Dislipidemie: importanza, endpoint clinici e razionale terapeutico. Prof. Alberto Corsini Univerisità degli Studi di Milano

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1 Dislipidemie: importanza, endpoint clinici e razionale terapeutico Prof. Alberto Corsini Univerisità degli Studi di Milano

2 Outline of the presentation Stato dell arte della terapia ipolipemizzante: il ruolo delle statine Unmeet medical need: il mancato raggiungimento del target Terapia di combinazione: il ruolo di ezetimibe Terapia ipolipidemizzante dopo SCA

3 Cholesterol Treatment Trialists (CTT) Collaboration Lancet, November 9 th, 2010; 6736(10)

4 EFFECTS ON EACH TYPE OF MAJOR VASCULAR EVENT Lancet, 2010; 6736:

5 Patients at high CHD risk who benefit from statin therapy diabetes with CHD w/o CHD Stroke ACS PAD Hypertensive Normal/low cholesterol levels elderly gender Nephropatic MS Venous thromboembolism

6 Patients with CHD event (%) LDL and the Risk of Coronary Artery Disease in Lipid-Lowering Trials S-P 1 prevention statin 1 prevention placebo S-S LIPID-P HPS-P CARE-P CARE-S LIPID-S LIPS-P HPS-S AtoZ 20 WOSCOPS-P PROVE-IT A TNT 10 LIPS-S PROVE-IT P WOSCOPS-S ASCOT-P TNT 80 AtoZ 80 AFCAPS-S ASCOT-S AFCAPS-P LDL cholesterol achieved 2 prevention statin 2 prevention placebo mg/dl Adapted From Ballantyne CM. Am J Cardiol O Keefe JH et al, JACC 2004

7 LDL reduction (%) and CHD event rates in major trials with lipid lowering drugs Poli A and Corsini A EJIM 2010; 21:

8 Lipid guidelines in the US, Canada and Europe Year / /2012 Guideline High-Risk or Very High-Risk Patients NCEP ATP III Guidelines 1 Canadian CV Society 2 ESC/EAS Guidelines 3 LDL-C < 100 mg/dl (< 2.6 mmol/l) < 80 mg/dl (< 2 mmol/l) < 70 mg/dl (< 1.8 mmol/l) < 70 mg/dl (< 1.8mmol/L) reasonable for high risk patients or 50% decrease in LDL-C and/or 50% LDL-C reduction Grundy S. et al. Circulation 2004; 110: Genest J. et al. Can J Cardiol 2009;25: Eur Heart J 2011; 32: Canadian Journal of Cardiology 29 (2013) Perk J et al. Eur Heart J May 3

9 Perk J et al. Eur Heart J May 3

10 Perk J et al. Eur Heart J May 3

11 ESC / EAS Guidelines Recommendations for treatment targets for LDL-C Patients LDL-C goal Very high CV risk - established CVD < 1.8 mmol/l - diabetes with target organ damage (70 mg/dl) - type 2 diabetes > 40 y, with 1 other CVD risk factor and/or - severe CKD ( FG ml/min) 50% LDL-C - SCORE level 10% reduction High CV risk - markedly elevated single risk factors < 2.5 mmol/l - all other type 2 diabetes (100 mg/dl) - moderate CKD (FG ml/min) - SCORE level 5-10% Eur Heart J 2011: 32:

12 Management of Dyslipidemia 1 st line therapy : Statins 2 nd line therapy : Add-on or combination therapies Other classes of drugs : CAI (ezetimibe), BAS, fibrates, nicotinic acid, fish oils

13 Preliminary and

14 Nota 13: quali le novità Visione sempre LDL centrica Rientroduzione della carta del rischio per i pazienti ad alto rischio senza patologia conclamata Ruolo HDL e Trigliceridi con il ritorno dei fibrati E stato riconosciuto un ruolo all ezetimibe, sia in monoterapia (nei pazienti intolleranti alle statine) che in associazione, estemporanea e/o precostituita, ad altre statine per il conseguimento del target terapeutico E stato eliminato il concetto del trattamenti di terzo livello per ezetimibe Sono stati riconosciuti, i risultati conseguiti con simva/eze nello studio SHARP, indicando simvastatina+ezetimibe come farmaco di prima scelta nei pazienti con insufficienza renale cronica (GFR compreso tra 15 e 60 ed LDL > 130 mg/dl)

