The new dyslipidemia guidelines

Swiss Society of Cardiology Annual congress

Lausanne – June 15, 2016

Hot news from heart failure and dyslipidemia guidelines

Disclosures

I have received honorarium for conferences and advisory board from:

Amgen, Astra-Zeneca, BMS, Daiichi-Sankyo, MSD, Pfizer and Sanofi.

Age and hypercholesterolemia are the principal

cardiovascular risk factors leading to coronary disease

Risk factors

leading to CVD

Age

Lipids

Age and dyslipidemia are major CV risk factors

implicated in atherothrombosis disease

From the working group

Lipids and Atherosclerosis

Swiss Society of Cardiology

(SSC) 2014

www.gsla.ch

What is a “normal” LDL-cholesterol ?

JACC 2004;43:2142

Men is the only species which can develop atherosclerosis

The new dyslipidemia guidelines

ESC/EAS guidelines for the management

of dyslipidemias.

Eur Heart J 2011;32:1769

The old dyslipidemia guidelines

ESC guidelines for Cardiovascular

Prevention

Eur Heart J May 23, 2016

The new prevention guidelines

“The Lower is better”

- CTT-Analyse Lancet 2005,

90’000 Patients, 14 Trials,

Statin vs. Placebo:

-> 1mmol/l LDL-C↓ 21% RR↓

- CTT-Analyse Lancet 2010,

170’000 Patients, 26 Trials; Statin

vs Placebo + intensive vs.

standard statin therapy:

-> 1mmol/l LDL-C↓ 28 RR↓

Cholesterol Treatment Trialists’ (CTT) Collaboration Lancet 2010;376:1670

Statin – lipid-lowering & CV events

Adapted from NEJM 2005;352:1425

EAS/ESC Guidelines for Dyslipidemia (2011)

LDL-C achieved mmol/L

WOSCOPS – Pl

AFCAPS - Pl

ASCOT - Pl

AFCAPS - RxWOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - PlLIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

CARE - Pl

HPS - Rx

0

5

10

15

20

25

30

2.0 2.5 3.0 3.5 4.0 4.5

Even

t ra

te (

%)

Secondary Prevention

Primary Prevention

Rx - Statin therapy

Pl - Placebo

Pra - pravastatin

Atv - atorvastatin

5.0

PROVE-IT - PraPROVE-IT – Atv

TNT – Atv10

TNT – Atv80 JUPITER Pl

JUPITER Rx

Statin – lipid-lowering & CV events

IMPROVE-IT Primary Endpoint - ITT

NEJM June 3, 2015;372:2387-97

Cardiovascular death, MI, documented unstable angina requiring

rehospitalization, coronary revascularization (≥30 days), or stroke

LDL-c – Lower is better

LDL-cholesterol levels

ESC guidelines for Cardiovascular

Prevention

Eur Heart J May 23, 2016

The new prevention guidelines

• SPUM-ACS (Bern-Geneva-Lausanne-Zurich)

• n=1472 pts after ACS

• Only 30% at target of 1.8 mmol/L

Atherosclerosis 2015;239:118-24

1 year after an ACS only 30% of patients

are at LDL-c goals

Lipid pathways

Familial Hypercholesterolemia

PCSK9 is a LDLR regulator

PCSK9 (Proprotein Convertase Subtilisin/Kexin 9)

mAb anti-PCSK9 is an innovative therapy. It inhibits PCSK9,

thereby blocking PCSK9/LDL-R interaction, increasing

LDL-R expression and increasing LDL-c clearance

Presence of mAb anti-PCSK9 = absence of PCSK9More LDL-RLower plasma LDL-c

PCSK9–evolocumab

Evolocumab

LDL-C

LDL-R

LDL-R recycling restored

LDL-R and PCSK9

degradation

Increased LDL-R

concentration

LDL-R recycling

bloodstream

hepatocyteendocytosis

PNAS USA 2009;106:9820-25

Phase 3 Trials: Evolocumab, Alirocumab, Bococizumab

Patient Pop’n Evolocumab (PROFICIO program) Alirocumab (ODYSSEY program) Bococizumab (SPIRE program)

Trial N Dur’n (m)

Predicted

Pt

Exposure

(Y)

Min B/L

LDL-C

(mg/dL)

TrialN

Dur’n

(m)

Predicted

Pt

Exposure

(Y)

Min B/L

LDL-C

(mg/dL)

Trial NDur’n

(m)

Predicted

Pt

Exposure

(Y)

Min B/L

LDL-C

(mg/dL)

