U.S. patent application number 16/217421 was filed with the patent office on 2019-04-04 for use of a dpp-4 inhibitor in podocytes related disorders and/or nephrotic syndrome.
The applicant listed for this patent is Boehringer Ingelheim Internation GmbH. Invention is credited to Thomas KLEIN, Michael MARK, Maximilian von EYNATTEN.
Application Number | 20190099427 16/217421 |
Document ID | / |
Family ID | 48430775 |
Filed Date | 2019-04-04 |
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United States Patent
Application |
20190099427 |
Kind Code |
A1 |
KLEIN; Thomas ; et
al. |
April 4, 2019 |
USE OF A DPP-4 INHIBITOR IN PODOCYTES RELATED DISORDERS AND/OR
NEPHROTIC SYNDROME
Abstract
The present invention relates to methods for treating and/or
preventing podocytes related disorders and/or nephrotic syndrome
comprising the administration of an effective amount of a certain
DPP-4 inhibitor, as well as to the use of a certain DPP-4 inhibitor
for treating and/or preventing a metabolic disease in a patient
with or at risk of podocytes related disorders and/or nephrotic
syndrome.
Inventors: |
KLEIN; Thomas; (Radolfzell,
DE) ; von EYNATTEN; Maximilian; (Wiesbaden, DE)
; MARK; Michael; (Biberach an der Riss, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim Internation GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
48430775 |
Appl. No.: |
16/217421 |
Filed: |
December 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15354053 |
Nov 17, 2016 |
10195203 |
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16217421 |
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14928048 |
Oct 30, 2015 |
9526730 |
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15354053 |
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13892529 |
May 13, 2013 |
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14928048 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 13/02 20180101;
A61P 25/28 20180101; A61P 27/12 20180101; A61P 3/08 20180101; A61P
9/12 20180101; A61K 31/4184 20130101; A61K 31/155 20130101; A61K
31/401 20130101; A61P 29/00 20180101; A61P 3/10 20180101; A61K
45/06 20130101; A61P 1/16 20180101; A61P 13/00 20180101; A61P 9/00
20180101; A61P 13/12 20180101; A61P 15/00 20180101; A61P 3/04
20180101; A61P 7/10 20180101; A61P 3/00 20180101; A61P 43/00
20180101; A61P 3/06 20180101; A61K 31/522 20130101; A61P 9/10
20180101; A61K 31/18 20130101; A61P 19/08 20180101; C07D 473/06
20130101; A61K 38/28 20130101; A61P 9/04 20180101; A61P 1/18
20180101; A61K 31/522 20130101; A61K 2300/00 20130101; A61K 31/401
20130101; A61K 2300/00 20130101; A61K 31/4184 20130101; A61K
2300/00 20130101; A61K 31/155 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 38/28 20060101 A61K038/28; A61K 31/18 20060101
A61K031/18; A61K 45/06 20060101 A61K045/06; C07D 473/06 20060101
C07D473/06; A61K 31/155 20060101 A61K031/155 |
Foreign Application Data
Date |
Code |
Application Number |
May 14, 2012 |
EP |
12167953.4 |
Jun 5, 2012 |
EP |
12170888.7 |
Sep 28, 2012 |
EP |
12006812.7 |
Oct 29, 2012 |
EP |
12190447.8 |
Claims
1. A method of preventing, reducing the risk of or delaying the
onset or progression micro- or macro-albuminaria, the onset of
chronic kidney disease (CKD), the worsening of CKD, the onset of
acute renal failure or death in a human type 2 diabetes patient,
said method comprising administering linagliptin in a daily oral
amount of 5 mg to the patient.
2. The method according to claim 1 for delaying the onset or
progression of micro- or macro-albuminuria in a human type 2
diabetes patient, said method comprising administering linagliptin
in a daily oral amount of 5 mg to the patient.
3. The method according to claim 2, where in the duration of
treatment is >=12 weeks.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a certain DPP-4 inhibitor
(preferably linagliptin, optionally in combination with one or more
other active agents) for use in treating, preventing and/or
reducing the risk or likelihood of podocyte related disorders,
disturbance of podocyte function, podocyte loss or injury,
podocytopathy, glomerulopathy, nephrotic syndrome, minimal change
disease (MCD, e.g. minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS), and/or diseases related or
associated therewith, to pharmaceutical compositions and
combinations comprising such active components, and to certain
therapeutic uses thereof.
BACKGROUND OF THE INVENTION
[0002] Disturbance of podocyte function as well as podocyte loss or
injury are a hallmark of a variety of primary or secondary
proteinuric glomerular diseases such as minimal change disease
(such as e.g. minimal change nephropathy, or steroid hormone
refractory minimal change nephropathy), focal segmental
glomerulosclerosis (FSGS) and membraneous nephropathy (such as e.g.
membranous glomerulonephritis). These diseases may present as a
nephrotic syndrome, which is characterized by proteinuria
(typically >3 g/day, or >3.5 g per 1.73 m.sup.2 per 24
hours), edema (which may be associated with weight gain),
hypoalbuminemia (typically albumin level .ltoreq.2.5 g/dL),
hyperlipidemia (e.g. hypercholesterolemia, hypertriglyceridemia, or
both in combined hyperlipidemia, particularly hypercholesterolemia,
mainly elevated LDL, usually with concomitantly elevated VLDL) and
optionally (sometimes) hypertension. Lipiduria may also occur, but
is not essential for the diagnosis of nephrotic syndrome.
Hyponatremia may also occur with a low fractional sodium
excretion.
[0003] Injury to the podocyte results in proteinuria and often
leads to progressive kidney disease. As podocytes have limited
ability to repair and/or regenerate, the extent of podocyte injury
is a major prognostic determinant in diabetic nephropathy and other
common causes of end-stage renal disease. Therapies aimed at
preventing or limiting podocyte injury and/or at promoting podocyte
repair or regeneration therefore have major potential clinical and
economic benefits. Many current therapies--including
glucocorticosteroids (e.g. prednisone, prednisolone),
cyclophosphamide, cyclosporine, rituximab and calcineurin
antagonists--have some effects on podocytes. However there are
conditions of nephrotic syndrome which are or become resistant or
refractory (relapsing) to conventional therapy, e.g. to steroid
treatment. Further, the nonspecific natures of these conventional
agents can lead to undesirable systemic adverse effects.
[0004] If protein excretion can not be controlled by adequate
therapy, these diseases often progress to end-stage renal disease.
This is particularly true for steroid hormone refractory minimal
change nephropathy and focal segmental glomerulosclerosis (FSGS).
The "normal" (steroid sensitive) minimal change nephropathy usually
responds well to treatment with steroids. With steroid hormone
refractory minimal change nephropathy and focal segmental
glomerulosclerosis (FSGS), however, there remain clinical
circumstances where no effective treatment is available today.
[0005] Nephrotic syndrome has many causes and may either be the
result of a disease limited to the kidney, called primary nephrotic
syndrome, or a condition that affects the kidney and other parts of
the body, called secondary nephrotic syndrome.
[0006] Primary Nephrotic Syndrome:
[0007] Primary causes of nephrotic syndrome are usually described
by the histology, i.e. minimal change disease (MCD) such as minimal
change nephropathy which is the most common cause of nephrotic
syndrome in children, focal segemental glomerulosclerosis (FSGS)
and membraneous nephropathy (MN) such as membraneous
glomerulonephritis which is the most common cause of nephrotic
syndrome in adults.
[0008] They are considered to be "diagnoses of exclusion", i.e.
they are diagnosed only after secondary causes have been
excluded.
[0009] Secondary Nephrotic Syndrome:
[0010] Secondary causes of nephrotic syndrome have the same
histologic patterns as the primary causes, though may exhibit some
differences suggesting a secondary cause, such as inclusion bodies.
They are usually described by the underlying cause.
[0011] Secondary Causes by Histologic Pattern:
[0012] Membranous Nephropathy (MN): [0013] Hepatitis B &
Hepatitis C [0014] Sjogren's syndrome [0015] Systemic lupus
erythematosus(SLE) [0016] Diabetes mellitus [0017] Sarcoidosis
[0018] Drugs (such as corticosteroids, gold, intravenous heroin)
[0019] Malignancy (cancer) [0020] Bacterial infections, e.g.
leprosy & syphilis [0021] Protozoal infections, e.g.
malaria
[0022] Focal Segmental Glomerulosclerosis (FSGS): [0023]
Hypertensive nephrosclerosis [0024] HIV [0025] Obesity [0026]
Kidney loss
[0027] Minimal Change Disease (MCD): [0028] Drugs, especially
NSAIDs in the elderly [0029] Malignancy, especially Hodgkin's
lymphoma [0030] Leukemia
[0031] Accordingly, nephrotic syndrome within the meaning of this
invention includes, is caused by or is associated with minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS).
SUMMARY OF THE INVENTION
[0032] The present invention relates to a certain DPP-4 inhibitor
(preferably linagliptin, optionally in combination with one or more
other active agents) for use in treating, preventing and/or
reducing the risk or likelihood of podocyte related disorders,
disturbance of podocyte function, podocyte loss or injury,
podocytopathy, glomerulopathy, nephrotic syndrome, minimal change
disease (MCD, e.g. minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS), and/or diseases related or
associated therewith, to pharmaceutical compositions and
combinations comprising such active components, and to certain
therapeutic uses thereof.
[0033] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing
and/or reducing the risk of disturbance of podocyte function,
podocyte loss or injury, and/or for use in protecting, preserving,
improving, repairing or regenerating podocytes and/or their
function.
[0034] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing
and/or reducing the risk of nephrotic syndrome either of primary or
secondary cause (e.g. including steroid-resistant or
steroid-refractory nephrotic syndrome), including minimal change
disease (MCD, e.g. minimal change nephropathy, such as steroid
hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS).
[0035] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing
and/or reducing the risk of nephrotic syndrome (e.g. including
steroid-resistant or steroid-ref ractory nephrotic syndrome),
minimal change disease (MCD, e.g. minimal change nephropathy, such
as steroid hormone refractory minimal change nephropathy),
membranous nephropathy (MN, e.g. membranous glomerulonephritis)
and/or focal segmental glomerulosclerosis (FSGS).
[0036] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing
and/or reducing the risk of minimal change disease (MCD, e.g.
minimal change nephropathy, such as steroid hormone refractory
minimal change nephropathy), membranous nephropathy (MN, e.g.
membranous glomerulonephritis) and/or focal segmental
glomerulosclerosis (FSGS).
[0037] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating and/or
preventing metabolic diseases, particularly diabetes, especially
type 2 diabetes mellitus, and/or conditions related thereto (e.g.
diabetic complications), in a patient (particularly human patient)
with or at risk of podocyte related disorders, disturbance of
podocyte function, podocyte loss or injury, glomerulopathy,
nephrotic syndrome, minimal change disease (MCD, e.g. minimal
change nephropathy, such as steroid hormone refractory minimal
change nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0038] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating and/or
preventing metabolic diseases, particularly diabetes, especially
type 2 diabetes mellitus, and/or conditions related thereto (e.g.
diabetic complications), in a patient (particularly human patient)
with or at risk of nephrotic syndrome (e.g. including
steroid-resistant or steroid-refractory nephrotic syndrome),
minimal change disease (MCD, e.g. minimal change nephropathy, such
as steroid hormone refractory minimal change nephropathy),
membranous nephropathy (MN, e.g. membranous glomerulonephritis)
and/or focal segmental glomerulosclerosis (FSGS).
[0039] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating and/or
preventing metabolic diseases, particularly diabetes, especially
type 2 diabetes mellitus, and/or conditions related thereto (e.g.
diabetic complications), in a patient (particularly human patient)
with or at risk of minimal change disease (MCD, e.g. minimal change
nephropathy, such as steroid hormone refractory minimal change
nephropathy).
[0040] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating and/or
preventing metabolic diseases, particularly diabetes, especially
type 2 diabetes mellitus, and/or conditions related thereto (e.g.
diabetic complications), in a patient (particularly human patient)
with or at risk of membranous nephropathy (MN, e.g. membranous
glomerulonephritis).
[0041] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating and/or
preventing metabolic diseases, particularly diabetes, especially
type 2 diabetes mellitus, and/or conditions related thereto (e.g.
diabetic complications), in a patient (particularly human patient)
with or at risk of focal segmental glomerulosclerosis (FSGS).
[0042] Further, the present invention relates to a method of
treating, preventing and/or reducing the likelihood or risk of
nephrotic syndrome (e.g. including steroid-resistant or
steroid-refractory nephrotic syndrome), minimal change disease
(MCD, e.g. minimal change nephropathy, such as steroid hormone
refractory minimal change nephropathy), membranous nephropathy (MN,
e.g. membranous glomerulonephritis) and/or focal segmental
glomerulosclerosis (FSGS) in a patient (particularly human patient)
in need thereof, comprising administering an effective amount of a
certain DPP-4 inhibitor (preferably linagliptin), optionally in
combination with one or more other active agents, to the
patient.
[0043] Further, the present invention relates to a method of
treating, preventing and/or reducing the likelihood or risk of
minimal change disease (MCD, e.g. minimal change nephropathy, such
as steroid hormone refractory minimal change nephropathy),
membranous nephropathy (MN, e.g. membranous glomerulonephritis)
and/or focal segmental glomerulosclerosis (FSGS) in a patient
(particularly human patient) in need thereof, comprising
administering an effective amount of a certain DPP-4 inhibitor
(preferably linagliptin), optionally in combination with one or
more other active agents, to the patient.
[0044] Moreover, the present invention further relates to a certain
DPP-4 inhibitor (preferably linagliptin, and/or optionally in
combination with one or more other active agents, such as e.g. one
or more antidiabetics, optionally in combination with an ACE
inhibitor and/or an ARB) for use in renoprotection and/or in
treating, preventing, delaying the onset of and/or delaying the
progress of albuminuria, in a patient (particularly human patient
with diabetes, especially type 2 diabetes mellitus) suffering from
nephropathy (diabetic nephropathy).
[0045] Moreover, the present invention further relates to a certain
DPP-4 inhibitor (preferably linagliptin, optionally in combination
with one or more other active agents, such as e.g. one or more
antidiabetics, and/or optionally in combination with an ACE
inhibitor and/or an ARB) for use in renoprotection and/or in
treating, preventing, reducing the risk and/or delaying the onset
of podocyte related disorders, disturbance of podocyte function,
podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic
syndrome, minimal change disease (MCD, e.g. minimal change
nephropathy such as steroid hormone refractory minimal change
nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS), in a patient (particularly human patient with diabetes,
especially type 2 diabetes mellitus) suffering from nephropathy
(diabetic nephropathy) and/or albuminuria.
