NZ711661B2

NZ711661B2 - Therapeutic uses of empagliflozin

Info

Publication number: NZ711661B2
Application number: NZ711661A
Authority: NZ
Inventors: Uli Broedl; Sreeraj Macha; Eynatten Maximilian Von; Hans Juergen Woerle
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2013-04-05
Filing date: 2014-04-03
Publication date: 2021-08-31

Abstract

The present invention relates to certain SGLT-2 inhibitors for treating and/or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD).

Description

THERAPEUTIC USES OF EMPAGLIFLOZIN ___________________________________________________________________ Technical Field of the ion The t invention relates to certain SGLT-2 inhibitors for treating and/or preventing metabolic disorders, such as type 2 or type 1 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CDK).

Background of the Invention Diabetes is a major public health problem, with a prevalence that is expected to reach 552 million people worldwide by 2030. Type 2 diabetes mellitus (T2DM) ts for 90% of all diabetes cases. Most medications for the ent of T2DM act through insulindependent mechanisms; the progressive loss of beta-cell function that is characteristic of T2DM means that most patients with T2DM ultimately require multiple therapies to maintain glycemic control.

Nephropathy is a well-established complication of poor glycemic control in patients with diabetes. An estimated 10–36% of patients with T2DM have some degree of renal impairment and chronic kidney disease (CKD) is present in approximately 40% of ts with es. CKD has been classified into 5 stages, where stage 1 is kidney damage with normal GFR (mL/min/1.73 m2) of ≥ 90; stage 2 is kidney damage with a mild decrease in GFR (GFR 60–89); stage 3 is a te decrease in GFR (GFR ; stage 4 is a severe decrease in GFR (GFR 15–29); and stage 5 is kidney failure (GFR <15 or dialysis).

The use of a number of anti-diabetes agents is restricted in patients with renal impairment.

Metformin is contraindicated in patients with renal dysfunction due to the risk of accumulation and lactic acidosis. Caution is advised with the use of insulin secretagogues in renally impaired patients. The DPP-4 inhibitors saxagliptin, sitagliptin and vildagliptin (but not linagliptin) are inantly excreted renally, so dose reduction is necessary in patients with advanced chronic kidney disease.

There is therefore a need for methods, medicaments and pharmaceutical compositions for the treatment of metabolic disorders, such as type 2 diabetes, in patients with renal ment or c kidney disease (CDK). (26885788_1):KZA Summary of the Invention A first aspect of the invention provides for use of use of empagliflozin in the manufacture of a ment for treating type 2 diabetes mellitus in patient or for improving glycemic control in a patient with type 2 diabetes mellitus, wherein the t has moderate B renal impairment or stage 3B chronic kidney disease (CKD), or wherein the patient’s ted glomerular filtration rate (eGFR) is ≥30 ml/min/1.73m2 and<45 ml/min/1.73m2, and wherein the medicament comprises 10 mg of empagliflozin and wherein the medicament is formulated for administration once daily.

The present invention relates to certain SGLT-2 inhibitors, in particular empagliflozin, for treating and/or preventing metabolic ers, such as type 2 diabetes mellitus, in ts with renal impairment or chronic kidney disease (CDK).

[THE NEXT PAGE IS PAGE 2] (26885788_1):KZA Accordingly, in one embodiment, the present invention provides a method for using empagliflozin in one or more of the following methods: preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, hyperinsulinemia and metabolic syndrome; or slowing the progression of, delaying or treating of pre-diabetes; or preventing, slowing the progression of, delaying or treating of an onset of type 2 es mellitus; or improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c; or ting, g, delaying or reversing progression from ed glucose tolerance, impaired g blood e, n resistance or from metabolic syndrome to type 2 diabetes mellitus; or preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group ting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic foot, dyslipidemia, arteriosclerosis, myocardial tion, accute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, eral arterial ive disease, cardiomyopathy, heart e, 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 facilitating a reduction in body weight and/or body fat; or preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal lation of ectopic fat, in particular liver fat; or for maintaining and/or ing the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance; in a patient with renal impairment or chronic kidney e (CDK), in particular a patient with mild or moderate renal impairment.

W0 2014/161919 2014/056657 _ 3 _ In one embodiment, the method comprises ng prediabetes, type 1 or type 2 diabetes mellitus. In one embodiment, the method ses improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus.

Accordingly, in one embodiment, the present invention provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus in patient comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment. In one embodiment, the patient has moderate A renal impairment. In one embodiment, the patient has moderate B renal impairment.

In one embodiment, the present invention further es a method for improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus comprising stering empagliflozin to the patient, wherein the patient has moderate renal impairment. In one embodiment, the patient has moderate A renal impairment. In one embodiment, the patient has moderate B renal impairment.

In one embodiment, the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus in patient comprising administering empagliflozin to the patient, wherein the patient has stage 3 chronic kidney disease (CKD). In one embodiment, the patient has stage 3A c kidney e (CKD). In one embodiment, the patient has stage 38 chronic kidney disease (CKD).

In one embodiment, the present invention further provides a method for improving ic control in a patient with prediabetes, type 1 or type 2 diabetes us comprising administering empagliflozin to the t, wherein the patient has stage 3 chronic kidney disease (CKD). In one embodiment, the patient has stage 3A chronic kidney disease (CKD).

In one embodiment, the patient has stage 38 chronic kidney disease (CKD).

In one embodiment, the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus or improving glycemic control in a patient with betes, type 1 or type 2 diabetes mellitus, said method comprising: a) assessing the renal on of a patient; b) ng a patient having moderate renal impairment with empagliflozin, but not ng a patient having severe renal impairment or kidney failure with empagliflozin.

W0 2014/161919 _ 4 _ In one embodiment, the method r comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.

In one embodiment, the present invention further provides a method comprising: a) identifying a patient in need of treatment for type 2 diabetes mellitus; b) assessing the renal function of said patient; c) treating a t having moderate renal impairment with empagliflozin, but not treating a patient having severe renal impairment or kidney failure with empagliflozin.

In one embodiment, the method further comprises treating a patient having mild renal impairment or normal renal function with empagliflozin.

In one ment, the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus or improving glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus, said method comprising: a) ing the renal function of said patient; b) ng a patient having moderate A renal impairment with empagliflozin, but not treating a patient having moderate B renal impairment, severe renal impairment or kidney e with empagliflozin.

In one embodiment, the method further comprises ng a patient having mild renal impairment or normal renal function with empagliflozin.

In one embodiment, the t ion further provides a method comprising: a) identifying a patient in need of ent for type 2 diabetes mellitus; b) assessing the renal function of said patient; c) ng a patient having moderate A renal impairment with empagliflozin, but not treating a patient having moderate B renal impairment, severe renal impairment or kidney failure with empagliflozin.

In one ment, the present invention further provides a method of treating type 2 diabetes comprising: a) determining the glomerular filtration rate (eGFR) of a patient in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; _ 5 _ b) stering empagliflozin to the patient, if the eGFR of the t is 230 m|/min/1.73 m2.

In one embodiment, empagliflozin is administered if the eGFR of the patient is between 230 m|/min/1.73 m2 and <60 m|/min/1.73 m2. In one embodiment, the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 30 m|/min/1.73 m2. In one embodiment, empagliflozin is administered if the eGFR of the patient is between 245 m|/min/1.73 m2 and <60 m|/min/1.73 m2. In one embodiment, the method further comprises discontinuing iflozin if the eGFR of the patient falls below 45 /1.73 In one embodiment, the present invention further provides a method comprising: a) assessing the renal function of a patient; b) administering empagliflozin to the t; c) discontinuing empagliflozin if the eGFR of the patient falls below 30 m|/min/1.73 2 In one embodiment, iflozin is administered if the eGFR of the patient is between 230 m|/min/1.73 m2 and <60 m|/min/1.73 m2.

In one embodiment, the present invention further es a method comprising: a) assessing the renal function of a patient; b) administering empagliflozin to the t; c) discontinuing empagliflozin if the eGFR of the t falls below 45 m|/min/1.73 In one embodiment, empagliflozin is administered if the eGFR of the patient is between 245 m|/min/1.73 m2 and <60 m|/min/1.73 m2.

In one embodiment, the present invention further provides a method of ng prediabetes, type 1 or type 2 diabetes mellitus comprising: a) determining that the eGFR of a patient in need of treatment for type 2 diabetes mellitus is between 230 m|/min/1.73 m2 and <60 m|/min/1.73 m2; b) administering empagliflozin to the patient.

In one embodiment, the method further comprises tinuing empagliflozin if the eGFR of the patient falls below 30 m|/min/1.73 m2.

In one embodiment, the present invention further provides a method of treating prediabetes, type 1 or type 2 diabetes mellitus comprising: W0 2014/161919 _ 6 _ a) determining that the eGFR of a patient in need of ent for type 2 diabetes me||itus is between 245 m|/min/1.73 m2 and <60 m|/min/1.73 m2; b) administering empagliflozin to the patient.

In one embodiment, the method further comprises discontinuing empagliflozin if the eGFR of the patient falls below 45 m|/min/1.73 m2.

In one embodiment, the present invention r provides a method of treating prediabetes, type 1 or type 2 diabetes me||itus in a patient having an estimated g|omeru|ar filtration rate (eGFR) between 230 m|/min/1.73 m2 and <60 m|/min/1.73 m2 comprising: a) measuring the patient’s estimated g|omeru|ar tion rate (eGFR) b) measuring the iveness of empagliflozin for ent of betes, type 1 or type 2 diabetes me||itus in said patients; and c) administering empagliflozin to the patient.

In one embodiment, the patient has a g|omeru|ar filtration rate (eGFR) between 245 m|/min/1.73 m2 and <60 m|/min/1.73 m2. The iveness of empagliflozin is for example ed by determining the % HbA1c of the free plasma glucose (FPG) in the patient.

In one embodiment, the t invention further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes me||itus; b) determining that the patient’s estimated g|omeru|ar filtration rate (eGFR) is 230 m|/min/1.73 m2; c) selecting a prediabetes, type 1 or type 2 diabetes me||itus treatment for the patient that comprises the administration of empagliflozin, based on the recognition that empagliflozin is effective for treatment of type 2 es me||itus in patients whose eGFR is 230 m|/min/1.73 m2 and not in patients whose eGFR is <30 m|/min/1.73 m2; and d) administering empagliflozin to the patient.

In one embodiment, the present invention further provides a method of treatment comprising: a) identifying a patient with prediabetes, type 1 ortype 2 diabetes mellitus in need of improvement of ic control; b) determining that the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2; c) selecting a prediabetes, type 1 or type 2 es mellitus treatment for the patient that ses the administration of iflozin, based on the recognition that empagliflozin is effective for treatment of prediabetes, type 1 or type 2 diabetes mellitus in patients whose eGFR is 230 ml/min/1.73 m2 and not in patients whose eGFR is <30 /1.73 m2; and d) administering empagliflozin to the patient.

In one embodiment, step b) comprises determining that the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2 and <90 ml/min/1.73 m2. In one embodiment, step b) comprises determining that the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2and <60 ml/min/1.73 m2.

In one embodiment, the t invention further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes us; b) measuring the patient’s ted glomerular filtration rate (eGFR); c) determining that the t’s eGFR is 230 ml/min/1.73 m2 and <60 ml/min/1.73 d) prescribing a prediabetes, type 1 or type 2 diabetes mellitus ent for the t that includes use of empagliflozin, based on the recognition that empagliflozin is effective for treatment of type 2 diabetes in patients whose eGFR is 230 /1.73 m2 and not in patients whose eGFR is <30 ml/min/1.73 m2; and e) administering empagliflozin to the patient.

