U.S. patent application number 17/179756 was filed with the patent office on 2021-06-10 for composition for reducing new-onset diabetes.
This patent application is currently assigned to MOCHIDA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is MOCHIDA PHARMACEUTICAL CO., LTD.. Invention is credited to Masunori MATSUZAKI, Yuji MATSUZAWA, Masahiko OHTA, Shinichi OIKAWA, Hideki ORIGASA, Yasushi SAITO, Mitsuhiro YOKOYAMA.
Application Number | 20210169837 17/179756 |
Document ID | / |
Family ID | 1000005407419 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210169837 |
Kind Code |
A1 |
OHTA; Masahiko ; et
al. |
June 10, 2021 |
COMPOSITION FOR REDUCING NEW-ONSET DIABETES
Abstract
A medical composition for reducing the rate of new-onset
diabetes caused by administration of a statin or for inhibiting an
increase in blood glucose level by administration of a statin, the
composition containing at least one ingredient selected from the
group consisting of icosapentaenoic acid and pharmaceutically
acceptable salts or esters thereof as an inactive ingredient.
Inventors: |
OHTA; Masahiko; (Tokyo,
JP) ; OIKAWA; Shinichi; (Tokyo, JP) ;
YOKOYAMA; Mitsuhiro; (Kobe-shi, JP) ; ORIGASA;
Hideki; (Toyama-shi, JP) ; MATSUZAKI; Masunori;
(Ube-shi, JP) ; MATSUZAWA; Yuji; (Takarazuka-shi,
JP) ; SAITO; Yasushi; (Chiba-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MOCHIDA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
MOCHIDA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
1000005407419 |
Appl. No.: |
17/179756 |
Filed: |
February 19, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16539330 |
Aug 13, 2019 |
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17179756 |
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15365247 |
Nov 30, 2016 |
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16539330 |
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14432012 |
Mar 27, 2015 |
9539230 |
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PCT/JP2013/075287 |
Sep 19, 2013 |
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15365247 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/232 20130101;
A61K 31/202 20130101 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/232 20060101 A61K031/232 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 28, 2012 |
JP |
2012-217553 |
Claims
1. A method of reducing an incidence of diabetes in a subject in
need thereof, the method comprising administering to the subject a
statin and a pharmaceutical composition containing at least one
member selected from the group consisting of eicosapentaenoic acid
and its pharmaceutically acceptable salts and esters, wherein the
subject has a serum triglyceride concentration of at least 150
mg/dL.
2. The method of claim 1, further comprising administering
rosiglitazone to the subject.
3. The method of claim 1, wherein the subject has
hypertriglyceridemia.
4. The method of claim 1, wherein the subject has a high risk of a
diabetes incidence.
5. The method of claim 1, wherein the subject has a serum total
cholesterol level at least about 250 mg/dL.
6. The method of claim 1, wherein the subject has a serum total
cholesterol level about 250 mg/dL.
7. The method of claim 1, wherein the subject has an LDL-C level of
about 120 mg/dL.
8. The method of claim 1, wherein the subject has a fasting blood
glucose of less than 126 mg/dL.
9. The method of claim 1, wherein the subject has a fasting blood
glucose of at least 110 mg/dL and less than 126 mg/dL.
10. The method of claim 1, wherein the subject has impaired glucose
tolerance or obesity.
11. The method of claim 1, wherein at least one member selected
from the group consisting of eicosapentaenoic acid and its
pharmaceutically acceptable salts and esters is ethyl eicosapentate
or eicosapentaenoic acid.
12. The method of claim 1, wherein the pharmaceutical composition
comprises at least about 96.5%, by weight, at least one member
selected from the group consisting of eicosapentaenoic acid and its
pharmaceutically acceptable salts and esters of a total weight of
fatty acids in the pharmaceutical composition.
13. The method of claim 1, wherein the pharmaceutical composition
is administered to the subject for at least about 2 years.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 16/539,330 filed Aug. 13, 2019, which is a Continuation of
application Ser. No. 15/365,247, filed Nov. 30, 2016 (abandoned),
which is a Continuation of application Ser. No. 14/432,012 (now
U.S. Pat. No. 9,539,230 B2) filed on Mar. 27, 2015, which was filed
as PCT International Application No. PCT/JP2013/075287 on Sep. 19,
2013, which claims the benefit under 35 U.S.C. .sctn. 119(a) to
Patent Application No. 2012-217553, filed in Japan on Sep. 28,
2012, all of which are hereby expressly incorporated by reference
into the present application.
TECHNICAL FIELD
[0002] This invention relates to a pharmaceutical composition for
reducing new incidence rate of diabetes by statin
administration.
BACKGROUND ART
[0003] Dyslipidemia is a large risk factor of arteriosclerosis, and
arteriosclerosis is the cause of coronary artery diseases such as
angina pectoris and myocardial infarction and cerebral stroke such
as cerebral hemorrhage and cerebral infarction which are major
death causes of Japanese. In the meanwhile, it has been
demonstrated that these cardiovascular diseases can be prevented
and treated by treating such dyslipidemia.
[0004] According to the diagnostic criteria of Atherosclerotic
Diseases Prevention Guideline (2012), dyslipidemia is divided into
hyper-LDL cholesterolemia (LDL cholesterol (hereinafter also
referred to as "LDL-C") .gtoreq.140 mg/dL), borderline
hyper-LDL-cholesterolemia (LDL-C, 120 to 139 mg/dL), low HDL
cholesterolemia (HDL cholesterol (hereinafter also referred to as
"HDL-C") <40 mg/dL), and hypertriglyceridemia (triglyceride
(hereinafter also referred to as "TG") .gtoreq.150 mg/dL).
Recently, the hyper-LDL cholesterolemia, the low
HDL-cholesterolemia, and the hypertriglyceridemia are conceived as
independent risk factors.
[0005] The therapeutic agent used for the dyslipidemia differs by
the type of the dyslipidemia, and statin is the first choice for
treating the hyper-LDL-cholesterolemia. Statin acts in mevalonic
acid synthetic pathway wherein biosynthesis of isopentenyl
diphosphoric acid and dimethyl allyl diphosphoric acid (starting
materials of steroid synthesis) from acetyl CoA takes place by
inhibiting HMG-CoA reductase (EC 1.1.1.34) (hereinafter also
referred to as "HMG-CoA") which is an enzyme catalyzing the
reaction of reducing hydroxymethyl glutaryl CoA to mevalonic acid,
and thereby suppressing the biosynthesis of the cholesterol. The
thus reduced cholesterol biosynthesis also invites effects such as
enhanced expression of liver LDL (low density lipoprotein)
receptor, increased incorporation of LDL-C from the blood into the
liver, suppressed VLDL (very low density lipoprotein) secretion
into the blood, and reduced serum TG and increased HDL-C. In view
of such function of the statin, statin is also referred to as
HMG-CoA reductase inhibitor (HMG-CoA RI).
[0006] Statin is effective for the treatment of cardiovascular
diseases and prevention of cardiovascular events, and statin has
been considered to be a safe drug with high tolerability. However,
recent reports indicate relation between the statin and the risk of
diabetes incidence. For example, Non-Patent Document 1 discloses
that, in the general evaluation conducted by collecting the results
of 16 clinical trials wherein participants were divided into the
group administered with statin (lipid lowering drug) and the group
not administered with the statin, the risk of diabetes incidence
was 9% higher in the group administered with the statin. In
addition, United States Food and Drug Administration announced a
safety communication on the increase of blood glucose and risk of
type 2 diabetes incidence by the statin administration in February,
2012, and the package insert of the statin preparation now includes
the description that the statin administration invited an increase
of hemoglobin A1c (hereinafter also referred to as "HbA1c") and
fasting blood glucose and significant increase in the diabetes
incidence (Non-Patent Document 2). However, it has been conceived,
even if the risk of diabetes incidence should increase by the
statin administration, the benefit of the reduced risk of the
cardiovascular event incidence by the statin exceeds such risk and
there is no reason for stopping the statin administration. On the
other hand, it has also been conceived that the statin should be
used with the monitoring of the blood glucose and the
glycohemoglobin blood glucose in the case of patients with
borderline blood glucose and the like suffering from high risk of
diabetes incidence (Non-Patent Document 3).
