actualites therapeutiques en lipidologie · data from studies of non-statin lipid-lowering...
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ACTUALITES
THERAPEUTIQUES
EN LIPIDOLOGIE
Dr. P. VAN DE BORNE
Cardiologue
Service de Cardiologie
ULB- Hôpital Erasme
51e CONGRES DE L’A.M.U.B.
Session ACTUALITES DIAGNOSTIQUES ET THERAPEUTIQUES
Modérateurs :
Drs A. FIRKET, M. MAHIEU, T. PEPERSACK
Samedi 9 septembre 2017 14h00-14h45
Conflits d’intérêt en rapport avec la
présentation
• Honoraires de conférence :– Sanofi
• Participation à un « Advisory Board » :– Sanofi, Amgen, MSD
• Etudes cliniques sponsorisées en cours :– Sanofi, Amgen
• Consultance :– <néant>
• Voyages-Congrès :– Sanofi, Amgen, MSD
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques
Clinical trial data support achieving lower levels of LDL-C, independent of baseline LDL-C
ACS, acute coronary syndrome; CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.
Rosenson RS. Exp Opin Emerg Drugs 2004;9:269–79; LaRosa JC, et al. N Engl J Med 2005;352:1425–35;
Cannon CP, et al. N Engl J Med 2015;372:2387–97.
4S
pbo
LIPID
pbo
4S
S40
CARE
pboHPS
pboLIPID
P40
CARE
P40HPS
S40
TNT
A10TNT
A80
PROVE-IT TIMI 22
P40PROVE-IT TIMI 22
A80
IMPROVE-IT
S40+EZE
IMPROVE-IT
S40
ACS study
Stable CAD study
men >55 yrs
women > 65 yrs
+ 1 cv risk factor
April 2, 2016
Every 39 mg/dL reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanism
Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists
Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental
LDL-C lowering on CV outcomes. [To convert, 100 mg/dL=2.59 mmol/L].
CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density
lipoprotein cholesterol.
CTT Collaboration. Lancet 2005:366;1267–78; CTT Collaboration. Lancet 2010;376:1670–81;
Cannon CP, et al. N Engl J Med 2015;372:2387–97.
There is no evidence of any lower LDL-C threshold
CTTC trials (statin)
Niacin
Diet/unsaturated fatty acid
Ileal bypass
Bile acid resin
Ezetimibe
Fibrate
More LDL lowering and risk reduction
Re
du
ctio
n in
CV
eve
nts
(%
)
0
10
20
30
40
50
IMPROVE-IT
10 20 30 40 50 60 70 80
Reduction in LDL-C (mg/dL)?
2 g of extended-release niacin (ie nicotinic acid, vitamin B3 or PP (Pellagra Preventive)) and 40 mg of laropiprant vs. placebo Primary outcome: 1st major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization).
LDL = - 10 mg/dl and HDL + 6 mg/dl
Expected to produce a 5 % proportional reduction in the risk of major vascular events
(mainly China)
Consistency of overall
findings with earlier
niacin trials suggests
niacin is the major problem
Great concern: 9% increase in the risk of
death (P = 0.08, number needed
to harm= 200)
HDL cholesterol level:risk marker, not a risk factor
(2) Larger
return
of CE-rich
LDL to the liver
Cholesterol eliminated from the
body
But if not enough LDL-R:
(1) Less CE
in reverse
cholesterol
transport
CE, cholesteryl esterFC, free cholesterol
LPL, LipoproteinlipaseHL,
Hepatic lipase
small-dense LDL-C
SR-B1, scavenger receptor-B1
CETP, cholesteryl ester transfer protein secreted
from the liver
LCAT, lecithin cholesterol acyltransferase
SR-B1, scavenger receptor-B1
Vascular Health and Risk Management 2012:8 483–493
(2) Less
return
of CE-rich
LDL to the liver
Cholesterol
eliminated
from the
body
(1) More CE
in reverse
cholesterol
transport
CE, cholesteryl esterFC, free cholesterol
LPL, LipoproteinlipaseHL,
Hepatic lipase
small-dense LDL-C
SR-B1, scavenger receptor-B1
The cetrapibs form a reversible bond between CETP and HDL-C.
Formation of this bond results in the inhibition of CETP-mediated CE and TG transfer
Vascular Health and Risk Management 2012:8 483–493
ACCELERATE: Phase 3, multicenter, double blind, randomized trial, 12 092 patients at high vascular risk:
Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched
Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization).
Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dL vs 46 mg/dL) and 37% decrease in LDL-C (55 mg/dL vs 84 mg/dL).