In one embodiment, the present invention r provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) determining that the patient’s eGFR is 230 ml/min/1.73 m2 and <60 ml/min/1.73 m2; C) selecting empagliflozin as a treatment for the patient based on the recognition that empagliflozin is effective for treatment of type 2 diabetes mellitus in patients who have an eGFR of 230 ml/min/1.73 m2 but may lack efficacy in patients with eGFR <30 ml/min/1.73 m2; 0') administering a pharmaceutical composition comprising empagliflozin to the patient; W0 2014/161919 _ 8 _ e) determining during treatment with the pharmaceutical composition that the patient’s eGFR has dropped below 30 ml/min/1.73 m2; and f) ceasing treatment of the patient with the pharmaceutical composition, based on the recognition that empagliflozin may lack efficacy in patients with eGFR <30 ml/min/1.73 m2.

In one embodiment, the present invention further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 es mellitus; b) measuring the patient’s estimated glomerular filtration rate (eGFR); c) determining that the t’s eGFR is 230 /1.73 m2 and <60 ml/min/1.73 d) prescribing a type 2 diabetes treatment for the patient that includes use of empagliflozin, based on the recognition that empagliflozin is effective for treatment of type 2 diabetes in ts whose eGFR is 230 ml/min/1.73 m2 and not in patients whose eGFR is <30 ml/min/1.73 m2; and e) advising the patient to self-administer empagliflozin.

In one embodiment, the present invention further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) treating the patient with a first treatment regimen that does not comprise use of empagliflozin; c) ining that the first ent regimen does not e adequate glycemic control in the t; d) measuring the patient’s estimated glomerular filtration rate (eGFR); e) determining that the t’s eGFR is 230 ml/min/1.73 m2 and <60 ml/min/1.73 f) prescribing an altered treatment regimen for the patient that includes use of empagliflozin, based on the recognition that empagliflozin is effective for treatment of prediabetes, type 1 or type 2 diabetes mellitus in ts whose eGFR is 230 ml/min/1.73 m2 and not in patients whose eGFR is <30 ml/min/1.73 m2; g) advising the patient to administer empagliflozin daily as part of the altered treatment regimen; and W0 2014/161919 _ g _ h) confirming that the patient’s glycemic control is improved on the altered treatment regimen, ed to on the first treatment regimen.

In one embodiment, the present invention further provides a method of treatment comprising: a) identifying a t as being in need of ent for prediabetes, type 1 or type 2 diabetes mellitus; b) determining that the patient’s estimated g|omeru|ar filtration rate (eGFR) is 245 /1.73 m2 and <60 ml/min/1.73 m2; c) selecting a type 2 diabetes ent for the patient that includes empagliflozin, based on the recognition that empagliflozin is effective for treatment of prediabetes, type 1 or type 2 diabetes mellitus in patients whose eGFR is 245 ml/min/1.73 m2 and not in patients whose eGFR is <45 ml/min/1.73 m2; and d) administering empagliflozin to the patient.

In one embodiment, the present ion further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes us; b) measuring the t’s estimated g|omeru|ar tion rate (eGFR); c) determining that the patient’s eGFR is 245 ml/min/1.73 m2 and <60 ml/min/1.73 m2; d) prescribing a prediabetes, type 1 or type 2 diabetes mellitus treatment for the patient that includes use of empagliflozin, based on the recognition that empagliflozin is effective for treatment of type 2 diabetes mellitus in patients whose eGFR is 245 ml/min/1.73 m2 and not in patients whose eGFR is <45 ml/min/1.73 m2; and e) administering empagliflozin to the patient.

In one embodiment, the t invention further provides a method of treatment comprising: a) identifying a t as being in need of treatment for prediabetes, type 1 ortype 2 diabetes us; b) determining that the patient’s eGFR is 245 ml/min/1.73 m2 and <60 ml/min/1.73 c) selecting empagliflozin as a treatment for the patient based on the recognition that empagliflozin is effective for treatment of prediabetes, type 1 or type 2 diabetes mellitus in patients who have an eGFR of 245 ml/min/1.73 m2 but may lack efficacy in patients with eGFR <45 ml/min/1.73 m2; _ 10 _ d) administering a pharmaceutical composition comprising iflozin to the patient; e) ining during treatment with the pharmaceutical composition that the patient’s eGFR has dropped below 45 ml/min/1.73 m2; and f) ceasing ent of the patient with the pharmaceutical composition, based on the recognition that empagliflozin may lack efficacy in patients with eGFR <45 ml/min/1.73 m2.

In one embodiment, the present ion further provides a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) measuring the patient’s estimated ular filtration rate (eGFR); c) determining that the patient’s eGFR is 245 ml/min/1.73 m2 and <60 ml/min/1.73 d) prescribing a type 2 es treatment for the patient that includes use of empagliflozin, based on the recognition that empagliflozin is effective for treatment of prediabetes, type 1 or type 2 diabetes mellitus in patients whose eGFR is 245 ml/min/1.73 m2 and not in patients whose eGFR is <45 ml/min/1.73 m2; and e) advising the patient to self-administer empagliflozin.

In one embodiment, the present invention r es a method of treatment comprising: a) identifying a patient as being in need of treatment for prediabetes, type 1 or type 2 diabetes mellitus; b) treating the patient with a first treatment regimen that does not comprise use of empagliflozin; c) determining that the first treatment regimen does not provide adequate glycemic control in the patient; d) measuring the patient’s estimated glomerular filtration rate (eGFR); e) determining that the patient’s eGFR is 245 ml/min/1.73 m2 and <60 ml/min/1.73 f) prescribing an altered treatment regimen for the patient that es use of empagliflozin, based on the ition that empagliflozin is ive for treatment of prediabetes, type 1 or type 2 diabetes mellitus in patients whose eGFR is 245 ml/min/1.73 m2 and not in patients whose eGFR is <45 ml/min/1.73 m2; _ 11 _ g) advising the patient to administer empagliflozin daily as part of the altered treatment regimen; and h) confirming that the patient’s glycemic l is improved on the altered treatment regimen, ed to on the first treatment regimen.

In one embodiment, in any one of the methods above empagliflozin is administered as a pharmaceutical composition, for example a tablet. In one embodiment, the pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin. In one embodiment, empagliflozin is administered once daily.

In one embodiment, the present invention further provides a method of improvement of glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus, wherein the t’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2 comprising the administration of a pharmaceutical ition comprising empagliflozin to the patient. In one embodiment, the patient’s estimated glomerular filtration rate (eGFR) is 245 /1.73 m2. In one embodiment, the present invention further provides a method of ement of glycemic control in a type 2 diabetes mellitus patient with moderate renal impairement sing the administration of a pharmaceutical composition comprising empagliflozin to the patient. In one embodiment, the patient is with moderate A renal (CKD stage 3A) ement. In one embodiment, the t is with moderate B renal (CKD stage 38) ement. In one embodiment, the pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin. In one embodiment, empagliflozin is administered once daily.

In one embodiment, the present invention further provides empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes mellitus in a t wherein the patient’s ted glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2.

In one embodiment, the present invention further es a pharmaceutical composition comprising empagliflozin for use in the ent of prediabetes, type 1 or type 2 diabetes mellitus in a patient wherein the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2.

In one embodiment, the present invention further provides empagliflozin for use in the improvement of glycemic control in a patient with prediabetes, type 1 or type 2 diabetes mellitus wherein the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 In one embodiment, the present invention further provides a pharmaceutical composition comprising empagliflozin for use in the improvement of glycemic control in a patient with prediabetes, type 1 or type 2 es me||itus wherein the patient’s estimated ular filtration rate (eGFR) is 230 ml/min/1.73 m2.

In one embodiment, in any of the use of empagliflozin or a pharmaceutical composition above, the patient’s estimated glomerular filtration rate (eGFR) is 230 /1.73 m2and <90 ml/min/1.73 m2. In one embodiment, the patient’s estimated glomerular filtration rate (eGFR) is 230 ml/min/1.73 m2 and <60 ml/min/1.73 m2. In one embodiment, the patient’s estimated glomerular filtration rate (eGFR) is 245 ml/min/1.73 m2. In one mebodiment, the patient’s estimated glomerular filtration rate (eGFR) is 245 /1.73 m2 and <90 ml/min/1.73 m2. In one embodiment, the patient’s estimated glomerular filtration rate (eGFR) is 245 ml/min/1.73 m2and <60 ml/min/1.73 m2.

In one embodiment, the present invention further provides empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes me||itus in a patient with moderate renal impairement. In one embodiment, the t invention provides a pharmaceutical composition comprising empagliflozin for use in the treatment of prediabetes, type 1 or type 2 diabetes me||itus in a patient with moderate renal impairement. In one embodiment, the present invention provides iflozin for use in the improvement of glycemic control in a betes, type 1 or type 2 diabetes me||itus patient with moderate renal impairement. In one embodiment, the present invetion provides a pharmaceutical composition comprising iflozin for use in the ement of glycemic control in a prediabetes, type 1 or type 2 diabetes me||itus patient with te renal impairement.

In one embodiment, in any use of iflozin or a pharmaceutical composition above, the t is with moderate A renal impairement or with moderate B renal impairment. In one embodiment, the use is as an adjunct to diet and exercise. In one embodiment, the patient is an adult patient. In one embodiment, the use is once daily. In one embodiment, the use is 10 mg or 25 mg once daily.

In a r aspect of the present ion, empagliflozin is administered orally, for example in a total daily amount of 10 mg or 25 mg. In one embodiment, empagliflozin is administering _ 13 _ as a pharmaceutical composition sing 10 mg or 25 mg of empagliflozin, for example as a .

In one aspect of the present invention, in a method or use disclosed herein a patient is patient with type 2 diabetes mellitus (or type 2 es mellitus patient), a patient treated for type 2 diabetes mellitus, a patient diagnosed with type 2 diabetes mellitus or a patient in need of treatment for type 2 diabetes mellitus. In one aspect, a t is a patient with pre- diabetes.

In a further aspect of the present invention, in a method or use as described herein empagliflozin is administered to a t at a starting dose of 10 mg daily, for example to a patient as described herein. In one aspect, the dose of empagliflozin is increased to 25 mg daily, for example if the patient requires additional ic control. Accordingly, in a further aspect, the present invention provides a method or use as bed herein comprising a) administering to a patient 10 mg of empagliflozin daily, b) determining that the patient requires onal glycemic control and c) administering to the patient 25 mg of empagliflozin daily.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method sing a) administering to a patient mg of empagliflozin daily, b) determining that the patient requires additional glycemic l and c) administering to the patient 25 mg of empagliflozin daily.

In a further aspect of the present invention, in a method or use described herein empagliflozin is stered to a patient at a starting dose of 10 mg daily, for example to a t having an eGFR 230 ml/min/1.73 m2 or to a patient having an eGFR 245 ml/min/1.73 m2. In one aspect, in said method or use, the dose is increased to 25 mg daily, for example if the patient requires additional glycemic control. In one aspect, the dose of iflozin is increased to 25 mg daily in a patient having an eGFR 230 ml/min/1.73 m2, in a patient having an eGFR 245 ml/min/1.73 m2 or in a patient having an eGFR 260 ml/min/1.73 m2.

