HK40011437A

HK40011437A - Therapeutic uses of empagliflozin

Info

Publication number: HK40011437A
Application number: HK42020001090.8A
Authority: HK
Inventors: U‧C‧布罗德尔; D‧彻尼; A‧戴贝尔; M‧冯艾纳滕; O-E‧约翰森; G‧W‧金; E‧W‧马尤; T‧明策尔; B‧A‧珀金斯; A‧萨尔萨利; N‧索利曼卢; H-J‧武尔勒
Original assignee: 勃林格殷格翰国际有限公司
Priority date: 2013-04-05
Filing date: 2016-02-23
Publication date: 2020-07-17

Description

Therapeutic use of empagliflozin

Field of the invention

The present invention relates to specific SGLT-2 inhibitors for the treatment and/or prevention of oxidative stress (e.g. in patients with type 1 or type 2 diabetes), and the use of such SGLT-2 inhibitors in patients (e.g. type 1 or type 2 diabetes) for the treatment and/or prevention of cardiovascular disease. The present invention further relates to specific SGLT-2 inhibitors for use in the treatment and/or prevention of metabolic disorders as well as the prevention, reduction of the risk or delay of the occurrence of cardiovascular events in a patient, e.g. a type 1 or type 2 diabetic patient.

Background

The increasing prevalence of type 2diabetes (type 2 diabetes) represents a major public health challenge worldwide. There are more than 2.2 billion type 2 diabetic patients worldwide, and this value is expected to increase by 2030 (world health organization 2010; international diabetes association 2010). The rate of type 2diabetes has tripled over the last 30 years as reported by the american centers for disease control. In the united states, diabetes currently affects about 2360 million people, and another 5700 million people have prediabetes. Prediabetes increases the absolute risk of developing type 2diabetes five to six times in the short term.

Type 2diabetes is an increasingly prevalent disease that results in a significant reduction in life expectancy due to a high frequency of complications. Because of the microvascular complications associated with diabetes, type 2diabetes is currently the most common cause of blindness, renal failure and amputation of adult onset in the industrial world. Furthermore, the presence of type 2diabetes is associated with a 2 to 5 fold increased risk of cardiovascular disease.

After long-term persistence of the disease, the oral therapy of most type 2 diabetic patients eventually fails and becomes insulin dependent, necessitating daily injections of insulin and multiple glucose measurements per day.

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated only limited improvement in glycemic control with metformin, sulfonylureas, or insulin potentiation (a difference of about 0.9% in HbA1 c). furthermore, glycemic control significantly worsened over time even in the patients in the potentiation group, due to deterioration in β cell function.

Oral antidiabetic agents commonly used in therapy (e.g., first or second line therapy and/or monotherapy or (add-on) combination therapy) include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides (glinides), DPP-4 inhibitors and α -glucosidase inhibitors.

The high incidence of treatment failure is the leading cause of a high proportion of complications associated with long-term hyperglycemia or chronic injury (including microvascular and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications) in type 2 diabetic patients.

Thus, there is an unmet medical need for methods, medicaments and pharmaceutical compositions having good efficacy related to glycemic control, related to disease modifying properties and related to reducing cardiovascular morbidity and mortality, while showing improved safety properties.

Summary of The Invention

The present invention relates to specific SGLT-2 inhibitors for the treatment and/or prevention of oxidative stress, e.g., in patients with type 1 or type 2diabetes, the present invention also relates to the use of such SGLT-2 inhibitors for the treatment and/or prevention of cardiovascular disease in patients, e.g., type 1 or type 2diabetes patients, the present invention also relates to the use of such SGLT-2 inhibitors for the treatment and/or prevention of metabolic disorders in patients with cardiovascular disease or at risk thereof, the present invention further relates to specific SGLT-2 inhibitors for the treatment and/or prevention of metabolic disorders and the prevention, reduction of risk or delay of the occurrence of cardiovascular events in patients, e.g., type 1 or type 2diabetes patients, the present invention further relates to specific SGLT-2 inhibitors for the prevention, slowing, delay or treatment of pancreatic β cell degeneration and/or pancreatic β cell dysfunction, and/or for the improvement and/or restoration of pancreatic β cell function, and/or the restoration of pancreatic insulin secretion function in patients with Latent Autoimmune Diabetes Adult (LADA).

In one embodiment, the present invention provides a method for the treatment and/or prevention of oxidative stress, vascular stress and/or endothelial dysfunction, comprising administering empagliflozin (empagliflozin), optionally in combination with one or more other therapeutic substances, to a patient in need thereof. In one embodiment, the patient is a non-diabetic patient or a patient with type 1 or type 2 diabetes. In one embodiment, the method is for treating and/or preventing endothelial dysfunction in a type 1 or type 2 diabetic patient.

In one embodiment, the invention provides a method for treating and/or preventing collagen deposition and/or vessel wall thickening comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to a patient in need thereof. In one embodiment, the patient is a non-diabetic patient or a patient with type 1 or type 2 diabetes. In one embodiment, the method is for treating and/or preventing endothelial dysfunction in a type 1 or type 2 diabetic patient.

In one embodiment, the invention provides a method of treating type 2diabetes in a patient suffering from or at risk of oxidative stress, vascular stress and/or endothelial dysfunction or a disease or condition associated with or associated with such, the method comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

In one embodiment, the present invention provides a method for using empagliflozin in one or more of the following methods:

-preventing, delaying or treating or slowing the progression of a metabolic disorder selected from the group consisting of: type 1 or type 2diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, hyperinsulinemia, and metabolic syndrome; or

-delaying or treating prediabetes or slowing its progression; or

-preventing, delaying or treating the onset or slowing the progression of type 2 diabetes; or

-improving glycemic control and/or for reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1 c; or

-preventing, slowing, delaying or reversing the progression of impaired glucose tolerance, impaired fasting glucose, insulin resistance or metabolic syndrome to type 2 diabetes; or

-preventing, delaying or treating or slowing the progression of a condition or disorder selected from the group consisting of: diabetic complications such as cataract and microvascular and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetic foot, dyslipidemia, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, and vascular restenosis; or

-reducing body weight and/or body fat or preventing an increase in body weight and/or body fat or causing a decrease in body weight and/or body fat; or

-preventing, slowing, delaying or treating degeneration of pancreatic β cells and/or hypofunction of pancreatic β cells, and/or for improving and/or restoring the function of pancreatic β cells, and/or restoring the function of pancreatic insulin secretion, or

-preventing, slowing, delaying or treating a disease or condition caused by abnormal accumulation of ectopic fat, in particular liver fat; or

For maintaining and/or improving insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance;

the method is used in patients suffering from or at risk of oxidative stress, vascular stress and/or endothelial dysfunction or diseases or conditions associated therewith or related thereto, or

For patients suffering from or at risk of cardiovascular disease selected from myocardial infarction, stroke, peripheral arterial occlusive disease, or

For use in a patient having one or more cardiovascular risk factors selected from a), B), C) and D):

A) past or present vascular disease selected from the group consisting of myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure and peripheral arterial occlusive disease,

B) advanced >/(60-70 years old), and

C) one or more cardiovascular risk factors selected from the group consisting of:

late stage type 1 or type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/═ 40

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea or a family history of vascular disease or cardiomyopathy among first degree relatives;

D) one or more of the following:

-a confirmed history of myocardial infarction,

unstable angina pectoris with multiple coronary diseases or positive stress test recordings,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

The method comprises administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

In one embodiment, the method comprises treating type 1 or type 2 diabetes. In one embodiment, the patient is a type 1 or type 2 diabetic patient having or at risk of a cardiovascular disease selected from myocardial infarction, stroke, peripheral arterial occlusive disease.

In one embodiment, the patient is a patient with type 1 or type 2diabetes or with prediabetes, having one or more cardiovascular risk factors selected from a), B), C) and D):

B) advanced >/(60-70 years old), and

late stage type 1 or type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

In another embodiment, the invention provides a method of preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient with type 1 or type 2diabetes or with pre-diabetes, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient. In one embodiment, the cardiovascular event is selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, and heart failure requiring hospitalization. In one embodiment, the cardiovascular death is due to fatal myocardial infarction or fatal stroke. In one embodiment, the patient has or is at risk for cardiovascular disease.

In one embodiment, the patient with type 1 or type 2diabetes or with prediabetes has one or more cardiovascular risk factors selected from a), B), C), and D):

B) advanced >/(60-70 years old), and

late stage type 1 or type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/═ 40

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

In one embodiment, the invention provides a method of treating a metabolic disorder and preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient. In one embodiment, the metabolic disorder is type 1 or type 2diabetes or prediabetes. In one embodiment, the cardiovascular event is selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, and heart failure requiring hospitalization.

In one embodiment, the patient with type 1 or type 2diabetes or pre-diabetes has one or more cardiovascular risk factors selected from a), B), C), and D):

B) advanced >/(60-70 years old), and

-late stage type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

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

a) identifying a patient in need of treatment for type 1 or type 2diabetes and suffering from or at risk of cardiovascular disease; and

b) administering empagliflozin to said patient.

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

a) selecting patients having or at risk of having cardiovascular disease from a population of patients in need of treatment for type 1 or type 2 diabetes;

b) selecting a type 1 or type 2diabetes treatment comprising empagliflozin; and

c) administering empagliflozin to the patient selected in step a).

In one embodiment, the present invention provides a method of preventing, reducing the risk of, or delaying the onset of a cardiovascular event in a patient diagnosed with type 1 or type 2diabetes, comprising:

a. determining the cardiovascular health of the patient;

b. identifying a patient having or at risk of cardiovascular disease;

c. administering empagliflozin to said patient.

In one aspect, empagliflozin is administered to the patient if the patient is at high risk for a cardiovascular event.

In one embodiment, the patient has or is at risk of a cardiovascular disease selected from the group consisting of myocardial infarction, stroke, peripheral arterial occlusive disease.

In one embodiment, the present invention provides a method for treating a metabolic disorder in a patient, comprising administering a pharmaceutical composition comprising empagliflozin to the patient, wherein the patient has a reduced risk or occurrence of a cardiovascular event. In one embodiment, the cardiovascular event is selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, and heart failure requiring hospitalization. In one embodiment, the risk or occurrence of a cardiovascular event is reduced when compared to a patient administered a treatment background drug standard placebo. In one embodiment, the risk or occurrence of a cardiovascular event is reduced by 15% or more. In one embodiment, the risk or occurrence of a cardiovascular event is reduced by 16% or more, 17% or more, 18% or more, 19% or more, 20% or more, 25% or more or 30% or more. In one embodiment, the pharmaceutical composition comprises 10mg or 25mg empagliflozin. In one embodiment, the metabolic disorder is type 1 or type 2diabetes or prediabetes.

In one embodiment, the patient is a patient with type 1 or type 2diabetes or prediabetes, with one or more cardiovascular risk factors selected from a), B), C), and D):

B) advanced >/(60-70 years old), and

late stage type 1 or type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

In one embodiment, the risk ratio at 0.025 unilateral α -level is < 1.3.

In one embodiment, the present invention provides a method for reducing arterial stiffness in a patient comprising administering empagliflozin to the patient. In one aspect, the patient is a patient according to the invention, in particular a patient suffering from type 1 or type 2diabetes or pre-diabetes.

In one aspect of the invention, the one or more other therapeutic substances are selected from the group consisting of other antidiabetic substances, active substances which lower blood glucose levels, active substances which lower total cholesterol in the blood, LDL-cholesterol, non-HDL-cholesterol and/or lp (a) levels, active substances which increase HDL-cholesterol levels in the blood, active substances which lower blood pressure, active substances which are suitable for treating atherosclerosis or obesity, antiplatelet agents, anticoagulants and vascular endothelial protectants, in one embodiment the other antidiabetic substances are selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, PPAR-gamma agonists, α -glucosidase inhibitors, insulin and insulin analogs, GLP-1 and GLP-1 analogs and DPP-4 inhibitors.

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

a) identifying a type 1 or type 2 diabetic patient for treatment of a cardiovascular disease with a drug;

b) administering empagliflozin to said patient; and

c) reducing the dose or regimen of said medicament for treating cardiovascular disease in said patient while continuing to administer empagliflozin to said patient.

In one embodiment, the method additionally comprises monitoring the heart health of the patient.

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

a. identifying a type 1 or type 2 diabetic patient being treated with a plurality of drugs for treating cardiovascular disease;

b. administering empagliflozin to said patient; and

c. reducing the number of drugs that treat cardiovascular disease in said patient while continuing to administer empagliflozin to said patient.

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

a) determining the number, dosage and/or regimen of drugs to treat cardiovascular disease in a patient diagnosed with type 1 or type 2 diabetes;

b) selecting empagliflozin for use as a treatment for said patient type 2 diabetes; and

c) administering empagliflozin to said patient while reducing the number and/or dose of drugs for treating cardiovascular disease.

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

a) administering empagliflozin to a patient diagnosed with type 1 or type 2 diabetes;

b) monitoring the patient's cardiac health;

c) adjusting the number, dosage and/or regimen of drugs to treat cardiovascular disease in said patient while continuing to administer empagliflozin to said patient.

In one embodiment, the present invention provides a method of reducing the risk of a fatal or non-fatal cardiovascular event in a type 1 or type 2 diabetic patient, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

In one embodiment, the patient at risk of a cardiovascular event has a history of coronary artery disease, peripheral artery disease, stroke, transient ischemic attack, or high risk diabetes (insulin-dependent or non-insulin-dependent) with end organ damage.

