Η ΝΕΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗΝ ...€¦ · OSLER: Safety and Tolerability 27 Adverse...

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Η ΝΕΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗΝ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ: ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 ΜΩΥΣΗΣ ΕΛΙΣΑΦ, ΚΑΘΗΓΗΤΗΣ ΠΑΘΟΛΟΓΙΑΣ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΙΩΑΝΝΙΝΩΝ OLD HOUSE DETAIL IOANNINA

Transcript of Η ΝΕΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗΝ ...€¦ · OSLER: Safety and Tolerability 27 Adverse...

Page 1: Η ΝΕΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗΝ ...€¦ · OSLER: Safety and Tolerability 27 Adverse events, % SOC N = 368 Evolocumab + SOC N = 736 Any adverse event 73.1 81.4 Serious 6.3

Η ΝΕΑ ΕΠΑΝΑΣΤΑΣΗ ΣΤΗΝ ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ: ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9

ΜΩΥΣΗΣ ΕΛΙΣΑΦ, ΚΑΘΗΓΗΤΗΣ ΠΑΘΟΛΟΓΙΑΣ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΙΩΑΝΝΙΝΩΝ

OLD HOUSE DETAIL IOANNINA

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ΥΠΟΛΙΠΙΔΑΙΜΙΚΗ ΑΓΩΓΗ: UNMET NEEDS

▪Ανάγκη επιθετικής υπολιπιδαιµικής αγωγής σε άτοµα πολύ υψηλού κινδύνου (ΣΤΟΧΟΣ: LDL CHOL <70mg/dl) ▪ Περιορισµοί της µονοθεραπείας µε στατίνες Περιορισµένη αποτελεσµατικότητα Μεταβλητότητα (variability) όσον αφορά τη µείωση της LDL CHOL Μειωµένη συµµόρφωση σε µακροχρόνια αγωγή Δοσοεξαρτώµενες ανεπιθύµητες ενέργειες (µυαλγίες / σακχαρώδης διαβήτης)

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2016

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ΑΣΘΕΝΕΙΣ ΠΟΛΥ ΥΨΗΛΟΥ ΚΙΝΔΥΝΟΥ

Hellenic Journal of Atherosclerosis 2014;5(3): 151-163

ΠΡΩΤΟΓΕΝΗΣ ΣΤΟΧΟΣ ΤΗΣ ΑΓΩΓΗΣ: Η ΜΕΙΩΣΗ ΤΗΣ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ

ΑΜΕΣΗ ΕΝΑΡΞΗ ΥΓΙΕΙΝΟΔΙΑΙΤΗΤΙΚΩΝ ΜΕΤΡΩΝ ΚΑΙ ΑΓΩΓΗΣ ΜΕ ΣΤΑΤΙΝΗ ΜΕ ΣΤΟΧΟ ΜΕΙΩΣΗ ΤΗΣ LDL ΧΟΛΗΣΤΕΡΟΛΗΣ

✓ ΣΥΝΙΣΤΑΤΑΙ Η ΧΟΡΗΓΗΣΗ ΥΨΗΛΗΣ ΔΟΣΗΣ ΤΩΝ ΠΙΟ ΑΠΟΤΕΛΕΣΜΑΤΙΚΩΝ ΣΤΑΤΙΝΩΝ

κατά >50% <70 mg/dL

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DYS

IS I

IESC 2015

70 mg/dL

34 mg/dL24 mg/dL

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ΧΟΡΗΓΗΣΗ ΤΩΝ ΠΙΟ ΑΠΟΤΕΛΕΣΜΑΤΙΚΩΝ

ΣΤΑΤΙΝΩΝ ΣΕ ΥΨΗΛΕΣ ΔΟΣΕΙΣ ΠΟΥ ΓΙΝΟΝΤΑΙ

ΚΑΛΑ ΑΝΕΚΤΕΣ:

• ATORVA 40-80mg/d

• ROSUVA 20-40mg/d

ΜΕΙΩΣΕΙΣ ΤΗΣ ΤΑΞΗΣ ΤΟΥ 50%

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ROSUVA 20mg/d

JUPITER TRIAL : EUR HEART J , 2016

46.3%

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ΣΤΕΦΑΝΙΑΙΑ ΝΟΣΟΣ ΚΑΙ ΟΙΚΟΓΕΝΗΣ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ

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PREVALENCE OF FH IN PATIENTS WITH CV DISEASE:

EUROASPIRE IV

PREVALENCE OF POTENTIAL FH: 8.3%

Atherosclerosis 2015;241:169

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ΠΕΡΙΟΡΙΣΜΕΝΗ ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ ΤΩΝ ΣΤΑΤΙΝΩΝ ΩΣ ΜΟΝΟΘΕΡΑΠΕΙΑ

Ο ΡΟΛΟΣ ΤΗΣ PCSK9

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LDL Receptor Function and Life Cycle

1515

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 (EVOLOCUMAB/ALIROCUMAB)

Μείωση της PCSK9

Αύξηση του αριθµού και της δραστηριότητας των LDLR

Αύξηση του καταβολισµού των LDL

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OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year

25

Baseline Parent StudyWeek 12

12 24 36 48 52OSLER Study Week

-60-50-40-30-20-10

10

UC

LD

L-C

Per

cent

age

Cha

nge

from

B

asel

ine

to W

eek

52, M

ean

(SE)

SE, standard error; SOC, standard of care; UC, ultracentrifugation

Not Evolocumab / Evolocumab + SOC (n = 192)Not Evolocumab / SOC Only (n = 96)Evolocumab / SOC Only (n = 272)Evolocumab / Evolocumab + SOC (n = 544)

-52%

-52%

-2%

-3%0

120➔ 48 mg/dL

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OSLER: LDL-C Goal Achievement

26

< 100 mg/dL

0

25

50

75

100

Week 12 Week 52 Any Visit Every Visit

Evolocumab + SOC

SOC

LDL-C values by ultracentrifugation. SOC, standard of care

< 70 mg/dL

0

25

50

75

100

Week 12 Week 52 Any Visit Every Visit

Pro

porti

on o

f Pat

ient

s, %

Pro

porti

on o

f Pat

ient

s, %

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OSLER: Safety and Tolerability

27

Adverse events, % SOC N = 368

Evolocumab + SOC N = 736

Any adverse event 73.1 81.4Serious 6.3 7.1Possibly treatment-related (none serious) NA 5.6*Leading to discontinuation of evolocumab NA 3.7Deaths 0.5 0.1Most common adverse events

Nasopharyngitis 9.8 12.2Upper respiratory tract infection 7.6 7.7Arthralgia 4.3 6.9Back pain 5.4 6.5

Muscle-related 9.8 9.2Injection-site reactions NA† 5.2

NA, not applicable; SOC, standard of care. *Percentage of adverse events. †Patients in the SOC group did not receive injections.

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Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo

28

-60

-45

-30

-15

0

15

LS m

ean

(SE)

% c

hang

e fr

om b

asel

ine

to W

eek

24

LS mean difference (SE)

vs. placebo:

N=163

Alirocumab

N=322

−57.9% (2.7) P<0.0001

N=81N=166

−51.4% (3.4) P<0.0001

FH IPlacebo

FH II

43.4% had dose

increase at W12

38.6% had dose

increase at W12

Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy

Intent-to-treat (ITT) Analysis

LDL-C: 155→77 mg/dL

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 –ΑΝΑΠΑΝΤΗΤΑ ΕΡΩΤΗΜΑΤΑ (1)

Επίδραση στο συνολικό λιπιδαιµικό προφίλ και σε άλλες παραµέτρους

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OSLER: Effect of Evolocumab on Other Lipid Parameters at 1 Year

32

Error bars represent standard error. Data in parentheses represent interquartile ranges. Week 52 vs baseline: * P < 0.0001; † P < 0.001; § P < 0.01; ‡ P < 0.05 Evolocumab vs placebo: § P< 0.0001; ¶ P< 0.001

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EVOLOCUMAB –ASSOCIATED REDUCTION OF LDL CHOL AND Lp (a)

J LIPID RES 2016;57: 1086

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CHANGES IN Lp(a) CORRELATED WITH CHANGES IN LDL CHOL

WEEK 12

J LIPID RES 2016;57: 1086

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9

!!!LDL-R

! του καταβολισµού της Lp(a) " # Lp(a) " # αθηροθροµβωτικής νόσου # αορτικής στένωσης?