15 Ipercolesterolemia non corretta dalla sola dieta, seguita per almeno 3 mesi, e ipercolesterolemia poligenica CATEGORIE DI RISCHIO TARGET Trattamento di 1 livello Trattamento di 2 livello Ipolipemizzanti: Pazienti con Rischio Medio Risk SCORE 2-3% C-LDL <130 mg/dl Modifica dello stile di vita per almeno 6 mesi simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Fibrati bezafibrato fenofibrato gemfibrozil Pazienti con Rischio Moderato Risk SCORE 4-5% C-LDL <115 mg/dl simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Statine simvastatina pravastatina fluvastatina lovastatina atorvastatina rosuvastatina Altri PUFA-N3(***) Ezetimibe Pazienti con Rischio Alto Risk SCORE >5% e <10% Dislipidemie familiari Ipertensione severa Diabetici senza fattori rischio CV e senza danno d organo Pazienti con IRC moderata (FG ml/min) Pazienti con Rischio Molto Alto Risk SCORE >10% Malattia coronarica Stroke ischemico Arteropatie periferiche Pregresso IMA Bypass aorto-coronarico Diabetici con 1 o più fattori di rischio CV e/o markers di danno d organo Pazienti con IRC grave (FG ml/min) C-LDL <100 mg/dl C-LDL <70 mg/dl (riduzione di almeno il 50% del C-LDL) simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Preferenzialmente atorvastatina se necessaria riduzione LDL >50% atorvastatina pravastatina fluvastatina lovastatina simvastatina (**) Rosuvastatina nei pazienti in cui ci sia stata evidenza di EA severi nei primi 6 mesi di terapia con altre statine rosuvastatina Ezetimibe più statine (in associazione estemporanea o precostituita) (**) Ezetimibe più statine (in associazione estemporanea o precostituita) (**) Pazienti in trattamento con statine con HDL basse (<40 mg nei M e <50 mg nelle F) e/o TG elevati (>200mg/dl) Fibrati (prima scelta fenofibrato) (**) Nei pazienti che siano intolleranti alle statine, per il conseguimento del target terapeutico è rimborsato il trattamento con ezetimibe in monoterapia. Nei pazienti con sindromi coronariche acute o in quelli sottoposti ad interventi di rivascolarizzazione percutanea è indicata atorvastatina a dosaggio elevato ( 40 mg)

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18 SCORE chart: 10- year risk of fatal cardiovascular disease (CVD) European Heart Journal 2012;33:

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21 Ipercolesterolemia non corretta dalla sola dieta, seguita per almeno 3 mesi, e ipercolesterolemia poligenica CATEGORIE DI RISCHIO TARGET Trattamento di 1 livello Trattamento di 2 livello Ipolipemizzanti: Pazienti con Rischio Medio Risk SCORE 2-3% C-LDL <130 mg/dl Modifica dello stile di vita per almeno 6 mesi simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Fibrati bezafibrato fenofibrato gemfibrozil Pazienti con Rischio Moderato Risk SCORE 4-5% C-LDL <115 mg/dl simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Statine simvastatina pravastatina fluvastatina lovastatina atorvastatina rosuvastatina Altri PUFA-N3(***) Ezetimibe Pazienti con Rischio Alto Risk SCORE >5% e <10% Dislipidemie familiari Ipertensione severa Diabetici senza fattori rischio CV e senza danno d organo Pazienti con IRC moderata (FG ml/min) Pazienti con Rischio Molto Alto Risk SCORE >10% Malattia coronarica Stroke ischemico Arteropatie periferiche Pregresso IMA Bypass aorto-coronarico Diabetici con 1 o più fattori di rischio CV e/o markers di danno d organo Pazienti con IRC grave (FG ml/min) C-LDL <100 mg/dl C-LDL <70 mg/dl (riduzione di almeno il 50% del C-LDL) simvastatina pravastatina fluvastatina lovastatina atorvastatina (**) Preferenzialmente atorvastatina se necessaria riduzione LDL >50% atorvastatina pravastatina fluvastatina lovastatina simvastatina (**) Rosuvastatina nei pazienti in cui ci sia stata evidenza di EA severi nei primi 6 mesi di terapia con altre statine rosuvastatina Ezetimibe più statine (in associazione estemporanea o precostituita) (**) Ezetimibe più statine (in associazione estemporanea o precostituita) (**) Pazienti in trattamento con statine con HDL basse (<40 mg nei M e <50 mg nelle F) e/o TG elevati (>200mg/dl) Fibrati (prima scelta fenofibrato) (**) Nei pazienti che siano intolleranti alle statine, per il conseguimento del target terapeutico è rimborsato il trattamento con ezetimibe in monoterapia. Nei pazienti con sindromi coronariche acute o in quelli sottoposti ad interventi di rivascolarizzazione percutanea è indicata atorvastatina a dosaggio elevato ( 40 mg)

