Altro e oltre le statine

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1 Convegno CSR Fondazione AMD Cernobbio 8 ottobre 2008 Altro e oltre le statine Dott. Carlo B. Giorda Centro Studi e Ricerche AMD

2 1988: la rivoluzione epocale The mevalonate pathway Acetyl-CoA HMG-CoA Reductase HMG-CoA Reductase Squalene Cholesterol Farnesyl Transferase 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

3 IL FUTURO DELLE STATINE Terapia ipolipemizzante di associazione Eze/statina Statina/Feno Statina/CETP Statina/nicotinico* HDL LDL TG Statina + omega 3

4 I fibrati

5 FIELD: Study Design 5-year study against a background of usual care, including the option to add other lipid-lowering therapies Fenofibrate 200 mg/day, n = Other lipid-lowering therapies 9795 Patients 5 Years or 500 CHD Events Placebo, n = Other lipid-lowering therapies FIELD Study Investigators. Cardiovasc Diabetol. 2004;3:9-24.

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7 End point primario: eventi coronarici End Point primario End Point primario aggiustato in relazione all uso delle statine Relative Risk, % % P=0.16 P= CHD Events -19% CHD Events

8 End point secondario: eventi CV totali End point secondario End point primario aggiustato in relazione all uso delle statine Relative Risk, % % P=0.035 P= CVD Events -15% CVD Events

9 FIBRATI = attivatori dei PPAR-α PPAR (Peroxisome Proliferator Activated Receptors) Regolano l omeostasi energetica, il metabolismo lipidico e glucidico, alcuni fattori dell infiammazione

10 Gli agonisti dei PPARα inibiscono la via del fattore di crescita endoteliale (VEGF), importante nell angiogenesi, nell infiammazione e nella migrazione cellulare. Fenofibrato ha dimostrato di: regolare la sopravvivenza della cellula retinica stimolare l espressione del VEGF mrna nella retina (trasduzione del segnale dell AMPK) migliorare la reattività vascolare endotelio-dipendente.

11 Lancet Nov 17;370(9600):

12 Primo intervento laser 238 pazienti (4.9%) - 31% 8 mesi 164 pazienti (3.4%)

13 Se trattati con fenofibrato si avranno 5.8 primi trattamenti laser in meno ogni 100 pazienti con retinopatia pregressa NNT numero necessario da trattare = 17

14 Fenofibrato riduce il rischio di amputazioni in pazienti con diabete di tipo 2 Nuove evidenze dallo studio FIELD mostrano benefici microvascolari aggiuntivi del fenofibrato E la prima volta che, in uno studio prospettico su un ampia popolazione, un farmaco ipolipemizzante dimostra di ridurre in modo significativo il rischio di amputazioni degli arti inferiori in pazienti con diabete di tipo 2

15 Benefits of long-term therapy on amputations in type 2 diabetes mellitus in FIELD trial Effetto del fenofibrato sulle amputazioni Riduzione del rischio relativo Valore p Amputazioni microvascolari 47% Amputazioni macrovascolari 23% 0.26 Tutte le prime amputazioni 38% 0.011

16 Ezetimibe: a novel option

17 Ezetimibe: First New Therapy for Hyperlipidemia in 15 years Niacin, 1955 Bile acid sequestrants, 1961 Fibrates, 1967 Statins (HMG-CoA reductase inhibitors), 1987 Cholesterol absorption inhibitor (ezetimibe), 2002 Adapted from Bays H Expert Opin Investig Drugs 2002;11: ; Mahley RW, Bersot TP. In: Goodman and Gilman s The Pharmacological Basis of Therapeutics 10th ed. New York: McGraw Hill, 2001: ; Ginsberg HN, Goldberg IJ. In Harrison s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998: ; Van Itallie TB et al N Eng J Med 1961;265: ; Altschul R et al Arch Biochem 1955;54:

18 Cholesterol Absorption in the Intestine mg 1000 mg Resins Plant stanols NPC1L1 ACAT=acyl-coenzyme A:cholesterol acyltransferase; NPC1L1=Niemann-Pick C1 Like 1 Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Ginsberg HN, Goldberg IJ. In Harrison s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998: ; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2 E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002: ; Davis JP et al Genomics 2000;65:

19 Cholesterol Absorption Correlates With Plasma LDL-C Cholesterol absorption (%) LDL-C (mg/dl) Eur J Clin Invest 17, 391, 1987

20 Dietary and fecal data at baseline and during atorvastatin (80 mg) treatment 20 TA Miettinen et al., Eur J Clin Invest 2003;33 (11):

21 0 10/10 mg (n=87) 10 mg (n=79) 10/20 mg (n=86) 20 mg (n=89) 10/40 mg (n=89) 40 mg (n=90) 10/80 mg (n=91) 80 mg (n=87) Δ% LDL-C %* 31% 51%* 35% 55%* 42% 61%* 46% *p<0,001 vs. dose corrispondente di simvastatina Eze/Simva Simvastatina Golberg AC et al - Mayo Clin Proc 79, 620, 2004

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23 LDL cholesterol 10 0 Baseline 24 months (mg/dl) (mg/dl) Simva 318 ± ±60 Percentage change from baseline P<0.01 Eze Simva 319 ± ± % incremental reduction Simva ENHANCE Months Eze Simva

24 Mean cimt During 24 Months of Therapy Longitudinal, repeated measures analysis P=0.88 Mean IMT (mm) ENHANCE Months Simva Eze Simva

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32 Peto R et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359 ( /NEJMsa )

33 Niacina ER + laropiprant

34 Niacin (Nicotinic Acid): Treatment of Dyslipidemia and Atherosclerosis First used as lipid-altering agent in 1955 Broad spectrum of lipid effects LDL-C (5% 25%) HDL-C (15% 35%) TG (20% 50%) Cardiovascular (CV) benefits CV events (Coronary Drug Project) Plaque progression (angiographic measurements) Niacin added to a statin may help lower CV risk 34 LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; TG = triglycerides. Altschul R et al. Arch Biochem Biophys. 1955;54: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: Blankenhorn DH et al. JAMA. 1987;257: Taylor AJ et al. Circulation. 2004;110: Chapman J. Eur Heart J. 2005;7(suppl F):F56 F62.

35 Nicotinic Acid and Atherosclerosis: A Positive Effect on Clinical Outcomes Randomized Controlled Clinical Trials of Nicotinic Acid and Effect on HDL-C and Clinical Outcomes Imaging studies Special agent(s) Patients receiving treatment, n/n (%) Increase in HDL-C levels, % Follow-up duration, years Outcomes a CDP CDP follow-up Niacin 1119/8341 (13.4) NR 6 Decreased (27%) nonfatal MI Niacin 1119/8341 (13.4) NR 15 Decreased (11%) death Stockholm Niacin + clofibrate 279/555 (50.3) NR 5 HATS Niacin + simvastatin 38/160 (23.8) Decreased (26%) death; decreased (36%) CAD death Decreased (90%) first death, MI, stroke, or revascularization AFREGS Niacin + gemfibrozil + cholestyramine 71/143 (49.7) Decreased (13%) composite clinical outcome of angina, MI, TIA, stroke, death, and cardiovascular procedures; decreased focal coronary stenosis (secondary outcome) CDP = Coronary Drug Project; Stockholm = Stockholm Ischemic Heart Disease Secondary Prevention Study; HATS = HDL Atherosclerosis Treatment Study; AFREGS = Armed Forces Regression Study; NR = not reported; MI = myocardial infarction; CAD = coronary artery disease; TIA = transient ischemic attack. a Death indicates all-cause mortality. 35 Adapted from Singh IM et al. JAMA. 2007;298: Please see corresponding speaker notes for study references.

36 Most Patients on ER Niacin Therapy Do Not Reach a 2-g Dose Users, % > 1500 mg mg mg mg 500 mg 0 4 weeks 8 weeks 12 weeks 24 weeks 1 year N = 14,386 n = 6349 n = 5277 n = 5402 n = Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database. Kamal-Bahl S, Burke T, Watson D et al. Dosage and titration patterns of extended release niacin in clinical practice. Abstract presented at the 7th American Heart Association Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke; May 2006; Washington,= DC, USA.