ACCELERATE: Phase 3, multicenter, double blind, randomized trial, 12 092 patients at high vascular risk:
Patients (77% male; age: 65 years) randomly assigned 1:1 to either 130 mg evacetrapib (n=6038) or placebo (n=6054) for at least 1.5 years. Baseline clinical characteristics matched
Primary end point: Time to first event of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization).
Stopped prematurely for clinical futility (evacetrapib, 12.8% vs placebo, 12.7%; hazard ratio:1.01; P=.85) despite 130% increase in HDL-C (104 mg/dL vs 46 mg/dL) and 37% decrease in LDL-C (55 mg/dL vs 84 mg/dL).
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques
Statin-associated autoimmune myopathy is an exceptionally rare
side effect of statin use. Incidence +/- 2 or 3 of every
100,000 patients treated with statins :
• Class II HLA allele DRB1*11:01 • Expression of HMG-CoA reductase markedly
increased when muscle exposed to statins• Regenerating muscle cells express high levels of
HMG-CoA reductase protein
??? Binding of statin to HMG-CoA reductase change the conformation of the protein, lead to the generation of cryptic epitopes to which the immune system is not tolerant ???
e
Docteur de Lorgeril
chercheur au CNRS
Docteur de Lorgeril
chercheur au CNRS
Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals
CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through
Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy.
http://www.escardio.org/about/press/press-releases/esc13-amsterdam/Pages/euroaspire-iv-success-challenges-
secondary-prevention-CVD-europe.aspx. [Accessed 11 May 2015].
Data collected from patients <80 years old with
established CHD, 25% women, mean age 64 years,
one-third <60 years
• EUROASPIRE IV
– n=7998, all patients with
established CHD
– 87% on LLTs, almost exclusively
statins
• Almost 80% of patients on LLTs
failed to reach an LDL-C goal of
<1.8 mmol/L (<70 mg/dL)
42%
79% NOT at goal
79% of patients on LLTs did
NOT achieve an LDL-C
goal of <1.8 mmol/L
(<70 mg/dL)
Only 21% of
patients on
LLTs were at
goal
Patients who completed the placebo run-in without
experiencing a skeletal muscle–related AE were
randomizedto alirocumab,
ezetimibe, or atorvastatin
13%
24% 34% 33%
unable to tolerate ≥2 statins, including one at the lowest starting dosedue to muscle symptoms
22%20%16%
During the open-label treatment period (41 wks), when patients knew they were not
receiving statins, rates of skeletal muscle–related
AEs were lower (24%) than during double-blind period (33%)
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques
Clinical Therapeutics
Volume 35, Issue 8, August 2013,
Pages 1082–1098
P= placebo / E= Evolucumab
?
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques
Effects of 3 sequence variations on Coronary Heart
Disease incidence
in
Atherosclerosis Risk in Communities (ARIC) study:
longitudinal,
biracial cohort study to assess
subclinical and clinical atherosclerosis.
PCSK9 mutations effects on LDL
2 % black subjects have 1 of 2 nonsense mutations
in PCSK9 gene:
426C→G, encoding Y142X
[replacement of the tyrosine at position 142 with a stop
codon]
2037C→A, encoding C679X
[replacement of the cysteine at position 679 with a stop
codon]
3% white subjects (vs. 0.6 % black) PCSK9
sequence variation:
137G→T, encoding R46L
[replacement of the arginine at position 46 with leucine]
nonsense mutations
=9,7%
The only carrier in whom CHD
developed was a black man,
BMI 34 kg/m², BP186/85 mm Hg,
smoker,
family history of CHD,
During the 15-year follow-up period
Familial hypercholesterolemia can be caused by mutations in 4 known genes
ApoB, apolipoprotein B; FH, familial hypercholesterolemia; GoF, gain of function; LDL, low-density lipoprotein;
LDLRAP1, low-density lipoprotein receptor adapter protein 1; PCSK9, proprotein convertase subtilisin/kexin type 9.
De Castro-Oros I, et al. Appl Clin Genet 2010;3:53–64.
ApoBacts as ligand, binding LDL particle to receptor
LDLRAP1(ARH)Mediates internalization via clarithrin coated pitsPCSK9 enzyme
degrades LDL receptors
LDL receptoron hepatocyte,binds to ApoB on LDL particle, inducing endocytosis of LDL
Liver cell
Circulation
LDL particle
17–33% of FH patients
harbour mutations in
unknown genes
Meta-analysis of 312,321 participants: long-term exposure to lower
LDL-C was associated with 54.5% reduction in risk of CHD for each
1 mmol/L (38.7 mg/dL) lower LDL-C1
Clear genetic and epidemiological evidence for
LDL-C as a risk factor
[To convert, 100 mg/dL=2.59 mmol/L].
CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor;
LLT, lipid-lowering therapy; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error.
