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XIX

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-

17/04/2013

Athero.ru



XIX



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PCSK9
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Global Burden of Disease Study



http://www.thelancet.com/themed/global-burden-of-disease

Global and regional mortality from 235 causes of death for 20 age
groups in 1990 and 2010: a systematic analysis for the Global Burden
of Disease Study 2010
235 20 1990 2010
Global mortality, disability, and the contribution of risk factors: Global
Burden of Disease Study
, ,
Selected major risk factors and global and regional burden of disease

Lancet Vol 380 December 15/22/29, 2012

1990 - 25 - 2010

, -



()

[] ,
2001-2011

10/2001-08/2011
(,
.)

n (% ) 300 (0.8%) 105 (0.2%)


,

, %

3832 (61.9%)

22.1

22.1

25.9

35

1.5

27

4.7

15

2.3

77

8.5

Webber BJ et al. JAMA 2012; 308: 2577-2583

/
-
( 2001-2011 )
N -

/
(%, 95%)

(%, 95%)

389/3506

11.1 (10.1-12.1)

1 [Reference]

1 [Reference]

37/166

22.3 (15.9-28.7)

2.01 (1.49-2.71)

1.47 (1.10-1.96)

18/128

14.1 (8.0-20.2)

1.27 (0.82-1.96)

1.12 (0.73-1.74)

17/39

43.6 (27.3-59.9)

3.93 (2.72-5.68)

1.88 (1.34-2.65)

14/28

50.0 (30.3-69.7)

4.51 (3.08-6.60)

2.09 (1.43-3.06)

2/10

20.0 (0.0-50.2)

1.80 (0.52-6.25)

0.58 (0.17-1.97)

4/8

50.0 (5.3-94.7)

4.51 (2.24-9.07)

3.14 (1.54-6.44)

Webber BJ et al. JAMA 2012; 308: 2577-2583



XIX



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The National Institutes of HealthAARP Diet and Health Study

, , ,
, , .

. 388229 50 -71
( )
(1995-1996).

.
12 ( )
7904 3874 - ,
.
51% 70% .
Xiao Q, et al. JAMA Intern Med 2013, published online Feb 4.

,
,
(12 )

/

(95% )

(95% )

Xiao Q, et al. JAMA Intern Med 2013, published online Feb 4.



The National Institutes of HealthAARP Diet and Health Study




( 1000 vs 0 /, 1.20; 95% , 1.05-1.36),
(, 1.19; 95% I, 1.03-1.37)

Xiao Q, et al. JAMA Intern Med 2013, published online Feb 4.


:

, 1987-90 .
61 433 ( 1914 1948),
19 .
() () 1997 (n=38 984).
+ .
(n=11 944),
(n=3862),
(n=1932), (n=1100).
Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average
associated with all cause or cause specific mortality but among calcium tablet users
witha dietary calcium intake above 1400 mg/day the hazard ratio for all cause
mortality was 2.57 (95% confidence interval 1.19 to 5.55).
Michalsson K et al BMJ 2013;346 (Published 13 Feb 2013)


:

600 - 1000 /,
1400 /
( 1.40, 95% 1.17 - 1.67),
(1 49, 1.09 -2.02),
(2.14, 1.48 to 3.09).
(6%, 500 )

.


1400 /
2.57 (95% 1.19 - 5.55).
Michalsson K et al BMJ 2013;346 (Published 13 Feb 2013)

?
- Cleland ,

,
,
, , , ,
.
?
,

Dr J Cleland recommended that people stop taking calcium supplements
"until efficacy/safety is shown," and this advice "should definitely include those taking them
for osteoporosis and should perhaps include those taking them for CKD."
His recommendation? "Having a healthy, balanced diet and avoiding water filters
that reduce calcium in drinking water is probably best."

http://www.theheart.org/article/1509041.do

25- D ,
.
Population-Based Study and Meta-Analyses of 18 and 17 Studies
25- D 10170
(Copenhagen City Heart Study),
, D.
29 3100 ,
1625 , 6747
17 18 :

D
39% (25%54%) 46% (31%64%)

Brndum-Jacobsen P et al Arterioscler Thromb Vasc Biol 2012;32:XX-XX

, 25- D

Multi-variable adjustment for sex, physical activity, smoking, diabetes as categorical and for age, BMI, pack-years smoked,
alcohol consumption, plasma total CH, HDL CH, systolic BP, and glomerular filtration rate as continuous variables
Brndum-Jacobsen P et al Arterioscler Thromb Vasc Biol 2012;32:XX-XX

25- D ,
.
Population-Based Study and Meta-Analyses of 18 and 17 Studies
25- D
1-4- 50-100-
40% (95% CI, 14%72%),
64% (25%114%), - 57% (38%78%),
/ - 81% (40%135%).