37 Niacin Induced Flushing Pathway: 2 Separate Sites of Action 1. Epidermal Langerhans Cells Niacin binds PGD 2 is produced and released V 2. Dermal Blood Vessels PGD 2 binds to DP1 Vasodilation results Artistic rendering. PGD 2 = prostaglandin D 2 ; DP1 = prostaglandin D 2 receptor 1. Benyó Z et al. Mol Pharmacol. 2006;70: ; Morrow JD et al. J Invest Dermatol. 1992;98: ; Cheng K et al. Proc Natl Acad Sci USA. 2006;103: ; Pike NB et al. J Clin Invest. 2005;115:

38 Factorial Study: Lipid Efficacy Primary end point 17.0 % Change HDL-C % Change LDL-C Weeks on Treatment ER niacin/laropiprant (n = 160) -40 Simvastatin (all doses pooled; n = 565) ER niacin/laropiprant + simvastatin (all doses pooled; n = 520) % Change Weeks on Treatment TG Weeks on Treatment 38

39 Lipid/Flushing Study: Lower Incidence of Moderate or Greater Flushing vs ER Niacin Average number of days per week with moderate or greater flushing symptoms across weeks 1 24 Percentage of patients with moderate or greater flushing symptoms across weeks dose advancement 60 dose advancement 50 Number of Days per Week 1 % Patients Weeks on Treatment Weeks on Treatment ER niacin (n = 508) ER niacin/laropiprant (n = 763) O Placebo (n = 268) 39

40 Conclusions ER niacin/laropiprant provides an opportunity to improve the therapeutic potential of niacin Long term use of niacin is necessary to achieve and sustain lipid efficacy and persistent outcomes benefit; a large clinical outcomes trial is underway to define the clinical benefits of ER niacin/laropiprant 40

41 n-3 (omega 3)

42 Mortalità totale : 15 studi

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44 A dosi diverse Diversi meccanismi d azione? Possibile azione sinergica? Una nuova ipotesi da testare

45 Un ipotesi affascinante da verificare In view of the diverse physiological effects of fish oil and their differing dose-response curves, the main benefit at lower levels of consumption might be prevention of primary ventricular arrhythmia, whereas at high levels of consumption (eg, more than 1 g per day of EPA and DHA), modest benefits for non-fatal coronary events could also begin to occur because of, for example, triglyceride-lowering, antihypertensive, or anti-infl ammatory effects. Compared with antiarrhythmic effects, these effects could require a prolonged duration of consumption to reduce risk. Dariush Mozaffarian Lancet 2007; 369: 1062 (edit)

46 Giapponesi MeF senza CAD seguiti 10 anni ( aa/persona) 5 quintile (180 g/die) vs 1 quintile (23 g/die) Hazard ratios Malattia coronarica fatale e non fatale 0,63 IMA non fatale 0,44 Morte cardiaca improvvisa 1,14

47 End point GISSI HF omega 3 fatty acid study: Primary and secondary outcomes Omega-3 fatty acids, n=3494 (%) Placebo, n=3481 (%) Adjusted hazard ratio (95% CI) Primary end points Mortality ( ) All-cause mortality or hospitalization for cardiovascular causes ( ) Secondary end points Death from cardiovascular ( ) causes Sudden cardiac death ( ) Patients admitted for ( ) cardiovascular causes Patients with fatal and ( ) nonfatal MI Patients with fatal and nonfatal stroke ( ) GISSI HF investigators. Lancet 2008; available at:

48 Eff ect of n 3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial Lancet 2008; 372:

49 Conclusioni Stanti le attuali linee di ricerca, il futuro delle terapie ipolipemizzanti sarà statina + altro Per ora, in tema di prevenzione CV, hanno discrete evidenze Niacina, omega-3 e fibrati Per alcune molecole (fenofibrato, omega-3) vi sono affascinanti prospettive non strettamente legate al metabolismo dei lipidi

50 Grazie per l attenzione