U.S. patent application number 14/918818 was filed with the patent office on 2016-02-11 for pharmaceutical composition, methods for treating and uses thereof.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Uli Christian BROEDL, David Z.I. CHERNEY, Odd-Erik JOHANSEN, Eric Williams MAYOUX, Bruce A. PERKINS, Nima SOLEYMANLOU, Maximilian von EYNATTEN, Hans-Juergen WOERLE.
Application Number | 20160038525 14/918818 |
Document ID | / |
Family ID | 50543578 |
Filed Date | 2016-02-11 |
United States Patent
Application |
20160038525 |
Kind Code |
A1 |
BROEDL; Uli Christian ; et
al. |
February 11, 2016 |
PHARMACEUTICAL COMPOSITION, METHODS FOR TREATING AND USES
THEREOF
Abstract
The present invention relates to certain SGLT-2 inhibitors for
treating, preventing, protecting against and/or delaying the
progression of chronic kidney disease in patients, for example
patients with prediabetes, type 1 or type 2 diabetes mellitus.
Inventors: |
BROEDL; Uli Christian;
(Mainz am Rhein, DE) ; JOHANSEN; Odd-Erik;
(Hoevik, NO) ; MAYOUX; Eric Williams;
(Schemmerhofen, DE) ; SOLEYMANLOU; Nima; (Maple,
CA) ; von EYNATTEN; Maximilian; (Mainz, DE) ;
WOERLE; Hans-Juergen; (Munich, DE) ; CHERNEY; David
Z.I.; (Toronto, CA) ; PERKINS; Bruce A.;
(Toronto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
50543578 |
Appl. No.: |
14/918818 |
Filed: |
October 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14253935 |
Apr 16, 2014 |
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14918818 |
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61823045 |
May 14, 2013 |
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61813223 |
Apr 18, 2013 |
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Current U.S.
Class: |
514/23 |
Current CPC
Class: |
A61P 13/12 20180101;
A61K 9/2866 20130101; A61K 31/522 20130101; A61P 43/00 20180101;
A61K 31/155 20130101; A61P 13/02 20180101; A61P 3/10 20180101; A61K
9/2018 20130101; A61K 45/06 20130101; A61K 31/7048 20130101; A61K
38/28 20130101; A61K 31/155 20130101; A61K 2300/00 20130101; A61K
31/7048 20130101; A61K 2300/00 20130101; A61K 38/28 20130101; A61K
2300/00 20130101; A61K 31/522 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 45/06 20060101 A61K045/06 |
Claims
1) A method of treating, preventing, protecting against, reducing
the risk of, delaying the occurrence of and/or delaying the
progression of chronic kidney disease in a patient, said method
comprising administering empagliflozin, optionally in combination
with one or more other therapeutic substances, to the patient.
2) The method according to claim 1, wherein the progression of said
chronic kidney disease is the progression to end stage renal
disease/kidney failure, or renal death in the patient.
3) The method according to claim 1, wherein said patient is at risk
for renal disease.
4) The method according to claim 1, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
5) The method according to claim 1, wherein the patient has or is
at risk of a cardiovascular disease.
6) The method according to claim 1, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus and
with or at risk of a cardiovascular disease.
7) A method of treating, preventing, protecting against or delaying
new onset of albuminuria in a patient, said method comprising
administering empagliflozin, optionally in combination with one or
more other therapeutic substances, to the patient.
8) The method according to claim 7, wherein said patient is at risk
for renal disease.
9) The method according to claim 7, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
10) The method according to claim 7, wherein the patient has or is
at risk of a cardiovascular disease.
11) The method according to claim 7, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus and
with or at risk of a cardiovascular disease.
12) A method of treating, preventing, protecting against or
delaying the progression from no albuminuria to micro- or
macroalbuminuria in a patient at risk for renal disease, said
method comprising administering empagliflozin, optionally in
combination with one or more other therapeutic substances, to the
patient.
13) The method according to claim 12, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
14) A method of treating, preventing, protecting against or
delaying the progression from microalbuminuria to macroalbuminuria
in a patient with chronic kidney disease, said method comprising
administering empagliflozin, optionally in combination with one or
more other therapeutic substances, to the patient.
15) The method according to claim 14, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
16) A method for treating, preventing, protecting against or
delaying the progression of chronic kidney disease in a patient,
said method administering empagliflozin, optionally in combination
with one or more other therapeutic substances, to the patient.
17) The method according to claim 16, comprising preventing,
protecting against or delaying loss of eGFR, for example sustained
eGFR loss of 50%, in said patient.
18) The method according to claim 16, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
19) A method of treating, preventing, protecting against or
delaying the occurrence of: new onset of albuminuria, doubling of
serum creatinine level accompanied by an eGFR (based on
modification of diet in renal disease (MDRD) formula) .ltoreq.45
mL/min/1.73 m.sup.2, need for continuous renal replacement therapy,
or death due to renal disease, in a patient, said method comprising
administering empagliflozin, optionally in combination with one or
more other therapeutic substances, to the patient.
20) The method according to claim 19, wherein the patient has
chronic kidney disease.
21) The method according to claim 19, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus.
22) The method according to claim 19, wherein the patient has or is
at risk of a cardiovascular disease.
23) The method according to claim 19, wherein the patient is a
patient with prediabetes, type 1 or type 2 diabetes and with or at
risk of a cardiovascular disease.
24) The method according to claim 19, wherein the patient has
chronic kidney disease and is a patient with prediabetes, type 1 or
type 2 diabetes mellitus.
25) The method according to claim 1, wherein the patient is a
patient with one or more cardiovascular risk factors selected from
A), B), C) and D): A) previous or existing vascular disease
selected from myocardial infarction, coronary artery disease,
percutaneous coronary intervention, coronary artery by-pass
grafting, ischemic or hemorrhagic stroke, congestive heart failure,
and peripheral occlusive arterial disease, B) advanced age
>1=60-70 years, and C) one or more cardiovascular risk factors
selected from advanced type 1 or type 2 diabetes mellitus >10
years duration, hypertension, current daily cigarette smoking,
dyslipidemia, obesity, age >/=40, metabolic syndrome,
hyperinsulinemia or insulin resistance, and hyperuricemia, erectile
dysfunction, polycystic ovary syndrome, sleep apnea, or family
history of vascular disease or cardiomyopathy in first-degree
relative; D) one or more of the following: confirmed history of
myocardial infarction, unstable angina with documented multivessel
coronary disease or positive stress test, multivessel Percutaneous
Coronary Intervention, multivessel Coronary Artery By-pass Grafting
(CABG), history of ischemic or hemorrhagic stroke, peripheral
occlusive arterial disease.
26) The method according to claim 1, wherein the one or more other
therapeutic substances are selected from other antidiabetic
substances.
27) The method according to claim 1, comprising administering
empagliflozin in combination with metformin, with linagliptin or
with metformin and linagliptin.
28) The method according to claim 1, wherein the one or more other
therapeutic substances is a RAAS inhibitor.
29) The method according to claim 1, wherein the one or more other
therapeutic substances is a direct renin inhibitor, an
Angiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB).
30) The method according to claim 1, comprising administering
empagliflozin in combination with a RAAS inhibitor.
31) The method according to claim 1, comprising administering
empagliflozin in combination with a direct renin inhibitor, an
Angiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB).
32) The method according to claim 1, wherein empagliflozin is
administered orally in a total daily amount of 10 mg or 25 mg.
33) The method according to claim 1, wherein empagliflozin is
administered as a pharmaceutical composition comprising 10 mg or 25
mg of empagliflozin.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to certain SGLT-2 inhibitors
for treating, preventing, protecting against and/or delaying the
progression of chronic kidney disease in patients, for example
patients with prediabetes, type 1 or type 2 diabetes mellitus.
BACKGROUND OF THE INVENTION
[0002] Chronic kidney disease (CKD), also known as chronic renal
disease, is a progressive loss in renal function over a period of
months or years. The symptoms of worsening kidney function are
non-specific, and chronic kidney disease is often diagnosed as a
result of screening of people known to be at risk of kidney
problems.
[0003] Chronic kidney disease may be identified by a blood test,
for example for creatinine. Higher levels of creatinine indicate a
lower glomerular filtration rate and as a result a decreased
capability of the kidneys to excrete waste products.
[0004] CKD has been classified into 5 stages, where stage 1 is
kidney damage with normal GFR (mL/min/1.73 m.sup.2) of .gtoreq.90;
stage 2 is kidney damage with a mild decrease in GFR (GFR 60-89);
stage 3 is a moderate decrease in GFR (GFR 30-59); stage 4 is a
severe decrease in GFR (GFR 15-29); and stage 5 is kidney failure
(GFR <15 or dialysis). Stage 5 CKD is often called End Stage
Renal Disease (ESRD) and is synonymous with the now outdated terms
chronic kidney failure (CKF) or chronic renal failure (CRF).
[0005] Albuminuria can also be a sign of kidney disease.
Albuminuria has been classified into 3 categories, where category
A1 reflects no album inuria with albumin normal to mildly
increased; category A2 which reflects microalbuminuria with albumin
moderately increased; category A3 which reflects macroalbuminuria
with albumin severely increased.
[0006] There is no specific treatment unequivocally shown to slow
the worsening of chronic kidney disease and severe CKD requires
renal replacement therapy, which may involve a form of dialysis,
but ideally constitutes a kidney transplant.
[0007] Therefore, there is an unmet medical need for methods,
medicaments and pharmaceutical compositions able to slow the
worsening or progression of chronic kidney disease in patients, in
particular patients at risk of renal diseases, for example patients
with prediabetes, type 1 or type 2 diabetes mellitus.
SUMMARY OF THE INVENTION
[0008] Accordingly, in one aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for treating,
preventing, protecting against, reducing the risk of, delaying the
occurrence of and/or delaying the progression of chronic kidney
disease in patients, for example patients with prediabetes, type 1
or type 2 diabetes mellitus.
[0009] In one embodiment, the present invention provides a method
of treating, preventing, protecting against, reducing the risk of,
delaying the occurrence of and/or delaying the progression of
chronic kidney disease in a patient, said method comprising
administering empagliflozin, optionally in combination with one or
more other therapeutic substances, to the patient. In one aspect,
the progression of said chronic kidney disease is the progression
to end stage renal disease/kidney failure, or renal death in the
patient.
[0010] In one embodiment, the present invention provides a method
of treating, preventing, protecting against or delaying new onset
of albuminuria in a patient, said method comprising administering
empagliflozin, optionally in combination with one or more other
therapeutic substances, to the patient. In one aspect, the patient
is at risk for renal disease.
[0011] In one aspect, in one of the above methods, the patient is a
patient with prediabetes, type 1 or type 2 diabetes mellitus. In
one aspect, the patient has or is at risk of a cardiovascular
disease. In one aspect, the patient is a patient with prediabetes,
type 1 or type 2 diabetes mellitus and with or at risk of a
cardiovascular disease.
[0012] In one embodiment, the present invention provides a method
of treating, preventing, protecting against or delaying the
progression from no albuminuria to micro- or macroalbuminuria in a
patient at risk for renal disease, said method comprising
administering empagliflozin, optionally in combination with one or
more other therapeutic substances, to the patient.
[0013] In one embodiment, the present invention provides a method
of treating, preventing, protecting against or delaying the
progression from microalbuminuria to macroalbuminuria in a patient
with chronic kidney disease, said method comprising administering
empagliflozin, optionally in combination with one or more other
therapeutic substances, to the patient.
[0014] In one aspect, in a method above the patient is a patient
with prediabetes, type 1 or type 2 diabetes mellitus.
[0015] In one embodiment, the present invention provides a method
for treating, preventing, protecting against or delaying the
progression of chronic kidney disease in a patient, in particular a
patient with chronic kidney disease, said method administering
empagliflozin, optionally in combination with one or more other
therapeutic substances, to the patient. In one aspect, the method
is for preventing, protecting against or delaying loss of eGFR, for
example sustained eGFR loss of .gtoreq.50%, in said patient. In one
aspect, the patient is a patient with prediabetes, type 1 or type 2
diabetes mellitus.
[0016] In one embodiment, the present invention provides a method
of treating, preventing, protecting against or delaying the
occurrence of: [0017] new onset of albuminuria, [0018] doubling of
serum creatinine level accompanied by an eGFR (based on
modification of diet in renal disease (MDRD) formula) .ltoreq.45
mL/min/1.73 m.sup.2, [0019] need for continuous renal replacement
therapy, or [0020] death due to renal disease, [0021] in a patient,
said method comprising administering empagliflozin, optionally in
combination with one or more other therapeutic substances, to the
patient.
[0022] In one aspect, the patient has chronic kidney disease. In
one aspect, the patient is a patient with prediabetes, type 1 or
type 2 diabetes mellitus. In one aspect, the patient has or is at
risk of a cardiovascular disease. In one aspect, the patient is a
patient with prediabetes, type 1 or type 2 diabetes and with or at
risk of a cardiovascular disease. In one aspect, the patient has
chronic kidney disease and is a patient with prediabetes, type 1 or
type 2 diabetes mellitus.
