Riunione Annuale Congiunta SID-AMD Giuseppe .pdf · Riunione Annuale Congiunta . SID-AMD. Napoli, 9...

Riunione Annuale Congiunta

SID-AMD

Napoli, 9 giugno 2018

Target e trattamento di dislipidemia e

ipertensione nel diabete

Giuseppe MemoliCad San luca Ariano Irpino (AV)

Dichiaro di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

Astra ZenecaBoehringher-Ingelheim

Eli Lilly ItalyJanssen

Novo Nordisk Farmaceutici Roche Diagnostics

SanofyTakeda

In FedeGiuseppe Memoli

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.).

Heart failure ↑2- to 5-

fold

Stroke risk

↑2- to 4-fold

~65% of deaths are due to CV disease

Coronary heart

disease deaths

↑2- to 4-fold

Cardiovascular complications of

T2DM

Bell DSH. Diabetes Care. 2003;26:2433-41Centers for Disease Control (CDC). www.cdc.gov.

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COSTANTE AGGREGAZIONE CON ALTRI FATTORI DI RISCHIO CARDIOVASCOLARE

OVVERO

“ I CATTIVI COMPAGNI E LE RELAZIONI PERICOLOSE”

IPERTENSIONEARTERIOSA

Target e trattamento nel diabete mellito

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

1733

NICE 2011: < 140/80 under 80 < 150/90 over 80

ESC/ESH 2013: from

STANDARD AMD-SID 2007 -2010

tutti > 1 gr proteinuria

PAS < 130 < 125

PAD < 80 < 75

STANDARD AMD-SID 2014-2016- 2018

tuttipz .più giovani, elevato rischio ictus, micro-macroalbuminuria,

1 o più F.R CVpz. anziani gravidanza

PAS < 140 < 130 < 150 110-129

PAD < 90 < 80 < 90 65-79

Problematiche aperteTargets e intervalli ottimali di valori pressori sisto-diastolici

PROVE A FAVORE DI UN TARGET PRESSORIO PIU’ CONSERVATIVO

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 10.1007/s00125-017-4537-3


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

INVEST TRIAL (6.400 PAZIENTI CON DMT2)

Cooper-DeHoff RM et al JAMA. 2010;304:61-68

PROVE A FAVORE DI UN TARGET PRESSORIO PIU’ BASSO

Wright JT et al. NEJM 2015

SPRINT Study

Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard

Intensive(243 events)

Median follow-up = 3.26 yearsNumber Needed to Treat (NNT)to prevent a primary outcome = 61

SPRINT Primary Outcome(MI, ACS, Stroke, HF, CV mortality)

(319 events)

Wright JT et al. NEJM 2015

Categories of BP in Adults

BP Category SBP DBP

Normal

Diabetes Mellitus

COR LOE Recommendations for Treatment of Hypertension in Patients With DM

ISBP:B-RSR

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. DBP:

C-EO

I ASRIn adults with DM and hypertension, all first-line classes of antihypertensive agents (i.e., diuretics, ACE inhibitors, ARBs, and CCBs) are useful and effective.

IIb B-NRIn adults with DM and hypertension, ACE inhibitors or ARBs may be considered in the presence of albuminuria.

2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults

Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2

Mean # MedsIntensive: 3.2 3.4 3.5 3.4Standard: 1.9 2.1 2.2 2.3

The ACCORD Study

The ACCORD Study Group. NEJM 2010

Chart1

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110.59691795970.59691795970.58396198010.5839619801

119.5133.50.59807831610.59807831610.57991487410.5799148741

119.9134.10.59363771280.59363771280.6126971690.612697169

220.58143315170.58143315170.61916771490.6191677149

118.5132.90.62359087090.62359087090.61380844680.6138084468

119.4133.20.61917493230.61917493230.59739038350.5973903835

330.63982400650.63982400650.60639684880.6063968488

118.91330.64098544030.64098544030.61848888890.6184888889

118.9133.70.63850987050.63850987050.6551540140.655154014

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118.7133.20.71538185240.71538185240.71893658840.7189365884

