“ Sapienza ” Università di Roma Dipartimento Cuore e Grossi Vasi “ A. Reale ”

1. “Sapienza” Università di Roma Dipartimento Cuore e Grossi Vasi “A. Reale” Prof. Francesco Barillà Importanza del target di colesterolo LDL sia in prevenzione primaria che secondaria in pazienti ad alto rischio cardiovascolare

2. LDL-C is a primary risk factor in CHD and causative for development of coronary atherosclerosis Environmental and genetic factors that increase the risk of atherosclerosis development Lipid disorders1 (LDL↑, HDL↓, TG↑) Hypertension1 Metabolic syndrome2 Smoking, physical inactivity1 Type 2 diabetes1 Increased CV risk Prior CV event/manifest atherosclerosis3 High CRP,4 chronic kidney disease5 Obesity1 Age, ethnicity, gender, family history/genetic variations1 1. World Heart Federation. Cardiovascular disease risk factors.2. Dekker et al. Circulation 2005;112:666–673. 3. Bhatt et al. JAMA 2010;304:1350–1357. 4. Lagrand et al. Circulation 1999;100:96–102. 5. Go et al. N Engl J Med 2004;351:1296–1305.6. Grundy et al. J Am Coll Cardiol1999;34:1348–1359.

3. “Atherosclerosis is a systemic, multifactorial and inflammatory disease, elicited by LDL-C accumulation in the artery wall”

4. 10 30 30 10 GeneticPCSK9 0 20 8 LDL-receptor Serum LDL-C CHD 12 0 20 4 0 Loss-of-function variants in PCSK9, with lifetime low LDL-C, are associated with a lower risk of CV events 250 200 150 300 100 50 100 300 250 200 150 50 Evidence!! Plasma LDL-C in black subjects (mg/dL) P=0.008 CHD(%) 88% PCSK9 nonsense mutation (n=85) No PCSK9 nonsense mutation (n=3,278) No Yes PCSK9 nonsense mutation Cohen et al. N Engl J Med 2006;354;1264–1272.

5. Evidence!! Mehta et al;Circulation Research June 8, 2007

6. Cumulative LDL-C exposure is required for the onset of coronary heart disease Familialhypercholesterolaemiapatientsreach LDL-C thresholdlevels for CHD at an earlyage Heterozygous FH Homozygous FH LDL-C 200 12.5 years 35 years Threshold for CHD 55 years mmol/L mg/dL 150 15 580 13 500 100 Cumulative LDL-C (mmol) 10 390 No FHhypercholesterolaemia 190 5 50 0 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Age in years The threshold for CHD is lower in the presence of other risk factors, such as male gender, smoking, hypertension and diabetes, and it is higher in females.1 Cuchel et al. Eur Heart J 2014;35:2146–2157. Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

7. In prevenzione primaria quali sono i valori ottimali raccomandati di LDL-C?

8. JUPITER - Primary EndpointTime to first occurrence of a CV death, non-fatal stroke, non-fatalMI, unstable angina or arterial revascularization No history of CAD men ≥50 yrs women ≥60 yrs LDL-C <130 mg/dL CRP ≥2.0 mg/L 9 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 8 7 6 5 Percent of patients with primary endpoint Rosuvastatin 20 mg 4 3 NNT for 2y = 95 5y* = 25 2 1 0 0 1 2 3 4 5 Years Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 Ridker P et al. N Eng J Med 2008;359: 2195-2207 *Extrapolated figure based on Altman and Andersen method

9. Cumulative incidence of CV events on the basis of the LDL-C levels 0.08 Placebo HR 1.0 (referent) 0.06 LDL > 70 mg/dL or hsCRP > 1 mg/L HR 0.59 (0.46-0.75) Cumulative Incidence 0.04 Rosuvastatin LDL < 70 mg/dL and hsCRP < 1 mg/L HR 0.21 (0.09-0.51) Rosuvastatin 0.02 0.00 0 1 2 3 4 Follow-up (years) P < 0.0001 Number at Risk Rosuvastatin 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 Placebo 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168 Ridker P et al. N Eng J Med 2008;359: 2195-2207

10. Predicted 5-year benefits of LDL cholesterol reductions with statin treatment at different levels of risk (B) vascular deaths (A) Major vascular events Lifetable estimates using major vascular event risk or vascular death risk in the respective risk categories and overall treatment effects per 1・0 mmol/L reduction in LDL cholesterol with statin.

11. Pharmacological evidence shows lower LDL-C levels are associated with lower CV event rates Treatment group Control group “The lower is better” Secondary prevention Primary prevention Events % IMPROVE-IT LDL-C (mg/dL) Besseling et al. Drugs 2013;73:293–301.