[0046] Moreover, the present invention further relates to a certain
DPP-4 inhibitor (preferably linagliptin, optionally in combination
with one or more other active agents, such as e.g. one or more
antidiabetics, and/or optionally in combination with an ACE
inhibitor and/or an ARB) for use in renoprotection and/or in
treating, preventing, delaying the onset of and/or delaying the
progress of albuminuria, in a patient (particularly human patient
with diabetes, especially type 2 diabetes mellitus suffering from
diabetic nephropathy) with or at risk of risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS).
[0047] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in the treatment of
diabetic nephropathy, particularly diabetic nephropathy with an
elevated serum creatinine and proteinuria (>300 mg/day) in
patients with type 2 diabetes.
[0048] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in treating or lowering
albuminuria or diabetic nephropathy on top of
angiotensin-converting enzyme (ACE) inhibitor therapy and/or
angiotensin II receptor blockade (ARB) therapy in type 2 diabetes
patients, particularly with diabetic nephropathy (e.g. early
diabetic nephropathy).
[0049] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in a method of treating,
preventing, reducing the risk of, delaying the onset or slowing the
progression of albuminuria (micro- or macro-albuminuria) or
diabetic nephropathy, preferably in type 2 diabetes patients, such
as e.g. type 2 diabetes patients with early diabetic nephropathy,
especially in those patients on (e.g. previous or ongoing) therapy
with an angiotensin-converting enzyme (ACE) inhibitor and/or an
angiotensin II receptor blocker (ARB), e.g. patients with
inadequate control of albuminuria despite therapy with an
angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB), particularly said method comprising
administering the DPP-4 inhibitor in combination with the
angiotensin-converting enzyme (ACE) inhibitor and/or the
angiotensin II receptor blocker (ARB) to the patient.
[0050] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents, such as e.g. including an ARB or
ACE inhibitor, such as e.g. with or without additional standard
background therapy such as e.g. with an ACEi or ARB) for use in
preventing, reducing the risk or likelihood of or delaying the
onset or slowing the progression of renal morbidity and/or
mortality, preferably in type 2 diabetes patients.
[0051] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in preventing, reducing
the risk of or delaying the onset or progression of micro- or
macro-albuminuria, chronic kidney disease (CKD), worsening of CKD,
and/or acute renal failure, preferably in type 2 diabetes
patients.
[0052] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in reducing the risk of or
delaying the onset or the progression of micro- or
macro-albuminuria, the onset of chronic kidney disease (CKD), the
worsening of CKD, the onset of acute renal failure and/or of death,
preferably in type 2 diabetes patients.
[0053] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in a method of preventing,
reducing the risk of or delaying the onset or progression of micro-
or macro-albuminuria, chronic kidney disease (CKD), worsening of
CKD, and/or acute renal failure, preferably in type 2 diabetes
patients, particularly type 2 diabetes patients with early diabetic
nephropathy, especially in those patients on (e.g. previous or
ongoing) therapy with an angiotensin-converting enzyme (ACE)
inhibitor and/or an angiotensin II receptor blocker (ARB), such as
e.g. patients with inadequate control of albuminuria despite
therapy with an angiotensin-converting enzyme (ACE) inhibitor
and/or an angiotensin II receptor blocker (ARB), particularly said
method comprising administering the DPP-4 inhibitor in combination
with the angiotensin-converting enzyme (ACE) inhibitor and/or the
angiotensin II receptor blocker (ARB) to the patient.
[0054] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin optionally in combination with
one or more other active agents, such as e.g. one or more
antidiabetics, and/or optionally in combination with one or more
further active agents, such as e.g. one or more antiplatelet
agents, antihypertensive and/or lipid lowering agents) for use in
preventing, reducing the risk of or delaying the onset or slowing
the progression of renal morbidity and/or mortality, such as
preventing, reducing or delaying the onset or progression of micro-
or macro-albuminuria, the onset of chronic kidney disease (CKD),
the worsening of CKD, and/or the onset of acute renal failure
and/or of death, particularly in a human patient with diabetes,
especially type 2 diabetes mellitus; such as e.g. in a patient
(particularly diabetes patient, especially type 2 diabetes mellitus
patient) having renal- and/or cardiovascular--history and/or
medications, such as diabetic nephropathy, macrovascular disease
(e.g. coronary artery diasease, periperal artery disease,
cerebrovascular disease, hypertension), microvascular disease (e.g.
diabetic nephropathy, neuropathy, retinopathy), coronary artery
disease, cerebrovascular disease, peripheral artery disease,
hypertension, ex-smoker or current smoker, and/or on
acetylsalicylic acid, antihypertensive and/or lipid lowering
medication, such as e.g. on (previous or ongoing) therapy with
acetylsalicylic acid, an ACE inhibitor, ARB, beta-blocker,
Calcium-anatgonist or diuretic, or combination thereof, and/or on
(previous or ongoing) therapy with a fibrate, niacin or statin, or
combination thereof.
[0055] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin optionally in combination with
one or more other active agents, such as e.g. one or more
antidiabetics, and/or optionally in combination with one or more
further active agents, such as e.g. one or more antiplatelet
agents, antihypertensive and/or lipid lowering agents) for use in
preventing, reducing the risk of or delaying the onset or slowing
the progression of renal morbidity and/or mortality, such as
preventing, reducing or delaying the onset or progression of micro-
or macro-albuminuria, the onset of chronic kidney disease (CKD),
the worsening of CKD, and/or the onset of acute renal failure
and/or of death, particularly in a human patient having diabetes,
especially type 2 diabetes mellitus, and/or for use in treating,
lowering, preventing, reducing the risk of, delaying the onset or
slowing the progression of albuminuria (micro- or macro-album
inuria) or diabetic nephropathy, particularly in a human patient
having diabetes, especially type 2 diabetes mellitus; such as e.g.
in a patient with diabetic nephropathy (with or without additional
standard background therapy such as e.g. with an ACEi or ARB), e.g.
including a vulnerable diabetic nephropathy patient such as who are
aged 65 years typically having longer diabetes duration (>5
years), renal impairment (such as mild (60 to <90 eGFR
ml/min/1.73 m.sup.2) or moderate (30 to <60 eGFR ml/min/1.73
m.sup.2) renal impairment) and/or higher baseline UACR (such as
advanced stages of micro- or macroalbuminuria).
BRIEF DESCRIPTION OF THE DRAWINGS
[0056] FIG. 1 shows the expression of podocalyxin as a marker for
podocyte integrity in linagliptin-, enalapril- or vehicle-treated
diabetic db/db mice and in healthy control mice.
DETAILED DESCRIPTION OF THE INVENTION
[0057] Within the scope of the present invention it has now been
found that a certain DPP-4 inhibitor (preferably linagliptin) as
defined herein as well as pharmaceutical combinations,
compositions, uses or methods according to this invention of that
DPP-4 inhibitor (preferably linagliptin) optionally in combination
with one or more other active agents as defined herein have
properties, which make them suitable for the purpose of this
invention and/or for fulfilling one or more of the needs mentioned
herein.
[0058] DPP-4 is analogous to CD26 a T-cell antigene which plays a
role in T-cell activation and immuno-modulation. Furthermore,
linagliptin, a selective DPP-4 inhibitor further qualifies for the
instant purposes with certain anti-oxidative and/or
anti-inflammatory features.
[0059] 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.
[0060] Linagliptin has a positive effect on podocytes (which is a
kidney specific cell population which is essential for the
filtration integrity of the kidney). Linagliptin compensates or
delays the loss of podocalyxin (a podocytic extracellular contact
protein). Typically, diabetic nephropathy as well as nephrotic
syndrome is characterized by a decrease of integral podocytic
proteins. Therefore, linagliptin is useful in the therapy and/or
prophylaxis, such as e.g. treatment, prevention, protection,
reducing the risk, delaying the onset and/or slowing the
progression, of such conditions and/or related diseases, in (human)
patients in need thereof (who may be with or without diabetes (e.g.
type 2 diabetes), such as e.g. independently from or beyond
glycemic control).
[0061] Thus, the present invention provides a certain DPP-4
inhibitor as defined herein (preferably linagliptin, optionally in
combination with one or more other active agents) for use in
treating, preventing and/or reducing the risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS), and/or diseases related or
associated therewith.
[0062] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing
and/or reducing the risk of podocyte related disorders, disturbance
of podocyte function, podocyte loss or injury, and/or
podocytopathy, and/or diseases related or associated therewith.
[0063] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing or
reducing the likelihood or risk of nephrotic syndrome.
[0064] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing or
reducing the likelihood or risk of minimal change disease (MCD,
e.g. minimal change nephropathy, such as steroid hormone refractory
minimal change nephropathy).
[0065] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing or
reducing the likelihood or risk of membranous nephropathy (MN, e.g.
membranous glomerulonephritis).
[0066] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in treating, preventing or
reducing the likelihood or risk of focal segmental
glomerulosclerosis (FSGS).
[0067] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in reducing mortality,
morbidity, duration or frequency of hospitalization, in a patient
with or at risk of podocyte related disorders and/or nephrotic
syndrome, including minimal change disease (MCD, e.g. minimal
change nephropathy, such as steroid hormone refractory minimal
change nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0068] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in the treatment of
diabetic nephropathy, particularly diabetic nephropathy with an
elevated serum creatinine and proteinuria (>300 mg/day) in
patients with type 2 diabetes.
[0069] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in treating or lowering
albuminuria or diabetic nephropathy on top of
angiotensin-converting enzyme (ACE) inhibitor therapy and/or
angiotensin II receptor blockade (ARB) therapy in type 2 diabetes
patients, particularly with early diabetic nephropathy.
[0070] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in a method of treating,
preventing, reducing the risk of, delaying the onset or slowing the
progression of albuminuria (micro- or macro-albuminuria) or
diabetic nephropathy, preferably in type 2 diabetes patients,
particularly type 2 diabetes patients with early diabetic
nephropathy, especially in those patients with inadequate control
of albuminuria despite therapy with an angiotensin-converting
enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker
(ARB), particularly said method comprising administering the DPP-4
inhibitor in combination with the angiotensin-converting enzyme
(ACE) inhibitor and/or the angiotensin II receptor blocker (ARB) to
the patient.
[0071] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents, such as e.g. including an ARB or
ACE inhibitor) for use in preventing, reducing the risk of or
delaying the onset or slowing the progression of renal morbidity
and/or mortality, preferably in type 2 diabetes patients.
[0072] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in preventing, reducing
the risk of or delaying the onset or progression of micro- or
macro-albuminuria, chronic kidney disease (CKD), worsening of CKD,
and/or acute renal failure, preferably in type 2 diabetes
patients.
[0073] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in reducing the risk of or
delaying the onset or the progression of micro- or
macro-albuminuria, the onset of chronic kidney disease (CKD), the
worsening of CKD, the onset of acute renal failure and/or of death,
preferably in type 2 diabetes patients.
[0074] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin (optionally in combination with
one or more other active agents) for use in a method of preventing,
reducing the risk of or delaying the onset or progression of micro-
or macro-albuminuria, chronic kidney disease (CKD), worsening of
CKD, and/or acute renal failure, preferably in type 2 diabetes
patients, particularly type 2 diabetes patients with early diabetic
nephropathy, especially in those patients with inadequate control
of albuminuria despite therapy with an angiotensin-converting
enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker
(ARB), particularly said method comprising administering the DPP-4
inhibitor in combination with the angiotensin-converting enzyme
(ACE) inhibitor and/or the angiotensin II receptor blocker (ARB) to
the patient.
[0075] Further, the present invention relates to a certain DPP-4
inhibitor, preferably linagliptin optionally in combination with
one or more other active agents, such as e.g. one or more
antidiabetics, and/or optionally in combination with one or more
further active agents, such as e.g. one or more antiplatelet
agents, antihypertensive and/or lipid lowering agents) for use in
preventing, reducing the risk of or delaying the onset or slowing
the progression of renal morbidity and/or mortality, such as
preventing, reducing or delaying the onset or progression of micro-
or macro-albuminuria, the onset of chronic kidney disease (CKD),
the worsening of CKD, and/or the onset of acute renal failure
and/or of death, particularly in a human patient with diabetes,
especially type 2 diabetes mellitus; such as e.g. in a patient
(particularly diabetes patient, especially type 2 diabetes mellitus
patient) having renal- and/or cardiovascular--history and/or
medications, such as diabetic nephropathy, macrovascular disease
(e.g. coronary artery disease, periperal artery disease,
cerebrovascular disease, hypertension), microvascular disease (e.g.
diabetic nephropathy, neuropathy, retinopathy), coronary artery
disease, cerebrovascular disease, peripheral artery disease,
hypertension, ex-smoker or current smoker, and/or on
acetylsalicylic acid, antihypertensive and/or lipid lowering
medication, such as e.g. on (ongoing) therapy with acetylsalicylic
acid, an ACE inhibitor, ARB, beta-blocker, Calcium-anatgonist or
diuretic, or combination thereof, and/or on (ongoing) therapy with
a fibrate, niacin or statin, or combination thereof.
[0076] The present invention further provides a certain DPP-4
inhibitor as defined herein (preferably linagliptin, optionally in
combination with one or more other active agents) for use in for
treating and/or preventing metabolic diseases, particularly
diabetes, especially type 2 diabetes mellitus, and/or conditions
related thereto (e.g. diabetic complications), in a patient
(particularly human patient) with or at risk of podocyte related
disorders and/or nephrotic syndrome, including minimal change
disease (MCD, e.g. minimal change nephropathy, such as steroid
hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS).
[0077] 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, 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, hypertension,
atherosclerosis, endothelial dysfunction, osteoporosis, chronic
systemic inflammation, non alcoholic fatty liver disease (NAFLD),
retinopathy, neuropathy, nephropathy, nephrotic syndrome,
polycystic ovarian syndrome, and/or metabolic syndrome.