In one embodiment, the present invention provides a method of reducing the risk of myocardial infarction, stroke, or death due to cardiovascular causes or heart failure, particularly heart failure requiring hospitalization, in a type 1 or type 2 diabetic patient, comprising administering empagliflozin, optionally in combination with one or more other therapeutic agents, to the patient in one embodiment, the patient is at high risk for cardiovascular events in one embodiment, a patient at high risk for cardiovascular events has a history of coronary artery disease, peripheral artery disease, stroke, transient ischemic attack, or high risk diabetes (insulin-dependent or non-insulin-dependent) with end organ damage.

In another embodiment, the invention provides a method for preventing, slowing, delaying or treating pancreatic β cell degeneration and/or pancreatic β cell function decline, and/or for improving and/or restoring pancreatic β cell function, and/or restoring function to pancreatic insulin secretion in a patient having latent autoimmune diabetes in adults (LADA), the method comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

In another embodiment, the invention provides a method for protecting pancreatic β cells and/or their function in a patient with latent autoimmune diabetes of the adult (LADA), comprising administering empagliflozin, optionally in combination with one or more other therapeutic agents, to the patient in one embodiment, the patient with LADA is a patient in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present.

In another embodiment, the invention provides a method for stimulating and/or preserving the function of pancreatic insulin secretion in a patient suffering from Latent Autoimmune Diabetes of Adults (LADA), said method comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to said patient. In one embodiment, the patient having LADA is a patient in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present.

In another embodiment, the invention provides a method for the treatment and/or prevention of LADA (latent autoimmune diabetes in adults), in particular in LADA patients presenting with one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

In one aspect of the invention, empagliflozin is administered orally, for example in a total daily amount of 10mg or 25 mg. In one embodiment, empagliflozin is administered in a pharmaceutical composition (e.g. a tablet) comprising 10mg or 25mg empagliflozin.

In one aspect of the invention, the patient in the methods or uses disclosed herein is a patient with type 2diabetes (or a type 2 diabetic patient), a patient treated for type 2diabetes, a patient diagnosed with type 2diabetes, or a patient in need of treatment for type 2 diabetes. In one aspect, the patient is a pre-diabetic patient.

The invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin for use as a medicament in any one of the methods described herein.

The invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin for use in the treatment of any one of the diseases or disorders described herein.

The invention further provides empagliflozin or a pharmaceutical composition comprising empagliflozin for use in the manufacture of a medicament for use in any of the methods described herein.

Disclosure of Invention

The present invention relates to the following aspects:

1. a method for the treatment and/or prevention of oxidative stress, collagen deposition, vessel wall thickening, vascular stress and/or endothelial dysfunction, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to a patient in need thereof.

2. The method of aspect 1, wherein the patient is a non-diabetic patient or a type 2 or type 1 diabetic patient.

3. The method of aspect 1, wherein the method is for treating and/or preventing endothelial dysfunction in a type 2 or type 1 diabetic patient.

4. A method of treating type 2 or type 1 diabetes in a patient suffering from or at risk of oxidative stress, vascular stress and/or endothelial dysfunction or a disease or condition associated therewith or related thereto,

5. A method of preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient with type 2 or type 1 diabetes or with prediabetes,

6. The method according to any one of the preceding aspects, wherein the patient has or is at risk of cardiovascular disease.

7. The method according to any one of the preceding aspects, wherein the patient has or is at risk of a cardiovascular disease selected from the group consisting of myocardial infarction, stroke, peripheral arterial occlusive disease.

8. A method of treating a metabolic disorder and preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

9. The method according to aspect 8, wherein the metabolic disorder is type 2 or type 1 diabetes or prediabetes.

10. The method according to aspect 8, wherein the cardiovascular event is selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, and heart failure requiring hospitalization.

11. The method according to aspect 8, wherein the cardiovascular death is due to fatal myocardial infarction or fatal stroke.

12. The method according to any of the preceding aspects, wherein the patient is a patient with type 2 or type 1 diabetes or with prediabetes, having one or more cardiovascular risk factors selected from a), B), C) and D):

B) advanced >/(60-70 years old), and

-late stage type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

13. A method of treatment, comprising:

a) identifying a patient in need of treatment for type 2 or type 1 diabetes and suffering from or at risk of cardiovascular disease; and

b) administering empagliflozin to said patient.

14. The method according to aspect 13, wherein the patient has or is at risk of a cardiovascular disease selected from the group consisting of myocardial infarction, stroke, peripheral arterial occlusive disease.

15. The method according to aspect 13 or 14, wherein the patient is a patient with type 2 or type 1 diabetes or with prediabetes, having one or more cardiovascular risk factors selected from a), B), C) and D):

B) advanced >/(60-70 years old), and

-late stage type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

16. A method for preventing, slowing, delaying or treating degeneration of pancreatic β cells and/or hypofunction of pancreatic β cells, and/or for improving and/or restoring and/or stimulating and/or protecting pancreatic β cell function, and/or restoring function of pancreatic insulin secretion in a patient having Latent Autoimmune Diabetes Adult (LADA), comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

17. A method for protecting pancreatic β cells and/or their function in a patient with Latent Autoimmune Diabetes of Adults (LADA), comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

18. A method for the treatment and/or prevention of LADA (latent autoimmune diabetes adult) in a patient, said method comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

19. The method according to any one of aspects 16-18, wherein the patient having LADA is a patient in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present.

20. A method for reducing arterial stiffness in a patient comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

21. The method according to any one of the preceding aspects, wherein the one or more other therapeutic substances are selected from other anti-diabetic substances.

22. The method according to any one of the preceding aspects, further comprising administering empagliflozin in combination with metformin, with linagliptin, or with metformin and linagliptin.

23. The method of any one of the preceding aspects, wherein empagliflozin is administered orally in a total daily amount of 10mg or 25 mg.

24. The method of any one of the preceding aspects, wherein empagliflozin is administered in a pharmaceutical composition comprising 10mg or 25mg empagliflozin.

Definition of

The term "active ingredient" of the pharmaceutical composition according to the invention refers to the SGLT2 inhibitor according to the invention. The "active ingredient" is sometimes also referred to herein as an "active".

Terminology of human patients"body Mass index" or "BMI" is defined as the weight in kilograms divided by the square of the height in meters, such that the BMI is in kg/m²。

The term "overweight" is defined as an individual with a BMI of more than 25kg/m²And less than 30kg/m²The disorder of (1). The terms "overweight" and "pre-obesity" are used interchangeably.

The term "obesity" or "obese" or the like is defined as an individual having a BMI equal to or greater than 30kg/m²The disorder of (1). According to the WHO definition, the term obesity can be classified as follows: the term "class I obesity" means a BMI equal to or greater than 30kg/m²But less than 35kg/m²The disorder of (a); the term "class II obesity" means a BMI equal to or greater than 35kg/m²But less than 40kg/m²The disorder of (a); the term "class III obesity" means a BMI equal to or greater than 40kg/m²The disorder of (1).

Obesity includes in particular exogenous obesity, hyperinsulinemic obesity, protoplasmic proliferative obesity, pituitary obesity, protoplasmic-reduced obesity, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, infant obesity, upper body obesity, nutritional obesity, hypogonadal obesity, central obesity, visceral obesity, abdominal obesity.

The term "visceral adiposity" is defined as a condition in which a male waist-to-hip ratio of greater than or equal to 1.0 and a female waist-to-hip ratio of greater than or equal to 0.8 is measured. Which defines insulin resistance and the risk of prediabetes development.

The term "abdominal obesity" is generally defined as a condition of waist circumference >40 inches or 102cm in men and >35 inches or 94cm in women. In the case of Japanese ethnic groups (Japanese ethnicity) or Japanese patients, abdominal obesity may be defined as waist circumference of 85cm or more in males and 90cm or more in females (see, for example, the Japanese Committee for the diagnosis and investigation of metabolic syndrome).

The term "euglycemia" is defined as the condition in which the subject's fasting plasma glucose concentration is within the normal range, i.e., greater than 70mg/dL (3.89mmol/L) and less than 100mg/dL (5.6 mmol/L). The term "fasting" has the general meaning of medical terms.

The term "hyperglycemia" is defined as a condition in which an individual has a fasting plasma glucose concentration above the normal range, i.e., greater than 100mg/dL (5.6 mmol/L). The term "fasting" has the general meaning of medical terms.

The term "hypoglycemia" is defined as an individual having a blood glucose concentration below the normal range, particularly less than 70mg/dL (3.89 mmol/L).

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

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

The term "impaired glucose tolerance" or "IGT" is defined as a condition in which the individual has a 2 hour post-prandial blood glucose or serum glucose concentration of greater than 140mg/dL (7.78mmol/L) and less than 200mg/dL (11.11 mmol/L). Abnormal glucose tolerance (i.e., 2 hours postprandial blood glucose or serum glucose concentration) can be measured as the blood glucose level in milligrams of glucose per deciliter of plasma 2 hours after intake of 75 grams of glucose after fasting. Individuals with "normal glucose tolerance" have a 2-hour postprandial blood glucose or serum glucose concentration of less than 140mg/dl (7.78 mmol/L).

The term "hyperinsulinemia" is defined as a condition in which fasting or postprandial serum or plasma insulin concentrations in a normoglycemic or hypoglycemic individual having insulin resistance are higher than in a normal lean individual without insulin resistance and having a waist-to-hip ratio <1.0 (male) or <0.8 (female).

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

The term "insulin resistance" is defined as a condition in which circulating insulin levels are required to exceed normal responses to glucose loading to maintain a normoglycemic state (Ford ES et al, JAMA. (2002)287: 356-9). The method for determining insulin resistance is euglycemia-hyperinsulinemia clamp test (euglycemia-hyperinsulinism clamp). The ratio of insulin to glucose was determined within the combined insulin-glucose infusion technique. Insulin resistance is considered to be present if glucose uptake is less than 25% of the background population studied (WHO definition). Much simpler than the jaw test is the so-called mini model (mini model), in which the insulin and glucose concentrations in the blood are measured at fixed time intervals during an intravenous glucose tolerance test, and the insulin resistance is calculated therefrom. In this way it is not possible to distinguish between hepatic insulin resistance and peripheral insulin resistance.

In addition, insulin resistance (i.e., the response of a patient with insulin resistance to therapy), insulin sensitivity, and hyperinsulinemia can be quantified by assessing a "homeostatic model assessment of insulin resistance (HOMA-IR)" score (a reliable indicator of insulin resistance) (Katsuka et al, Diabetes Care 2001; 24: 362-5). Reference is also made to the method of determining the HOMA index of insulin sensitivity (Matthews et al, Diabetologia 1985, 28: 412-19), the method of determining the ratio of intact proinsulin to insulin (Forst et al, Diabetes2003, 52 (suppl 1): A459) and the euglycemic clamp study. In addition, plasma adiponectin (adiponectin) levels can be monitored as a potential alternative to insulin sensitivity. Insulin resistance was estimated by calculating the steady state assessment model (HOMA) -IR score using the following formula (Galvin P et al, diabetes Med 1992; 9: 921-8):

HOMA-IR ═ fasting serum insulin (μ U/mL) ] × [ fasting plasma glucose (mmol/L)/22.5]

Insulin resistance in these individuals can be determined by calculating the HOMA-IR score. For the purposes of the present invention, insulin resistance is defined as a clinical condition in which an individual has a HOMA-IR score of >4.0 or a HOMA-IR score above the upper normal limit defined by laboratory glucose and insulin analyses.

Typically, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, e.g. the triglyceride concentration of the patient is used, as an increase in the triglyceride content is significantly correlated with the presence of insulin resistance.

An individual who is likely to have insulin resistance is an individual who has two or more of the following characteristics: 1) overweight or obesity, 2) hypertension, 3) hyperlipidemia, 4) one or more first-degree relatives diagnosed with IGT or IFG or type 2 diabetes.

Patients with a predisposition to develop IGT or IFG or type 2diabetes are those with hyperinsulinemia and are defined as euglycemic with insulin resistance. Typical patients with insulin resistance are generally overweight or obese. If insulin resistance is detectable, this is a strong indicator of the presence of prediabetes. Thus, in order to maintain glucose homeostasis, the individual may require 2-3 times as much insulin as a healthy individual, or else any clinical symptoms will result.

The generic term "prediabetes" refers to an intermediate stage between Normal Glucose Tolerance (NGT) and overt type 2diabetes (type 2 diabetes), also known as intermediate hyperglycemia. Thus, it represents 3 classes of individuals, either Impaired Glucose Tolerance (IGT) alone, Impaired Fasting Glucose (IFG) alone, or IGT combined IFG. IGT and IFG usually have different pathophysiological causes, but a mixture of both features is also present in patients. Thus, in the context of the present invention, a patient diagnosed with "pre-diabetes" is an individual diagnosed with IGT, or IFG, or IGT and IFG. According to the American Diabetes Association (ADA) definition and in the context of the present invention, patients diagnosed with "pre-diabetes" are:

a) fasting Plasma Glucose (FPG) concentration < 100mg/dL [1mg/dL ═ 0.05555mmol/L ] and 2 hour Plasma Glucose (PG) concentration measured by the oral 75g glucose tolerance test (OGTT) are ≥ 140mg/dL and < 200mg/dL (i.e. IGT); or

b) Fasting Plasma Glucose (FPG) concentration is ≥ 100mg/dL and < 126mg/dL, and 2-hour Plasma Glucose (PG) concentration as measured by the oral 75g glucose tolerance test (OGTT) < 140mg/dL (i.e., IFG); or

c) Fasting glucose (FPG) concentrations were ≥ 100mg/dL and < 126mg/dL, and 2-hour Plasma Glucose (PG) concentrations, as measured by the oral 75g glucose tolerance test (OGTT), were ≥ 140mg/dL and < 200mg/dL (i.e., IGT and IFG).