17 18
(77 155 15 447 ):

D
39% (25%54%) 46% (31%64%)
Brndum-Jacobsen P et al Arterioscler Thromb Vasc Biol 2012;32:XX-XX

D
B.G.Nordestgaard D
, ".
D
- Vitamin D and Omega-3 Trial (VITAL, n= 20 000),
2016 2017,
- - Vitamin D and Longevity (VIDAL).

B.G.Nordestgaard:
D
.
There's been a lot of focus on trying to avoid people getting too much sun, but maybe this has not been balanced.

-
, .
Nainggolan L. http://www.theheart.org/article/1451199.do



XIX



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,
PCSK9
?

PCSK9
/ 9
proprotein convertase subtilisin/kexin type 9
,

, :
;

.

!
Fazio S.

http://theheart.medscape.org/

athero.ru

PCSK9
PCSK9 (proprotein convertase subtilisin-like/kexin type 9
/ 9 )
,
.
PCSK9 is a secreted protease that mediates degradation of the LDL receptor.

Horton JD, Cohen JC , Hobbs H H. PCSK9: a convertase that coordinates LDL catabolism.
J Lipid Res 2009; 50: S172

PCSK9
PCSK9
, .
PCSK9 is secreted into the plasma by the liver and binds to an epidermal growth factor (EGF)like repeat within
the extracellular don of the LDL receptor. After internalization, the binding of PCSK9 to the LDL receptor strengthens,
preventing LDL receptors from recycling to the cell surface and leading to their destruction inside cells. Overexpression
of PCSK9 in transgenic mice or infusions of recombinant PCSK9 into mice lowers LDL receptor levels on the surface
of hepatocytes, leading to hypercholesterolemia.

Young SG, Fong LG. Lowering Plasma Cholesterol by Raising LDL Receptors - Revisited. NEJM 2012; 366;12

( - LDLR),
PCSK9 (PCSK9-mediated degradation of the LDLR).
Horton JD et al.
J. Lipid Res 2009;
50: S172

PCSK9

PCSK9

PCSK9 (ER).
() ().
. PCSK9
-. /PCSK9
() ( ). PCSK9 .

J.C.Cohen .

Sequence Variations in PCSK9,


Low LDL, and Protection Coronary Heart Disease

PCSK9,
.

, PCSK9
.
,
PCSK9 ,

Observations in genetically modified mice suggest that inhibition of PCSK9 activity would enhance
the LDL-lowering effects of statins. These findings, together with the results of the current
study, make PCSK9 an attractive new target for LDL-lowering therapy.

Cohen JC et al. N Engl J Med 2006; 354:1264-72.

, PCSK9

(
)

;


PCSK9

http://theheart.medscape.org
athero.ru



, %

LAPLACE-TIMI 57:

2 (n=78)
AMG145 105 /2 (n=79)

10

12

AMG145 70 /2 (n=79)
AMG145 140 /2 (n=78)



, %

2
4
6
8
10
12

AMG145 280 /4 (n=79)


4 (n=77)
AMG145 350 /4 (n=79)
AMG145 420 /4 (n=80)
Giugliano RP et al for the LAPLACE-TIMI 57 Investigators. Lancet 2012. Published Online Nov 6, www.thelancet.com

(%)

Giugliano RP et al. Lancet 2012. Published Online Nov 6, www.thelancet.com

LAPLACE:

<1.8 /
2


<2.6 /
(n=78)

<0.8

AMG145 70 (n=78)

AMG145 105 (n=78)

AMG145 280 (n=78)


AMG145 420 (n=78)athero.ru

AMG145 350 (n=79)

AMG145 140 (n=77)

(n=77)

PCSK9
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LAPLACE ,
MENDEL ,
GAUSS ,
PCSK9 ,
RUTHERFORD
, PCSK9, ..
2012 27/04/2012

ODISSEY Outcomes - c-
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2012

18000 >40 , 4-6 , >70 /


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2018

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athero.ru

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CETP
,
CETP , .
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CETP
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CETP [ ,
] , .
,
CETP
.