[0078] The present invention further relates to a certain DPP-4
inhibitor (preferably linagliptin, optionally in combination with
one or more other active agents) for use in at least one of the
following methods: [0079] 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, hypertension, atherosclerosis, endothelial
dysfunction, osteoporosis, chronic systemic inflammation, non
alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy,
nephropathy, nephrotic syndrome, polycystic ovarian syndrome,
and/or metabolic syndrome; [0080] 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; [0081]
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; [0082] 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, nephrotic syndrome, retinopathy,
cataracts, neuropathy, learning or memory impairment,
neurodegenerative or cognitive disorders, 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; [0083] 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;
[0084] 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; [0085] 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); [0086]
preventing, slowing the progression of, delaying the onset of or
treating type 2 diabetes with failure to conventional antidiabetic
mono- or combination therapy; [0087] achieving a reduction in the
dose of conventional antidiabetic medication required for adequate
therapeutic effect; [0088] reducing the risk for adverse effects
associated with conventional antidiabetic medication (e.g.
hypoglycemia or weight gain); and/or [0089] maintaining and/or
improving the insulin sensitivity and/or for treating or preventing
hyperinsulinemia and/or insulin resistance; in a patient in need
thereof (such as e.g. a patient as described herein, for example a
human patient having diabetes), and/or particularly in a patient
(particularly human patient) with or at risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS).
[0090] In an embodiment, the patient with or at risk of podocyte
related disorders, disturbance of podocyte function, podocyte loss
or injury, podocytopathy, glomerulopathy, nephrotic syndrome,
minimal change disease (MCD, e.g. minimal change nephropathy, such
as steroid hormone refractory minimal change nephropathy),
membranous nephropathy (MN, e.g. membranous glomerulonephritis)
and/or focal segmental glomerulosclerosis (FSGS) as described
herein is diabetic.
[0091] In another embodiment, the patient with or at risk of
podocyte related disorders, disturbance of podocyte function,
podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic
syndrome, minimal change disease (MCD, e.g. minimal change
nephropathy, such as steroid hormone refractory minimal change
nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS) as described herein is non-diabetic.
[0092] 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).
[0093] In particular, the subject within this invention may be a
human, e.g. human child, a human adolescent or, particularly, a
human adult.
[0094] Accordingly, in a particular embodiment, a preferred DPP-4
inhibitor within the meaning of this invention is linagliptin.
[0095] Pharmaceutical compositions or combinations for use in these
therapies (treatments or preventions) comprising a certain DPP-4
inhibitor (preferably linagliptin) as defined herein optionally
together with one or more other active agents are also
contemplated.
[0096] Further, the present invention relates to a certain DPP-4
inhibitor (preferably linagliptin), optionally in combination with
one, two or more further active agents, each as defined herein, for
use in the therapies (treatments or preventions) as described
herein.
[0097] Further, the present invention relates to the use of a
certain DPP-4 inhibitor (preferably linagliptin), optionally in
combination with one, two or more further active agents, each as
defined herein, for preparing a pharmaceutical composition which is
suitable for the treatment and/or prevention purposes of this
invention.
[0098] Further, the present invention relates to a therapeutic
(treatment or prevention) method as described herein, said method
comprising administering an effective amount of a certain DPP-4
inhibitor (preferably linagliptin) and, optionally, one or more
other active or therapeutic agents to the patient in need thereof,
each as described herein.
[0099] Other aspects of the present invention become apparent to
the skilled person from the foregoing and following remarks
(including the examples and claims).
[0100] The aspects of the present invention, in particular the
pharmaceutical compounds, compositions, combinations, methods and
uses, refer to a certain DPP-4 inhibitor (preferably linagliptin),
optionally in combination with one or more other active agents, as
defined hereinbefore and hereinafter.
[0101] 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. 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
Industrialised World because of diabetes induced complications and
is associated with a two to five fold increase in cardiovascular
disease risk.
[0102] Furthermore, diabetes (particularly type 2 diabetes) is
often coexistent and interrelated with obesity and these two
conditions together impose a particularly complex therapeutic
challenge. Because of the effects of obesity on insulin resistance,
weight loss and its maintenance is an important therapeutic
objective in overweight or obese individuals with prediabetes,
metabolic syndrome or diabetes. Studies have been demonstrated that
weight reduction in subjects with type 2 diabetes is associated
with decreased insulin resistance, improved measures of glycemia
and lipemia, and reduced blood pressure. Maintenance of weight
reduction over longer term is considered to improve glycemic
control and prevent diabetic complications (e.g. reduction of risk
for cardiovascular diseases or events). Thus, weight loss is
recommended for all overweight or obese individuals who have or are
at risk for diabetes. However, obese patients with type 2 diabetes
have much greater difficulty losing weight and maintain the reduced
weight than the general non-diabetic population.
[0103] Overweight may be defined as the condition wherein the
individual has a body mass index (BMI) greater than or 25
kg/m.sup.2 and less than 30 kg/m.sup.2. The terms "overweight" and
"pre-obese" are used interchangeably.
[0104] Obesity may be also defined as the condition wherein the
individual has a BMI equal to or greater than 30 kg/m.sup.2.
According to a WHO definition the term obesity may be categorized
as follows: class I obesity is the condition wherein the BMI is
equal to or greater than 30 kg/m.sup.2 but lower than 35
kg/m.sup.2; class II obesity is the condition wherein the BMI is
equal to or greater than 35 kg/m.sup.2 but lower than 40
kg/m.sup.2; class III obesity (extreme obesity) is the condition
wherein the BMI is equal to or greater than 40 kg/m.sup.2. Obesity
may include e.g. visceral or abdominal obesity.
[0105] Visceral obesity may be defined as the condition wherein a
waist-to-hip ratio of greater than or equal to 1.0 in men and 0.8
in women is measured. It defines the risk for insulin resistance
and the development of pre-diabetes.
[0106] Abdominal obesity may usually be defined as the condition
wherein the waist circumference is >40 inches or 102 cm in men,
and is >35 inches or 94 cm in women. With regard to a Japanese
ethnicity or Japanese patients abdominal obesity may be defined as
waist circumference .gtoreq.85 cm in men and .gtoreq.90 cm in women
(see e.g. investigating committee for the diagnosis of metabolic
syndrome in Japan).
[0107] 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.
[0108] 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 insulin 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.
[0109] 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.
[0110] 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, tolerability and dosing inconvenience of
conventional antihyperglycemic therapies.
[0111] 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 complications.
[0112] 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 nephropathy,
retinopathy or neuropathy, or cerebro- or cardiovascular
complications such as e.g. myocardial infarction, stroke or
vascular mortality or morbidity) in patients with diabetes.
[0113] Oral antidiabetic drugs conventionally used in therapy (such
as e.g. first- or second-line, and/or mono- or (initial or add-on)
combination therapy) include, without being restricted thereto,
metformin, sulphonylureas, thiazolidinediones, glinides and
.alpha.-glucosidase inhibitors.
[0114] Non-oral (typically injected) antidiabetic drugs
conventionally used in therapy (such as e.g. first- or second-line,
and/or mono- or (initial or add-on) combination therapy) include,
without being restricted thereto, GLP-1 or GLP-1 analogues, and
insulin or insulin analogues.
[0115] 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).
[0116] Therefore, it remains a need in the art to provide
efficacious, safe and tolerable antidiabetic therapies.
[0117] Further, within the therapy of type 2 diabetes, it is a need
for treating the condition effectively, avoiding the complications
inherent to the condition, and delaying disease progression, e.g.
in order to achieve a long-lasting therapeutic benefit.
[0118] Furthermore, it remains a need that antidiabetic treatments
not only prevent 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 complications, such as renal impairment.
[0119] Moreover, it remains a need to provide prevention or
reduction of risk for adverse effects associated with conventional
antidiabetic therapies.
[0120] 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.
[0121] For example, DPP-4 inhibitors and their uses are disclosed
in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469,
WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO
2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769,
WO2007/014886; WO 2004/050658, WO 2004/111051, WO 2005/058901, WO
2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO
2007/128721, WO 2007/128724, WO 2007/128761, or WO 2009/121945.
[0122] 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.
[0123] 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 7.5 to 10% (or, in another embodiment, from 7.5 to 11%).
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%.
[0124] 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 70-130 mg/dL (or
90-130 mg/dL) or <110 mg/dL, and of two-hour postprandial plasma
glucose are <180 mg/dL or <140 mg/dL.
[0125] In one 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 another embodiment, diabetes patients within the
meaning of this invention may include 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.
[0126] A further embodiment of diabetic patients within the meaning
of this invention refers to patients ineligible for metformin
therapy including [0127] patients for whom metformin therapy is
contraindicated, e.g. patients having one or more contraindications
against metformin therapy according to label, such as for example
patients with at least one contraindication selected from: [0128]
renal disease, renal impairment or renal dysfunction (e.g., as
specified by product [0129] information of locally approved
metformin), [0130] dehydration, [0131] unstable or acute congestive
heart failure, [0132] acute or chronic metabolic acidosis, and
[0133] hereditary galactose intolerance; and [0134] patients who
suffer from one or more intolerable side effects attributed to
metformin, particularly gastrointestinal side effects associated
with metformin, such as for example patients suffering from at
least one gastrointestinal side effect selected from: [0135]
nausea, [0136] vomiting, [0137] diarrhoea, [0138] intestinal gas,
and [0139] severe abdominal discomfort.
[0140] A further embodiment of the diabetes 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 not 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 (mildly) impaired/reduced renal function (including
elderly patients, such as e.g. .gtoreq.60-65 years).
[0141] A further embodiment of patients (e.g. which may be diabetic
or non-diabetic) within the meaning of this invention refers to
patients having renal disease, renal dysfunction, or insufficiency
or impairment of renal function (including mild, moderate and
severe renal impairment), e.g. as suggested by elevated serum
creatinine levels (e.g. serum creatinine levels above the upper
limit of normal for their age, e.g. .gtoreq.130-150 .mu.mol/l, or
.gtoreq.1.5 mg/dl (.gtoreq.136 .mu.mol/l) in men and .gtoreq.1.4
mg/dl (.gtoreq.124 .mu.mol/l) in women) or abnormal creatinine
clearance (e.g. glomerular filtration rate (GFR) .ltoreq.30-60
ml/min).
[0142] In this context, for more detailed example, mild renal
impairment may be e.g. suggested by a creatinine clearance of 50-80
ml/min (approximately corresponding to serum creatine levels of
.ltoreq.1.7 mg/dL in men and .ltoreq.1.5 mg/dL in women); moderate
renal impairment may be e.g. suggested by a creatinine clearance of
30-50 ml/min (approximately corresponding to serum creatinine
levels of >1.7 to .ltoreq.3.0 mg/dL in men and >1.5 to
.ltoreq.2.5 mg/dL in women); and severe renal impairment may be
e.g. suggested by a creatinine clearance of <30 ml/min
(approximately corresponding to serum creatinine levels of >3.0
mg/dL in men and >2.5 mg/dL in women). Patients with end-stage
renal disease require dialysis (e.g. hemodialysis or peritoneal
dialysis).
[0143] For other more detailed example, patients with renal
disease, renal dysfunction or renal impairment include patients
with chronic renal insufficiency or impairment, which can be
stratified according to glomerular filtration rate (GFR,
ml/min/1.73 m.sup.2) into 5 disease stages: stage 1 characterized
by normal GFR .gtoreq.90 plus either persistent albuminuria or
known structural or hereditary renal disease; stage 2 characterized
by mild reduction of GFR (GFR 60-89) describing mild renal
impairment; stage 3 characterized by moderate reduction of GFR (GFR
30-59) describing moderate renal impairment; stage 4 characterized
by severe reduction of GFR (GFR 15-29) describing severe renal
impairment; and terminal stage 5 characterized by requiring
dialysis or GFR <15 describing established kidney failure
(end-stage renal disease, ESRD).
[0144] A further embodiment of patients (e.g. which may be diabetic
or non-diabetic) within the meaning of this invention refers to
diabetes patients with or at risk of developing renal
complications, such as diabetic nephropathy (including chronic and
progressive renal insufficiency, albuminuria, proteinuria, fluid
retention in the body (edema) and/or hypertension).
[0145] In certain embodiments, the patients which may be amenable
to the therapies of this invention may have or are at-risk of one
or more of the following diseases, disorders or conditions: type 1
diabetes, type 2 diabetes, impaired glucose tolerance (IGT),
impaired fasting blood glucose (IFG), hyperglycemia, postprandial
hyperglycemia, postabsorptive hyperglycemia, latent autoimmune
diabetes in adults (LADA), overweight, obesity, dyslipidemia
(including e.g. atherogenic dyslipidemia), hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia,
postprandial lipemia, hypertension, atherosclerosis, endothelial
dysfunction, osteoporosis, chronic systemic inflammation, non
alcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome,
hyperuricemia, metabolic syndrome, nephropathy, micro- or
macroalbuminuria, proteinuria, nephrotic syndrome, retinopathy,
cataracts, neuropathy, learning or memory impairment,
neurodegenerative or cognitive disorders, 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 (including e.g. uremic cardiomyopathy), heart
failure, cardiac hypertrophy, heart rhythm disorders, vascular
restenosis, stroke, (renal, cardiac, cerebral or hepatic)
ischemia/reperfusion injuries, (renal, cardiac, cerebral or
hepatic) fibrosis, (renal, cardiac, cerebral or hepatic) vascular
remodelling; a diabetic disease, e.g. type 2 diabetes mellitus
being (with or without obesity) being particularly to be noted
(e.g. as an underlying disease).
[0146] In a further embodiment, the patients with or at-risk of
SIRS/sepsis which may be amenable to the therapies of this
invention have a diabetic disease, such as e.g. type 2 diabetes
mellitus, and, optionally, may have or are at-risk of one or more
other diseases, disorders or conditions, such as e.g. selected from
those mentioned immediately above.
[0147] Accordingly, the present invention thus relates to a certain
DPP-4 inhibitor as defined herein, preferably linagliptin (BI
1356), for use in the therapies (treatments and/or preventions)
described herein.
[0148] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with metformin, for use in the therapies (treatments
and/or preventions) described herein.
[0149] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with pioglitazone, for use in the therapies (treatments
and/or preventions) described herein.
[0150] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with telmisartan, for use in the therapies (treatments
and/or preventions) described herein.
[0151] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with a GLP-1 receptor agonist (such as e.g. exenatide,
exenatide LAR, liraglutide, taspoglutide, semaglutide, albiglutide,
lixisenatide, dulaglutide, or native GLP-1) for use in the
therapies (treatments and/or preventions) described herein.
