Intensivierte Cholesterin-Senkung: Wie und für wen ? Intensivierte

Intensivierte
Cholesterin-Senkung:
Wie und für wen ?
Senkung des LDL-Cholesterin-Spiegels mit Statinen
bei Patienten mit oder ohne vorige KHK
verbessert die kardiovaskuläre Prognose1,2 :
je niedriger desto besser
30
4S
Secondary prevention trials1
25
4S
CHD Events (%)
20
Primary prevention trials2
LIPID
TNT
CARE
HPS
(80mg
atorvastatin)
TNT
(10mg
atorvastatin)
5
0
50
1.3
Active treatment/Statin
LIPID
15
10
Active treatment/Statin
Placebo
ASCOT
70
1.8
90
2.3
WOSCOPS
ASCOT
AFCAPS
110
2.8
Placebo
CARE
HPS
WOSCOPS
AFCAPS
130
150
170
3.4
3.9
4.4
LDL Cholesterol
190
4.9
210
5.4
(mg/dL)
(mmol/L)
1. LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435. 2. O’Keefe J, et al. J Am Coll Cardiol. 2004;43:2142-2146.
Senkung des LDL-Cholesterin ist
primäres Behandlungsziel bei Patienten
mit Hypercholesterinämie und hohem KHK-Risiko
 Die Empfehlungen der
European Society of Cardiology (ESC) und
European Atherosclerosis Society (EAS)
sowie des National Cholesterol Education
Program (NCEP)-Adult Treatment Panel
(ATP) III empfehlen die Senkung des LDL-C
auf
… <100 mg/dL (< 2.6 mmol/L) bei
Hochrisikopatienten und
…. < 70 mg/dL (< 1.8 mmol/L) bei Patienten
mit höchstem KHK-Risiko 1,2
 Diese Ziele werden bei vielen Patienten mit
den derzeitig verfügbaren Therapien nicht
erreicht 3-6
High CV
risk
LDL-C Target
<100 mg/dL
2.5 mmol/L
Very High
CV risk
LDL-C Target
<70 mg/dL
1.8 mmol/L
1. Reiner Z, et al. ESC/EAS Guidelines. Eur Heart J. 2011;32:1769-818. 2. Grundy SM, et al. Circulation. 2004;110:227-239. 3. Go AS, et al. Circulation.
2013;127:e6-e245. 4. Jones PH, et al. J Am Heart Assoc. 2012;1:e001800. doi: 10.1161/JAHA.112.001800. 5. Stein EA, et al. Am J Cardiol. 2003;92:12871293. 6. Pijlman AH, et al. Atherosclerosis. 2010;209:189-194.
Percentage reduction of LDL cholesterol to achieve
goals according to starting levels and
efficacy of different statins at different dosages
Catapano et al.
EHJ 2016 in press
Patientengruppen die einer weiteren LDL-C
senkenden Therapie bedürfen
 Hoch-Risiko-Patienten mit unzureichend gesenktem
LDL-C trotz maximaler Statin-Behandlung
 Höchstrisikopatienten (Zielwert LDL-C < 1.8 mmol/L):
76% 1
 Hochrisikopatienten (Zielwert LDL-C < 2.6 mmol/L):
23% 2,3
 Fam. Hypercholesterinämie (Zielwert LDL-C < 2.6 mmol/L): 80% 2,3
 Patienten, die wegen Nebenwirkungen keine Statine
einnehmen können oder wollen
 (ca. 60% der Patienten, die eine Statintherapie abbrechen (12%) 4
1. Jones PH, et al. J Am Heart Assoc. 2012;1:e001800.
2. Stein EA, et al. Am J Cardiol. 2003;92:1287-1293.
3. Pijlman AH, et al. Atherosclerosis. 2010;209:189-194.
4. Cohen JD, et al. J Clin Lipidol. 2012;6:208-215.
IMPROVE‐IT: Study Design
Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
N=18,144
*3.2mM
**2.6mM
Standard Medical & Interventional Therapy
Simvastatin
40 mg
Uptitrated to Simva 80 mg if LDL‐C > 79
(adapted per FDA label 2011)
Ezetimibe / Simvastatin
10 / 40 mg
Follow-up Visit Day 30, every 4 months
90% power to detect ~9% difference
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
Cannon CP AHJ 2008;156:826‐32; Califf RM NEJM 2009;361:712‐7; Blazing MA AHJ 2014;168:205‐12 IMPROVE‐IT: LDL‐C Levels
1 Yr Mean
LDL‐C
TC
TG
HDL
hsCRP
Simva
69.9
145.1
137.1
48.1
3.8
EZ/Simva
53.2
125.8
120.4
48.7
3.3
Δ in mg/dL
‐16.7
‐19.3
‐16.7
+0.6
‐0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Cannon CP, et al. N Engl J Med. 2015;372(25):2387‐97.