In a further , the present invention es a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 ml/min/1.73 m2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR _ 14 _ 230 ml/min/1.73 m2. In one aspect, said patient in step a) requires additional glycemic control.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 ml/min/1.73 m2, b) determining that the patient has an eGFR 230 ml/min/1.73 m2 and c) stering 25 mg of empagliflozin daily to the patient. In one aspect, step b) further comprises determining that the patient requires additional glycemic l.

In a further aspect, the present invention provides a method of ing glycemic l in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 /1.73 m2 and b) increasing the dose of empagliflozin stered to the t to 25 mg daily in a patient having an eGFR 245 ml/min/1.73 m2. In one aspect, said patient in step a) requires additional glycemic control.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 es mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 ml/min/1.73 m2, b) determining that the patient has an eGFR 245 ml/min/1.73 m2 and c) administering 25 mg of empagliflozin daily to the t. In one aspect, step b) further comprises determining that the patient requires additional glycemic l.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 ml/min/1.73 m2 and b) increasing the dose of iflozin administered to the patient to 25 mg daily in a patient having an eGFR 260 ml/min/1.73 m2. In one , said patient in step a) requires additional glycemic control.

In a further , the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 230 ml/min/1.73 m2, b) determining that the patient has an eGFR 260 ml/min/1.73 m2 and c) administering 25 mg of empagliflozin daily to the patient. In one aspect, step b) further comprises determining that the patient requires additional glycemic control.

In a further , the present invention provides a method of improving glycemic control in a patient with type 2 diabetes me||itus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 245 ml/min/1.73 m2 and b) increasing the dose of empagliflozin administered to the t to 25 mg daily in a patient having an eGFR 245 ml/min/1.73 m2. In one aspect, said patient in step a) es additional glycemic control.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes me||itus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 245 ml/min/1.73 m2, b) determining that the t has an eGFR 245 ml/min/1.73 m2 and c) administering 25 mg of iflozin daily to the patient. In one aspect, step b) further comprises determining that the patient es additional ic control.

In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes me||itus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 245 ml/min/1.73 m2 and b) increasing the dose of empagliflozin administered to the patient to 25 mg daily in a patient having an eGFR 260 /1.73 m2. In one aspect, said patient in step a) requires additional glycemic control.

In a further , the present invention es a method of improving glycemic control in a patient with type 2 diabetes me||itus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 245 ml/min/1.73 m2, b) determining that the patient has an eGFR 260 ml/min/1.73 m2 and c) administering 25 mg of empagliflozin daily to the t. In one aspect, step b) further comprises determining that the patient requires additional glycemic control.

In a further embodiment, in a method or use described herein iflozin is administered to a t at a dose of 10 mg daily to a t having an eGFR 260 ml/min/1.73 m2 and the patient continues to be administered empagliflozin at a dose of 10 mg daily if the patient’s eGFR is reduced to 230 to <60 /1.73 m2 or to 245 to <60 ml/min/1.73 m2. Accordingly, in one aspect, the present invention provides a method of improving glycemic control in a WO 61919 patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a t having an eGFR 260 m|/min/1.73 m2, b) determining that the patient has an eGFR 230 to <60 m|/min/1.73 m2 and c) continuing to administer 10 mg of empagliflozin daily to the patient. In an another aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 260 m|/min/1.73 m2, b) determining that the patient has an eGFR 245 to <60 m|/min/1.73 m2 and c) continuing to ster 10 mg of iflozin daily to the patient.

In a r embodiment, in a method or use bed herein empagliflozin is administered to a patient at a starting dose of 10 mg daily to a patient having an eGFR 260 m|/min/1.73 m2, the dose of empagliflozin is increased to 25 mg daily, for example if the patient requires additional glycemic control, and the dose of empagliflozin administered to the patient stays at a dose of 25 mg daily if the patient’s eGFR is reduced to 230 to <60 m|/min/1.73 m2 or to 245 to <60 m|/min/1.73 m2. Accordingly, in one aspect, the present invention provides a method of improving ic l in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 260 m|/min/1.73 m2, b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for e if the patient requires additional ic l, c) determining that the patient has an eGFR 230 to <60 /1.73 m2 and d) administering 25 mg of empagliflozin daily to the patient. In a further aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 260 m|/min/1.73 m2, b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic control, c) determining that the patient has an eGFR 245 to <60 m|/min/1.73 m2 and d) administering 25 mg empagliflozin daily to the patient.

In a further embodiment, in a method or use described herein empagliflozin is administered to a patient at a starting dose of 10 mg daily to a patient having an eGFR 260 m|/min/1.73 m2, the dose of iflozin is increased to 25 mg daily, for e if the patient requires onal glycemic control, and the dose of empagliflozin administered to the patient is reduced to a dose of 10 mg daily if the patient’s eGFR is d to 230 to <60 m|/min/1.73 m2 or to 245 to <60 m|/min/1.73 m2. Accordingly, in one aspect, the present invention provides a method of improving glycemic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient W0 2014/161919 _ 17 _ having an eGFR 260 ml/min/1.73 m2, b) increasing the dose of empagliflozin administered to the patient to 25 mg daily, for e if the patient requires additional glycemic control, C) determining that the patient has an eGFR 230 to <60 ml/min/1.73 m2 and d) administering 10 mg of empagliflozin daily to the patient. In a further aspect, the present invention provides a method of improving ic control in a patient with type 2 diabetes mellitus, said method comprising a) administering 10 mg of empagliflozin daily to a patient having an eGFR 260 ml/min/1.73 m2, b) increasing the dose of iflozin administered to the patient to 25 mg daily, for example if the patient requires additional glycemic l, c) ining that the patient has an eGFR 245 to <60 /1.73 m2 and d) administering 10 mg of empagliflozin daily to the patient.

In one aspect, in any one of the methods of uses described above, iflozin is administered once daily to a patient, i.e. for example 10 mg or 25 mg of empagliflozin is administered once daily to a patient.

In one aspect of the present invention, empagliflozin is administered with one or more other antidiabetic substances. In one embodiment, the other antidiabetic substances are selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPARalpha- glucosidase inhibitors, insulin and insulin analogues, GLP-1 and GLP-1 ues and DPP- 4 inhibitors. In one aspect, the present invention comprises administering empagliflozin in combination with metformin and/or a DPP-4 inhibitor, for example linagliptin.

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

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

The present invention further provides for empagliflozin or a pharmaceutical composition sing empagliflozin for use in the cture of a medicament for use in any one of the methods described herein. _ 18 _ Definitions The term e ingredient" of a pharmaceutical composition according to the present invention means the SGLT2 inhibitor according to the present invention. An e ingredient is also sometimes referred to herein as an "active substance".

The term "body mass index" or "BMI" of a human t is defined as the weight in kilograms divided by the square of the height in , such that BMI has units of kg/m2.

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

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

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

The term "visceral obesity" is defined as the ion wherein a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for n resistance and the development of pre-diabetes.

The term "abdominal obesity" is usually defined as the condition wherein the waist circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women. With regard to a Japanese ethnicity or Japanese patients abdominal obesity may be defined as waist circumference 2 85 cm in men and 2 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic syndrome in Japan).

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

The term "hyperglycemia" is defined as the condition in which a subject has a fasting blood glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L). The word "fasting" has the usual meaning as a medical term.

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

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

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

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

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

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

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

Furthermore, n resistance, the se of a patient with n resistance to y, n sensitivity and hyperinsulinemia may be quantified by assessing the "homeostasis model assessment to n resistance (HOMA-IR)" score, a reliable indicator of insulin resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to s for the determination of the HOMA—index for insulin sensitivity ews et al., Diabetologia 1985, 28: 412-19), of the ratio of intact proinsulin to insulin (Forsteta/., Diabetes 2003, 52(Suppl. 1): A459) and to an euglycemic clamp study. In addition, plasma adiponectin levels can be red as a potential surrogate of insulin sensitivity. The estimate of insulin resistance by the homeostasis assessment model (HOMA)—|R score is ated with the formula (Galvin P, etal. Diabet Med 1992;9:921-8): HOMA-IR = [fasting serum insulin (uU/mL)] x [fasting plasma glucose(mmol/L)/22.5] Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score.

For the purpose of this invention, insulin resistance is defined as the al condition in which an individual has a HOMA-IR score > 4.0 or a R score above the upper limit of normal as defined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice to assess insulin resistance. Preferably, the patient's triglyceride concentration is used, for example, as increased triglyceride levels correlate significantly with the presence of insulin resistance. 2014/056657 Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1St degree relative with a diagnosis of IGT or IFG or type 2 diabetes.

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

"Pre-diabetes" is a general term that refers to an intermediate stage n normal glucose tolerance (NGT) and overt type 2 diabetes us (T2DM), also referred to as intermediate hyperglycaemia. As such, it represents 3 groups of individuals, those with impaired glucose tolerance (IGT) alone, those with impaired fasting glucose (IFG) alone or those with both IGT and IFG. IGT and IFG usually have distinct pathophysiologic etiologies, however also a mixed condition with features of both can exist in patients. Therefore in the context of the t invention a patient being diagnosed of having "pre-diabetes" is an individual with diagnosed IGT or sed IFG or diagnosed with both IGT and IFG.

Following the definition according to the American Diabetes Association (ADA) and in the context of the present ion a patient being sed of having "pre-diabetes" is an individual with: a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1 mg/dL = 0.05555 mmo|/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose nce test (OGTT), g between 2140 mg/dL and <200 mg/dL (i.e., IGT); or b) a fasting plasma glucose (FPG) concentration between 2100 mg/dL and <126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); or c) a fasting plasma glucose (FPG) concentration between 2100 mg/dL and <126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), g between 2140 mg/dL and <200 mg/dL (i.e., both IGT and IFG).

Patients with "pre-diabetes" are individuals being sposed to the development of type 2 diabetes. Pre-diabetes extends the definition of IGT to include individuals with a fasting blood glucose within the high normal range 2 100 mg/dL (J. B. Meigs, et al. Diabetes 2003; 2014/056657 _ 22 _ 52:1475-1484). The scientific and medical basis for identifying pre-diabetes as a serious health threat is laid out in a Position ent entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the an Diabetes Association and the National Institute of Diabetes and Digestive and Kidney es (Diabetes Care 2002; 25:742-749).

The methods to investigate the function of pancreatic beta-cells are similar to the above s with regard to insulin sensitivity, hyperinsulinemia or n resistance: An improvement of beta-cell function can be measured for example by determining a HOMA— index for beta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forstetal., es 2003, 52(Suppl. 1): A459), the insulin/C- peptide secretion after an oral glucose tolerance test or a meal tolerance test, or by employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled intravenous glucose tolerance test (Stumvo/I et al., EurJ Clin Invest 2001, 31: 380-81).

The term "type 1 diabetes" is defined as the condition in which a subject has, in the presence of autoimmunity s the atic beta-cell or insulin, a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 ). If a e tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an empty stomach, in the presence of autoimmunity towards the pancreatic beta cell or n. In a glucose tolerance test 75 g of glucose are administered orally to the patient being tested after 10-12 hours of g and the blood sugar level is ed immediately before taking the glucose and 1 and 2 hours after taking it. The presence of autoimmunity towards the pancreatic beta-cell may be observed by detection of circulating islet cell autoantibodies ["type 1A diabetes mellitus"], i.e., at least one of: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm], lA—2 [intracytoplasmatic domain of the tyrosine phosphatase-like protein lA—2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs of autoimmunity t the presence of typical circulating autoantibodies [type 18 diabetes], i.e. as detected through pancreatic biopsy or imaging). Typically a genetic predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this is not always the case.