[0152] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with an insulin or insulin analogue (e.g. basal
insulin, such as e.g. insulin glargin, insulin detemir or insulin
degludec, or NPH insulin) for use in the therapies (treatments
and/or preventions) described herein.
[0153] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with a diuretic, an ARB and/or an ACE inhibitor for use
in the therapies (treatments and/or preventions) described herein.
The present invention further relates to a certain DPP-4 inhibitor
as defined herein, preferably linagliptin (BI 1356), in combination
with a corticosteroid for use in the therapies (treatments and/or
preventions) described herein.
[0154] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with one or more other active agents, e.g. selected
from other antidiabetic substances, active substances that lower
the blood sugar level, active substances that lower the lipid level
in the blood, active substances that raise the HDL level in the
blood, active substances that lower blood pressure, and active
substances that are indicated in the treatment of atherosclerosis
or obesity, for use in the therapies (treatments and/or
preventions) described herein.
[0155] The present invention further relates to a certain DPP-4
inhibitor as defined herein, preferably linagliptin (BI 1356), in
combination with one or more other antidiabetics selected from the
group consisting of metformin, a sulphonylurea, nateglinide,
repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, an
alpha-glucosidase inhibitor, insulin or an insulin analogue, and
GLP-1 or a GLP-1 analogue, optionally in combination with one or
more further active agents (e.g. selected from a diuretic, ACE
inhibitor and/or ARB, such as e.g. telmisartan), for use in the
therapies (treatments and/or preventions) described herein.
[0156] The present invention further relates to a pharmaceutical
composition comprising a certain DPP-4 inhibitor as defined herein,
preferably linagliptin (BI 1356), for use in the therapies
described herein.
[0157] The present invention further relates to a pharmaceutical
composition comprising a certain DPP-4 inhibitor as defined herein,
preferably linagliptin (BI 1356), and metformin, for use in the
therapies described herein.
[0158] The present invention further relates to a pharmaceutical
composition comprising a certain
[0159] DPP-4 inhibitor as defined herein, preferably linagliptin
(BI 1356), and pioglitazone, for use in the therapies described
herein.
[0160] The present invention further relates to a combination
comprising a certain DPP-4 inhibitor (particularly linagliptin) and
one or more other active agents selected from those mentioned
herein, e.g. selected from other antidiabetic substances, active
substances that lower the blood sugar level, active substances that
lower the lipid level in the blood, active substances that raise
the HDL level in the blood, active substances that lower blood
pressure, active substances that are indicated in the treatment of
atherosclerosis or obesity, e.g. each as described herein;
particularly for simultaneous, separate or sequential use in the
therapies described herein.
[0161] The present invention further relates to a combination
comprising a certain DPP-4 inhibitor (particularly linagliptin) and
one or more other antidiabetics selected from the group consisting
of metformin, a sulphonylurea, nateglinide, repaglinide, a
thiazolidinedione, a PPAR-gamma-agonist, an alpha-glucosidase
inhibitor, insulin or an insulin analogue, and GLP-1 or a GLP-1
analogue, particularly for simultaneous, separate or sequential use
in the therapies described herein, optionally in combination with a
diuretic, ACE inhibitor and/or ARB, such as e.g. telmisartan.
[0162] The present invention further relates to therapies or
therapeutic or preventive methods or uses as described herein, such
as e.g. to a method for treating and/or preventing a metabolic
disease, such as e.g. type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications) comprising
administering (e.g. simultaneously, separately or sequentially) an
effective amount of a certain DPP-4 inhibitor (particularly
linagliptin) as defined herein and, optionally, one or more other
active agents, such as e.g. one or more other antidiabetics
selected from the group consisting of metformin, a sulphonylurea,
nateglinide, repaglinide, a thiazolidinedione, a
PPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or an
insulin analogue, and GLP-1 or a GLP-1 analogue,
[0163] optionally in combination with one or more further active
agents (e.g. a diuretic, ACE inhibitor and/or ARB, such as e.g.
telmisartan), to the patient (particularly human patient) in need
thereof, such as e.g. a patient as described herein, including a
patient with or at risk of podocyte related disorders, disturbance
of podocyte function, podocyte loss or injury, podocytopathy,
glomerulopathy, nephrotic syndrome, minimal change disease (MCD,
e.g. minimal change nephropathy, such as steroid hormone refractory
minimal change nephropathy), membranous nephropathy (MN, e.g.
membranous glomerulonephritis) and/or focal segmental
glomerulosclerosis (FSGS).
[0164] The present invention further relates to therapies or
therapeutic or preventive methods or uses as described herein, such
as e.g. a method for treating and/or preventing a metabolic
disease, such as e.g. type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications), comprising
administering an effective amount of linagliptin (BI 1356) and
metformin, and optionally one or more further active agents, to the
patient (particularly human patient) in need thereof, such as e.g.
a patient as described herein, including a patient with or at risk
of podocyte related disorders, disturbance of podocyte function,
podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic
syndrome, minimal change disease (MCD, e.g. minimal change
nephropathy, such as steroid hormone refractory minimal change
nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0165] The present invention further relates to therapies or
therapeutic or preventive methods or uses as described herein, such
as e.g. a method for treating and/or preventing a metabolic
disease, such as e.g. type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications), comprising
administering an effective amount of linagliptin (BI 1356) and
pioglitazone, and optionally one or more further active agents, to
the patient (particularly human patient) in need thereof, such as
e.g. a patient as described herein, including a patient with or at
risk of podocyte related disorders, disturbance of podocyte
function, podocyte loss or injury, podocytopathy, glomerulopathy,
nephrotic syndrome, minimal change disease (MCD, e.g. minimal
change nephropathy, such as steroid hormone refractory minimal
change nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0166] The present invention further relates to therapies or
therapeutic or preventive methods or uses as described herein, such
as e.g. a method for treating and/or preventing a metabolic
disease, such as e.g. type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications), comprising
administering an effective amount of linagliptin (BI 1356) and
telmisartan, and optionally one or more further active agents, to
the patient (particularly human patient) in need thereof, such as
e.g. a patient as described herein, including a patient with or at
risk of podocyte related disorders, disturbance of podocyte
function, podocyte loss or injury, podocytopathy, glomerulopathy,
nephrotic syndrome, minimal change disease (MCD, e.g. minimal
change nephropathy, such as steroid hormone refractory minimal
change nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0167] The present invention further relates to therapies or
therapeutic or preventive methods or uses as described herein, such
as e.g. a method for treating and/or preventing a metabolic
disease, such as e.g. type 2 diabetes mellitus and/or conditions
related thereto (e.g. diabetic complications), comprising
administering an effective amount of linagliptin (BI 1356) and an
insulin or insulin analogue (such as e.g. a basal insulin), and
optionally one or more further active agents, to the patient
(particularly human patient) in need thereof, such as e.g. a
patient as described herein, including a patient with or at risk of
podocyte related disorders, disturbance of podocyte function,
podocyte loss or injury, podocytopathy, glomerulopathy, nephrotic
syndrome, minimal change disease (MCD, e.g. minimal change
nephropathy, such as steroid hormone refractory minimal change
nephropathy), membranous nephropathy (MN, e.g. membranous
glomerulonephritis) and/or focal segmental glomerulosclerosis
(FSGS).
[0168] Further, the present invention relates to a method of
treating, preventing and/or reducing the risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS) in a patient (particularly a
human patient, who may suffer from diabetes, e.g. type 1 or type 2
diabetes or LADA, particularly type 2 diabetes, or who may be
non-diabetic) in need thereof, comprising administering an
effective amount of linagliptin, optionally in combination with one
or more other active agents (including active substances which are
indicated in the treatment of nephrotic syndrome, such as e.g.
selected from corticosteroids (e.g. prednisone or prednisolone),
diuretics, ACE inhibitors, ARBs such as e.g. telmisartan,
cyclophosphamide, cyclosporine, and/or anticoagulants), to the
patient.
[0169] Further, the present invention relates to a method of
treating, preventing and/or reducing the risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS) in a patient (particularly a
human patient, who may suffer from diabetes, e.g. type 1 or type 2
diabetes or LADA, particularly type 2 diabetes, or who may be
non-diabetic) in need thereof, comprising administering an
effective amount of linagliptin, optionally in combination with one
or more other active agents, e.g. selected from other antidiabetic
substances, active substances that lower the blood sugar level,
active substances that lower the lipid level in the blood, active
substances that raise the HDL level in the blood, active substances
that lower blood pressure, active substances that are indicated in
the treatment of atherosclerosis or obesity, and/or active
substances which are indicated in the treatment of nephrotic
syndrome, to the patient.
[0170] Further, the present invention relates to a method of
treating, preventing and/or reducing the risk of podocyte related
disorders, disturbance of podocyte function, podocyte loss or
injury, podocytopathy, glomerulopathy, nephrotic syndrome, minimal
change disease (MCD, e.g. minimal change nephropathy, such as
steroid hormone refractory minimal change nephropathy), membranous
nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal
segmental glomerulosclerosis (FSGS) in a patient (particularly a
human patient, who may suffer from diabetes, e.g. type 1 or type 2
diabetes or LADA, particularly type 2 diabetes, or who may be
non-diabetic) in need thereof, comprising administering an
effective amount of linagliptin and one or more other antidiabetics
selected from the group consisting of metformin, a sulphonylurea,
nateglinide, repaglinide, a thiazolidinedione, a
PPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or an
insulin analogue, and GLP-1 or a GLP-1 analogue, optionally in
combination with one or more further active agents (e.g. an active
substance which is indicated in the treatment of nephrotic
syndrome, such as a corticosteroid (e.g. prednisone or
prednisolone), a diuretic, ACE inhibitor, ARB such as e.g.
telmisartan, cyclophosphamide, cyclosporine, and/or an
anticoagulant), to the patient.
[0171] A DPP-4 inhibitor within the meaning of the present
invention includes, without being limited to, any of those DPP-4
inhibitors mentioned hereinabove and hereinbelow, preferably orally
and/or subcutaneously active DPP-4 inhibitors.
[0172] In a first embodiment (embodiment A), a DPP-4 inhibitor in
the context of the present invention is any DPP-4 inhibitor of
formula (I)
##STR00001##
or formula (II)
##STR00002##
or formula (III)
##STR00003##
or formula (IV)
##STR00004##
wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,
(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,
(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,
(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,
(4-methyl-pyrimidin-2-yl)methyl, or
(4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes
3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino
or (2-(S)-amino-propyl)-methylamino, or its pharmaceutically
acceptable salt.
[0173] Regarding the first embodiment (embodiment A), preferred
DPP-4 inhibitors are any or all of the following compounds and
their pharmaceutically acceptable salts: [0174]
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example
2(142)):
[0174] ##STR00005## [0175]
1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-ami-
no-piperidin-1-yl)-xanthine (compare WO 2004/018468, example
2(252)):
[0175] ##STR00006## [0176]
1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pipe-
ridin-1-yl)-xanthine (compare WO 2004/018468, example 2(80)):
[0176] ##STR00007## [0177]
2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-y-
lmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (compare WO
2004/050658, example 136):
[0177] ##STR00008## [0178]
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-ami-
no-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006/029769,
example 2(1)):
[0178] ##STR00009## [0179]
1-[(3-Cyano-quinolin-211)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(30)):
[0179] ##STR00010## [0180]
1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-y-
l)-xanthine (compare WO 2005/085246, example 1(39)):
[0180] ##STR00011## [0181]
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2--
amino-propyl)-methylamino]-xanthine (compare WO 2006/029769,
example 2(4)):
[0181] ##STR00012## [0182]
1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-
-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(52)):
[0182] ##STR00013## [0183]
1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-am-
ino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(81)):
[0183] ##STR00014## [0184]
1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)--
3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example
1(82)):
[0184] ##STR00015## [0185]
1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-pipe-
ridin-1-yl)-xanthine (compare WO 2005/085246, example 1(83)):
##STR00016##
[0186] These DPP-4 inhibitors are distinguished from structurally
comparable DPP-4 inhibitors, as they combine exceptional potency
and a long-lasting effect with favourable pharmacological
properties, receptor selectivity and a favourable side-effect
profile or bring about unexpected therapeutic advantages or
improvements when combined with other pharmaceutical active
substances. Their preparation is disclosed in the publications
mentioned.
[0187] In a second embodiment (embodiment B), a DPP-4 inhibitor in
the context of the present invention is a DPP-4 inhibitor selected
from the group consisting of sitagliptin, vildagliptin,
saxagliptin, alogliptin, gemigliptin, [0188]
(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidin-
e-2-carbonitrile, [0189]
(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acet-
yl}-pyrrolidine-2-carbonitrile, [0190]
(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyr-
ido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one, [0191]
(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-y-
l)pyrrolidin-2-yl)methanone, [0192]
(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)-
pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, [0193]
(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-ac-
etyl}-4-fluoropyrrolidine-2-carbonitrile, [0194]
(R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrim-
idin-1-ylmethyl]-4-fluoro-benzonitrile, [0195]
5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-
-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic
acid bis-dimethylamide, [0196]
3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrroli-
din-2-ylcarbonyl}thiazolidine, [0197]
[(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic
acid, [0198]
(2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl-
]-4-fluoropyrrolidine-2-carbonitrile, [0199]
2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,-
4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,
[0200]
6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-d-
imethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, and [0201]
(S)-2-methylpyrazolo[1,5-a]primidine-6-carboxylic acid
{2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide,
[0202] or its pharmaceutically acceptable salt.
[0203] A more preferred DPP-4 inhibitor among the abovementioned
DPP-4 inhibitors of embodiment A of this invention is
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine, particularly the free base thereof
(which is also known as linagliptin or BI 1356).
[0204] Preferably the DPP-4 inhibitor of this invention is 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.
[0205] A particularly preferred DPP-4 inhibitor to be emphasized
within the present invention is linagliptin. The term "linagliptin"
as employed herein refers to linagliptin or a pharmaceutically
acceptable salt thereof, including hydrates and solvates thereof,
and crystalline forms thereof, preferably linagliptin refers to
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine. Crystalline forms are described in
WO 2007/128721. Methods for the manufacture of linagliptin are
described in the patent applications WO 2004/018468 and WO
2006/048427 for example. Linagliptin is distinguished from
structurally comparable DPP-4 inhibitors, as it combines
exceptional potency and a long-lasting effect with favourable
pharmacological properties, receptor selectivity and a favourable
side-effect profile or bring about unexpected therapeutic
advantages or improvements in mono- or dual or triple combination
therapy.