IMPROVE‐IT: CV Death, Non‐fatal MI or Non‐fatal Stroke
HR 0.90 CI (0.84, 0.97)
p=0.003
NNT= 56
Simva — 22.2% 1704 events EZ/Simva — 20.4% 1544 events Cannon CP, et al. N Engl J Med. 2015;372(25):2387‐97.
Safety
No statistically significant differences in cancer or muscle‐ or gallbladder‐related events
Simva n=9077
%
EZ/Simva
n=9067
%
p
ALT and/or AST≥3x ULN
2.3
2.5
0.43
Cholecystectomy
1.5
1.5
0.96
Gallbladder‐related AEs
3.5
3.1
0.10
Rhabdomyolysis*
0.2
0.1
0.37
Myopathy*
0.1
0.2
0.32
Rhabdo, myopathy, myalgia with CK elevation*
0.6
0.6
0.64
Cancer* (7‐yr KM %)
10.2
10.2
0.57
% = n/N for the trial duration
Cannon CP, et al. N Engl J Med. 2015;372(25):2387‐97.
Log-Linear Association Between Genetically and
Pharmacologically Mediated Lower Low-Density Lipoprotein
Cholesterol and Risk of Coronary Heart Disease
Up to 63,746 Cases of CHD and 130,681 Control Subjects
Ference et al. J Am Coll Cardiol 2015;65:1552–61
PCSK9 Mutationen und LDL-Cholesterin
LDL-C 
S127R
F216L
D374Y
N425S
R496W
gain of function
Mutationen
SP
LDL-C 
loss of function
Mutationen
Prodomain
Catalytic domain
R46L DR97G106RY142X
Wildtyp
D35Y
L108R
S127R
F216L
R218S
D374Y
R46L
DR97
G106R
Y142X
C679X
C679X/C679X
DR97/Y142X
C terminal
L253F
A443T
C679X
105
249
266
287
227
216
350
86
58
89
53
PCSK9* gain of function Mutationen LDL-C 
68
15
14
0
PCSK9* loss of function Mutationen
50
100
150
200
LDL-C (mg/dl)
*PCSK9 = Protein Convertase Subtilisin/Kexin Typ 9
S. Poirier and G. Mayer, Drug Des Devel. Ther. 7, 1135 (2013).
250
300
LDL-C 
350
400
Afroamerikanische Probanden Wildtyp (n=3.278)
Kaukasische Probanden Wildtyp (n=9.223)
30
20
10
0
0
50
100
150
200
250
300 (mg/dl)
Frequenz (%)
LDL-Cholesterin
Afroamerikanische Probanden mit LOF*-Mutation (n=85)
Kaukasische Probanden mit LOF*-Mutation (n=301)
30
20
10
0
Amerikaner
europäischer
Abstammung
47%
Reduktion
(p=0,003)
12
Koronare Herzerkrankung (%)
Frequenz (%)
Loss of function (LOF) Mutationen in PCSK9 sind
mit niedrigem LDL-Cholesterin und verringertem
Risiko für kardiovaskulärer Erkrankungen assoziiert
8
Afroamerikaner
88%
Reduktion
(p=0,008)
4
0
0
50
100
150
200
250
LDL-Cholesterin
J. C. Cohen et al., N. Engl. J. Med. 354, 1264 (2006).
300 (mg/dl)
Nein
Ja
loss of function Mutation
PCSK9
verringert die
zelluläre
Aufnahme
von LDL
durch
LDLRezeptoren
23 %
nicht auf
Zielwert
Krähenbühl., Pavlik, von Eckardstein (2016): Drugs 76:1175–1190
Statin-Effekte auf
PCSK9, LDL-Rezeptor und LDL-Cholesterin
Berthold HK, et al. PLoS One. 2013;8(3).
