Target e trattamento di dislipidemia e ipertensione nel diabete

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1 Riunione Annuale Congiunta SID-AMD Target e trattamento di dislipidemia e ipertensione nel diabete Giuseppe Memoli Cad San luca Ariano Irpino (AV) Napoli, 9 giugno 2018

2 Dichiaro di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Astra Zeneca Boehringher-Ingelheim Eli Lilly Italy Janssen Novo Nordisk Farmaceutici Roche Diagnostics Sanofy Takeda Dichiaro altresì il proprio impegno ad astenersi, nell ambito dell evento, dal nominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.). In Fede Giuseppe Memoli

3 ~65% of deaths are due to CV disease Coronary heart disease deaths 2- to 4-fold Cardiovascular complications of T2DM Stroke risk 2- to 4- fold Heart failure 2- to 5- fold Bell DSH. Diabetes Care. 2003;26: Centers for Disease Control (CDC).

4 COSTANTE AGGREGAZIONE CON ALTRI FATTORI DI RISCHIO CARDIOVASCOLARE OVVERO I CATTIVI COMPAGNI E LE RELAZIONI PERICOLOSE Y UbdU^ cy_ ^ U"QbdUbY_ cq Y Ub \ Y YT U] YQ _ RUcYdQ` Q\ d Ub Qj Y_ ^ Y"TU\\Q"""" S _ QWe \ Qj Y_ ^ U U"T U\ \ Q"V YR b Y^ _ \ Yc Y Y Ub Y^ c e \ Y^ U] YQ"= Y^ c e \ Y^ _ b Uc Yc d U^ j Q

5 IPERTENSIONE ARTERIOSA Target e trattamento nel diabete mellito

6 The first direct blood pressure mesaurement is attribuited to the Reverend Stephen Hales in 1733

7 OBIETTIVI DEL TRATTAMENTO DELLA PRESSIONE ARTERIOSA PRESSORI NELLE VARIE LINEE GUIDA NICE 2011: < 140/80 under 80 < 150/90 over 80 ESC/ESH 2013: from <130/80 to < 140/85 JNC 8 (2013): < 140/90 ADA 2013: from <130/80 to < 140/80 ADA 2018 : tutti < 140/90 alto rischio CV< 130/80

8 STANDARD AMD-SID tutti > 1 gr proteinuria PAS < 130 < 125 PAD < 80 < 75 tutti STANDARD AMD-SID pz.più giovani, elevato rischio ictus, micro-macroalbuminuria, 1 o più F.R CV pz. anziani gravidanza PAS < 140 < 130 < PAD < 90 < 80 <

9 Problematiche aperte Targets e intervalli ottimali di valori pressori sisto-diastolici

10 PROVE A FAVORE DI UN TARGET PRESSORIO PIU CONSERVATIVO

11 Achieved SBP in randomised trials on type 2 diabetic individuals receiving antihypertensive treatment SBP BENEFICIO CV NESSUN BENEFICIO CV Mancia and Grassi (2018) Diabetologia DOI /s

12 Effect of 10 mmhg reduction of SBP on outcomes in 40 trials on 100,354 diabetic individuals SBP of 130 mmhg (mean 138 mmhg SBP <130 mmhg (mean 122 mmhg) Mancia and Grassi (2018) Diabetologia DOI /s

13 INVEST TRIAL (6.400 PAZIENTI CON DMT2) Cooper-DeHoff RM et al JAMA. 2010;304:61-68

14 PROVE A FAVORE DI UN TARGET PRESSORIO PIU BASSO

15 SPRINT Study Wright JT et al. NEJM 2015

16 SPRINT Primary Outcome (MI, ACS, Stroke, HF, CV mortality) Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89) Standard (319 events) Intensive (243 events) Median follow-up = 3.26 years Number Needed to Treat (NNT) to prevent a primary outcome = 61 Wright JT et al. NEJM 2015

17 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults Categories of BP in Adults BP Category SBP DBP Normal <120 mm Hg and <80 mm Hg Elevated mm Hg and <80 mm Hg Hypertension Stage mm Hg or mm Hg Stage mm Hg or 90 mm Hg

18 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults COR LOE I SBP: B-R SR DBP: C-EO Diabetes Mellitus Recommendations for Treatment of Hypertension in Patients With DM In adults with DM and hypertension, antihypertensive drug treatment should be initiated at a BP of 130/80 mm Hg or higher with a treatment goal of less than 130/80 mm Hg. I A SR antihypertensive agents (i.e., diuretics, ACE inhibitors, ARBs, In adults with DM and hypertension, all first-line classes of IIb B-NR and CCBs) are useful and effective. In adults with DM and hypertension, ACE inhibitors or ARBs may be considered in the presence of albuminuria.