The term "type 2 diabetes mellitus" or "T2DM" is defined as the condition in which a subject has a fasting blood glucose or serum e concentration greater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucose values is a standard procedure in routine medical analysis. If a glucose tolerance test is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of _ 23 _ glucose have been taken on an empty stomach. In a glucose tolerance test 75 g of glucose are stered orally to the patient being tested after 10-12 hours of fasting and the blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after taking it. In a healthy subject, the blood sugar level before taking the glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose and less than 140 mg per dL after 2 hours. If after 2 hours the value is between 140 and 200 mg, this is regarded as abnormal glucose tolerance.

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

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

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

The "metabolic syndrome", also called "syndrome X" (when used in the context of a metabolic disorder), also called the tabolic me" is a syndrome complex with the cardinal feature being insulin resistance (Laaksonen DE, et al. Am J Epidemiol 2002;156:1070-7). According to the ATP lll/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education m (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel lll) JAMA: Journal of the American Medical Association (2001) 285:2486-2497), WO 61919 _ 24 _ diagnosis of the metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as waist circumference > 40 inches or 102 cm in men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or Japanese patients d as waist circumference 2 85 cm in men and 2 90 cm in women; 2. Triglycerides: 2 150 mg/dL 3 HDL-cholesterol < 40 mg/dL in men 4. Blood pressure 2130/85 mm Hg (SBP 2130 or DBP 2 85) 5 Fasting blood glucose 2 100 mg/dL The NCEP definitions have been validated (Laaksonen DE, et al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in the blood can also be ined by standard methods in medical is and are described for example in Thomas L r): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

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

The term "glomerular filtration rate (GFR)" is d as the volume of fluid filtered from the renal (kidney) ular capillaries into the Bowman's capsule per unit time. It is indicative of overall kidney function. The glomerular filtration rate (GFR) can be calculated by measuring any chemical that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood. The GFR is typically recorded in units of volume per time, e.g., milliliters per minute and the formula below can be used: GFR = (Urine Concentration X Urine Volume)/ Plasma Concentration The GFR can be determined by injecting inulin into the . Since inulin is neither reabsorbed nor secreted by the kidney after glomerular filtration, its rate of excretion is directly proportional to the rate of filtration of water and solutes across the glomerular filter. A normal value is: GFR = 90-125 mL/min/1.73 m2, in particular GFR = 100-125 mL/min/1.73 Other principles to determine GFR involve measuring 51Cr-EDTA, [125I]iothalamate or iohexol.

The "estimated glomerular filtration rate (eGFR)" is defined as derived at screening from serum creatinine values based on e.g., the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in Renal Disease (MDRD) formula, which are all known in the art.

The term "empagliflozin" refers to the SGLT2 inhibitor 1-chloro(β-D-glucopyranos yl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene of the formula Cl O HO OH as described for example in . s of synthesis are described in the ture, for example WO 06/120208 and . According to this invention, it is to be understood that the definition of empagliflozin also comprises its hydrates, solvates and rphic forms thereof. An advantageous crystalline form of empagliflozin is bed in and WO 39107 which hereby are incorporated herein in their entirety. This crystalline form possesses good lity properties which enables a good bioavailability of the SGLT2 inhibitor. Furthermore, the lline form is physico-chemically stable and thus provides a good shelf-life stability of the pharmaceutical composition. Preferred pharmaceutical itions, such as solid formulations for oral administration, for example tablets, are described in WO 2010/092126, which hereby is incorporated herein in its entirety.

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

The terms "prophylactically treating , preventivally treating" and "preventing" are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned before, thus reducing said risk.

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

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

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

Brief Description of the Drawings Figure 1A—C: Change from baseline in HbA1C fasting plasma glucose (FPG), weight and blood re (BP) at week 24 in patients with renal impairment d with empagliflozin versus o.

Figure 2: Pharmacokinetic and pharmacodynamic parameters for empagliflozin after administration of a single oral 50 mg dose in patients with renal impairment.

Figure 3: Relative bioavailability of empagliflozin (50 mg qd) in subjects with impaired renal function compared with subjects with normal renal function (n=40).

Figure 4: Exposure to a single oral 50 mg dose of empagliflozin in subjects with normal and impaired renal function. (A) and (B) Mean plasma concentration-time es (insert: semi- log plot) (n=40). (C) AUC0_wand (D) Cmax; midline of boxes are medians, and boundaries are 25th and 75th percentiles; whiskers are the standard span for the quartiles (1.5 x interquartile range).

Figure 5: (A) CLR from 0—96 h; (B) AUC0_w, and (C) cumulative amount of glucose excreted in urine in 24 h versus estimated glomerularfiltration rate after administration of a single oral 50 mg dose in subjects with normal and impaired renal function .

Figure 6: Mean cumulative amounts of glucose excreted in urine after stration of a single oral 50 mg dose in subjects with normal and impaired renal function (n=31).

W0 2014/161919 _ 27 _ Figure 7A—D: Change from baseline in HbA1C fasting plasma glucose (FPG), weight and blood pressure (BP) at week 52 in patients with Type 2 Diabetes Mellitus (T2DM) and Stage 3A, 3B and 4 Chronic Kidney Disease (CKD) treated with empagliflozin versus placebo.

Detailed Description of the Invention The present invention relates to certain SGLT-2 inhibitors, in particular empagliflozin, for treating and/or preventing a metabolic disorder, in ular type 1 or type 2 diabetes or pre- diabetes and/or diseases related thereto (e.g. diabetic complications), in patients with renal impairment or chronic kidney disease (CKD). In one , the present invention s to certain SGLT-2 inhibitors, in particular empagliflozin, for improving glycemic control in patient with type 1 or type 2 diabetes or pre-diabetes and with renal ment or chronic kidney disease (CKD).

The treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy, and although conventional monotherapy may lly control blood glucose in some patients, it is however associated with a high secondary failure rate. The limitations of single-agent therapy for maintaining glycemic control may be me, at least in some patients, and for a limited period of time by combining multiple drugs to achieve reductions in blood glucose that cannot be sustained during long-term y with single agents. Available data support the conclusion that in most patients with type 2 diabetes t monotherapy will fail and ent with multiple drugs will be required.

But, because type 2 diabetes is a progressive disease, even patients with good initial responses to conventional combination therapy will eventually require an increase of the dosage or further treatment with insulin because the blood glucose level is very difficult to maintain stable for a long period of time. Although existing combination therapy has the potential to enhance ic control, it is not t limitations (especially with regard to long term efficacy). Further, traditional therapies may show an increased risk for side effects, such as hypoglycemia or weight gain, which may mise their efficacy and ability.

Thus, for many patients, these existing drug therapies result in progressive deterioriation in metabolic control despite treatment and do not iently control metabolic status especially over long-term and thus fail to achieve and to maintain glycemic control in advanced or late stage type 2 diabetes, including diabetes with inadequate glycemic control despite conventional oral or non-oral antidiabetic medication. 2014/056657 Therefore, although intensive treatment of hyperglycemia can reduce the nce of chronic damages, many patients with type 2 diabetes remain inadequately treated, partly because of tions in long term efficacy, tolerability and dosing inconvenience of conventional antihyperglycemic therapies.

This high incidence of therapeutic failure is a major contributor to the high rate of long-term hyperglycemia-associated complications or chronic damages (including micro- and makrovascular complications such as e.g. diabetic phathy, retinopathy or neuropathy, or cardiovascular complications such as e.g. myocardial infarction, stroke or vascular mortality or ity) in patients with type 2 es.

Oral antidiabetic drugs conventionally used in therapy (such as e.g. first- or second-line, and/or mono- or (initial or ) combination therapy) include, without being restricted thereto, metformin, sulphonylureas, thiazolidinediones, glinides and d-glucosidase inhibitors. al (typically injected) antidiabetic drugs conventionally used in therapy (such as e.g. first— or -line, and/or mono- or (initial or add-on) combination y) include, without being restricted thereto, GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemic agents can be associated with various adverse effects. For example, metformin can be associated with lactic acidosis or gastrointestinal side s; sulfonylureas, glinides and insulin or insulin ues can be associated with ycemia and weight gain; thiazolidinediones can be associated with edema, bone fracture, weight gain and heart e/cardiac effects; and alpha-glucosidase blockers and GLP-1 or GLP-1 analogues can be associated with gastrointestinal adverse effects (e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting) and, most sly (but rare), pancreatitis.

Type 1 diabetes mellitus (Type 1 diabetes), also called insulin dependent diabetes mellitus or juvenile diabetes, is a form of es mellitus that results from mune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood glucose concentrations and increased urinary glucose excretion. The classical symptoms are polyuria, polydipsia, polyphagia, and weight loss. Type 1 diabetes may be fatal unless treated with insulin. Complications from type I diabetes are the same or similar to complications from type 2 diabetes. Standard therapy of type 1 diabetes is insulin treatment. Therapies for type 1 diabetes are for example described in .

SGLT2 inhibitors (sodium-glucose co-transporter 2) represent a novel class of agents that are being ped for the treatment or improvement in glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivative are described as SGLT2 inhibitors, for e in WO 01/27128, WO 03/099836, , WO 2006/034489, WO 64033, , WO 17360, , , , , , WO 2008/049923, , . The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the ent of diabetes.

Renal filtration and ke of e contributes, among other mechanisms, to the steady state plasma glucose concentration and can therefore serve as an antidiabetic target. ke of filtered glucose across epithelial cells of the kidney proceeds via sodium- dependent glucose cotransporters (SGLTs) located in the brush-border membranes in the tubuli along the sodium gradient. There are at least 3 SGLT isoforms that differ in their expression n as well as in their physico-chemical properties. SGLT2 is exclusively sed in the kidney, whereas SGLT1 is expressed additionally in other tissues like intestine, colon, skeletal and cardiac muscle. SGLT3 has been found to be a glucose sensor in interstitial cells of the intestine without any transport function. Potentially, other related, but not yet characterized genes, may contribute further to renal e reuptake. Under lycemia, glucose is completely reabsorbed by SGLTs in the kidney, whereas the reuptake capacity of the kidney is ted at glucose concentrations higher than 10mM, resulting in glucosuria ("diabetes mellitus"). This threshold concentration can be decreased by SGLT2-inhibition. It has been shown in experiments with the SGLT inhibitor phlorizin that SGLT-inhibition will partially inhibit the reuptake of glucose from the glomerular filtrate into the blood leading to a decrease in blood glucose concentration and to glucosuria.

Empagliflozin is a novel SGLT2 inhibitor that is described for the ent or improvement in glycemic control in patients with type 2 diabetes mellitus, for e in WC 05/092877, WO 06/117359, WO 06/120208, , , , WO 2011/039108.

Accordingly, in a particular embodiment, a SGLT-2 inhibitor within the meaning of this invention is empagliflozin. _ 30 _ The present invention relates to a therapeutic ment or prevention) method as described herein, said method comprising administering an effective amount of a SGLT-2 inhibitor as described herein and, optionally, one or more other active or therapeutic agents as described herein to a patient with renal impairment.

Patients with renal disease, renal dysfunction or renal impairment may include patients with chronic renal insufficiency or impairment, which can be stratified (if not otherwise noted) ing to glomerular filtration rate (GFR, m|/min/1.73m2) into 5 disease stages: stage 1 characterized by normal GFR 2 90 plus either tent albuminuria (e.g. UACR 230 mg/g) or known structural or hereditary renal disease; stage 2 characterized by mild reduction of GFR (GFR 60-89) describing mild renal impairment; stage 3 characterized by moderate reduction of GFR (GFR 30-59) bing moderate renal impairment; stage 4 characterized by severe reduction of GFR (GFR 15-29) describing severe renal impairment; and terminal stage 5 characterized by requiring dialysis or GFR < 15 describing ished kidney failure (end-stage renal disease, ESRD).