[0007] Some reports examine relation between the type of statin and
the risk of the diabetes incidence. For example, Non-Patent
Document 4 evaluated new incidence of the diabetes in aged people
of at least 66 years old administered with statin, and reports that
the risk of the incidence of the diabetes significantly increased
in the case of atorvastatin, rosuvastatin, and simvastatin compared
to the case of pravastatin, and no significant difference was found
in the case of fluvastatin and lovastatin. Non-Patent Document 5
describes that, in the meta-analysis of the tolerability and safety
of the statin, the risk of the incidence of the diabetes increased
by the statin administration while no difference was found by the
type of the statin.
CITATION LIST
Non-Patent Literature
[0008] [Non-Patent Literature 1] Naveed Sattar et al. (2010)
Statins and risk of incident diabetes: a collaborative
meta-analysis of randomized statin trials. Lancet 375(9716):
735-742. [0009] [Non-Patent Literature 2] FULL PRESCRIBING
INFORMATION of CRESTOR, AstraZeneca, Revised 28th February, 2012.
[0010] [Non-Patent Literature 3] Allison B. Goldfine (2012)
Statins: Is it really time to reassess benefits and risks? New
Engl. J. Med. 366: 1752-1755. [0011] [Non-Patent Literature 4]
Aleesa A. Carter (2013) Risk of incident diabetes among patients
treated with statins: population based study BMJ 346: f2610. [0012]
[Non-Patent Literature 5] Huseyin Naci (2013) Comparative
Tolerability and Harms of Individual Statins: A Study-Level Network
Meta-Analysis of 246955
[0013] Participants From From 135 Randomized Controlled Trials.
Circ. Cardiovasc. Qual. and Outcomes Jul. 9, 2013.
SUMMARY OF INVENTION
Technical Problem
[0014] Usefulness of the statin in treating the cardiovascular
diseases and preventing the cardiovascular events is well
recognized, and it has been difficult to stop the lipid control by
the statin even if use of the statin involved an increase in the
risk of diabetes incidence. Accordingly, there is a demand for
suppressing increase of the blood glucose and new diabetes
incidence in the patients administered with the statin, and in
particular, in the patients with high risk of diabetes incidence
such as patients having a border range blood glucose while
continuing the dyslipidemia treatment by statin administration. The
mechanism of the increase of the new diabetes incidence risk by
statin, however, is yet unclear, and there has been so far no drug
capable of reducing the new diabetes incidence risk in the patients
administered with the statin. Accordingly, an object of the present
invention is to provide a pharmaceutical composition for
suppressing new incidence of diabetes of the patient administered
with the statin. In the present invention, the term "diabetes" is
used for type II diabetes unless otherwise noted.
Solution to Problems
[0015] The inventors of the present invention analyzed the trial
data obtained in a large scale randomized controlled trial (Japan
EPA Intervention Study (JELIS)) examining the effects of
suppressing onset of the coronary artery events (primary prevention
and secondary prevention) in Japanese hyperlipidemia patients
administered with statin by long term administration of high purity
EPA preparation, and for the first time found that the patients
administered with the high purity EPA preparation exhibit no
significant increase of the new incidence rate of the diabetes; and
hence, that the new incidence rate of the diabetes is reduced in
the patients administered with the statin by the administration of
at least one member selected from the group consisting of
icosapentaenoic acid and pharmaceutically acceptable salts and
esters thereof (hereinafter also referred to as "EPA", and unless
otherwise noted, this also applies to the following), and in
particular ethyl icosapentate (hereinafter also referred to as
"EPA-E"). The inventors of the present invention also found by an
in vitro test using cultivated skeletal muscle cells that, while
statin decreases glucose uptake by the skeletal muscle cells, the
EPA suppresses such glucose uptake decrease by the skeletal muscle
cell by statin, and hence, that the EPA is capable of suppressing
the blood glucose increase by statin.
[0016] Accordingly, the present invention provides the
pharmaceutical composition as described below.
[0017] (1) A pharmaceutical composition for reducing new incidence
rate of diabetes due to administration of statin (HMG-CoA RI)
containing at least one member selected from the group consisting
of icosapentaenoic acid and its pharmaceutically acceptable salts
and esters as its effective component.
[0018] (2) A pharmaceutical composition according to the above (1)
which is administered to a patient having a serum HDL cholesterol
concentration of less than 40 mg/dL.
[0019] (3) A pharmaceutical composition according to the above (1)
which is administered to a low HDL cholesterolemia patient.
[0020] (4) A pharmaceutical composition according to the above (2)
or (3) which is administered to a patient having a serum
triglyceride concentration of at least 150 mg/dL.
[0021] (5) A pharmaceutical composition according to the above (2)
or (3) which is administered to a hypertriglyceridemia patient.
[0022] (6) A pharmaceutical composition according to any one of the
above (1) to (5) which is administered to a patient administered
with HMG-CoA RI having a fasting blood glucose of less than 126
mg/dL.
[0023] (7) A pharmaceutical composition according to any one of the
above (1) to (6) which is administered to a patient administered
with HMG-CoA RI having a fasting blood glucose of at least 110
mg/dL and less than 126 mg/dL.
[0024] (8) A pharmaceutical composition according to any one of the
above (1) to (6) which is administered to a patient administered
with HMG-CoA RI having a fasting blood glucose of at least 100
mg/dL and less than 110 mg/dL.
[0025] (9) A pharmaceutical composition according to any one of the
above (1) to (8) which is administered to a patient administered
with HMG-CoA RI having impaired glucose tolerance or obesity.
[0026] (10) A pharmaceutical composition according to any one of
the above (1) to (9) wherein at least one member selected from the
group consisting of icosapentaenoic acid and its pharmaceutically
acceptable salts and esters is ethyl icosapentate or
icosapentaenoic acid (free acid).
[0027] (11) A pharmaceutical composition for suppressing increase
of the blood glucose due to administration of statin (HMG-CoA RI)
containing at least one member selected from the group consisting
of icosapentaenoic acid and its pharmaceutically acceptable salts
and esters as its effective component.
[0028] (12) A pharmaceutical composition according to the above
(11) which is administered to a patient having a serum HDL
cholesterol concentration of less than 40 mg/dL.
[0029] (13) A pharmaceutical composition according to the above
(11) which is administered to a low HDL cholesterolemia
patient.
[0030] (14) A pharmaceutical composition according to the above
(12) or (13) which is administered to a patient having a serum
triglyceride concentration of at least 150 mg/dL.
[0031] (15) A pharmaceutical composition according to the above
(12) or (13) which is administered to a hypertriglyceridemia
patient.
[0032] (16) A pharmaceutical composition according to any one of
the above (11) to (15) which is administered to a patient
administered with HMG-CoA RI having a fasting blood glucose of less
than 126 mg/dL.
[0033] (17) A pharmaceutical composition according to any one of
the above (11) to (16) which is administered to a patient
administered with HMG-CoA RI having a fasting blood glucose of at
least 110 mg/dL and less than 126 mg/dL.
[0034] (18) A pharmaceutical composition according to any one of
the above (11) to (16) which is administered to a patient
administered with HMG-CoA RI having a fasting blood glucose of at
least 100 mg/dL and less than 110 mg/dL.
[0035] (19) A pharmaceutical composition according to any one of
the above (11) to (18) which is administered to a patient
administered with HMG-CoA RI having impaired glucose tolerance or
obesity.
[0036] (20) A pharmaceutical composition according to any one of
the above (11) to (19) wherein at least one member selected from
the group consisting of icosapentaenoic acid and its
pharmaceutically acceptable salts and esters is ethyl icosapentate
or icosapentaenoic acid (free acid).
[0037] (21) A pharmaceutical composition according to any one of
the above (1) to (20) wherein EPA content ratio in total fatty acid
and its derivatives is at least 96.5% by weight.
[0038] (22) A pharmaceutical composition according to any one of
the above (1) to (21) wherein the EPA is orally administered at a
dose of 0.9 g/day to 2.7 g/day.
[0039] (23) A pharmaceutical composition according to any one of
the above (1) to (22) wherein the EPA is administered at least for
2 years.
[0040] (24) A pharmaceutical composition according to any one of
the above (1) to (23) wherein the composition is used in
combination with HMG-CoA RI.
[0041] (25) A pharmaceutical composition according to any one of
the above (1) to (24) wherein the composition contains the EPA and
the HMG-CoA RI.
[0042] (26) A pharmaceutical composition according to any one of
the above (1) to (25) wherein the composition is used in
combination with a diet therapy.
[0043] (27) A pharmaceutical composition according to any one of
the above (1) to (26) wherein the composition is capable of, in a
patient administered with statin (HMG-CoA RI), reducing the
incidence rate of the cardiovascular event, and in particular,
incidence rate of the cardiovascular event that could not be
prevented by the single administration of the HMG-CoA RI, or serum
T-Cho concentration and/or serum TG concentration.