12. (Primary prevention)

13. Antithrombotictherapy DAPT or other antithrombotic combination therapies after ACS Angiotensin-converting enzyme inhibitors or AT2 blockers OtherDrugs: Beta-blockers,Ivabradine, Nitrates; Calciumantagonists; aldosterone receptorantagonists Smoking cessation Diet and weight control Exercise-based cardiac rehabilitation Blood pressure control Alcohol Control other risk factors (Hyperuricemia, Diabetes, Hyperomocisteina) Adherence to treatments The last ACS-STEMI Guidelineson the secondaryprevention Long-term strategies for improving prognosis in patients with ACS Lifestyle interventions and risk factor control LIPID- LOWERING THERAPY

14. …Evidenze!! EFFETTI NON IPOLIPEMIZZANTI (effetto precoce/rapido) Disfunzione/attivazione endoteliale Infiammazione/ attivazione immunologica Infiammazione/ attivazione immunologica inibitorio Statine inibitorio inibitorio inibitorio Rottura della placca/ occlusione trombotica trombo Nucleo lipidico Placca aterosclerotica ricca di lipidi Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1425-1433. Perché le statine hanno migliorato la prognosi nei pazienti con SCA? EFFETTI IPOLIPEMIZZANTI (effetto lento/ritardato) inibitorio Statine eNOS Fegato Sintesi colesterolo epatico funzione piastrinica ossid. LDL Macrofagi Stabilizzazione della placca ateromasica Riduzione del rischio di MACE post-SCA

15. Lenderink et al, EurHeartJ 2006;27:1799-1804 HR 0.16 (95% CI 0.08-0.37) (n=6771) HR 0.44 (95% CI 0.31-0.64) (n=1426) 7 Very early (<24 hrs) statin therapy in patients with ACS associated with reduced mortality Euro Heart Survey 2000-01 (10,484 patiens)

16. All-cause mortality Coronaryevents and revascularization RRR 30%

18. STATINE: effetti collaterali Dolori muscolariaumento cpkaumento transaminasirabdomiolisi Necessita’ di associare nuove molecole : l’Ezetimibe Statine+ Ezetimibe Doppia inibizione dell’assorbimento e della produzione di colesterolo

19. Ezetimibe Inibisce l’Assorbimento del Colesterolo nel Piccolo Intestino Ezetimibe: Meccanismo d’azione Riduzione del colesterolo epatico 3 Aumentata espressione di recettori per LDL 4 Inibizione della NPC1-L1 protein 1 Aumentata clearance del LDL-C 5 Riduzione del trasporto di colesterolo al fegato 2 Fegato HMG-CoA Pool Colesterolo (Micelle) Colesterolo 4 3 Pool Colesterolo Espressione Recettori LDL Ezetimibe NPC1L1 Recettori Remnant X 1 5 CMR 2 2 LDL-C CM Sangue NPC1L1 = Niemann-Pick C1-like 1 Protein; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicronemnant. 1.Gri ore L et al. Vas Health Risk Manag. 2008;4:267–278. Ateroma

20. Do the IMPROVE-IT data demand lower target levels? <70 mg/dl <1,9 mmol/l Cannon C, N Engl J Med 2015 (372):2387-97

21. Major Pre-specified Subgroups IMPROVE-IT study * †7-yearevent rates 0.7 1.0 1.3 Ezetimibe/Simva Better Simva Better LLT=Lipid-lowering therapy *p-interaction = 0.023, otherwise > 0.05

22. Farmaci importanti per il raggiungimento del targhet di LDL-Colesterolo sono gli inibitori del recettore PCSK9 PCSK9 reduces LDLR recycling, thereby increasing plasma LDL-C • PCSK9 a serine proprotein convertase that reduces hepatic LDLR levels and increases plasma LDL-C1 • Expressed in hepatocytes, kidney mesenchymal cells, intestinal ileum and colon epithelial, CNS2 • Regulates hepatic LDLRs, which bind and internalise LDL particles3 LDL particles PCSK9 routes LDLR for lysosomal degradation LDLR LDLR recycling blocked 1. Abifadel et al. Hum Mutat 2009;30:520–529. 2. Seidah et al. Proc Natl Acad Sci USA 2003;100:928–933. 3. Horton et al. J Lipid Res 2009;50:S172–S177. PCSK9 secretion

23. Statin-intolerant patients3 Patients with HeFH2 Up to 94% of PCSK9 inhibitor-treated patients achieved LDL-C <70mg/dL (1.8mmol/L) High-risk patients on high-intensity statin1 94% 67% 51% Percent of subjects achieving LDL-C <70mg/dL (1.8mmol/L) (95% CI) 46% 14% 2% 2% n 55 56 112 54 110 51 103 Evolocumab140mgQ2W Placebo Q2W Ezetimibe + placebo Q2W 1. Robinson et al. JAMA 2014;311:1870–1882. 2. Raal et al. Lancet 2015;385:331–340. 3. Stroes et al. J Am Coll Cardiol 2014;63:2541–2548.