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118.9132.60.91560557870.91560557870.93135968960.9313596896

120.5134.21.02447330271.02447330271.02963430741.0296343074

661.33794591521.33794591521.31831061931.3183106193

118131.41.82612218161.82612218161.81678539641.8167853964

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118.5132.42.43234798842.43234798842.07932699452.0793269945

121.2131.52.3684932822.3684932822.16427386642.1642738664

882.5735796882.5735796882.1428399812.142839981

Int. N = 2174 1973 1150 156Std. N = 2208 2077 1241 201

Intensive

Standard

Years Post-Randomization

SBP (mm Hg)

139

139.4

120.5

134.1

119

134

119.5

133.6

120

134.1

119.2

134

120

133.8

118.2

133.8

121.6

134.4

Sheet1

VisitIntensiveStandard

0139139.40.64943240330.64943240330.62391006610.6239100661

123.1133.40.62743394510.62743394510.60486180090.6048618009

122.1134.50.62305632810.62305632810.59767643360.5976764336

1120.5134.10.59691795970.59691795970.58396198010.5839619801

119.5133.50.59807831610.59807831610.57991487410.5799148741

119.9134.10.59363771280.59363771280.6126971690.612697169

21191340.58143315170.58143315170.61916771490.6191677149

118.5132.90.62359087090.62359087090.61380844680.6138084468

119.4133.20.61917493230.61917493230.59739038350.5973903835

3119.5133.60.63982400650.63982400650.60639684880.6063968488

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118.9133.70.63850987050.63850987050.6551540140.655154014

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8121.6134.42.5735796882.5735796882.1428399812.142839981

Pat

ient

s w

ith E

vent

s (%

)

0

5

10

15

20

Years Post-Randomization0 1 2 3 4 5 6 7 8

Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death

HR = 0.8895% CI (0.73-1.06)

p=0.20

The ACCORD StudyPrimary End-point


Relative Risk for Primary / Selected Secondary Outcomes in ACCORD

Primary outcome

Nonfatal MI

Stroke

CV death

All cause death

CHF

HR

0.5 1.0 2.0

Favours standard therapy

(SBP 133.5 mmHg)

Favours intensive therapy

(SBP 119.3 mmHg)

RR

0.88

0.87

0.59

1.06

1.19

0.94

P

0.20

0.25

0.01

0.74

0.55

0.50



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)

ETEROGENEITA’ D’ORGANO

ETEROGENEITA’ D’ORGANOEVIDENZE PER IL CERVELLO

S. Frontoni Panorama Diabete 2017

ETEROGENEITA’ D’ORGANOEVIDENZE PER IL RENE

S. Frontoni Panorama Diabete 2017

…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

Ulteriori problematiche aperte

Qual è la metodica ideale di misurazione dei valori pressori?

PA clinica

PA ambulatoriale

PA domiciliare

PA centrale

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

“….un livello di pressione sanguigna al di sopra del quale il trattamento fa più bene del male....”

Sir Geoffrey Rose (epidemiologist)

DISLIPIDEMIATarget e trattamento nel diabete mellito

b-VLDLHDL ricche di trigliceridiLDL piccole e denseIperlipemia postprandiale

Alterazioniqualitative

Alterazioni

quantitative

FFATrigliceridi

HDL-ColesteroloColesterolo Totale

Apo B

LA DISLIPIDEMIA DIABETICA

STANDARD AMD-SID 2007 -2010 -2014-2016

Parametro Obiettivo

Colesterolo LDL(obiettivo primario)

50 mg/dl F

Colesterolo non HDL(obiettivo secondario in particolare nei diabetici con Tg >200 mg/dl)

Parametro ObiettivoColesterolo LDL(obiettivo primario)

A. Zambon Panorama Diabete 2017

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%

There was a significant 21% proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol in people with diabetes (0·79, 0·72–0·86; p

BMJ 2006;332:1115

Lancet 2011; 377: 2181–92 Colin Baigent et al. on behalf of the SHARP Investigators

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

• 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 0.89-0.99; 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. 69.5 mg/dL

Results

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

32,7% 34,7%

0%

25%

50%

Per

cent

red

ucti

on

Primary composite CV endpoint

Ezetimibe/simvastatin(n = 9,067)

Simvastatin(n = 9,077)

(P=0.016)

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;372:2387-2397.

