PHARMACEUTICAL COMPOSITION, METHODS FOR TREATING AND USES THEREOF

Abstract

The invention relates to a pharmaceutical composition according to the claim 1 comprising an SGLT2 inhibitor and a GLP-1 receptor agonist which is suitable in the treatment or prevention of diabetes mellitus, impaired glucose tolerance, hyperglycemia or other conditions. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. A method for treating a disease or condition selected from the group consisting of diabetes mellitus, type 2 diabetes mellitus and a disease or condition which requires treatment with insulin or a GLP-1 receptor agonist in a patient in need thereof characterized in that a GLP-1 receptor agonist and an SGLT2 inhibitor are administered in combination or alternation or sequentially to the patient,. wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide, wherein the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

8. The method according to claim 7, wherein the GLP-1 receptor agonist is exenatide or exenatide LARwherein the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

9. A method for treating a disease or condition selected from the group consisting of for treating diabetes mellitus; for treating diabetes mellitus, where treatment with insulin or a GLP-1 receptor agonist is required; for treating, preventing or reducing the risk of hypoglycemia; for preventing, slowing progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus; preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, diabetes related to cystic fibrosis; or improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c; or preventing, slowing, delaying or reversing progression from impaired glucose tolerance, insulin resistance and/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 consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis, myocardial infarction, accute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and vascular restenosis; or reducing body weight and/or body fat or preventing an increase in body weight and/or body fat or 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 for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of ectopic fat; or maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance; preventing, slowing progression of, delaying, or treating new onset diabetes after transplantation (NODAT) and/or post-transplant metabolic syndrome (PTMS); preventing, delaying, or reducing NODAT and/or PTMS associated complications including micro- and macrovascular diseases and events, graft rejection, infection, and death; treating hyperuricemia and hyperuricemia associated conditions; treating or preventing kidney stones; treating hyponatremia; in a patient in need thereof characterized in that a GLP-1 receptor agonist and an SGLT2 inhibitor are administered in combination or alternation or sequentially to the patient,. wherein the SGLT2 inhibitor is 1-chloro-4-((β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide, wherein the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

10. The method according to claim 9, wherein the GLP-1 receptor agonist is exenatide or exenatide LAR.

11. A method for weight reduction, for reduction of body fat, for preventing an increase of body weight or for attenuating an increase of body weight comprising an administration of a GLP-1 receptor agonist in a patient in need thereof followed by an administration of a SGLT2 inhibitor in said patient, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide, wherein the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

12. Method according to claim 11, wherein the GLP-1 receptor agonist is exenatide or exenatide LAR

13. A method for treating a metabolic disorder, in particular of diabetes mellitus and/or complications associated with diabetes mellitus, in a patient who is diagnosed of being overweight or obese, characterized by a first therapy comprising the administration of a GLP-1 receptor agonist to the patient followed by a second therapy comprising the administration of a SGLT2 inhibitor to the patient, wherein the SGLT2 inhibitor is 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, wherein the GLP-1 receptor agonist is selected from the group consisting of exenatide, exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide, wherein the patient is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.

14. The method according to claim 13, wherein the GLP-1 receptor agonist is exenatide or exenatide LAR

Description

BRIEF DESCRIPTION OF THE FIGURES

[0144] The FIG. 1 shows the glucose excursion in ZDF rats after administration of a SGLT2 inhibitor and a GLP-1 receptor agonist.

DETAILED DESCRIPTION

[0145] The aspects according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to SGLT2 inhibitors and GLP-1 receptor agonists. In the methods and uses according to this invention a third antidiabetic agent may optionally be administered, i.e. the SGLT2 inhibitor, the GLP-1 receptor agonist or both the the SGLT2 inhibitor and the GLP-1 receptor agonist are administered in combination with a third antidiabetic agent or without a third antidiabetic agent.

[0146] Preferably the SGLT2 inhibitor is selected from the group G1 consisting of dapagliflozin, canagliflozin, atigliflozin, ipragliflozin, tofogliflozin, remogliflozin, sergliflozin and glucopyranosyl-substituted benzene derivatives of the formula (I)

##STR00001##

wherein R.sup.1 denotes Cl, methyl or cyano; R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug of one of the beforementioned SGLT2 inhibitors.

[0147] Compounds of the formula (I) and methods of their synthesis are described for example in the following patent applications: WO 2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO 2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO 2008/055870.

[0148] In the above glucopyranosyl-substituted benzene derivatives of the formula (I) the following definitions of the substituents are preferred.

[0149] Preferably R.sup.1 denotes chloro or cyano; in particular chloro.

[0150] Preferably R.sup.2 denotes H.

[0151] Preferably R.sup.3 denotes ethyl, cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even more preferably R.sup.3 denotes cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Most preferably R.sup.3 denotes ethynyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

[0152] Preferred glucopyranosyl-substituted benzene derivatives of the formula (I) are selected from the group of compounds (I.1) to (I. 11):

##STR00002## ##STR00003## ##STR00004##

[0153] According an embodiment of the present invention the SGLT2 inhibitor is selected from the group G1a consisting of compounds of the beforementioned formula (I). Even more preferably the group G1a consists of glucopyranosyl-substituted benzene derivatives of the formula (I) which are selected from the compounds (I.6), (I.7), (I.8), (I.9) and (I.11). An preferred example of a SGLT2 inhibitor according to the group G1a is the compound (I.9).

