Gestione a lungo termine del paziente diabetico ipercolesterolemico: quale terapia e per quale rischio Antonio Mafrici UCIC Dipartimento Cardio-toraco-vascolare A.O. Ospedale Niguarda Cà Granda Milano Milano 3 Dicembre 20111

Proiezione a 30 anni USA (2006) 35 milioni Heart attacks 13 milioni Strokes 6 milioni IRC 2 milioni Amputazioni 8 milioni Cecità/chirurgia oculare 62 milioni Morti Spesa totale: 6.6 TRILIONI DI DOLLARI

Age-Adjusted Risk Ratio Relative Risk of CVD in Subjects With and Without Diabetes: Framingham Heart Study Male Female Any CVD event * * Stroke Intermittent claudication † † * Cardiac failure * CHD † ‡ MI ‡ * Angina pectoris Sudden death § Three decades of epidemiologic research from the Framingham Study have shown diabetes to be a powerful predisposing factor for cardiovascular disease in general, and of coronary disease in particular Diabetes predisposed subjects to all of the major atherosclerotic diseases, and coronary heart disease was the most common and most lethal The authors noted that although the influence of diabetes on cardiovascular disease is greatly dependent on coexistent risk factors, there is an independent effect of diabetes after all of these coexistent factors have been taken into account. This indicates that there is some unique effect of the diabetes that is not explained by higher levels of the associated risk factors (age, serum cholesterol, systolic blood pressure, cigarettes per day, and LVH) Coronary mortality † † 1 2 3 4 5 6 Age-Adjusted Risk Ratio *P<0.001; †P<0.05; ‡P<0.01; §P<0.1. Kannel WB et al. Am Heart J. 1990;120:672-676. Reference Kannel WB, D’Agostino RB, Wilson PW, et al. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J. 1990;120:672-676. [Kannel, p673, col 2, Table 11]

Uno studio su 51.735 soggetti finlandesi di entrambi i sessi con età compresa tra 25 e 74 anni ha evidenziato che l’hazard ratio (HR) per la mortalità coronarica, aggiustata per tutti gli altri fattori di rischio era, rispetto a soggetti sani, 2,1 per i diabetici, 4 per gli infartuati e 6,4 per gli infartuati affetti da diabete Nelle donne l’HR era rispettivamente 4,9, 2,5 e 9,4. Anche la mortalità totale era marcatamente incrementata nei soggetti affetti da diabete e infarto del miocardio. Hu G, et al. Diabetologia 48: 856–861, 2005

Glycemic Levels Predict Negative Outcomes: EPIC–Norfolk Prospective study of 10,232 residents of Norfolk, UK, followed for mean of 6 years (4662 men, 5570 women, ages 45-79) Incidence (%) ≥ ≥ The European Prospective Investigation into Cancer in Norfolk (EPIC–Norfolk) is a prospective population study of 25,623 men and women who were between 40 and 79 years of age and resided in Norfolk, United Kingdom. They were followed for an average of 6 years Risk for coronary heart or cardiovascular disease and total mortality increased throughout the whole range of A1c concentrations; those with A1c concentrations <5% had the lowest rates For men, a gradient of increasing rates through the distribution was apparent for all end points For women, odds ratios for cardiovascular or coronary heart disease did not increase significantly until the A1c concentration reached 6%; odds ratios were very high in women with concentrations >7% An increase in A1c concentration of 1 percentage point was associated with a 20% to 30% increase in event rates A1c significantly predicted all-cause mortality and coronary and cardiovascular disease, even below the threshold commonly accepted for the diagnosis of diabetes and independent of age and classic risk factors Males Females HbA1c Levels (%) EPIC–Norfolk = European Prospective Investigation into Cancer in Norfolk. Khaw KT et al. Ann Intern Med. 2004;141:413-420. Reference Khaw KT, Wareham N, Bingham S, Luben R, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141:413-420. [Khaw, p416, Table 2]

Glucose and CV Events: Meta-Analysis of 95,783 Patients in 20 Studies Using an Exponential Model 3.0 2.5 Relative Risk Relative Risk of CV events 2.0 1.5 95% Confidence Intervals 1.0 4 5 6 7 8 9 Fasting Glucose (mmol/L) 3.0 Relative Risk 2.5 Relative Risk of CV events This paper was a meta-analysis that reviewed all prospective studies of the risk of cardiovascular disease according to baseline glucose determinations The review analyzed 20 studies which comprised 95,783 people (94% male) who had 3707 cardiovascular events over 12.4 years (1,193,231 person-years) Using an exponential model, data were compared with the reference fasting glucose of 4.2 mmol/L (75 mg/dL) A fasting glucose of 6.1 mmol/L (110 mg/dL, the threshold value for the classification of impaired fasting glucose) was associated with a relative risk of cardiovascular events of 1.33 (95% CI, 1.06-1.67) A 2-hour glucose of 7.8 mmol/L (140 mg/dL, the threshold value for impaired glucose tolerance) was associated with a relative risk of cardiovascular events of 1.58 (95% CI, 1.19-2.10) 2.0 95% Confidence Intervals 1.5 1.0 4 6 8 10 12 2-Hour Glucose (mmol/L) Coutinho M et al. Diabetes Care. 1999;22:233-240. Reference Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233-240. [Coutinho, p237, Figure 3]

