Uso de Estatinas y sus efectos cardiometabolicos

El CIC Centro de Investigación Cardiometabólica de Aguascalientes SA de CV

“Investigamos para prevenir y curar”

Estatinas Efectos cardiometabólicos

Dr. Enrique Morales Villegas Investigador, consultor y/o conferencista

. Abbott

. Astra Zeneca

Boehringer Ingelheim

. Daiichi-Sankyo

. Janssen-Cilag

. Lilly

. Merck Sharp and Dohme

. Novartis

. Pfizer

. Roche

. Servier

. Takeda

Conflicto de interés: Ninguno

Preámbulo Dimensionando el peso especifico de cada

factor de riesgo cardiovascular…

Sattar N et al. Lancet 2010; available at: http://www.lancet.com.

174 Nuevos Casos de DM en el grupo tratado con estatinas por 4 años.

NNH: Número Necesario de Tratar para producir 1 nuevo caso de DM

NNT: Número Necesario de Tratar para evitar 1 caso de ECV (Fatal y No Fatal)

N R.R. NNH NNT

91,140 +9 % 255 5.4

Estatinas y Diabetes Mellitus

Intervención NNT 5 años

↓ 40 mg LDL 08

↓ 4 mmHg TAS 13

↓ 1% A1c 69


NNT: Número Necesario de Tratar para evitar 1 caso de ECV (Fatal y no Fatal)

Ray KK. Lancet 2009;373:1765

CTT Collaborators. Lancet 2008;371:117

Turnbull. Arch Intern Med 2005;165:1410

Sattar N et al. Lancet 2010; available at: http://www.lancet.com.

Beneficio

Riesgo


= 51

Agenda

Estatinas . Efectos biocelulares

↓ Placa

↓ Inflamación

↓ LDL - LDLox

Morales E. Atlas de Estatinas, Aterotrombosis y Pleiotropismo. Ed 2008

Morales E, Di Sciascio G, Briguori C. Endotelio, Aterotrombosis y Estatinas. Ed. 2010-11

Morales E, Di Sciascio G, Briguori C. Statins. Hyperacute uses. Int. J. Hypertension. March 2011

Aterogénesis

Endotelitis

Lesión endotelio




↓ Placa

↓ Inflamación

↓ LDL - LDLox




Bibliografia.

Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992;33:1569-1582.

Brown MS, Goldstein JL. A tribute to Akira Endo, discoverer of a “Penicillin” for the cholesterol. Atherosclerosis Supp. (5)

2004:13-16.

Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Nobel Lecture 9 december 1985.

Downloaded www.nobelprices.com.

Golstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425-430.

Goldstein JL, Brown MS. The LDL receptor. History of discovery. Arterioscler Thromb Vasc Biol 2009;29:431-438.

Goldstein JL, Brown MS. Hidrophobic Handoff mechanism. Nobel Laureate Lecture. American Heart Association Meeting.

Chicago Ill. Novembre 15 2010.

Cariou B, Ouguerram K, Zair Y, Guerois R, Langhi C, Kourimate S et al. PCSK9 dominant negative mutant results in increased

LDL catabolic rate and familial hypobetalipoproteinemia. Ateroscler Thromb Vasc Biol 2009;29:2191-2197.

Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein B production during treatment of

cholesteryl ester storage disease with lovastatin: implications for regulation of apolipoprotein B synthesis. J Clin Invest

1987;80:1692-1697.

Arad Y, Ramakrishnan R, Ginsberg HN. Lovastatin therapy reduces low-density lipoprotein apoB levels in subjects with combined

hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiologiy of apoB

production. J Lipid Res 1990;31:567-582.

Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160-1164.

McTaggart F, Buckett L, Davidson R et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-

methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87 (suppl):28B-32B.

Holdgate GA, Ward WH, McTaggart F. Molecular mechanisms for inhibition of 3-hydroxy-3methylglutaryl CoA (HMG-CoA)

reductase by rosuvastatin. Biochem Soc Trans 2003;31:528-531.

