Cardiosafe antidiabetic therapy

文档序号：913540 发布日期：2021-02-26 浏览：24次中文

阅读说明：本技术 心脏安全的抗糖尿病疗法 (Cardiosafe antidiabetic therapy ) 是由 O-E·乔汉森于 2019-07-16 设计创作，主要内容包括：本发明涉及心脏安全的抗糖尿病疗法。(The present invention relates to cardiosafe antidiabetic therapies.)

1. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment of a diabetic, preferably type 2 diabetes, patient, wherein treatment of the patient with linagliptin does not increase the risk of three-point major adverse cardiovascular events (3P-MACE) compared to a patient treated with glimepiride, wherein the three-point major adverse cardiovascular events (3P-MACE) comprise cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke.

2. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 1, wherein the risk is as shown in table 1 of the present specification, such as e.g. characterized by the following Hazard Ratio (HR):

hazard ratio (95％CI) 0.98(0.84,1.14)

3. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment of patients with diabetes, preferably type 2 diabetes, wherein treatment of said patients with linagliptin results in a sustained glycemic control (HbA1c < 7%) without moderate or severe hypoglycemia and/or a substantial gain in body weight > 2% from baseline, in a significantly higher number of patients compared to patients treated with glimepiride without additional antidiabetic drug therapy.

4. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 3, wherein the treatment sustainability is as shown in table 3 of the present specification, such as for example characterized by the following odds ratios:

ratio of advantages to each other (95％CI) 1.68(1.43,1.96)

5. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment of a diabetic (preferably type 2 diabetes) patient, wherein treatment of the patient with linagliptin does not increase the risk of all-cause death compared to a patient treated with glimepiride.

6. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 5, wherein the risk is as shown in Table 2 of the present specification, such as e.g. characterized by the following Hazard Ratio (HR):

7. linagliptin, optionally in combination with one or more other active agents, for use according to any one of claims 1 to 6 for the treatment of a diabetic (preferably type 2 diabetes) patient, wherein linagliptin affects the treatment as follows:

i) does not increase the risk of three point(s) of major adverse cardiovascular event(s) (3P-MACE) compared to patients treated with glimepiride, wherein said three point(s) (3P-MACE) comprise cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke,

ii) no additional antidiabetic drug therapy is required compared to patients treated with glimepiride, resulting in a significantly higher number of patients achieving sustained glycemic control (HbA1c < 7%) without moderate or severe hypoglycemia and/or a substantial gain in body weight > 2% from baseline,

iii) does not increase the risk of all-cause death compared to patients treated with glimepiride,

iv) does not increase the risk of four (one or more) major adverse cardiovascular event(s) (4P-MACE) compared to patients treated with glimepiride, wherein said four (one or more) major adverse cardiovascular event(s) (4P-MACE) comprises cardiovascular death, non-fatal Myocardial Infarction (MI), non-fatal stroke and/or hospitalization for unstable angina.

8. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 7, wherein the patient is exposed to treatment for at least 5.86 years, and/or is followed up for at least 6.25 years.

9. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 8, wherein the diabetic patient has an increased or high cardiovascular risk.

10. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 9, wherein the diabetic patient has an increased or high risk of a Cardiovascular (CV) event, such as an age > 70 years, based on a pre-existing CV disease (e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, peripheral arterial occlusive disease), end organ damage associated with blood vessels (e.g. selected from impaired renal function, (micro or macro) proteinuria, retinopathy), and/or two or more CV risk factors (e.g. selected from hypertension, smoking, dyslipidemia, duration of T2DM >10 years).

11. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 10, wherein the diabetic patient has one or more of the following a), B), C) and D):

A) previous or existing vascular diseases, such as those selected from the group consisting of myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure and peripheral arterial occlusive disease,

B) vascular-related diabetic end organ damage, such as those selected from (moderate) impaired renal function, (micro-or macro-proteinuria and retinopathy,

C) old (e.g.,/═ 70 years), and

D) at least two cardiovascular risk factors selected from:

late type 2 diabetes (e.g. duration >10 years),

-hypertension,

-smoking a cigarette currently on a daily basis,

-dyslipidemia.

12. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 11, wherein the patient has type 2 diabetes and insufficient glycemic control, i.e. either never treated, or despite mono-or dual therapy with metformin and/or an alpha-glucosidase inhibitor, or despite the use of sulfonylurea/glactin in mono-or dual therapy with metformin or an alpha-glucosidase inhibitor.

13. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 12, wherein the treatment of the patient with linagliptin is monotherapy or as adjunct therapy.

14. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of claims 1 to 13, wherein the treatment further comprises identifying diabetic patients at cardiovascular risk (increased or high), in particular diabetic patients at increased or high risk of a cardiovascular event prior to treatment with linagliptin.

15. Linagliptin, optionally in combination with one or more other active agents, for use according to claim 14, wherein the risk is based on pre-existing CV disease (e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, peripheral arterial occlusive disease), end-organ damage of blood vessels associated with diabetes (e.g. selected from impaired renal function, (micro or macro) proteinuria, retinopathy), age > -70 years, and/or two or more CV risk factors (e.g. selected from hypertension, smoking, dyslipidemia, T2DM duration >10 years), e.g. such as defined in claim 11.

16. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment, especially long-term treatment, of type 2 diabetes, especially wherein the treatment is characterized by cardiovascular and renal safety, including in patients at risk, such as for example suffering from or at risk of atherosclerotic CV disease, heart failure and/or chronic kidney disease.

17. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, wherein the patient comprises a patient with early type 2 diabetes and an increased risk of CV or an established complication.

18. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, wherein the patient comprises a patient with a high or increased risk of CV (cardio-renal) as evidenced by an established history of macrovascular and/or renal disease.

19. Linagliptin for use according to claim 16 or 17, optionally in combination with one or more other active agents, wherein linagliptin affects the treatment as follows:

iii) does not increase the risk of all-cause death compared to patients treated with glimepiride,

20. Linagliptin for use according to claim 16 or 18, wherein linagliptin affects the treatment by:

i) does not increase the risk of three point(s) of major adverse cardiovascular event(s) (3P-MACE) compared to patients treated with placebo, wherein said three point(s) of major adverse cardiovascular event(s) (3P-MACE) comprise cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke,

ii) does not increase the risk of hospitalization for heart failure compared to patients treated with placebo,

iii) does not increase the risk of key renal fate event(s) compared to patients treated with placebo, wherein the key renal fate event(s) comprise renal death, persistent end-stage renal disease (ESRD), and/or an estimated sustained reduction of glomerular filtration rate (eGFR) by 40% or more,

iv) preventing, delaying the onset of or reducing the risk of proteinuria progression comprising a change from normal proteinuria to micro-or macroproteinuria and/or from micro-proteinuria to macroproteinuria, and/or a change from micro-proteinuria to macroproteinuria, and/or

v) preventing, delaying the onset of, or reducing the risk of microvascular kidney and/or ocular complications comprising kidney death, persistent ESRD, sustained eGFR reduction ≧ 50%, proteinuria progression, use of retinal photocoagulation, use of intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage and/or blindness associated with diabetes, as compared to patients treated with placebo.

21. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, 17 or 19, wherein the patient is exposed to treatment for at least 5.9 years, and/or followed up for at least 6.25 years.

22. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, 18 or 20, wherein the patient is exposed to treatment for at least 1.8 years, or at least 1.9 years, and/or followed up for at least 2.2 years.

23. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, 17, 19 or 21, wherein the patient has one or more of the following a), B), C) and D):

B) vascular-related diabetic end organ damage, such as those selected from (moderate) impaired renal function, (micro-or macro-proteinuria and retinopathy,

C) old (e.g.,/═ 70 years), and

D) at least two cardiovascular risk factors selected from:

late type 2 diabetes (e.g. duration >10 years),

-hypertension,

-smoking a cigarette currently on a daily basis,

-dyslipidemia.

24. Linagliptin, optionally in combination with one or more other active agents, for the use according to claim 16, 18, 20 or 22, wherein the patient has:

(i) proteinuria (micro-or macro-amounts) (such as, for example, Urine Albumin Creatinine Ratio (UACR) of ≥ 30mg/g creatinine or ≥ 30mg/l (mg albumin per liter of urine) or ≥ 30 μ g/min (microgram albumin per minute) or ≥ 30mg/24h (mg albumin per 24 hours)), and

previous macrovascular diseases such as for example defined as one or more of a) to f):

a) the previous myocardial infarction,

b) Advanced coronary artery disease,

c) High risk of single vessel coronary artery disease,

d) Previous ischemic or hemorrhagic stroke,

e) The existence of carotid artery disease,

f) The presence of peripheral artery disease;

and/or

(ii) Impaired renal function (e.g., with or without CV complications), such as defined, for example, as:

impaired renal function (e.g., as defined by the MDRD formula) is accompanied by an estimate of glomerular filtration rate (eGFR) of 15-45mL/min/1.73m²To any Urinary Albumin Creatinine Ratio (UACR), or

Impaired renal function (e.g., as defined by the MDRD formula) is accompanied by an estimate of glomerular filtration rate (eGFR) ≧ 45-75mL/min/1.73m²Creatinine ratio to Urine Albumin (UACR)>200mg/g creatinine or>200mg/l (milligrams albumin per liter of urine) or>200. mu.g/min (microgram albumin per minute) or>200mg/24h (mg albumin per 24 hours).

25. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of the preceding claims, wherein linagliptin is administered at an oral daily dose of 5 mg.

Technical Field

The present invention relates to a specific DPP-4 inhibitor, preferably linagliptin, optionally in combination with one or more other active agents, for use in cardiovascular safe antidiabetic treatment (especially long term treatment) in diabetic (preferably type 2 diabetes) patients, especially early type 2 diabetes patients, including (human) patients with increased cardiovascular risk or established complications.

Background

Cardiovascular disease (CVD) is a recognized complication of type 2 diabetes (T2DM) and there is a clinical need for hypoglycemic therapy that does not further increase the CV risk in this population.

People with type 2 diabetes have an increased risk of cardiovascular disease, and despite recent advances in treatment options, cardiovascular disease remains a leading cause of death in this population.

It is not clear how to compare specific agents in terms of long-term Cardiovascular (CV) effects, as there are only a few long-term head-to-head trials comparing the effects of different diabetes drugs on CV outcome or CV surrogate, and most of the duration is relatively short, with insufficient statistical detection.

Furthermore, although the united states Food and Drug Administration (FDA) has required the use of new hypoglycemic agents to demonstrate CV safety before and after regulatory approval since 2007, most of these CV fate tests were conducted in a placebo-controlled environment with no effective comparator. Therefore, they do not allow evaluation of comparative effectiveness.

Current practice guidelines recommend metformin as a first line therapy for treating T2DM individuals, and provide a variety of treatment options as second line therapy if glycemic control is not achieved within 3 months after metformin initiation. Both Sulfonylureas (SU) and DPP-4 inhibitors are possible second-line options (or possible first-line options in the case of inadequate or unacceptable metformin). SU was the earliest available oral hypoglycemic drug and has been used clinically since the late 50 s of the 20 th century. The low cost and familiarity of SU in clinical practice is a possible potential factor for its continued use as a first line or adjunct therapy to T2 DM. However, the cardiovascular safety of widely used sulfonylureas is still uncertain.

Glimepiride is a second generation sulfonylurea that has certain benefits over other SUs and is often recommended as the preferred second line therapy.

The comparison of glimepiride with other mono-or second line therapies such as DPP-4 inhibitors, in particular linagliptin, for T2DM would be of great significance and relevant to current clinical practice.

Therefore, the aim was to study the long-term effects of treatment with linagliptin (5mg) on Cardiovascular (CV) morbidity and mortality compared to glimepiride (1 to 4mg) in type 2 diabetes (T2DM) patients with elevated or high CV risk and receiving routine care, as well as to demonstrate the cardiovascular safety of linagliptin compared to glimepiride in such patients.

Three clinically approved cardiovascular outcome tests (CVOT) for DPP-4 inhibitors in the european union are reported: saxagliptin, alogliptin and sitagliptin, each compared to placebo. The safety of atherosclerotic CV outcomes is uniformly demonstrated throughout the class, with all three agents having a neutral effect on the outcome of Major Adverse CV Events (MACE). However, the safety of this class against heart failure risk is uncertain, with a significant increase of 27% in the case of saxagliptin, which raises concerns that some antidiabetic agents that stimulate insulin signaling may increase heart failure risk. Non-insulin related mechanisms have been proposed that would otherwise contribute to the risk of heart failure in the case of some DPP-4 inhibitors.