HeFHRUTHERFORD-2 327 3 51 ≥100

FH I 471 18 471 ≥70

FH 300 12 200 >70FH II 250 18 250 ≥70

HAUSER (paeds) 150 6 50 ≥130 HIGH FH 105 18 105 ≥160

HoFHTESLA 50 3 8 ≥130

.TAUSSIG (OL) 300 60 1000 ≥100

Combo Therapy LAPLACE-2 1896 3 258 ≥80

COMBO I 316 12 209 ≥ 70 HR 600 12 400 >70

COMBO II 720 24 958 ≥70

OPTIONS I 345 6 51 ≥70 LDL 1932 12 1288 >70

OPTIONS II 300 6 150 ≥70

Monotherapy MENDEL-2 614 3 71 ≥100 MONO 103 6 24 ≥70 AI 300 3 50 ≥70

Statin IntoleranceGAUSS-2 307 3 47 None

ALTERNATIVE 314 6 47 ≥70 SI 150 6 23 ≥70

GAUSS-3 511 36 984 None

Long termDESCARTES 901 12 600 ≥75 LONG-TERM 2341 18 2341 ≥70

LL 690 12 460 ≥100

OSLER-2 (OL) 3671 24 5904 None OLE (OL) 1200 28 2800 None

Atheroma GLAGOV 970 18 970 ≥60

Totals Patients 10462 Predicted Pt Yrs ~ 9943 Patients 5465 Predicted Pt Yrs ~ 7302 Patients 3972 Predicted Pt Yrs ~ 2421

CVD Outcomes FOURIER 27,564Event

drivenNA ≥70 OUTCOMES 18,000

Event

drivenNA ≥70

SPIRE-1 17,000Event

drivenNA ≥70 & <100

SPIRE-2 9,000Event

drivenNA ≥100

Neurocognitive

eventsEBBINGHAUS 1972 in

FOURIER

End of

FOURIERN/A ≥70

Ann Intern Med Jul 7, 2015;163:40-51

Effects of PCSK9 mAb in adults with hypercholesterolemia

LDL-c percentage of change from baseline

-45%

Effects of PCSK9 mAb in adults with hypercholesterolemia

Ann Intern Med Jul 7, 2015;163:40-51

HDL-c percentage of change from baseline

+7%

Effects of PCSK9 mAb in adults with hypercholesterolemia

Ann Intern Med Jul 7, 2015;163:40-51

Lp(a) percentage of change from baseline

-25%

Effects of PCSK9 mAb in adults with hypercholesterolemia

Ann Intern Med Jul 7, 2015;163:40-51

Increase in CPK levels Serious adverse events

Effects of PCSK9 mAb in adults with hypercholesterolemia

Summary of phase III-Studies

LDL-c-at goals

1%

20%

51%

2%3%

17%

62%

0%

74%

88%

94%

46%

71%

86%

93%

42%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

MENDEL-2 LAPLACE-2(Atorvastatin

10 mg*)

LAPLACE-2(Atorvastatin

80 mg*)

GAUSS-2

2% 2%6%

67%

80%82%

RUTHERFORD-2 DESCARTES

P…

Pa

tie

nte

n, d

ieL

DL

-C <

70

mg

/dl e

rre

ich

ten

(%)

Ezetimib QD + PBO Q2W

Evolocumab 140 mg Q2W + PBO QD

Ezetimib QD + PBO QM

Evolocumab 420 mg QM + PBO QD

Evolocumab 140 mg Q2W

Evolocumab 420 mg QM

Placebo Q2W

Placebo QM

First subject treated

with PCSK9 mAb

PCSK9-targeted mAb preclinicalPCSK9 discovery

Proof of concept in animals

Phase 2

studies

published

Human targetvalidation

PCSK9 – Rapid progress from bench to clinic

in less than a decade

2000 2001 2002 2007 2008 20112003 2004 2005 2006 2009 2010 2012 2013

First Phase 3

data available

FOURIER: cardiovascular outcomes with PCSK9

inhibition in subjects with elevated CV risk

CV, cardiovascular; CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI,

myocardial infarction; PAD, peripheral arterial disease; Q2W, once every 2 weeks; QM, once monthly; SC, subcutaneous; UA, unstable angina.

Evolocumab SC Q2W or QM

~13,750 subjects

PlaceboQ2W or QM

~13,750 subjects

LDL-C

≥70 mg/dL

or

non-HDL-C

≥100 mg/dL

To

tal

follo

w-u

p 4

–5 y

rsScreening, placebo

run-in, and lipid

stabilization

period

Effective statin therapy

(atorvastatin ≥20 mg or

an equivalent statin dose

± ezetimibe)

>27,500 patients with clinically evident CVD (prior MI, stroke or PAD)

Age 40 to 85 years, ≥1 other high-risk features

Primary endpoint: CV death, MI, hospitalization for UA, stroke, coronary revascularization

PCSK9 inhibitors indications before clinical

outcomes data available

FH, very high CV risk (CVD and T2DM+) patients not at LDL

target despite maximum current LDL lowering therapy (high

intensity statin + Ezetimibe)