[0023] In one aspect, in any one of the methods above the patient
is a patient with one or more cardiovascular risk factors selected
from A), B), C) and D), for example a patient with type 1 or type 2
diabetes mellitus or with pre-diabetes with one or more
cardiovascular risk factors selected from A), B), C) and D):
A) previous or existing vascular disease selected from myocardial
infarction, coronary artery disease, percutaneous coronary
intervention, coronary artery by-pass grafting, ischemic or
hemorrhagic stroke, congestive heart failure, and peripheral
occlusive arterial disease, B) advanced age >/=60-70 years, and
C) one or more cardiovascular risk factors selected from [0024]
advanced type 1 or type 2 diabetes mellitus >10 years duration,
[0025] hypertension, [0026] current daily cigarette smoking, [0027]
dyslipidemia, [0028] obesity, [0029] age >/=40, [0030] metabolic
syndrome, hyperinsulinemia or insulin resistance, and [0031]
hyperuricemia, erectile dysfunction, polycystic ovary syndrome,
sleep apnea, or family history of vascular disease or
cardiomyopathy in first-degree relative; D) one or more of the
following: [0032] confirmed history of myocardial infarction,
[0033] unstable angina with documented multivessel coronary disease
or positive stress test, [0034] multivessel Percutaneous Coronary
Intervention, [0035] multivessel Coronary Artery By-pass Grafting
(CABG), [0036] history of ischemic or hemorrhagic stroke, [0037]
peripheral occlusive arterial disease.
[0038] In one aspect of the present invention, a patient having
cardiovascular disease is defined as having at least one of the
following: [0039] Confirmed history of myocardial infarction; or
[0040] Evidence of multivessel coronary artery disease, in 2 or
more major coronary arteries, irrespective of the revascularization
status, i.e. [0041] a) Either the presence of a significant
stenosis (imaging evidence of at least 50% narrowing of the luminal
diameter measured during a coronary angiography or a multi-sliced
computed tomography angiography), in 2 or more major coronary
arteries, [0042] b) Or a previous revascularisation (percutaneous
transluminal coronary angioplasty with or without stent, or
coronary artery bypass grafting), in 2 or more major coronary
arteries, [0043] c) Or the combination of previous
revascularisation in one major coronary artery (percutaneous
transluminal coronary angioplasty with or without stent, or
coronary artery bypass grafting), and the presence of a significant
stenosis in another major coronary artery (imaging evidence of at
least 50% narrowing of the luminal diameter measured during a
coronary angiography or a multi-sliced computed tomography
angiography), [0044] Note: A disease affecting the left main
coronary artery is considered as a 2-vessel disease. [0045]
Evidence of a single vessel coronary artery disease with: [0046] a)
The presence of a significant stenosis i.e. the imaging evidence of
at least 50% narrowing of the luminal diameter of one major
coronary artery in patients not subsequently successfully
revascularised (measured during a coronary angiography or a
multi-sliced computed tomography angiography) [0047] b) And at
least one of the following (either (i) or (ii)): [0048] i. A
positive non invasive stress test, confirmed by either: [0049] 1. A
positive exercise tolerance test in patients without a complete
left bundle branch block, Wolff-Parkinson-White syndrome, or paced
ventricular rhythm, or [0050] 2. A positive stress echocardiography
showing regional systolic wall motion abnormalities, or [0051] 3. A
positive scintigraphic test showing stress-induced ischemia, i.e.
the development of transient perfusion defects during myocardial
perfusion imaging; [0052] ii. Or patient discharged from hospital
with a documented diagnosis of unstable angina within 12 months
prior to selection. [0053] Episode of unstable angina with
confirmed evidence of coronary multivessel or single vessel disease
as defined above. [0054] History of ischemic or haemorrhagic stroke
[0055] Presence of peripheral artery disease (symptomatic or not)
documented by either: previous limb angioplasty, stenting or bypass
surgery; or previous limb or foot amputation due to circulatory
insufficiency; or angiographic evidence of significant (>50%)
peripheral artery stenosis in at least one limb; or evidence from a
non-invasive measurement of significant (>50% or as reported as
hemodynamically significant) peripheral artery stenosis in at least
one limb; or ankle brachial index of <0.9 in at least one
limb.
[0056] In one aspect of the present invention, a patient having
cardiovascular disease is defined as having at least one of the
following: [0057] a) Confirmed history of myocardial infarction,
[0058] b) Unstable angina with documented multivessel coronary
disease (at least two major coronary arteries in angiogram) or
positive stress test (ST segment depression >=2 mm or a positive
nuclear perfusion scintigram), [0059] c) Multivessel Percutaneous
Coronary Intervention (PCI), [0060] d) Multivessel Coronary Artery
By-pass Grafting (CABG), including with recurrent angina following
surgery, [0061] e) History of ischemic or hemorrhagic stroke,
[0062] f) Peripheral occlusive arterial disease (previous limb
bypass surgery or percutaneous transluminal angioplasty; previous
limb or foot amputation due to circulatory insufficiency,
angiographic or imaging detected (for example: ultrasound, Magnetic
Resonance Imaging) significant vessel stenosis of major limb
arteries).
[0063] In one aspect, in any one of the methods above the one or
more other therapeutic substances are selected from other
antidiabetic substances.
[0064] In one aspect, any one of the methods above comprises
administering empagliflozin in combination with metformin, with
linagliptin or with metformin and linagliptin.
[0065] In one aspect, in any one of the methods above the one or
more other therapeutic substances is a RAAS inhibitor. In one
aspect, the one or more other therapeutic substances is a direct
renin inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor
and/or an angiotensin II receptor blocker (ARB).
[0066] In one aspect, any one of the methods above comprises
administering empagliflozin in combination with a RAAS inhibitor.
In one aspect, any one of the methods above comprises administering
empagliflozin in combination with a direct renin inhibitor, an
Angiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB).
[0067] In one aspect, in any one of the methods above empagliflozin
is administered orally in a total daily amount of 10 mg or 25 mg.
In one aspect empagliflozin is administered as a pharmaceutical
composition comprising 10 mg or 25 mg of empagliflozin.
[0068] In one aspect of the present invention, in a method or use
disclosed herein a patient is a patient with type 2 diabetes
mellitus (or type 2 diabetes patient), a patient treated for type 2
diabetes mellitus, a patient diagnosed with type 2 diabetes
mellitus or a patient in need of treatment for type 2 diabetes
mellitus. In one aspect, a patient is a patient with
pre-diabetes.
[0069] In one aspect of the present invention, in a method or use
disclosed herein a patient is a patient with obesity-related
Glomerulopathy, a patient with perihilar fokal-segmental
glomerulosclerosis or a patient with IgA nephropathy.
[0070] Accordingly, in one embodiment, the present invention
provides a method of treating, preventing, protecting against,
reducing the risk of, delaying the occurrence of and/or delaying
the progression of chronic kidney disease in a patient with
obesity-related Glomerulopathy, in a patient with perihilar
fokal-segmental glomerulosclerosis or in a patient with IgA
nephropathy.
[0071] The present invention further provides for empagliflozin or
a pharmaceutical composition comprising empagliflozin for use as a
medicament in any one of the methods described herein.
[0072] The present invention further provides for empagliflozin in
combination with one or more other therapeutic substances, for
example selected from other antidiabetic substances, in particular
metformin, linagliptin or metformin and linagliptin, or a
pharmaceutical composition comprising empagliflozin and one or more
other therapeutic substances, for example selected from other
antidiabetic substances, in particular metformin, linagliptin or
metformin and linagliptin, for use as a medicament in any one of
the methods described herein.
[0073] The present invention further provides for empagliflozin in
combination with a RAAS inhibitor, in particular a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), or a pharmaceutical
composition comprising empagliflozin and a RAAS inhibitor, in
particular a direct renin inhibitor, an Angiotensin-Converting
Enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker
(ARB), for use as a medicament in any one of the methods described
herein.
[0074] The present invention further provides for empagliflozin or
a pharmaceutical composition comprising empagliflozin for use in
the treatment of any one of the diseases or conditions described
herein.
[0075] The present invention further provides for empagliflozin in
combination with one or more other therapeutic substances, for
example selected from other antidiabetic substances, in particular
metformin, linagliptin or metformin and linagliptin, or a
pharmaceutical composition comprising empagliflozin and one or more
other therapeutic substances, for example selected from other
antidiabetic substances, in particular metformin, linagliptin or
metformin and linagliptin, for use in the treatment of any one of
the diseases or conditions described herein.
[0076] The present invention further provides for empagliflozin in
combination with a RAAS inhibitor, in particular a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), or a pharmaceutical
composition comprising empagliflozin and a RAAS inhibitor, in
particular a direct renin inhibitor, an Angiotensin-Converting
Enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker
(ARB), for use in the treatment of any one of the diseases or
conditions described herein.
[0077] The present invention further provides for empagliflozin or
a pharmaceutical composition comprising empagliflozin for use in
the manufacture of a medicament for use in any one of the methods
described herein.
[0078] The present invention further provides for empagliflozin in
combination with one or more other therapeutic substances, for
example selected from other antidiabetic substances, in particular
metformin, linagliptin or metformin and linagliptin, or a
pharmaceutical composition comprising empagliflozin and one or more
other therapeutic substances, for example selected from other
antidiabetic substances, in particular metformin, linagliptin or
metformin and linagliptin, for use in the manufacture of a
medicament for use in any one of the methods described herein.
[0079] The present invention further provides for empagliflozin in
combination with a RAAS inhibitor, in particular a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), or a pharmaceutical
composition comprising empagliflozin and a RAAS inhibitor, in
particular a direct renin inhibitor, an Angiotensin-Converting
Enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker
(ARB), for use in the manufacture of a medicament for use in any
one of the methods described herein.
DEFINITIONS
[0080] The term "active ingredient" of a pharmaceutical composition
according to the present invention means the SGLT2 inhibitor
according to the present invention. An "active ingredient" is also
sometimes referred to herein as an "active substance".
[0081] The term "body mass index" or "BMI" of a human patient is
defined as the weight in kilograms divided by the square of the
height in meters, such that BMI has units of kg/m.sup.2.
[0082] The term "overweight" is defined as the condition wherein
the individual has a 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.
[0083] The terms "obesity" or "being obese" and the like are
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: the term "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; the term "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; the term "class
III obesity" is the condition wherein the BMI is equal to or
greater than 40 kg/m.sup.2.
[0084] The indication obesity includes in particular exogenic
obesity, hyperinsulinaemic obesity, hyperplasmic obesity,
hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity,
hypothalamic obesity, symptomatic obesity, infantile obesity, upper
body obesity, alimentary obesity, hypogonadal obesity, central
obesity, visceral obesity, abdominal obesity.
[0085] The term "visceral obesity" is 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.
[0086] The term "abdominal obesity" is usually 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).
[0087] The term "euglycemia" is defined as the condition in which a
subject has a fasting blood glucose concentration within the normal
range, greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL
(5.6 mmol/L). The word "fasting" has the usual meaning as a medical
term.
[0088] The term "hyperglycemia" is defined as the condition in
which a subject has a fasting blood glucose concentration above the
normal range, greater than 100 mg/dL (5.6 mmol/L). The word
"fasting" has the usual meaning as a medical term.
[0089] The term "hypoglycemia" is defined as the condition in which
a subject has a blood glucose concentration below the normal range,
in particular below 70 mg/dL (3.89 mmol/L).
[0090] The term "postprandial hyperglycemia" is defined as the
condition in which a subject has a 2 hour postprandial blood
glucose or serum glucose concentration greater than 200 mg/dL
(11.11 mmol/L).
[0091] The term "impaired fasting blood glucose" or "IFG" is
defined as the condition in which a subject has a fasting blood
glucose concentration or fasting serum glucose concentration in a
range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l), in
particular greater than 110 mg/dL and less than 126 mg/dl (7.00
mmol/L). A subject with "normal fasting glucose" has a fasting
glucose concentration smaller than 100 mg/dl, i.e. smaller than 5.6
mmol/l.
[0092] The term "impaired glucose tolerance" or "IGT" is defined as
the condition in which a subject has a 2 hour postprandial blood
glucose or serum glucose concentration greater than 140 mg/dl (7.78
mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal
glucose tolerance, i.e. the 2 hour postprandial blood glucose or
serum glucose concentration can be measured as the blood sugar
level in mg of glucose per dL of plasma 2 hours after taking 75 g
of glucose after a fast. A subject with "normal glucose tolerance"
has a 2 hour postprandial blood glucose or serum glucose
concentration smaller than 140 mg/dl (7.78 mmol/L).
