PCSK9 inhibitors New option for dyslipidemia Alireza EsteghamatiMD November 2018 Agenda Residual risk after Statin PCCSK9 Inhibitors physiology amp mechanism of action PCSK9 Inhibitor trials ID: 931831
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Slide1
PCSK9 Inhibition:
LDL Lowering
PCSK9 inhibitorsNew option for dyslipidemia
Alireza Esteghamati,MD
November 2018
Slide2Agenda
Residual risk after Statin PCCSK9 Inhibitors physiology & mechanism of actionPCSK-9 Inhibitor trials: FOURIER,
ODYSSEY , GLAGOV
ADA , AACE, AHA Guideline based indications
2
Slide3Program Goals
Slide4Efficacy of Lipid-Lowering Drug Treatment for Diabetic and Nondiabetic PatientsMeta-Analysis of Randomized Controlled Trials
Slide5I
n
te
r
nati
o
nal
Analy
s
is
o
f 17
G
u
i
del
i
nes
and
42
O
bs
e
r
v
atio
n
al St
u
d
i
es
Pa
t
i
e
n
ts
(Very High Risk) Not Achieving NCEP-ATP-III GuidelinesLDL-C Level Target, < 70 mg/dL (1.81 mmol/L)
Middle East/Asia
Europe
US
Global
96.0
100
78.0
77.0
80
60
40
20
0
Arafaet al., 2013 (N = 533, Arabian Gulf Countries)
Chanet al., 2012 (N = 655, China[Hong Kong])
Munawar et al., 2013 (N = 290, Indonesia)
Wanget al., 2014 (N = 501, Taiwan)
Gomez-Beldaet al., 2006 (N = 211, Spain)
Persellet al., 2006 (N = 655, US)
Wonget al., 2013a (N = 225, US)
Waterset al., 2009
(N = 2,334, US, Canada, Mexico, Brazil, Spain, Netherlands, France, Taiwan, Korea)
*Very high risk defined as patients with CHD or who had two or more CVD risk factors, CHD risk-equivalent conditions, or diabetes; Notes: Treated and untreated patients. The N represents patients at high risk, a subset of the total number of patients studi ed.LDL-C = low-density lipoprotein cholesterol; NCEP-ATP-III = National Cholesterol Education Program–Adult Treatment Panel III;US = United States.Mitchell S, et al. BMC Cardiovasc Disord. 2016;16:74.
Not Achieving Goals (%)
87
.9
84.8
68
.1
70
.0
16
.9
In Real World Data
, Many Very High
Risk
CHD Patients Do
Not
Achieve
LDL-C Targets
Slide6*If
target defined as <
70 mg/dL
(
1
.8
mmol
/
L
);
†
T
h
e
e
x
t
en
t
to
w
hich pat
ients were
receiv
ing ma
ximally t
olerat
ed s
tati
n ther
apy wa
s not
availa
ble i
n th
e da
ta.ASV
CD = at
herosclero
tic cardiovascular disease; LDL-C = low-density lipoprotein cholesterol. Menzin et al. JMCP 2017.Even With Addition of Ezetimibe, Many ASCVD Patients Do Not Achieve LDL-C Goal
LDL-C Target* Attainment After Adding
Ezetimibe to Statin
T
herapy
fo
r
Patients
W
ith Baseline
LDL
-C
>
1
00
mg/dL (> 2.6 mmol/L) After
Statins†Achieved LDL-C < 70 mg/dL (1.
8 mmol/L)Did Not Achieve LDL-C <
70 mg/dL (1.8 mmol/L)100%80%60%
40%20%0%ASCVD, Baseline LDL-C 100–129 mg
/dL(2.6 mmol/L) (n = 286)ASCVD
, Baseline LDL-C 130 mg/dL (3.4
mmol/L) (n = 305)
86%93%14%7%Patients:N = 1,309ASCVD ofHeFH90 d
ay Follow-up: Assessed for achievement of LDL-C< 70 mg/dL(< 1.8 mmol/L)
Slide7Inci
d
ence
of Major
CVD
E
v
en
t
s
and
Le
v
els of LD
L
-
C
in
Patien
t
s
Recei
v
ing
Moderate-
or
Hig
h-
In
t
ensi
ty Statin
Therapy1-3Moderate-intensity statin therapyHigh-intensity statin therapy4035302520158.7
1050P
ROVE IT
-TIMI
2214,162
IDE
AL2
8,888TNT
310,001
N
LDL-C,* m
g/dL LDL-
C,* mm
ol/L
952.46621.601042.69812.091012.6177
1.99Mean or median LDL-C after treatment.CV = car
diovascular; CVD = cardiovascular disease; LDL-C = low-
density lipoprotein cholesterol.1. Cannon CP, et
al. N Engl J Med. 2004;350:1495-1504. 2. Pederson
TR, et al. JAMA. 2005;294:2437-
2445.3. LaRosa JC, et al. N Engl
J Med. 2005;352:1425-1435.