[0206] For avoidance of any doubt, the disclosure of each of the
foregoing and following documents cited above in connection with
the specified DPP-4 inhibitors is specifically incorporated herein
by reference in its entirety.
[0207] An embodiment of this invention refers to a DPP-4 inhibitor
suitable for use in the treatment and/or prevention of metabolic
diseases (particularly type 2 diabetes mellitus) in patients,
wherein said patients further suffering from renal disease, renal
dysfunction or renal impairment, particularly characterized in that
said DPP-4 inhibitor is administered to said patients in the same
dose levels as to patients with normal renal function, thus e.g.
said DPP-4 inhibitor does not require downward dosing adjustment
for impaired renal function.
[0208] For example, a DPP-4 inhibitor according to this invention
(especially one which may be suited for patients with impaired
renal function) may be such an oral DPP-4 inhibitor, which and
whose active metabolites have preferably a relatively wide (e.g.
about >100 fold) therapeutic window and/or, especially, that are
primarily eliminated via hepatic metabolism or biliary excretion
(preferably without adding additional burden to the kidney).
[0209] In more detailed example, a DPP-4 inhibitor according to
this invention (especially one which may be suited for patients
with impaired renal function) may be such an orally administered
DPP-4 inhibitor, which has a relatively wide (e.g. >100 fold)
therapeutic window (preferably a safety profile comparable to
placebo) and/or which fulfils one or more of the following
pharmacokinetic properties (preferably at its therapeutic oral dose
levels): [0210] The DPP-4 inhibitor is substantially or mainly
excreted via the liver (e.g. >80% or even >90% of the
administered oral dose), and/or for which renal excretion
represents no substantial or only a minor elimination pathway (e.g.
<10%, preferably <7%, of the administered oral dose measured,
for example, by following elimination of a radiolabelled carbon
(.sup.14C) substance oral dose); [0211] The DPP-4 inhibitor is
excreted mainly unchanged as parent drug (e.g. with a mean of
>70%, or >80%, or, preferably, 90% of excreted radioactivity
in urine and feces after oral dosing of radiolabelled carbon
(.sup.14C) substance), and/or which is eliminated to a
non-substantial or only to a minor extent via metabolism (e.g.
<30%, or <20%, or, preferably, 10%); [0212] The (main)
metabolite(s) of the DPP-4 inhibitor is/are pharmacologically
inactive. Such as e.g. the main metabolite does not bind to the
target enzyme DPP-4 and, optionally, it is rapidly eliminated
compared to the parent compound (e.g. with a terminal half-life of
the metabolite of .ltoreq.20 h, or, preferably, .ltoreq. about 16
h, such as e.g. 15.9 h).
[0213] In one embodiment, the (main) metabolite in plasma (which
may be pharmacologically inactive) of a DPP-4 inhibitor having a
3-amino-piperidin-1-yl substituent is such a derivative where the
amino group of the 3-amino-piperidin-1-yl moiety is replaced by a
hydroxyl group to form the 3-hydroxy-piperidin-1-yl moiety (e.g.
the 3-(S)-hydroxy-piperidin-1-yl moiety, which is formed by
inversion of the configuration of the chiral center).
[0214] Further properties of a DPP-4 inhibitor according to this
invention may be one or more of the following: Rapid attainment of
steady state (e.g. reaching steady state plasma levels (>90% of
the steady state plasma concentration) between second and fifth day
of treatment with therapeutic oral dose levels), little
accumulation (e.g. with a mean accumulation ratio
R.sub.A,AUC.ltoreq.1.4 with therapeutic oral dose levels), and/or
preserving a long-lasting effect on DPP-4 inhibition, preferably
when used once-daily (e.g. with almost complete (>90%) DPP-4
inhibition at therapeutic oral dose levels, >80% inhibition over
a 24 h interval after once-daily intake of therapeutic oral drug
dose), significant decrease in 2 h postprandial blood glucose
excursions by 80% (already on first day of therapy) at therapeutic
dose levels, and cumulative amount of unchanged parent compound
excreted in urine on first day being below 1% of the administered
dose and increasing to not more than about 3-6% in steady
state.
[0215] Thus, for example, a DPP-4 inhibitor according to this
invention may be characterized in that said DPP-4 inhibitor has a
primarily non-renal route of excretion, i.e. said DPP-4 inhibitor
is excreted to a non-substantial or only to a minor extent (e.g.
<10%, preferably <7%, e.g. about 5%, of administered oral
dose, preferably of oral therapeutic dose) via the kidney
(measured, for example, by following elimination of a radiolabelled
carbon (.sup.14C) substance oral dose).
[0216] Further, a DPP-4 inhibitor according to this invention may
be characterized in that said DPP-4 inhibitor is excreted
substantially or mainly via the liver, bile or feces (measured, for
example, by following elimination of a radiolabelled carbon
(.sup.14C) substance oral dose).
[0217] Further, a DPP-4 inhibitor according to this invention may
be characterized in that said DPP-4 inhibitor is excreted mainly
unchanged as parent drug (e.g. with a mean of >70%, or >80%,
or, preferably, 90% of excreted radioactivity in urine and feces
after oral dosing of radiolabelled carbon (.sup.14C)
substance),
said DPP-4 inhibitor is eliminated to a non-substantial or only to
a minor extent via metabolism, and/or the main metabolite of said
DPP-4 inhibitor is pharmacologically inactive or has a relatively
wide therapeutic window.
[0218] Further, a DPP-4 inhibitor according to this invention may
be characterized in that said DPP-4 inhibitor does not
significantly impair glomerular and/or tubular function of a type 2
diabetes patient with chronic renal insufficiency (e.g. mild,
moderate or severe renal impairment or end stage renal disease),
and/or
said DPP-4 inhibitor trough levels in the blood plasma of type 2
diabetes patients with mild or moderate renal impairment are
comparable to the levels in patients with normal renal function,
and/or said DPP-4 inhibitor does not require to be dose-adjusted in
a type 2 diabetes patient with impaired renal function (e.g. mild,
moderate or severe renal impairment or end stage renal disease,
preferably regardless of the stage of renal impairment).
[0219] Further, a DPP-4 inhibitor according to this invention may
be characterized in that said DPP-4 inhibitor provides its
minimally effective dose at that dose that results in >50%
inhibition of DPP-4 activity at trough (24 h after last dose) in
>80% of patients, and/or said DPP-4 inhibitor provides its fully
therapeutic dose at that dose that results in >80% inhibition of
DPP-4 activity at trough (24 h after last dose) in >80% of
patients.
[0220] Further, a DPP-4 inhibitor according to this invention may
be characterized in that being suitable for use in type 2 diabetes
patients who are with diagnosed renal impairment or complication
and/or who are at risk of developing renal complications, e.g.
patients with or at risk of diabetic nephropathy (including chronic
and progressive renal insufficiency, albuminuria, proteinuria,
fluid retention in the body (edema) and/or hypertension).
[0221] GLP-1 receptor agonists include, without being limited,
exogenous GLP-1 (natural or synthetic), GLP-1 mimetics or analogues
(including longer acting analogues which are resistant to or have
reduced susceptibility to enzymatic degradation by DPP-4 and NEP
24.11) and other substances (whether peptidic or non-peptidic, e.g.
small molecules) which promote signalling through the GLP-1
receptor.
[0222] Examples of GLP-1 analogues may include (group G2):
exenatide (synthetic exendin-4, e.g. formulated as Byetta.RTM.);
exenatide LAR (long acting release formulation of exenatide, e.g.
formulated as Bydureon.RTM.); liraglutide (e.g. formulated as
Victoza.RTM.); taspoglutide; semaglutide; albiglutide (e.g.
formulated as Syncria); lixisenatide; dulaglutide; and the
di-PEGylated GLP-1 compound comprising the amino acid sequence of
the pegylated SEQ ID NO:1, wherein Xaa at position 2 is D-Ala, Gly,
Val, Leu, Ile, Ser or Thr; Xaa at position 16 is Gly, Glu, Asp or
Lys; and Xaa at position 27 is Val or Ile, and wherein one PEG
molecule is covalently attached to the Cys residue at position 39
[[Cys.sub.45]] and one PEG molecule is covelently attached to the
Cys residue at position 40 [[Cys.sub.46-NH.sub.2]], wherein each of
the PEG molecules used for PEGylation reaction is a 20,000 dalton
linear methoxy PEG maleimide. Preferably the GLP-1 consists of the
amino acid sequence of SQ ID NO:2.
[0223] Preferred examples of GLP-1 receptor agonists (GLP-1
analogues) of this invention are exenatide, exenatide LAR,
liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide
and dulaglutide.
[0224] GLP-1 analogues have typically significant sequence identity
to GLP-1 (e.g. greater than 50%, 75%, 90% or 95%) and may be
derivatised, e.g. by conjunction to other proteins (e.g. albumin or
IgG-Fc fusion protein) or through chemical modification.
[0225] In an embodiment, the GLP-1 receptor agonist is preferably
administered by injection (preferably subcutaneously).
[0226] Unless otherwise noted, according to this invention it is to
be understood that the definitions of the active agents (including
the DPP-4 inhibitors and GLP-1 receptor agonists) mentioned
hereinabove and herein below may also contemplate their
pharmaceutically acceptable salts, and prodrugs, hydrates, solvates
and polymorphic forms thereof. Particularly the terms of the
therapeutic agents given herein refer to the respective active
drugs. With respect to salts, hydrates and polymorphic forms
thereof, particular reference is made to those which are referred
to herein.
[0227] An effective amount of a compound as used herein means an
amount sufficient to cure, alleviate or partially arrest the
clinical manifestations of a given state or condition, such as a
disease or disorder, and its complications. An amount adequate to
accomplish this is defined as "effective amount". Effective amounts
for each purpose will depend on the severity of the condition,
disease or injury as well as the weight and general state of the
subject and mode of administration, or the like. It will be
understood that determining an appropriate dosage may be achieved
using routine experimentation, e.g. by constructing a matrix of
values and testing different points in the matrix, which is all
within the ordinary skills of a trained physician or
veterinary.
[0228] In the present context, treatment or treating mean the
management and care of a patient or subject for the purpose of
combating a condition, a disease or a disorder. The term is
intended to include the full spectrum of treatments for a given
condition from which the patient or subject is suffering, such as
administration of the active compound to alleviate the symptoms or
complications, to delay the progression of the disease, disorder or
condition, to alleviate or relief the symptoms and complications,
to improve patient's status or outcome, and/or to cure or eliminate
the disease, disorder or condition as well as to prevent the
condition, wherein prevention is to be understood as the management
and care of a patient for the purpose of combating the disease,
condition, or disorder and includes the administration of the
active compounds to prevent or delay the onset of the symptoms or
complications.
[0229] Within this invention it is to be understood that the
combinations, compositions or combined uses according to this
invention may envisage the simultaneous, sequential or separate
administration of the active components or ingredients.
[0230] 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) and uses, such as
e.g. the simultaneous, sequential or separate use of the components
or ingredients.
[0231] The combined administration of this invention may take place
by administering the active components or ingredients together,
such as e.g. by administering them simultaneously in one single or
in two separate formulations or dosage forms. Alternatively, the
administration may take place by administering the active
components or ingredients sequentially, such as e.g. successively
in two separate formulations or dosage forms.
[0232] For the combination therapy of this invention the active
components or ingredients may be administered separately (which
implies that they are formulated separately) or formulated
altogether (which implies that they are formulated in the same
preparation or in the same dosage form). 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.
[0233] 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.
[0234] With respect to embodiment A, the methods of synthesis for
the DPP-4 inhibitors according to embodiment A of this invention
are known to the skilled person. Advantageously, the DPP-4
inhibitors according to embodiment A of this invention can be
prepared using synthetic methods as described in the literature.
Thus, for example, purine derivatives of formula (I) can be
obtained as described in WO 2002/068420, WO 2004/018468, WO
2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of
which are incorporated herein. Purine derivatives of formula (II)
can be obtained as described, for example, in WO 2004/050658 or WO
2005/110999, the disclosures of which are incorporated herein.
Purine derivatives of formula (III) and (IV) can be obtained as
described, for example, in WO 2006/068163, WO 2007/071738 or WO
2008/017670, the disclosures of which are incorporated herein. The
preparation of those DPP-4 inhibitors, which are specifically
mentioned hereinabove, is disclosed in the publications mentioned
in connection therewith. Polymorphous crystal modifications and
formulations of particular DPP-4 inhibitors are disclosed in WO
2007/128721 and WO 2007/128724, respectively, the disclosures of
which are incorporated herein in their entireties. Formulations of
particular DPP-4 inhibitors with metformin or other combination
partners are described in WO 2009/121945, the disclosure of which
is incorporated herein in its entirety.
[0235] Typical dosage strengths of the dual fixed combination
(tablet) of linagliptin/metformin IR (immediate release) are
2.5/500 mg, 2.5/850 mg and 2.5/1000 mg, which may be administered
1-3 times a day, particularly twice a day.
[0236] Typical dosage strengths of the dual fixed combination
(tablet) of linagliptin/metformin XR (extended release) are 5/500
mg, 5/1000 mg and 5/1500 mg (each one tablet) or 2.5/500 mg,
2.5/750 mg and 2.5/1000 mg (each two tablets), which may be
administered 1-2 times a day, particularly once a day, preferably
to be taken in the evening with meal.
[0237] The present invention further provides a DPP-4 inhibitor as
defined herein for use in (add-on or initial) combination therapy
with metformin (e.g. in a total daily amount from 500 to 2000 mg
metformin hydrochloride, such as e.g. 500 mg, 850 mg or 1000 mg
once or twice daily).
[0238] With respect to embodiment B, the methods of synthesis for
the DPP-4 inhibitors of embodiment B are described in the
scientific literature and/or in published patent documents,
particularly in those cited herein.
[0239] The elements of the combination of this invention may be
administered by various ways, for example by oral, buccal,
sublingual, enterical, parenteral (e.g., transdermal, intramuscular
or subcutaneous), inhalative (e.g., liquid or powder inhalation,
aerosol), pulmonary, intranasal (e.g. spray), intraperitoneal,
vaginal, rectal, or topical routes of administration and may be
formulated, alone or together, in suitable dosage unit formulations
containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants and vehicles appropriate for each route of
administration.