FH, very high CV risk (CVD and T2DM+) qualifying for LDL

lowering treatment not tolerating the minimum indicated statin

dose

Eur Heart J September 2015:36;2438-45

Diagnosis of Familial Hypercholesterolemia

Diagnosis of Familial Hypercholesterolemia

LDL cholesterol burden in individuals with or without familial

hypercholesterolemia

as a function of the age of initiation of statin therapy

Eur Heart J 2013;34:3478

The lower the better, but also the sooner the better

Cummulative LDL-c and heart attacks

The lower the better,

but also the sooner the better

Age (years)

Cum

mula

tive L

DL

-c

(gra

m/y

ear)

6 -

9 -

12 -

0 -20

-

40

-

60-

80

-

100

-

MI threshold

9 gram-year

of LDL-c

A women with 150mg/dl (3.88mmol/L) = 9 gram-year of LDL-c at the age of 60

A FH men with 300mg/dl (7.76mmol/L) = 9 gram-year of LDL-c at the age of 30 !!!

A women with PCSK9-/+ and 70mg/dl (1.8mmol/L) = 9 gram-year of LDL-c at the age of >100 !!!

Conclusions/Messages

Dyslipidemia is a major CV risk factor and contributes

to atherogenesis and subsequent acute coronary

syndromes.

Lipid lowering with statins and ezetrol has shown to

markedly reduce CV events.

Conclusions/Messages

Dyslipidemia is a major CV risk factor and contributes

to atherogenesis and subsequent acute coronary

syndromes.

Lipid lowering with statins and ezetrol has shown to

markedly reduce CV events.

Conclusions/Messages

Dyslipidemia is a major CV risk factor and contributes

to atherogenesis and subsequent acute coronary

syndromes.

Familial hypercholesterolemia is underdiagnosed, and

undertreated.

Conclusions/Messages

There is a need to further reduce LDL-c, especially in

high risk patients, for which new guidelines

recommend <1.8 mmol/L (<70 mg/dL), or a reduction

of at least 50% if the baseline is between1.8 and 3.5

mmol/L (70 and 135 mg/dL).

Conclusions/Messages

mAb-anti-PCSK9 have been shown to markedly

reduce LDL-c, with more patients on target, especially

FH patients, and with a very safe profile.

There is a need to further reduce LDL-c, especially in

high risk patients, for which new guidelines

recommend <1.8 mmol/L (<70 mg/dL), or a reduction

of at least 50% if the baseline is between1.8 and 3.5

mmol/L (70 and 135 mg/dL).

Conclusions/Messages

Hopefully this LDL-c lowering with mAb-anti-PCSK9

will be translated in CV event reduction.

It’s cardio-logic…

The BEST way to improve lipids values...

Dr. Reto Auer

Dr. Vincent Barthassat

Anne Bevand

Martine Bonhôte

Dr. Pascal Gache

Marianne Gandon

Dr. David Carballo

Dr. Sebastian Carballo

Armèle Delort

Prof. Steffen Gay

Dr. Pierre Chopard

Suzanna Convert

Prof. Jacques Cornuz

Dr. Baris Gencer

Prof. Alain Golay

PD Dr. Dik Heg

Prof. Peter Jüni

Dr. Pierre-Frédéric Keller

Dr. Philipp Jakob

Dr. Roland Klingenberg

Prof. Ulf Landmesser

Anika Lewandowski

Prof. Thomas F. Lüscher

Prof. François Mach

Prof. Christian M. Matter

Maya Müller

Suzanne Mueller

Dr. David Nanchen

Dr. Stéphane Noble

Prof. Thomas Perneger

PD Dr. Lorenz Raeber

Prof. Nicolas Rodondi

Marie-Noelle Roth

Prof. Marco Roffi

Allen Savard

Florence Scherrer

Dr. Christian Schmied

Philippe Sigaud

Dr. Barbara Stähli

Dr. Giulio Stefanini

Dr. Johanna Sommer

PD Dr. Christian Templin

PD Dr. Sven Trelle

Prof. Arnold von Eckardstein

Dr. Berry van Tits

Prof. Pierre Vogt

Prof. Gérard Waeber

Prof. Stephan Windecker

www.spum-acs.ch

www.elips.ch

Thank you

Swiss Soicety of Cardiology Annual congress

Lausanne – June 15, 2016

Hot news from heart failure and dyslipidemia guidelines

The new prevention guidelines

The new prevention guidelines

The new prevention guidelines

attainable with

statin monotherapy

attainable with

statin + ezetimibe

A practical approach to reach LDL-c goal

ESC pocket guidelines 2011:

NEJM 2015;372:1489-99 NEJM 2015;372:1500-9

Anti-PCSK9 mAb und LDL-c

Primary endpoints: CHD death, Non-fatal MI, Fatal and non-fatal

ischemic stroke,UA requiring hospitalisation

ESC Late Clinical Breaking Trial 2014 NEJM 2015;372:1500-9

mAB-anti-PCSK9 and CV events

The new prevention guidelines

The new prevention guidelines

EBBINGHAUS: Evaluating PCSK9 antibody influence

on cognitive health in high cardiovascular risk

subjects

PAL, paired associated learning; Q2W, once every 2 weeks; QM, once monthly; RTI, reaction time; SPW, special working

memory.

