Use of a dpp-4 inhibitor in podocytes related disorders and/or nephrotic syndrome

Abstract

The present invention relates to methods for treating and/or preventing podocytes related disorders and/or nephrotic syndrome comprising the administration of an effective amount of a certain DPP-4 inhibitor, as well as to the use of a certain DPP-4 inhibitor for treating and/or preventing a metabolic disease in a patient with or at risk of podocytes related disorders and/or nephrotic syndrome.

What is claimed is: 
     
         1 . A method of using a DPP-4 inhibitor which is of formula (h 
       
         
           
           
               
               
           
         
         or formula (II) 
       
       
         
           
           
               
               
           
         
         or formula (III) 
       
       
         
           
           
               
               
           
         
         or formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R1 denotes ([1,5]naphthyridin-2-ylmethyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino, 
         or a pharmaceutically acceptable salt thereof; 
         optionally in combination with one or more other active agents, 
         for treating, preventing and/or reducing the risk of podocyte related disorders, disturbance of podocyte function, podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS) in a patient. 
       
     
     
         2 . The method according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing and/or reducing the risk of podocyte related disorders, disturbance of podocyte function, podocyte loss or injury, and/or podocytopathy. 
     
     
         3 . The method according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing or reducing the risk of nephrotic syndrome. 
     
     
         4 . The method according to  claim 3 , wherein the nephrotic syndrome includes, is caused by or is associated with minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS). 
     
     
         5 . The method according to  claim 4 , wherein the nephrotic syndrome is primary or secondary. 
     
     
         6 . The method according to  claim 4 , wherein the nephrotic syndrome is resistant or refractory to conventional therapy. 
     
     
         7 . The method according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing and/or reducing the risk of minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS). 
     
     
         8 . The method according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing and/or reducing the risk of minimal change disease (MCD) which is minimal change nephropathy. 
     
     
         9 . The emethod according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing and/or reducing the risk of membranous nephropathy (MN). 
     
     
         10 . The method according to  claim 1 , wherein the DPP-4 inhibitor is linagliptin, optionally in combination with one or more other active agents, and the method is for treating, preventing and/or reducing the risk of focal segmental glomerulosclerosis (FSGS). 
     
     
         11 . The method according to  claim 1 , wherein the patient has type 1 diabetes, type 2 diabetes, or LADA. 
     
     
         12 . The method according to  claim 1 , wherein the patient has type 2 diabetes mellitus. 
     
     
         13 . The method according to  claim 1 , wherein the patient is non-diabetic. 
     
     
         14 . The method according to  claim 1 , wherein the patient is impaired in renal function and/or has nephropathy and/or albuminuria. 
     
     
         15 . The method according to  claim 1 , wherein the one or more other active agents include active substances which are indicated in the treatment of nephrotic syndrome are selected from the group consisting of corticosteroids, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), cyclophosphamide, cyclosporine, and/or anticoagulants. 
     
     
         16 . A method of using linagliptin, optionally in combination with one or more other active agents, for treating and/or preventing a metabolic disease, and/or conditions related thereto, in a patient with or at risk of podocyte related disorders, disturbance of podocyte function, podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS). 
     
     
         17 . The method according to  claim 16 , wherein the metabolic disease is at least one selected from 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, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, nephrotic syndrome, polycystic ovarian syndrome, and metabolic syndrome. 
     
     
         18 . A method of using linagliptin, optionally in combination with one or more other active agents, for at least one of the following methods:
 preventing, slowing the progression of, delaying the onset of or treating a metabolic disorder or disease selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, nephrotic syndrome, polycystic ovarian syndrome, and/or metabolic syndrome;   improving and/or maintaining glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose, of postabsorptive plasma glucose and/or of glycosylated hemoglobin HbA1c, or preventing, reducing the risk of, slowing the progression of, delaying the onset of or treating worsening or deterioration of glycemic control, need for insulin therapy or elevated HbA1c despite treatment;   preventing, slowing, delaying the onset of or reversing progression from pre-diabetes, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus;   preventing, reducing the risk of, slowing the progression of, delaying the onset of or treating of complications of diabetes mellitus such as micro- and macrovascular diseases, such as nephropathy, micro- or macroalbuminuria, proteinuria, nephrotic syndrome, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardio- or cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis, and/or stroke;   reducing body weight and/or body fat and/or liver fat and/or intra-myocellular fat or preventing an increase in body weight and/or body fat and/or liver fat and/or intra-myocellular fat or facilitating a reduction in body weight and/or body fat and/or liver fat and/or intra-myocellular fat;   preventing, slowing, delaying the onset of or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving, preserving and/or restoring the functionality of pancreatic beta cells and/or stimulating and/or restoring or protecting the functionality of pancreatic insulin secretion;   preventing, slowing, delaying the onset of or treating non alcoholic fatty liver disease (NAFLD) including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis;   preventing, slowing the progression of, delaying the onset of or treating type 2 diabetes with failure to conventional antidiabetic mono- or combination therapy;   achieving a reduction in the dose of conventional antidiabetic medication required for adequate therapeutic effect;   reducing the risk for adverse effects associated with conventional antidiabetic medication;   and/or   maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance;   
       in a patient with or at risk of podocyte related disorders, disturbance of podocyte function, podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS). 
     
     
         19 . The method according to  claim 16 , wherein the patient has diabetes and has or is at risk of nephrotic syndrome. 
     
     
         20 . The method according to  claim 19 , wherein the nephrotic syndrome includes, is caused by or is associated with minimal change disease (MCD), membranous nephropathy (MN) and/or focal segmental glomerulosclerosis (FSGS). 
     
     
         21 . The method according to  claim 16 , wherein the one or more other active agents include active substances selected from other antidiabetic substances, active substances that lower the blood sugar level, active substances that lower the lipid level in the blood, active substances that raise the HDL level in the blood, active substances that lower blood pressure, and/or active substances that are indicated in the treatment of atherosclerosis or obesity. 
     
     
         22 . The method according to  claim 21 , wherein the one or more other active agents include active substances selected from diuretics, ARBs and/or ACE inhibitors. 
     
     
         23 . The method according to  claim 1 , wherein the nephrotic syndrome is manifested by proteinuria, edema (which may be associated with weight gain), hypoalbuminemia, hyperlipidemia and, optionally, hypertension. 
     
     
         24 . A method of using linagliptin for treating, preventing, reducing the risk of, delaying the onset or slowing the progression of albuminuria or diabetic nephropathy in type 2 diabetes patients with early diabetic nephropathy, wherein said patients have inadequate control of albuminuria despite therapy with an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB), said method comprising administering said linagliptin in combination with the angiotensin-converting enzyme (ACE) inhibitor and/or the angiotensin II receptor blocker (ARB) to the patient. 
     
     
         25 . A method of using linagliptin in preventing, reducing the risk of or delaying the onset or slowing the progression of renal morbidity and/or mortality. 
     
     
         26 . A method of using linagliptin in preventing, reducing the risk of or delaying the onset or progression of micro- or macro-albuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, and/or the onset of acute renal failure.