[0044] The present invention also provides the method as described
below.
[0045] (28) A method for reducing new incidence rate of diabetes
due to administration of HMG-CoA RI comprising the step of
administering a pharmaceutical composition containing at least one
member selected from the group consisting of icosapentaenoic acid
and its pharmaceutically acceptable salts and esters as its
effective component to a patient administered with statin (HMG-CoA
RI).
[0046] (29) A method according to the above (28) wherein the
patient has a serum HDL cholesterol concentration of less than 40
mg/dL.
[0047] (30) A method according to the above (28) wherein the
patient simultaneously suffers from low HDL cholesterolemia.
[0048] (31) A method according to the above (29) or (30) wherein
the patient has a serum triglyceride concentration of at least 150
mg/dL.
[0049] (32) A method according to the above (29) or (30) wherein
the patient simultaneously suffers from hypertriglyceridemia.
[0050] (33) A method according to any one of the above (28) to (32)
wherein the patient has a fasting blood glucose of less than 126
mg/dL.
[0051] (34) A method according to any one of the above (28) to (33)
wherein the patient has a fasting blood glucose of at least 110
mg/dL and less than 126 mg/dL.
[0052] (35) A method according to any one of the above (28) to (33)
wherein the patient has a fasting blood glucose of at least 100
mg/dL and less than 110 mg/dL.
[0053] (36) A method according to any one of the above (28) to (35)
wherein the patient has impaired glucose tolerance or obesity.
[0054] (37) A method according to any one of the above (28) to (36)
wherein at least one member selected from the group consisting of
icosapentaenoic acid and its pharmaceutically acceptable salts and
esters is ethyl icosapentate or icosapentaenoic acid (free
acid).
[0055] (38) A method for suppressing increase of blood glucose due
to administration of HMG-CoA RI comprising the step of
administering a pharmaceutical composition containing at least one
member selected from the group consisting of icosapentaenoic acid
and its pharmaceutically acceptable salts and esters as its
effective component to a patient administered with statin (HMG-CoA
RI).
[0056] (39) A method according to the above (38) wherein the
patient has a serum HDL cholesterol concentration of less than 40
mg/dL.
[0057] (40) A method according to the above (38) wherein the
patient simultaneously suffers from low HDL cholesterolemia.
[0058] (41) A method according to the above (39) or (40) wherein
the patient has a serum triglyceride concentration of at least 150
mg/dL.
[0059] (42) A method according to the above (39) or (40) wherein
the patient simultaneously suffers from hypertriglyceridemia.
[0060] (43) A method according to any one of the above (38) to (42)
wherein the patient has a fasting blood glucose of less than 126
mg/dL.
[0061] (44) A method according to any one of the above (38) to (43)
wherein the patient has a fasting blood glucose of at least 110
mg/dL and less than 126 mg/dL.
[0062] (45) A method according to any one of the above (38) to (43)
wherein the patient has a fasting blood glucose of at least 100
mg/dL and less than 110 mg/dL.
[0063] (46) A method according to any one of the above (38) to (45)
wherein the patient has impaired glucose tolerance or obesity.
[0064] (47) A method according to any one of the above (38) to (46)
wherein at least one member selected from the group consisting of
icosapentaenoic acid and its pharmaceutically acceptable salts and
esters is ethyl icosapentate or icosapentaenoic acid (free
acid).
[0065] (48) A method for improving abnormal glucose tolerance or
obesity of a patient administered with HMG-CoA RI having abnormal
glucose tolerance or obesity comprising the step of administering a
pharmaceutical composition containing at least one member selected
from the group consisting of icosapentaenoic acid and its
pharmaceutically acceptable salts and esters as its effective
component to a patient administered with statin (HMG-CoA RI) having
abnormal glucose tolerance or obesity.
[0066] (49) A method according to the above (48) wherein the
patient has a serum HDL cholesterol concentration of less than 40
mg/dL.
[0067] (50) A method according to the above (48) wherein the
patient simultaneously suffers from low HDL cholesterolemia.
[0068] (51) A method according to the above (49) or (50) wherein
the patient has a serum triglyceride concentration of at least 150
mg/dL.
[0069] (52) A method according to the above (49) or (50) wherein
the patient simultaneously suffers from hypertriglyceridemia.
[0070] (53) A method according to any one of the above (48) to (52)
wherein the patient has a fasting blood glucose of less than 126
mg/dL.
[0071] (54) A method according to any one of the above (48) to (53)
wherein the patient has a fasting blood glucose of at least 110
mg/dL and less than 126 mg/dL.
[0072] (55) A method according to any one of the above (48) to (53)
wherein the patient has a fasting blood glucose of at least 100
mg/dL and less than 110 mg/dL.
[0073] (56) A method according to any one of the above (48) to (55)
wherein at least one member selected from the group consisting of
icosapentaenoic acid and its pharmaceutically acceptable salts and
esters is ethyl icosapentate or icosapentaenoic acid (free
acid).
[0074] (57) A method according to any one of the above (28) to (56)
wherein EPA content ratio in total fatty acid and its derivatives
is at least 96.5% by weight.
[0075] (58) A method according to any one of the above (28) to (57)
wherein the EPA is orally administered at a dose of 0.9 g/day to
2.7 g/day.
[0076] (59) A method according to any one of the above (28) to (58)
wherein the EPA is administered at least for 2 years.
[0077] (60) A method according to any one of the above (28) to (59)
wherein the pharmaceutical composition is used in combination with
HMG-CoA RI.
[0078] (61) A method according to any one of the above (28) to (60)
wherein the composition contains the EPA and the HMG-CoA RI.
[0079] (62) A method according to any one of the above (28) to (61)
wherein the composition is used in combination with a diet
therapy.
[0080] (63) A method according to any one of the above (28) to (62)
wherein the composition is capable of, in a patient administered
with statin (HMG-CoA RI), reducing the incidence rate of the
cardiovascular event, and in particular incidence rate of the
cardiovascular event that could not be prevented by the single
administration of the HMG-CoA RI, or serum T-Cho concentration
and/or serum TG concentration.
[0081] (64) A method for advertising a pharmaceutical composition
used in any one of the methods:
[0082] 1) a method for reducing new incidence rate of diabetes due
to administration of HMG-CoA RI,
[0083] 2) a method for suppressing increase of blood glucose due to
administration of the HMG-CoA RI, and
[0084] 3) a method for improving abnormal glucose tolerance or
obesity of a patient administered with HMG-CoA RI having abnormal
glucose tolerance or obesity,
[0085] which comprises the step of administering a pharmaceutical
composition containing at least one member selected from the group
consisting of icosapentaenoic acid and its pharmaceutically
acceptable salts and esters as its effective component to a patient
administered with statin (HMG-CoA RI).
[0086] The information on the method as described above of the
present invention is provided to physicians and test participants.
More specifically, such information is provided, for example, by
the distribution of brochure or electric medium or by the provision
of the information through the internet.
Advantageous Effects of Invention
[0087] The pharmaceutical composition of the present invention
provides a means for reducing the new incidence rate of diabetes
due to statin administration in the patients administered with
statin (HMG-CoA RI). Of the patients administered with statin, the
pharmaceutical composition of the present invention is particularly
effective for those having higher risk of diabetes incidence. The
pharmaceutical composition of the present invention also provides a
means for suppressing increase of blood glucose due to statin
administration in the patients administered with statin (HMG-CoA
RI). Of the patients administered with statin, the pharmaceutical
composition of the present invention is particularly effective for
those who are susceptible to undergo blood glucose increase.
Furthermore, the pharmaceutical composition of the present
invention has high safety and reduced side effects.
[0088] The pharmaceutical composition of the present invention also
provides a means for reducing the new incidence rate of diabetes
due to statin administration and/or suppressing increase of blood
glucose due to statin administration in the patients administered
with statin (HMG-CoA RI), and in particular, a means for realizing
effects such as the effect of preventing the incidence of
cardiovascular events which could not be prevented by solely
administering the HMG-CoA RI and the effect of reducing the serum
T-Cho concentration and serum TG.
BRIEF DESCRIPTION OF DRAWING
[0089] FIG. 1 is a graph showing the effect of the statin and the
EPA on glucose uptake by cultivated human rhabdomyosarcoma
cell.
DESCRIPTION OF EMBODIMENTS
[0090] Next, the present invention is described in detail.
1. Pharmaceutical Composition
(1) Effective Components
[0091] The pharmaceutical composition of the present invention
contains at least one member selected from the group consisting of
icosapentaenoic acid and its pharmaceutically acceptable salts and
esters as its effective component.