Patients with "prediabetes" are individuals prone to develop type 2 diabetes. Prediabetes extends the definition of IGT to include individuals with fasting blood glucose within the high normal range (≧ 100mg/dL) (J.B.Meigs et al Diabetes 2003; 52: 1475-1484). The American Diabetes Association (American Diabetes Association) and The National Institute of Diabetes and Digestive and nephropathy (National Institute of Diabetes and Digestive and Kidney Diseases) set forth The scientific and medical basis for identifying prediabetes as a serious health threat in a commonly published status report entitled "The preliminary or Delay of Type 2 Diabetes" (Diabetes Care 2002; 25: 742-.

The method of studying pancreatic β cell function is similar to that described above with respect to insulin sensitivity, hyperinsulinemia or insulin resistance, and the improvement in cell function can be measured, for example, by determining the HOMA index (homeostatic model assessment) of β cell function, HOMA-B, (Matthews et al, Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al, diabets 2003, 52 (suppl. 1): A459), first and second phase insulin secretion following an oral or dietary tolerance test (Stumvoll et al, diabets care 2000, 23: 295-.

The term "type 1 diabetes" is defined as a condition in which the subject has fasting glucose or serum glucose concentrations greater than 125mg/dL (6.94mmol/L) in the presence of autoimmunity to pancreatic β cells or insulin if a glucose tolerance test is conducted, plasma levels 2 hours after intake of 75g glucose in the fasting state in diabetic patients will exceed 200mg glucose per liter of plasma (11.1mmol/L) in the presence of autoimmunity to pancreatic β cells or insulin in the glucose tolerance test, 75g glucose will be orally administered to test patients 10-12 hours in the fasting state, and blood glucose levels will be recorded immediately before and 1 and 2 hours after intake of glucose in the glucose tolerance test.

The term "type 2 diabetes" or "type 2 diabetes" is defined as a condition in which an individual has fasting blood glucose or a serum glucose concentration greater than 125mg/dL (6.94 mmol/L). Measurement of blood glucose values is a standard practice in conventional medical analysis. If a glucose tolerance test is performed, the blood glucose level 2 hours after intake of 75g glucose in fasting state of a diabetic patient will exceed 200mg glucose per deciliter of plasma (11.1 mmol/l). In the glucose tolerance test, 75g of glucose was orally administered to a test patient after 10-12 hours of fasting, and the blood glucose level was recorded immediately before and 1 hour and 2 hours after the intake of glucose. In healthy individuals, the blood glucose level prior to glucose ingestion will be 60mg to 110mg per deciliter of plasma, will be less than 200mg/dL 1 hour after glucose ingestion, and will be less than 140mg/dL 2 hours after ingestion. If the value is 140mg to 200mg 2 hours after ingestion, this is considered abnormal glucose tolerance.

The term "advanced type 2 diabetes" includes patients with secondary drug failure, indications for insulin therapy, and progression to microvascular and macrovascular complications, such as diabetic nephropathy or Coronary Heart Disease (CHD).

The term "LADA" ("latent autoimmune diabetes adult") refers to a patient who is clinically diagnosed with type 2diabetes, but detected to have autoimmunity to the pancreas β cells Latent Autoimmune Diabetes Adult (LADA) is also referred to as slow progressing type 1 diabetes (T1DM), "mild" T1DM, non-insulin dependent type 1 diabetes, type 1 1/2 diabetes, dual diabetes, or antibody positive type 2diabetes (T2 DM). LADA is generally not clearly defined and, in contrast to type 1 diabetes, rarely or never exhibits significant weight loss and ketoacidosis due to rapid progressing β cell failure.

The term "HbA 1 c" refers to the product of nonenzymatic glycosylation of the B chain of hemoglobin. The person skilled in the art is familiar with the determination thereof. The HbA1c value is particularly important when monitoring the treatment of diabetes. Since the production of HbA1c depends essentially on the blood glucose level and the lifespan of the red blood cells, HbA1c reflects the mean blood glucose level of the first 4-6 weeks in the sense of "glycemic memory". The HbA1c value was significantly better protected from diabetic microangiopathy by diabetic patients who were consistently well-regulated by diabetes intensive therapy (i.e. less than 6.5% of the total hemoglobin of the sample). For example, metformin itself achieves an average improvement in HbA1c values of 1.0-1.5% in diabetic patients. This reduction in HbA1c values is not sufficient to reach the desired target range of HbA1c < 7% or < 6.5% and preferably < 6% in all diabetic patients.

In the context of the present invention, the term "insufficient glycemic control" or "insufficient glycemic control" refers to the case of a patient showing a HbA1c value of above 6.5%, in particular above 7.0%, even more preferably above 7.5%, in particular above 8%.

"Metabolic syndrome", also known as "syndrome X" (used in the context of metabolic disorders), also known as "dystrophic syndrome", is a complex syndrome primarily characterized by insulin resistance (Laaksonen DE et al, Am J Epidemiol 2002; 156: 1070-7). According to the ATP III/NCEP guidelines (Executive Summary of the third report of the National Cholesterol Emission Program (NCEP) Expert Panel on detection, Evaluation, and Evaluation of High Blood Cholesterol in additives (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001)285: 2486-:

1. abdominal obesity, defined as waist circumference >40 inches or 102cm for men and >35 inches or 94cm for women; or in the case of Japanese race or Japanese patient, defined as waist circumference of > 85cm for male and > 90cm for female;

2. triglyceride: not less than 150mg/dL

3. Male HDL-cholesterol <40mg/dL

4. Blood pressure not less than 130/85mm Hg (SBP not less than 130 or DBP not less than 85)

5. Fasting blood glucose is more than or equal to 100mg/dL

The NCEP definition has been validated (Laaksonen DE et al, Am J Epidemiol. (2002) 156: 1070-7). Also by medical analysis and e.g. Thomas L (eds): the triglyceride and HDL cholesterol in blood were determined by the standard method described in "Labor und Diagnose", TH-BooksVerlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to the usual definition, hypertension is diagnosed if the Systolic Blood Pressure (SBP) exceeds a value of 140mm Hg and the Diastolic Blood Pressure (DBP) exceeds a value of 90mm Hg. If a patient suffers from overt Diabetes (manifest Diabetes), a systolic pressure drop to below 130mm Hg and a diastolic pressure drop to a level below 80mm Hg are currently recommended.

The term "empagliflozin" refers to the SGLT2 inhibitor of the formula 1-chloro-4- (β -D-glucopyranos-1-yl) -2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene

Which is described, for example, in WO 2005/092877. The literature describes methods for their synthesis, for example WO 06/120208 and WO 2011/039108. According to the present invention, it is understood that the definition of empagliflozin also includes hydrates, solvates, polymorphs and prodrugs thereof. Advantageous crystalline forms of empagliflozin are described in WO2006/117359 and WO 2011/039107, which are incorporated herein in their entirety. The crystal form has good solubility property, so that the SGLT2 inhibitor has good bioavailability. In addition, the crystalline form is physico-chemically stable, thus providing good shelf-life stability to the pharmaceutical composition. Preferred pharmaceutical compositions, e.g. oral solid formulations, e.g. tablets, are described in WO2010/092126, which is herein incorporated in its entirety.

The term "treatment" encompasses the therapeutic treatment of a patient in whom the condition (particularly the dominant form) has arisen. A therapeutic treatment can be a symptomatic treatment that alleviates symptoms of a particular indication, or a causal treatment that reverses or partially reverses the condition of the indication or halts or slows progression of the disease. Thus, the compositions and methods of the invention are useful, for example, as therapeutic treatments over time and for long-term therapy.

The terms "prophylactic treatment", "prophylactic treatment" and "prevention" are used interchangeably and include treating a patient at risk of developing a condition described above, thereby reducing the risk.

The term "tablet" includes uncoated tablets as well as tablets having one or more coatings. Furthermore, the term "tablet" includes tablets and press-coated tablets having one, two, three or even more layers, wherein each of the above-mentioned tablet types may be uncoated or have one or more coatings. The term "tablet" also encompasses miniature, melt, chewable, effervescent and orally disintegrating tablets.

The terms "pharmacopoeia" ("pharmacopoe" and "pharmacopoeias") refer to standard pharmacopoeias such as "USP 31-NF 26 second supplementary edition" (United States pharmacopoeia (United States pharmaceutical Convention)) or "European pharmacopoeia 6.3" (European directive for the Quality of the medicine and Health Care (European council)), 2000-2009.

Brief Description of Drawings

FIG. 1: weight gain, blood glucose (non-fasting and fasting, n-6-8) and HbA1c (n-5-6) in animals treated with empagliflozin.

Fig. 2A and 2B: diastolic (endothelial function) deterioration in STZ-treated (diabetic) animals and after treatment with empagliflozin. The GTN curve of fig. 2B is a positive control to show that all tissue aliquots showed vessel wall integrity during nitric oxide administration.

FIG. 3: zyma was used to stimulate oxygen burst (leukocyte-derived Reactive Oxygen Species (ROS)) in blood at 30 minutes.

FIG. 4: zyma was used to stimulate oxygen burst (leukocyte-derived ROS) in blood at 60 minutes.

FIG. 5: time course of oxygen burst (leukocyte-derived ROS) in blood stimulated with ZymA.

FIG. 6: zyma stimulation (at 30 min) of oxygen burst (leukocyte-derived ROS) in blood with inhibitors of Nox2 activity (VAS2870) and intracellular calcium chelators was used.

FIG. 7: zyma stimulation (at 60 min) of oxygen burst (leukocyte-derived ROS) in blood with inhibitors of Nox2 activity (VAS2870) and intracellular calcium chelators was used.

FIG. 8: PDBu was used to stimulate oxygen burst (leukocyte-derived ROS) in blood at 15 minutes.

FIG. 9: oxygen burst (leukocyte-derived ROS) time course in blood stimulated with PDBu.

FIG. 10: membrane NADPH oxidase activity.

Fig. 11A and 11B: hepatic ALDH-2 activity.

Fig. 12A and 12B: vascular superoxide formation was detected by fluorescent DHE microtopography (micropography).

FIGS. 13A-D: serum levels of cholesterol, triglycerides, insulin and interferon gamma, respectively.

FIG. 14: average Systolic Blood Pressure (SBP) per hour at 12 weeks (mmHg).

FIG. 15: average Systolic Blood Pressure (SBP) per hour at 12 weeks (mmHg).

Fig. 16A and 16B: microscopic examination of aortic wall thickness and collagen content was performed by treating aortic sections with sirius red staining paraffin.

Detailed Description

The present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of oxidative stress, for example in patients suffering from type 1 or type 2 diabetes. The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of endothelial dysfunction. The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, to reduce glycotoxicity in tissues and associated oxidative stress and inflammation. The invention also relates to the use of such SGLT-2 inhibitors for the treatment and/or prevention of cardiovascular diseases in patients, e.g. in type 1 or type 2 diabetic patients. The invention also relates to the use of such SGLT-2 inhibitors, in particular empagliflozin, for the treatment and/or prevention of metabolic disorders in a patient suffering from or at risk of cardiovascular disease. The present invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of metabolic disorders as well as in the prevention, reduction of the risk or delay of the occurrence of cardiovascular events in a patient, e.g. a patient suffering from type 1 or type 2 diabetes.

The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of oxidative stress, vascular stress and/or endothelial dysfunction (e.g. in diabetic or non-diabetic patients), said treatment being in particular unrelated to or exceeding the scope of glycemic control.

The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of collagen deposition and/or vessel wall thickening (e.g. in diabetic or non-diabetic patients), said treatment being in particular unrelated to or exceeding the scope of glycemic control.

The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for the treatment and/or prevention of hyperglycemia-induced or associated oxidative stress (e.g. outside the scope of glycemic control), and the use of such SGLT-2 inhibitors in anti-diabetic therapy.

The invention further relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of metabolic disorders, such as diabetes, in particular type 1 and type 2diabetes mellitus and/or diseases associated therewith (e.g. diabetic complications), in particular in patients suffering from or at risk of oxidative stress, vascular stress and/or endothelial dysfunction or diseases or conditions associated therewith or associated therewith.

Furthermore, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of metabolic disorders, such as diabetes, in particular type 1 and type 2diabetes, and/or diseases associated therewith (e.g. diabetic complications), in patients suffering from or at risk of cardiovascular diseases (e.g. myocardial infarction, stroke or peripheral arterial occlusive disease) or microalbuminuria.

Furthermore, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of metabolic disorders, such as diabetes, in particular type 1 and type 2diabetes, and/or diseases associated therewith, in patients suffering from or at risk of microvascular or macrovascular diabetic complications, such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or cardiovascular diseases, such as myocardial infarction, stroke or peripheral arterial occlusive disease.

Furthermore, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in modulating, blocking or reducing (chronic or transient diabetes) the deleterious metabolic memory effects of hyperglycemia, in particular diabetic complications.

