KR102117282B1 - Vasoprotective and cardioprotective antidiabetic therapy - Google Patents

Abstract

The present invention provides diabetes or non-diabetic patients including certain DPP-4 inhibitors for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, and groups of patients at risk for cardiovascular disease and / or kidney disease. It relates to the use of the DPP-4 inhibitor in the treatment and / or prevention of.

Description

Vasoprotective and cardioprotective anti-diabetic therapy {VASOPROTECTIVE AND CARDIOPROTECTIVE ANTIDIABETIC THERAPY}

The present invention is directed to the treatment and / or prevention of diabetic or non-diabetic patients, including certain DPP-4 inhibitors for treating and / or preventing oxidative stress, and groups of patients at risk for cardiovascular and / or renal disease. It relates to the use of the DPP-4 inhibitor.

The present invention also relates to certain DPP-4 inhibitors for treating and / or preventing endothelial dysfunction.

The invention also relates to certain DPP-4 inhibitors for use as antioxidants and / or anti-inflammatory agents.

The present invention also provides for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction (e.g., in diabetic or non-diabetic patients), particularly in addition to or without glycemic control. It relates to certain DPP-4 inhibitors.

The present invention also uses certain DPP-4 inhibitors for the treatment and / or prevention of hyperglycemic-induced or hyperglycemic-related oxidative stress (eg, in addition to glycemic control) and the use of the DPP-4 inhibitors in anti-diabetic therapy. It is about.

The present invention also provides metabolic diseases, such as diabetes, in particular type 2 diabetes mellitus, and especially in patients with or at risk of having oxidative stress, vascular stress and / or endothelial dysfunction, or a disease or condition associated with or associated therewith. And / or specific DPP-4 inhibitors for treating and / or preventing diseases associated therewith (eg, diabetes complications).

In addition, the present invention has the risk of having or having cardiovascular disease and / or kidney disease, such as myocardial infarction, stroke or peripheral arterial occlusive disease and / or diabetic nephropathy, microalbuminuria or macroalbuminuria, or acute or chronic kidney failure. It relates to certain DPP-4 inhibitors for the treatment and / or prevention of metabolic diseases, such as diabetes, in particular type 2 diabetes mellitus and / or related diseases (eg, diabetes complications) in patients with this.

In addition, the present invention provides microvascular or macrovascular diabetes complications, such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy or cardiovascular or cerebrovascular disease (e.g. myocardial infarction, stroke or peripheral artery occlusive disease). It relates to certain DPP-4 inhibitors for treating and / or preventing metabolic diseases, such as diabetes, in particular type 2 diabetes mellitus and / or related diseases in patients with or at risk of having.

The invention also relates to certain DPP-4 inhibitors for modulating, blocking, or reducing the adverse metabolic memory effect of hyperglycemia (of chronic or transient episodes), particularly against diabetes complications.

In addition, the present invention is directed to certain DPP-4 inhibitors for treating, preventing or reducing the risk of microvascular or macrovascular diseases that may be induced, memorized, or related by exposure to oxidative stress. It is about.

Additionally, the present invention comprises administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic substances, in a patient with or at risk of having cardiovascular and / or renal disease, particularly cardiovascular. Or metabolic disease, e.g. diabetes, in type 2 diabetes patients at risk of cerebrovascular events, e.g., type 2 diabetes patients having one or more risk factors selected from A), B), C) and D) below In particular, it relates to certain DPP-4 inhibitors for treating and / or preventing type 2 diabetes mellitus and / or diseases associated therewith (e.g., diabetes complications):

A) Previous or current vascular disease (e.g. myocardial infarction (e.g. asymptomatic or non-clinical), coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure ( For example, NYHA type I or type II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease),

B) vascular-related terminal-organ damage (eg nephropathy, retinopathy, neuropathy, kidney function impairment, chronic kidney disease and / or micro- or macroalbuminuria),

C) Old age (e.g. age> / = 60-70 years old) and

D)-advanced type 2 diabetes mellitus (eg,> 10 years duration),

Hypertension (e.g.,> 130 / 80mmHg, or systolic blood pressure> 140mmHg or at least one hypotensive treatment),

-Habitual daily smoking,

Dyslipidemia (e.g., atherosclerotic dyslipidemia, postprandial hyperlipidemia, or high levels of LDL cholesterol in the blood (e.g., LDL cholesterol> / = 130 to 135 mg / dL), low levels of HDL cholesterol (e.g. For example, <35 to 40 mg / dL in men or <45 to 50 mg / dL in women) and / or high levels of triglycerides (e.g.> 200 to 400 mg / dL), or at least one for lipid abnormalities In therapy),

-Obesity (eg, abdominal and / or visceral obesity, or body mass index> / = 45kg / m2),

-Age> / = 40 years and </ = 80 years,

-Metabolic syndrome, hyperinsulinemia or insulin resistance, and

-At least one cardiovascular risk factor selected from hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the first-degree relative.

In addition, the present invention preferably comprises the administration of a therapeutically effective amount of a DPP-4 inhibitor to a patient in combination with one or more other therapeutic agents, preferably in a type 2 diabetic patient, particularly at risk of cardiovascular or cerebrovascular events. Cardiovascular or cerebrovascular events, such as cardiovascular death, in type 2 diabetes patients with one or more risk factors selected from A), B), C) and D) Fatal or non-fatal myocardial infarction (e.g., asymptomatic or non-clinical MI), (fatal or non-fatal) stroke, or hospitalization (e.g., acute coronary syndrome, leg amputation, (emergency) vascular reconstruction) (revascularization procedures), in the case of heart failure or in the case of unstable angina, or to reduce the risk of expression of the disease, or to the specific DPP-4 inhibitor for use in a method for delaying the expression of the disease :

A) Previous or current vascular disease (e.g. myocardial infarction (e.g. asymptomatic or non-clinical), coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure ( For example, NYHA type I or type II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease),

B) vascular-related terminal-organ damage (eg nephropathy, retinopathy, neuropathy, kidney function impairment, chronic kidney disease and / or micro- or macroalbuminuria),

C) Old age (e.g. age> / = 60-70 years old) and

D)-advanced type 2 diabetes mellitus (e.g.> 10 years of illness),

  Hypertension (e.g.,> 130 / 80mmHg, or systolic blood pressure> 140mmHg or at least one hypotensive treatment),

  -Habitual daily smoking,

  Dyslipidemia (e.g. atherosclerotic dyslipidemia, postprandial hyperlipidemia, or high levels of LDL cholesterol in the blood (e.g. LDL cholesterol> / = 130 to 135 mg / dL), low levels of HDL cholesterol (e.g. For example, <35 to 40 mg / dL in men or <45 to 50 mg / dL in women) and / or high levels of triglycerides (e.g.> 200 to 400 mg / dL), or at least one for lipid abnormalities In therapy),

  -Obesity (eg, abdominal and / or visceral obesity, or body mass index> / = 45kg / m2),

  -Age> / = 40 years and </ = 80 years,

  -Metabolic syndrome, hyperinsulinemia or insulin resistance, and

  -One or more cardiovascular risk factors selected from hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the immediate family.

Additionally, the present invention comprises administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents, vascular-related terminal-organ damage, particularly nephropathy, renal impairment, chronic kidney disease, In patients with type 2 diabetes with micro- or macroalbuminuria, e.g. cardiovascular death, (fatal or non-fatal) myocardial infarction (e.g. asymptomatic or non-clinical MI), (fatal or non-fatal) stroke Or preventing the occurrence of cardiovascular or cerebrovascular events, such as the occurrence of hospitalization (e.g., acute coronary syndrome, leg amputation, (emergency) vascular reconstruction, heart failure or unstable angina) It relates to certain DPP-4 inhibitors for use in methods that reduce risk or delay the occurrence of the event.

Additionally, the present invention improves cognitive function (e.g., attenuation, reversal, or treatment of cognitive decline), comprising administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents. , improved β-cell function (e.g., improved insulin secretion rate derived from 3h meal tolerance test, improved long-term β-cell function), improved weekly glucose pattern (e.g., ambulatory glucose profile) glucose profile), blood glucose variability, oxidation, inflammation or improvement of biomarkers of endothelial cell function) and / or β-cell autoantibody status (e.g., glutamic acid decarboxylase GAD) in a method of improving the persistence of blood glucose control. Specific DPP-4 inhibitors for use.

Additionally, the present invention prevents, or reduces the risk of, cognitive impairment or cognitive decline, comprising administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents. Or a specific DPP-4 inhibitor for use in methods of slowing the progression of said disorders, delaying the expression of said disorders, attenuating, reversing, or treating said disorders.

Additionally, the present invention prevents, or risks of, latent autoimmune diabetes (LADA) in adults, comprising administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents. It relates to specific DPP-4 inhibitors for use in methods of reducing, slowing the progression of diabetes, delaying the onset of diabetes, attenuating, reversing, or treating the diabetes.

In addition, the invention provides a patient in need of treatment for the following disorders (e.g., as described herein) comprising administering to a patient a therapeutically effective amount of a DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents. Preventing cardiovascular or cerebrovascular diseases or events (e.g., those described herein), reducing the risk of the event, slowing the course of the event, or Delays expression, attenuates, reverses, treats, prevents diabetic nephropathy, reduces the risk of the disease, slows the progression of the disease, or delays the expression of the disease It relates to certain DPP-4 inhibitors for use in a (co-purpose) method of inducing, attenuating, reversing, or treating the disease.

In addition, the present invention relates to one or more of the following methods:

Patients in need (e.g., independently of or above blood glucose control), including administering to the patient an effective amount of a specific DPP-4 inhibitor, optionally in combination with an effective amount of one or more other active substances (e.g. , In patients with type 1 diabetes, LADA or, in particular, type 2 diabetes),

-Treat, reduce, prevent and / or protect oxidative stress, eg, non-diabetic- or diabetes- (hyperglycemic-) induced or related oxidative stress;

-Treating endothelial dysfunction, preventing the disorder, reducing the risk of the disorder, slowing the progression of the disorder, delaying the development of the disorder, attenuating the disorder, Reversing, improving endothelial cell function;

-Treating diseases or conditions related to oxidative stress, such as those described herein, preventing the disease, reducing the risk of the disease, slowing the progression of the disease, delaying the onset of the disease, Attenuating, reversing the disease;

-To treat ischemia / reperfusion injury (kidney, heart, brain or liver), prevent the damage, reduce the risk of the damage, slow the progression of the damage, delay the onset of the damage, Attenuating, reversing and / or reducing the damage (eg, after myocardial ischemia / reperfusion) reducing the size of myocardial infarction in the heart;

Treatment of (detrimental) vascular modifications, e.g. heart deformation (especially after myocardial infarction), which may be characterized by myocardial hypertrophy, interstitial fibrosis, ventricular dilatation, contractile dysfunction and / or cell death / apoptosis; or Prevent deformation, reduce the risk of the modification, slow the progression of the modification, delay the development of the modification, attenuate or reverse the modification;

-Treat chronic or acute renal failure and / or peripheral artery occlusion, prevent the diseases, reduce the risk of the diseases, slow the progression of the diseases, delay the onset of the diseases, or treat the diseases Attenuating, reversing;

-Treat congestive heart failure (e.g. NYHA type I, type II, type III or IV) and / or cardiac hypertrophy (e.g. left ventricular hypertrophy) and / or nephropathy and / or albuminuria, or , Preventing the diseases, reducing the risk of the diseases, slowing the progression of the diseases, delaying the onset of the diseases, attenuating or reversing the diseases;

-Treat urinary cardiomyopathy, interstitial dilatation and / or (heart) fibrosis (especially in patients with chronic kidney and heart disease often associated with type 2 diabetes), prevent these diseases, or reduce the risk of these diseases Or slow the progression of the disorders, delay the onset of the disorders, attenuate or reverse the disorders;

Modulate the detrimental metabolic effect of hyperglycemia (of chronic, early or transient episodes), especially on diabetes complications, block the effect, prevent the effect, reduce the effect, or protect against the effect;

Preventing or protecting against oxidation and / or atherosclerotic plaque formation of atherosclerotic or pre-atherosclerotic low density lipoproteins (particularly small particle LDL);

-Prevent or protect against oxidation-stress induced damage of the function or viability of pancreatic beta cells;

-Treat, prevent, improve or improve pancreatic islet inflammation or lipotoxicity and glucotoxicity in the pancreas, increase beta cell / alpha cell ratio, protect beta cells, Normalize / improve the islet form or function; And / or

Complications of diabetes mellitus, such as micro- and macrovascular diseases such as nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory disorders, neurodegenerative or cognitive disorders, cardiovascular Or cerebrovascular disease, endothelial dysfunction, tissue ischemia, diabetic foot or ulcus, atherosclerosis, hypertension, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy Prevents heart failure, heart rate disorders, vascular restenosis and / or stroke (e.g., uremic cardiomyopathy), reduces the risk of the diseases, slows the progression of the diseases, or delays the onset of the diseases Or a method of attenuating, reversing, or treating the disorders.

The invention also provides an angiotensin receptor blocker (e.g., comprising administering a therapeutically effective amount of a DPP-4 inhibitor to a patient, optionally in combination with one or more other therapeutic agents (e.g., ARB such as telmisartan). Prevents diabetic nephropathy in patients who do not respond appropriately to therapy with ARB (such as telmisartan) (e.g., patients with type 2 diabetes, as described herein), or reduce the risk of the disease Specific DPP-4 inhibitors for use in methods of prescribing, slowing the progression of the disease, delaying the onset of the disease, attenuating, reversing, or treating the disease.

The features of diabetic nephropathy are kidney and kidney filter functions that cause hyperfiltration (at an early stage), micro- or macroalbuminuria, nephrotic syndrome, proteinuria, hypertension, fluid retention, edema and / or ultimately renal failure or terminal kidney disease ( For example, it may include gradual damage or reduction of glomerular filtration rate (GFR). Additional features may include extensive or nodular glomerulosclerosis, afferent and efferent vitreous arteriosclerosis and / or tubulointerstitial fibrosis and atrophy. Additional features may include an abnormal albumin / creatinine or protein / creatinine ratio and / or an abnormal glomerular filtration rate.

The invention also relates to a specific DPP-4 for use in a method for preventing or treating diabetic nephropathy in a patient with an inappropriate response to therapy with an angiotensin receptor blocker (e.g., ARB such as telmisartan). The method may include administering a therapeutically effective amount of a DPP-4 inhibitor and telmisartan to the patient.

Thus, in certain embodiments, a preferred DPP-4 inhibitor within the meaning of the present invention is linagliptin.

Also contemplated are pharmaceutical compositions or combinations for use in such therapy, optionally comprising a DPP-4 inhibitor as defined herein in combination with one or more other active agents.

The invention also relates to DPP-4 inhibitors, optionally for use in combination with one, two or more additional active agents, each as defined herein, for use in a therapy as described herein.

In addition, the present invention provides DPP-4 inhibitors, optionally in combination with one, two or more additional active agents, as defined herein, respectively, for preparing pharmaceutical compositions suitable for the therapeutic and / or prophylactic purposes of the present invention. It relates to the use of.

In addition, the present invention is a therapeutic as described herein, comprising administering an effective amount of a DPP-4 inhibitor as described herein and, optionally, one or more other active agents or therapeutic agents as described herein to a patient in need thereof. (Treatment or prevention) method.