Jones PH, Davidson MH, Stein EA et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin

and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152-160.

McKenney JM, Jones PH, Adamczyk MA et al. Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin and

pravastatin in achieving lipid goals. Results from the STELLAR Trial. Curr Med Res Opin 2003;19:689-698.

Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of comparative efficacy of increasing dose of atorvastatin

versus rosuvastatina versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol 2010;105:69-67.

Dr. Akira Endo

AHA. 16 noviembre 2009

Michael Brown

1985-2010

AHA. Chicago

Joseph Goldstein

1985-2010

AHA Chicago

B100

Ce

Clathrin-coated pits with LDL.Receptor

Hepatocito

B100

Ce

Endosome

LDL

B100

Ce Hepatocito

B100

Ce

Endosome

Recycling

Proteolysis PCSK9

Hepatocito

B100

Ce

Endosome

B100

Ce

Lysosome

Hepatocito

B100

Ce

Lysosome

AA

C

Lysis

Desterification

Resterification

ACAT1

Ce

Hepatocito

NP2 NP1 C

Hydrophobic transport

Hepatocito

NP2 NP1 C

Col

RES-AG

Hepatocito

Col

RES-AG

SCAP-SREBP

Hepatocito

Gen LDL.Receptor

Col

RES-AG

SREBP

↓Colesterol HMG-CoA-R E

HMGCoA

Mevalonato

B100

Ce Estatinas, inductores de LDLR

Gen LDL.Receptor

Potencia de inhibición de la HMGCoA-R

Ácido Di-Hidroxi-Heptanóico. HMGCoA-R “like”

K-Michaelis de HMGCoA = 4mM

Estatina Número Uniones

HMGCoA-R

IC50

HMGCoA-R

Rosuvastatina* 09 5.4nM

Pitavastatina** -- 6.8nM

Atorvastatina*** 08 8.2nM

Simvastatina 06 11nM

Pravastatina 06 44nM

Lovastatina 06 27nM

Fluvastatina NA 28nM

* Hidrofílica (I octanol/agua <1). Trasportada por Organic-Anion-Transporter-Polypeptide-C (OATP-C). Gpo metilsulfonamida.

** Lipofílica no metabolizada por CYP, metabolizada por glucuronización con utilización de OATP-2.

*** Lipofílica (I octanol/agua >1). Difusion directa + utilización de OATP-C similar a Rosuvastatina

Efecto reductor de colesterol LDL Dosis equipotentes entre Rosuvastatina, Atorvastatina y Pitavastatina

Dosis equipotentes Rosuvastatina Atorvastatina Pitavastatina

05 = 10 = 2 mg -38.8% -35.5% -38.5%

10 = 20 = 4 mg -44.1% -41.4% -45.0%

20 = 40 = ? mg -49.5% -46.2% ?

40 = 80 = ? mg -54.7% -50.2% ?

↓ Placa

↓ Inflamación

↓ LDL - LDLox




Bibliografia:

Casey PJ. Protein lipidation in cell signaling. Science 1995; 268:221-225.

Zhang FL, Casey PJ. Protein prenylation: molecular mechanism and functional consequences. Annu Rev Biochem 1996;

65:241-249.

Liao JK. Isoprenoids as mediators of the biological effects of statins. J Clin Invest 2002; 110:285-288.

Dichtl W, Dulak J, Frick H, Schwarzacher SP, Ares MPS, Nilsson J, Pachinger O, Weidinger F. HMG-CoA reductase

inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells. Arterioscler

Thromb Vasc Biol 2003; 23:58-66.

McFarlane SI, Muniyappa R, Francisco R, Sowers JR. Pleiotropic effects of statins: Lipid reduction and beyond. J Clin

Endocrinol Metab 2002; 87:1451-1458.

Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45:89-118.