Furthermore, long-term renal function has particular clinical significance for the treatment of DPP-4 inhibitors, except for linagliptin excreted via the kidney (which requires adjustment of the dose due to reduced renal function); however, to date, emerging renal evidence for the DPP-4 inhibitor CVOT is not complete and inconsistent across the entire class. The limitation of previous CVOT with saxagliptin, alogliptin and sitagliptin was that only a few patients in the study group had reduced renal function at baseline (estimated glomerular filtration rate (eGFR) <60ml/min/1.73m 2). Even fewer patients had severely reduced renal function (eGFR <30ml/min/1.73m2) or had extensive proteinuria. Indeed, while it is estimated that about 50% of T2D patients are affected by CKD, no CVOT has previously been designed to include this population, and in some cases, patients with reduced renal function are actively excluded. Thus, while CKD is one of the most common complications of T2D, there is little information available regarding the long-term clinical safety profile of DPP-4 inhibitors in this important but understudied and clinically challenging patient population with renal burden and high risk of cardio-renal failure.

Safety outcome analysis by baseline renal risk stratification underscores the increased incidence experienced by CKD patients in addition to T2D. Since the incidence of coincidence between heart failure and CKD is driven by a variety of cardio-renal interactions, including hemodynamic and neurohormonal mechanisms, the risk of heart failure may be of particular concern in these patients. Thus, impaired renal function in T2D patients is a major predictor of excess mortality and adverse outcome (including CV death and other CV events), and T2D is the most common cause of end-stage renal disease. Since renal function declines naturally with age and diabetes is a life-long disease, even patients without significant CKD are at risk of developing complications in the future, it is widely recommended to screen T2D patients for the presence of CKD.

Therefore, there is a need for clinical studies of the long term (cardiovascular and renal) safety profile of DPP-4 inhibitors in a wide range of type 2 diabetes patients, including patients with early stage type 2 diabetes with an elevated risk of CV (such as e.g. compared to an effective comparator), and including patients with a so far high risk of CV or heart disease and/or Chronic Kidney Disease (CKD) with a representative deficiency, such as e.g. patients with established CV and/or kidney disease (such as e.g. compared to placebo/standard of care).

Disclosure of Invention

Within the scope of the present invention, it has now been found that certain DPP-4 inhibitors, preferably linagliptin, optionally in combination with one or more other active agents as defined herein (e.g. as monotherapy or as adjunct therapy), have properties or effects that make them useful for the purposes of the present invention and/or for meeting one or more of the needs or purposes mentioned herein.

Linagliptin (5mg, once daily, as monotherapy or as adjunct therapy) showed long-term clinical cardiovascular safety as well as certain benefits (e.g., treatment sustainability) in a cardiovascular safety trial (assessing increased or high cardiovascular risk or cardiovascular safety compared to glimepiride in type 2 diabetic patients with established cardiovascular disease).

The test includes adults with elevated CV risk or established CV disease and with early stage type 2 diabetes, such as median disease duration of 6.2 years, who either received no treatment at all or received 1-2 hypoglycemic agents (e.g., metformin).

These subjects reflect patients that physicians typically see in daily clinical practice.

This test evaluated the safety of linagliptin for the longest time studied in the DPP-4 inhibitor cardiovascular outcome test, with median duration and follow-up time exceeding 6 years.

The cardiovascular safety trial evaluated the CV safety and long-term impact on CV morbidity and mortality in type 2 diabetic patients with increased or high CV risk and receiving routine care (such as addition to stable background hypoglycemic drugs and cardiovascular standard care) compared to glimepiride (1 to 4mg) treatment (both monotherapy or adjunctive therapy).

Conventional care includes hypoglycemic agents (including metformin and/or alpha-glucosidase inhibitors) and cardiovascular drugs (including hypotensive and lipid lowering agents).

Patients for this cardiovascular safety trial (to assess cardiovascular safety of linagliptin compared to glimepiride in type 2 diabetic patients with increased or high cardiovascular risk or established cardiovascular disease) were treated once daily with 5mg linagliptin, with a median duration of 5.86 years, and observed for a median duration of 6.25 years.

Together with another (placebo-controlled) cardiovascular (safety) and renal fate test (assessing cardiovascular safety and renal/renal microvascular fates in type 2 diabetic patients at high or very high risk for heart and/or kidney disease), this (effective comparator) cardiovascular safety test demonstrates a long-term overall safety profile for linagliptin in a broad range of type 2 diabetic adults, including patients with increased/elevated cardiovascular risk (certain risk factors) or established complications (e.g., atherosclerotic cardiovascular disease) and especially patients with high or very high risk for heart and/or kidney disease (e.g., cardiovascular and/or renal complications or events).

Drawings

FIG. 1 (time of first occurrence of 3P-MACE in cardiovascular safety testing) shows the time of first occurrence of three-point (3P) MACE (3P-MACE, defined as cardiovascular death or non-fatal Myocardial Infarction (MI) or major adverse cardiac event of non-fatal stroke) in the cardiovascular safety testing.

Figure 2 (time to first occurrence of 3P-MACE in cardiovascular and renal microvascular fate trials) shows the time to first occurrence of three-point (3P) MACE (3P-MACE, defined as cardiovascular death or non-fatal Myocardial Infarction (MI) or major adverse cardiac event of non-fatal stroke) in the cardiovascular (safety) and renal (microvascular) fate trials.

Detailed Description

In more detail, the following findings are derived:

cardiovascular safety test

In this cardiovascular safety trial (multicenter, multinational, randomized, double-blind parallel group trial) the effect of linagliptin on cardiovascular risk in adult patients with early type 2 diabetes and increased CV risk or established complications was evaluated. Based on regional standards of HbA1c and CV risk factors, the trial compared the risk of experiencing Major Adverse Cardiovascular Events (MACE) between linagliptin and glimepiride when added to standard of care (background therapy including metformin). The trial was event-driven and patients were followed until at least 631 major outcome events were accumulated.

A total of 6033 patients were treated (linagliptin 5mg ═ 3023; glimepiride 1mg to 4mg ═ 3010) with a median follow-up time of 6.25 years (median treatment time 5.9 years). Approximately 73% of the study population were caucasians, 18% were asians, and 5% were blacks. The mean age was 64 years and 60% were males.

At baseline, disease characteristics are balanced. The mean HbA1c was 7.15%, and the mean duration of type 2 diabetes in the participants was approximately 7.6 years, with another 20% being current smokers. The trial population included 2030 (34%) > 70 years old patients, 2089 (35%) cardiovascular disease patients and 1130 (19%) kidney impaired patients with eGFR <60mL/min/1.73m2 at baseline. Overall, previously used diabetes drugs were balanced between treatment groups (metformin 83% continued as background therapy and sulfonylureas 28% discontinued before randomization), excluding patients who used insulin. The use of drugs that reduce cardiovascular risk is also balanced (aspirin 47%, statin 65%, ACE inhibitor or ARB 74%, beta blocker 39%, and calcium channel blocker 30%).

The primary endpoint of this cardiovascular safety test is the time at which three-point (3P) MACE first occurs. Major adverse cardiac events were defined as cardiovascular death or non-fatal Myocardial Infarction (MI) or non-fatal stroke. The statistical analysis program tested the non-inferiority of 3P MACE occurrence. The key secondary endpoint evaluated the complex of treatment sustainability, defined as the proportion of patients under study treatment, maintaining glycemic control (HbA1c ≦ 7.0%), without additional anti-diabetic drug therapy (rescue medication), without any moderate (symptomatic, blood glucose values <70mg/dL) or severe (requiring assistance) hypoglycemic episodes and with no > 2% increase in body weight from baseline.

Table 1 and figure 1 show the results of the primary endpoint of the cardiovascular safety test. Linagliptin added to the standard of care did not increase the risk of major adverse cardiovascular events compared to glimepiride. The incidence of 3P MACE was similar in both treatment groups; linagliptin (20.7 MACE per 1000 patient years) and glimepiride (21.2 MACE per 1000 patient years). The estimated hazard ratio for MACE associated with linagliptin relative to glimepiride was 0.98 (95% CI; 0.84, 1.14). The upper bound of the Confidence Interval (CI)1.14 excludes a predefined risk boundary greater than 1.3. Patients treated with or without metformin gave consistent results.

Table 1 Major Adverse Cardiovascular Events (MACE) and additionally determined cardiovascular and mortality endpoints of the treatment groups in the cardiovascular safety test described in table 1

PY patient year

Non-inferiority tests were performed to demonstrate that the upper bound of 95% CI for hazard ratio was less than 1.3

A life status of 99.3% of the subjects was obtained in the trial. A total of 644 deaths were recorded during the cardiovascular safety test (table 2). Of these deaths, 52% were judged cardiovascular deaths. The risk of all-cause death did not differ statistically between treatment groups (HR: 0.91; 95% CI: 0.78, 1.06).

Table 2 cardiovascular and mortality endpoints of major additional determinations of the treatment groups in the cardiovascular safety test described in table 2

Table 3 shows the results of the secondary endpoints of the cardiovascular safety tests. After the initial titration period (16 weeks), a significantly higher number of patients treated with linagliptin achieved sustained glycemic control (HbA1c ≦ 7.0%) without moderate or severe hypoglycemia or a substantial gain in body weight > 2% from baseline, compared to patients treated with glimepiride without additional antidiabetic drug therapy.

Key minor complexes in the treatment groups in the cardiovascular safety tests described in table 3

Minor complex is defined as the complex of treatment sustainability, defined as the proportion of patients who were in study treatment at the final visit, who maintained glycemic control (HbA1c ≦ 7.0%) at the end of the stabilization period (end of study drug titration after 16 weeks) to treatment without additional antidiabetic drugs (rescue) at the final visit, and who did not have any moderate/severe hypoglycemic episodes and did not gain body weight > 2%.

Moderate/severe hypoglycemic episodes are defined as:

-moderate hypoglycaemic episodes: there was a recorded symptomatic hypoglycemia with plasma glucose concentrations less than or equal to 70 mg/dL. The event is accompanied by typical hypoglycemic symptoms, but without external assistance

-severe hypoglycemic episodes: with recorded hypoglycemic episodes requiring assistance from others to actively administer carbohydrates, glucagon, or other resuscitation actions requiring external assistance

Odds ratios and confidence intervals are based on logistic regression of the treatment factors.

For the entire treatment period (median treatment time 5.9 years), the rate of moderate or severe hypoglycemia with linagliptin was 6.5%, compared to 30.9% for glimepiride treatment, 0.3% for severe hypoglycemia (requiring assistance) with linagliptin, and 2.2% for glimepiride treatment.

Thus:

the present invention relates to linagliptin, optionally in combination with one or more other active agents, for use in the treatment of patients with diabetes, preferably type 2 diabetes, wherein linagliptin affects the treatment without increasing the risk of 3-point major adverse cardiovascular events (3P-MACE) compared to glimepiride, wherein the 3-point major adverse cardiovascular events (3P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke.

The present invention relates to linagliptin, optionally in combination with one or more other active agents, for use in the treatment of patients with diabetes, preferably type 2 diabetes, wherein linagliptin affects the treatment more persistently than glimepiride, such as is characterized by a significantly higher sustainable response rate for the combined endpoint of patients who were in trial drug therapy at the end of the trial, with HbA1c ≦ 7.0%, without rescue medication, with no > 2% weight gain, and with or without moderate/severe hypoglycemic episodes.

