U.S. patent application number 17/209365 was filed with the patent office on 2021-07-08 for medical use of pharmaceutical combination or composition.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Thomas MEINICKE, Maximilian VON EYNATTEN.
Application Number | 20210205315 17/209365 |
Document ID | / |
Family ID | 1000005475710 |
Filed Date | 2021-07-08 |
United States Patent
Application |
20210205315 |
Kind Code |
A1 |
MEINICKE; Thomas ; et
al. |
July 8, 2021 |
MEDICAL USE OF PHARMACEUTICAL COMBINATION OR COMPOSITION
Abstract
The present invention relates to a certain DPP-4 inhibitor for
use in combination with metformin in CKD patients.
Inventors: |
MEINICKE; Thomas;
(Mittelbiberach, DE) ; VON EYNATTEN; Maximilian;
(Wiesbaden, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
1000005475710 |
Appl. No.: |
17/209365 |
Filed: |
March 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16788608 |
Feb 12, 2020 |
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17209365 |
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16170134 |
Oct 25, 2018 |
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16788608 |
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15616974 |
Jun 8, 2017 |
10155000 |
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16170134 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/522 20130101; A61K 9/2018 20130101; A61K 9/0053 20130101;
A61K 31/50 20130101; A61K 9/00 20130101; A61K 31/155 20130101; A61K
9/20 20130101 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 9/20 20060101 A61K009/20; A61K 9/00 20060101
A61K009/00; A61K 31/155 20060101 A61K031/155; A61K 45/06 20060101
A61K045/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 10, 2016 |
EP |
16174075.8 |
Feb 1, 2017 |
EP |
17154248.3 |
Claims
1. A method of using linagliptin, or a pharmaceutically acceptable
salt thereof, in combination with metformin, and optionally one or
more further active agents selected from the group consisting of
insulin and a sulfonylurea to treat a type 2 diabetes patient
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or down to 30.
2. The method of claim 1, wherein the type 2 diabetes patient has
an estimated glomerular filtration rate (eGFR;
mL/minute/1.73m.sup.2) level down to 45.
3. The method of claim 1, wherein the type 2 diabetes patient has
an estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) level down to 30.
4. The method of claim 2, wherein linagliptin and metformin are
administered in a single pharmaceutical composition, such as e.g.
in form of a single oral dosage form (e.g. tablet).
5. The method of claim 4, wherein the linagliptin is present in the
composition in a dosage strength of 2.5 mg; or of 5 mg.
6. The method of claim 5, wherein the metformin is present in the
composition in a dosage strength of 500 mg, 850 mg or 1000 mg in
form of immediate release metformin; or 500 mg, 750 mg, 1000 mg,
1500 mg or 2000 mg in form of extended release metformin.
7. The method of claim 4, wherein the pharmaceutical composition
comprises 2.5 mg linagliptin and 500 mg, 850 mg or 1000 mg
metformin in immediate release form, and optionally one or more
pharmaceutically auxiliaries
8. The method of claim 4, wherein the pharmaceutical composition
comprises 5 mg linagliptin and 1000 mg metformin in extended
release form, and optionally one or more pharmaceutically
auxiliaries, or wherein the pharmaceutical composition comprises
2.5 mg linagliptin and 750 mg or 1000 mg metformin in extended
release form, and optionally one or more pharmaceutically
auxiliaries.
9. The method of claim 1, wherein linagliptin is administered in a
total oral daily dose of 5 mg.
10. The method of claim 2, wherein linagliptin is administered in a
total oral daily dose of 5 mg, wherein the 5 mg daily dose is
administered as 2.5 mg linagliptin twice daily or 5 mg linagliptin
once daily.
11. A method of using linagliptin, or a pharmaceutically acceptable
salt thereof, in combination with metformin, to treat a type 2
diabetes patient having eGFR level 30-44, wherein the maximum daily
dose of metformin hydrochloride is 1000 mg, wherein linagliptin and
metformin are administered in a single oral dosage form comprising
2.5 mg linagliptin and 500 mg metformin, and optionally one or more
pharmaceutically auxiliaries, and wherein the single oral dosage
form is administered orally twice daily to the patient.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a certain DPP-4 inhibitor
(preferably linagliptin) for use in combination with metformin
(particularly in the form of metformin hydrochloride) in CKD
(chronic kidney disease) patients, particularly in patients having
CKD up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45, or even down
to 30, such as in patients with CKD of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
such as having eGFR levels 45-59 or of moderate-to-severe stage
such as having eGFR levels 30-44 (CKD stage 3b), optionally in
combination with one or more other active substances.
BACKGROUND OF THE INVENTION
[0002] Type 2 diabetes mellitus is a common chronic and progressive
disease arising from a complex pathophysiology involving the dual
endocrine effects of insulin resistance and impaired insulin
secretion with the consequence not meeting the required demands to
maintain plasma glucose levels in the normal range. This leads to
chronic hyperglycaemia and its associated micro- and macrovascular
complications or chronic damages, such as e.g. diabetic
nephropathy, retinopathy or neuropathy, or macrovascular (e.g.
cardio- or cerebro-vascular) complications, and/or cognitive
function impairment. The vascular disease component plays a
significant role, but is not the only factor in the spectrum of
diabetes associated disorders. The high frequency of complications
leads to a significant reduction of life expectancy. Diabetes is
currently the most frequent cause of adult-onset loss of vision,
renal failure, and amputation in the Industrialized World because
of diabetes induced complications and is associated with a two to
five fold increase in cardiovascular disease risk. The elevated
risk for macrovascular disease is primarily related to increased
risk for athero-thrombosis that leads to increased morbidity and
premature mortality from cardiovascular (CV) disease and an
important predictor for CV diseases is renal impairment,
nephropathy and/or chronic kidney disease (CKD) which often
co-exists.
[0003] The treatment of type 2 diabetes typically begins with diet
and exercise, followed by oral antidiabetic monotherapy, and
although conventional monotherapy may initially control blood
glucose in some patients, it is however associated with a high
secondary failure rate. The limitations of single-agent therapy for
maintaining glycemic control may be overcome, at least in some
patients, and for a limited period of time by combining multiple
drugs to achieve reductions in blood glucose that cannot be
sustained during long-term therapy with single agents. Available
data support the conclusion that in most patients with type 2
diabetes current monotherapy will fail and treatment with multiple
drugs will be required. But, because type 2 diabetes is a
progressive disease, even patients with good initial responses to
conventional combination therapy will eventually require an
increase of the dosage or further treatment with an additional oral
or non-oral antidiabetic drug (often finally with insulin therapy)
because the blood glucose level is very difficult to maintain
stable for a long period of time. Although existing combination
therapy has the potential to enhance glycemic control, it is not
without limitations (especially with regard to long term efficacy).
Further, traditional therapies may show an increased risk for side
effects, such as hypoglycemia or weight gain, which may compromise
their efficacy and acceptability.
[0004] Thus, for many patients, these existing drug therapies
result in progressive deterioration in metabolic control despite
treatment and do not sufficiently control metabolic status
especially over long-term and thus fail to achieve and to maintain
glycemic control in advanced, progressed or late stage type 2
diabetes, including diabetes with inadequate glycemic control
despite conventional oral and/or non-oral antidiabetic
medication.
[0005] Therefore, although intensive treatment of hyperglycemia can
reduce the incidence of chronic damages, many patients with
diabetes remain inadequately treated, partly because of limitations
in long term efficacy, safety/tolerability and dosing inconvenience
of conventional antihyperglycemic therapies.
[0006] In addition, obesity, overweight or weight gain (e.g. as
side or adverse effect of some conventional antidiabetic
medications) further complicates the treatment of diabetes and its
microvascular or macrovascular, and/or cognitive,
complications.
[0007] This high incidence of therapeutic failure is a major
contributor to the high rate of long-term hyperglycemia-associated
complications or chronic damages (including micro- and
macrovascular complications such as e.g. diabetic nephrophathy,
retinopathy or neuropathy, or cerebro- or cardiovascular
complications such as e.g. myocardial infarction, stroke or
vascular mortality or morbidity) in patients with diabetes.
[0008] Oral antidiabetic drugs conventionally used in therapy (such
as e.g. first-, second- or third-line, and/or mono- or (initial or
add-on) combination therapy) may include, without being restricted
thereto, metformin, sulphonylureas, thiazolidinediones, glinides
and .alpha.-glucosidase inhibitors.
[0009] Non-oral (typically injected) antidiabetic drugs
conventionally used in therapy (such as e.g. first-, second- or
third-line, and/or mono- or (initial or add-on) combination
therapy) may include, without being restricted thereto, GLP-1 or
GLP-1 analogues, and insulin or insulin analogues.
[0010] However, the use of these conventional antidiabetic or
antihyperglycemic agents can be associated with various adverse
effects. For example, metformin can be associated with lactic
acidosis or gastrointestinal side effects; sulfonylureas, glinides
and insulin or insulin analogues can be associated with
hypoglycemia and weight gain; thiazolidinediones can be associated
with edema, bone fracture, weight gain and heart failure/cardiac
effects; and alpha-glucosidase blockers and GLP-1 or GLP-1
analogues can be associated with gastrointestinal adverse effects
(e.g. dyspepsia, flatulence or diarrhea, or nausea or
vomiting).
[0011] In addition to morbidity associated with each of these side
effects, they could also have adverse cardiovascular implications.
For example, hypoglycaemia and weight gain are postulated as
contributors to adverse CV mortality outcomes.
[0012] Hypoglycemic episodes have also been identified detrimental
to cognitive skills and are associated with a greater risk of
cognitive impairment or dementia. The risk of hypoglycemia is
further increased in the elderly with comorbidities and multiple
medication use.
[0013] Therefore, it remains a need in the art to provide
efficacious, safe and tolerable antidiabetic therapies.
[0014] In particular, a certain amount of people with type 2
diabetes mellitus have chronic kidney disease (CKD). For these
individuals, the current standard of care is intensive glycemic
control and treatment with angiotensin-converting enzyme (ACE)
inhibitors or angiotensin II receptor blockers (ARBs).
[0015] Despite such treatment, type 2 diabetes patients with
chronic kidney disease (particularly having residual albuminuria)
still have substantial risk for cardio-renal morbidity and
mortality, an unmet need that is driving a search for novel
therapies for diabetic kidney disease.
[0016] Accordingly, it remains a need in the art to provide
efficacious, safe and tolerable antidiabetic therapies both for
diabetic patients such as who have not previously been treated with
an antidiabetic drug (drug-naive patients) and, particularly, for
patients with advanced or late stage type 2 diabetes mellitus,
including patients with inadequate glycemic control on conventional
oral and/or non-oral antidiabetic drugs, such as e.g. metformin,
sulphonylureas, thiazolidinediones, glinides and/or
.alpha.-glucosidase inhibitors, and/or GLP-1 or GLP-1 analogues,
and/or insulin or insulin analogues; particularly in patients with
(chronic) renal disease, renal dysfunction or renal impairment,
including in patients having chronic kidney disease (CKD) such as
e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or even down
to 30, such as in patients with (chronic) renal impairment of
moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59, or
even of moderate-to-severe stage having eGFR levels 30-44 (CKD
stage 3b).
[0017] Particularly, it is a need for therapies for diabetic
patients with moderate-to-severe microvascular burden, such as
advanced kidney disease.
[0018] Further, within the therapy of type 2 diabetes, it is a need
for treating the condition effectively, avoiding the (micro- and/or
macrovascular) complications inherent to the condition, and
delaying or modifying disease progression, e.g. in order to achieve
a long-lasting therapeutic benefit.
[0019] Furthermore, it remains a need that antidiabetic treatments
not only prevent and/or treat the long-term complications often
found in advanced stages of diabetes disease, but also are a
therapeutic option in those diabetes patients who have developed or
are at-risk of developing such complications (e.g. chronic kidney
disease/diabetic nephropathy, renal impairment and/or
albuminuria).
[0020] There is a need that antidiabetic treatments prevent and/or
treat preferably both microvascular (renal) complications and
macrovascular (CV) complications together, preferably within one
therapy.
[0021] There is also a need to provide a therapeutic option in
those diabetes patients who have developed or are at-risk of
developing both microvascular (renal) complications and
macrovascular (CV) complications.
[0022] Also, there is a need that antidiabetic treatments prevent
and/or treat accelerated cognitive decline (which may be associated
with micro- and/or macrovascular complications), preferably
together with both microvascular (renal) complications and
macrovascular (CV) complications, preferably within one
therapy.
[0023] Moreover, it remains a need to provide prevention or
reduction of risk for adverse effects associated with conventional
antidiabetic therapies.
SUMMARY OF THE INVENTION
[0024] The present invention relates to use of a certain DPP-4
inhibitor (preferably linagliptin) in combination with metformin
(particularly in the form of metformin hydrochloride) in CKD
(chronic kidney disease) patients, particularly in patients having
CKD up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45, or even down
to 30, such as in patients with CKD of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
such as having eGFR levels 45-59 or of moderate-to-severe stage
such as having eGFR levels 30-44 (CKD stage 3b), optionally in
combination with one or more other active substances.
[0025] The present invention relates to certain medical uses of a
combination or a pharmaceutical composition comprising a certain
DPP-4 inhibitor (preferably linagliptin) and metformin
(particularly in the form of metformin hydrochloride), such as e.g.
for treating and/or preventing metabolic diseases, especially type
2 diabetes mellitus and/or conditions related thereto (e.g.
diabetic complications), including in patients with (chronic) renal
disease, renal dysfunction or renal impairment, particularly in
patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b); optionally in combination with one or more other active
substances.
[0026] The present invention further relates to the medical use of
a combination or a pharmaceutical composition comprising a certain
DPP-4 inhibitor (preferably linagliptin) and metformin
(particularly in the form of metformin hydrochloride), for treating
and/or preventing chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or even down to 30, such
as of moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) such as having eGFR levels
45-59 or of moderate-to-severe stage such as having eGFR levels
30-44 (CKD stage 3b); optionally in combination with one or more
other active substances (such as e.g. antidiabetic and/or an
angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II
receptor blocker (ARB)).