24. ENDPOINT PRIMARIO DI EFFICACIA: MACE FOURIERoutcomes ODYSSEY outcomes Sabatine MS, N Engl J Med. 2017 May 4;376(18):1713-1722

25. Primary composite endpoint in patients with vs without PAD Major problem with Fourier: No effect on cardiovascular mortality!

26. 95% CI Plaque microstructure was more stable in statin-treated patients with lower LDL-C levels Mean % atheroma volume (PAV) Very low LDL-C levels are associated with more stable plaque features “The lower is better” Verypotent LDL loweringisassociated with atherosclerosisregression 2%  PAV 1% 0% On-treatment LDL-C (mg/dL) -1% -2% PAV= Percent atheroma volume Nicholls et al. JAMA 2007;297:499–508. Kataoka et al. Atherosclerosis 2015;242:490–495.

27. EUROASPIRE IV After a CV event, only 1:5 patients achieve LDL-C <70mg/dL despite statin prescription and good adherence Kotseva et al. Eur J PrevCardiol 2015;Feb 16. pii:2047487315569401.www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/EUROASPIRE-IV-reveals-success-and-challenges-in-secondary-prevention-of-CVD-acro. Accessed 22 Jan 16.

28. 23% Among statin-treated patients Variation in LDL-C level is associated with an increased risk of CV events Visit-to-visit variability in LDL-C levels is an independent predictor of CV events Persistently low LDL-C minimises lifetime exposure and therefore risk of CV events 17% 16% 11% 10% Any coronary event Any CV event MI Stroke Death Increased risk of events per 1 SD increase in LDL-C variability Bangalore et al. J Am Coll Cardiol 2015;65:1539–1548.

29. Implicazioni clinicheIn quali pazienti è raccomandato un controllo accurato del LDL-C? Post infarto/Angina Prevenzione secondaria -target <70 mg/dl -ottimale < 60 mg/dl Altre manifestazioni di arterioslerosi (PAD) Arteriosclerosisubclinica target< 100 mg/dl ottimale <70 mg/dl Prevenzione primaria Multipli fattori di rischio CV Un intervento farmacologico o non, per ridurre i livelli di LDL-C, qualora siano elevati (> 120 mg/dl), potrebbe e dovrebbe essere preso in considerazione Basso rischio

30. Conclusion The war against residual CV risk II. Antithrombotic I. Lipids III. Inflammation??

31. Colesterolo-LDL = col. totale – (col.HDL + 1/5 trigliceridi) Quando il valore dei trigliceridi supera 400 mg/dl, la formula di Friedewald non è attendibile ed è pertanto necessario eseguire la determinazione del colesterolo LDL con metodiche di ultracentrifugazione

32. Trials vs. Real-world: not negligible limitations • Trials generally include selected patients, with a high level of adherenceto lipid-lowering therapy, and frequent follow-up visits. • In real-world tolerability issues and adverse effectsare frequently reported, with a suboptimal level of adherence to lipid-lowering therapy.

33. LDL-C is involved at every stage of atherosclerotic plaque formation Aterosclerosi: malattia multifattoriale, cronica, infiammatoria e fibroproliferativa • Acute CV events • Cardiac vessels − AMI • Brain vessels − stroke • Peripheral vessels − critical limb ischaemia Fatty acid streaks Vulnerable plaque Obstructive atherosclerotic disease Endothelial dysfunction Plaque Rupture Thrombus High concentration of lipid-filled macrophages, thin fibrous cap, necrotic core2 Pro-coagulant pathways may dominate, leading to occlusive blood clot3 LDL-C reduces eNOS activity1 LDL-C Increasing foam cell formation2 Lesion enlarges, arterial lumen narrows, blood flow hampered3 LDL and macrophages within the vessel wall form foam cells2 LDL-C increasingFoam cell necrosis2 Coagulation and platelet recruitment on exposure to tissue factor2 1. Davignon et al. Circulation 2004;109(23 Suppl 1):III27–III32. 2. Glass et al. Cell 2001;104:503–516. 3. Libby. Nature 2002;420:868–874.