.
Barter PJ, Rye K-A. Cholesteryl ester transfer protein (CETP) inhibition as a strategy
to reduce cardiovascular risk. J. Lipid Res. jlr.R024075. First Published on May 1, 2012,

dal-OUTCOMES:
() () ()

(/)

(/)

Schwartz GG et al. for the dal-OUTCOMES Investigators. NEJM 2012, published Nov 5, 2012, NEJM.org.
Schwartz GG et al. for the dal-OUTCOMES Investigators. NEJM 2012, published Nov 5, 2012, NEJM.org.

dal-OUTCOMES:
, ,


(%)

Schwartz GG et al. for the dal-OUTCOMES Investigators. NEJM 2012, published Nov 5, 2012, NEJM.org.

dal-OUTCOMES:


(%)


(%)

(/),

(/) , 1- ,
Schwartz GG et al. for the dal-OUTCOMES Investigators. NEJM 2012, published Nov 5, 2012, NEJM.org.


( )

dal-OUTCOMES: -

+ 0.6 ,
<0.001

-
(/, )

+ 0.2 /,
<0.001

3
Schwartz GG. Sci Sessions 2012

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:

( ) ,
(, )
,

- REVEAL

30000
2011
2017

- ACCELERATE

11000
2012
2015

AIM-HIGH
The HPS2-THRIVE trial. AIM-HIGH,
, ..
(/ vs
, n=25000).
HPS2-THRIVE 2013 .
The HPS2-THRIVE trial. Despite AIM-HIGH, the verdict is not yet in for niacin because there is still a much larger niacin RCT in progress.
HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) (niacin/laropiprant vs. placebo on a background
of simvastatin ezetimibe, N = 25,000), is anticipated to be completed in 2013.

HPS2-THRIVE 2012
HPS2-THRIVE ,

, ,

( ).
"The preliminary HPS2-THRIVE results show that, when added to an effective statin-based treatment, the combination
of extended release niacin and laropiprant does not produce clinically meaningful reductions in the rate of major vascular events
(such as heart attacks and strokes."

Merck: HPS 2- THRIVE TREDAPTIVE


( /)

HPS2-THRIVE .

25673 (14741 10932 )


- .
3.9 ().
.
/
,
[], .



.
http://www.mercknewsroom.com/press-release/. December 20, 2012 8:30 am EST

(?)
EMA
/ ( 20130
PRAC , - Tredaptive, Pelzont and
Trevaclyn ( /) :
2013 EMA
(PRAC) ,
Tredaptive, Pelzont Trevaclyn, ,
,
, []
.
PRAC considers that benefit-risk balance of Tredaptive, Pelzont and Trevaclyn (nicotinic acid/laropiprant) is negative
Recommendation by PRAC to be considered by CHMP for final opinion.
During its January 2013 meeting, the EMAs Pharmacovigilance Risk Assessment Committee (PRAC) concluded that the
risks are greater than the benefits for Tredaptive, Pelzont and Trevaclyn, identical medicines used to treat adults with
dyslipidaemia , and it recommended that these medicines should be suspended.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/
Tredaptive,_Pelzont_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0b01ac05805c516f

!

( )
Merck Provides Update on Next Steps for TREDAPTIVE
(extended-release niacin/laropiprant)

TREDAPTIVE.

, TREDAPTIVE,
TREDAPTIVE
.
Merck is recommending that physicians stop prescribing TREDAPTIVE. Merck is also recommending that physicians
review treatment plans for patients taking TREDAPTIVE in a timely manner to discontinue TREDAPTIVE
and consider other changes in therapy to achieve their dyslipidemia management goals.

Friday, January 11, 2013 7:39 am EST

http://www.mercknewsroom.com/press-release/research-and-development-news/
merck-provides-update-next-steps-tredaptive-extended-rel

:

(Plasma HDL cholesterol and risk of myocardial infarction:
a mendelian randomisation study)

( )

(
- )
,


( )

Thomas DC , V Conti DV. Commentary: The concept of Mendelian Randomization.