Accordingly, chronic kidney disease and its stages (CKD 1-5) can be usually characterized or classified accordingly, such as based on the presence of either kidney damage (albuminuria) or ed estimated glomerular filtration rate (GFR <60 n/1.73m2], with or without kidney damage).

For the e of the present invention, the degree of renal impairment in a patient is defined by the ing estimated glomerular filtration rate (eGFR): Normal renal function: eGFR 2 90 m|/min/1.73 m2 Mild renal impairment: eGFR 260 to <90 m|/min/1.73 m2 Moderate renal impairment: eGFR 230 to <60 m|/min/1.73 m2 Severe renal impairment: eGFR 215 to <30 m|/min/1.73 m2 Kidney e: eGFR <15 m|/min/1.73 m2 Accordingly, in the context of the present invention, a patient with normal renal function has an eGFR 2 90 m|/min/1.73 m2, a patient with mild renal impairment has an eGFR 260 to <90 /1.73 m2, a patient with moderate renal impairment has an eGFR 230 to <60 m|/min/1.73 m2, a patient with severe renal impairment has an eGFR 215 to <30 m|/min/1.73 m2, a patient with kidney failure has an eGFR <15 m|/min/1.73 m2. _ 31 _ According to the present ion moderate renal impairment can be further divided into two sub-stages: te A renal impairment (CKD 3A): eGFR 245 to <60 m|/min/1.73 m2 Moderate B renal impairment (CKD 3B): eGFR 230 to <45 m|/min/1.73 m2 Accordingly, in the context of the present invention, a patient with moderate A renal impairment has an eGFR 245 to <60 /1.73 m2 and a patient with moderate B renal impairment has an eGFR 230 to <45 m|/min/1.73 m2.

For the purpose of the t invention, the ted glomerular filtration rate (eGFR) is derived from the serum creatinine (SCr) value based on the MDRD formula below: eGFR (mL/min/1.73m2) = 175 X [SCr (umol/L)/88.4]—1.154 X [age]—0.203 X [0.742 if patient is female] X [1.212 if patient is of African origin] For additional analyses, renal function can also be classified by the estimated creatinine clearance rate (eCCr) value, based on the oft-Gault formula below: eCCr (mL/min) = (140 — age) X (weight in kg) X [0.85 if patient is female]/ (72 X SCr (mg/dL)) Renal function classification based on eCCr is similar to the eGFR classification: normal renal function (290 mL/min), mild impairment (60 to <90 mL/min), moderate impairment (30 to <60 mL/min), and severe impairment (215 to <30 mL/min).

Generally, mild renal impairment according to the present invention corresponds to stage 2 chronic kidney disease, moderate renal impairment according to the present invention generally corresponds to stage 3 chronic kidney disease, and severe renal ment according to the present invention generally corresponds to stage 4 chronic kidney disease.

Likewise, moderate A renal impairment according to the present ion generally corresponds to stage 3A chronic kidney e and moderate B renal impairment ing to the present invention generally corresponds to stage 3B chronic kidney disease.

Therefore, the methods and uses of SGLT-2 inbitors, particularly empagliflozin, in the context of the present ion and applied to ts having renal impairment as defined herein also apply to patients having the corresponding stage of c kidney disease.

In some aspects, renal disease, renal dysfunction, or insufficiency or impairment of renal function (including mild, moderate and/or severe renal impairment) may also be suggested (if _ 32 _ not otherwise noted) by elevated serum creatinine levels (e.g. serum creatinine levels above the upper limit of normal for their age, e.g. 2 130 - 150 , or 2 1.5 mg/dl (2 136 umol/l) in men and 2 1.4 mg/dl (2 124 umol/l) in women) or abnormal creatinine clearance (e.g. glomerular filtration rate (GFR) S 30 - 60 ml/min).

In some further aspects, mild renal ment may be also suggested (if not othenNise noted) by a creatinine clearance of 50-80 ml/min (approximately corresponding to serum creatine levels of 51.7 mg/dL in men and 51.5 mg/dL in women); moderate renal impairment may be e.g. suggested (if not otherwise noted) by a creatinine nce of 30-50 ml/min (approximately corresponding to serum creatinine levels of >1.7 to 53.0 mg/dL in men and >15 to 52.5 mg/dL in women); and severe renal impairment may be e.g. suggested (if not otherwise noted) by a nine clearance of < 30 ml/min ximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >25 mg/dL in women). Patients with end- stage renal e require dialysis (e.g. hemodialysis or peritoneal dialysis).

Albuminuria stages may be for example classified as disclosed herein and/or by urine albumin nine ratio (such as usually UACR 230 mg/g, in some instances 220 ug/min albumin excretion rate), such as e.g. microalbuminuria may be for example classified by UACR 30-300 mg/g (in some instances 20-200 ug/min) or, in another ment, by UACR 30-200 mg/g, and/or macroalbuminuria may be for example classified by UACR >300 mg/g (in some instances >200 ), or, in another embodiment, by UACR >200 mg/g. Very high UACR 22000 mg/g may be classified as nephrotic.

Accordingly, in one embodiment, the t invention es a method of treating type 2 diabetes in patient comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment (or CKD stage 3). In one embodiment, the patient has moderate A renal impairment (or CKD stage 3A). In one embodiment, the t has moderate B renal impairment (or CKD stage 3B).

In a further embodiment, the present invention provides a method for improving glycemic control in a patient with type 2 diabetes comprising administering empagliflozin to the patient, wherein the patient has moderate renal impairment (or CKD stage 3). In one embodiment, the patient has moderate A renal impairment (or CKD stage 3A). In one embodiment, the patient has moderate B renal impairment (or CKD stage 38). _ 33 _ In one aspect, in a method of the present invention, the renal function of a patient is monitored during the treatment with empagliflozin, for example by measuring the eGFR of the patient. For e, the renal function of a patient is monitored during the treatment with empagliflozin if the eGFR of the patient is below 60 ml/min/1.73 m2 or below 45 ml/min/1.73 m2. In one aspect, in such a method, the treatment with empagliflozin is discontinued if the eGFR of the t falls below a n value, for example below 30 ml/min/1.73 m2 or below 45 ml/min/1.73 m2.

In one embodiment, diabetes patients within the g of this invention may include patients who have not previously been treated with an antidiabetic drug (drug-nai've patients). Thus, in an embodiment, the therapies described herein may be used in naive patients. In another embodiment, diabetes patients within the meaning of this invention may include patients with advanced or late stage type 2 diabetes mellitus (including ts with failure to conventional antidiabetic therapy), such as e.g. patients with inadequate glycemic control on one, two or more tional oral and/or non-oral antidiabetic drugs as defined herein, such as e.g. patients with insufficient glycemic control despite (mono-)therapy with metformin, a lidinedione (particularly pioglitazone), a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue, insulin or insulin analogue, or an d-glucosidase inhibitor, or despite dual combination therapy with metformin/sulphonylurea, metformin/thiazolidinedione (particularly pioglitazone), sulphonylurea/ osidase inhibitor, pioglitazone/sulphonylurea, metformin/insulin, pioglitazone/insulin or sulphonylurea/insulin. Thus, in an embodiment, the therapies described herein may be used in patients experienced with therapy, e.g. with conventional oral and/or non-oral antidiabetic mono- or dual or triple combination medication as mentioned herein.

A further embodiment of the diabetes patients which may be amenable to the therapies of this invention may include, without being limited, those diabetes patients ially type 2 diabetes) with ed age and/or with advanced diabetes disease, such as e.g. patients on insulin treatment, patients on triple antidiabetic oral therapy, patients with pre-existing cardiovascular events and/or patients with advanced disease duration (e.g. >/= 5 to 10 years).

The t invention further relates to a pharmaceutical composition comprising a certain SGLT-2 tor as defined herein, iflozin, for use in the therapies bed herein. _ 34 _ When this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and prevention in humans. In the scope of this invention adult ts are preferably humans of the age of 18 years or older. Also in the scope of this invention, patients are adolescent humans, i.e. humans of age 10 to 17 years, preferably of age 13 to 17 years. It is assumed that in a adolescent population the administration of the pharmaceutical composition according to the invention a very good HbA1c lowering and a very good lowering of the fasting plasma glucose can be seen. In addition it is assumed that in an adolescent population, in particular in ovenNeight and/or obese patients, a pronounced weight loss can be observed.

As described hereinbefore by the administration of the pharmaceutical composition according to this invention and in ular in view of the high SGLT2 inhibitory activity of the SGLT2 inhibitors therein, excessive blood glucose is excreted through the urine of the patient, so that no gain in weight or even a reduction in body weight may result. Therefore, a treatment or prophylaxis according to this invention is advantageously suitable in those ts in need of such treatment or prophylaxis who are sed of one or more of the conditions selected from the group consisting of ovenNeight and obesity, in ular class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity. In addition a treatment or prophylaxis according to this invention is advantageously suitable in those patients in which a weight increase is contraindicated. The pharmaceutical composition as well as the methods according to the present ion allow a ion of the HbA1c value to a desired target range, for example < 7 % and ably < 6.5 %, for a higher number of patients and for a longer time of therapeutic treatment compared with a corresponding monotherapy or a therapy using only two of the combination partners.

The pharmaceutical composition according to this invention and in particular the SGLT2 inhibitor therein exhibits a very good cy with regard to glycemic control, in particular in view of a reduction of fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin ). By administering a pharmaceutical composition according to this invention, a reduction of HbA1c equal to or greater than preferably 0.5 %, even more preferably equal to or greater than 1.0 % can be achieved and the reduction is ularly in the range from 1.0 % to 2.0 %.

Furthermore, the method and/or use according to this invention is advantageously able in those ts who show one, two or more of the ing conditions: W0 2014/161919 2014/056657 _ 35 _ (a) a fasting blood glucose or serum e concentration r than 100 mg/dL, in ular greater than 125 mg/dL; (b) a andial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or greater than 6.5 %, in ular equal to or greater than 7.0 %, especially equal to or greater than 7.5 %, even more particularly equal to or greater than 8.0 %.

The present invention also discloses the use of the ceutical composition for improving glycemic control in patients having type 1 or type 2 diabetes or showing first signs of pre-diabetes. Thus, the invention also includes diabetes prevention. lf therefore a pharmaceutical composition according to this invention is used to improve the glycemic control as soon as one of the above-mentioned signs of pre-diabetes is present, the onset of manifest type 2 diabetes mellitus can be delayed or prevented.

Furthermore, the pharmaceutical composition according to this invention is particularly suitable in the treatment of patients with insulin dependency, i.e. in ts who are treated or othenNise would be treated or need treatment with an insulin or a derivative of n or a substitute of insulin or a formulation comprising an insulin or a derivative or substitute thereof. These patients include patients with diabetes type 2 and patients with es type 1.

Therefore, according to a preferred embodiment of the present invention, there is provided a method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c in a patient in need thereof who is diagnosed with impaired e tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome and/or with type 2 or type 1 es mellitus characterized in that an SGLT2 inhibitor as d hereinbefore and hereinafter is administered to the patient.

According to another preferred embodiment of the present invention, there is provided a method for improving gycemic control in patients, in particular in adult patients, with type 2 diabetes mellitus as an adjunct to diet and exercise.