Furthermore, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment, prevention or reduction of the risk of microvascular or macrovascular diseases which may be induced by exposure to oxidative stress, memory or associated therewith.

Furthermore, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of a metabolic disorder, such as diabetes, in particular type 1 and type 2diabetes mellitus and/or a disease associated therewith (such as diabetic complications) in a patient suffering from or at risk of a cardiovascular event, in particular in a type 1 or type 2diabetes mellitus patient at risk of a cardiovascular event (such as a type 1 or type 2diabetes mellitus patient having one or more risk factors selected from the group consisting of past or present vascular disease (such as myocardial infarction (e.g. asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure (e.g. grade I or II NYHA, e.g. left ventricular function < 40%) or peripheral occlusive arterial disease)), the method comprises administering to the patient a therapeutically effective amount of the SGLT-2 inhibitor, optionally in combination with one or more other therapeutic substances.

Oxidative stress represents an imbalance between the production of reactive oxygen species (which include free radicals, which typically have oxygen or nitrogen unpaired electrons in the external orbital, as well as peroxides) and the ability of biological systems to readily detoxify reactive intermediates or repair the resulting damage. Interference with the normal redox state of a tissue can lead to toxic effects by producing peroxides and free radicals that damage all components of the cell, including proteins, lipids and nucleic acids/DNA. Oxidative stress can be targeted to a variety of organs (e.g., blood vessels, eyes, heart, skin, kidneys, joints, lungs, brain, immune system, liver, or multiple organs) and can be included in a variety of diseases and disorders. Examples of such diseases or disorders associated with oxidative stress include atherosclerosis (e.g., platelet activation and atheroma formation), endothelial dysfunction, restenosis, hypertension, peripheral occlusive vascular disease, ischemia-reperfusion injury (e.g., renal, hepatic, cardiac, or cerebral ischemia-reperfusion injury), fibrosis (e.g., renal, hepatic, cardiac, or pulmonary fibrosis); macular degeneration, retinal degeneration, cataracts, retinopathy; coronary heart disease, ischemia, myocardial infarction; psoriasis and dermatitis; chronic kidney disease, nephritis, acute renal failure, glomerulonephritis, nephropathy; rheumatoid arthritis, osteoarthritis; asthma, COPD, respiratory distress syndrome; stroke, neurodegenerative diseases (e.g., alzheimer's disease, parkinson's disease, huntington's disease), schizophrenia, bipolar disorder, obsessive-compulsive disorder; chronic systemic inflammation, perivasculitis, autoimmune disease, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, ulcerative colitis; NAFLD/NASH; chronic fatigue syndrome, polycystic ovary syndrome, septicemia, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hyperlipidemia, and the like. In addition to the original pharmacological properties, certain drugs used clinically, including but not limited to, antihypertensive agents, angiotensin receptor blockers, and antihyperlipidemic agents, such as statins, protect various organs via antioxidant stress mechanisms.

Patients with or at risk of oxidative and/or vascular stress can be diagnosed by determining markers of oxidative stress in the patient, such as oxidized LDL, markers of inflammatory status (e.g., proinflammatory interleukins), 8-OHdG, isoprostane (e.g., F2-isoprostane, 8-isoprostane F2 α), nitrotyrosine, or N-Carboxymethyllysine (CML).

Endothelial dysfunction (clinically commonly assessed as impaired endothelium-dependent vasomotor, e.g. an imbalance between vasodilation and vasoconstriction) is the physiological disabling of endothelial cells (cells lining the inner surfaces of blood vessels, arteries and veins), preventing them from performing their normal biochemical functions. Normal endothelial cells are involved in the process of mediating coagulation, platelet adhesion, immune function, volume control and electrolyte content in the intravascular and extravascular spaces. Endothelial dysfunction is associated with pro-inflammatory, pro-oxidative and pro-coagulative changes in the arterial wall as well as increased vessel wall thickness and collagen content. Endothelial dysfunction is considered an important event in the development and progression of atherosclerosis and arterial stiffness and precedes clinically significant vascular complications. Endothelial dysfunction has prognostic significance for the detection of vascular disease and the prediction of adverse vascular events. Risk factors for atherosclerosis and vascular disease/events are associated with endothelial dysfunction. Endothelial injury also leads to kidney damage and/or the development of chronic or progressive kidney injury, such as tubulointerstitial fibrosis, glomerulonephritis, microalbuminuria, renal disease and/or chronic kidney disease or renal failure. There is evidence that oxidative stress leads not only to endothelial dysfunction or damage, but also to vascular disease.

Type 2diabetes is a common chronic and progressive disease resulting from complex pathophysiology, which involves a dual endocrine role of insulin resistance and impaired insulin secretion with the consequence that the required requirements for maintaining blood glucose levels within the normal range cannot be met, which leads to hyperglycemia and its associated microvascular and macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (e.g. cardiovascular) complications the vascular disease components have an important role but are not the only factors within the scope of diabetes-related conditions high frequency of complications leading to a significant reduction in life expectancy, diabetes is the most common cause of adult-onset visual loss, renal failure and amputation in the industrial world due to diabetes-induced complications and is associated with a two to five fold increase in cardiovascular risk type 1 diabetes (type 1 diabetes), also known as insulin-dependent diabetes or juvenile diabetes, is a form of autoimmune destruction derived from β cells producing insulin in the pancreas, subsequent insulin deficiency and increased blood glucose concentration and increased glucose concentration, resulting in the same diabetic complications as classic diabetes mellitus, diabetes.

Large randomized studies have been conducted with intensive and intensive control of blood glucose in the early stages of diabetes (within 5 years of the most recent diagnosis) with long-lasting beneficial effects and with reduced risk of diabetic complications (micro-and macrovascular). However, despite receiving enhanced glycemic control, many diabetic patients still develop diabetic complications.

Epidemiological and predictive data support the long-term impact of early (up to 5 years of recent diagnosis) metabolic control on clinical outcome. It has been found that hyperglycemia has a long-lasting deleterious effect on both type 1 and type 2diabetes, and is not sufficient to completely reduce complications if glycemic control is not initiated or not intensified or intensive in the very early stages of the disease.

It has also been found that brief episodes of hyperglycemia (e.g., hyperglycemic events) can induce molecular changes, and that these changes can persist or be irreversible after returning to normoglycemia.

Taken together, these data suggest that metabolic memory is stored early in the diabetic process, and in certain diabetic conditions, oxidative and/or vascular stress may persist after glucose normalization. This phenomenon of early glycemic environment and/or even transient hyperglycemia, along with clinical consequences, being memorized in the target end organs (e.g., blood vessels, retina, kidney, heart, limbs) is recently referred to as "metabolic memory".

The underlying mechanisms that propagate this "memory" are certain epigenetic changes, namely non-enzymatic glycosylation of cellular proteins and lipids (e.g., formation of advanced glycosylation endproducts), oxidatively modified atherogenic lipoproteins, and/or excess cellular Reactive Oxygen and Nitrogen Species (RONS), particularly arising from glycosylated mitochondrial protein content that may act in concert with each other to maintain stress signaling.

Mitochondria are one of the major sources of Reactive Oxygen Species (ROS) in cells. Mitochondrial dysfunction can increase electron leakage and ROS production from the Mitochondrial Respiratory Chain (MRC). The high content of glucose and lipid impairs the activity of MRC complex enzymes. For example, the MRC enzyme NADPH oxidase produces superoxide from NADPH in cells. Increased NADPH oxidase activity can be detected in diabetic patients.

Furthermore, evidence suggests that overproduction of free radicals (e.g., Reactive Oxygen Species (ROS)) leads to oxidative and vascular stress after glucose normalization and to the development and/or maintenance of metabolic memory, and thus leads to a consistent link between hyperglycemia and cellular memory effects, for example, in endothelial dysfunction or other complications of diabetes.

Thus, mainly in connection with sustained (chronic) oxidative stress induced by or associated with (chronic, early or transient onset) hyperglycemia, there are certain metabolic disorders in which even if blood glucose is normalized, long-term sustained activation of many pathways involved in the pathogenesis of diabetic complications may still be present. Thus, one of the main findings in the course of diabetes has shown that there can be significant overproduction of free radicals even when blood glucose levels are normal and that it is independent of the actual blood glucose level. For example, endothelial dysfunction (a causative marker of diabetic vascular complications) will persist even after normalization of blood glucose. However, evidence suggests that combining antioxidant therapy with normalization of blood glucose can be used for nearly interrupted endothelial dysfunction.

Thus, for example, the treatment of oxidative and/or vascular stress, especially beyond the scope of glycemic control, by reducing cellular reactive substances and/or reducing glycosylation (e.g. by inhibiting the production of oxygen and nitrogen radicals, which are preferably independent of the glycemic state), may beneficially modulate, reduce, block or counteract the memory effects of hyperglycemia and reduce the risk of, prevent, treat or delay the onset of long-term diabetic complications, especially those complications associated with or induced by oxidative stress, in a patient in need thereof.

The standard therapy for type 1 diabetes is insulin treatment. Therapies for type 1 diabetes are described, for example, in WO 2012/062698.

Treatment of type 2diabetes is generally initiated by diet and exercise, followed by oral antidiabetic monotherapy, and although conventional monotherapy initially controls blood glucose in some patients, it is associated with high secondary failure rates. The limitations of single drug therapy for maintaining glycemic control can be overcome in at least some patients, and blood glucose reduction is achieved by combining multiple drugs for a limited period of time, which is not sustainable during long-term treatment with a single drug. The current data support the conclusion that in most type 2 diabetic patients, current monotherapies will fail and will require treatment with multiple drugs.

However, since type 2diabetes is a progressive disease, even patients with a good initial response to conventional combination therapy will eventually require increased doses or further treatment with insulin because blood glucose levels are extremely difficult to maintain stable over an extended period of time. While existing combination therapies have the ability to enhance glycemic control, they are not without limitation (particularly with respect to long term efficacy). Furthermore, traditional treatments may exhibit an increased risk of side effects, such as hypoglycemia or weight gain, which may reduce their efficacy and acceptability.

Thus, for many patients, regardless of the treatment situation, these existing drug treatments still result in a progressive worsening of metabolic control and in particular do not adequately control metabolic state over the long term, and therefore glycemic control cannot be achieved and maintained in advanced or late stage type 2diabetes, including diabetes where glycemia is not adequately controlled despite the use of conventional oral or non-oral antidiabetic drugs.

Thus, while intensive treatment of hyperglycemia may reduce the incidence of chronic injury, many type 2 diabetic patients still receive inadequate treatment, due in part to the limitations of long-term efficacy, tolerability, and inconvenience of administration of conventional antihyperglycemic therapies.

In type 2 diabetic patients, the high incidence of failure of this treatment is the leading cause of the high incidence of long-term hyperglycemia-related complications or chronic injury (including microvascular and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, or cardiovascular complications, such as myocardial infarction, stroke or vascular mortality or morbidity).

Oral antidiabetic agents that are routinely used in therapy (e.g., first or second line, and/or monotherapy or (initial or supplemental) combination therapy) include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, glinides, and α -glucosidase inhibitors.

Non-oral (typically injectable) antidiabetic agents conventionally used in therapy (e.g., first or second line, and/or monotherapy or (initial or supplemental) combination therapy) include, but are not limited to, GLP-1 or GLP-1 analogs, as well as insulin or insulin analogs.

However, the use of these conventional antidiabetic agents or antihyperglycemic agents may be associated with various adverse effects, for example, metformin may be associated with lactic acidosis or gastrointestinal side effects, sulfonylureas, glinides, and insulin or insulin analogs may be associated with hypoglycemia and weight gain, thiazolidinediones may be associated with edema, bone fractures, weight gain, and heart failure/cardiac action, and α -glucosidase blockers and GLP-1 or GLP-1 analogs may be associated with gastrointestinal adverse effects (e.g., dyspepsia, gastrointestinal gas accumulation or diarrhea, or nausea or vomiting) and most severely (but rarely) pancreatitis.

Thus, there remains a need in the art to provide effective, safe and tolerable anti-diabetic treatments.

Furthermore, in the treatment of type 2diabetes, there is a need for effective treatment of the condition, avoiding complications associated with the condition, and delaying disease progression, e.g., to achieve a long-lasting therapeutic benefit.

Furthermore, there is still a need for an anti-diabetic treatment that not only prevents long-term, but in addition, prevents or reduces the risk of adverse effects associated with conventional anti-diabetic treatments.

SGLT2 inhibitors (sodium-glucose cotransporter 2) represent a new class of drugs developed for the treatment or improvement of glycemic control in type 2diabetes patients. Glucopyranosyl-substituted benzene derivatives are described as SGLT2 inhibitors, for example in WO01/27128, WO03/099836, WO2005/092877, WO2006/034489, WO2006/064033, WO2006/117359, WO2006/117360, WO2007/025943, WO2007/028814, WO2007/031548, WO2007/093610, WO2007/128749, WO2008/049923, WO2008/055870, WO 2008/055940. The glucopyranosyl-substituted benzene derivatives are provided as urinary system sugar excretion inducers and as medicaments for the treatment of diabetes.