[0154] According to another embodiment of the present invention the SGLT2 inhibitor is selected from the group consisting of dapagliflozin, canagliflozin, atigliflozin, ipragliflozin and tofogliflozin.

[0155] According to this invention, it is to be understood that the definitions of the above listed SGLT2 inhibitors, including the glucopyranosyl-substituted benzene derivatives of the formula (I), also comprise their hydrates, solvates and polymorphic forms thereof, and prodrugs thereof. With regard to the preferred compound (I.7) an advantageous crystalline form is described in the international patent application WO 2007/028814 which hereby is incorporated herein in its entirety. With regard to the preferred compound (I.8), an advantageous crystalline form is described in the international patent application WO 2006/117360 which hereby is incorporated herein in its entirety. With regard to the preferred compound (I.9) an advantageous crystalline form is described in the international patent application WO 2006/117359 which hereby is incorporated herein in its entirety. With regard to the preferred compound (I.11) an advantageous crystalline form is described in the international patent application WO 2008/049923 which hereby is incorporated herein in its entirety. These crystalline forms possess good solubility properties which enable a good bioavailability of the SGLT2 inhibitor. Furthermore, the crystalline forms are physico-chemically stable and thus provide a good shelf-life stability of the pharmaceutical composition.

[0156] The term “dapagliflozin” as employed herein refers to dapagliflozin, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods of its synthesis are described in WO 03/099836 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/116179 and WO 2008/002824 for example.

[0157] The term “canagliflozin” as employed herein refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00005##

[0158] The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.

[0159] The term “atigliflozin” as employed herein refers to atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00006##

[0160] The compound and methods of its synthesis are described in WO 2004/007517 for example.

[0161] The term “ipragliflozin” as employed herein refers to ipragliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00007##

[0162] The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.

[0163] The term “tofogliflozin” as employed herein refers to tofogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

##STR00008##

[0164] The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.

[0165] The term “remogliflozin” as employed herein refers to remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.

[0166] The term “sergliflozin” as employed herein refers to sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.

[0167] For avoidance of any doubt, the disclosure of each of the foregoing documents cited above in connection with the specified SGLT2 inhibitors is specifically incorporated herein by reference in its entirety.

[0168] The aspects according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to a GLP-1 receptor agonist, which includes exogenous GLP-1 (natural or synthetic), GLP-1 analogues and other substances (whether peptidic or non-peptidic, e.g. small molecules) which promote signalling through the GLP-1 receptor.

[0169] Examples of GLP-1 analogues are selected from the group G2 consisting of exenatide (exendin-4); exenatide LAR (long acting release formulation of exenatide); liraglutide; taspoglutide; semaglutide; albiglutide; lixisenatide; dulaglutide; and the PEGylated GLP-1 compound comprising the amino acid sequence according to the claim 1 of WO 2006/124529 (the disclosure of which is incorporated herein) and the GLP-1 derivative comprising the amino acid sequence according to SEQ ID NO:21 as disclosed in the WO 2009/020802 (the disclosure of which is incorporated herein).

[0170] Preferred examples of GLP-1 receptor agonists (GLP-1 analogues) of this invention are exenatide, exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide and dulaglutide, in particular exenatide (exendin-4).

[0171] GLP-1 analogues have typically significant sequence identity to GLP-1 (e.g. greater than 50%, 75%, 90% or 95%) and may be derivatised, e.g. by conjunction to other proteins (e.g. albumin or IgG-Fc fusion protein) or through chemical modification.

[0172] Unless otherwise noted, according to this invention it is to be understood that the definitions of the active agents (including the SGLT2 inhibitors and GLP-1 receptor agonists) mentioned hereinbefore and hereinafter may also contemplate their pharmaceutically acceptable salts, and prodrugs, hydrates, solvates and polymorphic forms thereof. Particularly the terms of the therapeutic agents given herein refer to the respective active drugs. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to herein.

[0173] In an embodiment the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor and the GLP-1 receptor agonist are preferably selected according to the entries in the Table 1:

TABLE-US-00001 TABLE 1 SGLT2 Inhibitor GLP-1 receptor agonist selected from group G1 selected from group G2 selected from group G1 exenatide selected from group G1 exenatide LAR selected from group G1 liraglutide selected from group G1 taspoglutide selected from group G1 semaglutide selected from group G1 albiglutide selected from group G1 lixisenatide selected from group G1 dulaglutide selected from group G1a selected from group G2 selected from group G1a exenatide selected from group G1a exenatide LAR selected from group G1a liraglutide selected from group G1a taspoglutide selected from group G1a semaglutide selected from group G1a albiglutide selected from group G1a lixisenatide selected from group G1a dulaglutide compound (I.9) selected from group G2 compound (I.9) exenatide compound (I.9) exenatide LAR compound (I.9) liraglutide compound (I.9) taspoglutide compound (I.9) semaglutide compound (I.9) albiglutide compound (I.9) lixisenatide compound (I.9) dulaglutide

[0174] In a particular embodiment (embodiment E) the combinations, compositions, methods and uses according to this invention relate to combinations wherein the SGLT2 inhibitor is the compound of the formula (I.9).

