JP2021185204A - Vasoprotective and cardioprotective antidiabetic therapy - Google Patents

Abstract

To provide a pharmaceutical composition for treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction.SOLUTION: Disclosed is the use of linagliptin for preparation of a pharmaceutical composition for use in a method of treating and/or preventing oxidative stress, vascular stress and/or endothelial dysfunction, including the step of administering linagliptin.SELECTED DRAWING: None

Description

The present invention relates to certain DPP-4 inhibitors that treat and / or prevent oxidative stress, vascular stress and / or endothelial dysfunction, and for diabetic or non-diabetic patients (cardiovascular and / or renal disease). With respect to the use of such DPP-4 inhibitors in the treatment and / or prevention of (including groups of patients at risk).

The present invention relates to certain DPP-4 inhibitors that treat and / or prevent oxidative stress, vascular stress and / or endothelial dysfunction, and for diabetic or non-diabetic patients (cardiovascular and / or renal disease). Provided are methods for the treatment and / or prevention of (including groups of patients at risk), pharmaceutical compositions, and methods of utilizing DPP-4 inhibitors used in the preparation of such pharmaceutical compositions.

The present invention relates to certain DPP-4 inhibitors that treat and / or prevent oxidative stress, vascular stress and / or endothelial dysfunction, and for diabetic or non-diabetic patients (cardiovascular and / or renal disease). With respect to the use of such DPP-4 inhibitors in the treatment and / or prevention of (including groups of patients at risk).
The invention further relates to the use of certain DPP-4 inhibitors for the treatment and / or prevention of endothelial dysfunction.
The invention further relates to certain DPP-4 inhibitors used as antioxidants and / or anti-inflammatory agents.
The invention further treats and / or prevents oxidative stress, vascular stress and / or endothelial dysfunction (eg, in diabetic or non-diabetic patients), especially separately or beyond glycemic control. For certain DPP-4 inhibitors.
The present invention further presents certain DPP-4 inhibitors for treating and / or preventing oxidative stress induced by or associated with hyperglycemia (eg, beyond the control of blood glucose). In addition to the use of such DPP-4 inhibitors in anti-diabetes therapy.
The invention further comprises metabolic disorders (eg, diabetes, in particular type 2 diabetes mellitus) and / or diseases associated with the above (eg, diabetic complications), particularly oxidative stress, vascular stress and / or endothelial dysfunction, or said. With respect to certain DPP-4 inhibitors that treat and / or prevent in patients with or at risk of having or having a disease or condition associated with or associated with the above.

The present invention further comprises metabolic disorders (eg, diabetes, in particular type 2 diabetes mellitus) and / or diseases associated with the above (eg, diabetic complications), cardiovascular and / or renal disorders, such as myocardial infarction. Certain DPPs treated and / or prevented in patients with or at risk of stroke or peripheral arterial obstructive disease and / or diabetic nephropathy, microalbumin or macroalbuminuria, or acute or chronic nephropathy -4 Regarding inhibitors.
The present invention further presents metabolic disorders (eg, diabetes, especially type 2 diabetes mellitus) and / or diseases associated with the above with diabetic complications in microvascular or macrovascular, such as diabetic retinopathy, diabetic neuropathy, diabetes. Certain DPP-4 inhibitions to treat and / or prevent in patients with or at risk of nephropathy or cardiovascular or cerebrovascular disease (eg, myocardial infarction, stroke or peripheral arterial occlusive disease) Regarding agents.
The invention further relates to certain DPP-4 inhibitors that regulate, block or alleviate the detrimental metabolic memory effects (especially for diabetic complications) of hyperglycemia (chronic or transient episodes).
The present invention also further presents certain DPP-4s that treat, prevent, or mitigate the risk of diseases in microvascular or macrovascular diseases that can be induced, remembered, or associated with exposure to oxidative stress. Regarding inhibitors.

The present invention further comprises or has a metabolic disorder (eg, diabetes, in particular type 2 diabetes mellitus) and / or a disease associated with the above (eg, diabetic complications), a cardiovascular disease and / or a renal disease. One or more risk factors selected from patients at risk, especially those with type 2 diabetes who are at risk for cardiovascular or cerebrovascular events, such as A), B), C) and D) below. With respect to certain DPP-4 inhibitors that are treated and / or prevented in patients with type 2 diabetes, the method comprises a therapeutically effective amount of the DPP-4 inhibitor, optionally with one or more other therapeutic agents. Including the step of administering to the patient together:
A) Previous or existing vasculature disease (eg myocardial infarction (eg asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure (eg, congestive heart failure) For example NYHA class I or II, such as left ventricular function <40%) or peripheral obstructive arterial disease);
B) Vascular-related terminal organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg age 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one hypotensive treatment),
− Daily smoking at this time,
-Abnormal fatemia (atheromeogenic abnormal fatemia, postprandial lipoprotein, or high level LDL cholesterol (eg LDL cholesterol 130 or higher-135 mg / dL), low level HDL cholesterol (eg <35-40 mg / in men) dL, <45-50 mg / dL in women), and / or high levels of triglyceride in the blood (eg> 200-400 mg / dL), or at least one treatment for lipid abnormalities),.
-Obesity (eg, abdominal obesity and / or visceral obesity, or body volume index of 45 kg / m ² or higher),
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.

Furthermore, the present invention relates to cardiovascular or cerebrovascular events (eg, cardiovascular death, (fatal or non-fatal) myocardial infarction (eg, asymptomatic or symptomatic MI), (fatal or non-fatal). The appearance of a fatal) stroke or hospitalization (eg, due to acute coronary syndrome, leg amputation, (emergency) revascularization, heart failure, or unstable angina), preferably in patients with type 2 diabetes. Type 2 diabetes with one or more risk factors selected from, for example, A), B), C) and D) below, especially in type 2 diabetic patients at risk for cardiovascular or cerebrovascular events. With respect to certain DPP-4 inhibitors used in methods of preventing, reducing the risk of their appearance, or delaying their appearance in patients, the method comprises the case of a therapeutically effective amount of the DPP-4 inhibitor. Includes the step of administering to the patient with one or more other therapeutic agents by:
A) Previous or existing vasculature disease (eg myocardial infarction (eg asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure (eg, congestive heart failure) For example NYHA class I or II, such as left ventricular function <40%) or peripheral obstructive arterial disease);
B) Vascular-related terminal organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg age 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one hypotensive treatment),
-Daily smoking at the moment,
-Abnormal fatemia (atheromeogenic abnormal fatemia, postprandial lipoprotein, or high level LDL cholesterol (eg LDL cholesterol 130 or higher-135 mg / dL), low level HDL cholesterol (eg <35-40 mg / in men) dL, <45-50 mg / dL in women), and / or high levels of triglyceride in the blood (eg> 200-400 mg / dL), or at least one treatment for lipid abnormalities).
-Obesity (eg, abdominal obesity and / or visceral obesity, or body volume index of 45 kg / m ² or higher),
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.

Furthermore, the present invention relates to cardiovascular or cerebrovascular events (eg, cardiovascular death, (fatal or non-fatal) myocardial infarction (eg, asymptomatic or symptomatic MI), (fatal or non-fatal). The appearance of a (fatal) stroke or hospitalization (eg, acute coronary syndrome, leg amputation, (emergency) revascularization, heart failure, or unstable angina), vessel-related terminal organ disease, Certain DPPs used in methods to prevent, reduce the risk of their appearance, or delay their appearance, especially in patients with type 2 diabetes with nephropathy, renal dysfunction, chronic renal disease, microalbumin or macroalbuminuria. -4 With respect to the inhibitor, the method comprises administering to the patient a therapeutically effective amount of the DPP-4 inhibitor, optionally with one or more other therapeutic agents.
Furthermore, the present invention improves cognitive function (eg, weakens, reverses or treats cognitive decline), improves β-cell function (eg, improves insulin secretion rate derived from 3h diet resistance, and provides long-term β-cell function. (Improve), improve daily glucose pattern (eg, improve biomarkers of behavioral glucose profile, glycemic variability, oxidation, inflammation or endothelial function), and / or improve sustained glucose management by β-cell autoantibody status. With respect to certain DPP-4 inhibitors used in methods for (eg, glutamate decarboxylase (GAD)), the method may optionally contain one or more DPP-4 inhibitors in a therapeutically effective amount. It comprises the step of administering to said patient with other therapeutic agents.
Furthermore, the present invention is a type of DPP-used in methods of preventing cognitive dysfunction or cognitive decline, reducing its risk, slowing its progression, prolonging its onset, weakening, reversing or treating it. 4 With respect to the inhibitor, the method comprises administering to the patient a therapeutically effective amount of the DPP-4 inhibitor, optionally with one or more other therapeutic agents.

Furthermore, the invention is used in methods of preventing, reducing the risk of, slowing its progression, prolonging its onset, weakening, reversing or treating latent autoimmune diabetes (LADA) in adults. With respect to a species of DPP-4 inhibitor, the method comprises administering to the patient a therapeutically effective amount of the DPP-4 inhibitor, optionally with one or more other therapeutic agents.
Furthermore, the invention prevents cardiovascular or cerebrovascular diseases or events (eg, those described herein), reduces their risk, slows their progression, prolongs or weakens their onset. Reversing or treating, and preventing diabetic nephropathy in patients in need thereof (eg, patients described herein, in particular those with type 2 diabetes), reducing its risk, slowing its progression, and initiating it. With respect to certain DPP-4 inhibitors used in methods of stretching, weakening, reversing or treating, said method may optionally add one or more other DPP-4 inhibitors in a therapeutically effective amount. The step of administering to the patient together with the therapeutic substance is included.

Furthermore, the present invention is one or more of the following methods of administering to a patient an effective amount of certain DPP-4 inhibitors, optionally with an effective amount of one or more other active substances. Regarding how to include:
-Methods for treating, alleviating, preventing and / or protecting against oxidative stress, such as non-diabetic or diabetic (hyperglycemic) -induced, or non-diabetic or diabetic-associated oxidative stress;
-How to treat and prevent endothelial dysfunction, reduce its risk, slow its progression, prolong its onset, weaken it, reverse it, or improve endothelial function;
-A method of treating, preventing, reducing the risk, delaying its progression, prolonging, weakening, or reversing its onset of diseases or symptoms associated with oxidative stress (eg, those described herein);
-Treat and prevent ischemia / reperfusion injury (in the kidney, heart, brain or liver), reduce its risk, slow its progression, prolong, weaken or reverse its onset, and / or ( How to reduce the size of myocardial infarction in the heart (after myocardial infarction / reperfusion);
-(Harmful) vascular remodeling, such as cardiac remodeling (especially post-myocardial infarction remodeling, characterized by cardiomyocyte hypertrophy, interstitial fibrosis, ventricular dilatation, systolic dysfunction and / or cell death / apoptosis. How to treat, prevent, mitigate its risk, slow its progression, prolong its onset, weaken it, or reverse it;
-A method of treating, preventing, reducing the risk of chronic or acute renal failure and / or peripheral arterial occlusion, delaying its progression, prolonging, weakening, or reversing its onset;
-Treat, prevent and reduce the risk of congestive heart failure (eg NYHA class I, II, III or IV) and / or cardiac hypertrophy (eg left ventricular hypertrophy) and / or nephropathy and / or albuminuria. , How to slow down its progression, prolong its onset, weaken it, or reverse it;
-Treat, prevent, and risk urinary cardiomyopathy, gap dilation, and / or (cardiac) fibrosis, especially those found in patients with chronic kidney disease and heart disease often associated with type 2 diabetes. How to mitigate, slow down its progression, prolong its onset, weaken or reverse it;
-Methods of regulating, blocking, preventing, alleviating or protecting the adverse metabolic memory effects of hyperglycemia (chronic, early or transient episodes), especially for diabetic complications;
-Methods for preventing or protecting atherosclerotic or preatherogenic low-density lipoproteins (especially small, dense LDL particles) from oxidation and / or atherosclerosis plaque formation;
-How to prevent or protect from impaired pancreatic beta cell function or viability induced by oxidative stress;
-Methods in treating, preventing, alleviating or ameliorating inflammation of pancreatic islets or lipid and glycotoxicities in islets, or increasing beta / alpha cell ratios to protect beta cells or normalizing pancreatic islets morphology or function Methods to develop / improve; and / or-complications of diabetes mellitus, such as micro and macrovascular diseases such as nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory Disorders, neurodegenerative or cognitive abnormalities, cardiovascular or cerebrovascular disease, endothelial dysfunction, tissue ischemia, diabetic legs or diabetic ulcers, atherosclerosis, hypertension, myocardial infarction, acute coronary syndrome , Unstable angina, stable angina, peripheral arterial obstructive disease, myocardial disease (including, for example, urinary myocardial disease), heart failure, cardiac rhythm abnormalities, revascular re-stenosis, and / or stroke, especially of blood glucose. Prevent, reduce its risk, slow its progression, and initiate its initiation in patients in need of it (eg, patients with type 1 diabetes, LADA or especially type 2 diabetes), either separately from management or beyond control of blood glucose. A method of stretching, weakening, reversing or treating.

Furthermore, the present invention prevents diabetic nephropathy in patients who do not respond appropriately to treatment with angiotensin receptor blockers (ARBs, such as thermisartan) (eg, patients described herein, in particular patients with type 2 diabetes). With respect to certain DPP-4 inhibitors used in methods that mitigate its risk, slow its progression, prolong its onset, weaken, reverse or treat it, the method is in a therapeutically effective amount. It comprises the step of administering the DPP-4 inhibitor to the patient, optionally together with one or more other therapeutic agents (eg, ARB, eg, thermisartan).
Diabetic nephropathy is characterized by overfiltration (early stage), microalbuminuria or macroalbuminuria, nephrotic syndrome, proteinuria, hypertension, fluid retention, edema, and / or renal and renal filtering functions (eg, glomerular filtration). It may include progressive impairment or reduction of rate GFR) (eventually leading to renal failure or end-stage renal disease). Yet another feature may include chronic or nodular glomerulosclerosis, imported and exported hyaline-like arteriosclerosis, and / or interstitial fibrosis and atrophy. Yet another feature may include abnormal albumin / creatinine or protein / creatinine ratios and / or abnormal glomerular filtration rates.

The invention further relates to certain DPP-4 inhibitors used in methods of preventing or treating diabetic nephropathy in patients who respond inappropriately to treatment with angiotensin receptor blockers (ARBs, eg, thermisartan). .. The method comprises administering to the patient a therapeutically effective amount of a DPP-4 inhibitor and telmisartan.
Therefore, in a specific embodiment, the preferred DPP-4 inhibitor within the intended range of the invention is linagliptin.
Pharmaceutical compositions or combinations used in these therapeutic methods are also contemplated, comprising the DPP-4 inhibitors defined herein, optionally together with one or more other active substances.
Furthermore, the present invention is optionally combined with one, two or three or more additional active agents, each of which is defined herein, as used in the therapeutic methods defined herein. Regarding DPP-4 inhibitors.
Furthermore, the present invention is optionally combined with one, two or three or more additional active agents, each of which is defined herein, as used in the therapeutic methods defined herein. The present invention relates to the use of a DPP-4 inhibitor for the production of a pharmaceutical composition (the composition is suitable for therapeutic and / or prophylactic purposes of the present invention).
Furthermore, the present invention relates to the therapeutic (therapeutic and prophylactic) methods described herein, wherein the method is an effective amount of the DPP-4 inhibitor described herein and optionally the 1 described herein. It comprises the step of administering one or more other active or therapeutic agents to a patient in need thereof.