Among other mechanisms, renal filtration and reabsorption of glucose contributes to steady state plasma glucose concentrations and thus can be used as an anti-diabetic target. Reabsorption of filtered glucose across the renal epithelial cells will proceed along a sodium gradient via a sodium-dependent glucose co-transporter (SGLT) located in the brush border membrane (brush-border membrane) of the tubules. There are at least three SGLT subtypes that differ in their expression patterns and physicochemical properties. SGLT2 is expressed only in the kidney, while SGLT1 is also expressed in other tissues such as the intestine, colon, bone and myocardium. SGLT3 has been found to be a glucose sensor in intestinal stromal cells without any transport function. Other related but uncharacterized genes may further promote renal glucose reabsorption. In the case of normal blood glucose concentrations, glucose is completely reabsorbed by SGLT in the kidney, and the reabsorption capacity of the kidney is saturated at glucose concentrations greater than 10mM, resulting in diabetes ("diabetes"). This threshold concentration may be reduced by inhibition of SGLT 2. In experiments with the SGLT inhibitor phlorizin, it has been shown that inhibition of SGLT will partially inhibit the reabsorption of glucose from glomerular filtrate into the blood, leading to a decrease in blood glucose concentration and to diabetes.

Empagliflozin is a novel SGLT2 inhibitor described for the treatment and improvement of glycemic control in type 2diabetes patients, for example in WO 05/092877, WO06/117359, WO 06/120208, WO2010/092126, WO 2010/092123, WO 2011/039107, WO 2011/039108.

Thus, in a particular embodiment, the SGLT-2 inhibitor within the meaning of the present invention is empagliflozin.

Furthermore, the present invention relates to a therapeutic (therapeutic or prophylactic) method as described herein, comprising administering an effective amount of an SGLT-2 inhibitor as described herein and optionally one or more other active or therapeutic agents to a patient in need thereof

In one embodiment, diabetic patients within the meaning of the present invention may include patients who have not previously been treated with an antidiabetic agent (drug naive patients) and thus, in one embodiment, the therapy described herein may be used in drug naive patients, hi another embodiment, diabetic patients within the meaning of the present invention may include advanced or advanced type 2 diabetic patients (including patients who have failed conventional antidiabetic agent therapy), such as patients who have insufficient glycemic control by one, two or more conventional oral and/or non-oral antidiabetic agent therapy as defined herein, such as patients who have insufficient glycemic control despite metformin, thiazolidinedione (especially pioglitazone), sulfonylurea, glinide, DPP-4 inhibitor, GLP-1 or GLP-1 analogue, insulin or insulin analogue or α -glucosidase inhibitor (monotherapy), or patients who have insufficient glycemic control despite metformin/sulfonylurea, metformin/thiazolidinedione (especially pioglitazone), metformin/DPP-4 inhibitor, insulin/α -glucosidase inhibitor, pioglitazone/insulin or insulin/monotherapy or a combination thereof, such as can be treated with a conventional antidiabetic agent, such as a sulfonylurea/insulin combination, or a combination thereof.

Another embodiment of a diabetic patient within the meaning of the present invention refers to a type 1 or type 2 diabetic patient having or at risk of developing microvascular or macrovascular diabetic complications, such as those described herein (e.g., those at risk patients as described below).

Another embodiment of diabetic patients amenable to treatment by the present invention may include, but is not limited to, those type 1 or type 2 diabetic patients who have or are at risk of having progressive retinal complications, such as diabetic retinopathy.

Another embodiment of diabetic patients amenable to treatment by the present invention may include, but is not limited to, those type 1 or type 2 diabetic patients having or at risk of progressive macrovascular complications, such as myocardial infarction, coronary artery disease, ischemic or hemorrhagic stroke, and/or peripheral arterial occlusive disease.

Another embodiment of diabetic patients amenable to treatment by the present invention may include, but is not limited to, those type 1 or type 2 diabetic patients having or at risk of a cardiovascular disease or event (such as those cardiovascular risk patients described herein).

Another embodiment of diabetic patients that may be suitable for treatment according to the present invention may include, but are not limited to, those of advanced age and/or with advanced diabetic disease (especially type 2 diabetes), such as insulin-treated patients, patients with triple antidiabetic oral therapy, patients with pre-existing cardiovascular events and/or patients with advanced disease duration (e.g., >/═ 5 to 10 years).

According to one aspect of the invention, the patient is a type 1 or type 2 diabetic.

In one embodiment, the patient is a type 1 or type 2 diabetic patient having one or more cardiovascular risk factors selected from a), B), C), and D):

B) advanced >/(60-70 years old), and

-late stage type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

In a further aspect of the invention, a patient at risk for cardiovascular disease is defined as having at least one of:

-a confirmed history of myocardial infarction; or

Evidence of multiple coronary artery disease in 2 or more major coronary arteries, irrespective of the revascularization status, i.e.

a) There is a significant stenosis in 2 or more major coronary arteries (imaging evidence of a narrowing of lumen diameter of at least 50% as measured in coronary angiography or multi-slice helical CT angiography),

b) or prior revascularization in 2 or more major coronary arteries (percutaneous transluminal coronary angioplasty with or without a stent, or coronary artery bypass graft),

c) or prior revascularization in one major coronary artery (percutaneous transluminal coronary angioplasty with or without a stent, or coronary artery bypass grafting), and the presence of a significant stenosis in the other major coronary artery (imaging evidence of narrowing of the lumen diameter by at least 50% as measured in coronary angiography or multi-slice helical CT angiography),

note: diseases affecting the left coronary artery main stem are considered to be 2 branch diseases.

Evidence of single-branch coronary artery disease with:

a) there is evidence of imaging (as measured in coronary angiography or multi-slice helical CT angiography) of significant stenosis, i.e., narrowing of at least 50% of the lumen diameter of one major coronary artery in patients with subsequent unsuccessful revascularization

b) And at least one of (i) or (ii)):

i. a positive non-invasive pressure test, confirmed by either:

1. positive motor load test in patients without complete left bundle branch block, Wolff-Parkinson-White syndrome, or pacing ventricular rhythms, or

2. Positive loading echocardiography showing regional contractile wall motion abnormalities, or

3. Positive scintillation testing showing stress-induced ischemia, i.e. the development of transient perfusion defects during myocardial perfusion imaging;

or a patient discharged from the hospital has a diagnostic record of unstable angina within 12 months prior to selection.

Unstable angina events with confirmed multiple or single coronary artery disease as defined above.

History of ischemic or hemorrhagic stroke

Presence of peripheral arterial disease (symptomatic or asymptomatic) recorded by: prior limb angioplasty, stenting, or bypass surgery; or limb or foot amputations previously resulting from circulatory insufficiency; or angiographic evidence of significant (> 50%) peripheral arterial stenosis in at least one limb; or evidence from non-invasive detection of peripheral arterial stenosis that is significant (> 50% or as reported hemodynamically significant) in at least one limb.

In another aspect of the invention, a patient at risk for cardiovascular disease is defined as having at least one of:

a) the confirmed history of the myocardial infarction,

b) unstable angina, with recordings of multiple coronary artery disease (at least two major coronary arteries in angiography) or positive stress tests (ST segment shift-down > -2 mm or positive nuclear perfusion scintigraphy),

c) multiple Percutaneous Coronary Intervention (PCI),

d) multiple Coronary Artery Bypass Grafting (CABG), including cases with recurrent angina after surgery,

e) a history of ischemic or hemorrhagic stroke,

f) peripheral arterial occlusive disease (prior limb bypass or percutaneous transluminal angioplasty; prior amputations of limbs or feet due to circulatory insufficiency, significant vascular stenosis of the arteries of the main limbs detected by angiography or imaging (e.g., ultrasound, magnetic resonance imaging).

Furthermore, the present invention relates to specific SGLT-2 inhibitors for preventing, reducing the risk of or delaying the occurrence of a cardiovascular event, such as cardiovascular death, (fatal or non-fatal) myocardial infarction (e.g. asymptomatic or symptomatic myocardial infarction), (fatal or non-fatal) stroke or hospitalization (e.g. due to acute coronary syndrome, lower leg amputation, (emergency) revascularization processes, heart failure or due to unstable angina), preferably in type 1 or type 2diabetes patients, especially in those type 1 or type 2diabetes patients at risk for a cardiovascular event, such as type 1 or type 2diabetes patients having one or more risk factors selected from a), B), C) and D):

A) past or present with vascular disease (e.g., myocardial infarction (e.g., asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure (e.g., grade I, II, III or IV NYHA, e.g., left ventricular function < 40%), or peripheral occlusive arterial disease),

B) advanced age (e.g., age >/═ 60-70 years), and

late type 1 or type 2diabetes (e.g. >10 years duration),

hypertension (e.g. >130/80mm Hg, or systolic blood pressure >140mmHg or in at least one blood pressure lowering treatment),

-smoking is currently carried out daily,

dyslipidemia (e.g. atherogenic dyslipidemia, postprandial lipemia, or high LDL cholesterol level in the blood (e.g. LDL cholesterol >/═ 130-dL 135mg/dL), low HDL cholesterol level (e.g. <35-40mg/dL in men or <45-50mg/dL in women) and/or high triglyceride level (e.g. >200-400mg/dL), or in at least one treatment of lipid disorders),

-obesity (e.g. abdominal and/or visceral obesity, or body mass index >/═ 45kg/m2),

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea or a family history of vascular disease or cardiomyopathy among first degree relatives,

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

The method comprises administering to the patient a therapeutically effective amount of the SGLT-2 inhibitor, optionally in combination with one or more other therapeutic substances.

In another aspect, the present invention relates to specific SGLT-2 inhibitors for use in a method of reducing arterial stiffness in a patient. In one aspect, the patient is a patient according to the invention, in particular a patient suffering from type 1 or type 2diabetes or pre-diabetes. Increased arterial stiffness is associated with increased risk of cardiovascular events and the effect of empagliflozin on arterial stiffness is shown, for example, in the examples below.

The present invention further relates to a pharmaceutical composition comprising a specific SGLT-2 inhibitor empagliflozin as defined herein for use in the treatment described herein.

When the present invention refers to a patient in need of treatment or prevention, it is primarily directed to treatment and prevention in humans, but the pharmaceutical composition may also be used accordingly in veterinary medicine in mammals. Within the scope of the present invention, the adult patient is preferably a human being 18 years of age or older. Adolescent humans (i.e., humans between 10 and 17 years of age, preferably between 13 and 17 years of age) are also within the scope of the invention. It is speculated that a very good HbA1c reduction and a very good fasting glucose reduction is seen in the young population when administering the pharmaceutical composition according to the invention. Furthermore, it is speculated that significant weight loss may be observed in the juvenile population, especially in overweight and/or obese patients.

As mentioned above, by administering the pharmaceutical composition according to the present invention and especially in view of the high SGLT2 inhibitory activity of the SGLT2 inhibitors described herein, excess blood glucose is excreted in the urine of the patient, which may then result in no or even a reduction of body weight. Thus, the treatment or prevention according to the present invention is advantageously applicable to those patients in need of such treatment or prevention who have been diagnosed with one or more disorders selected from the group consisting of: overweight and obesity, especially class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. Furthermore, the treatment or prevention according to the invention is advantageously applicable to those patients for which weight gain is contraindicated. The pharmaceutical compositions and methods according to the invention can reduce HbA1c values to a desired target range, e.g. < 7% and preferably < 6.5%, for a higher number of patients and at a longer therapeutic dosing time compared to corresponding monotherapies or treatments using only two of the combination partners.

The pharmaceutical composition according to the invention and in particular the SGLT2 inhibitor described herein exhibits very good efficacy with respect to glycemic control, in particular with respect to reduction of fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin (HbA1 c). By administering the pharmaceutical composition according to the invention, a reduction in HbA1c preferably equal to or greater than 0.5%, even more preferably equal to or greater than 1.0%, and especially in the range of 1.0% to 2.0% can be achieved.

Furthermore, the method and/or use according to the invention is advantageously applicable to those patients who exhibit one, two or more of the following conditions:

(a) fasting plasma glucose or serum glucose concentrations greater than 100mg/dL, particularly greater than 125 mg/dL;

(b) postprandial blood glucose equal to or greater than 140 mg/dL;

(c) HbA1c values are equal to or greater than 6.5%, specifically equal to or greater than 7.0%, specifically equal to or greater than 7.5%, and even more specifically equal to or greater than 8.0%.

The invention also discloses the use of the pharmaceutical composition for improving glycemic control in patients with type 1 or type 2diabetes or showing early signs of prediabetes. Thus, the present invention also includes diabetes prevention. Thus, if the use of the pharmaceutical composition according to the invention improves glycemic control once the above-mentioned prediabetic signs are present, the onset of overt type 2diabetes can be delayed or prevented.

Furthermore, the pharmaceutical composition according to the invention is particularly suitable for treating patients with insulin dependence, i.e. patients treated with insulin or insulin derivatives or insulin substitutes or formulations comprising insulin or derivatives or substitutes thereof or patients who will additionally be treated therewith or in need thereof. These patients include type 2 diabetic patients and type 1 diabetic patients.

Thus, according to a preferred embodiment of the present invention, there is provided a method for improving glycemic control and/or for reducing fasting glucose, postprandial blood glucose and/or glycosylated hemoglobin HbA1c in a patient diagnosed with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), with insulin resistance, with metabolic syndrome and/or with type 2 or type 1 diabetes mellitus in need thereof, characterized in that an SGLT2 inhibitor as defined above and below is administered to said patient.

According to a further preferred embodiment of the present invention, a method for improving glycemic control in type 2 diabetic patients, in particular in type 2 diabetic adult patients, as an aid to diet and exercise is provided.