Coronary heart disease (CHD) risk in patients with type 2 diabetes 50 No diabetes (n=1373) 45 Type 2 diabetes (n=1059) 40 30 7-year MI event rate† 19 20 20 10 4 Approximately three-quarters of patients with type 2 diabetes will die from cardiovascular disease (Abuissa et al 2005). Patients with type 2 diabetes without prior MI have a similar risk of cardiovascular death as those without diabetes who had previously had an MI (Haffner et al 1998). This finding has led to the concept of diabetes as a cardiovascular-risk equivalent. In addition, the risk of major cardiovascular events (coronary events, strokes and revascularisations) in diabetes is increased. In approximately 6000 patients with diabetes, the 5-year event rate was 13% in patients without, and 36% for patients with a history of atherosclerosis (HPS 2003). The excess CHD risk associated with diabetes is reflected in guidelines for CHD prevention, which now view type 2 diabetes as a ‘CHD-risk equivalent’ (NCEP ATP III 2001; De Backer et al 2003). References Abuissa H et al. Strategies to prevent type 2 diabetes. Curr Med Res Opin 2005; 21: 1107–1114. De Backer G et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003; 24: 1601–1610. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497. Haffner SM et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234. HPS Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016. Abbreviations CHD=coronary heart disease; MI=myocardial infarction No prior MI Prior MI CHD=coronary heart disease; MI=myocardial infarction †Events/100 person-years Haffner SM et al. N Engl J Med 1998; 339: 229–234

SOPRAVVIVENZA DOPO INFARTO MIOCARDICO ACUTO Affner dice che i pz diabetici che non hanno avuto l’infarto hanno lo stesso rischio di chi non ha il diabete, ma ha avuto l’infarto. Modificata da Haffner SM, N Engl J Med 1998; 339:229-34

Tassi di mortalità per cardiopatia ischemica in pazienti con e senza diabete* 17,0 14,2 6,8 7,6 7,4 4,2 2,4 1,9 20 15 -16,6% p=0,46 10 5 Uomini (1971) Donne (1971) Uomini (1982) Donne (1982) +10,7% p=0,76 -43,8% p=0,001 -20,4% p=0,12 Diabete Non diabete * In campioni nazionali di adulti in NHANES I (1971-75) Gu K et al., JAMA 1999; 281:1291-1297

Median follow-up: 7.9 years HR for coronary artery disease Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: UKPDS Median follow-up: 7.9 years 2.5 2.0 1.5 1.0 0.5 2.26 p=0.0086 p=0.0002 1.93 1.79 1.41 HR for coronary artery disease 1 1 <189 189-223 >223 <117 117-150 >150 Total cholesterol LDL cholesterol (mg/dl) (mg/dl) Turner RC et al. BMJ 316: 823-828, 1998

Colesterolemia e mortalità cardiovascolare Studio MRFIT Colesterolo (mg/dl) 140 160 180 200 220 240 260 280 300 Mortalità cardiovascolare a 6 anni (per 1000) 18 16 14 12 10 8 6 4 2 Pazienti Coronaropatici Diabete Mellito Ed in effetti, nello studio MRFIT i pazienti coronaropatici diabetici avevano, a parità di colesterolemia, un rischio di mortalità cardiovascolare maggiore rispetto ai non diabetici. Ciò sta ad indicare l’importanza, come rischio cardiovascolare, della dislipidemia associata al diabete. Neaton , Arch Intern Med 1992;152:56-64

Dislipidemia diabetica L’alterazione lipidica più comune e più tipica del diabete è rappresentata dall’ipertrigliceridemia, che si associa ad altre alterazioni strettamente interrelate dal punto di vista fisiopatologico, quali diminuzione del colesterolo HDL, aumento delle LDL e HDL più piccole e dense, aumento delle lipoproteine ricche in trigliceridi in fase postprandiale. L’insieme di queste alterazioni costituisce la cosiddetta “dislipidemia diabetica”,

Livelli lipidici anomali in uomini con diabete di tipo 2 Prevalenza (%) 50 40 TC  260 TG  235 30 20 10 C-VLDL  40 C-LDL  190 C-HDL  31 Uomini non diabetici Uomini diabetici 34* 9 26 11 12 14 19* 21* 13 *p<0,05 Adattato da Garg A, Grundy SM, Diabetes Care 1990; 13:153-169