19 The ACCORD Study Mean # Meds Intensive: Standard: Average after 1 st year: Standard vs Intensive, Delta = 14.2 The ACCORD Study Group. NEJM 2010

20 The ACCORD Study Primary End-point 20 Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Patients with Events (%) HR = % CI ( ) p= Years Post-Randomization The ACCORD Study Group. NEJM 2010

21 Relative Risk for Primary / Selected Secondary Outcomes in ACCORD HR RR P Primary outcome Nonfatal MI Stroke CV death All cause death CHF Favours intensive therapy Favours standard therapy (SBP mmhg) (SBP mmhg) The ACCORD Study Group. NEJM 2010

22 Risk (HR) and related level of statistical significance (p value) of outcomes in the subgroup of diabetic participants in the ACCORD trial who were randomised to intense (Int) or standard (Std) SBP reduction, following randomisation to intense or standard blood glucose reduction (which all trial participants underwent) Mancia and Grassi (2018) Diabetologia DOI /s

23 ETEROGENEITA D ORGANO

24 ETEROGENEITA D ORGANO EVIDENZE PER IL CERVELLO S. Frontoni Panorama Diabete 2017

25 ETEROGENEITA D ORGANO EVIDENZE PER IL RENE S. Frontoni Panorama Diabete 2017

26 PER LA PRESSIONE DIASTOLICA QUAL E L OBIETTIVO? HOT - UKPDS = 80 mmhg ESC-/ESH = < 85 mmhg DIFFICOLTA PRATICA DI RAGGIUNGERE L OBIETTIVO SISTOLICO SEPARATAMENTE DA QUELLO DIASTOLICO

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28 Ulteriori problematiche aperte Qual è la metodica ideale di misurazione dei valori pressori? PA clinica PA ambulatoriale PA domiciliare PA centrale

29 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/ APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

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31 Sir Geoffrey Rose (epidemiologist).un livello di pressione sanguigna al di sopra del quale il trattamento fa più bene del male...

32 DISLIPIDEMIA Target e trattamento nel diabete mellito

33 LA DISLIPIDEMIA DIABETICA Alterazioni quantitative Alterazioni qualitative FFA Trigliceridi HDL-Colesterolo Colesterolo Totale Apo B b-vldl HDL ricche di trigliceridi LDL piccole e dense Iperlipemia postprandiale

34 Parametro Colesterolo LDL (obiettivo primario) Trigliceridi Colesterolo HDL (obiettivi ulteriori) Colesterolo non HDL (obiettivo secondario in particolare nei diabetici con Tg >200 mg/dl) STANDARD AMD-SID Obiettivo <100 mg/dl <70 mg/dl in pz con pregressi eventi CV o fattori di rischio multipli < 150 mg/dl >40 md/dl M >50 mg/dl F <130 mg/dl <100 mg/dl in pz con pregressi eventi CV o fattori di rischio multipli

35 Parametro Colesterolo LDL (obiettivo primario) Trigliceridi (obiettivo ulteriore) Colesterolo non HDL (obiettivo secondario in particolare nei diabetici con Tg >200 mg/dl) Obiettivo <100 mg/dl <70 mg/dl in pz con pregressi eventi CV o fattori di rischio multipli < 150 mg/dl <130 mg/dl <100 mg/dl in pz con pregressi eventi CV o fattori di rischio multipli

36 A. Zambon Panorama Diabete 2017

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38 Reduction in LDL Cholesterol(mmol/l) La riduzione di almeno 1 mmol/38 mg dl di colesterolo LDL riduce il rischio di CHD di circa il 22%

39 Lancet 2008; 371: There was a significant 21% proportional reduction in major vascular events per mmol/l reduction in LDL cholesterol in people with diabetes (0 79, ; p<0 0001), which was similar to the effect observed in those without diabetes (0 79, ; p<0 0001)