[0175] According to another embodiment of the present invention the pharmaceutical composition, the methods and uses according to the invention additionally comprise a further antidiabetic agent.

[0176] According to one aspect of this embodiment the further antidiabetic agent is selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, insulin, DPP-4 inhibitors and amylin analogs, including pharmaceutically acceptable salts of the beforementioned agents. In the following preferred embodiments regarding the third antidiabetic agent are described.

[0177] The group G3 comprises biguanides. Examples of biguanides are metformin, phenformin and buformin. A preferred biguanide is metformin.

[0178] The term “metformin” as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids. It is preferred that the metformin employed herein is the metformin hydrochloride salt.

[0179] The group G3 comprises thiazolidindiones. Examples of thiazolidindiones (TZD) are pioglitazone and rosiglitazone.

[0180] The term “pioglitazone” as employed herein refers to pioglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the hydrochloride salt.

[0181] The term “rosiglitazone” as employed herein refers to rosiglitazone, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salt thereof such as the maleate salt.

[0182] The group G3 comprises sulfonylureas. Examples of sulfonylureas are glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride, glyburide, glisoxepide and gliclazide. Preferred sulfonylureas are tolbutamide, gliquidone, glibenclamide, glipizide and glimepiride, in particular glibenclamide, glipizide and glimepiride.

[0183] Each term of the group “glibenclamide”, “glimepiride”, “gliquidone”, “glibornuride”, “gliclazide”, “glisoxepide”, “tolbutamide” and “glipizide” as employed herein refers to the respective active drug or a pharmaceutically acceptable salt thereof.

[0184] The group G3 comprises glinides. Examples of glinides are nateglinide, repaglinide and mitiglinide.

[0185] The term “nateglinide” as employed herein refers to nateglinide, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salts and esters thereof.

[0186] The term “repaglinide” as employed herein refers to repaglinide, including its enantiomers, mixtures thereof and its racemate, or a pharmaceutically acceptable salts and esters thereof.

[0187] The group G3 comprises inhibitors of alpha-glucosidase. Examples of inhibitors of alpha-glucosidase are acarbose, voglibose and miglitol.

[0188] Each term of the group “acarbose”, “voglibose” and “miglitol” as employed herein refers to the respective active drug or a pharmaceutically acceptable salt thereof.

[0189] The group G3 comprises inhibitors of DPP-4 inhibitors. Examples of DPP-4 inhibitors are linagliptin, sitagliptin, vildagliptin, saxagliptin, denagliptin, alogliptin, carmegliptin, melogliptin, dutogliptin, including pharmaceutically acceptable salts thereof, hydrates and solvates thereof.

[0190] The group G3 comprises amylin analogs. An example of an amylin analog is pramlintide, including pharmaceutically acceptable salts thereof, hydrates and solvates thereof. For example pramlintide acetate is marketed under the tradename Symlin.

[0191] According to a further embodiment the pharmaceutical compositions, methods and uses according to the present invention relate to a combination of a SGLT2 inhibitor and a GLP-1 receptor agonist which additionally comprises a further antidiabetic agent. Preferred sub-embodiments are selected from the entries in the Table 2.

TABLE-US-00002 TABLE 2 Further antidiabetic SGLT2 Inhibitor GLP-1 receptor agonist agent selected from the group selected from the group metformin G1 G2 selected from the group selected from the group metformin G1a G2 compound (I.9) selected from the group metformin G2 compound (I.9) exenatide metformin compound (I.9) exenatide LAR metformin compound (I.9) liraglutide metformin compound (I.9) taspoglutide metformin compound (I.9) semaglutide metformin compound (I.9) albiglutide metformin compound (I.9) lixisenatide metformin compound (I.9) dulaglutide metformin selected from the group selected from the group linagliptin G1 G2 selected from the group selected from the group linagliptin G1a G2 compound (I.9) selected from the group linagliptin G2 compound (I.9) exenatide linagliptin compound (I.9) exenatide LAR linagliptin compound (I.9) liraglutide linagliptin compound (I.9) taspoglutide linagliptin compound (I.9) semaglutide linagliptin compound (I.9) albiglutide linagliptin compound (I.9) lixisenatide linagliptin compound (I.9) dulaglutide linagliptin