Livelli lipidici anomali in donne con diabete di tipo 2 Prevalenza (%) 50 40 TC  275 TG  200 30 20 10 C-VLDL  35 C-LDL  190 C-HDL  41 Donne non diabetiche Donne diabetiche 38 15 8 31 16 21 17* 25* 24 *p<0,05 Adattato da Garg A, Grundy SM, Diabetes Care 1990; 13:153-169

Rischio di malattia coronarica Livelli “normali” di LDL nei diabetici possono ingannare... Particelle di LDL piccole e dense sono più aterogene apoB LDL Senza diabete Con diabete Particelle di LDL Particelle di LDL LDL piccole e dense con maggior contenuto di apoB Livello “normale” di LDL, ma: Livello “normale” di LDL Numero di particelle LDL Concentrazione di apoB Minore Maggiore Valori “normali” di colesterolo LDL possono essere, nei soggetti diabetici, non indicativi. Le particelle LDL in questi soggetti tendono ad essere piccole, dense, numericamente aumentate e presentano un’alta concentrazione di apoB. Pertanto, anche se i livelli di colesterolo LDL sono “normali”, la qualità delle particelle LDL le rende più aterogeniche, aumentando così il rischio di CHD nei soggetti diabetici.15-17 In uno studio caso-controllo, un sottotipo di LDL caratterizzato da un prevalenza di particelle piccole e dense è stato associato ad un aumento di circa tre volte del rischio di infarto del miocardio.Nei soggetti con alti livelli di particelle LDL piccole e dense è anche probabile osservare bassi livelli di HDL ed alti livelli di trigliceridi. I pazienti diabetici possono presentare livelli normali di colesterolo LDL ma avere una combinazione di alti livelli di particelle LDL piccole e dense con alta concentrazione di apoB, che è la sottofrazione lipidica più aterogenica.17 Pertanto, nei soggetti diabetici, la presenza di valori “normali” di colesterolo LDL può essere ingannevole per l’alta aterogenicità delle particelle LDL piccole e dense. Rischio di malattia coronarica Adattato da : Austin MA, Edwards KL Curr Opin Lipidol 1996;7:167-171; Austin MA et al JAMA 1988;260:1917-1921; Sniderman AD et al Diabetes Care 2002;25:579-582.

Aumento % (HR) del rischio CHD LDL  pari a 1 mmol/L 57 Nello studio UKPDS Il colesterolo LDL si è rivelato il miglior predittore del rischio di malattia coronarica nei diabetici Aumento % (HR) del rischio CHD LDL  pari a 1 mmol/L 57 HDL  pari a 0.1 mmol/L –15 Press arter sistol  pari a 10 mmHg 15 Livello diHbA1c  pari a 1% 11 Il fumo è un altro importante fattore di rischio CHD Questi dati dimostrano l’importanza di ridurre i livelli di LDL per diminuire il rischio di cardiopatia coronarica (CHD) nei diabetici. Il controllo della glicemia è altrettanto importante per ridurre il rischio di complicanze microvascolari. Lo studio UKPDS dimostrò che, in aggiunta ad un importante controllo della glicemia per ridurre le complicanze microvascolari, il colesterolo LDL è un’obiettivo primario per ridurre il rischio di CHD nei soggetti diabetici. E’ stato valutato l’effetto dell’incremento di una unità nei fattori chiave di rischio (1 mmol/l per il colesterolo LDL, 0,1 mmol/l per l’HDL, 10 mmHg per la pressione sistolica [SBP] e l’1% per l’HbA1C) sul rischio di CHD. Ad ogni aumento di 1 mmol/l delle LDL si osservava un aumento di 1,57 volte (57%) del rischio di CHD. Per ogni incremento di 0,1 mmol/l delle HDL si osservava una riduzione del rischio di 0,15 volte (15%). Ad ogni aumento di 10 mmHg della pressione sistolica si osservava un aumento del rischio di 1,15 volte (15%) e per ogni aumento dell’1% della HbA1C si osservava un aumento del rischio di 1,11 volte (11%). Questa analisi conferma il fatto che elevati valori di LDL sono il principale determinante del rischio di CHD nei diabetici di tipo 2. Adattato da : Turner RC et al BMJ 1998;316:823-828.

