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    • 专利摘要:
    USE OF THE DDP-4 INHIBITOR, COMPOSITION OR PHARMACEUTICAL COMBINATION OF THE SAME, IN THE PREPARATION OF DRUGS FOR THE TREATMENT OF DIABETES AND PARTS KIT.The present invention relates to methods for preventing or treating metabolic disorders and related conditions, such as, in certain patient groups.
    公开号:BR112012012641A2
    申请号:R112012012641-5
    申请日:2010-11-26
    公开日:2020-08-11
    发明作者:Klaus Dugi；Eva Ulrike Graefe-Mody；Michael Mark；Hans-Juergen Woerle；Heike Zimdahl-Gelling
    申请人:Boehringer Ingelheim International Gmbh；
    IPC主号:
    专利说明:

    Descriptive Report of the Invention Patent for "USE OF THE DDP-4 INHIBITOR, COMPOSITION OR PHARMACEUTICAL COMBINATION OF THE SAME, IN THE PREPARATION OF DRUGS FOR THE TREATMENT OF DIABETES AND PARTS KIT". Technical Field of the Invention The present invention relates to DPP-4 inhibitors, pharmaceutical compositions or combinations comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, for use in methods of treatment or prevention as described herein, as for example, of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose and intergly hyperglycemia.
    In a particular embodiment, the therapeutic and / or preventive methods of this invention comprise, the step of identifying a patient who is susceptible to treatment and / or prevention, said identification comprising testing whether the patient has variation (s) in one or more genes associated with metabolic diseases (for example if the patient is of a TCF7L2 risk genotype as described here) or if the patient is of the respective wild type genotype (for example, if the patient is of the wild TCF7L2 genotype as described herein), and the other step of administering such a DPP-4 inhibitor, combination or pharmaceutical composition to the patient determined to be susceptible.
    In addition, in one embodiment, the utility of a DPP-4 inhibitor, a pharmaceutical composition, combination or drug, each as described herein for a therapeutic and / or preventive method or use according to this invention in a patient who has Variation (s) in one or more genes associated with metabolic disorders (such as, for example, a patient TCF7L2 risk genotype as described herein) is considered.
    Patients of TCF7L2 risk genotype according to this invention include, without limitation, patients (particularly patients with type 2 diabetes) harboring genetic risk variants in the TCF7L2 gene and often suffering from the pathological influences of the same.
    Patent Specification Report for "TREATMENT".
    TOOTH DIABETIC PATIENTS GENOTYPED WITH DPP-IV INHIBITORS SUCH AS LINAGLIPTIN ". Technical Field of the Invention 5 The present invention relates to DPP-4 inhibitors, pharmaceutical compositions or combinations comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, for use in treatment or prevention methods as described herein, such as, for example, one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, tolerance to impaired glucose, impaired fasting blood glucose and interg / a hyperglycemia In a particular embodiment, the therapeutic and / or preventive methods of this invention comprise, the step of identifying a patient who is susceptible to treatment and / or prevention, said identification.15 comprising testing whether the patient has variation (s) in one or more genes associated with metabolic diseases (for example if the patient is of a risk genotype of TCF7L2 as described herein) or if the patient is of the respective wild-type genotype (e.g., if the patient is of the TCF7L2 wild-type genotype as described herein), and the other step of administering such a DPPA inhibitor, combination, or pharmaceutical composition to the patient determined to be susceptible- In addition, in one embodiment, the utility of a DPP-4 inhibitor, a pharmaceutical composition, combination or drug, each as described herein for a therapeutic and / or preventive method or use in accordance with this invention in a patient who has variation (s) in one or more genes associated with metabolic diseases (such as for example, a risk genotype of TCF7L2 patient as described herein) is considered. Patients of TCF7L2 risk genotype according to this invention include, without limitation, patients (particularly patients with type 2 diabetes) harboring genetic risk variants in the TCF7L2 gene and often suffering from the pathological influences of the same. R%
    ,. particularly associated with the TCF7L2 rs7903146 risk T allele, such as patients harboring the heterozygous risk genotype TCF7L2 rs7903146 CT or patients harboring the homozygous high risk genotype TCF7L2 rs7903146 TT. In addition, in another embodiment, the utility of a DPP-4 inhibitor, a pharmaceutical composition, combination or medication, each as described herein for a therapeutic and / or preventive method or use according to this invention in a patient, which carries the wild genotype of TCF7L2, particularly the wild genotype TCF7L2 rs7903146 10 CC, is considered.
    In addition, the present invention provides a diagnostic method for identifying an individual (particularly a patient with type 2 diabetes) statistically more likely to have a favorable response (for example, in obtaining glycemic control, such as changes in HbA1c) to the
    . Administration of a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other active substances (for example, antidiabetics), said method comprising determining whether the individual is of the TCF7L2 risk genotype ( particularly, risk genotype TCF7L2 rs7903146 CT or TT) or the wild genotype of TCF7L2 20 (particularly, wild genotype TCF7L2 rs7903146 CC), in which the individual that is of homozygous wild genotype TCF7L2 rs7903146 CC (and, to a lesser extent, the individual who is of heterozygous risk genotype TCF7L2 rs7903146 CT) has an increased probability of favorable response to the DPP-4 inhibitor administered relative to an individual of homozygous risk genotype TCF7L2 rs7903146 TT.
    In addition, the invention describes a method - to prevent, slow the progression of, delay or treat a metabolic disorder; - to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; - to prevent, decrease, delay or reverse the progression of B %
    . . impaired glucose readiness, impaired fasting blood glucose impaired insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus; - to prevent, slow the progression of, delay or treat a condition or disorder selected from the group consisting of complications of diabetes mellitus; - to reduce body weight and / or body fat or prevent an increase in body weight and / or body fat or facilitate a reduction in body weight and / or body fat; 10 - to prevent or treat pancreatic beta cell degeneration and / or to improve and / or restore or protect the functionality of pancreatic beta cells and / or restore the functionality of pancreatic insulin secretion; +
    - to prevent, decrease, delay or treat diseases or conditions
    .- 15 attributed to an abnormal accumulation of ectopic or liver fat; or - to maintain and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance; - to prevent, slow the progression of, delay or treat new post-transplant initiation diabetes (NODAT) and / or post-transplant metabolic syndrome 20 (PTMS); - to prevent, delay or reduce complications associated with NODAT and / or PTMS, including micro- and macrovascular events and diseases, graft rejection, infection and death; - to treat hyperuricemia and conditions associated with hyperuricemia; in patients in need of it, for example, in those patients (particularly, patients with type 2 diabetes mellitus) who have variation (s) in one or more genes associated with metabolic diseases (such as, for example, in a TCF7L2 30 risk genotype patient as described herein) or in those patients who are of the respective wild type genotype (such as, for example, in a wild TCF7L2 genotype as described herein), wherein said method comprises testing the patient, if he / she has variation (s) in one or more genes associated with metabolic diseases (for example if he / she is of a TCF7L2 risk genotype as described here) or if the patient is of the respective wild type genotype (for example , if the patient is of the wild type 5 TCF7L2 as described herein), and administer a DPP-4 inhibitor as defined below (preferably Iinagliptin), optionally in combination with one or more other active substances. In addition, the present invention describes the use of a DPP-4 inhibitor 10 for the manufacture of a medicament for use in a method as described hereinbefore and hereinafter. In addition, the present invention describes a DPP-4 inhibitor for use in a therapy of a patient (particularly, a patient with human type 2 diabetes) as described hereinbefore and hereinafter.
    , - 15 In addition, the present invention describes a DPP-4 inhibitor for use in the treatment or prevention of a disease (particularly, metabolic), disorder or condition (particularly diabetes, especially type 2 diabetes, and conditions related thereto, such as, for example, diabetic complications) as described herein before and hereinafter. The invention also describes a use of a pharmaceutical combination or composition according to this invention for the manufacture of a medicament for use in a method as described hereinbefore and hereinafter. The invention also relates to DPP-4 inhibitors as defined herein for use in a method as described hereinabove and thereafter, said method comprising administering the DPP-4 inhibitor, optionally in combination with one or more other active substances (for example, which can be selected from those mentioned here), to the patient. Background to the Invention Type 2 diabetes is an increasingly prevalent disease that, J
    B - · 5/128 .h ~,% due to a high frequency of complications, leads to a significant reduction in life expectancy. Because of microvascular complications associated with diabetes, type 2 diabetes is currently the most common cause of adult onset of vision loss, kidney failure and amputations in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five-fold increase in the risk of cardiovascular disease. After the long duration of illness, most patients with type 2 diabetes will eventually not respond to oral therapy and will become insulin dependent with the need for daily injections and multiple daily glucose measurements. The UKPDS (United Kingdom Prospective Diabetes Study) has shown that intensive treatment with metformin, sulfonylureas or insulin, resulted in only a limited improvement in glycemic control (difference .- 15 difference in HbA1c -0.9% ). In addition, even in patients within the intensive care subdivision, glycemic control deteriorated significantly over time and this was attributed to the deterioration of B cell function. Importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, that is, 20 cardiovascular events. Therefore, many patients with type 2 diabetes remain inadequately treated, in part because of limitations on long-term efficacy, tolerability and inconvenience of dosing existing anti-hyperglycemic therapies. , Oral and non-oral antidiabetic drugs conventionally used in therapy (such as, for example, first or second line therapy and / or mono- or combination (initial or complementary)) include, but are not limited to, metformin, sulfonylureas , thiazolidinediones, glinides, α-glycoside inhibitors, GLP-1 or GLP-1 analogs, and insulin or insulin analogs. 30 The high incidence of therapeutic failure is a major contributor to the high rate of complications associated with long-term hyperglycemia or chronic damage (including micro- and macrovasculature complications).
    . . such as, for example, nephropathy, retinopathy or diabetic neuropathy or cardiovascular complications) in patients with type 2 diabetes. Genetic association studies have identified genetic variations in several genes that are associated with an increased risk of type 2 diabetes mellitus. For example, variations in the TCF7L2, KCNJ11 and PPARG genes independently and interactively increase the risk of impaired glucose and impaired fasting glucose tolerance and overt diabetes.
    While the variation in KCNJ11 can alter the secretion of insulin and the variation in PPARG can alter the action of insulin, TCF7L2 10 (transcription factor 7-simile 2) is the main susceptibility gene identified to date for type 2 diabetes. in various ethnic groups (for example, Europeans, Indian and Japanese people, Mexican Americans and West Africans). Polymorphisms (single nucleotide polymorphisms, 6 so-called SNPs) in TCF7L2, such as, for example,
    .- 15 rs12255372 and, particularly, rs7903146, are strongly associated with diabetes.
    The risk of developing type 2 diabetes is increased by approximately 45% (1.45 non-occurrence probability ratio) between vehicles with a TCF7L2 rs7903146 risk allele (heterozygous CT), and is at least doubled ( Probability ratio of non-occurrence of 2.41) 20 between TT homozygotes compared to wild genotypes of CC homozygotes (Grant et al., Nature Genetics, Vol, 38, 2006, pp. 320-323). Risk genotypes of TCF7L2 are associated with increased expression of TCF7L2 in pancreatic beta cells, impaired insulin secretion (stimulated by glucose), effects of incretin and enhanced rate of hepatic glucose production 25 as well as predisposition to and prediction of future type 2 diabetes (cf.
    Lissenko et al., The Journal of Clinical Research, Vol. 117, No 8, 2007, pp. 2155-2163). There is evidence that risk variants of TCF7L2 rs7903146 are associated with a lower incretin effect on insulin secretion, which may be based, at least in part, on impaired beta cell sensitivity to incretins.
    Thus, patients with diabetes harboring TCF7L2 risk variants, particularly vehicles of the TCF7L2 risk T allele
    . rs7903146, such as patients harboring the TCF7L2 genotype rs7903146 CT or, particularly, patients harboring the TCF7L2 genotype rs7903146 TT, is expected to be difficult to treat in antidiabetic therapy.
    Therefore, there is an unmet medical need for 5 methods, drugs and pharmaceutical combinations or compositions with good efficacy with respect to glycemic control, with respect to disease modification properties and with respect to the reduction of cardiovascular mortality and morbidity, while at the same time showing an improved security profile. 10 DPP-4 inhibitors represent another new class of agents that are being developed to treat or improve glycemic control in patients with type 2 diabetes. For example, DPP-4 inhibitors and their uses are described in «wo 2002/068420 , wo 2004/018467, wo 2004/018468, wo 2004/018469,
    .- 15 wo 2004/041820, wo 2004/046148, wo 2005/051950, wo 2005/082906, wo 2005/063750, wo 2005/085246, wo 2006/027204, wo 2006/029769, - wo2007 / 014886; wo 2004/050658, wo 2004/111051, wo 2005/058901, wo 2005/097798; wo 2006/068163, wo 2007/071738, wo 2008/017670; wo 2007/1 28721, wo 2007/128724, wo 2007/128761 or wo 20 2009 / 121945- objective of the present invention the objective of the present invention is to provide a drug and / or method to prevent, slow the progression of, delay or treat a metabolic disorder, in particular type 2 diabetes mellitus. 25 Another objective of the present invention is to provide a medication and / or method to improve glycemic control in a patient in need of it, in particular in patients with type 2 diabetes mellitus. 2, for example, in those patients who have variation (s) in one or more genes associated with metabolic diseases (such as, for example, a TCF7L2 risk genotype patient as described here) or in those patients who are of the respective wild type genotype.
    Another objective of the present invention is to provide a drug
    .. and / or method to improve glycemic control in a patient with insufficient glycemic control despite monotherapy with an antidiabetic drug, for example, metformin or despite combination therapy with two or three antidiabetic drugs, for example, in such a patient who has 5 variation (s) in one or more genes associated with metabolic diseases (such as, for example, a patient of TCF7L2 risk genotype as described herein) or in such a patient who is of the respective genotype type select-
    pod.
    Another objective of the present invention is to provide a drug 10 and / or method to prevent, decrease or delay the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus. Yet another objective of the present invention is to provide a medication and / or method to prevent, slow the progression of, delay or
    - 15 treating a condition or disorder in the group consisting of complications of diabetes mellitus. . Another objective of the present invention is to provide a medication and / or method to reduce weight or prevent weight gain in a patient in need of it, for example, in such a patient 20 who has variation (s) in a or more genes associated with metabolic diseases (such as, for example, a patient of TCF7L2 risk genotype as described herein) or in such a patient who is of the respective wild type genotype.
    Another objective of the present invention is to provide a drug 25 with high efficacy for the treatment of metabolic disorders, in particular diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), and / or hyperglycemia, which has good to very good pharmacological and / or pharmacokinetic and / or physiochemical properties. 30 Other objectives of the present invention are apparent to someone skilled in the art from the description here before and below, and the examples.
    Summary of the Invention Within the scope of the present invention, it has now been found that a DPP-4 inhibitor, preferably linagliptin, as well as a combination or pharmaceutical composition comprising the DPP-4 inhibitor and optionally one or more others active substances (eg antidiabetic- COS), is therapeutically effective to improve glycemic control and treat type 2 diabetes mellitus in patients with risk genotype TCF7L2 rs7903146 CT or TT and in patients with wild genotype TCF7L2 rs7903146 CC.
    In particular, it was found that all TCF7L2 genotype patients investigated (TCF7L2 rs7903146 CT or TT genotype risk patients or wild type TCF7L2 rs7903146 CC) have a clinically significant response to the DPP-4 inhibitor administered , preferably Iinagliptin.
    Thus, within the scope of the present invention, certain
    - 15 subgroups of patients with diabetes receptive to antidiabetic therapy according to this invention (comprising preferably using Iinagliptin, optionally in combination with one or more other active substances such as, for example, other antidiabetics as described herein), include, for example, without being limited to, those patients harboring genotype 20 TCF7L2 rs7903146 CC or CT or TT, respectively.
    Within the scope of the present invention, it has also been found that DPPA inhibitors as defined herein, as well as combinations or pharmaceutical compositions comprising a DPP 4 inhibitor as defined herein and optionally one or more other active substances, can be used in a method of preventing, slowing the progression of, delaying (for example, delaying the onset of) or treating a metabolic disorder (particularly diabetes, especially type 2 diabetes mellitus and conditions related to this, for example, complications diabetic), in particular a method to improve glycemic control in a patient, such as, in 30 a patient who has variation (s) in one or more genes associated with metabolic diseases (such as, for example, in patients with TCF7L2 risk as described here).
    Õ% 10/128 &.
    r Within the scope of the present invention, it has also been found that DPPA inhibitors as defined herein, as well as combinations or pharmaceutical compositions comprising a DPPA inhibitor as defined herein and optionally one or more other active substances, can be used in one a method of preventing, slowing the progression of, delaying (for example, delaying the onset of) or treating a metabolic disorder (particularly diabetes, especially type 2 diabetes mellitus and conditions related to it), in particular a method to improve control glycemic in a patient, such as in a patient who has a wild genotype of TCF7L2, 10 particularly a wild genotype TCF7L2 rs7903146 CC. In one embodiment, the method comprises the step of identifying a patient who is susceptible to the method that is used, for example, comprising testing whether the patient has variation (s) in one or more ge-. associated with metabolic diseases (for example, if the patient is a TCF7L2 risk genotype as described herein) or if the patient is of a wild type TCF7L2 genotype as described herein, and the stage of administering
    W such a DPPA inhibitor, combination or pharmaceutical composition to the patient determined to be susceptible. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and adjacent disease states, including such patients who have variation (s) in one or more genes associated with diseases metabolic (such as, for example, in patients of TCF7L2 risk genotype as described herein) and such patients who are of the respective wild type genotype 25 (such as, for example, patients of wild TCF7L2 genotype as described herein) . In addition, the present invention provides a method for determining a probability of the possibility of a favorable response (for example, in providing glycemic control) or the magnitude of a favorable change in HbA1c of an individual who is the result of treating the individual with a DPP-4 inhibitor, preferably linagliptin or the DPP-4 inhibitor in combination with one or more other substances
    . . active (for example, antidiabetic), said method comprising determining whether the individual is of the TCF7L2 risk genotype (particularly, the TCF7L2 rs7903146 TT genotype) or of the wild TCF7L2 genotype (particularly, the wild genotype TCF7L2 rs7903146 CC) , in 5 that the probability of the possibility of a favorable response or the significantly high magnitude of a favorable change in the HbA1c response for administration of the DPP-4 inhibitor, preferably linagliptin or the DPP-4 inhibitor in combination with one or plus other active substances (eg antidiabetic) is greater in an individual who is 10 homozygous wild genotype TCF7L2 rs7903146 CC, and less in an individual of homozygous risk genotype TCF7L2 rs7903146 TT (for example, however still clinically significant or significant). Therefore, in one aspect a combination or - pharmaceutical composition comprising
    .- 15 (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the G3 group, consisting of biguanides (particularly metformin), thiazolidindones, sulfonylureas, glinides, inhibitors of alpha-glycosidase, GLP-1 or analogues of GLP-1 and insulin or insulin analogs, and optionally 20 (C) a third antidiabetic agent that is different from (b) selected from the G3 group , consisting of biguanides (particularly metformin), thiazolidindiones, sulfonylureas, glinides, alpha-glucosidase inhibitors, GLP-1 or GLP-1 analogs and insulin or insulin analogs, or a pharmaceutically acceptable salt thereof. 25 In a sub-aspect, a pharmaceutical combination or composition is provided that comprises (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the G3 group, consisting of biguanides ( particularly metformin), thiazolidindione, sulfonylureas, glinides, alpha-glycosidase inhibitors, GLP-I or analogues of GLP-1 and insulin or insulin analogs, and, optionally, (C) a third antidiabetic agent which is different from (b) selecting
    . . from the group consisting of metformin, a sulfonylurea, pioglitazone, rosiglitazone, repaglinide, nateglinide, acarbose, voglibose, migliol, GLP-l or a GLP-l and insulin analogue or an insulin analogue, or an insulin analogue pharmaceutically acceptable salt thereof. 5 In another sub-aspect, a pharmaceutical combination or composition is provided which comprises (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the group consisting of metformin, a sulfonylurea , pioglitazone, rosiglitazone, repaglinide, nateglinide, acarbose, voglibose, miglitol, GLP-1 or a GLP-1 and insulin analogue or an insulin analogue, and, optionally, (C) a third antidiabetic agent that is different from ( b) selected from the G3 group, consisting of biguanides (particularly metformin), thiazolidindiones, sulfonylureas, glinides, alpha-inhibitors
    .- 15 glycosidase, GLP-1 or analogs of GLP-1 and insulin or insulin analogs, or a pharmaceutically acceptable salt thereof.
    In another sub-aspect, a pharmaceutical combination or composition is provided which comprises, (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the group consisting of metformin, a sulfonylurea and pioglitazone, and optionally (C) a third antidiabetic agent that is different from (b) selected from the group consisting of metformin, a sulphonylurea, pio-25 glitazone, rosiglitazone, repaglinide, nateglinide, acarbose , voglibose, migliol, GLP-1 or GLP-1 analog and insulin or insulin analog, or a pharmaceutically acceptable salt thereof.
    In another sub-aspect, a pharmaceutical combination or composition is provided which comprises, (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the group consisting of metformin, a sulfonylurea, pioglitazone, rosiglitazone,
    and . repaglinide, nateglinide, acarbose, voglibose, miglitol, GLP-1 or GLP-1 analogue and insulin or insulin analogue, and optionally (C) a third antidiabetic agent that is different from (b) selected from the group consisting of metformin, a sulfonylurea and 5 pioglitazone, or a pharmaceutically acceptable salt thereof.
    In yet another sub-aspect, a pharmaceutical combination or composition is provided which comprises, (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the group consisting of metformin and pioglitazone , and optionally (C) a third antidiabetic agent that is different from (b) selected from the group consisting of metformin, a sulfonylurea and 'pioglitazone,
    - 15 or a pharmaceutically acceptable salt thereof.
    In yet another sub-aspect, a pharmaceutical combination or composition is provided which comprises, (a) a DPP-4 inhibitor, and, optionally, (b) a second antidiabetic agent selected from the group consisting of metformin, a sulfonylurea and pioglitazone, and optionally (c) a third antidiabetic agent that is different from (b) selected from the group consisting of metformin and pioglitazone, or a pharmaceutically acceptable salt thereof. When - in addition to the second antidiabetic agent - a third antidiabetic agent is selected, said third antidiabetic agent is preferably selected from a different class than the second antidiabetic agent.
    Thus, it will be understood that the second and third antidiabetic agents are different, and preferably they are of different classes (for example, when the second antidiabetic agent is selected from the biguanide class, the third antidiabetic agent is preferably selected from another class). Classes of anti-daily agents
    betics are mentioned above, for example, biguanide class, thiazolidindione class, sulfonylurea class, glinide class, alpha-glucosidase inhibitor class, GLP-1 analogue class, insulin class, etc. A particular embodiment of this invention relates to monotherapy with a DPP-4 inhibitor as defined herein and / or pharmaceutical compositions comprising a DPP-4 inhibitor as the exclusive active ingredient. Within combinations and / or combination therapy of this invention, a particular modality refers to dual combinations and / or dual technology; another modality refers to triple combinations and / or triple therapy. According to another aspect, a method is provided to prevent, slow the progression of, delay or treat a metabolic disorder
    F selected from the group consisting of type 1 diabetes, type 2 diabetes, type 2 impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, disease, obesity and metabolic syndrome in a patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent 20 as previously defined here and then, they are administered, for example, in combination, to the patient. According to another aspect, a method is provided to prevent, slow down the progression of, delay or treat a metabolic disorder selected from the group consisting of insulin resistance, 25 hyperlipidemia, hypercholesterolemia, d islipidemia, hypertension, systemic inflammation chronic, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction, non-alcoholic fatty liver disease (NAFLD) and osteoporosis in a patient in need of the same, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    According to another aspect, a method is provided for me- ». Improve glycemic control and / or to reduce plasma glucose in the morning, postprandial plasma glucose and / or glycated hemoglobin HbA1c in a patient in need of it characterized by the fact that 5, a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    The pharmaceutical composition of this invention may also have valuable disease-modifying properties with respect to diseases or conditions related to impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome .
    According to another aspect, a method is provided to prevent, decrease, delay or reverse the progression of glucose tolerance
    - 15 judicada (IGT), impaired fasting blood glucose (IFG) insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus in a patient in need of it, characterized by the fact that an inhibitor of DPP-4 and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    When using a combination or pharmaceutical composition of this invention, an improvement in glycemic control in patients in need of it is obtainable, in the same way, those conditions and / or diseases related or caused by an increased blood glucose level 25, can be treated.
    According to another aspect, a method is provided to prevent, slow the progression of, delay or treat a condition or disorder selected from the group consisting of complications of diabetes mellitus such as, cataracts and micro- and macrovascular diseases, such as, 30 nephropathy, retinopathy, neuropathy, impaired memory and learning, neurodegenerative or cognitive disorders, cardio- or cerebrovascular diseases, arteriosclerosis, hypertension, endothelial dysfunction, heart attack
    . . myocardium, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, cardiomyopathy, heart failure, heart rhythm disorder, vascular restenosis, peripheral arterial occlusive disease, stroke, tissue ischemia or ulcer or diabetic foot , in a patient 5 in need of the same, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and are then administered, for example , in combination, to the patient.
    In particular, one or more aspects of diabetic nephropathy such as hyperperfusion, proteinuria and albuminuria (including micro- or macroalbuminuria) can be treated, their progression slowed or their onset delayed or prevented.
    The term "tissue ischemia" particularly comprises diabetic macroangiopathy, diabetic microangiopathy, impaired wound healing, and dia- ulcer. betic.
    The terms "micro- and macrovascular diseases" and "minimal complications"
    - 15 cro- and macrovascular "are used interchangeably in this application.
    In one embodiment, by administering a combination or pharmaceutical composition of this invention, no gain in weight or even a reduction in body weight is the result.
    According to another aspect, a method is provided 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 by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    In one embodiment, by administering a combination or pharmaceutical composition in accordance with this invention, a beta cell degeneration and a decline in beta cell functionality such as, for example, pancreatic beta cell apoptosis or necrosis , can be delayed or preventable.
    In addition, pancreatic cell functionality can be improved or restored, and the number and size of pancreatic beta cells has increased.
    It can be shown that the state of differentiation and hyperplasia of pancreatic beta cells hampered by hyperglycemia, can be normalized by treatment with a combination or pharmaceutical composition of this invention. 5 According to another aspect, a method is provided to prevent, decrease, delay or treat pancreatic beta cell degeneration and / or the decline in pancreatic beta cell functionality and / or to improve and / or restore pancreatic beta cell functionality and / or restore pancreatic insulin secretion functionality in one patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient. . In one embodiment, by administering a combination or
    In the pharmaceutical composition of the present invention, an abnormal accumulation of (ectopic) fat, particularly in the liver, can be reduced or can be inhibited.