The present invention relates to linagliptin, optionally in combination with one or more other active agents, for use in the treatment of patients with diabetes, preferably type 2 diabetes, wherein linagliptin affects 4-point major adverse cardiovascular events (4P-MACE) compared to glimepiride without increasing the risk of said 4-point major adverse cardiovascular events (4P-MACE), wherein the 4-point major adverse cardiovascular events (4P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI), non-fatal stroke, and/or hospitalization for unstable angina.

i) does not increase the risk of (one or more) three-point major adverse cardiovascular event(s) (3P-MACE) compared to patients treated with glimepiride, wherein said one or more three-point major adverse cardiovascular event(s) (3P-MACE) is selected from cardiovascular death, non-fatal Myocardial Infarction (MI), and non-fatal stroke,

ii) does not increase the risk of (one or more) four-point major adverse cardiovascular event(s) (4P-MACE) compared to patients treated with glimepiride, wherein said one or more four-point major adverse cardiovascular event(s) (3P-MACE) is selected from cardiovascular death, non-fatal Myocardial Infarction (MI), non-fatal stroke and hospitalization for unstable angina,

iii) does not increase the risk of all-cause death compared to patients treated with glimepiride,

iv) no additional antidiabetic drug therapy is required as compared to glimepiride-treated patients, resulting in a significantly higher number of patients achieving sustained glycemic control (HbA1c ≦ 7%) without moderate or severe hypoglycemia and/or a substantial increase in body weight > 2% from baseline,

and/or

v) does not increase the risk of CV death or hospitalization for heart failure compared to patients treated with glimepiride.

Patients according to the invention include patients with T2DM and inadequate glycemic control, whether or not untreated or despite mono-or dual therapy with metformin and/or an alpha-glucosidase inhibitor, or despite the use of sulfonylurea/glaseride in mono-or dual therapy with metformin and/or an alpha-glucosidase inhibitor (such as HbA1c 6.5.5 to ≦ 8.5% in the case of untreated or mono-or dual therapy with metformin and/or an alpha-glucosidase inhibitor; 6.5 to ≦ 7.5% in the case of treatment with sulfonylurea/glaseride in mono-or dual therapy with metformin or an alpha-glucosidase inhibitor).

Patients according to the invention with increased or high cardiovascular risk or established complications (especially with T2DM) may suffer from one or more of the following:

pre-existing CV disease (e.g. selected from the group consisting of myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, peripheral arterial occlusive disease),

end organ damage associated with blood vessels (e.g. selected from (moderate) impaired renal function, (micro or macro) proteinuria, retinopathy),

-age > -70 years, and/or

Two or more CV risk factors (e.g. selected from hypertension, smoking, dyslipidemia, duration of T2DM >10 years).

In one embodiment, the diabetic patient has one or more of the following a), B), C), and D):

B) vascular-related diabetic end organ damage, such as those selected from (moderate) impaired renal function, (micro-or macro-proteinuria and retinopathy,

C) old (e.g.,/═ 70 years), and

D) at least two cardiovascular risk factors selected from:

late type 2 diabetes (e.g. duration >10 years),

-hypertension,

-smoking a cigarette currently on a daily basis,

-dyslipidemia.

For the purposes of the present invention, the duration of treatment with linagliptin (preferably 5mg per day, orally administered, optionally in combination with one or more other active substances such as, for example, those described herein) may be of a lengthy duration, such as, for example, at least 1-9 years, preferably at least about 5-7 years. In one embodiment, the median therapeutic exposure is at least about 5.86 years. In one embodiment, the patient is followed up for at least 6.25 years.

Other aspects of the invention will be apparent to the skilled person from the foregoing and following description, including the examples and claims.

Detailed description of the invention

A particularly preferred DPP-4 inhibitor to be emphasized in the present invention is linagliptin. The term "linagliptin" as used herein refers to linagliptin or pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, as well as amorphous or crystalline forms thereof, preferably linagliptin refers to 1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine.

Preferably, linagliptin is administered at an oral dose of 5mg per day (e.g. 2.5mg twice per day, or preferably 5mg once per day).

Further (independent or dependent) aspects:

cardiovascular (safety) and renal microvascular fate tests

The effect of linagliptin on cardiovascular risk in adult patients with early type 2 diabetes and with increased or high or very high CV risk as evidenced by established history of macrovascular or renal disease was evaluated in cardiovascular and renal microvascular fate trials, multicenter, multi-national, randomized, double-blind parallel group trials. The trial compared the risk of Major Adverse Cardiovascular Events (MACE) occurring between linagliptin and placebo when added to and used concurrently with the standard of care treatment for diabetes and other cardiovascular risk factors. The trial was event-driven and patients were followed up until at least 611 major outcome events had accumulated.

A total of 6979 patients were treated (linagliptin 5 mg-3494; placebo-3485) with a median follow-up time of 2.2 years (median treatment time 1.9 years). Approximately 80% of the study population were caucasians, 9% were asians, and 6% were blacks. The mean age was 66 years, and males accounted for 63%.

The mean HbA1c at baseline was 8.0%, and the mean duration of type 2 diabetes in the participants was approximately 15 years, with the other 10% being current smokers. The trial population included 1211 (17.4%) of patients aged > 75 years and 4348 (62.3%) of patients with impaired kidney. Approximately 19% of the population had an eGFR of ≧ 45 to <60mL/min/1.73m2, 28% of the population had an eGFR of ≧ 30 to <45mL/min/1.73m2, and 15% of the eGFR <30mL/min/1.73m 2. Overall, the use of diabetes drugs was balanced between the individual treatment groups (metformin 54%, sulfonylurea 32%, and insulin 57%). The use of drugs that reduce cardiovascular risk is also balanced (aspirin 62%, statin 72%, ACE inhibitor or ARB 81%, beta blocker 60%, and calcium channel blocker 41%).

The primary endpoint of the cardiovascular and renal microvascular fate test is the time at which three points (3P) MACE first occur. Major adverse cardiac events were defined as cardiovascular death or non-fatal Myocardial Infarction (MI) or non-fatal stroke. The statistical analysis program tested the non-inferiority of (3P) MACE occurrences. The secondary endpoint was the renal complex, defined as renal death or persistent end-stage renal disease or a sustained reduction in eGFR of 40% or more.

Table 4 below and fig. 2 show the results of the primary endpoints of the cardiovascular and renal microvascular fate tests. The incidence of (3P) MACE was similar in both treatment groups; placebo (56.3 MACE per 1000 patient years) and linagliptin (57.7 MACE per 1000 patient years). The estimated hazard ratio for MACE associated with linagliptin relative to placebo was 1.02 (95% CI; 0.89, 1.17). The upper bound of the confidence interval 1.17 excludes predefined risk boundaries greater than 1.3.

TABLE 4 treatment group Major Adverse Cardiovascular Events (MACE) in the cardiovascular and renal microvascular fate test

PY patient year

In the cardiovascular and renal microvascular outcome tests, the risk of hospitalization due to heart failure did not increase, which is an otherwise adjudicated event. The estimated risk ratio for linagliptin-associated hospitalization for heart failure was 0.90 (95% CI; 0.74, 1.08) relative to placebo. In the trial, 209 (6.0%) linagliptin-treated patients and 226 placebo-treated (6.5-recipient) patients were hospitalized for heart failure.

A life status of 99.7% of the subjects was obtained in the trial. A total of 740 deaths were recorded in the cardiovascular and renal microvascular fatality tests (table 5). Of these deaths, 70% were judged cardiovascular deaths. The risk of all-cause death did not differ statistically between treatment groups (HR: 0.98; 95% CI: 0.84, 1.13).

Mortality in the treatment groups in the cardiovascular and renal microvascular fate test described in Table 5

The incidence of renal complexes was similar in both treatment groups (table 6); placebo (46.6 renal complexes per 1000 patient years) and linagliptin (48.9 renal complexes per 1000 patient years). The estimated risk ratio for the renal complex associated with linagliptin relative to placebo was 1.04 (95% CI; 0.89, 1.22).

Renal fate events in the treatment groups of cardiovascular and renal microvascular fate trials described in Table 6

PY patient year

When analyzing the progression of proteinuria (from normal proteinuria to microalbuminuria or microalbuminuria to macroproteinuria), the hazard ratio of linagliptin compared to placebo was 0.86 (95% CI0.78, 0.95).

Microvascular endpoint was defined as the complex of renal death, sustained ESRD, sustained eGFR reduction > 50%, proteinuria progression, use of retinal photocoagulation or intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage or blindness associated with diabetes. The estimated hazard ratio for linagliptin versus placebo at time to first occurrence of the composite microvascular endpoint was 0.86 (95% CI0.78, 0.95); mainly driven by proteinuria progression.

Further, in more detail, for cardiovascular and renal microvascular fate tests:

approximately three quarters of the patients in the cardiovascular and renal microvascular outcome trials had widespread CKD at baseline, defined as reduced renal function (eGFR <60mL/min/1.73m2) and/or profuse proteinuria (urinary albumin/creatinine ratio >300 mg/g).

KDIGO classifies renal prognosis (for adverse renal events) according to low, medium, high and very high risk based on a combination of proteinuria and renal risk. According to internationally accepted standards, 44% of patients in the cardiovascular and renal microvascular outcome test are at very high risk at baseline, another 27% are at high risk, and only 7% are at low risk.

Prior to the cardiovascular and renal microvascular outcome tests, the limitations of the dipeptidyl peptidase 4(DPP-4) inhibitor cardiovascular outcome test (CVOT) were that only a few patients in the study group had reduced renal function at baseline (estimated glomerular filtration rate (eGFR) <60ml/min/1.73m 2). Even fewer patients had severely reduced renal function (eGFR <30ml/min/1.73m2) or profuse proteinuria (urinary albumin/creatinine ratio >300 mg/g). In contrast, 62% and 15% of patients in the cardiovascular and renal microvascular outcome test had reduced or severe renal function at baseline, with a prevalence of substantial proteinuria of 39%, compared to 10% for saxagliptin CVOT at baseline. The prevalence of massive proteinuria of sitagliptin CVOT is based on the few patients for whom data are available; the prevalence of substantial proteinuria of alogliptin CVOT is not reported.

The heart and kidneys are intricately linked together by various interactions that drive a complication between heart failure and Chronic Kidney Disease (CKD). Patients with impaired renal function (as measured by eGFR) are at increased risk of hospitalization (HHF) due to heart failure. However, linagliptin did not affect the risk of HHF regardless of baseline renal function.

Persons with type 2 diabetes (T2D) with concomitant Chronic Kidney Disease (CKD) and Cardiovascular (CV) disease have an increased risk of recurrent CV events and hypoglycemia. Treatment of these individuals is clinically challenging, where there is a lack of evidence for the safety and efficacy of hypoglycemic drugs, particularly in the GFR classG3b(eGFR 30-44ml/min/1.73m2)、G4(eGFR<30) And G5 (eGFR)<15) In (1). We analyzed the baseline profile and effects on CV and renal fate using the DPP-4 inhibitor Linagliptin (LINA) compared to Placebo (PBO) in the GFR category of the cardiovascular and renal microvascular fate trials. Will have T2D and either i) UACR>30mg/g with concomitant CV disease, or ii) eGFR<45ml/min/1.73m²(without taking UACR into account), or eGFR ≧ 45-75mL/min/1.73m²And UACR>The 200mg/g people were randomized into LINA5mg or Placebo (PBO) once a day in a double-blind fashion. The primary outcome was the first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with secondary compound outcomes judged as ESKD, renal death, or a sustained eGFR decrease from baseline of greater than or equal to 40%. Other outcomes of the decision include hospitalized heart failure (hHF) and 3P-MACE components. Subgroup effects of the GFR classes (G.ltoreq.2, G3a, G3b and G.gtoreq.4) were also evaluated. Of 6979 participants, 15.2% were in the GFR class G.gtoreq.4, 27.8% G3b, 19.3% G3a, and 37.7% G.ltoreq.2 at baseline. Compared with G3a (eGFR 51.4 +/-4.4) and G ≤ 2(eGFR 81.6 +/-16.7), G ≥ 4 (mean value + -SD eGFR 23.4 +/-4.2 mL/min/1.73m²) Or G3b (eGFR 37.2 ± 4.1), had more proteinuria, longer duration of T2D, and more frequent treatment with insulin, but less frequent use of sulfonylureas and metformin. LINA did not affect 3P-MACE (HR.1.02[ 95% CI, 0.89, 1.17) within 2.2 years of median]) Complex outcome of minor kidney (1.04[0.89, 1.22)])、hHF(0.90[0.74，1.08]) Or CV mortality (0.96[0.81, 1.14)]) The risk of (c).

The progression of the proteinuria profile of linagliptin (763/2162[ 35.3% ]) (i.e., change from normal proteinuria to micro/macro proteinuria, or from micro proteinuria to macro proteinuria) occurred less frequently than in the placebo group (819/2129[ 38.5% ]); HR 0.86 (95% CI0.78, 0.95), p ═ 0.003.

