Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin

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 and metabolic syndrome, or

• 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, or 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, or
• 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, or
• for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight, or
• 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, or
• for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat, or
• 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, wherein the patient has one or more variations in one or more of the genes selected from TCF7L2 and GLP1R or in a patient who is of respective wild-type genotype,
• said method comprising
• testing whether the patient has one or more variations in one or more of the genes selected from TCF7L2 and GLP1R, and
• administering a DPP-4 inhibitor selected from linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin and dutogliptin, and, optionally, a second antidiabetic agent selected from biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues, and, optionally, a third antidiabetic agent selected from biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues, to the patient, optionally in combination, including in alternation.

A method of using a pharmaceutical composition comprising

• (a) DPP-4 inhibitor selected from linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin and dutogliptin, and, optionally,
• (b) a second antidiabetic agent selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues, and, optionally,
• (c) a third antidiabetic agent being different from (b) selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues,
• or a pharmaceutically acceptable salt thereof,
• 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, insulin resistance, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction, non-alcoholic fatty liver disease (NAFLD) and osteoporosis;
• or
• for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c;
• or
• for preventing, slowing, delaying or reversing progression from impaired glucose tolerance, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus;
• or
• 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;
• or
• for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight;
• or
• 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;
• or
• for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat;
• or
• 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,
• wherein the patient has variation(s) in one or more genes associated with metabolic diseases,
• the one or more of the genes selected from TCF7L2 and GLP1R, wherein said patient having a variation in the gene associated with TCF7L2 has one or more single nucleotide polymorphisms (SNPs) in the gene coding for TCF7L2 selected from rs7903146, rs12255372 and rs10885406,
• or
• in a patient being of
• of wild-type genotype at rs7903146 of TCF7L2.

A method of using a pharmaceutical composition comprising

• (a) DPP-4 inhibitor selected from linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin and dutogliptin, and, optionally,
• (b) a second antidiabetic agent selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues, and, optionally,
• (c) a third antidiabetic agent being different from (b) selected from the group G3 consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, inhibitors of alpha-glucosidase, GLP-1 or GLP-1 analogues, and insulin or insulin analogues,
• or a pharmaceutically acceptable salt thereof,
• 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 and metabolic syndrome;
• or
• for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c;
• or
• for preventing, slowing, delaying or reversing progression from impaired glucose tolerance, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus;
• or
• 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;
• or
• for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight;
• or
• 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;
• or
• for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat;
• and/or
• 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, said method comprising
• (i) testing whether the patient is of any TCF7L2 risk genotype, wherein the patient has one or more single nucleotide polymorphisms (SNPs) in the gene coding for TCF7L2, wherein at least one SNP is selected from rs7903146, rs12255372 and rs10885406,
• or testing whether the patient is of TCF7L2 rs7903146 wild genotype,
• and, optionally,
• (ii) administering to the patient the pharmaceutical composition.