Oxidative stress is a biological system that readily detoxifies or repairs damage caused by the production of reactive oxygen species (typically including free radicals with oxygen- or nitrogen-based hole electrons in the outermost orbital, and peroxides) and reactive intermediates. It represents an imbalance between abilities. Disturbance in tissue's normal redox state can cause toxic effects through the production of peroxides and free radicals that damage all components of cells, including proteins, lipids, and nucleic acids / DNA. Oxidative stress can target multiple organs (e.g., blood vessels, eyes, heart, skin, kidneys, joints, lungs, brain, immune system, liver or multi-organs) and may be involved in many diseases and conditions. Can be. Examples of such diseases or conditions associated with oxidative stress include atherosclerosis (e.g. platelet activation and atherosclerotic plaque formation), endothelial dysfunction, restenosis, hypertension, peripheral obstructive vascular disease, ischemia-reperfusion injury (e.g. , Kidney, liver, heart or cerebral ischemia-reperfusion injury), fibrosis (eg, kidney, liver, heart or lung fibrosis); Macular degeneration, retinal degeneration, cataracts, retinopathy; Coronary heart disease, ischemia, myocardial infarction; Psoriasis, dermatitis; Chronic kidney disease, nephritis, acute renal failure, glomerulonephritis, nephropathy; Rheumatoid arthritis, osteoarthritis; Asthma, COPD, and difficulty breathing; Stroke, neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, Huntington's disease), schizophrenia, bipolar disorder, obsessive compulsive disorder; Chronic systemic inflammation, perivascular inflammation, autoimmune disorders, multiple sclerosis, lupus erythematosus, inflammatory bowel syndrome, ulcerative colitis; NAFLD / NASH; Chronic fatigue syndrome, polycystic ovary syndrome, sepsis, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia, hypercholesterolemia, hyperlipidemia and the like. In addition to their original pharmacological properties, certain clinically used drugs, including, but not limited to, anti-hypertensive agents, angiotensin receptor blockers and antihyperlipidemic agents, such as statins, are used in various organs through anti-oxidative stress mechanisms. Protect them.

Patients who have or are at risk of having oxidative stress and / or vascular stress are patients' oxidative stress markers, eg, oxidized LDL, inflammatory markers (eg, pro-inflammatory interleukins), 8-OHdG, isopro It can be diagnosed by measuring stannes (eg F2-isoprostane, 8-iso-prostaplanin F2alpha), nitrotyrosine or N-carboxymethyl lysine (CML).

Endothelial dysfunction, which is clinically evaluated as impaired endothelium-dependent vasomotion (e.g., an imbalance between vasodilation and vasoconstriction), is a cell that fills the inner surface of blood vessels, arteries, and veins. Phosphorus endothelial cells are physiological disorders of endothelial cells that are the cells that fill the inner surfaces of blood vessels, arteries, and veins that prevent them from performing their normal biochemical functions. Normal endothelial cells are involved in mediating the process of coagulation, platelet adhesion, immune function, regulation of the volume and electrolyte content of intravascular and extravascular spaces. Endothelial dysfunction is associated with pro-inflammatory, pro-oxidative and pre-thrombotic changes within the arterial wall. Endothelial cell dysfunction is thought to be an important event in the development and progression of atherosclerosis and arterial stiffness, and occurs before clinically apparent vascular complications. Endothelial dysfunction is prognostic in detecting vascular disease and predicting adverse vascular events. Risk factors for atherosclerosis and vascular disease / event are associated with endothelial dysfunction. Endothelial cell damage also contributes to the development of kidney damage and / or chronic or progressive kidney damage, such as tubulointerstitial fibrosis, glomerulonephritis, micro- or macroalbuminuria, nephropathy and / or chronic kidney disease or kidney failure. There is evidence to support that oxidative stress not only contributes to endothelial dysfunction or damage, but also to vascular disease.

Type 2 diabetes mellitus is a common chronic and progressive disease resulting from complex pathophysiology, including dual endocrine effects of insulin resistance and impaired insulin secretion, a requirement required to maintain plasma glucose levels in the normal range Does not meet. This results in hyperglycemia and associated micro- and macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (eg, cardiovascular or cerebrovascular) complications. Vascular disease components play an important role in a wide range of diabetes-related disorders, but are not the only factors. The high frequency of complications leads to a significant reduction in life expectancy. Diabetes is the most frequent cause of adult-onset visual loss, renal failure and amputation in developed countries due to diabetes-induced complications in recent years, and is associated with a 2-5 fold increase in cardiovascular risk.

In a large randomized study, it has been established that intensive and strict blood sugar control during early (up to 5 years of newly diagnosed) stage diabetes has a permanent beneficial effect and reduces the risk of diabetes complications in both micro- and large vessels. However, many diabetic patients will still develop diabetes complications despite enhanced glycemic control.

Epidemiologic and prospective data support the long-term impact of metabolic control in early (newly diagnosed up to 5 years) on clinical outcomes. Hyperglycemia has a long-lasting deleterious effect in both type 1 and type 2 diabetes, and blood sugar control may not be sufficient to completely reduce complications unless it begins at a very early stage of the disease or is not intensively or strictly provided. It turned out to be. It has also been found that transient episodes of hyperglycemia (eg, hyperglycemia events) can induce molecular changes, which can persist, and are irreversible even after returning to normal blood sugar.

Collectively, these data suggest that metabolic memory is stored early during diabetes, and in certain diabetic conditions, oxidative and / or vascular stress may persist even after blood glucose normalization. This phenomenon in which the initial glycemic environment and / or even transient hyperglycemia is remembered as a clinical outcome in the target terminal organs (eg, blood vessels, retina, kidneys, heart, limbs) is called 'metabolism'.

Possible mechanisms for propagating this 'memory' include specific epigenetic changes, non-enzymatic glycosylation of cellular proteins and lipids (e.g., formation of final developmental glycosylation products), oxidatively modified atherosclerotic lipoproteins and / or excesses. Cellular Reactive Oxygen and Nitrogen Species (RONS), which are particularly derived from the level of glycosylated-mitochondrial proteins that probably act in concert with each other to maintain stress signaling.

Mitochondria are one of the main sources of reactive oxygen species (ROS) in cells. Mitochondrial dysfunction increases electron leakage and production of ROS from the mitochondrial respiratory chain (MRC). High levels of blood sugar and lipids impair the activity of the MRC complex enzyme. For example, the MRC enzyme NADPH oxidase produces superoxide from NADPH in cells. Increased NADPH oxidase activity can be detected in diabetic patients.

In addition, overproduction of free radicals, such as reactive oxygen species (ROS), for example, develops and / or maintains oxidative and vascular stress and metabolic memory after glucose normalization, and thus, for example, endothelial cell function. There is evidence that it contributes to a consistent link between hyperglycemia and cellular memory effects in disorders or other complications of diabetes.

Thus, even when normalizing glycemia, certain metabolic conditions (either chronic, early or transient episodes) induced or related to hyperglycemia in that long-term sustained activation of multiple pathways involved in the development of diabetes complications may still exist. Mainly associated with persistent (long-term) oxidative stress. Thus, one of the main findings during diabetes demonstrates that even in normal blood glucose, overproduction of free radicals can still be apparent regardless of the actual blood glucose level. For example, endothelial dysfunction (a marker that contributes to diabetic vascular complications) can persist even after normalizing glycemia. However, there is evidence that the combination of antioxidant therapy and glycemic normalization can almost prevent endothelial cell dysfunction.

Thus, for example, treatment of oxidative stress and / or vascular stress by surpassing blood sugar control, for example, by reducing cell-reactive species and / or glycation (e.g., by inhibiting the production of free oxygen and nitrogen radicals) Doing can advantageously modulate, reduce, block or protect the memory effects of hyperglycemia, preferably irrespective of glycemic status, and long-term diabetes, such as associated with or caused by oxidative stress, especially in patients in need thereof The risk of complications can be reduced, prevented, treated or delayed.

Treatment of type 2 diabetes typically begins with diet and exercise followed by oral anti-diabetic monotherapy, while conventional monotherapy can control blood glucose initially in some patients, but this is associated with high secondary failure rates. The limitations of single-agent therapy to maintain glycemic control can be overcome for a limited period in at least some patients by using multiple drugs in combination to achieve unsustainable blood sugar reduction during long-term therapy with a single agent. Available data support the conclusion that recent monotherapy in most Type 2 diabetic patients will fail and treatment with multiple drugs will be required. However, because type 2 diabetes is a progressive disease, it is very difficult to maintain a stable blood glucose level for a long period of time even for a patient who has an initial good response to a conventional combination therapy. Will need Although the current combination therapy has the potential to improve blood sugar control, it is not without limitation (especially with regard to long-term efficacy). In addition, conventional therapies may present an increased risk for side effects such as hypoglycemia or weight gain, which can compromise their efficacy and acceptability.

Thus, for a large number of patients, these current drug therapies cause gradual exacerbations in metabolic control despite treatment, and in particular fail to sufficiently control metabolic status over long periods of time, resulting in conventional oral or non-oral Despite anti-diabetic drugs, it is impossible to achieve and maintain glycemic control in advanced or late type 2 diabetes, including diabetes with improper glycemic control.

Thus, although intensive treatment of hyperglycemia may reduce the incidence of chronic damage, many Type 2 diabetic patients are adequately partly due to limitations in long-term efficacy, tolerability and discomfort of conventional antihyperglycemic therapy. Can not be cured

This high frequency of treatment failures results in a high rate of long-term hyperglycemic-related complications or chronic damage (micro- and macrovascular complications such as diabetic nephropathy, retinopathy or neuropathy, or brain- or cardiovascular complications) in type 2 diabetes patients. , For example, myocardial infarction, stroke or vascular mortality or morbidity).

Oral anti-diabetic drugs commonly used in therapy (eg, primary or secondary and / or single- or (initial or add-on) combination therapy) are metformin, sulfonylurea, and thiazoli Dindione, glinide and α-glycosidase inhibitors.

Non-oral (typically injected) anti-diabetic drugs commonly used in therapy (eg, primary or secondary and / or single- or (initial or additional combination therapy)) are GLP-1 or GLP- 1 analogue, and insulin or insulin analogues.

However, the use of such conventional antidiabetic or antihyperglycemic agents can be associated with various adverse effects. For example, metformin may be associated with lactic acidosis or gastrointestinal side effects; Sulfonylureas, glinides and insulin or insulin analogues may be associated with hypoglycemia and weight gain; Thiazolidinedione may be associated with edema, fracture, weight gain and heart failure / heart effects; Alpha-glucosidase blockers and GLP-1 or GLP-1 analogs may be associated with gastrointestinal adverse effects (e.g., indigestion, bloating or diarrhea, or nausea or vomiting) and most severely (rarely) pancreatitis

Therefore, there is a need in the art to provide an effective, safe, and tolerable anti-diabetic therapy.

In addition, within the treatment of type 2 diabetes, it is desired to effectively treat the condition, avoid complications inherent to the condition, and delay disease progression, for example, to achieve a long-lasting therapeutic benefit.

Moreover, anti-diabetic treatment not only prevents long-term complications often found in the stages of progression of diabetes, but also needs to be a therapeutic option in diabetic patients with or at risk of developing complications such as kidney failure.

It is also desired to provide prevention or reduction of risk for adverse effects associated with conventional antidiabetic therapies.

The enzyme DPP-4 (dipeptidyl peptidase IV), also known as CD26, is a serine protease known to cause cleavage of a dipeptide from the N-terminus of multiple proteins with proline or alanine residues at the N-terminus. . Because of these properties, DPP-4 inhibitors interfere with plasma levels of bioactive peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes mellitus.

For example, DPP-4 inhibitors and their use are described in International Patent Application Publication Nos. WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820 No. 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 2007/128721, WO 2007/128724, WO 2007/128761 or WO 2009/121945.

In monitoring the treatment of diabetes mellitus, the HbA1c value, which is the result of non-enzymatic glycosylation of the hemoglobin B chain, is of particular importance. HbA1c in the sense of "blood sugar memory" reflects the average blood glucose level from the previous 4 to 12 weeks, since its formation is essentially dependent on blood glucose levels and the lifespan of red blood cells. Diabetic patients with well-controlled HbA1c levels over a long period of time by more intensive diabetes treatment (ie, total hemoglobin <6.5% in the sample) are more significantly protected from diabetic microangiopathy. Treatment available for diabetes can provide diabetics with an average improvement of HbA1c levels of approximately 1.0-1.5%. This reduction in HbA1C levels is not sufficient to achieve a preferred target range of <7.0%, preferably <6.5%, more preferably <6% HbA1c in all diabetic patients.

Within the meaning of the present invention, improper or insufficient blood sugar control refers to a condition in which the patient exhibits an HbA1c value of at least 6.5%, especially at least 7.0%, even more preferably at least 7.5%, especially at least 8%. Aspects of patients with inappropriate or insufficient blood sugar control include, but are not limited to, patients with HbA1c values of 7.5 to 10% (or, in another embodiment, 7.5 to 11%). A special sub-modality of inadequately controlled patients refers to patients with poor blood sugar control, including but not limited to patients with HbA1c values> 9%.

Within blood sugar control, in addition to improving HbA1c levels, another recommended treatment goal for type 2 diabetes mellitus patients is to improve fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to normal or possibly nearly normal. will be. The recommended target target range for pre-meal (fasting) plasma glucose is 70-130 mg / dL (or 90-130 mg / dL) or <110 mg / dL, and the plasma sugar is <180 mg / dL or <140 mg / dL 2 hours after meals. .

In one embodiment, a diabetic patient can include patients (drug-naive patients) who have not been previously treated with anti-diabetic drugs within the meaning of the present invention. Thus, in one aspect, the therapy described herein can be used in naive patients. In another embodiment, the diabetic patient has advanced or late type 2 diabetes mellitus (including those who fail to treat antidiabetic therapy) within the meaning of the present invention, e.g., one, two as defined herein. Patients with improper glycemic control for dogs or more conventional oral and / or non-oral antidiabetic drugs, e.g. metformin, thiazolidinedione (especially pioglitazone), sulfonylurea, glinide, GLP-1 Or despite (single) therapy with GLP-1 analogs, insulin or insulin analogs, or α-glycosidase inhibitors or metformin / sulfonylurea, metformin / thiazolidinedione (especially pioglitazone), sulfonylurea / Patients with insufficient blood sugar control despite dual combination therapy with an α-glycosidase inhibitor, pioglitazone / sulfonylurea, metformin / insulin, pioglitazone / insulin or sulfonylurea / insulin may be included. Thus, in one embodiment, the therapy described herein undergoes therapy with, for example, conventional oral and / or non-oral antidiabetic single- or dual or triple combination drugs as mentioned herein. Can be used in one patient.

Additional aspects of diabetic patients are within the meaning of the present invention.

Patients with contraindications to metformin therapy, e.g. patients with one or more contraindications to metformin therapy according to the label, e.g.

Kidney disease, renal impairment or renal dysfunction (e.g. as noted by locally approved metformin product information),

Dehydration,

Unstable or acute congestive heart failure,

Acute or chronic metabolic acidosis and

Patients with at least one contraindication selected from hereditary galactose intolerance;

And

Patients with one or more unbearable side effects due to metformin, especially gastrointestinal side effects associated with metformin, for example,

nausea,

throw up,

diarrhea,

Intestinal gas and

Refers to patients not suitable for metformin therapy, including patients suffering from at least one gastrointestinal side effect selected from severe abdominal discomfort.

A further aspect of a diabetic patient who may receive the therapy of the present invention is due to reduced tolerability, intolerability or contraindications to diabetic patients, for example, metformin, for which normal metformin therapy is not suitable. ) May include, but is not limited to, diabetic patients requiring reduced doses of metformin therapy due to impaired / reduced kidney function (eg, including elderly patients such as> 60 to 65 years).

A further aspect of the diabetic patient is within the meaning of the present invention, e.g., increased serum creatinine levels (e.g., serum creatinine levels above the normal upper limit for age, e.g. ≥ 130 to 150 μmol / l. Or ≥ 1.5 mg / dl (≥ 136 μmol / l) for men, ≥ 1.4 mg / dl (≥ 124 μmol / l) for women) or abnormal creatinine clearance (eg, glomerular filtration rate (GFR) ≤ 30 to 60 ml / min) refers to patients with kidney disease, renal dysfunction or impaired or impaired renal function (including mild, moderate and severe renal impairment) as suggested by min).