    According to another aspect, a method is provided to prevent, decrease, delay or treat diseases or conditions attributed to an abnormal accumulation of ectopic or liver fat in a patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    Diseases or conditions that are attributed to an abnormal accumulation of ectopic or liver fat are particularly selected from the group consisting of general hepatic steatosis, non-alcoholic fatty liver (NAFL), non-alcoholic steatoepatitis (NASH) ), fatty liver-induced fatty liver, diabetic fatty liver, alcohol-induced fatty liver or toxic hepatic steatosis, particularly, non-alcoholic fatty liver disease (NAFLD), including liver fatty, non-alcoholic steatoepatitis (NASH) and / or fibrosis hepatic.
    According to another aspect of the present invention, it is provided. a method to prevent, slow down progression, delay, attenuate, treat or reverse hepatic steatosis, (hepatic) inflammation and / or an abnormal accumulation of fat in the liver in a patient in need of it, 5 characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    According to another aspect, a method is provided to manage and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance in a patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example,
    - 15 in combination, to the patient.
    According to another aspect of the invention, a method is provided. all to prevent, slow the progression of, delay or treat new onset post-transplant diabetes (NODAT) and / or post-transplant metabolic syndrome (PTMS) in a patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    In accordance with another aspect of the invention, a method is provided for preventing, delaying or reducing complications associated with NODAT and / or PTMS including, micro- and macrovascular events and diseases, graft rejection, infection, and death in a patient in need for it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient.
    According to another aspect of the invention, a method is provided
    all to treat hyperuricemia and conditions associated with hyperuricemia, such as, for example, gout, hypertension and renal failure, in a patient in need of it, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent 5 as defined hereinbefore and thereafter, are administered, for example, in combination, to the patient. According to another aspect, the use of a DPP-4 inhibitor is provided for the manufacture of a drug for use in a method of - preventing, slowing down the progression of, delaying or treating a bio metabolic disorder 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, overweight, obesity and metabolic syndrome; or
    V - improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin HbA1c; or. - prevent, decrease, delay or reverse the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus; or - prevent, slow the progression of, delay or treat 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 ischemia, 25 arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or - reduce body weight and / or body fat or prevent an increase in body weight and / or body fat or facilitate a reduction in body weight and / or body fat; or 30 - prevent, decrease, delay or treat pancreatic beta cell degeneration and / or the decline in pancreatic beta cell functionality and / or to improve and / or restore or protect the functionality of
    .- pancreatic beta cells and / or restore the functionality of pancreatic insulin secretion; or - preventing, decreasing, delaying or treating diseases or conditions attributed to an abnormal accumulation of ectopic or liver fat; or 5 - maintain and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance; or - prevent, slow the progression of, delay or treat new onset diabetes after transplantation (NODAT) and / or post-transplantation metabolic syndrome (PTMS); or 10 - prevent, delay or reduce complications associated with NODAT and / or PTMS, including micro- and macrovascular events and diseases, graft rejection, infection and death; or - treating hyperuricemia and conditions associated with hyperuricemia; . in a patient in need of it, comprising
    .- 15 administer the DPP-4 inhibitor alone or, optionally, in combination with a second and, optionally, with a third antidiabetic agent as defined hereinbefore and thereafter to the patient.
    According to another aspect, the use of a second antidiabetic agent is provided as defined hereinbefore and thereafter for the manufacture of a medicament for use in a method of - preventing, slowing the progression of, delaying or treating a disorder. metabolic rate 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, overweight, obesity and metabolic syndrome ; or - to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or - prevent, decrease, delay or reverse the progression of impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and / or metabolic syndrome for type 2 diabetes mellitus; or
    - prevent, slow the progression of, delay or treat a con. 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 ischemia, 5 arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease; or - reduce body weight and / or body fat or prevent an increase in body weight and / or body fat or facilitate a reduction in body weight and / or body fat; or 10 - prevent, decrease, delay or treat pancreatic beta cell degeneration and / or the decline in pancreatic beta cell functionality and / or to improve and / or restore pancreatic beta cell functionality and / or restore functionality pancreatic insulin secretion; or
    , - 15 - prevent, reduce, delay or treat diseases or conditions attributed to an abnormal accumulation of ectopic or liver fat; or - maintain and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance; in a patient in need thereof, comprising administering to the second antidiabetic agent in combination with a DPP-4 inhibitor and, optionally, with a third antidiabetic agent as defined hereinbefore and thereafter to the patient.
    According to another aspect, the use of a pharmaceutical composition according to the present invention is provided for the manufacture of a medicament for a therapeutic and preventive method as described hereinbefore and hereinafter.
    Patients with a TCF7L2 risk genotype (hereinafter referred to as TCF7L2 risk genotype here) within the meaning of this invention refers to those patients who have one or more unique poly- nucleotide morphisms (SNPS) especially in the gene encoding TCF7L2, an SNP selected from rs7903146, rs12255372 and rs10885406, especially rs7903146; in particular, those patients
    ,. testers that carry at least at least one T allele of SNP rs7903146 of TCF7L2, i.e., the CT genotype or TT genotype; especially those that carry two T alleles of SNP rs7903146 of TCF7L2, that is, the genotype TT, are of high risk and are expected to be difficult to treat (eg 5 to obtain adequate glycemic control) - The present invention provides a DPP-4 inhibitor (preferably, linagliptin), pharmaceutical composition, combination or medication according to the present invention, for use in a therapeutic and / or preventive method as described hereinabove and thereafter (for example , treat type 2 diabetes) in one or more of the following groups of patients: - TCF7L2 high-risk genotype patients who carry two SNP T alleles rs7903146 from TCF7L2, that is, TT genotype (where at clinically significant response by example, in glycemic control it is
    , - 15), - TCF7L2 risk genotype patients who carry a SNP T allele rs7903146 of TCF7L2, ie, CT genotype (where clinically favorable response for example, in glycemic control is provided), - genotype patients wild type of TCF7L2 carrying 20 two CC alleles of SNP rs7903146 of TCF7L2, ie, CC genotype (where a clinically more favorable response eg in glycemic control is provided). Within a particular aspect of the invention, the invention relates to a DPP-4 inhibitor, a pharmaceutical combination or composition of the present invention for a therapeutic and / or preventive method or use as described hereinbefore and hereinafter (for example , treating type 2 diabetes), said method or use comprising (i) identifying a patient who is susceptible to said therapeutic and / or preventive method or use comprising testing whether the patient is of any TCF7L2 risk genotype, particularly if the patient has one or more single nucleotide polymorphisms (SNPS) especially in the gene encoding TCF7L2, an SNP selected from rs7903146,
    - rs12255372 and rs10885406, for example, if the patient carries at least one T allele of SNP rs7903146 from TCF7L2, for example, if the patient is of genotype CT (ie, if the patient carries a T allele of SNP rs7903146 from TCF7L2) or, particularly, if the patient has a TT 5 genotype (that is, if the patient carries two SNP T alleles rs7903146 from TCF7L2) or test whether the patient is a TCF7L2 wild genotype, particularly if the patient carries two alleles C of SNP rs7903146 of TCF7L2 (i.e., if the patient is a wild genotype CC), and (ii) administering an effective amount of the DPP-4 inhibitor, combination or pharmaceutical composition 10 to the patient identified in step (i) . Within another particular aspect of the invention, the invention relates to a DPP-4 inhibitor, a pharmaceutical composition, combination or drug of the present invention for a therapeutic method and / or is preventive or use as described hereinbefore and in followed (by e-
    - "15 xample, treating type 2 diabetes) in patients with TCF7L2 risk genotype, for example, in those patients who have one or more unique nucleotide polymorphisms (SNPS) especially in the gene encoding TCF7L2, a selected SNP from rs7903146, rs12255372 and rs10885406, especially rs7903146, more particularly, in those patients carrying at least one SNP T allele rs7903146 from TCF7L2, that is, the CT genotype or TT genotype.
    Within another particular aspect of the invention, the invention relates to a DPP-4 inhibitor, a pharmaceutical composition, combination or medicament of the present invention for a therapeutic and / or preventive method or use as described hereinbefore and in followed (for example, treating type 2 diabetes) in patients with wild type TCF7L2 genotypes, for example, in those patients carrying two C alleles of SNP rs7903146 of TCF7L2, that is, the CC genotype.
    In this context, a particular subpopulation of patients 30 described here before and after (for example, patients in need of a therapeutic or preventive method as described here), refers to those patients who have one or more nucleotide polymorphisms.
    . unique peptides (SNPs) in the gene encoding TCF7L2, especially at least one SNP selected from rs7903146, rs12255372 and rs10885406, especially rs7903146, in particular those patients who carry at least one SNP T allele rs7903146 from TCF7L2 , 5 that is, the CT genotype or TT genotype.
    In particular, those patients that carry at least one T SNP allele rs7903146 of TCF7L2, that is, the CT genotype or TT genotype, especially that carries two T alleles of SNP rs7903146 of TCF7L2, that is, the genotype TT, is highly susceptible to the expression of 10 increased TCF7L2 in pancreatic beta cells, impaired insulin secretion, effects of incretin, enhanced rate of hepatic glucose production and / or diabetes.
    The T allele of rs7903146 TCF7L2 is associated with the impaired insulinotropic action of incretin hormones, reduced 24 h profiles. plasma insulin and glucagon, and increased hepatic glucose production
    .- 15 lied.
    Another particular subpopulation of the patients described here before and after (for example, patients in need of a therapeutic or preventive method as described here), refers to those patients who are of the wild genotype of TCF7L2, particularly those 20 that are of the wild genotype TCF7L2 rs7903146 CC.
    In accordance with one embodiment of this aspect of the invention, a DPP-4 inhibitor, a pharmaceutical composition, combination or medicament according to the present invention is provided for a therapeutic and / or preventive method or use as described hereinbefore and in followed (particularly to treat and / or prevent type 2 diabetes and / or obesity) in patients with reduced insulin secretion (stimulated by glucose) increased hepatic gluconeogenesis and / or reduced insulinotropic effect or action of incretin hormones (e.g., GLP-I and / or GlP), for example, impaired incretin sensitivity, associated with a TCF7L2 risk genotype, particularly with such a TCF7L2 risk genotype as mentioned above.
    According to another embodiment of this aspect of the invention, it is
    ,. provided a method of determining the patient's treatment response to a DPP-4 inhibitor, a pharmaceutical composition, combination or medication according to the present invention, said method comprising the step of determining whether the patient is 5 TCF7L2 risk genotype as described here, for example, testing whether the patient belongs to a particular subpopulation of TCF7L2 risk genotype vehicles or determining whether the patient is a wild TCF7L2 genotype, for example, testing whether the patient transports the wild type CC allele to rs7903146 in TCF7L2. According to another embodiment of this aspect of the invention, a DPP-4 inhibitor, a pharmaceutical composition, combination or medicament according to the present invention is provided for use in a therapeutic and / or preventive method as described hereinabove. and in se-. (particularly to treat and / or prevent type 2 diabetes and / or obesity
    .- 15) in a patient in need of the same, the aforementioned method which comprises testing whether the patient is of any TCF7L2 risk genotype. as described here.
    In accordance with another embodiment of this aspect of the invention, a DPP-4 inhibitor, a pharmaceutical composition, combination 20 or medicament according to the present invention is provided for use in a therapeutic and preventive method as described hereinbefore and in followed (particularly to treat and / or prevent type 2 diabetes and / or obesity) in a patient in need of it, said method which comprises testing whether the patient has a wild type of TCF7L2 as described herein.
    According to another aspect of the invention, the TCF7L2 risk genotype test can be used for patient stratification, for example, to enrich the patient population in clinical studies to test the effectiveness of the DPP-4 inhibitor. According to another aspect of the invention, the method of determining an individual's susceptibility to treatment (for example, comprising testing for wild-type or TCF7L2 risk genotypes as
    .. described here) can be used to determine whether the patient can respond to a lower level or may require a higher level of administered DPP-4 inhibitor, optionally in combination with one or more other active substances. According to another aspect of the invention, the determination of the treatment susceptibility of an individual comprising the test for wild type or TCF7L2 risk genotypes as described herein, can be used to determine whether the patient can be treated in monotherapy - laundering or in combination therapy with one or more additional antidiabetics 10 according to this invention, for example, to provide adequate glycemic control.
    For example, those patients with a decreased likelihood of a favorable response may require combination treatment, for example, to obtain adequate glycemic control. " Definitions
    .- 15 The term "active ingredient" of a combination or pharmaceutical composition of the present invention means the DPP-4 inhibitor and / or, if present, the second antidiabetic agent and / or, if present, the third agent antidiabetic agent of the present invention.
    The term "body mass index" or "BMI" of a human patient 20 is defined as the weight in kilograms divided by the height square in meters, such that BMI has units of kg / m "- The term" overweight "is defined as the condition in which the individual has a BMI greater than or 25 kg / m "and less than 30 kg / m". The terms "overweight" and "pre-obese" are used interchangeably. 25 The term "Obesity" is defined as the condition in which the individual has a BMI equal to or greater than 30 kg / m ". According to a WHO definition, the term obesity can be categorized as follows: the term "class I obesity" is the condition in which BMI is equal to or greater than 30 kg / m ', but less than 35 kg / m '; the term "obesity class ll" is the condition in which the BMI is equal to or greater than 35 kg / m ", but less than 40 kg / m"; the term "class lll obesity" is the condition in which BMI is equal to or greater than 40 kg / m ".
    ,. The term "visceral obesity" is defined as the condition in which a waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 in women is measured.
    This defines the risk for insulin resistance and the development of pre-diabetes. 5 The term "abdominal obesity" is usually defined as the condition where the waist circumference is ("40 inches) or 102 cm in men, and is (" 35 inches) or 94 cm in women.
    With respect to Japanese ethnicity or Japanese patients, abdominal obesity can be defined as waist circumference z 85 cm in men and z 90 cm in women (see, for example, investigation comm ittee for the diagnosis of metabolic syndrome in Japan ) - The term "euglycemia" is defined as the condition in which an individual has a fasting blood glucose concentration within. normal range, greater than 70 mg / dL (3.89 mmols / L) and less than 110
    .- 15 mg / dL (6.11 mmoIs / L) or 100 mg / dL (5.6 mmoIs / L). The word "fasting" has the usual meaning as a medical term. - The term "hyperglycemia" is defined as the condition in which an individual has a fasting blood glucose concentration above the normal range, greater than 110 mg / dL (6.11 mmol / L) or 100 mg / dL (5 , 6 20 mmols / L). The word "fasting" has the usual meaning as a medical term.
    The term "hypoglycemia" is defined as the condition in which an individual has a blood glucose concentration below the normal range of 60 to 115 mg / dL (3.3 to 6.3 mmoIs / L), in particular below 70 25 mg / dL (3.89 mmol / L). The term "postprandial hyperglycemia" is defined as the condition in which an individual has a two-hour postprandial blood glucose concentration or blood glucose greater than 200 mg / dL (11.11 mmols / L). 30 The term "impaired fasting blood glucose" or "IFG" is defined as the condition in which an individual has a fasting blood glucose concentration or fasting serum glucose concentration
    .. in a range of 100 to 125 mg / dl (ie, 5.6 to 6.9 mmols / l), in particular greater than 110 mg / dL and less than 126 mg / dl (7.00 mmols / L). An individual with "normal fasting glucose" has a fasting glucose concentration less than 100 mg / dl, that is, less than 5.6 mmol / l. 5 The term "impaired glucose tolerance" or "IGT" is defined as the condition in which an individual has a two-hour postprandial serum glucose or blood glucose concentration greater than 140 mg / dl (7.78 mmols) / L) and less than 200 mg / dL (11.11 mmol / L). Abnormal glucose tolerance, that is, the serum glucose or glucose concentration of two hours postprandial blood can be measured as the blood sugar level in mg of glucose per dL of plasma two hours later to take 75 g of glucose after a fast. An individual with "normal glucose tolerance" has a two-hour postprandial serum glucose or blood glucose concentration less than 140 mg / dl (7.78 mmoIs / L).
    - "15 The term" hyperinsulinemia "is defined as the condition in which an individual with insulin resistance, with or without euglycemia, has plasma insulin concentration or postprandial serum or fasting above normal, individuals skinny without insulin resistance, have a waist-to-hip ratio <1.0 (for men) or <0.8 (for women) .20 The term "insulin sensitization", "improving - insulin resistance "or" decreased insulin resistance "are synonymous and used interchangeably. The term" insulin resistance "is defined as a state in which circulating insulin levels in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, and another. JAMA. (2002) 287: 356-9). One method of determining insulin resistance is the euglycemic-hyperinsulinemic clamp test. The insulin ratio for glucose is determined within the scope of an insulin-glucose infusion technique with symbolized. Insulin resistance should be noted, 30 if glucose absorption is below the 25th percentile of the investigated base population (WHO definition). Somewhat less laborious than the cIampe test, they are called so-called minimal models in which, during an intravenous glucose tolerance test, glucose concentrations and in- 0
    . Sulin levels in the blood are measured at fixed time intervals, from which insulin resistance is calculated.
    With this method, it is not possible to distinguish between hepatic and peripheral insulin resistance. 5 In addition, insulin resistance, the response of a patient with insulin resistance to therapy, insulin sensitivity and hyperinsulinemia, can be quantified by assessing the "homeostasis model assessment score for insulin resistance ( HOMA-IR) ", a safe indicator of insulin resistance (Katsuki A, and another.
    Diabetes Care 2001; 24: 10 362-5). Another reference is made to methods for determining the HOMA index for insulin sensitivity (Mattews et al, Diabetologia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al, Diabetes 2003, 52 (Supp /. 1): A459) and a study of euglycemic clamp.
    Beyond . In addition, plasma adiponectin levels can be monitored as
    .. 15 a potential substitute for insulin sensitivity.
    The estimate of insulin resistance by the model of homeostasis assessment score (HOMA) - IR is calculated with the formula (Galvin P, and another.
    Diabet Med 1992; 9: 921-8): HOMA-IR = [fasting serum insulin (µU / mL)] x [fasting plasma glucose (mmol / L) / 22.5] 20 As a rule, other parameters are used in everyday clinical practice to assess insulin resistance.
    Preferably, the patient's triglyceride concentration is used, for example, when increased triglyceride levels correlate significantly with the presence of insulin resistance. 25 Patients with a predisposition to the development of IGT or IFG or type 2 diabetes are those who have euglycemia with hyperinsulinemia and are, by definition, resistant to insulin.
    A typical patient with insulin resistance is usually overweight or obese.
    If resistance to insulin can be discovered, this is a particularly strong indication of the presence of pre-diabetes.
    Thus, it may be that, to maintain glucose homo-eostasis, a person needs 2-3 times more insulin than a healthy person, without this resulting in any clinical symptoms.
    Methods to investigate the function of pan- beta cells. are similar to the above methods with respect to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement in beta cell function can be measured, for example, by determining a 5 HOMA index for beta cell function (Mattews et al, Diabeto / ogia 1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst et al., Diabetes 2003, 52 (Supp /. 1): A459), the secretion of insulin / C peptide after an oral glucose tolerance test or a meal tolerance test, or using a hyperglycemic clamp study and / or minimal model after a frequently sampled intravenous glucose tolerance test (Stumvoll et al, Eur J CIin lnveste 2001, 31: 380-81). The term "pre-diabetes" is the condition in which an individual is
    W pre-disposed to the development of type 2 diabetes. Pre-diabetics extends the .- 15 impaired glucose tolerance definition to include individuals with a fasting blood glucose within the high normal range z 100 mg / dL (J. « B. Meigs, et al., Diabetes 2003; 52: 1475-1484) and hyperinsulinemia in fasting (high plasma insulin concentration). The scientific and medical basis for identifying pre-diabetes as a serious health threat is provided in a Statement of Position entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25: 742-749). Individuals likely to have insulin resistance are those 25 who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more 1st degree relative with an IGT diagnosis or IFG or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this invention, insulin resistance is defined as the clinical condition in which an individual has a HOMA-IR score> 4.0 or a HOMA-IR score above the upper limit of normal, as defined for the lab - it is necessary to carry out glucose and insulin tests.
    The term "type 2 diabetes" is defined as the condition in which an individual has a fasting serum glucose or blood glucose concentration greater than 125 mg / dL (6.94 mmol / L). Measuring blood glucose values is a standard procedure in routine medical analysis. 5 If a glucose tolerance test is performed, the blood sugar level of a diabetic will be more than 200 mg of glucose per dL (11.1 mmols / l) of plasma two hours after 75 g of glucose has been added on an empty stomach.
    In a glucose tolerance test, 75 g of glucose is administered orally to the patient who is tested after 10-12 hours on 10 fastings, and the blood sugar level is recorded immediately before taking the glucose and a two hours after taking it.
    In a healthy individual, the blood sugar level before taking glucose will be between 60 and 110 mg per dL of plasma, less than 200 mg per dL, one hour after taking glucose and less than 140 mg per dL, after two hours.
    If
    .. 15 after two hours, the value is between 140 and 200 mg, this is considered as abnormal glucose tolerance.
    The term "end-stage type 2 diabetes mellitus" includes patients with type 2 diabetes with a secondary insufficiency of antidiabetic drug, indication for insulin therapy and progression to micro- and macrovascular complications, for example, diabetic nephropathy or cardio - coronary pathology (CHD). The term "HbA1c" refers to the product of a non-enzymatic glycation of the hemoglobin B chain.
    His determination is well known to someone skilled in the art.
    In monitoring the treatment of diabetes mellitus, the value of HbA1 c is of exceptional importance.
    Since its production depends essentially on the blood sugar level and the life of the erythrocytes, HbA1c in the sense of a "blood sugar memory" reflects the average blood sugar levels of the previous 4-6 weeks.
    Diabetic patients whose HbA1c value is constantly well adjusted 30 by intensive diabetes treatment (ie, "6.5 ° /) of the total hemoglobin in the sample), are significantly better protected against diabetic microangiopathy.
    For example, metformine alone achieves average improvement
    , in the value of HbA1c in diabetics in the order of 1.0 - 1.5%. This reduction in the HbA1C value is not sufficient in all diabetics to achieve the desired target range of <6.5 ° /) and preferably <6 ° / of HbA1c. The term "insufficient glycemic control" or "inadequate glycemic control" within the scope of the present invention means a condition in which patients show HbA1c values above 6.5%, in particular above 7.0%, even more preferably above 7.5%, especially above 8%. The "metabophic syndrome", in the same way called "meI X syndrome" (when used in the context of a metabolic disorder), in the same way called "dysmetabolic syndrome" is a syndrome complex with the cardinal characteristic of being resistant to insulin (Laaksonen DE, et al. Am J Epidemiol 2002; 156: 1070-7). According to the guidelines of ATP III / NCEP (Executive Summary of the Third Report of the National Cho- .- 15 lesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel lll) jAMA: Journal of the American Medical Association (2001) 285: 2486-2497), the diagnosis of metabolic syndrome is made when three or more of the following risk factors are present: 20 1. Abdominal obesity, defined as waist circumference "40 inches or 102 cm in men, and> 35 inches or 94 cm in women; or with respect to Japanese ethnicity or Japanese patients defined as waist circumference z 85 cm in men and z 90 cm in women ; 25 2. Triglycerides: z 150 mg / dL
    3. HDL cholesterol <40 mg / dL in men
    4. Blood pressure z 130/85 mm Hg (SBP z 130 or DBP z 85)
    5. Fasting blood glucose z 110 mg / dL or z 100 mg / dL The definitions of NCEP have been validated (Laaksonen DE, et al. 30 Am j Epidemiol. (2002) 156: 1070-7). Triglycerides and HDL cholesterol in the blood can be similarly determined by standard methods in medical analysis and are described, for example, in Thomas L (Editor): "Labor und
    Diagnosis ", TH-BooKS Verlagsgesellschaft mbH, Frankfurt / Main, 2000.. According to a commonly used definition, hypertension is diagnosed if systolic blood pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (BPD ) exceeds a value of 90 mm Hg. 5 If a patient is suffering from manifest diabetes, it is currently recommended that systolic blood pressure be reduced below 130 mm Hg and diastolic blood pressure reduced below 80 mm Hg.
    The definitions of NODAT (new onset diabetes after transplantation) and PTMS (metabolic syndrome after transplantation) strictly follow those of the American Diabetes Association's diagnostic criteria for type 2 diabetes, and those of the International Diabetes Federation ( IDF) and the American Heart Association / National Heart, Lung and Blood Institute. te, for metabolic syndrome.
    NODAT and / or PTMS are associated with
    .- 15 an increased risk of micro- and macrovascular events and diseases, graft rejection, infection and death.
    Several prognosticators have been identified as potential risk factors related to NODAT and / or PTMS, including a higher age at transplant, male gender, pre-transplant body mass index, pre-transplant diabetes and immunosuppression.
    The term "hyperuricemia" denotes a condition of high levels of total urate in the serum.
    In human blood, uric acid concentrations between 3.6 mg / dL (approximately 214 µmols / L) and 8.3 mg / dL (approximately 494 µmols / L) are considered normal by the American Medical 25 Association.
    High levels of total urate in the serum or hyperuricemia are often associated with various diseases.
    For example, high levels of total urate in the serum can lead to a type of arthritis in the joints known as gout.
    Gout is a condition created by the formation of crystals of monosodium urate or uric acid in the articular cartilage of the joints, tendons and surrounding tissues due to high concentrations of total urate levels in the blood flow.
    The formation of urate or uric acid in these tissues causes an inflammatory reaction in these tissues.
    n Levels of uric acid saturation in urine can result in the formation of kidney stones when uric acid or urate crystallizes in the kidney.
    In addition, high levels of total urate in serum are often associated with so-called metabolic syndrome, including cardiovascular disease and hypertension.
    The term "DPP-4 inhibitor" in the scope of the present invention refers to a compound that exhibits inhibitory activity in the enzyme dipeptidyl peptidase lV (DPP-4). Such inhibitory activity can be characterized by the value of lC50. A DPP-4 inhibitor preferably exhibits an IC50 10 value below 10,000 nM, preferably below 1000 nM.
    Certain DPP-4 inhibitors exhibit an LC50 value below 100 nM or even just 50 nM.
    LC50 values of DPP-4 inhibitors are usually above 0.01 nM or even above 0.1 nM. DPP-lV inhibitors may include. biological and non-biological compounds, in particular non-peptide.
    The effect
    .- 15 inhibitor over DPP-4 can be determined by methods known in the literature, in particular as described in application WO 02/068420 or WO - 2004/018468 (page 34), which are hereby incorporated by reference in their entirety.
    The term "DPP-4 inhibitor" also includes any pharmaceutically acceptable salts thereof, hydrates and solvates thereof, including the respective crystalline forms.
    The terms "treatment" and "treat" or similar terms include particularly therapeutic treatment of patients who have already developed the condition, particularly in the manifest form.