1. Ference BA, et al. J Am Coll Cardiol 2012;60:2631–9.
2. Ference BA, et al. J Am Coll Cardiol 2015;65:1552–61.
Mendelian randomization
analysis2
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques
Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in
Treatment of HypercholesterolemiaResults Up to 4 Years From the Open-Label OSLER-1 Extension Study
4,3 années de traitement
revascularisation
PRIMAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIAQUE,
HOSPITALISATION POUR ANGINE DE POITRINE INSTABLE
OU REVASCULARISATION CORONAIRE
SECONDAIRE : DECES CARDIOVASCULAIRES, INFARCTUS MYOCARDIQUE,
ACCIDENT CEREBROVASCULAIRE
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Baseline Characteristics
Characteristic Value
Age, years, mean (SD) 63 (9)
Male sex (%) 75
Type of cardiovascular disease (%)
Myocardial infarction 81
Stroke (non-hemorrhagic) 19
Symptomatic PAD 13
Cardiovascular risk factor (%)
Hypertension 80
Diabetes mellitus 37
Current cigarette use 28
Pooled data; no differences between treatment arms
Median time from most
recent event ~3 yrs
Rate of secondary
preventive therapies
high:
92% taking
antiplatelet therapy,
76% taking beta-
blockers,
and 78% taking an
ACE/ARB/aldosterone
antagonist,
.
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Lipid Lowering Therapy
& Lipid Levels at Baseline
Characteristic Value
Statin use (%)*
High-intensity 69
Moderate-intensity 30
Ezetimibe use (%) 5
Median lipid measures (IQR) – mg/dL
LDL-C 92 (80-109)
Total cholesterol 168 (151-189)
HDL-C 44 (37-53)
Triglycerides 133 (100-182)
Pooled data; no differences between treatment arms
*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.
1% were on low intensity or intensity data were missing.
Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.
10% of patients
had alterations in their
background lipid-lowering
therapy
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120
LD
L C
ho
leste
rol
(mg
/dl)
Weeks
LDL Cholesterol
Cohort of 11,077 patients who
• had all measurements through 120 weeks
• did not discontinue study drug
• did not D concomitant background lipid-lowering Rx
Evolocumab
Placebo
Similar data out to 4 years
in OSLER-1
(JAMA Cardiology online)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical SchoolConfidential
LDL Cholesterol
At 48 weeks, LDL cholesterol level was reduced to:
Evolocumab group:
<70 mg per deciliter (1.8 mmol per liter) in 87% of the patients,
<40 mg per deciliter (1.0 mmol per liter) in 67% of the patients,
<25 mg per deciliter (0.65 mmol per liter) in 42% of the patients,
Placebo group:
<70 mg per deciliter (1.8 mmol per liter) in 18% of the patients,
<40 mg per deciliter (1.0 mmol per liter) in 0.5% of the patients,
<25 mg per deciliter (0.65 mmol per liter) in 0.1% of the patients, P<0.001 for all comparisons of evolocumab vs. placebo).
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke,
Ho
sp
fo
r U
A,
or
Co
rR
evasc
0 6 12 18 24 30 36
Hazard ratio 0.85
(95% CI, 0.79-0.92)
P<0.0001 12.6%
14.6%
Primary end point occurred
in 1344 patients (9.8%)
in the evolocumab group and
in 1563 patients (11.3%)
in the placebo group
Magnitude of risk reduction tended to increase
over time, from 12% (95% CI, 3 to 20)
in the first year to 19% (95% CI, 11 to 27)
beyond the first year.
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Key Secondary Endpoint
Months from Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
Hazard ratio 0.80
(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo7.9%
9.9%
Key secondary end point in
816 patients (5.9%) in
evolocumab group and in
1013 patients (7.4%) in
the placebo group.
Risk reduction increased from
16% (95% CI, 4 to 26) in the first year
to 25% (95% CI, 15 to 34) beyond the first year.
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Types of CV Outcomes
Endpoint
Evolocumab
(N=13,784)
Placebo
(N=13,780) HR (95% CI)
3-yr Kaplan-Meier rate
CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)
Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)
Death due to acute MI 0.26 0.32 0.84 (0.49-1.42)
Death due to stroke 0.29 0.30 0.94 (0.58-1.54)
Other CV death 1.9 1.8 1.10 (0.90-1.35)
MI 4.4 6.3 0.73 (0.65-0.82)
Stroke 2.2 2.6 0.79 (0.66-0.95)
Evolocumab had no observed effect on cardiovascular mortality,
and hence P values for other outcomes should be considered exploratory.
-2%
-0,5%
No effect
Overall, 74 patients would need to be treated over a
period of 2 years to prevent a cardiovascular death,
myocardial infarction, or stroke.