[0192] The combination of an SGLT2 inhibitor and a GLP-1 receptor agonist according to this invention significantly improves the glycemic control, in particular in patients as described hereinafter, compared with a monotherapy using either a SGLT2 inhibitor or a GLP-1 receptor agonist alone. Furthermore the combination of an SGLT2 inhibitor and a GLP-1 receptor agonist according to this invention may allow a reduction of the dose of the GLP-1 receptor agonist compared with a monotherapy of said GLP-1 receptor agonist. With a reduction of the dose of the GLP-1 receptor agonist any side effects associated with the therapy using said GLP-1 receptor agonist may be prevented or attenuated. A dose reduction is beneficial for patients which otherwise would potentially suffer from side effects in a therapy using a higher dose of one or more of the active ingredients, in particular with regard to side effect caused by the GLP-1 receptor agonist. Therefore, the pharmaceutical composition as well as the methods according to the present invention, may show less side effects, thereby making the therapy more tolerable and improving the patients compliance with the treatment. In addition the efficacy of the GLP-1 receptor agonist may be prolonged by a combined treatment with a SGLT2 inhibitor. Therefore the time interval between two applications, for example subcutaneous injections or infusions via a pump, of the GLP-1 receptor agonist may be prolonged. For example in a combination therapy employing a GLP-1 receptor agonist and a SGLT2 inhibitor according to the invention the dose of the GLP-1 receptor agonist, the dose of the SGLT2 inhibitor, the time interval! between two applications of the GLP-1 receptor agonist and the time interval! between the application of the GLP-1 receptor agonist and the SGLT2 inhibitor are chosen such that a good glycemic control is provided to the patient for a given time period, in particular for 24 hours.

[0193] When this invention refers to patients requiring treatment or prevention, it relates primarily to treatment and prevention in humans, but the pharmaceutical composition may also be used accordingly in veterinary medicine in mammals. In the scope of this invention the term “patient” covers adult humans (age of 18 years or older), adolescent humans (age 10 to 17 years) and children (age 6-9 years).

[0194] As described hereinbefore by the administration of the pharmaceutical composition according to this invention and in particular in view of the effect of the GLP1-1 receptor agonist and of the SGLT2 inhibitors therein, 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 patients in need of such treatment or prophylaxis who are diagnosed of one or more of the conditions selected from the group consisting of overweight and obesity, in particular 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. Any weight increasing effect in the therapy, for example due to the administration of the third antidiabetic agent, may be attenuated or even avoided thereby.

[0195] According to an 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 glucose tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome and/or with type 1 diabetes mellitus or type 2 diabetes mellitus characterized in that a GLP-1 receptor agonist and an SGLT2 inhibitor as defined hereinbefore and hereinafter are administered, for example in combination or alternation or sequentially, to the patient.

[0196] According to another 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 characterized by an adiministration of a GLP-1 receptor agonist and an SGLT2 inhibitor as defined hereinbefore and hereinafter, for example in combination or alternation or sequentially, to the patient.

[0197] It can be found that by using a pharmaceutical composition according to this invention, an improvement of the glycemic control can be achieved even in those patients who have insufficient glycemic control in particular despite treatment with a GLP-1 receptor agonist, for example despite maximal recommended or tolerated dose of monotherapy with the GLP-1 receptor agonist.

[0198] Furthermore, the pharmaceutical composition, the methods and uses according to this invention are particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions [0199] (a) obesity (including class I, II and/or III obesity), visceral obesity and/or abdominal obesity, [0200] (b) triglyceride blood level 150 mg/dL, [0201] (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50 mg/dL in male patients, [0202] (d) a systolic blood pressure 130 mm Hg and a diastolic blood pressure 85 mm Hg, [0203] (e) a fasting blood glucose level 100 mg/dL.

[0204] 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. A glycemic control according to this invention may result in a reduction of the cardiovascular risks.

[0205] Furthermore, the pharmaceutical composition, the methods and uses according to this invention are particularly suitable in the treatment of patients after organ transplantation, in particular those patients who are diagnosed having one or more of the following conditions [0206] (a) a higher age, in particular above 50 years, [0207] (b) male gender; [0208] (c) overweight, obesity (including class I, II and/or III obesity), visceral obesity and/or abdominal obesity, [0209] (d) pre-transplant diabetes, [0210] (e) immunosuppression therapy.

[0211] Furthermore, the pharmaceutical composition, the methods and the uses according to this invention are particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions: [0212] (a) hyponatremia, in particular chronical hyponatremia; [0213] (b) water intoxication; [0214] (c) water retention; [0215] (d) plasma sodium concentration below 135 mmol/L.

[0216] Furthermore, the pharmaceutical composition, the methods and uses according to this invention are particularly suitable in the treatment of patients who are diagnosed having one or more of the following conditions: [0217] (a) high serum uric acid levels, in particular greater than 6.0 mg/dL (357 μmol/L); [0218] (b) a history of gouty arthritis, in particular recurrent gouty arthritis; [0219] (c) kidney stones, in particular recurrent kidney stones; [0220] (d) a high propensity for kidney stone formation.

[0221] A pharmaceutical composition according to this invention, in particular due to the SGLT2 inhibitor exhibits a good safety profile. Therefore, a treatment according to this invention is advantageous in those patients for which a reduction of the dose of the GLP-1 receptor agonist is recommended.

[0222] 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 hereinbefore and hereinafter, in particular in the long term glycemic control in patients with type 2 diabetes mellitus.

[0223] The term “long term” as used hereinbefore and hereinafter indicates a treatment of or administration in a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.

