LA RIDUZIONE DEL RISCHIO CARDIOVASCOLARE ATTRAVERSO UNA TERAPIA IPOLIPEMIZZANTE INTENSIVA

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1 LA RIDUZIONE DEL RISCHIO CARDIOVASCOLARE ATTRAVERSO UNA TERAPIA IPOLIPEMIZZANTE INTENSIVA Enzo Manzato Servizio scientifico offerto alla classe medica da MSD Italia S.r.l VYT-2011-IT-5484-SS

2 Linee Guida ATP III per SCA 2004: L importanza del raggiungimento del target

3 LA DOPPIA INIBIZIONE DELL ASSORBIMENTO E DELLA SINTESI DEL COLESTEROLO raddoppio la dose dose iniziale di statina +6% +6% +6% INIBIZIONE DELLA SINTESI dose iniziale di simvastatina + Ezetimibe 10 mg DOPPIA INIBIZIONE % riduzione del colesterolo LDL

4 Studio INFORCE: Riduzione C LDL vs. raddoppio della statina

5 Eur J Clin Invest 37, 357, 2007

6 Studio CHENOT: raggiungimento target 70mg/dl

7 N Engl J Med 356, 1503, 2007

8 EZETIMIBE J Am Coll Cardiol 55, 1348, 2010

9 Studio INCROSS: riduzione ApoB

10 SHARP: Eligibility History of chronic kidney disease not on dialysis: elevated creatinine on 2 occasions Men: 1.7 mg/dl (150 µmol/l) Women: 1.5 mg/dl (130 µmol/l) on dialysis: haemodialysis or peritoneal dialysis Age 40 years No history of myocardial infarction or coronary revascularization Uncertainty: LDL lowering treatment not definitely indicated or contraindicated

11 SHARP: Assessment of LDL lowering

12 SHARP: Major Atherosclerotic Events 25 Proportion suffering event (%) Risk ratio 0.83 ( ) Logrank 2P= Placebo Eze/simv Years of follow up

13 SHARP 32 mg/dl Lancet 366, 1267, 2005

14 SHARP Clin Ther 31, 236, 2009

15 Proportional reduction in atherosclerotic event rate (95% CI) 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 32 mg/dl 0% Mean LDL cholesterol difference between treatment groups (mg/dl) Lancet 376, 1670, 2010

16 Proportional reduction in atherosclerotic event rate (95% CI) 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 17% risk reduction 0% Mean LDL cholesterol difference between treatment groups (mg/dl) Lancet 376, 1670, 2010

17 SHARP: Major 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%) Haemorrhagic 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

18 SHARP: Safety Myopathy Eze/simv (n=4650) Placebo (n=4620) CK >10 x but 40 x ULN 17 (0.4%) 16 (0.3%) CK >40 x ULN 4 (0.1%) 5 (0.1%) Hepatitis 21 (0.5%) 18 (0.4%) Persistently elevated ALT/AST >3x ULN 30 (0.6%) 26 (0.6%) Complications of gallstones 85 (1.8%) 76 (1.6%) Other hospitalization for gallstones 21 (0.5%) 30 (0.6%) Pancreatitis without gallstones 12 (0.3%) 17 (0.4%)

19 SHARP: Cancer incidence 25 Proportion suffering event (%) Risk ratio 0.99 ( ) Logrank 2P=0.89 Eze/simv Placebo Years of follow up

20 SHARP: Conclusions No increase in risk of myopathy, liver and biliary disorders, cancer, or nonvascular mortality No substantial effect on kidney disease progression Two thirds compliance with eze/simv reduced the risk of major atherosclerotic events by 17% (consistent with meta analysis of previous statin trials) Similar proportional reductions in all subgroups (including among dialysis and non dialysis patients) Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding events per 1000 treated for 5 years

21 La attuale terapia della dislipidemia LDL LDL+VLDL VLDL ACIDO NICOTINICO

22 Percentage of patients with moderate, severe or extreme flushing (GFSS 4) Patients % ER niacina ER niacina/laropripant placebo settimane di terapia Int J Clin Pract 62,1959, 2008

23 J Clin Invest 115, 3400, 2005

24 LAROPRIPANT F O N OH O S CH 3 O Cl Proc Natl Acad Sci U S A 103, 6682, 2006 J Clin Invest 115, 3400, 2005

25 Percentage of patients with moderate, severe or extreme flushing (GFSS 4) Patients % ER niacina ER niacina/laropripant placebo settimane di terapia Int J Clin Pract 62,1959, 2008

26 Curr Atheroscl Rep 2009;11:45

27 LDL ERN/LRPT SIMVA ERN/LRPT+SIMVA Br J Cardiol 2009;16:90

28 HDL ERN/LRPT+SIMVA ERN/LRPT SIMVA Br J Cardiol 2009;16:90

29 trigliceridi SIMVA ERN/LRPT ERN/LRPT+SIMVA Br J Cardiol 2009;16:90

30 Lp(a) Median % change in Lp(a) SIMVA ERN/LRPT+SIMVA ERN/LRPT Weeks on treatment Br J Cardiol 2009;16:90

31 J Am Coll Cardiol 8, 1245, 1986

32 MAJOR CORONARY EVENTS Atherosclerosis 210, 353, 2010

33 HPS2 - THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) Pazienti : pazienti ad alto rischio cardiovascolare, età compresa fra 50 e 80 anni, con infarto, malattia vascolare periferica o cerebrovascolare, diabete + malattia vascolare aterosclerotica. Un terzo pazienti diabetici Endpoint primario : eventi vascolari maggiori (infarto, ictus, procedure di rivascolarizzazione) Run-in acido nicotinico/laropripant 1g* 2g* acido nicotinico/laropripantt 2 g/40 mg - - simvastatina 40 ± ezetimibe (di base) Settimane -12 to Placebo 4 anni di follow-up * I pazienti sono arruolati assumendo già simvastatina 40 mg +/- ezetimibe /ezetimibe-simvastatina 10/40 mg.

34 La attuale terapia della dislipidemia LDL LDL+VLDL VLDL ACIDO NICOTINICO