[0092] Examples of the pharmaceutically acceptable salt include
inorganic salts such as sodium salt and potassium salt, salts with
an organic base such as benzylamine salt and, diethylamine salt,
and salts with a basic amino acid such as arginine salt and lysine
salt.
[0093] Examples of the pharmaceutically acceptable ester include
alkyl esters such as ethyl ester and glycerin ester such as mono-,
di-, and tri-glycerides.
[0094] The EPA is preferably ethyl icosapentate (hereinafter also
referred to as "EPA-E"), icosapentaenoic acid (free acid) or sodium
eicosapentate (hereinafter also referred, to as "EPA-Na"), and more
preferably, EPA-E.
[0095] The EPA is not particularly limited for its purity. However,
content of the EPA in the all fatty acids in the pharmaceutical
composition of the present invention is typically at least 25% by
weight, preferably at least 40% by weight, more preferably at least
50% by weight, still more preferably at least 70% by weight, still
more preferably at least 85% by weight, still more preferably at
least 96.5% by weight, and the most preferred is the embodiment
wherein the composition is substantially free from the fatty acid
other than the EPA.
[0096] When the at least one member selected from the group
consisting of icosapentaenoic acid and its pharmaceutically
acceptable salts and esters is EPA-E, content of the impurities
which are preferable for cardiovascular events such as saturated
fatty acid and arachidonic acid will be reduced, and the desired
action and effect will be realized without the problems of
excessive nutrition or excessive intake of vitamin A. Since EPA-E
is an ester, it has a higher stability to oxidation compared to
fish oils which mainly comprises a triglyceride, and a sufficiently
stable composition will be produced by adding a commonly used
antioxidant. The antioxidant added may be, for example, at least
one antioxidant selected from butylated hydroxytoluene, butylated
hydroxyanisole, propyl gallate, gallic acid, and pharmaceutically
acceptable quinone and .alpha.-tocopherol, and such agent may be
added at an effective amount.
[0097] When the at least one member selected from the group
consisting of icosapentaenoic acid and its pharmaceutically
acceptable salts and esters is EPA (free acid), content of the
impurities which are unpreferable for cardiovascular events such as
saturated fatty acid and arachidonic acid will be reduced, and the
desired action and effect will be realized without the problems of
excessive nutrition or excessive intake of vitamin A. In addition,
since the EPA is a free acid, cleavage of ester bond by elastase is
unnecessary in the absorption in the intestinal tract, and
absorption higher than that of EPA-E or triglyceride form is
expected particularly in the case of fasting administration. The
antioxidant added may be, for example, at least one antioxidant
selected from butylated hydroxytoluene, butylated hydroxyanisole,
propyl gallate, gallic acid, and pharmaceutically acceptable
quinone and .alpha.-tocopherol, and such agent may be added at an
effective amount.
[0098] Exemplary dosage form of the preparation include oral
administration to the patient in the form of tablet, capsule,
microcapsule, granules, fine granules, powder, oral liquid
preparation, emulsion, self-emulsifying preparation, syrup, and
jelly, and the particularly preferred is oral administration by
incorporating the composition in the capsule such as soft capsule
or microcapsule. Exemplary EPA-E include a soft capsule containing
high purity EPA-E (at least 96.5% by weight) (product name, Epadel,
manufactured by Mochida Pharmaceutical Co., Ltd.) which are
available in Japan as therapeutic agents for arteriosclerosis
obliterans or hypertriglyceridemia, and a soft capsule containing
high purity EPA-E (product name, Vascepa, manufactured by Amarin
Pharma Inc.), a soft capsule containing about 46% by weight of
EPA-E and about 38% by weight of DHA-E in the total fatty acid
(Lovaza manufactured by GlaxoSmithKline and Omacor manufactured by
ProNova Inc.), and a soft capsule containing 50 to 60% by weight of
EPA (free acid) and 15 to 25% by weight of DHA (free acid) in the
total fatty acid (Epanova manufactured by Omthera) which are
approved in the U.S. as therapeutic agents for severe
hypertriglyceridemia.
[0099] When the pharmaceutical composition of the present invention
is orally administered, preferably 0.1 to 10 g/day, more preferably
0.3 to 6 g/day, still more preferably 0.6 to 4 g/day, and even more
preferably 0.9 to 2.7 g/day of EPA-E is administered in 1 to 3
doses, and if necessary or if desired, the composition may be
administered in 1 to several doses. The composition is preferably
administered during or after the meal, and more preferably,
immediately (within 30 minutes) after the meal. In the case of
self-emulsifying preparation (for example, see WO 2010/134614)
which exhibits high fasting absorption, the preparation may be
administered not during the meal, after the meal, or immediately
after the meal. The pharmaceutical composition of the present
invention may also be used in combination with the diet therapy
(for example, limitation of daily calorie, regular meal, balanced
diet, balanced intake of nutritional elements (carbohydrate,
protein, fat, mineral, vitamin, dietary fiber, and the like),
etc.), and in such a case, daily dose, frequency, and/or timing of
the administration can be adjusted as desired. The daily dose and
frequency of the EPA (free acid) administration when the
pharmaceutical composition of the present invention contains the
EPA (free acid) may be determined by referring to the
pharmaceutical composition containing EPA-E.
[0100] When the dose as described above is orally administered, the
administration is preferably conducted while administering the
statin. For example, the administration period is at least 1 year,
preferably at least 2 years, more preferably at least 3 years, and
still more preferably at least 5 years, and the administration is
preferably continued while there is the risk of the incidence rate
of new diabetes and/or blood glucose increase due to the statin
administration is still present. If desired, drug withdrawal period
of approximately 1 day to 3 months, and preferably approximately 1
week to 1 month may be included.
[0101] The administration period may be adequately set depending on
the type of the disease to be treated and the degree of the
symptom. For example, when the disease to be treated is
dyslipidemia, the administration period is not particularly limited
when the administration is conducted to achieve the effects of
improving or treating dyslipidemia-related biochemical marker or
pathologies or to suppress the progress into metabolic syndrome,
cardio-cerebrovascular events, peripheral ulcer, gangrene, and the
like. Exemplary conditions include improvement in the concentration
of lipid markers in plasma (total cholesterol (hereinafter referred
to as Cho), TG, TG after the meal, low density lipoprotein Cho,
high density lipoprotein Cho, very low density lipoprotein Cho,
non-high density lipoprotein Cho, intermediate density lipoprotein
Cho, very high density lipoprotein Cho, free fatty acid,
phospholipid, chylomicron, ApoB, lipoprotein (a), and remnant-like
protein Cho, small dense low density lipoprotein Cho, etc.),
increase in the peripheral skin temperature which can be measured
by thermography or the like, increase in the walk distance,
improvement of the test value such as serum creatinine
phosphokinase, and improvement of symptoms such as numbness,
coldness, pain, pain at rest, itching, cyanosis, redness,
chilblain, neck stiffness, anemia, unhealthy complexion, pruritus,
and crawling; and the administration may be conducted by monitoring
improvement or therapeutic effects for these conditions. The
administration may be conducted by monitoring the improvement or
the therapeutic effects using other biochemical, pathological, or
disease parameters. Desirably, the administration is continued
while biochemical marker values such as plasma lipid concentration
and abnormal pathology are still observed.
(2) Fatty Acid which May be Incorporated in Addition to the EPA
[0102] Examples of other fatty acids (not limited to free fatty
acid and including pharmaceutically acceptable salts, esters, and
other derivatives, and this also applies to the following
description in this item) which may be incorporated include
.omega.3 long chain unsaturated fatty acid, which is more
preferably at least one member selected from the group consisting
of docosahexaenoic acid, docosapentaenoic acid, and
pharmaceutically acceptable salts and esters thereof (hereinafter
also simply referred to as "DHA", and unless otherwise noted, this
also applies to the following), and more preferably DHA, and still
more preferably ethyl docosahexaenoate (hereinafter also referred
to as "DHA-E").