[0093] The term "hyperinsulinemia" is defined as the condition in
which a subject with insulin resistance, with or without
euglycemia, has fasting or postprandial serum or plasma insulin
concentration elevated above that of normal, lean individuals
without insulin resistance, having a waist-to-hip ratio <1.0
(for men) or <0.8 (for women).
[0094] The terms "insulin-sensitizing", "insulin
resistance-improving" or "insulin resistance-lowering" are
synonymous and used interchangeably.
[0095] The term "insulin resistance" is defined as a state in which
circulating insulin levels in excess of the normal response to a
glucose load are required to maintain the euglycemic state (Ford E
S, et al. JAMA. (2002) 287:356-9). A method of determining insulin
resistance is the euglycaemic-hyperinsulinaemic clamp test. The
ratio of insulin to glucose is determined within the scope of a
combined insulin-glucose infusion technique. There is found to be
insulin resistance if the glucose absorption is below the 25th
percentile of the background population investigated (WHO
definition). Rather less laborious than the clamp test are so
called minimal models in which, during an intravenous glucose
tolerance test, the insulin and glucose concentrations in the blood
are measured at fixed time intervals and from these the insulin
resistance is calculated. With this method, it is not possible to
distinguish between hepatic and peripheral insulin resistance.
[0096] Furthermore, insulin resistance, the response of a patient
with insulin resistance to therapy, insulin sensitivity and
hyperinsulinemia may be quantified by assessing the "homeostasis
model assessment to insulin resistance (HOMA-IR)" score, a reliable
indicator of insulin resistance (Katsuki A, et al. Diabetes Care
2001; 24: 362-5). Further reference is made to methods for the
determination of the HOMA-index for insulin sensitivity (Matthews
et al., Diabetologia 1985, 28: 412-19), of the ratio of intact
proinsulin to insulin (Forst et al., Diabetes 2003, 52(Suppl.1):
A459) and to an euglycemic clamp study. In addition, plasma
adiponectin levels can be monitored as a potential surrogate of
insulin sensitivity. The estimate of insulin resistance by the
homeostasis assessment model (HOMA)-IR score is calculated with the
formula (Galvin P, et al. Diabet Med 1992; 9:921-8):
HOMA-IR=[fasting serum insulin (.mu.U/mL)].times.[fasting plasma
glucose(mmol/L)/22.5]
[0097] Insulin resistance can be confirmed in these individuals by
calculating the HOMA-IR score. For the purpose of this invention,
insulin resistance is defined as the clinical condition in which an
individual has a HOMA-IR score >4.0 or a HOMA-IR score above the
upper limit of normal as defined for the laboratory performing the
glucose and insulin assays.
[0098] As a rule, other parameters are used in everyday clinical
practice to assess insulin resistance. Preferably, the patient's
triglyceride concentration is used, for example, as increased
triglyceride levels correlate significantly with the presence of
insulin resistance.
[0099] Individuals likely to have insulin resistance are those who
have two or more of the following attributes: 1) overweight or
obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more
1.sup.st degree relative with a diagnosis of IGT or IFG or type 2
diabetes.
[0100] Patients with a predisposition for the development of IGT or
IFG or type 2 diabetes are those having euglycemia with
hyperinsulinemia and are by definition, insulin resistant. A
typical patient with insulin resistance is usually overweight or
obese. If insulin resistance can be detected, this is a
particularly strong indication of the presence of pre-diabetes.
Thus, it may be that in order to maintain glucose homoeostasis a
person needs 2-3 times as much insulin as a healthy person, without
this resulting in any clinical symptoms.
[0101] "Pre-diabetes" is a general term that refers to an
intermediate stage between normal glucose tolerance (NGT) and overt
type 2 diabetes mellitus (T2DM), also referred to as intermediate
hyperglycaemia. As such, it represents 3 groups of individuals,
those with impaired glucose tolerance (IGT) alone, those with
impaired fasting glucose (IFG) alone or those with both IGT and
IFG. IGT and IFG usually have distinct pathophysiologic etiologies,
however also a mixed condition with features of both can exist in
patients. Therefore in the context of the present invention a
patient being diagnosed of having "pre-diabetes" is an individual
with diagnosed IGT or diagnosed IFG or diagnosed with both IGT and
IFG. Following the definition according to the American Diabetes
Association (ADA) and in the context of the present invention a
patient being diagnosed of having "pre-diabetes" is an individual
with:
a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1
mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG)
concentration, measured by a 75-g oral glucose tolerance test
(OGTT), ranging between 140 mg/dL and <200 mg/dL (i.e., IGT); or
b) a fasting plasma glucose (FPG) concentration between .gtoreq.100
mg/dL and <126 mg/dL and a 2-hour plasma glucose (PG)
concentration, measured by a 75-g oral glucose tolerance test
(OGTT) of <140 mg/dL (i.e., IFG); or c) a fasting plasma glucose
(FPG) concentration between .gtoreq.100 mg/dL and <126 mg/dL and
a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral
glucose tolerance test (OGTT), ranging between .gtoreq.140 mg/dL
and <200 mg/dL (i.e., both IGT and IFG).
[0102] Patients with "pre-diabetes" are individuals being
pre-disposed to the development of type 2 diabetes. Pre-diabetes
extends the definition of IGT to include individuals with a fasting
blood glucose within the high normal range .gtoreq.100 mg/dL (J. B.
Meigs, et al. Diabetes 2003; 52:1475-1484). The scientific and
medical basis for identifying pre-diabetes as a serious health
threat is laid out in a Position Statement entitled "The Prevention
or Delay of Type 2 Diabetes" issued jointly by the American
Diabetes Association and the National Institute of Diabetes and
Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749).
[0103] The methods to investigate the function of pancreatic
beta-cells are similar to the above methods with regard to insulin
sensitivity, hyperinsulinemia or insulin resistance: An improvement
of beta-cell function can be measured for example by determining a
HOMA-index for beta-cell function (Matthews et al., Diabetologia
1985, 28: 412-19), the ratio of intact proinsulin to insulin (Forst
et al., Diabetes 2003, 52(Suppl.1): A459), the insulin/C-peptide
secretion after an oral glucose tolerance test or a meal tolerance
test, or by employing a hyperglycemic clamp study and/or minimal
modeling after a frequently sampled intravenous glucose tolerance
test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).
[0104] The term "type 1 diabetes" is defined as the condition in
which a subject has, in the presence of autoimmunity towards the
pancreatic beta-cell or insulin, a fasting blood glucose or serum
glucose concentration greater than 125 mg/dL (6.94 mmol/L). If a
glucose tolerance test is carried out, the blood sugar level of a
diabetic will be in excess of 200 mg of glucose per dL (11.1
mmol/l) of plasma 2 hours after 75 g of glucose have been taken on
an empty stomach, in the presence of autoimmunity towards the
pancreatic beta cell or insulin. In a glucose tolerance test 75 g
of glucose are administered orally to the patient being tested
after 10-12 hours of fasting and the blood sugar level is recorded
immediately before taking the glucose and 1 and 2 hours after
taking it. The presence of autoimmunity towards the pancreatic
beta-cell may be observed by detection of circulating islet cell
autoantibodies ["type 1A diabetes mellitus"], i.e., at least one
of: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell
cytoplasm], IA-2 [intracytoplasmatic domain of the tyrosine
phosphatase-like protein IA-2], ZnT8 [zinc-transporter-8] or
anti-insulin; or other signs of autoimmunity without the presence
of typical circulating autoantibodies [type 1B diabetes], i.e. as
detected through pancreatic biopsy or imaging). Typically a genetic
predisposition is present (e.g. HLA, INS VNTR and PTPN22), but this
is not always the case.
[0105] The term "type 2 diabetes mellitus" or "T2DM" is defined as
the condition in which a subject has a fasting blood glucose or
serum glucose concentration greater than 125 mg/dL (6.94 mmol/L).
The measurement of blood glucose values is a standard procedure in
routine medical analysis. If a glucose tolerance test is carried
out, the blood sugar level of a diabetic will be in excess of 200
mg of glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of
glucose have been taken on an empty stomach. In a glucose tolerance
test 75 g of glucose are administered orally to the patient being
tested after 10-12 hours of fasting and the blood sugar level is
recorded immediately before taking the glucose and 1 and 2 hours
after taking it. In a healthy subject, the blood sugar level before
taking the glucose will be between 60 and 110 mg per dL of plasma,
less than 200 mg per dL 1 hour after taking the glucose and less
than 140 mg per dL after 2 hours. If after 2 hours the value is
between 140 and 200 mg, this is regarded as abnormal glucose
tolerance.
[0106] The term "late stage type 2 diabetes mellitus" includes
patients with a secondary drug failure, indication for insulin
therapy and progression to micro- and macrovascular complications
e.g. diabetic nephropathy, or coronary heart disease (CHD).
[0107] The term "HbA1c" refers to the product of a non-enzymatic
glycation of the haemoglobin B chain. Its determination is well
known to one skilled in the art. In monitoring the treatment of
diabetes mellitus the HbA1c value is of exceptional importance. As
its production depends essentially on the blood sugar level and the
life of the erythrocytes, the HbA1c in the sense of a "blood sugar
memory" reflects the average blood sugar levels of the preceding
4-6 weeks. Diabetic patients whose HbA1c value is consistently well
adjusted by intensive diabetes treatment (i.e. <6.5% of the
total haemoglobin in the sample), are significantly better
protected against diabetic microangiopathy. For example, metformin
on its own achieves an average improvement in the HbA1c value in
the diabetic of the order of 1.0-1.5%. This reduction of the HbA1C
value is not sufficient in all diabetics to achieve the desired
target range of <7% or <6.5% and preferably <6% HbA1c.
[0108] The term "insufficient glycemic control" or "inadequate
glycemic control" in the scope of the present invention means a
condition wherein patients show HbA1c values above 6.5%, in
particular above 7.0%, even more preferably above 7.5%, especially
above 8%.
[0109] The "metabolic syndrome", also called "syndrome X" (when
used in the context of a metabolic disorder), also called the
"dysmetabolic syndrome" is a syndrome complex with the cardinal
feature being insulin resistance (Laaksonen D E, et al. Am J
Epidemiol 2002; 156:1070-7). According to the ATP III/NCEP
guidelines (Executive Summary of the Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) JAMA: Journal of the American Medical
Association (2001) 285:2486-2497), diagnosis of the metabolic
syndrome is made when three or more of the following risk factors
are present: [0110] 1. Abdominal obesity, defined as waist
circumference >40 inches or 102 cm in men, and >35 inches or
94 cm in women; or with regard to a Japanese ethnicity or Japanese
patients defined as waist circumference .gtoreq.85 cm in men and
.gtoreq.90 cm in women; [0111] 2. Triglycerides: .gtoreq.150 mg/dL
[0112] 3. HDL-cholesterol <40 mg/dL in men [0113] 4. Blood
pressure .gtoreq.130/85 mm Hg (SBP .gtoreq.130 or DBP .gtoreq.85)
[0114] 5. Fasting blood glucose .gtoreq.100 mg/dL
[0115] The NCEP definitions have been validated (Laaksonen D E, et
al. Am J Epidemiol. (2002) 156:1070-7). Triglycerides and HDL
cholesterol in the blood can also be determined by standard methods
in medical analysis and are described for example in Thomas L
(Editor): "Labor and Diagnose", TH-Books Verlagsgesellschaft mbH,
Frankfurt/Main, 2000.
[0116] According to a commonly used definition, hypertension is
diagnosed if the systolic blood pressure (SBP) exceeds a value of
140 mm Hg and diastolic blood pressure (DBP) exceeds a value of 90
mm Hg. If a patient is diagnosed with diabetes it is currently
recommended that the systolic blood pressure be reduced to a level
below 130 mm Hg and the diastolic blood pressure be lowered to
below 80 mm Hg.
[0117] The term "chronic kidney disease (CDK)" is defined as
abnormalities of kidney structure or function, present for more
than three months, with implications for health. CKD is classified
based on cause, GFR category, and albuminuria category (CGA).
[0118] CKD has been classified into 5 stages, where stage 1 is
kidney damage with normal GFR (mL/min/1.73 m2) of 90 or above;
stage 2 is kidney damage with a mild decrease in GFR (GFR 60-89);
stage 3 is a moderate decrease in GFR (GFR 30-59); stage 4 is a
severe decrease in GFR (GFR 15-29); and stage 5 is kidney failure
(GFR <15 or dialysis). Stage 3 has been subdivided into stage
3A, which is a mild to moderate decrease in GFR (GFR 45-59), and
stage 3B, which is a moderate to severe decrease in GFR (GFR
30-44).