    Therapeutic treatment can be symptomatic treatment to relieve symptoms 25 of the specific indication or causal treatment to reverse or partially reverse the conditions of the indication or interrupt or slow the progression of the disease.
    Thus, the compositions and methods of the present invention can be used, for example, as therapeutic treatment for a certain time as well as for chronic therapy. 30 The terms "prophylactically treating", "preventive treatment" and "prevent" or similar terms are used interchangeably and comprise a treatment of patients at risk of developing a mental condition.
    not mentioned here earlier, thereby reducing said risk.
    Detailed Description Aspects of the present invention, in particular pharmaceutical compounds, compositions, combinations, methods and uses, relate to 5 DPP-4 inhibitors, second and / or third antidiabetic agents as defined hereinbefore and hereinafter.
    In a first embodiment (modality A), a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of formula (I)
    o, == "" '-N ^ yÁ ^ n A ~ n> ""' (')
    .- 10 or formula (ll)
    O, == "
    "'" à: PR2 "" or formula (lll)
    The ~ = "
    ': t; j "" "' or formula (IV) --- = -" "o ~ =="
    "" 'Jj-r' ('v) cn where Rl denotes ([1,5] naphthyridin-2-yl) methyl, (quinazolin-2-. Ii) methyl, (quinoxalin-6A) 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) - 5 amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -amino-propyl) -methylamino or its pharmaceutically acceptable salt.
    In a second modality (modality B), a DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, 10 alogliptin, gemigliptin, (2S ) -1 - {[2- (5-methyl | -2-pheni | -oxazo | -4-i |) -ethi | amino] -aceti |} -pyrrh | idine- 2-carbonitrile, (2S) -1 - {[1, 1, -dimethyl-3- (4-pyridin-3-yl-imidazol-1-yl) -propylamino] -. acetyl} -pyrrolidine-2-carbonitrile,
    - - 15 (S) -1 - ((2S, 3S, 11bS) -2-amino-9,1O-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pjridol2,1- a] isoquino | in-34 |) -4-f | uorometi | -pyrrolidin-2-one, (3,3-Dif | uoropyrro | idin-1-i |) - ((2S, 4S) A- (4 - (pyrimidin-2-i |) piperazin-1-yl) pyrrolidin-2-yl) methanone, (1 ((3S, 4S) -4-amino-1- (4- (3,3-dinuoropyrrolidin-1- j |) -1,3,5-triazin-2- 20 il) pyrrolidin-3-ü) -5,5-difluoropiperidin-2-one, (2S, 4S) -1- {2 - [(3S, 1 R) -3- (1 H-1,2,4-triazo | -1-i | methyl |) cic | openti | am j- no] -acetyl} -4-fluoropyrrolidine-2-carbonitrile, (R) - 2- [6- (3-amino-piperidin-1-i |) -3-methyl | -2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl] A-fluoro-benzonitrüa , 5 - {(S) -2- [2 - ((S) -2-cyano-pyrrolidin-1-yl) -2-oxo-ethylamino] -propyl} -5- (1H-) bis-dimethylamide tetrazoP5-yl) -1 O, 11-dihydro-5H-dibenzo [a, d] cycloheptene-2,8-d icarboxylic, 3 - {(2S, 4S) A- [4- (3 -methyl-1-phenyl-1 H-pyrazok5-yl) piperazin-1-yl] pyrrolidin-2-ylcarbonyl} thiazolidine, 30 [[2R) -1 - {[(3R) -pyrrolidin-3-i acid | amino] aceti |} pyrrho | idin-2-i |] boronic, (2S, 4S) -1- [2 - [(4-ethoxycarbonylbicic | o [2.2.2] o ct-1-yl) amino] acetyl |] -4-fluoropyrrolidine-2-carbonitrile,
    2 - ({6 - [(3R) -3-amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo- - 1,2,3,4-tetrahydro-5H-pyrrho | o [3,2-d] pyrimidin-5-i |} meti |) -4-fluorobenzonitrile, 6 - [(3R) -3-amjno-piperidin-1-j |] -5- (2-c | oro-5-f | uoro-benzj]) - 1, 3-dimethyl-1,5-dihydro-pyrrolo [3,2-d] pyrimidine-2,4-dione and 5 {2 - [(2- Cyanopyrr | idin-1-yl) -2-oxoethylamino] -2-methyl | propi |} (S) -2-methylpyrazolo [1,5-a] primidine-6-carboxylic acid, or its pharmaceutically acceptable salt.
    Regarding the first modality (modality A), preferred DPP-4 inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts: "1 - [(4-meti | -quinazo | in-2-i |) meti | ] -3-methyl | -7- (2-butin-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine (compare WO 2004/018468, example 2 (142) ):
    the ~ = "
    'Á) GÚ! / "N: NH2
    "1 - [([1,5] naRiridin-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8 - ((R) -3- 15 amino-piperidin-1 -yl) -xanthine (compare WO 2004/018468, example 2 (252)):
    The ~ = "
    7L7t>: /> N:) NH,
    · 1 - [(Quinazo | in-2-i |) meti |] -3-meti | -7- (2-butin-1-j [) - 8 - ((R) -3- amino-piperidin-1 -yl) -xanthine (compare WO 2004/018468, example 2 (80)):
    O, == "
    CC = n:) NH2
    "2 - ((R) -3-amino-piperidin-1-yl) -3- (but-2-yinyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3,5-dihydro -imidazo [4,5-d] pyridazin-4-one (compare WO 2004/050658, example 136): O ~ = "
    '>: "r2-í:' /> N:) NH2
    . "· 1 - [(4-meti | -quinazo | jn-2-i |) meti |] -3-meti | -7- (2-butiin-1-i |) -8 - [(2-
    . 5 amino-2-metiMpropyl) -methylamino] -xanthine (compare WO 2006/029769, example 2 (1)): O, = Z2 "
    cccÚtU "· 1 - [(3-Cyano-quino | in-2-i |) meti |] -3-meti | -7- (2-butin-1-iI) -8 - ((R) - 3- amino-piperidin-1-yl) -xanthine (compare WO 2005/085246, example 1 (30)): no, == "
    1Çn, tí: / '- N: </ nh,
    · 1- (2-Cyano-benzyl) -3-methyl-7- (2-butin-1-iI) -8 - ((R) -3-amino-. Piperidin-1-yl) -xanthine (compare WO 2005/085246, example 1 (39)):
    NO ~ = "G, íX" N:) NH, · 1 - [(4-meti | -quinazo | in-2-i |) meti |] -3-meti | -7- (2-butin-1- i |) -8 - [(S) - (2-amino-propyl) -methylamino] -xanthine (compare WO 2006/029769, example - 5 2 (4)): O ~ = "í JU, 'A NH, · 1 - [(3-Cyano-pyridin-2-i |) methyl |] -3-methyl-7- (2-butin-1-i |) -8 - ((R) -3- amino-piperidin- 1-yl) -xanthine (compare WO 2005/085246, example 1 (52)):
    NO ~ == ---- = - "" ÇN, Íj: / '- N:) NH2 · 1 - [(4-meti [-pyrimidin-2-i |) meti |] -3-meti | - 7- (2-butin-1-i |) -8 - ((R) -3-amino-piperidin-1-yl) -xanthine (compare WO 2005/085246, example 1 (81)):
    The ~% "
    íjFu :: '- N:) NH,
    · 1 - [(4,6-Dimethyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butin-1-iI) -8- ((R) -3-amino-piperidin-1 -yl) -xanthine (compare WO 2005/085246, example 1 (82)):
    The ~ = "
    Yjuí: / "N:) NH,
    "1 - [(Quinoxa | in-6-i |) meti |] -3-metj | -7- (2-butin-1-i |) -8 - ((R) -3- amino-piperidin-1 -yl) -xanthine (compare WO 2005/085246, example 1 (83)): O ~ == -
    ¢ CCÚ: »n:) NH2
    A more preferred DPP-4 inhibitor among the above mentioned DPP-4 inhibitors of modality A of this invention is 1 - [(4-methyl-quinazo | in-2-i |) meti |] -3-meti | -7 - (2-butin-1-i |) -8- (3- (R) -amino-piperidin-1-i |) - xanthine, particularly the free base thereof (which is likewise known as linagliptin or Bl 1356). Like other DPP-4 inhibitors, the following compounds can be mentioned: - Sitagliptin (MK-0431) having structural formula A below is (3R) -3-ammonium-1- [3- (trifluoromethyl) -5, 6,7,8-tetrahydro-5H- [1,2,4] triazo | oI4,3-a] pi-razin-7-yl] -4- (2,4,5-trifluorophenyl) butan-1-one , similarly named (2R) A-oxoA- [3- (trif | uorometi |) -5,6-dihydro [1,2,4] triazo | o [4,3-a] pyrazin-7 ( 8H) - yl] -1 - (2,4,5-trifluorophenyl) butan-2-amine,
    FF NH, O '^ Á ^^' gr ":" (A) F-7 — F
    F In one embodiment, sitagliptin is in the form of its dihydrogen phosphate salt, that is, sitagliptin phosphate. In another embodiment, sitagliptin phosphate is in the form of a crystalline monohydrate or anhydrate. One class of this modality refers to sita-5-glyptine phosphate monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are described in US Patent No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is described in WO 2005/003135 and WO 2007/050485. . For more information, for example, in a process to .- 10 manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. 4 A tablet formulation for sitagliptin is commercially available under the trade name Januvia®. A tablet formulation for sitagliptin / metformin combination is commercially available under the trade name Janumet®. - Vildagliptin (LAF-237) having structural formula B below is (2S) - {[(3-hydroxiadamantan-1-i |) amino] aceti |} pyrrho | idine-2-carbonitri | a, in the same way named ( S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine, 20 N Of rrr.
    77'J) OH (B)
    Vildagliptin is specifically described in US Patent No. -.
    6,166,063 and in Example 1 of WO 00/34241. Specific salts of vildagliptin are described in WO 2007/019255. A crystalline form of vildagliptin, as well as a tablet formulation of vildagliptin is described in WO 5 2006/078593. Vildagliptin can be formulated as described in WO 00/34241 or WO 2005/067976. A formulation of modified release vildagliptin is described in WO 2006/135723. For more information, for example, in a process to manufacture, formulate or use this compound or its salt, in this way 10 reference is made to these documents. A tablet formulation for vildagliptin is commercially available under the trade name Galvus®. A tablet formulation for vildagliptin / metformin combination is commercially available under the trade name Eucreas®.
    - 15 - Saxagliptin (BMS-477118) having structural formula C below is (1S, 3S, 5S) -2 - {(2S) -2-amino-2- (3-hydroxyadiene-1-yl) acetyl} -2 - azabjcic | o [3.1.0] hexane-3-carbonitri | a, similarly named (S) -3-hydroxyadmanti | g | icine-L-cis-4,5-metanoprojinenitri | a, 'ttj ±) i | Ô HÓ
    N (C) Saxagliptin is specifically described in US Patent No. 20 6,395,767 and in Example 60 of WO 01/68603. In one embodiment, saxagliptin is in the form of its HCl salt or its monobenzoate salt as described in WO 2004/052850. In another modality, saxagliptin is in the form of the free base. In yet another embodiment, saxagliptin is in the form of the free base 25 monohydrate as described in WO 2004/052850. Crystalline forms of the HCl salt and
    , of the saxagliptin free base are described in WO 2008/131149. A process for preparing saxagliptin is likewise described in WO 2005/106011 and WO 2005/115982. Saxagliptin can be formulated into a tablet as described in WO 2005/117841. 5 For further information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. - Alogliptin (SYR-322) having structural formula E below is 2- ({6 - [(3R) -3-aminopiperidin-1-i |] -3-methyl | -2,4-dioxo-3,4- dihydro-2H-pyrimidin-1- 10 yl} methyl) benzonitrile ~ -'ZIN: ry-ANH,
    (E) Alogliptin is specifically described in US 2005/261271, EP 1586571 and WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt, each as described in WO 2007/035629. One class of this modality refers to alogliptin benzoate. Polymorphs of alogliptin benzoate are described in WO 2007/035372. A process for preparing alogliptin is described in WO 2007/112368 and, specifically, WO 2007/035629. Alogliptin (i.e., its benzoate salt) can be formulated into a tablet and can be administered as described in WO 2007/033266. A solid preparation of a | og | iptin / piog | jtazone and its preparation and use are described in WO 2008/093882. A solid preparation of alogliptin / metformin and its preparation and use are described in WO 2009/011451.
    For more information, for example, in a process for. manufacture, formulate or use this compound or a salt thereof, so reference is made to these documents. - (2S) -1 - {[2- (5-methyl | -2-pheni | -oxazo | -4-i |) -ethi | amino] -acetyl} -pyrrh | id j- 5 na-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably mesylate or (2S) -1 - {[1, 1, -dimethyl-3- (4-pyridin-3-yl-imidazol-1-ii) -propylamino] - acetyl} -pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof: 10 These compounds and methods for their preparation are described in WO 03/037327. The mesylate salt of the above compound, as well as crystalline polymorphs thereof, are described in WO 2006/100181. The fumarate salt 0 of the posterior compound, as well as crystalline polymorphs of the same are
    , - 15 credits in WO 2007/071576. These compounds can be formulated in a pharmaceutical composition as described in WO 2007/017423. . For more information, for example, in a process to manufacture, formulate or use these compounds or a salt thereof, reference is made to these documents. 20 - (S) -1 - ((2S, 3S, 11bS) -2-amino-9,1O-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2.1 -a] isoquino | in-3-jl) -4-f | uoromethyl-pjrro | idin-2-one (likewise called carmegliptine) or a pharmaceutically acceptable salt thereof: I — f
    Ldyy "O
    This compound and methods for its preparation are described in WO 2005/000848. A process for preparing this compound (specifically its dihydrochloride salt) is described in the same way in WO
    2008/031749, WO 2008/031750 and WO 2008/055814. This compound can - be formulated in a pharmaceutical composition as described in WO 2007/017423. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. - ((3,3-Dif | uoropyrrolidin-1-iI) - (((2S, 4S) -4- (4- (pyrimidin-2-i |) piperazin- 1-yl) pyrrolidin-2-yl) methanone (da same form called gosogliptin) or a pharmaceutically acceptable salt thereof: 10 This compound and methods for its preparation are described in WO 2005/116014 and US 7291618. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, so reference is made to these documents.
    _- 15 - (1 ((3S, 4S) A-amino-1- (4- (3,3-difluoropyrr | idin-1-yl) -1,3,5-triazin-2-i |) pyrrho | idin-3-i |) -5,5-dif | uoropiperidin-2-one or a pharmaceutically 'q acceptable salt thereof:' 4— "" ('; "" C'y'yÀj,' o nsn Este compound and methods for its preparation are described in WO 2007/148185 and US 20070299076. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents .
    - (2S, 4S) -1- {2 - [(3S, 1R) -3- (1 H-1,2,4-triazol-1-ylmethyl) cyclopentik amino] -aceti |} -4-f | uoropirro [idine-2-carbonitri | a (in the same way called melogliptin) or a pharmaceutically acceptable salt thereof:
    C,: n "" "OAÂ, S '. ~
    F This compound and methods for its preparation are described in WO 2006/040625 and WO 2008/001195. Specifically claimed salts include methanesulfonate and p-toluenesulfonate. For further information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents.
    - (R) -2- [6- (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-i | meti | ] -4-f | uoro-benzonitri | a or a pharmaceutically acceptable salt thereof: 'JLJ ""' oAAnT "" "'This compound and methods for its preparation and use are described in WO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO 2007/074884, WO 2007/112368, WO 2008/033851, WO 2008/114800 and WO 2008/114807. Salts specifically claimed including succinate (WO 2008 / 067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R) -mandelate and hydrochloride. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, in this way reference is made to these 5 - {(S) -2- [2 - ((S) -2-cyano-pyrrolidin-1-yl) - 2-oxo-ethylamino] -propyl} -5- (1) bis-dimethylamide H-tetrazol-5-yl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene-2,8-dicarboxylic or a pharmaceutically acceptable salt thereof: O O
    "N í; Lj" gi Z: N: NH \
    ^ c'i N
    This compound and methods for its preparation are described in WO 2006/116157 and US 2006/270701. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. 5 - 3 - {(2S, 4S) A- [4- (3-methyl-1-phenyl-1 H-pyrazol-5-yl) piperazin-1-yl] pyrogen | idin-2-i | carboni |} thiazo | jdina (also called teneligliptina) or a pharmaceutically acceptable salt thereof:. This compound and methods for its preparation are described in WO 02/14271. Specific salts are described in WO 2006/088129 and WO 10 2006/118127 (including hydrochloride, hydrobromide, inter a / ia). Combination therapy using this compound is described in WO 2006/129785. For more information, for example, on a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. 15 - Boronic acid ((2R) -1 - {[(3R) -pyrrolidin-3-ylamino] acetiI} pyrrolidin-2-yl] (similarly called dutogliptin) or a pharmaceutically acceptable salt thereof: This compound and methods for its preparation are described in WO 2005/047297, WO 2008/109681 and WO 2009/009751. Specific salts are described in WO 2008/027273 (including, citrate, tartrate). A formulation of this compound is described in WO 2008/144730. A formulation of dutogliptin (as its tartrate salt) with metformin is described in WO 2009/091663. For further information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents.
    - (2S, 4S) -1- [2 - [(4-ethoxycarboni | bicic | o [2.2.2] oct-1-i |) amino] aceti |] - .. 4-fluoropyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof: This compound and methods for its preparation are described in WO 2005/075421, US 2008/146818 and WO 2008/114857. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents.
    - 2 - ({6 - [(3R) -3-amino-3-methylpiperidin-1-yl] -1,3-dimethyl-2,4-dioxo- 10 1,2,3,4-tetrahydro-5H- pyrrho | o [3,2-d] pyrimidin-5-i |} meti |) -4-f | uorobenzonitri | a or a pharmaceutically acceptable salt thereof or 6 - [(3R) -3-amino-piperidin- 1 -i |] -5- (2-c | oro-5-f | uoro-benzyl) -1,3-dimethyl-1,5-dihydro-pyrrho] o [3,2-d] pyrimidine- 2 , 4-dione or a pharmaceutically acceptable salt thereof:. These compounds and methods for their preparation are described, in WO 2009/084497 and WO 2006/068163, respectively. Combination therapy using the latter of these two compounds is described in WO b 2009/128360. For more information, for example, in a process to manufacture, formulate or use these compounds or a salt thereof, reference is made to these documents. 20 - {2 - [(2-Cyanopyrr | idin-1-i |) -2-oxoethi | amino] -2-methylpropyl |} (S) -2-methylpyrazolo [1,5-a] primidine- amide 6-carboxylic (likewise called anagliptin) or a pharmaceutically acceptable salt: This compound and methods for its preparation are described in WO 2004/067509. Combination therapy using this compound is described in WO 2009/139362. For more information, for example, in a process to manufacture, formulate or use this compound or a salt thereof, reference is made to these documents. Preferably, the DPP-4 inhibitor is selected from the G2 group consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, carmegliptine, gosogliptin, teneligliptine, melogliptin and ductoglyptine or a pharmaceutically acceptable salt of one of the inhibitors of DPP-4 mentioned here or a prodrug thereof.
    More preferably, the DPP-4 inhibitor is selected from -. from the G2 group consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptine and dutogliptin or a pharmaceutically acceptable salt of one of the DPP-4 inhibitors mentioned here or a prophylactic of the same.
    A particularly preferred inhibitor of DPP-4 within the present invention is linagliptin.
    The term "linagliptin" when used herein, refers to linagliptin and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof and crystalline forms thereof. 10 Crystalline forms are described in WO 2007/128721. Methods for making Iinagliptin are described in patent applications WO 2004/018468 and WO 2006/048427, for example.
    Linagliptin is distinguished from structurally comparable DPP-4 inhibitors, as it combines exceptional potency and a long-lasting effect with favorable pharmacological properties.
    .- 15 variables, receptor selectivity and a favorable coIateral effect profile, or brings almost unexpected therapeutic advantages or improvements in monotherapy ¢ and / or when used in combination with a second and, optionally, a third antidiabetic agent according to this invention.
    For the avoidance of doubt, the description of each of the 20 previous documents cited above with respect to the specified DPP-4 inhibitors is specifically incorporated herein by reference in its entirety.
    In one aspect of the present invention, the pharmaceutical compositions, methods and uses according to this invention, refer to those compositions which comprise the DPP-4 inhibitor as the exclusive active ingredient (i.e., the second and third agent antidiabetic drugs are both absent) and / or, respectively, to monotherapy using the DPPA inhibitor alone.
    In another aspect of the present invention, the pharmaceutical compositions, combinations, methods and uses according to this invention refer to those compositions or combinations that comprise the DPP-4 inhibitor and the second antidiabetic agent as exclusive active ingredients ( that is, the third antidiabetic agent is absent) and / or,
    .., to dual combination therapy using the DPP-4 inhibitor and the second antidiabetic agents.
    In another aspect of the present invention, the pharmaceutical compositions, combinations, methods and uses according to this invention refer to those compositions or combinations comprising the DPP-4 inhibitor, the second and the third antidiabetic agents and / or, respectively, to the triple combination therapy using the DPP-4 inhibitor, the second and the third antidiabetic agents.
    In addition, a DPP-4 inhibitor according to this invention 10 can also be characterized by the fact that said DPP-4 inhibitor does not significantly impair the glomerular and / or tubular function of a type 2 diabetes patient with chronic renal failure (eg mild, moderate or severe cognitive impairment or end-stage kidney disease), and / or the said DPP-4 inhibitor does not require the dose to be
    .- 15 adjusted in a type 2 diabetes patient with impaired renal function (eg mild, moderate or severe renal impairment or end-stage renal disease). The second antidiabetic agent and, if present, the third antidiabetic agent are selected from the G3 group, consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, alpha-glycosidase inhibitors, GLP-l or GLP-l analogs, and insulin or insulin analogs or a pharmaceutically acceptable salt thereof.
    The following preferred modalities for the second and / or third antidiabetic agent (s) are described. 25 The G3 group comprises biguanides.
    Examples of biguanides are metformin, phenformin and buformin.
    A preferred biguanide is metformin.
    A DPP-4 inhibitor in combination with a biguanide, in particular metformin, can provide more effective glycemic control and / or can work together with the biguanide, for example, to reduce weight, which has 30 for example, beneficial effects on the metabolic syndrome that is generally associated with type 2 diabetes mellitus. The term "metformin" when used here, refers to
    formalin or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt, the metformin fumarate salt (2: 1), and the metformin succinate salt (2: 1), the hydrobromide salt, the p-chlorophenoxy acetate or embonate, and other known metformin salts of mono- and 5-dibasic carboxylic acids.
    It is preferred that the metformin employed herein is the metformin hydrochloride salt.
    The G3 group comprises thiazolidindiones- Examples of thiazolidinediones (TZD) are pioglitazone and rosiglitazone.
    TZD therapy is associated with weight gain and fat redistribution.
    In addition, TZD causes fluid retention and is not indicated in patients with congestive heart failure.
    Long-term treatment with TZD is also associated with an increased risk of bone fractures.
    A DPP-4 inhibitor in combination with a thiazolidindione, in particular pioglitazone, can. provide more effective glycemic control and / or can minimize side effects
    .- 15 raises of TZD treatment.
    The term "pioglitazone" when used herein, refers to pio-. glitazone, including its enantiomers, mixtures thereof and its racemate or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. 20 The term "rosiglitazone" when used herein, refers to ro-siglitazone, including its enantiomers, mixtures thereof and its racemate or a pharmaceutically acceptable salt thereof, such as maleate salt.
    The G3 group comprises sulfonylureas.
    Examples of sulfonylureas are glibenclamide, tolbutamide, glimepiride, glipizide, glycidone, glyciduride, glyburide, glisoxepide and gliclazide.
    Preferred sulfonylureas are tolbutamide, glycidone, glibenclamide and glimepiride, in particular glibencamide and glimepiride.
    Since the effectiveness of sulfonylureas gradually decreases the course of treatment, a combination of a DPP-4 30 inhibitor with a sulfonylurea can offer additional benefit to the patient in terms of better glycemic control.
    Likewise, treatment with sulphylureas is usually associated with gradual weight gain during
    - the course of treatment and a DPP-4 inhibitor can minimize this side effect of treatment with a sulfonylurea and / or improve metabolic syndrome.
    Likewise, a DPP-4 inhibitor in combination with a sulphonylurea can minimize hypoglycemia, which is another undesirable side effect of sulphonylureas.
    This combination can likewise allow a reduction in the dose of sulfonylureas, which can also translate into less hypoglycemia.
    Each term in the group "glibenclamide", "glimepiride", "gliquidone", "glibornuride", "gliclazide", "glisoxepide", "tolbutamide" and "glipizide" when used herein, refers to the respective active drug or a salt pharmaceutically acceptable.
    The G3 group comprises glinides.
    Examples of glinides are na- teglinide, repaglinide and mitiglinide.
    Since its effectiveness decreases gradually. course of treatment, a combination of a DPP-4 inhibitor
    .- 15 with a meglitinide can offer additional benefit to the patient in terms of better glycemic control.
    Likewise, treatment with meglitini-. das is usually associated with gradual weight gain during the course of treatment, and a DPP-4 inhibitor can minimize this side effect of treatment with a meglitinide and / or improve the metabolic syndrome 20.
    Likewise, a DPP-4 inhibitor in combination with a meglithinide can minimize hypoglycemia, which is another undesirable side effect of meglitinides.
    This combination can likewise allow a reduction in the dose of meglitinides, which can likewise translate into less hypoglycemia. 25 The term "nateglinide" when used herein refers to nateglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof.
    The term "repaglinide" when used herein refers to repaglinide, including its enantiomers, mixtures thereof and its racemate, or pharmaceutically acceptable salts and esters thereof.
    The G3 group comprises alpha-glucosidase inhibitors.
    Examples of alpha-glucosidase inhibitors are acarbose, voglibose and miglitol.
    Benefit-
    .- Additional combinations of a DPP-4 inhibitor and an alpha glucosidase inhibitor may refer to more effective glycemic control, for example, in lower doses of individual drugs, and / or reduction of gastrointestinal side effects undesirable effects of alpha-glycosidase inhibitors. 5 Each term in the group "acarbose", "voglibose" and "miglitol" when used here refers to the respective active drug or a pharmaceutically acceptable salt. The G3 group comprises inhibitors of GLP-1 analogs. Examples of GLP-1 analogues are exenatide, liraglutide, taspoglutide, siloxide, albigglutide, and Iixisenatide. The combination of a DPP-4 inhibitor and a GLP-1 analogue can achieve superior glycemic control, for example, at lower doses of individual drugs. In addition, for example, the body weight reduction ability of the GLP-1 m analogue can positively act together with the properties of the .- 15 DPP-4 inhibitor. On the other hand, a reduction in side effects (for example, nausea, gastrointestinal side effects like vomiting) can be achieved,
    K for example, when a reduced dose of the GLP-1 analogue is applied in combination with a DPP-4 inhibitor. Each term in the group "exenatide", "liraglutide", "taspoglutide", 20 "semagglutide", "albiglutide", and "lixisenatide" when used herein refers to the respective active drug or a pharmaceutically acceptable salt thereof. In one embodiment (modality El), the pharmaceutical compositions, combinations, methods and uses according to this invention refer to those combinations in which the DPP-4 inhibitor and the second antidiabetic agent are preferably selected according to the entries in Table 1.