Patients ExperiencingMajor CVD Events (%)26.322.
413.7 1210.9Residual CV Risk Exists Even in Those CHD Patients Receiving Treatment With High-Intensity Statins
Slide8What should we do in the next step?
What is PCSK9?It’s a protein that regulates cholesterolmetabolism8
Slide9Proprotein convertases
Proprotein convertases are a family of enzymes involved in converting precursors of secretory proteins, such as hormones, enzymes and receptors, into bioactive
molecules at their intended target tissue. These enzymes are
part of regulatory pathways
that help the body to maintain homeostasis
Slide10PCSK9
PCSK9 (proprotein convertase subtilisin/
kexin type 9) was first described in 2003
In
its active form, PCSK9
regulates
cell surface receptors, in particular
the LDL receptor.
The
enzyme
encoded by the PCSK9 gene is primarily
expressed in the liver.
Slide11Proprotein convertase
subtilisin/kexin type 9 (PCSK9) Is a Key Regulator of LDL-R Recycling
1. Horton JD, et al.
J Lipid Res
. 2009;50:S172-S177. 2. Qian YW, et al.
J Lipid Res.
2007;48:1488-1498. 3. Zhang DW, et al.
J
Biol
Chem.
2007;282:18602-18612. 4. Lopez D.
Biochim
Biophys
Acta
. 2008;1781:184-191.
PCSK9 mediates degradation of the LDL-R by interacting with the extracellular domain and targeting the receptor for degradation
1
PCSK9 is highly expressed in the liver, small intestine, and kidney
4
Slide12Slide13PCSK9 inhibitors
Are monoclonal antibodiesTarget and inactivate PCSK9 in the liverDramatically decrease LDL-C
Slide14PCSK9 Inhibition
Rapid Progress From Discovery to Clinic
Seidah NG.
Proc Natl Acad Sci USA
2003;100(3):928-33, Abifadel M.
Nat Genet
2003;34(2):154-6, Maxwell KN.
Proc Natl Acad Sci USA
2004;101(18):7100-5, Rashid S. Proc Natl Acad Sci USA 2005;102(15):5374-79, Lagace TA et al. JCI 2006;116:2995-3005 Cohen JC.
N Engl J Med
2006;354(12):1264-72, Zhao Z.
Am
J Hum Genet
2006;79(3):514-23, Hooper AJ.
Atherosclerosis
2007;193(2):445-8, Chan JC.
Proc Natl Acad Sci USA
2009;106(24):9820-5; Stein et al
N Engl J Med
2012;366:1108-18
First publication POC in patients
First patients with FH & nonFH treated with PCSK9 mAb
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2012
PCSK9 LOF mutations found with 28%
LDL-C
and 88%
CHD risk
Humans null for PCSK9 have LDL-C ~15 mg/
dL
LDL-C in mice and non-human primates treated with anti-PCSK9 mAb
PCSK9 (NARC-1) discovered
PCSK9 GOF mutations associated with ADH
First subject treated with PCSK9 mAb
Adenoviral
expression in mice
PCSK9 KO mouse
LDL-C
Plasma PCSK9 binds to
LDLr
Slide15Timeline of development
Slide16Population Studies
PCSK9 Loss-of-Function Mutations
Slide17The PCSK9 Variant Story
Slide18Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels
1. Horton JD, et al.
J Lipid Res
. 2009;50:S172-S177. 2.
Lakoski
SG, et al.
J
Clin
Endocrinol
Metab
.
2009;94:
2537-2543. 3.
Abifadel
M, et al.