[0119] The term "glomerular filtration rate (GFR)" is defined as
the volume of fluid filtered from the renal (kidney) glomerular
capillaries into the Bowman's capsule per unit time. It is
indicative of overall kidney function. The glomerular filtration
rate (GFR) can be calculated by measuring any chemical that has a
steady level in the blood, and is freely filtered but neither
reabsorbed nor secreted by the kidneys. The rate therefore measured
is the quantity of the substance in the urine that originated from
a calculable volume of blood. The GFR is typically recorded in
units of volume per time, e.g., milliliters per minute and the
formula below can be used:
GFR=(Urine Concentration.times.Urine Volume)/Plasma
Concentration
[0120] The GFR can be determined by injecting inulin into the
plasma. Since inulin is neither reabsorbed nor secreted by the
kidney after glomerular filtration, its rate of excretion is
directly proportional to the rate of filtration of water and
solutes across the glomerular filter. A normal value is: GFR=90-125
mL/min/1.73 m.sup.2, in particular GFR=100-125 mL/min/1.73
m.sup.2
[0121] Other principles to determine GFR involve measuring
51Cr-EDTA, [125I]iothalamate or iohexol.
[0122] The "estimated glomerular filtration rate (eGFR)" is defined
as derived at screening from serum creatinine values based on e.g.,
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation, the Cockcroft-Gault formula or the Modification of Diet
in Renal Disease (MDRD) formula, which are all known in the
art.
[0123] The term "albuminuria" is defined as a condition wherein
more than the normal amount of albumin is present in the urine.
Albuminuria can be determined by the albumin excretion rate (AER)
and/or the albumin-to-creatine ratio (ACR) in the urine (also
refered to as UACR). Albuminuria categories in CKD are defined as
follows:
TABLE-US-00001 ACR AER (approximate equivalent) Category (mg/24
hours) (mg/mmol) (mg/g) Terms A1 <30 <3 <30 Normal to
mildly increased A2 30-300 3-30 30-300 Moderately increased A3
>300 >30 >300 Severely increased
[0124] Category A1 reflects no albuminuria, category A2 reflects
microalbuminuria, category A3 reflects macroalbuminuria. The
progression of category A1 usually leads to microalbuminuria (A2)
but may also directly result in macroalbuminuria (A3). Progression
of microalbuminuria (A2) results in macroalbuminuria (A3).
[0125] The term "empagliflozin" refers to the SGLT2 inhibitor
1-chloro-4-(.beta.-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy-
)-benzyl]-benzene of the formula
##STR00001##
as described for example in WO 2005/092877. Methods of synthesis
are described in the literature, for example WO 06/120208 and WO
2011/039108. According to this invention, it is to be understood
that the definition of empagliflozin also comprises its hydrates,
solvates and polymorphic forms thereof, and prodrugs thereof. An
advantageous crystalline form of empagliflozin is described in WO
2006/117359 and WO 2011/039107 which hereby are incorporated herein
in their entirety. This crystalline form possesses good solubility
properties which enables a good bioavailability of the SGLT2
inhibitor. Furthermore, the crystalline form is physico-chemically
stable and thus provides a good shelf-life stability of the
pharmaceutical composition. Preferred pharmaceutical compositions,
such as solid formulations for oral administration, for example
tablets, are described in WO 2010/092126, which hereby is
incorporated herein in its entirety.
[0126] The terms "treatment" and "treating" comprise therapeutic
treatment of patients having already developed said condition, in
particular in manifest form. Therapeutic treatment may be
symptomatic treatment in order to relieve the symptoms of the
specific indication or causal treatment in order to reverse or
partially reverse the conditions of the indication or to stop or
slow down progression of the disease. Thus the compositions and
methods of the present invention may be used for instance as
therapeutic treatment over a period of time as well as for chronic
therapy.
[0127] The terms "prophylactically treating", "preventivally
treating" and "preventing" are used interchangeably and comprise a
treatment of patients at risk to develop a condition mentioned
hereinbefore, thus reducing said risk.
[0128] The term "tablet" comprises tablets without a coating and
tablets with one or more coatings. Furthermore the "term" tablet
comprises tablets having one, two, three or even more layers and
press-coated tablets, wherein each of the beforementioned types of
tablets may be without or with one or more coatings. The term
"tablet" also comprises mini, melt, chewable, effervescent and
orally disintegrating tablets.
[0129] The terms "pharmacopoe" and "pharmacopoeias" refer to
standard pharmacopoeias such as the "USP 31-NF 26 through Second
Supplement" (United States Pharmacopeial Convention) or the
"European Pharmacopoeia 6.3" (European Directorate for the Quality
of Medicines and Health Care, 2000-2009).
DETAILED DESCRIPTION OF THE INVENTION
[0130] In one aspect, the present invention relates to certain
SGLT-2 inhibitors, for example empagliflozin, for use in treating,
preventing, protecting against, reducing the risk of, delaying the
occurrence of and/or delaying the progression of chronic kidney
disease in patients, for example patients with prediabetes, type 1
or type 2 diabetes mellitus.
[0131] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying new onset of
albuminuria in patients.
[0132] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying the
progression from no albuminuria to micro- or macroalbuminuria in a
patient at risk for renal disease.
[0133] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying the
progression from microalbuminuria to macroalbuminuria in a patient
with chronic kidney disease.
[0134] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying the
progression of chronic kidney disease in a patient with chronic
kidney disease.
[0135] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying the occurrence
of: [0136] new onset of albuminuria, [0137] doubling of serum
creatinine level accompanied by an eGFR (based on modification of
diet in renal disease (MDRD) formula) .ltoreq.45 mL/min/1.73
m.sup.2, [0138] need for continuous renal replacement therapy, or
[0139] death due to renal disease.
[0140] In one aspect, a patient according of the present invention
is a patient with prediabetes, type 1 or type 2 diabetes mellitus.
In one aspect, a patient according to the present invention is a
patient is a patient at risk for renal disease. In one aspect, a
patient according to the present invention is a patient with or at
risk of a cardiovascular disease. In one aspect, a patient
according to the present invention is a patient with prediabetes,
type 1 or type 2 diabetes mellitus and with or at risk of a
cardiovascular disease.
[0141] In one aspect of the present invention, in a method or use
disclosed herein a patient is a patient with obesity-related
Glomerulopathy, a patient with perihilar fokal-segmental
glomerulosclerosis or a patient with IgA nephropathy.
[0142] Accordingly, in one embodiment, the present invention
provides a method of treating, preventing, protecting against,
reducing the risk of, delaying the occurrence of and/or delaying
the progression of chronic kidney disease in a patient with
obesity-related Glomerulopathy, in a patient with perihilar
fokal-segmental glomerulosclerosis or in a patient with IgA
nephropathy.
[0143] SGLT2 inhibitors (sodium-glucose co-transporter 2) represent
a novel class of agents that are being developed for the treatment
or improvement in glycemic control in patients with type 2
diabetes. Glucopyranosyl-substituted benzene derivative are
described as SGLT2 inhibitors, for example in WO 01/27128, WO
03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO
2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO
2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO
2008/055870, WO 2008/055940. The glucopyranosyl-substituted benzene
derivatives are proposed as inducers of urinary sugar excretion and
as medicaments in the treatment of diabetes.
[0144] Renal filtration and reuptake of glucose contributes, among
other mechanisms, to the steady state plasma glucose concentration
and can therefore serve as an antidiabetic target. Reuptake of
filtered glucose across epithelial cells of the kidney proceeds via
sodium-dependent glucose cotransporters (SGLTs) located in the
brush-border membranes in the tubuli along the sodium gradient.
There are at least 3 SGLT isoforms that differ in their expression
pattern as well as in their physico-chemical properties. SGLT2 is
exclusively expressed in the kidney, whereas SGLT1 is expressed
additionally in other tissues like intestine, colon, skeletal and
cardiac muscle. SGLT3 has been found to be a glucose sensor in
interstitial cells of the intestine without any transport function.
Potentially, other related, but not yet characterized genes, may
contribute further to renal glucose reuptake. Under normoglycemia,
glucose is completely reabsorbed by SGLTs in the kidney, whereas
the reuptake capacity of the kidney is saturated at glucose
concentrations higher than 10 mM, resulting in glucosuria
("diabetes mellitus"). This threshold concentration can be
decreased by SGLT2-inhibition. It has been shown in experiments
with the SGLT inhibitor phlorizin that SGLT-inhibition will
partially inhibit the reuptake of glucose from the glomerular
filtrate into the blood leading to a decrease in blood glucose
concentration and to glucosuria.
[0145] Empagliflozin is a novel SGLT2 inhibitor that is described
for the treatment or improvement in glycemic control in patients
with type 2 diabetes mellitus, for example in WO 05/092877, WO
06/117359, WO 06/120208, WO 2010/092126, WO 2010/092123, WO
2011/039107, WO 2011/039108.
[0146] Accordingly, in a particular embodiment, a SGLT-2 inhibitor
within the meaning of this invention is empagliflozin.
[0147] Further, the present invention relates to therapeutic
(treatment or prevention) methods as described herein, in
particular methods for the prevention or treatment of renal
diseases, said method comprising administering an effective amount
of a SGLT-2 inhibitor as described herein and, optionally, one or
more other active or therapeutic agents as described herein to the
patient in need thereof.
[0148] Chronic kidney disease (CKD), also known as chronic renal
disease, is a progressive loss in renal function over a period of
months or years. Patients with renal disease, renal dysfunction or
renal impairment may include patients with chronic renal
insufficiency or impairment, which can be stratified (if not
otherwise noted) according to glomerular filtration rate (GFR,
ml/min/1.73 m.sup.2) into 5 disease stages: stage 1 characterized
by normal GFR 90 plus either persistent albuminuria (e.g. UACR
.gtoreq.30 mg/g) 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).
[0149] Chronic kidney disease and its stages (CKD 1-5) can be
usually characterized or classified accordingly, such as based on
the presence of either kidney damage (albuminuria) or impaired
estimated glomerular filtration rate (GFR <60 [ml/min/1.73
m.sup.2], with or without kidney damage).
[0150] For the purpose of the present invention, the estimated
glomerular filtration rate (eGFR) is derived from the serum
creatinine (SCr) value based on the MDRD formula below:
eGFR (mL/min/1.73m2)=175.times.[SCr
(.mu.mol/L)/88.4]-1.154.times.[age]-0.203.times.[0.742 if patient
is female].times.[1.212 if patient is of African origin]
[0151] For additional analyses, renal function can also be
classified by the estimated creatinine clearance rate (eCCr) value,
based on the Cockcroft-Gault formula below:
eCCr (mL/min)=(140-age).times.(weight in kg).times.[0.85 if patient
is female]/(72.times.SCr (mg/dL))
[0152] Renal function classification based on eCCr is similar to
the eGFR classification: normal renal function (.gtoreq.90 mL/min),
mild impairment (60 to <90 mL/min), moderate impairment (30 to
<60 mL/min), and severe impairment (.gtoreq.15 to <30
mL/min).
[0153] Generally, mild renal impairment according to the present
invention corresponds to stage 2 chronic kidney disease, moderate
renal impairment according to the present invention generally
corresponds to stage 3 chronic kidney disease, and severe renal
impairment according to the present invention generally corresponds
to stage 4 chronic kidney disease. Likewise, moderate A renal
impairment according to the present invention generally corresponds
to stage 3A chronic kidney disease and moderate B renal impairment
according to the present invention generally corresponds to stage
3B chronic kidney disease.
[0154] Accordingly, in one aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, for use in
treating, preventing, protecting against or delaying the
progression of chronic kidney disease in a patient, in particular a
patient according to the present invention, for example the
progression from stage 1 chronic kidney disease to stage 2 chronic
kidney disease, for example the progression from stage 2 chronic
kidney disease to stage 3 chronic kidney disease, for example the
progression from stage 3 chronic kidney disease to stage 4 chronic
kidney disease, for example the progression from stage 4 chronic
kidney disease to stage 5 chronic kidney disease.
[0155] In a further aspect of the present invention, the
progression of chronic kidney disease in a patient is for example
the progression from stage 2 chronic kidney disease to stage 3A
chronic kidney disease, for example the progression from stage 3A
chronic kidney disease to stage 3B chronic kidney disease, for
example the progression from stage 3B chronic kidney disease to
stage 4 chronic kidney disease.
[0156] In a further aspect of the present invention, the
progression of chronic kidney disease in a patient is for example
the progression from stage 2 chronic kidney disease to stage 4 or 5
chronic kidney disease, for example the progression from stage 3
chronic kidney disease to stage 5 chronic kidney disease, for
example the progression from stage 3A or 3B chronic kidney disease
to stage 5 chronic kidney disease.
[0157] In a further aspect, a patient with chronic kidney disease
according to the present invention is a patient with stage 1
chronic kidney disease, stage 2 chronic kidney disease, stage 3
chronic kidney disease, stage 4 chronic kidney disease, or stage 5
chronic kidney disease. In a further aspect, a patient with chronic
kidney disease according to the present invention is a patient with
stage 3A chronic kidney disease or stage 3B chronic kidney
disease,
[0158] In some aspects, renal disease, renal dysfunction, or
insufficiency or impairment of renal function (including mild,
moderate and/or severe renal impairment) may also be suggested (if
not otherwise noted) 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).