By using the pharmaceutical composition according to the invention it is possible to find that an improvement in glycemic control can be achieved even in those patients with insufficient glycemic control (especially those patients with insufficient glycemic control despite treatment with an antidiabetic drug, for example despite oral monotherapy with the maximum recommended or tolerated dose of metformin). The maximum recommended dose for metformin is, for example, 2000 mg/day or three times 850 mg/day or any equivalent thereof.

Thus, the method and/or use according to the invention is advantageously applicable to those patients who exhibit one, two or more of the following conditions:

(a) inadequate blood glucose control with diet and exercise alone;

(b) insufficient glycemic control despite oral monotherapy with metformin, particularly despite oral monotherapy with metformin at the maximum tolerated dose;

(c) in spite of the oral monotherapy with the additional antidiabetic agent inadequate glycemic control, especially in spite of the oral monotherapy with the maximum tolerated dose of the other antidiabetic agent.

The reduction in blood glucose levels achieved by administration of the SGLT2 inhibitor according to the invention is non-insulin dependent. Thus, the pharmaceutical composition according to the invention is particularly suitable for treating patients diagnosed with one or more of the following conditions:

-the resistance of insulin to insulin,

-a form of Hyperinsulinemia (HPS),

-a pre-diabetic condition selected from the group consisting of pre-diabetes,

type 2diabetes, especially with late stage type 2diabetes,

-type 1 diabetes.

Furthermore, the pharmaceutical composition according to the invention is particularly suitable for treating patients diagnosed with one or more of the following conditions:

(a) obesity (including type I, type II and/or type III obesity), visceral obesity and/or abdominal obesity,

(b) the blood content of triglyceride is more than or equal to 150mg/dL,

(c) HDL-cholesterol blood levels in females are <40mg/dL and in males are <50mg/dL,

(d) the systolic pressure is more than or equal to 130mm Hg and the diastolic pressure is more than or equal to 85mm Hg,

(e) the fasting blood sugar content is more than or equal to 100 mg/dL.

It is speculated that patients diagnosed with Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), insulin resistance and/or with metabolic syndrome suffer from an increased risk of developing cardiovascular diseases, such as myocardial infarction, coronary heart disease, cardiac insufficiency, thrombotic events. Glycemic control according to the present invention may result in a reduction of cardiovascular risk.

Furthermore, the pharmaceutical composition according to the invention is particularly suitable for treating patients after organ transplantation, especially those diagnosed with one or more of the following conditions:

(a) the elderly, especially older than 50 years,

(b) male;

(c) overweight, obesity (including type I, type II and/or type III obesity), visceral obesity and/or abdominal obesity,

(d) the diabetes before the transplantation of the blood sugar-reducing agent,

(e) and (4) carrying out immunosuppressive treatment.

(a) hyponatremia, especially chronic hyponatremia;

(b) water poisoning;

(c) water retention;

(d) plasma sodium concentration was less than 135 mmol/L.

The patient may be a diabetic or non-diabetic mammal, especially a human.

(a) high serum uric acid levels, especially above 6.0mg/dL (357. mu. mol/L);

(b) a history of gouty arthritis, particularly recurrent gouty arthritis;

(c) kidney stones, especially recurrent kidney stones;

(d) high propensity for renal stone formation.

In particular embodiments, patients amenable to treatment by the present invention may have, or be at risk for, one or more of the following diseases, disorders, or conditions: type 1 diabetes, type 2diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), hyperglycemia, postprandial hyperglycemia, post-absorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypernefa blood levels, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, metabolic syndrome, nephropathy, microalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegeneration or cognitive disorders, cardiovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, diabetic foot or ulcer, Acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (including, for example, uremic cardiomyopathy), heart failure, cardiac hypertrophy, arrhythmia, vascular restenosis, stroke, (renal, cardiac, brain, or liver) ischemia/reperfusion injury, (renal, cardiac, brain, or liver) fibrosis, (renal, cardiac, brain, or liver) vascular remodeling; diabetes, particularly preferably type 2diabetes (e.g. underlying disease).

In another embodiment, a patient amenable to treatment by the present invention has diabetes, particularly type 2diabetes, and may have, or be at risk for, one or more other diseases, disorders, or conditions (e.g., selected from those described above).

In other embodiments, the invention also relates to the effect of specific SGLT-2 inhibitors (in particular empagliflozin) on β cell and/or β cell function, for example in patients with Latent Autoimmune Diabetes Adult (LADA).

Thus, in one embodiment, the present invention relates to a specific SGLT-2 inhibitor, in particular empagliflozin, for use in the prevention, slowing, delay or treatment of pancreatic β cell degeneration and/or pancreatic β cell dysfunction, and/or for use in improving and/or restoring pancreatic β cell function, and/or restoring pancreatic insulin secretion function, in a patient suffering from latent autoimmune diabetes mellitus (LADA) in adults.

In another embodiment, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in protecting pancreatic β cells and/or their function in a patient suffering from Latent Autoimmune Diabetes Adult (LADA).

In another embodiment, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in stimulating and/or protecting the function of pancreatic insulin secretion in patients with Latent Autoimmune Diabetes of Adults (LADA).

Generally, diagnosing LADA requires three criteria to be met:

1) adult age at onset of diabetes (>30 years),

2) there are circulating islet autoantibodies (β cellular autoimmune markers that differentiate LADA from type 2diabetes, such as islet cell antibodies (ICA, anti-cytoplasmic protein in β cells, islet cell cytoplasm), glutamate decarboxylase antibodies (GAD-65, anti-GAD), insulin autoantibodies (IAA), and/or IA-2A antibodies to the tyrosine phosphatase-like protein IA-2 cytoplasmic domain), and

3) insulin requirement is absent for at least 6 months after diagnosis (to differentiate LADA from typical type 1 diabetes).

However, alternative definitions of LADA include GAD (glutamate decarboxylase) antibody titers of ≧ 0.08U/mL and 1) lifestyle and oral therapy or 2) insulin therapy started 12 months after diagnosis or 3) insulin therapy started 12 months after diagnosis but fasting C-peptide content >150 pmol/l.

Individuals with LADA often have low (although sometimes moderate) C-peptide content as the disease progresses.

For this reason, LADA is sometimes proposed only as a "low titer type 1 diabetes condition", however, the LADA population often shares phenotypic characteristics with type 2diabetes over type 1 diabetes, and thus LADA may represent a unique disease unit etiologically characterized by a more rapid β cell function decline compared to type 2 diabetes.

The incidence of insulin dependence in LADA has been demonstrated in several studies to be higher than in subjects with normal type 2 diabetes.

Thus, in one aspect, a patient with LADA according to the invention is a patient in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present, and in one aspect, in a method or use according to the invention, a patient with LADA is a patient in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) are present.

It is believed that the prevalence of LADA in the population with type 2diabetes is at least 5-10%. Furthermore, adults with LADA are often initially misdiagnosed as having type 2 diabetes; based on age rather than etiology. In a survey conducted by the australian type 1 diabetes network, one third of all australians with type 1 diabetes were reported to have an initial misdiagnosis as having the more common type 2 diabetes.

Currently, there is no "gold standard" for the treatment or management of LADA in general, treatment of LADA should focus not only on controlling blood glucose and preventing any complication from occurring, but also to allow protection of residual β cell function, insulin treatment in LADA is generally effective, but may be most beneficial in patients with both high titers of GAD (>10U/mL) and protected insulin secretion (C peptide >10 ng/mL).

Thus, in another embodiment, the present invention relates to specific SGLT-2 inhibitors, in particular empagliflozin, for use in the treatment and/or prevention of LADA (latent autoimmune diabetes in adults), especially in those LADA patients in which one or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present.

It has now been found within the scope of the present invention that a specific SGLT-2 inhibitor as defined herein, optionally in combination with one or more other therapeutic substances (e.g. selected from those described herein), as well as the pharmaceutical combinations, compositions or combined use according to the present invention of such SGLT-2 inhibitors as defined herein, have properties which make them suitable for supporting the present invention and/or for fulfilling one or more of the above needs.

The efficacy of empagliflozin for cardiovascular diseases, in particular for the risk of cardiovascular events (e.g. as defined herein) is corroborated e.g. as described in the examples below.

The efficacy of empagliflozin on β cells and/or on β cell function was confirmed, for example, as described in the examples below.

The present invention thus relates to a specific SGLT-2 inhibitor as defined herein, preferably empagliflozin, for use in the treatment described herein.

Furthermore, it was found that administration of the pharmaceutical composition according to the invention results in no or low risk of hypoglycemia. Thus, it is also possible to advantageously employ the treatment or prevention according to the invention in those patients who show or have an increased risk of hypoglycemia.

The pharmaceutical composition according to the invention is particularly suitable for the long-term treatment or prevention of diseases and/or disorders as described above and below, in particular long-term glycemic control in type 2diabetes patients.

The term "long-term" as used in the context means that the treatment or administration is carried out in the patient over a period of longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

Accordingly, a particularly preferred embodiment of the present invention provides a method for the treatment, preferably oral treatment, for improving, in particular long-term improvement of glycemic control in type 2 diabetic patients, in particular in advanced type 2 diabetic patients, in particular in patients additionally diagnosed with overweight, obesity (including grade I, grade II and/or grade III obesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of a pharmaceutical composition according to the invention to be administered to a patient and to be used in the treatment or prevention according to the invention will vary with the route of administration, the nature and severity of the condition to be treated or prevented, the age, weight and physical condition of the patient, the concomitant medication, and will ultimately be at the discretion of the resident physician (physician). However, in general, the SGLT2 inhibitor according to the invention is contained in a pharmaceutical composition or dosage form in an amount sufficient to improve glycemic control in a patient to be treated by administration thereof.

For the treatment of hyperuricemia or a hyperuricemia-related disorder, the SGLT2 inhibitor according to the invention is included in the pharmaceutical composition or dosage form in an amount sufficient to treat hyperuricemia without disrupting the patient's glycemic homeostasis, in particular without inducing hypoglycemia.

For the treatment or prevention of kidney stones, the SGLT2 inhibitor according to the invention is included in the pharmaceutical composition or dosage form in an amount sufficient to treat or prevent kidney stones without disturbing the patient's glycemic homeostasis, in particular without inducing hypoglycemia.

For the treatment of hyponatremia and related conditions, the SGLT2 inhibitor according to the present invention is included in a pharmaceutical composition or dosage form in an amount sufficient to treat hyponatremia or related conditions without disturbing the patient's glycemic homeostasis, in particular without inducing hypoglycemia.

Preferred ranges for the SGLT2 inhibitory dose used in the pharmaceutical compositions and methods and uses according to the present invention are described below. These ranges refer to the amount administered daily to an adult patient (particularly, for example, a human having a body weight of about 70 kg), and the ranges can be adjusted accordingly for 2, 3, 4 or more daily administrations, and other administration routes and patient ages.

Within the scope of the present invention, the pharmaceutical composition is preferably administered orally. Other administration forms are also possible and are described below. Preferably, one or more dosage forms comprising the SGLT2 inhibitor are oral or generally well known.

In general, the amount of SGLT2 inhibitor in the pharmaceutical compositions and methods according to the invention is preferably the generally recommended amount for monotherapy using the SGLT2 inhibitor.

The preferred dosage range for the SGLT2 inhibitor is from 0.5mg to 200mg, even more preferably from 1 to 100mg, most preferably from 1 to 50mg per day. In one aspect, a preferred dose of the SGLT2 inhibitor empagliflozin is 10mg or 25 mg/day. Oral administration is preferred. Thus, the pharmaceutical composition may comprise the amounts mentioned above, in particular 1-50mg or 1-25 mg. Particular dosage strengths (e.g. per tablet or per capsule) are, for example, 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50mg of SGLT2 inhibitor, in particular empagliflozin. In one aspect, the pharmaceutical composition comprises 10mg or 25mg empagliflozin. The use of the active ingredient may occur up to three times a day, preferably once or twice a day, most preferably once a day.

Pharmaceutical compositions in single or multiple dosage forms, preferably in kit of parts, are useful in combination therapy to flexibly adapt to the individual therapeutic needs of a patient.

According to a first embodiment, a preferred kit of parts comprises a container containing a dosage form comprising the SGLT2 inhibitor and at least one pharmaceutically acceptable carrier.

Another aspect of the invention is an article of manufacture comprising a pharmaceutical composition in the form of individual pharmaceutical dosage forms according to the invention and a label or package insert comprising instructions for the combined or alternating administration of said individual pharmaceutical dosage forms.

According to a first embodiment, an article of manufacture comprises (a) a pharmaceutical composition comprising an SGLT2 inhibitor according to the invention and (b) a label or package insert comprising instructions for administration of the drug.

The desired dose of the pharmaceutical composition according to the invention may conveniently be provided in divided doses (e.g. two, three or more doses per day) provided once per day or administered at appropriate intervals.

The pharmaceutical compositions may be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration in liquid or solid form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. Where appropriate, the formulations are preferably in discrete dosage units and may be prepared by any of the methods well known in the pharmaceutical art. All methods comprise the following steps: the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as a liquid carrier or a finely divided solid carrier or both, and the product is then shaped, if necessary, into the desired formulation.