It can be found that by using a pharmaceutical ition according to this invention, an ement of the glycemic control can be achieved even in those patients who have insufficient glycemic control in particular despite treatment with an antidiabetic drug, for _ 36 _ example despite maximal recommended or tolerated dose of oral monotherapy with metformin. A maximal recommended dose with regard to metformin is for example 2000 mg per day or 850 mg three times a day or any equivalent thereof.

Therefore, the method and/or use according to this invention is advantageously applicable in those patients who show one, two or more of the following conditions: (a) insufficient glycemic control with diet and exercise alone; (b) insufficient glycemic control despite oral monotherapy with metformin, in ular despite oral erapy at a maximal tolerated dose of metformin; (c) insufficient glycemic control despite oral monotherapy with another antidiabetic agent, in particular despite oral monotherapy at a maximal tolerated dose of the other abetic agent.

The lowering of the blood glucose level by the stration of an SGLT2 inhibitor ing to this invention is insulin-independent. Therefore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions - insulin resistance, - hyperinsulinemia, - pre-diabetes, - type 2 es mellitus, particular having a late stage type 2 diabetes us, - type 1 diabetes us.

Furthermore, a pharmaceutical composition according to this invention is ularly suitable in the treatment of ts who are diagnosed having one or more of the following conditions (a) obesity (including class I, ll and/or lll obesity), al obesity and/or abdominal obesity, (b) triglyceride blood level 2 150 mg/dL, (c) HDL-cholesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in male patients, (d) a systolic blood pressure 2 130 mm Hg and a diastolic blood pressure 2 85 mm Hg, (e) a fasting blood glucose level 2 100 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), with insulin resistance and/or with metabolic syndrome suffer from an increased risk of developing a cardiovascular disease, such as for example myocardial infarction, coronary heart disease, heart insufficiency, thromboembolic events.

Furthermore, a ceutical composition according to this invention is ularly suitable in the treatment of patients after organ transplantation, in ular those patients who are diagnosed having one or more of the following conditions (a) a higher age, in particular above 50 years, (b) male gender; (c) ovenNeight, obesity ding class I, II and/or ||| y), visceral obesity and/or abdominal obesity, (d) pre-transplant diabetes, (e) suppression therapy.

Furthermore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the ing conditions: (a) hyponatremia, in ular chronical hyponatremia; (b) water intoxication; (c) water retention; (d) plasma sodium concentration below 135 mmol/L.

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

Furthermore, a pharmaceutical composition according to this invention is particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions: (a) high serum uric acid levels, in particular greater than 6.0 mg/dL (357 umol/L); (b) a history of gouty arthritis, in particular recurrent gouty arthritis; (c) kidney stones, in particular recurrent kidney stones; (d) a high propensity for kidney stone formation.

In certain embodiments, the patients which may be le to to the therapies of this ion may have or are at-risk of one or more of the following es, disorders or conditions: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, ipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA—emia, postprandial |ipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic ic inflammation, non alcoholic fatty liver disease (NAFLD), polycystic ovarian WO 61919 _ 38 _ syndrome, metabolic syndrome, nephropathy, micro- or lbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or ive disorders, cardiovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis, ension, endothelial dysfunction, myocardial infarction, acute ry syndrome, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy ding e.g. uremic cardiomyopathy), heart failure, cardiac hypertrophy, heart rhythm disorders, vascular restenosis, stroke, (renal, cardiac, cerebral or hepatic) ischemia/reperfusion injuries, (renal, c, cerebral or hepatic) is, , cardiac, cerebral or hepatic) vascular remodeling; a diabetic disease, especially type 2 diabetes, mellitus may be preferred (eg. as underlying disease).

In a further ment, the patients which may be amenable to to the therapies of this invention have a diabetic disease, especially type 2 diabetes mellitus, and may have or are at-risk of one or more other diseases, disorders or conditions, such as eg. selected from those ned immediately above.

Within the scope of the present invention it has now been found that certain SGLT-2 inhibitors as defined herein, optionally in combination with one or more other therapeutic substances (e.g. selected from those described herein), as well as pharmaceutical ations, compositions or combined uses according to this invention of such SGLT-2 inhibitors as defined herein have properties, which make them suitable for the purpose of this invention and/or for fulfilling one or more of above needs.

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

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

A pharmaceutical composition according to this invention is particularly suitable in the long term treatment or prophylaxis of the diseases and/or conditions as described before and hereinafter, in particular in the long term glycemic control in patients with type 2 diabetes mellitus.

The term "long term" as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more ably longer than 1 year.

Therefore, a particularly preferred ment of the present invention provides a method for therapy, preferably oral therapy, for improvement, especially long term improvement, of glycemic control in patients with type 2 diabetes mellitus, especially in patients with late stage type 2 diabetes mellitus, in particular in patients additionally diagnosed of overweight, y (including class I, class II and/or class III obesity), visceral y and/or abdominal obesity.

It will be iated that the amount of the pharmaceutical composition according to this invention to be administered to the patient and required for use in treatment or prophylaxis according to the present invention will vary with the route of administration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant tion and will be ultimately at the discretion of the attendant physician. In general, however, the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that by its administration the glycemic control in the patient to be d is improved.

For the treatment of hyperuricemia or hyperuricemia ated conditions the SGLT2 inhibitor according to this invention is included in the pharmaceutical composition or dosage form in an amount sufficient that is ient to treat hyperuricemia without disturbing the t's plasma glucose homeostasis, in particular without inducing ycemia.

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

For the treatment of tremia and associated conditions the SGLT2 inhibitor according to this ion is included in the pharmaceutical composition or dosage form in an amount sufficient that is sufficient to treat hyponatremia or the ated conditions without disturbing the patient's plasma glucose homeostasis, in particular t inducing hypoglycemia.

In the following preferred ranges of the amount of the SGLT2 inhibitor to be employed in the pharmaceutical composition and the methods and uses according to this invention are bed. These ranges refer to the amounts to be stered per day with respect to an adult t, in particular to a human being, for example of approximately 70 kg body weight, and can be adapted accordingly with regard to an stration 2, 3, 4 or more times daily and with regard to other routes of administration and with regard to the age of the patient.

Within the scope of the present invention, the pharmaceutical composition is preferably administered orally. Other forms of administration are le and described hereinafter.

Preferably the one or more dosage forms comprising the SGLT2 inhibitor is oral or usually well known.

In general, the amount of the SGLT2 inhibitor in the pharmaceutical composition and methods according to this invention is preferably the amount usually recommended for a monotherapy using said SGLT2 inhibitor.

The preferred dosage range of the SGLT2 inhibitor is in the range from 0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferably from 1 to 50 mg per day. In one aspect, a red dosage of the SGLT2 inhibitor empagliflozin is 10 mg or 25 mg per day.

The oral administration is preferred. Therefore, a pharmaceutical composition may se the hereinbefore mentioned amounts, in particular from 1 to 50 mg or 1 to 25 mg. Particular dosage strengths (e.g. per tablet or capsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, or 50 mg of the SGLT2 inhibitor, in particular empagliflozin. In one aspect, a pharmaceutical composition comprises 10 mg or 25 mg of empagliflozin. The application of the active ingredient may occur up to three times a day, ably one or two times a day, most preferably once a day.

A pharmaceutical composition which is present as a separate or multiple dosage form, preferably as a kit of parts, is useful in combination therapy to flexibly suit the individual therapeutic needs of the patient.

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

A further aspect of the present invention is a manufacture sing the ceutical composition being present as separate dosage forms according to the present invention and _ 41 _ a label or package insert comprising instructions that the separate dosage forms are to be administered in combination or alternation.

According to a first embodiment a manufacture comprises (a) a pharmaceutical composition sing a SGLT2 inhibitor according to the present invention and (b) a label or e insert which comprises instructions that the medicament is to be stered.

The desired dose of the pharmaceutical composition according to this invention may conveniently be presented in a once daily or as divided dose administered at appropriate intervals, for example as two, three or more doses per day.

The pharmaceutical composition may be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including uscular, sub- cutaneous and intravenous) stration in liquid or solid form or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The formulations may, where appropriate, be conveniently presented in te dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of ng into association the active ient with one or more ceutically acceptable carriers, like liquid carriers or finely d solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspension, fast dissolving tablets, oral fast-dispersing tablets, etc..

The pharmaceutical composition and the dosage forms preferably comprises one or more pharmaceutical 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 able carriers are known to the one 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 s each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a sion or as an emulsion, for example as syrups, elixirs or self-emulsifying _ 42 _ delivery systems (SEDDS). The active ingredients may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as g 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 e, aqueous or oily suspensions, solutions, emulsions, syrups or s, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain tional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.

The pharmaceutical composition according to the invention may also be formulated for parenteral stration (e.g. by injection, for example bolus injection or continuous infusion) and may be ted in unit dose 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 atory agents such as suspending, stabilizing and/or dispersing agents. atively, the active ingredients may be in powder form, obtained by aseptic ion of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. e, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose itories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound(s) with the softened or melted carrier(s) followed by chilling and shaping in moulds.

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

Methods for the manufacture of SGLT2 inhibitors according to this invention and of prodrugs thereof are known to the one d in the art. Advantageously, the nds according to this invention can be prepared using synthetic s as described in the literature, including patent applications as cited hereinbefore. red methods of manufacture are described in the and . With regard to empagliflozin an advantageous crystalline form is described in the international patent application which hereby is orated herein in its entirety.

The active ients may be present in the form of a pharmaceutically acceptable salt.

Pharmaceutically acceptable salts include, without being restricted thereto, such as salts of inorganic acid like hydrochloric acid, sulfuric acid and phosphoric acid; salts of organic carboxylic acid like oxalic acid, acetic acid, citric acid, malic acid, c acid, maleic acid, fumaric acid, ic acid, succinic acid and glutamic acid and salts of c sulfonic acid like methanesulfonic acid and p-toluenesulfonic acid. The salts can be formed by combining the compound and an acid in the appropriate amount and ratio in a solvent and decomposer.

They can be also obtained by the cation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a e or alcohol adduct.

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

Further, the present invention relates to the SGLT—2 inhibitors, optionally in combination with one, two or more further active agents, each as defined herein, for use in the therapies as described herein.

Further, the present invention relates to the use of the SGLT-2 inhibitors, optionally in combination with one, two or more further active agents, each as d herein, for preparing pharmaceutical compositions which are suitable for the ent and/or prevention purposes of this invention.

The present invention further relates to a pharmaceutical composition comprising a certain SGLT-2 inhibitor as defined herein, preferably empagliflozin, and min and/or a DPP-4 inhibitor, for example linagliptin, for use in the therapies described .

The present ion further relates to a combination comprising a certain SGLT-2 inhibitor (particularly empagliflozin) and one or more other abetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, an _ 44 _ alpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, particularly for simultaneous, separate or sequential use in the therapies described herein.

The present invention further relates to a method for treating and/or preventing metabolic diseases, especially type 2 diabetes mellitus and/or conditions related o (e.g. diabetic complications) sing the combined (e.g. simultaneous, separate or sequential) administration of an effective amount of one or more other antidiabetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, an glucosidase inhibitor, insulin or an insulin analogue, GLP- 1 or a GLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly human patient) in need f, such as e.g. a patient as described herein.

The present invention further relates to therapies or therapeutic s described herein, such as e.g. a method for treating and/or preventing metabolic diseases, ally type 2 es mellitus and/or conditions related thereto (e.g. diabetic complications), comprising administering a eutically effective amount of empagliflozin and, optionally, one or more other eutic agents, such as e.g. abetics selected from the group consisting of metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma- agonist, an alpha-glucosidase inhibitor, insulin or an n analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly human patient) in need thereof, such as e.g. a t as described herein.