Rosuvastatin Clinical Overview December 2004 The CARDS primary prevention study in type 2 diabetes patients fits the secondary prevention line showing lowering LDL-C lowers CV event rates Summary of outcomes trials 30% CARDS baseline Final 1° prevention – placebo 2° prevention – placebo 1° prevention – statin 2° prevention - statin 4S 25% Secondary prevention 20% 4S 15% LIPID LIPID CARE Incidence of major coronary events PROSPER PROSPER HPS ALLHAT 10% PROVE-IT prava WOSCOPS CARE PROVE-IT atorva AFCAPS/ TexCAPS CARDS HPS TNT atorva 10 mg ALLHAT WOSCOPS 5% A number of landmark studies have shown that the reduction of LDL-C with statin therapy improves cardiovascular morbidity and mortality in patients with and without established cardiovascular disease. In both primary and secondary prevention studies a greater reduction in LDL-C resulted in greater reductions in cardiovascular (CV) events. The fact that ’lower is better is now widely accepted. The data clearly show that whether you have CV disease or not and whatever your baseline LDL-C is, however much you lower LDL-C you reduce CV risk and the lower you can get your LDL-C the better. The international guidelines for screening and intervention are based on evidence such as that presented together with epidemiological data. It is therefore reasonable that the achievement of evidence-based treatment guideline goals can be used as a good surrogate for outcomes data until that becomes available. References 1. Ballantyne C. Low-density lipoproteins and risk for coronary artery disease. Am J Cardiol 1998;82:3Q-12Q 2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 3. Sever, PS et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm: a multicentre randomised controlled trial. Lancet 2003;361:1149-58 Adapted from Am J Cardiol 1998;82:3Q-12Q with permission from Excerpta Medica Inc. CARDS TNT atorva 80 mg Primary prevention ASCOT ASCOT AFCAPS/ TexCAPS 0% 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) Adapted from : Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279, LaRosa JC et al. N Engl J Med 2005;352:e-version. Colhoun, HM et al. Lancet 2004; 364:685-96

Rivascolarizza zione coronarica Variazione rispetto a placebo (%) Efficacia del trattamento con statine in soggetti diabetici Meta-analisi di 14 studi randomizzati Mortalità per Tutte le cause IMA o morte coronarica Rivascolarizza zione coronarica Mortalità vascolare Eventi CV maggiori Ictus -5 -10 -9 * Variazione rispetto a placebo (%) -15 -13 -13 ** ** -16 -20 -18 ** ** -21 -21 -21 Il trattamento della dislipidemia nel paziente diabetico è quindi particolarmente importante, come dimostrato da una recente meta-analisi di 14 studi randomizzati condotti in 18.686 soggetti affetti da diabete mellito di tipo 1 o 2, seguiti per 4,3 anni. Il trattamento preventivo con statine in questi individui si è dimostrato efficace tanto quanto quello di individui non diabetici. -22 -25 ** ** -23 ** ** -24 ** -25 ** ** -30 Non diabetici (n=71.370) Diabetici (n=18.686) *p<0,05; **p<0,01 Cholesterol Treatment Trialists. Lancet 2008;371:117-125

Nuove Linee Guida ADA Diabetes Care volume 34 suppl1 Jaunuary 2011

Nuove Linee Guida ADA Diabetes Care volume 34 suppl1 Jaunuary 2011

Nuove Linee Guida ADA Diabetes Care volume 34 suppl1 Jaunuary 2011

Nuove Linee Guida ADA Diabetes Care volume 34 suppl1 Jaunuary 2011

STANDARD ITALIANI PER LA CURA DEL DIABETE MELLITO 2009-2010

NOTA 13 “L’uso dei farmaci ipolipemizzanti deve essere continuativo e non occasionale ,cosi come il controllo degli stili di vita ( alimentazione ,fumo, attivita fisica etc.)….”

Rosuvastatin Clinical Overview December 2004 Even With Dose Titration, Many Patients Fail to Achieve LDL-C Goals The ACCESS Study 80 Atorvastatin 10–80 mg Simvastatin 10–40 mg Lovastatin 20–80 mg 60 Fluvastatin 20–80 mg Pravastatin 10–40 mg Patients at LDL-C goal (%) 40 20 This is data from the ACCESS study in which patients with coronary heaqrt disease were titrated to the maximum dose available over one year. Results showed that even with the maximum dose of atorvastatin, the proportion of patients reaching their treatment goal was only 70% and with simvastatin even more patients failed to achieve their treatment goals. This study confirms that even at the maximum dose of a highly effective statin such as atorvastatin, there is still room for improvement. CHD Patient numbers: Statin Number Number (%) at LDL goal Atorvastatin 1286 926 (72.0) Simvastatin 303 156 (51.5) Lovastatin 332 145 (43.7) Fluvastatin 322 97 (30.1) Pravastatin 300 74 (24.7) Reference 1. Ballantyne CM et al. Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88:265–269 At week 54, n=2543 CHD patients Ballantyne CM et al. Am J Cardiol 2001;88:265–269

Statins: LDL-C lowering in patients with type 2 diabetes MERCURY I ANDROMEDA URANUS CORALL 8 weeks 8 weeks 4 weeks 6 weeks Rosuvastatin (10mg) Atorvastatin (20mg) n=140 n=140 n=265 n=227 n=229 n=231 n=229 n=131 n=132 -10% -20% %Change from baseline -30% -37 -39 -39 -41 -40% -44 -45 -47 -48 † # -51 # -50% * -60% #p<0.0001 vs atorvastatin 10 mg *P<0.001 vs atorvastatin 10 mg †P<0.05 vs atorvastatin 20 mg Berne C, Siewert-Delle A. Atherosclerosis Supplements 2004; 5:107, Abs M.463. Franken A, Wolffenbuttel B, Vincent H. Atherosclerosis Supplements 2004; Betteridge D, Gibson M. Atherosclerosis Supplements 2004; 5:107, Abs M.464. 5:118, Abs M.513. 1036–43. Schuster H et al. Diabetalogia 2004; 47 (suppl), AW09; 1146