The incidence of reduced renal function is higher, e.g., 2.4 fold for G.gtoreq.4 (9.6/100 patient year) 3P-MACE PBO relative to G.gtoreq.2 (4.0/100 patient year), 9.8 fold for renal complex (14.7 and 1.5/100 patient year), 4.1 fold for hHF (6.2 and 1.5/patient year) and 3.0 fold for CV death (6.8 and 2.3/100 patient year).

A consistent neutral effect was observed in all GFR classes (P-value for the interaction: 0.84[3P-MACE ], 0.36[ renal complex ], 0.88[ hHF ], 0.23[ CV mortality ]).

Overall, linagliptin significantly reduced the progression of proteinuria compared to placebo, and a consistent beneficial effect was observed in all eGFR classes (interaction p-value: 0.35).

Adverse Events (AE) increased with reduced renal function, but the proportion of > 1AE or >1 severe AE between LINA and PBO was balanced in the GFR category. In all GFR categories, LINA significantly reduces HbA1c compared to PBO, but does not increase the risk of hypoglycemia.

In adults with T2DM with high CV and renal risk, the median time for linagliptin use (each added to regular care) was 2.2 years compared to placebo, resulting in a non-adverse risk of complex CV outcome with no effect on minor renal outcome.

In this patient population, where the risk of hHF and its complications is very high, linagliptin can be used without increasing the risk of hHF.

These findings in the large international cardiovascular (safety) and renal microvascular fate trial among patients with T2D with concomitant CV and renal disease support the safety and tolerability of LINA as a T2D therapy that can be used for a wide range of renal diseases, even including clinically challenging patients (high risk of heart and kidney), with a lack of evidence for the safety and efficacy of hypoglycemic drugs, particularly in GFR categories G3b (eGFR30-44ml/min/1.73m2), G4(eGFR <30) and G5(eGFR < 15).

In the further context of this cardiovascular (safety) and renal microvascular fate test, reference may be made to EP 18184034.9, EP 18187272.2, EP 18197472.6 and EP 18202843.1, the disclosures of which are incorporated herein by reference and made a part hereof.

In particular aspects:

x1. accordingly, in a further aspect (aspect X1), the invention relates to linagliptin, optionally in combination with one or more other active agents, for use in the treatment, particularly long-term treatment, of type 2 diabetes, particularly wherein the treatment is characterized by cardiovascular and renal safety (such as, e.g., disclosed herein), including patients at risk (such as, e.g., disclosed herein), such as, e.g., suffering from or at risk of atherosclerotic CV disease, heart failure and/or chronic kidney disease.

X2. linagliptin optionally in combination with one or more other active agents for use according to the invention (such as for example aspect X1), wherein the patients include patients with early type 2 diabetes and increased CV risk or established complications (such as for example disclosed herein).

X3. linagliptin optionally in combination with one or more other active agents for use according to the invention (such as for example aspect X1), wherein the patient comprises a patient (such as for example disclosed herein) with an increased or high risk of CV as evidenced by an established history of macrovascular and/or renal disease.

X4. linagliptin for use according to the invention (such as for example aspect X1 or X2), optionally in combination with one or more other active agents, wherein linagliptin affects the treatment as disclosed herein, such as the following:

i) does not increase the risk of three major adverse cardiovascular events (3P-MACE) compared to patients treated with glimepiride, wherein the three major adverse cardiovascular events (3P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke,

iii) does not increase the risk of all-cause death compared to patients treated with glimepiride,

iv) does not increase the risk of four major adverse cardiovascular events (4P-MACE) compared to patients treated with glimepiride, wherein the four major adverse cardiovascular events (4P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI), non-fatal stroke, and/or hospitalization for unstable angina.

X5 linagliptin according to the invention (such as for example aspect X1 or X3) for the use, wherein linagliptin affects the treatment as disclosed herein, such as the following:

i) does not increase the risk of three major adverse cardiovascular events (3P-MACE) compared to patients treated with placebo, wherein the three major adverse cardiovascular events (3P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke,

ii) does not increase the risk of hospitalization for heart failure compared to patients treated with placebo,

iii) does not increase the risk of key renal fate events, including renal death, persistent end-stage renal disease (ESRD), and/or an estimated sustained reduction in glomerular filtration rate (eGFR) of 40% or more, compared to patients treated with placebo,

v) preventing, delaying the onset of, or reducing the risk of microvascular renal and/or ocular complications comprising renal death, sustained ESRD, sustained eGFR reduction > 50%, proteinuria progression, use of retinal photocoagulation, use of intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage and/or blindness associated with diabetes, as compared to patients treated with placebo.

X6. linagliptin, optionally in combination with one or more other active agents, for use according to the invention (such as, for example, aspect X1, X2 or X4), wherein the patient is exposed to treatment for at least 5.9 years, and/or followed up for at least 6.25 years.

X7. linagliptin, optionally in combination with one or more other active agents, for use according to the invention (such as, for example, aspect X1, X3 or X5), wherein the patient is exposed to treatment for at least 1.8 years, or at least 1.9 years, and/or followed up for at least 2.2 years.

X8. for use in linagliptin according to the invention (such as, for example, aspect X1, X2, X4 or X6) for the use, optionally in combination with one or more other active agents, wherein the patient has one or more of the following a), B), C) and D):

B) vascular-related diabetic end organ damage, such as those selected from (moderate) impaired renal function, (micro-or macro-proteinuria and retinopathy,

C) old (e.g.,/═ 70 years), and

D) at least two cardiovascular risk factors selected from:

late type 2 diabetes (e.g. duration >10 years),

-hypertension,

-smoking a cigarette currently on a daily basis,

-dyslipidemia.

X9. linagliptin for use according to the invention (such as, for example, aspect X1, X3, X5 or X7), optionally in combination with one or more other active agents, wherein the patient has:

previous macrovascular diseases such as for example defined as one or more of a) to f):

a) the previous myocardial infarction,

b) Advanced coronary artery disease,

c) High risk of single vessel coronary artery disease,

d) Previous ischemic or hemorrhagic stroke,

e) The existence of carotid artery disease,

f) The presence of peripheral artery disease;

and/or

(ii) Impaired renal function (e.g., with or without CV complications), such as defined, for example, as:

Further embodiments:

in one embodiment, a diabetic patient as referred to herein may include a patient who has not been previously treated with an antidiabetic drug (primary drug-treated patient). Thus, in one embodiment, the treatment described herein may be applied to a patient who has never received treatment. In certain embodiments of the treatment of the present invention, the DPP-4 inhibitor (preferably linagliptin) may be used alone or in combination with one or more other antidiabetic agents in such patients. In another embodiment, diabetic patients within the meaning of the present invention may comprise patients pre-treated with a conventional anti-diabetic background drug, such as e.g. patients with advanced (advanced or late stage) type 2 diabetes (including patients with failed conventional anti-diabetic therapy), such as e.g. patients with insufficient glycemic control when treated with one, two or more conventional oral and/or non-oral anti-diabetic drugs as defined herein, such as e.g. despite (mono) therapy with metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glinides, GLP-1 or GLP-1 analogues, insulin or insulin analogues, or alpha-glucosidase inhibitors or despite (mono) therapy with metformin/sulfonylureas, metformin/thiazolidinediones (especially pioglitazone), Patients with inadequate glycemic control who have undergone dual combination therapy with sulfonylurea/alpha-glucosidase inhibitors, pioglitazone/sulfonylurea, metformin/insulin, pioglitazone/insulin or sulfonylurea/insulin. Thus, in one embodiment, the treatment described herein may be used in patients who have undergone therapy, for example with a conventional oral and/or non-oral antidiabetic single or dual or triple combination drug as mentioned herein. In certain embodiments of the therapies of the present invention, the DPP-4 inhibitor, preferably linagliptin, may be used or supplemented in such patients on top of existing or ongoing conventional oral and/or non-oral antidiabetic single or dual or triple combination drugs, which such patients were previously treated or experienced with such drugs.

For example, a diabetic patient (particularly a type 2 diabetic patient with insufficient glycemic control) as referred to herein may have never been treated or previously treated with one or more (e.g. one or two) conventional antidiabetic agents selected from metformin, thiazolidinediones (particularly pioglitazone), sulfonylureas, glipizide, alpha-glucosidase inhibitors (e.g. acarbose, voglibose) and insulin or insulin analogues, such as for example with or having undergone the following prior treatment:

metformin, an alpha-glucosidase inhibitor, a sulfonylurea or glinide monotherapy, or metformin + alpha-glucosidase inhibitor, metformin + sulfonylurea, metformin + glinide, alpha-glucosidase inhibitor + sulfonylurea or alpha-glucosidase inhibitor + glinide double combination therapy.

In certain embodiments in connection with such never-treated patients, the DPP-4 inhibitor, preferably linagliptin, may be used as monotherapy or as initial combination therapy, such as for example with metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glibenclamide, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), GLP-1 or GLP-1 analogues, or insulin analogues; preferably as monotherapy.

In certain embodiments related to such patients who have been previously treated with one or two conventional antidiabetic agents or who have undergone one or two conventional antidiabetic agents, the DPP-4 inhibitor, preferably linagliptin, may be used as an additional combination therapy, i.e., added to an existing or background therapy with the one or two conventional antidiabetic agents selected from metformin, thiazolidinediones (particularly pioglitazone), sulfonylureas, glinides, alpha-glucosidase inhibitors (e.g., acarbose, voglibose), GLP-1 or GLP-1 analogs, and insulin or insulin analogs, in patients with insufficient glycemic control despite therapy with the one or more conventional antidiabetic agents, such as, for example, as an additional therapy to the one or more (e.g., one or two) conventional antidiabetic agents, such as for example:

as an add-on therapy to metformin, alpha-glucosidase inhibitors, sulfonylureas, or glinides;

or as an adjunct therapy to metformin + α -glucosidase inhibitor, metformin + sulfonylurea, metformin + glyburide, α -glucosidase inhibitor + sulfonylurea or α -glucosidase inhibitor + glyburide;

or as an adjunct therapy to insulin, with or without metformin, thiazolidinediones (especially pioglitazone), sulfonylureas, glibenclamide or alpha-glucosidase inhibitors (e.g. acarbose, voglibose).

Further embodiments of the diabetic patients described herein may relate to patients ineligible for metformin therapy, including

-patients who are prohibited from metformin therapy, for example patients who have one or more contraindications for metformin therapy according to the label, such as for example patients who have at least one contraindication selected from:

renal disease, kidney damage, or renal insufficiency (e.g., as specified by locally approved product information for metformin),

the dehydration is carried out in the first step,

unstable or acute congestive heart failure,

acute or chronic metabolic acidosis and

genetic galactose intolerance;

and

-patients suffering from one or more intolerable side effects due to metformin, in particular gastrointestinal side effects associated with metformin, such as for example patients suffering from at least one gastrointestinal side effect selected from:

the nausea was caused by the attack of the stomach,

the vomiting is caused by the vomiting of the stomach,

the diarrhea is caused by the diarrhea of the patient,

intestinal qi and

severe abdominal discomfort.

Further embodiments of diabetic patients as referred to herein may include, but are not limited to, those diabetic patients who are not eligible for normal metformin therapy, such as for example those diabetic patients (including elderly patients, such as for example ≧ 60-65 years) who require a reduced metformin therapy dose due to reduced tolerance, intolerance or contraindication against metformin or (mild) impaired/reduced renal function.

Further embodiments of diabetic patients may refer to patients with renal disease, renal insufficiency, or renal insufficiency or impairment (including mild, moderate, and/or severe renal impairment), as indicated, for example, by elevated levels of clear creatinine (e.g., serum creatinine levels above its normal upper limit of age, such as ≥ 130 μmol/l, or ≥ 1.5mg/dl (. gtoreq.136 μmol/l) in men, ≥ 1.4mg/dl (. gtoreq.124 μmol/l) in women) or abnormal creatinine clearance (e.g., Glomerular Filtration Rate (GFR) ≤ 30-60ml/min), if not otherwise indicated.

In such cases, in further embodiments, mild renal impairment may be suggested (if not otherwise indicated) by creatinine clearance rates of, for example, 50-80ml/min (approximately equivalent to a male serum creatine level of ≦ 1.7mg/dL, a female serum creatine level of ≦ 1.5 mg/dL); moderate renal impairment may be advised (if not indicated otherwise) by a creatinine clearance rate of 30-50ml/min (approximately equivalent to a male serum creatinine level >1.7 to ≦ 3.0mg/dL, a female serum creatinine level >1.5 to ≦ 2.5 mg/dL); and severe renal impairment may be suggested (if not otherwise indicated) by a creatinine clearance rate of <30ml/min (approximately equivalent to a male serum creatinine level >3.0mg/dL, a female serum creatinine level >2.5 mg/dL). Patients with end stage renal disease require dialysis (e.g., hemodialysis or peritoneal dialysis).