    Table 1 DPP-4 inhibitor Second selected Antidiabetic Agent of mode B selected from group G3 selected of mode B Metformin selected from mode B Pioglitazone selected from mode B Rosiglitazone selected from mode B Glibenclamide selected from mode B Glimepiride selected from mode B Gliquidone selected from mode B Nateglinide selected from mode B Repaglinide selected from mode B Acarbose selected from mode B Voglibose selected from mode B Miglitol selected from mode B Liraglutida selected from mode B Taspoglutida selected from mode B Semagglutida selected from mode B Albiglutida selected from mode B mode B Lixisenatide Linagliptin selected from the group G3 Linagliptin Metformin Linagliptin Pioglitazone Linagliptin Rosiglitazone Linagliptin Glibenclamide Linagliptin Glimepiride Linagliptin GIiguidone Linagliptin Nateglinide Li nagliptina repaglinide Linagliptin Acarbose Linaq | iDtina Vodibose DPP-4 lnibidor Second Agent Antidiabetic Linagliptin Miglitol Linagliptin Exenatide Linagliptin Liraglutide Linagliptin Taspoglutida Linagliptin Semaglutida Linagliptin Albiglutida Linagliptin lixisenatide Sitagliptin selected from the group G3 Sitagliptin Metformin Sitagliptin Pioglitazone Sitagliptin Rosiglitazone Sitagliptin Glibenclamide Sitagliptin Glimepiride Sitagliptin Gliguidona Sitagliptin nateglinide Sitagliptin Repaglinide Sitagliptin Acarbose SitagMna Voglibose Sitagliptin Miglitol Sitagliptin Exenatide Sitagliptin Liraglutide Sitagliptin Taspoglutida Sitagliptin Semagglutide Sitagliptin Sitigiptine Lixisenatide Vildagliptin Gildygliptinamine Gildyptiptin Gildyptiptin
    DPP-4 inhibitor Second Agent Antidiabetic vildagliptin Glimepiride vildagliptin gliquidone vildagliptin nateglinide vildagliptin repaglinide vildagliptin Acarbose vildagliptin Voglibose vildagliptin Miglitol vildagliptin Exenatide Vildagliptin Liraglutide vildagliptin Taspoglutida vildagliptin Semaglutida vildagliptin Albiglutida vildagliptin lixisenatide alogliptin selected from the group G3 alogliptin Metformin alogliptin Pioglitazone alogliptin Rosiglitazone alogliptin Glibenclamide alogliptin Glimepiride alogliptin gliquidone alogliptin nateglinide repaglinide alogliptin alogliptin Acarbose alogliptin Voglibose alogliptin Miglitol alogliptin Exenatide alogliptin Liraglutide alogliptin Taspoglutida alogliptin Semaglutida a | q | iptina Albidutida DPP-4 lnibidor Second Agent Antidiabetic alogliptin lixisenatide Saxagliptin selected from the group G3 Saxagliptin Saxagliptin Metformin Pioglitazone Rosiglitazone Saxagliptin Saxagliptin Glibenclamid the Saxagliptin Glimepiride Saxagliptin gliquidone Saxagliptin nateglinide Saxagliptin repaglinide Saxagliptin Acarbose Saxagliptin Voglibose Saxagliptin Miglitol Saxagliptin Exenatide Saxagliptin Liraglutide Saxagliptin Taspoglutida Saxagliptin Semaglutida Saxagliptin Albiglutida Saxagliptin lixisenatide Carmegliptina selected from the group G3 Carmegliptina Metformin Carmegliptina Pioglitazone Carmegliptina Rosiglitazone Carmegliptina GIibenclamida Carmegliptina Glimepiride Carmegliptina gliquidone Carmegliptina nateglinide Carmegliptina repaglinide Carmegliptina Acarbose Carmediotina Voalibose DPP-4 lnibidor Second Agent Antidiabetic Carmegliptina Miglitol Carmegliptina Exendin Carmegliptina Liraglutide Carmegliptina Taspoglutida Carmegliptina Semaglutida Carmegliptina Albiglutida Carmegliptina lixisenatide Melogliptina selected from the group G3 Melogliptina Melogliptina Metformin Pioglitazone Rosiglitazone Melogliptina Melogliptina GIibenclamida Melogliptina Glimepi rapid Melogliptina gliquidone Melogliptina nateglinide Melogliptina repaglinide Melogliptina Acarbose Melogliptina Voglibose Melogliptina Miglitol Melogliptina Exenatide Melogliptina Liraglutide Melogliptina Taspoglutida Melogliptina Semaglutida Melogliptina Albiglutida Melogliptina lixisenatide Dutogliptina selected from G3 Dutogliptina Metformin Dutogliptina Pioglitazone Dutogliptina Rosiglitazone Dutocl group | iIjtina Glibenclamide DPP-4 lnibidor Second Agent Antidiabetic Dutogliptina Glimepiride Dutogliptina gliquidone Dutogliptina nateglinide repaglinide Dutogliptina Dutogliptina Acarbose Dutogliptina Voglibose Dutogliptina Miglitol Dutogliptina Exenatide Dutogliptina Liraglutide Dutogliptina Taspoglutida Dutogliptina Semaglutida Dutogliptina Albiglutida Dutogliptina lixisenatide Gosogliptina selected from the group G3 Gosogliptina Gosogliptina Metformin Pioglitazone Rosiglitazone Gosogliptina Gosogliptina Glibenclamide Glimepiride Gosogliptina Gosogliptina GIiquidona Gosoglip Nateglinide Gosogliptin Repaglinide Gosogliptin Acarbose Gosogliptin Voglibose Gosogliptin Miglitol Gosogliptine Exenatide Gosogliptin Liraglutida Gosogliptina Taspoglutida DPP-4 inhibitor Second Antidiabetic Agent Gosogliptin Semaglutida
    Albiglutide Gosogliptin
    Gosogliptin Lixisenatide
    Teneligliptina selected from group G3
    Teneligliptina Metformin
    Teneligliptin P ioglitazone
    Teneligliptin Rosiglitazone
    Teneligliptin Glibenclamide
    Teneligliptin GIimepiride
    Teneligliptin GIiquidone
    Teneligliptin Nateglinide
    Teneligliptin Repaglinide
    Teneligliptina Acarbose
    Teneligliptin Voglibose
    Teneligliptina Miglitol
    Teneligliptin Exenatide
    Teneligliptin Liraglutide
    Teneligliptina Taspoglutida
    Teneligliptine Semagglutide
    Teneligliptin Albiglutide
    Teneligliptin Lixisenatide
    In a particular embodiment (modality E2), the pharmaceutical compositions, combinations, methods and uses according to this invention refer to those combinations in which the DPPA inhibitor is linagliptin.
    According to modality E2, the second antidiabetic agent is selected preferably according to the entries in Table 2.
    W. Table 2 Modality According to Antidiabetic Agent E2.1 selected from the group G3 E2.2 Metformin E2.3 Pioglitazone E2.4 Rosiglitazone E2.5 Glibenclamide E2.6 Glimepiride E2.7 Giquiquone E2.8 Nateglinide E2.9 Repaglinide E2.10 Acarbose E2 .11 Voglibose E2.12 Miglitol
    W E2.13 Exenatide h E2.14 Liraglutide E2.15 Taspoglutide E2.16 Semagglutide E2.17 Albiglutide E2-18 Lixisenatide E2.19 insulin or insulin analogue E2.20 GLP-l or GLP-l analog The combination of a DPP-4 inhibitor and a second and, optionally, a third antidiabetic agent according to this invention can be found to improve glycemic control, in particular, in 5 patients as described here, in comparison with a monotherapy using a DPP-4 inhibitor or the second or third antidiabetic agent only, for example, with a metformin monotherapy, or with a double therapy using the second and third antidiabetic agent. In addition, the triple combination of a DPP-4 inhibitor and a second and third antidiabetic agent 10 according to this invention can be found to improve glycemic control, in particular, in patients as described here, W
    N compared to a combination therapy using a DPP-4 inhibitor and the second or third antidiabetic agent, or using the second and third antidiabetic agent. The improved glycemic control is determined as an increased reduction in blood glucose and an increased reduction in HbA1c. With monotherapy in one patient, in particular, in patients as described here, glycemic control may also not be significantly improved by administering the drug at a certain higher dose. In addition, long-term treatment using a higher dose may not be desired due to potential side effects. 10 Therefore, satisfactory glycemic control may not be achievable in all patients by monotherapy using the DPP-4 inhibitor or the second or third antidiabetic agent alone. In the event that monotherapy does not produce complete glycemic control, dual therapy may become necessary. Even with combination therapy using two selected agents - .- 15 DPP-4 inhibitors and second and third antidiabetic agents may not produce complete glycemic control in all patients -u and / or for a long time. In the event that dual therapy does not produce complete glycemic control, triple therapy may become necessary. In such patients with inadequate glycemic control, progression of diabetes mellitus 20 may continue and complications associated with diabetes mellitus may occur, such as macrovascular complications. The pharmaceutical composition or combination as well as the methods according to the present invention allows a reduction of the HbA1c value to a desired target range, for example, <7 ° /) and preferably <6.5 ° /), to a greater number high of 25 patients and for a longer time of therapeutic treatment, for example, in the case of double or triple combination therapy compared to a monotherapy using one of or, respectively, a double therapy using two of the combination pairs. In addition, the combination of a DPP-4 inhibitor and the second 30 and, optionally, the third therapeutic agent according to this invention can be found to allow for a reduction in the dose of the DPP-4 inhibitor or the second or third agent antidiabetic or even two or three of the active ingredients. A dose reduction is beneficial for patients who would otherwise potentially experience side effects in a therapy using a higher dose of one or more of the active ingredients, in particular with respect to the side effect caused by the 5 second and / or third antidiabetic agent, therefore, the pharmaceutical combination as well as the methods according to the present invention, may show fewer side effects, thereby making therapy more tolerable and improving patient compliance with treatment. 4 according to the present invention is able - through increases in active GLP-1 levels - to reduce a glucagon secretion in a patient, thus limiting hepatic glucose production. elevated active GLP-1 levels produced by the DPP-4 inhibitor will have beneficial effects on beta cell regeneration and neogenesis. All of these characteristics of DPP-4 inhibitors can .- 15 make a composition o u pharmaceutical combination or method of this very useful and therapeutically relevant invention.
    X When this invention relates to patients who require treatment or prevention, it mainly relates to treatment and prevention in humans, however, the pharmaceutical composition can likewise be used accordingly in veterinary medicine in mammals. Within the scope of this invention, adult patients are preferably humans aged 18 years or older. Similarly within the scope of this invention, patients are adolescent humans, that is, humans aged 10 to less than 18 years old, preferably aged 13 to less than 18 years old. 25 In one embodiment, patients in need of treatment or prevention as described here can be identified by determining whether they have variation (s) (eg, polymorphisms) in one or more genes associated with metabolic disease and / or whether they have variation (s) (for example, polymorphisms) in one or more of the selected genes from 30 TCF7L2, KCNJ11, PPARG and GLPIR, in particular, if they are of TCF7L2 risk genotype as described here. In another modality, patients in need of treatment
    ,. or prevention as described herein can be identified by determining whether they are of the respective wild-type genotype, in particular, whether they are of the wild-type TCF7L2 genotype as described here.
    A particular subpopulation of patients in need of treatment or prevention as described here, refers to those patients who have one or more unique nucleotide polymorphisms (SNPS) in the gene encoding for TCF7L2, especially a SNP selected from rs7903146, rs12255372 and rs10885406, especially rs7903146, more particularly, those patients who carry at least one T 10 allele of SNP rs7903146 of TCF7L2, i.e., the CT genotype or TT genotype.
    Another particular subpopulation of patients in need of treatment or prevention as described here, refers to those patients carrying wild TCF7L2 rs7903146 CC genotype. "So, in one aspect of this invention, a treatment or
    , - 15 prophylaxis according to this invention is suitable in these patients in need of such treatment or prophylaxis who are diagnosed as having variation (s) (for example, polymorphisms) in one or more genes associated with diseases and / or variation ( metabolic (s) (eg, SNPs) in one or more of the selected TCF7L2, KCNJ11, PPARG and 20 GLPIR genes, in particular TCF7L2 risk genotype as described here.
    In another aspect of this invention, a treatment or prophylaxis according to this invention is particularly suitable in those patients in need of such treatment or prophylaxis who are diagnosed as having a wild genotype of TCF7L2 as described herein. In a sub-aspect of this invention, a treatment or prophylaxis according to this invention is suitable in those patients in need of such treatment or prophylaxis who are diagnosed as having one or more unique nucleotide polymorphisms (SNPS) in the gene encoding TCF7L2, for example , at least one SNP selected from rs7903146, 30 rs12255372 and rs10885406, for example, rs7903146, in particular, carrying at least one T allele of rs7903146, (ie, CT or TT genotype), among them, in more particular, those carrying a T allele of
    , B
    .. rs7903146 (ie, CT risk genotype) or, less particularly, those carrying two rs7903146 T alleles (ie, high risk TT genotype). In another sub-aspect of this invention, a treatment or prophylaxis according to this invention is particularly favorable in those patients in need of such treatment or prophylaxis who are diagnosed to carry two wild type C alleles of rs7903146 in TCF7L2 (ie, genotype). In one embodiment of this invention, a treatment or prophylaxis 10 according to this invention is suitable in these patients in need of such treatment or prophylaxis who are diagnosed with one or more of the conditions selected from the group consisting of overweight and obesity, in particular, obesity of class I, class II obesity, class II obesity, visceral obesity and abdominal obesity.
    In addition, a treatment
    .- 15 or prophylaxis according to this invention are advantageously suitable in those patients in whom an increase in weight is contraindicated-. of.
    Any effect of weight gain in therapy, for example, due to the administration of the second and / or the third antidiabetic agent, can be attenuated or even avoided in this way. In a further embodiment of this invention, the pharmaceutical composition or combination of this invention exhibits very good efficacy with respect to glycemic control, in particular, due to a reduction in fasting plasma glycoside, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c). By administering a pharmaceutical composition or combination according to this invention, a reduction in HbA1c equal to or greater than preferably 1.0%, more preferably equal to or greater than 2.10%, even more preferably equal to or greater than 3.0 ° 6 can be obtained and the reduction is particularly in the range of 1.0 ° / o to 3.0 ° / o.
    In addition, the method and / or use according to this invention is applicable to these patients who show one, two or more of the following conditions: (a) a fasting blood glucose or glucose concentration
    W b in the serum greater than 110 mg / dL or greater than 100 mg / dL, in particular greater. that 125 mg / dL; (b) a postprandial plasma glucose equal to or greater than 140 mg / dL; 5 (C) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 7.0%, especially equal to or greater than 7.5%, even more particularly equal to or greater than 8.0 %. The present invention also describes the use of the pharmaceutical composition or combination to improve glycemic control in patients 10 having type 2 diabetes or showing first signs of pre-diabetes. Accordingly, the invention also includes the prevention of diabetes. If, therefore, a pharmaceutical composition or combination of this invention is used to improve glycemic control as soon as one of the aforementioned signs of pre-diabetes is present, the onset of manifest type 2 diabetes mellitus may be 0. 15 be time consuming or prevented. In addition, the pharmaceutical composition or combination of this invention is particularly suitable for the treatment of patients with
    Insulin dependence, that is, in patients who are treated or otherwise would be treated or need treatment with an insulin or an insulin derivative or an insulin substitute or a formulation comprising an insulin or a derivative or substitute thereof . These patients include patients with type 2 diabetes and patients with type 1 diabetes. Therefore, according to one embodiment of the present invention, 25 a method is provided to improve glycemic control and / or to reduce fasting plasma glucose, glucose plasma concentration and / or glycosylated hemoglobin HbA1c in a patient in need of it who is diagnosed with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG) with insulin resistance, with metabolic syndrome 30 and / or with type 2 or type 1 diabetes, characterized by the fact that a DPP-4 inhibitor and, optionally, a second and, optionally, a third antidiabetic agent as previously defined and in
    The N is then administered, for example, in combination, to the patient.
    In accordance with another embodiment of the present invention, a method is provided for improving glycemic control in patients, in particular, in adult patients, with type 2 diabetes mellitus as a supplement 5 for diet and exercise.
    In addition, in a particular embodiment of this invention, a therapeutic or preventive method and / or use according to this invention is suitable in these patients who have variation (s) (for example, polymorphisms) in one or more genes associated with diseases metabolic and / or that 10 have variation (s) (for example, polymorphisms) in one or more of the selected TCF7L2, KCNJ11, PPARG and GLPIR genes.
    In this context, a subpopulation of the patients described here before and next refers to patients of TCF7L2 risk genotype, such as, for example, those patients who have one or more people.
    .- 15 Unique nucleotide imorphisms (SNPS) in the gene encoding TCF7L2, especially at least one SNP selected from rs7903146, rs12255372 6 and rs10885406, especially rs7903146. More particularly, those patients who carry at least one rs7903146 SNP T allele of TCF7L2, i.e., the CT genotype or TT genotype, especially that 20 carry two rs7903146 SNP T alleles of TCF7L2, that is, the genotype of TT, is highly susceptible to increased TCF7L2 expression in pancreatic beta cells, impaired insulin secretion, incretin effects, increased rate of hepatic glucose production and / or diabetes.
    The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of 25 incretin hormones, reduced 24-hour plasma insulin and glucagon profiles, and increased hepatic glucose production.
    Therefore, the present invention also includes the compounds, pharmaceutical compositions or combinations according to this invention for use in the treatment and / or prevention of those diseases, disorders or conditions mentioned here in these patients who have one or more nucleotide polymorphisms. unique (SNPS) in the gene encoding TCF7L2, especially at least one SNP selected from rs7903146, rs12255372 and rs10885406, especially rs7903146; more particularly, in those patients that carry at least one SNP T allele rs7903146 of TCF7L2, i.e., the CT genotype or TT genotype, particularly in those patients that carry a SNP T allele rs7903146 of TCF7L2, 5 this that is, the CT genotype, or that carry two T alleles of SNP rs7903146 of TCF7L2, that is, the TT genotype.
    Patients of TCF7L2 risk genotype as described here include, but are not limited to, Caucasian, Northern European, Asian, Indian and / or Afro-descendant patients. The present invention also includes a therapeutic and / or preventive method or use according to this invention for application to a patient in need of it, said method or use comprising the step of determining whether the patient has variation (s) (for example, polymorphisms) in one or more of the selected TCF7L2 genes, KCNJ11,
    - 15 PPARG and GLPIR, particularly if the patient is of a TCF7L2 risk genotype as described here.
    The determination or diagnosis of whether the patient has variation (s) (eg, polymorphisms) in one or more of the selected TCF7L2, KCNJ11, PPARG and GLPIR genes, particularly if the patient is 20 of a risk genotype TCF7L2 as described here, or if the patient is of the wild genotype, particularly, if the patient is of the wild genotype of TCF7L2 as described here, can be used to determine the probability (for example, increased, decreased, or no likelihood) of a favorable therapeutic and / or preventive response of the patient to treatment with a DPP-4 inhibitor (or with a combination of a DPP-4 inhibitor with the second and / or third antidiabetic agent as defined here) in a therapeutic and / or preventive method or use as described above or here afterwards (for example, in the treatment of diabetes or in the improvement of glycemic control), and thereby to identify an individual being susceptible to such treatment .
    Thus, in addition, in another embodiment of this invention, a method of determining the probability of indication (by e-
    Example, increased, decreased, or no likelihood) of a favorable response to administration of a pharmaceutically acceptable amount of a DPP-4 inhibitor (or a combination of a DPPA inhibitor with the second and / or third antidiabetic agent as described here) in an individual (particularly, a patient with diabetes), said method comprising the step of determining whether the individual has variation (s) (for example, polymorphisms) in one or more of the selected TCF7L2 genes , KCNJ11, PPARG and GLPIR, particularly if the individual is of a TCF7L2 risk genotype as described here, or determining whether the individual is of the wild TCF7L2 genotype, testing particularly if the individual is of the wild genotype TCF7L2 rs7903146 CC.
    In accordance with another particular embodiment of this invention, the present invention provides a DPP-4 inhibitor, composition or compound. pharmaceutical combination according to the present invention for use in a
    .- 15 therapeutic or preventive method as described here previously or thereafter (particularly, to treat or prevent type 2 diabetes and / or obesity), said method comprising (i) identifying an individual being susceptible to the therapeutic method or preventive, said identification comprising testing whether the individual has variation (s) (eg, polymorphisms) in one or more of the selected TCF7L2, KCNJ11, PPARG and GLPIR genes, in particular if the individual is of any TCF7L2 risk genotype as described here, more particularly if he / she has one or more unique nucleotide polymorphisms (SNPS) in the gene coding for TCF7L2, especially at least one SNP selected from rs7903146, rs12255372 and rs10885406, especially rs7903146, for example, if the individual carries at least one SNP T allele rs7903146 from TCF7L2, for example, if the individual is of CT genotype (that is, if the patient carries an SNP T allele rs7903146 from TCF7L2) or if the individual is of TT genotype (ie, if the patient carries two T alleles of SNP rs7903146 of TCF7L2), or test whether the individual is of wild TCF7L2 genotype, in particular if the individual is the wild genotype of TCF7L2 rs7903146 CC; and thus -THE
    -. terminate the likelihood of indicating a favorable response (for example, favorable change in HbA1c) resulting from the individual's therapeutic or preventive treatment with the DPPA inhibitor, pharmaceutical composition or combination; 5 and (ii) administering an effective amount of the DPP-4 inhibitor, pharmaceutical composition or combination to the individual where said individual is determined to have a high probability of indicating a favorable response (for example, favorable change in HbA1c) resulting from therapeutic or preventive treatment with the DPP-4 inhibitor, pharmaceutical composition or combination.
    The present invention also provides a therapeutic and / or preventive method or use of this invention for application to a patient in need of it, said method or use comprising the
    - 15 countries
    % - obtain and analyze a nucleic acid sample from an individual with type 2 diabetes mellitus,
    - determine the efficacy and / or, optionally, the probability of indicating a favorable response (for example, in providing glycemic control, such as favorable change in HbA1c) to treatment with a DPP-4 inhibitor, preferably linagliptin, or the DPP-4 inhibitor in combination with one or more other active substances (for example, antidiabetics), comprising detecting genotype of TT or CT or CC allele in rs7903146 of TCF7L2 gene in the patient sample, 25 where the presence of the genotype of TT, CT or CC is indicative of treatment efficacy, and / or, optionally, where the presence of the TT genotype is indicative of a decreased probability of the favorable response and / or presence of the CC genotype is indicative of an increased probability favorable response to treatment, and
    - administer a therapeutically effective amount of the DPP-4 inhibitor, preferably linagliptin, or the DPP-4 inhibitor in
    "B
    ., combination with one or more other active substances (for example, antidiabetics) to the individual.
    It can also be seen that using a pharmaceutical composition or combination according to this invention, an improvement in glycemic control can be obtained even in those patients who have insufficient glycemic control, in particular, despite treatment with the second one. or third antidiabetic agent or a combination of the second with the third antidiabetic agent, for example, despite the maximum tolerated dose of oral monotherapy with metformin, a thiazolidinedione (eg 10 pioglitazone) or a sulfonylurea, or a combination of metformin with a thiazolidinedione (for example, pioglitazone), metformin with a sulfonylurea, or a thiazolidinedione (for example, pioglitazone) with a sulfonylurea.
    It can also be seen that using a com-
    - 15 combination according to this invention, an improvement in glycemic control can be obtained even in patients who have insufficient glycemic control, in particular, despite treatment with a DPP-4 inhibitor or a combination of a DPPA inhibitor with the second or third anti-diabetic agent, for example, despite the maximum tolerated dose of oral monotherapy 20 with a DPPA inhibitor or a double combination of a DPP-4 inhibitor with the second or third anti-diabetic agent.
    A maximum tolerated dose with respect to metformin is, for example, 2000 mg per day, 1500 mg per day (for example, in Asian countries) or 850 mg three times per day or any equivalent thereof. Therefore, the method and / or use according to this invention is applicable to those patients who show one, two or more of the following conditions: (a) insufficient glycemic control only with diet and exercise; (b) insufficient glycemic control despite monotherapy with metformin, a thiazolidinedione (eg, pioglitazone), a sulfonylurea, GLP-1 or GLP-1 analogue, or insulin or insulin analogue, in particular, despite monotherapy oral in a maximum tolerated dose of metformin, a thiazolidinedione (eg, pioglitazone) or a sulfonylurea; (C) insufficient glycemic control despite combination therapy with two agents selected from the group consisting of metformin, 5 a thiazolidinedione (eg, pioglitazone), a sulfonylurea, GLP-1 or GLP-1 analogue, and insulin or analogue insulin, for example, despite combination therapy with a selected double combination of metformin / pioglitazone, metformin / sulfonylurea, metformin / insulin, sulphonylurea / pioglitazone, sulfonylurea / insulin and pioglitazone / insulin; The double or triple combination method and / or use according to this invention is also applicable to those patients who show the following conditions (e) or (f), respectively: (d) insufficient glycemic control despite oral monotherapy. with the DPP-4 inhibitor, in particular, despite oral monotherapy in a
    - 15 maximum tolerated dose of DPP-4 inhibitor; (e) insufficient glycemic control despite combination therapy (oral) with the DPP-4 inhibitor and the second or third antidiabetic agent, in particular, despite oral double therapy at a maximum tolerated dose of at least one combination pairs. In one embodiment of this invention, a pharmaceutical composition or combination is suitable for treating patients who are diagnosed as having one or more of the following conditions - insulin resistance, - hyperinsulinemia, 25 - pre-diabetes, - diabetes type 2 mellitus, particularly having end-stage type 2 diabetes mellitus, - type 1 diabetes mellitus. In addition, a pharmaceutical composition or combination according to this invention is particularly suitable for treating patients who are diagnosed as having one or more more of the following conditions
    (a) obesity (including class I, ll and / or III obesity), visceral obesity and / or abdominal obesity, (b) blood triglyceride level 2 150 mg / dL, (c) HDL cholesterol level in blood <40 mg / dL in 5 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 glucose level fasting blood pressure,>, 110 mg / dL or,> 100 mg / dL.10 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 contracting cardiovascular disease, such as, for example, myocardial infarction, coronary heart disease, heart failure, events
    - 15 thromboembolic.