Shows the effect of linagliptin on thymosan A (ZymA) -induced ROS in human PMN (LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophils, Bl1356 = linagliptin, Nebi = nebivolol). It shows the effect of linagliptin on the adhesion of human leukocytes (PMN) to human endothelial cells following LPS stimulation (Turks and CF-DA staining, BL1356 = linagliptin). Shows the effect of linagliptin on LPS (50 μg / mL) -induced adhesion of neutrophils to EA.hy cells (measured by oxidation of Amplex Red). Shows the effect of glyptin on the oxidative burst of isolated human neutrophils when stimulated with LPS or Timothan A as measured by luminol / wasabiperoxidase (HRP) -enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = polymorphonuclear). Neutrophils, LG = Bl1356 = linagliptin, AG = allogliptin, VG = vildagliptin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nevibolol). Shows the effect of glyptin on oxidative bursts of isolated human monocytes / lymphocytes upon stimulation with LPS or timosan A as measured by luminol / isabiperoxidase (HRP) -enhanced chemiluminescence (LPS = lipopolysaccharide, PMN = poly). Form nucleus neutrophils, LG = Bl1356 = linagliptin, AG = allogliptin, VG = bildaglycin, SaG = saxagliptin, SiG = sitagliptin, Nebi = nevibolol). It is a table comparing glyptins with respect to in vitro direct antioxidant activity. LPS activation of L-012 scavenging of peroxidase-induced ROS The effect of linagliptin on neutrophil-driven oxidation and inhibition of NADPH oxidase activity is shown. ^{Quantification of the oxidation burst of isolated human PMN (5x10 5} cells / mL) with increasing LPS and linagliptin concentrations was performed by enhanced chemiluminescence with the luminol analog L-012 (100 μM) (PBS = phosphate). Buffered saline, LPS = lipopolysaccharide, PMN = polymorphonuclear neutrophils, LG = Bl1356 = linagliptin). Shows the effect of linagliptin on whole blood oxidative burst / oxidative stress in nitroglycerin-induced nitrate tolerance (LPS = lipopolysaccharide, EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). Shows the effect of linagliptin on whole blood oxidative burst / oxidative stress in nitroglycerin-induced nitrate tolerance (LPS = lipopolysaccharide, EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). It shows improvement of endothelial dysfunction by linagliptin in GTN or LPS-treated rats (pretreatment with linagliptin (3-10 mg / kg), induction of endothelial dysfunction by nitrate or LPS (3 days)). FIG. 8A shows the effects of GTN-induced endothelial dysfunction and linagliptin on endothelial-dependent relaxation (EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). FIG. 8B shows the effects of LPS (10 mg / kg / day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). It shows improvement of endothelial dysfunction by linagliptin in GTN or LPS-treated rats (pretreatment with linagliptin (3-10 mg / kg), induction of endothelial dysfunction by nitrate or LPS (3 days)). FIG. 8A shows the effects of GTN-induced endothelial dysfunction and linagliptin on endothelial-dependent relaxation (EtOH Ctr = ethanol control, GTN s.c. = trinitroglycerin-subcutaneous, Bl1356 = linagliptin). FIG. 8B shows the effects of LPS (10 mg / kg / day i.p.) in vivo treatment and linagliptin treatment on endothelium-dependent relaxation (LPS = lipopolysaccharide, EtOH Ctr = ethanol control). Shows the direct vasodilatory effect of glyptin. Griptin-induced vasodilation is determined by recording isometric tension in isolated vascular ring fragments and relaxation in response to increased cumulative concentrations of linagliptin, sitagliptin or saxagliptin (1 nM to 32 μM) (Fig. 9A). In another set of experiments, aortic relaxation is tested in response to increased cumulative concentrations of linagliptin, alogliptin or vildagliptin (1 nM to 32 or 100 μM) (Fig. 9B). Data are mean ± SEM of 12 (Fig. 9A) or 4 (Fig. 9B) circles of willis in a total of 10 rats. *, P <0.05 for DMSO (solvent control); ^# , p <0.05 for sitagliptin / vildagliptin; superscript section sign, p <0.05 for saxagliptin / agrogliptin. Figure 9A continued. Shows the direct vasodilatory effect of glyptin. Griptin-induced vasodilation is determined by recording isometric tension in isolated vascular ring fragments and relaxation in response to increased cumulative concentrations of linagliptin, sitagliptin or saxagliptin (1 nM to 32 μM) (Fig. 9A). In another set of experiments, aortic relaxation is tested in response to increased cumulative concentrations of linagliptin, alogliptin or vildagliptin (1 nM to 32 or 100 μM) (Fig. 9B). Data are mean ± SEM of 12 (Fig. 9A) or 4 (Fig. 9B) circles of willis in a total of 10 rats. *, P <0.05 for DMSO (solvent control); ^# , p <0.05 for sitagliptin / vildagliptin; superscript section sign, p <0.05 for saxagliptin / agrogliptin. Shows renal function based on detected blood glucose after linagliptin, thermisartan or a combination thereof or placebo treatment in STZ-treated animals: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14); 2) mimicry Treated diabetic eNOS ko mice, placebo (natrosol) (n = 17); 3) Termisartan (po 1 mg / kg) treated diabetic eNOS ko mice (n = 17); 4) linagliptin (po 3 mg / kg) treated diabetic eNOS ko mice (N = 14); 5) Termisartan (po 1 mg / kg) + linagliptin (po 3 mg / kg) -treated diabetic eNOS ko mice (n = 12). Shows albumin / creatinine ratios in non-diabetic and diabetic animals: 1) non-diabetic eNOS ko control mice, placebo (natrosol) (n = 14); 2) mimetically treated diabetic eNOS ko mice, placebo (natrosol) (n =) 17); 3) Termisartan (po 1mg / kg) treated diabetic eNOS ko mice (n = 17); 4) Linagliptin (po 3mg / kg) treated diabetic eNOS ko mice (n = 14); 5) Termisartan (po 1mg / kg) kg) + linagliptin (po 3 mg / kg) treated diabetic eNOS ko mice (n = 12). Results of rat experiments showing the effect of telmisartan (Telmi) and linagliptin (Bl1356) combination and telmisartan alone (Telmi solo) or linagliptin alone (Bl1356 solo) treatment on blood pressure in a hypertension-induced cardiac hypertrophy (leading to heart failure) model. Is. Between time points 3 and 6 in Figure 12, the first line from the top shows placebo 2K1C (maximum RR systole), the second line from the top shows linagliptin, and the middle line shows telmisartan. , The second line from the bottom shows placebo imitation, and the first line from the bottom shows telmisartan + linagliptin (lowest RR systole). It is a table of experimental results of a chronic renal failure model showing the effect of linagliptin on cardiac fibrosis markers and left ventricular dysfunction markers in cardiac tissue (TGF-β = transforming growth factor beta, TIMP = tissue inhibition of metalloproteinase). Factor, Col1α = collagen type 1 alpha, Col3α = collagen type 3 alpha, BNP = type B sodium excretion-increasing peptide). The experimental results in diabetic eNOS knockout C57BL / 6J mice as a diabetic nephropathy model (resistant to ARB treatment) are shown, and the effects of linagliptin and telmisartan on albuminuria are shown.

Detailed Description of the Invention Oxidative stress is an imbalance in the ability of the biological system to rapidly detoxify reactive oxygen species and reactive intermediates or repair the damage caused (reactive oxygen species are free radicals). , Which typically include oxygen-based or nitrogen-based unpaired electrons and peroxides in their outer electron orbits). Disruption of the normal redox state of tissue can cause harmful effects by the production of peroxides and free radicals that damage all intracellular components, including proteins, lipids and nucleic acids / DNA. Oxidative stress targets many organs (eg, blood vessels, eyes, heart, skin, kidneys, joints, lungs, brain, immune system, liver, or multiple organs) and can be centrally involved in many diseases or symptoms. Examples of diseases or symptoms closely related to oxidative stress include atherosclerosis (eg, activation of platelets and formation of atherogenic plaques), endothelial dysfunction, re-stenosis, hypertension, peripheral obstructive vascular disease, etc. Ischemic-reperfusion injury (eg kidney, liver, heart or cerebral ischemia-reperfusion injury), fibrosis (eg kidney, liver, heart or pulmonary fibrosis); yellow spot degeneration, retinal degeneration, cataract, retinopathy; coronary Arterial heart disease, ischemia, myocardial infarction; psoriasis, dermatitis; chronic renal disease, nephritis, acute renal failure, glomerular nephritis, nephropathy; rheumatoid arthritis, osteoarthritis; asthma, COPD, respiratory distress syndrome; stroke, nerves Degenerative diseases (eg Alzheimer's disease, Parkinson's disease, Huntington's disease), psychiatric dysfunction, bipolar disorder, compulsive disorder; chronic systemic inflammation, perivascular inflammation, autoimmune disease, multiple sclerosis, erythematosus, inflammatory bowel disease, Ulcerative colitis; NAFLD / NASH; Chronic fatigue syndrome, polycystic ovary syndrome, septicemia, diabetes, metabolic syndrome, insulin resistance, hyperglycemia, hyperinsulinemia, abnormal lipemia, hypercholesterolemia, hyperfat Includes illness. In addition to their intrinsic pharmacological properties, certain clinically used agents, including, but not limited to, antihypertensive agents, angiotensin receptor blockers and antihyperlipidemic agents (eg, statins). ) Protects diverse organs through antioxidant stress mechanisms.

Patients with or at risk of oxidative stress and / or vascular stress may have oxidative stress markers (eg, oxidative LDL), inflammatory status markers (eg, pro-inflammatory interleukins), 8-OHdG, isoprostain (eg, oxidative LDL). Diagnosis can be made, for example, by determining F2-isoprostain, 8-isoprostain F2alpha), nitrotyrosine or N-carboxymethyllysine (CML).
Endothelial dysfunction (usually clinically determined as an endothelial-dependent vasomotor disorder (eg, an imbalance between vasodilation and vasoconstriction)) is an endothelial cell (cells that align with the medial surface of blood vessels, arteries, and veins). ) Is physiologically impossible, and these cells interfere with the performance of their normal biochemical functions. Normal endothelial cells are required for coagulation, platelet adhesion, immune function, volume and control of electrolyte content in the intervascular and vascular interstitial spaces. Endothelial dysfunction is closely associated with pro-inflammatory, pro-oxidative and thrombus-promoting changes in the arterial wall. Endothelial dysfunction is considered to be an important event in the development and progression of atherosclerosis and arteriosclerosis and precedes clinically distinct vascular complications. The prognosis of endothelial dysfunction is important for the detection of vascular disease and the prediction of adverse vascular events. Risk factors for atherosclerosis and vascular disease / events are closely associated with endothelial dysfunction. Endocardial damage also contributes to renal damage and / or chronic or progressive renal damage, such as interstitial fibrosis, glomerulonephritis, microalbumin or macroalbuminuria, nephropathy and / or chronic renal disease or renal failure. It becomes. There is evidence to support that oxidative stress contributes to vascular disease as well as endothelial dysfunction or damage to the endothelium.

Type 2 diabetes mellitus is a complex pathophysiology that is centrally involved in the dual endocrine effects of insulin resistance and impaired insulin secretion (resulting in the failure to meet the requirements to maintain plasma glucose levels within the normal range). It is a common chronic and progressive disease that results from physiology. The above results in hyperglycemia and associated microvascular and macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy or neuropathy, or macrovascular (eg, cardiovascular or cerebrovascular) complications. .. Although the elements of vascular disease play an important role, they are not only factors in the diabetes-related disease area. Frequent complications result in a significant reduction in life expectancy. At present, diabetes is the leading cause of adult-onset blindness, renal failure, and leg amputation in industrialized societies due to diabetes-induced complications, with a 2- to 5-fold increase in cardiovascular-related death risk.

Thorough and rigorous glycemic control during early (new diagnosis up to 5 years) diabetes has sustained and beneficial effects and reduces the risk of diabetic complications (both microvascular and macrovascular). That was established in a large-scale voluntary extraction test. However, despite thorough glycemic control, many patients with diabetes still develop diabetic complications.
Epidemiological and predictive data support the long-term effects of early (up to 5 years from new diagnosis) metabolic management on clinical outcomes. Hyperglycemia has long-lasting detrimental effects in both type 1 and type 2 diabetes, and glycemic control must be initiated very early in diabetes, or provided thoroughly or strictly. It has been found that it cannot be sufficient to completely relieve complications.
Furthermore, transient episodes of hyperglycemia (eg, hyperglycemic events) can induce molecular changes, and these changes can be sustained or irreversible after reversion to normoglycemia. Was found.
Taken together, these data show that metabolic memory is preserved early in the diabetic process, and that in certain diabetic symptoms, oxidative and / or vascular stress can persist after glucose normalization. Advocate. This phenomenon, in which the initial glycemic environment and / or even transient hyperglycemia is remembered with clinical outcomes in target terminal organs (eg, blood vessels, retina, kidney, heart, limbs), has recently been referred to as "metabolic memory". It is called.

Potential mechanisms for propagating this "memory" are certain metamorphic changes, non-enzymatic glycation of cellular proteins and lipids (eg, formation of further glycated end products), oxidatively modified ateloformability. Lipoproteins and / or excess intracellular reactive oxygen and nitrogen species (RONS), which occur specifically at the glycated mitochondrial protein level and probably work in concert with each other to maintain stress signaling. ..
Mitochondria are one of the major sources of intracellular reactive oxygen species (ROS). Mitochondrial dysfunction increases electron leakage and ROS development of the mitochondrial respiratory chain (MRC). High levels of glucose 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.
Furthermore, overproduction of free radicals, such as reactive oxygen species (ROS), causes and / or maintains oxidative and vascular stress and metabolic memory after glucose normalization, thus eg, endothelial dysfunction or other diabetic complications. There is evidence that it contributes to the integration of hyperglycemia and cell memory effects in.

Therefore, even if the blood glucose is normalized by being induced by (chronic, early or transient episodes of) hyperglycemia, or primarily related to the persistent (long-term) oxidative stress associated with it. There are certain metabolic symptoms, in that long-term persistent activation of many pathways involved in the pathogenesis of diabetes can still exist. Therefore, one of the major discoveries in the course of diabetes was the presentation that overproduction of free radicals could still be apparent, even at normoglycemic levels or apart from actual blood glucose levels. For example, endothelial dysfunction, a causative marker of diabetic vascular complications, can persist after normalization of blood glucose. However, there is evidence that a combination of antioxidant therapy and glycemic normalization can be used to nearly block endothelial dysfunction.
Therefore, treatment of oxidative and / or vascular stress is particularly glycemic, especially beyond glycemic control (eg, by reducing cellular reactive species and / or glycation (eg, by suppressing the production of free oxygen or nitrogen radicals)). Independent treatment beneficially regulates, alleviates, blocks or protects the memory effects of hyperglycemia, further reduces the risk, and is associated with long-term diabetic complications, especially oxidative stress. The onset of complications induced by the above can be prevented, treated or prolonged in the patient in need thereof.

Treatment of type 2 diabetes is typically initiated by diet and exercise followed by oral anti-diabetes monotherapy, although blood glucose is initially controllable in some patients, although said treatment is high. With a secondary failure rate. The limitations of monotherapy for glycemic control can be overcome for a limited period of time, at least in some patients, by combining multiple agents to achieve a reduction in blood glucose that cannot be maintained during long-term monotherapy. The data available support the conclusion that traditional monotherapy fails and requires multidrug therapy in most patients with type 2 diabetes. However, because type 2 diabetes is a progressive disease, it is very difficult to maintain stable blood glucose levels for a long period of time, even in patients who have a good initial response to conventional combination therapy. Will require increased dosage or another treatment with insulin. Existing combination therapies have the potential to enhance glycemic control, but the therapies have limitations (especially with respect to long-term efficacy). Furthermore, conventional treatment methods may exhibit an increased risk of side effects (eg, hypoglycemia or weight gain (the side effects may be the result of a compromise in the efficacy and tolerance of the treatment method)).
Therefore, for many patients, these pre-existing drug therapies result in progressive deterioration of glycemic control despite treatment, especially long-term metabolic status cannot be adequately controlled and thus progressive or late 2 Achievement and maintenance of glycemic control fails in type 2 diabetes (including diabetes with inadequate glycemic control despite conventional oral or parenteral antidiabetic treatment).

Therefore, while thorough treatment of hyperglycemia reduces the occurrence of chronic injury, many patients with type 2 diabetes, in part, have limited, tolerable and long-term efficacy of conventional antihyperglycemic therapy. It remains improperly treated due to the inconvenience of medication.
The high incidence of this treatment failure is the complication or chronic injury (microvascular and macrovascular complications (eg, diabetic nephropathy, retinopathy or neuropathy)) or brain associated with high rates of long-term hyperglycemia in patients with type 2 diabetes. It is a major contributor to vascular or cardiovascular complications (including, for example, myocardial infarction, stroke or vascular mortality or prevalence).
Oral anti-diabetic agents commonly used in treatment (eg, first or second and / or single or (first or additional) combination therapy) include metformin, sulfonylureas, thiazolidinediones, glinides and α-glucosidases. Inhibitors are included, but not limited to.
GLP-1 or GLP are the parenteral (typically injectable) antidiabetic agents commonly used in treatment (eg, first or second, and / or single or (first or additional) combination therapy). -Includes, but is not limited to, analogs and insulin or insulin analogs.
However, the use of these conventional anti-diabetic or anti-hyperglycemic agents can be associated with a variety of side effects. For example, metformin is associated with lactic acid disease or gastrointestinal side effects, sulfonylureas, glinides and insulin or insulin analogues are associated with hypoglycemia and weight gain, and thiazolidinedione is associated with edema, fractures, weight gain and heart failure / heart effects. In addition, alpha-glucosidase blockers and GLP-1 or GLP-1 analogues can be associated with gastrointestinal side effects (eg, indigestion, intestinal or diarrhea, or nausea or vomiting) and, more seriously (but rarely), pancreatitis.
Therefore, there is still a need for effective, safe and acceptable anti-diabetes treatment methods in the industry.

Furthermore, in the treatment method of type 2 diabetes, in order to achieve a long-term therapeutic effect, it is required to avoid complications specific to the symptom and to effectively treat the symptom while delaying the progression of the symptom. Will be done.
Furthermore, anti-diabetes treatment should not only prevent long-term complications often found in advanced-stage diabetes, but should also be a treatment option for diabetic patients who have developed or are at risk of complications (eg, renal impairment). Is still sought after.
Furthermore, it is still sought to provide prevention or mitigation of the side effects or risks associated with conventional anti-diabetes treatment.
The enzyme DDP-4 (dipeptidyl peptidase IV), also known as CD26, is known to cause cleavage of the N-terminal dipeptides of many proteins with proline or alanine residues at the N-terminus. It is a protease. Because of this property, DPP-4 inhibitors interfere with plasma levels of bioactive peptides, including peptide GLP-1, and are considered to be promising agents for the treatment of diabetes mellitus.
For example, DDP-4 inhibitors and their use are disclosed below: WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769, WO2007 / 014886, WO 2004/050658, WO 2004/111051, WO 2005/058901, WO 2005 / 097798, WO 2006/068163, WO 2007/071738, WO 2008/017670, WO 2007/128721, WO 2007/128724, WO 2007/128761 or WO 2009/121945.

HbA1c levels (a product of non-enzymatic glycation of the hemoglobin B chain) are extremely important in the monitoring of diabetes mellitus. Since its production is essentially dependent on blood glucose levels and erythrocyte lifespan, HbA1c reflects the average blood glucose level 4-12 weeks ago in the sense of "memory of blood glucose". Diabetic patients whose HbA1c levels are well controlled by more thorough diabetic treatment (ie, less than 6.5% of total hemoglobin in the sample) are extremely well protected from diabetic microangiopathy. Treatments available for diabetes can provide diabetics with an average improvement in HbA1c levels on a scale of 1.0-1.5%. This reduction at HbA1c levels is not sufficient for all diabetics to reach the desired target range of HbA1c below 7.0%, preferably less than 6.5%, more preferably less than 6%.
Inappropriate or inadequate glycemic control is intended by the present invention in which a patient exhibits an HbA1c value greater than 6.5%, particularly greater than 7.0%, more preferably greater than 7.5%, particularly greater than 8%. Means the state. Aspects of patients with inadequate or inadequate glycemic control include, but are not limited to, patients with HbA1c levels of 7.5 to 10% (or 7.5 to 11% in another aspect). A specific aspect of the improperly controlled patient aspect is poor glycemic control, including, but not limited to, patients with HbA1c levels of 9% or higher.

In glycemic control, in addition to improving HbA1c levels, other therapeutic goals recommended for patients with type 2 diabetes mellitus are normal or as normal postprandial plasma glucose (FPG) and postprandial plasma glucose levels as possible. It is an improvement to the neighborhood. The recommended desired target range for pre-meal (starvation) plasma glucose is less than 70-130 mg / dL (or 90-140 mg / dL) or 110 mg / dL, and plasma glucose 2 hours after meal is less than 180 mg / dL or 140 mg / dL. Is less than.
In certain embodiments, the diabetic patient as defined by the present invention may include a patient who has not previously been treated with an anti-diabetic drug (drug naive patient). Therefore, in certain embodiments, the treatment methods described herein can be used for naive patients. In another embodiment, diabetic patients as defined by the present invention include patients with advanced or late type 2 diabetes mellitus (including patients who have failed conventional antidiabetic drug treatment), eg, 1 as defined herein. Patients with improperly controlled blood glucose by one, two or more conventional oral and / or parenteral anti-diabetic agents, such as metformin, thiazolidinedione (particularly pioglitazone), sulfonylurea, glinide, GLP-1 or GLP- 1 Despite (single) therapy with analogs, insulin or insulin analogs, or α-glucosidase inhibitors, or metformin / sulfonylurea, metformin / thiazolidinedione (especially pioglycidone), sulfonylurea / α glucosidase inhibitors, pioglitazone / sulfonylurea, Patients with inadequate glycemic control despite dual-drug therapy with metformin / insulin, pioglitazone / insulin or sulfonylurea / insulin may be included. Accordingly, in certain embodiments, experience of treating the treatment methods described herein with, for example, the conventional oral and / or parenteral anti-diabetes single-agent or two- or three-agent combinations described herein. Can be used in certain patients.