[0159] In some further aspects, mild renal impairment may be also
suggested (if not otherwise noted) by a creatinine clearance of
50-80 ml/min (approximately corresponding to serum creatine levels
of 1.7 mg/dL in men and 1.5 mg/dL in women); moderate renal
impairment may be e.g. suggested (if not otherwise noted) 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 (if not otherwise noted) 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).
[0160] In some further aspects, albuminuria can also be a sign of
kidney disease. Albuminuria stages may be classified as disclosed
herein, and patients may be stratified in category A1, which
reflects no albuminuria, category A2, which reflects
microalbuminuria, and category A3, which reflects
macroalbuminuria.
[0161] Accordingly, in a further aspect, a patient with chronic
kidney disease according to the present invention is a patient with
microalbuminuria or with macroalbuminuria.
[0162] In one aspect of the present invention, it has been found
that empagliflozin has nephroprotective properties, in particular
as described herein. In particular, it has been shown that
administration of empagliflozin has the property to maintain or
improve renal function over time in certain patient group, for
example as described herein, as demonstrated after discontinuation
of administration of empagliflozin.
[0163] In one aspect, a patient in the context of the present
invention is a patient at risk of renal disease. A patient at risk
of renal disease is for example a patient with at least one of the
following: [0164] prediabetes, type 1 or 2 diabetes mellitus,
[0165] hypertension, [0166] metabolic syndrome, [0167]
cardiovascular disease.
[0168] In one aspect, a patient in the context of the present
invention is a patient with prediabetes, type 1 or 2 diabetes
mellitus.
[0169] 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
hyperglycaemia and its associated micro- and macrovascular
complications or chronic damages, such as e.g. diabetic
nephropathy, retinopathy or neuropathy, or macrovascular (e.g.
cardiovascular) 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. Type 1 diabetes
mellitus (Type 1 diabetes), also called insulin dependent diabetes
mellitus or juvenile diabetes, is a form of diabetes mellitus that
results from autoimmune destruction of insulin-producing beta cells
of the pancreas. The subsequent lack of insulin leads to increased
blood glucose concentrations and increased urinary glucose
excretion. The classical symptoms are polyuria, polydipsia,
polyphagia, and weight loss. Type 1 diabetes may be fatal unless
treated with insulin. Complications from type 1 diabetes are the
same or similar to complications from type 2 diabetes.
[0170] Large randomized studies have established that intensive and
tight glycemic control during early (newly diagnoses to 5 years)
stage diabetes has enduring beneficial effects and reduces the risk
of diabetic complications, both micro- and macrovascular. However,
many patients with diabetes still develop diabetic complications
despite receiving intensified glycemic control.
[0171] Standard therapy of type 1 diabetes is insulin treatment.
Therapies for type 1 diabetes are for example described in WO
2012/062698.
[0172] 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.
[0173] 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.
[0174] 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, DPP-4 inhibitors,
glinides and .alpha.-glucosidase inhibitors.
[0175] 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.
[0176] The SGLT2 inhibitor therein also exhibits a very good
efficacy with regard to glycemic control, in particular in view of
a reduction of fasting plasma glucose, postprandial plasma glucose
and/or glycosylated hemoglobin (HbA1c). By administering a
pharmaceutical composition according to this invention, a reduction
of HbA1c equal to or greater than preferably 0.5%, even more
preferably equal to or greater than 1.0% can be achieved and the
reduction is particularly in the range from 1.0% to 2.0%.
[0177] In a further embodiment, a patient according to the present
invention is a patient who shows one, two or more of the following
conditions: [0178] (a) a fasting blood glucose or serum glucose
concentration greater than 100 mg/dL, in particular greater than
125 mg/dL; [0179] (b) a postprandial plasma glucose equal to or
greater than 140 mg/dL; [0180] (c) an HbA1c value equal to or
greater than 6.5%, in particular equal to or greater than 7.0%,
especially equal to or greater than 7.5%, even more particularly
equal to or greater than 8.0%.
[0181] In a further embodiment, a patient according to the present
invention is a patient who shows one, two or more of the following
conditions: [0182] (a) insufficient glycemic control with diet and
exercise alone; [0183] (b) insufficient glycemic control despite
oral monotherapy with metformin, in particular despite oral
monotherapy at a maximal tolerated dose of metformin; [0184] (c)
insufficient glycemic control despite oral monotherapy with one or
more other antidiabetic agent, in particular despite oral
monotherapy at a maximal tolerated dose of the other antidiabetic
agent.
[0185] In a further embodiment, a patient according to the present
invention is a patient who shows one, two or more of the following
conditions: [0186] (a) obesity (including class I, II and/or III
obesity), visceral obesity and/or abdominal obesity, [0187] (b)
triglyceride blood level .gtoreq.150 mg/dL, [0188] (c)
HDL-cholesterol blood level <40 mg/dL in female patients and
<50 mg/dL in male patients, [0189] (d) a systolic blood pressure
.gtoreq.130 mm Hg and a diastolic blood pressure .gtoreq.85 mm Hg,
[0190] (e) a systolic blood pressure .gtoreq.130 mm Hg and a
diastolic blood pressure .gtoreq.80 mm Hg, [0191] (f) a fasting
blood glucose level .gtoreq.100 mg/dL.
[0192] In one embodiment, a patient according to the present
invention is a patient with prediabetes, type 1 or 2 diabetes
mellitus and hypertension. In one embodiment, a patient according
to the present invention is a patient with prediabetes, type 1 or 2
diabetes mellitus and a systolic blood pressure .gtoreq.130 mm Hg
and a diastolic blood pressure .gtoreq.80 mm Hg.
[0193] 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, a DPP-4
inhibitor, 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), metformin/DPP-4 inhibitor,
sulphonylurea/.alpha.-glucosidase inhibitor,
pioglitazone/sulphonylurea, metformin/insulin, pioglitazone/insulin
or sulphonylurea/insulin.
[0194] In one embodiment, a patient according to the present
invention is a patient receiving treatment with a non-oral
antidiabetic drug, for example GLP1-analog (for example short
acting GLP-1 analog such as exenatide, liraglutide or lixisenatide,
or long-acting GLP-1 analog such as exenatide extended-release,
albiglutide or dulaglutide), for example insulin or insulin
analogue, for example basal insulin, such as glargine, detemir
and/or NPH insulin.
[0195] In one embodiment, a patient according to the present
invention is a patient receiving treatment with insulin or insulin
analogue. An insulin or insulin analogue may include normal
insulin, human insulin, insulin derivatives, zinc insulins and
insulin analogues, including formulations thereof with modified
release profiles, in particular as used in the therapy of humans.
The insulin may be selected from the group consisting of: [0196]
rapid-acting insulins, [0197] short-acting insulins, [0198]
intermediate-acting insulins, [0199] long-acting insulins, and
mixtures thereof.
[0200] Mixtures of insulins may comprise mixtures of short- or
rapid-acting insulins with long-acting insulins. For example such
mixtures are marketed as Actraphane/Mixtard or Novomix.
[0201] The term "insulin" in the scope of the present invention
covers insulins as described hereinbefore and hereinafter which are
administered to the patient via injection, preferably subcutaneous
injection, via infusion, including pumps, via inhalation or other
routes of administration. Insulins to be administered via
inhalation are for example Exubera (Pfizer), AIR (Lilly) and AER
(Novo Nordisk).
[0202] Rapid-acting insulins usually start lowering the blood
glucose within about 5 to 15 minutes and are effective for about 3
to 4 hours. Examples of rapid-acting insulins are insulin aspart,
insulin lispro and insulin glulisine. Insulin Lispro is marketed
under the trade name Humalog and Liprolog. Insulin Aspart is
marketed under the trade names NovoLog and NovoRapid. Insulin
glulisine is marketed under the trade name Apidra.
[0203] Short-acting insulins usually start lowering the blood
glucose within about 30 minutes and are effective about 5 to 8
hours. An example is regular insulin or human insulin.
[0204] Intermediate-acting insulins usually start lowering the
blood glucose within about 1 to 3 hours and are effective for about
16 to 24 hours. An example is NPH insulin, also known as Humulin N,
Novolin N, Novolin NPH and isophane insulin. Another example are
lente insulins, such as Semilente or Monotard.
[0205] Long-acting insulins usually start lowering the blood
glucose within 1 to 6 hours and are effective for up to about 24
hours or even up to or beyond 32 hours. Long-acting insulin usually
provides a continuous level of insulin activity (for up to 24-36
hours) and usually operates at a maximum strength (with flat action
profile) after about 8-12 hours, sometimes longer. Long-acting
insulin is usually administered in the morning or before bed.
Examples of long-acting insulin may include, but are not limited
to, insulin glargine, insulin detemir or insulin degludec, which
are insulin analogues, and ultralente insulin, which is regular
human insulin formulated for slow absorption. Long-acting insulin
is suited to provide for basal, as opposed to prandial, insulin
requirements (e.g. to control hyperglycemia). Long-acting insulin
may be typically administered ranging from twice or once daily,
over thrice weekly up to once weekly (ultra long-acting insulin).
Insulin glargine is marketed under the trade name Lantus for
example. Insulin detemir is marketed under the tradename Levemir
for example.
[0206] In one embodiment, a long-acting insulin is an acylated
derivative of human insulin. Acylated insulin derivatives may be
such wherein a lipophilic group is attached to the lysine residue
in position B29. A commercial product is Levemir.RTM. comprising
Lys.sup.B29(N.sup.t-tetradecanoyl) des(B30) human insulin (insulin
detemir). Another example is
N.sup.tB29-(N.sup..alpha.-(.omega.-carboxypentadecanoyl)-L-.gamma.-glutam-
yl) des(B30) human insulin (insulin degludec).
[0207] In one embodiment, a long-acting insulin is such comprising
positively charged amino acids such as Arg attached to the
C-terminal end of the B-chain. A commercial product is Lantus.RTM.
(insulin glargine) comprising Gly.sup.A21, Arg.sup.B31, Arg.sup.B32
human insulin.
[0208] In one embodiment, a patient according to the present
invention is a patient receiving treatment with a mixture of
insulin and GLP-1 analog, for example a mixture of insulin glargine
and lixisenatide.
[0209] In a further aspect, a patient according to the present
invention is a patient with or at risk of a cardiovascular
disease.
[0210] In one embodiment, the patient is a patient with one or more
cardiovascular risk factors selected from A), B), C) and D), for
example a patient with type 1 or type 2 diabetes mellitus or with
pre-diabetes with one or more cardiovascular risk factors selected
from A), B), C) and D):
A) previous or existing vascular disease selected from myocardial
infarction, coronary artery disease, percutaneous coronary
intervention, coronary artery by-pass grafting, ischemic or
hemorrhagic stroke, congestive heart failure, and peripheral
occlusive arterial disease, B) advanced age >/=60-70 years, and
C) one or more cardiovascular risk factors selected from [0211]
advanced type 2 diabetes mellitus >10 years duration, [0212]
hypertension, [0213] current daily cigarette smoking, [0214]
dyslipidemia, [0215] obesity, [0216] age >/=40, [0217] metabolic
syndrome, hyperinsulinemia or insulin resistance, and [0218]
hyperuricemia, erectile dysfunction, polycystic ovary syndrome,
sleep apnea, or family history of vascular disease or
cardiomyopathy in first-degree relative; D) one or more of the
following: [0219] confirmed history of myocardial infarction,
[0220] unstable angina with documented multivessel coronary disease
or positive stress test, [0221] multivessel Percutaneous Coronary
Intervention, [0222] multivessel Coronary Artery By-pass Grafting
(CABG), [0223] history of ischemic or hemorrhagic stroke, [0224]
peripheral occlusive arterial disease.