[0224] Therefore, a particularly preferred embodiment 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, obesity (including class I, class II and/or class III obesity), visceral obesity and/or abdominal obesity.

[0225] Unless otherwise noted, the combination therapy according to the invention may refer to first line, second line or third line therapy, or initial or add-on combination therapy or replacement therapy.

[0226] According to one embodiment the the GLP-1 receptor agonist and SGLT2 inhibitor and optionally the further antidiabetic agent are administered in combination, i.e. simultaneously, for example in one single formulation or in two separate formulations or dosage forms, or in alternation or sequentially, for example successively in two or three separate formulations or dosage forms. Hence, the administration of one combination partner, i.e. the SGLT2 inhibitor or the GLP-1 receptor agonist, may be prior to, concurrent to, or subsequent to the administration of the other combination partner. In one embodiment, for the combination therapy according to this invention the GLP-1 receptor agonist and the SGLT2 inhibitor are administered in different formulations or different dosage forms. In another embodiment, for the combination therapy according to this invention the SGLT2 inhibitor and the GLP-1 receptor agonist are administered in the same formulation or in the same dosage form.

[0227] Therefore according to an embodiment of the present invention there is provided a pharmaceutical composition or fixed dose combination comprising [0228] a) a SGLT2 inhibitor as defined herein, and [0229] b) a GLP-1 receptor agonist as defined herein,
and, optionally, one or more pharmaceutically acceptable carriers and/or diluents.

[0230] Within the scope of the present invention, the SGLT2 inhibitor is preferably administered orally or by injection, preferably orally. The GLP-1 receptor agonist is preferably administered by injection, preferably subcutaneously, or by infusion. Other forms of administration are possible and described hereinafter. Preferably the optionally administered other antidiabetic agent is administered orally. In this case the SGLT2 inhibitor and the other antidiabetic agent may be comprised together in one dosage form or in separate dosage forms.

[0231] Therefore according to another embodiment the present invention provides a pharmaceutical composition, delivery system or device for systemic use, in particular for administration by injection or infusion, for example subcutaneous injection, comprising [0232] a) a SGLT2 inhibitor as defined herein, and, optionally, [0233] b) a GLP-1 receptor agonist as defined herein,
and, optionally, one or more pharmaceutically acceptable carriers and/or diluents.

[0234] It will be appreciated that the amount of the SGLT2 inhibitor and the GLP-1 receptor agonist and optionally of the further antidiabetic agent 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 medication and will be ultimately at the discretion of the attendant physician. In general, however, the SGLT2 inhibitor, the GLP-1 receptor agonist and optionally the further antidiabetic agent according to this invention are included in the pharmaceutical composition or dosage form in an amount sufficient that by their administration in combination and/or alternation or sequentially the glycemic control in the patient to be treated is improved.

[0235] For the treatment of hyperuricemia or hyperuricemia associated conditions 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 hyperuricemia without disturbing the patient's plasma glucose homeostasis, in particular without inducing hypoglycemia.

[0236] 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.

[0237] For the treatment of hyponatremia and associated conditions 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 hyponatremia or the associated conditions without disturbing the patient's plasma glucose homeostasis, in particular without inducing hypoglycemia.

[0238] In the following preferred ranges of the amount of the SGLT2 inhibitor, the GLP-1 receptor agonist and optionally the further antidiabetic agent to be employed in the pharmaceutical composition and the methods and uses according to this invention are described. These ranges refer to the amounts to be administered per day with respect to an adult patient, in particular to a human being, for example of approximately 70 kg body weight, and can be adapted accordingly with regard to an administration 1 or 2 times daily and with regard to other routes of administration and with regard to the age of the patient. The ranges of the dosage and amounts are calculated for the inidividual active moiety. Advantageously, the combination therapy according to the present invention utilizes lower dosages of the individual SGLT2 inhibitor, of the individual GLP-1 receptor agonist and/or optionally of the individual further antidiabetic agent used in monotherapy or used in conventional therapeutics, thus avoiding possible adverse side effects incurred when those agents are used as monotherapies.

[0239] In general, the amount of the SGLT2 inhibitor in the pharmaceutical composition, methods and uses according to this invention is preferably in the range from 1/5 to 1/1 of the amount usually recommended for a monotherapy using said SGLT2 inhibitor.

[0240] 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. The oral administration is preferred. Therefore, a pharmaceutical composition may comprise 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, 25 or 50 mg of the compound of the formula (I), in particular of the compound (I. 9). The application of the active ingredient may occur one, two or three times a day, preferably once a day.

[0241] In general, the amount of the GLP-1 receptor agonist in the pharmaceutical composition, methods and uses according to this invention is preferably in the range from 1/5 to 1/1 of the amount usually recommended for a monotherapy using said GLP-1 receptor agonist.

[0242] The GLP-1 receptor agonist is typically administered by subcutaneous injection, e.g. ranging from once, twice, three or more times daily. For example the GLP-1 receptor agonist is administered subcutaneously via injection about 30 to 60 minutes before a meal. Suitable doses and dosage forms of the GLP-1 receptor agonist may be determined by a person skilled in the art.