The pharmaceutical composition may be formulated in the form of: tablet, granule, fine granule, powder, capsule, small capsule, soft capsule, pill, oral solution, syrup, dry syrup, chewable tablet, sugar coated tablet, effervescent tablet, drop, suspension, quick dissolving tablet, oral quick dispersible tablet, etc.

Pharmaceutical compositions and dosage forms preferably comprise one or more pharmaceutically acceptable carriers, which must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, including soft gelatin capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, suspension or as an emulsion, for example as a syrup, elixir or self-emulsifying delivery system (SEDDS). The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or a suitable vehicle before use. Such liquid formulations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

The pharmaceutical compositions according to the invention may also be formulated for parenteral administration (e.g. by injection, e.g. intramuscular injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by mixing the active ingredient(s) with the softening or melting carrier, followed by cooling and shaping in a mould.

The pharmaceutical compositions and methods according to the present invention show advantageous effects for the treatment and prevention of diseases and disorders such as those described above. Advantageous effects can be found, for example, with regard to efficacy, dose intensity, dose frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse reactions, convenience, compliance, etc.

Methods for making SGLT2 inhibitors and prodrugs thereof according to the present invention are known to those skilled in the art. Advantageously, the preparation of the compounds according to the invention can use synthetic methods as described in the literature (including the patent applications cited above). Preferred manufacturing processes are described in WO 2006/120208 and WO 2007/031548. With respect to empagliflozin, an advantageous crystalline form is described in international patent application WO2006/117359, which is hereby incorporated in its entirety.

The active ingredient may be presented in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, but are not limited to, salts of, for example, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; salts of organic carboxylic acids such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid and salts of organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. The salt may be formed by mixing the compound and the acid in the solvent and decomposer in appropriate amounts and ratios. They can also be obtained by cation or anion exchange from other salt forms.

The active ingredient or a pharmaceutically acceptable salt thereof may also be present in the form of solvates such as hydrates or alcohol adducts.

Pharmaceutical compositions or combinations comprising an SGLT-2 inhibitor as defined herein, optionally together with one or more other active substances, for use in these treatments are also contemplated.

Furthermore, the present invention relates to SGLT-2 inhibitors, each as defined herein, optionally in combination with one, two or more additional active agents, for use in a treatment as described herein.

Furthermore, the present invention relates to the use of SGLT-2 inhibitors, each as defined herein, optionally in combination with one, two or more additional active agents, for the preparation of a pharmaceutical composition suitable for the therapeutic and/or prophylactic purposes of the present invention.

The present invention further relates to a pharmaceutical composition comprising a specific SGLT-2 inhibitor as defined herein (preferably empagliflozin) and metformin for use in the treatment described herein.

The present invention furthermore relates to a combination comprising a specific SGLT-2 inhibitor, in particular empagliflozin, and one or more further active substances selected from those mentioned herein, for example from other antidiabetic substances, active substances which lower the blood glucose level, active substances which lower the lipid level in the blood, active substances which increase the HDL level in the blood, active substances which lower blood pressure, active substances suitable for the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulants and vascular endothelial protectants, for example as described herein; it is particularly useful for simultaneous, separate or sequential use in the treatment described herein.

The invention further relates to a combination comprising a specific SGLT-2 inhibitor, especially empagliflozin, and one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, α -glucosidase inhibitors, insulin or insulin analogues, GLP-1 or and GLP-1 analogues and DPP-4 inhibitors, especially for simultaneous, separate or sequential use in a treatment as described herein.

The invention further relates to a method for the treatment and/or prevention of metabolic disorders, especially type 2diabetes and/or conditions associated therewith, such as diabetic complications, comprising administering in combination (e.g. simultaneously, separately or sequentially) an effective amount of one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, PPAR-gamma agonists, α -glucosidase inhibitors, insulin or insulin analogues, GLP-1 or and GLP-1 analogues and DPP-4 inhibitors to a patient in need thereof, especially a human patient, such as a patient as described herein, including a group of patients at risk.

The invention further relates to a method of treatment or therapy as described herein, for example for the treatment and/or prophylaxis of a metabolic disorder, especially type 2diabetes and/or a condition associated therewith (e.g. diabetic complications), which comprises administering a therapeutically effective amount of empagliflozin and optionally one or more other therapeutic agents, for example other antidiabetic agents selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, PPAR-gamma agonists, α -glucosidase inhibitors, insulin or insulin analogues, GLP-1 or and GLP-1 analogues and DPP-4 inhibitors, to a patient (especially a human patient) in need thereof, for example a patient as described herein (e.g. a patient at risk as described herein).

It is to be understood within the present invention that the active ingredients or components may be considered to be administered simultaneously, sequentially or separately in accordance with the COMBINATION, COMPOSITIONS OR COMBINATION USES OF THE INVENTION.

In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed (e.g. free) forms (including kits) and uses, e.g. simultaneous, sequential or separate use of the components or ingredients.

The combined administration of the invention may be carried out by administering the active ingredients or ingredients together, for example by administering them simultaneously in one single or two separate formulations or dosage forms. Alternatively, administration may be carried out by sequential administration of the active ingredients or ingredients, e.g. by sequential administration of two separate formulations or dosage forms.

For the combination therapies of the present invention, the active ingredients or ingredients may be administered separately (which means they are formulated separately) or formulated together (which means they are formulated in the same formulation or in the same dosage form). Thus, administration of one element of the combination of the invention may be carried out before, simultaneously with or after administration of the other element of the combination.

Unless otherwise indicated, combination therapy may refer to first, second or third line therapy, or to initial or supplemental combination therapy or alternative therapy.

The present invention further relates to a specific SGLT-2 inhibitor as defined herein, preferably empagliflozin, in combination with metformin, for use in a treatment as described herein.

Metformin is typically administered in doses varying from about 500mg to 2000mg, up to 2500mg per day, using various dosing regimens from about 100mg to 500mg or 200mg to 850mg (1-3 times per day) or about 300mg to 1000mg (once or twice per day), or sustained release metformin is administered in doses from about 100mg to 1000mg or preferably 500mg to 1000mg (once or twice per day) or about 500mg to 2000mg (once per day). Specific dosage strengths may be 250, 500, 625, 750, 850 and 1000mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose of metformin is 500mg administered once daily. If the dose does not produce adequate results, the dose may be increased to 500mg twice daily. Further increases may be given at 500mg in divided doses (e.g. 2 or 3 divided doses) weekly up to a maximum of 2000mg per day. Metformin may be administered with food to reduce nausea.

An example of a DPP-4 inhibitor is linagliptin, which is typically administered at a dose of 5 mg/day.

The dose of pioglitazone is usually about 1-10mg, 15mg, 30mg or 45mg once daily.

Rosiglitazone is usually administered in doses of 4mg to 8mg once (or divided twice) a day (typical dose strengths are2, 4 and 8 mg).

Glibenclamide (glyburide) is typically administered in a dose of 2.5-5 to 20mg, once (or divided) daily (typical dose strengths of 1.25, 2.5 and 5mg), or micronized glibenclamide in a dose of 0.75-3 to 12mg, once (or divided) daily (typical dose strengths of 1.5, 3, 4.5 and 6 mg).

Glipizide is typically administered at a dose of 2.5 to 10-20mg, once daily (or up to 40mg, in two portions) (typical dose strengths of 5mg and 10mg), or extended release glipizide is administered once daily at a dose of 5-10mg (up to 20mg) (typical dose strengths of 2.5, 5 and 10 mg).

Glimepiride is usually administered in doses of 1-2 to 4mg (up to 8mg), once per day (typical dose strengths are 1, 2 and 4 mg).

Nateglinide, a non-sulfonylurea insulin secretagogue, is usually given with meals in doses of 60 to 120mg (up to 360 mg/day, with typical dose strengths of 60 and 120 mg); repaglinide is usually given in doses of 0.5 to 4mg with meals (up to 16 mg/day, typical dose strengths are 0.5, 1 and 2 mg). The repaglinide/metformin dual combination may be used in dosage strengths of 1/500 and 2/850 mg.

In one aspect of the invention, the one or more other therapeutic substances are active substances that lower blood glucose levels, active substances that lower lipid levels in the blood, active substances that increase HDL levels in the blood, active substances that lower blood pressure, active substances suitable for the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulant agents, and vascular endothelial protectant agents.

In one aspect, the invention provides a method of treatment comprising identifying a type 2 diabetic patient for treatment with a plurality of agents for treating cardiovascular disease, administering empagliflozin to the patient; and reducing the number, dose or regimen of drugs for treating cardiovascular disease in said patient, particularly while continuing to administer empagliflozin to said patient. In one embodiment, the method additionally comprises monitoring the heart health of the patient.

Examples of drugs for treating cardiovascular diseases include blood pressure lowering drugs such as β blockers, diuretics, calcium channel blockers, Angiotensin Converting Enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs).

Examples of blood pressure lowering drugs are β blockers such as acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, propranolol, timolol, and carvedilol, the dosages of some of these drugs being shown, for example, in the following:

acebutolol (Sectral), 200 or 400mg acebutolol in the form of the hydrochloride

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

Betaxolol (Kerlone), 10-mg and 20-mg tablets for oral administration

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

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

Metoprolol (Lopressor, Toprol XL), 50-and 100-mg tablets for oral administration and 5-mL ampoules for intravenous administration

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

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

Examples of blood pressure lowering drugs are diuretics such as bumetanide, hydrochlorothiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, xipamide, indapamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; for example, the drugs are thiazide diuretics such as chlorthalidone, HCT, loop diuretics such as furosemide, torasemide, or potassium sparing diuretics such as eplerenone, or combinations thereof; the doses of some of these drugs are shown, for example, in the following:

amiloride (Midamor), 5mg Aniloli Anhydrous HCl

Bumetanide (Bumex), 0.5mg (pale green), 1mg (yellow) and 2mg (pink) available scored tablet for oral administration

The compound of chlorothiazide (Diuril),

chlorothioketone (Hygroton)

Furosemide (Lasix)

Hydrochlorothiazide (Esix, Hydrodiuril)

Indapamide (Lozol) and spironolactone (Aldactone)

Eplerenone (Inspra)

Examples of blood pressure lowering drugs are calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanidipine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem;

examples of blood pressure lowering drugs are Angiotensin Converting Enzyme (ACE) inhibitors such as benazepril, captopril, ramipril, lisinopril, moexipril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; the doses of some of these drugs are shown, for example, in the following:

benazepril (Lotensin), 5mg, 10mg, 20mg and 40mg captopril (Capoten) for oral administration, 12.5mg, 25mg, 50mg and 100mg scored tablets for oral administration

Enalapril (Vasotec) in the form of 2.5mg, 5mg, 10mg and 20mg tablets for oral administration

Fosinopril (Monopril), 10mg, 20mg and 40mg tablet lisinopril (Prinivil, Zestril) for oral administration, 5mg, 10mg and 20mg tablet for oral administration

Moxipril (Univasc), 7.5mg and 15mg for oral administration

Perindopril (Aceon), 2mg, 4mg and 8mg specification for oral administration

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

Ramipril (Alpace), 1.25mg, 2.5mg, 5mg, 10mg

Trandolapril (Mavik), examples of drugs for lowering blood pressure of 1mg, 2mg or 4mg of trandolapril for oral administration are angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan; the doses of some of these drugs are shown, for example, in the following:

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

Eprosartan (Teveten), 400mg or 600mg

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

Losartan (Cozaar), 25mg, 50mg or 100mg losartan potassium

Telmisartan (Micardis), 40mg/12.5mg, 80mg/12.5mg and 80mg/25mg telmisartan and hydrochlorothiazide

A typical dose of valsartan (Diovan), valsartan telmisartan 40mg, 80mg, 160mg or 320mg is 20mg to 320 mg/day or 40mg to 160 mg/day.

Other embodiments, features and advantages of the present invention will be apparent from the following examples. The following examples serve to illustrate the principles of the invention by way of example and not to limit it.

Examples

Example 1: effects of SGLT2 inhibitors on STZ-induced oxidative stress in diabetes (type I), vessel wall thickness and collagen content and endothelial dysfunction in rats.

Type I diabetes in Wistar rats (8 weeks old, 250-300g) was induced by a single intravenous injection of STZ (60 mg/kg). Blood glucose levels were measured 3 days after STZ injection (to test whether diabetes was induced) and at the day of sacrifice. Empagliflozin (SGLT2-i) was given with drinking water for an additional 7 weeks after one week of injection (10 and 30mg/kg/d, oral). Treatment with empagliflozin showed a significant reduction in blood glucose levels in diabetic rats, while weight gain loss was unaffected. Isometric tension records showed normalization of empagliflozin-dependent endothelial function in diabetic animals and reduced oxidative stress in aortic vessels and blood was detected by aortic cryosection DHE staining and PDBu/zymosan a-stimulated chemiluminescence, respectively. In addition, a trend was observed in diabetic animals for an increase in NADPH oxidase activity in the heart and a significant decrease in ALDH-2 activity in the liver, reflecting a decrease in oxidative stress induced by empagliflozin treatment. The results are shown in FIGS. 1-13.

FIG. 1: shows the effect of empagliflozin at low (10mg/kg) and high (30mg/kg) doses administered in drinking water on weight gain, blood glucose and glycated hemoglobin (HbA 1C).

FIG. 2: a: endothelium-dependent vasodilation. This figure shows the improvement in endothelial function measured with isolated aortic rings after 7 weeks of treatment.