Hum
Mutat
.
2009;30:520-529. 4. Cohen J, et al.
Nat Genet.
2005;37:161-165.
5. Steinberg D, et al.
PNAS.
2009;106:9546-9547. 6. Cohen JC, et al. N Engl J Med
. 2006;354:1264-1272. 7. Benn M, et al. J Am
Coll Cardiol. 2010;55:2833-2842.
PCSK9 Gain of Function (GOF) =
Less LDL-Rs
1,3,5
PCSK9 Loss of Function (LOF) =
More
LDL-Rs2,4,5
1-3% of population6,7
Slide19Slide20Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
20
Image
available from: https://www.repathahcp.com
/
Slide21Adapted from Raymond, Cleveland
Clin J Med, Jan, 2014 LDL: Lower is Better
IMPROVE-IT S40/E10
Slide22PCSK9 TRIALS
DM & Non DM
Slide23Evolocumab Mechanism of Action
Fully humanized monoclonal antibody23
Image
available from: https://www.repathahcp.com
/
Slide24PCSK9 Inhibitors
PCSK9 inhibitors are highly effective lipid-lowering agents that can dramatically lower circulating LDL.Currently, two PCSK9 inhibitors:
Alirocumab (Praluent
,
Sanofi
/
Regeneron
)
Evolocumab
(
Repatha
, Amgen)
have
been approved by
FDA and
are available for clinical use.
Slide25Evolocumab
In meta-analysis from three phase 3 studies evolocumab has also shown favorable changes in lipid profile in diabetic patients
Prespecified analysis
of diabetics
from the pivotal FOURIER trial sheds light on
the effect
of
evolocumab on outcomes in
diabetics
.
Slide26Evolocumab FOURIER trial
11031 diabetics (40%) 16533 non-diabetics with stable ASCVD and deranged lipid profiles
On statin therapy Median
of 2.2 years
Found
that
it similarly
reduced the primary composite endpoint of
CV death
, stroke, MI, hospitalization of angina, or coronary
revascularization
in
Diabetics
(HR 0.83, 95% CI 0.75–0.93)
Non-
diabetics
(HR 0.87 95% CI
0.79–0.96
)
Importantly
, the trial showed no increase in
new-onset diabetes
or glycemic derangements with PCSK9 inhibition.
Slide27PCSK9 Inhibitors & DM
Slide28Alirocumab
A pooled analysis of 5 placebo-controlled phase 3 trials of alirocumab showed that :it reduced LDL
as significantly in patients with type 2 diabetes compared to non-diabetics with
a similar
safety profile as
well.
This analysis of diabetics
with mixed
dyslipidemia treated with
150 mg of alirocumab
every 2
weeks for 24
weeks resulted in
:
57
% reduction in LDL
47
% reduction in non-HDL cholesterol, similar to non-diabetics.
Slide29Alirocumab
The most common adverse effect was:Upper respiratory tract infection (5%) Injection
site reaction (3%) Overall rate was similar between diabetics and non-diabetics
.
B
eneficial
improvements in lipid profile have also been shown
in
ODYSSEY DM-DYSLIPIDEMIA
ODYSSEY DM INSULIN
ODYSSEY
COMB
II
.
Slide30PCSK9 Inhibitors & DM
Slide31Slide32BACKGROUND
Patients who have had an ACS are at high risk for recurrent ischemic cardiovascular events.
We sought to determine whether alirocumab, would
improve
cardiovascular outcomes after an
ACS
in patients
receiving high-intensity
statin therapy.
Slide33Alirocumab ODYSSEY
OUTCOMES Included 18,924 patients with abnormal lipid profiles on maximally tolerated statin therapy who
had an ACS within the last 12 months.
Of this population, 29% (n = 4971) had diabetes.
G
oal
of
trial
was
an LDL
between
25 and 50
mg/
dL
and
those with LDL < 15 mg/
dL
has therapy down titrated
or stopped
.
Slide34Slide35ODYSSEY OUTCOMES
Median follow-up of 2.8 years LDL in the alirocumab group was 53.3 mg/
dL compared with 101.4
mg/
dL
in
placebo
arm
.
The
incidence of adverse events
was similar
in the two groups, with the exception of
local injection-site reactions (3.8%
in the
alirocumab group vs. 2.1% in the placebo group).
