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El CIC Centro de Investigación Cardiometabólica de Aguascalientes SA de CV

“Investigamos para prevenir y curar”


Estatinas Efectos cardiometab贸licos


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 interĂŠs: Ninguno


Preåmbulo Dimensionando el peso especifico de cada factor de riesgo cardiovascular‌


Estatinas y Diabetes Mellitus N

R.R. NNH NNT

91,140 +9 %

255

5.4

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)

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


Estatinas y Diabetes Mellitus Intervención ↓ 40 mg LDL ↓ 4 mmHg TAS ↓ 1% A1c

NNT 5 años 08 13 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


Estatinas y Diabetes Mellitus

Beneficio Riesgo

= 51

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


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


Aterog茅nesis Endotelitis Lesi贸n endotelio 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


↓ 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


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-3methylglutaryl 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


Ce

Hepatocito

B100

Clathrin-coated pits with LDL.Receptor


LDL Ce B100

Endosome

Ce B100

Hepatocito


Hepatocito

Endosome Recycling Proteolysis PCSK9

Ce B100


Hepatocito

Endosome

Ce Lysosome Ce B100

B100


Hepatocito

Lysosome Ce B100

Resterification ACAT1

Ce

Lysis AA

Desterification

C


Hepatocito

NP2 C NP1 Hydrophobic transport


Hepatocito

RES-AG

Col

NP2 C NP1


Hepatocito

Gen LDL.Receptor

SCAP-SREBP RES-AG

Col


Estatinas, inductores de LDLR

Ce B100

Gen LDL.Receptor SREBP

HMGCoA RES-AG

E

HMG-CoA-R

↓Colesterol

Mevalonato

Col


Potencia de inhibición de la HMGCoA-R Ácido Di-Hidroxi-Heptanóico. HMGCoA-R “like” K-Michaelis de HMGCoA = 4mM Número Uniones HMGCoA-R

IC50 HMGCoA-R

Rosuvastatina* Pitavastatina**

09 --

5.4nM 6.8nM

Atorvastatina*** Simvastatina Pravastatina Lovastatina Fluvastatina

08 06 06 06 NA

8.2nM 11nM 44nM 27nM 28nM

Estatina

* 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 10 = 20 = 4 mg 20 = 40 = ? mg

-38.8% -44.1% -49.5%

-35.5% -41.4% -46.2%

-38.5% -45.0% ?

40 = 80 = ? mg

-54.7%

-50.2%

?


↓ 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


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; 29:10091016.


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

C茅lula endotelial y Estatinas

Lox

G

Isoprenilaci贸n

K NFkB

Selectinas ICAM VCAM PCAM Genes: PCR MCP1 MCSF


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

Estatinas, efecto antinflamatorio

Lox

G

Isoprenilaciテウn

K NFkB

HMGCoA

E

HMG-CoA-R

Selectinas ICAM VCAM PCAM Genes: PCR MCP1 MCSF

竊的soprenoides

Mevalonato


Efecto reductor de colesterol LDL/PCR 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

* 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 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


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. RodĂŠs-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 lip铆dico+ Pool inflamatorio Media-Adventicia: Remodelaci贸n positiva Espacio subendotelial: Macr贸fagos multiplicados Membrana basal CE activadas: Selectinas Inmunoglobulinas MCP-1 C茅lulas endoteliales Membrana basal

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


Nissen S et al. JAMA 2006;295: express-preliminary communication


REVERSAL. Regresi贸n en 18 meses


Volumen Total de Ateroma Efecto de la reducci贸n de LDL en DM

Cambio en mm3

+2.5 0.0 -2.5 -5.0 -7.5 -10.0

LDL < 80mg/dl LDL > 80mg/dl


REVERSAL. Regresión en 18 meses Progresión, estabilización o regresión

↓PCR <50%

↑1.4%

↑7.4%

↓PCR >50%

↓2.4%

↑4.0%

↓LDL >50% ↓LDL <50%


ERASE. Regresiรณn en 8 semanas Progresiรณn 05%

PCR LDL

0% Regresiรณn -05% Regresiรณn -10% Regresiรณn -15%

PCR-LDL basal


TWINS. Cambio cuali-cuantitativo

2

3

4

5

6

250um

1


TWINS. Cambio cuali-cuantitativo


TWINS. Cambio cuali-cuantitativo MIRACL PROVE-IT


Estabilizaci贸n

Semana 28 Atorvastatina 10-20mg

Regresi贸n

TWINS. Cambio cuali-cuantitativo

Basal

Semana 80 Atorvastatina 10-20mg


TWINS. Cambio cuali-cuantitativo

Î&#x201D; Volumen de placa


↓ 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


â&#x2020;&#x201C; Eventos


Reducci贸n de eventos cardiovasculares

Estudios en Prevenci贸n Primaria 0% 1

25%

3 2

54 8

35% 50% 0mg/dl

6

7

9

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

10

50mg/dl

80mg/dl

Reducci贸n de colesterol LDL Lancet. 2005;366:1267-78 NEJM 2008; 359:2195-2207


Riesgo de Eventos Cardio Vasculares Cl鱈nicos

2.0 1.5 1.0 0.5 00

Intermedio-alto

0.77/100-a単o 1.36/100-a単o LDL <130+PCR >2 LDL <70

44

0.38/100-a単o LDL <70+PCR <2

Intermedio-bajo

72

Bajo


% de individuos con eventos cardiovasculares

90,056 individuos/14 ensayos:

30% 8 6

10% 1

0% 60mg/dl

32

4

5

7

100mg/dl

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

200mg/dl

Nivel de colesterol LDL alcanzado

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


Concluyendo


Estatinas Efectos biocelulares


↓ Aterogénesis ↓ Endotelitis ↓ Lesión endotelio 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


â&#x2020;&#x2018; CitoprotecciĂłn . RISK path . AMP Kinase 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


↓ Eventos Uso crónico: Prevención Uso agudo: SICAs Uso hiperagudo: ICP

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


Slides disponibles: www.cicags.com.mx


Uso de Estatinas y sus efectos cardiometabolicos