[0027] The present invention yet further relates to a certain DPP-4
inhibitor (preferably linagliptin) in combination with metformin
(particularly in the form of metformin hydrochloride) (and
optionally in combination with one or more other active agents) for
use in therapy, prophylaxis, treatment or prevention of diabetic
(preferably type 2 diabetes) patients (preferably for use in
cardio- and/or renoprotective therapy preferably of type 2 diabetes
in human patients),
including in patients (preferably type 2 diabetes patients) with
(chronic) renal disease, renal dysfunction or renal impairment,
particularly in patients having chronic kidney disease (CKD) such
as e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45, or even down
to 30, such as in patients with (chronic) renal impairment of
moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) such as having eGFR levels
45-59 or of moderate-to-severe stage such as having eGFR levels
30-44 (CKD stage 3b); optionally in combination with one or more
other active substances.
[0028] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin) for use in combination with
metformin (particularly in the form of metformin hydrochloride),
such as e.g. such as e.g. for treating type 2 diabetes and
treating, decreasing, delaying the onset and/or delaying the
progression of diabetic nephropathy, chronic kidney disease,
albuminuria (e.g. micro- or macro-albuminuria), renal impairment,
retinopathy, neuropathy, learning or memory or cognitive impairment
or decline, neurodegenerative or cognitive disorders such as
dementia, and/or macrovascular complications such as cardio- or
cerebrovascular events such as stroke or myocardial infarction, in
patients with type 2 diabetes and micro- or macroalbuminuria, with
or without renal function impairment, such as patients with CKD
(chronic kidney disease), particularly patients having CKD up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or even down to 30, such
as patients with CKD of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) such as
having eGFR levels 45-59 or of moderate-to-severe stage such as
having eGFR levels 30-44 (CKD stage 3b), optionally in combination
with one or more other active substances.
[0029] The present invention relates to a DPP-4 inhibitor
(preferably linagliptin) in combination with metformin
(particularly in the form of metformin hydrochloride), for use in
treating and/or preventing (including slowing the progression or
delaying the onset) of metabolic diseases, particularly diabetes
(especially type 2 diabetes mellitus) and/or conditions related
thereto (e.g. diabetic complications, particularly diabetic chronic
kidney disease); including in patients with (chronic) renal
disease, renal dysfunction or renal impairment (impairment of renal
function), particularly in patients having chronic kidney disease
(CKD) such as e.g. up to stage 3 and/or having estimated glomerular
filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or
even down to 30, such as in patients with (chronic) renal
impairment of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) such as
having eGFR levels 45-59, or even of moderate-to-severe stage such
as having eGFR levels 30-44 (CKD stage 3b), with or without
residual albuminuria (micro- or macroalbuminuria), optionally in
combination with one or more other active substances.
[0030] Accordingly, the present invention further relates to a
DPP-4 inhibitor (preferably linagliptin, preferably in a daily dose
of 5 mg, administered 5 mg once daily or 2.5 mg twice daily) for
use in combination with metformin (particularly in the form of
metformin hydrochloride) in treating and/or preventing (including
slowing the progression or delaying the onset) of metabolic
diseases, particularly diabetes (especially type 2 diabetes
mellitus) and/or conditions related thereto (e.g. diabetic
complications, such as one or more selected from diabetic chronic
kidney disease, nephropathy, micro- or macroalbuminuria, renal
impairment, retinopathy, neuropathy, learning or memory or
cognitive impairment or decline, neurodegenerative or cognitive
disorders such as dementia, and/or macrovascular complications such
as cardio- or cerebrovascular events such as stroke and/or
myocardial infarction); including in patients with (chronic) renal
disease, renal dysfunction or renal impairment (impairment of renal
function), particularly in patients having chronic kidney disease
(CKD) such as e.g. up to stage 3 and/or having estimated glomerular
filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or
even down to 30, such as in patients with (chronic) renal
impairment of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) such as
having eGFR levels 45-59, or even of moderate-to-severe stage such
as having eGFR levels 30-44 (CKD stage 3b), with or without
residual albuminuria (micro- or macroalbuminuria), optionally in
combination with one or more other active substances (such as
selected from other antidiabetics and/or ACE inhibitors or ARBs),
particularly wherein the maximum daily dose of metformin
(particularly in the form of metformin hydrochloride) administered
to patients of mild-to-moderate stage (CKD stage 3a, such as having
eGFR levels 45-59) is 2000 mg, and/or particularly wherein the
maximum daily dose of metformin (particularly in the form of
metformin hydrochloride) administered to patients of
moderate-to-severe stage (CKD stage 3b, such as having eGFR levels
30-44) is 1000 mg.
[0031] Also, the present invention relates to a pharmaceutical
combination or composition comprising a DPP-4 inhibitor (preferably
linagliptin), metformin (particularly in the form of metformin
hydrochloride) and optionally one or more pharmaceutically
acceptable auxiliaries, for use in treating and/or preventing
(including slowing the progression or delaying the onset) of
metabolic diseases, particularly diabetes (especially type 2
diabetes mellitus) and/or conditions related thereto (e.g. diabetic
complications, particularly diabetic chronic kidney disease),
including in patients with (chronic) renal disease, renal
dysfunction or renal impairment (impairment of renal function),
particularly in patients having chronic kidney disease (CKD) such
as e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or even down
to 30, such as in patients with (chronic) renal impairment of
moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) such as having eGFR levels
45-59, or of moderate-to-severe stage such as having eGFR levels
30-44 (CKD stage 3b), with or without residual albuminuria (micro-
or macroalbuminuria); optionally in combination with one or more
other active substances.
[0032] Also, the present invention relates to a combination therapy
comprising using a DPP-4 inhibitor (preferably linagliptin) and
metformin (particularly in the form of metformin hydrochloride) for
treating and/or preventing (including slowing the progression or
delaying the onset) of metabolic diseases, particularly diabetes
(especially type 2 diabetes mellitus) and/or conditions related
thereto (e.g. diabetic complications, particularly diabetic chronic
kidney disease), including in patients with (chronic) renal
disease, renal dysfunction or renal impairment (impairment of renal
function), particularly in patients having chronic kidney disease
(CKD) such as e.g. up to stage 3 and/or having estimated glomerular
filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or
even down to 30, such as in patients with (chronic) renal
impairment of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) such as
having eGFR levels 45-59, or of moderate-to-severe stage such as
having eGFR levels 30-44 (CKD stage 3b), with or without residual
albuminuria (micro- or macroalbuminuria); optionally in combination
with one or more other active substances.
[0033] The present invention further relates to a certain DPP-4
inhibitor (preferably linagliptin) in combination with metformin
(particularly in the form of metformin hydrochloride), and
optionally in combination with one or more other active agents, for
use in therapy or treatment of diabetes (preferably type 2
diabetes) in (human) patients in need thereof, preferably for use
in cardio- and/or renoprotective therapy preferably of type 2
diabetes in human patients, such as e.g. including treating type 2
diabetes and/or preventing diabetic complications
such as decreasing, protecting against, delaying the onset, slowing
progression and/or reducing the risk of (cardio)vascular and/or
renal morbidity and/or mortality, such as e.g. [0034] i) treating,
preventing or delaying the progression of chronic kidney disease
(diabetic nephropathy); and/or [0035] ii) treating, decreasing,
preventing, protecting against, delaying the progression, delaying
the occurrence and/or reducing the risk of albuminuria (e.g. micro-
or macro-albuminuria) and/or renal impairment; and/or [0036] iii)
preventing, protecting against, reducing the risk of and/or
delaying the occurrence of a cardio- or cerebrovascular disease,
complication or event selected from: cardiovascular (CV) death
(including fatal stroke, fatal myocardial infarction and sudden
death), non-fatal stroke, non-fatal myocardial infarction (MI)
(silent MI may be excluded) and, optionally, hospitalization for
unstable angina pectoris; and/or [0037] iv) preventing, protecting
against, reducing the risk of, delaying the progression and/or
delaying the occurrence of a renal microvascular disease,
complication or event selected from: renal death, end-stage renal
disease and loss in estimated glomerular filtration rate (e.g. eGFR
.gtoreq.50% from baseline); and/or [0038] v) decreasing,
preventing, protecting against, delaying (e.g. occurrence or
progression) and/or reducing the risk of (accelerated) cognitive
decline or cognitive impairment or dementia; [0039] including in
patients (preferably type 2 diabetes patients) with (chronic) renal
disease, renal dysfunction or renal impairment, particularly in
patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b); optionally in combination with one or more other active
substances; wherein such patients may be with or at-risk of further
(major) (micro- and/or macro-)vascular diseases, complications or
events, e.g. such patients may be at high vascular risk.
[0040] Other aspects of the present invention become apparent to
the skilled person from the foregoing and following remarks
(including the examples and claims).
DETAILED DESCRIPTION OF THE INVENTION
[0041] Within the scope of the present invention it has now been
found that certain DPP-4 inhibitors as defined herein as well as
combinations or pharmaceutical compositions of these DPP-4
inhibitors with metformin (particularly in the form of metformin
hydrochloride) as well as their use have particularly useful
properties or effects, which make them suitable for the purpose of
this invention and/or for fulfilling one or more of the needs
mentioned herein.
[0042] For example, combinations or pharmaceutical compositions of
these DPP-4 inhibitors with metformin (particularly in the form of
metformin hydrochloride) are useful for improving glycemic control
and/or for treating and/or preventing (including slowing the
progression or delaying the onset) of metabolic diseases,
particularly diabetes (especially type 2 diabetes mellitus) and/or
conditions related thereto (e.g. diabetic complications,
particularly diabetic chronic kidney disease, or diabetic
nephropathy, micro-or macroalbuminuria and/or renal impairment),
such as in drug naive type 2 diabetes patients and/or in patients
with advanced or late stage type 2 diabetes, including patients
with insufficient glycemic control despite a therapy with an oral
and/or a non-oral antidiabetic or antihyperglycemic drug and/or
with indication on insulin; including in patients with (chronic)
renal disease, renal dysfunction or renal impairment, particularly
in patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59, or even of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b), with or without residual albuminuria, especially
including in patients with (chronic) renal impairment of
mild-to-moderate stage (CKD stage 3a) such as having estimated
glomerular filtration rate [eGFR] 45-59 mL/minute/1.73 m.sup.2 or
creatinine clearance [CrCl] 45-59 mL/min, optionally in combination
with one or more other active substances.
[0043] For example, patients having chronic kidney disease (CKD)
such as e.g. up to stage 3 and/or having estimated glomerular
filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or
even down to 30 are amenable to the combination therapy according
to the present invention comprising using linagliptin (in a total
daily dose of 5 mg) in combination with metformin (e.g. up to
maximum total daily dose of 1000 mg metformin hydrochloride (such
as e.g. for CKD 3a patients) or 2000 mg metformin hydrochloride
(such as e.g. for CKD 3b patients)), preferably using a tablet
containing 2.5 mg linagliptin and 500 mg, 850 mg or 1000 mg
metformin hydrochloride (in immediate release form) each
administered twice daily, or using a tablet containing 5 mg
linagliptin and 1000 mg metformin hydrochloride (in extended
release form) administered once daily, or using a tablet containing
2.5 mg linagliptin and 750 mg or 1000 mg metformin hydrochloride
(in extended release form) each administered as two tablets once
daily.
[0044] In an embodiment, the maximum daily dose of metformin
(particularly in the form of metformin hydrochloride) administered
to patients of mild-to-moderate stage (CKD stage 3a, such as having
eGFR levels 45-59) may be 2000 mg, which may be given as two
divided doses, such as e.g. 1000 mg twice daily; (the starting dose
may be at most half of the maximum dose).
[0045] In an embodiment, the maximum daily dose of metformin
(particularly in the form of metformin hydrochloride) administered
to patients of moderate-to-severe stage (CKD stage 3b, such as
having eGFR levels 30-44) may be 1000 mg, which may be given as two
divided doses, such as e.g. 500 mg twice daily; (the starting dose
may be at most half of the maximum dose).
[0046] For patients with severe or very severe stage of renal
impairment (CKD stage 4, such as having eGFR levels <30; or CKD
stage 5, such as having eGFR levels <15, end-stage renal
disease), metformin is contraindicated.
[0047] The combination therapy according to the present invention
using linagliptin (in a total daily dose of 5 mg) in combination
with metformin is also useful for patients in need of >1000 mg
metformin daily (e.g. 850 mg or 1000 mg metformin hydrochloride
BID) for sufficient glycemic control and having chronic kidney
disease (CKD), such as e.g. up to stage 3 and/or having estimated
glomerular filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels
down to 45 (or, in certain instances, even down to 30); preferably
by using a tablet containing 2.5 mg linagliptin and 850 mg or 1000
mg metformin hydrochloride (in immediate release form) each
administered twice daily, or using a tablet containing 2.5 mg
linagliptin and 750 mg or 1000 mg metformin hydrochloride (in
extended release form) each administered as two tablets once
daily.
[0048] For further example, patients in need of >1000 mg
metformin daily (e.g. 1000 mg metformin hydrochloride BID) for
sufficient glycemic control but with dose limitation for metformin
due to renal impairment (e.g. maximum total daily dose of 1000 mg
metformin hydrochloride), such as having moderate renal impairment,
e.g., in certain instances, patients with (chronic) renal
impairment of mild-to-moderate stage (CKD stage 3a) such as having
eGFR levels 45-59 mL/minute/1.73 m.sup.2, or especially of
moderate-to-severe stage (CKD stage 3b) such as having eGFR levels
30-44 mL/minute/1.73 m.sup.2, benefit from the combination therapy
according to the present invention comprising using linagliptin (in
a total daily dose of 5 mg) in combination with metformin (e.g. up
to maximum total daily dose of 1000 mg metformin hydrochloride),
preferably using a tablet containing 2.5 mg linagliptin and 500 mg
metformin hydrochloride, administered twice daily.
[0049] Accordingly, patients with dose limitation for metformin due
to renal impairment (e.g. maximum total daily dose of 2000 mg
metformin hydrochloride), e.g. with (chronic) renal impairment of
mild-to-moderate stage (CKD stage 3a) such as having eGFR levels
45-59 mL/minute/1.73 m.sup.2, benefit from the combination therapy
according to the present invention comprising using linagliptin (in
a total daily dose of 5 mg) in combination with metformin (e.g. up
to maximum total daily dose of 2000 mg metformin hydrochloride),
preferably using a tablet containing 2.5 mg linagliptin and 1000 mg
metformin hydrochloride, administered twice daily.
