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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