In another further embodiment, patients suffering from renal disease, insufficiency, or impairment of kidney may include patients suffering from chronic renal insufficiency or impairment, which may be based on glomerular filtration rate (GFR, ml/min/1.73 m)²) It is divided (if not otherwise stated) into 5 disease stages: stage 1 is characterized by normal GFR ≧ 90 (optionally plus persistent proteinuria (e.g., UACR ≧ 30mg/g) or known structural or hereditary nephropathy); stage 2 is characterized by a mild reduction in GFR (GFR 60-89), indicating mild renal impairment; stage 3 is characterized by a moderate decrease in GFR (GFR 30-59), indicating moderate renal impairment [ or more detailed](ii) a Stage 3a is characterized by a mild-moderate decrease in GFR (GFR 45-59) indicating mild-moderate renal impairment, and stage 3b is characterized by a moderate-severe decrease in GFR (GFR 30-44) indicating moderate-severe renal impairment; stage 4 is characterized by a severe reduction in GFR (GFR 15-29), indicating severe renal impairment; and a terminal phase 5, characterized by the need for dialysis or GFR<15, indicating that renal failure (end stage renal disease, ESRD) has been established.

Chronic kidney disease and stages thereof (CKD 1-5) can generally be characterized or classified accordingly, e.g., based on impairment of the kidney (proteinuria) or an estimate of impaired Glomerular Filtration Rate (GFR)<60[ml/min/1.73m²]With or without kidney damage).

The proteinuria stage may be classified, for example, according to the disclosure herein and/or by a urinary albumin creatinine ratio (such as typically a UACR ≧ 30mg/g, in some cases ≧ 20 μ g/min albumin excretion rate), such as, for example, microalbuminuria may be classified, for example, by UACR 30-300mg/g (in some cases 20-200 μ g/min), or in another embodiment UACR 30-200mg/g, and/or macroproteinuria may be classified, for example, by UACR >300mg/g (in some cases >200 μ g/min), or in another embodiment, by UACR >200 mg/g. A very high UACR of 2000mg/g or more can be classified as renal disease.

A further embodiment of a diabetic patient may refer to a patient with inadequate proteinuria control despite therapy with an Angiotensin Converting Enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB).

Further embodiments of diabetic patients may refer to patients (preferably diabetic patients, in particular type 2 diabetic patients) with a history of micro (renal) and/or macro (cardiovascular) diseases and/or drug treatment, such as CKD/diabetic nephropathy, renal impairment and/or (micro or macro) proteinuria and/or macrovascular diseases (e.g. coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension) and/or microvascular diseases (e.g. diabetic nephropathy, neuropathy, retinopathy); and/or treatment with acetylsalicylic acid, antihypertensive and/or lipid-lowering drugs, such as, for example, therapy with acetylsalicylic acid, ACE inhibitors, ARBs, beta-blockers, calcium antagonists or diuretics, or combinations thereof (prior or ongoing) and/or with fibrates, nicotinic acid or statins, or combinations thereof (prior or ongoing).

The DPP-4 inhibitor may be administered to (e.g., over, in addition to) the patient in combination with a background drug, such as, for example, an Angiotensin Converting Enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB).

In the present invention, it is understood that the combinations, compositions or combined use according to the invention may envisage administration of the active ingredients or ingredients simultaneously, sequentially or separately.

Herein, "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, for example, simultaneous, sequential or separate use of components or ingredients.

The combined administration of the present invention may be carried out by administering the active ingredients or ingredients together, for example, by administering them simultaneously in a single formulation or dosage form or in two separate formulations or dosage forms. Alternatively, administration may be by sequential administration of the active ingredients or ingredients, such as, for example, sequential administration in two separate formulations or dosage forms.

For the combination therapy of the present invention, the active ingredients or ingredients may be administered separately (which means they are formulated separately) or formulated together (which means they are formulated in the same formulation or in the same dosage form). Thus, administration of one element of the combination of the invention may be performed before, simultaneously with or after administration of the other elements of the combination.

Unless otherwise indicated, combination therapy may refer to first line, second line, or third line therapy, or initial or additional combination therapy or replacement therapy.

Unless otherwise indicated, monotherapy may refer to first line therapy (e.g., therapy performed on patients who are eating and exercising only but have inadequate glycemic control, such as, for example, patients on primary drug therapy, typically early after diagnosis and/or patients who have not previously been treated with an anti-diabetic agent and/or patients who are ineligible for metformin therapy (such as, for example, patients who are contraindicated for metformin therapy due to renal impairment, or such as, for example, patients who are not eligible for metformin therapy due to intolerance).

Unless otherwise indicated, additional combination therapy may refer to second-or third-line therapy (e.g., therapy for patients with inadequate glycemic control despite therapy with one or two conventional antidiabetic agents, typically patients pre-treated with one or two antidiabetic agents, such as, for example, patients with such existing antidiabetic background drugs).

Unless otherwise indicated, initial combination therapy may refer to first-line therapy (e.g., therapy performed on patients who are eating and exercising only but have inadequate glycemic control, such as, for example, patients on initial drug therapy, typically early-after-diagnosis patients and/or patients who have not previously been treated with an anti-diabetic agent).

Since different metabolic dysfunctions usually occur simultaneously, it is often indicated to combine a number of different active ingredients with one another. Thus, depending on the diagnosed functional disorder, an improved therapeutic outcome may be obtained if the DPP-4 inhibitor is combined with one or more commonly used active substances for the respective disorder, such as, for example, one or more active substances selected from other antidiabetic substances, in particular active substances which lower blood glucose levels or lipid levels in the blood, raise HDL levels in the blood, lower blood pressure or are indicated in the treatment of atherosclerosis or obesity.

The above mentioned DPP-4 inhibitors may be used in combination with one or more other active substances in addition to monotherapy, whereby improved therapeutic results may be obtained. Such combination therapies may be administered as a free combination of substances or as a fixed combination, for example in a tablet or capsule. Pharmaceutical formulations of the combination partners required for this purpose are either commercially available as pharmaceutical compositions or can be formulated by the skilled worker using customary methods. Active substances which are commercially available as pharmaceutical compositions are described in many places in the prior art, for example in the annual drug listing, the "Rote" of the federal association of the pharmaceutical industryThe compilation of annually updated manufacturer-related prescription information, otherwise known as "physician case reference".

Examples of anti-diabetic combination partners are metformin; sulfonylureas such as glibenclamide, tosylbutamide, glimepiride, glipizide, caridinide, glibenclamide, and gliclazide; nateglinide; repaglinide; mitiglinide; thiazolidinediones such as rosiglitazone and pioglitazone; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; insulin and insulin analogs such as human insulin, insulin lispro, insulin glulisine, r-DNA-insulin aspart, NPH insulin, insulin detemir, insulin deguelin, insulin tegasertib (insulin tregpoil), insulin zinc suspension and insulin glargine; amylin and amylin analogs (e.g., pramlintide or dalvarin peptide); GLP-1 and GLP-1 analogs, such as exendin-4, e.g., exenatide LAR, liraglutide, taslutamide, lixisenatide (AVE-0010), LY-2428757 (pegylated version of GLP-1), dolabrutide (LY-2189265), semaglutide, or abiglutide; and/or SGLT2 inhibitors such as, for example, dapagliflozin, sjogren (KGT-1251), alogliflozin, canagliflozin, ivagliflozin, luagliflozin, or togagliflozin.

Metformin is typically administered in doses varying from about 500mg to 2000mg to 2500mg per day, using various dosing regimens: from about 100mg to 500mg or 200mg to 850mg (1-3 times per day) or about 300mg to 1000mg once or twice per day, or delayed release metformin in the following doses: from about 100mg to 1000mg or preferably from 500mg to 1000mg once or twice daily, or from about 500mg to 2000mg once daily. Specific dosage strengths may be 250, 500, 625, 750, 850 and 1000mg of metformin hydrochloride.

The dose of pioglitazone is generally about 1-10mg, 15mg, 30mg or 45mg once daily.

Rosiglitazone is usually administered in doses of 4 to 8mg once (or twice) daily (typical dose strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is typically administered in a dose of 2.5-5 to 20mg once (or twice) a day (typical dose strengths are 1.25, 2.5 and 5mg), or micronized glibenclamide in the following doses: 0.75-3 to 12mg once (or twice) daily (typical dose strengths are 1.5, 3, 4.5 and 6 mg).

Glipizide is typically administered once daily (or up to 40mg in two) at a dose of 2.5 to 10-20mg (typical dose strengths are 5 to 10mg), or as a slow-release glibenclamide at the following dose: once daily 5 to 10mg (maximum 20mg) (typical doses are 2.5, 5 and 10 mg).

Glimepiride is typically administered in doses of 1-2 to 4mg (up to 8mg) once daily (typical dose strengths are 1,2 and 4 mg).

The glibenclamide/metformin double combination is typically administered in a dose of 1.25/250 to 10/1000mg twice daily. (typical dose strengths are 1.25/250, 2.5/500 and 5/500 mg).

The glipizide/metformin double combination is typically administered in doses ranging from 2.5/250 to 10/1000mg twice daily (typical dose strengths are 2.5/250, 2.5/500 and 5/500 mg).

The glimepiride/metformin double combination is usually administered in a dose of 1/250 to 4/1000mg twice daily.

The dual combination rosiglitazone/glimepiride is usually administered in doses of 4/1 to 4/2mg once or twice daily (typical dose strengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

The dual combination pioglitazone/glimepiride is usually administered in doses ranging from 30/2 to 30/4mg once daily (typical doses are 30/4 and 45/4 mg).

The dual rosiglitazone/metformin combination is usually administered in doses ranging from 1/500 to 4/1000mg twice daily (typical dose strengths are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg).

The dual pioglitazone/metformin combination is usually administered in a dose of 15/500 once or twice daily to a dose of 15/850mg three times daily (typical dose strengths are 15/500 and 15/850 mg).

The non-sulfonylurea insulin secretagogue nagracelin is usually administered with meals at doses of 60 to 120mg (up to 360 mg/day, typical dose strengths of 60 and 120 mg); repaglinide is usually given with meals in doses of 0.5 to 4mg (up to 16 mg/day, typical dose strengths are 0.5, 1 and 2 mg). The useful dosage strengths of the double combination repaglinide/metformin are 1/500 and 2/850 mg.

Acarbose is usually administered with meals in doses of 25 to 100 mg. Miglitol is usually given with meals in doses of 25 to 100 mg.

Examples of combination partners that lower the lipid level in the blood are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin; fibrin such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etoricoxifibrate; nicotinic acid and its derivatives, such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; PPAR-alpha/delta agonists; acyl-coenzyme A: inhibitors of cholesterol glycosyltransferases (ACAT; EC 2.3.1.26), such as avasimibe; cholesterol absorption inhibitors such as ezetimib (ezetimib); substances that bind bile acids, such as cholestyramine, colestipol and colesevelam; a bile acid transport inhibitor; HDL modulating actives such as D4F, reverse D4F, LXR modulating actives and FXR modulating actives; CETP inhibitors such as Tochester, JTT-705 (Dacetrapib), or compound 12 of WO 2007/005572 (anacetrapib); a LDL receptor modulator; MTP inhibitors (e.g., lomitapide); and ApoB100 antisense RNA.

The dose of atorvastatin is usually 1mg to 40mg or 10mg to 80mg once daily.

Examples of blood pressure lowering combination partners are beta blockers such as atenolol, bisoprolol, cilobolol, metoprolol and carvedilol; diuretics such as hydrochlorothiazide, chlorthalidone, ximetamine, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanidine, manidipine, isradipine, nilvadipine, verapamil, galopamid, and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril, and trandolapril; and angiotensin II receptor blockers (ARBs) telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan, and eprosartan.

The dose of telmisartan is generally 20mg to 320mg or 40mg to 160mg per day.