In this context, for a more detailed example, mild renal impairment may include, for example, a creatinine clearance of 50 to 80 ml / min (approximately <1.7 mg / dL for men, <1.5 mg / dL for women, and serum creatine levels). (Corresponding to); Moderate renal impairment, for example, a creatinine clearance of 30-50 ml / min (approximately equivalent to serum creatinine levels of> 1.7 to ≤3.0 mg / dL for men and> 1.5 to ≤2.5 mg / dL for women) Can be suggested by; Severe renal impairment can be suggested, for example, by a creatinine clearance rate of <30 ml / min (approximately equivalent to serum creatinine levels of> 3.0 mg / dL for men and> 2.5 mg / dL for women). Patients with terminal renal disease require dialysis (eg, hemodialysis or peritoneal dialysis).

For another more detailed example, patients with renal disease, renal impairment or renal impairment include patients with chronic renal insufficiency or impairment, which are based on glomerular filtration rate (GFR, ml / min / 1.73 m 2), five diseases. Can be divided into stages: Stage 1 is characterized by normal GFR ≥ 90 + persistent albuminuria or known structural or genetic kidney disease; Stage 2 is characterized by a slight decrease in GFR (GFR 60-89) indicating mild renal impairment; Stage 3 is characterized by a moderate reduction in GFR (GFR 30-59) indicating moderate renal impairment; Stage 4 is characterized by a severe reduction in GFR (GFR 15-29) indicating severe renal impairment; Stage 5 is characterized by requiring GFR <15 or dialysis, which indicates chronic kidney failure (end stage renal disease, ESRD).

A further aspect of the diabetic patient is within the meaning of the present invention, for example, a type 2 diabetic patient with or at risk of developing micro- or macrovascular diabetes complications as described herein (e.g., as described below) Patients at risk.

Additional aspects of diabetic patients are within the meaning of the present invention and are at risk of developing or developing kidney complications such as diabetic nephropathy (including chronic and progressive kidney failure, albuminuria, proteinuria, fluid retention in the body (edema) and / or hypertension). This indicates a type 2 diabetes patient.

Additional aspects of diabetic patients who may receive the therapy of the invention may include, but are not limited to, type 2 diabetic patients with or at risk of developing retinal complications such as diabetic retinopathy.

A further aspect of a diabetic patient who may receive the therapy of the present invention is Type 2, which is at risk of developing or at risk of major vascular complications such as myocardial infarction, coronary artery disease, ischemic or hemorrhagic stroke and / or peripheral obstructive arterial disease. Diabetes patients.

Additional aspects of diabetic patients who may receive therapies of the present invention may include type 2 diabetic patients (eg, cardiovascular risk patients described herein) who have or are at risk of having a cardiovascular or cerebrovascular disease or event. However, it is not limited thereto.

A further aspect of a diabetic patient who can receive the therapy of the present invention is a diabetic patient with advanced and / or advanced diabetes (especially type 2 diabetes), e.g., an insulin treatment patient, a triple antidiabetic oral treatment patient , Patients with pre-existing cardiovascular and / or cerebrovascular events and / or patients with advanced disease duration (eg,> / = 5 to 10 years).

Additional aspects of diabetic patients who may receive the therapy of the present invention may include diabetic patients (especially type 2 diabetic patients) with one or more cardiovascular risk factors selected from A), B), C) and D). , But not limited to:

A) Previous or current vascular disease (e.g. myocardial infarction (e.g. asymptomatic or non-clinical), coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure ( For example, NYHA type I or type II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease),

B) vascular-related terminal-organ damage (eg nephropathy, retinopathy, neuropathy, kidney function impairment, chronic kidney disease and / or micro- or macroalbuminuria),

C) Old age (e.g. age> / = 60-70 years old) and

D)-advanced type 2 diabetes mellitus (eg,> 10 years duration),

Hypertension (e.g.,> 130 / 80mm Hg, or systolic blood pressure> 140mmHg or at least one hypotensive treatment),

-Habitual daily smoking,

Dyslipidemia (e.g. atherosclerotic dyslipidemia, postprandial hyperlipidemia or high levels of LDL cholesterol in the blood (e.g. LDL cholesterol> / = 130-135 mg / dL), low levels of HDL cholesterol (e.g. For example, <35 to 40 mg / dL in men or <45 to 50 mg / dL in women) and / or high levels of triglycerides (e.g.> 200 to 400 mg / dL), or at least one for lipid abnormalities In therapy),

-Obesity (eg, abdominal and / or visceral obesity, or body mass index> / = 45 kg / m2),

-Age> / = 40 years and </ = 80 years,

-Metabolic syndrome, hyperinsulinemia or insulin resistance, and

-One or more cardiovascular risk factors selected from hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the immediate family.

In certain embodiments, patients eligible for the treatment of the present invention may have or be at risk of one or more of the following diseases, disorders or conditions: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), fasting blood sugar Disorder (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia (e.g. atherosclerotic dyslipidemia) Hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypernephremia, postprandial hyperlipidemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), polycystic) Ovarian syndrome, hyperuricemia, metabolic syndrome, nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot ulcer , Atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral artery occlusive disease, cardiomyopathy (for example, including uremic cardiomyopathy), heart failure, heart hypertrophy, heart failure , Vascular restenosis, stroke, ischemic / reperfusion injury (kidney, heart, brain or liver), fibrosis (kidney, heart, brain or liver), vascular deformation (kidney, heart, brain or liver); Diabetes, especially type 2 diabetes mellitus, is preferred (eg, as underlying disease).

In a further aspect, a patient who is eligible for treatment of the present invention has diabetes, in particular type 2 diabetes mellitus, for example, has one or more other diseases, disorders or conditions, such as selected from those mentioned immediately above, or There may be risks.

Within the scope of the present invention, as defined herein, as well as certain DPP-4 inhibitors as defined herein in combination with one or more other therapeutic agents (optionally selected from those described herein), It has been found that pharmaceutical combinations, compositions or combinations according to the present invention of such DPP-4 inhibitors as such have the characteristics of making them suitable for the purposes of the present invention and / or meeting one or more of the above requirements.

Accordingly, the present invention relates to certain DPP-4 inhibitors, preferably linagliptin (BI 1356), as defined herein for use in the therapies described herein.

The invention also relates to certain DPP-4 inhibitors, preferably linagliptin (BI 1356), as defined herein in combination with metformin, for use in the therapies described herein.

The invention also relates to a specific DPP-4 inhibitor, preferably linagliptin (BI 1356), as defined herein in combination with pioglitazone, for use in the therapies described herein.

The invention also relates to a specific DPP-4 inhibitor, preferably linagliptin (BI 1356) as defined herein in combination with telmisartan, for use in the therapies described herein.

The present invention also relates to a pharmaceutical composition comprising a specific DPP-4 inhibitor as defined herein, preferably linagliptin (BI 1356), for use in the therapies described herein.

The present invention also relates to a pharmaceutical composition comprising a specific DPP-4 inhibitor as defined herein, preferably linagliptin (BI 1356) and metformin, for use in the therapies described herein.

The invention also relates to a pharmaceutical composition comprising a specific DPP-4 inhibitor as defined herein, preferably linagliptin (BI 1356) and pioglitazone, for use in the therapies described herein.

The present invention is also selected from certain DPP-4 inhibitors (especially BI 1356) and those mentioned herein, e.g., other anti-diabetic substances, blood glucose, for simultaneous, separate or continuous use in the therapy described herein. Active substances that lower levels, active substances that lower blood lipid levels, active substances that increase HDL levels in blood, active substances that lower blood pressure, active substances directed to the treatment of atherosclerosis or obesity, antiplatelets, anticoagulants, and vascular endothelial Protective agents, such as combinations, each comprising one or more other active substances selected from those described herein.

The present invention is also optionally used in combination with telmisartan for certain DPP-4 inhibitors (especially BI 1356) and metformin, sulfonylurea, nateglinide, repagli, for simultaneous, separate or continuous use, particularly in the treatment regimens described herein. In combination with one or more other antidiabetic agents selected from the group consisting of need, thiazolidinedione, PPAR-gamma-agonist, alpha-glucosidase inhibitor, insulin or insulin analogues, and GLP-1 or GLP-1 analogues. It is about.

The invention also provides metformin, sulfonylurea, nateglinide, lepaglinide, thiazolidinedione, PPAR-gamma-agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and GLP-1 or GLP-1 analogs An effective amount of one or more other anti-diabetic agents selected from the group consisting of an effective amount of a DPP-4 inhibitor as defined herein (especially BI 1356) and, optionally, a patient in need thereof (especially a human patient). Metabolic disorders, in particular type 2 diabetes mellitus and / or conditions related thereto (e.g., administering in combination (e.g., concurrent, separate or continuous) to a patient as described herein, including, for example, a group of at risk patients) For example, it relates to a method of treating and / or preventing diabetes complications.

The present invention also provides therapeutically effective amounts of linagliptin (BI 1356) and, optionally, one or more other therapeutic agents, e.g. metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma Patients in need of antidiabetics selected from the group consisting of agonists, alpha-glucosidase inhibitors, insulin or insulin analogues, and GLP-1 or GLP-1 analogues, and / or telmisartan (especially human patients), Therapies or methods of treatment described herein, e.g., metabolic diseases, in particular types, comprising administering to, for example, a patient as described herein (e.g., a patient at risk as described herein) 2 A method for treating and / or preventing diabetes mellitus and / or conditions related thereto (eg, diabetes complications).

The invention also provides a patient (especially a human patient) in need of a therapeutically effective amount of linagliptin (BI 1356), for example a patient as described herein, including a patient at risk as described herein Therapies or methods of treatment described herein, e.g., metabolism, comprising administering to a patient at or at risk of having or at risk of having a cardiovascular or cerebrovascular disease or event and / or a patient at risk of having kidney disease) It relates to a method of treating and / or preventing a disease, in particular type 2 diabetes mellitus and / or a condition associated therewith (eg, diabetes complications).

The invention also provides a patient in need of a therapeutically effective amount of linagliptin (BI 1356) and metformin (especially a human patient), e.g. a patient as described herein, including a patient at risk as described herein Therapies or methods of treatment described herein, e.g., metabolic diseases, especially type 2 diabetes mellitus and / or the like, comprising administering to (especially a patient with or at risk of having a cardiovascular or cerebrovascular disease or event) It relates to a method for treating and / or preventing a related condition (eg, diabetes complications).

The present invention is also described herein, including patients in need of a therapeutically effective amount of linagliptin (BI 1356) and telmisartan (especially human patients), e.g. patients at risk as described herein. Therapies or methods of treatment described herein, including, for example, administering to the same patient (especially a patient with or at risk of having or at risk of having a cardiovascular or cerebrovascular disease or event), e.g. It relates to a method of treating and / or preventing metabolic diseases, particularly type 2 diabetes mellitus and / or conditions associated therewith (eg, diabetes complications).

Examples of such metabolic disorders or disorders that may receive the treatment of the present invention, particularly in patients with or at risk of having cardiovascular and / or renal disease are type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, post-absorption hyperglycemia, latent autoimmune diabetes (LADA) in adults, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA, postprandial hyperlipidemia, Hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome and / or metabolic syndrome Does not.

The invention also relates to at least one of the following methods:

Administering a therapeutically effective amount of a specific DPP-4 inhibitor, optionally in combination with one or more other therapeutic agents as described herein,

In patients in need thereof (e.g., patients as described herein, especially type 2 diabetics),

Especially in patients with or at risk of having oxidative stress, vascular stress and / or endothelial dysfunction, or diseases or conditions related to or associated with, or

In patients with or at risk of having cardiovascular and / or renal disease (e.g., myocardial infarction, stroke or peripheral artery occlusive disease and / or diabetic nephropathy, micro- or macroalbuminuria, or acute or chronic kidney failure), or

In patients with one or more cardiovascular risk factors selected from A), B), C) and D):

A) Previous or current vascular disease (e.g. myocardial infarction (e.g. asymptomatic or non-clinical), coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure ( For example, NYHA type I or type II, e.g. left ventricular function <40%), or peripheral occlusive arterial disease),

B) vascular-related terminal-organ damage (eg nephropathy, retinopathy, neuropathy, kidney function impairment, chronic kidney disease and / or micro- or macroalbuminuria),

C) Old age (e.g. age> / = 60-70 years old) and

D)-advanced type 2 diabetes mellitus (eg,> 10 years duration),

Hypertension (e.g.,> 130/80 mm Hg, or systolic blood pressure> 140 mmHg or at least one hypotensive treatment),

-Habitual daily smoking,

Dyslipidemia (e.g. atherosclerotic dyslipidemia, postprandial hyperlipidemia, or high levels of LDL cholesterol in the blood (e.g. LDL cholesterol> / = 130 to 135 mg / dL), low levels of HDL cholesterol (e.g. For example, <35 to 40 mg / dL in men or <45 to 50 mg / dL in women) and / or high levels of triglycerides (e.g.> 200 to 400 mg / dL), or at least one for lipid abnormalities In therapy),

-Obesity (eg, abdominal and / or visceral obesity, or body mass index> / = 45kg / m2),

-Age> / = 40 years and </ = 80 years,

-Metabolic syndrome, hyperinsulinemia or insulin resistance, and

One or more cardiovascular risk factors selected from hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or a family history of vascular disease or cardiomyopathy in the immediate family;

-Metabolic disorders or diseases, such as type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), fasting blood sugar disorder (IFG), high blood sugar, high blood sugar after eating, high blood sugar after absorption, latent autoimmune diabetes in adults ( LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFA, postprandial hyperlipidemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver A method of preventing, slowing, delaying, or treating diseases (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome and / or metabolic syndrome;

-A method of improving and / or maintaining glycemic control and / or reducing fasting plasma sugar, post-prandial plasma sugar, post-absorption plasma sugar and / or glycated hemoglobin HbA1c;

-A method of preventing, slowing, delaying or reversing the progression of pre-diabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus;

Complications of diabetes mellitus, e.g. micro- and macrovascular diseases, e.g. nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment, cardiovascular Or cerebrovascular disease, tissue ischemia, diabetic foot ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (e.g., urine) Toxic cardiomyopathy), heart failure, heart rate disorders, preventing vascular restenosis and / or stroke, reducing the risk of the disorders, slowing the progression of the disorders, delaying, or treating the disorders;

-A method of reducing body weight and / or body fat, preventing weight and / or body fat gain, or promoting weight and / or body fat loss;

-Prevents, slows, delays, treats and / or improves, preserves and / or restores pancreatic beta cell function and / or pancreatic insulin secretion To stimulate and / or recover or protect the function of the body;

-A method for preventing, slowing, delaying, or treating the non-alcoholic fatty liver disease (NAFLD), including liver steatosis, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis (E.g., preventing liver fatosis, (liver) inflammation and / or abnormal accumulation of liver fat, slowing the progression of the diseases, delaying the diseases, attenuating, treating, or reversing the diseases) Prescribing method);

-A method of preventing, delaying, or delaying the progression of type 2 diabetes that fails conventional antidiabetic monotherapy or combination therapy;

-A method of achieving a dose reduction of conventional anti-diabetic agents required for a suitable therapeutic effect;

-A method of reducing the risk of adverse effects (eg hypoglycemia and / or weight gain) associated with conventional antidiabetic agents; And / or

-A method of maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance.

Another aspect of the invention becomes apparent to those skilled in the art from the above and below descriptions (including examples and claims).

Aspects of the invention, in particular pharmaceutical compounds, compositions, combinations, methods and uses, represent DPP-4 inhibitors as defined above and below.

DPP-4 inhibitors include, but are not limited to, DPP-4 inhibitors mentioned above and below, preferably orally active DPP-4 inhibitors within the meaning of the present invention.

An aspect of the invention is characterized in that the DPP-4 inhibitor is administered to the following patients at the same dose level as those with normal renal function, in a type 2 diabetes patient further suffering from renal disease, renal impairment or renal impairment. It relates to DPP-4 inhibitors for use in treating and / or preventing metabolic diseases (especially type 2 diabetes mellitus), and thus, for example, the DPP-4 inhibitors require down-dose control of renal impairment. Do not.

For example, the DPP-4 inhibitor according to the present invention (especially those suitable for patients with renal impairment) may be an oral DPP-4 inhibitor, the active metabolites thereof preferably being relatively broad (eg For example, about> 100 times) have a therapeutic window and / or are eliminated primarily through liver metabolism or bile excretion, particularly (preferably without placing additional strain on the kidneys).