Krähenbühl., Pavlik, von Eckardstein (2016):
Drugs 76:1175–1190
Hemmung
von PCSK9
durch
Antikörper
erhöht die
Verfügbarkeit
von LDLRezeptoren
und die
zelluläre
Aufnahme
von LDL
Krähenbühl., Pavlik, von Eckardstein (2016): Drugs 76:1175–1190
Phase I Studien zu verschiedenen PCSK9 Inhibitoren
Dadu, R. T. & Ballantyne, C. M. Nat. Rev. Cardiol. 11, 563–575 (2014)
Plasmakinetiken von Alirocumab, PCSK9 und LDL-C
0
180
‐10
160
‐20
140
120
‐30
100
Freies PCSK9, Gesamt-AlirocumabKonz. und Mean %
Änderung LDL-C vs Zeit
80
60
‐40
‐50
40
‐60
20
‐70
0
0
500
1000
1500
2000
Zeit (Stunden)
Alirocumab (total)
*Alirocumab=SAR236553/REGN727
Stein EA et al. NEJM. 2012; 366:1008-18
free PCSK9
LDL‐c
2500
LDL‐C % Änderung (mean)
Freies/Gesamt‐PCSK9 Konz. (ng/ml)
Gesamt‐Alirocumab (ng/mL) x 0,01
200
LAPLACE-2: LDL-C Response at Mean of
Weeks 10 and 12
Mean Percent Change from
Baseline in LDL-C and 95% CI
Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo
Ezetimibe: 19 to 32% reductions in LDL-C versus placebo
Atorvastatin
80 mg
Placebo Q2W
Placebo QM
Rosuvastatin
40 mg
Atorvastatin
10 mg
Ezetimibe QD + Placebo Q2W
Ezetimibe QD + Placebo QM
Rosuvastatin
5 mg
Simvastatin
40 mg
Evolocumab Q2W
Evolocumab QM
All treatment differences versus placebo and ezetimibe were statistically significant (P < 0.001). Vertical lines represent 95% CIs.
No notable differences were observed between the mean of weeks 10 and 12 and week 12 alone.
LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly.
18
Der PCSK9-Hemmer Evolocumab senkt den LDL-C Spiegel
um ca. 60% unabhängig von der parallelen lipidsenkenden
Therapie (Diät, tief- oder hochdosiertes Statin, Ezetimib)
901 patients were started on
background lipid-lowering
therapy with diet alone or diet
plus atorvastatin at a dose of 10
mg daily, atorvastatin
at a dose of 80 mg daily, or
atorvastatin at a dose of 80 mg
daily plus ezetimibe at
a dose of 10 mg daily, for a runin period of 4 to 12 weeks.
Patients with an LDL
cholesterol level of 75 mg per
deciliter (1.9 mmol per liter) or
higher were then
randomly assigned in a 2:1 ratio
to receive either evolocumab
(420 mg) or placebo
every 4 weeks.
Blom and DESCARTES investigators N Engl J Med 2014;370:1809-19
Alirocumab Maintained Consistent LDL-C
Reductions Over 52 Weeks
Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT
FH I
Placebo:
FH I
Alirocumab:
FH II
FH II
4.0 mmol/L
4
174
155
3.5
3.7 mmol/L
3.5 mmol/L
3
1.9 mmol/L
1.8 mmol/L
97
77
2
1.5
135
116
2.5
1.8 mmol/L
1.7 mmol/L
58
39
1
0
4
8
12
16
20
Dose ↑ if LDL-C >70 mg/dL at W8
20
4.0 mmol/L
24
28
Week
32
36
40
44
48
52
Intent-to-treat (ITT) Analysis
LLT = lipid-lowering therapy
mg/dL
LDL-C, LS mean (SE), mmol/L
4.5
Most heFH Patients Receiving Alirocumab on
Background Statin  Other LLT Achieved LDL-C Goals
Proportion of patients reaching LDL-C goal† at Week 24
FH I
90
80
FH II
81.4%
Alirocumab
72.2%
% patients
70
Placebo
60
50
40
30
20
10
11.3%
2.4%
0
P<0.0001
†Very
21
high-risk: <1.81 mmol/L (70 mg/dL); high-risk: <2.59 mmol/L (100 mg/dL). LLT = lipid-lowering therapy.