    A glycemic control according to this invention can result in a reduction in cardiovascular risks.
    In addition, the pharmaceutical composition and methods according to this invention are particularly suitable for the treatment of organ transplant patients, in particular, those patients who are diagnosed as having one or more of the following conditions (a) an older age, in particular over 50, (b) male; (C) overweight, obesity (including, class I, ll and / or lll obesity), visceral obesity and / or abdominal obesity, 25 (d) pre-transplant diabetes, (e) immunosuppression therapy.
    A pharmaceutical composition or combination according to this invention, in particular due to the DPP-4 inhibitor in it, exhibits a good safety profile.
    Therefore, a treatment or prophylaxis according to this invention is possible in those patients to whom mono-therapy with another antidiabetic drug, such as, for example, metformin, is contraindicated and / or has an intolerance against such drugs in doses therapeutic.
    In particular, a treatment or prophylaxis according to this invention may be advantageously possible in those patients who show or are at increased risk for one or more of the following disorders: kidney failure or disease, heart disease, heart failure, 5 liver disease, lung diseases, catabolic states and / or danger of lactate acidosis, or female patients who are pregnant or during lactation.
    In addition, it can be seen that the administration of a pharmaceutical composition or combination according to this invention does not result in a risk or a low risk of hypoglycemia.
    Therefore, a treatment or prophylaxis according to this invention is likewise advantageously possible in these patients showing or having an increased risk for hypoglycemia.
    A pharmaceutical composition or combination according to
    - this invention is particularly suitable for long-term treatment or - prophylaxis of diseases and / or conditions as previously described here and then, in particular for long-term glycemic control in patients with type 2 diabetes mellitus. term "as previously used here and then 20 indicates treatment of or administration to a patient within a period of time longer than 12 weeks, preferably longer than 25 weeks, even more preferably longer than 1 year.
    Therefore, a particular 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 type 2 diabetes mellitus in final stage, in particular in patients additionally diagnosed with overweight, obesity (including class I, class II and / or class ll obesity), visceral obesity and / or abdominal obesity. The effects mentioned above are observed equally when the DPP-4 inhibitor and the second and, optionally, the third antidiabetic agent are administered together, for example, simultaneously in a single or two or three separate formulations, and / or when they they are administered alternately, for example, successively in two or three separate formulations.
    Within this invention it should be understood that combinations or 5 combined uses considers separate, sequential, simultaneous, concomitant, chronologically alternating or alternating administration of the components.
    It will be appreciated that the DPP-4 inhibitor and the other active substance (s) can be administered in a single dosage form or each in separate dosage forms. In this context, "combination" or "combined" in the same way within the meaning of this invention also includes, without being limited to fixed and non-fixed forms and uses.
    It will be appreciated that the amount of the pharmaceutical composition according to this invention to be administered to the patient and required
    - 15 for use in treatment or prophylaxis according to the present invention will vary with the administration routine, the nature and severity of the condition. which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will ultimately be at the discretion of the attending physician.
    However, in general, the DPP-4 inhibitor and, optionally, the second and / or third antidiabetic agent according to this invention is (are) included in the pharmaceutical composition, combination or dosage form in an amount enough that by its administration, the glycemic control in the patient to be treated is improved.
    In the following preferred ranges of the amount of the DPP-4 inhibitor, the second and / or third 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, a human being, for example, of about 70 kg of body weight, and can be adapted accordingly with respect to an administration of 2, 3, 4 or more times a day and with respect to other administration routines and with respect to the patient's age.
    Dosage ranges and amounts are calculated for the one-time active portion.
    Advantageously, the combination therapy of the present invention uses lower dosages of the individual DPP-4 inhibitor and / or the second and / or third individual anti-diabetic agent used (s) as monotherapy or used in conventional therapeutics. thus avoiding the possible toxicity and adverse side effects incurred when these agents are used as monotherapies.
    Within the scope of the present invention, the pharmaceutical composition or combination is preferably administered orally.
    Other forms of administration are possible and described below.
    Preferably, one or more dosage forms comprising the DPP-4 inhibitor and / or the second and / or third antidiabetic agent is (San) oral (s) or usually well known (s). In general, the amount of the DPP-4 inhibitor in the combinations, combination methods or combined uses of this invention is preferred
    .- 15 usually in the range of 1/5 to 1/1 of the recommended amount per
    -d - a monotherapy using said DPP-4 inhibitor. A preferred dosage range for linagliptin when administered orally is 0.5 mg to 10 mg per day, preferably 2.5 mg to 10 mg, preferably 1 mg to 5 mg per day.
    The preferred range of amounts in the pharmaceutical composition is 0.5 to 10 mg, in particular 1 to 5 mg.
    Examples of particular dosage intensities are 1, 2.5, 5 or 10 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    Suitable formulations for linagliptin can be those formulations described in application WO 2007/128724, the description of which is incorporated herein in its entirety. Typical dosing essentials for the linagliptin / metformin IR (immediate release) double fixed dose (tablet) combination are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg, which can be administered 1-3 times a day, particularly twice a day. 30 typical dosing essentials of the double fixed dose (tablet) combination of Iinagliptin / metformin XR (prolonged release) are 5/500 mg, 5/1000 mg and 5/1500 mg, which can be administered 1-2 times a day, particularly once, preferably to be taken in the evening with a meal, or 2.5 / 500 mg, 2.5 / 750 mg and 2.5 / 1000 mg, which can be administered 1-2 times a day, particularly once a day two pills, preferably to be taken at night with a meal. 5 A preferred dose range for sitagliptin when administered orally is 10 to 200 mg, in particular 25 to 150 mg per day.
    An indicated dose of sitagliptin is 100 mg calculated for the active portion (free base anhydrate) once daily or 50 mg twice daily.
    The preferred range of quantities in the pharmaceutical composition is 10 to 150 mg, in particular 25 to 100 mg.
    Examples are 25, 50, 75 or 100 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    Equivalent amounts of sitagliptin salts, in particular, of phosphate monohydrate can be calculated accordingly.
    Adjusted dosages of sitagliptin, for example, 25 and 50 mg, are preferred
    . 15 widely used for patients with renal failure.
    A preferred dosage range for Vildagliptin when administered orally is 10 to 150 mg per day, in particular 25 to 150 mg, 25e100mg or 25e50 mg or 50e 100 mg per day.
    For example, the daily administration of Vildagliptin is 50 or 100 mg.
    The preferred range of amounts in the pharmaceutical composition is 10 to 150 mg, in particular 25 to 100 mg.
    Examples are 25, 50, 75 or 100 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    A preferred dosage range for alogliptin when administered orally is 5 to 250 mg per day, in particular 10 to 150 mg per 25 days.
    The preferred range of amounts in the pharmaceutical composition is 5 to 150 mg, in particular 10 to 100 mg.
    Examples are 10, 12.5, 20, 25, 50, 75 and 100 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    A preferred dosage range for Saxagliptin when administered orally is 2.5 to 100 mg per day, in particular 2.5 to 50 mg per day.
    The preferred range of amounts in the pharmaceutical composition is 2.5 to 100 mg, in particular 2.5 and 50 mg.
    Examples are 2.5, 5, 10, 15, 20, 30,
    40, 50 and 100 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    A preferred dosage range for dutogliptin when administered orally is 50 to 400 mg per day, in particular 100 to 400 mg for 5 days.
    The preferred range of amounts in the pharmaceutical composition is 50 to 400 mg.
    Examples are 50, 100, 200, 300 and 400 mg.
    The application of the active ingredient can occur up to three times a day, preferably once or twice a day.
    A special modality of the DPP-4 inhibitors of this invention relates to those orally administered DPP-4 inhibitors that are therapeutically effective at low dose levels, for example, at dose levels <100 mg or <70 mg per patient per day, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably 1. mg to 10 mg (if required, divided into 1 to 4 single doses, particularly 1
    .- 15 or two single doses, which can be the same size), particularly - from 1 mg to 5 mg (more particularly 5 mg), per patient per day, preferably. cially, administered orally once a day, more preferably, at any time of the day, administered with or without food.
    Thus, for example, the 5 mg oral daily amount of Bl 1356 can be produced in a once daily dosing regimen (ie, 5 mg Bl 1356 once daily) or in a dosing regimen. twice a day (ie 2.5 mg Bl 1356 twice a day), at any time of the day, with or without food.
    In general, the amount of the second and / or third antidiabetic agent in the combinations, combination methods and / or combined uses of this invention is preferably normally in the range of 1/5 to 1/1 of the amount recommended by a monotherapy using the said antidiabetic agent.
    The use of lower dosages of the second and / or third individual antidiabetic people compared to monotherapy could avoid or minimize possible toxicities and adverse side effects incurred when these agents are used as monotherapy.
    A preferred metformin dosage range when administered
    , orally delivered is 250 to 3000 mg, in particular 500 to 2000 mg per day. The preferred range of amounts in the pharmaceutical composition is 250 to 1000, in particular 500 to 1000 mg or 250 to 850 mg respectively. Examples are 500, 750, 850 or 1000 mg. Preferably, the administration of the said quantities is once, twice or three times a day. For example, the amounts of 500, 750 and 850 mg preferably require administration once a day, twice a day or three times a day and the amount of 1000 mg requires dosing once a day or twice a day. - zes a day. Certain controlled or prolonged release formulations allow for a dosage once a day. Metformin can be administered, for example, in the form as it is marketed under the trademarks GLUCOPHAGE ", GLUCOPHAGE-D" or GLUCOPHAGE-XR ".
    A preferred dosage range for pioglitazone when adm. administered orally is 5 to 50 mg per day. The preferred range of amounts in the pharmaceutical composition is 5 to 50 mg, 10 to 45 mg and 15 to 45 mg respectively. Examples are 15, 30 or 45 mg. Preferably, the administration of said amounts is once or twice a day, in particular - once a day. Pioglitazone can be administered as it is marketed, for example, under the trademark ACTOS "m. 20 A preferred dosage range for rosiglitazone when administered orally is 1 mg to 10 mg per day. The preferred range of quantities in the pharmaceutical composition it is 1 to 10 mg, 2 to 8 mg, 4 to 8 mg and 1 to 4 mg Examples are 1, 2, 4 or 8 mg Preferably, the administration of said amounts is once or twice Preferably, the dose should not exceed 8 mg per day. Rosiglitazone can be administered in the form as it is marketed, for example, under the trademark A-VANDIA®. A preferred dosage range for a thiazolidindione (different from pioglitazone or rosiglitazone as described above) when administered orally is 2 to 100 mg daily The preferred range of amounts in the pharmaceutical composition for administration once, twice or three times a day is 2 to 100, 1 to 50 and 1 to 33 mg, respectively.
    A preferred dosage range for glibenclamide when administered orally is 0.5 to 15 mg, in particular 1 to 10 mg per day. The preferred range of amounts in the pharmaceutical composition is 0.5 to 5 mg, in particular 1 to 4 mg. Examples are 1.0, 1.75 and 3.5 mg. Preferably, the administration of said quantities is once, twice or three times a day. GIibenclamide can be administered as it is marketed, for example, under the registered trademark EUGLUCON®.
    A preferred dosage range for glimepiride when administered orally is 0.5 to 10 mg, in particular 1 to 6 mg per day. The preferred range of quantities in the pharmaceutical composition is 0.5 to 10 mg, in particular 1 to 6 mg. Examples are 1, 2, 3, 4, and 6 mg. Preferably, the administration of said amounts is once, twice or three times a day, preferably once a day. Glimepiride can be administered in the form as it is marketed, for example, under the trademark AMARYL ®.
    - 15 A preferred dosage range of gliquidone when administered orally is 5 to 150 mg, in particular 15 to 120 mg per day. The preferred range of amounts in the pharmaceutical composition is 5 to 120 mg, in particular 5 to 30 mg. Examples are 10, 20, 30 mg. Preferably, the administration of said amounts is once, twice, three times or four times a day. Gliquidone can be administered as it is marketed, for example, under the trademark GLURENORM®.
    A preferred dosage range for glibornuride when administered orally is 5 to 75 mg per day. The preferred range of amounts in the pharmaceutical composition is 5 to 75 mg, in particular 10 to 50 mg. Preferably, the administration of said amounts is once, twice or three times a day. A preferred dosage range for gliclazide when administered orally is 20 to 300 mg, in particular 40 to 240 mg per day. The preferred range of amounts in the pharmaceutical composition is 20 to 240 mg, in particular 20 to 80 mg. Examples are 20, 30, 40 and 50 mg. Preferably, the administration of said amounts is once, twice or three times a day.
    A preferred dosage range for glisoxepide when administered orally is 1 to 20 mg, in particular 1 to 16 mg per day. The preferred range of amounts in the pharmaceutical composition is 1 to 8 mg, in particular 1 to 4 mg. Preferably, the administration of said amounts is once, twice, three times or four times a day. A preferred dosage range for tolbutamide when administered orally is 100 to 3000 mg, preferably 500 to 2000 mg per day. The preferred range of amounts in the pharmaceutical composition is 100 to 1000 mg. Preferably, said amounts are administered once or twice a day. A preferred dosage range for glipizide when administered orally is 1 to 50 mg, in particular 2.5 to 40 mg per day. The preferred range of amounts in the pharmaceutical composition for administration of. once, twice or three times spordia is 1 to 50,0,5 to 25eO, 3a17mg - 15 respectively. A preferred dosage range for nateglinide when administered orally is 30 to 500 mg, in particular 60 to 360 mg per day. The preferred range of amounts in the pharmaceutical composition is 30 to 120 mg. Examples are 30, 60 and 120 mg. Preferably, the administration of said amounts is once, twice or three times a day. Nateglinide can be administered as it is marketed, for example, under the trademark STARLIX ". A preferred dosage range of repaglinide when administered orally is 0.1 to 16 mg, in particular 0.5 to 6 mg daily. The preferred range of amounts in the pharmaceutical composition is 0.5 to 4 mg, Examples are 0.5, 1, 2 or 4 mg Preferably, the administration of said amounts is once, twice, three times or four times a day. Repaglinide can be administered as it is marketed, for example, under the trademark NOVONORM ".
    30 A preferred dosage range for acarbose when administered orally is 50 to 1000 mg, in particular 50 to 600 mg per day. The preferred range of amounts in the pharmaceutical composition is 50 to 150 mg. AND-
    examples are 50 and 100 mg. Preferably, the administration of said amounts is once, twice, three times or four times a day- A-carbose can be administered in the form as it is marketed, for example, under the trademark G | ucobay®.
    5 A preferred dosage range for voglibose when administered orally is 100 to 1000 mg, in particular 200 to 600 mg per day. The preferred range of amounts in the pharmaceutical composition is 50 to 300 mg. Examples are 50, 100, 150, 200 and 300 mg. Preferably, the administration of said amounts is once, twice, three times or four times a day. Voglibose can be administered as it is marketed, for example, under the trademark Basen® or Voglisan®.
    A preferred dosage range for miglitol when administered orally is 25 to 500 mg, in particular 25 to 300 mg per day. The preferred range. of quantities in the pharmaceutical composition is 25 to 100 mg. Examples - 15 are 25, 50 and 100 mg. Preferably, the administration of said amounts is once, twice, three times or four times a day. Miglitol ~ can be administered as it is marketed, for example, under the + trademark Glyset®. A preferred dosage range for GLP-1 analogs, in particular exenatide is 5 to 30 µg, in particular 5 to 20 µg per day. The preferred range of quantities in the pharmaceutical composition is 5 to 10 µg. Examples are 5 and 10 µg. Preferably, the administration of said amounts is once, twice, three times or four times a day by subcutaneous injection. Exenatide can be administered as it is marketed, 25 for example, under the trademark Byetta "". A long-acting formulation, preferably for subcutaneous injection once a week, comprises an amount of 0.1 to 3.0 mg, preferably 0.5 to 2.0 mg of exenatide. Examples are 0.8 mg and 2.0 mg. An example of a long-acting formulation of exenatide is Byetta LAR®.
    A preferred dosage range for liraglutide is 0.5 to 3 mg, in particular 0.5 to 2 mg per day. The preferred range of amounts in the pharmaceutical composition is 0.5 to 2 mg. Examples are 0.6, 1.2 and 1.8 mg. Preferable-
    In particular, the administration of these amounts is once or twice a day by subcutaneous injection. The amount of the DPPA inhibitor and the second and / or third therapeutic agent in the pharmaceutical composition and methods and uses of this invention correspond to the respective dosage ranges as provided herein above. For example, preferred dosage ranges in a pharmaceutical composition, combination, method and use according to this invention are an amount of 0.5 to 10 mg (in particular, 1 to 5 mg, especially 2.5 mg or 5 mg). mg) of linagliptin and / or, optionally, an amount of 250 to 10 1000 mg (especially 500 mg, 850 mg or 1000 mg) of metformin. Oral administration once or twice a day is preferred. In the combination methods and combined uses according to the present invention, the DPP-4 inhibitor and the second and / or third agent. therapeutic is / are administered in combination including, but not limited to .- 15 of the active ingredients that are administered at the same time, that is, simultaneously, or essentially at the same time, or the ingredients ¶
    W assets are administered alternately, that is, that in principle, one or two
    W active ingredients are administered and after a period of time the other two or one active ingredient are administered, that is, at least two of the three active ingredients are administered consecutively. The time period can be in the range of 30 min to 12 hours. Administration that is in combination or alternating may be once, twice, three times or four times a day, preferably once or twice a day. With respect to the combined administration of the DPP-4 inhibitor and 25 the second and / or the third antidiabetic agent, all three active ingredients can be present in a single dosage form, for example, in a tablet or capsule, or one or two of the active ingredients can be present in a separate dosage form, for example, in two different or identical dosage forms. 30 Regarding its alternating administration, one or two of the active ingredients are present in a separate dosage form, for example, in two different or identical dosage forms.
    Therefore, a pharmaceutical combination of this invention can be present as the only dosage form comprising the DPP-4 inhibitor and the second and, optionally, the third antidiabetic agent. Alternatively, a pharmaceutical combination of this invention may be present as two separate dosage forms in which one dosage form comprises the DPP-4 inhibitor and the other dosage form comprises the second plus, optionally , the third antidiabetic agent, or, in the case of a triple combination, a dosage form comprises the DPP-4 inhibitor plus the second or third antidiabetic agent, and the other dosage form comprises the third or second agent antidiabetic, respectively. Alternatively, in the case of a triple combination, a pharmaceutical combination of this invention may be present as three separate dosage forms in which one dosage form comprises the DPP-4 inhibitor and a second dosage form with-. 15 comprises the second antidiabetic agent and the third dosage form
    W - comprises the third antidiabetic agent. Alternatively, in the case of a double combination, a pharmaceutical combination of this invention can
    D be present as two separate dosage forms in which one dosage form comprises the DPP-4 inhibitor and the second dosage form comprises the second antidiabetic agent. The case may arise in which an active ingredient has to be administered more frequently, for example, twice a day, than O (S) other active ingredient (s), which, for example, requires administration. - traction once a day. Therefore, "combination administration" also includes an administration schedule in which all active ingredients are first administered in combination and after a period of time an active ingredient is administered again or vice versa. Therefore, the present invention also includes pharmaceutical combinations that are present in separate dosage forms wherein one dosage form comprises the DPP-4 inhibitor and the second and, optionally, the third therapeutic agent and the other dosage form it comprises only the second and / or the third therapeutic agent.
    Accordingly, the present invention also includes pharmaceutical compositions or combinations for separate, sequential, simultaneous, concomitant, alternating or chronologically alternating use of the active ingredients or components. A pharmaceutical composition that is present as a separate or multiple dosage form, preferably as a kit of parts, is useful in combination therapy to flexibly adapt the patient's individual therapeutic needs. According to a first embodiment, a complete kit of parts comprises (a) a first compartment containing a dosage form comprising the DPPA inhibitor and at least one pharmaceutically acceptable carrier, and '(b) a second compartment containing a dosage form. "15 gem comprising the second antidiabetic agent and at least one pharmaceutically acceptable carrier, and, optionally, (C) a third compartment containing a dosage form
    D comprising the third antidiabetic agent and at least one pharmaceutically acceptable carrier. According to a second embodiment, a kit of parts comprises (a) a first compartment containing a dosage form comprising the DPP-4 inhibitor and the second or third antidiabetic agent and at least one pharmaceutically acceptable carrier, and (B) a second compartment containing a dosage form comprising the third or second antidiabetic agent, respectively, and at least one pharmaceutically acceptable carrier. According to a third embodiment, a kit of parts comprises 30 (a) a first compartment containing a dosage form comprising the DPP-4 inhibitor and at least one pharmaceutically acceptable carrier, and
    (b) a second compartment containing a dosage form comprising the second and third antidiabetic agent and at least a pharmaceutically acceptable carrier.
    Another aspect of the present invention is a manufacture comprising the pharmaceutical combination which is present as separate dosage forms in accordance with the present invention and a label or package supplement comprising instructions in which the dosage forms separate doses should be administered in combination.
    According to a first embodiment, a compound manufacture comprises (a) a pharmaceutical composition comprising a DPP-4 inhibitor according to the present invention and (b) a package label or supplement comprising instructions in which the medicine can or should be administered, for example,
    .15 in combination, with a medicament comprising a second antidiabetic agent according to the present invention or with a fixed or free combination (e.g., a medicament) comprising a second antidiabetic agent and a third antidiabetic agent according to the present invention- 20 According to a second embodiment, a manufacture comprises (a) a second antidiabetic agent according to the present invention and (b) a label or package supplement comprising instructions in which the medicament can or should be administered, for example, in combination, with a medicament comprising a DPP-4 inhibitor according to the present invention or with a fixed or free combination agent (e.g., a medicament) comprising a DPP- inhibitor 4 and a third antidiabetic agent according to the present invention.30 According to a third embodiment, a manufacture comprises (a) a pharmaceutical composition comprising a DPPA inhibitor and a second antidiabetic agent according to the present invention and (b) a package label or supplement comprising instructions that the drug can or should be administered, for example, in combination, with a drug comprising a third agent antidiabetic according to the present invention- The desired dose of the pharmaceutical composition according to this invention can be conveniently presented once a day or as a divided dose administered at appropriate intervals, for example, 10 as two, three or more doses per day.
    The pharmaceutical composition can be formulated for oral, rectal, nasal, topical (including, buccal and sublingual), transdermal, vaginal or parenteral (including, intramuscular, subcutaneous and intravenous) administration in liquid or solid form or in a suitable form for administration by inhalation or
    - 15 insufflation.
    Oral administration is preferred.
    The formulations can, where appropriate, be conveniently presented in discrete dosage units and can be prepared by any of the methods well known in the pharmacy art.
    All methods include the step of bringing the active ingredient in combination with one or more pharmaceutically acceptable vehicles, 20 such as liquid vehicles or finely divided solid vehicles or both, and then, if necessary, shaping the product into the desired formulation .
    The pharmaceutical composition can be formulated as tablets, granules, fine granules, powders, capsules, capsules, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspension, rapidly dissolving tablets, rapidly dispersing tablets, etc. The pharmaceutical composition and dosage form preferably comprise one or more acceptable pharmaceutical carriers.
    Preferred vehicles must be "acceptable" in the sense of being compatible with the other 30 ingredients in the formulation and not harmful to their container.
    Examples of pharmaceutically acceptable vehicles are known to someone skilled in the art.
    Pharmaceutical compositions suitable for oral administration can conveniently be presented as discrete units such as capsules, including soft gelatin capsules, seals or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion, for example, as syrups, elixirs or self-emulsifying release systems (SEDDS). The active ingredients can be presented in the same way as a cake, item or paste.
    Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
    The tablets can be coated according to methods well known in the art.
    Liquid oral preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they can be presented as a dry product.
    "15 co for constitution with water or another suitable vehicle before use.
    Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
    The pharmaceutical composition according to the invention can be formulated in the same way for parenteral administration (for example, by injection, for example, bolus injection or continuous infusion) and can be presented as a unit dose in ampoules, syringes preloaded, small volume infusion or in multiple dose containers with an added condom.
    The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.
    Alternatively, the active ingredients can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution, for constitution with a suitable vehicle, for example, 30 sterile, pyrogen-free water, before use.
    Pharmaceutical compositions suitable for rectal administration in which the carrier is a solid are preferably presented as suppositories.
    unit dose sites.
    Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories can be conveniently formed by mixing the active compound (s) with the softened vehicle (s) or melted (s) followed by cooling and molding in the molds.
    For pharmaceutical application in homeothermic vertebrates, particularly humans, the compounds of this invention are normally used in dosages from 0.001 to 100 mg / kg of body weight, preferably at 0.1-15 mg / kg, in each case 1 to 4 times a day.
    For this purpose, the compounds, optionally combined with other active substances, can be incorporated together with one or more diluents and / or conventional inert vehicles, for example, with corn starch, Iactose, glucose, microcrystalline cellulose, magnesium, polyvinylpyrrolidone, acid. citric, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water-
    - 15 water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures of. "same in conventional galenic preparations such as smooth or coated tablets, capsules, powders, suspensions or suppositories.
    The pharmaceutical compositions according to this invention 20 comprising DPPA inhibitors as defined herein are prepared in this manner by the skilled person using pharmaceutically acceptable formulation excipients as described in the art.
    Examples of such excipients include, but are not limited to, diluents, binders, vehicles, fillers, lubricants, flow promoters, crystallization retardants, disintegrants, solubilizers, dyes, pH regulators, surfactants and emulsifiers.
    Examples of suitable diluents for compounds according to modality A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pre-gelatinized starch or xylitol.
    Among these diluents, mannitol, low substituted hydroxypropyl cellulose and pregelatinized starch should be emphasized.
    Examples of suitable lubricants for compounds according to modality A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate. Among these lubricants, magnesium stearate should be emphasized. Examples of suitable binders for compounds according to modality A include copovidone (glassPolymerized vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, or low substitution hydroxypropylcellulose (L-HPC). Among these binders, copovidone and pregelatinized starch should be emphasized. Examples of suitable disintegrants for compounds according to modality A include corn starch or crospovidone. Among these disintegrants, corn starch should be emphasized. Appropriate methods of preparing pharmaceutical formulations. of DPP-4 inhibitors according to modality A of the invention are - 15 · direct tabletting of the active substance in mixtures
    W - powder coatings with suitable tablet-forming excipients; · Granulation with suitable excipients and subsequent mixing. hot with suitable excipients and subsequent tabletting as well as film coating; or 20 · packaging of powder or granule mixtures in capsules. Suitable granulation methods are · wet granulation in the intensive mixer followed by drying in fluidized form; · Granulation of a pot; 25 · fluidized bed granulation; or · dry granulation (for example by roller compaction) with suitable excipients and subsequent tabletting or in capsules. An exemplary composition of a DPP-4 inhibitor according to embodiment A of the invention comprises the first mannitol diluent, pregelatinized starch as a second diluent with additional binding properties, the binder copovidone, corn starch disin-
    tegrante, and magnesium stearate as a lubricant; wherein copovidone and / or corn starch may be optional. For details on dosage forms, formulations and administration of DPP-4 inhibitors of this invention, reference is made to the scientific literature and / or published patent documents, particularly those cited here. Pharmaceutical compositions (or formulations) can be conditioned in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Tablets are typically packaged in a primary package suitable for easy handling, distribution and storage and to ensure proper composition stability in prolonged contact with the environment during storage. Primary containers. pill streams can be bottles or blister packs.