[0225] In a further aspect of the present invention, a patient
having cardiovascular disease is defined as having at least one of
the following: [0226] Confirmed history of myocardial infarction;
or [0227] Evidence of multivessel coronary artery disease, in 2 or
more major coronary arteries, irrespective of the revascularization
status, i.e. [0228] a) Either the presence of a significant
stenosis (imaging evidence of at least 50% narrowing of the luminal
diameter measured during a coronary angiography or a multi-sliced
computed tomography angiography), in 2 or more major coronary
arteries, [0229] b) Or a previous revascularisation (percutaneous
transluminal coronary angioplasty with or without stent, or
coronary artery bypass grafting), in 2 or more major coronary
arteries, [0230] c) Or the combination of previous
revascularisation in one major coronary artery (percutaneous
transluminal coronary angioplasty with or without stent, or
coronary artery bypass grafting), and the presence of a significant
stenosis in another major coronary artery (imaging evidence of at
least 50% narrowing of the luminal diameter measured during a
coronary angiography or a multi-sliced computed tomography
angiography), [0231] Note: A disease affecting the left main
coronary artery is considered as a 2-vessel disease. [0232]
Evidence of a single vessel coronary artery disease with: [0233] a)
The presence of a significant stenosis i.e. the imaging evidence of
at least 50% narrowing of the luminal diameter of one major
coronary artery in patients not subsequently successfully
revascularised (measured during a coronary angiography or a
multi-sliced computed tomography angiography) [0234] b) And at
least one of the following (either (i) or (ii)): [0235] i. A
positive non invasive stress test, confirmed by either: [0236] 1. A
positive exercise tolerance test in patients without a complete
left bundle branch block, Wolff-Parkinson-White syndrome, or paced
ventricular rhythm, or [0237] 2. A positive stress echocardiography
showing regional systolic wall motion abnormalities, or [0238] 3. A
positive scintigraphic test showing stress-induced ischemia, i.e.
the development of transient perfusion defects during myocardial
perfusion imaging; [0239] ii. Or patient discharged from hospital
with a documented diagnosis of unstable angina within 12 months
prior to selection. [0240] Episode of unstable angina with
confirmed evidence of coronary multivessel or single vessel disease
as defined above. [0241] History of ischemic or haemorrhagic stroke
[0242] Presence of peripheral artery disease (symptomatic or not)
documented by either: previous limb angioplasty, stenting or bypass
surgery; or previous limb or foot amputation due to circulatory
insufficiency; or angiographic evidence of significant (>50%)
peripheral artery stenosis in at least one limb; or evidence from a
non-invasive measurement of significant (>50% or as reported as
hemodynamically significant) peripheral artery stenosis in at least
one limb; or ankle brachial index of <0.9 in at least one
limb.
[0243] In a further aspect of the present invention, a patient
having cardiovascular disease is defined as having at least one of
the following: [0244] a) Confirmed history of myocardial
infarction, [0245] b) Unstable angina with documented multivessel
coronary disease (at least two major coronary arteries in
angiogram) or positive stress test (ST segment depression >=2 mm
or a positive nuclear perfusion scintigram), [0246] c) Multivessel
Percutaneous Coronary Intervention (PCI), [0247] d) Multivessel
Coronary Artery By-pass Grafting (CABG), including with recurrent
angina following surgery, [0248] e) History of ischemic or
hemorrhagic stroke, [0249] f) Peripheral occlusive arterial disease
(previous limb bypass surgery or percutaneous transluminal
angioplasty; previous limb or foot amputation due to circulatory
insufficiency, angiographic or imaging detected (for example:
ultrasound, Magnetic Resonance Imaging) significant vessel stenosis
of major limb arteries).
[0250] Accordingly, in one aspect, the present invention relates to
a certain SGLT-2 inhibitor, in particular empagliflozin, for use in
a method as described herein, in a patient with one or more risk
factors selected from A), B), C) and D):
A) previous or existing vascular disease (such as e.g. myocardial
infarction (e.g. silent or non-silent), coronary artery disease,
percutaneous coronary intervention, coronary artery by-pass
grafting, ischemic or hemorrhagic stroke, congestive heart failure
(e.g. NYHA class I, II, III or IV, e.g. left ventricular function
<40%), or peripheral occlusive arterial disease), B) advanced
age (such as e.g. age >/=60-70 years), and C) one or more
cardiovascular risk factors selected from [0251] advanced type 1 or
type 2 diabetes mellitus (such as e.g. >10 years duration),
[0252] hypertension (such as e.g. >130/80 mm Hg, or systolic
blood pressure >140 mmHg or on at least one blood pressure
lowering treatment), [0253] current daily cigarette smoking, [0254]
dyslipidemia (such as e.g. atherogenic dyslipidemia, postprandial
lipemia, or high level of LDL cholersterol (e.g. LDL cholesterol
>/=130-135 mg/dL), low level of HDL cholesterol (e.g. <35-40
mg/dL in men or <45-50 mg/dL in women) and/or high level of
triglycerides (e.g. >200-400 mg/dL) in the blood, or on at least
one treatment for lipid abnormality), [0255] obesity (such as e.g.
abdominal and/or visceral obesity, or body mass index >/=45
kg/m2), [0256] age >/=40, [0257] metabolic syndrome,
hyperinsulinemia or insulin resistance, and [0258] hyperuricemia,
erectile dysfunction, polycystic ovary syndrome, sleep apnea, or
family history of vascular disease or cardiomyopathy in
first-degree relative, D) one or more of the following: [0259]
confirmed history of myocardial infarction, [0260] unstable angina
with documented multivessel coronary disease or positive stress
test, [0261] multivessel Percutaneous Coronary Intervention, [0262]
multivessel Coronary Artery By-pass Grafting (CABG), [0263] history
of ischemic or hemorrhagic stroke, [0264] peripheral occlusive
arterial disease. said method comprising administering a
therapeutically effective amount of the SGLT-2 inhibitor,
optionally in combination with one or more other therapeutic
substances, to the patient.
[0265] In one aspect, a patient in the context of the present
invention is a patient with hypertension. In one aspect, a patient
in the context of the present invention is a patient with metabolic
syndrome.
[0266] The present invention further relates to a pharmaceutical
composition comprising a certain SGLT-2 inhibitor as defined
herein, empagliflozin, for use in the therapies described herein,
for example in a patient or patient group as described herein.
[0267] When this invention refers to patients requiring treatment
or prevention, it relates primarily to treatment and prevention in
humans, but the pharmaceutical composition may also be used
accordingly in veterinary medicine in mammals. In the scope of this
invention adult patients are preferably humans of the age of 18
years or older. Also in the scope of this invention, patients are
adolescent humans, i.e. humans of age 10 to 17 years, preferably of
age 13 to 17 years.
[0268] In a further aspect, a method according to the present
invention further comprises improving glycemic control in patients
having type 1 or type 2 diabetes mellitus or showing first signs of
pre-diabetes.
[0269] In a further aspect, a method according to the present
invention further comprises improving glycemic control and/or for
reducing of fasting plasma glucose, of postprandial plasma glucose
and/or of glycosylated hemoglobin HbA1c in a patient in need
thereof who is diagnosed with impaired glucose tolerance (IGT),
impaired fasting blood glucose (IFG) with insulin resistance, with
metabolic syndrome and/or with type 2 or type 1 diabetes
mellitus.
[0270] In a further aspect, a method according to the present
invention further comprises improving glycemic control in patients,
in particular in adult patients, with type 2 diabetes mellitus as
an adjunct to diet and exercise.
[0271] Within the scope of the present invention it has now been
found that certain SGLT-2 inhibitors as defined herein, optionally
in combination with one or more other therapeutic substances (e.g.
selected from those described herein), as well as pharmaceutical
combinations, compositions or combined uses according to this
invention of such SGLT-2 inhibitors as defined herein have
properties, which make them suitable for the purpose of this
invention and/or for fulfilling one or more of above needs. The
present invention thus relates to a certain SGLT-2 inhibitor as
defined herein, preferably empagliflozin, for use in the therapies
described herein.
[0272] Furthermore, it can be found that the administration of a
pharmaceutical composition according to this invention results in
no risk or in a low risk of hypoglycemia. Therefore, a treatment or
prophylaxis according to this invention is also advantageously
possible in those patients showing or having an increased risk for
hypoglycemia.
[0273] It will be appreciated that the amount of the pharmaceutical
composition according to this invention to be administered to the
patient and required for use in treatment or prophylaxis according
to the present invention will vary with the route of
administration, the nature and severity of the condition for which
treatment or prophylaxis is required, the age, weight and condition
of the patient, concomitant medication and will be ultimately at
the discretion of the attendant physician. In general, however, the
SGLT2 inhibitor according to this invention is included in the
pharmaceutical composition or dosage form in an amount sufficient
that by its administration the glycemic control in the patient to
be treated is improved.
[0274] In the following preferred ranges of the amount of the SGLT2
inhibitor to be employed in the pharmaceutical composition and the
methods and uses according to this invention are described. These
ranges refer to the amounts to be administered per day with respect
to an adult patient, in particular to a human being, for example of
approximately 70 kg body weight, and can be adapted accordingly
with regard to an administration 2, 3, 4 or more times daily and
with regard to other routes of administration and with regard to
the age of the patient. Within the scope of the present invention,
the pharmaceutical composition is preferably administered orally.
Other forms of administration are possible and described
hereinafter. Preferably the one or more dosage forms comprising the
SGLT2 inhibitor is oral or usually well known.
[0275] In general, the amount of the SGLT2 inhibitor in the
pharmaceutical composition and methods according to this invention
is preferably the amount usually recommended for a monotherapy
using said SGLT2 inhibitor.
[0276] The preferred dosage range of the SGLT2 inhibitor is in the
range from 0.5 mg to 200 mg, even more preferably from 1 to 100 mg,
most preferably from 1 to 50 mg per day. In one aspect, a preferred
dosage of the SGLT2 inhibitor empagliflozin is 10 mg or 25 mg per
day. The oral administration is preferred. Therefore, a
pharmaceutical composition may comprise the hereinbefore mentioned
amounts, in particular from 1 to 50 mg or 1 to 25 mg. Particular
dosage strengths (e.g. per tablet or capsule) are for example 1,
2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mg of the SGLT2 inhibitor,
in particular empagliflozin. In one aspect, a pharmaceutical
composition comprises 10 mg or 25 mg of empagliflozin. The
application of the active ingredient may occur up to three times a
day, preferably one or two times a day, most preferably once a
day.
[0277] A pharmaceutical composition which is present as a separate
or multiple dosage form, preferably as a kit of parts, is useful in
combination therapy to flexibly suit the individual therapeutic
needs of the patient.
[0278] According to a first embodiment a preferred kit of parts
comprises a containment containing a dosage form comprising the
SGLT2 inhibitor and at least one pharmaceutically acceptable
carrier.
[0279] A further aspect of the present invention is a manufacture
comprising the pharmaceutical composition being present as separate
dosage forms according to the present invention and a label or
package insert comprising instructions that the separate dosage
forms are to be administered in combination or alternation.
[0280] According to a first embodiment a manufacture comprises (a)
a pharmaceutical composition comprising a SGLT2 inhibitor according
to the present invention and (b) a label or package insert which
comprises instructions that the medicament is to be
administered.
[0281] The desired dose of the pharmaceutical composition according
to this invention may conveniently be presented in a once daily or
as divided dose administered at appropriate intervals, for example
as two, three or more doses per day.
[0282] The pharmaceutical composition may be formulated for oral,
rectal, nasal, topical (including buccal and sublingual),
transdermal, vaginal or parenteral (including intramuscular,
subcutaneous and intravenous) administration in liquid or solid
form or in a form suitable for administration by inhalation or
insufflation. Oral administration is preferred. The formulations
may, where appropriate, be conveniently presented in discrete
dosage units and may be prepared by any of the methods well known
in the art of pharmacy. All methods include the step of bringing
into association the active ingredient with one or more
pharmaceutically acceptable carriers, like liquid carriers or
finely divided solid carriers or both, and then, if necessary,
shaping the product into the desired formulation.
[0283] The pharmaceutical composition may be formulated in the form
of tablets, granules, fine granules, powders, capsules, caplets,
soft capsules, pills, oral solutions, syrups, dry syrups, chewable
tablets, troches, effervescent tablets, drops, suspension, fast
dissolving tablets, oral fast-dispersing tablets, etc.
[0284] The pharmaceutical composition and the dosage forms
preferably comprises one or more pharmaceutical acceptable carriers
which must be "acceptable" in the sense of being compatible with
the other ingredients of the formulation and not deleterious to the
recipient thereof. Examples of pharmaceutically acceptable carriers
are known to the one skilled in the art.
[0285] Pharmaceutical compositions suitable for oral administration
may conveniently be presented as discrete units such as capsules,
including soft gelatin capsules, cachets or tablets each containing
a predetermined amount of the active ingredient; as a powder or
granules; as a solution, a suspension or as an emulsion, for
example as syrups, elixirs or self-emulsifying delivery systems
(SEDDS). The active ingredients may also be presented as a bolus,
electuary or paste. Tablets and capsules for oral administration
may contain conventional excipients such as binding agents,
fillers, lubricants, disintegrants, or wetting agents. The tablets
may be coated according to methods well known in the art. Oral
liquid preparations may be in the form of, for example, aqueous or
oily suspensions, solutions, emulsions, syrups or elixirs, or may
be presented as a dry product for constitution with water or other
suitable vehicle before use. Such liquid preparations may contain
conventional additives such as suspending agents, emulsifying
agents, non-aqueous vehicles (which may include edible oils), or
preservatives.
[0286] The pharmaceutical composition according to the invention
may also be formulated for parenteral administration (e.g. by
injection, for example bolus injection or continuous infusion) and
may be presented in unit dose form in ampoules, pre-filled
syringes, small volume infusion or in multi-dose containers with an
added preservative. The compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredients may
be in powder form, obtained by aseptic isolation of sterile solid
or by lyophilisation from solution, for constitution with a
suitable vehicle, e.g. sterile, pyrogen-free water, before use.