[0103] When the pharmaceutical composition of the present invention
contains EPA-E and DHA-E, the proportion of the total content of
the EPA-E and the DHA-E in the total fatty acid content of the
pharmaceutical composition of the present invention is not
particularly limited. The proportion, however, is preferably at
least 40% by weight, more preferably at least 60% by weight, still
more preferably at least 80% by weight, and still more preferably
at least 90% by weight, and the most preferred is the embodiment
wherein the fatty acid other than the .omega.3 long chain
unsaturated fatty acid is substantially absent. In other words,
purity of the .omega.3 long chain unsaturated fatty acid in all
fatty acids is preferably high, and more preferably, purity of the
EPA and the DHA which are .omega.3 long chain unsaturated fatty
acids is high, and still more preferably, purity of the EPA is
high. For example, when the pharmaceutical composition of the
present invention contains the EPA-E and the DHA-E, the ratio of
the content of the EPA-E to the DHA-E (EPA-E/DHA-E) in all fatty
acids of the pharmaceutical composition of the present invention is
not particularly limited, and the ratio is preferably at least 0.8,
more preferably at least 1.0, and more preferably at least 1.2.
When the pharmaceutical composition of the present invention
contains the EPA (free acid) and the DHA (free acid), total
proportion of the EPA (free acid) and the DHA (free acid) in all
fatty acids in the pharmaceutical composition of the present
invention and the ratio of the EPA (free acid) to the DHA (free
acid) (EPA/DHA) in all fatty acids in the pharmaceutical
composition of the present invention corresponds to those of the
pharmaceutical composition containing the EPA-E and the DHA-E.
[0104] When the pharmaceutical composition of the present invention
contains EPA-E and the DHA-E, the daily dose of the EPA-E and the
DHA-E which is not particularly limited is preferably 0.3 to 10
g/day, more preferably 0.5 to 6 g/day, and still more preferably 1
to 4 g/day as the total of the EPA-E and DHA-E, and if necessary or
if desired, the composition may be administered in 1 to several
doses. The composition is preferably administered during or after
the meal, and more preferably, immediately (within 30 minutes)
after the meal. In the case of self-emulsifying preparation (for
example, see WO 2010/134614) which exhibits high fasting
absorption, the preparation may be administered not during the
meal, after the meal, or immediately after the meal. The
pharmaceutical composition of the present invention may also be
used in combination with the diet therapy, and in such a case,
daily dose, frequency, and/or timing of the administration can be
adjusted as desired. The daily dose and frequency of the EPA (free
acid) and and DHA (free acid) administration when the
pharmaceutical composition of the present invention contains the
EPA (free acid) and DHA (free acid) may be determined in
consideration of the corresponding case of the pharmaceutical
composition containing EPA-E and DHA-E as described above.
[0105] When the dose as described above is administered, the
administration period is preferably during the administration of
the statin. For example, the administration period is at least 1
year, preferably at least 2 years, more preferably at least 3
years, and still more preferably at least 5 years, and the
administration is preferably continued while there is the risk of
the incidence rate of new diabetes and/or blood glucose increase
due to the statin administration is still present. If desired, drug
withdrawal period of approximately 1 day to 3 months, and
preferably approximately 1 week to 1 month may be included.
[0106] The administration period may be adequately set depending on
the type of the disease to be treated and the degree of the
symptom. For example, when the disease to be treated is
dyslipidemia, the administration period is not particularly limited
when the administration is conducted to achieve the effects of
improving or treating dyslipidemia-related biochemical marker or
pathologies or to suppress the progress into metabolic syndrome,
cardio-cerebrovascular events, peripheral ulcer, gangrene, and the
like. Exemplary conditions include improvement in the concentration
of lipid markers in plasma (total cholesterol (hereinafter referred
to as Cho), TG, TG after the meal, low density lipoprotein Cho,
high density lipoprotein Cho, very low density lipoprotein Cho,
non-high density lipoprotein Cho, intermediate density lipoprotein
Cho, very high density lipoprotein Cho, free fatty acid,
phospholipid, chylomicron, ApoB, lipoprotein (a), and remnant-like
protein Cho, small dense low density lipoprotein Cho, etc.),
increase in the peripheral skin temperature which can be measured
by thermography or the like, increase in the walk distance,
improvement of the test value such as serum creatinine
phosphokinase, and improvement of symptoms such as numbness,
coldness, pain, pain at rest, itching, cyanosis, redness,
chilblain, neck stiffness, anemia, unhealthy complexion, pruritus,
and crawling; and the administration may be conducted by monitoring
improvement or therapeutic effects for these conditions. The
administration may be conducted by monitoring the improvement or
the therapeutic effects using other biochemical, pathological, or
disease parameters. Desirably, the administration is continued
while biochemical marker values such as plasma lipid concentration
and abnormal pathology are still observed.
[0107] Preferably, content of the long chain unsaturated fatty
acids other than the EPA and the DHA is minimized as far as
possible, and in particular, content of the .omega.6 long chain
unsaturated fatty acids, and in particular, arachidonic acid should
be minimized as far as possible, and the content is preferably less
than 2% by weight, more preferably less than 1% by weight, still
more preferably less than 0.5% by weight, and the most preferable
is the embodiment wherein the .omega.6 long chain unsaturated fatty
acid is substantially absent.
(3) Use in Combination with Statin
[0108] The pharmaceutical composition of the present invention is
used in combination with the statin.
[0109] The "use in combination with the statin" includes both a
simultaneous administration of the composition containing the EPA
as its effective component with the statin and separate
administration of such composition with the statin.
[0110] In the case of simultaneous administration, the
pharmaceutical composition of the present invention and the statin
may be formulated as a combined drug, a kit comprising the
combination of these two drugs, or two separate drugs.
[0111] In the case of separate administration, the pharmaceutical
composition of the present invention and the statin may be used at
an adequate dose and ratio.
[0112] In addition, in the case of separate administration, the EPA
may be administered either before or after the HMG-CoA RI. When
these drugs are administered at different timings, the drugs may be
administered, for example, by first administering one of the drugs
and then administering the other drug at the timing when the
effects of the first drug starts to be developed or during the full
development of such effect for the action of the second drug. In
other cases, one drug may be prepared in the form of a
controlled-release drug and administered once a day, and the other
drug may be administered two or more times, for example, twice or
three times a day, or once a day as in the case of the first drug.
The administration of both drugs once a day, or simultaneous
administration both drugs once a day, or use of a preparation
containing both drugs is preferable due to the reduced
participant's burden of taking the drugs, and such administration
is expected to result in the improved compliance and improved
preventive/ameliorating or treating effects as well as improved
effect of reducing the side effects. Alternatively, both drugs may
be administered and the administration of one of the drugs may be
stopped when the effects of the first drug starts to be developed
or during the full development of such effect. In stopping the drug
administration, the drug dose may be incrementally reduced.
Furthermore, one of the drugs may be administered during drug
withdrawal period of the other drug.
[0113] The "use in combination" is not necessarily limited to the
cases of simultaneous presence in body, for example, in blood of
the participants. The "use in combination" as used in the present
invention however refers to the embodiment of the drug use wherein
one of the drugs is administered while the action or the effect of
the other drug is still expressed in the body of the patient.
[0114] The action mechanism how the new incidence rate of the
diabetes due to statin is reduced or the increase of the blood
glucose due to statin is suppressed by the pharmaceutical
composition of the present invention in the patients administered
with the statin not fully elucidated. Since EPA suppresses the
decrease of the glucose take up by skeletal muscle cell by the
statin, there is a possibility that EPA is suppressing the increase
of the blood glucose due to statin. Suppressing of the blood
glucose increase should result in the decrease of the risk of the
diabetes incidence.
[0115] Furthermore, the pharmaceutical composition of the present
invention is known to have the action of preventing the incidence
of cardiovascular events, and in particular, the cardiovascular
events which cannot be prevented by the single administration of
the HMG-CoA RI as well as the action of reducing the serum T-Cho
concentration and serum TG in the hyperlipidemia patients
administered with the statin (HMG-CoA RI). Accordingly, increase of
the new diabetes incidence rate and/or the blood glucose due to the
statin administration will be suppressed, the incidence of
cardiovascular events, and in particular, the cardiovascular events
which cannot be prevented by the single administration of the
HMG-CoA RI will be prevented, and the serum T-Cho concentration and
serum TG will be reduced in the patients administered with statin
(HMG-CoA RI).
2. Diabetes
(1) Diagnostic Criteria of Diabetes
[0116] In the present invention, the patient who was at least once
observed to have the fasting blood glucose of 126 mg/dL or higher
is recognized as a patient suffering from diabetes.
[0117] It is to be noted that, in the clinical diagnostic criteria
of the diabetes, a patient is diagnosed as diabetes when a) both
blood glucose and HbA1c are diabetic in the initial examination
(preferably measured on the same day, and this applies to the
following), b) only blood glucose is diabetic in the initial
examination, and typical diabetic symptoms or accurate diabetic
retinopathy is found in the initial test, c) only blood glucose is
diabetic in the initial examination, and both typical diabetic
symptoms and accurate diabetic retinopathy are absent, and the
blood glucose and/or the HbA1c is diabetic in the reexamination,
and d) HbA1c is diabetic in the initial examination, and both blood
glucose and HbA1c are diabetic, or only the blood glucose is
diabetic in the reexamination.