    A suitable bottle, for example, for a pharmaceutical composition or combination comprising a DPP-4 inhibitor according to embodiment A of the invention, can be made of glass or polymer (preferably polypropylene (PP) or high density polyethylene (HD-PE)) and sealed with a screw cap. The screw cap can be provided with a child resistant safety lock (for example, compression and screw lock) to prevent or prevent access to the contents by a child. If necessary (for example, in regions with high humidity), by the additional use of a desiccant (such as, for example, bentonite clay, molecular sieves, or, preferably, silica gel) the shelf life of the composition packaged can be extended. A blister pack suitable, for example, for a pharmaceutical composition or combination comprising a DPP-4 inhibitor according to modality A of the invention, comprises or is formed of a top sheet (which is breakable by the tablets) and a part of the base (which contains 30 bags for the pills). The top sheet may contain a metal sheet, particularly an aluminum or aluminum alloy sheet (for example, having a thickness of 20µm to 45µm, preferably 20µm to
    25µm) which is coated with a heat-sealing polymer layer on its inner side (sealing side). The base part may contain a multilayer polymer sheet (such as, for example, polyvinyl chloride (PVC) coated with polyvinylidene chloride (PVDC); or a sheet of PVC laminated with poh (chlorotrifluoroethylene) (PCTFE)) or a multilayer polymer-metal-polymer sheet (such as, for example, a cold formable laminated PVC / aluminum / polyamide composition). The article may also comprise a package label or supplement, which refers to the instructions usually included in commercial packages of therapeutic products that may contain information about the indications, use, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products. In one embodiment, the label or package supplements indicate that the composition can be used for any of the purposes described here.
    The pharmaceutical compositions and methods according to this invention show advantageous effects in the treatment and prevention of these diseases and conditions as previously described herein. The du- combinations. They show advantageous effects compared to monotherapy with an active ingredient. The triple combinations show advantageous effects compared to dual therapy with one or two of the three active ingredients. Advantageous effects can be seen, for example, with respect to efficacy, dosing intensity, dosing frequency, pharmacodynamic properties, pharmacokinetic properties, less adverse effects, convenience, complacency, etc. 25 With respect to Yinagliptin, the synthesis methods are known to the person skilled and as described in the Literature, in particular as described in WO 2002/068420, WO 2004/018468, or WO 2006/048427, the descriptions of which are incorporated herein. Modifications of polymorphic crystals and particular DPPA inhibitor formulations are described in WO 2007/128721 and WO 2007/128724, respectively, the descriptions of which are incorporated herein in their entirety. Formulations of particular DPP-4 inhibitors with metformin or other combination pairs are described in WO 2009/121945, the description of which are fully incorporated here.
    Synthesis methods for other DPP-4 inhibitors are described in the scientific literature and / or in published patent documents, 5 particularly in those previously cited here.
    The active ingredients, in particular the DPP-4 inhibitor and / or the second and / or the third antidiabetic agent, can be present in the form of a pharmaceutically acceptable salt.
    Pharmaceutically acceptable salts include, but are not limited to, such as salts of inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid; organic carboxylic acid salts such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid and salts of organic sulfonic acid such as methanesulfonic acid and p-toluenesulfonic acid.
    Salts can be formed
    _ 15 combining the compound and an acid in the appropriate amount and ratio in a solvent and decomponent.
    They can be obtained in the same way by exchanging cations or anions in the form of other salts.
    The active ingredients or a pharmaceutically acceptable salt can be present in the form of a solvate such as a hydrate or alcohol adduct.
    As different metabolic functional disorders often occur simultaneously, it is often indicated entirely to combine several different active ingredients with one another.
    Therefore, depending on the functional disorders diagnosed, improved treatment results can be obtained if a DPP-4 inhibitor is combined with active substances customary for the respective disorders, such as, for example, one or more substances selected active substances among other antidiabetic substances, especially active substances that lower blood sugar or blood lipid levels, increase HDL blood levels, lower blood pressure or are indicated for the treatment of atherosclerosis or obesity.
    The DPPA inhibitors mentioned above - in addition to their use as monotherapy - can likewise be used together with other active substances through which the results of improved treatment can be obtained. Such a combined treatment can be produced as a free combination of substances or in the form of a fixed combination, for example, in a tablet or capsule. Pharmaceutical formulations of the combination pair required for this can be obtained commercially as pharmaceutical compositions or can be formulated by someone skilled in the art using conventional methods. The active substances that can be obtained commercially as pharmaceutical compositions 10 are described in numerous places in the prior art, for example, in the list of drugs that appear annually, the "Rote Liste®" of the federal association of the pharmaceutical industry, or in the annually updated compilation information from manufacturers on prescription drugs known as the "Physicians' Desk Reference".
    "15 Examples of antidiabetic combination pairs are metformin; sulfonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinedadine. Such as rosiglitazone and pioglitazone; metaglidases; PPAR-gamma agonists such as rivoglitazone, mito-20 glitazone, INT-I 31 or balaglitazone; PPAR-gamma antagonists; PPAR-gamma / alpha modulators such as tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297 ; PPAR-gamma / alpha / delta modulators such as, for example, lobeglitazone; AMPK activators such as AICAR; acetyl-CoA carboxylase inhibitors (ACCl and ACC2); diacylglycerol-25 acetyltransferase (DGAT) inhibitors; GCRP agonists of pancreatic beta cell such as SMT3 and GPR119 receptor agonists, such as GPR119 agonists 5-ethyl-2- {4- [4- (4-tetrazo | -1-i | -phenoxymethyl |) -thiazo | -2 -i |] -piperidin-1-i |} - pyrimidine or 5- [1- (3-is opropi | - [1,2,4] oxadiazol-5-i |) -piperidinA-i | methoxy] -2- (4-methanesulfonikphenyl) -pyridine; 118-HSD inhibitors; FGF19 agonists or analogs 30; alpha-glycosidase blockers such as acarbose, voglibose and miglitol; alpha2 antagonists; insulin and insulin analogs such as human insulin, lispro insulin, glusiline insulin, r-DNA-insu / inaspart, insulin
    NPH, insulin detemir, insulin degludec, insulin tregopil, insulin zinc suspension and insulin glargine; Gastric inhibitor peptide (GIP); amylin and amylin analogues (for example, pranlintide or davalintide); GLP-1 and GLP-1 analogues such as Exendin-4, for example, exenatide, exenatide LAR, 5 Iiraglutide, taspoglutide, Iixisenatide (AVE-OO1O), LY-2428757, dulaglutide (LY-2189265), semaglutida or albiglutide; SGLT2 inhibitors such as dapagliflozin, sergliflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin or tofogliflozin; protein tyrosine phosphatase inhibitors (for example, trodusquemine); glucose-6-phosphatase inhibitors; modulators of 10-se-1,6-bisphosphatase; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvatocarboxinase (PEPCK) inhibitors; piruvati dehydrogenasecinase (PDK) inhibitors; tyrosine kinase inhibitors (50 mg to 600 mg) such as PDGF receptor kinase (according to EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281, and
    -, WO 2006/041976) or serine / threonine kinases; glycocinase modulators / regulatory protein incl. glucokinase activators; glycogen synthase kinase inhibitors; 5-phosphatase inhibitors containing inositol "SH2 type 2 (SHlP2) domain; IKK inhibitors such as high dose salicylate; jNKI inhibitors; protein kinase C-theta inhibitors; beta 3 20 agonists such as ritobegrone , YM 178, soIabegrone, talibegrone, N-5984, GRC-1087, rafabegrone, FMP825; aldoserreductase inhibitors such as AS 3201, zenarestate, fidarestate, epalrestate, ranirestate, NZ-314, CP-744809, and CT-112; SGLT-I or SGLT-2, such as for example dapagliflozin, sergliflozin, atigliflozin, canagliflozin or (1S) -1,5-anhydrous 1- [3- (1- 25 benzothiofen-2-i | meti |) - 4-f | uoropheni |] -Dg | ucito |; KV 1.3 channel inhibitors; GPR40 modulators such as [(3S) -6 - ({2 ', 6'-dimethylA'- [3- (metiIsu | foni |) propoxy] bifenj | -3-i |} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic; SCD-1 inhibitors; CCR-2 antagonists; agonists dopamine receptor (bromocriptine mesylate [Cycloset]); 4- (3- (2,6-30 dimethylbenzyloxy) phenyl) -4-ox acid obutanoic; sirtuin stimulants; and other DPP lV inhibitors.
    Metformin is usually determined in doses ranging from about 500 mg to 2000 mg to 2500 mg per day using various dosage 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 or twice a day, or delayed release metformin at doses of about 100 mg to 1000 mg or 5 preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day. Particular dosing essentials can be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride. For children 10 to 16 years of age, the recommended starting dose of metformin is 500 mg given once daily. If this dose 10 does not produce adequate results, the dose can be increased twice a day by 500 mg. Further increases can be made in increments of 500 mg weekly at a maximum daily dose of 2000 mg, given in divided doses (for example, 2 or 3 divided doses). Metformin can be administered with food to reduce nausea.
    . 15 A dosage of pioglitazone is usually about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day. Rosiglitazone is usually given in doses of 4 to 8 mg (or divided into two) per day (typical dosing intensities are 2, 4 and 8 mg). 20 GIibenclamide (glyburide) is usually given once in doses of 2.5 - 5 to 20 mg (or divided into two) per day (typical dosing intensities are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses of 0.75-3 to 12 mg once (or divided into twice) a day (typical dosing intensities are 1.5, 3, 4.5 and 6 mg) - 25 GIipizide is usually given once in doses of 2.5 to 10-20 mg (or up to 40 mg divided twice) per day (typical dosage intensities are 5 and 10 mg), or prolonged release glyburide at doses of 5 to 10 mg (up to 20 mg) once a day (typical dosing intensities are 2.5, 5 and 10 mg). 30 Glimepiride is usually given in doses of 1-2 to 4 mg (up to 8 mg) once a day (typical dosing intensities are 1, 2 and 4 mg). A double combination of glibenclamide / metformin is usually
    given in doses from 1.25 / 250 to 10/1 000 mg twice a day (typical dosing intensities are 1.25 / 250, 2.5 / 500 and 5/500 mg). A double combination of glipizide / metformin is usually given in doses of 2.5 / 250 to 10/1000 mg twice daily (typical dose intensities are 2.5 / 250, 2.5 / 500 and 5/500 mg ). A double combination of glimepiride / metformin is usually given in doses of 1/250 to 4/1000 mg twice a day.
    A dual rosiglitazone / glimepiride combination is usually given in doses of 4/1 once or twice daily for 4/2 mg 10 twice daily (typical dosing intensities are 4/1, 4/2, 4 / 4, 8/2 and 8/4 mg). A double combination of pioglitazone / glimepiride is normally given in doses of 30/2 to 30/4 mg once a day (typical dosing intensities are 30/4 and 45/4 mg) - 15 A double combination of rosiglitazone / metformin is usually given in doses twice daily 1/500 to 4/1000 mg twice
    - per day (typical dosing intensities are 1/500, 2/500, 4/500, 2/1000 and 4/1 000 mg). A dual pioglitazone / metformin combination is normally given in doses of 15/500 to 15/850 mg three times a day (typical dosing intensities are 15/500 and 15/850 mg). The nateglinide non-sulfonylurea insulin secretagogue is usually given in doses of 60 to 120 mg with meals (up to 360 mg / day, typical dosage intensities are 60 and 120 mg); repaglinide is usually given in doses of 0.5 to 4 mg with meals (up to 16 mg / day, typical dosing intensities are 0.5, 1 and 2 mg). A double repaglinide / metformin combination is available in dosage intensities of 1/500 and 2/850 mg.
    Acarbose is usually given in doses of 25 to 100 mg with 30 meals.
    Miglitol is usually given in doses of 25 to 100 mg with meals.
    Examples of combination pairs that lower the lipid level
    in the blood are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, iovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate, genfibrozil, etofibrate and etophyllinclofibrate; nicotinic acid and derivatives thereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; acylcoenzyme A inhibitors: cholesterolacyltransferase (ACAT; EC 2.3.1.26) as avasimib; cholesterol reabsorption inhibitors such as ezetimibe; substances that bind to bile acid, such as cholestyramine, colestipol and colesevelam; bile acid transport inhibitors; HDL modulating active substances such as D4F, reverse D4F, LXR modulating active substances and FXR modulating active substances; inhibitors of CETP such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 of WO 2007/005572 (anacetrapib); LDL receptor modulators; MTP inhibitors (for example, lomitapide); and ApoBIOO antisense RNA. 15 A dosage of atorvastatin is typically 1 mg to 40 mg r- or 10 mg to 80 mg once daily.
    . Examples of combination pairs that decrease blood pressure are beta-blockers such as atenolol, bisoprolol, celiprolol, methoprolol and carvedilol; diuretics such as hydrochlorothiazide, cyortalidone, xipa-20 mida, furosemide, piretanide, torasemide, spironolactone, eplerenone, amyloride and triamterene; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, Ierca-nipidine, manidipine, isradipine, nilvadipine, verapamil, galopamil and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; as well as angiotensin receptor blockers |] (ARBS) such as telmisartan, cande- sartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan. A dosage of telmisartan is usually 20 mg to 30 320 mg or 40 mg to 160 mg per day. Examples of combination pairs that increase the level of HDL in the blood are inhibitors of the cholesterol ester transfer protein
    teryl (CETP); endothelial lipase inhibitors; ABCI regulators; antagonists of LXRalfa; LXRbeta agonists; PPAR-delta agonists; 1-XRalpha / beta regulators, and substances that increase the expression and / or concentration of apolipoprotein A-1 plasma. 5 Examples of combination pairs for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizime (cetilistat); dex-fenfluramine; axocin; cannabinoid 1 receptor antagonists such as the rimonobant CBl antagonist; MCH-I receptor antagonists; MC4 receptor agonists; NPY5 as well as NPY2 antagonists (for example, velneperite); beta3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such as APD 356 (lorcasterin); myostatin inhibitors; Acrp30 and adiponectin; sterile COA desaturase inhibitors (SCD1); fatty acid synthase (FAS) inhibitors; CCK receptor agonists; ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; and tesofensina; as well as dual combinations
    P bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine and - pranlintide / metreleptin. Examples of combination pairs for the treatment of atherosclerosis are phospholipase A2 inhibitors; tyrosine kinase inhibitors 20 (50 mg to 600 mg) such as PDGF receptor kinase (according to EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281, and WO 2006/041976); OXLDL antibodies and oxLDL vaccines; apoA-1 Milano; WING; and VCAM-I inhibitors. The present invention should not be limited in scope by the 25 specific modalities described here. Various modifications of the invention, in addition to those described here, may be apparent to those skilled in the art of the present description. Such modifications are intended to be included in the scope of the appended claims. All patent applications cited here are hereby incorporated by reference in their entirety. Other modalities, characteristics and advantages of the present invention may be evident from the following examples. The following examples serve to illustrate, by way of example, the principles of the invention without restricting it.
    Examples Example 1: Bl 1356, a potent and selective DPP-4 inhibitor, is sequestered and effective in Patients with Type 2 Diabetes Inadequately Controlled despite Metformin Therapy Effectiveness and safety of Bl 1356 (1, 5, or 10 mg qd), a potent and selective dipeptidit peptidase-4 (DPP-4) inhibitor, was examined in inadequately controlled type 2 diabetic patients treated with metformin (MET,> 1 g per day) (T2DM; HbA1c in the reference line 7.5-10.0 ° 6). The effects were compared to the addition of placebo (PBO) or open label glimepiride (GLIM; 1 to 3 mg qd) in a double-blind, randomized, 12-week study.
    The anti-diabetic drug other than metformin was washed for 6 weeks (34.7 ° / o of patients). 15 The primary goal was to change the reference line in HbA1c, r adjusted for previous antidiabetic medication. 333 patients (Iinha de
    "mean HbA1c ference 8.3%; fasting plasma glucose [fpg] 185 mg / dL) were randomized into Bl 1356, PBO or open label GLIM.
    After 12 weeks, treatment with Bl 1356 resulted in significant mean placebo-corrected reductions in HbA1c (Bl 1356 1 mg, n = 65, 0.39 ° 6; 5 mg, n = 66, 0.75% ; 10 mg, n = 66, 0.73%). Patients receiving GLIM demonstrated a slightly greater mean PBO-corrected reduction in HbA1c at Week 12 (n = 64, 0.90%). Reductions in FPG from the reference line for Week 12 with Bl 1356 were statistically significant (1 mg, - 25 19 mg / dL; 5 mg, -35 mg / dL; 10 mg, -30 mg / dL). Consequently, a dose-response relationship has been demonstrated for HbA1c and FPG, reaching an effect level of 5 mg Bl 1356. For this dose,> 80% inhibition of DPP-4 in the vat in> 80% of patients in week 12 they were reached.
    In total, 106 patients (43.1%) experienced adverse events (AES) with similar incidences for all treatments.
    Episodes most frequently reported were nasopharyngitis (7.5%), diarrhea (3.3%), and nausea (3.0%). Drug-related hypoglycemia did not occur with Bl 1356 or PBO, but in 3 patients receiving GLIM.
    Ten patients (3.7%) experienced serious AES, but none of these events were considered drug-related.
    The addition of Bl 1356 to MET in patients with T2DM poorly controlled on MET alone achieved clinically relevant and statistically significant reductions in HbA1c.
    Combination treatment with Bl 1356 1, 5, and 10 mg and MET was well tolerated and no case of hypoglycemia was reported.
    The incidence of AES was comparable with Bl 1356 and PBO. Example 2: The usefulness of a DPP-4 inhibitor or combination according to this invention for the purpose of the present invention (for example, the beneficial effect on glycemic control) can be tested using clinical experiences. 15 For example, in a randomized, double-blind, pIacebo-controlled, parallel group experiment, the safety and efficacy of a DPP-4 inhibitor according to the invention (eg, 5 mg of linagliptin administered orally) once a day) is tested in patients with type 2 diabetes with insufficient glycemic control (HbA1c from 7.0% to 10 ° 6 or 7.5% 20 to 10 ° / o or 7.5% to 11%) despite of therapy with one or two conventional antihyperglycemic agents, for example, selected from metformin, thiazolidindiones (eg, pioglitazone), sulfonylureas, glinides, alpha-glucosidase inhibitors, GLP-1 or GLP-1 analogs , and insulin or insulin analogues. 25 In the study with the drug sulfonylurea, the efficacy and safety of a DPP-4 inhibitor according to this invention versus placebo added to a fundamental therapy of a sulfonylurea are investigated (2 weeks of experimental phase with placebo; 18 weeks of double shit treatment followed by 1 week follow-up after the end of study medication; fundamental therapy with a sulfonylurea drug is administered throughout the duration of the trial, including experimental phase with placebo, in one unchanged dosage).
    The success of the treatment is tested by determining the value of HbA1c, by comparison with the initial value and / or with the value of the placebo group.
    A significant change in the HbA1c value compared to the initial value and / or the placebo value demonstrates the efficacy of the DPP-5 4 inhibitor by treatment.
    Treatment success can be tested in the same way by determining fasting plasma glucose values, compared to baseline and / or placebo group values.
    A significant drop in fasting glucose levels demonstrates the effectiveness of the treatment.
    Likewise, the occurrence of a treatment for the target response (that is, an HbA1c under treatment <7%) demonstrates the effectiveness of the treatment.
    The safety and tolerability of the treatment are investigated by assessing the patient's condition and relevant changes in the reference line, for example, incidence and intensity of adverse events (such as, for example, hypoglycemic episodes or similar) or weight gain.
    Example 3: Treatment of prediabetes The effectiveness of a pharmaceutical composition or combination according to the invention in the treatment of prediabetes characterized by pathological fasting glucose and / or impaired glucose tolerance can be tested (s) ) using clinical studies.
    In studies over a shorter period (for example, 2-4 weeks) the success of treatment is examined by determining fasting glucose values and / or glucose values after a meal or after a loading test ( oral glucose tolerance or food tolerance test after a defined reference) after the end of the therapy period for the study and comparing it with the values before the study started and / or with those in a placebo group.
    In addition, the value of fructosamine can be determined before and after therapy and compared to the initial value and / or the placebo value.
    A significant drop in fasting or non-fasting glucose levels demonstrates the effectiveness of the treatment.
    In studies over a longer period (12 weeks or more), the success of the treatment is tested by determining the value of HbA1c, by comparison with the initial value and / or with the value of the pIacebo group.
    A significant change in the HbA1c value compared to the initial value and / or the placebo value demonstrates the efficacy of DPP-4 inhibitors or combinations according to the present invention for treating pre-diabetes. 5 Example 4: Prevention of overt type 2 diabetes The treatment of patients with pathological fasting glucose and / or impaired glucose tolerance (pre-diabetes) is similarly pursuing the goal of preventing the transition to overt type 2 diabetes.
    The effectiveness of a treatment can be investigated in a comparative clinical study in which prediabetic patients are treated for a prolonged period (eg, 1-5 years) with a pharmaceutical composition or combination in accordance with this invention or with placebo or with a drug-free therapy or other medications.
    During and at the end of therapy, by determining fasting glucose and / or a loading test (for example, OGTT), a check is made to determine how many patients exhibit overt type 2 diabetes, ie , a fasting glucose level
    - "125 mg / dl and / or a 2 hour value according to OGTT> 199 mg / dl.
    A significant reduction in the number of patients exhibiting overt type 2 diabetes when treated with a DPP-4 inhibitor or combination according to the present invention when compared to one of the other forms of treatment, demonstrates the effectiveness in preventing a transition from pre-diabetes to overt diabetes.
    Example 5: Treatment of type 2 diabetes The treatment of patients with type 2 diabetes with the pharmaceutical composition or combination according to the invention, in addition to producing an acute improvement in the metabolic situation of glucose, prevents a deterioration in the long-term metabolic situation.
    This can be seen in patients who are treated for a longer period, for example, 3 months to 1 year or even 1 to 6 years, with the pharmaceutical composition or combination according to the invention and are compared with patients who were treated with other antidiabetic drugs.
    There is evidence of therapeutic success compared to patients treated with other antidiabetic drugs if no or only an elevated increase in fasting glucose and / or HbA1c value is observed.
    Further evidence of therapeutic success is obtained if a significantly smaller percentage of patients treated with a pharmaceutical composition or combination 5 according to the invention, compared to patients who have been treated with other drugs, suffer a deterioration in the metabolic position. glucose (for example, an increase in HbA1c to> 6.5% or "7 ° / 0) to the point where treatment with an additional oral antidiabetic medication or with insulin or with an insulin analogue is indicated.
    Example 6: Treatment of Insulin Resistance In clinical studies operating for different lengths of time (for example, two weeks to 12 months), treatment success is verified using a hyperinsulinemic euglycemic glucose clamp study.
    A significant increase in the rate of glucose infusion at the end of the study, compared with the initial value or compared with a placebo group, or a group given in a different therapy, proves the effectiveness of a DPP-4 inhibitor, composition or pharmaceutical combination according to the present invention according to the invention in the treatment of insulin resistance.
    Example 7: Treatment of Hyperglycemia In clinical studies operating for different lengths of time (for example, 1 day to 24 months), successful treatment in patients with hyperglycemia is verified by determining fasting glucose or fasting glucose ( for example, after a meal or a loading test with OGTT or a defined meal). A significant drop in these glucose values during or at the end of the study, compared to the initial value or compared to a placebo group, or a group given in a different therapy, proves the effectiveness of a DPP-4 inhibitor, composition or pharmaceutical combination according to the present invention according to the invention in the treatment of hyperglycemia.
    Example 8: Prevention of Micro or Macrovascular Complications The treatment of type 2 diabetes or pre-diabetes patients with a DPP-4 inhibitor, pharmaceutical composition or combination according to the invention prevents or reduces the risk of developing complications microvascular (eg, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic foot, diabetic ulcer) or crovascular ma complications (eg, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, accident cerebral vascular disease, peripheral arterial occlusive disease, cardiomyopathy, cardiac arrest, cardiac rhythm disorders, vascular restenosis). Type 2 diabetes or patients with pre-diabetes is treated for a long term, for example, for 1-6 years, with a pharmaceutical composition or combination according to the invention compared to patients who have been treated with antidiabetic drugs or with placebo.
    Evidence of therapeutic success compared to patients who have been treated with other antidiabetic drugs or with placebo can be found in the smallest number of single or multiple complications.
    In the case of macrovascular events, diabetic foot and / or diabetic ulcer, the numbers are counted by anamnesis and various test methods.
    In the case of diabetic retinopathy, treatment success is determined by computer-controlled lighting and evaluation of the base to the eye or other ophthalmic methods.
    In the case of diabetic neuropathy, in addition to anamnesis and clinical examination, the rate of nerve conduction can be measured using a calibrated oscillating fork, for example.
    With respect to diabetic nephropathy, the following parameters can be investigated before the beginning, during and at the end of the study: secretion of albumin, release of cretinin, values of serum creatinine, time taken for the values of cretinin of serum, doubling the time it takes for dialysis to become necessary.
    Example 9: Treatment of Metabolic Syndrome The effectiveness of a DPP-4 inhibitor, pharmaceutical composition or combination according to the present invention according to the invention can be tested in clinical studies with varying operating times (for example, 12 weeks to 6 years) by determining fasting glucose or fasting glucose (for example, after a meal or a loading test with OGTT or a defined meal) or the HbA1c value.
    A significant drop in these glucose values or HbA1c values during or at the end of the study, compared to the initial value or compared to a placebo group, or a group given in a different therapy, proves the effectiveness of an active substance or combination of active substances in the treatment of Metabolic Syndrome.
    Examples of this are a reduction in systolic and / or diastolic blood pressure, a reduction in plasma triglycerides, a reduction in total or LDL cholesterol, an increase in HDL cholesterol or a reduction in weight, compared to the starting value of 10 study or in comparison with a group of patients treated with pIacebo or a different therapy.
    Example 10: Therapeutic Response for the Treatment of DPP-4 Inhibitor Genomic DNA samples from individual patients enrolled in a clinical trial (for example, a clinical study as described here) for a DPP-4 inhibitor ( eg Iinagliptin, eg 4 in an oral daily amount of 5 mg, optionally in combination with
    . one or more other antidiabetic agents) are obtained and genotyped for variation (s) (for example, polymorphisms) in one or more candidate genes selected from TCF7L2, KCNJ11, PPARG and GLPIR, particularly for one risk genotype of TCF7L2 as described here, and assessed for each patient response in clinical experience (as, for example, Example 21) - The association between the probability (for example, increased, decreased or no probability) of a response to favorable DPPA inhibitor therapy (eg, favorable change in HbA1c values) and genetic variations (eg, TCF7L2 risk genotypes) or references can be investigated by applying statistical analysis to the genotyping results .