In a more detailed example, the DPP-4 inhibitor according to the invention (especially those suitable for patients with impaired renal function) can be DPP-4 inhibitors administered orally, which are relatively broad (e.g.,> 100 Pear) has a treatment window (preferably a safety profile comparable to placebo) and / or meets one or more of the following pharmacokinetic properties (preferably at its therapeutic oral dose level):

-DPP-4 inhibitors are excreted substantially or predominantly through the liver (e.g.> 80% or even> 90% of the oral dose administered), and kidney excretion is not the primary route of elimination and is only a secondary route of elimination. Is (eg <10%, preferably <7%) of the administered oral dose as determined by removal of the radiolabeled carbon ( ¹⁴ C) substance oral dose;

DPP-4 inhibitors are primarily parent drug excreted unchanged and / or (e.g., the average radioactivity released in urine and feces after oral administration of radiolabeled carbon ( ¹⁴ C) material> 70%, or> 80%, or preferably 90%), which is not significantly removed through metabolism or only removed in trace amounts (eg <30%, or <20%, or preferably 10%);

-The (main) metabolite (s) of the DPP-4 inhibitor is pharmacologically inactive. For example, the major metabolite is not bound to the target enzyme DPP-4, and optionally, it is removed faster than the parent compound (e.g., the final half-life of the metabolite ≤ 20h, or preferably ≤ about 16h, For example, 15.9h).

In one embodiment, the (main) metabolite in plasma (which may be pharmacologically inactive) of a DPP-4 inhibitor with a 3-amino-piperidin-1-yl substituent is 3-amino-piperidine- The amino group of the 1-day moiety is replaced with a hydroxyl group to form a 3-hydroxy-piperidin-1-yl moiety (e.g., 3- (S) formed by reversal of the chiral center coordination. ) -Hydroxy-piperidin-1-yl moiety).

Additional properties of the DPP-4 inhibitor according to the present invention may be one or more of the following: rapid arrival of steady state (e.g., normal between 2-5 days after treatment with therapeutic oral dose levels) State plasma levels (> 90% of steady state plasma concentrations are reached), low accumulation (e.g., average accumulation ratio R _{A, AUC} ≤ 1.4 at therapeutic oral dose levels) and / or preferably 1 day Maintain a long-lasting effect on DPP-4 inhibition in single use (e.g., almost complete (> 90%) DPP-4 inhibition at therapeutic oral dose level, 24h intervals after ingestion of therapeutic oral drug dose once daily) Over 80% inhibition), significant reduction in post-prandial blood glucose excursion by ≥ 80% at the therapeutic dose level (already on day 1 of therapy), and steady state below 1% of the dose administered The cumulative amount of unchanged parent compound excreted in urine on the first day, increasing by about 3 to 6% or less.

Thus, for example, a DPP-4 inhibitor according to the present invention, the DPP-4 inhibitor mainly has a non-renal excretory pathway, i.e., the DPP-4 inhibitor (e.g., radiolabeled carbon ( ¹⁴ C) not excreted to a considerable extent through the kidneys (measured by removal of the oral dose of the substance) or only excreted in trace amounts (e.g. <10% of the oral dose administered, preferably <10% of the oral treatment dose, preferably < 7%, for example, about 5%).

In addition, DPP-4 inhibitors according to the present invention are substantially or predominantly through the liver or stool in which the DPP-4 inhibitor is measured (e.g., by removal of radioactively labeled carbon ( ¹⁴ C) substance oral dose). It can be characterized as excreted.

In addition, the DPP-4 inhibitor according to the present invention,

The DPP-4 inhibitor is excreted primarily unchanged as a parent drug (e.g.,> 70%, or> 80% of excreted radioactivity in urine and feces after oral administration of radiolabeled carbon ( ¹⁴ C) material , Or preferably 90%),

The DPP-4 inhibitor is not removed to a significant extent through metabolism or only in trace amounts, and / or

The main metabolite of the DPP-4 inhibitor may be characterized as being pharmacologically inactive or having a relatively wide therapeutic window.

In addition, the DPP-4 inhibitor according to the present invention,

The DPP-4 inhibitor does not significantly impair glomerular and / or tubular function in type 2 diabetes patients with chronic kidney failure (e.g., mild, moderate or severe renal impairment or terminal renal disease),

The DPP-4 inhibitor trough level in plasma of a type 2 diabetic patient with mild or moderate renal impairment is comparable to that in a patient with normal renal function, and / or

The DPP-4 inhibitor does not require dose control in patients with type 2 diabetes who have renal impairment (e.g., regardless of the stage of mild, moderate or severe renal impairment or end stage renal disease, preferably renal impairment). It can be characterized as not.

In addition, the DPP-4 inhibitor according to the present invention,

The DPP-4 inhibitor provides a minimum effective dose at a dose that results in> 50% inhibition of DPP-4 activity at the lowest level (> 24h after the last dose) in> 80% of patients, and / or

The DPP-4 inhibitor can be characterized by providing the full therapeutic dose at a dose that results in> 80% inhibition of DPP-4 activity at the lowest level (> 24h after the last dose) in> 80% of patients.

In addition, the DPP-4 inhibitor according to the present invention is diagnosed with kidney disorder and / or is a type 2 diabetic patient at risk of developing kidney complications, for example, diabetic nephropathy (chronic and progressive kidney failure, albuminuria, proteinuria , Characterized by being suitable for use in patients with or at risk of having body fluid residual (including edema) and / or hypertension.

In a first aspect (Aspect A), a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of Formula I or Formula II or Formula III or Formula IV or a pharmaceutically acceptable salt thereof.

[Formula I]

[Formula II]

[Formula III]

[Formula IV]

In the above formulas I to IV,

R1 is ([1,5] naphthyridin-2-yl) methyl, (quinazolin-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl , 2-cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridin-2-yl) methyl, (4-methyl-pyrimidin-2-yl) methyl or (4,6-dimethyl-pyrimidin-2-yl) methyl, R2 is 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino Or (2- (S) -amino-propyl) -methylamino.

For the first aspect (Aspect A), preferred DPP-4 inhibitors are any or all of the following compounds and pharmaceutically acceptable salts thereof:

1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidine- 1-day) -xanthine (compared to International Patent Application Publication No. WO 2004/018468, Example 2 (142)):

1-[([1,5] naphthyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidine -1-day) -xanthine (compared with International Patent Application Publication No. WO 2004/018468, Example 2 (252)):

1-[(quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidin-1-yl) -Xanthine (compared with International Patent Application Publication No. WO 2004/018468, Example 2 (80)):

2-((R) -3-amino-piperidin-1-yl) -3- (but-2-ynyl) -5- (4-methyl-quinazolin-2-ylmethyl) -3,5 -Dihydro-imidazo [4,5-d] pyridazine-4-one (International Patent Application Publication No. WO 2004/050658, compared to Example 136):

1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[(2-amino-2-methyl-propyl)- Methylamino] -xanthine (International Patent Application Publication No. WO 2006/029769, compared to Example 2 (1)):

1-[(3-cyano-quinolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidine- 1-day) -Xanthine (International Patent Application Publication No. WO 2005/085246, compared to Example 1 (30)):

1- (2-cyano-benzyl) -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidin-1-yl) -xanthine (Compared with International Patent Application Publication No. WO 2005/085246, Example 1 (39)):

1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-[( S )-(2-amino-propyl)- Methylamino] -xanthine (International Patent Application Publication No. WO 2006/029769, compared to Example 2 (4)):

1-[(3-cyano-pyridin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidine- 1-day) -xanthine (International Patent Application Publication No. WO 2005/085246, compared to Example 1 (52)):

1-[(4-methyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidine- 1-day) -Xanthine (International Patent Application Publication No. WO 2005/085246, compared to Example 1 (81)):

1-[(4,6-dimethyl-pyrimidin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperid Dean-1-yl) -xanthine (compared to International Patent Application Publication No. WO 2005/085246, Example 1 (82)):

1-[(quinoxalin-6-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8-(( R ) -3-amino-piperidin-1-yl) -Xanthine (compared with International Patent Application Publication No. WO 2005/085246, Example 1 (83)):

These DPP-4 inhibitors have excellent efficacy and long-lasting effects and favorable pharmacological properties, receptor selectivity and favorable adverse effect profiles, or when combined with other pharmaceutically active substances, bring unexpected therapeutic benefits or improvements. Therefore, it is distinct from structurally similar DPP-4 inhibitors. Their production is described in the mentioned publication.

Among the DPP-4 inhibitors described above in aspect A of the present invention, more preferred DPP-4 inhibitors are 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1 -Yl) -8- (3- ( R ) -amino-piperidin-1-yl) -xanthine, especially its free base (also known as linagliptin or BI 1356).

A particularly preferred DPP-4 inhibitor within the present invention is linagliptin. The term “linagliptin” as used herein refers to linagliptin, or a pharmaceutically acceptable salt thereof, including hydrates and solvates thereof and crystalline forms thereof, preferably linagliptin is 1-[(4- Methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- ( R ) -amino-piperidin-1-yl) -xanthine Indicates. The crystal form is described in International Patent Application Publication No. WO 2007/128721. Methods for the manufacture of linagliptin are described, for example, in International Patent Application Publication Nos. WO 2004/018468 and WO 2006/048427. Linagliptin combines excellent efficacy and long-lasting effects with favorable pharmacological properties, receptor selectivity and favorable adverse effect profiles, or brings unexpected therapeutic benefits or improvements in monotherapy or dual or triple combination therapy. , Distinct from structurally similar DPP-4 inhibitors.

For the avoidance of doubt, the description of each of the above and below documents cited above in connection with the DPP-4 inhibitors mentioned is specifically incorporated herein by reference in its entirety.

It is to be understood that within the present invention, the combination, composition or combination use according to the present invention can contemplate simultaneous, sequential or separate administration of the active ingredient or components.

In this context, “combination” or “combination” is within the meaning of the present invention in fixed and non-fixed (eg free) forms (including kits) and, for example, components or components (ingredient). ), Such as simultaneous, sequential or separate use.

 The combination administration of the present invention, for example, by administering the active ingredients or active ingredients as one single formulation or dosage forms or simultaneously as two separate dosage forms or dosage forms, the active ingredients or active ingredients It can be performed by administering them together. Alternatively, the administration may be performed by sequentially administering the active ingredients or active ingredients, for example, by sequentially administering the active ingredients or active ingredients in two separate formulations or dosage forms. Can be.

For the combination therapy of the invention, the active ingredients or components are administered separately (which means that they are formulated separately) or formulated together (which means that they are formulated in the same formulation or in the same dosage form). can do. Thus, administration of one element of the combination of the present invention may occur prior to, concurrent with, or after administration of the other elements of the combination.

Unless otherwise noted, combination therapy may refer to primary, secondary or tertiary therapy, or initial or additional combination therapy or alternative therapy.

For aspect A , methods for synthesizing DPP-4 inhibitors according to aspect A of the present invention are known to those skilled in the art. Advantageously, DPP-4 inhibitors according to aspect A of the present invention can be prepared using synthetic methods as described in the literature. Thus, for example, purine derivatives of formula (I) are described in international patent applications WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427 Can be obtained as described, the contents of which are incorporated herein. Purine derivatives of formula II can be obtained, for example, as described in International Patent Application Publication Nos. WO 2004/050658 or WO 2005/110999, the contents of which are incorporated herein. Purine derivatives of formulas III and IV can be obtained, for example, as described in International Patent Application Publication Nos. WO 2006/068163, WO 2007/071738 or WO 2008/017670, the description of which It is cited herein. The preparation of DPP-4 inhibitors specifically specified herein is described in the publications mentioned in this regard. Polymorphic crystal modifications and formulations of certain DPP-4 inhibitors are described in International Patent Application Publication Nos. WO 2007/128721 and WO 2007/128724, respectively, the contents of which are incorporated herein in its entirety. Formulations of certain DPP-4 inhibitors with metformin or other combination partners are described in International Patent Application Publication No. WO 2009/121945, the contents of which are incorporated herein in its entirety.

Typical dose content of the dual fixed combination (tablet) of linagliptin / methformin IR (immediate release) is 2.5 / 500mg, 2.5 / 850mg and 2.5 / 1000mg, which is administered 1 to 3 times a day, especially twice a day Can be.

Typical dose content of the dual fixed combination (tablet) of linagliptin / methformin XR (extended release) is 5 / 500mg, 5 / 1000mg and 5 / 1500mg (one tablet each), or 2.5 / 500mg, 2.5 / 750mg and 2.5 / 1000 mg (two tablets each), which can be administered 1 to 2 times a day, especially once a day, preferably taken with meals in the evening.

The present invention also relates to (additional or initial) combination therapy with metformin (e.g., a total daily amount of 500 to 2000 mg of metformin hydrochloride, e.g. 500 mg, 850 mg or 1000 mg once or twice a day). DPP-4 inhibitors as defined herein for use are provided.

For pharmaceutical application in constant temperature vertebrates, especially humans, the compounds of the present invention are typically in doses of 0.001 to 100 mg / kg body weight, preferably 0.01 to 15 mg / kg or 0.1 to 15 mg / kg, in each case It is used 1 to 4 times a day. For this purpose, the compounds, optionally with other active substances, together with one or more conventional inert carriers and / or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, poly Vinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances, such as cured fat or Along with suitable mixtures of these, it can be incorporated into conventional galenic preparations such as plain tablets or coated tablets, capsules, powders, suspensions or suppositories.

Accordingly, pharmaceutical compositions according to the invention comprising a DPP-4 inhibitor as defined herein are prepared by a skilled person using pharmaceutically acceptable formulation excipients described in the art and suitable for the desired route of administration. do. Examples of such excipients include, but are not limited to, diluents, binders, carriers, fillers, lubricants, flow improvers, crystallization retarders, disintegrants, solubilizers, colorants, pH adjusters, surfactants and emulsifiers.

Oral formulations or dosage forms of the DPP-4 inhibitors of the invention can be prepared according to known techniques.

Examples of suitable diluents for compounds according to aspect A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.

Examples of suitable lubricants for the compounds according to aspect A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.

Examples of suitable binders for the compounds according to aspect A include copovidone (copolymer of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (Povidone), pregelatinized starch or low-substituted hydroxypropylcellulose (L-HPC).

Examples of disintegrants suitable for the compounds according to aspect A include corn starch or crospovidone.

A method suitable for preparing a pharmaceutical formulation of a DPP-4 inhibitor according to aspect A of the present invention is

Direct purification of the active substance in powder mixtures with suitable tabletting excipients;

Granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tableting and film coating; or

· Packing of powder mixtures or granules into capsules.

Suitable granulation methods

Wet granulation in a powerful mixer followed by fluid bed drying;

One-pot granulation;

Fluid bed granulation; or

Dry granulation (eg by roller compaction) with suitable excipients and subsequent tableting or packing into capsules.

Exemplary compositions of DPP-4 inhibitors (e.g., tablet cores) according to aspect A of the present invention include first diluent mannitol, pregelatinized starch as second diluent with additional binder properties, binder copovidone, disintegrant Corn starch, and magnesium stearate as a lubricant; Here, copovidone and / or corn starch may be optional.

Tablets of the DPP-4 inhibitor according to aspect A of the invention may be film coated, preferably the film coating is hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide (e.g. For example, red and / or yellow).

Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, a product for distribution includes one or more containers containing one or more pharmaceutical compositions in a suitable form. Tablets are typically packed in suitable primary packages for easy handling, distribution and storage and to ensure proper stability of the composition upon extended contact with the environment during storage. The primary container for purification may be a bottle or blister pack.

For example, a bottle suitable for a pharmaceutical composition or combination (tablet) comprising a DPP-4 inhibitor according to aspect A of the present invention is a glass or polymer (preferably polypropylene (PP) or high density polyethylene (HD-PE) )), And can be sealed with a screw cap. The screw cap may be provided with a child protective safety stopper (eg, a press-and-twist closure) to prevent or restrict children from accessing the contents. If necessary (e.g., in a high humidity area), the shelf life of the packaged composition can be extended by further use of a desiccant (e.g., bentonite clay, molecular sieve, or preferably silica gel). have.