(2) New Incidence and New Incidence Rate of the Diabetes
[0118] In the present invention, the term "new incidence of the
diabetes" is used when a fasting blood glucose of 126 mg/dL or
higher is measured at least once in the patient who has never been
diagnosed as diabetes, and preferably in the patient who has no
experience of the measurement of 126 mg/dL or higher.
[0119] The "new incidence rate of the diabetes" is percentage of
the number of patient who has experienced the new incidence of the
diabetes in the number of all patients administered with HMG-CoA
RI.
3. Patients Who are Subject to the Administration of the
Pharmaceutical Composition of the Present Invention
(1) The Pharmaceutical Composition for Reducing the New Diabetes
Incidence
[0120] The patients subject to the administration of the
pharmaceutical composition of the present invention for reducing
the new incidence of the diabetes due to the administration of
statin are not particularly limited as long as the patient is
administered with the statin (HMG-CoA RI) and the patient has no
experience of the incidence of the diabetes. Such patients are
preferably those who have not experienced the incidence of the
diabetes but who have higher risk of incidence since the effect of
the pharmaceutical composition of the present invention to reduce
the new diabetes incidence due to statin is more significant in
patients who have higher risk of diabetes incidence.
[0121] Exemplary patients who have higher risk of diabetes
incidence include those who are suffering from
hyper-LDL-cholesterolemia or borderline hyper-LDL-cholesterolemia
simultaneously with preferably low HDL-cholesterolemia, and more
preferably low HDL-cholesterolemia and hypertriglyceridemia. It is
to be noted that the diagnostic criteria of the
hyper-LDL-cholesterolemia, the borderline
hyper-LDL-cholesterolemia, the low HDL-cholesterolemia, and the
hypertriglyceridemia are respectively serum LDL-C equal to or
greater than 140 mg/dL, serum LDL-C of 120 to 139 mg/dL, serum
HDL-C of less than 40 mg/dL, and serum TG equal to or greater than
150 mg/dL. These diagnostic criteria, however, are preferably
renewed when the diagnostic criteria is revised.
[0122] Another group of patients who have higher risk of diabetes
incidence is, for example, patients whose fasting blood glucose is
in the borderline range or at a normal high value. The "borderline
range" is the fasting blood glucose of at least 110 mg/dL and less
than 126 mg/dL, and the "normal high value" is the fasting blood
glucose of at least 100 mg/dL and less than 110 mg/dL. However,
these thresholds are preferably renewed when the thresholds are
revised.
[0123] Another group of patients who have higher risk of diabetes
incidence is, for example, patients who are suffering from impaired
glucose tolerance or obesity. The patients who are suffering from
impaired glucose tolerance or obesity are conceived to be those
having higher risk of diabetes incidence compared to the patients
who are not suffering from the impaired glucose tolerance or
obesity.
[0124] In the present invention, "impaired glucose tolerance" means
that the value at 2 hours in OGTT (75 g oral glucose tolerance
test) is neither normal type nor diabetes type. The 2 hour OGTT
value is normal type when the 2 hour OGTT value is less than 140
mg/dL, and the 2 hour OGTT value is diabetes type when the 2 hour
OGTT value is 200 mg/dL or higher.
[0125] In the present invention, "obesity" means the state of
excessive adipose tissue accumulation. While the criteria may vary
by the country, the term "obesity" is determined by the diagnostic
criteria of Japan Society for the Study of Obesity, namely, the
body-mass index (hereinafter, also referred to as "BMI") of at
least 25.
(2) The Pharmaceutical Composition for Suppressing the Increase of
the Blood Glucose
[0126] The patients subject to the administration of the
pharmaceutical composition of the present invention for suppressing
the increase of the blood glucose due to the administration of
statin are not particularly limited as long as the patient is
administered with statin (HMG-CoA RI). Such patients are preferably
those who have not experienced the incidence of the diabetes, and
more preferably, those who have not experienced the incidence of
the diabetes but who are susceptible to experience increase in the
blood glucose since the effect of the pharmaceutical composition of
the present invention to suppress the increase of the blood glucose
due to statin is more significant in patients who are susceptible
to experience increase in the blood glucose.
[0127] Exemplary patients who are susceptible to experience
increase of the blood glucose include those who are suffering from
hyper-LDL-cholesterolemia or borderline hyper-LDL-cholesterolemia
simultaneously with preferably low HDL-cholesterolemia, more
preferably low HDL-cholesterolemia and hypertriglyceridemia. It is
to be noted that the diagnostic criteria of the
hyper-LDL-cholesterolemia, the borderline
hyper-LDL-cholesterolemia, the low HDL-cholesterolemia, and the
hypertriglyceridemia are respectively serum LDL-C equal to or
greater than 140 mg/dL, serum LDL-C of 120 to 139 mg/dL, serum
HDL-C of less than 40 mg/dL, and serum TG equal to or greater than
150 mg/dL. These diagnostic criteria, however, are preferably
renewed when the diagnostic criteria is revised.
[0128] Another group of patients who are susceptible to experience
increase of the blood glucose is, for example, patients whose
fasting blood glucose is in the borderline range or at a normal
high value. The "borderline range" is the fasting blood glucose of
at least 110 mg/dL and less than 126 mg/dL, and the "normal high
value" is the fasting blood glucose of at least 100 mg/dL and less
than 110 mg/dL. These thresholds, however, are preferably renewed
when the thresholds are revised.
[0129] Another group of patients who are susceptible to experience
increase of the blood glucose is, for example, patients who are
suffering from impaired glucose tolerance or obesity. The patients
who are suffering from impaired glucose tolerance or obesity are
conceived to be those having higher risk of diabetes incidence
compared to the patients who are not suffering from the impaired
glucose tolerance or obesity.
[0130] In the present invention, "impaired glucose tolerance" means
that the value at 2 hours in OGTT (75 g oral glucose tolerance
test) is neither normal type nor diabetes type. The 2 hour OGTT
value is normal type when the 2 hour OGTT value is less than 140
mg/dL, and the 2 hour OGTT value is diabetes type when the 2 hour
OGTT value is 200 mg/dL or higher.
[0131] In the present invention, "obesity" means the state of
excessive adipose tissue accumulation. While the criteria may vary
by the country, the term "obesity" is determined by the diagnostic
criteria of Japan Society for the Study of Obesity, namely, the BMI
of at least 25.
(3) Statin
[0132] The statin (HMG-CoA RI) is not particularly limited as long
as it is a drug which inhibits HMG-CoA reductase, and examples
include atorvastatin, simvastatin, cerivastatin, fluvastatin,
pravastatin, rosuvastatin, pitavastatin, lovastatin, and their
pharmaceutically acceptable salts. Exemplary commercially available
products include atorvastatin calcium (product name, Lipitor,
Astellas Pharma/Pfizer Inc.), simvastatin (product name, Lipovas,
MSD), cerivastatin sodium, fluvastatin sodium (product name,
Lochol, Novartis Pharma), pravastatin sodium (product name,
Mevalotin, Daiichi Sankyo), rosuvastatin calcium (product name,
Crestor, Shionogi), pitavastatin calcium (product name, Livalo,
Kowa), and lovastatin (product name, Mevacor, MSD). The term
"statin" and "HMG-CoA RI" as used herein in relation to the
pharmaceutical composition of the present invention include all of
those as mentioned above.
[0133] The type of statin is not particularly limited. However,
combination with a statin which is highly effective for reducing
the cardiovascular risk is preferable since the statin which is
highly effective for reducing the cardiovascular risk is also
likely to have a high risk of diabetes incidence. For example, the
preferred are atorvastatin, rosuvastatin, and simvastatin, and the
more preferred are atorvastatin and rosuvastatin. The most
preferred is atorvastatin.
[0134] Statin is preferably used by the prescribed method and at
the prescribed dose, and the dose may be adjusted depending on the
type, dosage form, administration route and daily frequency of the
statin, degree of the symptom, body weight, sex, age, and the like.
In the case of oral administration, 0.05 to 200 mg/day, and
preferably 0.1 to 100 mg/day of statin may be administered at once
or in two divided doses, and if desired, total dose may be
administered in several divided doses. The dose may be reduced
depending on the amount of the EPA-E administered.