[0050] Accordingly, patients with dose limitation for metformin due
to renal impairment (e.g. maximum total daily dose of 1000 mg
metformin hydrochloride), e.g. with (chronic) renal impairment of
moderate-to-severe stage (CKD stage 3b) such as having eGFR levels
30-44 mL/minute/1.73 m.sup.2, benefit from the combination therapy
according to the present invention comprising using linagliptin (in
a total daily dose of 5 mg) in combination with metformin (e.g. up
to maximum total daily dose of 1000 mg metformin hydrochloride),
preferably using a tablet containing 2.5 mg linagliptin and 500 mg
metformin hydrochloride, administered twice daily.
[0051] In an embodiment, patients on linagliptin (in a total daily
dose of 5 mg) in combination with metformin (up to maximum total
daily dose of 2000 mg metformin hydrochloride), using a tablet
containing 2.5 mg linagliptin and 850 mg, administered twice daily,
or a tablet containing 2.5 mg linagliptin and 1000 mg metformin
hydrochloride, administered twice daily, can maintain these
treatments until they reach an eGFR of 45 mL/min/1.73 m.sup.2 (this
would not be the case for patients using another major DPP-4
inhibitor (gliptin) other than linagliptin, requiring dose
adjustment of the DPP-4 inhibitor component leading to change in
the treatment scheme, except for linagliptin).
[0052] In a further embodiment, patients with an eGFR between 45
and 59 mL/min/1.73 m.sup.2 (CKD stage 3a) already on the maximum
dose of metformin (e.g. maximum total daily dose of 2000 mg
metformin hydrochloride) can use linagliptin (in a total daily dose
of 5 mg) in combination with metformin (e.g. maximum total daily
dose of 2000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 1000 mg metformin hydrochloride,
administered twice daily, when additional therapy is deemed
necessary.
[0053] In a further embodiment, patients on linagliptin (in a total
daily dose of 5 mg) in combination with metformin (e.g. up to
maximum total daily dose of 1000 mg metformin hydrochloride), using
a tablet containing 2.5 mg linagliptin and 500 mg, administered
twice daily, can maintain these treatments until they reach an eGFR
of 30 mL/min/1.73 m.sup.2 (this would not be the case for patients
using another major DPP-4 inhibitor (gliptin) other than
linagliptin, requiring dose adjustment of the DPP-4 inhibitor
component leading to change in the treatment scheme, except for
linagliptin).
[0054] In a further embodiment, patients with an eGFR between 30
and 44 mL/min/1.73 m.sup.2 (CKD stage 3b) already on the maximum
dose of metformin (e.g. maximum total daily dose of 1000 mg
metformin hydrochloride) can use linagliptin (in a total daily dose
of 5 mg) in combination with metformin (e.g. maximum total daily
dose of 1000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 500 mg metformin hydrochloride,
administered twice daily, when additional therapy is deemed
necessary.
[0055] In a yet further embodiment, patients with an eGFR between
45 and 59 mL/min/1.73 m.sup.2 (CKD stage 3a) who are not receiving
metformin can up-titrate to the maximum dose of metformin (e.g. up
to maximum total daily dose of 2000 mg metformin hydrochloride) and
can then start to use linagliptin (in a total daily dose of 5 mg)
in combination with metformin (e.g. up to maximum total daily dose
of 2000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 850 mg or 1000 mg metformin
hydrochloride, administered twice daily.
[0056] In a yet further embodiment, patients with an eGFR between
30 and 44 mL/min/1.73 m.sup.2 (CKD stage 3b) who are not receiving
metformin can up-titrate to the maximum dose of metformin (e.g. up
to maximum total daily dose of 1000 mg metformin hydrochloride) and
can then start to use linagliptin (in a total daily dose of 5 mg)
in combination with metformin (e.g. up to maximum total daily dose
of 1000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 500 mg metformin hydrochloride,
administered twice daily.
[0057] In a still yet further embodiment, patients with an eGFR
between 45 and 59 mL/min/1.73 m.sup.2 (CKD stage 3a) who are not
receiving metformin can use linagliptin (in a total daily dose of 5
mg) in combination with metformin (e.g. up to maximum total daily
dose of 2000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 850 mg or 1000 mg metformin
hydrochloride, administered twice daily, to start treatment.
[0058] In a still yet further embodiment, patients with an eGFR
between 30 and 44 mL/min/1.73 m.sup.2 (CKD stage 3b) who are not
receiving metformin can use linagliptin (in a total daily dose of 5
mg) in combination with metformin (e.g. up to maximum total daily
dose of 1000 mg metformin hydrochloride), preferably using a tablet
containing 2.5 mg linagliptin and 500 mg metformin hydrochloride,
administered twice daily, to start treatment.
[0059] It has been found that 2.5 mg linagliptin/500 mg metformin
hydrochloride BID combination therapy is at least as effective as
1000 mg metformin BID monotherapy, thereby offering an alternative
for patients intolerant to such high dose of metformin or with dose
limit for metformin due to renal impairment.
[0060] The combination therapy according to this invention using a
DPP-4 inhibitor (particularly linagliptin) and metformin (e.g. 2.5
mg linagliptin/500 mg metformin hydrochloride BID) is more
effective for patients with (chronic) renal impairment, such as of
mild-to-moderate stage (CKD stage 3a) or even of moderate-to-severe
stage (CKD stage 3b), than metformin alone.
[0061] Accordingly, a particular embodiment of the combination
therapy according to the present invention for patients with
(chronic) renal impairment (CKD) relates to 2.5 mg linagliptin/500
mg metformin hydrochloride BID.
[0062] A more particular embodiment of the combination therapy
according to the present invention relates to 2.5 mg
linagliptin/500 mg metformin hydrochloride administered twice daily
to patients with (chronic) renal impairment of moderate-to-severe
stage such as having eGFR levels 30-44 (CKD stage 3b).
[0063] Further, the combination therapy according to this invention
using a DPP-4 inhibitor (particularly linagliptin) and metformin
(optionally in combination with one or more further active agents)
has beneficial potential on cardio-renal morbidity and/or mortality
(cardio-and/or renoprotection) in diabetic kidney disease patients
as described herein (especially in type 2 diabetes patients with
advanced CKD and/or over long-term treatment):
[0064] For example, the combination therapy according to the
present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0065] i) prevents, protects against,
reduces the risk of and/or delays the occurrence of a cardio- or
cerebrovascular disease, complication or event selected from:
cardiovascular (CV) death (including fatal stroke, fatal myocardial
infarction and sudden death), non-fatal stroke, non-fatal
myocardial infarction (MI) (silent MI may be excluded) and,
optionally, hospitalisation for unstable angina pectoris; and/or
[0066] ii) prevents, protects against, reduces the risk of, delays
the progression and/or delays the occurrence of a renal
microvascular disease, complication or event selected from: renal
death, end-stage renal disease and loss in estimated glomerular
filtration rate (e.g. eGFR .gtoreq.50% from baseline).
[0067] For further example, the combination therapy according to
the present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0068] i) prevents, protects against,
reduces the risk of, delays the progression and/or delays the
occurrence of a renal microvascular disease, complication or event
selected from: renal death, end-stage renal disease and loss in
estimated glomerular filtration rate (e.g. eGFR .gtoreq.50% from
baseline).
[0069] For yet further example, the combination therapy according
to the present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0070] i) decreases, prevents, protects
against, delays (e.g. occurrence or progression) and/or reduces the
risk of (accelerated) cognitive decline or cognitive impairment or
dementia.
[0071] For yet further example, the combination therapy according
to the present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0072] i) treats, decreases, prevents,
protects against, delays (e.g. occurrence or progression) and/or
reduces the risk of diabetic nephropathy.
[0073] For yet further example, the combination therapy according
to the present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0074] i) treats, decreases, prevents,
protects against, delays (e.g. occurrence or progression) and/or
reduces the risk of albuminuria (e.g. micro- or
macroalbuminuria).
[0075] For yet further example, the combination therapy according
to the present invention using a DPP-4 inhibitor (particularly
linagliptin) and metformin (optionally in combination with one or
more further active agents) [0076] i) treats, decreases, prevents,
protects against, delays (e.g. occurrence or progression) and/or
reduces the risk of renal impairment.
[0077] Accordingly, a combination therapy according to the present
invention using a DPP-4 inhibitor (particularly linagliptin) and
metformin is particularly useful for treating and/or preventing
(including delaying the onset or slowing the progression) of
metabolic diseases, particularly diabetes (especially type 2
diabetes mellitus) and/or conditions related thereto (e.g. diabetic
complications, particularly diabetic chronic kidney disease, or
diabetic nephropathy, micro-or macroalbuminuria and/or renal
impairment), in patients with (chronic) renal disease, renal
dysfunction or renal impairment, particularly in patients having
chronic kidney disease (CKD) such as e.g. up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as in patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
such as having eGFR levels 45-59, or even of moderate-to-severe
stage such as having eGFR levels 30-44 (CKD stage 3b), with or
without albuminuria, especially including in patients with
(chronic) renal impairment of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59; [0078] optionally in combination with one
or more other active substances, such as e.g. any of those
mentioned herein, [0079] such as e.g. optionally in combination
with one or more other antidiabetics such as selected from a
sulphonylurea, a thiazolidinedione (e.g. pioglitazone), a glinide,
an alpha-glucosidase blocker, GLP-1 or a GLP-1 analogue, and
insulin or an insulin analogue, and/or an angiotensin converting
enzyme (ACE) inhibitor or an angiotensin receptor blocker
(ARB).
[0080] Further, the combination therapy according to the present
invention using a DPP-4 inhibitor (particularly linagliptin) and
metformin is particularly useful for treating and/or preventing
(including delaying the onset or slowing the progression) of renal
microvascular disease, such as selected from (diabetic) chronic
kidney disease (CKD), diabetic nephropathy, albuminuria (e.g.
micro- or macro-albuminuria), renal impairment, renal death,
end-stage renal disease and/or loss in estimated glomerular
filtration rate (e.g. eGFR>=50% from baseline), in patients
(particularly in type 2 diabetes patients) with (chronic) renal
disease, renal dysfunction or renal impairment, particularly in
patients having chronic kidney disease
[0081] (CKD, particularly advanced CKD), such as e.g. up to stage 3
and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59, or even of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b), with or without albuminuria, especially including in
patients with (chronic) renal impairment of mild-to-moderate stage
(CKD stage 3a) having eGFR levels 45-59; optionally in combination
with one or more other active substances, such as e.g. any of those
mentioned herein,
such as e.g. optionally in combination with one or more other
antidiabetics such as selected from a sulphonylurea, a
thiazolidinedione (e.g. pioglitazone), a glinide, an
alpha-glucosidase blocker, GLP-1 or a GLP-1 analogue, and insulin
or an insulin analogue, and/or an angiotensin converting enzyme
(ACE) inhibitor or an angiotensin receptor blocker (ARB);
particularly over long-term treatment.
[0082] An embodiment of patients with (chronic) renal impairment
(CKD) as described herein relates to type 2 diabetes patients
having impaired renal function such as indicated herein with micro-
or macroalbuminuria (e.g. urine albumin creatinine ratio (UACR)
30-3000 mg/g creatinine).
[0083] Another embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having impaired renal function such as indicated herein
without micro- or macroalbuminuria (e.g. urine albumin creatinine
ratio (UACR) 30-3000 mg/g creatinine).
[0084] A sub-embodiment of patients with (chronic) renal impairment
(CKD) as described herein relates to type 2 diabetes patients
having impaired renal function of moderate-to-severe stage (CKD 3b)
with any albuminuria (e.g. urine albumin creatinine ratio (UACR)
>=30 mg/g creatinine).
[0085] Another sub-embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having impaired renal function of up to mild-to-moderate
stage (CKD 3a) with macro-albuminuria (e.g. urine albumin
creatinine ratio (UACR) >200 mg/g creatinine).
[0086] A further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients at early stages of prevalent renal microvascular
complications, such as e.g. having microalbuminuria (e.g. 30-200 or
30-300 mg/g creatinine) and/or early impaired renal function (eGFR,
and/or early CKD stage).
[0087] Another further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients at advanced stages of prevalent renal microvascular
complications, such as e.g. having macroalbuminuria (e.g. >200
or >300 mg/g creatinine) and/or advanced impaired renal function
(eGFR, and/or advanced CKD stage).
[0088] A further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having micro- or macroalbuminuria; optionally with or
without renal function impairment.
[0089] A yet further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having microalbuminuria, with renal function
impairment.
[0090] A yet further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having macroalbuminuria, with renal function
impairment.
[0091] A further embodiment of patients with (chronic) renal
impairment (CKD) as described herein relates to type 2 diabetes
patients having impaired renal function such as indicated herein,
with or without micro- or macroalbuminuria, and having a previous
macrovascular disease (e.g. myocardial infarction, coronary artery
disease, stroke, carotid artery disease or peripheral artery
disease).
[0092] In a further embodiment, the patients as described herein
are treated with a DPP-4 inhibitor (particularly linagliptin) and
metformin (particularly in the form of metformin hydrochloride) on
top of or in add-on combination with one or more other
(conventional) antidiabetics and/or an angiotensin converting
enzyme (ACE) inhibitor or an angiotensin receptor blocker
(ARB).
[0093] In a further embodiment, the patients as described herein
may be with or at-risk of further (major) (micro- and/or
macro-)vascular diseases, complications or events, such as e.g.
such patients may be at high vascular risk.
[0094] For example, such patients at high vascular risk may have:
[0095] both [0096] albuminuria (e.g. micro- or macro-albuminuria)
[0097] and [0098] previous macrovascular (e.g. cardio- or
cerebrovascular) disease (such as e.g. myocardial infarction,
coronary artery disease, (ischemic or haemorrhagic) stroke, carotid
artery disease and/or peripheral artery disease), [0099] and/or
[0100] either [0101] (mild or moderate) renal impairment (e.g. CKD
stage 1, 2 or 3, such as CKD stage 1, 2 (mild) or 3a
(mild-moderate), preferably eGFR .gtoreq.45-75 mL/min/1.73 m.sup.2)
with macro-albuminuria, [0102] or (moderate [or severe]) renal
impairment (e.g. CKD stage 3 [or 4], such as CKD stage 3b
(moderate-severe) [or 4 (severe), preferably eGFR 15-45 mL/min/1.73
m.sup.2]), with or without any albuminuria (such as e.g. with or
without micro- or macro-albuminuria).