For example, blister packs suitable for pharmaceutical compositions or combinations (tablets) comprising a DPP-4 inhibitor according to aspect A of the present invention include an upper foil (which can be ruptured by tablets) and a bottom portion (tablet pockets). Containing). The upper foil has a metal foil coated with a heat-sealed polymer layer on the inner surface (sealing surface), in particular aluminum or aluminum alloy foil (eg, 20 μm to 45 μm, preferably 20 μm to 25 μm) ). The bottom part is a multi-layered polymer foil (e.g. poly (vinyl chloride) (PVDC) coated with poly (vinylidene chloride) (PVDC); or PVC foil laminated with poly (chlorotrifluoroethylene) (PCTFE)) Or multi-layer polymer-metal-polymer foils (eg cold-formable laminated PVC / aluminum / polyamide compositions).

Additional overlaps or pouches made of multi-layer polymer-metal-polymer foils (e.g. layered polyethylene / aluminum / polyester compositions) can be used in blister packs, especially to ensure long shelf life under hot and humid climatic conditions. Can be. Additional desiccants (eg bentonite clay, molecular sieves, or preferably silica gel) in such pouch packages can further extend shelf life under these harsh conditions.

The product may further include a label or package insert, which may contain information on indications, use, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products. Indicates guidelines that are typically included in commercial packages. In one aspect, a label or package insert indicates that the composition can be used for any purpose described herein.

For the first aspect (Aspect A ), the typically required dosage of the DPP-4 inhibitor mentioned herein in Aspect A is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, when administered intravenously, orally administered When possible, it is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, and in each case, 1 to 4 times a day. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino -The dose of piperidin-1-yl) -xanthine is 0.5 mg to 10 mg per patient per day when administered orally, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

The dosage form prepared with the pharmaceutical composition comprising the DPP-4 inhibitor mentioned herein in aspect A contains the active ingredient in a dosage range of 0.1 to 100 mg. Thus, for example, 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino -Piperidin-1-yl) -xanthine has specific oral dose contents of 0.5mg, 1mg, 2.5mg, 5mg and 10mg.

A particular embodiment of the DPP-4 inhibitor of the invention is at a low dose level, for example <100 mg or <70 mg per patient per day, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably Is divided into oral dose levels of 1 mg to 10 mg, especially 1 mg to 5 mg (more particularly 5 mg) (if necessary, divided into 1 to 4 single doses, in particular 1 or 2 single doses, which may be the same size, preferential) Orally administered once or twice daily (preferably once a day) and advantageously administered orally with or without food at any time of day. 4 indicates inhibitor. Thus, for example, the daily oral dose of 5 mg BI 1356 is administered once daily (i.e., 5 mg BI 1356 once a day) or twice daily administered regimen (i.e., 2.5 mg BI 1356 twice a day). As such, it can be served at any time of the day with or without food.

The dosage of the active ingredient in the combinations and compositions according to the invention may vary, but the amount of active ingredient may be such that a suitable dosage form is obtained. Accordingly, the selected dosage and selected dosage form will depend on the desired therapeutic effect, route of administration and duration of treatment. Suitable dosage ranges for the combination are from a maximum tolerated dose to a lower dose, for example 1/10 of the maximum tolerated dose for a single formulation.

A particularly preferred DPP-4 inhibitor highlighted within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl) methyl] -3-methyl-7- (2-butyn-1-yl) -8 -(3- (R) -amino-piperidin-1-yl) -xanthine (also known as BI 1356 or linagliptin). BI 1356 shows high efficacy, 24h duration of action and a wide treatment window. In type 2 diabetes patients receiving multiple oral doses of BI 1356 once daily, 1, 2.5, 5 or 10 mg for 12 days, BI 1356 has an advantageous pharmacodynamic and pharmacokinetic profile (see, eg, Table 1 below). And steady-state rapid arrival (e.g., steady-state plasma levels (> 90% of pre-dose plasma concentration on Day 13) reached between days 2 and 5 of treatment in all dose groups), less accumulation (e.g. For example, at a dose of 1 mg or more, the average accumulation ratio R _{A, AUC} ≤ 1.4) and maintaining a long-lasting effect on DPP-4 inhibition (e.g., almost complete (> 90%) DPP-4 inhibition at 5 mg and 10 mg dose levels) , I.e. 92.3% and 97.3% inhibition, respectively, at steady state, and> 80% inhibition over 24h intervals after drug intake) as well as a significant increase in blood glucose elevation after 2h from dose ≥ 2.5mg to ≥ 80% (already on day 1) It shows a decrease and shows that the cumulative amount of the unchanged parent compound excreted in urine on day 1 is less than 1% of the dose administered and increases to about 3-6% or less on day 12 (kidney clearance CL _{R , ss} is the oral dose administered). About 14 to about 70 mL / min for the dose, e.g., kidney clearance for the 5 mg dose is about 70 ml / min). In people with type 2 diabetes, BI 1356 shows placebo-like safety and tolerability. At a low dose of about ≧ 5 mg, BI 1356 acts as a true once daily oral drug with DPP-4 inhibition lasting a total of 24 h. At the therapeutic oral dose level, BI 1356 is excreted primarily through the liver and only in trace amounts through the kidneys (about <7% of the oral dose administered). BI 1356 is excreted primarily unchanged through bile. The fraction of BI 1356 removed through the kidneys only slightly increases over time with increasing dose, so it is unlikely that the dose of BI 1356 needs to be changed based on the patient's renal function. Non-kidney clearance of BI 1356 with low accumulation potential and broad safety margin can be quite beneficial in a patient population with a high morbidity of renal failure and diabetic nephropathy.

Because different metabolic dysfunctions often occur simultaneously, it is very often indicated to combine a number of different active principles with each other. Thus, depending on the dysfunction diagnosed, the DPP-4 inhibitor may lower the level of active blood, or other anti-diabetic substances, particularly blood glucose levels or lipids, or increase HDL levels in the blood for each disorder. , If lowered blood pressure or combined with one or more active substances selected from active substances indicated for the treatment of atherosclerosis or obesity, improved therapeutic performance can be obtained.

The DPP-4 inhibitors mentioned above (except for use in monotherapy) can also be used in combination with other active substances where improved treatment results can be obtained. Such combination treatment can be provided as a free combination of substances or in the form of a fixed combination, for example, as a tablet or capsule. The pharmaceutical formulation of the combination partner required for this is commercially available as a pharmaceutical composition, or can be formulated by a skilled person using conventional methods. The commercially available active substances as pharmaceutical compositions can be found in numerous parts of the prior art, such as the annual drug list, the "Rote Liste®" of the Federal Association of the Pharmaceutical Industry, or the "Physicians' Desk Reference". It is listed in the annually updated compilation of manufacturer's information for known prescription drugs.

Examples of antidiabetic combination partners include metformin; Sulfonylureas, such as glibenclamide, tolbutamide, glimepiride, glipizid, glycidone, glibornuride and gliclazide; Nateglinide; Repaglinide; Mitiglinide; Thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gamma modulators, such as metaglidases; PPAR-gamma agonists such as riboglitazone, mitoglitazone, INT-131, and balaglitazone; PPAR-gamma antagonist; PPAR-gamma / alpha modulators such as tesaglitazar, muraglitazar, alleglitazar, indeglitazar and KRP297; PPAR-gamma / alpha / delta modulators such as lobeglitazone; AMPK-activators such as AICAR; Acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; Diacylglycerol-acetyltransferase (DGAT) inhibitors; Pancreatic beta cell GCRP agonists, eg SMT3-receptor-agonists and GPR119, eg GPR119 agonists 5-ethyl-2- {4- [4- (4-tetrazol-1-yl-phenoxymethyl) -Thiazol-2-yl] -piperidin-1-yl} -pyrimidine or 5- [1- (3-isopropyl- [1,2,4] oxadiazol-5-yl) -piperidine Din-4-ylmethoxy] -2- (4-methanesulfonyl-phenyl) -pyridine; 11β-HSD-inhibitor; FGF19 agonists or analogs; Alpha-glucosidase blockers such as acarbose, voglibose and miglitol; Alpha2-antagonists; Insulin and insulin analogues, such as human insulin, insulin lispro, insulin glucinline, r-DNA-insulin aspart, NPH insulin, insulin detamir, insulin desludec, insulin tregofil, insulin zinc suspension and insulin glargine ; Gastric juice inhibitory peptide (GIP); Amylin and amylin analogues (eg, pramlintide or davalintide); GLP-1 and GLP-1 analogs, e.g., exendin-4, e.g., exenatide, exenatide LAR, liraglutide, tasphoglutide, lixisenatide (AVE-0010), LY-2428757 (PEGylated version of GLP-1), dulaglutide (LY-2189265), semaglutide or albiglutide; SGLT2-inhibitors such as dapagliflozin, sergliflozin (KGT-1251), atigliflozin, canagliflozin, ifragliflozin or topogliflozin; Inhibitors of protein tyrosine-phosphatase (eg, trodusquemine); Inhibitors of glucose-6-phosphatase; Fructose-1,6-bisphosphatase modulator; Glycogen phosphorylase modulators; Glucagon receptor antagonists; Phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; Pyruvate dehydrogenase kinase (PDK) inhibitors; Inhibitors of tyrosine-kinase (50 mg to 600 mg), such as PDGF-receptor-kinase (European Patent Publication No. EP-A-564409, International Patent Application Publication No. WO 98/35958, US Patent Publication No. US 5093330) , International Patent Application Publication Nos. WO 2004/005281 and WO 2006/041976) or inhibitors of serine / threonine kinase; Glucokinase / regulatory protein modulators, including glucokinase activators; Glycogen synthase kinase inhibitors; Inhibitors of SH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, such as high-dose salicylate; JNK1 inhibitors; Protein kinase C-Theta inhibitors; Beta 3 agonists, such as ritovegron, YM 178, solaraberon, talibegron, N-5984, GRC-1087, rapaveron, FMP825; Aldoserreductase inhibitors such as AS 3201, zerenastat, fidarastat, epalestat, ranirestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitor; GPR40 modulator, for example [(3S) -6-({2 ', 6'-dimethyl-4'-[3- (methylsulfonyl) propoxy] biphenyl-3-yl} methoxy) -2 , 3-dihydro-1-benzofuran-3-yl] acetic acid; SCD-1 inhibitors; CCR-2 antagonist; Dopamine receptor agonists (bromocriptine mesylate [Cycloset]); 4- (3- (2,6-dimethylbenzyloxy) phenyl) -4-oxobutanoic acid; Sirtuin stimulants; And other DPP IV inhibitors.

Metformin varies from about 500 mg to 2000 mg to 2500 mg per day using various dosage regimens, typically about 100 mg to 500 mg or 200 mg to 850 mg (1 to 3 times a day), or once or twice a day. Provided in a dose, or delayed-release metformin is provided at a dose of about 100 mg to 1000 mg once or twice a day or preferably about 500 mg to 1000 mg or about 500 mg to 2000 mg once a day. The specific dose content can be metformin hydrochloride 250, 500, 625, 750, 850 and 1000 mg.

For children ages 10 to 16, the recommended starting dose of metformin is 500 mg given once a day. If these doses do not produce sufficient results, the dose can be increased to 500 mg twice daily. Further increases can be made up to a maximum dose of 2000 mg per day in increments of 500 mg weekly, and are provided in divided doses (eg, two or three divided doses). Metformin can be administered with food to reduce nausea.

The dose of pioglitazone is usually about 1 to 10 mg, 15 mg, 30 mg or 45 mg once a day.

Rosiglitazone is usually given in doses of 4 to 8 mg once a day (or twice in divided portions) (typical dose contents are 2, 4 and 8 mg).

Glibenclamide (Glyburide) is usually given once daily (or twice in divided) at a dose of 2.5 to 5 to 20 mg (typical dose content is 1.25, 2.5 and 5 mg), or finely divided gliben. Clamide is given in doses of 0.75 to 3 to 12 mg once daily (or twice in divided doses) (typical dose contents are 1.5, 3, 4.5 and 6 mg).

Glypizid is typically given once daily (or twice in divided doses of 40 mg or less) in doses of 2.5 to 10 to 20 mg (typical dose content is 5 and 10 mg), or extended-release glycbenclamide 1 per day It is available in doses of 5 to 10 mg (20 mg or less) of the ash (typical dose contents are 2.5, 5 and 10 mg).

Glymepiride is usually given in doses of 1 to 2 to 4 mg (up to 8 mg) once a day (typical dose contents are 1, 2 and 4 mg).

The dual combination of glibenclamide / methformin is usually provided in a dose of 1.25 / 250 mg once a day to 10/1000 mg twice a day. (Typical dose contents are 1.25 / 250, 2.5 / 500 and 5/500 mg).

The dual combination of Glipizide / Metformin is typically provided in doses of 2.5 / 250 to 10/1000 mg twice daily (typical dose contents are 2.5 / 250, 2.5 / 500 and 5/500 mg).

The dual combination of glimepiride / methformin is usually given at a dose of 1/250 to 4/1000 mg twice daily.

The dual combination of rosiglitazone / glycimide is usually provided in a dose of 4/1 mg once or twice daily to 4/2 mg twice daily (typical dose content is 4/1, 4/2, 4/4, 8/2 and 8 / 4mg).

The dual combination of pioglitazone / glymepiride is usually provided in doses of 30/2 to 30/4 mg once daily (typical dose contents are 30/4 and 45/4 mg).

The dual combination of rosiglitazone / methformin is typically provided in doses of 1/500 to 4/1000 mg twice daily (typical dose content is 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg) to be).

The dual combination of pioglitazone / methformin is typically provided in doses of 15/500 mg once or twice a day to 15/850 mg three times a day (typical dose contents are 15/500 and 15/850 mg).

The non-sulfonylurea insulin secretagogue nateglinide is usually provided with a dose of 60 to 120 mg with meals (360 mg / day or less, typical dose content is 60 and 120 mg); Repaglinide is usually given at a dose of 0.5 to 4 mg with meals (up to 16 mg / day, typical dose content is 0.5, 1 and 2 mg). The dual combination of repaglinide / methformin is available in dose contents of 1 / 500mg and 2 / 850mg.

Acarbose is typically provided at a dose of 25 to 100 mg with meals. Miglitol is usually provided in a dose of 25 to 100 mg with meals.

Examples of combination partners that lower blood lipid levels include HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; Fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etophylline clofibrate; Nicotinic acid and its derivatives, for example acipimox; PPAR-alpha agonists; PPAR-delta agonists such as {4-[(R) -2-ethoxy-3- (4-trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-phenoxy} -acetic acid ; Inhibitors of acyl-coenzyme A: cholesterol acyltransferase (ACAT; EC 2.3.1.26), for example avacimib; Cholesterol reuptake inhibitors such as ezetimibe; Substances that bind to bile acids, such as cholestyramine, cholestipol, and colesevelam; Inhibitors of bile acid transport; HDL modulating active substances, such as D4F, reversing D4F, LXR modulating active substances and FXR modulating active substances; CETP inhibitors, such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 (anacetrapib) from international patent application publication WO 2007/005572 or evacetrapib; LDL receptor modulators; MTP inhibitors (eg lomitapide); And ApoB100 antisense RNA.

The dosage of atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once a day.

Examples of combination partners that lower blood pressure include beta-blockers, such as atenolol, bisoprolol, cellifrolol, metoprolol, nebivolol, and carvedilol; Diuretics, such as hydrochlorothiazide, chlorthalidone, zipamide, furosemide, pyrethanid, torasemide, spironolactone, eplerenone, amiloride and triamterene; Calcium channel blockers such as amlodipine, nifedipine, nirendipine, nisoldipine, nicardipine, pelodipine, laccidipine, lercanifidine, manidipine, isradipine, nilbodydipine, verapanil, gallopamil and Diltiazem; ACE inhibitors, such as ramipril, lisinopril, silazapril, quinapril, captopril, enalapril, benazapril, perindopril, posinopril and trandolapril; As well as angiotensin II receptor blockers (ARBs), such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan.