Change in LDL-C in diabetic subgroup Results from the VOYAGER individual patient data meta-analysis Rosuvastatin Atorvastatin Simvastatin Dose (mg) 5 10 20 40 10 20 40 80 10 20 40 80 n=41 n=3373 n=1076 n=768 n=2286 n=1465 n=356 n=602 n=14 n=827 n=173 n=32 -10 -20 -30 LS mean (SE) % change from baseline -40 * Comparisons of rosuvastatin with equal/higher doses of atorvastatin and simvastatin were calculated using only those trials which directly randomized between the treatments being compared. -50 † †† # -60 ‡ *p<0.001 rosuvastatin 10mg vs atorvastatin 10mg & 20mg; simvastatin 10mg, 20mg & 40mg; †p<0.003 rosuvastatin 20mg vs atorvastatin 20mg & 40mg; simvastatin 20mg & 40mg; ‡p<0.001 rosuvastatin 40mg vs atorvastatin 40mg & 80mg; simvastatin 40mg; ††p<0.003 atorvastatin 80mg vs rosuvastatin 5mg, 10mg; #p=0.027 simvastatin 80mg vs rosuvastatin 5mg Nicholls S, Brandrup-Wognsen G, Palmer M et al. Am J Cardiol 2010; 105:69-76 35

Rosuvastatin Clinical Overview December 2004 Statin efficacy: LDL-C Efficacy Across the Dose Range The STELLAR Study Change in LDL-C from baseline (%) –5 –10 –15 –20 –25 –30 –35 –40 –45 –50 –55 –60 10 mg * 20 mg † 40 mg ‡ 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin 10 mg 20 mg 40 mg 80 mg Simvastatin Pravastatin Rosuvastatin 10 mg reduced LDL-C to a significantly greater extent than atorvastatin 10 mg; simvastatin 10, 20 or 40 mg; and pravastatin 10, 20 or 40 mg (p<0.002). Reference Jones PH 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 10 mg 20 mg 40 mg Rosuvastatin 10 mg (–46%) *p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg †p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk Rosuvastatin Clinical Overview December 2004 Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% In the USA, the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that each 1% decrease in LDL-C equates to a 1% reduction in CHD risk. In addition, every 1% increase in HDL-C equates to a 3% reduction in CHD risk. Reference 1. Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

HDL-C remains predictive of CVD events regardless of LDL-C levels: the TNT results 12 10 8 6 4 2 Q1 Q2 Q3 Q4 Q5 (<38) (38-<43) (43-<48) (48-<55) (>55) In Pts with LDL-C <70 mg/dl +39% Q1 vs Q5 5 Yr Risk of Major CV Events (%) Quintile of HDL-C Level (mg/dl) Multivariate analysis including: sex, age, BMI, Smoking SBP, Fasting glucose, TG, Diabetes, MI, hypertension Barter P et al. NEJM 357:1301-10, 2007 38 Lipid Management in Clinical Practice - Section 1

The Impact of Statins on HDL-C The STELLAR Study Rosuvastatin Clinical Overview December 2004 The Impact of Statins on HDL-C The STELLAR Study Change in HDL-C from baseline (%) 12 Rosuvastatin Atorvastatin * † 10 ns n=473 8 6 4 2 n=634 Data from STELLAR demonstrates that rosuvastatin produces a significant HDL-C raising effect which is maintained across the dose range, in contrast to atorvastatin where the HDL-C raising effect diminishes with increasing dose1. In practice, this means that increasing the atorvastatin dose to achieve the same level of LDL-C reduction as rosuvastatin will result in less favourable effect on HDL-C. rosuvastatin 10 mg raised HDL-C statistically significantly more than pravastatin 10 mg (p<0.002). rosuvastatin 20 mg raised HDL-C statistically significantly more than atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20, 40 mg (p<0.002). rosuvastatin 40 mg raised HDL-C statistically significantly more than atorvastatin 40 and 80 mg, simvastatin 40 mg, and pravastatin 40 mg (p<0.002). Mean baseline HDL-C for rosuvastatin group: 51 mg/dL. Remember that the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that every 1% increase in HDL-C equates to a 3% reduction in CHD risk2. References Jones PH 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 Third report of the NCEP expert panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. 10 20 40 80 Dose (mg); log scale *p<0.002 vs atorvastatin 20, 40 and 80 mg †p<0.002 vs atorvastatin 40 and 80 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Change in HDL-C in diabetic subgroup Results from the VOYAGER individual patient data meta-analysis 9 8 * 7 † ‡ 6 5 LS mean (SE) % change from baseline 4 3 2 1 Comparisons of rosuvastatin with equal/higher doses of atorvastatin and simvastatin were calculated using only those trials which directly randomized between the treatments being compared. n=41 n=3373 n=1076 n=768 n=2286 n=1465 n=356 n=602 n=14 n=827 n=173 n=32 Dose (mg) 5 10 20 40 10 20 40 80 10 20 40 80 Rosuvastatin Atorvastatin Simvastatin *p<0.005 rosuvastatin 10mg vs atorvastatin 10mg, 20mg, 40mg and p=0.012 vs atorvastatin 80mg; †p<0.005 rosuvastatin 20mg vs atorvastatin 20mg, 40mg & 80mg; ‡p<0.001 rosuvastatin 40mg vs atorvastatin 40mg & 80mg; Nicholls S, Brandrup-Wognsen G, Palmer M et al. Am J Cardiol 2010; 105:69-76 40