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
More Intensive LDL-C Lowering
& CV Death
# of CV Deaths
Trial Year More
Intensive
Rx Arm
Less
Intensive
Rx Arm
HR (95% CI)
PROVE-IT TIMI 22 2004 27 36 0.74 (0.45-1.22)
A2Z 2004 86 111 0.76 (0.57-1.01)
TNT 2005 101 127 0.80 (0.61-1.03)
IDEAL 2005 223 218 1.03 (0.85-1.24)
SEARCH 2010 565 572 0.99 (0.88-1.11)
IMPROVE-IT 2015 538 537 1.00 (0.89-1.13)
Summary 1540 1601 0.96 (0.90-1.03)
More intensive
therapy better
Less intensive
therapy better
0.2 0.5 1 2 5NEJM 2004;350:1495-504
JAMA 2004;292:1307-16
NEJM 2005;352:1425-35
JAMA 2005;294:2437-45
Lancet 2010;376:1658-69
NEJM 2015;372:2387-97
No clear benefit on CV mortality
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Types of CV Outcomes
Endpoint
Evolocumab
(N=13,784)
Placebo
(N=13,780) HR (95% CI)
3-yr Kaplan-Meier rate
CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92)
CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88)
Cardiovascular death 2.5 2.4 1.05 (0.88-1.25)
MI 4.4 6.3 0.73 (0.65-0.82)
Stroke 2.2 2.6 0.79 (0.66-0.95)
Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18)
Coronary revasc 7.0 9.2 0.78 (0.71-0.86)
Urgent 3.7 5.4 0.73 (0.64-0.83)
Elective 3.9 4.6 0.83 (0.73-0.95)
Death from any cause 4.8 4.3 1.04 (0.91-1.19)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Comparison to Cholesterol
Treatment Trialists Collaboration
Major Coronary Events
Stroke
Coronary revascularization
Urgent
Elective
Major Vascular Events
0.78 (0.70-0.86)
0.80 (0.71-0.90)
0.77 (0.66-0.91)
0.77 (0.63-0.94)
0.75 (0.67-0.84)
0.73 (0.62-0.86)
0.84 (0.73-0.98)
0.77 (0.73-0.82)
0.83 (0.76-0.90)
Lipid-lowering therapy better Lipid-lowering therapy worse
Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C
2.01.0
CTTC Meta-analysis Year 2
FOURIER Year 2
CTTC data from Lancet 2010;376:1670-81
0.5
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Lower LDL-C Is Better
P<0.0001
Patients divided by quartile of baseline LDL-C and by treatment arm
Q4
Q3
Q2
Q1
Q4Q3
Q2
Q1
Placebo
Evolocumab
The magnitude of benefit of evolocumab in largely consistent with the
benefit with statins on a
per–millimole-per-liter basis
of LDL cholesterol lowering
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Safety Evolocumab
(N=13,769)
Placebo
(N=13,756)
Adverse events (%)
Any 77.4 77.4
Serious 24.8 24.7
Allergic reaction 3.1 2.9
Injection-site reaction 2.1 1.6
Treatment-related and led to d/c of study drug 1.6 1.5
Muscle-related 5.0 4.8
Cataract 1.7 1.8
Diabetes (new-onset) 8.1 7.7
Neurocognitive 1.6 1.5
Laboratory results (%)
Binding Ab 0.3 n/a
Neutralizing Ab none n/a
New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Conclusions
In patients with known cardiovascular disease:
1. PCSK9 inhibition with evolocumab
significantly & safely major cardiovascular
events when added to statin therapy
2. Benefit was achieved with lowering LDL
cholesterol well below current targets
Overall, 74 patients would need to be treated over a
period of 2 years to prevent a cardiovascular death,
myocardial infarction, or stroke.
52
PCSK9 Therapeutic Hypothesis: Phase 1 RNAi therapeutic targeting PCSK9 protein synthesis
PCSK9 mRNA
PCSK9
synthesis
LDLR
synthesis
PCSK9
LDL
Lysosomal
degradation
Endosome
Nucleus
ALN-PCS
Anti-
PCSK9
Mabs Transiently
block
PCSK9
binding
to
LDL
receptor
(LDLR)
PCSK9 Synthesis
Inhibitors
Durably block
PCSK9 synthesis
and all intracellular
and extracellular
PCSK9 functions
LDLR
Khvorova A. N Engl J Med 2017;376:4-7.
53
54
In the multiple-dose phase, the most common adverse events (occurring in ≥10% of the participants in the inclisiran
group) were headache (in 6 of 33 participants [18%]), back pain and diarrhea (in 5 [15%] each), and
nasopharyngitis (in 4 [12%])
PLAN :LDL C et pathologie cardiovasculaire
Statines : Effets secondaires ?
PCSK9: mode d’action, variations d’activité,études cliniques