Yet another embodiment of the diabetic patient as defined by the present invention is a patient who is unsuitable for metformin therapy, including:
-Patients with contraindications to Metformin therapy, such as patients with one or more contraindications to Metformin therapy according to the sticker, such as renal disease, renal impairment or renal dysfunction (according to the product information of Metformin approved in the area). (Specified); dehydration; unstable or acute congestive heart failure; acute or chronic metabolic acidosis; and patients with at least one contraindication selected from hereditary galactose intolerance,
-At least one gastrointestinal selected from patients suffering from one or more unacceptable side effects due to metformin, especially the gastrointestinal side effects associated with metformin, such as nausea, vomiting, diarrhea, intestinal gas and severe abdominal discomfort. Patients suffering from vascular side effects.
In yet another embodiment of the diabetic patient who may be compatible with the treatment method of the present invention, a diabetic patient to whom conventional metformin therapy is not suitable, for example, a reduced dose of metformin therapy, reduces resistance to metformin, is intolerable or contraindicated. Includes, but is not limited to, patients who are required (including, but not limited to, older (eg, 60-65 years) patients) for or due to (mild) impairment / reduction of renal function.

Yet another embodiment of the diabetic patient as defined by the present invention is a patient with renal disease, renal dysfunction or inadequate or impaired renal function (including mild, moderate and severe renal impairment). The above may be, for example, an increase in serum creatinine levels (eg, serum creatinine levels above the normal upper limit for the age of the patient, eg 130-150 μmol / L or higher for men, or 1.5 mg / dL or higher, 1.4 mg / dL or higher for females. (124 μmol / L or more)), or abnormal creatinine clearance (eg, glomerular filtration rate (GFR) of 30-60 mL / min or less).
As a more detailed illustration of the above, mild renal damage is suggested, for example, by creatinine clearance of 50-80 mL / min, which closely matches serum creatinine levels of 1.7 mg / dL or less in men and 1.5 mg / dL or less in women. Moderate renal impairment is suggested, for example, by creatinine clearance of 30-50 mL / min (which closely matches serum creatinine levels of 1.7 <to 3.0 mg / dL or less in men and 1.5 <to 2.5 mg / dL or less in women). Severe renal damage can be suggested, for example, by creatinine clearance <30 mL / min (which closely matches serum creatinine levels of 3.0 mg / dL <in men and 2.5 mg / dL <in women). Patients with end-stage renal disease require dialysis (eg hemodialysis or peritoneal dialysis).
As a more detailed example, patients with renal disease, renal failure or disorder include patients with chronic renal failure or disorder, the glomerular filtration rate (GFR, mL / min / 1.73 m). ^{According to 2} ), it can be stratified into the following five stages: stage 1 characterized by 90 or more normal GFR + persistent albuminuriasis or known structural or hereditary renal disease; mild kidney Stage 2 characterized by a mild decrease in GFR (GFR 60-89) indicating disability; Stage 3 characterized by moderate decrease in GFR (GFR 30-59) indicating moderate renal failure; Severe Stage 4 characterized by severe reduction in GFR (GFR 15-29) indicating renal impairment; and terminal 5 (terminal stage 5) characterized by GFR less than 15 requiring dialysis or indicating complete renal failure Kidney disease, ESRD).

Yet another aspect of the diabetic patient as defined by the present invention is renal complications such as diabetic nephropathy (chronic and progressive renal dysfunction, albuminuria, proteinuria, fluid retention (edema) of the body and / or Patients with type 2 diabetes who have (high blood pressure) or are at risk of developing it.
Yet another embodiment of a diabetic patient who may be compatible with the treatment method of the present invention may include (but not limited to) type 2 diabetic patients who have or are at risk of developing renal complications such as diabetic retinopathy. Not done).
Yet another aspect of the diabetic patient who may be compatible with the treatment method of the present invention has macrovascular complications such as myocardial infarction, coronary artery disease, ischemic or hemorrhagic attack, and / or peripheral obstructive arterial disease. Includes, but is not limited to, type 2 diabetic patients at risk of developing the disease.
Yet another aspect of a diabetic patient who may be compatible with the treatment method of the present invention is a type 2 diabetic patient who has or is at risk for a cardiovascular or cerebrovascular disease or event (eg, the heart described herein). Patients at risk of the vasculature) may be included (but not limited to).
Yet another embodiment of a diabetic patient who may be compatible with the treatment method of the present invention is a diabetic patient with elderly and / or advanced diabetes (particularly type 2 diabetes), such as a patient with insulin treatment, triple anti-diabetic oral therapy. Patients, patients with pre-existing cardiovascular system and / or cerebrovascular events, and / or patients with long-term disease (eg, 5 to 10 years) may be included (but not limited to).

Yet another embodiment of a diabetic patient who may be compatible with the treatment method of the present invention is diabetes with one or more cardiovascular risk factors selected from A), B), C) and D) below. Patients (especially patients with type 2 diabetes) may be included (but not limited to):
A) Previous or existing vasculature disease (eg myocardial infarction (eg asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure (Eg NYHA Class I or II, eg left ventricular function less than 40%), or peripheral obstructive arterial disease);
B) Vascular-related terminal organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one hypotensive treatment,
− Daily smoking at this time,
-Abnormal fatemia (eg, atherogenic abnormal fatemia, postprandial fatemia, or high level LDL cholesterol (eg LDL cholesterol 130 or higher-135 mg / dL), low level HDL cholesterol (eg <35-40 mg in men) / DL or <45-50 mg / dL in women), and / or high levels of triglyceride in the blood (eg> 200-400 mg / dL), or at least one treatment for lipid abnormalities),.
-Obesity (eg, abdominal obesity and / or visceral obesity, or body volume index of 45 kg / m ² or higher),
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.

In certain embodiments, a patient who may be fit for the treatment method of the invention may have or is at risk of having one or more of the following diseases, abnormalities or symptoms: type 1 diabetes, type 2 diabetes, glucose. Resistance disorder (IGT), blood glucose disorder during starvation (IGF), hyperglycemia, postprandial hyperglycemia, post-absorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, abnormal fat blood Diseases (including, for example, atherosclerotic mallipidemia), hyperlipidemia, hypercholesterolemia, hypertriglyceremia, hyperNEFAemia, postprandial fatemia, hypertension, atherosclerosis, endothelial dysfunction, Osteoporosis, chronic systemic inflammation, non-alcoholic steatosis (NAFLD), polycystic ovary syndrome, hyperuricemia, metabolic syndrome, nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataracts , Neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction , Acute coronary syndrome, unstable angina, stable angina, peripheral arterial obstructive disease, myocardial disease (including urinary toxic myocarditis), heart failure, cardiac hypertrophy, cardiac rhythm abnormalities, vascular re-stenosis, stroke , Ischemic / reperfusion injury (in the kidney, heart, brain or liver), fibrosis (in the kidney, heart, brain or liver), vascular remodeling (in the kidney, heart, brain or liver); diabetes, especially type 2. Diabetes (preferably true (eg as an underlying disease)).

In yet another embodiment, the patient who may be fit for the therapeutic method of the invention has diabetes (particularly type 2 diabetes mellitus) and yet has one or more other diseases, abnormalities or symptoms (eg, from those previously described). (Selected) may or may have a risk thereof.
To the extent of the invention, certain DPP-4 inhibitors as defined herein, optionally one or more other therapeutic agents (eg, selected from those described herein) or pharmaceutical combinations, (Combined with a pharmaceutical composition), or the combined use of such DPP-4 inhibitors as defined herein according to the invention, and / or fulfills one or more of the above requirements. It has now been found to have the property of making those DPP-4 inhibitors suitable for.
The invention therefore relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), as used in the therapeutic methods described herein.
The invention further relates to certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356), which are combined with metformin for use in the therapeutic methods described herein.
The invention further relates to certain DPP-4 inhibitors, preferably linagliptin (Bl1356), as defined herein, which are combined with pioglitazone for use in the therapeutic methods described herein.
The invention further relates to certain DPP-4 inhibitors, preferably linagliptin (Bl1356), as defined herein, which are combined with telmisartan for use in the therapeutic methods described herein.

The invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors, preferably linagliptin (Bl1356), as defined herein, used in the therapeutic methods described herein.
The invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356) and metformin, used in the therapeutic methods described herein.
The invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as defined herein, preferably linagliptin (Bl1356) and pioglitazone, used in the therapeutic methods described herein.
The invention is further selected from certain DPP-4 inhibitors (particularly Bl1356) and those described herein that are used separately or sequentially, particularly simultaneously with the therapeutic methods described herein. For combinations comprising one or more other active substances, said other active substances are, for example, other anti-diabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, blood HDL. It is selected from active substances that increase levels, active substances that lower blood pressure, active substances indicated in the treatment of atherosclerosis or obesity, anti-platelet agents, anticoagulants, and vascular endothelial protectants, for example each of them. It is described herein.

The invention further also comprises certain DPP-4 inhibitors (particularly Bl1356) and one or more, which are used specifically simultaneously, separately or sequentially, and optionally in combination with thermisartane, in the therapeutic methods described herein. For combinations that include other anti-diabetic agents, the anti-diabetic agents include metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and GLP-1 or GLP. -Selected from a group of analogs.
The invention further relates to a method of treating and / or preventing metabolic disorders, in particular type 2 diabetes mellitus and / or symptoms associated with the above (eg, diabetic complications), wherein the methods include metformin, sulfonylurea, nateglinide, lepaginide. , PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and effective amounts of one or more other antidiabetic agents selected from the group consisting of GLP-1 or GLP-1 analogs. Effective amounts of the DPP-4 inhibitors (particularly Bl1356) specified herein, and optionally the effective amount of thermisartan, to patients in need thereof (particularly human patients), eg, patients described herein (risk patients). Includes the step of administering in combination (simultaneous, separate or continuous) to (including groups).

The invention further relates to the therapies or therapeutic methods described herein, eg, methods of treating and / or preventing metabolic disorders, particularly type 2 diabetes mellitus and / or symptoms associated with the above (eg, diabetic complications). The method comprises a therapeutically effective amount of linagliptin (Bl1356) and optionally one or more other therapeutic agents such as metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor. Antidiabetic agents selected from the group consisting of, insulin or insulin analogs, and GLP-1 or GLP-1 analogs, and / or thermisartane, are described herein, eg, in patients in need thereof (particularly human patients). Includes the step of administering to a patient (eg, a risky patient described herein).
The invention further relates to the therapies or therapeutic methods described herein, eg, methods of treating and / or preventing metabolic diseases, in particular type 2 true diabetes and / or symptoms associated with the above (eg, diabetic complications). The method comprises providing a therapeutically effective amount of linagliptin (Bl1356) to a patient in need thereof (particularly a human patient), eg, a patient described herein (a risky patient described herein (particularly cardiac)). Includes (including) patients with vasculature or cerebrovascular disease or events or risk patients and / or patients with renal disease or risk patients).

The invention further relates to the therapies or therapeutic methods described herein, eg, methods of treating and / or preventing metabolic diseases, in particular type 2 true diabetes and / or symptoms associated with the above (eg, diabetic complications). The method comprises providing therapeutically effective amounts of linagliptin (Bl1356) and metformin to patients in need thereof (particularly human patients), eg, patients described herein (risk patients described herein). In particular, the step of administering to (including patients with cardiovascular system or cerebrovascular disease or event or risk patients)) is included.
The invention further relates to the therapies or therapeutic methods described herein, eg, methods of treating and / or preventing metabolic diseases, in particular type 2 true diabetes and / or symptoms associated with the above (eg, diabetic complications). The method comprises providing therapeutically effective amounts of linagliptin (Bl1356) and thermisartan to patients in need thereof (particularly human patients), eg, patients described herein (risk patients described herein). In particular, it comprises a step of administration to) including patients with cardiovascular or cerebrovascular disease or events or risky patients and / or risky patients with renal disease).
Examples of such metabolic disorders or disorders that may be compatible with the treatment methods of the invention, particularly in patients with or at risk of cardiovascular and / or renal disease, include type 1 diabetes, 2. Type Diabetes, Glucose Tolerance Disorder (IGT), Fasting Blood Glucose Disorder (IFG), Hyperglyceridemia, Postprandial Hyperglyceremia, Postabsorption Hyperglyceremia, Adult Latent Autoimmune Diabetes (LADA), Overweight, Obesity , Abnormal lipemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non- It may include, but is not limited to, alcoholic lipohepatic disease (NAFLD), retinopathy, neuropathy, nephropathy, hypertriglyceridemia ovary syndrome, and / or metabolic syndrome.

The invention further comprises the step of administering a therapeutically effective amount of certain DPP-4 inhibitors, optionally in combination with one or more of the other therapeutic agents described herein: Regarding at least one of the methods:
Patients in need thereof (eg, patients described herein, in particular those with type 2 diabetes), in particular oxidative stress, vascular stress and / or endothelial dysfunction, or diseases or symptoms associated with or associated with the above. In patients with or at risk of, or cardiovascular and / or renal disease (eg, myocardial infarction, stroke, or peripheral arterial obstructive disease, and / or diabetic nephropathy, microalbuminuria or macroalbuminuria) , Or in patients with or at risk of acute or chronic nephropathy), or
A) Previous or existing vasculature disease (eg myocardial infarction (eg asymptomatic or symptomatic), coronary artery disease, percutaneous coronary intervention, coronary bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure (Eg NYHA Class I or II, eg left ventricular function less than 40%), or peripheral obstructive arterial disease);
B) Vascular-related terminal organ diseases (eg nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and / or microalbumin or macroalbuminuria);
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-Hypertension (eg> 130/80 mmHg, or systolic blood pressure> 140 mmHg, or at least one hypotensive treatment),
− Daily smoking at this time,
-Abnormal fatemia (eg, atheromogenic abnormal fatemia, postprandial fatemia, or high level LDL cholesterol (eg LDL cholesterol 130 or higher-135 mg / dL), low level HDL cholesterol (eg <35-40 mg in men) / DL, <45-50 mg / dL in women), and / or high levels of triglyceride in the blood (eg> 200-400 mg / dL), or at least one treatment for lipid abnormalities),
-Obesity (eg, abdominal obesity and / or visceral obesity, or body volume index of 45 kg / m ² or higher),
-Age over 40 and under 80,
-Metabolic syndrome, hyperinsulinemia or insulin resistance, and-Family history of hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular or myocardial disease in the first degree,
Patients with one or more cardiovascular risk factors selected from A), B), C) and D) above.
− Metabolic disorders or disorders such as type 1 diabetes mellitus, type 2 diabetes mellitus, glucose tolerance disorder (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, adults Latent Autoimmune Diabetes (LADA), Overweight, Obesity, Abnormal Fatemia, Hyperlipidemia, Hypercholesterolemia, Hypertriglyceridemia, HyperNEFAemia, Postprandial Lipidemia, Hypertension, Atherosclerosis Prevents and slows the progression of illness, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic steatosis (NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or metabolic syndrome. , How to stretch or treat;
-Methods for improving and / or maintaining glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevents, slows, prolongs, or progresses prediabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), insulin resistance, and / or progression from metabolic syndrome to type 2 diabetes mellitus. How to reverse;
-Complications of diabetes mellitus, such as microvascular or macrovascular disease, such as nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, learning or memory impairment, neurodegenerative or cognitive abnormalities , Cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary artery syndrome, unstable angina, stable angina Prevents, reduces the risk of, and slows the progression of heart disease, peripheral arterial obstructive disease, myocardial disease (including, for example, urotoxic cardiomyopathy), heart failure, cardiac rhythm abnormalities, vascular re-stenosis, and / or stroke. , How to stretch or treat;
-A method of reducing body weight and / or body fat, or preventing an increase in body weight and / or body fat, or promoting a decrease in body weight and / or body fat;
-How to prevent, slow down, or treat pancreatic beta cell degeneration and / or diminished functionality of pancreatic beta cells, and / or to improve, retain, and / or restore pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the functionality of pancreatic insulin secretion;
-How to prevent, slow down, prolong or treat non-alcoholic steatohepatitis (NAFLD) (including liver steatomatosis), non-alcoholic steatohepatitis (NASH) and / or liver fibrosis (eg, liver steatomatosis) , How to prevent (liver) inflammation and / or abnormal accumulation of liver fat, slow, slow down, weaken, treat or reverse);
-How to prevent, slow down, prolong, or treat type 2 diabetes, where conventional anti-diabetes alone or combination therapy has failed;
-How to achieve the reduction in the dose of conventional anti-diabetes drugs required for proper therapeutic effect;
-How to reduce the risk of side effects associated with conventional anti-diabetes drugs (eg, hypoglycemia and / or weight gain); and / or-How to maintain and / or improve insulin sensitivity, and / or hyperinsulinemia And / or a method for treating or preventing insulin resistance.

Other features of the invention will be apparent to those skilled in the art from the above and the following views (including examples and claims).
The features of the invention, in particular pharmaceutical compounds, compositions, combinations, methods and uses, relate to the DPP-4 inhibitors defined above and below.
The DPP-4 inhibitors intended by the present invention include, but are limited to, any of the DPP-4 inhibitors described above and below, preferably orally active DPP-4 inhibitors. Not done.
Embodiments of the invention are used in the treatment and / or prevention of metabolic disorders (particularly type 2 diabetes mellitus) in patients with type 2 diabetes and also in patients suffering from renal disease, renal dysfunction or renal impairment. With respect to DPP-4 inhibitors, in particular the DPP-4 inhibitor is administered to the patient at the same dose level as a patient with normal renal function, thus, for example, the DPP-4 inhibitor is for renal dysfunction. It is characterized by not requiring downward dose adjustment.
For example, the DPP-4 inhibitor of the present invention (which may be particularly suitable for patients with renal dysfunction) has a relatively wide (about> 100-fold) treatment window for the DPP-4 inhibitor and its active metabolites. And / or can be an oral DPP-4 inhibitor such that it is removed primarily by liver metabolism or bile excretion (preferably without adding yet another addition to the kidney).

In a more detailed example, the DPP-4 inhibitors of the invention (which may be particularly suitable for patients with renal dysfunction) have a relatively wide (about> 100-fold) treatment window (preferably safe comparable to placebo). It can be an orally administered DPP-4 inhibitor having a sex profile) and / or satisfying one or more of the following pharmacokinetic properties (preferably at its oral therapeutic dose level):
-The DPP-4 inhibitor is excreted substantially or primarily (eg, more than 80% or even more than 90% of the administered orally administered dose) through the liver and / or for that purpose. Renal excretion does not occupy a substantial or negligible route of excretion (eg, oral doses measured by tracking the excretion of oral doses of ^{radiolabeled carbon (14 C) substances, eg.} Less than 10%, preferably less than 7%);
-The DPP-4 inhibitor is excreted predominantly unchanged from the parent drug (eg, on average in urine and stool, in excess of 70% of the orally administered dose of ^{radiolabeled carbon (14 C) substance.} Or more than 80%, or preferably 90%), and / or by metabolism to a non-substantial or negligible (eg, less than 30%, less than 20%, preferably 10%) removal.
-The (major) metabolite of the DPP-4 inhibitor is pharmacologically inactive. For example, the major metabolite does not bind to the target enzyme DPP-4 and, in some cases, is removed more rapidly than the parent compound (eg, the metabolite has a final half-life of 20 hours or less, or preferably about 16 hours or less). , For example 15.9 hours).
In certain embodiments, the (major) metabolite (which can be pharmacologically inactive) of a DPP-4 inhibitor having a 3-amino-piperidine-1-yl substituent in plasma is 3-amino-piperidine. The amino group of the -1-yl component is replaced by a hydroxyl group, and the 3-hydroxy-piperidine-1-yl component (eg, 3- (S) -hydroxy-piperidine-1-yl component, by reversing the configuration of the chiral center. It is a derivative that forms).

Yet another property of the DPP-4 inhibitors of the invention can be one or more of the following: rapid achievement of steady state (eg, steady state on days 2-5 of treatment with therapeutic oral dose levels): Reaching plasma levels (> 90% of steady-state plasma concentration), little accumulation (eg, mean accumulation rate _{RA, AUC} of 1.4 or less at therapeutic oral dose levels), and / or DPP-4 inhibition Maintaining a long-lasting effect on (preferably when used once daily) (eg, almost complete (> 90%) DPP-4 inhibition at therapeutic oral dose levels, once daily at therapeutic oral doses Inhibition of more than 80% during 24 hours after ingestion), marked reduction in blood glucose fluctuation range 2 hours after meal at therapeutic dose level (more than 80% already on the first day of treatment), and excretion in urine The accumulated amount of unchanged parent compound should be less than 1% of the dose and should not exceed about 3-6% in steady state when increased.
Thus, for example, the DPP-4 inhibitors of the invention have a predominantly non-renal excretion route (ie, said DPP-4 inhibitors are non-substantial or insignificant (eg, oral doses, preferably oral therapeutic doses). Less than 10%, preferably less than 7%, eg about 5%) can be excreted from the kidney (eg, measured by tracking the excretion of oral doses of ^{radiolabeled carbon (14 C) substance).} ..
Furthermore, the DPP-4 inhibitors of the invention may be characterized by being substantially or primarily excreted via the liver or feces (eg, tracking the excretion of oral doses of ^{radiolabeled carbon (14 C) substances).} Measured by doing).

Furthermore, the DPP-4 inhibitor of the present invention is mainly excreted unchanged as a parent agent (eg, excreted radioactivity in urine and feces after oral administration of a ^{radiolabeled carbon (14 C) substance).} An average of more than 70%, or more than 80%, or preferably 90% unchanged), said DPP-4 inhibitor is excreted very little or very little through metabolism, And / or the major metabolites of said DPP-4 inhibitors may be characterized by being pharmacologically inactive or having a relatively wide therapeutic window.
Furthermore, the DPP-4 inhibitors of the invention are the glomerular function and / or tubules of type 2 diabetic patients with chronic renal dysfunction (eg, mild, moderate or severe renal impairment or end-stage renal disease). The troph level of the DPP-4 inhibitor in the plasma of type 2 diabetic patients who do not significantly impair function and / or have mild or moderate renal impairment is similar to that of patients with normal renal function. And / or the DPP-4 inhibitor is type 2 diabetes with renal dysfunction (preferably regardless of the stage of renal disorder, eg mild, moderate or severe renal disorder or end-stage renal disease). It may be characterized by the absence of dose adjustment in the patient.
Furthermore, the DPP-4 inhibitors of the invention are doses at which the minimum effective dose results in inhibition of more than 50% in patients with more than 80% of DPP-4 activity in trophs (24 hours after the last dose). And / or its sufficiently therapeutic dose is characterized by a dose that results in more than 80% inhibition of DPP-4 activity in trophs (24 hours after the last dose) in more than 80% of patients. Can be.
Furthermore, the DPP-4 inhibitors of the invention are for type 2 diabetic patients who have been diagnosed with renal impairment and / or are at risk of developing renal complications, such as diabetic nephropathy (chronic and progressive kidney). It may be characterized by being suitable for use in patients with or at risk of (including dysfunction, albuminuria, proteinuria, body fluid retention (edema) and / or hypertension).

In the first embodiment (Phase A), the DPP-4 inhibitor of the present invention is any DPP- of the following formula (I) or formula (II) or formula (III) or formula (IV). 4 Inhibitor, or its pharmaceutically acceptable salt:

式（I）

Equation (I)

式（II）

Equation (II)

式（III）

Equation (III)

（式IV）

(Equation IV)

During the ceremony
R1 is ([1,5] naphthylidine-2-yl) methyl, (quinazoline-2-yl) methyl, (quinoxalin-6-yl) methyl, (4-methyl-quinazolin-2-yl) methyl, 2- Cyano-benzyl, (3-cyano-quinolin-2-yl) methyl, (3-cyano-pyridine-2-yl) methyl, (4-methyl-pyrimidine-2-yl) methyl, or (4,6-dimethyl) -Pyrimidine-2-yl) Methyl, where R2 is 3- (R) -amino-piperidin-1-yl, (2-amino-2-methyl-propyl) -methylamino or (2- (S) -Amino-propyl) -means methylamino.

With respect to the first embodiment (Phase A), the preferred DPP-4 inhibitor is any or all of the following compounds and pharmaceutically acceptable salts thereof:
1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-(3- (R) -amino-piperidine-1-yl) -Xanthine (WO 2004/018468, compare with Example 2 (142)):

1-[([1,5] naphthylidine-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidin-1-yl) )-Xanthine (WO 2004/018468, compare with Example 2 (252)):

1-[(quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1-yl) -xanthine (WO) 2004/018468, compare with Example 2 (80)):

2-((R) -3-amino-piperidine-1-yl) -3- (but-2-inyl) -5- (4-methyl-quinazoline-2-ylmethyl) -3,5-dihydro-imidazole [ 4,5-d] Pyridazine-4-one (WO 2004/050658, compare with Example 136):

1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-[(2-amino-2-methyl-propyl) -methylamino ]-Xanthine (WO 2006/029769, compare with Example 2 (1)):

1-[(3-cyano-quinoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1-yl) -Xanthine (WO 2005/085246, compare with Example 1 (30)):

1- (2-Cyano-benzyl) -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1-ylxanthine (WO 2005/085246, implementation) Compare with Example 1 (39)):

1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-[(S)-(2-amino-propyl) -methylamino ]-Xanthine (WO 2006/029769, compare with Example 2 (4)):

1-[(3-Cyano-pyridin-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1-yl) -Xanthine (WO 2005/085246, compare with Example 1 (52)):

1-[(4-Methyl-pyrimidine-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1-yl) -Xanthine (WO 2005/085246, compare with Example 1 (81)):

1-[(4,6-dimethyl-pyrimidine-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-((R) -3-amino-piperidine-1- Ilxanthine (WO 2005/085246, compare with Example 1 (82)):

1-[(Quinoxaline-6-yl) Methyl] -3-Methyl-7- (2-Butyne-1-yl) -8-((R) -3-Amino-Piperidin-1-yl) -Xanthine (WO) 2005/085246, compare with Example 1 (83)):

These DPP-4 inhibitors are distinguished from structurally similar DPP-4 inhibitors. Because when combined with other pharmaceutically active substances, they combine very good potential and long-lasting action with favorable pharmacological properties, receptor selectivity and favorable side effect profile, or unexpected treatment. This is because it brings about an advantage or improvement. Their preparation is disclosed in the publications mentioned.
Among the above-mentioned DPP-4 inhibitors of Embodiment A of the present invention, the more preferable DPP-4 inhibitor is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7-( 2-Butin-1-yl) -8-(3- (R) -amino-piperidin-1-yl) -xanthine, especially its free base (also known as linagliptin or Bl1356).
A particularly preferred DPP-4 inhibitor in the present invention is linagliptin. As used herein, the term linagliptin refers to linagliptin or an acceptable salt thereof (including hydrates and solvates) and its crystalline form, preferably linagliptin is 1-[(4-methyl-quinazoline-). 2-Il) Methyl] -3-Methyl-7- (2-butyne-1-yl) -8-(3- (R) -amino-piperidine-1-yl) -xanthine. The crystalline form is described in WO 2007/128721. Methods for producing linagliptin are described, for example, in patent applications WO 2004/018468 and WO 2006/048427. Linagliptin is distinguished from structurally similar DPP-4 inhibitors. Because linagliptin has very good potential and long-lasting action with favorable pharmacological properties, receptor selectivity and favorable side effect profile, or unexpected treatment with one-, two- or three-drug combination therapy. This is because it produces a positive advantage or improvement.

In order to avoid any doubt, the disclosures of each of the above and below references cited above in the context of the specifically indicated DPP-4 inhibitors are incorporated herein by reference in their entirety.
It should be understood in the present invention that the combinations, compositions or combinations of the present invention may be intended for simultaneous, continuous or separate administration of active ingredients or elements.
In this context, the "combination" or "combined" as used in the present invention is a fixed or non-fixed (eg, free) form (including a kit) and use (eg, simultaneous, continuous or separate of active ingredients or elements). Includes, but is not limited to, use.
Combination administration of the present invention may be carried out by administering the active ingredients or elements together, eg, as one single formulation or simultaneously as two separate formulations or formulations. Alternatively, administration may be carried out by administering the active ingredient or element sequentially, eg, in two separate formulations or formulations.
For the combination therapies of the invention, the active ingredients or elements can be administered separately (the above suggests they are prescribed separately) or together (the above are they). Suggested to be prescribed as the same preparation or as the same formulation). Thus, administration of one component of the combination of the invention may be prior to, simultaneous with, or subsequent administration of the other component of the combination.
Unless otherwise stated, combination therapy can refer to first, second or third treatment, or first or additional combination therapy or replacement therapy.

With respect to Embodiment A, those skilled in the art will know how to synthesize the DPP-4 inhibitor of Embodiment A of the present invention. Advantageously, the DPP-4 inhibitor of Embodiment A of the present invention can be prepared using the synthetic method described in the literature. Thus, for example, the purine derivative of formula (I) may be of WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427 (the references are incorporated herein by reference). Available as described. Purine derivatives of formula (II) can be obtained, for example, as described in WO 2004/050658 or WO 2005/110999 (the above documents are incorporated herein by reference). Purine derivatives of formulas (III) and (IV) can be obtained, for example, as described in WO 2006/068163, WO 2007/071738 or WO 2008/017670 (the above documents are incorporated herein by reference). In particular, the preparation of the DPP-4 inhibitor mentioned above is disclosed in the publications mentioned in its context. The polymorphic crystal modifications and formulations of specific DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively (disclosures of the above are incorporated herein by reference in their entirety). ing. Formulations of specific DPP-4 inhibitors with metformin or other combination partners are described in WO 2009/121945, which is incorporated herein by reference in its entirety.

Typical dispensing intensities of the two-factor fixed combination (tablets) of linagliptin / metformin IR (immediate release) are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg, the above being 1-3 times daily, especially twice daily. Can be administered.
Typical dispensing intensities of the two-factor fixed combination (tablets) of linagliptin / metformin XR (long-term release) are 5/500 mg, 5/1000 mg and 5/1500 mg (one tablet each), or 2.5 / 500 mg, 2.5 / 750 mg and 2.5 / 1000 mg (2 tablets each), the above can be administered 1-2 times daily, especially once daily, preferably taken with meals in the evening.
The invention is further used in (additional or initial) combination therapy with metformin (eg, 500-2000 mg of metformin hydrochloride in total daily dose, eg 500 mg, 850 mg or 1000 mg once or twice daily). , Provided herein are DPP-4 inhibitors.
For pharmaceutical applications in warm-blooded vertebrates (especially humans), the compounds of the invention are usually dispensed at 0.001 to 100 mg / kg body weight, preferably 0.01-15 mg / kg (1 daily in each case). Used 4 times). For this purpose, the compound, optionally in combination with other active substances, is one or more inert carriers and / or diluents (eg, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate). , Polyvinylpyrrolidone, citric acid, tartrate, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances (eg solid fats or suitable mixtures thereof). Can be incorporated into conventional galenos preparations (eg, plain or coated tablets, capsules, powders, suspensions or suppositories) with.

The pharmaceutical compositions of the invention comprising the DPP-4 inhibitors defined herein are therefore described in the art and further provide pharmaceutically acceptable prescribing excipients suitable for the desired route of administration. Prepared by one of ordinary skill in the art. Examples of such excipients are diluents, binders, carriers, fillers, lubricants, dispersion promoters, crystallization retarders, disintegrants, solubilizers, colorants, pH adjusters, surfactants. Includes, but is not limited to, activators and emulsifiers.
Oral preparations or formulations of the DPP-4 inhibitor of the present invention can be prepared according to known techniques.
Examples of suitable diluents for the compound of Embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.
Examples of lubricants suitable for the compound of Embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
Examples of suitable binders for the compound of Embodiment A are copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (). Povidone), pregelatinized starch, or low-substituted hydroxypropyl cellulose (L-HPC).
Suitable disintegrants for the compound of Embodiment A include corn starch or crospovidone.

A suitable method for preparing a pharmaceutical formulation of the DPP-4 inhibitor of Embodiment A of the present invention is:
-Direct tableting of the active substance in a powder mixture containing the appropriate tableting excipient;
-Film coating in addition to granulation with the appropriate excipient and subsequent mixing with the appropriate excipient and subsequent tableting; or-Filling of the powder mixture or granules into capsules.
Suitable granulation methods are:
-Wet granulation in a powerful mixer followed by fluidized bed drying;
-One container granulation;
-Fluidized bed granulation; or-Dry granulation with suitable excipients (eg by roller compression) and subsequent tableting or filling into capsules.
An exemplary composition of the DPP-4 inhibitor of Embodiment A of the invention (eg, tablet core) is a first diluent, mannitol, a pregelatinized starch as a second diluent with additional binding properties, binding. The agent copovidone, the disintegrant corn starch, and magnesium stearate as a lubricant are included, where copovidone and corn starch can be optional.
The tablets of the DPP-4 inhibitor of Embodiment A of the present invention can be film coated, preferably the film coat is hydroxypropylmethyl cellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide. Includes (eg red and / or yellow).

Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, the delivered product comprises one or more containers containing the one or more pharmaceutical compositions in the appropriate form. Typically, the tablets are bundled in a suitable primary packaging for easy handling, delivery and storage, and for proper stability of the composition during long-term contact with the surroundings during storage. For tablets the primary container can be a bottle or a blister pack.
Suitable bins for, for example, pharmaceutical compositions or combinations (tablets) containing the DPP-4 inhibitor of Embodiment A of the invention are glass or polymers (preferably polypropylene (PP) or high density polyethylene (HD-). Manufactured from PE)) and can be sealed with a screw lid. The screw lid can be provided with a pediatric-friendly safety closure (eg, push-and-turn closure) to prevent or prevent the child from approaching the contents. If necessary (eg in areas of high humidity), additional use of desiccants (eg bentonite clay, molecular sieves or preferably silica gel) can extend the displayable period of the packaging composition.
Suitable blister packs, for example for pharmaceutical compositions or combinations (tablets), comprising the DPP-4 inhibitor of Embodiment A of the invention are a top foil (which can be broken by a tablet) and a bottom (for tablets). (Has pockets) or forms the above. The upper foil may include a metal foil whose inside (seal side) is coated with a heat-sealed polymer layer, in particular an aluminum foil or an aluminum alloy foil (eg, having a thickness of 20 μm to 45 μm, preferably 20 μm to 25 μm). can. The bottom is a multilayer polymer foil (eg, polyvinylidene chloride (PVDC) coated poly (vinyl chloride) (PVC); or poly (chlorotrifluoroethylene) (PCTFE) laminated PVC foil) or multilayer polymer-metal-polymer foil. (For example, low temperature forming laminated PVC / aluminum / polyamide compositions) can be included.

Additional overpacks or pouches made from multi-layer polymer-metal-polymer foils (eg laminated polyethylene / aluminum / polyester compositions) in blister packs to ensure long shelf life, especially in hot and humid climatic conditions. Can be used for The replenishing desiccant in this pouch package (eg, bentonite clay, molecular sieves, or preferably silica gel) can further extend the displayable period under such severe conditions.
The product can also include labels or packaging inserts. They should include information regarding instructions, treatment, dosage, administration, contraindications and / or warnings regarding the use of such therapeutic products with respect to the instructions customarily contained in the product packaging of the therapeutic products. Can be done. In certain embodiments, the label or packaging insert indicates that the composition can be used for any of the purposes described herein.
With respect to the first embodiment (Phase A), the typically required dosage of the DPP-4 inhibitor described herein in Embodiment A is 0.1 mg to 10 mg, preferably 0.1 mg to 10 mg for intravenous administration. 0.25 mg to 5 mg, 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 for oral administration, 1 daily in each case. From 4 times. Therefore, for example, 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-(3- (R) -amino-piperidine-1) -Il) -The dosage of xanthine is 0.5 mg to 10 mg / patient / day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg / patient / day for oral administration.
Formulations prepared with the pharmaceutical composition comprising the DPP-4 inhibitor described herein in Embodiment A contain the active ingredient in a dosage range of 0.1-100 mg. Therefore, for example, 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8-(3- (R) -amino-piperidine-1) -Il)-Specific dosage intensity of xanthine is 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

A particular embodiment of the DPP-4 inhibitor of the invention relates to a therapeutically effective oral DPP-4 inhibitor at low dose levels, wherein the DPP-4 inhibitor is, for example, <100 mg or <70 mg / patient / Daily, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably 1 mg to 10 mg, particularly 1 mg to 5 mg (particularly 5 mg) / patient / day oral dose level is therapeutically effective. If necessary, it is divided into 1 to 4 single doses, particularly 1 or 2 single doses (which can be of the same size), preferably orally once or twice daily (more preferably). Is administered once daily), advantageously administered with or without food at any time of the day. So, for example, a daily oral dose of 5 mg of Bl1356 may be given in a once-daily regimen (ie, 5 mg of Bl1356 once daily) or twice-daily regimen (ie, 2.5 mg of Bl1356 daily). Twice) at any time of the day with or without food.
Dosages of the ingredients in the combinations and compositions of the present invention may vary, but the amount of the active ingredient will be such that a suitable formulation can be obtained. Therefore, the dosage and formulation selected will depend on the desired therapeutic effect, route of administration and duration of treatment. The appropriate dosage range for the combination is from the maximum tolerated dose of a single drug to a lower dose, eg 1/10 of the maximum tolerated dose.

Particularly preferred DPP-4 inhibitors to be emphasized in the intent of the invention are 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-). Il) -8-(3- (R) -amino-piperidine-1-yl) -xanthine (also known as Bl1356 or linagliptin). Bl1356 exhibits high potential, 24-hour duration of action, and a wide treatment window. In patients with type 2 diabetes who received Bl1356 orally in multiple doses once daily for 12 days, Bl1356 showed a favorable pharmacodynamic and drug fate profile (see, eg, Table 1 below) and to steady state. Rapid arrival (eg, reaching steady-state plasma levels (90% <of predose plasma concentration on day 13) between day 2 and day 5 treatment in all dose groups), very slight accumulation (eg 1 mg) Average accumulation ratio _{RA, AUC} of 1.4 or less at doses above, and maintenance of long-lasting action with DPP-4 inhibition (eg, near complete (> 90%) DPP-4 inhibition at dose levels of 5 mg and 10 mg) , 92.3 and 97.3% inhibition in steady state, and more than 80% inhibition during the 24-hour interval after drug ingestion), and blood glucose amplitude 2 hours after meal (already on day 1 at doses 2.5 mg and above). Significant decrease (more than 80%), and cumulative amount of unchanged parent compound excreted in the urine on day 1 was less than 1% of the dose and increased by more than about 3-6% on day 12. It was shown to be absent (renal clearance C _{LR, SS} is about 14 to about 70 mL / min for oral doses, for example renal clearance is about 70 mL / min for 5 mg doses). In people with type 2 diabetes, Bl1356 exhibits placebo-like safety and tolerance. At low doses of about 5 mg and above, Bl1356 functions as a very once-daily oral drug with complete 24-hour sustained DPP-4 inhibition. At the therapeutic oral dose level, Bl1356 is excreted primarily through the liver and, to a very small extent, through the kidneys (less than about 7% of the oral dose). Bl1356 is excreted unchanged via bile in principle. The portion of Bl1356 removed via the kidney increases very slightly over time and with increasing dose, so it is probably not necessary to modify the dose of Bl1356 according to the patient's renal function. Non-renal removal of Bl1356, along with its low storage capacity and wide safety margin, may be an important advantage in a population of patients with a high rate of renal dysfunction and diabetic nephropathy.

*中央値及び範囲[最小−最大]
NC：ほとんどの値が定量の下限未満であるので計算していない Table 1: Geometric mean (gMean) and variation geometric coefficient (gCV) of Bl1356 drug fate parameters in steady state (day 12)

* Median and range [minimum-maximum]
NC: Not calculated because most of the values are below the lower limit of quantification

Since various metabolic dysfunctions often occur simultaneously, it is very often indicated to combine a number of different principles of action. Therefore, DPP-4 inhibitors lower conventional active substances, such as other anti-diabetic substances, especially blood blood lipid levels or blood lipid levels, raise blood HDL levels, and lower blood pressure for the corresponding abnormalities. When combined with one or more active agents selected from the active agents indicated in the treatment of atherosclerosis or obesity, improved outcomes can be obtained depending on the diagnosed dysfunction. ..
The above DPP-4 inhibitors can also be used in combination with other active substances in addition to their use in monotherapy, which can result in improved therapeutic outcomes. Such combinatorial treatment may be provided in any combination of the substances or in fixed combinatorial form (eg, tablets or capsules). Pharmaceutical formulations containing the combination partners required for the above are available on the market as pharmaceutical compositions or can be formulated by one of ordinary skill in the art using conventional methods. Active substances available on the market as pharmaceutical prescriptions are available in numerous places in the prior art, eg, on the annual drug list, the American Pharmaceutical Industry Association's "Rpte Liste ™", or as the "Physicians' Desk Reference". It is described in the manufacturer's compilation, which is updated annually for known prescription drugs.

Examples of anti-diabetic drug combination partners are: metformin; sulfonylurea, such as glubenclammid, tolbutamide, glymepyride, glypidide, glycidone, griborenulinid and glycladide; nateglunide; repaglinide; mitiglinide; thiazolidinedione, eg rosiglytazone and pioglycazone. Regulators such as metaglidase; PPAR-gamma agonists such as riboglycazone, mitoglytazone, INT-131 and baraglitazone; PPAR-gamma antagonists; PPAR-gamma / alpha regulators such as tesaglytazar, muraglitazar, allegritazaal, indeglitazaal. And KRP297; PPAR-gamma / alpha / delta regulators such as robegritazone; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cells GCRP agonists such as SMT3-receptor-agonist and GPR119, eg GPR119 agonist 5-ethyl-2- {4- [4- (4-tetrazole-1-yl-phenoxymethyl) -thiazol-2-yl] -piperidin-1 -Il} -pyrimidine or 5- [1- (3-isopropyl-[1,2,4] oxadiasol-5-yl) -piperidin-4-ylmethoxy] -2- (4-methanesulfonyl-phenyl) -pyridine; 11β-HSD-inhibitors; FGF19 agonists or analogs; alpha-glucosidase blockers such as acarbose, boglibose and miglycol; alpha 2-antagonists; insulin and insulin analogs such as human insulin, insulin lispro, insulin glucillin, r-DNA-insulin Aspart, NPH Insulin, Insulin Detemia, Insulin Degludec, Insulin Tregopill, Insulin Zinc Suspension and Insulin Glargine; Gastric Suppressant Peptide (GIP); Amylin and Amylin Analogs (eg Plumlintide or Davalintide); GLP- 1 and GLP-1 analogs such as Exendin-4, such as exenatide, exenatide LAR, lylagritide, taspoglycide, lixisenazide (AVE-0010), LY-2428757 (PEGylated form of GLP-1), de. Duraglutide (LY-2189265), semaglutide or albiglutide; SGLT2-inhibitors such as dapagliflozin, cergliflozin (KGT-1251), achiglyflozin, canaglyfrosin, ipragliflozin or tohogliflozin; inhibitors of protein tyrosine phosphatase (eg troduschemin) Inhibitor of glucose-6-phosphatase; Fluctose-1,6-bisphosphatase regulator; Glycogen phosphorylase regulator; Glucagon receptor antagonist; Phosphoenol pyruvate carboxykinase (PEPCK) inhibitor; Pilvate dehydrogenase kinase (PDK) inhibition Agents; inhibitors of tyrosine kinases (50 mg to 600 mg), such as PDGF-receptor-kinases (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976) or serine / threonine kinases. Inhibitors of glucokinase / regulatory protein regulators (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, eg, high doses. Salicylate; JNK1 Inhibitors; Protein Kinase C-Theta Inhibitors; Beta 3 agonists such as Litobeglon, YM178, Sorabegron, Talibegron, N-5984, GRC-1087, Rafabegron, FMP825; Ardos reductase inhibitors such as AS3201, Xenarestat, Fi Dullestat, Epalrestat, Lanilestat, NZ-314, CP-744809 and CT-112; SGLT-1 or SGLT-2 inhibitors; KV1.3 channel inhibitors; GPR40 regulators, eg [(3S) -6-({ 2', 6'-dimethyl-4'-[3- (methylsulfonyl) propoxy] biphenyl-3-yl} methoxy) -2,3-dihydro-1-benzofuran-3-yl] acetic acid; SCD-1 inhibitor CCR-2 antagonist; dopamine receptor agonist (bromocryptine mesylate [Cycloset]); 4- (3- (2,6-dimethylbenzyloxy) phenyl) -4-oxobutanoic acid; sirtuin stimulant; and other DPP IV inhibitors Agent.

Metformin is usually administered at doses from about 500 mg to 2000 mg, up to 2500 mg per day using the following various dose regimens: about 100 mg to 500 mg, or 200 mg to 850 mg (1-3 times daily), or about. 300 mg to 1000 mg once or twice daily, or sustained release metformin, about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice daily, or about 500 mg to 2000 mg once daily. Specific dosage intensities can be metformin hydrochloride 250, 500, 625, 750, 850 and 1000 mg.
For children aged 10 to 16 years, the recommended starting dose of metformin is 500 mg once daily. If this dose does not give adequate results, the dose can be increased to 500 mg twice daily. Further increases can be made by increasing the daily dose up to 2000 mg by 500 mg weekly and in divided doses (eg, 2 to 3 divided doses). Metformin can be given with food to reduce nausea.
The dosage of pioglitazone is usually about 1-10 mg, 15 mg, 30 mg or 45 mg once daily.
Rosiglitazone is usually given in doses of 4 to 8 mg once (or in two divided doses) daily (typical dosing intensity is 2, 4 and 8 mg).
Glibenclamide (glibrid) is usually given at a dose of 2.5-20 mg once (or in two divided doses) daily (typical dosage intensities are 1.25, 2.5 and 5 mg) or micronized glibenclamide. Is administered at a dose of 0.75-3 to 12 mg once (or in two divided doses) daily (typical dosing intensities are 1.5, 3, 4.5 and 6 mg).
Glipizide is usually given at a dose of 2.5 to 10-20 mg once daily (or up to 40 mg in two divided doses) (typical dosing intensity is 5 and 10 mg), or long-term release glibenclamide. It is given in doses of 5 to 10 mg (up to 20 mg) once daily (typical dosing intensities are 2.5, 5 and 10 mg).
Glimepiride is usually given in doses of 1-2 to 4 mg (up to 8 mg) once daily (typical dosing intensity is 1, 2 and 4 mg).

The glibenclamide / metformin dual combination is usually given at 1.25 / 250 once daily to 10/1000 mg twice daily (typical dose intensities are 1.25 / 250, 2.5 / 500 and 5). / 500 mg).
The two-drug combination of glipizide / metformin is usually given in doses of 2.5 / 250 to 10/1000 mg twice daily (typical dosage intensities are 2.5 / 250, 2.5 / 500 and 5/500 mg). ..
The glimepiride / metformin dual combination is usually given at 1/250 to 4/1000 mg in twice-daily doses.
The rosiglitazone / glimepiride dual combination is usually given at doses of 4/1 once or twice daily to 4/2 mg twice daily (typical dosing intensity is 4/1, 4). / 2, 4/4, 8/2 and 8/4 mg).
The pioglitazone / glimepiride dual combination is usually given at 30/2 to 30/4 mg once daily (typical dosing intensity is 30/4 and 45/4 mg).
The rosiglitazone / metformin dual combination is usually given at 1/500 to 4/1000 mg twice daily (typical dosing intensities are 1/500, 2/500, 4/500, 2). / 1000 and 4/1000 mg).
The pioglitazone / metformin dual combination is usually given at 15/500 once or twice daily to 15/850 mg three times daily (typical dosing intensity is 15/500 and 15 /). 850 mg).

The non-sulfonylurea insulin-promoting agent nateglinide is usually given with a meal at a dose of 60 to 120 mg (up to 360 mg / day, typical dosing intensity is 60 and 120 mg); repaglinide is usually 0.5 mg. Administered with meals at doses from to 4 mg (up to 16 mg / day, typical dosing intensities are 0.5, 1 and 2 mg). The repaglinide / metformin dual combination is available at 1/500 and 2/850 mg dosing intensities.
Acarbose is usually given with a meal in doses of 25 to 100 mg. Miglitol is usually given with a meal in doses of 25 to 100 mg.
Examples of combination partners that lower blood lipid levels are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, robastatin, fluvastatin, pravastatin, pitabastatin and losbustatin; fibrates such as bezafibrate, phenofibrate, clofibrate. , Gemfibrodil, etofibrate and etophyllinkrofibrate; nicotinic acid and its derivatives such as acipimox; PPAR-alpha agonist; PPAR-delta agonist, eg {4-[(R) -2-ethoxy-3- (4-) Trifluoromethyl-phenoxy) -propylsulfanyl] -2-methyl-henoxy} -acetic acid; acyl-coase A; cholesterol acyltransferase (ACAT; EC2.3.1.26), eg avasimib; cholesterol absorption inhibitor, eg ezetimib; Bile acid-binding substances such as cholestyramine, cholesterol and cholesterol; bile acid transport inhibitors; HDL-regulating active substances such as D4F, reverse D4F, LXR-regulating active substances and FXR-regulating active substances; CETP inhibitors such as tolcetrapib, JTT-705. (Dalcetrapib) or a compound of WO 2007/005572 (anacetrapib) or evasetrapib; LDL receptor regulator; MTP inhibitor (eg, lomitapide); and ApoB100 antisense RNA.
The dose of atorvastatin is usually 1 mg to 40 mg or 10 mg to 80 mg once daily.

Examples of combination partners that lower blood pressure are beta blockers such as atenolol, bisoprolol, seriprol, metprolol, nifevolol and carvegilol; diuretics such as hydrochlorothiazide, chlortalidone, xipamide, frosemide, pyrethanide, trasemide, spironolactone, eprelenone, amlodipine and triam. Calcium channel blockers such as amlodipine, nifedipine, nitrendine, nisoldipine, nicardipine, ferrodipine, lasidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, galopamil and diltiazem; ACE inhibitors such as lamipril, lisinopril, lisinopril , Benazepril, perindopril, fosinopril and trandrapril; and angiotensin II receptor blockers (ARBs) such as thermisartan, candesartan, balsartan, losartan, ilbesartan, ormesartan, azilsartan and eprosartan.
The dosage of telmisartan is usually 20 mg to 320 mg, or 40 mg to 160 mg / day.
Examples of combination partners that increase plasma levels are cholesteryl ester transfer protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1; LXR alpha antagonists; LXR beta agonists; PPAR-delta agonists; LXR alpha. / Beta regulators and substances that increase the expression and / or plasma concentration of apolipoprotein AI.

Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); allyzyme (cetilystat); dexphenfluramine; acoxins; cannabinoid receptor 1 antagonists such as CB1 antagonist remonobant; MCH-1 receptor antagonist; MC4 receptor agonists; NPY5, NPY2 antagonists in addition to the above (eg Berneperito); beta 3-AR agonists such as SB-418790 and AD-9677; 5HT2C receptor agonists such as APD356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; Stelloyl CoA desaturase (SCD1) inhibitor; fatty acid synthase (FAS) inhibitor; CCK receptor agonist; gerelin receptor regulator; Pyy3-36; olexin receptor antagonist; and tesofencin; Bupropion / Zonisamide, Topiramate / Fentermin and Plumlyntide / Metrereptin.
Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; tyrosine kinase inhibitors (50 mg to 600 mg), such as PDGF-receptor kinase (EP-A-564409, WO 98/35958, US 5093330). , WO 2004/005281 and WO 2006/041976); oxLDL antibody and oxLDL vaccine; Apo A-1 Milano; ASA; and VCAM-1 inhibitor.

Furthermore, within the scope of the invention, the DPP-4 inhibitor can optionally be combined with one or more 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 tetomilast, roflumilast, or 3- [7-ethyl-2- (methoxymethyl)-. 4- (5-Methyl-3-pyridinyl) pyrolo [1,2-b] pyrizadin-3-yl] propanoic acid (or US 7153854, WO 2004/063197, US 7459451 and / or WO 2006/004188. Other species).
Yet another example of an anti-inflammatory partner drug is a caspase inhibitor such as (3S) -5-fluoro-3-({[(5R) -5-isopropyl-3-(1-isoquinolinyl) -4,5-dihydro). -5-isoxazolyl] carbonyl} amino-4-oxopentanoic acid (or other species disclosed in WO 2005/021516 and / or WO 2006/090997).
An example of a vascular endothelial protectant is a PDE-5 inhibitor such as sildenafil, verdenafil or tadalafil, another example of a vascular endothelial protectant is a nitric oxide donor or stimulant (eg L-arginine or tetrahydrobiopterin).

Furthermore, within the scope of the invention, further 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. It can be combined with a / COX-2 inhibitor, or ADP receptor inhibitor, such as thienopyridine (eg, crepidogrel or prasugrel), erinogrel or ticagrel, or a thrombin receptor antagonist, such as volapaxer.
Furthermore, within the scope of the invention, further optionally, the DPP-4 inhibitor is one or more anticoagulants, such as heparin, warfarin, or a direct thrombin inhibitor (eg, dabigatran), or a factor Xa inhibitor (eg, eg). It can be combined with rivaloxaban or apixaban or edoxaban or otamixaban).
Furthermore, within the scope of the invention, further optionally, the DPP-4 inhibitor can be combined with one or more agents for the treatment of heart failure.
Examples of combination partners for the treatment of heart failure are beta blockers such as atenolol, bisoprol, seriprolol, metoprolol and nevibolol; diuretics such as hydrochlorothiazide, chlortalidone, xipamide, frosemide, pyretanide, trasemido, spironolactone, eprelenone, amylolide and triamterene. ACE inhibitors such as lamipril, lisinopril, spirazapril, quinapril, captopril, enarapril, benazepril, perindopril, fosinopril and trandrapril; angiotensin II receptor blockers (ARBs) such as thermisartan, candesartan, balsartan, losartan, losartan, losartan, losartan Losartan; cardiac glycosides such as digoxin and digitoxin; bound alpha / beta blockers such as carvediol; vasodilators; antiarrhythmic agents; or type B sodium excretion-increasing peptides (BNPs) and BNP-inducible peptides and BNP-fusion products. be.
Furthermore, within the scope of the invention, further optionally, the DPP-4 inhibitor is irreversible in addition to one or more CCK-2 or gastrin agonists such as proton pump inhibitors (H + / K + -ATPase reversible inhibitors). Can be combined with (including sex inhibitors), such as omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.

The invention should not be limited in scope by the individual embodiments described herein. Various modifications in addition to those described herein will be apparent to those of skill in the art from this disclosure. Such modifications are within the scope of the present invention.
All patent applications cited herein are hereby incorporated by reference in their entirety.

Some specific embodiments of the present invention are exemplified below.
(1) Use of linagliptin for the preparation of pharmaceutical compositions for use in any one or more of the following methods:
Type 1 diabetes mellitus, type 2 diabetes mellitus, glucose tolerance disorder (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, abnormal lipemia, hyperlipidemia, hypercholesterolemia, hyperglycemia, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD) ), Retinopathy, Neuropathy, Nephropathy, Polycystic Ovary Syndrome, and / or Methods of Preventing, Delaying, Prolonging, or Treating Metabolic Abnormalities or Diseases Selected from Metabolic Syndrome;
-Methods for improving and / or maintaining glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevents, slows, prolongs, or progresses prediabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), insulin resistance, and / or progression from metabolic syndrome to type 2 diabetes mellitus. How to reverse;
-Microvascular or macrovascular disease, nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive abnormalities, cardiovascular system Or cerebrovascular disease, tissue ischemia, diabetic foot or diabetic ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arteries How to prevent, reduce the risk of, slow, prolong, or treat the complications of diabetes mellitus, which is obstructive disease, myocardial disease, heart failure, cardiac rhythm abnormalities, vascular re-stenosis, and / or stroke. ;
-A method of reducing body weight and / or body fat, or preventing an increase in body weight and / or body fat, or promoting a decrease in body weight and / or body fat;
-How to prevent, slow down, or treat pancreatic beta cell degeneration and / or diminished functionality of pancreatic beta cells, and / or to improve, retain, and / or restore pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the functionality of pancreatic insulin secretion;
-How to prevent, slow down, prolong or treat non-alcoholic steatohepatitis (NAFLD), liver fatty disease, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis;
-How to prevent, slow down, prolong, or treat type 2 diabetes, where conventional anti-diabetes alone or combination therapy has failed;
-How to achieve the reduction in the dose of conventional anti-diabetes drugs required for proper therapeutic effect;
-How to reduce the risk of side effects associated with conventional anti-diabetes; and / or-How to maintain and / or improve insulin sensitivity, and / or to treat or prevent hyperinsulinemia and / or insulin resistance the method of;
In one or more of
Patients with or at risk for cardiovascular and / or renal disease, or have one or more cardiovascular risk factors selected from A), B), C) and D) below. In patients, using linagliptin,
A method for using said linagliptin, wherein the method comprises administering to the patient a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents:
A) Previous or existing pulse selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure, and peripheral obstructive arterial disease. Vascular disease;
B) Vascular-related terminal organ diseases selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and microalbumin or macroalbuminuria;
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin tolerance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.
(2) The use according to (1), wherein the method comprises the treatment of type 2 diabetes mellitus.
(3) Cardiovascular disease in which the patient is selected from myocardial infarction, stroke, peripheral arterial obstructive disease, diabetic nephropathy, microalbuminuria or macroalbuminuria, acute or chronic nephropathy, hyperuricemia, and / or hypertension. The use according to (1) or (2), which is a type 2 diabetic patient who has or is at risk for vascular disease and / or renal disease.
(4) Any of (1) to (3), the patient is a type 2 diabetic patient having one or more of the cardiovascular risk factors selected from the following A), B), C) and D). Use described in Crab:
A) Previous or existing pulse selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure, and peripheral obstructive arterial disease. Vascular disease;
B) Vascular-related terminal organ diseases selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and microalbumin or macroalbuminuria;
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin tolerance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.
(5) Cardiovascular system or cerebrovascular system selected from cardiovascular death, myocardial infarction, stroke and hospitalization (eg due to acute coronary syndrome, leg amputation, revascularization, heart failure or unstable angina) A method of preventing the appearance of sexual events, preferably in patients with type 2 diabetes, reducing the risk of appearance, or prolonging the appearance, wherein the method optionally comprises one or more therapeutically effective amounts of linagliptin. Use of linagliptin for the preparation of a pharmaceutical composition for use in the method, comprising the step of administering to the patient in need thereof along with other therapeutic agents.
(6) Patients with type 2 diabetes are at risk for cardiovascular or cerebrovascular events and are associated with one or more of the risk factors selected from A), B), C) and D) below. Use described in (5):
A) Previous or existing vessels selected from myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attacks, congestive heart failure, and peripheral obstructive arterial disease. System diseases;
B) Vascular-related terminal organ diseases selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and microalbumin or macroalbuminuria;
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin tolerance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree.
(7) Patients with type 2 diabetes have vascular-related terminal organ diseases selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and microalbumin or macroalbuminuria, (5) or Use as described in (6).
(8) Cardiovascular system or brain The appearance of cardiovascular or cerebrovascular events selected from hospitalization for cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke and unstable angina. A method of preventing, reducing or prolonging the risk of appearance in patients with type 2 diabetes at risk of vascular events, with a therapeutically effective amount of linagliptin, optionally one or more other therapeutic agents. Use of linagliptin for the preparation of a pharmaceutical composition for use in said method, comprising the step of administering to the patient together with.
(9) The use according to any one of (5) to (8), wherein the type 2 diabetic patient has nephropathy, renal dysfunction, chronic renal disease, and / or microalbumin or macroalbuminuria.
(10) The use according to any one of (5) to (9), wherein the type 2 diabetic patient has mild, moderate or severe renal disorder or end-stage renal disease.
(11) The use according to any one of (5) to (10), wherein the type 2 diabetic patient has microalbuminuria or diabetic nephropathy.
(12) One or more other therapeutic substances include other anti-diabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, active substances that raise blood HDL levels, and lower blood pressure. The active substance to be caused, an active substance indicated in the treatment of atherosclerosis or obesity, an anti-platelet agent, an anti-coagulant, and a vascular endothelial protective agent, which is described in any of (1) to (11). use.
(13) Other anti-diabetic substances are selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogs, and GLP-1 and GLP-1 analogs. , (12).
(14) The use according to (12) or (13), wherein the active substance that lowers blood pressure is selected from angiotensin receptor blocker (ARB), angiotensin converting enzyme (ACE) inhibitor, and beta-blocker.
(15) The angiotensin receptor blocker (ARB) is thermisartan and / or the angiotensin converting enzyme (ACE) inhibitor is ramipril and / or the beta-blocker is carvedilol, neviball or metoprolol, according to (14). Use of.
(16) The active substance that lowers blood lipid levels and / or raises blood HDL levels is selected from statins, nicotinic acid or derivatives thereof, fibrates, cholesterol absorption inhibitors, and bile acid blockers. Use according to any one of (12) to (15).
(17) The statin is atorvastatin, simvastatin or rosuvastatin, and / or nicotinic acid or a derivative thereof is niacin, and / or fibrate is phenofibrate, and / or the cholesterol absorption inhibitor is ezetimive. And / or the use according to (16), wherein the bile acid sequestering agent is colesevelam.
(18) The use according to any of (12) to (17), wherein the antiplatelet agent is selected from low dose aspirin, clopidogrel, prasugrel, borapaxer and chicagrel.
(19) The use according to any of (12) to (18), wherein the anticoagulant is selected from heparin, warfarin, dabigatran, rivaloxaban and apixaban.
(20) The method further selects linagliptin from metformin, sulfonylurea, nateglycinide, repaglinide, thiazolidinedione, PPAR-gamma agonist, alpha-glucosidase inhibitor, insulin or insulin analog, and GLP-1 or GLP-1 analog 1 The use according to any of (1) to (19), comprising the step of administering with one or more other anti-diabetic substances, and optionally thermisartan.
(21) The use according to any one of (1) to (20), wherein the method further comprises the step of administering linagliptin together with metformin.
(22) The use according to any one of (1) to 20, wherein the method further comprises the step of administering linagliptin together with telmisartan.
(23) The use according to any one of (1) to (20), wherein the method comprises the step of administering a pharmaceutical composition containing linagliptin and metformin.
(24) The use according to any one of (1) to (23), wherein linagliptin is orally administered in a total daily dose of 5 mg.
(25) In the patient
-Treat and prevent ischemic / reperfusion injury (in the kidney, heart, brain or liver), reduce its risk, slow its progression, prolong, weaken or reverse its onset, and / or the heart Reduces myocardial infarction size; or-may be characterized by hypertrophy of myocardial cells, interstitial fibrosis, ventricular dilatation, systolic dysfunction and / or cell death / apoptosis, (harmful) vascular remodeling, eg cardiac remodeling. Whether to treat, prevent, mitigate its risk, slow its progression, prolong, weaken, or reverse its onset; or-treat and prevent chronic or acute renal failure and / or peripheral arterial occlusion. , Reduce its risk, slow its progression, prolong, weaken, or reverse its onset; or-treat and prevent congestive heart failure and / or cardiac hypertrophy and / or nephropathy and / or albuminuria And reduce its risk, slow its progression, prolong its onset, weaken or reverse it; or-treat and prevent urotoxic cardiomyopathy, interstitial dilation, and / or (cardiac) fibrosis. A method of reducing its risk, slowing its progression, prolonging, weakening, or reversing its onset, in which an effective amount of linagliptin is optionally combined with an effective amount of one or more other active agents. Use of linagliptin for the preparation of pharmaceutical compositions for use in said methods comprising the step of administering to.
(26) Prevent diabetic nephropathy in patients who do not respond appropriately to treatment with angiotensin receptor blockers (ARBs), reduce its risk, slow its progression, prolong its onset, weaken, reverse or treat it. A pharmaceutical composition for use in a method, comprising the step of administering to the patient a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents. Use of linagliptin for preparation.
(27) Preparation of pharmaceutical compositions for use in methods of using linagliptin with telmisartan to treat diabetic nephropathy, including albuminuria, in patients who do not respond appropriately to angiotensin receptor blockers (ARBs). Use of linagliptin for.
(28) The use according to (26), wherein the method comprises administering a therapeutically effective amount of linagliptin in combination with ARB.
(29) The use according to (28), wherein the ARB is telmisartan.
(30) The use according to (26)-(29), wherein linagliptin is orally administered at a total daily dose of 5 mg.
(31) Use of linagliptin for the preparation of pharmaceutical compositions for use in methods of treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction in patients with sepsis.
(32) The use according to (31), wherein the patient has non-diabetic sepsis or diabetic sepsis.
(33) Use of linagliptin for the preparation of pharmaceutical compositions for the treatment and / or prevention of sepsis.

Yet another embodiment, feature and advantage of the present invention will be apparent from the following examples. The following examples are provided to illustrate and illustrate the principles of the invention without limiting the invention.

Antioxidant :
Linagliptin's anti-inflammatory and vasodilatory potential Glyptin (linagliptin, alogliptin, vildagliptin, saxagliptin, sitagliptin) has a direct antioxidant effect on xanthine oxidase, peroxidase (intrinsic and Sin-1 inducible) or hydrogen peroxide. / Peroxidase mediated 1-Electronic-Assessed by obstruction of superoxide formation by oxidation. These oxidations are detected by phenol fluorescence, chemiluminescence and nitrification (traced by HPLC). The indirect antioxidant activity of glyptin was measured in isolated human leukocytes (PMN) by interfering with oxidative bursts (NADPH oxidase activation) induced by formorester PDBu, endotoxin LPS and timosan A and the chemotactic peptide fMLP. To.
The direct vasodilatory effect of glyptin is measured by isometric tension techniques in isolated vascular ring fragments. The indirect antioxidant effect of linagliptin is also nitroglycerin-induced nitrate resistance and acetylcholine in the phenylefrin precontracted aortic vascular fragment in a rat model of linagliptin treatment (3-10 mg / kg / day for 7 days with special diet). -Dependent relaxation), smooth muscle function (nitroglycerin-dependent relaxation) is tested by measurement by isotonic tension recording. Furthermore, reactive oxygen and nitrogen species (RONS) formation is measured in isolated cardiac mitochondria and in whole blood LPS or PDBu-initiated oxidation bursts. Furthermore, the anti-inflammatory potential of linagliptin will be tested in an experimental model of LPS (10 mg / kg 24-hour ip) -induced septic shock in Wistar rats. The effects of sepsis and linagliptin co-therapy (7-day special diet 3-10 mg / kg / day) are determined by isotonic tension recording, vascular, cardiac and vascular RONS formation and protein expression by Western blotting.

Result :
(See Figure 1-6)
Direct antioxidant properties :
Only all glyptins showed inadequate direct antioxidant capacity. A slight (but significant) inhibition of superoxide formation is observed for vildagliptin and linagliptin in response to peroxynitrite formation / -mediated nitrification. All glyptins except saxagliptin show significant interference with 1-electron oxidation by the hydrogen peroxide / peroxidase system, with linagliptin being the most potent compound.
Indirect antioxidant properties in isolated human neutrophils : Linagliptin exhibits the best inhibition of the oxidative burst of isolated human leukocytes in response to NADPH oxidase activation by LPS and Timosan A. When L-012 enhanced chemiluminescence was used, LPS (0.5, 5 and 50 μg / mL) increased the PMN-derived RONS signal in a concentration-dependent manner, and linagliptin suppressed this signal in a concentration-dependent manner.
In experiments with luminos / peroxidases that enhance chemiluminescence, linagliptin is far more effective than other glyptins in suppressing LPS or thymosan A-initiated oxidative bursts of isolated PMNs. In this assay, linagliptin is as effective as nebivolol. This efficacy of inhibiting LPS-dependent RONS formation is somewhat stronger than its inhibitory effect on Timosan A-initiated RONS. All of these measurements support the superior antioxidant activity of linagliptin in isolated neutrophils when compared to other glyptins.
Inhibition of Adhesion of Activated Neutrophils to Endothelial Cells : By Examining Adhesion of LPS-Stimulated Human Neutrophils to Cultured Endothelial Cells (Number of Adhesive PMNs is PDBu-Started Oxidation Burst (Amplex Red / Peroxidase Fluorescence Measurements) Correlates with)), linagliptin suppresses the adhesion of leukocytes to endothelial cells in the presence of LPS.

Treatment of vascular dysfunction and / or oxidative stress :
Effect of Linagliptin Treatment on Vascular Dysfunction and Oxidative Stress in Nitrate-Resistant Rats : Equal length tension experiments in organ baths reveal that nitroglycerin and LPS treatment induces significant endothelial dysfunction and nitrate resistance. .. Endothelial dysfunction caused by both factors is significantly improved by linagliptin therapy (FIGS. 8A and 8B), but nitrate tolerance does not change. Nitroglycerin treatment causes ROS formation in cardiac mitochondria and LPS / Timosan A-initiated oxidative bursts in whole blood. All of these side effects are ameliorated by linagliptin treatment (Fig. 7). Neither nitroglycerin treatment nor linagliptin treatment affects animal body weight, but blood glucose levels are slightly increased in the nitroglycerin group, which is normalized by linagliptin treatment.
In summary, in vivo treatment of linagliptin alleviates nitroglycerin-induced endothelial dysfunction and also shows a slight improvement in isolated cardiac mitochondrial ROS formation and nitrate-tolerant rat-derived whole blood oxidative bursts.
Effect of linagliptin on vascular dysfunction and oxidative stress in septic rats : A very similar protective effect of linagliptin is observed in an experimental model of septic shock. Vascular function (Ach-, GTN-, and diethylamine NONOate-dependent relaxation) is severely impaired by LPS, which is largely normalized by linagliptin treatment. Mitochondrial and whole blood (LPS, PDBu-stimulated) RONS production is dramatically increased by LPS and ameliorated by linagliptin treatment. Vascular oxidative stress (measured by DHE-dependent fluorescence microscopy) and vascular inflammation markers (VCAM-1, Cox-2, and NOS-2) are dramatically increased by LPS treatment and significantly improved by linagliptin therapy. Similar effects are observed for aortic protein tyrosine nitrification and malondialdehyde content (both are markers of oxidative stress) and aortic NADPH oxidase subunit expression (Nox1 and Nox2). As evidence of the concept, DPP-4 activity and GLP-1 levels were detected in the corresponding animals, revealing a strong inhibition of DPP-4 and a nearly 10-fold increase in plasma GLP-1 levels.
Direct vasodilatory effects of glyptin : Isometric tension records show that some glyptins show direct vasodilatory effects in the 10-100 μM concentration range. Linagliptin is the most potent compound, followed by alogliptin and vildagliptin, while sitagliptin and saxagliptin are less effective than solvent control (DMSO) in inducing vasodilation (see Figures 9A and 9B).
These observations support the multifaceted antioxidant and anti-inflammatory properties of linagliptin, which are not (or to a small extent) shared with other glyptins. Furthermore, linagliptin reduces leukocyte adhesion to endothelial cells due to the presence of LPS and further improves nitroglycerin-induced and inflammation-induced endothelial dysfunction and oxidative stress. This may contribute to improving the endothelial function of linagliptin and supporting the cardioprotective effect. Therefore, there is evidence that linagliptin imparts antioxidant effects that have a beneficial effect on cardiovascular disease, secondary to diabetic complications with high levels of prevalence and mortality.

Treatment of diabetic nephropathy and albuminuria :
Endothelial damage is characteristic of type 2 diabetes and contributes to its progression to end-stage renal disease. Furthermore, NO synthase (eNOS) activity in the vascular endothelium is altered in T2D, and genetic abnormalities in the corresponding gene (NOS3) are closely linked to the further progression of diabetic nephropathy in patients with type 1 and type 2 diabetes. Involved. The use of low doses of STZ to induce T2D in this genetic phenotype (eNOS-/-) has recently been reported (Brosius et al. JASN 2009) and is a valid experimental model for DN. Intraperitoneal injection of streptozotocin (100 mg / kg / day for 2 consecutive days) makes 8-week-old eNOS-/-mice diabetic. The onset of diabetes (blood glucose is defined as> 250 mg / dL) is demonstrated 1 week after streptozotocin injection. Insulin is not given because it can prevent the development of diabetic nephropathy. Treat mice for 4 weeks with:
1) Non-diabetic control mouse, placebo (Natrosol) (n = 14)
2) Placebo (natrosol) (n = 17), placebo (natrosol), diabetic eNOS ko mouse
3) Telmisartan (po 1 mg / kg) treated diabetic eNOS ko mice (n = 17)
4) Linagliptin inhibitor (po 3mg / kg) treated diabetic eNOS ko mice (n = 14)
5) Telmisartan (1 mg / kg) + linagliptin (3 mg / kg) treated diabetic eNOS ko mice (n = 12)
Renal function (s-creatinine, albumin) and blood glucose levels are detected.
No significant difference in blood glucose in STZ-treated animals was detected between linagliptin, telmisartan or the combination described above and placebo (see Figure 10).
Although no effect on blood glucose was detected, the albumin / creatinine ratio was significantly reduced in the linagliptin + telmisartan group (middle bar, 5 in Figure 11). The corresponding one-drug treatment also reduces the albumin / creatinine ratio, but it is not significant. The albumin / creatinine ratio in non-diabetic to diabetic animals is also significantly reduced (see Figure 11). These effects support the use of linagliptin and telmisartan in renal protection and in the treatment and / or prevention of diabetic nephropathy and albuminuria. The combination of linagliptin and telmisartan provides a novel therapeutic approach for patients with diabetic nephropathy and albuminuria or at risk thereof.

Treatment of Congestive Heart Failure and Cardiac Hypertrophy :
We propose the hypothesis that glucose / energy supply is particularly important in cardiac dysfunction characterized by cardiac hypertrophy. Inappropriate energy supply is considered to be one of the most important steps from compensatory to compensatory left ventricular hypertrophy leading to cardiac dysfunction. The classic model of hypertension-induced left ventricular hypertrophy caused by long-lasting left ventricular insufficiency and pathological remodeling is the 2 kidney 1 renal vascular stenosis hypertension (gold bat) model (2K1C model).
Animals are treated with a regimen of up to 3 months:
1.2K1C-rat, telmisartan in drinking water (10mg / kg KG) (n = 14)
2.2K1C-rat, linagliptin (Bl1356) in the diet (89ppm, 3-10mg / kg comparable to oral gastric tube nutrition) (n = 15)
3.2K1C-rat, telmisartan (10mg / kg) + linagliptin (Bl1356) (89ppm) (n = 15) in the diet
4.2 K1C-rat, placebo (n = 17)
Five. SHAM-rat, placebo (n = 11)
Non-invasive, systolic blood pressure is measured at multiple time points in all groups (for each compound, 1. before treatment; 2. 1 week after treatment; 3. 4 weeks after treatment; 4. 6 weeks after treatment. After; 5. 12 weeks after treatment; and 6. 6 weeks after treatment).
Prior to treatment, only mimicry treated animals show significant differences from the other groups. From the first week of treatment to the end of the experiment, telmisartan and combinations of telmisartan with linagliptin are always significant for excipient-treated animals. The combination of telmisartan and linagliptin reaches the level of placebo-mimetically treated animals and shows additional effects in addition to telmisartan 1-drug treatment (see Figure 12). These effects support the use of linagliptin and telmisartan for the treatment and / or prevention of cardiac hypertrophy and / or congestive heart failure. The combination of linagliptin and telmisartan provides a novel therapeutic approach for patients with or at risk of cardiac hypertrophy and / or congestive heart failure.

Treatment of uremic cardiomyopathy :
Uremia cardiomyopathy is a substantial contributor to the prevalence and mortality of patients with chronic kidney disease, which is also a frequent complication of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) can improve cardiac function, and GLP-1 is primarily degraded by dipeptidyl peptidase (DPP-4). Linagliptin is the only DPP-4 inhibitor that can be used clinically (eg, in patients with type 2 diabetes and diabetic nephropathy) without dose adjustment in all stages of renal failure.
Scrutinize linagliptin in a rat model with chronic renal dysfunction (5/6 nephrectomy [5 / 6N]) : 5 / 6N or 8 weeks after sham surgery, give the rat 3.3 mg / kg linagliptin or Orally treated with the form for 4 weeks, followed by sampling plasma for 72 hours for quantification of DPP-4 activity and GLP-1 levels. At the end of the experiment, heart tissue is collected for mRNA analysis.
5 / 6N markedly decreased (p <0.01) GFR (measured by creatinine clearance) (2510 ± 210 mU24h for mimic surgery; 1665 ± 104.3 mU24h for 5 / 6N) and increased cystatin levels (700 for mimic surgery). It causes ± 35.7 ng / mL; 1434 ± 77.6 ng / mL at 5 / 6N. DPP-4 activity was significantly reduced at all time points and there was no difference between mimicry surgery and 5 / 6N animals. In contrast, active GLP-1 levels were maximum plasma concentration (C _max ; 6.36 ± 2.58 pg / mL for 5 / 6N, 3.91 ± 1.86 pg / mL for mimicry surgery) and AUC _(0-72h) (5). It increases significantly in 5 / 6N animals when measured by 201 pg.h / mL for 6N and 114 pg.h / mL for mimicry surgery; p <0.001). Cardiac fibrosis markers (prefibrosis factors) such as TGF-β, a tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and collagen 1α1 and 3α1 plus left ventricular dysfunction markers such as brain sodium excretion-increasing peptides ( BNP) mRNA levels are significantly increased at 5 / 6N in all mimicry surgical animals, resulting in reduction or normalization by linagliptin treatment (all p <0.05, see FIG. 13).
Linagliptin increases the AUC of GLP-1 almost 2-fold in a rat renal failure model, and in the heart of uremic rats, in addition to BNP (marker of left ventricular dysfunction), a marker of cardiac fibrosis (TGF-β, It reduces the gene expression of TIMP-1, Col1α1 and Col3α1). These effects support the use of linagliptin in the treatment and / or prevention of uremic cardiomyopathy. Linagliptin provides a new therapeutic approach for patients with uremic cardiomyopathy.

Effects on infarct size and cardiac function after myocardial ischemia / reperfusion :
The purpose of this experiment is to control the cardiac effects of the xanthine-based DPP-4 inhibitors of the present invention (particularly the effects on myocardial ischemia / reperfusion, cardiac function or infarct size), for example, stromal cell-derived factor-1alpha (SDF-). It is to be evaluated by the symptoms involving 1α).
Male Wistar rats are divided into the following three groups: mimic surgery, ischemia / reperfusion (I / R), and I / R + DPP-4 inhibitor of the invention; n = 10 / group. DPP-4 inhibitors are given once daily starting 2 days before I / R. The left ventral descending coronary artery is ligated for 30 minutes. Echocardiography is performed 5 days later, and cardiac catheterization is performed 7 days later. DPP-4 inhibitors included absolute infarct size (-27.8%; p <0.05), ratio of infarcted tissue to total risk area (-18.5%; p <0.05), and range of myocardial fibrosis (-31.6%; It significantly reduces p <0.05). DPP-4 inhibitors significantly increase the accumulation of stem / progenitor cells characterized by CD34-, CXCR4- and C-kit-expression and cardiac immune responsiveness to active SDF-1α of infarcted myocardium. The left ventricular pumping fraction is similar in all MI groups after 7 days, but DPP-4 inhibition reduces infarct size, reduces fibrous remodeling, and further blocks the degradation of SDF-1α in the infarct region. Increases stem cell density.
The xanthine-based DPP-4 inhibitor of the present invention can reduce the infarct size after myocardial infarction. Mechanisms of action can include decreased degradation of SDF-1α and subsequent ^{increased recruitment of circulating CXCR-4 +} stem cells and / or incretin receptor-dependent pathways.
These data show that in the treatment or prevention of myocardial ischemia / reperfusion and / or cardiac protection, increased stem cell replacement, improved tissue repair, activated myocardial regeneration, decreased infarct size, decreased fibrous remodeling. And / or enhance the usefulness of the xanthin-based DPP-4 inhibitors of the invention in increasing the density of stem cells in the infarcted heart region.
According to the fact that infarct size is a predictor of future events (including mortality), the xanthin-based DPP-4 inhibitors of the present invention are cardiac (systolic) function, cardiac contractility and / or myocardial deficiency. It may be more useful for improving mortality after blood / reperfusion.

Effect of linagliptin on infarct size and cardiac function after myocardial ischemia / reperfusion :
Materials and Methods : Male Wistar rats are divided into the following three groups: pseudosurgery, I / R, and I / R + linagliptin (n = 16-18 / group). Linagliptin is started 30 days before I / R and is administered once daily (3 mg / kg). IR is triggered by a 30-minute ligation of the left ventral descending coronary artery, with echocardiography 58 days later and cardiac catheterization 60 days later.
Linagliptin reduces the absolute infarct size (-18%; p <0.05) in addition to the ratio of infarcted tissue to total risk area (-21%; p <0.001) in this ischemia-reperfusion injury model. Furthermore, glucagon-like peptide-1 (GLP-1) levels are increased 18-fold (p <0.0001) and DPP-4 activity is decreased by 78% (p <0.0001). Echocardiographic parameters were similar between groups in addition to left ventricular left ventricular diastolic and systolic pressure, with _{a marked improvement in the isotropic contractile index (dP / dT min} ) (-4771 ± 79 mmHg / s to -4957). ± 73 mmHg / s) or shows an improvement in the maximum rate of decrease in left ventricular pressure. These data further support the cardioprotective function of linagliptin at the onset of acute myocardial infarction.

Treatment of ARB-resistant diabetic nephropathy :
The demand for ameliorated treatment for diabetic nephropathy is extremely high in patients who do not respond appropriately to angiotensin receptor blockers (ARBs). In this experiment, the effect of linagliptin alone or in combination with ARB telmisartan on the progression of diabetic nephropathy in diabetic eNOS ko mice (a novel model similar to human pathology) will be investigated.
Sixty-five male eNOS knockout C57BL / 6J mice were divided into the following four groups after intraperitoneal administration of high-dose streptozosine: telmisartan (1 mg / kg), linagliptin (3 mg / kg), linagliptin + thermisartan (3 + 1 mg /). kg), and excipients. 14 mice are used as non-diabetic controls. After 12 weeks, urine and blood are obtained and blood pressure is measured. Glucose levels increased, which is similar in all diabetic groups. Telmisartan alone mildly (5.9 mmHg) lowers blood pressure (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; n = 14; p = 0.071, respectively) for diabetes control, with all other treatments Not significant. The combination treatment significantly alleviates albuminuria compared to diabetes control (71.7 ± 15.3 μg / 24h vs 170.8 ± 34.2 μg / 24h; n = 12-13; p = 0.017), but thermisartan (97.8 ± 26.4). The effect of monotherapy with either μg / 24h; n = 14) or linagliptin (120.8 ± 37.7 μg / 24h; n = 11) is not statistically significant (see Figure 14). Linagliptin (alone and in combination) results in significantly lower plasma osteopontin levels compared to telmisartan alone (values similar to diabetes control). Plasma TNF-α concentrations were significantly lower in all treatment groups than in the excipient treatment group. Plasma neutrophil gelatinase-associated lipocalin (NGAL) levels are significantly increased after treatment with telmisartan compared to untreated diabetes control, and this effect is prevented by combination treatment with linagliptin.
Furthermore, although linagliptin (alone and in combination with telmisartan) significantly alleviates renal glomerulosclerosis compared to diabetes control when measured by histological score (2.1 +/- 0.0 vs 2.4 + /). -0.0; p <0.05), the mitigation achieved with telmisartan alone is not a significant difference. In conclusion, linagliptin significantly reduces urinary albumin excretion (eg, in a blood pressure-independent manner) in ARB-refractory diabetic eNOS knockout mice. These effects may support the use of linagliptin in renal protection and in the treatment and / or prevention of ARB-resistant diabetic nephropathy. Linagliptin can provide a novel therapeutic approach for patients who are resistant to ARB treatment.

Delays the onset of diabetes and retains beta cell function in non-obese type 1 diabetes :
Decreased pancreatic T cell migration and altered cytokine production are considered important factors in the development of insulinitis, but the exact mechanism and action in the pancreatic cell pool is not yet fully understood. An attempt to assess the effects of linagliptin on pancreatic inflammation and beta-cell mass, combining diabetic progression in non-obese diabetic (NOD) mice over a 60-day experimental period with a terminal serological assessment of pancreatic cellular changes. Investigate.
60 female NOD mice (10 weeks old) were included in this experiment and fed a normal diet or a linagliptin-containing (0.083 g linagliptin / kg diet; corresponding to 3-10 mg / kg (po)) diet throughout the experiment. .. Plasma samples are obtained every 2 weeks to determine the onset of diabetes (BG> 11 mmol / L). At the end, the pancreas is removed and a terminal blood sample is obtained for evaluation of active GLP-1 levels.
At the end of the experimental period, the incidence of diabetes was significantly reduced in linagliptin-treated mice (9 of 30 mice) compared to the control group (18 of 30 mice; p = 0.021). Subsequent serological assessments of beta cell mass (identified by insulin immunoreactivity) showed significantly higher beta cell mass (installer 0.18 ± 0.03 mg; linagliptin 0.48 ± 0.09 mg, p <0.01) in linagliptin-treated mice. The total island amount (injection 0.40 ± 0.04 mg; linagliptin 0.70 ± 0.09 mg, p <0.01) is shown. Linagliptin tends to have peri-island infiltrative lymphopenia (1.06 ± 0.15; linagliptin 0.79 ± 0.12 mg; p = 0.17). As expected, active plasma GLP-1 is high in linagliptin-treated mice.
In summary, the data show that linagliptin can delay the onset of diabetes in a type 1 diabetes model (NOD mice). The strong beta cell consoling effect observed in this animal model is that such DPP-4 inhibitors not only protect beta cells by increasing active GLP-1 levels, but also have direct or indirect anti-inflammatory effects. It shows that can be shown. These effects may support the use of linagliptin in the treatment and / or prevention of type 1 diabetes or latent autoimmune diabetes (LADA) in adults. Linagliptin may provide a novel therapeutic approach for patients with type 1 diabetes or LADA or at risk as described above.

Effects of linagliptin on body weight, total fat, liver fat and intramuscular fat :
In yet another experiment, the effects of long-term treatment of linagliptin on body weight, total fat, intramuscular fat and liver fat in a non-diabetic model of diet-induced obesity (DIO) will be investigated in comparison to appetite-suppressing subtramin.
Rats are fed a high-fat diet for 3 months, followed by an excipient, linagliptin (10 mg / kg) or sibutramine (5 mg / kg) for an additional 6 weeks to continue the high-fat diet. Magnetic resonance spectroscopy (MRS) analysis of whole fat, muscle fat and liver fat is performed before treatment and at the end of the experiment.
Sibutramine causes significant weight loss (-12%) compared to controls, but linagliptin shows no significant effect. Overall fat is also significantly reduced by sibutramine (-12%), but linagliptin-treated animals show no significant reduction (-5%). However, linagliptin and sibutramine result in a strong reduction in muscle intracellular fat (-24% and -34%, respectively). Furthermore, linagliptin treatment results in a severe reduction in liver fat (-39%), but the effect of sibutramine (-30%) is not significant (see table below). Therefore, linagliptin improves intracellular lipid and hepatic lipid accumulation, although it is unclear in terms of weight. Relief of hepatic steatosis, inflammation and fibrosis as measured by histological scoring is also observed for linagliptin treatment.

結論すれば、リナグリプチン処置は、筋細胞内脂質及び肝脂質の強い低下を惹起し、前記は両方とも体重低下とは別個である。リナグリプチン処置は、さらに別に肝脂肪症（例えばNAFLD）の影響を受ける糖尿病患者に対し更なる利益を提供する。シブトラミンの筋肉脂肪及び肝臓脂肪に対する影響は、主としてこの化合物によって誘発される既知の体重低下による。 Table: Effect of linagliptin on body weight, total fat, liver fat and intracellular fat in muscle cells

In conclusion, linagliptin treatment causes a strong decrease in muscle intracellular lipids and hepatic lipids, both of which are distinct from body weight loss. Linagliptin treatment also provides additional benefits for diabetic patients affected by hepatic steatosis (eg NAFLD). The effect of sibutramine on muscle and liver fat is primarily due to the known weight loss induced by this compound.

Linagliptin has similar efficacy to glimepiride, but improves cardiovascular safety over a two-year period in patients with type 2 diabetes improperly managed with metformin :
A two-year double-blind study will examine the long-term efficacy and safety of adding linagliptin or glimepiride to metformin in use for the treatment of type 2 diabetes. Patients with stable metformin (1500 mg / day or more) for 10 weeks or longer are voluntarily extracted for 2 years of linagliptin (5 mg / day, N = 764) or glimepiride (1-4 mg / day, N = 755). .. Efficacy analysis is based on changes in HbA1c from baseline in the complete analysis set (FAS) population and each protocol (PP) population. Safety assessment includes capture of pre-specified, predictive and further ruling cardiovascular (CV) events (CV death, non-fatal myocardial infarction or stroke, unstable angina with hospitalization). included. The characteristics of the baseline are well balanced in the two groups (HbA1c 7.7% for both groups). In the PP population, adjusted mean (± SE) HbA1c changes from baseline were -0.4% (± 0.04%) for linagliptin (5 mg / day) versus -0.5% (±) for glimepiride (mean dose 3 mg / day). 0.04%). The mean difference between groups is 0.17% (95% CI, 0.08-0.27%; p = 0.0001 for non-inferiority). Similar results are observed in the FAS population. Much fewer patients with linagliptin than glimepiride experience the investigator-specified drug-related hypoglycemia (7.5% vs 36.1%; p <0.0001). Body weight decreases with linagliptin and increases with glimepiride (-1.4 kg vs + 1.3 kg; adjusted mean difference, -2.7 kg; p <0.0001). CV events occur in 13 linagliptin patients (1.7%) compared to 26 glimepiride patients (3.4%) and show a significant 50% reduction in relative risk for the overall CV end point (RR, 0.50; 95% CI, 0.26-0.96; p = 0.04). In conclusion, linagliptin provides a similar HbA1c reduction as glimepiride when added to metformin monotherapy, but linagliptin has hypoglycemia, less relative weight loss, and a significantly higher number of CV events for which a ruling was performed. few.

Cardiovascular risk from linagliptin in patients with type 2 diabetes: Pre-specified predictive and further ruling based on Phase III extensive program Post-analysis :
The benefits of the cardiovascular system (CV) in lowering glucose in type 2 diabetes mellitus (T2DM) are currently controversial, especially if the lowering of blood glucose is too strong. Some drug use has been reported to be associated with unexpectedly worsening CV consequences.
Linagliptin is the first once-daily DPP-4 inhibitor available as a single dose that does not require dose adjustment for impaired renal function. Linagliptin achieves glycemic control (which can be an advantage of CV) without weight gain or increased risk of hypoglycemia.
To closely examine the CV profile of the DPP-4 inhibitor linagliptin, a pre-specified post-analysis will be performed on all CV events obtained from the eight Phase III voluntary extraction double-blind management trials (12 weeks or longer). CV events are predictively decided by an unrelated expert committee that has not been informed in advance. The primary end point of this analysis is a complex of CV death, non-fatal stroke, non-fatal myocardial infarction (MI) and hospitalization for unstable angina (UAP). Other secondary and tertiary end points, including the FDA's conventional major CV event side effects (MACE), are also evaluated.
Of the 5239 patients included ( _{mean baseline of HbA 1c} is 8.0%), 3319 received linagliptin once daily (5 mg: 3159, 10 mg: 160) and 1920 were comparative substances (placebo). : 997, glimepiride: 781, voglibose: 162). Cumulative exposure (years per person) is 2060 for linagliptin and 1372 for the comparative substance. As a result, the primary CV event for which the ruling was carried out occurs in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparative substances. The hazard ratio for the primary end point is significantly lower for linagliptin to the comparative material, and the hazard ratio for the comparative material for all other end points is similar or significantly lower for linagliptin (TABLE).
This is the first post-CV analysis in the Extensive Phase III program in which a pre-specified, predictive and separate ruling of DPP-4 inhibitors was performed. Although a post-analysis with obvious limitations, this data supports a reduction in potential CV events for linagliptin.

*有意に低いハザード比（上限95％CI＜1.0；p＜0.05） TABLE: TABLE:

* Significantly lower hazard ratio (upper limit 95% CI <1.0; p <0.05)

Treatment of patients with type 2 diabetes mellitus at high risk of cardiovascular system :
The long-term effects of linagliptin treatment on cardiovascular prevalence and mortality and related efficacy parameters in related populations of type 2 diabetes mellitus are investigated as follows:
Inadequate glycemic control (naive to treatment or currently treated with, for example, metformin and / or alpha-glucosidase inhibitors (1 or 2 drug therapy) (eg, HbA1c 6.5-8.5%), or currently Treated with, for example, sulfonylureas or glinides (1 or 2 drug therapy) in the presence or absence of metformin or alpha-glucosidase inhibitors (eg, HbA1c 7.5-8.5%), and high cardiovascular system. Type 2 diabetic patients with event risk (eg, defined in one or more of the risk factors A), B), C) and D) shown below are treated with linagliptin (possibly one or more other active substances (optionally). Treated for a period of time (eg, 2 years or longer, 4-5 years or 1-6 years) in combination with (eg, those described herein)), and yet other anti-diabetic medications (eg, sulfonylureas, eg). Compare with patients treated with glymepyrid) or placebo. Evidence of successful treatment compared to other anti-diabetic medications or placebo-treated patients is the low number of single or multiple complications (complications are, for example, the cardiovascular system or cerebrovascular system). Sexual events such as cardiovascular death, myocardial infarction, stroke or hospitalization (eg acute coronary syndrome, leg amputation, hospitalization for emergency vascular regeneration or unstable angina), or preferably its By increasing the time required for the initial appearance of such complications (eg, the components of the following primary compound end points (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina) It can be known (by lengthening the time of the first appearance of any of the hospitalizations).
Yet another therapeutic success is that a greater proportion of patients undergoing study treatment have no need for emergency care at the end of the study, no weight gain (eg 2% or more), and glycemic control (eg HbA1c 7% or less). ) Is maintained. Yet another therapeutic success is that a greater proportion of patients undergoing study treatment have no need for emergency care at the end of the study, no episodes of moderate / severe hypoglycemia, and weight gain (eg, 2% or more). It can be known from the fact that blood glucose control (for example, HbA1c is 7% or less) is maintained.
Yet another therapeutic success can be seen in the CV superiority of treatment with linagliptin, which exhibits reduced risk (eg, preferably a 20% reduction in risk) compared to treatment with glimepiride.
Risk factors for cardiovascular events A), B), C) and D) are:
A) Previous vasculature (eg age 40-85 years):
-Myocardial infarction (eg 6 weeks or more),
-Coronary artery disease (eg, stenosis of 50% or more of the luminal diameter in the left main coronary artery or at least two major coronary arteries in angiography),
-Percutaneous coronary intervention (eg 6 weeks or more),
-Coronary artery bypass grafting (eg, 4 years or more, or showing recurrent angina after surgery),
-Ischemic or hemorrhagic stroke (eg, 3 months or longer),
-Peripheral obstructive arterial disease (eg, previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or leg amputation due to circulatory insufficiency; major limb arteries detected by angiography or ultrasound (total) Significant vascular stenosis (> 50% stenosis) of iliac arteries, internal iliac arteries, external iliac arteries, femoral arteries, patellar arteries, history of intermittent lameness (for ankle joints); at least one side Arm blood pressure ratio is less than 0.90),
B) Vascular-related end organ diseases (eg age 40-85 years):
− Renal dysfunction (eg, eGFRF30 −59 mL / min / 1.73 m ² for moderate renal dysfunction as specified by MDRD prescription),
-Microalbumin or macroalbuminuria (eg microalbuminuria, or random spot urinary albumin: creatine ratio of 30 μg / mg or higher),
-Retinopathy (eg, proliferative retinopathy, or retinal neovascularization or previous retinal laser coagulation therapy),
C) Elderly (for example, age 70 and over):
D) At least two of the following cardiovascular risk factors (eg age 40-85 years):
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-Hypertension (eg, systolic blood pressure> 140 mmHg or at least one hypotensive treatment),
− Daily smoking at this time,
-Treatment of (atherogenic) dyslipidemia or high blood levels of LDL cholesterol (eg, LDL cholesterol above 135 mg / dL) or at least one dyslipidemia,
-(Visceral and / or abdominal) obesity (eg body volume index of 45 kg / m ² or higher),
-Age over 40 and under 80.

Cognitive function (eg cognitive decline, changes in psychomotor rate, psychological stability), β-cell function (eg insulin secretion rate for 3h diet tolerance test, long-term β-cell function), renal function parameters, daily glucose pattern (eg behavior) When glucose profile, glycemic variability, oxidative, inflammatory and endothelial function biomarkers, cognition, and CV prevalence / mortality), asymptomatic MI (eg ECG parameters, CV prophylactic properties), LADA (eg emergency treatment) The beneficial effects (eg, improvement) of linagliptin treatment on the persistence of glucose management in use or disease progression in LADA) and / or β-cell autoantibody status (eg, GAD) are scrutinized in tributary studies.

Claims (31)

A method for treating and / or preventing oxidative stress, vascular stress and / or endothelial dysfunction, comprising the step of administering linagliptin to a patient in need thereof. The method of claim 1, wherein the patient is a non-diabetic patient or a diabetic patient selected from, for example, type 1 diabetes, adult latent autoimmune diabetes (LADA) and type 2 diabetic patients. The method according to claim 1, for treating and / or preventing endothelial dysfunction in a type 2 diabetic patient. A method for using linagliptin,
-For example, type 1 diabetes mellitus, type 2 diabetes mellitus, glucose tolerance disorder (IGT), fasting blood glucose disorder (IFG), hyperglycemia, postprandial hyperglycemia, postabsorption hyperglycemia, latent autoimmunity in adults Diabetes mellitus (LADA), overweight, obesity, abnormal lipemia, hyperlipidemia, hypercholesterolemia, hyperglycemia, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic steatosis (LADA) NAFLD), retinopathy, neuropathy, nephropathy, polycystic ovary syndrome, and / or methods of preventing, delaying, prolonging, or treating metabolic disorders or diseases selected from metabolic syndrome;
-Methods for improving and / or maintaining glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, post-absorption plasma glucose and / or glycosylated hemoglobin HbA1c;
-Prevents, slows, prolongs, or progresses prediabetes, impaired glucose tolerance (IGT), fasting blood glucose disorder (IFG), insulin resistance, and / or progression from metabolic syndrome to type 2 diabetes mellitus. How to reverse;
-Complications of diabetes mellitus, such as microvascular or macrovascular disease, nephropathy, microalbumin or macroalbuminuria, proteinuria, retinopathy, cataract, neuropathy, learning or memory impairment, neurodegenerative or Cognitive abnormalities, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic legs or diabetic ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary artery syndrome, unstable angina, Prevents, reduces the risk, slows or prolongs the progression of stable angina, peripheral arterial obstructive disease, myocardial disease, heart failure, cardiac rhythm abnormalities, vascular restenosis, and / or stroke. Or how to treat;
-A method of reducing body weight and / or body fat, or preventing an increase in body weight and / or body fat, or promoting a decrease in body weight and / or body fat;
-How to prevent, slow down, or treat pancreatic beta cell degeneration and / or diminished functionality of pancreatic beta cells, and / or to improve, retain, and / or restore pancreatic beta cell functionality. And / or a method of stimulating and / or restoring or protecting the functionality of pancreatic insulin secretion;
-How to prevent, slow down, prolong or treat non-alcoholic steatohepatitis (NAFLD), liver fatty disease, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis;
-How to prevent, slow down, prolong, or treat type 2 diabetes, where conventional anti-diabetes alone or combination therapy has failed;
-How to achieve the reduction in the dose of conventional anti-diabetes drugs required for proper therapeutic effect;
-How to reduce the risk of side effects associated with conventional anti-diabetes; and / or-How to maintain and / or improve insulin sensitivity, and / or to treat or prevent hyperinsulinemia and / or insulin resistance the method of;
In one or more of
In patients with or at risk of oxidative stress, vascular stress and / or endothelial dysfunction, or diseases or symptoms associated with or associated with the above, or, for example, myocardial infarction, stroke, peripheral arterial obstructive disease, diabetes. Patients with or at risk of cardiovascular system and / or renal disease selected from nephropathy, microalbuminuria or macroalbuminuria, and acute or chronic nephropathy, or A), B), In patients with one or more cardiovascular risk factors selected from C) and D), linagliptin was used and
A method for using said linagliptin, wherein the method comprises administering to the patient a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents:
A) Previous or existing pulse selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure, and peripheral obstructive arterial disease. Vascular disease;
B) Vascular-related terminal organ diseases selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease and microalbumin or macroalbuminuria;
C) Older age (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree. The method of claim 4, comprising treating type 2 diabetes mellitus. Cardiovascular system in which the patient is selected from, for example, myocardial infarction, stroke, peripheral arterial obstructive disease, diabetic nephropathy, microalbuminuria or macroalbuminuria, acute or chronic nephropathy, hyperuricemia, and / or hypertension. The method according to at least one of claims 1 to 5, which is a type 2 diabetic patient having or at risk of having or / or having a disease and / or renal disease. 12. At least one of claims 1-6, wherein the patient is a type 2 diabetic patient with one or more of the cardiovascular risk factors selected from A), B), C) and D) below. Method:
A) Previous or existing pulse selected from, for example, myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attack, congestive heart failure, and peripheral obstructive arterial disease. Vascular disease;
B) Vascular-related terminal organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and microalbumin or macroalbuminuria;
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree. Cardiovascular or cerebrovascular events selected from cardiovascular deaths, myocardial infarctions, strokes and hospitalizations (eg due to acute coronary syndrome, leg amputation, revascularization, heart failure or unstable angina) A method of preventing the appearance, preferably in patients with type 2 diabetes, reducing the risk of the appearance, or prolonging the appearance, wherein the method comprises a therapeutically effective amount of linagliptin, optionally one or more. The method comprising administering to a patient in need thereof with a therapeutic substance. Claim 8 that a type 2 diabetic patient is at risk for cardiovascular or cerebrovascular events and is associated with one or more of the risk factors selected from A), B), C) and D) below. Method described in:
A) Previous or existing vessels selected from myocardial infarction, coronary artery disease, percutaneous coronary artery intervention, coronary artery bypass transplantation, ischemic or hemorrhagic attacks, congestive heart failure, and peripheral obstructive arterial disease. System diseases;
B) Vascular-related terminal organ disease selected from nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and microalbumin or macroalbuminuria;
C) Elderly (eg 60+-70); and
D) One or more cardiovascular risk factors selected from:
-Progressed type 2 diabetes mellitus (eg, for a period of more than 10 years),
-High blood pressure,
− Daily smoking at this time,
-Abnormal lipemia,
-Obesity,
-Age over 40 and under 80,
-Family history of metabolic syndrome, hyperinsulinemia or insulin resistance, and-hyperuricemia, erectile dysfunction, polycystic ovary syndrome, sleep apnea, or vascular disease or myocardial disease in the first degree. 28. 9 according to claim 8 or 9, wherein the type 2 diabetic patient has nephropathy, retinopathy, neuropathy, renal dysfunction, chronic renal disease, and a vessel-related terminal organ disease selected from microalbumin or macroalbuminuria. the method of. The appearance of cardiovascular or cerebrovascular events selected from cardiovascular-related death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for unstable angina, cardiovascular or cerebrovascular events A method of preventing, reducing or prolonging the risk of appearance in patients with type 2 diabetes who are at risk of developing a therapeutically effective amount of linagliptin, optionally with one or more other therapeutic agents. The method comprising administering to a patient. The method according to at least one of claims 8 to 11, wherein the type 2 diabetic patient has nephropathy, renal dysfunction, chronic renal disease, and / or microalbumin or macroalbuminuria. The method according to at least one of claims 8 to 12, wherein the type 2 diabetic patient has mild, moderate or severe renal disorder or end-stage renal disease. The method according to at least one of claims 8 to 13, wherein the type 2 diabetic patient has microalbuminuria or diabetic nephropathy. One or more other therapeutic substances are other anti-diabetic substances, active substances that lower blood glucose levels, active substances that lower blood lipid levels, active substances that raise blood HDL levels, active substances that lower blood pressure. The method according to at least one of claims 4 to 14, selected from active substances, anti-platelet agents, anti-coagulants, and vascular endothelial protective agents indicated in the treatment of atherosclerosis or obesity. Claimed that other anti-diabetic substances are selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin and insulin analogs, and GLP-1 and GLP-1 analogs. 15. The method according to 15. 15. The method of claim 15 or 16, wherein the active agent that lowers blood pressure is selected from angiotensin receptor blocker (ARB), angiotensin converting enzyme (ACE) inhibitor, and beta-blocker. 17. The method of claim 17, wherein the angiotensin receptor blocker (ARB) is thermisartan and / or the angiotensin converting enzyme (ACE) inhibitor is ramipril and / or the beta-blocker is carvedilol, neviball or metoprolol. 15. An active substance that lowers blood lipid levels and / or raises blood HDL levels is selected from statins, nicotinic acid or derivatives thereof, fibrates, cholesterol absorption inhibitors, and bile acid blockers. To 18 according to at least one of the methods. The statin is atorvastatin, simvastatin or rosuvastatin, and / or nicotinic acid or a derivative thereof is niacin, and / or fibrate is phenofibrate, and / or the cholesterol absorption inhibitor is ezetimive, and / or. 19. The method of claim 19, wherein the bile acid sequestering agent is colesevelam. The method according to at least one of claims 15 to 20, wherein the antiplatelet agent is selected from low-dose aspirin, clopidogrel, prasugrel, borapaxer and chicagrelar. The method of at least one of claims 15-21, wherein the anticoagulant is selected from heparin, warfarin, dabigatran, rivaloxaban and apixaban. In addition, linagliptin can be selected from metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin or insulin analogs, and one or more other GLP-1 or GLP-1 analogs. The method according to at least one of claims 1 to 22, comprising the step of administering the anti-diabetic substance, and optionally with thermisartan. The method according to at least one of claims 1 to 23, further comprising the step of administering linagliptin together with metformin. The method according to at least one of claims 1 to 23, further comprising the step of administering linagliptin together with telmisartan. The method according to at least one of claims 1 to 23, comprising the step of administering a pharmaceutical composition containing linagliptin and metformin. The method of claim 1-26, wherein linagliptin is orally administered in a total daily dose of 5 mg. Especially in patients who need it separately or beyond glycemic control, such as patients with type 1 diabetes, LADA or especially type 2 diabetes.
-Treat and prevent ischemic / reperfusion injury (in the kidney, heart, brain or liver), reduce its risk, slow its progression, prolong, weaken or reverse its onset, and / or ( Reduces the size of myocardial infarction in the heart (eg after ischemic / reperfusion of the myocardium); or-may be characterized by hypertrophy of myocardial cells, interstitial fibrosis, ventricular dilatation, systolic dysfunction and / or cell death / apoptosis. Treats and prevents (harmful) vascular remodeling, such as cardiac remodeling (especially post-myocardial infarction remodeling), reduces its risk, slows its progression, prolongs, weakens, or reverses its onset. Or-treat and prevent chronic or acute renal failure and / or peripheral arterial occlusion, reduce its risk, slow its progression, prolong, weaken, or reverse its onset; or-congestive Treat, prevent, reduce the risk and progress of cardiac insufficiency (eg NYHA class I, II, III or IV) and / or cardiac hypertrophy (eg left ventricular hypertrophy) and / or nephropathy and / or albuminuria. Delay, prolong, weaken, or reverse its onset; or-of urotoxic cardiomyopathy, interstitial dilation, and / or (cardiac) fibrosis (especially chronic renal and cardiac disorders often associated with type 2 diabetes). A method of treating (seen in patients), preventing, reducing its risk, slowing its progression, prolonging, weakening, or reversing its onset, said method being an effective amount of certain DPPs. -4. The method comprising administering to a patient an inhibitor optionally with an effective amount of one or more other active agents, wherein the DPP-4 inhibitor is linagliptin. Preventing diabetic nephropathy in patients who do not respond appropriately to treatment with angiotensin receptor blockers (ARBs, such as thermisartan) (eg, patients with type 2 diabetes), reduce their risk, slow their progression, and prolong their onset. A method of weakening, reversing or treating, wherein a therapeutically effective amount of a DPP-4 inhibitor is optionally combined with one or more other therapeutic agents (eg, ARB, eg, thermisartan). The method, wherein the DPP-4 inhibitor is linagliptin, comprising the step of administering to. A method of using linagliptin with telmisartan to treat diabetic nephropathy, including albuminuria, in patients who do not respond appropriately to angiotensin receptor blockers (ARBs). Substantially a DPP-4 inhibitor for use in the therapeutic methods described herein, wherein said is linagliptin, wherein said method is any of the methods according to this description, eg, treatment or prevention of an embodiment thereof. The DPP-4 inhibitor comprising a method relating to the above.

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