[0243] Exenatide is usually administered once, twice or more times, preferably twice daily by subcutaneous injection with a dose in the range form 5 to 30 μg, particularly 5 to 20 μg, preferably 5 to 10 μg. Specific dosage strengths are for example 5 or 10μg per administration. A tradename of exenatide is Byetta. For example exenatide is administered twice daily via subcutaneous injection each of 5 μg. The therapy is continued for at least one month. The dose may be increased to 10 μg twice daily. The time of each injection is preferably within 60 minutes before a meal, for example before a meal in the morning and before a meal in the evening.

[0244] Exenatide LAR is usually administered once weekly by subcutaneous injection (0.1-3 mg, particularly 0.5 mg to 2.0 mg, specific dosage strengths are 0.8 mg or 2.0 mg).

[0245] Liraglutide is usually administered once daily by subcutaneous injection (0.5-3 mg, particularly 0.5 mg to 2 mg, specific dosage strengths are 0.6 mg, 0.9 mg, 1.2 mg or 1.8 mg).

[0246] Taspoglutide is usually administered once weekly by subcutaneous injection (1-30 mg, specific dosage strengths are 1 mg, 8 mg, 10 mg, 20 mg or 30 mg).

[0247] Semaglutide is usually administered once weekly by subcutaneous injection (0.1-1.6 mg). Albiglutide is administered once weekly by subcutaneous injection (4-30 mg, specific dosage strengths are 4 mg, 15 mg or 30 mg).

[0248] Lixisenatide is usually administered once daily by subcutaneous injection (10-20 μg, specific dosage strengths are 10 μg, 15 μg or 20 μg).

[0249] Dulaglutide is usually administered once weekly by subcutaneous injection (0.25-3 mg, specific dosage strengths are 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg or 3.0 mg).

[0250] In case the SGLT2 inhibitor and the GLP-1 receptor agonist are to be combined with a further antidiabetic agent, the dose of the further antidiabetic agent is preferably in the range from 1/5 to 1/1 of the dose usually recommended for a monotherapy using said further antidiabetic agent. Using lower dosages of the individual further antidiabetic agent compared with monotherapy could avoid or minimize possible toxicity and adverse side effects incurred when those agents are used as monotherapies.

[0251] With regard to metformin as a preferred further antidiabetic agent metformin is usually given in doses varying from about 500 mg to 2000 mg up to 3000 mg per day using various dosing regimens 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, twice or thrice 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 metformin hydrochloride.

[0252] For children 10 to 16 years of age, the recommended starting 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 increments 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.

[0253] With regard to pioglitazone as a preferred further antidiabetic agent a dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day.

[0254] With regard to linagliptine as a preferred further antidiabetic agent a dosage of linagliptine is usually of about 1-10 mg, for example 1, 2.5, 5 or 10 mg once a day.

[0255] In the methods and uses according to the present invention the GLP-1 receptor agonist and the SGLT2 inhibitor are administered in combination or alternation or sequentially. The term “administration in combination” means that the active ingredients are administered at the same time, i.e. simultaneously, or essentially at the same time. The term “administration in alternation” means that at first one of the two active ingredients, i.e. the SGLT2 inhibitor or the GLP-1 receptor agonist, is administered and after a period of time the other active ingredient, i.e. the GLP-1 receptor agonist or the SGLT2 inhibitor, is administered whereby this administration scheme may be repeated one or more times. The period of time between the administration of the first and of the second active ingredient may be in the range from 1 min to 12 hours. The administration which is in combination or in alternation may be once, twice, three times or four times daily, preferably once or twice daily. The term “sequentially” means that to a patient the first active ingredient, in particular the GLP-1 receptor agonist, is administered to the patient one or more times in a first period of time followed by an administration of the second active ingredient, in particular the SGLT2 inhibitor which is adminstered to the patient one or more times in a second period of time. In other words the term “sequentially” includes a first therapy, in particular with the GLP-1 receptor agonist, in a first period of time followed by a second therapy, in particular with the SGLT2 inhibitor, in a second period of time. The time periods may be in a range from one to more days, one to more weeks or one to more months. According to one embodiment the first and the second period of time is in a range from one to more weeks, in particular one to more months.

[0256] 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.

[0257] According to a first embodiment a preferred kit of parts comprises [0258] (a) a first containment containing a dosage form comprising the SGLT2 inhibitor and at least one pharmaceutically acceptable carrier, and [0259] (b) a second containment containing a dosage form comprising the GLP-1 receptor agonist and at least one pharmaceutically acceptable carrier.

[0260] According to a second embodiment a preferred kit of parts comprises [0261] (a) a first containment containing a dosage form comprising the SGLT2 inhibitor and at least one pharmaceutically acceptable carrier, and [0262] (b) a second containment containing a dosage form comprising the GLP-1 receptor agonist and at least one pharmaceutically acceptable carrier, and [0263] (b) a third containment containing a dosage form comprising a further antidiabetic agent (for example metformin, pioglitazone or linagliptine) and at least one pharmaceutically acceptable carrier.