40 BMJ 2006;332:1115

41 SHARP Colin Baigent et al. on behalf of the Investigators Lancet 2011; 377:

42 IMPROVE-IT: Improved Reduction of Outcomes, Vytorin Efficacy International Trial Trial design: Patients with recent ACS were randomized 1:1 to either ezetimibe 10 mg + simvastatin 40 mg or simvastatin 40 mg and followed for a median of 6 years Percent reduction 50% 25% 0% Primary composite CV endpoint 32,7% 34,7% Ezetimibe/simvastatin (n = 9,067) (P=0.016) Simvastatin (n = 9,077) Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Cannon CP, et al. N Engl J Med. 2015;372: Results Primary endpoint (CV death/mi/ua/coronary revasc/stroke/moderate/severe bleeding) for ezetimibe/simvastatin vs. simvastatin: 32.7% vs. 34.7% (HR 0.94, 95% CI ; P=0.016) MI: 13.1% vs. 14.8%, P=0.002; stroke: 4.2% vs. 4.8%, P=0.05; CVD/MI/stroke: 20.4% vs. 22.2%, P=0.003 Median LDL follow-up average: 53.7 vs mg/dl Conclusions In patients with high-risk ACS, ezetimibe 10 mg/simvastatin 40 mg was superior to simvastatin 40 mg alone in reducing adverse CV events This is the first study powered for clinical outcomes to show a benefit with a non-statin agent Reaffirms the lower is better hypothesis with LDL-C

43 Major Prespecified Subgroups: IMPROVE-IT Baseline data Simva EZE/Simva Mean LDL 69.5 LDL 53.7 mg/dl Male Female Age <65 years Age 65 years No diabetes Diabetes * Prior LLT No prior LLT LDL-C >95 mg/dl LDL-C 95 mg/dl year event rates *P-interaction=0.023, otherwise >0.05 Ezetimibe/Simva Better Cannon CP, et al. N Engl J Med. 2015;372: Supplementary Appendix. Simva Better Abbreviations: LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.

44 STATIN Hypotesis effetti pleiotropici delle statine uno dei motivi aggiuntivi al semplice abbassamento del colesterolo per spiegare la riduzione degli eventi cardiovascolari ottenuti con le Statine

45 LOWER IS BETTER centralità dell abbassamento del colesterolo, specie delle LDL, con qualsiasi mezzo per avere una corrispondente riduzione degli eventi cardiovascolari

46 FOURIER Trial: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk This randomized, double-blind, placebo-controlled trial investigated the effects of adding evolocumab to highintensity statin therapy compared with high-intensity statins alone. Study results included data for over 27,500 individuals with clinically evident atherosclerotic disease and baseline LDL-C levels 70 mg/dl and non-hdl-c levels 100 mg/dl; mean patient follow-up was 2.2 years. All study participants were receiving statin therapy with or without ezetimibe, and the evolocumab and placebo groups had the same baseline LDL-C (92 mg/dl). Abbreviations:; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

47 FOURIER Evolocumab Study LDL-C Levels Over time No. at Risk LDL Cholesterol (mg/dl) Placebo Evolocumab Weeks Placebo 13,779 13,251 13,151 12,954 12,596 12,311 10, Evolocumab 13,784 13,288 13,144 12,964 12,645 12,359 10, Absolute difference (mg/dl) Percentage difference P-value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Abbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol. Sabatine MS, et al. NEJM. 2017; epub ahead of print.

48 FOURIER Evolocumab Study Endpoints Cumulative event rates for the primary efficacy endpoint (Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) Abbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; MI, myocardial infarction. Sabatine MS, et al. NEJM. 2017; epub ahead of print. Cumulative rates for the key secondary efficacy endpoint (Composite of cardiovascular death, MI, or stroke)

49 NUOVA INDICAZIONE DI EVOLOCUMAB L`k`ssh` b` qchnu` r bnk` qd ` sdqnr bkdqnshb` ` bbdqs` s` 9 dunknbt l ` a d hmchb`sn mdfkh `ctksh bnm l `k`ssh` b`qchnu`rbnk`qd ` sdqnr bkdqnshb` ` bbdqs` s` ' hme` qsn cdk l hnb` qchn+ hbst r n ` qsdqhno` sh` odqhedqhb` ( odq qhct qqd hk qhr bghn b` qchnu` r bnk` qd qhct bdmcn h khudkkh ch B,KCK+ hm ` f f ht ms` ` kk` bn qqd y hn md c h ` ksqh e` ssn qh c h qhr bg hn 9 hm `rrnbh`yhnmd `kk` cnr d l ` r r hl ` snkkdq` s` ch r s` shm` bnm n r dmy` ` ksqd sdq` ohd honkhodl hyy` msh noot qd+ hm l nmnsdq` oh` n hm ` r r nbh` yhnmd ` c ` ksqd sdq` ohd honkhodl hyy` msh hm o` yhdmsh hmsnkkdq` msh ` kkd r s` shmd n odq h pt ` kh k t r n c h r s` shmd d bnmsqnhmchb` sn- 22 March 2018 EMA/CHMP/799799/2017 Committee for Medicinal Products for Human Use (CHMP)

50 TERAPIA DELLA DISLIPIDEMIA

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