[0103] In more detail, such a patient at high vascular risk (e.g.
at high risk of CV events) may be a patient (preferably diabetic,
particularly type 2 diabetes patients) as follows: [0104] with
[0105] albuminuria (such as e.g. urine albumin creatinine ratio
(UACR) 30 mg/g creatinine or .gtoreq.30 mg/l (milligram albumin per
liter of urine) or .gtoreq.30 .mu.g/min (microgram albumin per
minute) or .gtoreq.30 mg/24 h (milligram albumin per 24 hours)) and
[0106] previous macrovascular disease, such as e.g. defined as one
or more of a) to f): [0107] a) previous myocardial infarction,
[0108] b) advanced coronary artery disease, [0109] c) high-risk
single-vessel coronary artery disease, [0110] d) previous ischemic
or haemorrhagic stroke, [0111] e) presence of carotid artery
disease, [0112] f) presence of peripheral artery disease, [0113]
and/or [0114] with [0115] impaired renal function (e.g. with or
without CV co-morbidities), such as e.g. defined by: [0116]
impaired renal function (e.g. as defined by MDRD formula) with an
eGFR [15 or] 30-45 mL/min/1.73 m.sup.2 with any urine albumin
creatinine ratio (UACR), and/or [0117] impaired renal function
(e.g. as defined by MDRD formula) with an eGFR .gtoreq.45-75 [0118]
mL/min/1.73 m.sup.2 with an urine albumin creatinine ratio (UACR)
>200 mg/g creatinine or >200 mg/l (milligram albumin per
liter of urine) or >200 .mu.g/min (microgram albumin per minute)
or >200 mg/24 h (milligram albumin per 24 hours).
[0119] The present invention relates to a combination or a
pharmaceutical composition comprising a certain DPP-4 inhibitor
(particularly linagliptin) and metformin (particularly in the form
of metformin hydrochloride) such as for simultaneous, separate or
sequential use in the therapies or treatments described herein.
[0120] The present invention also relates to a fixed or free
combination or pharmaceutical composition comprising, consisting
essentially of or made of a certain DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride) each as defined herein, and optionally one or more
pharmaceutically acceptable auxiliaries (such as e.g. including
excipients, stabilizers, carriers or the like), for medical uses as
described herein, such as e.g. for improving glycemic control
and/or for use in treating and/or preventing (including slowing the
progression and/or delaying the onset) of metabolic diseases,
especially type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications, such as e.g. diabetic chronic
kidney disease, diabetic nephropathy, micro-or macroalbuminuria,
renal impairment, diabetic retinopathy and/or diabetic neuropathy,
and/or a macrovascular complication), such as e.g. [0121] either as
first line therapy, i.e. in type 2 diabetes patients who have not
previously treated with an antihyperglycemic agent (drug-naive
patients), [0122] or as second or third line therapy, i.e. in type
2 diabetes patients with insufficient glycemic control despite
therapy with one or two conventional antihyperglycemic agents
selected from metformin, sulphonylureas, thiazolidinediones (e.g.
pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or GLP-1
analogues, and insulin or insulin analogues; [0123] including in
patients with (chronic) renal disease, renal dysfunction or renal
impairment, particularly in patients having chronic kidney disease
(CKD) such as e.g. up to stage 3 and/or having estimated glomerular
filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or
even down to 30, such as in patients with (chronic) renal
impairment of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) such as
having eGFR levels 45-59, or even of moderate-to-severe stage such
as having eGFR levels 30-44 (CKD stage 3b); [0124] optionally in
combination with one or more other active substances, such as e.g.
any of those mentioned herein, [0125] such as e.g. optionally in
combination with one conventional antihyperglycemic agent selected
from sulphonylureas, thiazolidinediones (e.g. pioglitazone),
glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and
insulin or insulin analogues, and/or angiotensin converting enzyme
(ACE) inhibitors or an angiotensin receptor blockers (ARBs).
[0126] The present invention also relates to medical uses as
described herein of a pharmaceutical composition comprising a fixed
dose combination formulation of a DPP-4 inhibitor and metformin
(particularly in the form of metformin hydrochloride) and
optionally one or more pharmaceutically acceptable auxiliaries.
[0127] In one embodiment, the present invention also relates to a
fixed or free combination or pharmaceutical composition comprising
or consisting essentially of a DPP-4 inhibitor (particularly
linagliptin), metformin (particularly in the form of metformin
hydrochloride) and optionally one or more pharmaceutically
acceptable auxiliaries, for use in treating and/or preventing
(including slowing the progression and/or delaying the onset) of
metabolic diseases, especially type 2 diabetes mellitus and/or
conditions related thereto (e.g. diabetic complications), such as
e.g. [0128] either as first line therapy, i.e. in type 2 diabetes
patients who have not previously treated with an antihyperglycemic
agent (drug-naive patients), [0129] or as second or third line
therapy, i.e. in type 2 diabetes patients with insufficient
glycemic control despite therapy with one or two conventional
antihyperglycemic agents selected from metformin, sulphonylureas,
thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 or
GLP-1 analogues, and insulin or insulin analogues; [0130] including
in patients with (chronic) renal disease, renal dysfunction or
renal impairment, particularly in patients having chronic kidney
disease (CKD) such as e.g. up to stage 3 and/or having estimated
glomerular filtration rate (eGFR; mL/minute/1.73 m.sup.2) levels
down to 45 or even down to 30, such as in patients with (chronic)
renal impairment of moderate stage (CKD stage 3, eGFR 30-60),
particularly of mild-to-moderate stage (CKD stage 3a) having eGFR
levels 45-59, or even of moderate-to-severe stage having eGFR
levels 30-44 (CKD stage 3b); [0131] optionally in combination with
one or more other active substances, [0132] such as e.g. optionally
in combination with one or more other antidiabetics such as
selected from sulphonylureas, thiazolidinediones (e.g.
pioglitazone), glinides, alpha-glucosidase blockers, GLP-1 or GLP-1
analogues, and insulin or insulin analogues, and/or an angiotensin
converting enzyme (ACE) inhibitor or an angiotensin receptor
blocker (ARB).
[0133] In a particular embodiment, the present invention relates to
a combination or pharmaceutical composition comprising a DPP-4
inhibitor (particularly linagliptin), metformin (particularly in
the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for use in treating and/or
preventing (including slowing the progression and/or delaying the
onset) of metabolic diseases, especially type 2 diabetes mellitus
and/or conditions related thereto (e.g. diabetic complications,
such as e.g. diabetic chronic kidney disease, diabetic nephropathy,
micro-or macroalbuminuria, renal impairment, diabetic retinopathy
and/or diabetic neuropathy, and/or a macrovascular complication
such as a cardio- or cerebrovascular event), in type 2 diabetes
patients with insufficient glycemic control despite mono-therapy
with metformin; [0134] wherein the patients have (chronic) renal
disease, renal dysfunction or renal impairment, particularly in
patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) having eGFR levels 45-59, or even of
moderate-to-severe stage having eGFR levels 30-44 (CKD stage
3b).
[0135] In another particular embodiment, the present invention also
relates to a combination or pharmaceutical composition comprising a
DPP-4 inhibitor (particularly linagliptin), metformin (particularly
in the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for use in combination
with a sulphonylurea in treating and/or preventing (including
slowing the progression and/or delaying the onset) of metabolic
diseases, especially type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications, such as e.g. diabetic
chronic kidney disease, diabetic nephropathy, micro-or
macroalbuminuria, renal impairment, diabetic retinopathy and/or
diabetic neuropathy, and/or a macrovascular complication such as a
cardio- or cerebrovascular event), in type 2 diabetes patients with
insufficient glycemic control despite dual combination therapy with
metformin and a sulphonylurea; [0136] wherein the patients have
(chronic) renal disease, renal dysfunction or renal impairment,
particularly patients having chronic kidney disease (CKD) such as
e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or even down
to 30, such as patients with (chronic) renal impairment of moderate
stage (CKD stage 3, eGFR 30-60), particularly of mild-to-moderate
stage (CKD stage 3a) having eGFR levels 45-59 or even of
moderate-to-severe stage having eGFR levels 30-44 (CKD stage
3b).
[0137] In another particular embodiment, the present invention also
relates to a combination or pharmaceutical composition comprising a
DPP-4 inhibitor (particularly linagliptin), metformin (particularly
in the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for use in combination
with a thiazolidinedione (e.g. pioglitazone) in treating and/or
preventing (including slowing the progression and/or delaying the
onset) of metabolic diseases, especially type 2 diabetes mellitus
and/or conditions related thereto (e.g. diabetic complications,
such as e.g. diabetic chronic kidney disease, diabetic nephropathy,
micro-or macroalbuminuria, renal impairment, diabetic retinopathy
and/or diabetic neuropathy, and/or a macrovascular complication
such as a cardio- or cerebrovascular event), in type 2 diabetes
patients with insufficient glycemic control despite dual
combination therapy with metformin and a thiazolidinedione (e.g.
pioglitazone); wherein the patients have (chronic) renal disease,
renal dysfunction or renal impairment, particularly patients having
chronic kidney disease (CKD) such as, e.g., up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59 or even of moderate-to-severe stage having
eGFR levels 30-44 (CKD stage 3b).
[0138] In another particular embodiment, the present invention also
relates to a combination or pharmaceutical composition comprising a
DPP-4 inhibitor (particularly linagliptin), metformin (particularly
in the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for use in combination
with an insulin (e.g. basal insulin) in treating and/or preventing
(including slowing the progression and/or delaying the onset) of
metabolic diseases, especially type 2 diabetes mellitus and/or
conditions related thereto (e.g. diabetic complications, such as
e.g. diabetic chronic kidney disease, diabetic nephropathy,
micro-or macroalbuminuria, renal impairment, diabetic retinopathy
and/or diabetic neuropathy, and/or a macrovascular complication
such as a cardio- or cerebrovascular event), in type 2 diabetes
patients with insufficient glycemic control despite dual
combination therapy with metformin and an insulin (e.g. basal
insulin); [0139] wherein the patients have (chronic) renal disease,
renal dysfunction or renal impairment, particularly patients having
chronic kidney disease (CKD) such as e.g. up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59 or even of moderate-to-severe stage having
eGFR levels 30-44 (CKD stage 3b).
[0140] In another particular embodiment, the present invention also
relates to a combination or pharmaceutical composition comprising a
DPP-4 inhibitor (particularly linagliptin), metformin (particularly
in the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for use in treating and/or
preventing (including slowing the progression and/or delaying the
onset) of metabolic diseases, especially type 2 diabetes mellitus
and/or conditions related thereto (e.g. diabetic complications), in
drug-naive type 2 diabetes patients (e.g. as first line therapy),
such as e.g. as early or initial combination therapy; [0141]
wherein the patients have (chronic) renal disease, renal
dysfunction or renal impairment, particularly patients having
chronic kidney disease (CKD) such as, e.g., up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59 or even of moderate-to-severe stage having
eGFR levels 30-44 (CKD stage 3b).
[0142] The present invention further provides the use of a
combination or pharmaceutical composition comprising a DPP-4
inhibitor (particularly linagliptin), metformin (particularly in
the form of metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, for the manufacture of a
medicament for treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), e.g. as first, second or
third line therapy as described herein, including in the patients
as described herein.
[0143] The present invention further relates to a pharmaceutical
package comprising a pharmaceutical composition as defined herein
and optionally instructions for its use, optionally in combination
with one or more other active substances, in the treatment and/or
prevention of metabolic diseases, particularly type 2 diabetes
mellitus and/or conditions related thereto (e.g. diabetic
complications), such as e.g. in drug-naive patients or in patients
with insufficient glycemic control despite therapy with one or two
conventional antihyperglycemic agents selected from metformin,
sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase
blockers, GLP-1 or GLP-1 analogues, and insulin or insulin
analogues; preferably in patients with (chronic) renal disease,
renal dysfunction or renal impairment, particularly in patients
having chronic kidney disease (CKD) such as, e.g., up to stage 3
and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59, or even of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b).
[0144] The present invention further relates to a medicament for
use in the treatment and/or prevention of metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), such as e.g. in drug-naive
patients or in patients with insufficient glycemic control despite
therapy with one or two conventional antihyperglycemic agents
selected from metformin, sulphonylureas, thiazolidinediones,
glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and
insulin or insulin analogues; preferably in patients with (chronic)
renal disease, renal dysfunction or renal impairment, particularly
in patients having chronic kidney disease (CKD) such as, e.g., to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59, or even of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b); said medicament comprising a pharmaceutical composition
comprising a DPP-4 inhibitor (particularly linagliptin), metformin
(particularly in the form of metformin hydrochloride) and
optionally one or more pharmaceutically acceptable auxiliaries;
optionally in combination with one or more other active substances,
such as e.g. any of those mentioned herein, such as e.g. for
separate, sequential, simultaneous, concurrent or chronologically
staggered use of the active ingredients.
[0145] The present invention further provides a method of treating
and/or preventing metabolic diseases, particularly type 2 diabetes
mellitus and/or conditions related thereto (e.g. diabetic
complications), such as e.g. in drug-naive patients (e.g. as first
line therapy) or in patients with insufficient glycemic control
despite therapy with one or two conventional antihyperglycemic
agents selected from metformin, sulphonylureas, thiazolidinediones,
glinides, alpha-glucosidase blockers, GLP-1 or GLP-1 analogues, and
insulin or insulin analogues (e.g. as second or third line
therapy); preferably in patients with (chronic) renal disease,
renal dysfunction or renal impairment, particularly in patients
having chronic kidney disease (CKD) such as e.g. up to stage 3
and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59, or even of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b); said method comprising administering to a subject in
need thereof (particularly a human patient) an effective amount of
a pharmaceutically composition comprising a DPP-4 inhibitor
(particularly linagliptin), metformin (particularly in the form of
metformin hydrochloride) and optionally one or more
pharmaceutically acceptable auxiliaries, optionally alone or in
combination, such as e.g. separately, sequentially, simultaneously,
concurrently or chronologically staggered, with an effective amount
of one or more other active substances, such as e.g. any of those
mentioned herein.