The dosage of telmisartan is usually 20 mg to 320 mg or 40 mg to 160 mg per day.

Examples of combination partners that increase HDL levels in the blood include cholesteryl ester transfer protein (CETP) inhibitors; Inhibitors of endothelial lipase; Modulators of ABC1; LXR alpha antagonist; LXR beta agonist; PPAR-delta agonists; LXR alpha / beta modulator, and a substance that increases the expression and / or plasma concentration of apolipoprotein A-I.

Examples of combination partners for treating obesity include sibutramine; Tetrahydrolipstatin (orlistat); Allyzyme (cetilistat); Dexfenfluramine; Axocaine; Cannabinoid receptor 1 antagonists, for example CB1 antagonist limonobant; MCH-1 receptor antagonist; MC4 receptor agonists; NPY5 as well as NPY2 antagonists (eg, beneferit); Beta3-AR agonists, such as SB-418790 and AD-9677; 5HT2c receptor agonists, such as APD 356 (lorcasein); Myostatin inhibitors; Acrp30 and adiponectin; Steroyl CoA desaturase (SCD1) inhibitors; Fatty acid synthase (FAS) inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36; Orexin receptor antagonist; And thesofensin; In addition, the dual combinations are bupropion / naltrexone, bupropion / zonisamide, topiramate / pentermine and pramlinted / metrelebtin.

Examples of combination partners for treating atherosclerosis include phospholipase A2 inhibitors; Inhibitors of tyrosine-kinase (50 mg to 600 mg), such as PDGF-receptor-kinase (European Patent Publication No. EP-A-564409, International Patent Application Publication No. WO 98/35958, US Patent Publication No. US 5093330) , International Patent Application Publication Nos. WO 2004/005281 and WO 2006/041976); oxLDL antibody and oxLDL vaccine; apoA-1 Milano; ASA; And VCAM-1 inhibitors.

Further, within the meaning of the present invention, optionally, the DPP-4 inhibitor may be used in combination with one or more other antioxidants, anti-inflammatory agents and / or vascular endothelial protective agents.

Examples of antioxidant combination partners are selenium, betaine, vitamin C, vitamin E and beta carotene.

An example of an anti-inflammatory combination partner is pentoxifylline; Another example of an anti-inflammatory combination partner is a PDE-4 inhibitor such as tetomylast, roflumilast or 3- [7-ethyl-2- (methoxymethyl) -4- (5-methyl-3- Pyridinyl) pyrrolo [1,2-b] pyridazin-3-yl] propanoic acid (or US Patent Publication No. US 7153854, International Patent Application Publication No. WO 2004/063197, US Patent Publication No. US 7459451 and And / or other chemical species described in International Patent Application Publication No. WO 2006/004188).

Further examples of anti-inflammatory partner drugs are caspase inhibitors such as (3S) -5-fluoro-3-({[(5R) -5-isopropyl-3- (1-isoquinolinyl)) -4,5-dihydro-5-isoxazolyl] carbonyl} amino-4-oxopentanoic acid (or other chemistry described in International Patent Application Publication Nos. WO 2005/021516 and / or WO 2006/090997 Species).

Examples of vascular endothelial protective agents are PDE-5 inhibitors such as sildenafil, vardenafil or tadalafil; Another example of a vascular endothelial protective agent is a nitrogen monoxide donor or stimulant (eg L-arginine or tetrahydrobiopterin).

In addition, within the meaning of the present invention, optionally, the DPP-4 inhibitor is one or more antiplatelet agents, such as (low-dose) aspirin (acetylsalicylic acid), selective COX-2 or non-selective COX-1 / COX. In combination with a -2 inhibitor, or an ADP receptor inhibitor, e.g. thienopyridine (e.g. clopidogrel or prasulgren), elinogrel or ticagrelor, or a thrombin receptor antagonist, e.g. boracaxar can do.

Also within the meaning of the present invention, optionally, the DPP-4 inhibitor is one or more anticoagulants, e.g., heparin, warfarin, or direct thrombin inhibitors (e.g. dabigatran), or Faktor Xa inhibitors (e.g. For example, it can be used in combination with rivaroxaban or apixaban or edoxaban or otamic saban).

Still also, within the meaning of the present invention, optionally, the DPP-4 inhibitor may be combined with one or more agents for the treatment of heart failure.

Examples of combination partners for treating heart failure include beta-blockers, such as atenolol, bisoprolol, cellifrolol, metoprolol and nebivolol; Diuretics, such as hydrochlorothiazide, chlorthalidone, zipamide, furosemide, pyrethanid, torasemide, spironolactone, eplerenone, amiloride and triamterene; ACE inhibitors, such as ramipril, lisinopril, silazapril, quinapril, captopril, enalapril, benazapril, perindopril, posinopril and trandolapril; Angiotensin II receptor blockers (ARBs), for example telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan; Heart glycosides, such as digoxin and digitoxin; Combined alpha / beta-blockers such as carvedilol; Vasodilators; Antiarrhythmic agents; Or B-type sodium diuretic peptide (BNP) and BNP-derived peptide and BNP-fusion product.

Moreover, within the meaning of the present invention, optionally, the DPP-4 inhibitor is one or more CCK-2 or gastrin agonists, such as proton pump inhibitors (including reversible inhibitors of the above H + / K + -ATPase as well as irreversible inhibitors), For example, it can be used in combination with omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.

The invention is not to be limited in scope by the specific embodiments described herein. Various modifications of the invention other than those described herein can be apparent to those skilled in the art from the description of the invention. It is intended that such modifications fall within the scope of the appended claims.

All patent applications cited herein are incorporated by reference in their entirety.

Further aspects, features and advantages of the present invention can be apparent from the following examples. The following examples serve to illustrate, for example, the principles of the invention without limiting it.

The present invention uses DPP-4 inhibitors to treat and / or prevent oxidative stress, vascular stress and / or endothelial dysfunction, or diabetes or non-diabetic patients, including groups of patients at risk for cardiovascular disease and / or kidney disease. -Provides a method of treatment and / or prevention of diabetic patients.

1 shows the effect of linagliptin on Zymosan A (ZymA) initiated ROS in human PMN (LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophil, BI1356 = linagliptin, Nebi = nebivolol).
2 shows the effect of linagliptin on adhesion of human leukocytes (PMN) to human endothelial cells after LPS stimulation (Turks and CF-DA staining, BI1356 = linagliptin).
FIG. 3 shows the effect of linagliptin on adhesion of LPS (50 μg / ml) -induced neutrophils to EA.hy cells measured by oxidation of amplex red.
FIG. 4A shows the effect of gliptin on oxidative bursts in isolated human neutrophils upon stimulation of LPS or zymosan A measured by luminol / horseradish peroxidase (HRP) enhanced chemiluminescence (LPS). = Lipid polysaccharide, PMN = polymorphonuclear neutrophil, LG = BI1356 = linagliptin, AG = allogliptin, VG = vildagliptin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nebivolol).
Figure 4b shows the effect of gliptin on oxidative explosion in isolated human monocytes / lymphocytes upon stimulation of LPS or Zymosan A as measured by luminol / horseradish peroxidase (HRP) enhanced chemiluminescence (LPS = lipids). Polysaccharides, WBC = leukocytes, LG = BI1356 = linagliptin, AG = allogliptin, VG = vildagliptin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nebivolol).
5 is a table comparing glyptins for anti-oxidation effects directly in vitro.
FIG. 6 shows the effect of linagliptin on LPS-activated neutrophil driven oxidation of L-012-scavenging of peroxidase-induced ROS and inhibition of NADPH oxidase activity. Oxidative explosion in isolated human PMN (5x105 cells / ml) was quantified using increasing LPS and linagliptin concentrations by augmented chemiluminescence method using luminol analog L-012 (100 μM). (PBS = phosphate buffered saline, LPS = lipid polysaccharide, PMN = polymorphonuclear neutrophil, LG = BI1356 = linagliptin).
7A and 7B show the effect of linagliptin on whole blood oxidative explosion / oxidative stress in nitroglycerin-induced nitrate resistance (LPS = lipid polysaccharide, EtOH Ctr = ethanol control, GTN sc = glyceryl trinitrate) Subcutaneous, BI1356 = linagliptin).
8A and 8B show the improvement of endothelial dysfunction by linagliptin in rats treated with GTN or LPS (pretreatment with linagliptin (3-10 mg / kg, of endothelial dysfunction caused by nitrate or LPS). Judo (3 days).
8A shows the effect of GTN induced endothelial dysfunction and linagliptin treatment on endothelium dependent relaxation (EtOH Ctr = ethanol control, GTN sc = glyceryl trinitrate-subcutaneous, BI1356 = Lina Gliptin).
8B shows the effect of LPS (10 mg / kg / d ip) in vivo treatment and linagliptin treatment on endothelial-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = control).
9A and 9B show the direct vasodilating effect of gliptin. Gliptin-induced vasodilation is achieved by isometric tension recording in isolated aortic ring fragments and relaxation in response to increasing cumulative concentrations (1 nM to 32 μM) of linagliptin, sitagliptin or saxagliptin. It is measured (Fig. 9A). In another test set, aortic relaxation in response to increasing cumulative concentrations (1 nM to 32 or 100 μM) of linagliptin, allogliptin or vildagliptin is tested (FIG. 9B). Data are mean ± SEM of 12 (FIG. 9A) or 4 (FIG. 9B) aortic rings from a total of 10 rats. ^* , p <0.05 vs. DMSO (solvent control); ^# , p <0.05 vs. Theta- / Vildagliptin and ^§ , p <0.05 vs. Saxa- / Allogliptin.
FIG. 10 shows kidney function based on detected blood glucose after treatment with linagliptin, telmisartan or combinations versus placebo in STZ treated animals:
1) Non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14)
2) diabetic eNOS ko mice treated with sham, placebo (natrosol) (n = 17)
3) Diabetic eNOS ko mice treated with telmisartan (po 1 mg / kg) (n = 17)
4) Diabetic eNOS ko mice treated with linagliptin (po 3mg / kg) (n = 14)
5) Diabetic eNOS ko mice treated with telmisartan (1 mg / kg) + linagliptin (3 mg / kg) (n = 12).
11 shows the albumin / creatinine ratio of non-diabetic animals to diabetic animals:
1) Non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14)
2) Diabetic eNOS ko mice treated with siamese, placebo (natrosol) (n = 17)
3) Diabetic eNOS ko mice treated with telmisartan (po 1 mg / kg) (n = 17)
4) Diabetic eNOS ko mice treated with linagliptin (po 3mg / kg) (n = 14)
5) Diabetic eNOS ko mice treated with telmisartan (1 mg / kg) + linagliptin (3 mg / kg) (n = 12).
12 is a combination of telmisartan (Telmi) and linagliptin (BI 1356) for blood pressure and telmisartan alone treatment (Telmi solo) or linagliptin in blood pressure in a hypertensive induced cardiac hypertrophy model causing heart failure. The results of a rat study showing the effectiveness of the monotherapy (BI 1356 solo) are shown. In FIG. 12, between time points 3 and 6, the first line from top represents placebo 2K1C (highest RR contraction), the second line from top represents linagliptin, the middle line represents telmisartan, and the second from bottom The line represents the placebo sham, and the first line from the bottom represents telmisartan + linagliptin (lowest RR contraction).
13 is a table showing the results of a study in a rat model of chronic renal dysfunction showing the effect of linagliptin on markers of cardiac fibrosis and left ventricular dysfunction in heart tissue (TGF-β = transforming growth factor beta , TIMP = tissue inhibitor of metalloproteinase, Col1α = collagen type 1 alpha, Col3α = collagen type 3 alpha, BNP = B-type sodium diuretic peptide).
FIG. 14 shows the results of studies in diabetic eNOS knockout C57BL / 6J mice as a refractory diabetic nephropathy model for ARB treatment showing the effect of linagliptin and telmisartan on albuminuria.

Example

Antioxidant effect:

Linagliptin's anti-inflammatory and vasodilation potential

The direct antioxidant effects of gliptin (linagliptin, alogliptin, vildagliptin, saxagliptin, sitagliptin) are xanthine oxidase, peroxynitrite (real and Sin-1 derived) or hydrogen peroxide / It is evaluated by interfering with the formation of superoxide from peroxidase mediated 1-electron-oxidation. This oxidation is detected by fluorescence, chemiluminescence and nitration of phenol (traced by HPLC). Glyphtin's indirect antioxidant effect is in human leukocytes (PMN) isolated by interfering with oxidative detonation (NADPH oxidase activation) induced by the phorbol ester PDBu, endotoxin LPS and zymosan A and the chemotactic peptide fMLP. Measure.

The direct vasodilating effect of gliptin is measured by isometric tension technique in isolated aortic ring fragments. The indirect antioxidant effect of linagliptin also measures nitroglycerin by measuring endothelial function (acetylcholine-dependent relaxation of phenylephrine pre-shrinked aortic vascular fragments), smooth muscle function (nitroglycerin-dependent relaxation) by isometric tension recording. -Tested in a rat model of induced nitrate resistance and linagliptin treatment (3-10 mg / kg / d by a special diet for 7 days). Reactive oxygen and nitrogen species (RONS) formation is also measured in isolated cardiac mitochondria, and LPS or PDBu-initiated oxidative explosions are measured in whole blood. In addition, the anti-inflammatory potential of linagliptin is tested in an experimental model of LPS (for 10 mg / kg i.p. 24 h) -induced septic shock in Wistar rats. The effect of sepsis and linagliptin cotherapy (3-10 mg / kg / d by a special diet for 7 days) is assessed by isometric tension recording, vascular, cardiac and blood RONS formation and protein expression is Western Evaluate by blotting.

result:

(See FIGS. 1 to 6)

Direct antioxidant properties:

All glitins show only the lowest direct antioxidant performance. A minor (not significant) inhibition of superoxide formation was observed for vildagliptin and linagliptin in response to peroxynitrite formation / -mediated nitrification. All gliptins except saxagliptin exhibit significant interference with 1-electron-oxidation by the hydrogen peroxide / peroxidase system, and linagliptin is the most potent compound.

Indirect antioxidant properties in isolated human neutrophils:

Linagliptin exhibits the best inhibition of oxidative explosion in isolated human white blood cells in response to NADPH oxidase activation by LPS and Zymosan A. Using L-012 augmented chemiluminescence, LPS (0.5, 5 and 50 μg / ml) increases PMN induced RONS signal in a concentration-dependent manner, and linagliptin inhibits the signal concentration-dependently. .

In experiments using luminol / peroxidase-enhanced chemiluminescence, linagliptin is much more effective at inhibiting LPS or zymonic acid A-initiated oxidative explosion in isolated PMN than other glitins. In these tests, linagliptin is as effective as nebivolol. The efficacy of inhibiting LPS-dependent RONS formation is somewhat more pronounced than the inhibitory effect on Zymosan A-initiated RONS. All of these measurements support the better antioxidant effect of linagliptin in isolated neutrophils compared to other gliptins.

Inhibition of adhesion of activated neutrophils to endothelial cells:

By studying the adhesion of LPS-stimulated human neutrophils to cultured endothelial cells (the number of attached PMNs correlates with PDBu-initiated oxidative explosion as measured by Amplex Red / Peroxidase Fluorescence), Lina Gliptin inhibits leukocyte adhesion to endothelial cells in the presence of LPS.

Treatment of vascular dysfunction and / or oxidative stress:

Effect of oral linagliptin treatment on vascular dysfunction and oxidative stress in nitrate-resistant rats:

In an isometric tension study in an organ bath, nitroglycerin and LPS treatment has been shown to induce marked endothelial dysfunction and nitrate resistance. Endothelial dysfunction caused by both factors is significantly improved by linagliptin therapy (FIGS. 8A and 8B), while nitrate resistance is unchanged. Nitroglycerin treatment results in increased cardiac mitochondrial ROS formation and whole blood LPS / zymosan A-initiated oxidative explosion. All these adverse effects are improved by linagliptin treatment (FIG. 7). None of the nitroglycerin and linagliptin treatments affected the body weight of the animals, while blood sugar levels increased slightly in the nitroglycerin group normalized by linagliptin treatment.