Within this invention it is to be tood that the combinations, compositions or combined uses according to this invention may envisage the simultaneous, sequential or separate administration of the active components or ingredients.

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

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

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

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

The present ion further relates to a certain SGLT-2 inhibitor as defined , ably empagliflozin, in combination with metformin, for use in the therapies described herein.

Metformin is usually given in doses varying from about 500 mg to 2000 mg up to 2500 mg per day using various dosing ns from about 100 mg to 500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mg once or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day. Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of min hydrochloride.

For children 10 to 16 years of age, the recommended ng dose of metformin is 500 mg given once daily. If this dose fails to produce adequate results, the dose may be increased to 500 mg twice daily. Further increases may be made in ents of 500 mg weekly to a maximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3 divided doses).

Metformin may be administered with food to decrease nausea.

An example of a DPP-4 inhibitor is linagliptin, which is usually given in a dosage of 5 mg per day. Therefore, a pharmaceutical composition may comprise 5 mg linagliptin in addition to the SGLT2 inhibitor, in particular empagliflozin in an amount of 10 mg or 25 mg.

A dosage of tazone is usually of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or divided twice) a day (typical dosage strengths are 2, 4 and 8 mg). 2014/056657 Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mg once (or divided twice) a day (typical dosage strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mg once (or divided twice) a day al dosage strengths are 1.5, 3, 4.5 and 6 mg). ide is usually given in doses from 2.5 to 10-20 mg once (or up to 40 mg d twice) a day (typical dosage strengths are 5 and 10 mg), or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) once a day (typical dosage strengths are 1, 2 and 4 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually given in doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is usually given in doses from 0.5 to 4 mg with meals (up to 16 mg/day, l dosage strengths are 0.5, 1 and 2 mg). A dual combination of repaglinide/metformin is ble in dosage strengths of 1/500 and 2/850 mg.

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

Examples Example 1: iflozin in patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI).

A Phase III trial investigated the efficacy and safety of empagliflozin (EMPA) as add-on to existing therapy for 52 weeks in patients with T2DM and RI. Patients with mild Rl (eGFR [MDRD equation] 260 to <90 mL/min/1.73 m2; n=290; mean age 62.6 years; mean BMI 31.5 kg/m2) received EMPA 10 or 25 mg qd or placebo (PBO). Patients with moderate Rl (eGFR 230 to <60 mL/min/1.73 m2; n=374; mean age 64.9 years; mean BMI 30.2 kg/m2) received EMPA 25 mg qd or PBO. The primary endpoint was change from baseline in HbA1C at week 24. Exploratory endpoints included s from baseline in fasting plasma glucose (FPG), weight and blood pressure (BP) at week 24 (Figure 1).

EMPA significantly reduced HbA1C vs PBO at week 24. Further analyses showed significant reductions in FPG, weight and BP. At week 24, adverse events (AEs) were ed by 79.6%, 75.4% and 72.7% of all patients ding an exploratory group with severe Rl [n=74] on EMPA 25 mg or PBO) on EMPA 10 mg, 25 mg and P80, respectively. Hypoglycemia (plasma glucose S70 mg/dL and/ or requiring assistance) was ed in 23.5% of patients on EMPA 10 mg, 22.1% on EMPA 25 mg and 22.9% on PBO. AEs consistent with urinary tract ion were reported in 10.2% of patients on EMPA 10 mg, 9.0% on EMPA 25 mg and 8.2% on PBO. AEs tent with genital infection were reported in 6.1% of patients on EMPA 10 mg, 2.5% on EMPA 25 mg and 1.3% on PBO.

To conclude, in patients with T2DM and mild or moderate Rl, EMPA reduced HbA1c, weight, and BP vs P80, and was well tolerated.

The y endpoint was also analysed for ts with moderate A and te B renal impairment. For the patients with moderate A renal impairment, the difference to placebo for the adjusted mean change in HbA1C from baseline at Week 24 was -0.46% (95% Cl: -0.66, -0.27). For the patients with moderate B renal impairment, the difference to placebo for the adjusted mean change in HbA1C from baseline at Week 24 was -0.39% (95% Cl: -0.58, 019).

Example 2: Mixed Effects Modeling to Quantify the Effect of Empagliflozin Exposure on the Renal Glucose Threshold in Patients with Type 2 Diabetes Mellitus. iflozin, a selective and potent SGLT2 inhibitor, reduces renal glucose reabsorption by lowering the renal threshold for glucose (RTG) leading to increased y glucose excretion (UGE) and decreased plasma glucose (PG) in patients with type 2 diabetes mellitus (T2DM).

This analysis aimed to quantify the impact of empagliflozin on RTG by characterizing the _ 48 _ onship between empagliflozin exposure and UGE in patients with T2DM using nonlinear mixed-effects modeling.

A pharmacokinetic (PK)—pharmacodynamic (PD) model was developed using UGE, PG, PK and estimated glomerular filtration rate (eGFR) data from three Phase II" trials (N=223; placebo, empagliflozin 1 to 100 mg once daily [QD]). The model assumed that when PG>RTG, UGE increased with increasing PG and eGFR; and when PGSRTG slight glucose e into urine occurred (estimated as fraction reabsorbed [FRAC]). Reabsorption was estimated by a nonlinear function parameterized in terms of maximum reabsorbed glucose concentration (Gmax) and PG concentration to reach half maximum transport (Km). Maximum inhibitory effect (lmax) and half maximal inhibitory concentration (IC50) described inhibition of renal glucose absorption. RTG was calculated as the difference between maximum rption (including drug effect) and KM. The model was ted via bootstrap and external predictive check of an iflozin renal ment study.

The parameter estimates (95% Cl) were Gmax: 374 (347, 391) mg/dL; Km: 144 (113, 163) mg/dL; lmax: 0.559 (0.545, 0.607); |C50: 5.28 (3.53, 8.91) nmol/L; FRAC: 0.999 (0.998, 0.999).

The ated RTG for placebo was 230 mg/dL. RTG decreased with increasing empagliflozin concentration; doses of 1, 5, 10, and 25 mg yielded RTG values of 100.5, 43.8, 33.1, and 26.0 mg/dL, respectively. External predictive check demonstrated unbiased prediction of UGE across a range of eGFR values tage renal disease to normal renal function). Simulation indicated that for 10 and 25 mg QD, >50% and 90% of subjects, respectively, ined steady-state iflozin trations >IC80 for RTG lowering over the dosing interval.

Example 3: Pharmacokinetics and pharmacodynamics of empagliflozin in subjects with renal impairment.

Subjects. Male and female subjects aged 18 to 75 years weighing at least 45 kg es only) and with a body mass index (BMI) of 18 to 34 kg/m2 were eligible for inclusion in this study. Participants with normal renal function (eGFR >90 mL/min/1.73m2; control) were required to have T2DM. Patients with mild renal impairment (eGFR 60—89 mL/min/1.73m2), moderate renal impairment (eGFR 30—59 mL/min/1.73m2), severe renal ment (eGFR <30 mL/min/1.73m2) or renal failure/ESRD (requiring dialysis) did not need to have T2DM. eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) formula: 186 x serum creatinine‘1'154 x age—0'203 x [0.742 if female].

Subjects were excluded from the study if they had recently participated in a study (multiple- dose: within 2 months; single-dose: within 1 , were abusing alcohol (males >60 g/day; females >40 g/day) or drugs, had donated >100 mL blood in the previous 4 weeks, were taking concomitant medications known to inhibit or induce p-glycoprotein or cytochrome P450 3A, or had any medical or laboratory results deviating from normal and of clinical relevance. ts with renal impairment were excluded if they had significant es other than renal impairment or T2DM, including moderate and severe concurrent hepatic impairment, hemoglobin <8 g/dL indicating severe renal anemia (erythropoietin could be used to in hemoglobin levels), and intake of drugs with a long half-life (>24 h) within the previous month (or within 10 half-lives of that drug, if ), except for those being taken for the ent of renal disease.

The igators, in cooperation with nephrology centers, aimed to recruit 8 subjects for every group. Subjects with normal renal function were matched to those in the renal impairment groups by age (:5 years) and weight (i15%), where possible.

Study design. This 2-center, open-label, parallel-group study was undertaken to assess the effect of renal function on the pharmacokinetics, pharmacodynamics, and safety of a single 50 mg dose of empagliflozin. Subjects were screened for eligibility up to 21 days prior to study drug administration. Following an overnight fast, subjects were admitted to the research unit and received a 50 mg dose of empagliflozin with 240 mL of water (day 1).

Water was allowed ad libitum except for 1 h before and 1 h after study drug administration.

Following medical surveillance for 24 h, subjects were discharged (day 2) and were monitored as outpatients until they attended an end-of-study examination (within 14 days after the last trial procedure).

Pharmacokinetic endpoints. One objective of the study was to determine the effect of renal ment on the relative ilability of empagliflozin, based on the primary endpoints of AUCOM and Cmax. Secondary pharmacokinetic nts included: tmax,t1,2, fe0_96, CLR,0_96, and plasma protein binding of empagliflozin.

Pharmacodynamic endpoint. The codynamic endpoint of the study was the cumulative amount of UGE over a 24 h period following drug administration (UGE0_24), relative to baseline, with a baseline measurement obtained over 24 h ing administration of study drug.

Sample collection and analysis. Approximately 124 mL of blood was taken from every subject over the course of the study for clinical laboratory tests (44 mL), pharmacokinetic ments (50 mL), and determination of protein binding (30 mL). Blood s for clinical laboratory testing were collected after subjects had fasted for at least 10 h.

W0 2014/161919 2014/056657 _ 50 _ For quantification of empagliflozin plasma concentrations 2.7 mL of blood was taken from a forearm vein in a K3-EDTA (tripotassium ethylenediaminetetraacetic acid)—anticoagulant blood drawing tube at pre-dose and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12,14, 24, 36, 48, 72, and 96 h post-dose. Within 30 min of collection, the samples were centrifuged for 10 min at 000 g and 4—8°C. The EDTA plasma obtained was stored at —18°C until it was shipped on dry ice for analysis.

Urine was collected over 24 h prior to drug administration and at the ing intervals following drug administration: 0—4, 4—8, 8—12, 12—24, 24—36, 36—48, 48—72, and 72—96 h.

Urine ners were weighed empty and at the end of every sampling period and the difference was recorded as the urine volume (weight was set equal to volume, i.e. 1 kg = 1 L). Urine containers were refrigerated until 25 h after drug administration and aliquots were stored at —18°C until shipped on dry ice for is.

Empagliflozin concentrations in plasma and urine were determined by validated high performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) .

Empagliflozin and the internal standard [13C5]-empagliflozin were extracted from urine or plasma by supported liquid extraction. After evaporation under en, the residue was tituted and analyzed using liquid chromatography with MS/MS detection. The lower limit of quantification for empagliflozin in human plasma was 1.11 nmol/L, with linearity to 1110 nmol/L using a sample volume of 0.15 mL, and in human urine was 4.44 nmol/L, with linearity to 4440 nmol/L using a sample volume of 0.05 mL. For both plasma and urine, results were calculated using peak area ratios and calibration curves were created using weighted (1/x2) quadratic regression.