Baseline data Simva† EZE/Simva†

Male 34.9 33.2Female 34.0 31.0

Age 95 mg/dL 31.2 29.6

LDL-C ≤95 mg/dL 38.4 36.0

Major Prespecified Subgroups: IMPROVE-IT

Ezetimibe/Simva Better

Simva Better

0.7 1.0 1.3

†7-year event rates

*

*P-interaction=0.023, otherwise >0.05

LDL 53.7 mg/dLMean LDL 69.5

Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. Supplementary Appendix.

Abbreviations: LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.

STATIN Hypotesis

effetti pleiotropici delle statine uno deimotivi aggiuntivi al sempliceabbassamento del colesterolo perspiegare la riduzione degli eventicardiovascolari ottenuti con le Statine

“LOWER IS BETTER”

centralità dell’abbassamento del colesterolo, specie delle LDL, con

qualsiasi mezzo per avere una corrispondente riduzione degli eventi

cardiovascolari

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 high-intensity 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.

FOURIER Evolocumab StudyLDL-C Levels Over time

Abbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol.


0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

LDL C

hole

ster

ol (m

g/dl

)

Weeks

Placebo

Evolocumab

4

Placebo 13,779 13,251 13,151 12,954 12,596 12,311 10,812 6926 3352 790Evolocumab 13,784 13,288 13,144 12,964 12,645 12,359 10,902 6958 3323 768

Absolute difference (mg/dL) 54 58 57 56 55 54 52 53 50Percentage difference 57 61 61 59 58 57 55 56 54P-value

FOURIER Evolocumab Study Endpoints

Abbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; MI, myocardial infarction.


Cumulative event rates for the primary efficacy endpoint

(Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary

revascularization)

Cumulative rates for the key secondary efficacy endpoint (Composite of

cardiovascular death, MI, or stroke)

22 March 2018EMA/CHMP/799799/2017Committee for Medicinal Products for Human Use (CHMP)

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NUOVA INDICAZIONE DI EVOLOCUMAB

TERAPIA DELLA DISLIPIDEMIA

Diapositiva numero 1Diapositiva numero 2Diapositiva numero 3Diapositiva numero 4Diapositiva numero 5Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14SPRINT StudySPRINT Primary Outcome�(MI, ACS, Stroke, HF, CV mortality) Categories of BP in AdultsDiabetes MellitusDiapositiva numero 19Diapositiva numero 20Diapositiva numero 21Diapositiva numero 22Diapositiva numero 23Diapositiva numero 24Diapositiva numero 25Diapositiva numero 27Diapositiva numero 28Diapositiva numero 30Diapositiva numero 31Diapositiva numero 32Diapositiva numero 33Diapositiva numero 34Diapositiva numero 35Diapositiva numero 36Diapositiva numero 37Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40Diapositiva numero 41Diapositiva numero 42Diapositiva numero 43IMPROVE-IT: Improved Reduction of Outcomes, �Vytorin Efficacy International Trial �Major Prespecified Subgroups: IMPROVE-ITDiapositiva numero 46Diapositiva numero 47FOURIER Trial: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated RiskFOURIER Evolocumab Study�LDL-C Levels Over time�FOURIER Evolocumab Study EndpointsDiapositiva numero 52Diapositiva numero 53Diapositiva numero 54Diapositiva numero 56

Riunione Annuale Congiunta SID-AMD Giuseppe .pdf · Riunione Annuale Congiunta . SID-AMD. Napoli, 9...

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