[0146] In a particular embodiment, the present invention provides a
method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in drug-naive patients (e.g.
as first line therapy); including in patients with (chronic) renal
disease, renal dysfunction or renal impairment, particularly in
patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) having eGFR levels 45-59, or even of
moderate-to-severe stage having eGFR levels 30-44 (CKD stage 3b);
said method comprising administering to a subject in need thereof
(particularly a human patient) an effective amount of a
pharmaceutically composition of a DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride) such as described herein.
[0147] In another particular embodiment, the present invention
provides a method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in patients with
insufficient glycemic control despite mono-therapy with metformin
(e.g. as second line therapy); including in patients with (chronic)
renal disease, renal dysfunction or renal impairment, particularly
in patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45 or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) having eGFR levels 45-59, or even of
moderate-to-severe stage having eGFR levels 30-44 (CKD stage 3b);
said method comprising administering to a subject in need thereof
(particularly a human patient) an effective amount of a
pharmaceutically composition of a DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride) such as described herein.
[0148] In another particular embodiment, the present invention
provides a method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in patients with
insufficient glycemic control despite dual combination therapy with
metformin and a thiazolidinedione (e.g. as third line therapy);
including in patients with (chronic) renal disease, renal
dysfunction or renal impairment, particularly in patients having
chronic kidney disease (CKD) such as e.g. up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as in patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59, or even of moderate-to-severe stage
having eGFR levels 30-44 (CKD stage 3b); said method comprising
administering to a subject in need thereof (particularly a human
patient) an effective amount of a pharmaceutically composition of a
DPP-4 inhibitor (particularly linagliptin) and metformin
(particularly in the form of metformin hydrochloride) such as
described herein, and a thiazolidinedione.
[0149] In another particular embodiment, the present invention
provides a method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in patients with
insufficient glycemic control despite dual combination therapy with
metformin and a sulphonylurea (e.g. as third line therapy);
including in patients with (chronic) renal disease, renal
dysfunction or renal impairment, particularly in patients having
chronic kidney disease (CKD) such as e.g. up to stage 3 and/or
having estimated glomerular filtration rate (eGFR; mL/minute/1.73
m.sup.2) levels down to 45 or even down to 30, such as in patients
with (chronic) renal impairment of moderate stage (CKD stage 3,
eGFR 30-60), particularly of mild-to-moderate stage (CKD stage 3a)
having eGFR levels 45-59, or even of moderate-to-severe stage
having eGFR levels 30-44 (CKD stage 3b); said method comprising
administering to a subject in need thereof (particularly a human
patient) an effective amount of a pharmaceutically composition of a
DPP-4 inhibitor (particularly linagliptin) and metformin
(particularly in the form of metformin hydrochloride) such as
described herein, and a sulphonylurea.
[0150] In a further embodiment, the present invention provides a
method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in patients with
insufficient glycemic control despite dual combination therapy with
metformin and insulin or insulin analog; including in patients with
(chronic) renal disease, renal dysfunction or renal impairment,
particularly in patients having chronic kidney disease (CKD) such
as e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or even down
to 30, such as in patients with (chronic) renal impairment of
moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59, or
even of moderate-to-severe stage having eGFR levels 30-44 (CKD
stage 3b); said method comprising administering to a subject in
need thereof (particularly a human patient) an effective amount of
a pharmaceutically composition of a DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride) such as described herein, and insulin or insulin
analog.
[0151] In a further embodiment, the present invention provides a
method of treating and/or preventing metabolic diseases,
particularly type 2 diabetes mellitus and/or conditions related
thereto (e.g. diabetic complications), in patients treated with
insulin or insulin analog; [0152] including in patients with
(chronic) renal disease, renal dysfunction or renal impairment,
particularly in patients having chronic kidney disease (CKD) such
as e.g. up to stage 3 and/or having estimated glomerular filtration
rate (eGFR; mL/minute/1.73 m.sup.2) levels down to 45 or even down
to 30, such as in patients with (chronic) renal impairment of
moderate stage (CKD stage 3, eGFR 30-60), particularly of
mild-to-moderate stage (CKD stage 3a) having eGFR levels 45-59, or
even of moderate-to-severe stage having eGFR levels 30-44 (CKD
stage 3b); said method comprising administering to a subject in
need thereof (particularly a human patient) an effective amount of
a pharmaceutically composition of a DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride) such as described herein, thereby replacing said
insulin or insulin analog (i.e. switching from insulin therapy to a
BI 1356 & metformin combination according to this
invention).
[0153] Examples of metabolic disorders or diseases amenable by the
therapy of this invention may include, without being limited to,
type 1 diabetes, type 2 diabetes, diabetic complications (e.g. as
described herein), impaired glucose tolerance (IGT), impaired
fasting blood glucose (IFG), hyperglycemia, postprandial
hyperglycemia, postabsorptive hyperglycemia, latent autoimmune
diabetes in adults (LADA), overweight, obesity, dyslipidemia,
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,
hyperNEFA-emia, fasting or postprandial hyperlipidemia such as
postprandial lipemia (e.g. postprandial hypertriglyceridemia),
hypertension, atherosclerosis, endothelial dysfunction,
osteoporosis, chronic systemic inflammation, non alcoholic fatty
liver disease (NAFLD), retinopathy, neuropathy, nephropathy,
polycystic ovarian syndrome, and/or metabolic syndrome.
[0154] The present invention further relates to a certain DPP-4
inhibitor (preferably linagliptin) in combination with metformin
(particularly in the form of metformin hydrochloride), and
optionally in combination with one or more other active agents, for
use in at least one of the following methods: [0155] preventing,
slowing the progression of, delaying the onset of or treating a
metabolic disorder or disease, such as e.g. type 1 diabetes
mellitus, type 2 diabetes mellitus, impaired glucose tolerance
(IGT), impaired fasting blood glucose (IFG), hyperglycemia,
postprandial hyperglycemia, postabsorptive hyperglycemia, latent
autoimmune diabetes in adults (LADA), overweight, obesity,
dyslipidemia, hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia (e.g.
postprandial hypertriglyceridemia), hypertension, atherosclerosis,
endothelial dysfunction, osteoporosis, chronic systemic
inflammation, non alcoholic fatty liver disease (NAFLD),
retinopathy, neuropathy, nephropathy, polycystic ovarian syndrome,
and/or metabolic syndrome; [0156] improving and/or maintaining
glycemic control and/or for reducing of fasting plasma glucose, of
postprandial plasma glucose, of postabsorptive plasma glucose
and/or of glycosylated hemoglobin HbA1c, or preventing, reducing
the risk of, slowing the progression of, delaying the onset of or
treating worsening or deterioration of glycemic control, need for
insulin therapy or elevated HbA1c despite treatment; [0157]
preventing, slowing, delaying the onset of or reversing progression
from pre-diabetes, impaired glucose tolerance (IGT), impaired
fasting blood glucose (IFG), insulin resistance and/or from
metabolic syndrome to type 2 diabetes mellitus; [0158] preventing,
reducing the risk of, slowing the progression of, delaying the
onset of or treating of complications of diabetes mellitus such as
micro- and macrovascular diseases, such as nephropathy, micro- or
macroalbuminuria, proteinuria, retinopathy, cataracts, neuropathy,
learning or memory or cognitive impairment or decline,
neurodegenerative or cognitive disorders (e.g. dementia), cardio-
or cerebrovascular diseases, tissue ischaemia, diabetic foot or
ulcus, atherosclerosis, hypertension, endothelial dysfunction,
myocardial infarction, acute coronary syndrome, unstable angina
pectoris, stable angina pectoris, peripheral arterial occlusive
disease, cardiomyopathy, heart failure, heart rhythm disorders,
vascular restenosis, and/or stroke; [0159] reducing body weight
and/or body fat and/or liver fat and/or intra-myocellular fat or
preventing an increase in body weight and/or body fat and/or liver
fat and/or intra-myocellular fat or facilitating a reduction in
body weight and/or body fat and/or liver fat and/or
intra-myocellular fat; [0160] preventing, slowing, delaying the
onset of or treating the degeneration of pancreatic beta cells
and/or the decline of the functionality of pancreatic beta cells
and/or for improving, preserving and/or restoring the functionality
of pancreatic beta cells and/or stimulating and/or restoring or
protecting the functionality of pancreatic insulin secretion;
[0161] preventing, slowing, delaying the onset of or treating non
alcoholic fatty liver disease (NAFLD) including hepatic steatosis,
non-alcoholic steatohepatitis (NASH) and/or liver fibrosis (such as
e.g. preventing, slowing the progression, delaying the onset of,
attenuating, treating or reversing hepatic steatosis, (hepatic)
inflammation and/or an abnormal accumulation of liver fat); [0162]
preventing, slowing the progression of, delaying the onset of or
treating type 2 diabetes with failure to conventional antidiabetic
mono- or combination therapy; [0163] achieving a reduction in the
dose of conventional antidiabetic medication (e.g. of a
sulphonylurea or an insulin) required for adequate therapeutic
effect; [0164] reducing the risk for adverse effects associated
with conventional antidiabetic medication (e.g. hypoglycemia or
weight gain, such as associated with e.g. insulin or sulphonylurea
medication); and/or [0165] maintaining and/or improving the insulin
sensitivity and/or for treating or preventing hyperinsulinemia
and/or insulin resistance;
[0166] in a patient in need thereof (such as e.g. a patient as
described herein), particularly [0167] in patients with (chronic)
renal disease, renal dysfunction or renal impairment, particularly
in patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or even down to 30, such
as in patients with (chronic) renal impairment of moderate stage
(CKD stage 3, eGFR 30-60), particularly of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b.
[0168] Such therapy according to this invention (e.g. as described
hereinabove or hereinbelow in further detail) may include treatment
with such certain DPP-4 inhibitor (preferably linagliptin,
optionally in combination with one or more other active agents)
over a lengthy period, such as described in more detail (duration
of treatment) herein.
[0169] In certain embodiments, the therapy or prophylaxis according
to the present invention (e.g. such as described hereinabove and
hereinbelow) may include duration of treatment with a certain DPP-4
inhibitor, particularly linagliptin (preferably 5 mg per day,
administered orally, in combination with metformin (and optionally
in combination with one or more other active substances, e.g. such
as those described herein) over a lengthy period (such as e.g. at
least 1-6 years, >/=2 years, or 3-7 years such as 3-4 years, 3-5
years, 3-6 years, 4-5 years, 4-6 years, 5-6 years or 5-7 years,
preferably at least 48 months, more preferably at least 3 years);
such as e.g. to provide a long term effect or improvement on
(cardio)vascular and/or renal (microvascular) safety, morbidity
and/or mortality (e.g. including effect on cognitive impairment)
according to the present invention; such as e.g. in patients (e.g.
diabetic patients, especially type 2 diabetes patients) as
described herein.
[0170] For example, the therapy or prophylaxis according to the
present invention (e.g. such as described hereinabove and
hereinbelow) may include duration of treatment with a certain DPP-4
inhibitor, particularly linagliptin (preferably 5 mg per day,
administered orally), in combination with metformin (and optionally
in combination with one or more other active substances, e.g. such
as those described herein) over a lengthy period, preferably at
least 48 months, more preferably at least 3 years (such as e.g. at
least 3-4 years, or at least 5-6 years).
[0171] In the monitoring of the treatment of diabetes mellitus the
HbA1c value, the product of a non-enzymatic glycation of the
haemoglobin B chain, is of exceptional importance. As its formation
depends essentially on the blood sugar level and the life time of
the erythrocytes the HbA1c in the sense of a "blood sugar memory"
reflects the average blood sugar level of the preceding 4-12 weeks.
Diabetic patients whose HbA1c level has been well controlled over a
long time by more intensive diabetes treatment (i.e. <6.5% of
the total haemoglobin in the sample) are significantly better
protected from diabetic microangiopathy. The available treatments
for diabetes can give the diabetic an average improvement in their
HbA1c level of the order of 1.0-1.5%. This reduction in the HbA1C
level is not sufficient in all diabetics to bring them into the
desired target range of <7.0%, preferably <6.5% and more
preferably <6 % HbA1c.
[0172] Within glycemic control, in addition to improvement of the
HbA1c level, other recommended therapeutic goals for type 2
diabetes mellitus patients are improvement of fasting plasma
glucose (FPG) and of postprandial plasma glucose (PPG) levels to
normal or as near normal as possible. Recommended desired target
ranges of preprandial (fasting) plasma glucose are 90-130 mg/dL (or
70-130 mg/dL) or <110 mg/dL, and of two-hour postprandial plasma
glucose are <180 mg/dL or <140 mg/dL.
[0173] Within the meaning of this invention, inadequate or
insufficient glycemic control means in particular a condition
wherein patients show HbA1c values above 6.5%, in particular above
7.0%, even more preferably above 7.5%, especially above 8%. An
embodiment of patients with inadequate or insufficient glycemic
control include, without being limited to, patients having a HbA1c
value from 6.5 to 10% (or, in another embodiment, from 7.5 to 10%;
or, in another embodiment, from 7.5 to 11%, or, in another
embodiment, from 6.5 to 8.5% or, in another embodiment, from 6.5 to
7.5%). A special sub-embodiment of inadequately controlled patients
refers to patients with poor glycemic control including, without
being limited, patients having a HbA1c value 9%.
[0174] In an embodiment, diabetes patients within the meaning of
this invention may include patients who have not previously been
treated with an antidiabetic drug (drug-naive patients). Thus, in
an embodiment, the therapies described herein may be used in naive
patients. In certain embodiments of the therapies of this
invention, the DPP-4 inhibitor (preferably linagliptin) may be used
alone or in combination with one or more other antidiabetics in
such patients. In another embodiment, diabetes patients within the
meaning of this invention may include patients pre-treated with
conventional antidiabetic background medication, such as e.g.
patients with advanced or late stage type 2 diabetes mellitus
(including patients with failure to conventional antidiabetic
therapy), such as e.g. patients with inadequate glycemic control on
one, two or more conventional oral and/or non-oral antidiabetic
drugs as defined herein, such as e.g. patients with insufficient
glycemic control despite (mono-)therapy with metformin, a
thiazolidinedione (particularly pioglitazone), a sulphonylurea, a
glinide, GLP-1 or GLP-1 analogue, insulin or insulin analogue, or
an .alpha.-glucosidase inhibitor, or despite dual combination
therapy with metformin/sulphonylurea, metformin/thiazolidinedione
(particularly pioglitazone), sulphonylurea/.alpha.-glucosidase
inhibitor, pioglitazone/sulphonylurea, metformin/insulin,
pioglitazone/insulin or sulphonylurea/insulin. Thus, in an
embodiment, the therapies described herein may be used in patients
experienced with therapy, e.g. with conventional oral and/or
non-oral antidiabetic mono- or dual or triple combination
medication as mentioned herein. In certain embodiments of the
therapies of this invention, in such patients the DPP-4 inhibitor
(preferably linagliptin) may be used on top of or added on the
existing or ongoing conventional oral and/or non-oral antidiabetic
mono- or dual or triple combination medication with which such
patients are pre-treated or experienced.