Banerjee S, Mir S, Lin Z, Hamik A, Atkins GB, Das H, Banerjee P, Kumar A, Jain MK. Kruppel-Like Factor 2 as a novel

mediator of statin effects in endothelial cell. Circulation 2005; 112:720-726.

Kircher MF, Grimm J, Swirski FK, Libby P, Gerszten RE, Allport JR et al. Noninvasive in vivo imaging of monocyte

trafficking to atherosclerotic lesions. Circulation 2008; 117:388-395.

Rudd JHF, Hyafil F, Fayad ZA. Inflammation imaging in atherosclerosis. Arterioscler Thromb Vasc Biol 2009; 29:1009-

1016.

G

Lox

LDL

NFkB

K

Genes:

Selectinas

ICAM

VCAM

PCAM

PCR

MCP1

MCSF

Célula endotelial y Estatinas

Isoprenilación

* Morales-Villegas Enrique, Di Sciascio G, Briguori Carlo. Atlas de Endotelio, Aterotrombosis y Estatinas 2011

G

Lox

LDL

NFkB

K

Genes:

Selectinas

ICAM

VCAM

PCAM

PCR

MCP1

MCSF

Estatinas, efecto antinflamatorio

↓Isoprenoides HMG-CoA-R E

HMGCoA

Mevalonato

Isoprenilación

* Morales-Villegas Enrique, Di Sciascio G, Briguori Carlo. Atlas de Endotelio, Aterotrombosis y Estatinas 2011

LDL/PCR Estatina dosis baja Estatina dosis alta

↓ c-LDL % 34.8 (32-37.5) 51.3 (48.1-54.5)**

↓ PCR as % 20.8 (8.3-31.6) 54.9 (48.5-60.6)*

*p < 0.001

**p < 0.001

Efecto reductor de colesterol LDL/PCR

* Bonet J, McPherson R, Tedgui. Clin Ther 2008;30:2298-2313.

PET (18-FDG)/CT pre y post estatina

18-FDG positivo

basal

18-FDG negativo

24 hr post-estatina

↓ Placa

↓ Inflamación

↓ LDL - LDLox




Bibliografia:

Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA et al. REVERSAL Investigators. Effect of

intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. A randomized

controlled trial. JAMA 2004; 291:1071-1080.

Nissen SE, Tuscu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J et al. REVERSAL Investigators. Statin therapy, LDL

cholesterol, C-Reactive Protein and coronary artery disease. N Engl J Med 2005; 352:29-38.

Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM et al. ASTEROID Investigators. Effect of very

high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. J Am Med Assoc 2006;

295:1556-1565.

Rodés-Cabau J, Tardif JC, Cossette M, Bertrand OF, Ibrahim R, Larose E et al. Acute effects of statin therapy on

coronary atherosclerosis following acute coronary syndromes. Am J Cardiol 2009; 104:750-757.

. Nicholls S et al. J Am Coll Cardio 2008;52:255-62.

. Hyrayama A, Saito S, Ueda Y, Takayama T, Honye J, Komatsu S et al. Qualitative and quantitative changes in coronary

plaque associated with atorvastatin therapy. Circ J 2009;73:718-725

. Hirayama A, Saito S, Ueda Y, Takayama T, Honye J, Komatsu S et al. Plaque-stabilizinf effect of atorvastatin is stronger

for plaques evalated as more unstable by angioscopy and intravenous ultrasound. Advance publication by J-Stage 20 may

2011.

Pool lipídico+ Pool inflamatorio

Células endoteliales

Membrana basal

Membrana basal

Media-Adventicia:

Remodelación positiva

CE activadas:

Selectinas

Inmunoglobulinas

MCP-1

Espacio subendotelial:

Macrófagos multiplicados

Morales-Villegas Enrique, Di Sciascio G, Briguori Carlo. Atlas de Endotelio, Aterotrombosis y Estatinas 2011