Intent-to-treat (ITT) Analysis
ODYSSEY ALTERNATIVE Study Design
Double-Blind Treatment Period (24 Weeks)
N=100
Alirocumab 75/150 mg SC Q2W + placebo PO QD
OLTP/8 week FU
Statin
intolerant
patients*
(by medical
history)
with LDL-C
≥70 mg/dL
(very-high
CV risk) or
≥100 mg/dL
(moderate/
high risk)
administered via single 1 mL injection using prefilled pen for self-administration
Placebo
PO QD
N=100
+
Placebo R
SC
Q2W†
N=50
Per-protocol dose ↑ possible depending on W8 LDL-C
Ezetimibe 10 mg PO QD + placebo SC Q2W
Atorvastatin 20 mg PO QD + placebo SC Q2W
Assessments
W -4
W0
Patients discontinued if
muscle-related AEs reported
with placebos during run-in
W4
W8
W12
Per-protocol dose increase if
Week 8 LDL-C ≥70 or ≥100 mg/dL
(depending on CV risk)
W16
W24
Primary endpoint
(LDL-C % change from baseline,
ALI and EZE only)
Safety analysis (all groups)
*Unable
to tolerate
least
two different
including
at the lowest
dose,
to muscle-related
symptoms
*Unable
to tolerate
at leastattwo
different
statins,statins,
including
one at one
the lowest
dose, due
to due
muscle-related
symptoms
†4-week
22
single-blind placebo run-in follows 2-week washout of statins, ezetimibe and red yeast rice.
OLTP: Alirocumab open-label treatment period; W, Week.
Alirocumab Significantly Reduced LDL-C from
Baseline to Week 24 versus Ezetimibe
% change from baseline to Week 24 in LDL-C
On-treatment (key secondary endpoint)
ITT (primary endpoint)
LS mean (SE) % change from
baseline to Week 24
0
-10
n=126
n=122
49.5%†
received
150 mg
Q2W at
W12
-20
Absolute
change of
-33 (4.2) mg/dL
n=118
-20
-17.1%
Absolute
change of
-38 (4.2) mg/dL
-30
-40
-40
Alirocumab
-50
-60
-45.0%
Absolute
change of
-84 (4.1) mg/dL
LS mean difference (SE) vs ezetimibe:
-30.4 (3.1); P<0.0001
23
n=123
-10
-14.6%
-30
0
†49.5%
-50
-60
-52.2%
Ezetimibe
Absolute
change of
-96 (3.9) mg/dL
LS mean difference (SE) vs ezetimibe:
-35.1 (2.8); P<0.0001
of 109 patients who received at least one injection after Week 12 had dose increase.
Fewer Skeletal Muscle AEs with Alirocumab
than with Atorvastatin
Kaplan-Meier estimates for time to first skeletal muscle event†
Atorvastatin
0.50
Ezetimibe
Cumulative probability of event
0.45
Alirocumab
0.40
0.35
0.30
0.25
0.20
0.15
Cox model analysis:
HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042
HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096
0.10
0.05
0.00
0
4
8
12
16
20
24
28
Week
†Pre-defined
24
category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.
ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.
32
36
Efficacy and Safety of Alirocumab in
Reducing Lipids and Cardiovascular Events
Randomized trial involving 2341 patients
at high risk for cardiovascular events who
had LDL cholesterol levels of 70 mg per
deciliter (1.8 mmol per liter) or more and
were receiving treatment with statins at
the maximum tolerated dose (the highest
dose associated with an acceptable sideeffect profile), with or without other lipidlowering therapy. Patients were randomly
assigned in a 2:1 ratio to receive
alirocumab (150 mg) or placebo as a 1-ml
subcutaneous injection every 2 weeks for
78 weeks. The primary efficacy end point
was the percentage change in calculated
LDL cholesterol level from baseline to
week 24.
Robinson et al. N Engl J Med 2015;372:1489-99
Efficacy and Safety of Evolocumab in
Reducing Lipids and Cardiovascular Events
Two open-label, randomized trials,
enrolling 4465 patients who had
completed 1 of 12 phase 2 or 3 studies
(“parent trials”) of evolocumab.
Eligible patients were randomly assigned
in a 2:1 ratio to receive either evolocumab
(140 mg every 2 weeks or 420 mg
monthly) plus standard therapy or
standard therapy alone.