[0264] According to a third embodiment a preferred kit of parts comprises [0265] (a) a first containment containing a dosage form comprising the SGLT2 inhibitor and a further antidiabetic agent and at least one pharmaceutically acceptable carrier, and [0266] (b) a second containment containing a dosage form comprising the GLP-1 receptor agonist and at least one pharmaceutically acceptable carrier.

[0267] A further aspect of the present invention is a manufacture comprising the pharmaceutical composition being present as separate dosage forms according to the present invention and a label or package insert comprising instructions that the separate dosage forms are to be administered in combination or alternation or sequentially.

[0268] According to a first embodiment a manufacture comprises (a) a pharmaceutical composition comprising a SGLT2 inhibitor according to the present invention and (b) a label or package insert which comprises instructions that the medicament may or is to be administered, for example in combination or alternation or sequentially, with a medicament comprising a GLP-1 receptor agonist according to the present invention or with a medicament comprising both a GLP-1 receptor agonist and a further antidiabetic agent according to the present invention.

[0269] According to a second embodiment a manufacture comprises (a) a pharmaceutical composition comprising a GLP-1 receptor agonist according to the present invention and (b) a label or package insert which comprises instructions that the medicament may or is to be administered, for example in combination or alternation or sequentially, with a medicament comprising a SGLT2 inhibitor according to the present invention or with a medicament comprising both a SGLT2 inhibitor and a further antidiabetic agent according to the present invention.

[0270] According to a third embodiment a manufacture comprises (a) a pharmaceutical composition comprising a SGLT2 inhibitor and a further antidiabetic agent according to the present invention and (b) a label or package insert which comprises instructions that the medicament may or is to be administered, for example in combination or alternation or sequentially, with a medicament comprising a GLP-1 receptor agonist according to the present invention.

[0271] 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.

[0272] The pharmaceutical composition may be formulated for oral, parenteral (including sub-cutaneous) or other routes of administration in liquid or solid form. Oral administration of the SGLT2 inhibitor is preferred. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with one or more pharmaceutically acceptable carriers, like liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. Examples of pharmaceutical compositions comprising the SGLT2 inhibitor compound (I.9) are described in WO 2010/092126. Examples of pharmaceutical compositions comprising the SGLT2 inhibitor compound (I.9) and linagliptin are described in WO 2010/092124.

[0273] Injectable formulations of the GLP-1 receptor agonists of this invention may be prepared according to known formulation techniques, e.g. using suitable liquid carriers, which usually comprise sterile water, and, optionally, further additives e.g. for aiding solubility or for preservation or the like, to obtain injectable solutions or suspensions.

[0274] The pharmaceutical composition may be formulated in the form of solutions, suspensions, emulsions, tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, fast dissolving tablets, oral fast-dispersing tablets, etc. Preferably the pharmaceutical composition of the SGLT2 inhibitor is in the form of tablets.

[0275] The pharmaceutical composition and the dosage forms preferably comprises one or more pharmaceutical acceptable carriers. Preferred carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to the one skilled in the art.

[0276] The pharmaceutical composition according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented 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 formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredients may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0277] Injectable formulations of the GLP-1 receptor agonist and/or the SGLT2 inhibitor of this invention (particularly for subcutaneous use) may be prepared according to known formulation techniques, e.g. using suitable liquid carriers, which usually comprise sterile water, and, optionally, further additives such as e.g. preservatives, pH adjusting agents, buffering agents, isotoning agents, solubility aids and/or tensides or the like, to obtain injectable solutions or suspensions. In addition, injectable formulations may comprise further additives, for example salts, solubility modifying agents or precipitating agents which retard release of the drug(s). In further addition, injectable GLP-1 receptor agonist formulations may comprise stabilizing agents. The component GLP-1 receptor agonist of the combination according to the invention is preferably administered by injection (preferably subcutaneously).

[0278] For further details on dosage forms, formulations and administration of SGLT2 inhibitors of this invention and/or GLP-1 receptor agonist of this invention, reference is made to scientific literature and/or published patent documents, particularly to those cited herein.

[0279] The pharmaceutical compositions (or formulations) may be packaged in a variety of ways. Generally, an article for distribution includes one or more containers that contain the one or more pharmaceutical compositions in an appropriate form. Tablets are typically packed in an appropriate primary package for easy handling, distribution and storage and for assurance of proper stability of the composition at prolonged contact with the environment during storage. Primary containers for tablets may be bottles or blister packs.

[0280] Solutions for injection may be available in typical suitable presentation forms such as vials, cartridges or prefilled (disposable) pens, which may be further packaged.

[0281] The article may further comprise a label or package insert, which refers to instructions customarily included in commercial packages of therapeutic products, that may contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. In one embodiment, the label or package inserts indicates that the composition can be used for any of the purposes described hereinbefore or hereinafter.

[0282] 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 compared with pharmaceutical compositions and methods which comprise only one of the two active ingredients. Additional advantageous effects may be seen for example with respect to efficacy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic properties, fewer adverse effects, convenience, compliance, etc.