For determination of protein binding of empagliflozin, 10 mL blood was collected at pre-dose, 1.5 and 3 h post-dose. Blood was centrifuged for 10 min at 4000 g and 4°C, and the plasma was stored at —20°C until it was shipped on dry ice for analysis. The binding of empagliflozin and the internal standard [13C6]-empagliflozin to human plasma protein was determined by equilibrium dialysis at 37°C. As a quality control measure, protein binding analyses were performed using the pre-dose plasma samples. cokinetic parameters were calculated using linTM software , Pharsight Corporation, Mountain View, CA, USA). Cmax and tmax values were directly determined from the plasma concentration time profiles of each subject. The apparent terminal rate constant (AZ) was estimated from a sion of ln(C) versus time over the terminal log-linear drug disposition portion of the concentration-time profiles. The t1/2 was calculated as the quotient of ln(2) and AZ. Area under the plasma concentration-time curve to the last time point (AUC0_ t2) was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The AUCOM value was estimated as W0 2014/161919 _ 51 _ the sum of AUC to the last measured concentration, with the extrapolated area given by the quotient of the last measured concentration and AZ. The amount of drug (Ae) excreted unchanged in urine in each collection interval was determined by the product of the urine concentration and the urine volume. The fraction of the dose (fe) that was excreted unchanged in urine was determined by the quotient of the sum of drug excreted over all dosing als and the dose administered. Renal clearance (CLR) was determined as the quotient of Ae over AUC. Cumulative UGE was calculated using the glucose concentration measured in every urine sample collected from -24—0 h and 0—96 h after . UGE (mg) was ated as follows: glucose concentration [mg/dL] x urine volume [dL]). Results are shown in Figures 2 to 6. tical analysis. All subjects who provided at least one observation for at least one primary endpoint without any protocol violations relevant to cokinetic evaluation were included in the analysis of relative bioavailability (pharmacokinetic analysis set). All ts with a baseline UGE value (0—24 h pre-dose) and a UGE value from 0—24 h ose without any protocol violations nt to UGE analysis were included in the UGE analysis set. All safety analyses were performed on all ts who received study drug (treated set).

One objective of the study was to investigate the relative bioavailability of empagliflozin in subjects with normal renal function (R) compared with subjects with s degrees of renal impairment (T1—4), by presenting point estimators (adjusted geometric mean [gMean] T/R ratios) of AUC0_.° and Cmax and their 2-sided 90% Cls. AUCOM and Cmax were analyzed using an analysis of variance (ANOVA) model on the logarithmic scale including a fixed effect corresponding to the renal function (normal, mild impairment, te impairment, severe impairment, or renal failure/ESRD). The change in UGE 0—24 h from baseline after drug administration was analyzed by an analysis of covariance (ANCOVA) model including baseline UGE values as a continuous covariate, and a fixed effect corresponding to the renal function. Descriptive statistics were calculated for all cokinetic and pharmacodynamic parameters. Safety es were descriptive in nature. e 4: Empagliflozin in patients with type 2 diabetes mellitus (T2DM) and Stage 3A, 3B and 4 Chronic Kidney Disease (CKD).

A Phase III trial igated the efficacy and safety of empagliflozin (EMPA) as add-on to existing therapy for 52 weeks in patients with T2DM and CKD stage 3A, 3B and 4.

Patients with CKD stage 3A (eGFR [MDRD equation] 245 to <60 ml/min/1.73 m2; n=180; mean [SD] age 64.5 [8.0] years; mean [SD] BMI 30.5 [5.2] kg/m2), CKD stage 38 (eGFR 230 to <45 ml/min/1.73 m2; n=194; mean [SD] age 65.2 [9.0] years; mean [SD] BMI 30.0 [5.4] W0 2014/161919 _ 52 _ kg/m2) or CKD stage 4 (eGFR 215 to <30 ml/min/1.73 m2; n=74; mean [SD] age 64.1 [11.1] years; mean [SD] BMI 30.4 [5.6] kg/m2) ed EMPA 25 mg qd or PBO for 52 weeks. In exploratory analyses, we assessed the erm efficacy and safety of EMPA, including s from baseline in HbA1c, fasting plasma e (FPG), weight and systolic and diastolic blood pressure (SBP and DBP) at week 52 (Figure 7).

EMPA 25 mg significantly reduced HbA1C vs PBO at week 52 in ts with CKD stage 3A and 3B (Table). EMPA 25 mg did not reduce HbA1C in patients with CKD stage 4 (Table).

EMPA significantly reduced FPG, weight, SBP and DBP in patients with CKD stage 3A, and significantly reduced FPG and weight in patients with CKD stage 3B (Table). Reductions in FPG, weight and BP were observed in patients with CKD stage 4 (Table). During 52 weeks’ treatment, adverse events (AEs) were reported by 86.8% and 79.8% of patients with CKD stage 3A on EMPA 25 mg and PBO, respectively, by 80.2% and 86.7% of patients with CKD stage 3B on EMPA 25 mg and PBO, respectively, and by 91.9% and 83.8% of patients with CKD stage 4 on EMPA 25 mg and PBO, respectively. AEs consistent with volume depletion were reported by 4.4% and 2.2% of patients with CKD stage 3A on EMPA 25 mg and PBO, respectively, by 3.1% of patients with CKD stage 3B on EMPA 25 mg or PBO, and by 5.4% patients with CKD stage 4 on EMPA 25 mg or PBO. AEs consistent with urinary tract infection were reported by 16.5% and 18.0% of patients with CKD stage 3A on EMPA 25 mg and PBO, respectively, by 16.7% and 13.3% of patients with CKD stage 3B on EMPA 25 mg and PBO, respectively, and by 18.9% and 8.1% of patients with CKD stage 4 on EMPA 25 mg and PBO, respectively.

EMPA 25 mg for 52 weeks was associated with significant and clinically meaningful reductions in HbA1ccompared with placebo in patients with T2DM and CKD stage 3A or 3B.

EMPA led to favourable reductions in body weight and BP in patients with T2DM and CKD stage 3A, 3B or 4.

Example 5: Treatment of type 2 diabetes mellitus Treating patients with type 2 diabetes mellitus with empagliflozin, in addition to ing an acute improvement in the glucose metabolic situation, prevents a deterioration in the metabolic situation in the long term. This can be observed is patients are treated for a longer period, e.g. 3 months to 1 year or even 1 to 6 years, with a combination according to the ion and are compared with patients who have been d with other antidiabetic and/ or antiobesity medicaments. There is evidence of therapeutic success compared with other treatments if no or only a slight increase in the fasting glucose and/or HbA1c value is ed. Further evidence of therapeutic success is obtained if a significantly smaller percentage of the ts treated with a combination according to the invention, compared W0 2014/161919 _ 53 _ with patients who have received r treatment, undergo a deterioration in the glucose metabolic position (e.g. an increase in the HbA1c value to >6.5% or >7%) to the point where treatment with an (additional) oral antidiabetic medicament or with insulin or with an insulin analogue is indicated.

Example 6: Treatment of insulin resistance In clinical studies running for different lengths of time (e.g. 2 weeks to 12 months) the success of the treatment is checked using a hyperinsulinaemic aemic glucose clamp study. A significant rise in the glucose infusion rate at the end of the study, compared with the initial value or compared with a placebo group, or a group given a different therapy, proves the efficacy of a treatment according to the invention in the treatment of n resistance.

Example 7: Treatment of hyperglycaemia In clinical studies running for different s of time (e.g. 1 day to 24 months) the success of the treatment in patients with hyperglycaemia is checked by determining the fasting e or non-fasting e (e.g. after a meal or a loading test with oGTT or a defined meal). A significant fall in these glucose values during or at the end of the study, compared with the initial value or compared with a o group, or a group given a different y, proves the efficacy of a combination treatment according to the invention in the treatment of hyperglycaemia.

Example of Pharmaceutical ition and Dosage Form The following example of solid pharmaceutical compositions and dosage forms for oral administration serves to illustrate the present invention more fully without restricting it to the contents of the e. Further examples of compositions and dosage forms for oral administration, are described in WO 92126. The term "active substance" denotes empagliflozin according to this invention, especially its crystalline form as described in WO 17359 and . _ 54 _ Tablets containing 2.5mg, 5mg, 10mg, 25mg, 50mg of active substance 2.5 mg/ 5 mg/ 10 mg/ 25 mg/ 50 mg/ ‘ ctive substance per tablet per tablet per tablet per tablet per tablet et granulation active substance 2.5000 5.000 25.00 50.00 Lactose 40.6250 81.250 113.00 226.00 Monohydrate Microcrystalline 12.5000 25.000 40.00 80.00 Cellulose Hyd opyl 1.8750 3.750 12.00 Cellulose Croscarmellose 1.2500 2.500 . . 8.00 —""Purified Water Dry Adds rocrystalline 3.1250 6.250 10.00 20.00 Cellulose Colloidal silicon 0.3125 0.625 . 1.00 2.00 o. 5'5. o. CD ium stearate--0.3125 0.625 1.00 2.00 —|oE)"g0 2CD --62.5000 125.000 200.00 400.00 Film Coating -- Film coating system --2.5000 4.000 Purified Water mm Total --65.000 129.000 206.00 409.00 Details regarding the manufacture of the tablets, the active pharmaceutical ient, the excipients and the film coating system are described in , in particular in the Examples 5 and 6, which hereby is incorporated herein in its entirety.

Claims

We Claim :

1. Use of empagliflozin in the manufacture of a medicament for treating type 2 diabetes mellitus in patient or for improving glycemic control in a patient with type 2 diabetes mellitus, wherein the patient has moderate B renal impairment or stage 3B chronic 5 kidney disease (CKD), or wherein the patient’s estimated glomerular filtration rate (eGFR) is ≥30 ml/min/1.73m2 and <45 ml/min/1.73m2, and n the medicament comprises 10 mg of empagliflozin and wherein the medicament is formulated for administration once daily.

2. The use according to claim 1, wherein the medicament is for use as an adjunct to 10 diet and exercise.

3. The use according to any one of the preceding claims, wherein the medicament is for treating type 2 diabetes mellitus in an adult t or for improving glycemic control in an adult patient with type 2 diabetes mellitus wherein empagliflozin is ated for administration orally in a total daily amount of 10 mg. 15

4. The use according to claim 1 or 2, n the patient is an adult patient.

5. The use according to any one of the preceding claims, wherein empagliflozin is ated for administration with one or more other antidiabetic substances.

6. The use according to any one of the preceding claims, n empagliflozin is formulated for administration in ation with metformin and/or linagliptin. 20

7. The use according to any one of the previous claims wherein the medicament is for treating type 2 diabetes mellitus in a patient, n the ment comprises 10 mg of empagliflozin, and the medicament is formulated for administration orally once daily, wherein the medicament is formulated for administration to the patient if the eGFR of the patient is ≥30 ml/min/1.73 m2 and <45 ml/min/1.73 m2; and wherein the medicament is 25 formulated to be discontinued if the eGFR of the patient falls below 30 ml/min/1.73m2. (26885788_1):KZA

8. The use according to any one of the previous claims wherein the medicament is for improving glycemic control in a patient with type 2 diabetes mellitus; wherein the renal function of the patient is assessed before administration of the ment; 5 wherein the medicament comprises 10 mg of empagliflozin, and the medicament is formulated for administration orally once daily, wherein the medicament is formulated for administration to the t if the eGFR of the patient is ≥30 ml/min/1.73 m2 and <45 ml/min/1.73 m2; and n the medicament is formulated to be discontinued if the eGFR of the patient falls below 30 ml/min/1.73m2. 10 Boehringer Ingelheim International GmbH By the Attorneys for the Applicant SPRUSON & ON Per: (26885788_1):KZA