Change in non-HDL-C in diabetic subgroup Results from the VOYAGER individual patient data meta-analysis Rosuvastatin Atorvastatin Simvastatin Dose (mg) 5 10 20 40 10 20 40 80 10 20 40 80 n=41 n=3373 n=1076 n=768 n=2286 n=1465 n=356 n=602 n=14 n=827 n=173 n=32 -10 -20 -30 LS mean (SE) % change from baseline -40 * Comparisons of rosuvastatin with equal/higher doses of atorvastatin and simvastatin were calculated using only those trials which directly randomized between the treatments being compared. -50 † †† ‡ -60 *p<0.001 vs atorvastatin 10mg & 20mg; simvastatin 10mg, 20mg & 40mg; †p<0.003 vs atorvastatin 20mg & 40mg; simvastatin 20mg & 40mg; ‡p<0.001 vs atorvastatin 40mg & 80mg; simvastatin 40mg; ††p<0.003 atorvastatin 80mg vs rosuvastatin 5mg, 10mg; Nicholls S, Brandrup-Wognsen G, Palmer M et al. Am J Cardiol 2010; 105:69-76

The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Hulten, Arch Intern Med 2006;166:1814–1821. 13 trials and 17963 Pts Early statin therapy safe and had a positive impact on outcome. Beneficial effects on the rate of death and cardiovascular event over 2 years of follow-up (HR 0.81, 95% CI,0.77–0.87, P< 0.001). Survival benefit was apparent only after 4 months, achieving statistical significance by 12 months. IMA No ideal per reclut tardivo (dopo 14 gg), non reversal per altro end point, no princess per interruz A.I./Rivascol Morte card

si assomma a quello delle statine a dose standard Trattamento intensivo per 5 anni: -35000 eventi (14000 morti/IMA) per milione di pazienti trattati. NNT 29 (a due anni per ACS, 5 anni per altri). Questo vantaggio si assomma a quello delle statine a dose standard 27540 pz: TNT sospetto di aum morte non cardiaca, coronary death or any cardiovascular event (myocardial infarction, stroke, hospitalization for unstable angina, or revascularization) (p
0.0001

Effetti “pleiotropici”

colesterolemia LDL (%) Rosuvastatina 20mg equivale ad Atorvastatina 80mg dopo Sindrome Coronarica Acuta :effetto sul C-LDL Studio CENTAURUS 1 mese 3 mesi -10 -20 -30 -40 colesterolemia LDL (%) Riduzione mediana -50 -49 -48 -50 -60 -51 La diapositiva mostra la riduzione percentuale della colesterolemia LDL con i due trattamenti a 1 mese e a 3 mesi. Ambedue i trattamenti hanno ridotto la colesterolemia, in maniera non significativamente diversa tra loro. -70 -80 Rosuvastatina 20 mg Atorvastatina 80 mg -90 Lablanche J-M 2010 45

Rosuvastatina 20mg equivale ad Atorvastatina 80mg dopo Sindrome Coronarica Acuta : pazienti a target Studio CENTAURUS

Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):68 Statin Discontinuation after NSTE-ACS: “San Filippo Neri” Prospective Registry 2234 patients; mean age 72 yrs Discharge During the 12-month follow-up, 27.3% patients discontinued statin therapy; median time to discontinuation 35 days (IQR 21-79). Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):68

Reported causes of discontinuation of statin therapy after an acute coronary event “Too many pills” Reported Side Effects Dyspepsia Fatigue Headache Myalgias Asymptomatic increase in liver enzymes Asymptomatic increase in total CK Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):68