[0287] Pharmaceutical compositions suitable for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dose suppositories. Suitable carriers include
cocoa butter and other materials commonly used in the art, and the
suppositories may be conveniently formed by admixture of the active
compound(s) with the softened or melted carrier(s) followed by
chilling and shaping in moulds.
[0288] The pharmaceutical compositions and methods according to
this invention show advantageous effects in the treatment and
prevention of those diseases and conditions as described
hereinbefore. Advantageous effects may be seen for example with
respect to efficacy, dosage strength, dosage frequency,
pharmacodynamic properties, pharmacokinetic properties, fewer
adverse effects, convenience, compliance, etc.
[0289] Methods for the manufacture of SGLT2 inhibitors according to
this invention and of prodrugs thereof are known to the one skilled
in the art. Advantageously, the compounds according to this
invention can be prepared using synthetic methods as described in
the literature, including patent applications as cited
hereinbefore. Preferred methods of manufacture are described in the
WO 2006/120208 and WO 2007/031548. With regard to empagliflozin an
advantageous crystalline form is described in the international
patent application WO 2006/117359 which hereby is incorporated
herein in its entirety.
[0290] The active ingredients may be present in the form of a
pharmaceutically acceptable salt. Pharmaceutically acceptable salts
include, without being restricted thereto, such as salts of
inorganic acid like hydrochloric acid, sulfuric acid and phosphoric
acid; salts of organic carboxylic acid like oxalic acid, acetic
acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric
acid, tartaric acid, succinic acid and glutamic acid and salts of
organic sulfonic acid like methanesulfonic acid and
p-toluenesulfonic acid. The salts can be formed by combining the
compound and an acid in the appropriate amount and ratio in a
solvent and decomposer. They can be also obtained by the cation or
anion exchange from the form of other salts.
[0291] The active ingredients or a pharmaceutically acceptable salt
thereof may be present in the form of a solvate such as a hydrate
or alcohol adduct.
[0292] Pharmaceutical compositions or combinations for use in these
therapies comprising the SGLT-2 inhibitor as defined herein
optionally together with one or more other active substances are
also contemplated.
[0293] Further, the present invention relates to the SGLT-2
inhibitors, optionally in combination with one, two or more further
active agents, each as defined herein, for use in the therapies as
described herein.
[0294] Further, the present invention relates to the use of the
SGLT-2 inhibitors, optionally in combination with one, two or more
further active agents, each as defined herein, for preparing
pharmaceutical compositions which are suitable for the treatment
and/or prevention purposes of this invention.
[0295] The present invention further relates to a combination
comprising a certain SGLT-2 inhibitor (particularly empagliflozin)
and one or more other active substances selected from other
antidiabetic substances, particularly for simultaneous, separate or
sequential use in the therapies described herein.
[0296] The present invention further relates to a combination
comprising a certain SGLT-2 inhibitor (particularly empagliflozin)
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, GLP-1 or a GLP-1
analogue and a DPP-4 inhibitor, particularly for simultaneous,
separate or sequential use in the therapies described herein.
[0297] The present invention further relates to a method according
to the present invention further comprising treating and/or
preventing metabolic disorders, especially type 2 diabetes mellitus
and/or conditions related thereto (e.g. diabetic complications)
comprising the combined (e.g. simultaneous, separate or sequential)
administration of an effective amount of empagliflozin and one or
more other antidiabetics selected from the group consisting of
metformin, a sulphonylurea, nateglinide, repaglinide, a
PPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or an
insulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor,
to the patient (particularly human patient) in need thereof, such
as e.g. a patient as described herein.
[0298] The present invention further relates to therapies or
therapeutic methods described herein, further comprising treating
and/or preventing metabolic disorders, especially type 2 diabetes
mellitus and/or conditions related thereto (e.g. diabetic
complications), comprising administering a therapeutically
effective amount of empagliflozin and, optionally, one or more
other therapeutic agents, such as e.g. antidiabetics selected from
the group consisting of metformin, a sulphonylurea, nateglinide,
repaglinide, a PPAR-gamma-agonist, an alpha-glucosidase inhibitor,
insulin or an insulin analogue, GLP-1 or a GLP-1 analogue and a
DPP-4 inhibitor, to the patient (particularly human patient) in
need thereof, such as e.g. a patient as described herein.
[0299] 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.
[0300] The present invention further relates to a certain SGLT-2
inhibitor as defined herein, preferably empagliflozin, in
combination with metformin, for use in the therapies described
herein.
[0301] 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.
[0302] 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.
[0303] An example of a DPP-4 inhibitor is linagliptin, which is
usually given in a dosage of 5 mg per day.
[0304] A dosage of pioglitazone is usually of about 1-10 mg, 15 mg,
30 mg, or 45 mg once a day. 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).
[0305] 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).
[0306] 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).
[0307] 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).
[0308] 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.
[0309] In one aspect of the present invention, the one or more
other therapeutic substances are RAAS inhibitors
(Renin-Angiotensin-Aldosterone System). In one aspect of the
present invention, the one or more other therapeutic substances is
a direct renin inhibitor, an Angiotensin-Converting Enzyme (ACE)
inhibitor and/or an angiotensin II receptor blocker (ARB).
[0310] In one aspect, a SGLT-2 inhibitor, in particular
empagliflozin is used in a method according to the present
invention in addition to a RAAS inhibitor, in particular a direct
renin inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor
and/or an angiotensin II receptor blocker (ARB).
[0311] In another embodiment of the present invention, certain
SGLT-2 inhibitors, in particular empagliflozin, are useful in the
therapy of a patient with chronic kidney disease and albuminuria
despite therapy with a direct renin inhibitor, an
angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB), in particular a patient described
herein.
[0312] In another embodiment of the present invention, certain a
SGLT-2 inhibitors, in particular empagliflozin, are useful in a
method according to the present invention on top of direct renin
inhibitor therapy, angiotensin-converting enzyme (ACE) inhibitor
therapy and/or angiotensin II receptor blockade (ARB) therapy.
[0313] Accordingly, in a further embodiment, the present invention
relates to a certain SGLT-2 inhibitor, in particular empagliflozin,
in combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), for use in the therapy as
described herein, for example in a patient as described herein.
[0314] In one aspect, the present invention relates to certain
SGLT-2 inhibitors, for example empagliflozin, in combination with a
RAAS inhibitor, for example a direct renin inhibitor, an
Angiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin
II receptor blocker (ARB), for use in treating, preventing,
protecting against, reducing the risk of, delaying the occurrence
of and/or delaying the progression of chronic kidney disease in
patients, for example patients with prediabetes, type 1 or type 2
diabetes mellitus.
[0315] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, in
combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), for use in treating,
preventing, protecting against or delaying new onset of albuminuria
in patients.
[0316] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, in
combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker
[0317] (ARB), for use in treating, preventing, protecting against
or delaying the progression from no albuminuria to micro- or
macroalbuminuria in a patient at risk for renal disease.
[0318] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, in
combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), for use in treating,
preventing, protecting against or delaying the progression from
microalbuminuria to macroalbuminuria in a patient with chronic
kidney disease.
[0319] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, in
combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), for use in treating,
preventing, protecting against delaying the progression of chronic
kidney disease in a patient with chronic kidney disease.
[0320] In a further aspect, the present invention relates to
certain SGLT-2 inhibitors, for example empagliflozin, in
combination with a RAAS inhibitor, for example a direct renin
inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or
an angiotensin II receptor blocker (ARB), for use in treating,
preventing, protecting against or delaying the occurrence of:
[0321] new onset of albuminuria, [0322] doubling of serum
creatinine level accompanied by an eGFR (based on modification of
diet in renal disease (MDRD) formula) mL/min/1.73 m2, [0323] need
for continuous renal replacement therapy, or [0324] death due to
renal disease.
[0325] In one aspect, a patient according of the present invention
is a patient with prediabetes, type 1 or type 2 diabetes mellitus.
In one aspect, a patient according to the present invention is a
patient is a patient at risk for renal disease. In one aspect, a
patient according to the present invention is a patient with or at
risk of a cardiovascular disease. In one aspect, a patient
according to the present invention is a patient with prediabetes,
type 1 or type 2 diabetes mellitus and with or at risk of a
cardiovascular disease.
[0326] Examples of Angiotensin-Converting Enzyme (ACE) inhibitors
are Benazepril, Captopril, ramipril, lisinopril, Moexipril,
cilazapril, quinapril, captopril, enalapril, benazepril,
perindopril, fosinopril and trandolapril; the dosage(s) of some of
these medications are for example shown below: [0327] Benazepril
(Lotensin), 5 mg, 10 mg, 20 mg, and 40 mg for oral administration
[0328] Captopril (Capoten), 12.5 mg, 25 mg, 50 mg, and 100 mg as
scored tablets for oral administration [0329] Enalapril (Vasotec),
2.5 mg, 5 mg, 10 mg, and 20 mg tablets for oral administration
[0330] Fosinopril (Monopril), for oral administration as 10 mg, 20
mg, and 40 mg tablets [0331] Lisinopril (Prinivil, Zestril), 5 mg,
10 mg, and 20 mg tablets for oral administration [0332] Moexipril
(Univasc), 7.5 mg and 15 mg for oral administration [0333]
Perindopril (Aceon), 2 mg, 4 mg and 8 mg strengths for oral
administration [0334] Quinapril (Accupril), 5 mg, 10 mg, 20 mg, or
40 mg of quinapril for oral administration [0335] Ramipril
(Altace), 1.25 mg, 2.5 mg, 5, mg, 10 mg [0336] Trandolapril
(Mavik), 1 mg, 2 mg, or 4 mg of trandolapril for oral
administration
[0337] Examples of angiotensin II receptor blockers (ARBs) are
telmisartan, candesartan, valsartan, losartan, irbesartan,
olmesartan, azilsartan and eprosartan; the dosage(s) of some of
these medications are for example shown below: [0338] Candesartan
(Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil
[0339] Eprosartan (Teveten), 400 mg or 600 mg [0340] Irbesartan
(Avapro), 75 mg, 150 mg, or 300 mg of irbesartan. [0341] Losartan
(Cozaar), 25 mg, 50 mg or 100 mg of losartan potassium [0342]
Telmisartan (Micardis), 40 mg/12.5 mg, 80 mg/12.5 mg, and 80 mg/25
mg telmisartan and hydrochlorothiazide [0343] Valsartan (Diovan),
40 mg, 80 mg, 160 mg or 320 mg of valsartan
[0344] A dosage of telmisartan is usually from 20 mg to 320 mg or
40 mg to 160 mg per day.
[0345] An example of a direct renin inhibitor is aliskiren
(Tekturna). A dosage of aliskiren may be 150 mg or 300 mg per
day.
[0346] 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.
[0347] 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.
[0348] 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.
[0349] 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.
[0350] In a further aspect, the present invention provides a
pharmaceutical composition comprising a SGLT-2 inhibitor, for
example empagliflozin, in combination with a RAAS inhibitor, for
example a direct renin inhibitor, an Angiotensin-Converting Enzyme
(ACE) inhibitor and/or an angiotensin II receptor blocker (ARB),
for example as described herein.
[0351] 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
Example 1
Empagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) and
Renal Impairment (RI)
[0352] A Phase III trial investigated the efficacy and safety of
empagliflozin (EMPA) as add-on to existing therapy for 52 weeks in
patients with T2DM and RI. Patients with mild RI (eGFR [MDRD
equation] .gtoreq.60 to <90 mL/min/1.73 m.sup.2) received EMPA
10 or 25 mg qd or placebo (PBO). Patients with moderate RI (eGFR 30
to <60 mL/min/1.73 m.sup.2) received EMPA 25 mg qd or PBO.
Patients with severe RI (eGFR 5 to <30 mL/min/1.73 m.sup.2)
received EMPA 25 mg qd or PBO.
[0353] In patients with type 2 diabetes and mild renal impairment,
treatment with empagliflozin 10 and 25 mg at week 52 resulted in a
small decrease in eGFR. However, mean eGFR increased to a value
slightly above baseline at the 3-week follow up visit in the
empagliflozin treatment groups; in contrast, in the placebo group,
mean eGFR further decreased (Table 1A).