Evolocumab SC Q2W or QM

+ effective statin dose

PlaceboQ2W or QM

+ effective statin dose To

tal

follo

w-u

p 4

yearsRandomized

into study

FOURIER

~1972 subjects

Excludes subjects with

current or known past

diagnosis of dementia or

mild cognitive impairment

• Primary outcome measure: mean change from baseline over time in SWM index of executive function

• Secondary outcome measures:

• Mean change from baseline over time in SWM between error scores

• Mean change from baseline over time in PAL total errors adjusted

• Mean change from baseline over time in RTI median 5-choice reaction time

Randomization

Ongoing trial to show effect of evolocumab on cognitive functions

• Sub-study of FOURIER

Diagnosis of Familial Hypercholesterolemia

Eur Heart J 2013:34;3478-3490

Familial hypercholesterolemia (FH) is a genetically modulated clinical

syndrome in which the phenotype is characterized by a high LDL-c

level from birth, a propensity to tendon xanthomata, and early onset

CHD.

Its established causes are LDLR mutations (most common), gain-of-

function PCSK9 mutations (<5 percent of cases in most clinics),

and familial defective apoB (<5 percent of cases), generally the

apoB3500 mutation.

Eur Heart J 2013:34;3478-3490

Diagnosis of Familial Hypercholesterolemia

Estimated millions of individuals worldwide with familial

hypercholesterolaemia by WHO regions and by income groups

Eur Heart J 2013:34;3478-3490

Dutch FH

criterias

Diagnosis of Familial Hypercholesterolemia

The new prevention guidelines

Incidence of recurrent coronary events in young patients with premature

acute coronary syndrome, by presence of familial hypercholesterolemia

(n=1,369)

Nanchen D. et al., Circulation (in press)

Prognosis of Familial Hypercholesterolemia

Lancet May 27, 2016

Diagnosis of Familial Hypercholesterolemia

Lancet May 27, 2016

Diagnosis of Familial Hypercholesterolemia

Regardless of how low the LDL-c level is, there does

not appear to be an increase in adverse events in

the IMPROVE-IT study

10

8

6

4

2

0

% p

atie

nts

(n/N

)

Myalgia

with CK↑

P=NS

AE →Discont

P=NS

AST or ALT

>3x

P=NS

Gall bladder

P=NS

Neurocognitive

P=NS

LDL-c at 1 month (mmol/L)

<0.790.8 -1.291.3 – 1.79≥1.8

Regardless of how low the LDL-c level is, the incidence

of clinical safety endpoints is unchanged in

the IMPROVE-IT study

12

8

4

0

KM

% r

ate

at 7 y

ears

Hem stroke

Adj P=NS

CHF → hosp

Adj P=NS

Non-CV death

Adj P=NS

Cancer

Adj P=NS

LDL-c (mmol/L)

LDL-c at 1 month (mmol/L)

<0.790.8 -1.291.3 – 1.79≥1.8

We recommend:

children, adults, and families should be screened for FH if:

• Family member presents with FH• P-cholesterol in adult ≥8mmol/L (≥310mg/dL) • P-cholesterol in child ≥6mmol/L (≥230mg/dL)• Premature CHD• Tendon xanthomas• Sudden premature cardiac death

Eur Heart J 2013;34:3478

LDL cholesterol targets:(heterozygous & homozygous FH)

• <3.5mmol/L (<135mg/dL) for children

• <2.5mmol/L (<100mg/dL) for adults

• <1.8mmol/L (<70mg/dL) for adults with CHD or diabetes

Eur Heart J 2013;34:3478

Familial Hypercholesterolemia

In addition to lifestyle and dietary counselling, treatment priorities are:

Children (from age 8-10):

1.Statin

2.Ezetimibe

3.Bile acid binding resin

4.Lipoprotein apheresis in homozygotes

Adults:

1.Maximal potent statin dose

2.Ezetimibe

3.Bile acid binding resins

4.Lipoprotein apheresis in homozygotes & treatment-resistant

heterozygotes with CHD

Eur Heart J 2013;34:3478

Treatment of Familial Hypercholesterolemia

LDL-cholesterol and CV Risk

Eur Heart J 2015:36:1146-8