[0135] It is to be noted that daily dose is preferably 5 to 60 mg,
and more preferably 10 to 20 mg in the case of sodium pravastatin;
preferably 2.5 to 60 mg, and more preferably 5 to 20 mg in the case
of simvastatin; preferably 10 to 180 mg, and more preferably 20 to
60 mg in the case of fluvastatin sodium; preferably 5 to 120 mg,
and more preferably 10 to 40 mg in the case of atorvastatin calcium
hydrate; preferably 0.5 to 12 mg, and more preferably 1 to 4 mg in
the case of pitavastatin calcium; preferably 1.25 to 60 mg, and
more preferably 2.5 to 20 mg in the case of rosuvastatin calcium;
preferably 5 to 160 mg, and more preferably 10 to 80 mg in the case
of lovastatin; and preferably 0.075 to 0.9 mg, and more preferably
0.15 to 0.3 mg in the case of cerivastatin sodium; although the
dose is not limited to those as described above.
[0136] The pharmaceutical composition and the method of the present
invention may be used by incorporating other drug in addition to
the EPA. The additional drug used in the present invention is not
particularly limited as long as it does not adversely affect the
merit of the present invention, and exemplary such drugs include
hypoglycemic/antidiabetic, lipid-lowering drug, antihypertensive,
antioxidant, and anti-inflammatory agent.
[0137] Exemplary hypoglycemic/antidiabetic drugs include
.alpha.-glucosidase inhibitors such as acarbose, voglibose, and
miglitol, sulfonyl urea hypoglycemics such as gliclazide,
glibenclamide, glimepiride, and tolbutamide, rapid-acting insulin
secretagogues such as nateglinide, repaglinide, and mitiglinide,
biguanide hypoglycemics such as metformin hydrochloride, and
buformin hydrochloride, dipeptidyl phosphatase 4 inhibitors such as
sitagliptin, vildagliptin, alogliptin, and saxagliptin,
thiazolidine drugs such as pioglitazone hydrochloride and
rosiglitazone maleate, glucagon-like peptide 1 derivatives such as
exenatide and liraglutide, insulin, and insulin derivatives.
[0138] Exemplary lipid-lowering drugs include fibrate drugs such as
simfibrate, clofibrate, clinofibrate, bezafibrate, and fenofibrate,
and lipase inhibitors such as orlistat and cetilistat, resins such
as cholestyramine and colestimide, and ezetimibe.
[0139] Exemplary antihypertensives include angiotensin II receptor
blockers such as irbesartan, olmesartan medoxomil, candesartan
cilexetil, telmisartan, valsartan, losartan potassium,
angiotensin-converting enzyme inhibitors such as alacepril,
imidapril hydrochloride, enalapril maleate, captopril, quinapril
hydrochloride, cilazapril hydrate, temocapril hydrochloride,
delapril hydrochloride, trandolapril, benazepril hydrochloride,
perindopril, and lisinopril hydrate, calcium antagonists such as
azelnidipine, amlodipine besylate, aranidipine, efonidipine
hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine,
nimodipine, nitrendipine, nilvadipine, barnidipine hydrochloride,
felodipine, benidipine, and manidipine, a blockers such as
tolazoline and phentolamine, .beta. blockers such as atenolol,
metoprolol, acebutolol, propranolol, pindolol, carvedilol, and
labetalol hydrochloride, a stimulants such as clonidine and
methyldopa, and diuretics such as eplerenone, hydrochlorothiazide,
and furosemide.
[0140] Exemplary antioxidants include vitamins such as ascorbic
acid (vitamin C), tocopherol (vitamin E), and tocopherol nicotinic
acid ester, N-acetyl cysteine, and probucol.
[0141] Exemplary anti-inflammatory agents include cytokine
production inhibitor such as pentoxifylline, leukotriene receptor
antagonist, leukotriene biosynthesis inhibitor, NSAIDs, COX-2
selective inhibitor, M2/M3 antagonist, steroids such as
corticosteroid and prednisolone farnesylate, Hi (histamine)
receptor antagonist, aminosalicylic acids such as
salazosulfapyridine and mesalazine. Exemplary immunosuppressants
include azathioprine, 6-mercaptoprine, and tacrolimus. Exemplary
antiviral agents for hepatitis C virus (HCV) include interferon,
protease inhibitor, helicase inhibitor, and polymerase
inhibitor.
EXAMPLES
[0142] [Suppression of the New Incidence of Diabetes in Patients
Administered with HMG-CoA RI by EPA Administration]
[0143] The test data obtained in JELIS (Japan EPA Lipid
Intervention Study) which is a large-scale randomized comparative
test conducted since 1996 was examined for examining the effect of
suppressing the incidence (primary and secondary prevention) of the
coronary artery event induced by long-term administration of high
purity EPA preparation in Japanese hyperlipidemia patients
1. Summary of the JELIS Test
(1) Subjects
[0144] Hyperlipidemia patients with serum total cholesterol of at
least 250 mg/dL (men aged 40 to 75 years and postmenopausal women
aged up to 75 years with serum total cholesterol of at least 250
mg/dL) were eligible for the study, and a total of 18,645 cases
(14,981 primary prevention cases, 3,664 secondary prevention cases)
were studied.
(2) Test Method
[0145] The hyperlipidemia patients were divided into 2 groups,
namely, the control group (9,319 cases, the group with no EPA
administration) and EPA group (9,326 cases), and the EPA group was
administered with 1800 mg/day of high purity EPA preparation.
Simultaneously, both groups were administered with statin (10 to 20
mg/day of pravastatin sodium, 5 to 10 mg/day of simvastatin, or 10
to 20 mg/day of atorvastatin calcium in terms of atorvastatin). The
groups were followed for about 5 years, and evaluation was
conducted. It is to be noted that the hyperlipidemia patients in
the JELIS test were those having the serum total cholesterol (TC)
concentration of at least 250 mg/dL including the patients whose
serum TC concentration would be at least 250 mg/dL if the lipid was
not controlled.
2. Analysis of New Incidence of Diabetes
(1) Subject
[0146] 15,605 cases without definite diagnosis of the diabetes (EPA
group, 7,810 cases; control group 7,795 cases) were extracted from
18,645 cases registered in JELIS, and these cases were designated
"group 1". As a consequence, 3,040 cases with definite diagnosis of
the diabetes (not limited to Type 2 diabetes and including all
types) were excluded from the entire registered cases.
[0147] Next, 15,311 cases including the cases with the fasting
blood glucose of less than 126 mg/dL and the cases wherein the
fasting blood glucose had not been measured (EPA group, 7,650
cases; control group, 7,661 cases) were extracted from group 1, and
this group was designated "group 2". As a consequence, 294 cases
with the blood glucose at the time of registration of at least 126
mg/dL were excluded from the group 1.
[0148] Next, 7,875 cases including the cases wherein the fasting
blood glucose had been measured at least once in the observation
period (EPA group, 3,976 cases; control group, 3,899 cases) were
extracted from group 2, and this group was designated "group 3". As
a consequence, 7,436 cases wherein the fasting blood glucose was
not at all measured in the observation period were excluded from
the group 2.
[0149] Furthermore, the cases wherein the serum HDL-C concentration
was less than 40 mg/dL with no limitation in the serum TG were
extracted from each of the group 1, group 2, and group 3, and this
group was designated subgroup "HDL-C<40, no limitation in TG",
and the cases wherein the serum HDL-C concentration was less than
40 mg/dL and the serum TG was at least 150 mg/dL were extracted
from each of the group 1, group 2, and group 3, and this group was
designated subgroup "HDL-C<40 and TG.gtoreq.150"
[0150] The number of patients who experienced new incidence of the
diabetes (DM: Diabetes Mellitus) during the JELIS test (number of
DM incidence), proportion of such patients (DM incidence rate, %),
and the suppression rate of DM incidence by EPA administration (%)
are shown in Table 1.