Examples of combination partners that can increase HDL levels in blood are Cholesteryl Ester Transfer Protein (CETP) inhibitors; an endothelial lipase inhibitor; modulators of ABC 1; an LXR α antagonist; LXR β agonists; PPAR-delta agonists; LXR α/β modulators, and agents that increase apolipoprotein a-I expression and/or plasma concentration.

Examples of combination partners for the treatment of obesity are siberiamine; tetrahydrostatin (orlistat); alizyme (cetilistat); dexfenfluramine; the cable is pulled open; cannabinoid receptor 1 antagonists such as the CB1 antagonist linotumab; an MCH-1 receptor antagonist; MC4 receptor agonists; NPY5 and NPY2 antagonists (e.g., willibate); beta 3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists, such as APD 356 (chlorocasein); a myostatin inhibitor; acrp30 and adiponectin; inhibitors of stearoyl-CoA desaturase (SCD 1); fatty Acid Synthase (FAS) inhibitors; a CCK receptor agonist; growth hormone releasing polypeptide receptor modulators; pyy 3-36; an orexin receptor antagonist; and tesofensine; and a double combination of bupropion/naltrexone, bupropion/zonisamide, topiramate/phentermine, and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosis are phospholipase a2 inhibitors; tyrosine kinase inhibitors (50mg to 600mg), such as PDGF-receptor kinase (see EP-A-564409, WO 98/35958, US 5093330, WO 2004/005281 and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.

Further, for the purposes according to the present invention, it is possible that, in addition to GLP-1, certain DPP-4 inhibitors of the present invention may be used in combination with a DPP-4 substrate (in particular with an anti-inflammatory substrate for DPP-4), such DPP-4 substrates including, for example and without limitation, one or more of the following:

incretins:

glucagon-like peptide (GLP) -1

Glucose-dependent insulinotropic peptide (GIP)

A neuroactive agent:

substance P

Neuropeptide Y (NPY)

Peptide YY

Energy-stabilizing agent:

GLP-2

prolactin and prolactin preparation

Pituitary Adenylate Cyclase Activating Peptide (PACAP)

Other hormones:

PACAP 27

human chorionic gonadotropin alpha chain

Growth Hormone Releasing Factor (GHRF)

Luteinizing hormone alpha chain

Insulin-like growth factor (IGF-1)

CCL 8/eotaxin

CCL 22/macrophage derived chemokine

CXCL 9/gamma-interferon-induced monokine

Chemokines:

CXCL 10/gamma-interferon-induced protein 10

CXCL 11/interferon-induced T cell a chemoattractant

CCL3L 1/macrophage inflammatory protein 1 alpha subtype

LD78β

CXCL 12/stroma derived factor 1 alpha and beta

And others:

enkephalin, gastrin releasing peptide, angiostatin-1,

Peptide histidine methionine, thyrotropin alpha

Further or additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more active substances specified in the treatment of renal disease, such as selected from diuretics, ACE inhibitors and/or ARBs.

Further or additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more active substances specified in the treatment or prevention of cardiovascular diseases or events, such as major cardiovascular events.

Furthermore, optionally additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more antiplatelet agents such as, for example, (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), enoogrel or ticagrel, or thrombin receptor antagonists such as vorapasha.

Still further, optionally additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more anticoagulants such as, for example, heparin, a coumarin (such as warfarin or phenylpropanol), a pentasaccharide inhibitor of factor Xa (such as fondaparinux sodium), or a direct thrombin inhibitor (such as dabigatran), or a factor Xa inhibitor (such as, for example, rivaroxaban or apixaban or edoxaban or otaxaban).

Still yet further, optionally additionally, certain DPP-4 inhibitors of the present invention may be used in combination with one or more agents for the treatment of heart failure, such as for example those mentioned in WO 2007/128761.

The scope of the invention is not limited by the specific embodiments described herein. Various modifications of the invention in addition to those described herein will 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 incorporated by reference herein in their entirety.

Examples

The examples given herein are set forth in order to provide a more complete understanding of the invention. Further embodiments, features, effects, characteristics or aspects of the present invention may become apparent from the examples. The described embodiments are illustrative of the principles of the present invention and are not to be construed as limiting thereof.

Cardiovascular fate test of linagliptin compared to glimepiride in type 2 diabetes-

The long-term cardiovascular effects of linagliptin compared to sulfonylurea glimepiride on subjects with early type 2 diabetes and increased cardiovascular risk or established complications were evaluated.

Treatment of type 2 diabetes patients with increased or high cardiovascular risk

The long-term effects of linagliptin treatment on the morbidity and mortality of cardiovascular disease and related efficacy parameters (e.g. HbA1c, fasting plasma glucose, treatment sustainability) in a relevant population of type 2 diabetic patients were studied as follows:

inadequate glycemic control (never treated or currently treated with, for example, metformin and/or alpha-glucosidase inhibitors (mono or dual therapy) (e.g., with HbA1c 6.5% -8.5%), or current treatment with e.g. sulfonylureas or glibenclamide (single or dual therapy), type 2 diabetes patients with or without metformin or alpha-glucosidase inhibitors (e.g. with HbA1C 6.5.5% -7.5%)) and an increased or high risk of cardiovascular events (e.g. defined as one or more of the risk factors a), B), C) and D) are randomized and administered over a prolonged period (e.g. up to 432 weeks) linagliptin (5mg, once daily, optionally with one or more other active substances, e.g., such as added to an existing anti-diabetic background) and compared to patients treated with the sulfonylurea glimepiride (1-4mg once daily).

After randomization, if the patient uses SU or tagrina, the secretagogue therapy should be discontinued and replaced with study drug. For patients who did not use secretagogues, study drugs were added to the existing protocol.

Efficacy evaluation criteria

Primary endpoint

Time to first occurrence of any of the following identified components of the primary composite endpoint:

CV death (including fatal stroke and fatal MI), non-fatal stroke, or non-fatal MI (excluding silent MI) (also referred to as the time of 'first 3-point major adverse cardiovascular event [3P-MACE ]').

Critical secondary endpoint

1) Time to first occurrence of any of the following decision components for the composite endpoint: CV deaths (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalizations for unstable angina (also referred to as 'time to first 4P-MACE').

2) Composite end point of treatment sustainability: proportion of patients who were in trial medication at study end, maintained glycemic control at final visit (HbA1c ≦ 7.0%), without rescue medication (between end of titration at visit 6 and final visit), no > 2% weight gain (between visit 6 and final visit), and no moderate/severe hypoglycemic episodes (between visit 6 and final visit).

3) Composite end point of treatment sustainability: proportion of patients who were in trial medication at the end of the study, maintained glycemic control at the final visit (HbA1c ≦ 7.0%), without rescue medication (between visit 6 and final visit), and had no > 2% weight gain (between visit 6 and final visit).

Secondary endpoint

Secondary CV end point:

at least one of the following components occurs: CV deaths (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), and non-fatal stroke (also known as '3P-MACE onset').

At least one of the following components occurs: CV deaths (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalization for unstable angina (also referred to as 'development of 4P-MACE').

The occurrence and time of first occurrence of any of the following components of the composite endpoint of all events determined: CV death (including fatal stroke and fatal MI), non-fatal MI, non-fatal stroke, hospitalization for unstable angina, Transient Ischemic Attack (TIA), hospitalization for heart failure, hospitalization for coronary revascularization surgery (CABG, PCI).

Minor diabetes related endpoints

Change from baseline to final visit of the following laboratory parameters: HbA1c, Fasting Plasma Glucose (FPG), total cholesterol, Low Density Lipoprotein (LDL) cholesterol, High Density Lipoprotein (HDL) cholesterol, triglycerides, creatinine, estimated glomerular filtration rate (eGFR, MDRD formula), urinary albumin.

Any shift in proteinuria class based on urinary albumin/creatinine ratio (UACR).

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

A) previous (cardiovascular) vascular diseases (e.g. 40-85 years of age):

myocardial infarction (e.g. > 6 weeks),

Coronary artery disease (e.g. narrowing of the vessel lumen of the left main coronary artery or at least two main coronary arteries in angiography > -50%)

Percutaneous coronary interventions (e.g. > 6 weeks),

Coronary artery bypass grafting (e.g., > 4 years or postoperatively recurrent angina pectoris),

Ischemic or hemorrhagic stroke (e.g. >3 months),

Peripheral arterial occlusive disease (e.g. previous limb bypass surgery or percutaneous transluminal angioplasty; previous limb or foot amputation due to insufficient circulatory function, angiographic or ultrasound detection of significant vascular stenosis (> 50%) of the major limb arteries (common iliac, internal iliac, external iliac, femoral, popliteal) with history of intermittent claudication and at least one ankle: arm blood pressure ratio <0.90),

B) end organ damage in diabetes related to blood vessels (e.g. 40-85 years of age):

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

Microalbuminuria or macroalbuminuria (e.g. microalbuminuria or random spot urine albumin: creatinine ratio >/═ 30 μ g/mg),

Retinopathy (e.g. proliferative retinopathy, or retinal neovascularization or previous retinal laser photocoagulation therapy),

C) elderly (e.g. age >/═ 70 years),

D) at least two of the following cardiovascular risk factors (e.g., 40-85 years of age):

late type 2 diabetes (e.g. duration >10 years),

Hypertension (e.g. systolic pressure >140mmHg or at least one hypotensive treatment, e.g. < -6 months),

-smoking a cigarette currently on a daily basis,

- (atherogenic) dyslipidemia or high LDL cholesterol blood level (e.g. LDL cholesterol >/═ 135mg/dL) or at least one treatment for lipid abnormalities (e.g. <6months).

Results

Conclusion of the summary

Test patients and compliance with the test protocol:

configuration of

A total of 6077 patients were randomized and treated 6068. Analyzing the data set to exclude data from patients at one site; thus, the TS included 6033 patients. Overall, the frequency of premature discontinuation of the test was low and a balance was maintained between the two groups (linagliptin: 4.1%, glimepiride: 3.8%). Less than 1% of patients lost follow-up on the life status (linagliptin: 0.8%, glimepiride: 0.7%). Between treatment groups, the premature discontinuation of the test drug was comparable (linagliptin: 37.3%, glimepiride: 39.1%), most commonly due to adverse events (AE; linagliptin: 15.1%, glimepiride 17.4%), or because patients refused to continue taking the test drug (not due to AE) (linagliptin: 10.2%, glimepiride: 10.9%).

Demographics

The population of the trial met expectations and, according to inclusion criteria, the patient had an increased risk of CV events. The demographic characteristics were well balanced between the treatment groups. The main baseline characteristics (mean and standard deviation [ SD ] or patient ratio) were as follows:

the patient was 64.0 years (9.5 years) of age.

60.0% of patients are male, while 40.0% are female.

Patients were predominantly caucasian (73.0%) or asian (17.6%); 17.1% are hispanic or hispanic.

The time since the self-diagnosis was 7.6 years (6.1 years).

The BMI of the patient was 30.08kg/m2(5.1kg/m 2).

The patient had HbA1c levels of 7.15% (0.57%).

The patient's Fasting Plasma Glucose (FPG) level was 140.0mg/dL (30.5 mg/dL).

The patient's eGFR (MDRD formula) was 76.8mL/min/1.73m2(19.8mL/min/1.73m 2).

The proportion of patients with UACR <30mg/g is 74.0%

Exposing

Median time to trial was 6.25 years for both treatment groups and median exposure to trial drug was 5.86 years for both treatment groups.

Efficacy results

3P-MACE and 4P-MACE (Primary endpoint and first Key Secondary endpoint) and composition

The primary endpoint was reached and demonstrated that linagliptin was not inferior to glimepiride over the time of 3P-MACE because the upper bound of 95.47% CI was below 1.3 (P <0.0001 on one side). Overall, 356 patients (11.8%) were reported to have 3P-MACE events in the linagliptin group, and 362 patients (12.0%) (HR ═ 0.98; 95.47% CI 0.84, 1.14) in the glimepiride group. Since the upper bound of 95.47% CI is above 1.0, the primary endpoint analysis for linagliptin superiority was not met at the next step in the test hierarchy (single-sided p ═ 0.3813). The proportion of patients with 3PMACE resulting from each event type was generally balanced between treatment groups (CV deaths: linagliptin 4.3%, glimepiride 4.2%; non-fatal MI: 4.7% and 4.6%; non-fatal stroke: 2.8% and 3.4%).

All further analysis was considered exploratory as the test hierarchy was not met.