Switching from intensive to moderate statin therapy after an acute coronary event 1,321 patients discharged on atorvastatin 80mg/day* 486 (37%) continued atorvastatin 80mg/day 278 (21%) discontinued therapy Median time to discontinuation 37 days (IQR 19–81 days) 557 (42%) switched to moderate statin therapy Median time to switching 28 days (IQR 16–67 days) 102 (18%) switched to a lower dose of atorvastatin Mean dose 24mg/day 327 (59%) switched to simvastatin Mean dose 27mg/day 57 (16%) switched to pravastatin Mean dose 40mg/day 41 (7%) switched to fluvastatin Mean dose 80mg/day *1321 consecutive patients (886 men, mean age 71.1 ± 8.7 years) discharged on atorvastatin 80mg/day after an ACS in a 6.5-year period Colivicchi F, et al. Eur Heart J 2008; 29 (suppl. 1):67

Reported causes of Switch form High-dose Statin Therapy after ACS “Dosage too high” “Afraid of major adverse reactions” Reported Side Effects Dyspepsia Fatigue Headache Myalgias Asymptomatic increase in liver enzymes Asymptomatic increase in total CK Switching was reported by patients and primary care physicians as due to mild side effects in 56% of cases. However, no case of any major adverse reaction was reported. In the remaining cases, the decision to switch was taken by the primary care physician, who either considered Atorvastatin dosage as too high for the patient (52%), or was afraid of potential major liver or muscle damage (48%). Colivicchi F, et al. Eur Heart J 2008;29 (Suppl. 1):67

Association between switching and MACE Colivicchi F, et al. Int J Cardiol (2010), doi:10.1016/j.ijcard.2010.07.006

La terapia con statine dopo SCA Deve tendere al raggiungimento degli obiettivi terapeutici previsti in rapporto al profilo di rischio del singolo paziente (C-LDL almeno al di sotto di 100 mg/dl, meglio se al di sotto di 70-80 mg/dl). Deve proseguire indefinitamente. Deve essere prestata particolare attenzione all’aderenza del paziente al trattamento prescritto. La scelta di una molecola con migliore rapporto rischio/beneficio riduce la probabilità di interruzione del trattamento

Aderenza e statine L’interruzione della terapia con statine dopo SCA comporta un inevitabile peggioramento del profilo lipidico ed il mancato raggiungimento dei target di intervento previsti nelle linee guida. Il fenomeno è spesso riconducibile ad effetti collaterali e reazioni avverse. L’interruzione della terapia comporta un significativo peggioramento della prognosi clinica con incremento della mortalità.

It is important to note that our safety and efficacy results were obtained in a carefully selected and monitored study population……. Although both drugs were generally well tolerated, there were significantly more liver related side effects with high-dose atorvastatin than with standard-dose pravastatin. Patients in clinical practice generally have more coexisting conditions than did our patients, and they may not tolerate a high-dose statin regimen……. Thus, clinicians must take these factors into account when applying the results of our trial in clinical practice.

Dietro l’efficacia degli alti dosaggi Evidence from well designed randomised controlled trials shows that myopathy correlates most closely with dose of statins and is independent of reductions in LDL-C Lipophilic statins (for example, simvastatin, atorvastatin, lovastatin) are more likely to produce muscular effects than are relatively hydrophilic agents (such as pravastatin, rosuvastatin, and fluvastatin) Lipophilic compounds (such as simvastatin, atorvastatin, lovastatin) are more likely to penetrate into muscle tissue, enhancing the potential for myotoxic effects.

Lipofilia relativa* delle statine -1,0 -0,5 0,0 0,5 1,0 1,5 2,0 Cerivastatina Simvastatina Fluvastatina Atorvastatina Rosuvastatina Pravastatina Rosuvastatina è un singolo enantiomero di sintesi (3R, 55) somministrabile come sale calcico dell’idrossiacido attivo. Come osservato nella diapositiva precedente, la spiccata inibizione enzimatica della rosuvastatina è dovuta al maggior numero di legami con l’HMG-CoA reduttasi, rispetto alle altre statine. Oltre al caratteristico raggruppamento farmacoforo delle statine, rosuvastatina presenta un gruppo polare metan-sulfonico che conferisce una relativa idrofilia alla molecola (= bassa lipofilia), vicina a quella di pravastatina. Le caratteristiche di relativa idrofilia contribuiscono a conferire alta selettività sulla sintesi epatica di colesterolo rispetto a quella in cellule non epatiche. * log D con pH 7,4 McTaggart F et al. Am J Cardiol 2001;87:28B-32B

SAFETY OF HIGH—DOSE ATORVASTATIN THERAPY Waters DD, Am J Cardiol 2005;96[suppl]: 69F–75F