[0240] In an embodiment, the DPP-4 inhibitor according to the
invention is preferably administered orally.
[0241] Suitable doses and dosage forms of the DPP-4 inhibitors may
be determined by a person skilled in the art and may include those
described herein or in the relevant references.
[0242] For pharmaceutical application in warm-blooded vertebrates,
particularly humans, the compounds of this invention are usually
used in dosages from 0.001 to 100 mg/kg body weight, preferably at
0.01-15 mg/kg or 0.1-15 mg/kg, in each case 1 to 4 times a day. For
this purpose, the compounds, optionally combined with other active
substances, may be incorporated together with one or more inert
conventional carriers and/or diluents, e.g. with corn starch,
lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene
glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof into conventional galenic preparations
such as plain or coated tablets, capsules, powders, suspensions or
suppositories.
[0243] The pharmaceutical compositions according to this invention
comprising the DPP-4 inhibitors as defined herein are thus prepared
by the skilled person using pharmaceutically acceptable formulation
excipients as described in the art and appropriate for the desired
route of administration. Examples of such excipients include,
without being restricted to diluents, binders, carriers, fillers,
lubricants, flow promoters, crystallisation retardants,
disintegrants, solubilizers, colorants, pH regulators, surfactants
and emulsifiers.
[0244] Oral formulations or dosage forms of the DPP-4 inhibitor of
this invention may be prepared according to known techniques.
[0245] A pharmaceutical composition or dosage form (e.g. oral
tablet) of a DPP-4 inhibitor according to embodiment A of the
invention may typically contain as excipients (in addition to an
active ingredient), for example: one or more diluents, a binder, a
disintegrant, and a lubricant, preferably each as disclosed
herein-below. In an embodiment, the disintegrant may be
optional.
[0246] Examples of suitable diluents for compounds according to
embodiment A include cellulose powder, calcium hydrogen phosphate,
erythritol, low substituted hydroxypropyl cellulose, mannitol,
pregelatinized starch or xylitol.
[0247] Examples of suitable lubricants for compounds according to
embodiment A include talc, polyethyleneglycol, calcium behenate,
calcium stearate, hydrogenated castor oil or magnesium
stearate.
[0248] Examples of suitable binders for compounds according to
embodiment A include copovidone (copolymerisates of vinylpyrrolidon
with other vinylderivates), hydroxypropyl methylcellulose (HPMC),
hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),
pregelatinized starch, or low-substituted hydroxypropylcellulose
(L-HPC).
[0249] Examples of suitable disintegrants for compounds according
to embodiment A include corn starch or crospovidone.
[0250] Suitable methods of preparing (oral) preparations or dosage
forms of the DPP-4 inhibitors according to embodiment A of the
invention are [0251] direct tabletting of the active substance in
powder mixtures with suitable tabletting excipients; [0252]
granulation with suitable excipients and subsequent mixing with
suitable excipients and subsequent tabletting as well as film
coating; or [0253] packing of powder mixtures or granules into
capsules.
[0254] Suitable granulation methods are [0255] wet granulation in
the intensive mixer followed by fluidised bed drying; [0256]
one-pot granulation; [0257] fluidised bed granulation; or [0258]
dry granulation (e.g. by roller compaction) with suitable
excipients and subsequent tabletting or packing into capsules.
[0259] An exemplary composition (e.g. tablet core) of a DPP-4
inhibitor according to embodiment A of the invention comprises the
first diluent mannitol, pregelatinized starch as a second diluent
with additional binder properties, the binder copovidone, the
disintegrant corn starch, and magnesium stearate as lubricant;
wherein copovidone and/or corn starch may be optional.
[0260] A tablet of a DPP-4 inhibitor according to embodiment A of
the invention may be film coated, preferably the film coat
comprises hydroxypropylmethylcellulose (HPMC), polyethylene glycol
(PEG), talc, titanium dioxide and iron oxide (e.g. red and/or
yellow).
[0261] In a further embodiment, the DPP-4 inhibitor according to
the invention may be administered by injection (preferably
subcutaneously). In another embodiment, the GLP-1 receptor agonist
is preferably administered by injection (preferably subcutaneously)
as well.
[0262] Injectable formulations of the GLP-1 receptor agonist and/or
the DPP-4 inhibitor of this invention (particularly for
subcutaneous use) may be prepared according to known formulation
techniques, e.g. using suitable liquid carriers, which usually
comprise sterile water, and, optionally, further additives such as
e.g. preservatives, pH adjusting agents, buffering agents,
isotoning agents, solubility aids and/or tensides or the like, to
obtain injectable solutions or suspensions. In addition, injectable
formulations may comprise further additives, for example salts,
solubility modifying agents or precipitating agents which retard
release of the drug(s). In further addition, injectable GLP-1
formulations may comprise GLP-1 stabilizing agents (e.g. a
surfactant).
[0263] For example, an injectable formulation (particularly for
subcutaneous use) containing the GLP-1 receptor agonist (e.g.
exenatide), optionally together with the DPP-4 inhibitor of this
invention, may further comprise the following additives: a
tonicity-adjusting agent (such as e.g. mannitol), an antimicrobial
preservative (such as e.g. metacresol), a buffer or pH adjusting
agent (such as e.g. glacial acetic acid and sodium acetate
trihydrate in water for injection as a buffering solution at pH
4.5), and optionally a solubilizing and/or stabilizing agent (such
as e.g. a surfactant or detergent).
[0264] In a further embodiment, the DPP-4 inhibitor according to
the invention may be administered by a transdermal delivery system.
In another embodiment, the GLP-1 receptor agonist is preferably
administered by a transdermal delivery system as well.
[0265] Transdermal formulations (e.g. for transdermal patches or
gels) of the GLP-1 receptor agonist and/or the DPP-4 inhibitor of
this invention may be prepared according to known formulation
techniques, e.g. using suitable carriers and, optionally, further
additives. To facilitate transdermal passage, different
methodologies and systems may be used, such as e.g. techniques
involving formation of microchannels or micropores in the skin,
such as e.g. iontophoresis (based on low-level electrical current),
sonophoresis (based on low-frequency ultrasound) or microneedling,
or the use of drug-carrier agents (e.g. elastic or lipid vesicles
such as transfersomes) or permeation enhancers.
[0266] For further details on dosage forms, formulations and
administration of DPP-4 inhibitors of this invention and/or GLP-1
receptor agonist of this invention, reference is made to scientific
literature and/or published patent documents, particularly to those
cited herein.
[0267] The pharmaceutical compositions (or formulations) may be
packaged in a variety of ways. Generally, an article for
distribution includes one or more containers that contain the one
or more pharmaceutical compositions in an appropriate form. Tablets
are typically packed in an appropriate primary package for easy
handling, distribution and storage and for assurance of proper
stability of the composition at prolonged contact with the
environment during storage. Primary containers for tablets may be
bottles or blister packs.
[0268] A suitable bottle, e.g. for a pharmaceutical composition or
combination (tablet) comprising a DPP-4 inhibitor according to
embodiment A of the invention, may be made from glass or polymer
(preferably polypropylene (PP) or high density polyethylene
(HD-PE)) and sealed with a screw cap. The screw cap may be provided
with a child resistant safety closure (e.g. press-and-twist
closure) for preventing or hampering access to the contents by
children. If required (e.g. in regions with high humidity), by the
additional use of a desiccant (such as e.g. bentonite clay,
molecular sieves, or, preferably, silica gel) the shelf life of the
packaged composition can be prolonged.
[0269] A suitable blister pack, e.g. for a pharmaceutical
composition or combination (tablet) comprising a DPP-4 inhibitor
according to embodiment A of the invention, comprises or is formed
of a top foil (which is breachable by the tablets) and a bottom
part (which contains pockets for the tablets). The top foil may
contain a metallic foil, particularly aluminium or aluminium alloy
foil (e.g. having a thickness of 20 .mu.m to 45 .mu.m, preferably
20 .mu.m to 25 .mu.m) that is coated with a heat-sealing polymer
layer on its inner side (sealing side). The bottom part may contain
a multi-layer polymer foil (such as e.g. poly(vinyl chloride) (PVC)
coated with poly(vinylidene choride) (PVDC); or a PVC foil
laminated with poly(chlorotriflouroethylene) (PCTFE)) or a
multi-layer polymer-metal-polymer foil (such as e.g. a
cold-formable laminated PVC/aluminium/polyamide composition).
Examples of blister packs may include alu/alu,
alu/PVC/polyvinylacetate copolymer-acrylate or alu/PVC/PCTFE/PVC
blisters.
[0270] To ensure a long storage period especially under hot and wet
climate conditions an additional overwrap or pouch made of a
multi-layer polymer-metal-polymer foil (e.g. a laminated
polyethylene/aluminium/polyester composition) may be used for the
blister packs. Supplementary desiccant (such as e.g. bentonite
clay, molecular sieves, or, preferably, silica gel) in this pouch
package may prolong the shelf life even more under such harsh
conditions.
[0271] Solutions for injection may be available in typical suitable
presentation forms such as vials, cartridges or prefilled
(disposable) pens, which may be further packaged.
[0272] The article may further comprise a label or package insert,
which refer to instructions customarily included in commercial
packages of therapeutic products, that may contain information
about the indications, usage, dosage, administration,
contraindications and/or warnings concerning the use of such
therapeutic products. In one embodiment, the label or package
inserts indicates that the composition can be used for any of the
purposes described herein.
[0273] With respect to the first embodiment (embodiment A), the
dosage typically required of the DPP-4 inhibitors mentioned herein
in embodiment A when administered intravenously is 0.1 mg to 10 mg,
preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg
to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more
preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4
times a day. Thus, e.g. the dosage of
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine when administered orally is 0.5 mg to
10 mg per patient per day, preferably 2.5 mg to 10 mg or 1 mg to 5
mg per patient per day.
[0274] For example, doses of linagliptin when administered
subcutaneously or i.v. for human patients are in the range of
0.3-10 mg, preferably from 1 to 5 mg, particularly 2.5 mg, per
patient per day.
[0275] In a further embodiment, for example, doses of linagliptin
when administered subcutaneously for human patients (such as e.g.
in obese human patients or for treating obesity) are in the range
of 0.1-30 mg, preferably from 1 to 10 mg, particularly 5 mg, per
patient per day.
[0276] A dosage form prepared with a pharmaceutical composition
comprising a DPP-4 inhibitor mentioned herein in embodiment A
contain the active ingredient in a dosage range of 0.1-100 mg.
Thus, e.g. particular oral dosage strengths of
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10
mg.
[0277] With respect to the second embodiment (embodiment B), the
doses of DPP-4 inhibitors mentioned herein in embodiment B to be
administered to mammals, for example human beings, of, for example,
approximately 70 kg body weight, may be generally from about 0.5 mg
to about 350 mg, for example from about 10 mg to about 250 mg,
preferably 20-200 mg, more preferably 20-100 mg, of the active
moiety per person per day, or from about 0.5 mg to about 20 mg,
preferably 2.5-10 mg, per person per day, divided preferably into 1
to 4 single doses which may, for example, be of the same size.
Single oral dosage strengths comprise, for example, 10, 25, 40, 50,
75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.
[0278] An oral dosage strength of the DPP-4 inhibitor sitagliptin
is usually between 25 and 200 mg of the active moiety. A
recommended dose of sitagliptin is 100 mg calculated for the active
moiety (free base anhydrate) once daily. Unit dosage strengths of
sitagliptin free base anhydrate (active moiety) are 25, 50, 75,
100, 150 and 200 mg. Particular unit dosage strengths of
sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. An equivalent
amount of sitagliptin phosphate monohydrate to the sitagliptin free
base anhydrate is used in the pharmaceutical compositions, namely,
32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg, respectively.
Adjusted dosages of 25 and 50 mg sitagliptin are used for patients
with renal failure. Typical dosage strengths of the dual
combination of sitagliptin/metformin are 50/500 mg and 50/1000
mg.
[0279] An oral dosage range of the DPP-4 inhibitor vildagliptin is
usually between 10 and 150 mg daily, in particular between 25 and
150 mg, 25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily.
Particular examples of daily oral dosage are 25, 30, 35, 45, 50,
55, 60, 80, 100 or 150 mg. In a more particular aspect, the daily
administration of vildagliptin may be between 25 and 150 mg or
between 50 and 100 mg. In another more particular aspect, the daily
administration of vildagliptin may be 50 or 100 mg. The application
of the active ingredient may occur up to three times a day,
preferably one or two times a day. Particular dosage strengths are
50 mg or 100 mg vildagliptin. Typical dosage strengths of the dual
combination of vildagliptin/metformin are 50/850 mg and 50/1000
mg.
[0280] Alogliptin may be administered to a patient at an oral daily
dose of between 5 mg/day and 250 mg/day, optionally between 10 mg
and 200 mg, optionally between 10 mg and 150 mg, and optionally
between 10 mg and 100 mg of alogliptin (in each instance based on
the molecular weight of the free base form of alogliptin). Thus,
specific oral dosage amounts that may be used include, but are not
limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of
alogliptin per day. Alogliptin may be administered in its free base
form or as a pharmaceutically acceptable salt.
[0281] Saxagliptin may be administered to a patient at an oral
daily dose of between 2.5 mg/day and 100 mg/day, optionally between
2.5 mg and 50 mg. Specific oral dosage amounts that may be used
include, but are not limited to 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg,
30 mg, 40 mg, 50 mg and 100 mg of saxagliptin per day. Typical
dosage strengths of the dual combination of saxagliptin/metformin
are 2.5/500 mg and 2.5/1000 mg.
[0282] 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
oral 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, particularly from 1 mg to 5 mg
(more particularly 5 mg), per patient per day (if required, divided
into 1 to 4 single doses, particularly 1 or 2 single doses, which
may be of the same size, preferentially, administered orally once-
or twice daily (more preferentially once-daily), advantageously,
administered at any time of day, with or without food. Thus, for
example, the daily oral amount 5 mg BI 1356 can be given in an 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.
[0283] The dosage of the active ingredients in the combinations and
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.