22 Effect of fibrates on clinical outcomes Jun M et al. Lancet 2010; 375:

23 Efficacy of fibrates for cardiovascular event reduction in persons with Atherogenic Dyslipidemia: A meta-analysis 5068 subjects with high triglycerides (TG>200 mg/dl, 2.2 mmol/l) and low HDL-C (HDL- C<40 mg/dl, 1.0 mmol/l), 9872 subjects with neither high triglycerides nor low HDL-C 6 trials: ACCORD, BIP, FIELD, HHS, LOCAT, VA-HIT Subjects with ATHEROGENIC DYSLIPIDEMIA Odds Ratio (95% CI) POPULATION Diabetes as entry criteria 0.74 ( ) -26% Diabetes not as entry criteria 0.61 ( ) -39% PREVENTION Primary (<50% patients with CVD) 0.68 ( ) -32% Secondary 0.72 ( ) -28% TREATMENT REGIMEN Gemfibrozil 0.55 ( ) -45% Bezafibrate 0.59 ( ) -41% Fenofibrate 0.72 ( ) -28% MONOTHERAPY vs COMBINATION Fibrate alone 0.70 ( ) -30% Fibrate + Statin 0.71 ( ) -29% END POINT USED FOR ANALYSIS CVD 0.74 ( ) -26% CHD 0.49 ( ) -51% Small, dense LDL TG HDL-C CV Event Reduction 25-35% Lee M. et al. Atherosclerosis (2011), doi: /, April 2011

24 La terapia dovrebbe essere intrapresa contemporaneamente alla modifica dello stile di vita nei pazienti a rischio molto alto con livelli di C-LDL >70 mg/dl e in quelli a rischio alto con livelli di LDL-C >100 mg/dl L uso dei farmaci ipolipemizzanti deve essere continuativo E sempre necessario assicurare l ottimizzazione del dosaggio della statina prima di prendere in considerazione la sua sostituzione o la sua associazione Per i pazienti con dislipidemia aterogenica (TG>200 mg/dl, HDL<34 mg/dl) e per quelli con ipertrigliceridemia i farmaci di seconda linea da somministrare in associazione alle statine sono i fibrati. Tra questi, il farmaco di prima scelta è il fenofibrato per la maggiore sicurezza di uso nei pazienti in terapia con statine; la combinazione di statine e gemfibrozil è invece associata ad un aumentato rischio di miopatia

26 Patients Not at LDL-C Goal, b % DYSIS ( ): Almost Half of Statin-Treated Patients Were Not at LDL-C Goal 1,a % 47% 45% 42% 20 0 All High-risk Diabetes CVD (n=21,797) (n=17,583) (n=4,524) (n=10,587) All patients were on statin therapy High-risk = patients with preexisting CVD, diabetes, and/or ESC score 5%. a Study population: 22,063 statin-treated outpatients enrolled from 2,954 sites across 11 European countries and Canada. All data were collected from clinical examination and medical charts from single outpatient visits between April 2008 and February b LDL-C 3 mmol/l in patients with ESC score <5% and LDL-C 2.5 mmol/l in patients with ESC score 5%, diabetes, and/or CVD. DYSIS = Dyslipidemia International Study; CVD = cardiovascular disease; ESC = European Society of Cardiology. 1. Gitt AK et al. Eur J Prevent Cardiol. 2011;19:

27 CUMULATIVE RATE OF PERSISTENCE WITH FIRST INTENTION OF STATIN TREATMENTS Perreault S et al, Eur J Clin Pharmacol 61: , 2005

28 Estimates of Time to Death for Statin Users According to Adherence Level Rasmussen JN et al. JAMA. 2007;297:

29 Factors affecting the response to statins Extrinsic factors (extraneous influences) Intrinsic factors (genetically-determined) poor compliance background diet dose and uptitration of drug concomitant drug therapy LDL-receptor gene mutations apo-b-100 gene mutations rate of cholesterol biosynthesis rate of cholesterol absorption CYP/transporter polymorphism apoe polymorphism

30 Elevated Transaminases (% of Patients) % Decrease in LDL-C Risk:Benefit Ratio of Statin Titration Atorvastatin Lovastatin Simvastatin 0 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 40 mg 80 mg mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 40 mg 80 mg Data from prescribing information for atorvastatin, lovastatin, simvastatin. This does not represent data from a comparative study.

31 Muscular symptoms were reported in 10% of statin treated patients and led to discontinuation in 30% of the symptomatic patients Nutrition, Metabolism & Cardiovascular Diseases 1-5, 2012 in press

32 PLOS ONE August 2012 Vol 7 Issue 8 e42866

33 Risk Factors for Myopathy/Myalgia Increasing dose Increasing concentration: Increasing age, female CYP450 interactions (pharmacokinetic) Clinical conditions: Poly-therapy Transplanted Diabetes Hypothyroidism History of muscular symptoms after LLT

34 CK levels in men treated with 40 mgidj1 lovastatin or placebo before treatment, after 4 wk of lovastatin or placebo, and daily for 4 d after downhill walking Parker BA ahd Thompson PD Exerc. Sport Sci. Rev., Vol. 40, No. 4, pp. 188Y194, 2012

35 Preiss D et al

36 Increases in blood sugar levels (hyperglycemia) have been reported with statin use. Patients being treated with statins may have a small increased risk of increased blood sugar levels and of being diagnosed with type 2 diabetes mellitus. Feb 28, 2012

37 Meta-analysis of New-Onset Diabetes and First Major CV Events in 5 Large Trials Comparing Intensive- to Moderate-Dose Statin Therapy NTT/yr 155 for CV events NNH/yr 498 for new-onset diabetes Preiss et al. JAMA 2011; 305:

38 Selected Drugs That May Increase Risk of Myopathy and Rhabdomyolysis When Used Concomitantly With Statins CYP3A4 inhibitors/substrates Cyclosporine, tacrolimus Amiodarone Macrolides Azole antifungals (itraconazole, ketoconazole,fluconazole) Calcium antagonists Grape fruit juice Nefazodone Protease inhibitors Sildenafil Warfarin, acenocoumarol Others Digoxin Fibrates (gemfibrozil) Niacin Adapted from Corsini A, et al. Pharmacol Ther 1999; 84: Bellosta S, Paoletti R, Corsini A. Circulation 2004

39 Factors affecting the response to statins Extrinsic factors (extraneous influences) Intrinsic factors (genetically-determined) poor compliance background diet dose and uptitration of drug concomitant drug therapy LDL-receptor gene mutations apo-b-100 gene mutations rate of cholesterol biosynthesis rate of cholesterol absorption CYP/transporter polymorphism apoe polymorphism

40 Individual LDL-C % Response to Atorvastatin 10mg/day Pedro-Botet J et al. Atherosclerosis 158 (2001)

43 Strategies targeting LDL/ non-hdlc Patients not at goal on statin therapy Statin + Ezetimibe Statin + BAS (Colesevelam) Statin + Ezetimibe + BAS

44 Pharmacological rationale for a combination therapy Ezetimibe: a unique mechanism of action (MOA) Eze/simva co-administration provides a complementary MOA Impact on lipid metabolism by inhibiting cholesterol absorption and production

