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, a DPPIV inhibitor and a third antidiabetic agent which is suitable in the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions

1 . A pharmaceutical composition comprising
 (a) an SGLT2 inhibitor, and   (b) a DPPIV inhibitor, and   (c) a third antidiabetic agent selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 analogues or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The pharmaceutical composition according to the  claim 1  wherein the SGLT2 inhibitor is selected from the group G1 consisting of dapagliflozin, canagliflozin, atigliflozin, remogliflozin, sergliflozin and glucopyranosyl-substituted benzene derivatives of the formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
       
     
     
         3 . The pharmaceutical composition according to the  claim 1  wherein the DPP IV inhibitor is selected from the group G2 consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, denagliptin, carmegliptin, melogliptin and dutogliptin, or a pharmaceutically acceptable salt of one of the beforementioned DPPIV inhibitors, or a prodrug thereof. 
     
     
         4 . The pharmaceutical composition according to  claim 1  wherein the third antidiabetic agent is selected from the group consisting of metformin, pioglitazone, rosiglitazone, troglitazone, ciglitazone, glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornurid, glyburide, glisoepide, gliclazide, nateglinide, repaglinide, mitiglinide, acarbose, voglibose, miglitol, exenatide and liraglutide or a pharmaceutically acceptable salt of one of the beforementioned therapeutic agents. 
     
     
         5 . The pharmaceutical composition according to  claim 1  wherein the composition is suitable for combined or simultaneous or sequential use of the SGLT2 inhibitor, the DPP IV inhibitor and the third antidiabetic agent. 
     
     
         6 . Method for 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, new onset diabetes after transplantation (NODAT) and complications associated therewith, and post-transplant metabolic syndrome (PTMS) and complications associated therewith in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         7 . Method according to  claim 6  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         8 . 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 characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         9 . Method according to  claim 8  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         10 . Method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance, impaired fasting blood glucose, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         11 . Method according to  claim 10  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         12 . Method for 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, in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         13 . Method according to  claim 12  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         14 . Method for 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 in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         15 . Method according to  claim 14  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         16 . Method for 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 in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         17 . Method according to  claim 16  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         18 . Method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of ectopic fat in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         19 . Method according to  claim 18  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         20 . Method for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         21 . Method according to  claim 20  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent. 
 
     
     
         22 . Method for treating and preventing hyperuricemia and hyperuricemia associated conditions, kidney stones and hyponatremia in a patient in need thereof characterized in that an SGLT2 inhibitor, a DPP IV inhibitor and optionally a third antidiabetic agent according to  claim 1  are administered in combination or alternation to the patient. 
     
     
         23 . Method according to  claim 22  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 110 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; 
 (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (b) triglyceride blood level ≥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 ≥130 mm Hg and a diastolic blood pressure ≥85 mm Hg, 
 (e) a fasting blood glucose level ≥100 mg/dL; or 
 
 (4) has insufficient glycemic control despite diet and exercise or despite monotherapy with either the SGLT2 inhibitor, the DPPIV inhibitor or the third antidiabetic agent, or despite combination therapy with two agents selected from the group of the SGLT2 inhibitor, the DPPIV inhibitor and the third antidiabetic agent.