[0284] A particularly preferred DPP-4 inhibitor to be emphasized
within the meaning of this invention is
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a-
mino-piperidin-1-yl)-xanthine (also known as BI 1356 or
linagliptin). BI 1356 exhibits high potency, 24 h duration of
action, and a wide therapeutic window. In patients with type 2
diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg of BI
1356 once daily for 12 days, BI 1356 shows favourable
pharmacodynamic and pharmacokinetic profile (see e.g. Table 3
below) with rapid attainment of steady state (e.g. reaching steady
state plasma levels (>90% of the pre-dose plasma concentration
on Day 13) between second and fifth day of treatment in all dose
groups), little accumulation (e.g. with a mean accumulation ratio
R.sub.A,AUC.ltoreq.1.4 with doses above 1 mg) and preserving a
long-lasting effect on DPP-4 inhibition (e.g. with almost complete
(>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e.
92.3 and 97.3% inhibition at steady state, respectively, and
>80% inhibition over a 24 h interval after drug intake), as well
as significant decrease in 2 h postprandial blood glucose
excursions by 80% (already on Day 1) in doses 2.5 mg, and with the
cumulative amount of unchanged parent compound excreted in urine on
Day 1 being below 1% of the administered dose and increasing to not
more than about 3-6% on Day 12 (renal clearance CL.sub.R,ss is from
about 14 to about 70 mL/min for the administered oral doses, e.g.
for the 5 mg dose renal clearance is about 70 ml/min). In people
with type 2 diabetes BI 1356 shows a placebo-like safety and
tolerability. With low doses of about 5 mg, BI 1356 acts as a true
once-daily oral drug with a full 24 h duration of DPP-4 inhibition.
At therapeutic oral dose levels, BI 1356 is mainly excreted via the
liver and only to a minor extent (about <7% of the administered
oral dose) via the kidney. BI 1356 is primarily excreted unchanged
via the bile. The fraction of BI 1356 eliminated via the kidneys
increases only very slightly over time and with increasing dose, so
that there will likely be no need to modify the dose of BI 1356
based on the patients' renal function. The non-renal elimination of
BI 1356 in combination with its low accumulation potential and
broad safety margin may be of significant benefit in a patient
population that has a high prevalence of renal insufficiency and
diabetic nephropathy.
TABLE-US-00001 TABLE 3 Geometric mean (gMean) and geometric
coefficient of variation (gCV) of pharmacokinetic parameters of BI
1356 at steady state (Day 12) 1 mg 2.5 mg 5 mg 10 mg Parameter
gMean (gCV) gMean (gCV) gMean (gCV) gMean (gCV) AUC.sub.0-24 40.2
(39.7) 85.3 (22.7) 118 (16.0) 161 (15.7) [nmol h/L] AUC.sub.T,SS
81.7 (28.3) 117 (16.3) 158 (10.1) 190 (17.4) [nmol h/L] C.sub.max
[nmol/L] 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69 (29.8)
C.sub.max,ss 4.53 (29.0) 6.58 (23.0) 11.1 (21.7) 13.6 (29.6)
[nmol/L] t.sub.max* [h] 1.50 [1.00-3.00] 2.00 [1.00-3.00] 1.75
[0.92-6.02] 2.00 [1.50-6.00] t.sub.max,ss* [h] 1.48 [1.00-3.00]
1.42 [1.00-3.00] 1.53 [1.00-3.00] 1.34 [0.50-3.00] T.sub.1/2,ss [h]
121 (21.3) 113 (10.2) 131 (17.4) 130 (11.7) Accumulation 23.9
(44.0) 12.5 (18.2) 11.4 (37.4) 8.59 (81.2) t.sub.1/2, [h]
R.sub.A,Cmax 1.44 (25.6) 1.25 (10.6) 1.33 (30.0) 1.40 (47.7)
R.sub.A,AUC 2.03 (30.7) 1.37 (8.2) 1.33 (15.0) 1.18 (23.4)
fe.sub.0-24 [%] NC 0.139 (51.2) 0.453 (125) 0.919 (115) fe.sub.T,SS
[%] 3.34 (38.3) 3.06 (45.1) 6.27 (42.2) 3.22 (34.2) CL.sub.R,ss
14.0 (24.2) 23.1 (39.3) 70 (35.0) 59.5 (22.5) [mL/min] *median and
range [min-max] NC not calculated as most values below lower limit
of quantification
[0285] 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 is combined with one or more
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.
[0286] The DPP-4 inhibitors mentioned above--besides their use in
mono-therapy--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.
[0287] 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".
[0288] Examples of antidiabetic combination partners are metformin;
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), such as the GPR119 agonists
5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-
-yl}-pyrimidine or
5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-meth-
anesulfonyl-phenyl)-pyridine; 11.beta.-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.
[(3S)-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.
[0289] Metformin is usually given in doses varying from about 500
mg to 2000 mg up to 2500 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.
[0290] For children 10 to 16 years of age, the recommended starting
dose of metformin is 500 mg given once daily. If this dose fails to
produce adequate results, the dose may be increased to 500 mg twice
daily. Further increases may be made in increments of 500 mg weekly
to a maximum daily dose of 2000 mg, given in divided doses (e.g. 2
or 3 divided doses). Metformin may be administered with food to
decrease nausea.
[0291] A dosage of pioglitazone is usually of about 1-10 mg, 15 mg,
30 mg, or 45 mg once a day.
[0292] 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).
[0293] 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).
[0294] Glipizide is usually given in doses from 2.5 to 10-20 mg
once (or up to 40 mg divided twice) a day (typical dosage strengths
are 5 and 10 mg), or extended-release glibenclamide in doses from 5
to 10 mg (up to 20 mg) once a day (typical dosage strengths are
2.5, 5 and 10 mg).
[0295] 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).
[0296] 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).
[0297] 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).
[0298] A dual combination of glimepiride/metformin is usually given
in doses from 1/250 to 4/1000 mg twice daily.
[0299] 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).
[0300] 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).
[0301] 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).
[0302] 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).
[0303] 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.
[0304] Acarbose is usually given in doses from 25 to 100 mg with
meals. Miglitol is usually given in doses from 25 to 100 mg with
meals.
[0305] 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;
PPAR-alpha agonists; PPAR-delta agonists such as e.g.
{4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2--
methyl-phenoxy}-acetic acid; 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.
[0306] A dosage of atorvastatin is usually from 1 mg to 40 mg or 10
mg to 80 mg once a day.
[0307] 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.
[0308] A dosage of telmisartan is usually from 20 mg to 320 mg or
40 mg to 160 mg per day.
[0309] 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.
[0310] Examples of combination partners for the treatment of
obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme
(cetilistat); dexfenfluramine; axokine; cannabinoid receptor 1
antagonists such as the CB1 antagonist rimonobant; MCH-1 receptor
antagonists; MC4 receptor agonists; NPY5 as well as NPY2
antagonists (e.g. velneperit); beta3-AR agonists such as SB-418790
and AD-9677; 5HT2c receptor agonists such as APD 356 (lorcaserin);
myostatin inhibitors; Acrp30 and adiponectin; steroyl CoA
desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors;
CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36;
orexin receptor antagonists; and tesofensine; as well as the dual
combinations bupropion/naltrexone, bupropion/zonisamide,
topiramate/phentermine and pramlintide/metreleptin.
[0311] 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.
[0312] 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:
[0313] Glucagon-like peptide (GLP)-1 Glucose-dependent
insulinotropic peptide (GIP)
Neuroactive:
Substance P
Neuropeptide Y (NPY)
Peptide YY
[0314] Energy homeostasis:
GLP-2
Prolactin
[0315] Pituitary adenylate cyclase activating peptide (PACAP) Other
hormones:
PACAP 27
[0316] Human chorionic gonadotrophin alpha chain Growth hormone
releasing factor (GHRF) Luteinizing hormone alpha chain
Insulin-like growth factor (IGF-1)
CCL8/eotaxin
[0317] CCL22/macrophage-derived chemokine
CXCL9/interferon-gamma-induced monokine
Chemokines:
[0318] CXCL10/interferon-gamma-induced protein-10
CXCL11/interferon-inducible T cell a chemoattractant
CCL3L1/macrophage inflammatory protein 1alpha isoform
LD78beta
[0319] CXCL12/stromal-derived factor 1 alpha and beta
Other:
[0320] Enkephalins, gastrin-releasing peptide, vasostatin-1,
peptide histidine methionine, thyrotropin alpha
[0321] 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 nephrotic
syndrome, such as selected from corticosteroids (e.g. prednisone or
prednisolone), diuretics, ACE inhibitors, ARBs such as e.g.
telmisartan, cyclophosphamide, cyclosporine, and/or
anticoagulants.
[0322] 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.
[0323] 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, warfarin, 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).
[0324] 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.
[0325] 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.
[0326] All patent applications cited herein are hereby incorporated
by reference in their entireties.
[0327] 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.
Examples
[0328] Reduction in Loss of Podocytes; Expression of Podocalyxin as
a Marker of Podocyte Integrity:
[0329] The expression of podocalyxin is analyzed by
immunohistochemistry using a podocalyxin specific antibody. Kidney
sections from male diabetic db/db mice (10 weeks old at start and
treated for 3 months) in the following groups are analyzed:
[0330] Diabetic control (n=10), linagliptin 3 mg/kg (n=8),
enalapril 20 mg/kg (n=10) and heterozygous control mice (n=8).
[0331] All of the evaluations of the glomerular staining
intensities are done semiquantitatively by two different experts of
kidney pathology blinded for the slides.
[0332] The predefined scoring gradient is 0, 1, 2, and 3. 0 means
no expression, whereas 3 is given when expression is highest. Group
means are compared with a non-parametric test. P values less than
0.05 are considered significant.
[0333] FIG. 1 shows the expression of podocalyxin as a marker for
podocyte integrity in linagliptin-, enalapril- or vehicle-treated
diabetic db/db mice and in healthy control mice.
[0334] This prove of concept study in db/db mice (abstract see
below) indicates that DPP-4 inhibition might offer an new
therapeutic approach for the treatment of proteinuric diseases
associated with podocyte loss. This study clearly demonstrates that
the DPP-4 inhibitor linagliptin significantly reduces the loss of
podocytes in a blood glucose independent manner in db/db mice (FIG.
1). Podocyte loss is determined by podocalyxin staining.
Podocalyxin, a sialoglycoprotein, is thought to be the major
constituent of the glycocalyx of podocytes. It is a member of the
CD34 family of transmembrane sialomucin. It coats the secondary
foot processes of the podocytes. It is negatively charged and thus
functions to keep adjacent foot processes separated, thereby
keeping the urinary filtration barrier open. This function is
further supported by knockout studies in mice which reveal an
essential role in podocyte morphogenesis.
[0335] Renoprotective Effects of Linagliptin; Protection of
Podocytes:
[0336] Diabetic nephropathy is the main cause of end-stage renal
disease. This study investigated the effects of linagliptin on
diabetic nephropathy in severe insulin-resistant and old db/db mice
as a model for diabetic nephropathy. Male diabetic db/db mice (10
weeks) were divided into 3 groups and treated for 12 weeks with
vehicle (n=10), linagliptin 3 mg/kg/day (n=8), or the angiotensin
converting enzyme (ACE) inhibitor enalapril 20 mg/kg/day (n=10).
Heterozygous db/+ mice treated with vehicle were used as controls
(n=8). Levels of glucose, triglycerides, insulin, cystatin C and
creatinine were analyzed in serum and urine samples at baseline and
monthly thereafter. Body weight, urinary albumin excretion and OGTT
were monitored periodically.
[0337] Renal histology (glomerulosclerosis, tubulointerstitial
fibrosis) and expression of the sialoglycoprotein podocalyxin (a
marker of podocyte integrity in the glomeruli, marker for
glomerular damage), glucagon-like peptide 1 receptor (GLP-1R),
alpha-smooth muscle actin and type I collagen were evaluated at the
end of the study.
[0338] Results:
[0339] At 22 weeks, db/db mice showed significantly (p<0.01)
higher levels of fasting plasma glucose, insulin, and
triglycerides, and increased body weight compared with healthy db/+
mice. Linagliptin and enalapril had limited effects on fasted or
post-prandial glucose levels. However, histology analysis showed
that tubulointerstitial fibrosis and glomerular mesangial matrix
expansion were reduced almost to control levels in both treatment
groups compared with diabetic vehicle (p<0.05 for both). Urinary
albumin excretion rates and tubulointerstitial fibrosis were
significantly decreased in db/db mice treated with linagliptin
compared with those treated with enalapril (both p<0.05).
[0340] Podocalyxin expression in db/db vehicle treated mice was
significantly reduced compared with db/+ controls (1.59.+-.0.2 vs
2.65.+-.0.1; p<0.001). Mice treated with linagliptin and
enalapril had significantly higher podocalyxin expression compared
with diabetic mice (2.3.+-.0.2 and 2.4.+-.0.2, respectively;
p<0.05 for both).
[0341] The expression pattern of .alpha.-smooth muscle actin was
also determined in kidneys as a marker of mesangial cell damage.
Linagliptin treatment normalized the expression of .alpha.-smooth
muscle actin-positive myofibroblasts in the interstitium and
glomeruli of diabetic db/db mice. Similar results were obtained for
type I collagen deposition.
[0342] Immunohistochemical staining of kidney sections revealed a
decrease in GLP-1R expression in the cortical glomeruli of db/db
mice (1.67.+-.0.07) compared with healthy control mice
(2.15.+-.0.1; P<0.01). Linagliptin treatment significantly
increased the expression of GLP-1R in the glomeruli of db/db mice
(1.90.+-.0.04; P<0.05) compared to vehicle-treated diabetic
db/db mice.
[0343] In conclusion, this study suggests that linagliptin protects
podocytes from injury and may therefore be efficacious in the
treatment, prevention or delay in progression of diabetic
nephropathy independent of its effect on glucose homeostasis.
Further, this study suggests that linagliptin is useful for
treating, preventing or delaying progression of glomerulosclerosis
and/or tubulointerstitial fibrosis, or glomerular and/or
tubulointerstitial injury. Further, this study suggests that
linagliptin is useful for renoprotection through inhibition of
podocyte damage and myofibroblast transformation (reduction of
.alpha.-SMA expression).
[0344] The renoprotective effect of linagliptin in this model seems
to be as effective as treatment with an ACE inhibitor, the current
gold standard for treatment of diabetic nephropathy.
[0345] Linagliptin is as Efficacious as Telmisartan in Preventing
Renal Disease Progression in a Rat Model of Chronic Kidney Disease
(Rats with 5/6 Nephrectomy)
[0346] DPP-4 inhibitors may have kidney-protective properties
independent of glucose control. We compare the effect of
linagliptin (LIN) with an angiotensin II receptor
antagonist--currently clinical gold standard--on preventing renal
disease progression in a nondiabetic rat model of chronic renal
failure.