    The probability of indicating an individual's favorable response resulting from the treatment of that individual with the 30 DPP-4 inhibitor can be determined in this way by such genotyping of an individual's nucleic acid sample, for example, by detecting one or more unique nucleotide polymorphisms within the TCF7L2 gene, for example,
    a SNP selected from rs7903146, rs12255372 and rs10885406, or by detecting the respective wild type genotype (as per, for example, Example 21). Methods for genotyping, i.e., determining genetic variations (for example, polymorphisms, particularly those described here) from patient nucleic acid samples are known in the art.
    For example, molecular genetic methods for detecting unique nucleotide poIimorphisms, for example, within the TCF7L2 gene, can be based on genetic sequencing, microdisposition or PCR analysis. 10 Example 11: Linaçjfiptina Monotherapy Improves Glycemic Control and Measures of J3 Cell Function in Type 2 Diabetes In a 24-week, randomized, double-blind, parallel, placebo-controlled, multi-center group study, the effects of monotherapy with linagliptin (Ll) (5 mg qd) are compared with placebo 15 (PBO) in patients (pts) previously treated or who have not received tra-. drug treatment with type 2 diabetes mellitus (T2DM) (reference line HbA1c 4.9-10.6%). Randomization to Ll (n = 336) or PBO (n = 167) follows a 2-week PBO experiment (previously treated pts go through medication for 4 weeks before this). Average reference demographics (HbA1c, 8.0% [SD 0.87]; fasting plasma glucose (fpg), 166.0 mg / dL [41.1]; Body mass index (BMI), 29 , 05 kg / m '[4.81];
    55.7 years [1 0.2]) are similar in both groups.
    The primary goal is to change the reference line in HbA1c after 24 weeks of treatment.
    Ll shows a PBO-adjusted change in reference HbA1c 25 of -0.69% (p "0.0001) with a continuous reduction of HbA1c over time from -0.46% over 6 weeks to -0.69 % in 24 weeks (both p <0.0001) .L patients are> 4 times more likely to achieve a HbA1c reduction of.>. 0.5% in 24 weeks than PBO (47.1% vs 19.0%; p <0.0001) For patients with reference HbA1c Z7.0 ° / j, a significantly higher number of patients treated with Li compared to patients treated with PBO achieves a target reduction of HbA1c for <7.0% in 24 weeks (25.2 ° 6 vs. 11.6%; ratio of probability of non-occurrence of
    2.9, p = 0.0006). Patients with reference HbA1c levels of.>. 9.0% show the greatest reduction in reference HbA1c (-0.86%).
    FPG improves by -23.3 mg / dL (p "0.0001) vs. PBO.
    In a meal tolerance test, LL patients show a greater reduction in the adjusted mean change of the 5 reference line at week 24 during 2-hr postprandial glucose (PPG) (-58.4 mg / dL; p "0.0001) vs. PBO.
    Ll improves insulin secretion (p "0.05), as shown by changes in the HOMA- ° / o B index (Ll, 5.02 vs PBO, -17.2 [(mU / L) / (mmol / L)]), proinsulin / insulin ratio (Ll, -0.015 vs PBO, 0.024) and the disposition index (Ll, 3.05 vs PBO, -0.68) .The proportion of patients who report at least an adverse event (AE) is similar to both groups (52.4 ° 6 LI; 58.7% PBO) Hypoglycemia is rare, occurring in 1 patient in each group.
    Serious AES are reported in both groups (Ll, 3.0%; PBO, 4.2 ° / o), however it is not considered related to the drug.
    Linagliptin vat levels in patients with mild and moderate renal impairment are comparable to patients with normal renal function.
    Conclusion: Iinagliptin monotherapy shows a significant, clinically significant and continuous improvement in glycemic control reflected in changes in FPG and HbA1c, and accompanied by improvements in cell function.
    Linagliptin is safe and well tolerated without clinically significant changes in body weight or waist circumference.
    Levels of linagliptin in patients with mild and moderate renal impairment are comparable to patients with normal renal function, supporting that no dose adjustment is required in patients with renal impairment.
    Example 12: Efficacy and Safety of Linaqliptin in Type 2 Diabetes Allocated in Monotherapy with Metformin A 24-week, multi-center, randomized, placebo-controlled, double-blind, parallel study examines the efficacy and safety of Iinagliptin (Ll) administered as complementary therapy for metformin (MET) in patients with hyperglycemic type 2 diabetes mellitus (T2DM) with insufficient glycemic control (HbA1c,>. 7 a. <. 10.0 ° / o for patients
    previously treated with metformin alone, or,> 6.5 to <9.0% for patients previously treated with additional oral antihyperglycemic drugs). Subjects entering the evaluation period discontinued the previous antidiabetic drug other than MET ("1500 mg / day) for 56 weeks (including a placebo trial period (PBO) for the last 2 weeks) before randomization to Ll (n = 524) or PBO (n = 177), mean and demographic reference characteristics (HbA1c, 8.1%; fasting plasma glucose [fpg], 168.8 mg / dL; age, 56.5 years; BMI, 29, 9 kg / m ') are similar between groups.
    The primary goal is to change
    10 reference HbA1c after 24 weeks of treatment, assessed with a covariance analysis (ANCOVA) adjusted for reference HbA1c and previous antidiabetic medication.
    After 24 weeks of treatment, the adjusted average treatment difference between Ll + MET and PBO + MET is - 0.64% (p "0.0001) in favor of L1 + MET for change in HbA1c (° / 0). Patients with a reference HbA1c of,>, 7.0% who receive LI + MET are more likely to achieve an HbA1c <, 7.0 ° 6 compared to those who
    - receive placebo + MET (26.2% vs. 9.2%, respectively; non-occurrence probability ratio, 4.4; p = O, OOO1). At week 24, LI + MET is superior to PBO + MET in reducing mean fasting plasma glucose (FPG) 20 (-21.1 mg / dL; p "0.0001). At the end of the study, 2hr postprandial glucose (PPG) analyzed in meal tolerance tests shows a significantly greater mean reduction (p "0.0001) of reference for the group treated with LI + MET (-67.1 mg / dL) versus the PBO + MET.
    The proportion of patients who report at least one adverse event (LA) is comparable 25 within the LI + MET and PBO + MET groups (52.8% and 55.4%, respectively). Hypoglycemia is rare, occurring in 5 patients with PBO + MET (2.8%) and 3 patients with LI + MET (0.6%), all episodes being of moderate intensity.
    The change in reference body weight over 24 weeks is similar between the 2 treatment groups (-0.5 kg PBO + MET; -0.4 kg 30 L1 + MET). Conclusion, 5 mg qd of linagliptin as complementary therapy in patients with inadequately controlled T2DM in metformin are well tolerated and produce significant and clinically significant improvements in glycemic control (reductions in HbA1c, FPG and 2h PPG without weight gain). Linagliptin as a complementary therapy for metformin in patients with T2DM and insufficient glycemic control is well tolerated with the incidence of adverse events comparable to placebo.
    Example 13: Linagliptin Improves Glycemic Control in Patients with Type 2 Diabetes Not Adequately Controlled by Metformin and Sulfonylurea Without Weight Gain or Hypoqlycemia A 24-week, randomized, double-blind, parallel, multi-center, parallel study examines the efficacy and safety of the DPP-4 inhibitor linagliptin (Ll; 5 mg qd) in patients (pts) with type 2 diabetes (T2DM) with insufficient glycemic control (HbA1c 7.0 - 10.0%) in the combination of metformin (MET) plus a sulfonylurea (SU). The effects of Ll as a complement are compared with placebo (PBO). All pts have a 2-week PBO trial before being randomized to LI + MET + SU (n = 793) or PBO + MET + SU (n = 265). Average reference characteristics are: HbA1c, 8.14% (SD 0.8); fasting plasma glucose (fpg), 160.1 mg / dL (36.6); age, 58.1 years (9.8); BMI, 28.3 kg / m '(4.7). Most pts (73.3%) have T2DM for> 5 years before enrollment.
    The primary goal is to change the reference line in HbA1c after 24 weeks of treatment, adjusted to reference HbA1c.
    After 24 weeks of treatment, the mean HbA1c for LI + MET + SU is -0.62 ° 6 lower (p "0.0001) compared to PBO + MET + SU- The maximum mean HbA1c reduction with LI + MET + SU is seen at week 12 (-0.84%). Patients with reference HbA1c. ". 7.0% is> 5 times more likely to obtain a target HbA1c of <7, Õ ° / o when treated with LI + MET + SU (29.2%) compared with PBO + MET + SU (8.1%, non-occurrence probability ratios 5.5, p "0.0001) in 24 weeks.
    For the change in FPG, a statistically significant adjusted mean difference (p "0.0001) of -12.7 mg / dL is observed between reference L1 + MET + SU and BPBO + MET + SU at week 24 Measures in relation to cell function j3 (fasting plasma insulin and HOMA-% B) together with HOMA-IR are significantly (p, ". 0.05)
    improved with LI + MET + SU compared to PBO + MET + SU.
    The proportion of patients who reported a severe adverse event (AE) is low for groups LI + MET + SU and PBO + MET + SU (2.4% vs. 1.5%, respectively). The most frequent AE reported more generally in the LI + MET + SU group than 5 than in the PBO + MET + SU group is hypoglycemia (22.7% vs. 14.8%, respectively). This is expected due to the combination with SU.
    No significant change in weight is noted for any treatment group.
    Conclusion: Therapy with linagliptin added to the combination of metformin and a sulfonylurea is effective and safe, producing significant and clinically significant improvements in glycemic control in patients with T2DM.
    Linagliptin may provide an additional option prior to insulin therapy in many patients whose blood glucose is insufficiently controlled with metformin plus a sulfonylurea agent.
    Linagliptin has been shown to have a favorable safety and tolerability profile.
    However, when linagliptin is added to pre-existing sulfonylurea therapy, hypoglycemia can occur.
    Example 14: Efficacy and Sequencing of Initial Combination Therapy with Linaqliptin and Pioqlitazone in Patients with Inadequately Controlled Type 2 Diabetes A 24-week, multi-center, randomized, double-blind, parallel, pIacebo-controlled group study investigates the efficacy and safety of initial combination therapy with the DPP-4 inhibitor linagliptin (LI) and pioglitazone (PlO). Patients (pts) with type 2 diabetes mellitus (T2DM) and insufficient glycemic control (HbA1c 7.5 - 11.0%) who are receiving drug treatment or previously treated with any oral antihyperglycemic drug (OAD), are randomized to receive 5 mg Ll plus 30 mg qd IOP (n = 259) or 30 mg PlO plus placebo (PBO) qd (n = 130). Patients did not take any OAD for at least 6 weeks before randomization.
    Characteristics of average reference line (HbA1c 8.6 ° / o; fasting plasma glucose [fpg] 190 mg / dL; age 57.5 years; BMI 29.0 kg / m ') is similar between groups.
    The primary goal is to change the reference line in HbA1c after 24 weeks of treatment
    adjusted for reference HbA1c and previous antidiabetic medication.
    After 24 weeks of treatment, the adjusted mean change in HbA1c for patients in the Ll + PlO group (complete analysis set, last observation carried out) is -1.06% (standard error (SE) ± 0.06). The difference in the mean adjusted HbA1c for the Ll + PlO group compared to PBO + PlO is -0.51% (p "0.0001; 95 ° / o confidence interval (Cl), -0, 71, - 0.30). Reductions in FPG are likewise significantly greater for the Ll + PlO group compared to PBO + PIO with a treatment difference of -14.2 mg / dL (p "0.0001; 95 % confidence interval (Cl), - 21.1, -7.3) in 24 weeks.
    Patients in the Ll + PlO group are more likely to achieve a target HbA1c of <7 ° /, vs. those in PBO + PlO (42.9% vs. 30.5%, respectively, odds ratios of non-occurrence 2.1; p = O, 0051), as well as a reduction in HbA1c of,>, 0.5% (75% vs. 50.8%, respectively, odds ratio of non-occurrence 3.8; p "0.001). The proportion of patients who experienced at least one adverse event (AE) is similar for both LI + groups IOP and PBO + PlO (136, 52.5% vs. 53.1 ° / o, respectively). Hypoglycemia is rare, occurring in 3 patients (1.2%) in the Ll + PlO group and none in the PBO + PlO group .
    All hypoglycemic events are of moderate intensity.
    Conclusion: Initial combination therapy with linagliptin and pioglitazone shows significant and clinically significant improvements in FPG and HbA1c levels compared to IOP alone, along with a greater improvement in beta cell function. Co-administration of linagliptin with pioglita-zone is shown to be safe and well tolerated.
    Combination therapy with linagliptin and pioglitazone may provide an important initial synergistic treatment option for patients with T2DM with inadequate glycemic control or those with renal impairment to whom metformin is contraindicated.
    Example 15: Linaqliptin Monotherapy Improves Glycemic Control in Japanese Patients with Type 2 Diabetes Mellitus Over 12 Weeks A 12-week, randomized, double-blind, pIacebo-controlled, multi-center group study investigates efficacy and safety of the DPP-4 inhibitor Iinagliptin (Ll). Ll monotherapy effects (5 mg qd and 10 mg qd) are compared to placebo (PBO) in patients (pts) who have not received drug or Japanese treatment previously treated with type 2 diabetes mellitus (T2DM) (reference line HbA1c 7.0 5 - 1, 0 ° / o, if not treated with drug; 7.0 - 9.0%, if previously treated). Before being randomized into Ll 5 (n = 159) or 10 mg (n = 160), or PBO (n = 80), all patients have a 2-week trial of PBO (patients on an oral antihyperglycemic drug have no medication for 2 weeks before experimentation). Average and demographic reference characteristics (HbA1c, 8.0% [0.68]; fasting plasma glucose (fpg), 163.5 mg / dL [32.4]; BMI, 24.97 kg / m '[ 3.86]; age, 60.0 years [9.7]) are similar in all groups.
    The primary goal is to change the reference line in HbA1c after 12 weeks.
    The differences in adjusted mean reference line changes at 15 HbA1c at week 12 are -0.87 ° / o for LI 5 mg vs.
    PBO (p "0.0001) e - 0
    0.88 ° / o for LI 10 mg vs.
    PBO (p "0.0001). Proportions of patients who obtain HbA1c" 7.0 ° 6 after 12 weeks are 26.4% for Ll 5 mg and 35.7% for LI 10 mg vs. 10.0% for PBO.
    Proportions of patients whose HbA1c levels are at least 0.5% lower are 57.2% with LI 5mg, 20 59.9% with LI 10mg, and 8.8% with PBO.
    Both Ll 5mg and 10mg show a statistically significant difference compared to PBO (p <0.0001). FPG is significantly improved with both Ll 5 and 10 mg compared to PBO: after 12 weeks, differences in adjusted mean reference line changes are -19.7 mg / dL for Ll 5 mg vs. 25 PBO (p "0.0001) and -20.4 mg / dL for LI 10 mg vs.
    PBO (p "0.0001). As indicated by changes in the proinsulin / insulin ratio (LI 5mg, p = O, 0065; LI 10 mg, p = O, 0004), Ll likewise improves significantly insulin secretion.
    The proportion of patients experiencing at least one adverse event (LA) is comparable between the three groups 30 (56.0% LI 5 mg, 53.1% Ll 10 mg and 56.3% PBO). Of these; 9.4%, 8.8% and 1O, O ° / o, respectively, are evaluated as being related to the drug.
    There is no hypoglycemic episode defined by the investigator.
    Body weight is unchanged with both Ll 5 mg and 10 mg, -0.39 and -0.06 kg, respectively, which is not significantly different vs.
    PBO (-0.04 kg) - Conclusion: Linagliptin demonstrates a significant and clinically significant improvement in glycemic control, reflected in changes in 5 HbA1c and FPG in Japanese patients with T2DM.
    Both 5 and 10 mg doses of linagliptin have similar efficacy in decreasing HbA1c and are well tolerated within this population. 5 mg of linagliptin is the therapeutic dose in Japanese patients, which is identical to the therapeutic dose in Caucasians. 10 Example 16: Linaçjliptina Provides Superior Glycemic Control Compared to Voçjlibose as Monotherapy in Japanese Patients with Type 2 Diabetes A 26-week, multi-center, randomized, double-blind, active-controlled, parallel study compares efficacy and safety of the DPP-4 inhibitor Iinagliptin (Ll) vs. the a-15 glycosidase voglibose (VB) inhibitor in Japanese patients (pts) not treated with drug or previously treated with Type 2 diabetes mellitus (T2DM) (reference 7.0 - 10.0% HbA1c if not treated with drug, 7.0 - 9.0 ° / o if previously treated with an oral anti-hyperglycemic drug (OAD). Following a 2-week PBO experiment, patients are randomized to Ll 5 (n = 159) or 10 mg qd (n = 160), or BV (0.2 mg tid; n = 162). Any previous OAD treatment is interrupted 2 weeks before the experiment.
    Mean [SD] and demographic (HbA1c, 8.01% [0.68]) characteristics; fasting plasma glucose (FPG), 163.5 mg / dL [32.4]; BMI, 24, 97 kg / m '[3.86]; age, 60.0 years [9.7])
    25 are similar across groups.
    The primary goal is to change the reference line to HbA1c after 26 weeks.
    The differences in mean adjusted baseline changes in HbA1c at week 26 are - 0.32% for Ll 5 mg vs.
    BV (p = O, 0003) and -0.39% for Ll 10 mg vs.
    BV (p "0.0001). Proportions of patients who obtain HbA1c <7.0% after 26 30 weeks are 30.2% for Ll 5 mg and 34.4% for Ll 10 mg vs. 22.2% for VB.
    Proportions of patients whose HbA1c level decreased by> 0.5% are 57.2 ° 6 and 53.5% for Ll 5 and 10 mg, vs. 37.7 ° 6 for VB.
    FPG is significantly improved
    with both Ll 5 and 10 mg compared to BV: the differences in adjusted mean changes from the reference line are -6.9 mg / dL for Ll 5 mg vs.
    BV (p = 0.02) and -9.8 mg / dL for Ll 10 mg vs.
    VB (p = O, 0015). Both Ll 5mg and 10 mg show a significant decrease in HbA1c previously 5 in patients treated with 1 OAD compared with BV (p = O, 003 and p = O, OO11, respectively). The occurrence of. ", 1 adverse event (AE) is comparable between the groups (72.3% of Ll 5 mg, 77.5% of Ll 10 mg and 71.6% of BV). Of the AES, 11.3 %, 10.6% and 18.5%, respectively, are evaluated when related to the drug.
    Drug-related gastrointestinal disorders 10 are more common in VB groups (14.2%) than LI (8.2% 5 mg; 8.1 ° / o 10 mg). In the VB group, 1 hypoglycemic episode is reported vs. none in groups Ll.
    Conclusion: Linagliptin monotherapy demonstrates greater effectiveness than BV to improve glycemic control in Japanese patients with 15 T2DM.
    Both 5 mg linagliptin and 10 mg linagliptin have comparable efficacy. and shows statistically significant decreases in HbA1c and FPG
    - reference compared to VB after 26 weeks.
    Linagliptin is well tolerated in Japanese patients with T2DM compared to BV, with less gastrointestinal AEs, and can provide a valuable addition to the 20 therapies available to this population. 5 mg Iinagliptin is the therapeutic dose in Japanese patients that is identical to the therapeutic dose in Caucusans.
    Example 17: Linaqliptin restores j3 cell function and survival in isolated human islets: 25 Studies in diabetic animal models show that dipeptidyl peptidase-4 (DPP-4) inhibitors reverse hyperglycemia and increase f3 cell mass. Here, the role of linagliptin, a DPP-4 inhibitor in human j3 cell function is investigated: isolated human islets are exposed to increased glucose concentrations (5.5 - 33.3 mM), 0.5 mM of 30 palmitic acid, the mixture of 2 ng / mL IL- @ or 1,000 U / mL lFN-y for 4 days or 50 µM H2O2 for 8 hours.
    The islets are pre-treated with 500 ng / mL Interleukin-1 Receptor Antagonist (IL-I Ra, which has been shown to restore B cell function), 100 nM linagliptin or solvent for one hour before exposure to diabetic stimuli and during the treatment period of 4 whole days.
    Under control conditions, islets secrete 3.8 times more insulin in 16.7 mM than in 5 2.8 mM glucose.
    In comparison, Stimulus Index is decreased 1.9 and 2.4 times when the islets are exposed to 11.1 mM and 33.3 mM of glucose (P "0.05). Exposure of the islets to palmitate, cytokine mixture or H2O2 results in a reduction of 2.1, 2.2 and 1.9 times of glucose-stimulated insulin secretion (GSlS), respectively (P <0.05) .Linagliptin significantly restores cell function 10 B in all conditions (increase of 1,9,2,5,3,3,1,9 and 3,7 times without GSl Without 11,1 or 33,3 mMdeglicose, palmitic acid, cytokines or H2O2, P <0,05). LL-1Ra is similarly effective in restoring B cell function under conditions of high glucose, palmitic acid and cytokines, but lL-1Ra fails to restore B cell function 15 under oxidative stress conditions induced by H2O2 treatment. mediated by oxidative stress, the
    - nitrotyrosine concentration is measured in islet lysates.
    Nitrothrosine levels are highly elevated in human islets under all diabetic conditions (increased by 13, 14, 6, 14 and 8 times by 11.1 or 33.3 mM 20 glucose, palmitic acid, cytokines or H2O2, P <0.05), while no elevated nitrotyrosine production is observed in islets treated with linin-glyptine.
    In summary, it is shown that the DPP-4 inhibitor linagfiptin has comparable protective effects on glyco, lipo and cytokinatoxicity as 25 lL-1Ra and, in addition, could improve B cell function under oxidative stress conditions and block apoptosis ( induced by H2O2 treatment). The study provides evidence of a direct protective effect of linagliptin on j3 cell survival and insulin secretion.
    Example 18: Chronic Kidney Disease Does Not Change the Pharmacokinetics of Lina-30 jjliptina, but Increases the Exposure of Sitaçjliptina and Aloçjliptina in Rats: Renal impairment is a frequent complication of T2DM.
    The effect of chronic kidney disease on the pharmacokinetics of dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin, alogliptin) in a rat model of chronic renal failure (5/6 nephrectomy, 5 / 6N) is investigated: Eight weeks after surgery, the rats are treated orally with inhibitors for 4 days. 5 / 6N causes a highly significant decrease- 5 (P "0.001) of the glomerular filtration rate measured by creatinine release (simulation: 2510 ± 210 ml / 24 h; 5 / 6N: 1665 ± 104.3 ml / 24 h) and increases cystatin C level (simulation: 700 ± 35.7 ng / mL; 5 / 6N: 1434 ± 77.6 ng / mL). Tubular function is significantly (P "0.001) impaired as evidenced by lipocalin associated with neutrophil gelatinase plasma 10 (NGAL), (simulation: 286 ± 23 ng / ml; 5 / 6N: 680 ± 56.3 ng / ml) and j32 microglobulin (simulation: 20.4 ± 2.4 µg / mL; 5 / 6N: 33.3 ± 1.34 µg / mL). DPP-4 activity is comparable between groups.
    The administration of linagliptin (0.5 and 7 µmols / kg) to 5 / 6N rats does not show a significant change in AUC (0-oo); simulation: 316 ± 54.7 15 nmols * h / L; 5 / 6N: 257 ± 21.54 nmols * h / L; P = 0.771 and simulation: 1252 ± 372. nmols * h / L; 5 / 6N: 748 ± 74.5 nmol * h / L; P = 0.284, respectively.
    In comparison, both sitagliptin and alogliptin (7 µmols / kg) are significantly (P = O, OOO1 and P = O, 039) higher (41 ° 6 and 28%) AUC (Q-cc '); simulation with sitagliptin: 3690 ± 103 nmols * h / L; 5 / 6N: 6238 ± 423 nmols * h / L and simulation 20 with alogliptin: 1772 ± 225 nmols * h / L; 5 / 6N: 2445 ± 166 nmols * h / L). In addition, no correlation of tubular and glomerular function markers with linagliptin AUC is observed.
    In comparison, sitagliptin correlates significantly with the release of creatinine (r2 = 0.374, P <0.05), cystatin C (r2 = 0.499, P <0.01), NGAL (r2 = 0.604, P <0 , 01) and j32 25 microglobulin (r2 = 0.543, P "0.01). Alogliptin correlates less significantly with cystatin C (r2 = 0.376, P <0.05) and 32 microglobulin (r2 = 0.391, P <0.05), but not with creatinine and NGAL release.
    These results demonstrate that renal impairment does not affect the pharmacokinetics of Iinagliptin considering that it increases the exposure of sitagliptin and alogliptin.
    Therefore, compared to sitagliptin and alogliptin, linagliptin may not have to be dose-adjusted in patients with T2DM and renal impairment or diabetic nephropathy.
    In addition, linagliptin significantly inhibits mRNA expression of profibrotic factors, such as TGF- $ 1, T1MP-1 and collagen (Col3alpha1) in the heart of uremic rats, whose factors are markers of cardiac fibrosis tissue fibrosis and are increased in the heart. uremic. 5 Characteristic cardiomyopathy with intestinal expansion and fibrosis often develops in uremia.
    Thus, these antifibrotic properties of DPP-4 inhibitors can be used for the treatment of cardiac and renal damage, uremic heart, cardiac fibrosis and / or cardiomyopathy with intestinal expansion and fibrosis associated with uremia in patients with diabetes. 10 type 2 tes. The action of Iinagliptin antifibrotic may be an additional benefit for patients with chronic kidney diseases and / or heart diseases that often accompany type 2 diabetes. Example 19: Linagliptin improves liver steatosis in rodent models: Steatosis Hepatic is an official brand of patients with Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Linagliptin is a selective and non-renal excreted inhibitor of dipeptidyl peptidase-4 (DPP-4). In a model of diet-induced obesity (DlO, fed for 2 and 3 months), the effect of 4-week therapy with linagliptin (3 and 30 mg / kg / day, n = 1O) is investigated.
    The lipid content in the liver is detected by magnetic resonance spectroscopy (MRS) in vivo and by analysis of liver triglycerides ex vivo.
    Linagliptin significantly inhibits DPP-4 activity (P "0.001) by 67% to 80% and 79% to 89% (3 and 30 mg / kg / day, respectively) compared to controls.
    Blood glucose levels after an OGTT (AUC) are significantly (P "0.01) decreased by 16% to 20% (3 mg / kg / day) and 2 ° / o to 26% (30 mg / kg / day) Also, the fat content in the liver (MRS detection) is significantly reduced.