45 Ezetimibe and Statins Have Complementary Mechanisms of Action 1 Together, ezetimibe in combination with a statin provides: 1 Reduction of hepatic cholesterol 2 Increased LDL receptor expression 3 Increased clearance of plasma LDL-C Cholesterol Pool (Micelles) NPC1L1 X Ezetimibe Statins Remnant Receptors HMG-CoA X Cholesterol 1 Cholesterol Pool Liver 2 LDL Receptor Expression 3 CMR LDL-C CM Blood Atheroma NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant. 1. Grigore L et al. Vas Health Risk Manag. 2008;4:

46 Dual Inhibition : Ezetimibe and Statin Statin Synthesis of Cholesterol Bile LDL-C Cholesterol absorption Intestine DARM Ezetimibe Dietary cholesterol Excretion

47 MEAN LDL-C LOWERING 2,3 CHANGE OF SYNTHESIS As high as 60% LDL-C lowering via dual inhibition AND ABSORPTION MARKERS 1 Inhibition of absorption synthesis absorption Inhibition of synthesis synthesis absorption Dual inhibition Statin + EZETIMIBE synthesis absorption 10% 20% 30% 40% 50% LDL-C LDL-C LDL-C 20% 30-45% STATIN + EZETIMIBE As high as 60% 1. Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; 2. Goldberg AC, et al. Mayo Clin Proc May;79(5):620-9.; 3. Davidson M et al. J Am Coll Cardiol 2002; 40:

48 LDL-C (mg/dl) at study end Consistency of Co-Administration Studies Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone Lova Co-admin Prava Co-admin Simva Co-admin Atorva Co-admin Add-On Study Statin alone Statin + EZE % 23% % 19% 21% Lipka L, et al. J Am Coll Cardiol (Suppl) Melani L, et al. J Am Coll Cardiol (Suppl) Davidson M, et al. J Am Coll Cardiol (Suppl) Ballantyne C, et al. J Am Coll Cardiol (Suppl) Bays H, et al. J Am Coll Cardiol (Suppl)

49 Co-Administration of Ezetimibe with Simvastatin: % Reduction on LDL-C by Baseline Subgroup Parameters Anne C. Goldberg et al., Mayo Clin Proc 2004;79:

50 DdT Distanza dal target LDL colesterolo misurato LDL colesterolo target LDL colesterolo misurato Esempio: LDLc basale 169, LDLc target 100 DdT% = [( ) / 169] x 100 = 41%

51 Che percentuale di riduzione del C-LDL è necessaria per raggiungere il target? Simva 10 mg Simva 20 mg Simva 40 mg Atorvastatina 10 mg Atorvastatina 20 mg Atorvastatina 40 mg Atorvastatina 80 mg Rosuvastatina 10 mg Rosuvastatina 20 mg Rosuvastatina 40 mg Simva + Eze 20 mg/10 mg Simva + Eze 40 mg/10 mg

52 331% non a target: 42.3% <15% dal target 44.3% 15-40% dal target 13.4% > 40% dal target

53 Tra i pazienti ad alto o altissimo rischio: necessitano di farmaci in grado di ridurre LDL-c > 45% necessitano di farmaci in grado di ridurre LDL-c > 50%

54 Statin and Complementary GI -Acting Drugs vs Statin Titration 5 6 % 5 6 % 5 6 % Statin at starting dose 1st 2nd 3rd 3 -STEP TI TRATI ON Statin at starting dose Doubling % + GI-acting drug 1 -STEP COADMI NI STRATI ON % Reduction in LDL-C Bays H et al. Expert Opin Pharm acother 2003;4:

55 IN-CROSS Study : Study Design multi-center, randomized, double-blind, parallel group study 618 high-risk patients not at goal on statin treatment LDL-C 2.59 mmol/l (100 mg/dl), 4.14 mmol/l (160 mg/dl) TG 3.96 mmol/l (350 mg/dl) EZE/SIMVA 10/20 mg 6 weeks Run-in Stratum 1 Stratum 2 Atorva 10 Rosuva 5 Simva 20 Atorva 20 Prava 40 Simva 40 Fluva 80 6 weeks ROSUVA 10 mg Farnier et al. IJCP 2009; 63:

56 IN-CROSS Study : primary end-point in patients with and without T2DM Mean % Change from Baseline (SE) Mean % change from baseline in LDL-C 0 Overall population With T2DM Without T2DM n % -11.5% -18.0% EZE/SIMVA 10/20 mg ROSUVA 10 mg % p < % -26.5% treatment by subgroup interaction p-value = Vaverkova et al. Cardiovasc Ther 2010, Jul 7 56