[0175] For example, a diabetes patient (particularly type 2
diabetes patient, with insufficient glycemic control) of this
invention may be treatment-naive or pre-treated with one or more
(e.g. one or two) conventional antidiabetic agents selected from
metformin, thiazolidinediones (particularly pioglitazone),
sulphonylureas, glinides, .alpha.-glucosidase inhibitors (e.g.
acarbose, voglibose), and insulin or insulin analogues, such as
e.g. pre-treated or experienced with: [0176] metformin,
.alpha.-glucosidase inhibitor, sulphonylurea or glinide
monotherapy, or metformin plus .alpha.-glucosidase inhibitor,
metformin plus sulphonylurea, metformin plus glinide,
.alpha.-glucosidase inhibitor plus sulphonylurea, or
.alpha.-glucosidase inhibitor plus glinide dual combination
therapy.
[0177] In certain embodiments relating to such treatment-naive
patients, the DPP-4 inhibitor (preferably linagliptin) may be used
as monotherapy, or as initial combination therapy such as e.g. with
metformin, a thiazolidinedione (particularly pioglitazone), a
sulphonylurea, a glinide, an .alpha.-glucosidase inhibitor (e.g.
acarbose, voglibose), GLP-1 or GLP-1 analogue, or insulin or
insulin analogue; preferably as monotherapy.
[0178] In certain embodiments relating to such patients pre-treated
or experienced with one or two conventional antidiabetic agents,
the DPP-4 inhibitor (preferably linagliptin) may be used as add-on
combination therapy, i.e. added to an existing or background
therapy with the one or two conventional antidiabetics in patients
with insufficient glycemic control despite therapy with the one or
more conventional antidiabetic agents, such as e.g. as add-on
therapy to one or more (e.g. one or two) conventional antidiabetics
selected from metformin, thiazolidinediones (particularly
pioglitazone), sulphonylureas, glinides, .alpha.-glucosidase
inhibitors (e.g. acarbose, voglibose), GLP-1 or GLP-1 analogues,
and insulin or insulin analogues, such as e.g.: [0179] as add-on
therapy to metformin, to a .alpha.-glucosidase inhibitor, to a
sulphonylurea or to a glinide; [0180] or as add-on therapy to
metformin plus .alpha.-glucosidase inhibitor, to metformin plus
sulphonylurea, to metformin plus glinide, to .alpha.-glucosidase
inhibitor plus sulphonylurea, or to .alpha.-glucosidase inhibitor
plus glinide; [0181] or as add-on therapy to an insulin, with or
without metformin, a thiazolidinedione (particularly pioglitazone),
a sulphonylurea, a glinide or an .alpha.-glucosidase inhibitor
(e.g. acarbose, voglibose).
[0182] An embodiment of the patients which may be amenable to the
therapies of this invention may include, without being limited,
those diabetes patients for whom normal metformin therapy is less
appropriate, such as e.g. those diabetes patients who need reduced
dose metformin therapy due to reduced tolerability, intolerability
or contraindication against metformin or due to impaired/reduced
renal function (e.g. elderly patients, such as e.g. .gtoreq.60-65
years).
[0183] In a further embodiment, the patient described herein is a
subject having diabetes (e.g. type 1 or type 2 diabetes or LADA,
particularly type 2 diabetes).
[0184] In particular, the subject within this invention may be a
human, e.g. human child, a human adolescent or, particularly, a
human adult.
[0185] In further particular, the subject within this invention is
a human type 2 diabetes patient.
[0186] In certain embodiments, the subject within this invention is
a (human) type 2 diabetes patient in early diabetes stage or,
particularly, in advanced diabetes stage. In an embodiment, the
patient has long-standing type 2 diabetes (e.g. >10 years)
and/or is treated with insulin.
[0187] In further certain embodiments, the subject within this
invention is a (human) type 2 diabetes patient in early CKD stage
or, particularly, in advanced CKD stage.
[0188] The enzyme DPP-4 (dipeptidyl peptidase IV) also known as
CD26 is a serine protease known to lead to the cleavage of a
dipeptide from the N-terminal end of a number of proteins having at
their N-terminal end a prolin or alanin residue. Due to this
property DPP-4 inhibitors interfere with the plasma level of
bioactive peptides including the peptide GLP-1 and are considered
to be promising drugs for the treatment of diabetes mellitus.
[0189] A particularly preferred DPP-4 inhibitor to be emphasized
within the present invention is
1-[(4-methyl-quinazolin-2-Amethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-ami-
no-piperidin-1-yl)-xanthine, particularly the free base thereof
(which is also known as linagliptin or BI 1356).
[0190] The DPP-4 inhibitor of this invention may be selected from
the group consisting of linagliptin, sitagliptin, vildagliptin,
alogliptin, saxagliptin, teneligliptin, anagliptin, gemigliptin and
dutogliptin, or a pharmaceutically acceptable salt of one of the
herein mentioned DPP-4 inhibitors, or a prodrug thereof.
[0191] DPP-4 is analogous to CD26 a T-cell antigene which plays a
role in T-cell activation and immuno-modulation. Further, some
substrates of DPP-4 (beyond incretins) may have potential
cardio-renal effects.
[0192] Furthermore, linagliptin, a selective DPP-4 inhibitor may
qualify for the instant purposes with certain anti-oxidative and/or
anti-inflammatory features.
[0193] Linagliptin may further have a direct impact on the
integrity of the endothelium and podocytes of the glomerula and the
proximal tubular cells of the kidney as well as on endothelial
function and linagliptin has a relatively high tissue distribution,
including in the kidney.
[0194] Further, samples from human kidneys indicate that
proteinuric human diseases (such as e.g. diabetic nephropathy or
nephrotic syndrome) seem to be characterized by an upregulation of
glomerular DPP-4.
[0195] Moreover, linagliptin may further qualify for the instant
purposes by antidiabetic and anti-albuminuric effects/usability
preferably in type 2 diabetes patients, with micro- or
macroalbuminuria (e.g. 30-3000 mg/g creatinine), preferably on top
of current standard treatment for diabetic nephropathy (e.g. ACE
inhibitor or ARB).
[0196] It is further noteworthy that most major DPP-4 inhibitors
(e.g. sitagliptin, saxagliptin, alogliptin and vildagliptin)
require dose adjustment/reduction in the renally impaired (CKD)
population.
[0197] The DPP-4 inhibitor linagliptin, however, is unique in being
secreted via the bile and does not require adjustment of dose with
declining renal function.
[0198] Additionally, the DPP-4 inhibitor linagliptin can exert
anti-fibrotic effects, such as on kidney fibrosis.
[0199] A special embodiment of the DPP-4 inhibitors of this
invention refers to those orally administered DPP-4 inhibitors
which are therapeutically efficacious at low dose levels, e.g. at
dose levels <100 mg or <70 mg per patient per day, preferably
<50 mg, more preferably <30 mg or <20 mg, even more
preferably from 1 mg to 10 mg (if required, divided into 1 to 4
single doses, particularly 1 or 2 single doses, which may be of the
same size), particularly from 1 mg to 5 mg (more particularly 5
mg), per patient per day, preferentially, administered orally
once-daily, more preferentially, at any time of day, administered
with or without food. Thus, for example, the therapeutic daily oral
dose 5 mg BI 1356 can be given in a once daily dosing regimen (i.e.
5 mg BI 1356 once daily) or in a twice daily dosing regimen (i.e.
2.5 mg BI 1356 twice daily), at any time of day, with or without
food.
[0200] The present invention further relates to a pharmaceutical
composition or combination comprising or consisting essentially of
a certain DPP-4 inhibitor (particularly linagliptin) and metformin
(particularly in the form of metformin hydrochloride), optionally
in combination or alternation with one or more other therapeutic
agents, each as described herein, such as e.g. for simultaneous,
sequential or separate medical use in therapy or prophylaxis as
described herein.
[0201] Within this invention it is to be understood that the
combinations or combined uses according to this invention may
envisage the simultaneous, sequential or separate administration of
the active components.
[0202] In this context, "combination" or "combined" within the
meaning of this invention may include, without being limited, fixed
and non-fixed (e.g. free) forms (including kits, or other
administration, application or dosage forms) and uses, such as e.g.
the simultaneous, sequential or separate use of the components.
[0203] The combined administration or application of this invention
may take place by administering the therapeutic components
together, such as e.g. by administering them simultaneously in one
single or in two separate formulations. Alternatively, the
administration may take place by administering the therapeutic
components sequentially, such as e.g. successively in two separate
formulations.
[0204] For the combination therapy of this invention the
therapeutic components may be administered separately (which
implies that they are formulated separately) or formulated
altogether (which implies that they are formulated in the same
preparation). Hence, the administration of one element of the
combination of the present invention may be prior to, concurrent
to, or subsequent to the administration of the other element of the
combination.
[0205] Unless otherwise noted, combination therapy may refer to
first line, second line or third line therapy, or initial or add-on
combination therapy or replacement therapy.
[0206] Unless otherwise noted, monotherapy may refer to first line
therapy (e.g. therapy of patients with insufficient glycemic
control by diet and exercise alone, such as e.g. drug-naive
patients, typically patients early after diagnosis and/or who have
not been previously treated with an antidiabetic agent, and/or
patients ineligible for metformin therapy such as e.g. patients for
whom metformin therapy is contraindicated, such as e.g. due to
renal impairment, or inappropriate, such as e.g. due to
intolerance).
[0207] Unless otherwise noted, add-on combination therapy may refer
to second line or third line therapy (e.g. therapy of patients with
insufficient glycemic control despite (diet and exercise plus)
therapy with one or two conventional antidiabetic agents, typically
patients who are pre-treated with one or two antidiabetic agents,
such as e.g. patients with such existing antidiabetic background
medication).
[0208] Unless otherwise noted, initial combination therapy may
refer to first line therapy (e.g. therapy of patients with
insufficient glycemic control by diet and exercise alone, such as
e.g. drug-naive patients, typically patients early after diagnosis
and/or who have not been previously treated with an antidiabetic
agent).
[0209] A DPP-4 inhibitor according to the invention is preferably
administered orally.
[0210] In one embodiment, pharmaceutical compositions or fixed dose
combinations of a DPP-4 inhibitor (particularly linagliptin) and
metformin (particularly in the form of metformin hydrochloride)
such as described herein include, without being limited to, such
compositions which comprise immediate release metformin and the
DPP-4 inhibitor (preferably as an immediate release component). In
connection with such compositions, further reference is made for
example to WO 2009/121945, the disclosure of which is incorporated
herein. Particular reference is made to those tablet forms which
are described in more detail in the example section of WO
2009/121945; the mono-layer tablet hereby being preferred.
[0211] In another embodiment, pharmaceutical compositions or fixed
dose combinations of a DPP-4 inhibitor (particularly linagliptin)
and metformin (particularly in the form of metformin hydrochloride)
such as described herein include, without being limited to, such
compositions which comprise controlled or sustained (e.g. slow or
extended) release metformin and the DPP-4 inhibitor (preferably as
an immediate release component). Examples of such compositions
include, without being limited, drug (DPP-4 inhibitor)-coated
tablets (which may be optionally over-coated with a non-functional
film-coat), e.g. compositions comprising i) an extended release
core comprising metformin and one or more suitable excipients and
ii) a (preferably immediate release) film-coating comprising DPP-4
inhibitor (e.g. such as film-coat layer). In connection with such
compositions, further reference is made for example to WO
2012/120040, WO 2013/131967 and PCT/EP2015074030, the disclosures
of which are incorporated herein. Particular reference is made to
the tablet forms as described in more detail in the example section
of PCT/EP2015074030. Examples of slow release may include, without
being limited, a metformin composition (e.g. as tablet core) where
metformin is released at a rate where the peak plasma levels of
metformin are typically achieved about 8-22 h after
administration.
[0212] In more detailed example, a pharmaceutical composition as
mentioned herein comprises a certain DPP-4 inhibitor (particularly
linagliptin) and metformin (particularly in the form of metformin
hydrochloride), and optionally one or more pharmaceutically
acceptable auxiliaries.
[0213] Pharmaceutically acceptable auxiliaries for the
pharmaceutical compositions as described herein may comprise a
stabilizer, such as e.g. arginine, particularly L-arginine.
[0214] Particularly, a pharmaceutical composition as described
herein comprises linagliptin and metformin (particularly in the
form of metformin hydrochloride), L-arginine (such as e.g. as
inactive ingredient or as stabilizer), and optionally one or more
further pharmaceutically acceptable auxiliaries or excipients.
[0215] Pharmaceutically acceptable auxiliaries or excipients
mentioned herein may comprise optionally in addition to L-arginine
other auxiliaries such as e.g. one or more fillers, one or more
diluents, one or more binders, one or more lubricants, one or more
release agents, one or more disintegrants, one or more breakdown
agents, one or more flow agents, one or more coating agents, one or
more plasticizers, one or more pigments, etc.
[0216] In an embodiment, a pharmaceutical composition as described
herein comprises linagliptin (e.g. in an amount of 2.5 mg, such as
for twice daily administration, or in an amount of 5 mg, such as
for once daily administration) and metformin (particularly in the
form of metformin hydrochloride; e.g. in an amount of 500, 750, 850
or 1000 mg; e.g. in immediate release formulation or in extended
release formulation), L-arginine (particularly as stabilizer) and
optionally one or more other auxiliaries.
