La terapia della dislipidemia nel diabetico: quali farmaci usare e con quali obiettivi? Novità in arrivo? Maria Chantal Ponziani

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1 La terapia della dislipidemia nel diabetico: quali farmaci usare e con quali obiettivi? Novità in arrivo? Maria Chantal Ponziani

2 Dal La storia DEI TARGET IN LIPIDOLOGIA DELLE TERAPIE E DEI TRIALS IN LIPIDOLOGIA

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5 NCEP ATP III: I NUOVI TARGET PER IL COLESTEROLO LDL (MODIFICAZIONI PROPOSTE 2005) NCEP ATP III, JAMA 2001 NCEP ATP III 2005 rev. Opzioni terapeutiche da considerare Coronaropatia e equivalenti di rischio: 100 mg/dl Rischio CV globale (Fram.) 10-20%: <130 mg/dl Rischio CV globale (Fram.) <10%: <160 mg/dl Coronaropatia e equivalenti di rischio: <70 mg/dl Rischio CV globale (Fram.) 10-20%: <100 mg/dl Rischio CV globale (Fram.) <10%: <160 mg/dl NCEP = National Cholesterol Education Program; ATP = Adult Treatment Panel; TC = total cholesterol Wood D et al.,atherosclerosis 1998;140: NCEP ATP III JAMA 2001;285: Grundy SM et al. Circulation 2004;110: Grundy SM et al. Circulation 2005;112:

6 ATP IV ABBANDONO CONCETTO DI TARGET DI COLESTEROLO DA RAGGIUNGERE CON LA TERAPIA DEFINIZIONE DI 4 CATEGORIE DI PAZIENTI CON OGNUNO UNA INTENSITÀ APPROPRIATA DI TERAPIA STATINICA IDENTIFICARE MEGLIO QUALI SIANO I PAZIENTI CHE POTRANNO TRARRE IL MASSIMO BENEFICIO DAGLI INTERVENTI

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9 New Therapies in the Treatment of High Cholesterol: An Argument to Return to Goal-Based Lipid Guidelines William H. Shrank, MD, MSHS 1 ; Jane F. Barlow, MD, MPH 1 ; Troyen A. Brennan, MD, JD 1 JAMA 2015;314: Gli autori facendo riferimento alle linee guida sul trattamento del colesterolo rilasciate dall American College of Cardiology e dall American Heart Association scrivono «oggi è disponibile un insieme più ricco di opzioni terapeutiche per l iperlipidemia e la più recente serie di linee guida non fornisce chiarezza su come scegliere. In particolare le linee guida non raccomandano la titolazione della terapia basata sul controllo del LDL-c. Saranno i Medici a interpretare le linee guida per indicare che nei pazienti più a rischio debbano essere prescritti gli inibitori PCSK9? Si ipotizza che un approccio basato sul raggiungimento del target potrebbe ridurre i costi.

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14 La lezione dei trials con statine nei diabetici: Riduzione Rischio CHD Farmaco No. (pop.generale) (diabetici) Prevenzione Primaria AFCAPS/TexCAPS Lovastatina % -43% Prevenzione Secondaria CARE Pravastatina % -25% (P =.05) 4S Simvastatina % -55% (P =.002) LIPID Pravastatina % -19% 4S-Extended Simvastatina % -42% (P =.001)

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17 HEART PROTECTION STUDY Risk ratio and 95% CI EVENTI VASCOLARI SIMVASTATINA (10,296) PLACEBO (10,267) Eventi coronarici maggiori 898 (8.7%) 1212 (11.8%) Diabete 279 (9.4%) 377 (12.6%) No diabete 619 (8.5%) 835 (11.5%) Ictus 444 (4.3%) 585 (5.7%) Diabete 149 (5.0%) 193 (6.5%) No diabete 295 (4.0%) 392 (5.4%) Rivascolarizzazioni 939 (9.1%) 1205 (11.7%) Diabete 260 (8.7%) 309 (10.4%) No diabete 679 (9.3%) 896 (12.3%) Eventi vascolari maggiori 2033 (19.8%) 2585 (25.2%) Diabete 601 (20.2%) 748 (25.1%) No diabete 1432 (19.6%) 1837 (25.2%) STATIN Better PLACEBO Better 27% riduzione (15 38) p< % riduzione (6 39) p= % riduzione (3 30) p= % riduzione (13 30) p< Heart Protection Study Collaborative Group. Lancet 2003;361: Reprinted with permission from Elsevier Science

18 Variazione rispetto a placebo (%) EFFICACIA DEL TRATTAMENTO CON STATINE NEL DIABETICO (RIDUZIONE DEGLI EVENTI PER UN CALO DI LDL-C DI 1 MMOLE) Meta-analisi di 14 studi randomizzati Non diabetici (n=71.370) Diabetici (n=18.686) 0 Mortalità per Tutte le cause Mortalità Eventi IMA o morte vascolarecardiovascolare maggiori coronarica Rivascolarizzazione coronarica Ictus * ** -18 ** *p<0,05; **p<0,01-13 ** -21 ** -21 ** -23 ** -22 ** -24 ** -25 ** -16 ** -21 ** Cholesterol Treatment Trialists. Lancet 2008; 371:

19 % Major Coronary events SIMVASTATIN DID NOT REDUCE MACE IN THE HIGHEST QUARTILES OF CHOLESTEROL ABSORPTION -4S SUB-STUDY Quartiles of Cholesterol Absorption 38% 34% 25% 17% Relative Risk Placebo (n=434) Simvastatin mg (n=434) Low response to simvastatin Low Cholesterol Absorption 4S = Scandinavian Simvastatin Survival Study. High Cholesterol Absorption Miettinen et al. BMJ. 1998;316:1127

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21 WHY A DIABETIC PATIENT CAN BE MORE RESPONDER TO EZETIMIBE/STATIN THERAPY? mrna expression of NPC1L1 protein is increased, and of ABCG5 and G8 decreased both in animal models of diabetes as well as in patients with T2DM. Lally et al. Metabolism 2007; 56: Lally et al. Diabetologia 2007; 50: Hyperglycemia enhanced the protein expression of NPC1L1 in culture cells. Ravid et al. Am J Physiol Gastrointest Liver Physiol 2008; 295: G873-G885

22 EFFECT OF GLUCOSE CONCENTRATIONS ON CHOLESTEROL UPTAKE AND ON THE EXPRESSION OF NPC1L1 IN INTESTINAL CELLS RAVID ET AL. AM J PHYSIOL GASTROINTEST LIVER PHYSIOL 2008; 295: G873-G885

23 INTERFERENCE OF EZETIMIBE WITH THE UPTAKE OF CHOLESTEROL IN THE PRESENCE OF GLUCOSE Ravid et al. Am J Physiol Gastrointest Liver Physiol 2008; 295: G873-G885

24 Tasso di eventi % Ballantyne CM et al. Circulation 2001;104: Used with permission of Lippincott Williams & Wilkins. La triade aterogena nel 4S 40 Triade aterogena RR=0.48 ( ) 36.9 Aumento isolato del LDL-C RR=0.86 ( ) Simvastatin 30 Placebo

25 Bruckert E et al J Cardiovasc PharmacolT 57:267, 2011 Sacks FM et al. N Engl J Med 2010 Effect of fibrates in subgroups without (A) and with (B) dyslipidemia A total of 2428 fibrate-treated subjects (302 events) and 2298 placebo-treated subjects (408 events) with dyslipidemia were included in the analysis B Subgroups with Dyslipidemia Study ACCORD FIELD BIP HHS VA-HIT Odds Ratio (95% CI) 31% 27% 39% 78% 28% A Complementary Subgroups Study Odds Ratio (95% CI) ACCORD FIELD BIP HHS VA-HIT Summary 0.65 ( ) % Summary 0.94 ( ) % DYSLIPIDEMIA: TG 200 mg/dl, HDL-C mg/dl Fibrates reduce CVD among patients with the lipid phenotype of the atherogenic dyslipidemia

26 Clin Investig Arterioscler Mar-Apr;28(2):71-8. doi: /j.arteri Epub 2015 Dec 29. Circulating PCSK9 in patients with type 2 diabetes and related metabolic disorders. Ibarretxe D 1, Girona J 1, Plana N 1, Cabré A 1, Ferré R 1, Amigó N 2, Guaita S 1, Mallol R 2, Heras M 1, Masana L The results showed that PCSK9 levels are increased in patients with T2DM and MetS (14% and 13%; p<0.005, respectively). Circulating PCSK9 levels were correlated with an atherogenic lipid profile and with insulin resistance parameters. PCSK9 levels were also positively associated with AD, as defined by lipoprotein particle number and size. The rs genetic variant resulted in lower levels of circulating PCSK9 and LDL cholesterol (LDL-C).

27 Lancet Diabetes Endocrinol May;4(5): doi: /S (16) Epub2016 Feb 8. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Sattar N1, Preiss D2, Robinson JG3, Djedjos CS4, Elliott M5, Somaratne R4, Wasserman SM4, Raal FJ6. Three trials met our inclusion criteria, and included 413 patients with type 2 diabetes and 2119 patients without type 2 diabetes. In patients with type 2 diabetes evolocumab caused mean reductions in LDL cholesterol concentration that were 60% (95% CI 51-69) versus placebo and 39% (32-47) versus ezetimibe. In patients without type 2 diabetes, evolocumab caused mean reductions in LDL cholesterol that were 66% (62-70) versus placebo and 40% (36-45) versus ezetimibe. In patients with type 2 diabetes, evolocumab was associated with reductions in non-hdl cholesterol (55% [47-63] vs placebo and 34% [26-41] vs ezetimibe), total cholesterol (38% [32-44] vs placebo and 24% [16-31] vs ezetimibe), and lipoprotein(a) (31% [25-37] vs placebo and 26% [16-35] vs ezetimibe), and an increase in HDL cholesterol (7% [4-11] vs placebo and 8% [4-13] vs ezetimibe). Findings were similar across diabetes subgroups based on glycaemia, insulin use, renal function, and cardiovascular disease status. INTERPRETATION: Evolocumab markedly reduces atherogenic lipoproteins in patients with type 2 diabetes, an effect that is consistent across subgroups and similar to that seen in patients without type 2 diabetes. Results from ongoing cardiovascular outcome trials of PCSK9 inhibitors will provide additional data to inform the use of these drugs in patients with type 2 diabetes

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