[0347] Male Wistar rats are allocated to 4 groups: sham operated;
5/6 nephrectomy (5/6 NX); 5/6 NX plus LIN (0.083 mg/kg in chow);
5/6 NX plus telmisartan (TEL; 5 mg/kg/d in drinking water). Study
duration is 130 days; blood pressure and albumin excretion are
assessed repeatedly. At study end, kidneys and plasma biomarkers
are analyzed. Interstitial fibrosis increases by 69% in 5/6 NX rats
vs SHAM rats (p<0.05), and decreases by 48% (p<0.05) with LIN
and 24% with TEL (p=ns) vs PBO-treated 5/6 NX rats. Glomerular size
increases by 28% in PBO-treated 5/6 NX rats vs SHAM rats
(p<0.01), and decreases by 18% (p<0.001) with LIN but not
significantly with TEL vs PBO-treated 5/6 NX rats. The
glomerulosclerosic index is significantly increased in 5/6 NX rats
vs SHAM rats. There is a trend towards decreased glomerulosclerosis
with LIN and TEL. Analysis of collagen type I and III mRNA and
protein concentrations confirms histopathologic findings. The
urinary albumin/creatinine ratio increases 14-fold in 5/6 NX rats
vs SHAM rats (p<0.001), and decreases by 66% (p<0.05) with
LIN and 92% (p<0.01) with TEL vs PBO-treated 5/6 NX rats. Blood
pressure is lowered by TEL (31 mmHg; p<0.05) and unaffected by
LIN. TIMP-1, calbindin, osteopontin and beta 2 microglobulin (B2M)
are significantly increased in the PBO-treated 5/6 NX rats vs SHAM
rats. LIN decreases plasma concentrations of TIMP-1, calbindin,
osteopontin and B2M vs PBO-treated 5/6 NX rats (all p<0.05),
whereas TEL significantly decreases osteopontin and TGF-.beta.
expression. In summary, LIN is as effective as TEL, in preventing
renal disease progression in a model of chronic and progressive
renal failure (rats with 5/6 nephrectomy). The underlying molecular
mechanisms appear to be different. Linagliptin may be useful for
treating, preventing, protecting against, reducing the risk of,
slowing the progression of or delaying the onset of such
conditions, e.g. (micro- or macro-) albuminuria or proteinuria
and/or renal function impairment or deterioration of renal
filtration rate, such as e.g. in (diabetes or non-diabetes)
patients suffering therefrom or being at risk thereof.
[0348] Linagliptin for Use in Lowering Albuminuria on Top of
Recommended Standard Treatment for Diabetic Nephropathy:
[0349] Despite optimal therapy, people with type 2 diabetes (T2D)
remain at high risk for kidney damage, manifest as albuminuria, and
many develop progressive renal failure. Further, despite optimal
therapy with inhibitors of the renin-angiotensin-aldosterone
systeme (RAAS), patients with type 2 diabetes mellitus (T2DM)
remain at an increased risk of progressive renal failure and
cardiovascular disease, for which album inuria has emerged as a
predictive biomarker. Linagliptin, a DPP-4 inhibitor, has
previously shown evidence of albumin lowering on top of telmisartan
in mice. We explored the clinical effect of linagliptin on
albuminuria in T2D patients with early diabetic nephropathy. Four
randomized, double-blind, 24-week, placebo-controlled trials of
linagliptin (5 mg qd) on no, mono, or dual oral glucose-lowering
background therapy (such as e.g. linagliptin monotherapy,
linagliptin add-on to metformin or linagliptin add-on to metformin
plus a sulphonylurea, or linagliptin plus metformin initial
combination) had data available for urinary albumin-to-creatinine
ratio (UACR) and were pooled for analysis (n=2472). Participants
were included in this analysis if they had: i)
30.ltoreq.UACR.ltoreq.3000 mg/g creatinine; ii) stable treatment
with ACE/ARBs.gtoreq.4 weeks prior and during the trial; and iii)
eGFR >30 ml/min/1.73 m.sup.2. The endpoint was the percentage
change in geometric mean UACR. In this analysis, 492 (19.9%)
patients met UACR and eGFR thresholds of whom 46% received stable
ACE/ARB therapy (linagliptin n=168; placebo n=59). Mean baseline
A1C and median UACR were 8.2% vs 8.5% and 76 vs 78 mg/g creatinine
for the linagliptin and placebo groups, respectively. After 24
weeks, placebo-corrected changes in A1C and FPG were -0.71% and -26
mg/dl, respectively (both p<0.0001). Linagliptin significantly
lowered adjusted UACR by 33% (95% Cl 22 to 42%; p<0.05) with a
between group difference vs placebo of -29% (-3 to -48%;
p<0.05). Overall, kidney function and blood pressure were
unchanged although more patients on placebo received new
anti-hypertensive drugs (17% vs 11% with linagliptin). Sensitivity
analyses in patients not previously treated with RAS blockade
(n=265) found similar results. Linagliptin may have
kidney-protective properties beyond glucose-lowering effects. This
protective effect may be independent of race. Linagliptin may be
useful for treating or lowering albuminuria on top of standard of
care of angiotensin-converting enzyme (ACE) inhibition or
angiotensin II receptor blockade (ARB) in T2DM patients with early
diabetic nephropathy.
[0350] Linagliptin for Use in Treatment of Albuminuria in Patients
with Type 2 Diabetes and Diabetic Nephropathy:
[0351] Background and aims: Diabetes mellitus has become the most
common single cause of end-stage renal disease and a high
proportion of individuals with type 2 diabetes (T2D) are found to
have microalbuminuria and overt nephropathy shortly after the
diagnosis of their diabetes. Linagliptin, a DPP-4 inhibitor, has
recently demonstrated glycaemic efficacy and safety in T2D patients
at advanced stages of kidney disease. Here the clinical effect of
linagliptin on albuminuria in T2D patients with early diabetic
nephropathy is reported.
[0352] Materials and methods: Seven randomised, double-blind,
placebo-controlled trials (duration 24-52 weeks) of linagliptin (5
mg q.d.) as monotherapy or add-on to various glucose-lowering
background therapies had data available for urinary
albumin-to-creatinine ratio (UACR) and were eligible for this
analysis (n=4113). Data after 24 weeks of treatment were generated
to allow pooling and two sets were defined: 1) Diabetic nephropathy
in earlier stages of T2D (with and without oral glucose-lowering
background therapies, such as e.g. linagliptin monotherapy,
linagliptin add-on to metformin or linagliptin add-on to metformin
plus a sulphonylurea, or linagliptin plus metformin initial
combination): participants from four 24-week pivotal phase III
trials if they had persistent albuminuria, defined as
30.ltoreq.UACR.ltoreq.3000 mg/g (eGFR >30 ml/min/1.73 m.sup.2)
and stable treatment with an angiotensin-converting enzyme
inhibitor (ACEi) or angiotensin II receptor blocker (ARB) at
baseline (ongoing treatment with ACEi or ARB); 2) Diabetic
nephropathy in elderly patients (various glucose-lowering
background therapies including insulin, such as e.g. linagliptin
monotherapy, linagliptin add-on to metformin or linagliptin add-on
to metformin plus a sulphonylurea, or linagliptin plus metformin
initial combination, or linagliptin in combination with basal
insulin): patients from all seven trials, fulfilling UACR criteria
30.ltoreq.UACR.ltoreq.3000 mg/g (eGFR >30 ml/min/1.73 m.sup.2)
and aged .gtoreq.65 years (with or without ongoing treatment with
ACEi or ARB). The endpoint in both sets was the percentage change
in geometric mean UACR after 24 weeks.
[0353] Results: For set #1, 492 out of 2472 patients met UACR
criteria of whom 46% received stable ACEi/ARB therapy (linagliptin,
n=168; placebo, n=59). For set #2, 1331 patients were aged 65 years
of whom 377 (28%) met UACR criteria (linagliptin, n=232; placebo,
n=145). Mean baseline HbA1c and median UACR were 8.3% and 76 mg/g
overall for set #1, and 8.1% (overall), 77 mg/g (linagliptin) and
86 mg/g (placebo) for set #2. In set 1, placebo-corrected changes
in HbA1c and fasting plasma glucose were -0.71% and -1.4 mmol/L
(-26 mg/dL), respectively (both P<0.0001). Linagliptin
significantly lowered adjusted UACR by 33% (95% CI: 22%, 42%;
P<0.05) with a between-group difference versus placebo of -29%
(95% CI: -3%, -48%; P<0.05). In set 2, linagliptin also
significantly lowered adjusted UACR by 30% (95% CI: 13%, 43%;
P<0.05) with a trend towards a reduction versus placebo of -25%
(95% CI: -47%, +6%). In all seven studies, blood pressure and renal
function were not affected to a clinically meaningful extent by
either treatment.
[0354] Conclusions: In studies up to 52 weeks, linagliptin lowered
albuminuria beyond what may be expected by its glucose-lowering
effects. Changes in albuminuria were seen more rapidly (e.g. with
the overall UACR effect occurring as early as 12 weeks treatment
duration) than would be expected based on structural changes. A
decrease in albuminuria suggests a long-term renal benefit.
[0355] Further, linagliptin (5 mg qd) lowers (micro)albuminuria in
vulnerable diabetic nephropathy patients (with or without
additional standard background therapy such as e.g. with an ACEi or
ARB) such as who are aged .gtoreq.65 years typically having longer
diabetes duration (>5 years), renal impairment (such as mild (60
to <90 eGFR ml/min/1.73 m.sup.2) or moderate (30 to <60 eGFR
ml/min/1.73 m.sup.2) renal impairment) and/or higher baseline UACR
(such as advanced stages of micro- or macroalbuminuria).
[0356] In some instances, the diabetic nephropathy patients
amenable to the therapy of this invention may be on hypertension
and/or lipid lowering medication at baseline, such as e.g. on
(ongoing) therapy with an ACE inhibitor, ARB, beta-blocker,
Calcium-anatgonist or diuretic, or combination thereof, and/or on
(ongoing) therapy with a fibrate, niacin or statin, or combination
thereof.
[0357] Renal Safety and Outcomes with Linagliptin: Meta-Analysis in
5466 Patients with Type 2 Diabetes:
[0358] Long-term glycemic control in diabetes is associated with
reduced risk of renal microvascular complications. Linagliptin has
shown nephroprotective effects in animal models and significantly
reduced albuminuria in type 2 diabetes (T2D) associated
nephropathy. As these effects were independent of short-term
glycemic improvements, it was speculated that linagliptin may have
nephroprotective effects. The aim of this study was to evaluate
renal safety/outcomes with linagliptin in phase 3, randomized,
double-blind, placebo-controlled trials (.gtoreq.12 wks).
Predefined events from 13 trials were analyzed using a composite
primary endpoint: new onset of a) micro- (first documented UACR
.gtoreq.30 mg/g) or b) macro- (first documented UACR .gtoreq.300
mg/g) albuminuria, c) CKD (serum creatinine increase .gtoreq.250
.mu.mol/L), d) worsening of CKD (loss in eGFR >50% vs baseline),
e) acute renal failure (ARF, standardized MedDRA query) and f)
death (any cause). Of 5466 patients included (mean baseline HbA1c:
8.2% and eGFR: 91.4 ml/min/1.73 m2), 3505 received linagliptin 5 mg
qd and 1961 placebo; cumulative exposure (person yrs) was 1756 and
1057, respectively. Events occurred in 448 (12.8%) patients
receiving linagliptin vs 306 (15.6%) for placebo. The hazard ratio
(HR) for the composite endpoint for linagliptin vs. placebo was
0.84 (95% CI 0.72-0.97, p<0.05) and was not significantly
altered by race, but was lower in patients <65 vs >65 yrs
(HR: 0.77 vs 1.04). RRs were consistently reduced for individual
renal endpoints: micro- (-15%) and macroalbuminuria (-12%), new
onset (-56%) or worsening of CKD (-24%), ARF (-7%), and death
(-23%). In this large meta-analysis, renal safety and outcomes were
significantly improved in patients with T2D treated with
linagliptin. These data support a direct nephroprotective effect of
linagliptin. Linagliptin may be useful for preventing, reducing or
delaying the onset or progression of micro- or macro-albuminuria,
the onset of chronic kidney disease (CKD), the worsening of CKD,
the onset of acute renal failure and/or of death. Thus, linagliptin
may be useful for preventing, reducing the risk of or delaying the
onset or slowing the progression of renal morbidity and/or
mortality, preferably in T2DM patients.
[0359] In some instances, the (at-risk) patients amenable to the
renoprotection or risk-reduction of this invention (e.g.
prevention, reduction or delay of the onset or progression of
micro- or macro-albuminuria, the onset of chronic kidney disease
(CKD), the worsening of CKD, the onset of acute renal failure
and/or of death) may have renal/cardiovascular history and/or
medications, such as diabetic nephropathy, macrovascular disease
(e.g. coronary artery disease, periperal artery disease,
cerebrovascular disease, hypertension), microvascular disease (e.g.
diabetic nephropathy, neuropathy, retinopathy), coronary artery
disease, cerebrovascular disease, peripheral artery disease,
hypertension, ex-smoker or current smoker, and/or on
acetylsalicylic acid, antihypertensive and/or lipid lowering
medication, such as e.g. on (ongoing) therapy with acetylsalicylic
acid, an ACE inhibitor, ARB, beta-blocker, Calcium-anatgonist or
diuretic, or combination thereof, and/or on (ongoing) therapy with
a fibrate, niacin or statin, or combination thereof.
Sequence CWU 1
1
2140PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptideMOD_RES(2)..(2)D-Ala, Gly, Val, Leu, Ile, Ser
or ThrMOD_RES(16)..(16)Gly, Glu, Asp or LysMOD_RES(27)..(27)Val or
IleC-term amidated 1His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
Tyr Leu Glu Xaa1 5 10 15Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Xaa
Lys Gly Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Cys Cys 35
40240PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptideC-term amidated 2His Val Glu Gly Thr Phe Thr
Ser Asp Val Ser Ser Tyr Leu Glu Glu1 5 10 15Gln Ala Ala Lys Glu Phe
Ile Ala Trp Leu Ile Lys Gly Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro
Pro Cys Cys 35 40
* * * * *