[0217] In an embodiment, a pharmaceutical composition as described
herein comprises linagliptin (e.g. in an amount of 2.5 mg,
particularly in immediate release formulation such as for twice
daily administration), metformin (particularly metformin
hydrochloride, e.g. in an amount of 500, 850 or 1000 mg,
particularly in immediate release formulation), L-arginine
(particularly as stabilizer), a filler (e.g. maize starch), a
binder (e.g. copovidone), and a lubricant (e.g. magnesium stearate)
and optionally a flow agent (e.g. anhydrous colloidal silicon
dioxide).
[0218] In another embodiment of the present invention the tablets
mentioned herein include for example single-layer, double-layer or
triple-layer tablets, coated core tablets, film-coated tablets,
etc.
[0219] Typical dosage strengths of the dual fixed dose combination
(tablet) of linagliptin/metformin IR (immediate release) are
2.5/500 mg, 2.5/850 mg and 2.5/1000 mg (linagliptin/metformin
hydrochloride), which may be administered twice a day.
[0220] In a particular embodiment, for use in renally impaired
patients according to the present invention, especially for use in
patients with (chronic) renal impairment of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b), a particular dosage strength of linagliptin/metformin IR
(immediate release) is 2.5/500 mg (linagliptin/metformin
hydrochloride), administered twice daily.
[0221] Typical dosage strengths of the dual fixed dose combination
(tablet) of linagliptin/metformin XR (extended release) are 5/1000
mg (linagliptin/metformin hydrochloride), which may be administered
as one tablet once a day (preferably to be taken in the evening
preferably with meal), or 2.5/750 and 2.5/1000
(linagliptin/metformin hydrochloride), which may be administered as
two tablets once a day (preferably to be taken in the evening
preferably with meal).
[0222] In a further embodiment, for use in renally impaired
patients according to the present invention, especially for use in
patients with (chronic) renal impairment of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b), a particular dosage strength of linagliptin/metformin XR
(extended release) is 5/1000 mg (linagliptin/metformin
hydrochloride), administered once daily.
[0223] In a particular embodiment, for use in renally impaired
patients according to the present invention, especially for use in
patients with (chronic) renal impairment of mild-to-moderate stage
(CKD stage 3a) such as having eGFR levels 45-59 or of
moderate-to-severe stage such as having eGFR levels 30-44 (CKD
stage 3b), the maximum daily dose may be 1000 mg metformin
hydrochloride, preferably given as two divided doses, such as e.g.
500 mg BID.
[0224] Metformin is usually given in doses varying from about 500
mg to 2000 mg up to 2500 mg or 3000 mg per day using various dosing
regimens from about 100 mg to 500 mg or 200 mg to 850 mg (1-3 times
a day), or about 300 mg to 1000 mg once or twice a day, or
delayed-release metformin in doses of about 100 mg to 1000 mg or
preferably 500 mg to 1000 mg once or twice a day or about 500 mg to
2000 mg once a day. Particular dosage strengths may be 250, 500,
625, 750, 850 and 1000 mg of metformin hydrochloride.
[0225] As different metabolic functional disorders often occur
simultaneously, it is quite often indicated to combine a number of
different active principles with one another. Thus, depending on
the functional disorders diagnosed, improved treatment outcomes may
be obtained if a DPP-4 inhibitor or pharmaceutical combination or
composition according to this invention is combined with active
substances customary for the respective disorders, such as e.g. one
or more active substances selected from among the other
antidiabetic substances, especially active substances that lower
the blood sugar level or the lipid level in the blood, raise the
HDL level in the blood, lower blood pressure or are indicated in
the treatment of atherosclerosis or obesity.
[0226] The DPP-4 inhibitors or pharmaceutical combinations or
compositions mentioned herein--besides their use on their own--may
also be used in conjunction with other active substances, by means
of which improved treatment results can be obtained. Such a
combined treatment may be given as a free combination of the
substances or in the form of a fixed combination, for example in a
tablet or capsule. Pharmaceutical formulations of the combination
partner needed for this may either be obtained commercially as
pharmaceutical compositions or may be formulated by the skilled man
using conventional methods. The active substances which may be
obtained commercially as pharmaceutical compositions are described
in numerous places in the prior art, for example in the list of
drugs that appears annually, the "Rote Liste.RTM." of the federal
association of the pharmaceutical industry, or in the annually
updated compilation of manufacturers' information on prescription
drugs known as the "Physicians' Desk Reference".
[0227] Examples of antidiabetic combination partners (such as
beyond metformin) are sulphonylureas such as glibenclamide,
tolbutamide, glimepiride, glipizide, gliquidon, glibornuride and
gliclazide; nateglinide; repaglinide; mitiglinide;
thiazolidinediones such as rosiglitazone and pioglitazone; PPAR
gamma modulators such as metaglidases; PPAR-gamma agonists such as
e.g. rivoglitazone, mitoglitazone, INT-131 and balaglitazone;
PPAR-gamma antagonists; PPAR-gamma/alpha modulators such as
tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297;
PPAR-gamma/alpha/delta modulators such as e.g. lobeglitazone;
AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and
ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT)
inhibitors; pancreatic beta cell GCRP agonists such as GPR119
agonists (SMT3-receptor-agonists); 11B-HSD-inhibitors; FGF19
agonists or analogues; alpha-glucosidase blockers such as acarbose,
voglibose and miglitol; alpha2-antagonists; insulin and insulin
analogues such as human insulin, insulin lispro, insulin glusilin,
r-DNA-insulinaspart, NPH insulin, insulin detemir, insulin
degludec, insulin tregopil, insulin zinc suspension and insulin
glargin; Gastric inhibitory Peptide (GIP); amylin and amylin
analogues (e.g. pramlintide or davalintide); GLP-1 and GLP-1
analogues such as Exendin-4, e.g. exenatide, exenatide LAR,
liraglutide, taspoglutide, lixisenatide (AVE-0010), LY-2428757 (a
PEGylated version of GLP-1), dulaglutide (LY-2189265), semaglutide
or albiglutide; SGLT2-inhibitors such as e.g. dapagliflozin,
sergliflozin (KGT-1251), atigliflozin, canagliflozin,
ipragliflozin, luseogliflozin or tofogliflozin; inhibitors of
protein tyrosine-phosphatase (e.g. trodusquemine); inhibitors of
glucose-6-phosphatase; fructose-1,6-bisphosphatase modulators;
glycogen phosphorylase modulators; glucagon receptor antagonists;
phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvate
dehydrogenasekinase (PDK) inhibitors; inhibitors of
tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase
(cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO
2004/005281, and WO 2006/041976) or of serine/threonine kinases;
glucokinase/regulatory protein modulators incl. glucokinase
activators; glycogen synthase kinase inhibitors; inhibitors of the
SH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKK
inhibitors such as high-dose salicylate; JNK1 inhibitors; protein
kinase C-theta inhibitors; beta 3 agonists such as ritobegron, YM
178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825;
aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat,
epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or
SGLT-2 inhibitors; KV 1.3 channel inhibitors; GPR40 modulators such
as e.g.
[(35)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-
oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid; SCD-1 inhibitors;
CCR-2 antagonists; dopamine receptor agonists (bromocriptine
mesylate [Cycloset]);
4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuin
stimulants; and other DPP IV inhibitors.
[0228] A dosage of pioglitazone is usually of about 1-10 mg, 15 mg,
30 mg, or 45 mg once a day.
[0229] Rosiglitazone is usually given in doses from 4 to 8 mg once
(or divided twice) a day (typical dosage strengths are 2, 4 and 8
mg).
[0230] Glibenclamide (glyburide) is usually given in doses from
2.5-5 to 20 mg once (or divided twice) a day (typical dosage
strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in
doses from 0.75-3 to 12 mg once (or divided twice) a day (typical
dosage strengths are 1.5, 3, 4.5 and 6 mg).
[0231] Glipizide is usually given in doses from 2.5 to 10-20 mg
once (up to 40 mg divided twice) a day (typical dosage strengths
are 5 and 10 mg), or extended-release glipizide in doses from 5 to
10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5
and 10 mg).
[0232] Glimepiride is usually given in doses from 1-2 to 4 mg (up
to 8 mg) once a day (typical dosage strengths are 1, 2 and 4
mg).
[0233] A dual combination of glibenclamide/metformin is usually
given in doses from 1.25/250 once daily to 10/1000 mg twice daily
(typical dosage strengths are 1.25/250, 2.5/500 and 5/500 mg).
[0234] A dual combination of glipizide/metformin is usually given
in doses from 2.5/250 to 10/1000 mg twice daily (typical dosage
strengths are 2.5/250, 2.5/500 and 5/500 mg).
[0235] A dual combination of glimepiride/metformin is usually given
in doses from 1/250 to 4/1000 mg twice daily.
[0236] A dual combination of rosiglitazone/glimepiride is usually
given in doses from 4/1 once or twice daily to 4/2 mg twice daily
(typical dosage strengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).
[0237] A dual combination of pioglitazone/glimepiride is usually
given in doses from 30/2 to 30/4 mg once daily (typical dosage
strengths are 30/4 and 45/4 mg).
[0238] A dual combination of rosiglitazone/metformin is usually
given in doses from 1/500 to 4/1000 mg twice daily (typical dosage
strengths are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg).
[0239] A dual combination of pioglitazone/metformin is usually
given in doses from 15/500 once or twice daily to 15/850 mg thrice
daily (typical dosage strengths are 15/500 and 15/850 mg).
[0240] The non-sulphonylurea insulin secretagogue nateglinide is
usually given in doses from 60 to 120 mg with meals (up to 360
mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is
usually given in doses from 0.5 to 4 mg with meals (up to 16
mg/day, typical dosage strengths are 0.5, 1 and 2 mg). A dual
combination of repaglinide/metformin is available in dosage
strengths of 1/500 and 2/850 mg.
[0241] Acarbose is usually given in doses from 25 to 100 mg with
meals (up to 300 mg/day, typical dosage strengths are 25, 50 and
100 mg). Miglitol is usually given in doses from 25 to 100 mg with
meals (up to 300 mg/day, typical dosage strengths are 25, 50 and
100 mg).
[0242] Conventional antidiabetics and antihyperglycemics typically
used in mono- or dual or triple (add-on or initial) combination
therapy may include, without being limited to, metformin,
sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase
blockers, GLP-1 and GLP-1 analogues, as well as insulin and insulin
analogues, such as e.g. those agents indicated herein by way of
example, including combinations thereof.
[0243] 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; fibrates such as bezafibrate, fenofibrate,
clofibrate, gemfibrozil, etofibrate and etofyllinclofibrate;
nicotinic acid and the derivatives thereof such as acipimox;
[0244] PPAR-alpha agonists; PPAR-delta agonists such as e.g.
{4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-p-
henoxy}-acetic acid; PPAR-alpha/delta agonists; inhibitors of
acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC 2.3.1.26) such
as avasimibe; cholesterol resorption inhibitors such as ezetimib;
substances that bind to bile acid, such as cholestyramine,
colestipol and colesevelam; inhibitors of bile acid transport; HDL
modulating active substances such as D4F, reverse D4F, LXR
modulating active substances and FXR modulating active substances;
CETP inhibitors such as torcetrapib, JTT-705 (dalcetrapib) or
compound 12 from WO 2007/005572 (anacetrapib); LDL receptor
modulators; MTP inhibitors (e.g. lomitapide); and ApoB100 antisense
RNA.
[0245] A dosage of atorvastatin is usually from 1 mg to 40 mg or 10
mg to 80 mg once a day.
[0246] Examples of combination partners that lower blood pressure
are beta-blockers such as atenolol, bisoprolol, celiprolol,
metoprolol and carvedilol; diuretics such as hydrochlorothiazide,
chlortalidon, xipamide, furosemide, piretanide, torasemide,
spironolactone, eplerenone, amiloride and triamterene; calcium
channel blockers such as amlodipine, nifedipine, nitrendipine,
nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine,
manidipine, isradipine, nilvadipine, verapamil, gallopamil and
diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril,
quinapril, captopril, enalapril, benazepril, perindopril,
fosinopril and trandolapril; as well as angiotensin II receptor
blockers (ARBs) such as telmisartan, candesartan, valsartan,
losartan, irbesartan, olmesartan, azilsartan and eprosartan.
[0247] A dosage of telmisartan is usually from 20 mg to 320 mg or
40 mg to 160 mg per day.
[0248] Examples of combination partners which increase the HDL
level in the blood are Cholesteryl Ester Transfer Protein (CETP)
inhibitors; inhibitors of endothelial lipase; regulators of ABC1;
LXRalpha antagonists; LXRbeta agonists; PPAR-delta agonists;
LXRalpha/beta regulators, and substances that increase the
expression and/or plasma concentration of apolipoprotein A-I.
[0249] Examples of combination partners for the treatment of
obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme
(cetilistat); dexfenfluramine; axokine; cannabinoid receptor 1
antagonists such as the CBI antagonist rimonobant; MCH-1 receptor
antagonists; MC4 receptor agonists; NPYS as well as NPY2
antagonists (e.g. velneperit); beta3-AR agonists such as SB-418790
and AD-9677; 5HT2c receptor agonists such as APD 356(lorcaserin);
myostatin inhibitors; Acrp30 and adiponectin; steroyl CoA
desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors;
CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36;
orexin receptor antagonists; and tesofensine; as well as the dual
combinations bupropion/naltrexone, bupropion/zonisamide,
topiramate/phentermine and pramlintide/metreleptin.
[0250] Examples of combination partners for the treatment of
atherosclerosis are phospholipase A2 inhibitors; inhibitors of
tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase
(cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO
2004/005281, and WO 2006/041976); oxLDL antibodies and oxLDL
vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.