TABLE-US-00002 TABLE 1A Descriptive statistics for eGFR over time
in patients with mild renal impairment Empa Empa Placebo 10 mg 25
mg Number of patients 32 (100.0) 41 (100.0) 38 (100.0) N (%)
Baseline eGFR N* (%) 32 (100.0) 41 (100.0) 38 (100.0) Mean (SD)
72.24 (12.68) 68.42 (8.23) 72.01 (10.84) [mL/min/1.73 m.sup.2]
End-of treatment eGFR N* (%) 32 (100.0) 38 (92.7) 37 (97.4) Mean
(SD) 70.34 (11.42) 68.07 (11.36) 66.25 (13.00) [mL/min/1.73
m.sup.2] Mean change from -1.89 (11.14) -0.76 (9.42) -5.67 (10.37)
baseline (SD) [mL/min/1.73 m.sup.2] Follow-up eGFR N* (%) 30 (93.8)
38 (92.7) 37 (97.4) Mean (SD) 68.20 (11.16) 69.84 (11.29) 73.38
(13.67) [mL/min/1.73 m.sup.2] Mean change from -3.84 (11.63) 2.06
(8.91) 1.28 (8.89) baseline (SD) [mL/min/1.73 m.sup.2]
[0354] In patients with type 2 diabetes and moderate renal
impairment, treatment with empagliflozin 25 mg at week 52 resulted
a small decrease in eGFR while no change was seen for the placebo
group. However, at the 3-week follow-up visit mean eGFR increased
to a value slightly above baseline in the empagliflozin treatment
group (Table 1B). Similar results were seen in patients with CKD 3A
and B.
TABLE-US-00003 TABLE 1B Descriptive statistics for eGFR over time
in patients with moderate renal impairment Empa Placebo 25 mg
Number of patients N (%) 104 (100.0) 105 (100.0) Baseline eGFR N*
(%) 104 (100.0) 105 (100.0) Mean (SD) [mL/min/1.73 m.sup.2] 43.35
(10.39) 43.84 (8.70) End-of treatment eGFR N* (%) 102 (98.1) 101
(96.2) Mean (SD) [mL/min/1.73 m.sup.2] 43.70 (11.08) 40.58 (10.26)
Mean change from baseline (SD) 0.04 (7.16) -3.55 (6.63)
[mL/min/1.73 m.sup.2] Follow-up eGFR N* (%) 98 (94.2) 103 (98.1)
Mean (SD) [mL/min/1.73 m.sup.2] 42.99 (12.67) 45.39 (11.31) Mean
change from baseline (SD) 0.16 (9.14) 1.48 (6.70) [mL/min/1.73
m.sup.2]
[0355] In patients with type 2 diabetes and severe renal
impairment, treatment with empagliflozin 25 mg at week 52 resulted
in a small decrease in eGFR. However, at the 3-week follow-up visit
mean eGFR increased to a value slightly below baseline in the
empagliflozin treatment group (Table 1C).
TABLE-US-00004 TABLE 1C Descriptive statistics for eGFR over time
in patients with severe renal impairment Empa Placebo 25 mg Number
of patients N (%) 18 (100.0) 21 (100.0) Baseline eGFR N* (%) 18
(100.0) 21 (100.0) Mean (SD) [mL/min/1.73 m.sup.2] 22.90 (3.44)
24.22 (3.99) End-of treatment eGFR N* (%) 17 (94.4) 21 (100.0) Mean
(SD) [mL/min/1.73 m.sup.2] 21.80 (6.36) 20.23 (5.86) Mean change
from baseline (SD) -1.17 (5.82) -3.98 (5.80) [mL/min/1.73 m.sup.2]
Follow-up eGFR N* (%) 18 (100.0) 21 (100.0) Mean (SD) [mL/min/1.73
m.sup.2] 21.42 (6.58) 23.63 (7.40) Mean change from baseline (SD)
-1.48 (6.03) -0.59 (6.76) [mL/min/1.73 m.sup.2]
Example 2
Empagliflozin in Hypertensive Patients with Type 2 Diabetes
Mellitus (T2DM)
[0356] A Phase III trial investigated the efficacy and safety of
empagliflozin (EMPA) administered orally, once daily over 12 weeks
in hypertensive patients with T2DM (EMPA 10 or 25 mg, placebo
(PBO)). Patients with a systolic blood pressure (SBP) of 130 to 159
mmHg and a diastolic blood pressure (DSP) of 80 to 99 mmHg were
included in the trial.
[0357] Treatment with empagliflozin 10 and 25 mg at week 12
resulted in a small decrease in eGFR. However, mean eGFR increased
to a value slightly above baseline at the 2-week follow up visit in
the empagliflozin treatment groups; in contrast, in the placebo
group, mean eGFR remained slightly below baseline (Table 2).
TABLE-US-00005 TABLE 2 Descriptive statistics for eGFR (MDRD) over
time Empa Empa Placebo 10 mg 25 mg Baseline eGFR N* (%) 238 (100)
241 (100) 244 (100) Mean (SD) 84.47 (17.06) 83.01 (16.43) 83.97
(17.85) [mL/min/1.73 m.sup.2] Last value on treatment eGFR N* (%)
237 (99.6) 238 (98.8) 240 (98.4) Mean (SD) 84.16 (17.95) 82.70
(17.11) 81.24 (17.61) [mL/min/1.73 m.sup.2] Mean change from -0.27
(9.18) -0.20 (8.99) -2.60 (9.98) baseline (SD) [mL/min/1.73
m.sup.2] Follow-up eGFR N* (%) 236 (99.2) 238 (98.8) 243 (99.6)
Mean (SD) 83.52 (17.37) 86.25 (17.06) 86.60 (18.24) [mL/min/1.73
m.sup.2] Mean change from baseline (SD) [mL/min/1.73 m.sup.2] -0.82
(9.62) 3.06 (10.05) 2.75 (9.71) N* (%) 236 (99.2) 236 (97.9) 239
(98.0) Mean change from last -0.52 (9.39) 3.32 (9.75) 5.54 (9.44)
value on treatment (SD) [mL/min/1.73 m.sup.2] *Patients with values
at this time point
Example 3
Empagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM)
Receiving Treatment with Basal Insulin
[0358] A Phase IIb trial investigated the efficacy and safety of
empagliflozin (EMPA 10 or 25 mg, placebo (PBO)) administered
orally, once daily over 78 weeks in patients with T2DM receiving
treatment with basal insulin (glargine, detemir, or NPH insulin
only).
[0359] Treatment with empagliflozin 10 and 25 mg resulted in a
small decrease in eGFR. However, mean eGFR increased to a value
slightly below baseline at the 4-week follow up visit in the
empagliflozin treatment groups; in contrast, in the placebo group,
mean eGFR further slightly decreased (Table 3).
TABLE-US-00006 TABLE 3 Descriptive statistics for eGFR (MDRD) over
time Empa Empa Placebo 10 mg 25 mg Number of patients, 170 (100.0)
169 (100.0) 155 (100.0) N (%) Baseline eGFR N.sup.1 (%) 170 (100.0)
169 (100.0) 155 (100.0) Mean (SD) 83.89 (22.73) 85.01 (23.63) 82.88
(25.46) Week 18 eGFR N.sup.1 (%) 134 (78.8) 133 (78.7) 113 (72.9)
Mean (SD) 80.07 (20.15) 80.37 (23.03) 79.11 (21.63) Mean change
from -4.12 (12.27) -4.98 (11.40) -3.48 (10.10) baseline (SD) Week
54 eGFR N.sup.1 (%) 106 (62.4) 106 (62.7) 97 (62.6) Mean (SD) 78.54
(21.06) 82.55 (23.60) 77.12 (23.59) Mean change from -4.88 (10.85)
-5.68 (14.36) -4.76 (11.05) baseline (SD) Week 78 eGFR N.sup.1 (%)
102 (60.0) 100 (59.2) 86 (55.5) Mean (SD) 78.52 (21.11) 81.86
(24.17) 77.21 (20.68) Mean change from -5.27 (12.04) -5.52 (11.08)
-5.64 (10.20) baseline (SD) eGFR at follow-up N.sup.1 (%) 112 118
113 Mean (SD) 78.36 (21.39) 83.74 (21.69) 81.35 (21.78) Mean change
from -6.66 (12.06) -1.88 (13.02) -0.79 (12.00) baseline (SD)
.sup.1Percent of patient in population with values at this time
point eGFR = estimated glomerular filtration rate; MDRD =
Modification of diet in renal disease; SD = standard deviation
Example 4
Empagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM) and
Microalbuminuria and Macroalbuminuria
[0360] In a dedicated 52 week renal impairment study, patients were
categorised based on their urine albumin/creatinine ratio (UACR)
values at baseline, and 3 categories of patients were
distinguished: patients with normal urine albumin/creatinine ratio
values (<30 mg/g), patients with microalbuminuria (30 to <300
mg/g) and patients with macroalbuminurea (.gtoreq.300 mg/g).
Differences in mean changes from baseline between the placebo and
the empagliflozin treatment groups were noted for patients with
microalbuminuria or macroalbuminuria at baseline. For patients with
microalbuminuria, mean urine albumin/creatinine ratio values
increased with placebo treatment, remained nearly unchanged with
empagliflozin 10 mg treatment, and decreased with empagliflozin 25
mg treatment. In patients with macroalbuminuria at baseline, a
decrease in mean urine albumin/creatinine ratio was noted only in
the empagliflozin groups; (Table 4A).
TABLE-US-00007 TABLE 4A Urine albumin-to-creatinine ratio (mg/g) by
baseline urine albumin-to-creatinine ratio at week 52 in normal
patients and patients with microalbuminuria and macroalbuminuria
Change from baseline Microal- Macroal- Normal buminuria buminuria N
Mean SD N Mean SD N Mean SD Placebo 134 8.2 20.8 90 106.1 412.9 50
3.4 2050.5 Empag- 59 4.0 15.3 17 7.4 137.3 9 -716.3 1273.6 liflozin
10 mg Empag- 141 6.0 31.7 72 -39.4 93.8 61 -799.9 1543.7 liflozin
25 mg
[0361] Shifts between UACR categories at baseline and the end of
treatment were noted in the randomised treatment groups (Table 4B).
A higher frequency of patients in the empagliflozin treatment
groups shifted from macro- or microalbuminura at baseline towards
normal values and from macro- to microalbuminuria at the end of
treatment. In addition, a higher proportion of patients in the
placebo group shifted from normal values at baseline towards
microalbuminuria at the end of treatment.
TABLE-US-00008 TABLE 4B Frequency of patients [N (%)] with shifts
in urine albumin-to-creatinine ratio (mg/g) at Week 52 relative to
urine albumin-to-creatinine ratio categories at baseline Last value
on-treatment Micro- Macro- Normal albuminuria albuminuria Treatment
Baseline N (%) N (%) N (%) Placebo Normal 118 (81.9) 26 (18.1) 0
Microalbuminuria 22 (21.8) 67 (66.3) 12 (11.9) Macroalbuminuria 1
(1.7) 6 (10.0) 53 (88.3) Empa 10 mg Normal 59 (89.4) 7 (10.6) 0
Microalbuminuria 5 (27.8) 11 (61.1) 2 (11.1) Macroalbuminuria 1
(11.1) 5 (55.6) 3 (33.3) Empa 25 mg Normal 135 (89.4) 16 (10.6) 0
Microalbuminuria 19 (24.1) 57 (72.2) 3 (3.8) Macroalbuminuria 2
(2.7) 22 (30.1) 49 (67.1) Categories for urine
albumin-to-creatinine ratio: normal: <30 mg/g, microalbuminuria
30 to <300 mg/g, macroalbuminuria: .gtoreq.300 mg/g
Example of Pharmaceutical Composition and Dosage Form
[0362] The following example of solid pharmaceutical compositions
and dosage forms for oral administration serves to illustrate the
present invention more fully without restricting it to the contents
of the example. Further examples of compositions and dosage forms
for oral administration, are described in WO 2010/092126. The term
"active substance" denotes empagliflozin according to this
invention, especially its crystalline form as described in WO
2006/117359 and WO 2011/039107.
TABLE-US-00009 Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg
of active substance 2.5 mg/ 5 mg/ 10 mg/ 25 mg/ 50 mg/ per per per
per per Active substance tablet tablet tablet tablet tablet Wet
granulation active substance 2.5000 5.000 10.00 25.00 50.00 Lactose
40.6250 81.250 162.50 113.00 226.00 Monohydrate Microcrystalline
12.5000 25.000 50.00 40.00 80.00 Cellulose Hydroxypropyl 1.8750
3.750 7.50 6.00 12.00 Cellulose Croscarmellose 1.2500 2.500 5.00
4.00 8.00 Sodium Purified Water q.s. q.s. q.s. q.s. q.s. Dry Adds
Microcrystalline 3.1250 6.250 12.50 10.00 20.00 Cellulose Colloidal
silicon 0.3125 0.625 1.25 1.00 2.00 dioxide Magnesium stearate
0.3125 0.625 1.25 1.00 2.00 Total core 62.5000 125.000 250.00
200.00 400.00 Film Coating Film coating system 2.5000 4.000 7.00
6.00 9.00 Purified Water q.s. q.s. q.s. q.s. q.s. Total 65.000
129.000 257.00 206.00 409.00
[0363] Details regarding the manufacture of the tablets, the active
pharmaceutical ingredient, the excipients and the film coating
system are described in WO 2010/092126, in particular in the
Examples 5 and 6, which hereby is incorporated herein in its
entirety.
* * * * *