Consistent with the primary endpoint, the time of first 4P-MACE showed no treatment differences (HR ═ 0.99; 95.47% CI 0.86, 1.14; unilateral P ═ 0.4334). The linagliptin group had 398 patients (13.2%) with 4P-MACE events, and the glimepiride group had 401 patients (13.3%) with 4P-MACE events. The proportion of patients with each event type leading to 4P-MACE was generally balanced between treatment groups (CV death: linagliptin 4.1%, glimepiride 4.1%; non-fatal MI: 4.4% and 4.3%; non-fatal stroke: 2.8% and 3.3%; hospitalization due to unstable angina: 1.9% and 1.8%).

Sensitivity analysis of primary and critical secondary endpoints used different analysis sets and review methods, and the results were consistent with the primary analysis. Also, consistent results are generally observed in each subgroup.

Further analysis showed that there was no significant treatment difference between the all-cause mortality (linagliptin, 10.2% of patients, incidence per 1000 years at risk (incidence rate per 1000 years at risk) 16.8; glimepiride 12.3%, 18.4; hazard ratio 0.91, 95% CI0.78, 1.06, p ═ 0.2263), CV mortality (5.6%, 9.2; HR 1.00, 95% CI 0.81, 1.24, p ═ 0.9863 in both groups) and non-CV mortality (linagliptin, 4.6% of patients, incidence per 1000 years at risk 7.6; glimepiride 5.6%, 9.2; hazard ratio 0.82, 95% CI 0.66, 1.03, p ═ 0.0839).

In addition, heart failure outcomes were analyzed. Hospitalization for heart failure alone did not have significant treatment differences: linagliptin, 3.7% of patients, 6.4 incidence every 1000 years at risk; 3.1% of glimepiride and 5.3%; hazard ratio 1.21, 95% CI 0.92, 1.59, p 0.1761, or when analyzed in combination with CV death (7.8%, 13.4; HR 1.00, 95% CI 0.84, 1.20, p 0.9671 for both groups). Similarly, investigators reported no significant treatment differences for heart failure AE (linagliptin 5.5%, 9.5; glimepiride 5.2%, 9.0; HR 1.06, 95% CI 0.85, 1.32, p ═ 0.5844).

Treatment sustainability (secondary and tertiary key secondary endpoints) and composition

The secondary endpoints of the second and third keys all showed that linagliptin had higher therapeutic sustainability than glimepiride; the response rate was higher for the linagliptin group compared to the glimepiride group. For the second key secondary endpoint, 16.0% of patients in the linagliptin group and 10.2% in the glimepiride group were responders (OR ═ 1.68; 95.47% CI 1.43, 1.96; p < 0.0001). For the third key secondary endpoint, 17.4% of patients in the linagliptin group and 14.1% of patients in the glimepiride group were responders (OR ═ 1.29; 95.47% CI 1.11, 1.48; p ═ 0.0004). Sensitivity and subgroup analysis are generally consistent with principal analysis.

Further analysis of the composition of the treatment sustainability endpoints showed a significantly lower proportion of patients with moderate/severe hypoglycemic episodes between visit 6 and the end of the final visit titration in the linagliptin group compared to glimepiride (linagliptin: 5.6% of patients, glimepiride: 27.5%; odds ratio 0.16; 95% CI 0.13, 0.19; p < 0.0001).

Furthermore, while the glimepiride group showed an initial numerical weight gain, the linagliptin group showed a modest weight loss with a significant and sustained difference over time compared to the glimepiride group (mean difference after adjustment-1.61 kg; 95% CI-1.92, -1.29; p < 0.0001).

The time to first take the rescue medication was significantly shorter for patients in the linagliptin group (incidence per 1000 years at risk: linagliptin 128.6, glimepiride 115.5; p ═ 0.0035), while the rate of patients using the rescue medication was comparable between the two treatment groups (linagliptin: 49.3%, glimepiride: 47.1%). This is consistent with a large initial decrease in HbA1c in the glimepiride group at the end of the titration.

During the course of the trial, the HbA1c differences between treatment groups narrowed and the slopes crossed, indicating that HbA1c control over time was comparable/more sustained than glimepiride in HbA1c reduction over time (see table 7 change from baseline to final visit).

Any confirmed events (secondary CV endpoint)

There was no difference in the occurrence and timing of any of the events determined between the linagliptin group and the glimepiride group (linagliptin: 17.1% of patients, glimepiride: 17.8%; HR 0.96; 95% CI 0.85, 1.09).

Minor diabetes related endpoints

The change from baseline to final visit was generally comparable for both linagliptin and glimepiride treatment groups (table 7). Although some results showed statistically significant treatment differences, they were minor and not considered clinically relevant. UACR class transition from baseline to final visit is comparable between treatment groups; at the final visit, 58.4% of the linagliptin group still had normal UACR (< 30mg/g), 14.1% had microalbuminuria (> 30 to. ltoreq.300 mg/g), and 1.4% had macroalbuminuria (> 300 mg/g). In the glimepiride group, 57.7% of patients had normal UACR, 16.0% had microalbuminuria, and 1.4% had macroalbuminuria at baseline and final visit.

TABLE 7

Change from baseline to final visit of diabetes-related secondary endpoint-TS _ D; HbA_1cAnd FPG: all observed cases, other parameters: the observed cases, including in rescue medicationValue of after

Adjusting for baseline

And (4) conclusion:

this trial demonstrated that linagliptin was not inferior to glimepiride in the time of first cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3-point MACE) in type 2 diabetic patients with elevated cardiovascular risk and using standard of care (primarily with metformin background therapy). The superiority of linagliptin over glimepiride was not achieved for the 3-point MACE endpoint. Similarly, no treatment differences were observed at the first 4-point MACE (hospitalization for unstable angina other than the 3-point MACE component). There were no significant treatment differences in all-cause mortality, cardiovascular mortality, and heart failure outcome. Compared with glimepiride, the therapeutic effect of linagliptin is more continuous; the sustainability response rate was significantly higher for the combined endpoints of patients who were in trial drug therapy at the end of the trial, had HbA1c ≦ 7.0%, had no rescue medication, had no > 2% weight gain, and had or had no moderate/severe hypoglycemic episodes. Further treatment sustainability endpoint results underscore this observation.

In all hypoglycemia analyses, a clear and consistent reduction in the risk of hypoglycemia was observed in the linagliptin group compared to the glimepiride group. The patients in the linagliptin group showed a modest reduction in body weight compared to the glimepiride group, and had a sustained and significant difference over time. Control of HbA1c was similar in both treatment groups over time, except that the glimepiride group briefly reduced HbA1c levels during the initial week of treatment. Patients of similar proportion were treated with rescue medication prior to the end of the trial; the time to first use varied due to the lower initial HbA1c levels of the glimepiride group. All-cause mortality analysis showed comparable results in both groups.

The safety profile of linagliptin in this test population is consistent with the known safety profile of the drug; no new safety signals for linagliptin have been identified.

Further:

a non-significant estimate of non-cardiovascular death was observed for the benefit of linagliptin (HR 0.82 (95% CI, 0.66, 1.03[ p ═ 0.08 ]).

Description of the preferred embodiments

A) Rigliptin cardiovascular safety test

The cardiovascular safety study was a randomized, cohort study of 6033 patients with early type 2 diabetes and increased vascular risk or established complications who were treated with 5mg linagliptin (3023) or 1-4mg glimepiride (3010) added to standard of care (including 83% of patients on background therapy with metformin) against regional standards of HbA1c and CV risk factors. The mean age of the study population was 64 years and included 2030 (34%) > 70 patients. The study population included 2089 (35%) patients with cardiovascular disease and 1130 (19%) kidney-impaired patients with eGFR <60ml/min/1.73m2 at baseline. The mean HbA1c at baseline was 7.15%.

Following a median follow-up of 6.25 years (median time to treatment of 5.86 years), linagliptin did not increase the risk of major adverse cardiovascular events compared to glimepiride (table 8). Patients treated with or without metformin gave consistent results.

Table 8 Major Adverse Cardiovascular Events (MACE) and mortality of the treatment groups in the cardiovascular safety study

PY patient year

Non-inferiority tests were performed to demonstrate that the upper bound of 95% CI for hazard ratio was less than 1.3

The treatment sustainability complex, the key secondary endpoint, was defined as the proportion of patients who were in study treatment after the initial titration period (16 weeks), who maintained glycemic control at the final visit (HbA1c ≦ 7.0%), who did not require additional anti-diabetic drug therapy (rescue medication), who did not have any moderate (symptomatic, blood glucose values ≦ 70mg/dL) or severe (needed to assist) hypoglycemic episodes and did not gain weight by > 2%. This key secondary endpoint was achieved in a higher number of patients with linagliptin (481, 16.0%) compared to glimepiride (305, 10.2%).

For the entire treatment period (median treatment time 5.9 years), the moderate or severe hypoglycemia rate was 6.5% for patients using linagliptin, 30.9% compared to glimepiride, 0.3% for patients using linagliptin, and 2.2% compared to linaglimepiride.

Thus:

A1. linagliptin, optionally in combination with one or more other active agents, for use in the treatment of a diabetic, preferably type 2 diabetes, patient, wherein treatment of the patient with linagliptin does not increase the risk of three-point major adverse cardiovascular events (3P-MACE) compared to a patient treated with glimepiride, wherein the three-point major adverse cardiovascular events (3P-MACE) comprise cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke.

A2. Linagliptin, optionally in combination with one or more other active agents, for the use according to embodiment a1, wherein the risk is as shown in table 1 of the present specification, such as for example characterized by the following Hazard Ratio (HR):

hazard ratio
	(95％CI)
0.98(0.84,1.14)

A3. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment of patients with diabetes, preferably type 2 diabetes, wherein treatment of said patients with linagliptin results in a sustained glycemic control (HbA1c < 7%) without moderate or severe hypoglycemia and/or a substantial gain in body weight > 2% from baseline, in a significantly higher number of patients compared to patients treated with glimepiride without additional antidiabetic drug therapy.

A4. Linagliptin optionally in combination with one or more other active agents for the use according to embodiment a3, wherein the therapeutic sustainability is as shown in table 3 of the present specification, such as for example characterized by the following odds ratios:

ratio of advantages to each other
	(95％CI)
1.68(1.43,1.96)

A5. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of embodiments a1 to a4 for the treatment of a diabetic (preferably type 2 diabetes) patient, wherein linagliptin affects the treatment as follows:

ii) no additional antidiabetic drug therapy is required, resulting in a significantly higher number of patients achieving sustained glycemic control (HbA1c < 7%) without moderate or severe hypoglycemia and/or a substantial gain in body weight > 2% from baseline, as compared to patients treated with glimepiride.

A6. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a1 to a5, wherein the patient is exposed to treatment for at least 5.86 years, and/or followed up for at least 6.25 years.

A7. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a1 to a6, wherein the cardiovascular risk of the diabetic patient is increased or high.

A8. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a 1-a 7, wherein the diabetic patient has an increased or high risk of a CV event, such as end organ damage associated with blood vessels (e.g. selected from impaired renal function, (micro or macro) proteinuria, retinopathy), age > 70 years, and/or two or more CV risk factors (e.g. selected from hypertension, smoking, dyslipidemia, T2DM duration >10 years), based on a pre-existing CV disease (e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary bypass grafting, ischemic or hemorrhagic stroke, congestive heart failure, peripheral arterial occlusive disease).

A9. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a1 to A8, wherein the diabetic patient has one or more of the following a), B), C) and D):

B) vascular-related diabetic end organ damage, such as those selected from (moderate) impaired renal function, (micro-or macro-proteinuria and retinopathy,

C) old (e.g.,/═ 70 years), and

D) at least two cardiovascular risk factors selected from:

late type 2 diabetes (e.g. duration >10 years),

-hypertension,

-smoking a cigarette currently on a daily basis,

-dyslipidemia.

A10. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a1 to a9, wherein the patient has type 2 diabetes and insufficient glycemic control, i.e. either never treated, or despite mono-or dual therapy with metformin and/or an alpha-glucosidase inhibitor, or in spite of mono-or dual therapy with metformin or an alpha-glucosidase inhibitor, with sulfonylurea/glinide.

A11. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments a1 to a10, wherein the treatment of the patient with linagliptin is monotherapy or as additional therapy.