Follow up for a median of 11.1 months
Data from the two trials were combined
Sabatine et al. N Engl J Med 2015;372:1500-9
Meta-Analysis on Effects of PCSK9 Antibodies in
Adults With Hypercholesterolemia on Total and
Cardiovascular Mortality and Myocardial Infarction
Total Mortality: OR 0.45 [CI, 0.23 to 0.86]; P = 0.015
CV Mortality: OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084
AMI : OR 0.49 [CI, 0.26 to 0.93]; P = 0.030
Navarese et al. Ann Intern Med. 2015;163:40-51
Meta-Analysis on Serious Adverse Events (SAE) and
CK-Activity Elevation Caused by Treatment with PCSK9
Antibodies in Adults With Hypercholesterolemia
CK elevation: OR 0.72 [CI, 0.54 to 0.96]; P = 0.026
Navarese et al. Ann Intern Med. 2015;163:40-51
SAE: OR 1.01 [CI, 0.87–1.18]; n.s.
Zusammenfassung
 Epidemiologische, genetische und klinische Studien sprechen für die
kausale Bedeutung von LDL-Cholesterin in der Atherogenese.
 Statine oder Ezitimibe senken LDL-Cholesterin durch Hochregulation
der LDL-Rezeptor-Expression und reduzieren das Risiko
kardiovaskulärer Erkrankungen.
 Gain-of-function oder loss-of-function Mutationen in PCSK9
verursachen erhöhte bzw. erniedrigte LDL Cholesterin Spiegel.
 Statine erhöhen die Genexpression und die Plasmaspiegel von
PCSK9 und wirken dadurch der Hochregulation des LDLR durch
Statine entgegen.
 PCSK9 Inhibitoren bewirken eine 65–70% Senkung des LDL-C
zusätzlich zur Statintherapie
 Derzeit werden mehrere monoklonale Antikörper gegen PCSK9 in
Phase III Studien evaluiert.
 Bisherige Auswertungen und Meta-Analysen weisen auf eine Senkung
der Mortalität und Herzinfarktrate sowie auf Sicherheit
EAS/ESC
Recommendations
for the
pharmacological
treatment of hypercholesterolaemia
Schettler et al. für
Deutsche Gesellschaft für Nephrologie
(DGfN) · Verband Deutsche
Nierenzentren (DN)
Internist 2016 · 57:511–516
Diagnostisches und
therapeutisches
Vorgehen bei
vermuteter
Statin-Intoleranz
AGLA, modifiziert nach
ESC/EAS-Empfehlungen :
Stroes et al. Eur Heart J 2015; 36: 1012 – 22
Treatment algorithm for
severe familial hypercholesterolemia
23 %
nicht auf
Zielwert
Santos et al. for
International
Atherosclerosis
Society in
Lancet
Diabetes
Endocrinol 2016
in press
Therapiealgorithmus
zur LipoproteinApherese und PCSK9Inhibition bei
schwerer
Hypercholesterinämie
oder
isolierter
Lipoprotein(a)Hyperlipoproteinämie
Schettler et al. für
Deutsche Gesellschaft für Nephrologie
(DGfN) · Verband Deutsche
Nierenzentren (DN)
Internist 2016 · 57:511–516
Effect of PCSK9 Inhibitors on Total Health Care
Spending Over 5 Years
Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent 316’300 MACE
at a cost of $503’000 per QALY gained compared with adding ezetimibe to statins
(80% uncertainty interval [UI], $493’000-$1’737’000).
In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE
compared with adding ezetimibe at $414’000 per QALY (80% UI, $277’000-$1’539’000).
Kazi et al. JAMA. 2016;316(7):743-753
Incremental Cost-effectiveness Ratio (ICER)
of PCSK9 Inhibitor Therapy Among Patients With
Heterozygous Familial Hypercholesterolemia or
Atherosclerotic Cardiovascular Disease
23 %
nicht auf
6810 USD
Zielwert
4536 USD
2261 USD
Kazi et al. JAMA. 2016;316(7):743-753
In the base case, status quo statin
plus PCSK9 inhibitor therapy is
compared with status quo statin
plus ezetimibe (black line). When
PCSK9 inhibitor therapy costs less
than $7049 per year (inflection in
the graph), ezetimibe is eliminated
by extended dominance and status
quo statin plus PCSK9 inhibitory
therapy is compared directly with
status quo statin therapy (gray line).