B: endothelium-independent vasodilation obtained with Glyceryl Trinitrate (GTN), a NO donor. This figure shows the ability of all vessel walls to relax independent of the endothelium, demonstrating that there is no detrimental effect of treatment on smooth muscle cells.

FIGS. 3 to 9: reactive Oxygen Species (ROS) were quantified from zymosan a (zyma) -stimulated leukocytes. After 7 weeks of treatment, empagliflozin at low or high dose reduced ROS production in the blood to levels close to those in non-diabetic animals.

FIG. 10: treatment with empagliflozin was shown to reduce NADPH oxidase activity in heart tissue, an important source of superoxide.

FIG. 11: shows that treatment with empagliflozin partially restores the reduction in ALDH-2 activity in diabetic STZ animals.

Fig. 12A and 12B: it was shown to reduce superoxide formation in blood vessels in diabetic animals. Figure 12A shows the results for a partial set of animals and figure 12B shows the results for all animals.

FIGS. 13A-D: plasma cholesterol, triglycerides, insulin and interferon gamma levels in STZ diabetic rats compared to normal rats and diabetic rats treated with empagliflozin are shown. In the case of epraziquant restoring insulin content, epraziquant treatment highly reduces or inhibits the increase of interferon gamma (an inflammation marker) in diabetic rats.

Aortic wall thickness and collagen content were also measured microscopically after sirius red staining. Aortic sections were fixed in paraformaldehyde (4%) and embedded in paraffin. Sirius red staining for vascular fibrosis was performed using paraffin-deparaffinized paraffin-embedded aortic tissue samples. The nuclei were then prestained with alum violet. The samples were then stained in a 0.1% sirius red solution containing saturated picric acid (1.2%) for 1 hour. Finally, the tissue samples were dehydrated with 70%, 96% and 100% isopropanol and coverslipped with a solution of polymer in xylene. Each sample was measured 60-70 times, and n-6-7 animals/group. The results are shown in fig. 16A and 16B.

Fig. 16A and 16B: microscopic examination of aortic wall thickness and collagen content was performed by stellera staining paraffin processing aortic sections. Quantification (fig. 16A) and representative microscope images (fig. 16B). Aortic wall thickness and collagen content were slightly increased in diabetic rats and normalized by empagliflozin treatment.

Example 2: hourly measurement of blood pressure

Empagliflozin (10mg and 25mg) is administered orally once daily for 12 weeks in hypertensive patients with type 2 diabetes. Changes from baseline in mean Systolic (SBP) and Diastolic (DBP) pressures per hour over a 24 hour period after 12 weeks of treatment were measured compared to placebo and are shown in figures 14 and 15.

Example 3 treatment of type 2 diabetic patients with high cardiovascular risk

The long-term effects of empagliflozin treatment on cardiovascular morbidity and mortality and related efficacy parameters (e.g. HbA1c, fasting plasma glucose, treatment duration) in a population associated with type 2 diabetic patients were studied as follows:

patients with type 2diabetes who have a high risk of cardiovascular events (e.g., as defined below) are treated with empagliflozin (optionally in combination with one or more other active substances (e.g., as described herein)) over a long period of time (e.g., between about 6-8 years) and compared to patients treated with standard placebo of a background of care drug.

Empagliflozin is administered orally once daily (10 mg/day or 25 mg/day). Patients were diagnosed with type 2diabetes, with diet and exercise regimens and were not pretreated with drugs or with any background therapy. For patients with background therapy, it has HbA of 7.0% or more and 10% or less_1cOr HbA in the case of non-dosed patients_1cNot less than 7.0% and not more than 9.0%.

Defining a patient with a high cardiovascular risk as having at least one of:

-a confirmed history of myocardial infarction; or

Evidence of single-branch coronary artery disease with:

b) And at least one of (i) or (ii)):

i. a positive non-invasive pressure test, confirmed by either:

1. positive motor load test in patients without complete left bundle branch block, Wasp-Par-Huai syndrome or paced ventricular rhythms, or

History of ischemic or hemorrhagic stroke

Presence of peripheral arterial disease (symptomatic or asymptomatic) recorded by: prior limb angioplasty, stenting, or bypass surgery; or limb or foot amputations previously resulting from circulatory insufficiency; or angiographic evidence of significant (> 50%) peripheral arterial stenosis in at least one limb; or evidence from non-invasive detection of peripheral arterial stenosis that is significant (> 50% or as reported hemodynamically significant) in at least one limb; or an ankle index <0.9 in at least one limb.

The efficacy criteria are for example the following changes from baseline: HbA at 12 weeks, 52 weeks, once a year, or at the end of the study_1cFasting Plasma Glucose (FPG), body weight, waist circumference and blood pressure.

The time to first appearance of any Major Adverse Cardiovascular Event (primary composite Major Additive Cardiovascular Event (MACE)) endpoint determinant component (Cardiovascular death, including fatal stroke and fatal myocardial infarction), non-fatal stroke, non-fatal Myocardial Infarction (MI)) was determined compared to placebo in patients treated with empagliflozin.

The time to first appearance of the following decision events (combination therapy) was also determined compared to placebo in patients treated with empagliflozin: CV death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction (including asymptomatic myocardial infarction), non-fatal stroke, and hospitalization due to unstable angina.

The occurrence and timing of the following events were also determined:

asymptomatic myocardial infarction

Heart failure requiring hospitalization

New onset proteinuria defined as ACR ≥ 30mg/g

The new large amount of albuminuria is more than or equal to 300 mg/g.

Composite microvascular results defined as follows:

1) require retinal photocoagulation

2) Vitreous hemorrhage

3) Blindness associated with diabetes

4) New onset or worsening renal disease as defined below:

4a) new onset of abundant albuminuria; or 4b) doubling of serum creatinine content with eGFR (based on the kidney disease dietary Change (MDRD) formula). ltoreq.45 mL/min/1.73m²(ii) a Or

4c) A need for continuous renal replacement therapy; or d) death due to kidney disease.

The occurrence and timing of each of the following decision events was also determined:

CV death (including fatal stroke and fatal myocardial infarction)

Non-fatal myocardial infarction

Non-fatal stroke

Hospitalization for unstable angina

All cause mortality

TIA

The process of coronary revascularization.

Example 4: treatment of type 2diabetes

Treatment of type 2 diabetic patients with empagliflozin, in addition to producing an acute improvement in the metabolic status of glucose, also prevents a long-term worsening of the metabolic status. This effect is observed in patients treated with the combination according to the invention for a longer period of time (e.g. 3 months to 1 year, even 1 year to 6 years) and compared to patients treated with other anti-diabetic and/or anti-obesity drugs. If no or only a slight increase in fasting plasma glucose and/or HbA1c values is observed, there is evidence that it is a successful treatment compared to other treatment methods. Further evidence of the success of this treatment is: patients treated with the combination according to the invention develop a worsening of the metabolic position of glucose (e.g. an increase of the HbA1c value to > 6.5% or > 7%) compared to patients receiving another treatment such that the percentage of patients requiring treatment with (additional) oral hypoglycemic drugs or insulin analogues is significantly less.

Example 5: treatment of insulin resistance

In clinical studies running at different time periods (e.g. 2 weeks to 12 months) the success of treatment was tested using a hyperinsulinemic-euglucose clamp experiment. At the end of the study of the invention, the rate of glucose infusion was significantly increased compared to the initial value or compared to the placebo group, or compared to the group given different treatments, demonstrating the efficacy of the treatment according to the invention for insulin resistance.

Example 6: treatment of hyperglycemia

In clinical studies running different time periods, e.g. 1 day to 24 months, treatment success is determined by measuring fasting or non-fasting plasma glucose (e.g. after meal or oGTT stress test or after a meal (a defined meal)). The significant decrease in glucose values during or at the end of the study compared to the initial values or compared to the placebo group, or compared to the group given different treatments, demonstrates the efficacy of the combination treatment according to the invention for the treatment of hyperglycemia.

Example 7 Effect of empagliflozin versus Glimepiride on β cell function

The effects of empagliflozin and SU glimepiride as second line treatments were compared in a phase III study in type 2 diabetic patients who were still under control with Immediate Release (IR) therapy and diet/exercise therapy with metformin.

After running 2 weeks of placebo, patients were randomized to receive either empagliflozin 25mg once daily (qd) or glimepiride 1-4 mg qd for 104 double-blind weeks, except for metformin IR. Patients who participate in the initial 104-week randomized period will be eligible for a 104-week double-blind delay.

The primary endpoint was HbA from baseline_1cAnd (6) changing. Secondary endpoints are changes in body weight from baseline, diagnosed hypoglycemia incidence, and systolic and diastolic blood pressure changes. Exploratory endpoints include FPG changes from baseline, achievement of HbA_1c<7% of patients and effects on various β cell function biomarkers including insulin, C-peptide, HOMA-B and preproinsulin/insulin ratios, first and second phase insulin secretion after a meal tolerance test.

Furthermore, the primary, secondary and exploratory endpoints were assessed in a subgroup of adult Latent Autoimmune Diabetes (LADA) patients who identified by the presence of autoantibodies at baseline against insulin, islet cell cytosol, glutamate decarboxylase 65 or tyrosine phosphatase-like protein IA-2 cytosol domain.

Example 8: effect of empagliflozin on arterial stiffness

Blood pressure, arterial stiffness, Heart Rate Variability (HRV) and circulating adrenergic mediators were measured during clamp-on euglycemia and hyperglycemia in 40 normotensive type 1 diabetic patients. The study was repeated after 8 weeks empagliflozin (25mg daily).

Measuring augmentation index (AIx) of radial and carotid arteries and derivative aortic AIx and carotid, radial and femoral Pulse Wave Velocity (PWV) for useThe system (AtCor Medical inc., Itasca, IL) assesses arterial stiffness.

Empagliflozin reduces systolic blood pressure (111 ± 9 to 109 ± 9mmHg, p ═ 0.0187) and enhancement indices at radial arteries (-52 ± 16 to-57 ± 17%, p <0.0001), carotid arteries (+1.3 ± 17.0 to-5.7 ± 17.0%, p <0.0001) and aortic locations (+0.1 ± 13.4 to-6.2 ± 14.3%, p <0.0001) are reduced during normoglycemic conditions of clamping. A similar effect on arterial stiffness was observed during clamp hyperglycemia; however, the blood pressure effect was not significant. Carotid-radial pulse wave velocity decreased significantly (p ≦ 0.0001) in both blood glucose conditions, while carotid-femoral pulse wave velocity decreased significantly only during clamp hyperglycemia (5.7 ± 1.1 to 5.2 ± 0.9m/s, p ═ 0.0017). HRV, plasma norepinephrine and epinephrine were maintained under two blood glucose conditions.

This shows that empagliflozin reduces arterial stiffness in non-complex type 1 diabetic patients.

Examples of pharmaceutical compositions and dosage forms

The following examples of solid pharmaceutical compositions and dosage forms for oral administration are provided to more fully illustrate the invention and are not to be construed as limiting the scope of the examples. Further examples of compositions and dosage forms for oral administration are described in WO 2010/092126. The term "active substance" refers to empagliflozin according to the invention, in particular in its crystalline form as described in WO2006/117359 and WO 2011/039107.

Tablets containing 2.5mg, 5mg, 10mg, 25mg, 50mg of active substance

Details regarding the manufacture of such tablets, active pharmaceutical ingredients, excipients and film coating systems are described in WO2010/092126, in particular in examples 5 and 6, which are herein incorporated in their entirety.

Claims

2. A method of treating type 2 or type 1 diabetes in a patient suffering from or at risk of oxidative stress, vascular stress and/or endothelial dysfunction or a disease or condition associated therewith or related thereto,

3. A method of preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient with type 2 or type 1 diabetes or with prediabetes,

4. A method of treating a metabolic disorder and preventing, reducing the risk of or delaying the onset of a cardiovascular event in a patient, comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

5. The method according to any of the preceding claims, wherein the patient is a patient with type 2 or type 1 diabetes or with prediabetes, with one or more cardiovascular risk factors selected from a), B), C) and D):

B) advanced >/(60-70 years old), and

-late stage type 2diabetes mellitus >10 years duration,

-a blood pressure level which is higher than the blood pressure level,

-smoking is currently carried out daily,

-a blood lipid abnormality,

-an obesity of the human body,

-age >/(40) of the age,

-metabolic syndrome, hyperinsulinemia or insulin resistance, and

D) one or more of the following:

-a confirmed history of myocardial infarction,

-a multi-branch percutaneous coronary intervention,

multiple Coronary Artery Bypass Grafting (CABG),

-a history of ischemic or hemorrhagic stroke,

peripheral arterial occlusive disease.

6. A method of treatment, comprising:

b) administering empagliflozin to said patient.

7. A method for preventing, slowing, delaying or treating degeneration of pancreatic β cells and/or hypofunction of pancreatic β cells, and/or for improving and/or restoring and/or stimulating and/or protecting pancreatic β cell function, and/or restoring function of pancreatic insulin secretion in a patient having Latent Autoimmune Diabetes Adult (LADA), comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

8. A method for protecting pancreatic β cells and/or their function in a patient with Latent Autoimmune Diabetes of Adults (LADA), comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

9. A method for the treatment and/or prevention of LADA (latent autoimmune diabetes adult) in a patient, said method comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.

10. A method for reducing arterial stiffness in a patient comprising administering empagliflozin, optionally in combination with one or more other therapeutic substances, to the patient.