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 ΚΑΙ ΦΛΕΓΜΟΝΗ ΤΟΥ ΑΓΓΕΙΑΚΟΥ ΤΟΙΧΩΜΑΤΟΣ

❑Όχι µείωση της hs CRP

❑Ευνοϊκή επίδραση στην εξέλιξη της αθηρωµατικής νόσου στο αγγειακό τοίχωµα-δυνητική επίδραση σε οξέα αγγειακά συµβάµατα

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 –ΑΝΑΠΑΝΤΗΤΑ ΕΡΩΤΗΜΑΤΑ (2)

•Επίδραση στο συνολικό λιπιδαιµικό προφίλ και σε άλλες παραµέτρους

•Μείωση των καρδιαγγειακών συµβαµάτων

Προκαταρκτικά δεδοµένα

Μετα-αναλύσεις

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! 55%

! 50%

LDL CHOL: -48% Lp(a): -26.5%

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! 51%

! incidence of neurocognitive adverse events

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EFFECTS OF PCSK9 INHIBITORS IN ADULTS WITH

HYPERCHOLESTEROLEMIA: A SYSTEMIC REVIEW AND META-

ANALYSIS n=24 RCTs, 10.159 PATIENTS

PCSK9 INHIBITORS:

$ LDL CHOL BY 47.5%

$ ALL CAUSE MORTALITY BY 55%

$ CARDIOVASCULAR MORTALITY BY 50%

$ THE RATE OF MYOCARDIAL INFARCTION BY 51%

$ THE INCREASES IN THE SERUM CK BY 28%

ANN INTERN MED 2015;163:40-51

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EFFECT OF PCSK9 INHIBITORS ON LIPID LEVELS AND

OUTCOMES A NETWORK META-ANALYSIS

n=17 RCTs, 13.083 PATIENTS

PCSK9 INHIBITORS:

$ LDL CHOL BY 57% RELATIVE TO PLACEBO

$ LDL CHOL BY 36.1% RELATIVE TO EZETIMIBE

$ INCIDENCE OF ALL-CAUSE MORTALITY BY 57%

% INCIDENCE OF NEUROCOGNITIVE ADVERSE EVENTS

(OR=2.34)

EUR HEART J 2016;37:536

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! 53%

120➔ 48 mg/dL

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47

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48

7881550

7761534

7311446

7031393

6821352

6671335

321642

127252

00

No. at RiskPlaceboAlirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT0.10

0.08

0.06

0.04

0.02

0.0096847260483624120

Estim

ated

pro

babi

lity

of e

vent Alirocumab + max-tolerated statin ± other LLT

Cox model analysis: HR=0.52 (95% CI: 0.31 to 0.90)Nominal p-value = 0.02

†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed

W78 visit)

ODYSSEY LONG TERM: Post-hoc Adjudicated Cardiovascular TEAEs

! 48%123 ➔ 48 mg/dL-62%

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50

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51

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•Επίδραση στο συνολικό λιπιδαιµικό προφίλ και σε άλλες παραµέτρους

•Μείωση των καρδιαγγειακών συµβαµάτων

Προκαταρκτικά δεδοµένα

Μετα-αναλύσεις

ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 –ΑΝΑΠΑΝΤΗΤΑ ΕΡΩΤΗΜΑΤΑ (3)

•Μακροχρόνια ασφάλεια της αγωγής

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ΜΑΚΡΟΧΡΟΝΙΑ ΑΣΦΑΛΕΙΑ ΤΩΝ ΑΝΑΣΤΟΛΕΩΝ ΤΗΣ PCSK9

▪Συσχέτιση µε νευρονοητικές διαταραχές;

▪Ασφάλεια των πολύ χαµηλών επιπέδων LDL CHOL;

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•Επίδραση στο συνολικό λιπιδαιµικό προφίλ και σε άλλες παραµέτρους

•Μείωση των καρδιαγγειακών συµβαµάτων

Προκαταρκτικά δεδοµένα

Μετα-αναλύσεις

ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 –ΑΝΑΠΑΝΤΗΤΑ ΕΡΩΤΗΜΑΤΑ (4)

• Μακροχρόνια ασφάλεια της αγωγής

• ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ

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55

ALIROCUMAB AND NEW ONSET DIABETES MELLITUS

Pooled analysis of 10 ODYSSEY phase 3 trials (n=4974) n= 3448 individuals without diabetes

PLACEBO-CONTROLLED EZETIMIBE-CONTROLLED GROUP GROUP

Incident diabetes HR 0.64 HR 0.55 mellitus or diabetic complications TEAE

Prediabetic individuals (39.6%): The HR associated for transition from prediabetes to new-onset diabetes for alirocumab was 0.90 vs placebo and 1.10 vs ezetimibe

Eur Heart J 2016

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56Eur Heart J, 2016

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57

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PCSK9 INHIBITORS: AND NOW TO WHICH PATIENTS?