[0283] Methods for the manufacture of SGLT2 inhibitors according to this invention and of prodrugs thereof are known to the one skilled in the art. Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, including patent applications as cited hereinbefore. Preferred methods of manufacture are described in the WO 2006/120208 and WO 2007/031548. With regard to the preferred compound (1.9) an advantageous crystalline form is described in the international patent application WO 2006/117359 which hereby is incorporated herein in its entirety.

[0284] With respect to GLP-1 receptor agonists the methods of synthesis are known to the skilled person and as described in the scientific literature and/or in published patent documents, particularly in those cited hereinbefore.

[0285] The active ingredients, in particular the GLP-1 receptor agonist and/or the further antidiabetic agent, may be present in the form of a pharmaceutically acceptable salt. The active ingredients or a pharmaceutically acceptable salt thereof may be present in the form of a solvate such as a hydrate or alcohol adduct.

[0286] Any of the above mentioned combinations and methods within the scope of the invention may be tested by animal models known in the art. In the following, in vivo experiments are described which are suitable to evaluate pharmacologically relevant properties of pharmaceutical compositions and methods according to this invention:

[0287] Pharmaceutical compositions and methods according to this invention can be tested in genetically hyperinsulinemic or diabetic animals like db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested in animals with experimentally induced diabetes like HanWistar or Sprague Dawley rats pretreated with streptozotocin.

[0288] The effect on glycemic control of the combinations according to this invention can be tested after single dosing of the SGLT2 inhibitor and the GLP-1 receptor agonist alone and in combination in an oral glucose tolerance test in the animal models described hereinbefore. The time course of blood glucose is followed after an oral glucose challenge in overnight fasted animals. The combinations according to the present invention improve glucose excursion compared to each monotherapy as measured by reduction of peak glucose concentrations or reduction of glucose AUC. In addition, after multiple dosing of the SGLT2 inhibitor and the GLP-1 receptor agonist alone and in combination in the animal models described hereinbefore, the effect on glycemic control can be determined by measuring the HbA1c value in blood. The combinations according to this invention may reduce HbA1c compared to each monotherapy.

[0289] The possible dose reduction of one or both of the SGLT2 inhibitor and the GLP-1 receptor agonist can be tested by the effect on glycemic control of lower doses of the combinations and monotherapies in the animal models described hereinbefore. The combinations according to this invention at the lower doses may improve glycemic control compared to placebo treatment whereas the monotherapies at lower doses do not.

[0290] A superior effect of the combination of a SGLT2 inhibitor and a GLP-1 receptor agonist according to the present invention on beta-cell regeneration and neogenesis can be determined after multiple dosing in the animal models described hereinbefore by measuring the increase in pancreatic insulin content, or by measuring increased beta-cell mass by morphometric analysis after immunohistochemical staining of pancreatic sections, or by measuring increased glucose-stimulated insulin secretion in isolated pancreatic islets.

PHARMACOLOGICAL EXAMPLES

[0291] The following example shows the beneficial effect on glycemic control of the combination according to the present invention.

Example 1:

[0292] The following example shows the beneficial effect on glycemic control of the combination of a glucopyranosyl-substituted benzene derivative and the GLP-1 receptor agonist exendin-4 (1-39) as compared to the respective monotherapies. All experimental protocols concerning the use of laboratory animals were reviewed by a federal Ethics Committee and approved by governmental authorities. An oral glucose tolerance test was performed in overnight fasted 12-weeks old male Zucker diabetic fatty (ZDF) rats (ZDF/CRL-Lepr.sup.fa). A pre-dose blood sample was obtained by tail bleed. Blood glucose was measured with a glucometer, and the animals were randomized for blood glucose (n=5/group). Subsequently, the groups received a single oral administration of either vehicle alone (0.5% aqueous hydroxyethylcellulose) or this vehicle containing the glucopyranosyl-substituted benzene derivative. Fifteen minutes later, the groups received a single subcutaneous injection of either vehicle alone (physiological saline solution) or this vehicle containing exendin-4. The animals were orally dosed with glucose (2 g/kg) 30 min after the subcutaneous injection. Blood glucose was measured in tail blood 15 min, 30 min, 60 min, 90 min, and 120 min thereafter. Glucose excursion was quantified by calculating the reactive glucose AUC. The data are presented as mean ±S.E.M. The two-sided unpaired Student's t-test was used for statistical comparison of the groups. A p value <0.05 was considered to show a statistically significant difference. The result is shown in the FIG. 1. Therein “Cpd. A” denotes the glucopyranosyl-substituted benzene derivative (compound (I.9)) at a dose of 3 mg/kg. Exendin-4 was dosed at 0.01 mg/kg. The term “Combination A+Exendin-4” denotes the combination of the glucopyranosyl-substituted benzene derivative and exendin-4 at the same doses. P values versus control are indicated by symbols above the bars. P values of the combination versus the monotherapies are indicated below the figure (*, p<0.05; **,p<0.01; ***, p<0.001). The glucopyranosyl-substituted benzene derivative reduced glucose excursion by 57%, and exendin-4 reduced glucose excursion by 40%. The combination decreased glucose excursion in the oral glucose tolerance test by 83%, and this reduction in glucose AUC was statistically significant versus each monotherapy.