[0251] Further, the certain DPP-4 inhibitor of this invention may
be used in combination with a substrate of DPP-4 (particularly with
an anti-inflammatory substrate of DPP-4), which may be other than
GLP-1, for the purposes according to the present invention, such
substrates of DPP-4 include, for example--without being limited to,
one or more of the following:
Incretins:
[0252] Glucagon-like peptide (GLP)-1
[0253] Glucose-dependent insulinotropic peptide (GIP)
Neuroactive:
[0254] Substance P
[0255] Neuropeptide Y (NPY)
[0256] Peptide YY
Energy Homeostasis:
[0257] GLP-2
[0258] Prolactin
[0259] Pituitary adenylate cyclase activating peptide (PACAP)
Other Hormones:
[0260] PACAP 27
[0261] Human chorionic gonadotrophin alpha chain
[0262] Growth hormone releasing factor (GHRF)
[0263] Luteinizing hormone alpha chain
[0264] Insulin-like growth factor (IGF-1)
[0265] CCL8/eotaxin
[0266] CCL22/macrophage-derived chemokine
[0267] CXCL9/interferon-gamma-induced monokine
Chemokines:
[0268] CXCL10/interferon-gamma-induced protein-10
[0269] CXCL11/interferon-inducible T cell a chemoattractant
[0270] CCL3L1/macrophage inflammatory protein 1alpha isoform
[0271] LD78beta
[0272] CXCL12/stromal-derived factor 1 alpha and beta
Other:
[0273] Enkephalins, gastrin-releasing peptide, vasostatin-1,
[0274] peptide histidine methionine, thyrotropin alpha
[0275] Further or in addition, the certain DPP-4 inhibitor of this
invention may be used in combination with one or more active
substances which are indicated in the treatment of nephropathy,
such as selected from diuretics, ACE inhibitors and/or ARBs.
[0276] Further or in addition, the certain DPP-4 inhibitor of this
invention may be used in combination with one or more active
substances which are indicated in the treatment or prevention of
cardiovascular diseases or events (e.g. major cardiovascular
events).
[0277] Moreover, optionally in addition, the certain DPP-4
inhibitor of this invention may be used in combination with one or
more antiplatelet agents, such as e.g. (low-dose) aspirin
(acetylsalicylic acid), a selective COX-2 or nonselective
COX-1/COX-2 inhibitor, or a ADP receptor inhibitor, such as a
thienopyridine (e.g. clopidogrel or prasugrel), elinogrel or
ticagrelor, or a thrombin receptor antagonist such as
vorapaxar.
[0278] Yet moreover, optionally in addition, the certain DPP-4
inhibitor of this invention may be used in combination with one or
more anticoagulant agents, such as e.g. heparin, a coumarin (such
as warfarin or phenprocoumon), a pentasaccharide inhibitor of
Factor Xa (e.g. fondaparinux), or a direct thrombin inhibitor (such
as e.g. dabigatran), or a Faktor Xa inhibitor (such as e.g.
rivaroxaban or apixaban or edoxaban or otamixaban).
[0279] Still yet moreover, optionally in addition, the certain
DPP-4 inhibitor of this invention may be used in combination with
one or more agents for the treatment of heart failure (such as e.g.
those mentioned in WO 2007/128761).
[0280] The dosage of the active components in the combinations or
compositions in accordance with the present invention may be
varied, although the amount of the active ingredients shall be such
that a suitable dosage form is obtained. Hence, the selected dosage
and the selected dosage form shall depend on the desired
therapeutic effect, the route of administration and the duration of
the treatment. Dosage ranges for the combination may be from the
maximal tolerated dose for the single agent to lower doses.
[0281] The present invention is not to be limited in scope by the
specific embodiments described herein. Various modifications of the
invention in addition to those described herein may become apparent
to those skilled in the art from the present disclosure. Such
modifications are intended to fall within the scope of the appended
claims.
[0282] Further embodiments, features and advantages of the present
invention may become apparent from the following examples. The
following examples serve to illustrate, by way of example, the
principles of the invention without restricting it.
[0283] All patent applications cited herein are hereby incorporated
by reference in their entireties.
Examples
[0284] In order that this invention be more fully understood, the
herein-given examples are set forth. Further embodiments, features
or aspects of the present invention may become apparent from the
examples. The examples serve to illustrate, by way of example, the
principles of the invention without restricting it.
Treatment of Patients with Type 2 Diabetes Mellitus having
Albuminuria:
[0285] A multicentre, double-blind, placebo-controlled clinical
trial investigates glycaemic and renal effects of linagliptin in
patients with type 2 diabetes, albuminuria and estimated GFR
.gtoreq.30 ml/min/1.73 m2 (with or without renal function
impairment).
[0286] A total of 360 patients with type 2 diabetes (HbA1c 6.5-10%)
and persistent albuminuria (urinary albumin-to-creatinine ratio
[UACR] 30-3000 mg/gCr; i.e. micro- or macro-albuminuria) despite
stable background (standard-of-care) of single renin-angiotensin
system blockade (ARB or ACE inhibitor) are randomised to either
linagliptin 5 mg (n=182) or placebo (n=178) for 24 weeks. Primary
glycaemic and key secondary renal surrogate endpoints are HbA1c and
UACR change from baseline over 24 weeks, respectively.
[0287] Overall mean (SD) baseline HbA1c and geometric mean (gMean)
UACR are 7.8% (0.9) and 126 mg/gCr (microalbuminuria, 73.7%;
macroalbuminuria, 20.3%), respectively. At week 24, the adjusted
mean (SE) % change from baseline in HbA1c for linagliptin and
placebo is -0.63 (0.06) and -0.03 (0.06), respectively; the
placebo-adjusted mean HbA1c change from baseline is -0.60% (95% Cl
-0.78, -0.43; p<0.0001). The gMean for time-weighted average of
% change (95% Cl) from baseline in UACR over 24 weeks for
linagliptin and placebo is -11.0% (-16.8, -4.7) and -5.1% (-11.4,
1.6), respectively; the placebo-adjusted gMean for time-weighted
average of % change in UCAR from baseline is -6.0% (95% Cl -15.0,
3.0; NS).
[0288] Exploratory analyses of the subgroup of patients treated
with linagliptin on a background of metformin (as well as of those
with moderate renal impairment CKD3, eGFR of 30-60 ml/min/1.73m2)
in the above study show a numerically larger difference in the
changes from baseline vs. placebo in urinary albumin to creatinine
ratio (UACR) compared to patients without the combination with
metformin (post hoc subgroup analysis of key secondary
endpoint).
[0289] Alternatively, the renal effects can be evaluated by a
scoring system (diabetic nephropathy score) for staging diabetic
kidney disease such as generated from the profiles of a urinary
biomarker panel composed of alpha2-HS-glycoprotein,
alpha-1-antitrypsin and acid-1-glycoprotein.
Treatment of Patients with Type 2 Diabetes Mellitus at High
Cardiovascular and Renal Microvascular Risk:
[0290] The long term impact on cardiovascular and renal
(microvascular) safety, morbidity and/or mortality and relevant
efficacy parameters (e.g. HbA1c, fasting plasma glucose, treatment
sustainability) of treatment with linagliptin in combination with
metformin in a relevant population of patients with type 2 diabetes
mellitus (such as e.g. at high vascular risk, at advanced stage of
diabetic kidney disease) can be investigated as follows:
[0291] Type 2 diabetes patient with insufficient glycemic control
(naive or pre-treated with any antidiabetic background medication
including metformin, excluding treatment with GLP-1 receptor
agonists, DPP-4 inhibitors or SGLT-2 inhibitors if
.gtoreq.consecutive 7 days, e.g. having HbA1c 6.5-10%), and high
risk of cardiovascular events, e.g. defined by: albuminuria (micro
or macro) and previous macrovascular disease: e.g. defined
according to Condition I as indicated below; [0292] and/or [0293]
impaired renal function: e.g. as defined according to Condition II
as indicated below;
Condition I:
[0293] [0294] albuminuria (such as e.g. urine albumin creatinine
ratio (UACR) .gtoreq.30 mg/g creatinine or .gtoreq.30 mg/l
(milligram albumin per liter of urine) or .gtoreq.30 .mu.g/min
(microgram albumin per minute) or .gtoreq.30 mg/24 h (milligram
albumin per 24 hours)) and [0295] previous macrovascular disease,
such as e.g. defined as one or more of a) to f): [0296] a) previous
myocardial infarction (e.g. >2 months), [0297] b) advanced
coronary artery disease, such as e.g. defined by any one of the
following: [0298] .gtoreq.50% narrowing of the luminal diameter in
2 or more major coronary arteries (e.g. LAD (Left Anterior
Descending), CX (Circumflex) or RCA (Right Coronary Artery)) by
coronary angiography or CT angiography, [0299] left main stem
coronary artery with .gtoreq.50% narrowing of the luminal diameter,
[0300] prior percutaneous or surgical revascularization of 2 major
coronary arteries (e.g. .gtoreq.2 months), [0301] combination of
prior percutaneous or surgical revascularization, such as e.g. of 1
major coronary artery (e.g. .gtoreq.2 months) and .gtoreq.50%
narrowing of the luminal diameter by coronary angiography or CT
angiography of at least 1 additional major coronary artery, [0302]
c) high-risk single-vessel coronary artery disease, such as e.g.
defined as the presence of .gtoreq.50% narrowing of the luminal
diameter of one major coronary artery (e.g. by coronary angiography
or CT angiography in patients not revascularised) and at least one
of the following: [0303] a positive non invasive stress test, such
as e.g. confirmed by either: [0304] a positive ECG exercise
tolerance test in patients without left bundle branch block,
Wolff-Parkinson-White syndrome, left ventricular hypertrophy with
repolarization abnormality, or paced ventricular rhythm, atrial
fibrillation in case of abnormal ST-T segments, [0305] a positive
stress echocardiogram showing induced regional systolic wall motion
abnormalities, [0306] a positive nuclear myocardial perfusion
imaging stress test showing stress induced reversible perfusion
abnormality, [0307] patient discharged from hospital with a
documented diagnosis of unstable angina pectoris (e.g. .gtoreq.2-12
months), [0308] d) previous ischemic or haemorrhagic stroke (e.g.
>3 months), [0309] e) presence of carotid artery disease (e.g.
symptomatic or not), such as e.g. documented by either: [0310]
imaging techniques with at least one lesion estimated to be
.gtoreq.50% narrowing of the luminal diameter, [0311] prior
percutaneous or surgical carotid revascularization, [0312] f)
presence of peripheral artery disease, such as e.g. documented by
either: [0313] previous limb angioplasty, stenting or bypass
surgery, [0314] previous limb or foot amputation due to
macrocirculatory insufficiency, [0315] angiographic evidence of
peripheral artery stenosis .gtoreq.50% narrowing of the luminal
diameter in at least one limb (e.g. definition of peripheral
artery: common iliac artery, internal iliac artery, external iliac
artery, femoral artery, popliteal artery),
Condition II:
[0315] [0316] impaired renal function (e.g. with or without CV
co-morbidities), such as e.g. defined by: [0317] impaired renal
function (e.g. as defined by MDRD formula) with an estimated
glomerular filtration rate (eGFR) 15-45 mL/min/1.73 m.sup.2 with
any urine albumin creatinine ratio (UACR), and/or [0318] impaired
renal function (e.g. as defined by MDRD formula) with an with an
estimated glomerular filtration rate (eGFR) .gtoreq.45-75
mL/min/1.73 m.sup.2 with an urine albumin creatinine ratio (UACR)
>200 mg/g creatinine or >200 mg/l (milligram albumin per
liter of urine) or >200 .mu.g/min (microgram albumin per minute)
or >200 mg/24 h (milligram albumin per 24 hours); [0319] are
treated over a lengthy period (e.g. for 4-5 years, or preferably at
least 48 months) with linagliptin (preferably 5 mg per day,
administered orally) in combination with metformin (optionally in
combination with one or more further active substances, e.g. such
as those described herein) and compared with patients who have been
treated with placebo (as add-on therapy on top of standard of
care).
[0320] Evidence of the therapeutic success compared with patients
who have been treated with placebo can be found in non-inferiority
or superiority compared to placebo, e.g. in the (longer) time taken
to first occurrence of cardio- or cerebrovascular events, e.g. time
to first occurrence of any of the following components of the
composite CV endpoint: cardiovascular death (including fatal
stroke, fatal myocardial infarction and sudden death), non-fatal
myocardial infarction (excluding silent myocardial infarction),
non-fatal stroke, and (optional) hospitalization e.g. for unstable
angina pectoris; and/or [0321] in the (longer) time taken to first
occurrence of renal microvascular events, e.g. time to first
occurrence of any of the following components of the composite
renal endpoint: renal death, sustained end-stage renal disease, and
sustained decrease of 50% or more in eGFR.
[0322] Further therapeutic success can be found in the (smaller)
number of or in the (longer) time taken to first occurrence of any
of: cardiovascular death, (non)-fatal myocardial infarction, silent
MI, (non)-fatal stroke, hospitalization for unstable angina
pectoris, hospitalization for coronary revascularization,
hospitalization for peripheral revascularization, hospitalization
for congestive heart failure, all cause mortality, renal death,
sustained end-stage renal disease, loss in eGFR, new incidence of
macroalbuminuria, progression in albuminuria, progression in CKD,
need for anti-retinopathy therapy; or improvement in albuminuria,
renal function, CKD; or improvement in cognitive function or
prevention of/protection against accelerated cognitive decline.
[0323] Cognitive functions can be assessed by standardized tests as
measure of cognitive functioning such as e.g. by using the
Mini-Mental State Examination (MMSE), the Trail Making Test (TMT)
and/or the Verbal Fluency Test (VFT).
[0324] Additional therapeutic success (compared to placebo) can be
found in greater change from baseline in HbA1c and/or FPG.
[0325] Further additional therapeutic success can be found in
greater proportion of patients on study treatment at study end
maintain glycemic control (e.g. HbA1c</=7%).
[0326] Further additional therapeutic success can be found in
greater proportion of patients on study treatment who at study end
maintain glycemic control without need for additional antidiabetic
medication (during treatment) to obtain HbA1c</=7%.
[0327] Further additional therapeutic success can be found in lower
proportion of patients on study treatment initiated on insulin or
treated with insulin or in lower dose of insulin dose used.
[0328] Further additional therapeutic success can be found in lower
change from baseline in body weight or greater proportion of
patients with .ltoreq.2% weight gain or lower proportion of
patients with .gtoreq.2% weight gain at study end.
[0329] Respective subgroup analysis may be made in this study for
patients having chronic kidney disease (CKD) such as e.g. up to
stage 3 and/or having estimated glomerular filtration rate (eGFR;
mL/minute/1.73 m.sup.2) levels down to 45, or down to 30, such as
for patients with (chronic) renal impairment of moderate stage (CKD
stage 3, eGFR 30-60), particularly of mild-to-moderate stage (CKD
stage 3a) such as having eGFR levels 45-59 or of moderate-to-severe
stage (CKD stage 3b) such as having eGFR levels 30-44; optionally
with or without micro- or macroalbuminuria.
* * * * *