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1. ESTABLISHED CVD + LDL –C ≥ 100 mg/dL (2.6 mmol/L)

2. DIABETICS WITH ESTABLISHED CVD OR CKD OR TARGET ORGAN DAMAGE + LDL-C ≥ 100 mg/dL (2.6 mmol/L)

3. FH PATIENTS + LDL-C ≥ 130 mg/dL (3.4 mmol/L)

4. HIGH OR VERY HIGH RISK PATIENTS (HELLENIC SCORE > 5% OR >10%, RESPECTIVELY) WITH DOCUMENTED STATIN INTOLERANCE + LDL-C ≥ 130 mg/dL (3.4 mmol/L) OR ≥ 100 mg/dL (2.6 mmol/L), RESPECTIVELY

ON MAXIMUM TOLERATED HIGH-INTENSITY STATIN (ATORVASTATIN

40/80 mgROSUVASTATIN

20-40 mg) + EZETIMIBE 10 mg

ON MAXIMUM TOLERATED

HYPOLIPIDEMIC TREATMENT

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62

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63

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64

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 ΚΑΙ ΜΕΙΩΣΗ ΤΗΣ Lp(a)

ΣΗΜΑΣΙΑ;

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 ΚΑΙ ΜΕΤΑΒΟΛΙΣΜΟΣ ΤΩΝ ΠΛΟΥΣΙΩΝ

ΣΕ TRG ΛΙΠΟΠΡΩΤΕΪΝΩΝ

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9: ΑΝΑΠΑΝΤΗΤΑ ΕΡΩΤΗΜΑΤΑ

▪ Μείωση των καρδιαγγειακών συµβαµάτων; ▪Προκαταρκτικά δεδοµένα ▪ Μετα-αναλύσεις ▪ Επίδραση στην οµοιοστασία των υδατανθράκων; ▪ Ασφάλεια; ▪ Επίδραση στο συνολικό λιπιδαιµικό προφίλ και σε άλλες παραµέτρους

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EVOLOCUMAB 140mg/2W-420mg/4W

ALIROCUMAB 75, 150mg/2W

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Mean HbA1c Over Time (Safety population) (n=1051 patients with diabetes mellitus)

77

†75 mg Q2W increased to 150 mg Q2W at W12 if LDL-C levels at Week 8 were ≥ 70 mg/dL (1.81 mmol/L). HbA1c, glycated hemoglobin.

Mea

n (S

E) H

bA1c

, %

Placebo with DMAlirocumab with DM

Placebo without DMAlirocumab without DM

5

5,5

6

6,5

7

7,5

8

8,5

9

9,5

10

5

5,5

6

6,5

7

7,5

8

8,5

9

9,5

10

12 24 520 0 12 24 52Week Week

No change in ΗβΑ1c (%) was observed

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78

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79

Change in LDL CHOL

Change in TRGs

Change in HDL CHOL

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ΑΝΑΣΤΟΛΕΙΣ ΤΗΣ PCSK9 ΚΑΙ ΚΟΣΤΟΣ ΤΗΣ ΑΓΩΓΗΣ;

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Statin +

Ezetimibe

Statin +

Colesevelam

Normal triglycerides and HDL CHOL

Statin +

Fenofibrate

Statin +

ω-3 Fatty Acids

Goal achievement for LDL CHOL, triglycerides and HDL CHOL ➔ Maximum Cardiovascular Benefit

Treatment Algorithm for Patients with Dyslipidemia

Statin**

Statin dose titration***

LDL CHOL Not at goal

LDL CHOL Not at goal

LDL CHOL at goal

High triglycerides and low HDL CHOL

Hel

leni

c Jo

urna

l of

Athe

rosc

lero

sis

2014

;5(3

):

151-

163

*If fasting triglycerides >500 mg/dL fibrate and/or ω-3 fatty acids are recommended **For optimal lipid lowering treatment statin administration is recommended in the appropriate dose ***Every time statin dose is doubled a further 6% reduction of LDL CHOL is expected.

DYSLIPIDEMIA*

STATIN + EZETIMIBE +

PCSK9 INHIBITOR

LDL CHOL Not at goal