57 % Patients Reaching LDL-C Goal IN-CROSS Study : % of Patients Reaching LDL-C Goals at Study Endpoint *** p EZE/SIMVA vs. ROSUVA for adjusted odds ratio. 72% *** 56% <2.59 mmol/l (<100 mg/dl) 38% *** 19% <2.00 mmol/l (<77mg/dL) EZE/SIMVA 10/20 mg ROSUVA 10 mg 25% *** 11% <1.81 mmol/l (<70 mg/dl) Secondary Exploratory Secondary Farnier et al. IJCP 2009; 63:

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59 % change from baseline Pooled-analysis of 27 clinical trials comparing the efficacy of Eze/Statin vs Statin therapies in patients with and without diabetes 0 with diabetes LDL-C Non-HDL-C ApoB/ApoA1 without diabetes with diabetes without diabetes with diabetes without diabetes n ,7-22,3-21,7-20,3-16,3-15,9-29,4-27, ,9-37,2-36,7-41,1-13.6% -14.9% -15.0% p = % p < Statin alone Eze/Statin -11.9% -13.0% p = = difference vs statin alone Leiter et al. Diab Obes Metab 2011; 13:

60 La nota 13 ha riconsiderato, su aggiornate basi farmaco-terapeutiche, il ruolo dell associazione tra ezetimibe e statine; infatti l ezetimibe è un farmaco che inibisce l assorbimento del colesterolo e che, utilizzato in monoterapia, riduce i livelli di LDL-C dal 15% al 22% dei valori di base. Mentre il ruolo dell ezetimibe in monoterapia nei pazienti con elevati livelli di LDL-C è, perciò, molto limitato, l azione dell ezetimibe è complementare a quella delle statine; infatti le statine che riducono la biosintesi del colesterolo, tendono ad aumentare il suo assorbimento a livello intestinale; l ezetimibe che inibisce l assorbimento intestinale di colesterolo tende ad aumentare la sua biosintesi a livello epatico. Per questo motivo, l ezetimibe in associazione a una statina può determinare una ulteriore riduzione di LDL-C (indipendentemente dalla statina utilizzata e dalla sua posologia) del 15%-20%. Quindi, l associazione tra ezetimibe e statine sia in forma precostituita che estemporanea è utile e rimborsata dal SSN solo nei pazienti nei quali le statine a dose considerata ottimale non consentono di raggiungere il target terapeutico. Nei pazienti che siano intolleranti alle statine è altresì ammessa, a carico del SSN, la monoterapia con ezetimibe.

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63 SHARP: Rationale Risk of vascular events is high among patients with chronic kidney disease Lack of clear association between cholesterol level and vascular disease risk Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive

64 CARDIOVASCULAR AND RENAL EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS WITH AND WITHOUT DIABETES Shik J and Parfrey S, Curr Op Nephrol Hypert, 14: , 2005

65 Lancet Jun 18. [Epub ahead of print]

66 Unadjusted rates of clinical outcomes in each risk group Lancet Jun 18. [Epub ahead of print]

67 Effects on major vascular events per 1 0 mmol/l reduction in LDL cholesterol, by estimated GFR Lancet 2010; 6736:

68 The SHARP Trial (Study of Heart And Renal Protection) Am Heart J 2010;0:1-10.e10

69 SHARP: Baseline characteristics Characteristic Mean (SD) or % Age 62 (12) Men 63% Systolic BP (mm Hg) 139 (22) Diastolic BP (mm Hg) 79 (13) Body mass index 27 (6) Current smoker 13% Vascular disease 15% Diabetes mellitus 23% Non-dialysis patients only (n=6247) egfr (ml/min/1.73m 2 ) 27 (13) Albuminuria 80%