Int J Epidemiol 2004;33:21

:

(Plasma HDL cholesterol and risk of myocardial infarction:
a mendelian randomisation study)

19139 ()
50812 30 .
50763 6 ,
4228 .
25 (SNPs)
( 30 ).
25 ,
( genetic score)
p<510.

Voight BF et al. Lancet 2012; 380: 572-580

:


1. (SNIP),
(,
- LIPG Asn396Ser, rs61755018).

2. (a genetic score), 14
(SNPs), .


Ser
LIPG Asn396Ser
(SNP) (LIPG Asn396Ser)

(/)

Ser
Ser

FHS=Framingham Heart Study. CCHS=Copenhagen City Heart Study.


MDC=Malmo Diet and Cancer Study. ARIC=Atherosclerosis Risk in Communities Study.
(SNP)
(single nucleotide polymorphism)
Voight BF et al. Lancet 2012; 380: 572-580

LIPG Asn396Ser .
116320 20 . -


-
Voight BF et al. Lancet 2012; 380: 572-580

(95% )

LIPG Asn396Ser .
116320 20 .

Voight BF et al. Lancet 2012; 380: 572-580

(95% )

:

(a mendelian randomisation study)
,
, .
,

.
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk
of myocardial infarction. These data challenge the concept that raising of plasma
HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

Voight B.F, Kathiresan S


Lancet 11 August 2012 , 380: 572.



XIX


()
,
PCSK9

33

,
sterol regulatory element-binding protein (SREBP),
, ,
, .
, SREBP , miR-33a
( SREBF2) miR-33b ( SREBF1).

miR-33a SREBF2.
miR-33a/b
1 (ATP-binding cassette transporter A1 - ABCA1) ,
,
(, ) .
ABCA1
1 .

miR33 - q
- .

miR-33
(miRs)
18-20 ,
.
MicroRNAs (miRs) are recently emerging endogenous, noncoding, single-stranded RNAs of 1822 nucleotides that
constitute a novel class of gene regulators.

Chen L-J et al. Roles of microRNAs in atherosclerosis and restenosis.


Journal of Biomedical Science 2012, 19:79

, miR-33
(
, , ,
), ,
, ,
,
Several lines of evidence indicate that miR-33 is involved in atherosclerotic initiation and progression including lipid
metabolism (HDL biogenesis and cholesterol homeostasis, fatty acid, phospholipid and triglyceride, and bile acid
metabolism), inflam-matory response, insulin signaling and glucose/energy homeo-stasis, cell cycle progression and
proliferation, and myeloid cell differentiation.

Chen W-J et al. Atherosclerosis 227 (2013) 201e208

-33
miR-33
,
, , .

Chen W-J et al. Atherosclerosis 227 (2013) 201-208


()

mir-33

-miR33 miR-33
Ldlr/

Rayner KJ et al, J Clin Invest 2011;121(7):2921

(2)

Anti-miR33
Ldlr/

Rayner KJ et al, J Clin Invest 2011;121(7):2921

Rayner KJ et al,
JCI 2011;
121(7):2921

miR-33

Ldlr/

(2)

(%)

miR-33 -/-

Horie T et al. J Am Heart Assoc 2012;1, published Nov 8, 2012

-1 (/)

(/)

miR-33 -/- .

Horie T et al. J Am Heart Assoc 2012;1, published Nov 8, 2012

(%)

(%)

miR-33 (efflux)
-/-

Horie T et al. J Am Heart Assoc 2012;1, published Nov 8, 2012

(12 ) -miR-33 Ldlr/

Male, 10-week-old Ldlr / mice were injected intraperitoneally with 200 L saline
(n=5), or 7 mg/kg control (5-TCCTAGAAAGAGTAGA; n=13) or anti-miR-33 (5GCAACTACAATGCA; n=11) locked nucleic acid oligonucleotides (Miragen Therapeutics, Inc)
once a week. After 2 weeks on chow, mice were switched to a western diet (WD) containing
21% fat and 1.25% cholesterol for 12 weeks.

Marquart TJ et al. Arterioscler Thromb Vasc Biol. 2013;33:455-

(%)


(lesions) (m2105)

(12 ) -miR-33

Ldlr/

Marquart TJ et al. Arterioscler Thromb Vasc Biol. 2013;33:455-

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