TABLE-US-00001 TABLE 1 Number of patients experiencing new
incidence and new incidence rate of Diabetes Mellitus HDL-C < 40
Serum lipid HDL-C No limitation on No limitation HDL-C < 40
[mg/dL] TG HDL-C and TG on TG TG .gtoreq. 150 Group 1 EPA Total
number 7810 620 501 group DM Incidence 259 24 22 number Incidence
3.3% 3.9% 4.4% rate Control Total number 7795 642 523 group DM
Incidence 242 39 34 number Incidence 3.1% 6.1% 6.5% rate
Suppression rate of DM incidence -6.8% 36.3% 32.5% Group 2 EPA
Total number 7650 608 486 group DM Incidence 219 22 20 number
Incidence 2.9% 3.6% 4.1% rate Control Total number 7661 637 514
group DM Incidence 203 35 32 number Incidence 2.6% 5.5% 6.2% rate
Suppression rate of DM incidence -8.0% 34.1% 33.9% Group 3 EPA
Total number 3976 295 239 group DM Incidence 213 21 19 number
Incidence 5.4% 7.1% 7.9% rate Control Total number 3899 325 273
group DM Incidence 201 35 32 number Incidence 5.2% 10.8% 11.7% rate
Suppression rate of DM incidence -3.9% 33.9% 32.2%
[0151] Furthermore, the cases wherein the fasting blood glucose was
at least 110 mg/dL and less than 126 mg/dL were extracted from the
subgroup "HDL-C<40, no limitation in TG" and the subgroup
"HDL-C<40 and TG.gtoreq.150" of the group 3, and the number of
DM incidence, the DM incidence rate, and the suppression rate of DM
incidence are shown in Table 2.
TABLE-US-00002 TABLE 2 Number of patients experiencing new
incidence and new incidence rate of Diabetes Mellitus 110 .ltoreq.
FPG < 126 Fasting blood glucose (FPG) [mg/dL] HDL-C < 40 110
.ltoreq. FPG < 126 Serum lipid HDL-C No limitation HDL-C < 40
[mg/dL] TG on TG TG .gtoreq. 150 Group 3 EPA group Total number 25
19 DM Incidence 4 3 number Incidence 16.0% 15.8% rate Control Total
number 19 17 group DM Incidence 5 5 number Incidence 26.3% 29.4%
rate Suppression rate of DM incidence 39.2% 46.3%
[0152] It is to be noted that the incidence of the DM in Tables 1
and 2 means the new incidence of the DM, namely, the measurement of
the fasting blood glucose of 126 mg/dL or higher in the patient who
has never been diagnosed as diabetes, and preferably in the patient
who has no experience of the measurement of 126 mg/dL or
higher.
[0153] The overall results shown in Tables 1 and 2 were generally
summarized, and the following suppressive effects by EPA may be
expected as the effect of suppressing the new incidence of diabetes
due to statin administration:
[0154] (1) suppression of about 34 to 36% in the patients with the
HDL-C of less than 40 mg/dL,
[0155] (2) suppression of about 32 to 35% in the patients with the
HDL-C of less than 40 mg/dL and the TG of 150 mg/dL or higher,
[0156] (3) suppression of about 39% in the patients with the
fasting blood glucose of at least 110 mg/dL and less than 126 mg/dL
and the HDL-C of less than 40 mg/dL, and
[0157] (4) suppression of about 46% in the patients with the
fasting blood glucose of at least 110 mg/dL and less than 126
mg/dL, the HDL-C of less than 40 mg/dL, and the TG of at least 150
mg/dL.
[Suppression by EPA of the Decrease of Glucose Uptake by Skeletal
Muscle Cells Induced by Statin]
1. Materials and Methods
[0158] (1) Human fetal rhabdomyosarcoma cell line (RD cell, ATCC)
was inoculated in 24 well plate and cultured in a growth medium
(10% fetal bovine serum (FCS), Dulbecco's modified Eagle medium
(DMEM), low glucose, 1% nonessential amino acid) to confluency. (2)
The cells were then cultivated in differentiation medium (2% horse
serum (HS), Dulbecco's modified Eagle medium (DMEM), low glucose,
1% nonessential amino acid) for 3 to 5 days for differentiation
into muscle cell. (3) The cells were then cultivated in the
differentiation medium supplemented with 0.5% of bovine serum
albumin (BSA) (hereinafter referred to as "differentiation medium
(0.5% BSA)"), the differentiation medium (0.5% BSA) supplemented
with 30 .mu.M of statin (simvastatin), the differentiation medium
(0.5% BSA) supplemented with 50 .mu.M of EPA (sodium
eicosapentate), or the differentiation medium (0.5% BSA)
supplemented with 50 .mu.M of EPA (sodium eicosapentate) and 30
.mu.M of statin (simvastatin) for 1 hr, 6 hr, 24 hr, or 48 hr.
[0159] The differentiation medium (0.5% BSA) supplemented with
neither statin nor EPA was used for the control group (Cont.), the
one supplemented only with the 30 .mu.M of statin (simvastatin) was
used as "statin group (Statin)", the one supplemented only with the
50 .mu.M of EPA (sodium eicosapentate) was used as "EPA group
(EPA)", and the one supplemented with both the 30 .mu.M of statin
(simvastatin) and the 50 .mu.M of EPA was used as "statin+EPA group
(Statin+EPA)".
(3) After the incubation, the medium was removed by aspiration, and
the cells were incubated in an uptake buffer (140 mM NaCl, 5 mM
KCl, 2.5 mM MgSO.sub.4, 20 mM HEPES, 1 mM CaCl.sub.2, pH=7.4)
supplemented with 10 .mu.M of 2-3H-deoxyglucose at 37.degree. C.
for 12 minutes. (4) After the incubation, the cells were washed 4
times with cold stop solution (PBS(-)supplemented with 10 mM
glucose).
[0160] The PBS(-) contained 0.2 g of NaH.sub.2PO.sub.4.2H.sub.2O,
3.225 g of Na.sub.2HPO.sub.4.12H.sub.2O, and 8 g of NaCl in 1 L,
and the pH was at 7.2 to 7.4.
(5) After the washing, 500 .mu.L/well of aqueous solution of 0.4N
sodium hydroxide was added, and the cells were lyzed by heating to
56.degree. for 20 minutes. (6) 300 .mu.L of the well content (cell
lysate) was mixed with 4 mL of Atomlight (manufactured by
PerkinElmer), and .sup.3H count was measured with a liquid
scintillation counter. The well content (cell lysate) was also
measured for its protein concentration to calculate the .sup.3H
count per 1 .mu.g of the protein.
2. Results and Analysis
(1) Uptake of Radioactivity
[0161] Table 3 shows radioactivity per 1 .mu.g of protein (unit:
dpm/.mu.g protein) measured by using the liquid scintillation
counter. FIG. 1 is the graph showing the uptake of radioactivity (y
axis) in relation to the incubation time (x axis) for each
group.
TABLE-US-00003 TABLE 3 Uptake of radioactivity Incubation time [hr]
1 6 24 48 Cont. 521 519 485 627 EPA 503 513 537 673 Statin 563 489
343 170 Statin + EPA 504 491 424 399 Unit: dpm/.mu.g protein
(2) Effects of Statin
[0162] In the statin group (Statin), the uptake of the
radioactivity is little different from that of the control group
(Cont.) within 6 hr of cultivation. However, the radioactivity
uptake drastically decreased at 24 hr and 48 hr of cultivation, and
the rate of decrease at 48 hr of incubation was about 73%. In
summary, the glucose uptake ability by the skeletal muscle cell
decreases in the presence of statin.
[0163] This result indicates that the glucose uptake ability by the
skeletal muscle cell in the patients administered with statin is
impaired and they are in the condition of tendency of the blood
glucose increase.
(3) Effects of EPA
[0164] In the EPA group (EPA), the uptake of the radioactivity
tends to keep up with that of the control group (Cont.). However,
the radioactivity uptake somewhat improved at 24 hr and 48 hr of
incubation, and the rate of improvement at 48 hr of incubation was
about 7%. In summary, the glucose uptake ability by the skeletal
muscle cell somewhat increases in the presence of EPA.
[0165] This result indicates the possibility of somewhat improved
glucose uptake ability of the skeletal muscle cell in the patients
administered with EPA.
(4) Effects of the Copresence of Statin and EPA
[0166] In the statin+EPA group (Statin+EPA), the uptake of the
radioactivity is not much different from that of the control group
(Cont.) within 6 hr of incubation while the radioactivity uptake
considerably decreased at 24 hr and 48 hr of incubation and the
rate of decrease at 48 hr of incubation was about 36%. This
decrease, however, was smaller compared to the statin group
(Statin), and the suppression rate in the presence of the EPA was
about 50% of the decrease by the statin. In summary, decrease of
the glucose uptake ability by the skeletal muscle cell is
suppressed in the presence of the EPA.
[0167] It can be elucidated from the results that administration of
the EPA to a patient administered with the statin leads to the
suppression of the decrease of the glucose uptake ability of the
skeletal muscle cell due to the statin, and this in turn suppresses
the risk of blood glucose increase. In other words, the results
indicate the possibility that the EPA suppresses the increase of
the blood glucose due to the statin administration.
* * * * *