70 Patients With Events, % SHARP: Major Vascular Events in Patients Initially Assigned Ezetimibe/Simvastatin or Placebo Nonfatal MI or Cardiac Death, Stroke, or Any Revascularization Procedure 25 Placebo (n=4,191) Ezetimibe/simvastatin (n=4,193) Rate reduction 16% Log-rank P= Years of Follow-Up Major vascular events occurred in 639 patients (15.2%) treated with ezetimibe/simvastatin 10/20 mg vs 749 patients (17.9%) treated with placebo, corresponding to a 16% relative risk reduction SHARP = Study of Heart and Renal Protection; MI = myocardial infarction. 1. MSD. Worldwide product circular. WPC MK0653A-T

71 SHARP: Major Atherosclerotic/Vascular Events Event Eze/simv (n=4650) Placebo (n=4620) Risk ratio & 95% CI Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%) Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022) Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhaghic stroke 45 (1.0%) 37 (0.8%) Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57) Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012) Eze/simv better Placebo better

72 Relation between proportional reduction in incidence of major coronary and vascular events and absolute LDL cholesterol reduction at 1 year SHARP Cholesterol Treatment Trialists (CTT) Collaborators Lancet 2005;366:

75 A-to-Z vs. MIRACL & PROVE-IT Different patient populations MIRACL PROVE-IT A-to-Z % pts per ACS type UA :46 n-stemi:54 UA:33 N-STEMI:33 STEMI:33 UA:16,8 n-stemi:43,2 STEMI:40 % diabetic pts % pts treated with PCI: Therapy initiation (gg) (median:7) 5 (median:3.7) ua= Unstable Angina n-stemi= non ST-Elevation Myocardial Infarction STEMI= ST -Elevation Myocardial Infarction

76 STUDIO A-TO-Z: CFR VS MIRACL E PROVE-IT Il punto chiave: un differenziale LDL MIRACL PROVE-IT A-to-Z Profilo lipidico al basale CT: 207 LDL:124 HDL:46 TG:184 CT:181 LDL:106 HDL:38 TG:158 CT:185 LDL:111 HDL:39 TG:149 % di riduz. LDL Atorva 80: 40 Atorva80: 51 Prava40: 22 Simva 20: 31 Simva40: 40 Simva80: 45 Tempo necessario a centrare la significatività statistica su Endpoint Iario 4 mesi* 6 mesi nel periodo 4-24 mesi * Valore raggiunto esclusivamente grazie al p=0,02 sull ischemia da ricovero urgente. Nessuno degli altri 3 sotto-endpoint hard dell endpoint Iario è risultato statisticam. significativo

77 New EAS/ESC Guidelines Catapano AL et al. Eur H J (2011) 32,

78 Potential Mechanisms of Benefit of Statins LDL-C reduction Macrophages Reduction in chylomicron and VLDL remnants, IDL, LDL-C Statins Restore endothelial function Maintain SMC function Anti-inflammatory effects Decreased thrombosis Lipid Core Lumen Smooth Muscle Cells

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80 The Mevalonate Pathway The mevalonate pathway Acetyl-CoA HMG-CoA Reductase HMG-CoA Reductase Squalene Farnesyl Transferase Cholesterol Farnesylated proteins HMG-CoA Acetyl-CoA X HMG-CoA Mevalonate Isopentenyl-PP Mevalonate Geranyl-PP Farnesyl-PP Farnesyl-PP Squalene Statins Statins Geranylgeranylated protein Trans Trans Geranygeranyl-PP Dolichols Geranylgeranyl 2-cis Geranylgeranyl-PP Transferase Ubiquinones all-trans Geranylgeranyl-PP Cholesterol Prenylated Proteins Dolichols Ubiquinone

81 Are pleiotropic effects of statins real? A. Corsini, N. Ferri N and M.Cortellaro Vascular Health and Risk Management 2007:3(5) 1 3

82 Relationship Between Mean LDL-C and Atherosclerosis in Clinical Trials Using Intravascular Ultrasound Median change in atheroma volume (%) r 2 =0.97 p<0.001 CAMELOT Placebo REVERSAL Pravastatin REVERSAL Atorvastatin A-Plus Placebo ASTEROID Rosuvastatin Mean LDL-C (mg/dl) REVERSAL=Reversal of Atherosclerosis With Aggressive Lipid Lowering; CAMELOT=Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis; A-Plus=Avasimibe and Progression of Lesions on Ultrasound; ASTEROID=A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden Adapted from Nissen SE et al JAMA. 2006;295:

83 LDL-C and CHD events in primary prevention studies JUPITER Any myocardial infarction rosuvastatin 0,92% 5ys Any myocardial infarction placebo LDL 55 mg/dl (12 months) O Keefe JH et al. J Am Coll Cardiol 2004; 43 (11):

84 LDL-c and CRP reduction in clinical trials: a meta-analysis. -37% JUPITER (1 year) -50% Kinlay S et al, J Am Coll Cardiol 2007

85 Clinical Pharmacokinetics of Statins Absorptio n Parameter Atorva Rosuva Fluva Fluva XL Lova Prava Simva Fraction absorbed (%) T max (hr) C max (ng/ml) Bioavailability (%) Effect of food 13% 20% 15% to 25% 0 50% 30% 0 Transporter proteins substrate Yes Yes Yes Yes Yes Yes Yes Adapted from Corsini et al Pharmacol Ther 84: Circulation Supp liii:50-57, 2004

86 % of control Effect of Atorvastatin on plasma cholesterol LDL Atorvastatin single dose Atorvastatin repeated dose hours

87 Comparison of effect of single dose of 40 mg simva and atorva on plasma MVA in FH heterozygotes Naoumova, R. P. et al., J. Lipid Res :

88 The deprivation of circulating MVA-derived isoprenoids in the early phase of treatment could be the main mechanism responsible for the atheroprotective effect of statins. This early window of protection in the absence of LDL-C lowering suggests that the pleiotropic properties of statins may have clinical importance. A. Corsini, N. Ferri N and M.Cortellaro Vascular Health and Risk Management 2007:3(5)

89 STUDY DESIGN OF THE ARMYDA-RECAPTURE TRIAL Di Sciascio G et al, JACC, 54 (6), 2009 in press

90

91 Major adverse cardiac events curves at 30 days in high-dose statin vs control arms Patti G Circulation 2011;123:

92 Possible mechanism for the antiproliferative effect of statins Arnaboldi L and Corsini A Curr Op Lip 21: ; 2010

93 Open questions Which is the % of LDL successful rate at hospital discharge? Which is the % of adhesion / discontinuation therapy rate?

94 Am Heart J 2010;160: e3

95 Use of intensive LLT at discharge based on admission HDL-C and LDL-C levels Javed U. et al Am Heart J 2010;160: e3

96 Arch Intern Med 2006;166:

97 ASSOCIATION BETWEEN MEDICATION THERAPY DISCONTINUATION AND MORTALITY Ho PM et al. Arch Intern Med 2006;166:

98 Study Design Patients stabilized post Acute Coronary Syndrome < 10 days. LDL < 125 mg/dl (<3.25 mmol/l) or < 100 mg/dl (<2.6 mmol/l) if prior statin Double-blind ASA + Standard Medical Therapy N=18,000 Simvastatin 40 mg Ezetimibe/ simvastatin 10/40 mg Follow-Up Visit Day 30, Every 4 Months Simva 80 mg if LDL not at goal Duration: Minimum 2.5 year follow-up (>2955 events) Primary Endpoint: CV Death, MI, Documented UA req. hospitalization, revascularization (> 30 days after randomization), or Stroke

99 CONCLUSIONI Il beneficio clinico delle statine nella terapia cronica è sempre associato ad una riduzione del LDL-C Il concetto lower the better rimane valido sino a valori di colesterolo LDL di circa 50 mg/dl In condizioni cliniche acute quali la SCA, il benefico clinico delle alte dosi di statine è da attribuirsi nelle prime 48 ore ad un effetto indipendente dall azione ipocolesterolenizzante

100 Take home messages Optimal LDL-C lowering can be achieved by inhibiting cholesterol absorption and production with ezetimibe/simvastatin Ezetimibe / Simvastatin or Ezetimibe added to a statin is frequently required to reach these goals The SHARP trial establish the clinical benefits of eze/simv consistently with meta-analysis of statin trials in patients with metabolic disease

101 Combined lipid-lowering therapy Drug class LDL-C Decrease (%) Non-HDL-C Decrease (%) HDL-C Increase (%) TG Decrease (%) Statin Ezetimibe Feno