A12. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of embodiments a1 to a11, wherein the treatment further comprises a step of identifying diabetic patients at vascular risk (e.g. with a CV risk factor), particularly diabetic patients at increased or high risk of cardiovascular events, prior to treatment with linagliptin.

A13. Linagliptin, optionally in combination with one or more other active agents, for use according to embodiment a12, wherein the risk is based on pre-existing CV diseases (e.g. selected from myocardial infarction, coronary artery disease, percutaneous coronary intervention, coronary artery bypass graft, ischemic or hemorrhagic stroke, congestive heart failure, peripheral arterial occlusive disease), end-organ damage of blood vessels associated with diabetes (e.g. selected from impaired renal function, (micro-or macro-) proteinuria, retinopathy), age > 70 years, and/or two or more CV risk factors (e.g. selected from hypertension, smoking, dyslipidemia, T2DM duration >10 years), e.g. such as defined in embodiment a9.

Further aspects or embodiments:

B) linagliptin cardiovascular (safety) and renal microvascular fate tests

The cardiovascular and renal microvascular safety/outcome study was a randomized cohort study of 6979 type 2 diabetic patients with increased or high or even very high CV risk as evidenced by established history of macrovascular/cardiovascular or renal disease, who were treated with 5mg linagliptin (3494) or placebo (3485) added to standard of care for HbA1c, CV risk factors and regional standards of renal disease. The study population included 1,211 (17.4%) patients aged > 75 years and 4,348 (62.3%) patients with renal impairment. Approximately 19% of the population have an eGFR ≧ 45 to <60mL/min/1.73m2, 28% of the population have an eGFR ≧ 30 to <45mL/min/1.73m2, and 15% have an eGFR <30mL/min/1.73m 2. The mean HbA1c at baseline was 8.0%.

The study was aimed at demonstrating the non-adverse effects of the primary cardiovascular endpoint, which is the complex of cardiovascular death or non-fatal Myocardial Infarction (MI) or the first occurrence of non-fatal stroke (3P-MACE). The renal compound endpoint was defined as renal death or persistent end-stage renal disease or a sustained reduction in eGFR by 40% or more.

Linagliptin added to the standard of care did not increase the risk of adverse cardiovascular or renal fate events after a median follow-up of 2.2 years (median time to treatment of 1.9 years) (table 9 and figure 2). In type 2 diabetic patients, there was no increase in risk of hospitalization due to heart failure, another endpoint of the determination observed, compared to the standard of care without linagliptin (table 10).

Table 9 Major Adverse Cardiovascular Events (MACE) and renal fate events for the treatment groups in the cardiovascular safety and renal microvascular fate studies

PY patient year

Non-inferiority tests were performed to demonstrate that the upper bound of 95% CI for hazard ratio was less than 1.3

TABLE 10 hospitalization for heart failure and mortality in the treatment group in the cardiovascular safety and renal microvascular outcome study

PY patient year

When analyzing proteinuria progression (from normal proteinuria to microalbuminuria or macroproteinuria, or from microalbuminuria to macroproteinuria), the estimated hazard ratio for linagliptin compared to placebo was 0.86 (95% CI0.78, 0.95). The microvascular endpoint is defined as a complex of renal death, sustained ESRD, sustained eGFR reduction ≧ 50%, proteinuria progression, use of retinal photocoagulation or intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage or blindness associated with diabetes. The estimated risk ratio for time to first occurrence of the composite microvascular endpoint for linagliptin compared to placebo was 0.86 (95% CI0.78, 0.95), driven primarily by proteinuria progression.

Thus:

B1. linagliptin, optionally in combination with one or more other active agents, for use according to any one of the preceding (specific) embodiments (e.g. a1 to a13) in the treatment of a diabetic, preferably type 2 diabetes, patient, wherein treatment of the patient with linagliptin does not increase the risk of a three-point major adverse cardiovascular event (3P-MACE) compared to a placebo-treated patient, wherein the three-point major adverse cardiovascular event (3P-MACE) comprises cardiovascular death, non-fatal Myocardial Infarction (MI) and/or non-fatal stroke.

B2. Linagliptin, optionally in combination with one or more other active agents, for the use according to embodiment B1, wherein the risk is characterized by the following Hazard Ratio (HR):

hazard ratio
	(95％CI)
1.02(0.89,1.17)

B3. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of the preceding embodiments for the treatment of a diabetic (preferably type 2 diabetes) patient, wherein treatment of the patient with linagliptin does not increase the risk of hospitalization for heart failure compared to a placebo-treated patient.

B4. Linagliptin, optionally in combination with one or more other active agents, for use according to embodiment B3, wherein the risk is characterized by a Hazard Ratio (HR) of 0.90 (95% CI; 0.74, 1.08).

B5. Linagliptin, optionally in combination with one or more other active agents, for use according to any of the preceding (specific) embodiments, wherein treatment of the patient with linagliptin does not increase the risk of key renal fatalities events, including renal death, end-stage end-lasting renal disease (ESRD), and/or an estimated sustained reduction in glomerular filtration rate (eGFR) of 40% or more, compared to a patient treated with placebo.

B6. Linagliptin, optionally in combination with one or more other active agents, for the use according to embodiment B5, wherein the risk is characterized by the following Hazard Ratio (HR):

hazard ratio
	(95％CI)
1.04(0.89,1.22)

B7. Linagliptin, optionally in combination with one or more other active agents, for use according to any of the preceding (specific) embodiments in the treatment of a diabetic, preferably type 2 diabetic, patient, wherein treatment of the patient with linagliptin prevents, delays the onset of, or reduces the risk of progression of proteinuria compared to a patient treated with placebo, wherein the proteinuria progression comprises a change from normal proteinuria to microalbuminuria or macroproteinuria and/or a change from microalbuminuria to macroproteinuria.

B8. Linagliptin, optionally in combination with one or more other active agents, for use according to any of the preceding (specific) embodiments for treating a diabetic, preferably type 2 diabetic, patient, wherein treatment of the patient with linagliptin prevents, delays the onset of, or reduces the risk of microvascular renal and/or ocular complications, including renal death, persistent ESRD, sustained eGFR reduction ≧ 50%, proteinuria progression, use of retinal photocoagulation, use of intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage and/or blindness associated with diabetes, as compared to a placebo-treated patient.

B9. Linagliptin, optionally in combination with one or more other active agents, for use in the treatment of a diabetic (preferably type 2 diabetes) patient according to any one of embodiments B1 to B8, wherein linagliptin affects the treatment as follows:

i) does not increase the risk of three major adverse cardiovascular events (3P-MACE), wherein said three major adverse cardiovascular events (3P-MACE) include cardiovascular death, non-fatal Myocardial Infarction (MI), and/or non-fatal stroke,

ii) does not increase the risk of hospitalization due to heart failure,

iii) does not increase the risk of key renal fate events, wherein the key renal fate events include renal death, end-stage renal disease persistence (ESRD), and/or an estimated persistent 40% or more decrease in glomerular filtration rate (eGFR),

iv) preventing, delaying the onset of or reducing the risk of proteinuria progression, wherein said proteinuria progression comprises a change from normal proteinuria to micro-or macroproteinuria and/or from micro-proteinuria to macroproteinuria, and/or

v) preventing, delaying the onset of, or reducing the risk of microvascular renal and/or ocular complications, wherein said microvascular renal and/or ocular complications comprise renal death, sustained ESRD, sustained eGFR reduction ≥ 50%, proteinuria progression, use of retinal photocoagulation, use of intravitreal anti-VEGF therapy for diabetic retinopathy, vitreous hemorrhage and/or blindness associated with diabetes.

B10. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B9, wherein the patient is exposed to treatment for at least 1.8 years, or at least 1.9 years, and/or followed up for at least 2.2 years.

B11. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1-B10, wherein the diabetic patient has a high or (very) increased vascular risk, such as a high or very high risk of heart and kidney diseases (vascular), in particular cardiovascular and/or renal complications or events.

B12. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1-B11, wherein the patient is at high or very high risk of heart and kidney disease, such as cardiovascular and/or renal events, based on established macrovascular disease and/or kidney disease (e.g. proteinuria and/or impaired renal function); such as, for example, where the diabetic patient has evidence of: renal disease or impaired renal function is prevalent, with or without macrovascular (cardiovascular) disease, such as defined by i) proteinuria and previous macrovascular disease and/or ii) impaired renal function with a predefined Urinary Albumin Creatinine Ratio (UACR).

B13. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B12, wherein the diabetic patient has:

previous macrovascular diseases such as for example defined as one or more of a) to f):

a) the previous myocardial infarction,

b) Advanced coronary artery disease,

c) High risk of single vessel coronary artery disease,

d) Previous ischemic or hemorrhagic stroke,

e) The existence of carotid artery disease,

f) The presence of peripheral artery disease;

and/or

(ii) Impaired renal function (e.g., with or without CV complications), such as defined, for example, as:

Impaired renal function (e.g., as defined by the MDRD formula) is accompanied by an estimate of glomerular filtration rate (eGFR) ≧ 45-75mL/min/1.73m²Creatinine ratio to Urine Albumin (UACR)>200mg/g creatinine or>200mg/l (per one)Milligrams of albumin in liter of urine) or>200. mu.g/min (microgram albumin per minute) or>200mg/24h (mg albumin per 24 hours).

B14. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B13, wherein the patient has type 2 diabetes mellitus and insufficient glycemic control, i.e. has never received treatment or was pretreated with any antidiabetic background therapy including, for example, metformin, sulfonylureas, glinides, insulin, alpha-glucosidase inhibitors and/or thiazolidinediones.

B15. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B14, wherein the treatment of the patient with linagliptin is monotherapy or as additional therapy.

B16. Linagliptin, optionally in combination with one or more other active agents, for use according to any one of embodiments B1 to B15, wherein the treatment further comprises the step of identifying diabetic patients at vascular risk, in particular diabetic patients at high risk of cardiovascular and/or renal events, prior to treatment with linagliptin.

B17. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B16, wherein the treatment further comprises the step of identifying a diabetic patient at risk of heart failure prior to treatment with linagliptin.

B18. Linagliptin, optionally in combination with one or more other active agents, for the use according to embodiment B16 or B17, wherein the risk is based on established macrovascular disease and/or renal disease (e.g. proteinuria and/or impaired renal function), e.g. such as defined by i) proteinuria and previous macrovascular disease and/or ii) impaired renal function with a predefined albumin creatinine ratio (UACR), e.g. such as defined in embodiment B13.

B19. Linagliptin, optionally in combination with one or more other active agents, for the use according to any one of embodiments B1 to B18, wherein the patient has

Proteinuria, such as microalbuminuria (UACR 30-300mg/g) or macroproteinuria (UACR >300mg/g),

and/or

Impaired renal function, such as mild (eGFR ≧ 60 to <90mL/min/1.73m2), moderate (eGFR ≧ 45 to <60mL/min/1.73m2), moderate/severe (eGFR ≧ 30 to <45mL/min/1.73m2), or severe (eGFR <30mL/min/1.73m2) renal impairment.

Thus, in two distinct cardiovascular outcome tests a (cardiovascular (safety) and renal microvascular outcome test) and B (cardiovascular safety test), a long-term (cardiovascular and renal) safety profile of linagliptin in a broad range of type 2 diabetes patients has been established, including

A) Patients with increased risk of CV (early type 2 diabetes, duration ≦ 5 years, hba1c6.5% -8%, see aspect a above), such as e.g. according to any one of embodiments a1 to a 11; and

B) CV or a patient at high risk for heart and/or Chronic Kidney Disease (CKD) (CV and/or kidney disease established, HbA1c 6.5% -10%, see aspect B above), such as for example according to any one of embodiments B1 to B19.

The invention further provides linagliptin, optionally in combination with one or more other active agents, for use in the treatment of type 2 diabetes (especially characterized by cardiovascular and renal safety, especially over a long treatment duration), including in patients at risk (e.g. as described herein, especially according to aspects a and/or B above), such as e.g. suffering from or at risk of suffering from atherosclerotic CV disease, heart failure and/or chronic kidney disease.

The invention further provides linagliptin, optionally in combination with one or more other active agents, for use in the treatment of proteinuria (especially characterized by cardiovascular and renal safety, especially over a long treatment duration) in type 2 diabetes patients, including patients at risk (e.g. as described herein, especially according to aspects a and/or B above), such as e.g. suffering from or at risk of suffering from atherosclerotic CV disease, heart failure and/or chronic kidney disease.

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