    Changes in the fat content in the liver are already visible in the two weeks of treatment.
    The correlation between the lipid content in the liver when measured by MRS and liver triglyceride levels when measured ex vivo is r2 = 0.565 (P <0.0001).
    In addition, ob / ob rats are analyzed after 14 days of treatment with Iinagliptin (3 mg / kg / day or control) and the blind histological count is performed (severity and degree of fat content, inflammation markers) ). DPP-4 activity is inhibited by 8 ° / o and the AUC reduction of 5 blood glucose is 25% (P "0.05). Histological count reveals less hepatic steatosis and inflammation in the linagliptin group (2.2 ± 0.13, n = 9, P "0.01) versus control (3 ± 0.18, n = 10O). In conclusion, linagliptin significantly reduces the fat content in the liver and histological NAFLD in a high-fat diet model. 10 Linagliptin reverses the triglyceride content in the liver and fatty liver (with greater therapeutic impact when fatty liver is more pronounced). The reversal of hepatic steatosis supports the use of Iinagliptin in patients with Type 2 Diabetes as well as diseases associated with the liver (NAFLD). Example 20: Linaçjliptina Functionally Controls a De-balance in Dpp-4 Expression in Wounds Impaired by Diabetes: Impaired wound healing is a major complication
    . diabetes mellitus.
    The inhibitor of Iinagliptin dipeptidyl peptidase-4 (DPP-4) improves wound healing (as shown in ob / ob mice). The impact of linagliptin on inflammatory markers on the injured skin is examined and a reason for the beneficial action of linagliptin on wound healing is provided: Linagliptin wounds (3 mg / kg / day) and ob / ob treated by simulation for the inflammatory markers COX-2 and MlP by RNase protection assays are investigated without significant differences.
    In addition, linagliptin does not increase the number of F4 / 80-positive macrophages with apoptotic infiltration.
    Therefore, the expression of DPP-4 in the skin of diabetic and non-diabetic animals is assessed. Immunohistochemistry (IHC) and immunoblots reveal strong DPP-4 expression in the skin of healthy and diabetic mice (ob / ob) and keratinocytes as the main cell source of the enzyme.
    Online, the location of the DPPA protein in the skin accurately correlates with the whole body autoradiography obtained after treatment with [3H] labeled Iinagliptin. Analyzing the ex-
    pressure of DPP-4 in mice in the wide thick excisional wound, it is found that in healthy mice, the expression of DPP-4 protein declines for 3 days after the injury and the enzyme remains absent in the final stage of repair.
    Interestingly, skin damage leads to a strong sub-regulation of DPP-4 expression in the proliferation of keratinocytes from the margin of the wound (IHC) - In comparison, in acute wounds of diabetic mice, any expression of DPP- 4 cannot be observed.
    The DPP-4 protein, however, is expressed in the final stage of wound repair.
    The reverse regulation of DPP-4 protein in diabetic versus non-diabetic skin 10 provides a functional basis for the positive action of linagliptin in wound healing processes.
    Thus, improvement of the wound healing process mediated by a suitable DPP-4 inhibitor, such as Iinagliptin, depends on the compensation (inhibition) of unregulated DPP-4 in diabetic wounds in place of the anti-glycemic effects. or immunomodulators thereof.
    Thus, a start. DPP-4 probe that is suitable for improving wound healing is
    - such a DPP-4 inhibitor that can effectively bind to DPPA in the skin, for example, to unregulated DPP-4 in diabetic wounds, preferably in its therapeutic dose level. 20 In addition, in this context, a DPP-4 inhibitor that is suitable for improving wound healing, particularly in a patient with type 2 diabetes, is such a DPP-4 inhibitor that can be applied topically to wounds , for example, included in wound dressings or plasters or creams or ointments.
    Accordingly, the present invention also provides topical wound devices, such as, for example, wound dressings or plasters, comprising linagliptin and, optionally, one or more pharmaceutically acceptable vehicles and / or excipients.
    Example 21: Association Study (TCF7L2 genotyping, response to treatment) The polymorphisms and variants of the TCF7L2 gene as described in Table i can be analyzed as described in the following procedure:
    Variant nucleotide gene number of rs C.382-41435 C> T rs7903146 C.483 + 9017 G> T, rs12255372 TCF7L2 C.382-22060 A> G rs10885406 C.1102 C> G rs731788 Table i: Gene, variant nucleotides and rs numbers. Samples Patient DNA samples (conc .: 50 ng / µl) in 96-well plates are used for the analytical methods applied. 5 Genotyping by Direct Sanqer Sequencing Using gDNA as a standard, site-specific DNA fragments are amplified by polymerase chain reaction (PCR). PCR is performed using an ABI BioRad® Tetrad PCR System.
    Quality of PCR products is analyzed by agar gel electrophoresis
    P lO rose. Purified PCR products are used as a standard in sequencing reactions. According to the Sanger chain termination methodology and others, (1977), DNA sequence analysis is based on the termination of a developing DNA strand due to the incorporation of a 2 ', 3'- Didesoxyribonucleotideotriphosphate (ddNTP) labeled by 15 dye by DNA polymerase. Purified sequencing products are analyzed using an ABI PRISM®3730 Genetic Analyzer. The sequencing data is generated using the original So / bvare ABI. The subsequent KB // ing as well as the assembly is performed using the Staden Software Package. Baseca // ing KB assigns the quality values to all bases called automated sequencer tracks using the K8-baseca // er error probabilities. These quality values are used when assembling the isolated readings and are the basic requirement for calculating the sequence precision (Applied Biosystems, 3730 / 3730xI / DNA Analyzer Sequencing Analysis Software Training) - 25 A quality value (q ) of 20 corresponds to an error probability (ep) of 1/100, a value of 30 to an ep of 1/1000 and so on. In the assembly phase, these values are fixed in comparison with each other.
    In general, sequencing is continued until each consensus basis has a quality value (q) of 50 or more.
    This corresponds to an error probability (ep) of 1/100000. Due to the fact that most consensus bases have a quality score even higher than 5 the minimum, the cumulative error probability calculated for the finished sequence is again significantly lower.
    The sequencing data is transferred and analyzed using the jsi medical systems seqpatient software (version Seq Piloto 3.3.2, JSl medical systems GmbH, Friedhofstr. 5, 77971 Kippenheim, Germany). 10 Only traits that meet internal quality aspects are processed for additional genotype analysis.
    Genotyping is performed by analyzing single polymorphisms instead of whole gene analysis.
    Therefore, the genotyping results only refer to the variant positions described in Table i. 15 Genotyping by TaqMan PCR The TaqMan® technology comprises the amplification of a
    . PCR fragment with simultaneous detection of the degradation of a labeled probe.
    Probes are labeled at both ends with a specific allele dye and an extinguisher.
    During the amplification reaction, probe 20 specifically hybridized is displaced by the DNA polymerase.
    This displacement occurs as degradation by the 5 'exonuclease activity of the polymerase in the case of a perfect pairing with the probe, or without degradation in the case of an imbalance- In the degradation, the extinguisher and dye are separated and the fluorescence signal increased.
    An increase in the fluorescence signal is indicative of the presence of the respective allele.
    Fluorescence signals are recorded with the ABI PRISM 7700 system (Applied Biosystems). In detail, a master mixture is prepared containing all components for PCR reaction and aliquoted in the appropriate number of wells.
    Subsequently, DNA is added to each well according to the layout of the plate; with the exception of non-standard control (NTC) - Assay ID AB (rs7903146) C _ 29347861 _ 10 SNP context string:
    TAGAGAGCTAAGCAC IIII IAGATA [cmTATATAATTTAATTgccgTATgAgg The master mix per sample contains: Water without nuclease 0.25 µ1 5 2x PCR MasterMix 2.5 µ1 20x Mixer / Probe mix 0.25 µ1 DNA [10 ng / µl] 2 _W In total: 5 µ1 The cycling conditions are: 10 95 ° C 10 min.
    95 ° C 15 sec. } 50 cycles 60 ° C 90 sec.
    The pre- and post-readings of TaqMan® from AD are performed on the TaqMan "790OHT Fast Real System. The SDS V2.3 software calculates the fluorescence measurements made during the plate reading and plots the values of
    F Rn based on the signals from each cavity. The use of so / hvare is determined - whose SNP alleles are present in each sample. NTC should be taken as not determined.
    Statistical Analyzes 20 To assess the homogeneity of the treatment effect on the change of reference HbA1c after 24 weeks in the genotype subgroups defined by TCF7L2 SNP rs7903146 genotypes, an analysis of the covariance model (ANCOVA) including the treatment interaction with the covariate genotype is applied to data grouped over four studies. The statistical model includes' Treatment ',' Genotype ',' Study ',' Wash Period for previous oral antidiabetic drugs (yes / no) ',' Race ', as well as the interaction term' Treatment * Genotype as fixed effects and 'HbA1c reference line' as a linear covariate. The AN-COVA model provides estimates for the mean reference change in HbA1c 30 after 24 weeks of therapy for the different genotypes that carry the reference demographic and clinical information into account.
    Pairwise comparisons based on model between wild-type homozygous (CC genotype) and heterozygous (CT genotype) or rare homozygous (TT genotype) individuals in linagliptin or combination treatment (Iinagliptin + pioglitazone, linagliptin + metformin, linagliptin + metformin + a sulfonylurea) are performed. 5 Additionally, the results of the corresponding ANCOVA models without fixed effects of 'Genotype' and 'Treatment * Genotype' are given to the entire patient population of the studies (complete analysis set, FAS) as well as to the subpopulation which genetic analyzes are performed (complete analysis set for pharmacogenetic analyzes, FASG) to demonstrate the comparability of the observed effects. Statistical evaluation is prepared using the SAS software version 9.2 (SAS lnstitute lnc., Cary, North Carolina, USA) and S-PL US® 8.0 (Insightful Corp., Seattle, Washington, USA). Figure 1 shows average values and 95 ° / o confidence intervals
    W 15 ça for reference HbA1c values for the entire patient population of the studies (complete analysis set, FAS), for the subpopulation for which genetic analyzes are performed (complete analysis set for pharmacogenetic analyzes, FASG), as well as for the subgroups defined by genotype (CC, CT, TT) of this subpopulation. The numbers of patients for placebo control and treatment with Iinagliptin are determined on supports. Figure 2 shows a statistical association between TCF7L2 SNP rs7903146 genotypes with a probability of a favorable response in CC / CT genotype vehicles for the administration of a therapeutically effective amount of linagliptin or linagliptin in combination with another oral antidiabetic therapy. Results are shown as point estimates and 95 ° / o confidence intervals for the mean change in reference HbA1c [° / 0] after 24 weeks as calculated by ANCOVA models. The results are determined for the entire patient population of the studies (complete analysis set, FAS), for the subpopulation for which genetic analyzes are performed (complete analysis set for pharmaceutical analyzes).
    genetics, FASG), as well as for the subgroups defined by genotype (CC, CT, TT) of this subpopulation. Patient numbers for placebo control and linagliptin treatment are determined on supports. Point estimates and 95% confidence intervals for the 5 differences in changes in reference HbA1c [° / 0] for comparison between wild type homozygous (CC genotype) and heterozygous (CT genotype) or rare homozygote (genotype of TT) under treatment with linagliptin or combination treatment (linagliptin + pioglitazone, linagliptin + metformin, linagliptin + metformin + a sulfonylurea) are shown as well. They result in a statistically significant difference between TT and CC (p-value = 0.0192). (Other pairwise comparisons: CT vs. CC: p = 0.4359; CT vs. TT: p = 0.0712). This indicates a significant association between the homozygous wild-type genotype and lower HbA1c under treatment. 15 Figure 1 Reference HbA1c values for the entire patient population
    W of the studies (complete analysis set, FAS), for the subpopulation for which the kenetic analyzes are performed (complete analysis set for pharmacokinetic analyzes, FASG), as well as for the sub-groups defined by SNP rs7903146 in TCF7L2 jenotypes (CC, CT, TT) of this sub-population- Formulation Examples The following examples of formulations, which can be obtained analogously to methods known in the art, serve to illustrate the present invention more completely without restricting it to the contents of these e- 25 examples. The term "active substance" denotes one or more compounds according to the invention, that is, it denotes a DPP-4 inhibitor or a second or third antidiabetic compound according to this invention or a combination of two or three of said active ingredients, for example, selected from the combinations as listed in Table 1 or 2. Additional suitable formulations for the DPP-4 inhibitor linagliptin can be those formulations described in application WO 2007/128724, the description of which is incorporated here in its entirety. Additional suitable formulations for the other DPP-4 inhibitors may be those formulations that are available on the market, or formulations described in the patent applications cited above in the "background of the invention", or those described in the literature, for example, as discussed in current affairs of "Rote Lis- 5 te®" (Germany) or "Physician's Desk Reference". Example 1: Dry ampoule containing 75 mg of active substance per 10 ml Composition: Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation: The active substance and mannitol are dissolved in water.
    After conditioning, the solution is freeze-dried.
    To produce the ready-to-use solution, the product is dissolved in water for injections.
    Example 2: Dry ampoule containing 35 mg of active substance per 2 ml Composition: Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation: The active substance and mannitol are dissolved in water.
    After packaging, the solution is freeze-dried.
    To produce the solution ready for use, the product is dissolved in water for injections.
    Example 3: Tablet containing 50 mg of active substance Composition: (1) Active substance 50.0 mg (2) Mannitol 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mq 215.0 mg
    Preparation: (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granular material.
    From this mixture, the tablets are pressed, biplane, faceted on both 5 sides and with a split notch on one side.
    Diameter of tablets: 9 mm.
    Example 4: Tablet containing 350 mg of active substance Preparation: (1) Active substance 350.0 mg (2) Mannitol 136.0 mg (3) Corn starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 m / 600.0 mg (1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dry granular material.
    From this mixture, the tablets are pressed, biplanes, faceted on both sides and with a split notch on one side.
    Diameter of tablets: 12 mm.
    Example 5: Capsules containing 50 mj of active substance Composition: (1) Active substance 50.0 mg (2) Dry corn starch 58.0 mg (3) Mannitol 50.0 mg (4) Magnesium stearate 2.0 mj 160.0 mg Preparation: (1) is ground with (3). This crushing is added to the mixture of (2) and (4) with vigorous mixing.
    This powder mixture is packed in size 3 hard gelatin capsules in a capsule filling machine.
    Example 6: Capsules containing 350 mq of active substance Composition: (1) Active substance 350.0 mg (2) Dry corn starch 46.0 mg (3) Mannitol 30.0 mg (4) Magnesium stearate 4.0 mçj 430.0 mg Preparation: (1) is ground with (3). This crushing is added to the mixture of (2) and (4) with vigorous mixing.
    This powder mixture is packed in size 0 hard gelatin capsules in a capsule filling machine.
    权利要求:
    Claims (23)
    [1]
    1. Use of a pharmaceutical compound, composition or combination, comprising: (a) DPP-4 inhibitor, and, optionally, 5 (b) a second antidiabetic agent selected from the G3 group, consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, alpha-glycosidase inhibitors, GLP-1 or GLP-1 analogs, and insulin or insulin analogs; and, optionally, (c) a third antidiabetic agent that is different from (b) selected from the G3 group, consisting of biguanides, thiazolidindiones, sulfonylureas, glinides, alpha-glycosidase inhibitors, GLP-1 or GLP analogs -1, and insulin or insulin analogs or a pharmaceutically acceptable salt thereof; the said use being characterized by the fact that it is to prepare a medication, particularly, for use in a therapeutic or preventive therapeutic treatment, such as, for example, in the treatment of type 2 diabetes mellitus, the said treatment being comprises: testing whether the patient has variation (s) in one or more genes associated with metabolic diseases, for example, whether the patient has one or more variations (for example, polymorphisms) in one or more of the genes selected from TCF7L2 and GLP1R, in particular if he / she has one or more unique nucleotide polymorphisms (SNPs) in the gene encoding TCF7L2, such as, for example, an SNP selected from rs7903146, rs12255372 and rs10885406 or if the patient is their respective wild-type genotype, for example, if the patient is of the wild genotype of TCF7L2, in particular if he / she is of the wild genotype of TCF7L2 rs7903146, and administer the compound, composition or pharmaceutical combination to the patient.
    [2]
    2. Use, according to claim 1, characterized by the fact that the second and / or third antidiabetic agent, in the pharmaceutical composition or combination, is (are) selected (s) independently from the group consisting of metformin, pioglitazone, rosiglitazone, troglitazone, ciglitazone, glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glycolideurid, gliburide, glisoepide, glyclazide, nateglinide, repaglinide, mitiglinide, acarbose, voglibose, a pharlitol and a pharmaceuticide and exergate- therapeutic agents mentioned above.
    [3]
    3. Use according to claim 1 or 2, characterized by the fact that the DPP-4 inhibitor, in the pharmaceutical composition or combination, is selected from the G2 group consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin and dutogliptin or a pharmaceutically acceptable salt of one of the DPP-4 inhibitors mentioned above, or a prodrug thereof.
    [4]
    Use according to any one of claims 1 to 3, characterized in that the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers.
    [5]
    Use according to any one of claims 1 to 4, characterized by the fact that ingredients (a) and (b) are present, and ingredient (c) is absent in the pharmaceutical composition or combination.
    [6]
    6. Use according to any one of claims 1 to 4, characterized by the fact that ingredient (a) is present, and ingredients (b) and (c) are absent in the pharmaceutical composition.
    [7]
    7. Use according to any one of claims 1 to 5, characterized by the fact that the pharmaceutical composition or combination is suitable for simultaneous or sequential use of the active ingredients.
    [8]
    Use according to any one of claims 1 to 5, characterized by the fact that the active ingredients are present in a single dosage form or each in separate dosage forms, in a combination or pharmaceutical composition.
    [9]
    9. Use according to any of claims 1 to 4, characterized by the fact that the DPP-4 inhibitor and the second antidiabetic agent are present in a single dosage form and the third antidiabetic agent is present in a separate dosage form, in the pharmaceutical composition or combination.
    [10]
    10. Use of a DDP-4 inhibitor according to claim 3, characterized by the fact that it is for the preparation of a drug to prevent, slow down progression, reduce or treat 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 in a patient in need of it, for example, For example, in a patient who has one or more variations (for example, SNPs) in one or more of the genes selected from TCF7L2 and GLP1R or in a patient who is of the respective wild type genotype, said method comprising: testing whether the patient has one or more variations (for example, polymorphisms) in one or more of the genes selected from TCF7L2 and GLP1R, particularly if he / she has one or more unique nucleotide polymorphisms (SNPs) in the gene encoding for T CF7L2, such as, for example, an SNP selected from rs7903146, rs12255372 and rs10885406 or if the patient is of the respective wild type genotype, for example, if the patient is of the TCF7L2 wild genotype, in particular if he / it is of the wild genotype TCF7L2 rs7903146, and administering a DPP-4 inhibitor according to claim 3, and optionally a second antidiabetic agent according to claim 1 or 2, and optionally a third antidiabetic agent according to claim 1 or 2, to the patient, optionally in combination, including alternating.
    [11]
    11. Use of a pharmaceutical composition according to any one of claims 1 to 9, characterized by the fact that it is for the preparation of a medicine to: - prevent, slow the progression of, delay or treat a disorder metabolic rate selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia,
    brepes, 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 5 - to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or - prevent, decrease, delay or reverse the progression of impaired glucose tolerance, insulin resistance and / or the metabolic syndrome for type 2 diabetes mellitus; or - prevent, slow the progression of, delay or treat 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 ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and restenosis vascular; or - reduce body weight or prevent an increase in body weight or facilitate a reduction in body weight; or - prevent, decrease, delay or treat pancreatic beta cell degeneration and / or decline in pancreatic beta cell functionality and / or to improve and / or restore pancreatic beta cell functionality and / or restore the functionality of pancreatic insulin secretion; or - preventing, decreasing, delaying or treating diseases or conditions attributed to an abnormal accumulation of fat in the liver; or - maintain and / or improve insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance; in a patient in need of it, particularly in a patient who has variation (s) in one or more genes associated with metabolic diseases,
    in particular in a patient who has one or more variations (for example, polymorphisms) in one or more of the genes selected from TCF7L2 and GLP1R, more particularly in a patient having one or more single nucleotide polymorphisms ( SNPs) in the gene encoding TCF7L2, such as, for example, having an SNP selected from rs7903146, rs12255372 and rs10885406, or in a patient who is of the respective wild type genotype, particularly in a patient who is of the wild genotype of TCF7L2, more particularly in a patient who is of the wild type genotype in rs7903146 of TCF7L2.
    [12]
    12. Use according to any one of claims 1 to 11, characterized by the fact that the patient has one or more single nucleotide polymorphisms (SNPs) in the gene encoding TCF7L2, especially at least one SNP selected from from rs7903146, rs12255372 and rs10885406, especially rs7903146.
    [13]
    13. Use according to any of claims 1 to 12, characterized by the fact that the patient is diagnosed for, has been diagnosed with or carries at least one T allele of SNP rs7903146 of TCF7L2, that is, the CT genotype or TT genotype.
    [14]
    14. Use according to any of claims 1 to 13, characterized by the fact that the patient is diagnosed for, has been diagnosed with or carries two T alleles of SNP rs7903146 of TCF7L2, that is, the TT genotype.
    [15]
    15. Use according to any one of claims 1 to 13, characterized by the fact that the patient is diagnosed for, has been diagnosed with or carries a T allele of SNP rs7903146 of TCF7L2, that is, the CT genotype.
    [16]
    16. Use according to any of claims 1 to 11, characterized by the fact that the patient is diagnosed for, has been diagnosed with or carries a wild genotype of TCF7L2, especially a wild type genotype in TCF7L2 rs7903146.
    [17]
    17. Use according to any one of claims 1 to 11, characterized by the fact that the patient is diagnosed for, has been diagnosed with or carries the wild type genotype, especially that is diagnosed for or carries two C alleles of SNP rs7903146 to TCF7L2, i.e., the CC genotype.
    [18]
    18. Use of a pharmaceutical composition according to any one of claims 1 to 9, characterized by the fact that it is for the preparation of a medicine to: - prevent, slow the progression of, delay or treat a disorder metabolic 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 - to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycated hemoglobin HbA1c; or - prevent, decrease, delay or reverse the progression of impaired glucose tolerance, insulin resistance and / or the metabolic syndrome for type 2 diabetes mellitus; or - prevent, slow the progression of, delay or treat 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 ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorder and vascular restenosis; or - reduce body weight or prevent an increase in body weight or facilitate a reduction in body weight; or - prevent, decrease, delay or treat pancreatic beta cell degeneration and / or decline in pancreatic beta cell functionality and / or to improve and / or restore pancreatic beta cell functionality and / or restore the functionality of pancreatic insulin secretion; or - to prevent, decrease, delay or treat diseases or conditions attributed to an abnormal accumulation of fat in the liver; and / or 5 - maintain and / or improve insulin sensitivity and / or to treat or prevent 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, particularly if the patient has one or more unique nucleotide polymorphisms (SNPs) especially at least in the gene encoding for TCF7L2, an SNP selected from rs7903146, rs12255372 and rs10885406, for example, if the patient carries at least one rs7903146 SNP T allele from TCF7L2, for example, if the patient has a CT genotype (that is, if the patient carries a SNP T allele rs7903146 from TCF7L2) or if the patient is of TT genotype (ie, if the patient carries two SNP T cells from rs7903146 from TCF7L2) or test whether the patient is a TCF7L2 wild genotype, pair - ticularly if the patient has a wild genotype of TCF7L2 rs7903146, for example, if the patient has a CC genotype (that is, if the patient carries two C alleles of SNP rs7903146 from TCF7L2), and, optionally, (ii) administer a DPP-4 inhibitor to the patient according to claim 3, and optionally a second antidiabetic agent according to claims 1 to 2, and optionally a third antidiabetic agent according to claims 1 to 2, optionally in combination, which includes alternating.
    [19]
    19. Use according to any one of claims 1 to 18, characterized in that the DPP-4 inhibitor is linagliptin.
    [20]
    20. Use according to any one of claims 1 to 19, characterized in that the inhibitor DDP-4 is linagliptin, and the second antidiabetic agent is metformin or pioglitazone.
    [21]
    21. Use according to any one of claims 1 to 20, characterized by the fact that the patient suffers from or has been diagnosed with type 2 diabetes mellitus.
    [22]
    22. Kit of parts, characterized by the fact that it comprises: 5 (a) a first container containing a dosage form comprising the DPP-4 inhibitor, as defined in claim 1, and at least one pharmaceutically acceptable vehicle and / or a second and / or a third antidiabetic agent, as defined in claim 1; and (b) a second and / or a third container containing a dosage form comprising said second and / or said third anti-abetic agent and / or at least one pharmaceutically acceptable carrier.
    [23]
    23. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially disclosed in the patent application or in its examples presented here.
    类似技术:
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    KR20200028498A|2020-03-16|Diabetes therapy
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    同族专利:
    公开号 | 公开日
    CN107115530A|2017-09-01|
    US20190000855A1|2019-01-03|
    CA2782179A1|2011-06-03|
    US20130196898A1|2013-08-01|
    EP3646859A1|2020-05-06|
    MX2012006110A|2012-06-14|
    KR20120107080A|2012-09-28|
    EA034869B1|2020-03-31|
    KR20190071840A|2019-06-24|
    US10092571B2|2018-10-09|
    AU2010323068B2|2015-09-03|
    EA201200793A1|2014-04-30|
    JP2015164964A|2015-09-17|
    US20200046713A1|2020-02-13|
    US20160354380A1|2016-12-08|
    JP6104989B2|2017-03-29|
    CA2782179C|2020-06-23|
    EP2504002A1|2012-10-03|
    WO2011064352A1|2011-06-03|
    JP2013512229A|2013-04-11|
    KR20170136017A|2017-12-08|
    IL219014D0|2012-06-28|
    AU2010323068A1|2012-05-03|
    ES2760917T3|2020-05-18|
    MX364651B|2019-05-03|
    EP2504002B1|2019-10-09|
    CL2012001337A1|2012-08-17|
    US9457029B2|2016-10-04|
    CN102753161A|2012-10-24|
    KR102328772B1|2021-11-19|
    KR20210033559A|2021-03-26|
    NZ599298A|2014-11-28|
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    法律状态:
    2020-08-25| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-12-08| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-12-29| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-03-02| B06G| Technical and formal requirements: other requirements [chapter 6.7 patent gazette]|
    2021-05-25| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-09-14| B09B| Patent application refused [chapter 9.2 patent gazette]|
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2021-11-23| B12B| Appeal against refusal [chapter 12.2 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    EP09177418.2|2009-11-27|
    EP09177418|2009-11-27|
    EP10166714|2010-06-21|
    EP10166714.5|2010-06-21|
    PCT/EP2010/068349|WO2011064352A1|2009-11-27|2010-11-26|Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin|
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