In summary, linagliptin in vivo treatment improves nitroglycerin-induced endothelial dysfunction and shows a minor improvement in ROS formation in cardiac mitochondria isolated from nitrate-resistant rats and oxidative explosion in whole blood.

Effect of linagliptin treatment on vascular dysfunction and oxidative stress in rats of sepsis:

Very similar protective effects against linagliptin are observed in experimental models of septic shock. Vascular function (Ach-, GTN-, and diethylamine NONOate-dependent relaxation) is greatly impaired by LPS and is almost normalized by linagliptin therapy. Mitochondrial and whole blood (LPS, PDBu-stimulated) RONS production is dramatically increased by LPS and improved by linagliptin treatment. Vascular oxidative stress (as measured by DHE-dependent fluorescent microtopography) and markers of vascular inflammation (VCAM-1, Cox-2 and NOS-2) are dramatically increased by treatment with LPS, linagliptin It is significantly improved by therapy. Similar results are observed for aortic protein tyrosine nitration and malondialdehyde content (both markers for oxidative stress) as well as aortic NADPH oxidase subunit expression (Nox1 and Nox2). As proof of this concept, DPP-4 activity and GLP-1 levels are confirmed from each animal, demonstrating strong inhibition of DPP-4 and an approximately 10-fold increase in plasma GLP-1 levels.

The direct vasodilating effects of gliptin:

In the isometric tension record, it was found that some glitins had a direct vasodilating effect in a concentration range of 10 to 100 μM. While linagliptin is the most potent compound and immediately following allogliptin and vildagliptin, sitagliptin and saxagliptin are less effective in inducing vasodilation than the solvent alone control (DMSO) (Figures 9a and See 9b).

These observations support the multifaceted antioxidant and anti-inflammatory properties of linagliptin, which is not shared (or shared to a fine extent) with other gliptins. Moreover, linagliptin reduces leukocyte adhesion to endothelial cells due to the presence of LPS and improves nitroglycerin- and inflammation-induced endothelial dysfunction and oxidative stress. This may contribute to the improvement of linagliptin's improved endothelial function and cardioprotective action. Thus, there is evidence that linagliptin provides an antioxidant effect that has a beneficial effect on cardiovascular disease comparable to diabetes complications with high levels of morbidity and mortality.

Treatment of diabetic nephropathy and albuminuria :

Endothelial damage is characteristic of type 2 diabetes and contributes to the development of end-stage renal disease. In addition, vascular endothelial NO synthase (eNOS) activity is altered in T2D, and the genetic abnormality in each gene (NOS3) is associated with the development of advanced diabetic nephropathy (DN) in patients with type 1 and type 2 diabetes. do. It has recently been reported that the use of low dose STZ to induce T2D in this genetic phenotype (eNOS-/-) is a valid experimental model for DN (see Brosius et al, JASN 2009).

Eight weeks old eNOS-/-mice are diabetic by intraperitoneal injection of streptozotocin (100 mg / kg per day for 2 consecutive days). The onset of diabetes (defined as blood sugar> 250 mg / dl) is confirmed one week after streptozotocin injection. Insulin is not given because it can prevent the development of diabetic nephropathy. Mice are treated for 4 weeks as follows:

1) Non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14)

2) Diabetic eNOS ko mice treated with siamese, placebo (natrosol) (n = 17)

3) Diabetic eNOS ko mice treated with telmisartan (p.o. 1 mg / kg) (n = 17)

4) Diabetic eNOS ko mice treated with linagliptin inhibitor (p.o. 3 mg / kg) (n = 14)

5) Diabetic eNOS ko mice treated with telmisartan (1 mg / kg) + linagliptin (3 mg / kg) (n = 12).

Check kidney function (s-creatinine, albuminuria) and blood sugar levels.

Significant differences in blood glucose after treatment with linagliptin, telmisartan or combinations compared to placebo were not found in animals treated with STZ (see FIG. 10).

Although no effect on blood glucose was detected, albumin / creatinine ratios are significantly reduced in the group receiving linagliptin + telmisartan (middle bar in FIG. 11, number 5). Each single treatment also lowered the albumin / creatinine ratio, but did not reach significance. In addition, the albumin / creatinine ratio of non-diabetic animals is significantly reduced compared to diabetic animals (see FIG. 11). These effects support the use of linagliptin and telmisartan in the treatment and / or prevention of kidney protection and diabetic nephropathy and albuminuria. The combination of linagliptin and telmisartan provides a new therapeutic approach for patients with or at risk of diabetic nephropathy and albuminuria.

Treatment of congestive heart failure and cardiac hypertrophy:

Applicants have assumed that glucose / energy supply is particularly important for a failing heart characterized by hypertrophy of the heart. Inadequate energy supply is considered as one of the most important steps leading to heart failure from decompensated left ventricular hypertrophy to decompensated left ventricular hypertrophy. A typical model of hypertension-induced left ventricular hypertrophy that eventually leads to prolonged left ventricular dysfunction and pathological transformation is the two-kidney-one clip renal vascular hypertension model (2K1C model).

Animals are treated for 3 months with the following regimen:

1.Telmisartan (10mg / kg KG) in 2K1C-rat, drinking water (n = 14)

2. 2K1C-rat, linagliptin (BI1356) in meals (89 ppm, corresponding to 3-10 mg / kg oral gavage) (n = 15)

3. 2K1C-rat, telmisartan (10 mg / kg) + linagliptin (BI1356) (89 ppm) in meals (n = 15)

4. 2K1C-rat, placebo (n = 17)

5. Sham-rat, placebo (n = 11)

Non-invasive systolic blood pressure is measured in all groups at time points (1. before treatment; 2. after 1 week; 3. after 4 weeks; 4. after 6 weeks; 5. after 12 weeks; and 6. for each compound 6 weeks after treatment with).

Prior to treatment, only the Siamese treated animals were significantly different from all other groups. From 1 week after treatment until the end of the study, the combination of telmisartan and telmisartan with linagliptin is always significant compared to vehicle treated animals. The combination of telmisartan and linagliptin reaches the level of placebo-treated siamese animals and shows an additive effect compared to telmisartan alone treatment (see Figure 12).

These effects support the use of linagliptin and telmisartan in the treatment and / or prevention of cardiac hypertrophy and / or congestive heart failure. The combination of linagliptin and telmisartan provides a new therapeutic approach for patients with or at risk of having cardiac hypertrophy and / or congestive heart failure.

Treatment of urinary cardiomyopathy:

Urinary cardiomyopathy also contributes significantly to morbidity and mortality in patients with chronic kidney disease, a frequent complication of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can improve heart function, and GLP-1 is primarily destroyed by dipeptidyl peptidase-4 (DPP-4). Linagliptin is the only DPP-4 inhibitor that can be used clinically at all stages of renal dysfunction without dose adjustment (eg, in patients with type 2 diabetes and diabetic nephropathy).

Examine linagliptin in a rat model of chronic kidney failure (5/6 nephrectomy [5 / 6N]):

Eight weeks after 5 / 6N or sham surgery, rats were orally treated with 3.3 mg / kg linagliptin or vehicle for 4 days, followed by plasma for quantitation of DPP-4 activity and GLP-1 levels. Sample for 72 hours. At the end of the study, heart tissue is taken for mRNA analysis.

5 / 6N is a significant (p <0.001) decrease in GFR measured by creatinine clearance (sham: 2510 ± 210 mU24 h; 5 / 6N: 1665 ± 104.3 mU24 h) and increased cystatin C level (sham: 700 ± 35.7 ng / mL; 5 / 6N: 1434 ± 77.6 ng / mL). DPP-4 activity is significantly reduced at all time points with no difference between Siamese or 5 / 6N animals. In contrast, active GLP-1 levels were at the maximum plasma concentration (C _max ; 5 / 6N: 6.36 ± 2.58 pg / mL vs sham: 3.91 ± 1.86 pg / mL; p <0.001) and AUC _(0-72h) (5 / 6N: 201 pg · h / mL vs sham: 114 pg · h / mL; significantly increased in 5 / 6N animals as measured by p <0.001). Cardiac fibrosis markers (pro-fibrotic factors), such as TGF-β, tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and collagen 1α1 and 3α1 as well as markers of left ventricular dysfunction , For example, the mRNA levels of brain sodium diuretic peptide (BNP) are all significantly increased at 5 / 6N compared to Siamese animals, resulting in reduced or even normalization by linagliptin treatment (all p <0.05, FIG. 13). Reference).

Linagliptin increases the AUC of GLP-1 by approximately 2 times in a rat model of renal failure, and BNP, a marker of left ventricular dysfunction and a marker of cardiac fibrosis (TGF-β, TIMP-1, Col 1α1) in the heart of a uremic rat And Col 3α1). These effects support the use of linagliptin in the treatment and / or prevention of urinary toxic myocardial cardiomyopathy. Linagliptin provides a new therapeutic approach for patients with uremic cardiomyopathy.

Effect on infarct size and heart function after myocardial ischemia / reperfusion:

The purpose of this study is, for example, the cardiac effect of the xanthine-based DPP-4 inhibitors of the invention (especially myocardial ischemia / reperfusion, cardiac, with conditions including stromal cell-induced factor-1 alpha (SDF-1α)) To assess the effect on function or infarct size).

Male Wistar rats are divided into three groups: Siamese, ischemia / reperfusion (I / R) and I / R + DPP-4 inhibitors of the invention; N = 10-12 per group. DPP-4 inhibitors are given once daily, starting on the 2nd day before I / R. The left anterior descending coronary artery is ligated for 30 minutes. Echocardiography is performed after 5 days, and cardiac catheterization is performed after 7 days. DPP-4 inhibitors have an absolute infarct size (-27.8%; p <0.05), the proportion of infarct tissue compared to the total risk site (-18.5%; p <0.05) and the extent of myocardial fibrosis (-31.6%; p < 0.05) significantly. DPP-4 inhibitors significantly increase the accumulation of stem / progenitor cells as characterized by CD34-, CXCR4- and C-kit-expression in the infarcted myocardium and cardio immune response to active SDF-1α. Left ventricular ejection counts are similar in all MI groups after 7 days, but DPP-4 inhibition reduces infarct size at the infarct site by blocking degeneration of SDF-1α, reduces fibrotic remodelling, and stem cell density. Increases.

The xanthine-based DPP-4 inhibitor of the present invention may reduce infarct size after myocardial infarction. The mechanism of action may include reduced degradation of SDF-1α followed by increased supplementation of circulating CXCR-4 ⁺ stem cells and / or incretin receptor dependent pathways.

These data increase stem cell replenishment, improve tissue recovery, activate myocardial regeneration, reduce infarct size, and reduce fibrotic deformation in the treatment or prevention of myocardial ischemia / reperfusion and / or in cardiac-protection. Enhances the usefulness of the xanthine-based DPP-4 inhibitors of the invention to reduce and / or increase the density of stem cells in the infarcted heart region.

Based on the fact that infarct size is a predictor of future events (including mortality), the xanthine-based DPP-4 inhibitors of the present invention help improve cardiac (constriction) function, cardiac contractility and / or mortality after myocardial ischemia / reperfusion. I guess it can be more useful.

Myocardial ischemia / Reperfusion  For infarct size and cardiac function Linagliptin  effect:

Materials and Methods: Male Wistar rats are divided into 3 groups: Siamese, I / R and I / R + linagliptin (n = 16-18 per group). Linagliptin is given once a day (3mg / kg) starting from the 30th day before I / R. I / R is induced by ligation of the left anterior descending coronary artery for 30 minutes, echocardiography is performed after 58 days, and cardiac catheterization is performed after 60 days.

Linagliptin significantly improves the absolute infarct size (-18%; p <0.05) as well as the proportion of infarct tissue (-21%; p <0.001) compared to the total risk site in this ischemic reperfusion injury (I / R) model. Decreases. In addition, glucagon-like peptide-1 (GLP-1) levels increased 18-fold (p <0.0001), and DPP-4 activity decreased by 78% (p <0.0001). Left ventricular left end diastolic and systolic blood pressure as well as cardiac ultrasound parameters are similar between groups, and the isovolume contractile index (dP / dT _min ) is significantly improved from -4771 ± 79 mmHg / s to -4957 ± 73 mmHg / s or left ventricle The maximum speed of the pressure drop is improved. These data further support the cardioprotective function of linagliptin in acute myocardial infarction.

Treatment of ARB-resistant diabetic nephropathy:

In patients who do not respond sufficiently to angiotensin receptor blockers (ARBs), there is the greatest need for improved treatment of diabetic nephropathy. This study investigates the effects of linagliptin alone and linagliptin in combination with ARB telmisartan on the progression of diabetic nephropathy in a novel model of diabetic eNOS knockout mice that closely resembles human pathology.

65 male eNOS knockout C57BL / 6J mice were given intraperitoneally high-dose streptozotocin and then divided into 4 groups: telmisartan (1 mg / kg), linagliptin (3 mg / kg), linagliptin + Telmisartan (3 + 1 mg / kg), and vehicle. Fourteen mice are used as a non-diabetic control. After 12 weeks, urine and blood are collected and blood pressure is measured.

Glucose concentration increases and is similar in all diabetic groups. Telmisartan alone reduced blood pressure slightly to 5.9 mmHg compared to the diabetic control group (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; n = 14 each; p = 0.071), and any other treatment reached significance Did not. Combination treatment significantly reduced albuminuria (e.g., urinary albumin excretion and / or albumin / creatinine ratio per 24h) compared to diabetic controls (71.7 ± 15.3 μg / 24h vs 170.8 ± 34.2 μg / 24h; n = 12-13; p = 0.017), the effect of treatment alone with telmisartan (97.8 ± 26.4 μg / 24h; n = 14) or linagliptin (120.8 ± 37.7 μg / 24h; n = 11) was statistically significant. Does not (see Figure 14). Linagliptin alone and in combination significantly lowers plasma osteopontin levels compared to telmisartan alone, where values are similar to diabetic controls. Plasma TNF-α concentrations are significantly lower in all treatment groups than in the vehicle group. Plasma neutrophil gelatinase-related lipocalin (NGAL) levels increase significantly after treatment with telmisartan compared to non-treated diabetic mice, and this effect is prevented by treatment with linagliptin.

In addition, linagliptin in combination with linagliptin alone and telmisartan was found in the kidney measured by histological score (2.1 +/- 0.0 vs 2.4 +/- 0.0; p <0.05) compared to the diabetic control group. While significantly reducing glomerulosclerosis, the reduction achieved by telmisartan alone is not significantly different. In conclusion, linagliptin significantly reduces urinary albumin excretion in diabetic eNOS knockout mice that are refractory to ARB (eg, in a blood pressure-independent manner). This effect can support the use of linagliptin in the treatment and / or prevention of renal protection and ARB-resistant diabetic nephropathy. Linagliptin may provide a novel therapeutic approach for patients resistant to ARB treatment.

Delayed onset of diabetes and preservation of beta-cell function in non-obesity type 1 diabetes:

Reduced pancreatic T-cell migration and altered cytokine production are considered important players for the development of diabetes, but the exact mechanism and effect on pancreatic cell pool are still not fully understood. In an attempt to evaluate the effect of linagliptin on pancreatic inflammation and beta-cell mass, non-obesity over a 60-day experimental period in combination with regular stereoscopic assessment of cellular pancreatic changes. -Investigate the progression of diabetes in diabetic (NOD) mice.

Sixty female NOD mice (10 weeks of age) were included in the study and a normal chow diet or diet containing linagliptin throughout the study period (0.083 g linagliptin / kg meal; 3-10 mg / kg, corresponding to po). Plasma samples are taken every other week to measure the onset of diabetes (BG> 11mmol / l). At the end, the pancreas is removed and peripheral blood samples are taken for evaluation of active GLP-1 levels.