Nis

sen

S e

t al

. JA

MA

2006;2

95: ex

pre

ss-p

relim

inar

y co

mm

un

icat

ion

http://circ.ahajournals.org/content/vol103/issue4/images/large/hc0415065004.jpeg

REVERSAL. Regresión en 18 meses

LDL < 80mg/dl

LDL > 80mg/dl

-10.0

Cam

bio

en

mm

3

-7.5

-5.0

-2.5

0.0

+2.5

Volumen Total de Ateroma Efecto de la reducción de LDL en DM

Progresión, estabilización o regresión

↓PCR <50% ↑1.4%

↑4.0%

↑7.4%

↓LDL >50%

↓2.4% ↓PCR >50%

↓LDL <50%

REVERSAL. Regresión en 18 meses

ERASE. Regresión en 8 semanas

PCR-LDL basal

0%

Regresión -05%

Regresión -10%

Regresión -15%

Progresión 05%

PCR

LDL

TWINS. Cambio cuali-cuantitativo

1 2

4

3

5 6

250u

m


MIRACL

PROVE-IT

TW

INS

. C

am

bio

cu

ali

-cu

an

tita

tivo

Basal

Semana 28 Atorvastatina 10-20mg

Semana 80 Atorvastatina 10-20mg

Est

ab

iliz

ació

n

Reg

resi

ón

TW

INS

. C

am

bio

cu

ali

-cu

an

tita

tivo

Δ Volumen de placa

↓ Placa

↓ Inflamación

↓ LDL - LDLox




↓ Eventos

Lancet. 2005;366:1267-78

NEJM 2008; 359:2195-2207

1

4 3

2 5

9

Red

ucc

ión

de

even

tos

card

iova

scula

res

Reducción de colesterol LDL

0mg/dl 80mg/dl

0%

50%

50mg/dl

25%

107,000 individuos/15 ensayos:

1.- ALLHAT: Pravastatina 40mg

2.- AFCAPS: Lovastatina 40mg

3.- LIPID: Pravastatina 40mg

4.- HPS: Simvastatina 40mg

5.- CARE: Pravastatina 40mg

6.- CARDS: Atorvastatina 10mg

7.- ASCOT: Atorvastatina 10mg

8.- WOSCOPS: Pravastatina 40mg

9.- 4S: Simvastatina 40mg

10.- JUPITER. Rosuvastatina 20mg 35%

10

Estudios en Prevención Primaria

6 7

8

1.0

0.5

00

1.36/100-año

LDL <130+PCR >2 1.5

2.0

0.77/100-año

LDL <70

Rie

sgo

de E

ven

tos

Card

io V

asc

ula

res

Clí

nic

os

0.38/100-año

LDL <70+PCR <2

Intermedio-bajo

Intermedio-alto

44

72 Bajo

8

6

7 5

4

1

Nivel de colesterol LDL alcanzado

60mg/dl 200mg/dl 100mg/dl

30%

0%

10%

% d

e in

div

iduo

s co

n e

ven

tos

card

iova

scula

res

90,056 individuos/14 ensayos: 1.- TNT 2a. Atorvastatina 80 mg

2.- TNT 2a. Atorvastatina 10mg

3.- CARE 2a. Pravastatina 40mg

4.- LIPID 2a. Pravastatina 40mg

5.- CARE 1a. Pravastatina 40mg

6.- 4S 2a. Simvastatina 40mg

7.- LIPID 1a. Pravastatina 40mg

8.- 4S 1a. Simvastatina 40mg

3 2

Baignet C, Keech A, Kearney PM. Lancet. 2005;366:1267-78

Concluyendo

Estatinas Efectos biocelulares

↓ Aterogénesis

↓ Endotelitis

↓ Lesión endotelio




↑ Citoprotección

. RISK path

. AMP Kinase




↓ Eventos Uso crónico: Prevención

Uso agudo: SICAs

Uso hiperagudo: ICP




Slides disponibles:

www.cicags.com.mx

http://www.cicags.com.mx/

Uso de Estatinas y sus efectos cardiometabolicos

Documents

Transcript of Uso de Estatinas y sus efectos cardiometabolicos