Vasoprotective and cardioprotective antidiabetic therapy

Abstract

The present invention relates to certain DPP-4 inhibitors for treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction as well as to the use of such DPP-4 inhibitors in treatment and/or prevention of diabetic or non-diabetic patients, including patient groups at risk of cardiovascular and/or renal disease.

1 . A method for using linagliptin in one or more of the following methods:
 preventing, slowing the progression of, delaying or treating a metabolic disorder or disease selected from 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, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, 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;   preventing, slowing, delaying 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 or treating of complications of diabetes mellitus such as a micro- or macrovascular disease selected from nephropathy, micro- or macroalbuminuria, proteinuria, 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 or preventing an increase in body weight and/or body fat or facilitating a reduction in body weight and/or body fat;   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, 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 or treating non alcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis;   preventing, slowing the progression of, delaying 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 oxidative stress, vascular stress and/or endothelial dysfunction, or diseases or conditions related or associated therewith, or 
       in a patient with or at risk of cardiovascular and/or renal disease selected from myocardial infarction, stroke, peripheral arterial occlusive disease diereses, diabetic nephropathy, micro- or macroalbuminuria, and acute or chronic renal impairment, or 
       in a patient with one or more cardiovascular risk factors selected from A), B), C) and D): 
       A) previous or existing vascular disease selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery by-pass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive arterial disease, 
       B) vascular related end-organ damage selected from nephropathy, retinopathy, neuropathy, impaired renal function, chronic kidney disease, and micro- or macroalbuminuria, 
       C) advanced age >/=60-70 years, and 
       D) one or more cardiovascular risk factors selected from
 advanced type 2 diabetes mellitus >10 years duration, 
 hypertension, 
 current daily cigarette smoking, 
 dyslipidemia, 
 obesity, 
 age >/=40 and </=80, 
 metabolic syndrome, hyperinsulinemia or insulin resistance, and 
 hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or family history of vascular disease or cardiomyopathy in first-degree relative; 
 
       said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to the patient. 
     
     
         2 . The method of  claim 1 , said method comprising treating type 2 diabetes mellitus. 
     
     
         3 . The method of  claim 1 , wherein the patient is a type 2 diabetes patient with or at risk of a cardiovascular and/or renal disease selected from myocardial infarction, stroke, peripheral arterial occlusive diseases, diabetic nephropathy, micro- or macroalbuminuria, and acute or chronic renal impairment. 
     
     
         4 . The method of  claim 1 , wherein the patient is a type 2 diabetes patient with one or more of the cardiovascular risk factors selected from A), B), C) and D):
 A) previous or existing vascular disease selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery by-pass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive arterial disease,   B) vascular related end-organ damage selected from nephropathy, retinopathy, neuropathy, impaired renal function, chronic kidney disease, and micro- or macroalbuminuria),   C) advanced age >/=60-70 years, and   D) one or more cardiovascular risk factors selected from
 advanced type 2 diabetes mellitus >10 years duration, 
 hypertension, 
 current daily cigarette smoking, 
 dyslipidemia, 
 obesity, 
 age >/=40 and </=80, 
 metabolic syndrome, hyperinsulinemia or insulin resistance, and 
 hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or family history of vascular disease or cardiomyopathy in first-degree relative. 
   
     
     
         5 . A method for preventing, reducing the risk of or delaying the occurrence of cardio- or cerebrovascular events selected from cardiovascular death, myocardial infarction, stroke, and hospitalisation for acute coronary syndrome, leg amputation, revascularization procedures, heart failure or unstable angina pectoris in type 2 diabetes patients, said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to a patient in need thereof, wherein
 the type 2 diabetes patients are at risk of cardio- or cerebrovascular events with one or more risk factors selected from A), B), C) and D):   A) previous or existing vascular disease selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery by-pass grafting, ischemic or hemorrhagic stroke, congestive heart failure, and peripheral occlusive arterial disease,   B) vascular related end-organ damage selected from nephropathy, retinopathy, neuropathy, impaired renal function, chronic kidney disease, and micro- or macroalbuminuria,   C) advanced age >1=60-70 years, and   D) one or more cardiovascular risk factors selected from
 advanced type 2 diabetes mellitus >10 years duration, 
 hypertension, 
 current daily cigarette smoking, 
 dyslipidemia, 
 obesity, 
 age >/=40 and </=80, 
 metabolic syndrome, hyperinsulinemia or insulin resistance, and 
 hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or family history of vascular disease or cardiomyopathy in first-degree relative. 
   
     
     
         6 . The method of  claim 5 , wherein the type 2 diabetes patients have vascular related end-organ damage selected from nephropathy, retinopathy, neuropathy, impaired renal function, chronic kidney disease, and micro- or macroalbuminuria. 
     
     
         7 . A method of preventing, reducing the risk of or delaying the occurrence of a cardio- or cerebrovascular event selected from cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for unstable angina pectoris, in type 2 diabetes patients being at risk of cardio- or cerebrovascular events,
 said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to the patients.   
     
     
         8 . The method of  claim 7 , wherein the type 2 diabetes patients have nephropathy, impaired renal function, chronic kidney disease, and/or micro- or macroalbuminuria. 
     
     
         9 . The method of  claim 8 , wherein the type 2 diabetes patients have mild, moderate or severe renal impairment, or end stage renal disease. 
     
     
         10 . The method of  claim 9 , wherein the type 2 diabetes patients have microalbuminuria or diabetic nephropathy. 
     
     
         11 . The method of  claim 1 , wherein the one or more other therapeutic substances are 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, active substances that are indicated in the treatment of atherosclerosis or obesity, antiplatelet agents, anticoagulant agents, and vascular endothelial protective agents. 
     
     
         12 . The method of  claim 11 , wherein the other antidiabetic substances are selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogues, and GLP-1 and GLP-1 analogues. 
     
     
         13 . The method of  claim 11 , wherein the active substances that lower blood pressure are selected from angiotensin receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. 
     
     
         14 . The method of  claim 1 , further comprising administering linagliptin in combination with one or more other antidiabetic substances selected from metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist, an alpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 or GLP-1 analogue; and, optionally, telmisartan. 
     
     
         15 . The method of  claim 1 , further comprising administering linagliptin in combination with metformin. 
     
     
         16 . The method of  claim 1 , further comprising administering linagliptin in combination with telmisartan. 
     
     
         17 . The method of  claim 1 , wherein linagliptin is administered orally in a total daily amount of 5 mg. 
     
     
         18 . A method of preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing or treating diabetic nephropathy in a patient who does not adequately respond to therapy with an angiotensin receptor blocker (ARB), said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances to the patient. 
     
     
         19 . The method according to  claim 18 , wherein the method comprises administering a therapeutically effective amount of linagliptin in combination with an ARB. 
     
     
         20 . The method according to  claim 19 , wherein the ARB is telmisartan. 
     
     
         21 . The method according to  claim 18 , wherein linagliptin is administered orally in a total daily amount of 5 mg. 
     
     
         22 . A method of preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing or treating learning or memory impairment, neurodegenerative or cognitive disorders, cognitive dysfunction or cognitive decline in a patient in need thereof, said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to the patient. 
     
     
         23 . A method of preventing, reducing the risk of, slowing the progression of, delaying the onset of, attenuating, reversing or treating latent autoimmune diabetes in adults (LADA), said method comprising administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to the patient.