At the end of the study period, the incidence of diabetes is significantly reduced in linagliptin-treated mice (9 out of 30 mice) compared to controls (18 out of 30 mice, p = 0.021). Subsequent stereoscopic evaluation of the beta-cell amount (identified by insulin immunoreactivity) revealed a significantly greater beta cell amount (veh 0.18 ± 0.03 mg; lina 0.48 ± 0.09 mg, p <0.01) in linagliptin treated mice. And total islet mass (veh 0.40 ± 0.04 mg; lina 0.70 ± 0.09 mg, p <0.01). Linagliptin tends to reduce peri-islet infiltrating lymphocytes (1.06 ± 0.15; lina 0.79 ± 0.12mg, p = 0.17). As expected, active plasma GLP-1 is higher in linagliptin treated mice at termination.

In summary, the data demonstrate that linagliptin can delay the onset of diabetes in a type 1 diabetes model (NOD mice). The apparent beta-cell sparing effect observed in these animal models is that this DPP-4 inhibition not only protects beta-cells by increasing the level of active GLP-1, but also direct or indirect anti-inflammatory. It shows that the action can be exerted. These effects can support the use of linagliptin in treating and / or preventing type 1 diabetes or latent autoimmune diabetes (LADA) in adults. Linagliptin may provide a new therapeutic approach for patients with or at risk of having type 1 diabetes or LADA.

Effect of linagliptin on body weight, total body fat, liver fat and fat in muscle cells

In a further study, the efficacy of chronic treatment with linagliptin on body weight, total body fat, intramuscular fat and liver fat in a non-diabetic model of diet-induced obesity (DIO) compared to the appetite suppressant sibutramine was investigated. do:

Rats are fed a high-fat diet for 3 months and given a vehicle, linagliptin (10 mg / kg) or sibutramine (5 mg / kg) for an additional 6 weeks while continuing the high-fat diet. Magnetic resonance spectroscopy (MRS) analysis of total body fat, muscle fat and liver fat is performed before treatment and at the end of the study.

Sibutramine causes a significant decrease in body weight (-12%) compared to the control, while linagliptin has no significant effect (-3%). Total body fat is also significantly reduced by sibutramine (-12%), while linagliptin-treated animals show no significant decrease (-5%). However, both linagliptin and sibutramine cause a strong decrease in fat in muscle cells (-24% and -34%, respectively). In addition, treatment with linagliptin caused a significant decrease in liver fat (-39%), while the effect of sibutramine (-30%) did not reach significance (see table below). Thus, linagliptin has no properties in body weight but improves intracellular and liver lipid accumulation. Reductions of fatosis, inflammation and fibrosis in the liver, measured by histological score, are also observed with linagliptin treatment.

Table: Effect of linagliptin on body weight, total body fat, liver fat and intracellular muscle fat

In conclusion, linagliptin treatment causes a strong reduction of lipids and liver fat in muscle cells, both of which are independent of weight loss. Treatment with linagliptin provides additional benefits for diabetic patients with liver fatosis (eg, NAFLD). The effect of sibutramine on muscle and liver fat is mainly due to the known weight loss induced by these compounds.

Linagliptin Glymepiride  Having type 2 diabetes with similar efficacy but insufficiently controlled with metformin From the patient  Improve cardiovascular safety over two years:

In a two-year double-blind trial, the additional long-term efficacy and safety of linagliptin or glimepiride for ongoing metformin to treat type 2 diabetes (T2DM) is investigated. T2DM patients stable to metformin (≧ 1500 mg / d) for ≧ 10 weeks are randomized to linagliptin 5 mg / day (N = 764) or glimepiride 1-4 mg / day (N = 755) over 2 years. Efficacy analysis is based on HbA1c changes from baseline in the full analysis set (FAS) and per-protocol (PP) populations. Safety assessments capture pre-specified, predicted, and adjudicated capture of cardiovascular (CV) events (CV death, non-fatal myocardial infarction or stroke, unstable angina with hospitalization). Includes. Baseline features are well balanced in the 2 groups (HbA1c 7.7% for both). In the PP population, the adjusted mean (± SE) of HbA1c change from baseline was -0.4% (± 0.04%) for linagliptin 5 mg / day vs -0.5% (± for the average dose 3 mg / day). 0.04%). The difference between the mean groups is 0.17% (95% CI, 0.08 to 0.27%; p = 0.0001 for noninferiority). Similar results are observed in the FAS population. Fewer patients experience investigator-defined drug-related hypoglycemia in linagliptin than glimepiride (7.5% vs 36.1%; p <0.0001). Body weight decreases in linagliptin and increases in glimepiride (-1.4 kg vs +1.3 kg; adjusted mean difference, -2.7 kg; p <0.0001). The CV event occurred in 13 (1.7%) linagliptin patients vs 26 (3.4%) glimepiride patients, showing a significant 50% reduction in relative risk to the combined CV endpoint (RR, 0.50; 95% CI, 0.26-0.96; p = 0.04). In conclusion, when added to metformin monotherapy, linagliptin provides a reduction in HbA1c that is similar to glimepiride, but has less hypoglycemia, relatively less weight, and significantly fewer sentences for CV events.

Having type 2 diabetes From the patient Linagliptin  Cardiovascular Risk in Use: Pre-assigned, expected and declared meta-analysis from a large-scale Phase III program:

In type 2 diabetes mellitus (T2DM), the cardiovascular (CV) benefit of hypoglycemic depression has been recently debated, especially if it is too intensive. Some aspects have been reported to be related to unexpectedly worse CV results.

Linagliptin is a first-day, once-to-day DPP-4 inhibitor that is available in a single dose without requiring dose adjustment for renal function decline. Linagliptin achieves glycemic control without weight gain or increased hypoglycemic risk, which can be interpreted as a CV benefit.

To investigate the CV profile of the DPP-4 inhibitor linagliptin, a pre-specified meta-analysis of all CV events from an 8 stage III randomized, double blind, controlled trial (≧ 12 weeks) is performed. The CV case will be sentenced in the future by an independent, independent expert committee. The primary endpoint of this analysis is a composite of hospitalizations for CV death, non-fatal stroke, non-fatal myocardial infarction (MI), and unstable angina (UAP). Another secondary and tertiary CV endpoints, including FDA-custom major adverse CV events (MACE), are also evaluated.

Of the 5239 patients included (mean baseline HbA _1c 8.0%), 3319 received linagliptin once a day (5mg: 3159, 10mg: 160) and 1920 received a comparison (placebo: 977 People, glimepiride: 781 people, vogliibos: 162 people). Cumulative exposure (years per person) was 2060 for linagliptin and 1372 for comparatives. Overall, the major CV events that were reported occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) patients receiving comparisons. The hazard ratio for the primary endpoint is significantly lower for linagliptin compared to the comparator, and the hazard ratio is similar or significantly lower for linagliptin compared to the comparator for all other CV endpoints (Table ).

This is the primary pre-specified, expected and independently declared CV meta-analysis of DPP-4 inhibitors in a large-scale Phase III program. Despite meta-analysis with distinct limitations, the data support the possible reduction of CV events by linagliptin.

table:

^* Significantly lower risk ratio (upper 95% CI <1.0; p <0.05).

Cardiovascular High-risk  Treatment of type 2 diabetes mellitus

The long-term effects of cardiovascular morbidity and mortality and related efficacy parameters (e.g., HbA1c, fasting plasma glucose, treatment sustainability) of treatment with linagliptin in related populations of patients with type 2 diabetes mellitus are investigated as follows: do:

(In the presence or absence of a naive or metformin or alpha-glucosidase inhibitor (e.g. with HbA1c 7.5-8.5%), e.g. metformin and / or alpha-glucosidase inhibitor (e.g. HbA1c 6.5 -8.5%) or recently treated (single or double therapy), for example, recently treated with sulfonylurea or glinide (single or double therapy), or insufficient blood sugar control, e.g. , Linagliptin (optionally one or more other active substances, e.g., one or more other active substances, for example, a type 2 diabetic patient with a high risk of cardiovascular events as defined by one or more of the risk factors A), B), C) and D) shown below. (E.g., in combination with those described herein) over a long period of time (e.g., for> / = 2 years, 4 to 5 years or 1 to 6 years), and other anti-diabetic agents (e.g., glimepiride) Compare with patients treated with the same sulfonylurea) or placebo. Evidence of therapeutic success compared to patients treated with other anti-diabetic agents or placebo may include single or multiple complications (e.g., cardiovascular or cerebrovascular events, e.g. cardiovascular death, myocardial infarction, stroke, or hospitalization (e.g. For example, fewer times of acute coronary syndrome, leg amputation, emergency vascular reconstruction or unstable angina), or, preferably, a longer time taken for the first occurrence of this complication, eg primary synthesis The following factors at the endpoint: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and longer time to first occurrence of hospitalization in case of unstable angina can be found.

Additional therapeutic success is study treatment that maintains glycemic control (e.g. HbA1c </ = 7%) until the end of the study without weight gain (e.g.> / = 2%) without requiring emergency medication. It can be found in a higher proportion of patients in the process. Even further therapeutic success is blood sugar control (e.g. HbA1c </ = 7) until the end of the study without weight gain (e.g.> / = 2%) without intermediate / severe hypoglycemic episodes without the need for emergency medication. %) Can be found in a higher proportion of patients undergoing study treatment.

Further therapeutic success, e.g., treatment with linagliptin compared to treatment with glimepiride (each optionally as a monotherapy or as an additional treatment for metformin or alpha-glucosidase inhibitors), e.g. For example, it can be found in CV superiority, preferably with a risk reduction of about 20%.

Risk factors for cardiovascular events A), B), C) and D):

A) Previous vascular disease (e.g., ages 40-85):

-Myocardial infarction (eg> = 6 weeks),

-Coronary artery disease (eg> = 50% internal narrowing in at least two main coronary arteries in a left coronary artery or angiography),

-Percutaneous coronary intervention (eg,> = 6 weeks),

-Coronary artery bypass grafting (eg,> = 4 years or with recurrent angina after surgery),

-Ischemic or hemorrhagic stroke (eg> = 3 months),

Peripheral obstructive arterial disease (e.g., previous limb vascular bypass or percutaneous angioplasty; previous limb or foot amputation due to circulatory failure, major limb arteries (iliac artery, iliac artery, external iliac artery, external iliac artery, femoral artery) , Patellar artery), or angiographically detected significant stenosis (> 50%), history of intermittent claudication, ankle: arm blood pressure ratio <0.90 on at least one side),

B) Vascular related terminal-organ damage (e.g., ages 40-85):

Renal impairment (e.g., moderate renal impairment as defined by the MDRD formula, eGFRF 30-59 mL / min / 1.73 m2),

Micro- or macroalbuminuria (e.g. microalbuminuria, or random spot urinary albumin: creatinine ratio> / = 30 μg / mg),

Retinopathy (e.g., proliferative retinopathy, or retinal neovascularisation or previous retinal laser coagulation therapy),

C) Old age (e.g., age> / = 70 years old),

D) At least two of the following cardiovascular risk factors (e.g., ages 40-85):

-Advanced type 2 diabetes mellitus (eg,> 10 years duration),

Hypertension (eg, in systolic blood pressure> 140 mmHg or at least one hypotensive treatment),

-Habitual daily smoking,

(Atherosclerotic) at least one treatment for dyslipidemia or high LDL cholesterol blood levels (e.g., LDL cholesterol> / = 135mg / dL) or lipid abnormalities,

-(Intestinal and / or abdominal) obesity (eg body mass index> / = 45 kg / m2),

-Age> / = 40 and </ = 80.

Cognitive function of treatment with linagliptin (e.g. cognitive decline, changes in psychomotor speed, mental well-being), β-cell function (e.g. insulin secretion rate derived from 3h diet resistance test, long-term β -Cell function), renal function parameters, weekly blood glucose pattern (e.g., ambulatory glucose profile, blood glucose variability, oxidation, biomarkers of inflammatory and endothelial function, cognitive and CV morbidity / mortality), asymptomatic MI (E.g. ECG parameters, CV prophylactic properties), LADA (e.g., use of emergency treatment or disease progression in LADA) and / or blood glucose according to β-cell autoantibody status (e.g., GAD) The beneficial effects (eg, improvement) on the persistence of regulation are investigated in substudies.

Claims (31)

A pharmaceutical composition comprising linagliptin,
The pharmaceutical composition, A), B), C) and D), that is,
A) Previous or current vascular disease as selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure and peripheral occlusive arterial disease,
B) vascular-related end-organ damage selected from nephropathy, retinopathy, neuropathy, impaired renal function, chronic kidney disease and micro- or macroalbuminuria,
C) 70 years old or older and
D) At least two cardiovascular risk factors selected from advanced type 2 diabetes mellitus, hypertension, habitual daily smoking, dyslipidemia and obesity that have persisted for more than 10 years.
Use in a method for treating type 2 diabetes in a type 2 diabetes patient with or at risk of cardiovascular disease, kidney disease, or both, such as a type 2 diabetes patient having one or more cardiovascular risk factors selected from Is for
The method comprises administering a therapeutically effective amount of linagliptin to the patient, optionally in combination with one or more other therapeutic agents. The cardiovascular disease, kidney disease, or both diseases of claim 1, wherein the patient is selected from myocardial infarction, stroke, peripheral artery occlusive disease, diabetic nephropathy, micro- or macroalbuminuria, acute or chronic kidney failure, and hypertension. A type 2 diabetes patient with or at risk of having a pharmaceutical composition. A pharmaceutical composition comprising linagliptin,
The pharmaceutical composition prevents the occurrence of a cardiovascular or cerebrovascular event selected from hospitalization due to cardiovascular death, myocardial infarction, stroke, and heart failure or unstable angina in a type 2 diabetic patient, or reduces the risk of the occurrence of the event Or for use in a method of delaying the occurrence of the event,
The method comprises administering a therapeutically effective amount of linagliptin, optionally in combination with one or more other therapeutic substances, to a patient in need thereof,
The pharmaceutical composition, wherein the type 2 diabetic patient is at risk of a cardiovascular or cerebrovascular event with one or more risk factors selected from A), B), C) and D):
A) Previous or current vascular disease selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery, ischemic or hemorrhagic stroke, congestive heart failure and peripheral occlusive arterial disease,
B) Vascular-related terminal-organ damage selected from nephropathy, retinopathy, neuropathy, impaired kidney function, chronic kidney disease and micro- or macroalbuminuria,
C) 70 years old or older and
D)-advanced type 2 diabetes mellitus that has lasted for over 10 years,
- High blood pressure,
-Habitual daily smoking,
Dyslipidemia, and
-At least two cardiovascular risk factors selected from obesity. The pharmaceutical composition of claim 3, wherein the type 2 diabetes patient is a patient with nephropathy, retinopathy, neuropathy, kidney function impairment, chronic kidney disease and vascular related terminal-organ damage selected from micro- or macroalbuminuria. A pharmaceutical composition comprising linagliptin,
The pharmaceutical composition is characterized by the incidence of cardiovascular or cerebrovascular events selected from hospitalization due to cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina in patients with type 2 diabetes at risk of cardiovascular or cerebrovascular events. To prevent, reduce the risk of occurrence of the event, or use it in a method of delaying the occurrence of the event,
The method comprises administering a therapeutically effective amount of linagliptin to the patient, optionally in combination with one or more other therapeutic agents. The pharmaceutical composition according to any one of claims 3 to 5, wherein the type 2 diabetes patient is a patient with nephropathy, impaired renal function, chronic kidney disease and one or more of micro- or macroalbuminuria. The pharmaceutical composition according to any one of claims 3 to 5, wherein the type 2 diabetes patient is a patient with mild, moderate or severe renal impairment or terminal renal disease. The pharmaceutical composition according to any one of claims 3 to 5, wherein the type 2 diabetes patient is a patient with microalbuminuria or diabetic nephropathy. The pharmaceutical composition according to any one of claims 1 to 5, wherein linagliptin is orally administered in a total daily amount of 5 mg. The pharmaceutical composition according to any one of claims 1 to 5, wherein the type 2 diabetes patient is a patient with congestive heart failure. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient is treated over a long period of time of at least 6 years. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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