Miopatia secondaria Valutazione del rapporto efficacia/sicurezza Pravastatina 20 – 40 mg Rosuvastatina 10 - 20 - 40 mg Simvastatina 40 - 80 mg Atorvastatina 10 - 20 - 40 - 80 mg Cerivastatina 0,2 - 0,3 - 0,4 - 0,8 mg CK >10 i valori normali (%) 70 20 30 40 50 60 Riduzione del colesterolo LDL (%) 0,0 0,5 1,0 1,5 2,0 2,5 Grazie alle sue caratteristiche farmacologiche, rosuvastatina risulta non solo più efficace di altre statine ma anche meglio tollerata. Nella diapositiva è mostrata la relazione tra le riduzioni dei livelli di colesterolo LDL e l’aumento della creatina chinasi (CK) >10 volte il limite superiore della norma con cerivastatina, pravastatina, simvastatina, atorvastatina e rosuvastatina. Si noti come all’aumentare del dosaggio della statina aumentino gli effetti collaterali, con tutte le statine, anche se atorvastatina e rosuvastatina mostrano un incremento degli effetti collaterali meno ripido rispetto alle altre statine. Inoltre, a dosi equivalenti rosuvastatina risulta la statina con la migliore tollerabilità muscolare e, quindi, con il migliore rapporto efficacia/sicurezza. Brewer HB. AM J Cardiol 2003;92:23K-29K

ALTA EFFICACIA / ALTA DOSE

Rosuvsatatina Alta efficacia e sicurezza LDL Evento avverso CK ALT 10 20 30 40 50 60 70 80 90 1 2 3 Dose (mg) Riduzione LDL (%) Ck>10 i valori normali (%) Rosuvastatina Atorvastatina Simvastatina ALT >3 i valori normali (%) Il buon rapporto efficacia / sicurezza di rosuvastatina è illustrato in questa diapositiva. A parità di dosaggio, rosuvastatina determina infatti una maggiore riduzione della colesterolemia LDL rispetto ad atorvastatina e simvastatina, con una tollerabilità muscolare ed epatica decisamente migliore. Jacobson TA Am J Cardiol 2006;97(8A):44C-51C 60

Conclusioni Il paziente diabetico è un paziente ad alto rischio che si giova di un trattamento con statine sia in prevenzione primaria che secondaria. La letteratura e le linee guida ci indicano chiaramente quali sono i target terapeutici da raggiungere per ridurre il rischio di eventi cardiovascolari Le statine sono i farmaci di prima scelta da usare: la loro efficacia è dimostrata anche nei pazienti diabetici, sia in prevenzione primaria che secondaria, con una riduzione significativa degli eventi cardiovascolari e della mortalità

Conclusioni La riduzione del rischio relativo ed assoluto è indipendente dai livelli di colesterolo LDL iniziale Per ottenere questi risultati, abbiamo a disposizione più di una molecola con dimostrata efficacia sui principali parametri che influenzano la prognosi La scelta della molecola è legata all’obiettivo che ci siamo preposti e al suo completo o meno raggiungimento La compliance del paziente è un elemento fondamentale, assieme alla tollerabilità, per l’aderenza alla terapia nel follow-up La disponibilità di farmaci ad bassa dose ed alta efficacia può favorire la cura ottimale del nostro paziente

La terapia con statine dopo SCA Rosuvastatina è la statina di maggiore efficacia nel ridurre il C-LDL Rosuvastatina 20mg equivale ad Atorvastatina 80mg dopo Sindrome Coronarica Acuta La Rosuvastatina garantisce un “intensive lipid- lowering” senza i “rischi” delle alte dosi favorendo quindi la sostenibilità terapeutica

Effetti “pleiotropici”

Effetti delle Statine Comuni a tutte le statine – Modificazione dei lipidi – Ossidazione delle lipoproteine – Funzione endoteliale – Controllo pressorio ? Differenti tra statine Effetto sulle cellule muscolari lisce Effetto sulla formazione del trombo piastrinico Effetto sull'infiammazione(?) Effetto sul fibrinogeno Concentriamoci sulle differenze tra statine: per prima cosa, gli effetti sulle cellule muscolari lisce. Rosenson et al: JAMA 1998;279:1643–1650

Statine nella Prevenzione CV del pz. diabetico Studio (anni) Farmaco RRR di CVD nell’intera popolazione RRR di CVD nei soggetti con diabete Prevenzione Primaria HPS (5) Simvastatina 40mg 24 33 (P=.0003) ASCOT (3,3) Atorvastatina 10mg 20 23 (P=.036) CARDS (3,9) 37 (P=.001) Prevenzione Secondaria 4S (5,4) 4S Reanalisi Simvastatina 20-40mg 32 55 (P=.002) 42 (P=.001) CARE (5) Pravastatina 40mg 23 25 (P=.05) GREACE (3) Atorvastatina 20mg 51 58 (P<.0001) 12 (P<.05)

Figure 2.Top.Odds ratio (with 95%confidence interval ) of major adverse cardiac events at 30 daysin patients receiving high dose statin pre-treatement vs control)

Figure 1.Top.Odds ratio (with 95%confidence interval ) of periprocedural myocardila infarction in patients receiving high dose statin pre-treatement vs control)