further clinical parameters, for example as below, are investigated.

The patients with cardiovascular risk factors are treated according to standard of care, which includes symptomatic ent, and treatment of cardiovascular risk factors including hypertension, diabetes mellitus, and dyslipidemia.

Patients in the study follow the following ia: - age above 18 years - Diagnosis of heart failure (HF). tion of HF for inclusion in the study is left ventricular ejection fraction (LVEF) (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) > 40 % (per local reading). The ejection fraction value is preferably obtained within 6 months prior to randomization and after any Myocardial Infarction (Ml) or other event that would affect the ejection fraction.

- Symptom(s) of heart failure (HF) (NYHA class ||-|V) - Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram - At least one of the following: A heart e hospitalization within the last 9 months and/or an elevated BNP (> 300 pg/mL for patients not with atrial lation (AF) or > 900 pg/mL for patients with atrial fibrillation (AF)).

- Frailty, for example determined via a 6 minutes walking test in which the patient manages a distance of less than 350 meters.

- Background therapy for heart failure if needed - Antidiabetic background if needed - Body Mass Index (BMI) < 45 kg/m2 - eGFR 2 20 mL/min/1.73 m2 or eGFR 2 30 mL/min/1.73 m2 At the end of a d period of time, e.g. 12 weeks, the functional ty, in particular the exercise capacity, for example a 6 minutes walking test, is ined in the patients with heart failure with preserved ejection fraction (according to the criteria as bed hereinbefore) treated with empagliflozin (e.g. 10 mg once daily) or placebo.

One or more of the following events are determined: - change in NYHA classification - health related quality of life (for example as measured by KCCQ or 2, MLHFQ, fatique score, depression score, anxiety score, global assessment score) - change from baseline biomarkes, e.g. NT—proBNP - time to first hospitalisation for heart failure - time to re-hospitalisation for heart failure.

Example of Pharmaceutical Composition and Dosage Form The following example of solid pharmaceutical compositions and dosage forms for oral stration serves to illustrate the t invention more fully without restricting it to the ts of the example. Further examples of compositions and dosage forms for oral administration, are described in empagliflozin according to this invention, especially its crystalline form as described in Tablets containing 2.5 mg, 5 mg, 10 mg or 25 mg of the active substance empagliflozin.

Amounts of the ingredients are provided in mg per film-coated tablet. 2.5 mg/ 5 mg/ 10 mg/ 25 mg/ ‘ ctive substance per tablet per tablet per tablet per tablet at ation empagliflozin 2.5000 5.000 Lactose 40.6250 81.250 Monohydrate Microcrystalline 12.5000 25.000 Cellulose Hydroxypr0py | 1.8750 3.750 Croscarmellose 1.2500 2.500 —nmPurified Water Dry Adds ---Microcrystalline 3.1250 6.250 Cellulose Colloidal n 0.3125 0.625 o. 5'5. o. CD Magnesium stearate——0.3125 0.625 —|oE)"g0 2CD ——62.5000 125.000 Film Coating —— Film coating system ——2.5000 4.000 Purified Water :0 5" Total ——65.000 129.000 Details regarding the cture of the s, the active pharmaceutical ingredient, the excipients and the film coating system are described in Examples 5 and 6, which hereby is incorporated herein in its entirety.

Claims (19)

Claims

1. A method for treating, preventing, protecting against or ng the occurrence of chronic heart failure in a patient in need thereof comprising stering empagliflozin to the t.

2. A method for reducing the risk of cardiovascular death in a patient with chronic heart failure comprising administering empagliflozin to the t.

3. A method for reducing the risk of hospitalization for heart failure in a patient with chronic heart e comprising administering empagliflozin to the patient.

4. The method according to claim 3 wherein the risk of hospitalization for heart failure is the risk of first hospitalization for heart e.

5. A method for reducing all-cause mortality in a t with chronic heart failure comprising administering empagliflozin to the patient.

6. A method for reducing the risk of all-cause hospitalization in a patient with chronic heart failure comprising administering empagliflozin to the patient.

7. A method for reducing the risk of new onset of atrial fibrillation in a patient with chronic heart failure comprising administering empagliflozin to the patient.

8. A method for treating, preventing, protecting t, reducing the risk of or delaying the occurrence of acute heart failure, including acute decompensated heart failure, in a patient in need thereof comprising administering empagliflozin to the patient.

9. A method for ng, preventing, protecting against, reducing the risk of, delaying the occurrence of and/or delaying the progression of chronic kidney e in a patient with chronic heart failure comprising administering empagliflozin to the patient.

10. A method for improving the health related y of life and/or the functional capacity in a patient with chronic heart failure comprising administering empagliflozin to the patient.

11. The method according to one or more of the claims 1 to 10 n the patient is a patient with chronic heart failure ing to NYHA class II, III or IV.

12. The method according to one or more of the claims 1 to 11 wherein the patient is a patient with preserved ejection fraction.

13. The method according to one or more of the claims 1 to 11 n the patient is a patient with reduced ejection fraction.

14. The method according to one or more of the claims 1 to 13 wherein the patient is a patient with pre-diabetes, type 1 diabetes mellitus or type 2 diabetes mellitus.

15. The method according to one or more of the claims 1 to 13 wherein the patient is a non-diabetic patient.

16. The method according to one or more of the claims 1 to 15 wherein the patient has an eGFR equal to or greater than 20 n/1.73m2 or eGFR equal to or r than 30 mL/min/1.73m2 or eGFR equal to or greater than 45 mL/min/1.73m2 or eGFR equal to or greater than 60 mL/min/1.73m2 .

17. The method according to one or more of the claims 1 to 16 wherein empagliflozin is administered at a dose in a range from 1 mg to 25 mg.

18. The method according to one or more of the claims 1 to 17 n empagliflozin is administered in combination with one or more other therapeutic substances to the patient.

19. The method ing to claim 18 wherein the one or more other therapeutic substances are selected from the group consisting of active substances that are indicated in the treatment of chronic heart failure, abetic substances, active substances that lower the total cholesterol, LDL-cholesterol, Non-HDL-cholesterol and/or Lp(a) level in the blood, active substances that raise the HDL-cholesterol level in the blood, active substances that lower blood pressure, active substances that are indicated in the treatment of sclerosis or obesity, antiplatelet agents, anticoagulant agents, and vascular endothelial protective agents. Boehringer eim International GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON