Use of linagliptin in cardio- and renoprotective antidiabetic therapy

Abstract

To provide efficacious, safe and tolerable antidiabetic therapies.SOLUTION: The present invention relates to DPP-4 inhibitor linagliptin for use in cardio- and / or renoprotective therapy, in diabetic or non-diabetic patients at high vascular risk.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in the therapy of diabetic (preferably type 2 diabetes) or non-diabetic patients, including patients with or at risk of microvascular and / or macrovascular disease, such as patients with or at risk of cardiovascular and / or (renal) microvascular disease, e.g., patients at high vascular risk (preferably for use in cardioprotective and / or nephroprotective treatment of human type 2 diabetic patients), as well as to pharmaceutical compositions and combinations comprising such active ingredients and certain therapeutic uses thereof. [Background technology]

[0002] Type 2 diabetes mellitus is a common chronic and progressive disease resulting from a complex pathophysiology involving the dual endocrine effects of insulin resistance and impaired insulin secretion, resulting from the inability to meet the demands required to maintain plasma glucose levels within the normal range. This leads to chronic hyperglycemia and its associated microvascular or macrovascular complications or chronic damage, such as diabetic nephropathy, retinopathy, or neuropathy, or macrovascular (e.g., cardiovascular or cerebrovascular) complications, and / or associated cognitive dysfunction. While the vascular disease component plays a significant role, it is not the only factor in the spectrum of diabetes-related disorders. The high incidence of complications leads to a significant reduction in life expectancy. Diabetes is currently the most frequent cause of adult-onset loss of vision, renal failure, and amputation in the industrialized world due to diabetes-induced complications and is associated with a two- to five-fold increased risk of cardiovascular disease. Elevated risk of macrovascular disease is primarily associated with increased risk for atherothrombosis, which leads to increased morbidity and premature mortality from cardiovascular (CV) disease, the key predictor of which is renal impairment, nephropathy, and / or the often coexisting chronic kidney disease (CKD). Treatment of type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy. While conventional monotherapy can initially control blood glucose in some patients, it is associated with a high secondary failure rate. The limitations of single-drug therapy for maintaining glycemic control may be overcome by combining multiple drugs to achieve blood glucose reductions (which cannot be sustained during long-term treatment with a single drug), at least in some patients and for a limited period of time. Available data support the conclusion that most patients with type 2 diabetes will fail current monotherapy and require multidrug therapy. However, because type 2 diabetes is a progressive disease, even patients who have a good initial response to conventional combination therapy will eventually require increased doses or further treatment with additional oral or parenteral antidiabetic drugs (often ultimately insulin therapy) because blood glucose levels are very difficult to maintain stable over extended periods of time. Existing combination therapies have the potential to improve glycemic control, but it is not unlimited, especially with regard to long-term efficacy. Furthermore, conventional therapeutic agents may present an increased risk of side effects, such as hypoglycemia or weight gain, which can worsen their efficacy and tolerability.

[0003] Thus, for many patients, these existing drug therapies result in a progressive deterioration of metabolic control despite treatment, and do not adequately regulate the metabolic state, particularly over the long term, thus failing to achieve and maintain blood glucose control in advanced or late stage type 2 diabetes, including diabetes with inadequate glycemic control despite conventional oral and / or parenteral antidiabetic medications. Therefore, although intensive treatment of hyperglycemia may reduce the incidence of chronic damage, many patients with diabetes remain inappropriately treated, in part due to limitations in long-term efficacy, safety / tolerance, and inconvenience of dosing with conventional antihyperglycemic medications. In addition, obesity, excess weight, or weight gain (e.g., as a side effect or adverse effect of some conventional antidiabetic drugs) further complicates the treatment of diabetes and its microvascular or macrovascular complications, and / or associated cognitive complications.

[0004] This high incidence of treatment failure is a major contributing factor to the high rate of long-term hyperglycemia-related complications or chronic damage (microvascular and macrovascular complications, e.g., diabetic nephropathy, retinopathy, or neuropathy, or cerebrovascular or cardiovascular complications, e.g., myocardial infarction, stroke, or vascular mortality or morbidity) in diabetic patients. Oral antidiabetic agents commonly used in treatment (e.g., first-line, second-line, or third-line, and / or monotherapy or (initial or concomitant) combination therapy) may include, but are not limited to, metformin, sulfonylureas, thiazolidinediones, glinides, and alpha-glucosidase inhibitors. Parenteral (typically injected) antidiabetic drugs commonly used in treatment (e.g., first-line, second-line, or third-line, and / or single- or (initial or combined) combination therapy) may include, but are not limited to, GLP-1 or GLP-1 analogs, and insulin or insulin analogs. However, the use of these conventional antidiabetic or antihyperglycemic agents can be associated with various adverse effects: for example, metformin can be associated with lactic acidosis or gastrointestinal side effects, sulfonylureas, glinides, and insulin or insulin analogs can be associated with hypoglycemia and weight gain, thiazolidinediones can be associated with edema, bone fractures, weight gain, and heart failure / cardiac effects, and α-glucosidase blockers and GLP-1 or GLP-1 analogs can be associated with adverse gastrointestinal effects (e.g., dyspepsia, bloating, or diarrhea, or nausea or vomiting). In addition to the morbidity associated with each of these side effects, they may also have adverse cardiovascular implications. For example, hypoglycemia and weight gain are postulated to be contributing factors to adverse CV mortality outcomes. Hypoglycemic episodes have also been identified as detrimental to cognitive skills and are associated with a greater risk of cognitive impairment or dementia. The risk of hypoglycemia is further increased in the elderly by comorbidities and polymedication. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, there remains a need in the art to provide effective, safe and tolerable antidiabetic therapeutic agents. Furthermore, within the treatment of type 2 diabetes, there is a desire to effectively treat the condition, avoid micro- and / or macrovascular complications specific to the condition, and slow or attenuate disease progression, for example, to obtain long-lasting therapeutic benefits. Furthermore, there remains a need for antidiabetic therapies that not only prevent and / or treat the long-term complications often seen in advanced stages of diabetic disease, but also are a treatment option in those diabetic patients who have developed or are at risk of developing such complications (e.g., kidney damage). In particular, there is a need for antidiabetic treatments that prevent and / or treat both microvascular (renal) and macrovascular (CV) complications, preferably together, preferably within one treatment. Furthermore, there is a need to provide treatment options, especially in those diabetic patients who develop or are at risk of developing both microvascular (renal) and macrovascular (CV) complications. There is also a need for antidiabetic treatments that prevent and / or treat accelerated cognitive decline (which may be associated with microvascular and / or macrovascular complications), preferably together with both microvascular (renal) and macrovascular (CV) complications, preferably within one treatment. Additionally, there remains a need to provide prevention or risk reduction for the adverse effects associated with conventional antidiabetic therapeutic agents. [Means for solving the problem]

[0006] The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents), as well as pharmaceutical compositions and combinations comprising such active ingredients, and certain therapeutic uses thereof, for use in the treatment of diabetic (preferably type 2 diabetes) or non-diabetic patients (e.g., to reduce, prevent, protect against, delay the onset of, slow the progression of and / or reduce the risk of cardiovascular and / or renal morbidity and / or mortality in humans, diabetic or non-diabetic, preferably for use in cardioprotective and / or nephroprotective treatment of human type 2 diabetic patients), e.g., patients with or at risk of microvascular and / or macrovascular disease, e.g., patients with or at risk of cardiovascular and / or (renal) microvascular disease, e.g., patients at high vascular risk. Such treatments of the present invention (e.g., as described above or in more detail below) may include treatment with certain such DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) over a long-term period (duration of treatment), as described in more detail below.

[0007] The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in the treatment of diabetic (preferably type 2 diabetes) or non-diabetic patients, including patients with or at risk of microvascular and / or macrovascular disease, e.g., patients with or at risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (preferably for use in cardioprotective as well as renoprotective treatment of human type 2 diabetic patients, preferably beyond and / or independent of improving glycemic control), as well as to pharmaceutical compositions and combinations comprising such active ingredients, and certain therapeutic uses thereof. The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in patients with or at risk of cardiovascular disease and / or renal microvascular disease (preferably patients with diabetes, in particular type 2 diabetes), such as patients at high vascular risk (e.g. as described herein), such as patients according to at least one of embodiments 1-6 or 1-7 described herein below. The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing, preventing, protecting against, delaying and / or reducing the risk of morbidity and / or premature mortality from vascular disease, e.g., cardiovascular (CV) disease and / or renal microvascular disease (in embodiments, such vascular disease may further include cognitive decline or disability), preferably in diabetic patients (particularly type 2 diabetic patients), such as patients having or at risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), such as patients according to at least one of embodiments 1-6 or 1-7 described herein below.

[0008] Accordingly, the present invention also relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing the risk of, preventing, protecting against, delaying (e.g. the occurrence or progression of) and / or lowering the risk of any or all of the following CV morbidity, premature CV mortality, renal morbidity and / or premature renal mortality, preferably in diabetic patients (in particular type 2 diabetic patients), such as patients with or at risk of cardiovascular disease and / or renal microvascular disease, e.g. patients at high vascular risk (e.g. those patients described herein), such as those patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein below. In certain embodiments, the treatments of the invention (e.g., those described above or below, e.g., human type 2 diabetes patients, e.g., patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), e.g., cardioprotective and / or nephroprotective treatment of those patients according to at least one of embodiments 1-6 or 1-7 described herein below) may comprise a period of treatment with certain DPP-4 inhibitors, in particular linagliptin (administered orally, preferably 5 mg daily), optionally in combination with one or more other active substances, e.g., those described herein, for an extended period, e.g., at least 1-6 years, 2 years or more, or 3-7 years, e.g., 3-4 years, 3-5 years, 3-6 years, 4-5 years, 4-6 years, 5-6 years or 5-7 years, preferably at least 48 months, more preferably at least 3 years.

[0009] For example, the duration of treatment with certain DPP-4 inhibitors, in particular linagliptin (orally administered, preferably 5 mg daily, optionally in combination with one or more other active substances, such as those described herein) may extend for a long period of time, such as at least 1-6 years, 2 years or more, or 3-7 years, such as 3-4 years, 3-5 years, 3-6 years, 4-5 years, 4-6 years, 5-6 years or 5-7 years, preferably at least 48 months, more preferably at least 3 years, in order to optimize cardioprotective and / or nephroprotective treatment and / or ameliorate cardiovascular and / or renal morbidity and / or mortality in human patients, in particular human type 2 diabetes patients, such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, for example patients at high vascular risk (such as those patients described herein), such as patients according to at least one of embodiments 1-6 or 1-7 described herein below. By way of further example, the duration of treatment with certain DPP-4 inhibitors, in particular linagliptin (orally administered, preferably 5 mg daily, optionally in combination with one or more other active substances, such as those described herein) may extend for a long period, preferably at least 48 months, more preferably at least 3 years (e.g. at least 3-4 years, or at least 5-6 years), for example in patients with or at high risk of cardiovascular disease and / or renal microvascular disease (e.g. diabetic, in particular type 2 diabetic patients), for example in patients at high vascular risk (e.g. those patients described herein), such as patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein below.

[0010] In an embodiment, the present invention relates to a method for treating CV morbidity and / or (premature) CV mortality, such as CV death (e.g. fatal myocardial infarction, fatal stroke, fatal heart failure, cardiogenic shock or sudden cardiac death), non-fatal CV events, preferably in diabetic patients (especially type 2 diabetic patients), such as in patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g. in patients at high vascular risk (e.g. those patients described herein), such as those patients according to at least one of embodiments 1 to 7 described herein below. The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing the risk of, preventing, protecting against, delaying (e.g., occurrence or progression), and / or reducing one or more of fatal myocardial infarction, non-fatal stroke (e.g., (intracranial) hemorrhagic or non-hemorrhagic stroke, and / or asymptomatic or non-asymptomatic) and / or unstable angina (e.g., hospitalization for unstable angina), and / or, optionally, stable angina, transient ischemic attack, congestive heart failure, peripheral revascularization surgery, and / or coronary revascularization surgery (e.g., hospitalization for any of such conditions). In an embodiment, the present invention provides a method for reducing, preventing, protecting against, delaying (e.g., occurrence or progression) and / or reducing the risk of one or more morbidities (e.g., renal morbidities) and / or (premature) renal fatalities, such as retinopathy, nephropathy, neuropathy, cognitive decline, dementia, depressive disorders, emotional or anxiety disorders, microalbuminuria, macroalbuminuria, chronic kidney disease (CKD), renal impairment, renal death, end-stage renal disease and / or loss of estimated glomerular filtration rate (e.g., eGFR ≧ 50% from baseline), preferably in diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), such as those patients described herein below in at least one of embodiments 1 to 7. The present invention relates to an inhibitor, preferably linagliptin, optionally in combination with one or more other active agents.

[0011] In an embodiment, the present invention provides a method for preventing CV morbidity and / or (premature) CV mortality, e.g. CV death (e.g. fatal myocardial infarction, fatal stroke, fatal heart failure, cardiogenic shock or sudden cardiac death), preferably in diabetic patients (especially type 2 diabetic patients), e.g. in patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g. in patients at high vascular risk (e.g. those patients described herein), e.g. those patients according to at least one of embodiments 1 to 7 described herein below. for use in reducing the risk of, preventing, protecting against, delaying (e.g. occurrence or progression) and / or reducing one or more of the following: non-fatal myocardial infarction, non-fatal stroke (e.g. (intracranial) hemorrhagic or non-hemorrhagic stroke, and / or asymptomatic or non-asymptomatic) and / or unstable angina (e.g. hospitalization for unstable angina), and / or, where appropriate, stable angina, transient ischemic attack, congestive heart failure, peripheral revascularization surgery and / or coronary revascularization surgery (e.g. hospitalization for any of such conditions); and / or The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing the risk of, preventing, protecting against, delaying (e.g., the occurrence or progression of), and / or reducing one or more morbidities (e.g., renal morbidities) and / or (premature) renal lethality, such as retinopathy, nephropathy, neuropathy, cognitive decline, dementia, depressive disorders, emotional or anxiety disorders, microalbuminuria, macroalbuminuria, chronic kidney disease (CKD), renal impairment, renal death, end-stage renal disease, and / or loss of estimated glomerular filtration rate (e.g., eGFR ≧ 50% from baseline). The present invention also relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing the risk of, preventing, protecting against, delaying (e.g., occurrence or progression), and / or reducing at least one (preferably at least two, more preferably at least three, more preferably at least four) selected from CV morbidity, premature CV mortality, renal morbidity, and premature renal mortality, preferably in diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), such as those patients described in at least one of embodiments 1 to 6 or 1 to 7 described herein below.

[0012] Furthermore, the present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in treating, protecting against, preventing, reducing the risk of, and / or delaying the onset or progression of both macrovascular (e.g., cardiovascular (CV)) complications and renal microvascular complications (e.g., nephropathy), preferably in diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), such as those patients described in at least one of embodiments 1-6 or 1-7 described herein below. Furthermore, the present invention relates to treating, protecting against, preventing, reducing the risk of, and / or delaying the onset or progression of macrovascular (e.g., cardiovascular (CV)) complications, and / or in preferably diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., those patients described herein), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein below. The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in treating, protecting against, preventing, reducing the risk of, and / or delaying the onset or progression of renal microvascular complications (e.g., nephropathy).

[0013] Furthermore, the present invention provides a method for preventing, protecting against, reducing the risk of and / or delaying the occurrence of cardiovascular or cerebrovascular diseases or events, such as selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke and non-fatal myocardial infarction (MI) (including or excluding silent MI) and, optionally, hospitalization (e.g. for unstable angina, coronary revascularization surgery, peripheral revascularization or congestive heart failure), in preferably human diabetic patients (particularly type 2 diabetic patients), for example patients with or at high risk of cardiovascular events and / or renal microvascular disease, for example patients at high vascular risk (e.g. high risk of CV events) (e.g. those patients described herein), such as patients according to at least one of embodiments 1-6 or 1-7 described herein below. The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in a method for preventing, protecting against, reducing the risk of, slowing the progression of, and / or delaying the onset of (renal) microvascular diseases, such as selected from retinopathy, albuminuria (trace or overt), chronic kidney disease (CKD), renal impairment, renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧50% from baseline).

[0014] Furthermore, the present invention relates to a method for treating, preferably in human diabetic patients (in particular type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, such as patients at high vascular risk (e.g. high risk of CV events) (e.g. patients as described herein), such as patients according to at least one of embodiments 1 to 6 or 1 to 7 as described herein below, which are selected from cardiovascular or cerebrovascular diseases or (severe) events, such as cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded) and hospitalization for unstable angina (optional), and / or The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in a method for preventing, reducing the risk of, and / or delaying the occurrence of a renal microvascular disease or event, such as selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧50% from baseline). Furthermore, the present invention provides a method for preventing, reducing the risk of and / or delaying the occurrence of cardiovascular or cerebrovascular diseases or (severe) events, such as selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (where silent MI may be excluded) and hospitalization for unstable angina (optional), and / or in preferably human diabetic patients (in particular type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, such as patients at high vascular risk (high risk of CV events) (e.g. patients as described herein), such as patients according to at least one of embodiments 1 to 6 or 1 to 7 as described herein below. The present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for use in a (combined) method of preventing, reducing the risk of, and / or delaying the occurrence of renal microvascular diseases or events, such as renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧50% from baseline).

[0015] Furthermore, the present invention provides a method for preventing cardiovascular or cerebrovascular diseases or (severe) events, such as cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded) and hospitalization for unstable angina (optional), preferably in human diabetic patients (in particular type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, such as patients at high vascular risk (high risk of CV events) (e.g. patients described herein), such as patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein below, and The present invention relates to a certain DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in a (combined) method for preventing renal microvascular diseases or events, such as those selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧ 50% from baseline). Furthermore, the present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in reducing, preventing, protecting against, delaying (e.g. the onset or progression of) and / or reducing the risk of (accelerated) cognitive decline or impairment or dementia, preferably in diabetic patients (in particular type 2 diabetic patients), such as patients with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g. patients at high vascular risk (e.g. those patients described herein), such as those patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein below.

[0016] Such patients according to the present invention having or at risk of a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition, e.g. patients with high vascular risk (e.g. high risk of a CV event), who are amenable to the therapies (treatment and / or prevention) of the present invention, may be or include patients (preferably patients with diabetes, in particular type 2 diabetes) as described herein below (e.g. in embodiments 1-6 or 1-7 below). For example (embodiment 1), such patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition of the invention may be patients (preferably patients with diabetes, in particular type 2 diabetes) with a microvascular disease (e.g., retinopathy, neuropathy, or renal microvascular disease, e.g., nephropathy, albuminuria (e.g., micro- or macroalbuminuria), proteinuria, chronic kidney disease (e.g., CKD stage 1, 2, 3, 4 or 5) and / or renal impairment (e.g., mild, moderate or severe renal impairment or end-stage renal disease (ESRD)), and / or (previous) macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease and / or peripheral artery disease). For a further example (embodiment 2), such patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition of the present invention may be those with or without (previous) macrovascular (e.g. cardiovascular or cerebrovascular) disease (e.g. myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease and / or peripheral artery disease), nephropathy or chronic kidney disease (e.g. albuminuria (e.g. micro- or macroalbuminuria, proteinuria, especially macroalbuminuria) and / or renal impairment (e.g. mild, moderate or severe renal impairment or end-stage renal disease (ESRD) (e.g. at moderate, severe or ESRD stage, and / or especially with albuminuria, more especially macroalbuminuria)), including nephropathy or chronic kidney disease (e.g. CKD stage 1, 2, 3, 4 or 5, especially CKD 3 The patient may be a patient with any of the above-mentioned conditions (preferably a patient with diabetes, particularly type 2 diabetes).

[0017] For a particular example (embodiment 3), such patients having or at risk for cardiovascular and / or renal microvascular disease (e.g., such patients at high vascular risk, e.g., high risk of a CV event) who are amenable to the therapies (e.g., treatment and / or prevention and / or protection) of the present invention are Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria, or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m) with or without albuminuria (e.g., micro- or macroalbuminuria) 2 ) The patient may be a patient with diabetes (preferably a patient with diabetes, particularly type 2 diabetes).

[0018] More specifically (embodiment 4), such patients at high vascular risk (e.g., high risk of CV events) are treated as follows: Albuminuria (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)) and Previous large vessel disease, e.g., identified as one or more of a)-f): a) previous myocardial infarction, b) advanced coronary artery disease; c) high-risk single-vessel coronary artery disease; d) previous ischemic or hemorrhagic stroke; e) presence of carotid artery disease; f) Presence of peripheral arterial disease and and / or Renal dysfunction (e.g., with or without CV comorbidities), e.g., eGFR 15-45 mL / min / 1.73 m 2 and / or impaired renal function (e.g., as determined by the MDRD formula) with any urinary albumin creatinine ratio (UACR); and / or ·eGFR ≥ 45-75 mL / min / 1.73 m 2 Renal impairment (e.g., as determined by the MDRD formula) with a urinary albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams of albumin per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) The patient may be a patient with diabetes (preferably a patient with diabetes, particularly type 2 diabetes).

[0019] More particularly, such patients at high vascular risk (e.g., high risk of a CV event) may be patients with condition I (embodiment 5) and / or condition II (embodiment 6), respectively, as specified below (preferably patients with diabetes, in particular type 2 diabetes). In another embodiment (embodiment 7), such patients at high vascular risk (e.g., high risk of a CV event) may be patients (preferably patients with diabetes, in particular type 2 diabetes) with one or more of the following CV risk factors A), B), C) and / or D): A) Previous vascular disease, e.g. - Myocardial infarction (e.g., within the previous 6 weeks), - coronary artery disease (e.g., luminal diameter narrowing of >=50% in the left main coronary artery or at least two main coronary arteries on angiogram), - percutaneous coronary intervention (e.g., within the previous 6 weeks), - coronary artery bypass graft (e.g., recurrent angina within the previous 4 years or after surgery), - ischemic or hemorrhagic stroke (e.g., within the previous 3 months),

[0020] - Peripheral occlusive arterial disease (e.g., previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or foot amputation due to insufficient circulation, significant vascular stenosis (>50%) detected by angiogram or ultrasound of the major limb arteries (common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), history of intermittent claudication, and ankle:brachial blood pressure ratio <0.90 on at least one side), B) Vascular-associated end-organ damage, e.g. - Renal impairment (e.g., moderate renal impairment, e.g., as determined by the MDRD formula and eGFRF 30-59 mL / min / 1.73m2), - Micro- or macroalbuminuria (e.g., microalbuminuria or random spot urine albumin:creatinine ratio > / = 30 μg / mg), - retinopathy (e.g., proliferative retinopathy, or retinal neovascularization or previous retinal laser coagulation therapy), C) Older age (e.g., age > / = 70 years), D) At least two of the following CV risk factors: - advanced type 2 diabetes mellitus (e.g., > 10 years duration), - hypertension (e.g., systolic blood pressure >140 mmHg or at least one blood pressure-lowering treatment), - current daily smoking, - (atherogenic) dyslipidemia or high LDL cholesterol blood levels (e.g., LDL cholesterol > / =135 mg / dL) or at least one prior treatment for dyslipidemia.

[0021] Furthermore, the present invention is preferably directed to human diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, for example patients at high vascular risk (e.g., high risk of CV events), e.g. Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 2 or 3, preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, preferably eGFR 15-45 mL / min / 1.73 m 2 ) (with or without albuminuria) In patients with cardiovascular or cerebrovascular disease or event, for example selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded), and hospitalization for unstable angina; and Renal microvascular disease, e.g., renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline) The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in a method for preventing, protecting against, reducing the risk of and / or delaying the onset of diabetes mellitus.

[0022] Furthermore, the present invention is preferably directed to human diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, for example patients at high vascular risk (e.g., high risk of CV events), e.g. Albuminuria (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)) and Previous macrovascular disease, e.g., identified as one or more of a) through f): a) previous myocardial infarction, b) advanced coronary artery disease; c) high-risk single-vessel coronary artery disease; d) previous ischemic or hemorrhagic stroke; e) presence of carotid artery disease; f) presence of peripheral arterial disease; and / or Renal dysfunction (e.g., with or without CV comorbidities), e.g., Renal impairment (e.g., as determined by the MDRD formula) and eGFR 15-45 mL / min / 1.73 m 2 and either urinary albumin creatinine ratio (UACR), and / or Renal impairment (e.g., as determined by the MDRD formula) and eGFR ≥ 45-75 mL / min / 1.73 m 2 and identified by a urinary albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams of albumin per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) In patients with cardiovascular or cerebrovascular disease or event, for example selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded), and hospitalization for unstable angina; and Renal microvascular disease, e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline). The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in a method for preventing, reducing the risk of and / or delaying the onset of diabetic renal failure.

[0023] Accordingly, the present invention is preferably directed to human diabetic patients (particularly type 2 diabetic patients), such as patients with or at high risk of cardiovascular events and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., high risk of CV events), such as patients with symptom I and / or symptom II as identified below: cardiovascular or cerebrovascular disease or event, for example selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded), and hospitalization for unstable angina; and Renal microvascular disease, e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline). The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in a method for preventing, reducing the risk of and / or delaying the onset of diabetic renal failure. Symptom I: Albuminuria (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)) and Previous macrovascular disease, e.g., identified as one or more of a) through f): a) previous myocardial infarction (e.g., > 2 months), b) Advanced coronary artery disease, e.g., as defined by any one of the following: ≥ 50% narrowing of the luminal diameter in two or more major coronary arteries (e.g., LAD, CX, or RCA) by coronary angiogram or CT angiogram, Left main coronary artery with ≥ 50% narrowing of the luminal diameter, Previous percutaneous or surgical revascularization of ≥ 2 major coronary arteries (e.g., ≥ 2 months), For example, a combination of previous percutaneous or surgical revascularization of one major coronary artery (e.g., ≥ 2 months) and a ≥ 50% narrowing of the luminal diameter by coronary angiogram or CT angiogram of at least one additional major coronary artery,

[0024] c) High-risk single-vessel coronary artery disease, e.g., identified as a ≥ 50% narrowing of the luminal diameter of one major coronary artery (e.g., by coronary angiogram or CT angiogram in a patient who has not been revascularized) and the presence of at least one of the following: Positive non-invasive stress test, e.g. - Positive ECG exercise tolerance test in patients without left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy due to repolarization abnormalities, or paced ventricular rhythm, or atrial fibrosis in cases of abnormal ST-T segments. - Positive stress echocardiogram showing induced positional systolic wall motion abnormalities, - A positive nuclear myocardial perfusion imaging stress study demonstrating stress-induced reversible perfusion abnormalities, - Patients discharged from the hospital with a documented diagnosis of unstable angina (e.g., ≥ 2 - 12 months) As can be confirmed by d) ischemic or hemorrhagic stroke (e.g., > 3 months); e) Presence of carotid artery disease (symptomatic or asymptomatic), e.g. - imaging techniques with at least one lesion estimated to be a ≥ 50% narrowing of the luminal diameter; - Previous percutaneous or surgical carotid revascularization As recorded by f) Presence of peripheral arterial disease, e.g. - previous limb angioplasty, stenting or bypass surgery, - limb or foot amputation due to insufficient circulation; - Peripheral arterial stenosis: Angiographic evidence of ≥ 50% narrowing of luminal diameter in at least one limb (e.g., peripheral arteries: common iliac artery, internal iliac artery, external iliac artery, femoral artery, specific popliteal artery). Symptom II: Renal dysfunction (e.g., with or without CV comorbidities), e.g., eGFR 15-45 mL / min / 1.73 m 2 and impaired renal function (e.g., as determined by the MDRD formula) with any UACR, and / or ·eGFR ≥ 45-75 mL / min / 1.73 m 2 Renal impairment (e.g., as determined by the MDRD formula) with a urine albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) Renal dysfunction as identified by

[0025] Furthermore, the present invention is preferably directed to human diabetic patients (particularly type 2 diabetic patients), such as patients suffering therefrom or at high risk thereof, for example patients with or at high risk of such cardiovascular disease and / or renal microvascular disease, for example patients at high vascular risk (e.g. as specified herein, e.g. according to at least one of embodiments 1 to 6 or 1 to 7 hereinbefore described), e.g. Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 2 or 3, preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, preferably eGFR 15-45 mL / min / 1.73 m 2 ) (with or without albuminuria) In patients with Cardiovascular or cerebrovascular disease, event (e.g., a major cardiovascular event) or complication, such as cardiovascular death, (fatal or non-fatal) myocardial infarction (e.g., silent or non-silent MI), (fatal or non-fatal) stroke, sudden death, heart failure, and / or hospitalization (e.g., for acute coronary syndrome, leg amputation, coronary revascularization surgery, peripheral revascularization, heart failure, or for unstable angina) treating, preventing, protecting against, reducing the risk of, delaying the onset of, and / or slowing the progression of, and / or e.g. (preferably due to or among one and the same treatment or drug) microvascular disease or complications (non-renal or, preferably, renal), such as retinopathy, cognitive decline, nephropathy, (micro- or overt) albuminuria, chronic kidney disease (CKD), end-stage renal disease, renal impairment, acute or chronic renal failure, renal death, and / or loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline). The present invention relates to a DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in combination with or with treating, preventing, protecting against, reducing the risk of, delaying the onset of, and / or delaying the progression of

[0026] Furthermore, the present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for the treatment and / or prevention of metabolic diseases, such as diabetes, in particular type 2 diabetes mellitus, and / or diseases or conditions related thereto (e.g. diabetic complications), in patients (particularly human patients) having or at high risk of cardiovascular disease and / or renal microvascular disease (e.g. patients at high vascular risk as specified herein, e.g. patients according to at least one of embodiments 1-6 or 1-7 described herein above). Furthermore, the present invention relates to certain DPP-4 inhibitors (preferably linagliptin, optionally in combination with one or more other active agents) for the treatment and / or prevention of diabetes, in particular type 2 diabetes mellitus and / or diseases or conditions related thereto (e.g. diabetic complications, such as diabetic nephropathy and / or (micro- or macro-) albuminuria) in a patient (e.g. a human patient) in need thereof, the patient having or at high risk of cardiovascular disease and / or renal microvascular disease (e.g. a patient at high vascular risk as specified herein, e.g. a patient according to at least one of embodiments 1 to 6 or 1 to 7 as described herein above). Examples of metabolic disorders or diseases amenable to treatment by the present invention may include, but are not limited to, type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, fasting or postprandial hyperlipidemia, e.g., postprandial hypertriglyceridemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, nonalcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, nephrotic syndrome, polycystic ovary syndrome, and / or metabolic syndrome.

[0027] Furthermore, the present invention relates to a method for treating a patient in need thereof (e.g., a patient as described herein, e.g., a human patient with diabetes, in particular type 2 diabetes), and / or in particular a patient having or at high risk of a cardiovascular and / or renal microvascular disease or complication, e.g., a patient at high vascular risk (e.g., a patient as specified herein; according to at least one of embodiments 1 to 6 or 1 to 7 described herein above), e.g., Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 2 or 3, preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, preferably eGFR 15-45 mL / min / 1.73 m 2 ) (with or without albuminuria) In patients with: - a method of preventing, slowing the progression of, delaying the onset of, or treating a metabolic disorder or disease, such as type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), excess weight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, nephrotic syndrome, polycystic ovary syndrome, and / or metabolic syndrome; - a method for improving and / or maintaining glycemic control and / or reducing fasting plasma glucose, postprandial plasma glucose, postabsorption plasma glucose and / or glycosylated hemoglobin HbA1c, or preventing, reducing the risk of, slowing the progression of, delaying the onset of, or treating worsening or deterioration of glycemic control, the requirement for insulin treatment, or elevated HbA1c despite treatment; -A method for preventing, slowing, delaying, or reversing the progression of prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes mellitus;

[0028] - methods for preventing, reducing the risk of, slowing the progression of, delaying the occurrence of, or treating complications of diabetes mellitus, such as microvascular and macrovascular diseases, e.g., nephropathy, micro- or macroalbuminuria, proteinuria, nephrotic syndrome, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, dementia, cardiovascular or cerebrovascular diseases, tissue ischemia, diabetic foot or ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders, vascular restenosis, and / or stroke; - a method for reducing body weight and / or body fat and / or liver fat and / or intramyocellular fat, or preventing an increase in body weight and / or body fat and / or liver fat and / or intramyocellular fat, or promoting a reduction in body weight and / or body fat and / or liver fat and / or intramyocellular fat; - methods for preventing, slowing, delaying the onset or treating pancreatic beta cell degeneration and / or the decline in pancreatic beta cell function, and / or improving, preserving and / or restoring pancreatic beta cell function, and / or stimulating and / or restoring or protecting pancreatic insulin secretory function; - preventing, slowing, delaying the onset of, or treating non-alcoholic fatty liver disease (NAFLD), including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis (e.g., preventing, slowing the progression of, delaying, reducing, treating, or reversing hepatic steatosis, (liver) inflammation, and / or abnormal accumulation of liver fat); -A method for preventing, slowing the progression of, delaying the onset of, or treating type 2 diabetes when conventional antidiabetic monotherapy or combination therapy fails; - a method for achieving a reduction in the dose of conventional antidiabetic drugs (e.g. sulfonylureas or insulin) required for an adequate therapeutic effect; - a method for reducing the risk of adverse effects associated with conventional antidiabetic drugs (e.g., hypoglycemia or weight gain, such as those associated with insulin or sulfonylureas); and / or -Methods for maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance The present invention relates to a certain DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents) for use in at least one of the above.

[0029] Furthermore, the present invention provides a method for treating a diabetic renal failure comprising administering to a patient in need thereof an effective amount of a DPP-4 inhibitor (preferably linagliptin), optionally in combination with one or more other active agents, the method comprising administering to a patient (particularly a human patient having diabetes, in particular type 2 diabetes mellitus and / or a condition related thereto) (e.g. a patient having or at high risk of a cardiovascular or cerebrovascular disease and / or a renal (micro)vascular disease, event or condition, such as those described herein, e.g. a patient at high vascular risk, e.g. a patient specified herein, e.g. a patient according to at least one of embodiments 1 to 6 or 1 to 7 described herein above, Methods for treating, preventing, delaying the onset of, delaying the progression of, protecting against, and / or reducing the likelihood or risk of morbidity and / or premature mortality from atherosclerosis, atherothrombosis, endothelial dysfunction, and / or cardiovascular (CV) disease and / or renal microvascular disease, e.g., Treating, preventing, delaying the occurrence of, delaying the progression of, protecting against, and / or reducing the likelihood or risk of a cardiovascular or cerebrovascular disease or event (e.g., selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (which may exclude asymptomatic MI), and hospitalization for unstable angina); and The present invention relates to a combined method of treating, preventing, delaying the onset of, delaying the progression of, protecting against, and / or reducing the likelihood or risk of renal microvascular disease (e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate).

[0030] Furthermore, the present invention relates to a method for treating patients (particularly human patients with diabetes, in particular type 2 diabetes mellitus, and / or conditions associated therewith, such as diabetic nephropathy), such as patients with or at high risk of a cardiovascular or cerebrovascular disease and / or renal (micro)vascular disease, event, complication or condition, such as those described herein (e.g. patients at high vascular risk as specified herein, such as patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein above), such as Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 2 or 3, preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, preferably eGFR 15-45 mL / min / 1.73 m 2 ) (with or without albuminuria) In patients with for use in cardioprotection and renal protection, and / or cardiovascular or cerebrovascular disease or event (e.g., selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded), and hospitalization for unstable angina), and Renal microvascular disease (e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate) The present invention relates to a certain DPP-4 inhibitor (preferably linagliptin, optionally in combination with one or more other active agents, for example, optionally in combination with one or more antidiabetic agents and / or optionally in combination with one or more antihypertensive agents, for example, an ACE inhibitor and / or an ARB) for preventing, delaying the onset of, protecting against, delaying the progression of, or reducing the risk of, idiopathic pulmonary fibrosis.

[0031] In one embodiment, the treatment of the invention (e.g., as described above and below) is directed to, for example, patients with or at high risk of cardiovascular disease and / or renal microvascular disease (e.g., diabetic patients, in particular type 2 diabetic patients), e.g., patients at high vascular risk (e.g., those patients described herein), such as those patients according to at least one of embodiments 1 to 7 described herein, for example, to administer a certain DPP-4 inhibitor, in particular linagliptin (orally administered, preferably 5 times daily, optionally in combination with one or more other active substances, e.g., those described herein), over a long period of time (e.g., at least 1-6 years, 2 years or more, or 3-7 years, e.g., 3-4 years, 3-5 years, 3-6 years, 4-5 years, 4-6 years, 5-6 years or 5-7 years, preferably at least 48 months, more preferably at least 3 years) in order to obtain long-term effects on cardiovascular and / or renal (microvascular) safety, morbidity and / or mortality (e.g., including effects on cognitive impairment) in accordance with the invention. This may include a period of treatment with 1 mg. For example, the treatments of the present invention (e.g., as described herein above and below) may include a period of treatment with certain DPP-4 inhibitors, particularly linagliptin (administered orally, preferably 5 mg daily), optionally in combination with one or more other active substances, e.g., those described herein, for an extended period, preferably at least 48 months, more preferably at least 3 years (e.g., at least 3-4 years, or at least 5-6 years). Other aspects of the present invention will become apparent to those skilled in the art from the foregoing and following remarks (including the examples and claims). [Brief explanation of the drawings]

[0032] [Figure 1] 1 shows the expression of podocalyxin as a marker for podocyte integrity in diabetic db / db mice and healthy control mice treated with linagliptin, enalapril, or vehicle. DETAILED DESCRIPTION OF THE INVENTION

[0033] Within the scope of the present invention, it has now been found that the inventive pharmaceutical combinations, compositions, uses or methods of certain DPP-4 inhibitors (preferably linagliptin) specified herein, as well as those DPP-4 inhibitors (preferably linagliptin) optionally combined with one or more other active agents specified herein, have properties that make them useful for the purposes of the present invention and / or for satisfying one or more of the needs set out herein. The enzyme DPP-4 (dipeptidyl peptidase IV), also known as CD26, is a serine protease known to cause the cleavage of dipeptides from the N-terminus of several proteins that contain proline or alanine residues at their N-terminus. Due to this property, DPP-4 inhibitors interfere with the plasma levels of bioactive peptides, including the peptide GLP-1, and are considered promising drugs for the treatment of diabetes mellitus. For example, DPP-4 inhibitors and their uses are disclosed in 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. DPP-4 is an analog of CD26, a T cell antigen that plays a role in T cell activation and immunoregulation. Furthermore, some substrates of DPP-4 (beyond incretins) may have potential cardio-renal effects.

[0034] Furthermore, the selective DPP-4 inhibitor linagliptin may be suitable for this purpose due to certain antioxidant and / or anti-inflammatory properties. Linagliptin may also have direct effects on endothelial function as well as the integrity of the glomerular endothelium and podocytes and proximal tubular cells in the kidney, and linagliptin has a relatively high tissue distribution, including in the kidney. Furthermore, samples from human kidneys indicate that proteinuric human diseases (eg, diabetic nephropathy or nephrotic syndrome) appear to be characterized by upregulation of glomerular DPP-4. Furthermore, linagliptin may be suitable for this purpose due to its antidiabetic and antialbuminuric effects / availability in type 2 diabetic patients with micro- or macroalbuminuria (e.g., 30-3000 mg / g creatinine) on top of current conventional treatments for diabetic nephropathy (e.g., ACE inhibitors or ARBs). In further embodiments, the patient described herein is a subject with diabetes (eg, type 1 or type 2 diabetes or LADA, particularly type 2 diabetes). In particular, the subject within the present invention may be a human, such as a human infant, a human adolescent or, in particular, a human adult. More particularly, subjects within the present invention are human type 2 diabetes patients. In certain embodiments, the subject within the present invention is a (human) type 2 diabetic patient at an early diabetes stage (in one embodiment) or at an advanced diabetes stage (in another embodiment). In a further embodiment, the subject within the present invention is a (human) type 2 diabetic patient at the renal disease diabetes stage (ie, diabetes associated with renal disease).

[0035] Therefore, in a particular embodiment, a preferred DPP-4 inhibitor within the meaning of the present invention is linagliptin. In a further preferred embodiment, linagliptin is used as both a cardioprotective and nephroprotective drug (particularly an antidiabetic drug). Thus, linagliptin is for use in both cardioprotection and nephroprotection. Furthermore, linagliptin is for use in providing cardioprotective and nephroprotective effects or benefits to patients (particularly diabetic patients, e.g., type 2 diabetic patients), including at-risk patients, e.g., patients at high vascular risk (e.g., as specified herein; e.g., patients described in at least one of embodiments 1 to 6 hereinbefore). In a further preferred embodiment within the present invention, linagliptin is preferably For example, patients with or at high risk of cardiovascular events and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., patients at high risk of a CV event as described herein, e.g., a patient according to at least one of embodiments 1 to 6 described herein above), e.g., Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2 ) human diabetic patients (particularly type 2 diabetic patients), including patients with (with or without albuminuria) (e.g., with or without micro- or macroalbuminuria), cardiovascular or cerebrovascular disease or event (e.g., selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (silent MI may be excluded), and hospitalization for unstable angina), and / or Renal microvascular disease (e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline) It would be useful in methods of preventing, protecting against, reducing the risk of, and / or delaying the occurrence of.

[0036] In a further preferred embodiment within the present invention, linagliptin is, for example, Patients with or at high risk of cardiovascular events and / or renal microvascular disease, e.g., patients at high vascular risk (e.g., patients at high risk of CV events as described herein), e.g., Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2 ) are beneficial in the (cardioprotective and nephroprotective) treatment of diabetes, particularly type 2 diabetes, including patients with (with or without albuminuria) (e.g., with or without micro- or macroalbuminuria).

[0037] In a particular embodiment of the invention, linagliptin Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2) (with or without albuminuria) (e.g., with or without micro- or macro-albuminuria) are useful in treating patients, preferably diabetic patients, particularly type 2 diabetic patients. In a more particular embodiment of the invention, linagliptin Albuminuria (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)) and Previous large vessel disease, e.g., identified as one or more of a)-f): a) previous myocardial infarction, b) advanced coronary artery disease; c) high-risk single-vessel coronary artery disease; d) previous ischemic or hemorrhagic stroke; e) presence of carotid artery disease; f) Presence of peripheral arterial disease or Renal dysfunction (e.g., with or without CV comorbidities), e.g., eGFR 15-45 mL / min / 1.73 m 2 and / or impaired renal function (e.g., as determined by the MDRD formula) with any urinary albumin creatinine ratio (UACR); and / or ·eGFR ≥ 45-75 mL / min / 1.73 m 2 Renal impairment (e.g., as determined by the MDRD formula) with a urinary albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams of albumin per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) The present invention is useful for treating patients with diabetes, preferably those with type 2 diabetes.

[0038] In yet another particular embodiment of the invention, linagliptin is useful in the treatment of patients with condition I as specified herein (preferably diabetic patients, in particular type 2 diabetic patients). In yet another particular embodiment of the invention, linagliptin is useful in the treatment of patients with condition II as specified herein (preferably diabetic patients, in particular type 2 diabetic patients). In another embodiment of the invention, linagliptin (optionally in combination with one or more further active agents as described herein) is useful for treating patients (preferably diabetic patients, in particular type 2 diabetic patients) with or at high risk of cardiovascular and / or renal microvascular disease, such as patients at high vascular risk (high risk of CV events) as described herein, such as patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein, and optionally patients with inadequate control of albuminuria despite treatment with angiotensin converting enzyme (ACE) inhibitors and / or angiotensin II receptor blockers (ARBs).

[0039] In another embodiment of the invention, linagliptin (optionally in combination with one or more further active agents as described herein) is administered to patients as described herein (preferably diabetic patients, in particular type 2 diabetic patients) who may (further) have or be at risk of cognitive impairment, cognitive decline or dementia, for example, who may be at high risk of hypoglycemia and / or who may be elderly patients and / or who may have a history of one or more diabetic complications (e.g. retinopathy, neuropathy, nephropathy, macrovascular (CV) complications) and / or who have advanced diabetes (e.g. The present invention is useful for treating patients who may have diabetes mellitus (a diabetes duration of 10 years or more) and / or who may be undergoing one or more antidiabetic medications (previous or ongoing treatment with one or more conventional antidiabetic medications, e.g., metformin) and / or who may be poly-medicated (e.g., taking five or more medications daily) and / or who may be at high vascular risk (high risk of a CV event), e.g., as described herein, e.g., a patient according to at least one of embodiments 1-6 or 1-7 described herein. The effect of the treatment of the present invention on cognition may include and be analyzed by basic and instrumental activities of daily living scores, nutritional analysis scores, depression scale scores, cognitive skills and / or functional performance. Pharmaceutical compositions or combinations for use in these therapies (e.g., treatment or prevention or protection) of the present invention comprising certain DPP-4 inhibitors specified herein (preferably linagliptin), optionally together with one or more other active agents, are also contemplated.

[0040] Furthermore, the present invention relates to certain DPP-4 inhibitors (preferably linagliptin), optionally in combination with one, two or more further active agents (each as specified herein), for use in the therapies (e.g., treatment or prevention or protection) described herein. Furthermore, the present invention relates to the use of certain DPP-4 inhibitors, preferably linagliptin, optionally in combination with one, two or more further active agents (each as specified herein), for the preparation of pharmaceutical compositions suitable for the therapeutic and / or prophylactic and / or protective purposes of the present invention. Furthermore, the present invention relates to the use of certain DPP-4 inhibitors, preferably linagliptin, for the preparation of a pharmaceutical composition for use in the treatments described herein. The present invention further relates to methods of treatment as described herein, which methods comprise administering to a patient in need thereof an effective amount of a DPP-4 inhibitor (preferably linagliptin) and, optionally, one or more other active or therapeutic agents (each as described herein). Other aspects of the present invention will become apparent to those skilled in the art from the foregoing and following remarks (including the examples and claims).

[0041] Aspects of the present invention, in particular the pharmaceutical compounds, compositions, combinations, methods and uses, refer to a DPP-4 inhibitor, preferably linagliptin, optionally in combination with one or more other active agents as specified above and below. In monitoring the treatment of diabetes mellitus, the HbA1c value, a product of nonenzymatic glycation of hemoglobin B chains, is of particular importance. Because its production depends substantially on blood glucose levels and red blood cell lifespan, HbA1c, in the sense of "glycemic memory," reflects the average blood glucose level over the previous 4-12 weeks. Diabetic patients whose HbA1c levels are well-controlled over time with intensive diabetes treatment (i.e., less than 6.5% of the total hemoglobin in the sample) are significantly better protected from diabetic microangiopathy. Available treatments for diabetes can provide an average improvement in their HbA1c levels of the order of 1.0-1.5%. This reduction in HbA1c levels is not sufficient to bring all diabetics to the desired target range of HbA1c below 7.0%, preferably below 6.5%, and even more preferably below 6%. Within the meaning of the present invention, inadequate or insufficient glycemic control particularly refers to a condition in which a patient exhibits an HbA1C value above 6.5%, particularly above 7.0%, more preferably above 7.5%, particularly above 8%. Embodiments of patients with inadequate or insufficient glycemic control include, but are not limited to, patients with an HbA1C value of 6.5-10% (or in another embodiment, 7.5-10%; or in another embodiment, 7.5-11%, or in another embodiment, 6.5-8.5%, or in another embodiment, 6.5-7.5%). A particular subembodiment of inadequately regulated patients relates to patients with inadequate glycemic control, including, but not limited to, patients with an HbA1c value ≧9%. Within glycemic control, in addition to improving HbA1c levels, other recommended treatment goals for patients with type 2 diabetes mellitus are the improvement of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to normal or as close to normal as possible. The recommended desired target ranges for preprandial (fasting) plasma glucose are 70-130 mg / dL (or 90-130 mg / dL) or <110 mg / dL, and 2-hour postprandial plasma glucose is <180 mg / dL or <140 mg / dL. Furthermore, in some embodiments, patients of the invention (including preferably patients with diabetes, particularly type 2 diabetes) having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition, e.g., patients at high vascular risk (e.g., high risk of a CV event), e.g., those specifically disclosed herein, e.g., patients according to at least one of embodiments 1-6 or 1-7 described herein) may be further characterized as follows, or may further include, e.g., any of the following patients:

[0042] In embodiments, diabetic patients within the meaning of the present invention may include patients who have not been previously treated with an antidiabetic drug (drug-naive patients). Thus, in embodiments, the treatments described herein may be used in naive patients. In some embodiments of the treatments of the present invention, a DPP-4 inhibitor (preferably linagliptin) may be used alone or in combination with one or more other antidiabetic drugs in such patients. In another embodiment, diabetic patients within the meaning of the present invention may comprise patients pre-treated with conventional antidiabetic background medications, e.g. patients with advanced or late stage type 2 diabetes mellitus (including patients who have failed conventional antidiabetic treatment), e.g. patients with inadequate glycemic control with one, two or more conventional oral and / or parenteral antidiabetic drugs specified herein, e.g. patients with insufficient glycemic control despite (mono) treatment with metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides, GLP-1 or GLP-1 analogues, insulin or insulin analogues, or α-glucosidase inhibitors, or despite dual combination treatment with metformin / sulfonylurea, metformin / thiazolidinedione (especially pioglitazone), sulfonylurea / α-glucosidase inhibitors, pioglitazone / sulfonylurea, metformin / insulin, pioglitazone / insulin or sulfonylurea / insulin. Thus, in embodiments, the therapies described herein may be used in patients undergoing treatment, e.g., conventional oral and / or parenteral anti-diabetic single or dual or triple combination drugs as listed herein, and in some embodiments of the treatments of the invention may be used in such patients over or in addition to existing or ongoing conventional oral and / or parenteral anti-diabetic single or dual or triple combination drugs with which such patient has been pre-treated or is undergoing.

[0043] For example, a diabetic patient of the present invention (particularly a type 2 diabetic patient with insufficient glycemic control) may be treatment-naive, or may have been pretreated with one or more (e.g., one or two) conventional antidiabetic drugs selected from metformin, thiazolidinedione (particularly pioglitazone), sulfonylurea, glinide, α-glucosidase inhibitor (e.g., acarbose, voglibose), and insulin or an insulin analogue, and may have been pretreated with or previously treated with, for example, metformin, α-glucosidase inhibitor, sulfonylurea, or glinide monotherapy, or metformin + α-glucosidase inhibitor, metformin + sulfonylurea, metformin + glinide, α-glucosidase inhibitor + sulfonylurea, or α-glucosidase inhibitor + glinide dual combination therapy. In certain embodiments for such treatment-naive patients, a DPP-4 inhibitor (preferably linagliptin) may be used as monotherapy or as initial combination therapy with, for example, metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides, α-glucosidase inhibitors (e.g., acarbose, voglibose), GLP-1 or GLP-1 analogs, or insulin or insulin analogs, preferably as monotherapy. In certain embodiments for such patients who have been pre-treated with or have undergone one or two conventional antidiabetic agents, a DPP-4 inhibitor (preferably linagliptin) may be used in patients with inadequate glycemic control despite treatment with one or more conventional antidiabetic agents as a combination therapy with one or two conventional antidiabetic agents, i.e., added to existing or background therapy, for example, as a combination therapy with one or more (e.g., one or two) conventional antidiabetic agents selected from metformin, thiazolidinediones (particularly pioglitazone), sulfonylureas, glinides, α-glucosidase inhibitors (e.g., acarbose, voglibose), GLP-1 or GLP-1 analogs, and insulin or insulin analogs, for example: as combination therapy with metformin, alpha-glucosidase inhibitors, sulfonylureas or glinides, or As combination therapy with metformin plus an α-glucosidase inhibitor, metformin plus a sulfonylurea, metformin plus a glinide, an α-glucosidase inhibitor plus a sulfonylurea, or an α-glucosidase inhibitor plus a glinide; or It may also be used as a combination therapy with insulin and metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides or alpha-glucosidase inhibitors (e.g. acarbose, voglibose), or insulin alone.

[0044] A further embodiment for diabetic patients within the meaning of the present invention is - Patients for whom metformin treatment is contraindicated, e.g., patients who have one or more contraindications to metformin treatment according to the label, e.g., kidney disease, renal impairment, or renal insufficiency (e.g., as specified by locally approved metformin product information); dehydration, unstable or acute congestive heart failure, acute or chronic metabolic acidosis, and Hereditary galactose intolerance Patients with at least one of the following contraindications: and - Patients suffering from one or more intolerance side effects caused by metformin, in particular gastrointestinal side effects associated with metformin, e.g. nausea, vomiting, diarrhea, intestinal gas, and Severe abdominal discomfort The present invention relates to patients who are unsuitable for metformin treatment, including patients who suffer from at least one gastrointestinal side effect selected from the group consisting of: Further embodiments of diabetic patients who may be amenable to the treatment of the present invention may include, but are not limited to, those diabetic patients for whom conventional metformin therapy is not suitable, e.g., those diabetic patients who require reduced doses of metformin therapy due to reduced tolerance, intolerance or contraindications to metformin, or due to (mildly) impaired / reduced renal function (including elderly patients, e.g., ≥ 60-65 years of age).

[0045] A further embodiment of a patient (which may, for example, be diabetic or non-diabetic) within the meaning of the present invention may relate to a patient with kidney disease, renal insufficiency, or insufficient or impaired renal function (including mild, moderate, and / or severe renal impairment), as may be indicated, for example, by an elevated serum creatinine level (e.g., a serum creatinine level above the upper limit of normal for their age, e.g., ≧130-150 μmol / L, or ≧1.5 mg / dL (≧136 μmol / L) for men and ≧1.4 mg / dL (≧124 μmol / L) for women) or an abnormal creatinine clearance (e.g., a glomerular filtration rate (GFR) ≦30-60 ml / min). In this context, in further embodiments, mild renal impairment may be indicated, for example, by a creatinine clearance of 50-80 ml / min (approximately corresponding to a serum creatinine level of ≦1.7 mg / dL in men and ≦1.5 mg / dL in women) (if not otherwise noted), moderate renal impairment may be indicated, for example, by a creatinine clearance of 30-50 ml / min (approximately corresponding to a serum creatinine level of >1.7 to ≦3.0 mg / dL in men and >1.5 to ≦2.5 mg / dL in women) (if not otherwise noted), and severe renal impairment may be indicated, for example, by a creatinine clearance of <30 ml / min (approximately corresponding to a serum creatinine level of >3.0 mg / dL in men and >2.5 mg / dL in women) (if not otherwise noted). Patients with end-stage renal disease require dialysis (e.g., hemodialysis or peritoneal dialysis).

[0046] In another further embodiment, the patient with kidney disease, renal insufficiency or kidney impairment may include a patient with chronic renal failure or impairment, which may be a glomerular filtration rate (GFR, ml / min / 1.73m 2 ) into five disease stages (if not otherwise noted): stage 1, characterized by a normal GFR ≧90+ persistent albuminuria (e.g., UACR ≧30 mg / g) or known structural or genetic kidney disease; stage 2, characterized by a mild decrease in GFR (GFR 60-89), describing mild kidney impairment; stage 3, characterized by a moderate decrease in GFR (GFR 30-59), describing moderate kidney impairment; stage 4, characterized by a severe decrease in GFR (GFR 15-29), describing severe kidney impairment; and end-stage stage 5, characterized by a GFR < 15, describing the need for dialysis or established kidney failure (end-stage renal disease, ESRD). Chronic kidney disease and its stages (CKD 1-5) are therefore defined as, for example, kidney damage (albuminuria) or an impaired estimated glomerular filtration rate (GFR <60 [ml / min / 1.73m 2 ] (with or without kidney damage). Albuminuria stages may be classified, for example, as disclosed herein, and / or by urinary albumin creatinine ratio (e.g., albumin excretion rate, typically UACR ≥ 30 mg / g, sometimes ≥ 20 μg / min), e.g., microalbuminuria may be classified, for example, by a UACR of 30-300 mg / g (sometimes 20-200 μg / min) or, in another embodiment, a UACR of 30-200 mg / g, and / or macroalbuminuria may be classified, for example, by a UACR > 300 mg / g (sometimes > 200 μg / min) or, in another embodiment, a UACR > 200 mg / g. A very high UACR ≥ 2000 mg / g may be classified as nephrotic.

[0047] A further embodiment of a patient within the meaning of the present invention may relate to a patient having or at risk of developing a renal complication, such as diabetic nephropathy (including chronic and progressive renal failure, albuminuria, proteinuria, fluid retention in the body (edema) and / or hypertension). A further embodiment of a patient within the meaning of the present invention, which may be diabetic or non-diabetic, may relate to a patient, preferably a diabetic patient, with inadequate control of albuminuria despite treatment with angiotensin converting enzyme (ACE) inhibitors and / or angiotensin II receptor blockers (ARBs). Further embodiments of patients within the meaning of the present invention (which may be diabetic or non-diabetic) may relate to patients (preferably diabetic patients, in particular type 2 diabetic patients) with a history of kidney disease and / or cardiovascular disease and / or medications, such as diabetic nephropathy, macrovascular disease (e.g. coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension), microvascular disease (e.g. diabetic nephropathy, neuropathy, retinopathy), coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, ex-smoker or current smoker, and / or (previous or ongoing) treatment with acetylsalicylic acid, antihypertensive and / or lipid-lowering drugs, such as acetylsalicylic acid, ACE inhibitors, ARBs, beta-blockers, calcium antagonists or diuretics, or combinations thereof, and / or (previous or ongoing) treatment with fibrates, niacin or statins, or combinations thereof. A further embodiment of a patient within the meaning of the present invention (which may be diabetic or non-diabetic) may relate to a patient (preferably a diabetic patient, in particular a type 2 diabetic patient) with diabetic nephropathy (with or without additional usual background treatment, e.g., treatment with an ACEi or an ARB), for example a patient with fragile diabetic nephropathy, e.g., typically with a long diabetes duration (>5 years), renal impairment (e.g., mild (eGFR of 60 to <90 ml / min / 1.73 m 2 ) or moderate (30 to <60 eGFR ml / min / 1.73 m 2) renal impairment) and / or a high baseline UACR (e.g., advanced stages of micro- or macroalbuminuria). A further embodiment of a patient within the meaning of the present invention (which may be diabetic or non-diabetic) may relate to patients with diabetic nephropathy (preferably diabetic patients, in particular type 2 diabetic patients), in particular those patients on (e.g. previous or ongoing) treatment with angiotensin converting enzyme (ACE) inhibitors and / or angiotensin II receptor blockers (ARBs), e.g. patients with inadequate control of albuminuria despite treatment with angiotensin converting enzyme (ACE) inhibitors and / or angiotensin II receptor blockers (ARBs).

[0048] DPP-4 inhibitors may be administered to patients (e.g., those patients described above) in combination (e.g., on-top, in combination) with background medications, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). In some embodiments, patients who may be susceptible to treatment according to the invention may have or be at risk for one or more of the following diseases, disorders or conditions: type 1 diabetes, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), overweight, obesity, dyslipidemia (including, for example, atherogenic dyslipidemia), hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease. (NAFLD), polycystic ovary syndrome, hyperuricemia, metabolic syndrome, nephropathy, micro- or macroalbuminuria, proteinuria, nephrotic syndrome, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive impairment, dementia, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy (including, e.g., uremic cardiomyopathy), heart failure, cardiac hypertrophy, cardiac rhythm disorders, vascular restenosis, stroke, ischemia / reperfusion injury (of the kidney, heart, brain, or liver), fibrosis (of the kidney, heart, brain, or liver), vascular remodeling (of the kidney, heart, brain, or liver); diabetic diseases, for example, type 2 diabetes mellitus is of particular note (e.g., as the underlying disease).

[0049] Accordingly, the present invention thus relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with metformin for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with metformin and / or a sulfonylurea, for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with pioglitazone, for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with telmisartan, for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with insulin or an insulin analogue (e.g., a basal insulin, such as insulin glargine, insulin detemir or insulin degludec, or an NPH insulin), for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with a diuretic, an ARB and / or an ACE inhibitor, for use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with one or more other active agents, for example selected from other antidiabetic substances, active substances that lower blood glucose levels, active substances that lower lipid levels in the blood, active substances that increase HDL levels in the blood, active substances that lower blood pressure, and active substances indicated for the treatment of atherosclerosis or obesity, for use in the therapies (e.g. treatment and / or prevention and / or protection) described herein.

[0050] Furthermore, the present invention relates to certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), in combination with one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma-agonist, alpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 or GLP-1 analogue (optionally in combination with one or more further active agents (e.g. diuretics, ACE inhibitors and / or ARBs, e.g. telmisartan)), for use in the therapies (e.g. treatment and / or prevention and / or protection) described herein. Furthermore, the present invention relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), for use in the treatments described herein. The present invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), and metformin, for use in the treatments described herein. The present invention further relates to pharmaceutical compositions comprising certain DPP-4 inhibitors as specified herein, preferably linagliptin (BI 1356), and pioglitazone, for use in the treatments described herein.

[0051] Furthermore, the present invention particularly relates to combinations comprising certain DPP-4 inhibitors (particularly linagliptin) and one or more other active agents selected from those listed herein, for example selected from other antidiabetic substances, active substances that lower blood glucose levels, active substances that lower lipid levels in the blood, active substances that increase HDL levels in the blood, active substances that lower blood pressure, and active substances indicated for the treatment of atherosclerosis or obesity (e.g., each as described herein), for simultaneous, separate or sequential use in the therapies (e.g., treatment and / or prevention and / or protection) described herein. Furthermore, the present invention particularly relates to combinations comprising certain DPP-4 inhibitors (particularly linagliptin) and one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma-agonists, alpha-glucosidase inhibitors, insulin or insulin analogues, and GLP-1 or GLP-1 analogues (optionally in combination (e.g. simultaneously, separately or sequentially) with a diuretic, an ACE inhibitor and / or an ARB, e.g. telmisartan), for simultaneous, separate or sequential use in the therapies (e.g. treatment and / or prevention and / or protection) described herein. Furthermore, the present invention provides a method for administering to a patient (particularly a human patient) in need thereof, for example a patient having or at high risk of cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g., high risk of a CV event) (e.g., as described herein), preferably a human diabetic patient (e.g., a type 2 diabetic patient), including a patient described in at least one of embodiments 1-6 or 1-7 described herein, an effective amount of certain DPP-4 inhibitors as specified herein (especially linagliptin) and, optionally, one or more other active agents, for example, metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma-agonist, alpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 or GLP-1 The present invention relates to therapies or (treatment or prevention or protection) methods or uses described herein which comprise administering one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma-agonists, alpha-glucosidase inhibitors, and insulin or insulin analogues (preferably selected from the group consisting of metformin, sulfonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma-agonists, alpha-glucosidase inhibitors, and insulin or insulin analogues), optionally in combination (e.g. simultaneously, separately or sequentially) with one or more further active agents (e.g. diuretics, ACE inhibitors and / or ARBs, e.g. telmisartan).

[0052] Furthermore, the present invention relates to a therapy or a method or use (for treatment or prevention or protection) as described herein which comprises administering (e.g. simultaneously, separately or sequentially) an effective amount of linagliptin to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of a cardiovascular and / or renal microvascular disease, such as a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), preferably a patient as described in at least one of embodiments 1 to 6 or 1 to 7 described herein. Furthermore, the present invention relates to a therapy or (treatment or prevention or protection) method or use as described herein which comprises administering (e.g. simultaneously, separately or sequentially) effective amounts of linagliptin and metformin to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), preferably a patient as described in at least one of embodiments 1-6 or 1-7 described herein. Furthermore, the present invention relates to a therapy or (treatment or prevention or protection) method or use as described herein which comprises administering (e.g. simultaneously, separately or sequentially) effective amounts of linagliptin and metformin and a sulfonylurea to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), such as a patient described in at least one of embodiments 1-6 or 1-7 described herein. Furthermore, the present invention relates to a therapy or (treatment or prevention or protection) method or use as described herein which comprises administering (e.g. simultaneously, separately or sequentially) effective amounts of linagliptin and pioglitazone to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), such as a patient described in at least one of embodiments 1-6 or 1-7 described herein.

[0053] Furthermore, the present invention relates to a therapy or a method or use (of treatment or prevention or protection) as described herein which comprises administering (e.g. simultaneously, separately or sequentially) an effective amount of linagliptin and insulin or an insulin analogue (e.g. basal insulin) to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of a cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), such as a patient described in at least one of embodiments 1-6 or 1-7 described herein. Furthermore, the present invention relates to a therapy or (treatment or prevention or protection) method or use as described herein which comprises administering (e.g. simultaneously, separately or sequentially) effective amounts of linagliptin and telmisartan to a patient (particularly a human patient) in need thereof, such as a patient as described herein, preferably a human diabetic patient (particularly a type 2 diabetic patient), including, for example, a patient having or at high risk of cardiovascular and / or renal microvascular disease, for example a patient at high vascular risk (e.g. high risk of a CV event) (e.g. as described herein), such as a patient described in at least one of embodiments 1-6 or 1-7 described herein.

[0054] Furthermore, the present invention relates to a method for treating a patient (particularly a human patient who may be suffering from diabetes, e.g., type 1 or type 2 diabetes or LADA, particularly type 2 diabetes), such as a patient with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g., a patient at high vascular risk (e.g., high risk of a CV event) as described herein, particularly a patient according to at least one of embodiments 1 to 6 described herein), such as Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2 ) relates to the therapy (e.g., treatment, prevention, protection) of patients with (with or without albuminuria) (e.g., with or without micro- or macro-albuminuria), The method comprises administering to the patient an effective amount of linagliptin, optionally in combination with one or more other active agents (e.g. selected from those described above or below, e.g. selected from other antidiabetic substances, active substances which lower blood glucose levels, active substances which lower lipid levels in the blood, active substances which increase HDL levels in the blood, active substances which lower blood pressure, active substances indicated for the treatment of atherosclerosis or obesity, and / or active substances indicated for the treatment or prevention of major CV events and / or antiplatelet substances and / or anticoagulants).

[0055] Furthermore, the present invention relates to a patient in need thereof (particularly a human patient who may be suffering from diabetes, e.g. type 1 or type 2 diabetes or LADA, particularly type 2 diabetes), such as a patient with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g. a patient at high vascular risk (e.g. high risk of a CV event) as described herein, in particular a patient according to at least one of embodiments 1 to 6 or 1 to 7 described herein, e.g. Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2 ) prevent, protect against, reduce the risk of, and / or delay the occurrence of cardiovascular or cerebrovascular diseases or events (e.g., selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (which may exclude silent MI), and hospitalization for unstable angina) in patients (with or without albuminuria) (e.g., with or without micro- or macroalbuminuria); and a method of preventing, protecting against, reducing the risk of, and / or delaying the onset of renal microvascular disease (e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧50% from baseline)); It involves administering to a patient an effective amount of linagliptin, optionally in combination with one or more other active agents (e.g. selected from other antidiabetic substances, active substances which lower blood glucose levels, active substances which lower blood lipid levels, active substances which increase HDL levels in the blood, active substances which lower blood pressure, active substances indicated for the treatment of atherosclerosis or obesity, and / or active substances indicated for the treatment or prevention of major CV events and / or antiplatelet substances and / or anticoagulants).

[0056] Furthermore, the present invention relates to a patient in need thereof (particularly a human patient who may be suffering from diabetes, e.g. type 1 or type 2 diabetes or LADA, particularly type 2 diabetes), such as a patient with or at high risk of cardiovascular disease and / or renal microvascular disease, e.g. a patient at high vascular risk (e.g. high risk of a CV event) as described herein, in particular a patient according to at least one of embodiments 1 to 6 or 1 to 7 described herein, e.g. Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2) prevent, protect against, reduce the risk of, and / or delay the occurrence of cardiovascular or cerebrovascular diseases or events (e.g., selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (which may exclude silent MI), and hospitalization for unstable angina) in patients (with or without albuminuria) (e.g., with or without micro- or macroalbuminuria); and a method of preventing, protecting against, reducing the risk of, and / or delaying the onset of renal microvascular disease (e.g., selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≧50% from baseline)); It involves administering to a patient an effective amount of linagliptin and, optionally, one or more other antidiabetic agents selected from the group consisting of metformin, sulfonylurea, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma-agonist, alpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 or GLP-1 analogue, optionally in combination with one or more further active agents (e.g., a diuretic, an ACE inhibitor and / or an ARB, e.g., telmisartan).

[0057] Furthermore, the present invention relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in the treatment of diabetic nephropathy, in particular diabetic nephropathy and elevated serum creatinine and proteinuria (>300 mg / day), in patients with type 2 diabetes (including, for example, patients who have or are at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein)), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein.

[0058] Furthermore, the present invention relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in treating or reducing albuminuria or diabetic nephropathy on angiotensin-converting enzyme (ACE) inhibitor therapy and / or angiotensin II receptor blocker (ARB) therapy, preferably in patients with type 2 diabetes (including, for example, those patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein)), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein. Furthermore, the present invention preferably relates to a DPP-4 inhibitor, preferably linagliptin, optionally in combination with one or more other active agents (including, for example, an ARB or an ACE inhibitor, e.g. with or without additional conventional background therapy (e.g. with an ACEi or ARB)), for use in preventing, reducing the risk or likelihood of, delaying the onset of or slowing the progression of renal morbidity and / or mortality in patients with type 2 diabetes (including, for example, those patients who have or are at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g. patients at high vascular risk as specified herein)), such as those patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein. Furthermore, the present invention relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in treating, preventing, reducing the risk of, or delaying the onset or progression of diabetic nephropathy, micro- or macroalbuminuria, chronic kidney disease (CKD), exacerbation of CKD, and / or acute renal failure, preferably in type 2 diabetic patients (including, for example, those patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein)), such as those patients described in at least one of Embodiments 1-6 or 1-7 as described herein.

[0059] Furthermore, the present invention preferably relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in reducing or delaying the risk of the onset or progression of micro- or macroalbuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, acute renal failure and / or death in patients with type 2 diabetes (including, for example, those patients who have or are at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein)), such as those patients described in at least one of embodiments 1-6 or 1-7 described herein. Furthermore, the present invention relates to a method for preventing, reducing the risk of, delaying the onset of, or slowing the progression of renal morbidity and / or mortality, particularly in human patients with diabetes, particularly type 2 diabetes mellitus, for example for use in preventing, reducing, or delaying the onset or progression of micro- or macroalbuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, and / or the onset of acute renal failure and / or mortality; and / or The present invention relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents, such as one or more antidiabetic agents, and / or optionally in combination with one or more further active agents, such as one or more antiplatelet agents, antihypertensive agents and / or lipid-lowering agents), for use in treating, lowering, preventing, reducing the risk of, delaying the onset or slowing the progression of albuminuria (micro- or macroalbuminuria) or diabetic nephropathy, in particular in human patients with diabetes, in particular type 2 diabetes mellitus (including, for example, such patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein)), such as such patients as described in at least one of embodiments 1-6 or 1-7 described herein.

[0060] Furthermore, the present invention relates to a method for treating a cardiovascular or cerebrovascular disease, complication or event (e.g. selected from cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (which may exclude silent MI) and hospitalization for unstable angina) in patients in need thereof (particularly patients who may be suffering from diabetes, e.g. type 1 or type 2 diabetes or LADA, in particular type 2 diabetes, preferably type 2 diabetic patients (including, for example, those patients having or at risk of a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g. patients at high vascular risk as specified herein)), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein and / or those patients with inadequate control of albuminuria despite treatment with an angiotensin converting enzyme (ACE) inhibitor and / or angiotensin II receptor blocker (ARB)). and / or Renal microvascular disease or complication (e.g., selected from nephropathy, (micro- or overt) albuminuria, chronic kidney disease (CKD), renal death, end-stage renal disease, renal impairment, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline) The present invention relates to a DPP-4 inhibitor, preferably linagliptin, optionally in combination with one or more other active agents, for use in a method for treating, preventing, protecting against, reducing the risk of, delaying the onset of, or slowing the progression of, idiopathic pulmonary fibrosis (IPF), in particular the method comprises administering to a patient a DPP-4 inhibitor in combination with an angiotensin-converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB).

[0061] Furthermore, the present invention relates to certain DPP-4 inhibitors, preferably linagliptin (optionally in combination with one or more other active agents, e.g. another antidiabetic agent, and / or an ARB and / or an ACE inhibitor), for use in preventing, protecting against, reducing the risk of, delaying the onset of or slowing the progression of renal and / or cardiovascular morbidity and / or mortality, preferably both renal and cardiovascular morbidity and / or mortality, preferably in type 2 diabetic patients (e.g. those patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g. patients at high vascular risk as specified herein), including, for example, those patients according to at least one of embodiments 1-6 or 1-7 described herein and / or including, for example, those patients with inadequate control of albuminuria despite treatment with an angiotensin-converting enzyme (ACE) inhibitor and / or angiotensin II receptor blocker (ARB)). Furthermore, the present invention preferably relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in treating, preventing, reducing the risk of, or delaying the onset or progression of nephropathy, micro- or macroalbuminuria, chronic kidney disease (CKD), exacerbation of CKD, renal impairment and / or acute renal failure in type 2 diabetic patients (e.g., those patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein, and / or including, for example, those patients having inadequate control of albuminuria despite treatment with an angiotensin converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB)), and in particular the method comprises administering a DPP-4 inhibitor to an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) in combination with linagliptin. This includes administering to a patient in combination with an angiotensin-converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB).

[0062] Furthermore, the present invention preferably relates to a DPP-4 inhibitor, preferably linagliptin (optionally in combination with one or more other active agents), for use in reducing or delaying the risk of the onset or progression of micro- or macroalbuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, the onset of acute renal failure and / or death in type 2 diabetic patients (e.g., those patients having or at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g., patients at high vascular risk as specified herein), such as those patients according to at least one of embodiments 1-6 or 1-7 described herein, and / or including, for example, those patients having inadequate control of albuminuria despite treatment with an angiotensin-converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB)), and in particular this method relates to the administration of a DPP-4 inhibitor in combination with an angiotensin-converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB). This includes administering it to a patient in combination with an antiretroviral drug (ARB). Furthermore, the present invention particularly relates to patients with diabetes, in particular type 2 diabetes mellitus (e.g. those patients who have or are at risk of having a cardiovascular or cerebrovascular and / or renal (micro)vascular disease, event, complication or condition as described herein (e.g. patients at high vascular risk as specified herein), such as those patients according to at least one of embodiments 1 to 6 or 1 to 7 described herein, and who are, for example, receiving (ongoing) treatment with an antiplatelet drug, e.g. acetylsalicylic acid, and / or an antihypertensive drug, e.g. ACE inhibitors, ARBs, , beta-blockers, calcium-antagonists or diuretics, and / or (ongoing) treatment with lipid-lowering drugs, such as fibrates, niacin or statins, or combinations thereof, for use in preventing, protecting against, reducing the risk of, delaying the onset or slowing the progression of renal and / or cardiovascular morbidity and / or mortality, preferably both renal and cardiovascular morbidity and / or mortality, in patients receiving (ongoing) treatment with a diuretic, beta-blocker, calcium-antagonist or diuretic, and / or (ongoing) treatment with a lipid-lowering drug, such as a fibrate, niacin or statin, or a combination thereof.

[0063] In certain embodiments, the duration of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances, e.g., those described herein), in a treatment of the invention (e.g., including or relating to primary or, in particular, secondary prevention of CV events) may extend over a longer period (e.g., as described herein) so as to optimize cardiac and / or renal protective treatment and / or ameliorate cardiovascular and / or renal morbidity and / or mortality, e.g., in human patients, in particular human type 2 diabetes patients, e.g., patients with or at high risk of cardiovascular disease and / or renal microvascular disease (e.g., for secondary prevention of CV events), e.g., patients at high vascular risk (e.g., as described herein), e.g., patients according to at least one of embodiments 1-6 or 1-7 described herein. For example, the treatment of the present invention may relate to a period of at least 3 years of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances), for the primary or secondary prevention of, or to reduce the risk of, a CV event. For further examples, the treatments of the invention may be used for the primary or secondary prevention of (or to reduce the risk of) a CV event (e.g., for at least 3-4 years or 5-6 years for secondary prevention, or for at least 3-6 years for primary prevention). and / or certain DPP-4 inhibitors, in particular linagliptin (preferably at least 5 times a day, administered orally, optionally in combination with one or more other active substances), to reduce, prevent, protect against, delay (e.g., occurrence or progression) and / or reduce the risk of CV morbidity and / or (premature) CV mortality, e.g., CV death (e.g., fatal myocardial infarction, fatal stroke, fatal heart failure, cardiogenic shock, or sudden cardiac death), non-fatal myocardial infarction, non-fatal stroke (e.g., (intracranial) hemorrhagic or non-hemorrhagic stroke, and / or asymptomatic or non-asymptomatic) and / or unstable angina (e.g., hospitalization for unstable angina), and / or, optionally, stable angina, transient ischemic attack, congestive heart failure, peripheral revascularization surgery, and / or coronary revascularization surgery (e.g., hospitalization for any of such morbidities). mg) for a period of at least 3 years.

[0064] In an embodiment, the treatment of the present invention may relate to a period of at least 3-4 years of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances), for the secondary prevention of (or to reduce the risk of) a CV event. In an embodiment, the treatment of the present invention may relate to a period of at least 3-6 years of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances), for the primary prevention of (or to reduce the risk of) a CV event. In a further embodiment, the treatment according to the invention may relate to a period of at least 5-6 years of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances) for the secondary prevention of (or to reduce the risk of) a CV event. In a further embodiment, the treatment according to the invention may relate to a period of at least 7-10 years of treatment with certain DPP-4 inhibitors, in particular linagliptin (preferably 5 mg per day, administered orally, optionally in combination with one or more other active substances) for the primary prevention of (or to reduce the risk of) a CV event. Primary prevention of a CV event may relate to protection from (or a reduction in the risk of) developing the disease, e.g., in patients who are CV healthy. Secondary prevention of a CV event may relate to delaying its occurrence, or slowing the progression of, or protection from (or a reduction in the risk of) the disease, e.g., in patients who are at risk of a CV event / disease or who have CV disease. DPP-4 inhibitors within the meaning of the present invention include, but are not limited to, any of these DPP-4 inhibitors listed above and below, preferably orally active DPP-4 inhibitors. In a first embodiment (embodiment A), a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of the formula below or a pharmaceutically acceptable salt thereof:

[0065] Formula (I) [ka]

[0066] or formula (II) [ka]

[0067] or formula (III) [ka]

[0068] or formula (IV) [ka]

[0069] wherein R1 represents ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl, and R2 represents 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino, or (2-(S)-amino-propyl)-methylamino. With respect to the first embodiment (embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and pharmaceutically acceptable salts thereof: 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(142)): [ka]

[0070] 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(252)): [ka]

[0071] 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004 / 018468, Example 2(80)): [ka]

[0072] 2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (compare WO 2004 / 050658, Example 136): [ka]

[0073] 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006 / 029769, Example 2(1)): [ka]

[0074] 1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(30)): [ka]

[0075] 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(39)): [ka]

[0076] 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine (compare WO 2006 / 029769, Example 2(4)): [ka]

[0077] 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(52)): [ka]

[0078] 1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(81)): [ka]

[0079] 1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(82)): [ka]

[0080] 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005 / 085246, Example 1(83)): [ka]

[0081] These DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors because they combine exceptional potency and long-lasting effect with advantageous pharmacological properties, receptor selectivity and a favorable side effect profile, or provide unexpected therapeutic benefits or improvements when combined with other pharmaceutically active substances. Their preparation is disclosed in the cited publications. In a second embodiment (embodiment B), the DPP-4 inhibitor in the context of the present invention is Sitagliptin, vildagliptin, saxagliptin, alogliptin, gemigliptin, omarigliptin, evogliptin, (2S)-1-{[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile, (2S)-1-{[1,1,-dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile, (S)-1-((2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one, (3,3-difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile, (R)-2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, 5-{(S)-2-[2-((S)-2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, 3-{(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, 6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, and (S)-2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide or a pharmaceutically acceptable salt thereof.

[0082] Among the above DPP-4 inhibitors according to embodiment A of the present invention, a more preferred DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, particularly the free base thereof (which is known as linagliptin or BI 1356). The DPP-4 inhibitor of the present invention may be selected from the group consisting of linagliptin, sitagliptin, vildagliptin, alogliptin, saxagliptin, teneligliptin, anagliptin and gemigliptin, or a pharmaceutically acceptable salt of one of the DPP-4 inhibitors listed herein, or a prodrug thereof. A particularly preferred DPP-4 inhibitor to be highlighted within the present invention is linagliptin. As used herein, the term "linagliptin" refers to linagliptin or a pharmaceutically acceptable salt thereof (including hydrates and solvates thereof, as well as crystalline forms thereof), and linagliptin preferably refers to 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine. Crystalline forms are described in WO 2007 / 128721. Methods for preparing linagliptin are described, for example, in patent applications WO 2004 / 018468 and WO 2006 / 048427. Linagliptin is structurally distinct from comparable DPP-4 inhibitors. This is because they combine exceptional potency and long-lasting effect with advantageous pharmacological properties, receptor selectivity and a favorable side effect profile, or provide unexpected therapeutic benefits or improvements in monotherapy or dual or triple combination therapy.

[0083] For the avoidance of any doubt, the disclosure of each of the earlier and later documents cited above in connection with the identified DPP-4 inhibitors is hereby expressly incorporated by reference in its entirety. An embodiment of the present invention relates to a DPP-4 inhibitor suitable for use in a patient, said patient further suffering from renal disease, renal insufficiency or renal impairment, particularly characterized in that said DPP-4 inhibitor is administered to said patient at the same dosage level as for a patient with normal renal function, thus, for example, said DPP-4 inhibitor does not require downward dosage adjustment for renal impairment. For example, DPP-4 inhibitors of the present invention (which may be particularly suitable for patients with impaired renal function) may be oral DPP-4 inhibitors whose active metabolites preferably have a relatively wide (e.g., >100-fold) therapeutic window and / or are, in particular, primarily eliminated by hepatic metabolism or biliary excretion (preferably without placing additional strain on the kidneys). In more particular examples, DPP-4 inhibitors of the present invention (which may be particularly suitable for patients with impaired renal function) may be orally administered DPP-4 inhibitors that have a relatively wide (e.g., >100-fold) therapeutic window (preferably a safety profile comparable to placebo) and / or that satisfy one or more of the following pharmacokinetic properties (preferably at their therapeutic oral dose levels):

[0084] - DPP-4 inhibitors are substantially or primarily excreted by the liver (e.g., > 80% or even > 90% of an administered oral dose) and / or for which renal excretion does not represent a substantial or only minor route of elimination (e.g., radiolabeled carbon ( 14 C) < 10%, preferably < 7%, of the administered oral dose as measured by tracking the elimination of the oral dose of the substance; -DPP-4 inhibitors are excreted primarily unchanged as the parent drug (e.g., radiolabeled carbon ( 14C) on average >70%, or >80%, or preferably 90% of the radioactivity is excreted in urine and feces after oral administration of the substance, and / or it is not substantially eliminated by metabolism or is eliminated only to a small extent (e.g., <30%, or <20%, or preferably 10%); one or more (major) metabolites of the DPP-4 inhibitor are pharmacologically inactive, e.g., the major metabolite does not bind to the target enzyme DPP-4, and optionally it is eliminated rapidly compared to the parent compound (e.g., with a terminal half-life of the metabolite of ≦20 hours, or preferably ≦about 16 hours, e.g., 15.9 hours). In one embodiment, the (major) metabolite in plasma of a DPP-4 inhibitor having a 3-amino-piperidin-1-yl substituent (which may be pharmacologically inactive) is such a derivative in which the amino group of the 3-amino-piperidin-1-yl moiety is replaced by a hydroxyl group to form a 3-hydroxy-piperidin-1-yl moiety (e.g., a 3-(S)-hydroxy-piperidin-1-yl moiety formed by inversion of the configuration of a chiral center).

[0085] Additional properties of the DPP-4 inhibitors of the present invention may be one or more of the following: rapid achievement of steady state (e.g., reaching steady-state plasma levels (>90% of steady-state plasma concentrations)) between days 2 and 5 of treatment at therapeutic oral dose levels, minimal accumulation (e.g., a mean accumulation ratio R A,AUC ≦1.4), and / or preferably, retaining a long-lasting effect of DPP-4 inhibition when used once daily (e.g., near complete (>90%) DPP-4 inhibition at therapeutic oral dose levels after once-daily ingestion of a therapeutic oral drug dose, >80% inhibition over a 24-hour interval), a significant reduction in 2-hour postprandial blood glucose by ≧80% (already on the first day of treatment) at therapeutic dose levels, and a cumulative amount of unchanged parent compound excreted in urine on the first day that is less than 1% of the administered dose (increasing to no more than about 3-6% at steady state). Thus, for example, the DPP-4 inhibitors of the present invention may be administered to humans in which the DPP-4 inhibitor has a primary non-renal route of excretion, i.e., the DPP-4 inhibitor is excreted (e.g., by radiolabeling with carbon monoxide ( 14 C) It may be characterized as being substantially not excreted by the kidney (as measured by following the elimination of an oral dose of the substance) or excreted to a negligible extent (e.g., <10%, preferably <7%, e.g., about 5% of the administered oral dose, preferably the oral therapeutic dose). Furthermore, the DPP-4 inhibitor of the present invention may be a compound in which the DPP-4 inhibitor is (e.g., a radiolabeled carbon ( 14 C) may be characterized as being substantially or primarily excreted via the liver, bile duct, or feces (as measured by following the elimination of an oral dose of the substance). Furthermore, the DPP-4 inhibitors of the present invention are excreted primarily unchanged as the parent drug (e.g., radiolabeled carbon ( 14 C) on average >70%, or >80%, or preferably >90% of the radioactivity is excreted in urine and feces after oral administration of the substance, the DPP-4 inhibitor is not substantially eliminated by metabolism or is eliminated to a negligible extent, and / or The major metabolism of the DPP-4 inhibitors may be pharmacologically inactive or may be characterized as having a relatively wide therapeutic window. Furthermore, the DPP-4 inhibitors of the present invention are useful in patients with type 2 diabetes who have chronic renal failure (e.g., mild, moderate, or severe renal impairment or end-stage renal disease), and / or who have a history of renal failure due to the DPP-4 inhibitors. trough levels of said DPP-4 inhibitor in the blood plasma of type 2 diabetes patients with mild or moderate renal impairment are comparable to levels in patients with normal renal function, and / or The DPP-4 inhibitor may be characterized in that it does not require dose adjustment in type 2 diabetes patients with renal impairment (e.g., preferably regardless of the stage of renal impairment, mild, moderate or severe renal impairment or end-stage renal disease).

[0086] Furthermore, the DPP-4 inhibitors of the present invention provide a minimally effective dose at which said DPP-4 inhibitor provides >50% inhibition of DPP-4 activity at trough (24 hours after the last dose) in >80% of patients; and / or The DPP-4 inhibitor may be characterized as providing its sufficient therapeutic dose at that dose that results in >80% inhibition of DPP-4 activity at trough (24 hours after the last dose) in >80% of patients. Furthermore, the DPP-4 inhibitors of the present invention can be characterized as being suitable for use in type 2 diabetes patients who have been diagnosed with a kidney disease, disorder or complication and / or are at risk of developing a kidney disease, disorder or complication, for example, patients who have or are at risk of developing diabetic nephropathy (including chronic and progressive renal failure, albuminuria, proteinuria, fluid retention in the body (edema) and / or high blood pressure). Unless otherwise noted, it should be understood that, according to the present invention, the identification of the active agents (including DPP-4 inhibitors) listed above and below may also contemplate their pharmaceutically acceptable salts, as well as their prodrugs, hydrates, solvates, and polymorphic forms. In particular, the term therapeutic agent referred to herein refers to the respective active drug. With regard to salts, hydrates, and polymorphic forms thereof, particular reference is made to those mentioned herein. Within the present invention, it is to be understood that the combinations, compositions or combined uses of the invention may envisage simultaneous, sequential or separate administration of the active ingredients. In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed (e.g., free) forms (including kits) and uses, such as simultaneous, sequential, or separate use of the components. The combined administration of the present invention can be achieved by administering the active ingredients together, for example by administering them simultaneously in one single or two separate formulations or dosage forms, or administration can be achieved by administering the active ingredients sequentially, for example by administering them sequentially in two separate formulations or dosage forms. For the combination therapies of the invention, the active ingredients may be administered separately (by which we mean that they are formulated separately) or together (by which we mean that they are formulated in the same formulation or in the same dosage form). Thus, the administration of one element of the combination of the invention may be prior to, concurrent to, or subsequent to the administration of another element of the combination. Unless otherwise noted, combination treatment may refer to first-line, second-line or third-line treatment, or both initial or combined or replacement treatment.

[0087] Unless otherwise noted, monotherapy may refer to first-line therapy (e.g., treatment of patients with inadequate glycemic control with diet and exercise alone, e.g., drug-naive patients, typically early after diagnosis and / or patients not already treated with antidiabetic drugs, and / or patients unsuitable for metformin treatment, e.g., patients for whom metformin treatment is contraindicated, e.g., due to renal impairment, or unsuitable, e.g., due to intolerance). Unless otherwise noted, concomitant combination therapy may also refer to second- or third-line therapy (e.g., treatment of patients with inadequate glycemic control despite treatment with one or two conventional antidiabetic agents (plus diet and exercise), typically patients who have been pre-treated with one or two agents, e.g., patients with such existing antidiabetic background medications). Unless otherwise noted, initial combination therapy may refer to first-line treatment (e.g., treatment of patients with inadequate glycemic control with diet and exercise alone, e.g., drug-naive patients, typically early after diagnosis and / or patients not already treated with antidiabetic drugs).

[0088] With regard to embodiment A, synthetic methods for the DPP-4 inhibitors according to embodiment A of the present invention are known to those skilled in the art. Advantageously, the DPP-4 inhibitors according to embodiment A of the present invention can be prepared using synthetic methods described in the literature. Thus, for example, the purine derivatives of formula (I) can be obtained as described in WO 2002 / 068420, WO 2004 / 018468, WO 2005 / 085246, WO 2006 / 029769 or WO 2006 / 048427 (the disclosures of which are incorporated herein). Purine derivatives of formula (II) can be obtained, for example, as described in WO 2004 / 050658 or WO 2005 / 110999, the disclosures of which are incorporated herein. The purine derivatives of formula (III) and (IV) can be obtained, for example, as described in WO 2006 / 068163, WO 2007 / 071738, or WO 2008 / 017670 (the disclosures of which are incorporated herein by reference). The preparation of these DPP-4 inhibitors (described in detail above) is disclosed in the publications mentioned therein. Polymorphic crystalline modifications and formulations of particular DPP-4 inhibitors are disclosed in WO 2007 / 128721 and WO 2007 / 128724, respectively (the disclosures of which are incorporated herein by reference in their entirety). Formulations of particular DPP-4 inhibitors with metformin or other combination partners are described in WO 2009 / 121945 (the disclosures of which are incorporated herein by reference in their entirety). Typical active ingredient strengths of linagliptin / metformin IR (immediate release) dual fixed combination (tablets) are 2.5 / 500 mg, 2.5 / 850 mg and 2.5 / 1000 mg, which may be administered 1-3 times daily, particularly twice daily. Typical active ingredient strengths of linagliptin / metformin XR (extended release) dual fixed combination (tablets) 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 (two tablets each), which may be administered once or twice daily, in particular once daily, preferably in the evening with a meal. In some embodiments, a linagliptin / metformin XR (extended release) dual fixed combination (tablet) (e.g., active ingredient strengths of 5 / 1000 mg, 2.5 / 1000 mg, or 2.5 / 750 mg) is administered under fed or fasted conditions (e.g., once daily).

[0089] The present invention further provides a DPP-4 inhibitor as specified herein for use in (concomitant or initial) combination therapy with metformin (e.g., a total daily dose of 500 to 2000 mg of metformin hydrochloride (up to 2500 mg of metformin hydrochloride daily), e.g., 500 mg, 850 mg or 1000 mg once or twice daily). For example, the present invention further relates to a DPP-4 inhibitor as specified herein (particularly linagliptin, e.g. in a daily dose of 5 mg, preferably administered once daily) for use in combination therapy with metformin (e.g. administered once or twice daily), in a total daily amount of 500 to 2000 mg (or up to 2500 mg) of metformin hydrochloride (e.g. a daily amount of 1000 mg to 2000 mg, or 1500 mg to 2000 mg, e.g. 500 mg, 1000 mg, 1500 mg, 2000 mg or 2500 mg), for example administered at 500 mg, 750 mg, 850 mg or 1000 mg once or twice daily, for use in type 2 diabetic patients with inadequate glycemic control despite metformin treatment (e.g. second or third line treatment). For example, the present invention further relates to a DPP-4 inhibitor as specified herein (particularly linagliptin, e.g. in a daily dose of 5 mg, preferably administered once daily) for use in (initial) combination therapy with metformin (e.g. administered once or twice daily) in a total daily amount of 500 to 2000 mg (or up to 2500 mg) of metformin hydrochloride (e.g. administered as a daily amount of 1000 mg to 2000 mg, or 1500 mg to 2000 mg, e.g. 500 mg, 1000 mg, 1500 mg, 2000 mg or 2500 mg), for example as 500 mg, 750 mg, 850 mg or 1000 mg once or twice daily, particularly for use in (drug-naive) type 2 diabetic patients with inadequate glycemic control (e.g. first-line treatment). By way of further example, the present invention relates to a DPP-4 inhibitor as specified herein (particularly linagliptin, e.g., at a daily oral dose of 5 mg, preferably administered once daily) co-administered with metformin, e.g., in a total daily amount of 1000 mg of metformin hydrochloride, preferably administered once daily (preferably in the evening), for use in (drug-naive, newly diagnosed) type 2 diabetic patients with inadequate glycemic control with diet and exercise alone (e.g., patients on a diet and exercise regimen who are not already treated with first-line therapy, e.g., oral antidiabetic drugs or insulin).

[0090] By way of further example, the present invention relates to a DPP-4 inhibitor as specified herein (particularly, e.g., linagliptin, at a daily oral dose of 5 mg, preferably administered once daily) co-administered with metformin, preferably in immediate release form, e.g., in a total daily amount of 1500 mg to 2000 mg of metformin hydrochloride, for use in (drug-naive, newly diagnosed) type 2 diabetic patients with inadequate glycemic control with diet and exercise alone (e.g., HbA1c levels of 8.5% to 12.0%) (e.g., patients on a diet and exercise regimen who are not already being treated with first-line therapy, e.g., an oral antidiabetic drug or insulin or a GLP-1 receptor agonist), preferably administered once daily. With respect to embodiment B, methods for synthesizing the DPP-4 inhibitors of embodiment B are described in the scientific literature and / or published patent documents. The active compounds of the present invention may be administered by various methods, such as oral, buccal, sublingual, enteral, parenteral (e.g., transdermal, intramuscular, or subcutaneous), inhalation (e.g., liquid or powder inhalation, aerosol), pulmonary, intranasal (e.g., spray), intraperitoneal, vaginal, rectal, or topical routes of administration, and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each route of administration. In an embodiment, the DPP-4 inhibitors of the present invention are preferably administered orally. Suitable doses and dosage forms of the DPP-4 inhibitor may be determined by one of skill in the art and may include those described herein or in the relevant literature. For the pharmaceutical application in warm-blooded vertebrates, especially humans, the compound of the present invention is usually used at a dose of 0.001-100 mg per kg of body weight, preferably 0.01-15 mg / kg or 0.1-15 mg / kg, 1-4 times a day in each case.For this purpose, the compound, optionally in combination with other active substances, can be incorporated into a conventional galenic formulation, such as plain or coated tablets, capsules, powders, suspensions or suppositories, together with one or more inert conventional carriers and / or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hard fat or suitable mixtures thereof.

[0091] Pharmaceutical compositions of the present invention comprising the DPP-4 inhibitors identified herein are thus prepared by one skilled in the art using pharmaceutically acceptable formulation excipients as described in the literature and appropriate for the desired route of administration. Examples of such excipients may include, but are not limited to, diluents, binders, carriers, fillers, lubricants, glidants, crystallization retardants, disintegrants, solubilizers, colorants, pH adjusters, surfactants, and / or emulsifiers. Oral formulations or dosage forms of the DPP-4 inhibitors of the present invention may be prepared according to known techniques. A pharmaceutical composition or dosage form (e.g., oral tablet) of a DPP-4 inhibitor according to embodiment A of the present invention may typically include as excipients (in addition to the active ingredient), for example, one or more diluents, binders, disintegrants, and lubricants, preferably each disclosed below. In embodiments, disintegrants may be optional. Examples of suitable diluents for compounds of embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low-substituted hydroxypropyl cellulose, mannitol, pregelatinized starch, or xylitol. Examples of suitable lubricants for compounds of embodiment A include talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.

[0092] Examples of suitable binders for the compounds of embodiment A include copovidone (a copolymer of vinylpyrrolidone and other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, or low-substituted hydroxypropyl cellulose (L-HPC). Examples of suitable disintegrants for compounds of embodiment A include corn starch or crospovidone. A suitable method for preparing an (oral) formulation or dosage form of a DPP-4 inhibitor according to embodiment A of the present invention is Direct tableting of the active substance in a powder mixture with suitable tableting excipients; Granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tablet formation as well as film coating; or Filling capsules with powder mixtures or granules. A suitable granulation method is Wet granulation in an intensive mixer followed by fluid bed drying; One-pot granulation; Fluid bed granulation; or Dry granulation (e.g., by roll compaction) with suitable excipients followed by tablet formation or filling into capsules.

[0093] An exemplary composition (e.g., tablet core) of a DPP-4 inhibitor according to embodiment A of the present invention includes a first diluent mannitol, a pregelatinized starch as a second diluent with additional binder properties, a binder copovidone, a disintegrant corn starch, and magnesium stearate as a lubricant, wherein copovidone and / or corn starch are optional. The DPP-4 inhibitor tablets of embodiment A of the present invention may be film coated, preferably the film coat comprises hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide (e.g., red and / or yellow). For further details regarding dosage forms, formulations and administration of the DPP-4 inhibitors of the present invention, reference is made to the scientific literature and / or published patent documents, particularly those cited herein. Pharmaceutical compositions (or formulations) may be packaged in a variety of ways. Generally, an article for distribution includes one or more containers containing one or more pharmaceutical compositions in an appropriate form. Tablets are typically packaged in a primary package suitable for easy handling, distribution, and storage, and to ensure adequate stability of the composition upon prolonged contact with the environment during storage. The primary container for tablets may be a bottle or a blister pack. For example, a suitable bottle for a pharmaceutical composition or combination (tablets) comprising a DPP-4 inhibitor according to embodiment A of the present invention may be made from glass or a polymer (preferably polypropylene (PP) or high density polyethylene (HD-PE)) and may be sealed with a screw cap. The screw cap may be equipped with a child-resistant safety closure (e.g., a press and twist closure) to prevent or prevent access to the contents by children. If required (e.g., in areas of high humidity), the additional use of a desiccant (e.g., bentonite clay, molecular sieves, or, preferably, silica gel) may extend the shelf life of the packaged composition. For example, a blister pack suitable for a pharmaceutical composition or combination (tablet) comprising a DPP-4 inhibitor according to embodiment A of the present invention comprises or is formed from a top foil (which is breathable to the tablet) and a bottom (which contains a pocket for the tablet). The top foil may comprise a metal foil, in particular an aluminum or aluminum alloy foil (e.g., having a thickness of 20 μm to 45 μm, preferably 20 μm to 25 μm), coated on its inner side (sealing side) with a heat-sealable polymer layer. The bottom may comprise a multilayer polymer foil (e.g., poly(vinyl chloride) (PVC) coated with poly(vinylidene chloride (PVDC); or PVC foil laminated with poly(chlorotrifluoroethylene) (PCTFE)) or a multilayer polymer-metal-polymer foil (e.g., a low-temperature formable laminated PVC / aluminum / polyamide composition). Examples of blister packs might include alu / alu blisters, alu / PVC / polyvinyl acetate copolymer-acrylate blisters or alu / PVC / PCTFE / PVC blisters.

[0094] To ensure a long shelf life, especially under hot and humid weather conditions, an additional overwrap or pouch made from a multilayer polymer-metal-polymer foil (e.g., a laminated polyethylene / aluminum / polyester composition) may be used in the blister pack. A supplemental desiccant (e.g., bentonite clay, molecular sieves, or, preferably, silica gel) in this pouch package can extend the shelf life even under such harsh conditions. The article may further include a label or package insert, which may relate to instructions customarily included in commercial packaging of therapeutic products, which may include information about the directions, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic products. In one embodiment, the label or package insert indicates that the composition may be used for any of the purposes described herein. With respect to the first embodiment (Embodiment A), the typically required dose of a DPP-4 inhibitor recited herein in Embodiment A when administered intravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case administered 1 to 4 times per day. Thus, for example, when administered orally, the amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine is 0.5 mg to 10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day. Dosage forms prepared from pharmaceutical compositions containing DPP-4 inhibitors as recited herein in embodiment A contain active ingredient in the dosage range of 0.1-100 mg. Thus, for example, particular oral active ingredient strengths of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg, and 10 mg.

[0095] Particular embodiments of the DPP-4 inhibitors of the present invention relate to those orally administered DPP-4 inhibitors that are therapeutically effective at low dosage levels, for example oral dosage levels of < 100 mg or < 70 mg per patient per day, preferably < 50 mg per patient per day, more preferably < 30 mg or < 20 mg, more preferably 1 mg to 10 mg, especially 1 mg to 5 mg (more especially 5 mg) (which may, if required, be divided into 1 to 4 single doses, especially 1 or 2 single doses), which may be of the same size and are preferably administered orally once or twice daily (more preferably once daily), advantageously at any time of day, with or without food. Thus, for example, a daily oral dose of 5 mg of BI 1356 may be given with or without food, at any time of the day, in a once-daily dosing regimen (i.e., 5 mg BI 1356 once daily) or a twice-daily regimen (i.e., 2.5 mg BI 1356 twice daily). The dosage of the active ingredients in the combinations and compositions of the present invention may be varied, but the amount of the active ingredients should be such that a suitable dosage form is obtained. Therefore, the selected dosage and dosage form should depend on the desired therapeutic effect, the route of administration, and the duration of treatment. The dosage range of the combination may be from the maximum tolerated dose of the single agent to a lower dose. A particularly preferred DPP-4 inhibitor to be highlighted within the meaning of the present invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (also known as BI 1356 or linagliptin). BI 1356 exhibits high potency, a 24-hour duration of action, and a wide therapeutic window. In patients with type 2 diabetes receiving various oral doses of BI 1356 1, 2.5, 5, or 10 mg once daily for 12 days, BI 1356 exhibited favorable pharmacodynamic and pharmacokinetic profiles (e.g., see Table 3 below) along with rapid attainment of steady state (e.g., steady-state plasma levels (>90% of pre-dose plasma concentrations on Day 13) were reached between Days 2 and 5 of treatment in all dose groups), minimal accumulation (e.g., mean accumulation ratios R at doses above 1 mg). A,AUC≤ 1.4), and long-lasting retention of DPP-4 inhibition (e.g., nearly complete (> 90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e., 92.3 and 97.3% inhibition at steady-state levels, respectively, and > 80% inhibition over a 24-hour interval after drug intake), as well as a significant reduction in the 2-hour postprandial blood glucose excursion of ≥ 80% (already on day 1) at doses of ≥ 2.5 mg, and a cumulative amount of unchanged parent compound excreted in urine on day 1 that is less than 1% of the administered dose (increasing to ≤ 3-6% on day 12) (renal clearance is about 14 to about 70 ml / min for the administered oral dose; e.g., for a 5 mg dose, renal clearance is about 70 ml / min). In humans with type 2 diabetes, BI 1356 exhibits safety and tolerability similar to placebo. At low doses of approximately ≥ 5 mg, BI 1356 acts as a true once-daily oral drug with a full 24-hour duration of DPP-4 inhibition. At therapeutic oral dose levels, BI 1356 is primarily excreted by the liver and to a small extent by the kidneys (approximately < 7% of the administered oral dose). BI 1356 is primarily excreted unchanged via the bile duct. The fraction of BI 1356 eliminated by the kidney increases only slightly with increasing dose over time, and as a result, it is unlikely that the dose of BI 1356 will need to be modified based on the patient's renal function. The non-renal elimination of BI 1356, combined with its low accumulation potential and wide safety margin, may be significantly beneficial in patient populations with a high prevalence of renal failure and diabetic nephropathy.

[0096] Table 3: Geometric mean (gMean) and geometric percent change (gCV) of pharmacokinetic parameters of BI 1356 at steady state (day 12) [Table 1]

[0097] Since different metabolic dysfunctions often occur simultaneously, it is quite often indicated to combine several different active ingredients with each other. Thus, depending on the diagnosed dysfunction, improved therapeutic results can be achieved by combining DPP-4 inhibitors with one or more active substances customary for each disorder, such as other antidiabetic substances, in particular active substances that lower blood glucose levels or blood lipid levels, increase blood HDL levels, lower blood pressure, or are indicated for the treatment of atherosclerosis or obesity. In addition to their use in monotherapy, the above-mentioned DPP-4 inhibitors may also be used in conjunction with one or more other active substances, thereby obtaining improved therapeutic results. Such combined therapy may be administered as a free combination of substances or in the form of a fixed combination, for example, in a tablet or capsule. Pharmaceutical preparations of the combination partners required for this purpose may be commercially available as pharmaceutical compositions or may be formulated by those skilled in the art using conventional methods. Active substances that may be commercially available as pharmaceutical compositions are listed in many places in the prior art, for example, in the annually appearing drug list, the Federal Institute of Pharmaceutical Industry's "Rote Liste®," or in the annually updated compilation of prescription drug manufacturer information known as the "Physicians' Desk Reference."

[0098] Examples of antidiabetic combination partners are metformin; sulfonylureas, such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidone, glibornuride and gliclazide; nateglinide; repaglinide; mitiglinide; thiazolidinediones, such as rosiglitazone and pioglitazone; PPAR gamma modulators, such as metaglinase; PPAR-gamma agonists, such as rivoglitazone, mitoglitazone, INT-131 and balaglitazone; PPAR-gamma antagonists; PPAR-gamma / alpha modulators, such as tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297; PPAR-gamma / alpha / delta modulators, such as lobeglitazone; AMPK-activators, such as AICAR; acetyl-CoA carboxylase. (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists, such as GPR119 agonists (SMT3-receptor-agonists), for example the GPR119 agonist 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine or 5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-methanesulfonyl-phenyl)-pyridine; 11β-HSD-inhibitors; FGF19 agonists or analogs; alpha-glucosidase blockers, such as acarbose, voglibose, and miglitol; alpha2-antagonists; insulin and insulin analogs, such as human insulin, insulin lispro, insulin glucirin, r-DNA-insulin aspart, NPH insulin, insulin detemir, insulin degludec, insulin tregopil, insulin zinc suspension, and insulin glargine; gastric inhibitory peptide (GIP); amylin and amylin analogs (e.g., pramlintide or davalintide);GLP-1 and GLP-1 analogs, e.g., exendin-4, e.g., exenatide, exenatide LAR, liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (PEG-1 SGLT2 inhibitors, such as dapagliflozin, serguflozin (KGT-1251), atigliflozin, canagliflozin, ipragliflozin, luseogliflozin or tofogliflozin; inhibitors of protein tyrosine phosphatases (e.g., trodasquemine); inhibitors of glucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDK) inhibitors; inhibitors of tyrosine kinases (50 mg to 600 mg), such as PDGF-receptor-kinase (EP-A-564409, WO98 / 35958, US 5093330, WO2004 / 005281, and WO2006 / 041976) or inhibitors of serine / threonine kinases; glucokinase regulatory protein modulators (including glucokinase activators); glycogen synthase kinase inhibitors; inhibitors of SH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors, e.g., multidose salicylate; JNK1 inhibitors; protein kinase C-theta inhibitors; beta3 agonists, e.g., ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldose reductase inhibitors, e.g., AS 3201 , zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitors;GPR40 modulators, such as [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists (bromocriptine mesylate [Cyclocet]); 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; Sirtuin stimulators; and other DPP IV inhibitors.

[0099] Metformin is usually given in doses varying from about 500 mg to 2000 mg to 2500 mg per day using various dosing regimens, such as 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 delayed-release metformin is given in doses of 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. Particular active ingredient strengths may be 250, 500, 625, 750, 850, and 1000 mg of metformin hydrochloride. Doses of pioglitazone are 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 daily (or in two divided doses) (typical active ingredient strengths are 2, 4, and 8 mg). Glibenclamide (glyburide) is usually given in doses of 2.5-5 to 20 mg once daily (or in two divided doses) (typical active ingredient strengths are 1.25, 2.5, and 5 mg), or micronized glibenclamide is given in doses of 0.75-3 to 12 mg once daily (or in two divided doses) (typical active ingredient strengths are 1.5, 3, 4.5, and 6 mg). Glipizide is usually given in doses of 2.5 to 10-20 mg daily (or up to 40 mg in two divided doses) (typical active ingredient strengths are 5 and 10 mg), or extended-release glibenclamide is given in doses of 5 to 10 mg (up to 20 mg) once daily (typical active ingredient strengths 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 active ingredient strengths are 1, 2, and 4 mg).

[0100] The glibenclamide / metformin dual combination is usually given in doses ranging from 1.25 / 250 mg once daily to 10 / 1000 mg twice daily (typical strengths of active ingredient are 1.25 / 250, 2.5 / 500 and 5 / 500 mg). The dual glipizide / metformin combination is usually given in doses ranging from 2.5 / 250 mg to 10 / 1000 mg twice daily (typical strengths of active ingredient are 2.5 / 250, 2.5 / 500 and 5 / 500 mg). The dual glimepiride / metformin combination is usually given in doses ranging from 1 / 250 mg to 4 / 1000 mg twice daily. The dual combination of rosiglitazone / glimepiride is usually given in doses ranging from 4 / 1 mg once or twice daily to 4 / 2 mg twice daily (typical strengths are 4 / 1, 4 / 2, 4 / 4, 8 / 2 and 8 / 4 mg). The dual pioglitazone / glimepiride combination is usually given in doses of 30 / 2 to 30 / 4 mg once daily (typical active ingredient strengths are 30 / 4 and 45 / 4 mg). The rosiglitazone / metformin dual combination is usually given at doses of 1 / 500 to 4 / 1000 mg twice daily (typical active ingredient strengths are 1 / 500, 2 / 500, 4 / 500, 2 / 1000 and 4 / 1000 mg). The pioglitazone / metformin dual combination is usually given in doses ranging from 15 / 500 mg once or twice daily to 15 / 850 mg three times daily (typical active ingredient strengths are 15 / 500 and 15 / 850 mg).

[0101] The non-sulfonylurea insulin secretagogue nateglinide is usually given in doses of 60-120 mg with meals (up to 360 mg / day, typical active ingredient strengths are 60 and 120 mg), and repaglinide is given in doses of 0.5-4 mg with meals (up to 16 mg / day, typical active ingredient strengths are 0.5, 1, and 2 mg). Repaglinide / metformin dual combinations are available in active ingredient strengths of 1 / 500 and 2 / 850 mg. Acarbose is usually given in doses of 25-100 mg with meals. Miglitol is usually given in doses of 25-100 mg with meals. Examples of combination partners that lower blood lipid levels are HMG-CoA-reductase inhibitors, such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrates, such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofylline clofibrate; nicotinic acid and its derivatives, such as acipimox; PPAR-alpha agonists; PPAR-delta agonists, such as {4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-acetic acid; PPAR-alpha / delta agonists; inhibitors of acyl coenzyme A: cholesterol acetyltransferase (ACAT; EC 2.3.1.26), such as abasimide; cholesterol absorption inhibitors, such as azetimibe; substances that bind bile acids, such as cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; HDL-modulating active substances, such as D4F, reverse D4F, LXR-modulating active substances and FXR-modulating active substances; CETP inhibitors, such as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO 2007 / 005572 (anacetrapib); LDL receptor modulators; MTP inhibitors (e.g., lomitapide); and ApoB100 antisense RNA. Atorvastatin doses are usually 1 mg to 40 mg, or 10 mg to 80 mg, taken once daily.

[0102] Examples of blood pressure lowering combination partners are beta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol and carvedilol; diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril, as well as angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan and eprosartan. The usual dose of telmisartan is 20 mg to 320 mg, or 40 mg to 160 mg per day. Examples of combination partners that increase HDL levels in the blood 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.

[0103] Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat); dexfenfluramine; axokine; cannabinoid receptor 1 antagonists, such as the CB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 as well as NPY2 antagonists (e.g., velneperit); beta3-AR agonists, such as SB-418790 and AD-9677; 5HT2c receptor agonists, such as APD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin; steroyl-CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; and tesofensine, as well as dual combinations bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine, and pramlintide / metreleptin. Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine kinases, such as PDGF-receptor-kinases (50 mg to 600 mg) (see EP-A-564409, WO98 / 35958, US 5093330, WO2004 / 005281, and WO2006 / 041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano: ASA; and VCAM-1 inhibitors. Furthermore, certain DPP-4 inhibitors of the present invention may be used for the purposes of the present invention in combination with a substrate of DPP-4 (particularly an anti-inflammatory substrate of DPP-4), which may be other than GLP-1, such substrates of DPP-4 including, but not limited to, one or more of the following:

[0104] Incretins: Glucagon-like peptide (GLP)-1 Glucose-dependent insulinotropic peptide (GIP) Neuroactive substances: substance P Neuropeptide Y (NPY) Peptide YY Energy Homeostasis: GLP-2 Prolactin Pituitary adenylate cyclase-activating peptide (PACAP) Other hormones: PACAP 27 Human chorionic gonadotropin alpha chain Growth Hormone-Releasing Factor (GHRF) Progesterone alpha chain Insulin-like growth factor 1 (IGF-1) CCL8 / Eotaxin CCL22 / macrophage-derived chemokine CXCL9 / interferon-gamma-inducing monokine Chemokines: CXCL10 / interferon-gamma-induced protein-10 CXCL11 / interferon-induced T cell chemoattractant CCL3L1 / macrophage inflammatory protein 1 alpha isoform LD78 Beta CXCL12 / stromal-derived factor 1 alpha and beta others: Enkephalin, gastrin-releasing peptide, vasostatin-1, Peptide histidine methionine, thyrotropin alpha.

[0105] Additionally or additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more active substances indicated for the treatment of nephropathy, e.g., selected from diuretics, ACE inhibitors and / or ARBs. Additionally or additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more active agents indicated for the treatment or prevention of cardiovascular diseases or events (e.g., major cardiovascular events). Furthermore, if necessary, certain DPP-4 inhibitors of the present invention may be used in combination with one or more antiplatelet agents, such as (low-dose) aspirin (acetylsalicylic acid), selective COX-2 or non-selective COX-1 / COX-2 inhibitors, or ADP receptor inhibitors, such as thienopyridines (e.g., clopidogrel or prasugrel), elinogrel or ticagrelor, or thrombin receptor antagonists, such as vorapaxar. Furthermore, if necessary, certain DPP-4 inhibitors of the present invention may be used in combination with one or more anticoagulants, such as heparin, coumarins (e.g., warfarin or phenprocoumon), pentasaccharide inhibitors of factor Xa (e.g., fondaparinux), or direct thrombin inhibitors (e.g., dabigatran), or factor Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, or otamixaban). Furthermore, if desired, certain DPP-4 inhibitors of the present invention may be used in combination with one or more agents for the treatment of heart failure (for example, those listed in WO 2007 / 128761). The present invention should not be limited in scope by the specific embodiments described herein. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from this disclosure. Such modifications are intended to fall within the scope of the appended claims. All patent applications cited herein are hereby incorporated by reference in their entirety.

[0106] Reduction of podocyte loss; podocalyxin expression as a marker of podocyte integrity: Podocalyxin expression will be analyzed by immunohistochemistry using a podocalyxin-specific antibody. Kidney sections from the following groups of male diabetic db / db mice (10 weeks old at the start and treated for 3 months) will be analyzed: Diabetic control (n=10), linagliptin 3 mg / kg (n=8), enalapril 20 mg / kg (n=10) and heterozygous control mice (n=8). All assessments of glomerular staining intensity were performed semiquantitatively by two different nephrology experts who were blinded to the slides. Pre-specified scoring gradients are 0, 1, 2, and 3. 0 means no expression, while 3 indicates highest expression. Group means are compared with non-parametric tests. P values less than 0.05 are considered significant. FIG. 1 shows the expression of podocalyxin as a marker of podocyte integrity in linagliptin-, enalapril-, or vehicle-treated diabetic db / db mice and healthy control mice. This proof-of-concept study in db / db mice (see abstract below) indicates that DPP-4 inhibition may offer a novel therapeutic approach for treating podocyte loss and associated proteinuria. This study clearly demonstrates that the DPP-4 inhibitor linagliptin significantly reduces podocyte loss in db / db mice in a blood glucose-independent manner (Figure 1). Podocyte loss is measured by podocalyxin staining. Podocalyxin, a sialoglycoprotein, is thought to be the major component of the podocyte glycocalyx. It is a member of the CD34 family of transmembrane sialomucins. It coats the secondary foot processes of podocytes. It is negatively charged and thus functions to keep adjacent foot processes separate, thereby maintaining an open urinary filtration barrier. This function is further supported by knockout studies in mice, revealing their essential role in podocyte morphogenesis.

[0107] Renal protective effects of linagliptin; podocyte protection: Diabetic nephropathy is a major cause of end-stage renal disease. This study investigated the effects of linagliptin on diabetic nephropathy in severely insulin-resistant and aged db / db mice as a model of diabetic nephropathy. Male diabetic db / db mice (10 weeks old) were divided into three groups and treated with vehicle (n = 10), linagliptin 3 mg / kg / day (n = 8), or the angiotensin-converting enzyme (ACE) inhibitor enalapril 20 mg / kg / day (n = 10) for 12 weeks. Vehicle-treated heterozygous db / + mice served as controls (n = 8). Glucose, triglyceride, insulin, cystatin C, and creatinine levels were analyzed in serum and urine samples at baseline and monthly thereafter. Body weight, urinary albumin excretion, and oral guanosine-glucose thromboplastin (OGTT) were monitored periodically. Renal histology (glomerulosclerosis, tubulointerstitial fibrosis) and expression of the sialoglycoprotein podocalyxin (a marker of podocyte integrity in the glomerulus, a marker of glomerular injury), glucagon-like peptide 1 receptor (GLP-1R), alpha-smooth muscle actin, and type I collagen were assessed at the end of the study.

[0108] result: At 22 weeks, db / db mice exhibited significantly (p<0.01) higher levels of fasting plasma glucose, insulin, and triglycerides, and increased body weight compared with healthy db / + mice. Linagliptin and enalapril had limited effects on fasting or postprandial glucose levels. However, histological analysis showed that tubular interstitial fibrosis and mesangial matrix expansion were reduced to near-control levels in both treatment groups compared with diabetic vehicle (p<0.05 for both). Urinary albumin excretion rate and tubular interstitial fibrosis were significantly reduced in linagliptin-treated db / db mice compared with those treated with enalapril (p<0.05 for both). Podocalyxin expression in db / db vehicle-treated mice was significantly reduced compared to db / + controls (1.59±0.2 vs. 2.65±0.1; p<0.001). Mice treated with linagliptin and enalapril had significantly higher podocalyxin expression compared to diabetic mice (2.3±0.2 and 2.4±0.2, respectively; p<0.05 for both). The expression pattern of α-smooth muscle actin was also measured in the kidney as a marker of mesangial cell damage. Linagliptin treatment normalized the expression of α-smooth muscle actin-positive myofibroblasts in the interstitium and glomeruli of diabetic db / db mice. Similar results were obtained for type I collagen deposition. Immunohistochemical staining of kidney sections revealed decreased GLP-1R expression in the cortical glomeruli of db / db mice (1.67 ± 0.07) compared with healthy control mice (2.15 ± 0.1; P < 0.01). Linagliptin treatment significantly increased GLP-1R expression in the glomeruli of db / db mice (1.90 ± 0.04; P < 0.05) compared with vehicle-treated diabetic db / db mice. In conclusion, this study suggests that linagliptin protects podocytes from damage and may therefore be effective in treating, preventing, or slowing the progression of diabetic nephropathy, independently of its effects on glucose homeostasis. Furthermore, this study suggests that linagliptin is beneficial for treating, preventing, or slowing the progression of glomerular sclerosis and / or interstitial fibrosis, or glomerular and / or interstitial damage. Furthermore, this study suggests that linagliptin is beneficial for renal protection by suppressing podocyte damage and myofibroblast transformation (reduced α-SMA expression). The renal protective effects of linagliptin in this model appear to be as effective as treatment with ACE inhibitors, the current gold standard for the treatment of diabetic nephropathy.

[0109] Linagliptin for use in reducing albuminuria on recommended standard of care for diabetic nephropathy: Despite optimal treatment, people with type 2 diabetes mellitus (T2D) remain at high risk for kidney damage, manifested as albuminuria, and may develop progressive renal failure. Furthermore, despite optimal treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), patients with type 2 diabetes mellitus (T2DM) remain at increased risk for progressive renal failure and cardiovascular disease, for which albuminuria has emerged as a predictive biomarker. Linagliptin, a DPP-4 inhibitor, has already shown evidence of reduced albuminuria over telmisartan in mice. We investigated the clinical effects of linagliptin on albuminuria in T2D patients with early diabetic nephropathy. Four randomized, double-blind, 24-week, placebo-controlled trials of linagliptin (5 mg qd) versus no, single, or dual oral glucose-lowering background therapy (e.g., linagliptin monotherapy, linagliptin combined with metformin, or linagliptin combined with metformin and sulfonylurea, or linagliptin and metformin initial combination) had available data on urinary albumin-to-creatinine ratio (UACR) and were pooled for analysis (n=2472). Participants were required to meet the following criteria: i) UACR 30 ≤ 3000 mg / g creatinine; ii) stable treatment with an ACE / ARB ≥ 4 weeks prior to and during the study; and iii) eGFR > 30 ml / min / 1.73 m 2Patients were included in the study if they had a ≥100% risk of coronary heart disease. The endpoint was the percent change in geometric mean UACR. In this analysis, 492 (19.9%) patients met the UACR and eGFR thresholds, 46% of whom were on stable ACE / ARB therapy (linagliptin, n=168; placebo, n=59). Mean baseline A1C and median UACR were 8.2% vs. 8.5% and 76 vs. 78 mg / g creatinine for the linagliptin and placebo groups, respectively. After 24 weeks, placebo-corrected changes in A1C and FPG were -0.71% and -26 mg / dL, respectively (both p<.0001). Linagliptin significantly reduced adjusted UACR by 33% (95% CI 22% to 42%; p<.05), with a between-group difference versus placebo of -29% (-3% to -48%; p<.05). Overall, renal function and blood pressure were unchanged, but more placebo patients received new antihypertensive medications (17% vs. 11% for linagliptin). Sensitivity analyses in patients not previously treated with RAS blockade (n=265) found similar results. Linagliptin may have renal protective properties beyond its glucose-lowering effects. This protective effect may be independent of race. Linagliptin may be beneficial for treating or reducing albuminuria in T2DM patients with early diabetic nephropathy on standard of care angiotensin-converting enzyme (ACE) inhibition or angiotensin II receptor blockade (ARB).

[0110] Linagliptin for use in the treatment of albuminuria in patients with type 2 diabetes and diabetic nephropathy: Background and Objectives: Diabetes mellitus has become the single most common cause of end-stage renal disease, and a high proportion of individuals with type 2 diabetes (T2D) are found to have microalbuminuria and overt nephropathy soon after their diabetes diagnosis. Linagliptin, a DPP-4 inhibitor, has recently demonstrated glycemic efficacy and safety in T2D patients with advanced stages of renal disease. Here, the clinical effect of linagliptin on albuminuria in T2D patients with early diabetic nephropathy is reported.

[0111] Materials and Methods: Seven randomized, double-blind, placebo-controlled trials (24-52 weeks in duration) of linagliptin (5 mg qd) as monotherapy or addition to various glucose-lowering background therapies had available data on urinary albumin-to-creatinine ratio (UACR) and were eligible for this analysis (n=4113). Pooling of data after 24 weeks of treatment allowed for two cohorts to be identified: 1) early-stage T2D diabetic nephropathy (with and without oral glucose-lowering background therapy; e.g., linagliptin monotherapy, linagliptin plus metformin, or linagliptin plus metformin in combination with a sulfonylurea, or linagliptin plus metformin initial combination): participants from four 24-week pivotal Phase III trials (if they had a UACR of 30 ≤ 3000 mg / g (eGFR > 30 ml / min / 1.73 m)) 2 1) persistent albuminuria and stable treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) at baseline (ongoing treatment with ACEi or ARB); 2) diabetic nephropathy in elderly patients (various glucose-lowering background treatments including insulin, e.g., linagliptin monotherapy, linagliptin combined with metformin or linagliptin combined with metformin plus sulfonylurea, or linagliptin combined with metformin initial combination, or linagliptin combined with basal insulin): UACR criteria 30 ≤ UACR ≤ 3000 mg / g (eGFR > 30 ml / min / 1.73 m 2 Patients from all seven trials who met the following criteria and were 65 years of age or older (with or without ongoing treatment with an ACEi or ARB) were enrolled. The endpoint for both groups was the percent change in geometric mean UACR after 24 weeks.

[0112] Results: For set #1, 492 of 2472 patients met the UACR criteria, and 46% of them were receiving stable ACEi / ARB therapy (linagliptin, n=168; placebo, n=59). For set #2, 1331 patients were 65 years of age or older, and 377 (28%) of them met the UACR criteria (linagliptin, n=232; placebo, n=145). The mean baseline HbA1c and median UACR were 8.3% and 76 mg / g overall for set #1, and 8.1% (overall), 77 mg / g (linagliptin), and 86 mg / g (placebo) for set #2. In set 1, placebo-corrected changes in HbA1c and fasting plasma glucose were -0.71% and -1.4 mmol / L (-26 mg / dL), respectively (both P<0.0001). Linagliptin significantly reduced the adjusted UACR by 33% (95% CI: 22%, 42%; P<0.05), with a between-group difference vs. placebo of -29% (95% CI: -3%, -48%; P<0.05). In set 2, linagliptin also significantly reduced the adjusted UACR by 30% (95% CI: 13%, 43%; P<0.05), with a trend toward a reduction vs. placebo of -25% (95% CI: -47%, +6%). In all seven studies, blood pressure and renal function were not affected to a clinically significant extent by either treatment. Conclusions: In studies up to 52 weeks, linagliptin reduced albuminuria beyond what would be predicted by its glucose-lowering effect. Changes in albuminuria were seen more rapidly than would be expected based on structural changes (e.g., total UACR effects occurred as early as 12 weeks of treatment). The reduction in albuminuria suggests long-term renal benefit. Furthermore, linagliptin (5 mg qd) is indicated for patients with fragile diabetic nephropathy (e.g., with or without additional standard background treatment with an ACEi or ARB; e.g., age ≥ 65 years, typically with a long diabetes duration (> 5 years), renal impairment (e.g., mild (60 to < 90 eGFR ml / min / 1.73 m 2 ) or moderate (30 to <60 eGFR ml / min / 1.73 m2 ) renal impairment) and / or higher baseline UACR (e.g., in patients with advanced stages of micro- or macroalbuminuria). In some cases, patients with diabetic nephropathy who are amenable to the treatment of the present invention may be on (ongoing) treatment at baseline with hypertension and / or lipid-lowering drugs, such as ACE inhibitors, ARBs, beta-blockers, calcium-antagonists or diuretics, or combinations thereof, and / or on (ongoing) treatment with fibrates, niacin or statins, or combinations thereof.

[0113] Renal safety and outcomes with linagliptin: A meta-analysis in 5466 patients with type 2 diabetes mellitus: Long-term glycemic control in diabetes is associated with a reduced risk of renal microvascular complications. Linagliptin has demonstrated renal protective effects in animal models and significantly reduced albuminuria in type 2 diabetes (T2D) patients with associated nephropathy. Because these effects are independent of short-term glycemic improvement, linagliptin may have renal protective effects. The objective of this study was to evaluate the renal safety and outcomes of linagliptin in a phase 3, randomized, double-blind, placebo-controlled trial (≥ 12 weeks). Prespecified events from 13 trials were analyzed using the composite primary endpoint: new onset / occurrence of a) microalbuminuria (first recorded UACR ≥ 30 mg / g) or b) macroalbuminuria (first recorded UACR ≥ 300 mg / g), c) CKD (serum creatinine increase ≥ 250 μmol / L), d) worsening CKD (loss of eGFR > 50% vs. baseline), e) acute renal failure (ARF, standardized MedDRA question), and f) death (any cause). Of 5466 patients included (mean baseline HbA1c: 8.2% and eGFR: 91.4 ml / min / 1.73 m2), 3505 received linagliptin 5 mg qd and 1961 received placebo; cumulative exposure (person-years) was 1756 and 1057, respectively. Events occurred in 448 (12.8%) patients receiving linagliptin compared with 306 (15.6%) for placebo. The hazard ratio (HR) for the composite endpoint for linagliptin vs. placebo was 0.84 (95% CI 0.72-0.97, p<0.05) and was not significantly modified by race, but was lower in patients <65 years vs. >65 years (HR: 0.77 vs 1.04). RRs were consistently reduced for individual renal endpoints: microalbuminuria (-15%) and macroalbuminuria (-12%), new onset or worsening of CKD (-56%), ARF (-7%), and death (-23%).In this large meta-analysis, renal safety and outcomes were significantly improved in patients with T2D treated with linagliptin (5 mg / day, e.g., once daily; either as monotherapy in patients with inadequately controlled type 2 diabetes or in combination with other antidiabetic agents (e.g., metformin, sulfonylurea, insulin, metformin + sulfonylurea, metformin + insulin)). These data support a direct renal protective effect of linagliptin. Linagliptin may be beneficial in preventing, alleviating, or delaying the onset or progression of micro- or macroalbuminuria, the development of chronic kidney disease (CKD), worsening CKD, acute renal failure, and / or death. Thus, linagliptin may preferably be beneficial in preventing, reducing the risk of, or delaying the onset or slowing the progression of renal morbidity and / or mortality in patients with T2DM. In particular, linagliptin may be beneficial in preventing, reducing the risk of, or delaying the onset / occurrence of, or slowing the progression of, CDK, preferably in T2DM patients.

[0114] In some cases, patients (particularly those with type 2 diabetes) susceptible (at risk) to the kidney protection or risk reduction (e.g., prevention, reduction, or delay of the onset or progression of micro- or macroalbuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, the onset of acute kidney failure, and / or death) of the present invention may have a renal / cardiovascular history and / or medications (optionally in addition to antidiabetic medications), such as diabetic nephropathy, macrovascular disease (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension), microvascular disease (e.g., diabetic nephropathy, neuropathy, retinopathy), coronary artery disease, cerebrovascular disease, peripheral artery disease, hypertension, ex-smoker or current smoker, and / or are taking acetylsalicylic acid, antihypertensive and / or lipid-lowering medications, e.g., acetylsalicylic acid, ACE inhibitors, ARBs, or the like. , beta-blockers, calcium-antagonists or diuretics, or a combination thereof, and / or (ongoing) treatment with fibrates, niacin or statins, or a combination thereof. Additionally, in some cases, patients susceptible (at risk) to the kidney protection or risk reduction (e.g., prevention, reduction, or delay of the onset or progression of micro- or macroalbuminuria, the onset of chronic kidney disease (CKD), the worsening of CKD, the onset of acute kidney failure, and / or death) of the present invention are patients at increased risk of a renal event (e.g., patients with an eGFR < 60 mL / min or, particularly, < 30 mL / min / 1.73 m). 2 ), patients with micro- or macroalbuminuria, and / or elderly patients (e.g., >70 years old). [Example]

[0115] In order that the present invention may be more fully understood, examples are given herein. Further embodiments, features or aspects of the present invention may become apparent from the examples. The examples serve to illustrate the principles of the present invention by way of example, but not by way of limitation. Treatment of patients with type 2 diabetes mellitus who are at high cardiovascular and renal microvascular risk: The long-term effects of treatment with linagliptin on cardiovascular and renal (microvascular) safety, morbidity and / or mortality and related efficacy parameters (e.g., HbA1c, fasting plasma glucose, treatment persistence) in a valid population of patients with type 2 diabetes mellitus (e.g., at vascular risk) can be investigated as follows: For example, albuminuria (trace or overt) and previous macrovascular disease, identified according to Symptom I below: and / or For example, impaired kidney function, as identified according to symptom II below; Symptom I: Albuminuria (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)) and Previous macrovascular disease, e.g., identified as one or more of a) through f): a) previous myocardial infarction (e.g., > 2 months), b) Advanced coronary artery disease, e.g., as defined by any one of the following: ≥ 50% narrowing of the luminal diameter in two or more major coronary arteries (e.g., LAD (left anterior descending), CX (circumflex), or RCA (right coronary artery)) by coronary angiogram or CT angiogram, Left main coronary artery with ≥ 50% narrowing of the luminal diameter, Previous percutaneous or surgical revascularization of ≥ 2 major coronary arteries (e.g., ≥ 2 months), For example, a combination of previous percutaneous or surgical revascularization of one major coronary artery (e.g., ≥ 2 months) and ≥ 50% narrowing of the luminal diameter by coronary angiogram or CT angiogram of at least one additional major coronary artery,

[0116] c) High-risk single-vessel coronary artery disease, e.g., identified as a ≥ 50% narrowing of the luminal diameter of one major coronary artery (e.g., by coronary angiogram or CT angiogram in a patient who has not been revascularized) and the presence of at least one of the following: Positive non-invasive stress test, e.g. - Positive ECG exercise tolerance test in patients without left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy due to repolarization abnormalities, or paced ventricular rhythm, or atrial fibrosis in cases of abnormal ST-T segments. - Positive stress echocardiogram showing induced positional systolic wall motion abnormalities, - A positive nuclear myocardial perfusion imaging stress study demonstrating stress-induced reversible perfusion abnormalities, - Patients discharged from the hospital with a documented diagnosis of unstable angina (e.g., ≥ 2 - 12 months) As can be seen by d) previous ischemic or hemorrhagic stroke (e.g., > 3 months); e) Presence of carotid artery disease (symptomatic or asymptomatic), e.g. - imaging techniques with at least one lesion estimated to be ≥ 50% narrowing of the luminal diameter; - Previous percutaneous or surgical carotid revascularization As recorded by f) Presence of peripheral arterial disease, e.g. - previous limb angioplasty, stenting or bypass surgery, - Previous limb or foot amputation due to overt circulatory insufficiency, - Peripheral arterial stenosis: angiographic evidence of ≥ 50% narrowing of luminal diameter in at least one limb (e.g., peripheral arteries: common iliac artery, internal iliac artery, external iliac artery, femoral artery, specific popliteal artery), As recorded by

[0117] Symptom II: Renal dysfunction (e.g., with or without CV comorbidities), e.g., ·Estimated glomerular filtration rate (eGFR) 15-45 mL / min / 1.73 m 2 and impaired renal function (e.g., as determined by the MDRD formula) with any urinary albumin creatinine ratio (UACR), and / or ·Estimated glomerular filtration rate (eGFR) ≥ 45-75 mL / min / 1.73 m 2 Renal impairment as determined by renal dysfunction (e.g., as determined by the MDRD formula) with a urinary albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) Type 2 diabetes patients with inadequate glycemic control (naive or pre-treated with any antidiabetic background medication (excluding treatment with a GLP-1 receptor agonist, DPP-4 inhibitor or SGLT-2 inhibitor for 7 or more consecutive days), e.g., having an HbA1c of 6.5-10%), as identified by

[0014] and a high risk of cardiovascular events, are treated with linagliptin (preferably 5 mg per day, administered orally, preferably in tablet form, optionally in combination with one or more other active agents, e.g., those described herein) for a long period of time (e.g., 4-5 years, or preferably at least 48 months) and compared to patients treated with placebo (as a concomitant therapy above the standard of care).

[0118] Evidence of success of treatment compared to placebo-treated patients may be seen, for example, in the (longer) time taken to the first occurrence of a cardiovascular or cerebrovascular event, e.g., the time to the first occurrence of any of the following components of a composite CV endpoint: cardiovascular death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal myocardial infarction (excluding silent myocardial infarction), non-fatal stroke, and (any) hospitalization, e.g., for unstable angina; and / or The (longer) time to the first occurrence of a renal microvascular event, e.g., the time to the first occurrence of any of the following components of a composite renal endpoint: renal death, sustained end-stage renal disease, and a sustained decline of 50% or more in eGFR, was found to be non-inferior or superior to placebo. Further treatment success is seen in (fewer) or (longer) time to first occurrence of cardiovascular death, (non-)fatal myocardial infarction, silent MI, (non-)fatal stroke, hospitalization for unstable angina, hospitalization for coronary revascularization, hospitalization for peripheral revascularization, hospitalization for congestive heart failure, all-cause mortality, renal death, sustained end-stage renal disease, loss of eGFR, new onset of overt albuminuria, progression of albuminuria, progression of CKD, need for anti-retinal treatment; or improvement in albuminuria, renal function, CKD; or improvement in cognitive function or prevention / protection against accelerated cognitive decline.

[0119] Cognitive function can be evaluated by standardized tests used as a measure of cognitive function, for example, by using the Mini-Mental State Examination (MMSE), Trail Making Test (TMT) and / or Verbal Fluency Test (VFT). The success of additional treatment (compared to placebo) is seen in a greater change from the baseline of HbA1c and / or FPG. The success of further additional treatment is seen in a greater proportion of patients in the study treatment maintaining glycemic control (e.g., HbA1c <!--= 7%) at the end of the study. <br-->The success of further additional treatment is seen in a greater proportion of patients in the study treatment maintaining glycemic control without the need for additional anti-diabetic drugs (during treatment) to obtain HbA1c <!--= 7% at the end of the study. <br-->The success of further additional treatment is seen in a lower proportion of patients in the study treatment initiated or treated with insulin or a lower dose of the insulin dose used. The success of further additional treatment is seen in a lower change from the baseline of body weight or a greater proportion of patients with a weight gain of ≦ 2% or a lower proportion of patients with a weight gain of ≧ 2% at the end of the study.

Claims

1. Linagliptin or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other active agents, for use in the treatment of patients having or at risk of cardiovascular and / or renal microvascular disease, e.g., patients at high vascular risk.

2. 2. Linagliptin or a pharmaceutically acceptable salt thereof, optionally in combination with one or more other active agents, for use according to claim 1, wherein the treatment is both cardioprotective treatment and nephroprotective treatment.

3. Linagliptin, optionally in combination with one or more other active agents, for use according to claim 1 or 2, wherein the treatment comprises preventing, protecting against, delaying the onset of, delaying the progression of and / or reducing the risk of at least one selected from CV morbidity, premature CV mortality, renal morbidity and premature renal mortality.

4. Treatment, For example, a cardiovascular or cerebrovascular disease or event selected from the group consisting of cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, fatal heart failure, cardiogenic shock and / or sudden death), non-fatal stroke (hemorrhagic or non-hemorrhagic) and non-fatal myocardial infarction (MI) (including or excluding silent MI), and, optionally, hospitalization (e.g., for unstable angina, stable angina, transient ischemic attack, coronary revascularization surgery, peripheral revascularization, or congestive heart failure). prevent, protect against, reduce the risk of and / or delay the occurrence of, and / or renal microvascular disease, e.g., selected from the group consisting of albuminuria (e.g., micro- or macroalbuminuria), chronic kidney disease (CKD), renal impairment, renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline); Preventing, protecting against, reducing the risk of, slowing the progression of, and / or slowing the onset of, Linagliptin, optionally in combination with one or more other active agents, for use according to claim 1, 2 or 3.

5. Treatment, prevention of cardiovascular or cerebrovascular diseases or events selected from the group consisting of cardiovascular (CV) death (including fatal stroke, fatal myocardial infarction, and sudden death), non-fatal stroke, non-fatal myocardial infarction (MI) (which may exclude silent MI), and, optionally, hospitalization for unstable angina; Prevention of renal microvascular diseases or events selected from renal death, end-stage renal disease, and loss of estimated glomerular filtration rate (e.g., eGFR ≥ 50% from baseline) 5. Linagliptin, optionally in combination with one or more other active agents, for use according to claim 1, 2, 3 or 4, comprising the combined method of:

6. Treatment is as follows: - for preventing, slowing the progression of, delaying the onset of, or treating metabolic disorders or diseases, such as type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptive hyperglycemia, latent autoimmune diabetes in adults (LADA), excess weight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperNEFAemia, postprandial lipemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy, nephropathy, nephrotic syndrome, polycystic ovary syndrome, and / or metabolic syndrome; - a method for improving and / or maintaining glycemic control and reducing fasting plasma glucose, postprandial plasma glucose, postabsorptive plasma glucose and / or glycosylated hemoglobin HbA1c; - a method of preventing, slowing, delaying or reversing the progression of prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus; - methods for preventing, reducing the risk of, slowing the progression of, delaying the occurrence of, or treating complications of diabetes mellitus, such as microvascular and macrovascular diseases, e.g., nephropathy, micro- or macroalbuminuria, proteinuria, nephrotic syndrome, retinopathy, cataracts, neuropathy, learning or memory impairment, neurodegenerative or cognitive disorders, cardiovascular or cerebrovascular diseases, tissue ischemia, diabetic foot or ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac rhythm disorders, vascular restenosis, and / or stroke; - a method for reducing body weight and / or body fat and / or liver fat and / or intramuscular fat, or for preventing an increase in body weight and / or body fat and / or liver fat and / or intramuscular fat, or for promoting a reduction in body weight and / or body fat and / or liver fat and / or intramuscular fat; - methods for preventing, slowing, delaying the onset of or treating pancreatic beta cell degeneration and / or the decline in pancreatic beta cell function, and / or improving, preserving and / or restoring pancreatic beta cell function, and / or stimulating and / or restoring or protecting pancreatic insulin secretory function; - preventing, slowing, delaying the onset of, or treating non-alcoholic fatty liver disease (NAFLD), including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and / or liver fibrosis (e.g., preventing, slowing the progression of, delaying, reducing, treating, or reversing hepatic steatosis, (liver) inflammation, and / or abnormal accumulation of liver fat); - a method for preventing, slowing the progression of, delaying the onset of, or treating type 2 diabetes when conventional antidiabetic monotherapy or combination therapy fails; - a method for achieving a reduction in the dose of conventional antidiabetic drugs required for an adequate therapeutic effect; - a method for reducing the risk of adverse effects associated with conventional antidiabetic drugs (e.g., hypoglycemia or weight gain); and / or - Methods for maintaining and / or improving insulin sensitivity and / or treating or preventing hyperinsulinemia and / or insulin resistance 6. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 5, comprising at least one of:

7. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 6, wherein treatment comprises preventing, protecting against, delaying the onset of, delaying the progression of and / or reducing the risk of accelerated cognitive decline or impairment, dementia, and / or depressive, affective or anxiety disorders.

8. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 7, wherein the treatment includes the treatment of diabetes, in particular type 2 diabetes mellitus, and / or diabetic nephropathy and / or (micro- or overt) albuminuria.

9. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 8, wherein the patient has or is at high risk of cardiovascular disease and / or renal microvascular disease, e.g., the patient is at high vascular risk (e.g., high risk of a CV event).

10. The patient, (a) microvascular disease (e.g., retinopathy, neuropathy, or renal microvascular disease, e.g., nephropathy, albuminuria (e.g., micro- or macroalbuminuria), proteinuria, chronic kidney disease (e.g., CKD stage 1, 2, 3, 4, or 5) and / or renal impairment (e.g., mild, moderate, or severe renal impairment or end-stage renal disease (ESRD)), and / or (b) (Previous) large vascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) 10. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 9, having the formula:

11. The patient, have nephropathy or chronic kidney disease (e.g. CKD stage 1, 2, 3, 4 or 5, particularly CKD 3-5) (e.g. albuminuria (e.g. micro- or macroalbuminuria, proteinuria, particularly macroalbuminuria) and / or renal impairment (e.g. mild, moderate or severe renal impairment or end-stage renal disease (ESRD), particularly moderate, severe or ESRD stage renal impairment and / or particularly albuminuria, more particularly macroalbuminuria), Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 10 in patients with or without (previous) macrovascular (e.g. cardiovascular or cerebrovascular) disease (e.g. myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease and / or peripheral artery disease).

12. The patient, Albuminuria (e.g., micro- or macroalbuminuria) and Previous macrovascular (e.g., cardiovascular or cerebrovascular) disease (e.g., myocardial infarction, coronary artery disease, (ischemic or hemorrhagic) stroke, carotid artery disease, and / or peripheral artery disease) Both and / or (Mild or moderate) renal impairment (e.g., CKD stage 1, 2, or 3, e.g., CKD stage 1, 2 (mild) or 3a (mild-moderate), preferably eGFR ≥ 45-75 mL / min / 1.73 m 2 ) and overt albuminuria or (Moderate or severe) renal impairment (e.g., CKD stage 3 or 4, e.g., CKD stage 3b (moderate-severe) or 4 (severe), preferably eGFR 15-45 mL / min / 1.73 m 2 ), with or without albuminuria (e.g., with or without micro- or macroalbuminuria), Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 11.

13. The patient, (i) Albuminuria (trace or overt) (e.g., urinary albumin creatinine ratio (UACR) ≥ 30 mg / g creatinine or ≥ 30 mg / l (milligrams of albumin per liter of urine) or ≥ 30 μg / min (micrograms of albumin per minute) or ≥ 30 mg / 24 h (milligrams of albumin per 24 hours)); and Previous macrovascular disease, e.g., identified as one or more of a) through f): a) previous myocardial infarction, b) advanced coronary artery disease; c) high-risk single-vessel coronary artery disease; d) previous ischemic or hemorrhagic stroke; e) presence of carotid artery disease; f) presence of peripheral arterial disease; and / or (ii) renal dysfunction (e.g., with or without CV comorbidities), e.g., Renal dysfunction and eGFR 15-45 mL / min / 1.73 m 2 and either urinary albumin creatinine ratio (UACR), and / or Renal dysfunction and eGFR ≥ 45-75 mL / min / 1.73 m 2 and a urine albumin creatinine ratio (UACR) > 200 mg / g creatinine or > 200 mg / l (milligrams of albumin per liter of urine) or > 200 μg / min (micrograms of albumin per minute) or > 200 mg / 24 h (milligrams of albumin per 24 hours) Renal dysfunction as identified by 13. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 12, having the formula:

14. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 13, wherein the patient is a diabetic, in particular a type 2 diabetic.

15. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 14, wherein the one or more other active agents are selected from other antidiabetic substances, active substances which lower blood glucose levels, active substances which lower blood lipid levels, active substances which increase HDL levels in the blood, active substances which lower blood pressure, active substances indicated for the treatment of atherosclerosis or obesity, and / or active substances indicated for the treatment or prevention of major CV events and / or antiplatelet substances and / or anticoagulants.

16. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 15, wherein the one or more other active agents are selected from other antidiabetic agents and / or antihypertensive agents.

17. 17. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 16, wherein the other active agents comprise an antidiabetic agent selected from metformin, repaglinide, nateglinide, sulfonylureas, pioglitazone, alpha-glucosidase blockers and insulin.

18. Linagliptin, optionally in combination with metformin, a sulfonylurea and / or insulin, for use according to any one of claims 1 to 17.

19. 19. Linagliptin, optionally in combination with metformin, for use according to any one of claims 1 to 18.

20. 20. Linagliptin, optionally in combination with insulin, for use according to any one of claims 1 to 19.

21. 21. Linagliptin, optionally in combination with a diuretic, an angiotensin converting enzyme (ACE) inhibitor and / or an angiotensin II receptor blocker (ARB), such as telmisartan, for use according to any one of claims 1 to 20.

22. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 21, wherein the patient is a non-diabetic or diabetic patient, for example a LADA or, preferably, a type 2 diabetic patient.

23. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 22, wherein the patient is a diabetic (preferably type 2 diabetes) patient who is naive or pre-treated with one or more conventional antidiabetic drugs, for example a patient with inadequate glycemic control with diet and exercise alone, or a patient with inadequate glycemic control despite treatment with diet and exercise plus one or more conventional antidiabetic drugs.

24. 24. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 23, wherein the patient is a (pre-treated) diabetic (preferably type 2 diabetes) patient with insufficient glycemic control despite treatment with one or two conventional antidiabetic drugs selected from the group consisting of metformin, thiazolidinediones (particularly pioglitazone), sulfonylureas, glinides, α-glucosidase inhibitors (e.g. acarbose, voglibose), and insulin or insulin analogues, and preferably linagliptin is used in a concomitant combination therapy with said one or two conventional antidiabetic drugs.

25. 24. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 23, wherein the patient is a (naive) diabetic (preferably type 2 diabetes) patient with inadequate glycemic control by diet and exercise alone, and wherein linagliptin is preferably used in monotherapy or in initial combination therapy with a conventional antidiabetic drug selected from the group consisting of metformin, thiazolidinediones (particularly pioglitazone), sulfonylureas, glinides, α-glucosidase inhibitors (e.g. acarbose, voglibose), and insulin or insulin analogues.

26. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 25, wherein the patient is on background metformin treatment.

27. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 26, wherein the patient is a diabetic (particularly type 2 diabetes) patient in the early stages of diabetes.

28. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 26, wherein the patient is a diabetic (particularly type 2 diabetes) patient in an advanced stage of diabetes.

29. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 26, wherein the patient is a diabetic (particularly type 2 diabetes) patient whose diabetes is associated with kidney disease or kidney damage.

30. 30. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 29, wherein the patient is treated with linagliptin, optionally in combination with one or more other active agents, for a long period of time, such as at least 1-6 years, more than 2 years, or 3-7 years, for example 3-4 years, 3-5 years, 3-6 years, 4-5 years, 4-6 years, 5-6 years or 5-7 years, preferably at least 48 months, more preferably at least 3 years.

Images