Slide36Alirocumab resulted in a reduced composite primary end point of first occurrence of coronary heart disease death, nonfatal MI, unstable angina requiring hospitalization, or ischemic stroke
of 9.5% vs. 11.1% in the placebo arm (HR 0.85, 95% CI 0.78–0.93, p = 0.0003).
Slide37Alirocumab
There was also a reduction in the secondary endpoint of all-cause mortality (3.55% vs. 4.1%, p = 0.03). These reductions were more
marked in patients with a baseline LDL > 100 mg/dL.These promising data show that PCSK9 inhibition
achieved through
either alirocumab or evolocumab can
play an
important role
in reducing residual risk in selected diabetics at high risk
.
Slide38PCSK9 Inhibitors & DM
Slide39Slide40Inclisiran
Inclisiran is a small interfering RNA designed to target PCSK9 messenger RNA.
In ORION-1, a multicenter
phase
2
randomized double-blind placebo controlled trial of
501 patients
with ASCVD or ASCVD equivalent on
maximally tolerated
statin
therapy
S
ingle
dose of injectable
inclisiran
resulted
in an LDL mean reduction of 27.9 (42% reduction
)
Two
doses led to a reduction of 35.5 (53% reduction)
at 180
days.
Slide41Inclisiran
Serious side effects occurred in 11% of patients receiving inclisiran and 8% receiving placebo. Injection site reactions occurred in 5% of patients and were most
common. Of these patients, 67 (14%) had diabetes, and these patients experienced
similar LDL reductions without any
worsening in
glycemic
profile.
While more data is
required, these
initial reports are encouraging.
Slide42Evolocumab OSLER Trial Cumulative Incidence of Cardiovascular Events*
Slide43FOURIER
Further cardiovascular OUtcomes R
esearch with PCSK9 Inhibition in subjects with E
levated
R
isk
MS Sabatine, RP Giugliano, AC Keech, N Honarpour,
SM Wasserman, PS Sever, and TR Pedersen,
for the FOURIER Steering Committee & Investigators
American College of Cardiology – 66
th
Annual Scientific Session
Late-Breaking Clinical Trial
March 17,
2017
SC-MEA-AMG145-00095
Mar 17
Slide44FOURIER Trial: Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects with Elevated Risk
This randomized, double-blind, placebo-controlled trial investigated the effects of adding evolocumab to high-intensity statin therapy compared with high-intensity statins alone.Study results included data for over 27,500 individuals with clinically evident atherosclerotic disease and LDL-C ≥
70 mg/dL and non-HDL-C
≥100 mg/
dL; mean patient follow-up was 2.2 years
.
All study participants were receiving statin therapy with or without ezetimibe, and the evolocumab and placebo groups had the same
LDL-C (92 mg/dL).
Abbreviations:
; LDL-C, low-density lipoprotein cholesterol
;
MI, myocardial infarction.
Sabatine
MS, et al.
NEJM.
2017; epub ahead of print.
Slide45Trial
DesignEvolocumab SC140 mg
Q2W or 420 mg QM
Placebo
SC
Q2W or
QM
LDL-C
≥70 mg/dL
(1.8
mmol/L)
or
non-HDL-C
≥100 mg/dL
(2.6
mmol/L)
Follow-up
Q
12 weeks;
Median
f/up
2.2
yrs
Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity
statin
therapy
(±
ezetimibe)
27,564 high-risk, stable patients
with
established CV disease (prior
MI,
prior stroke, or
symptomatic
PAD)RANDOMIZED DOUBLE BLINDSabatine MS et al. Am Heart J 2016;173:94-101Primary Endpoint: CVD/MI/Stroke/UA/Coronary Revasc Key Secondary Endpoint: CVD/MI/Stroke
Slide46Study Endpoints
Primary Efficacy EndpointMajor cardiovascular events, defined as the composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization
Key Secondary Efficacy EndpointComposite of CV death
, MI, or
stroke
Safety Endpoints
Adverse events
Development of anti-
evolocumab
antibodies (binding and neutralizing
)
46
Slide47FOURIER Evolocumab Study
LDL-C Levels Over timeAbbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol. Sabatine MS, et al.
NEJM. 2017; epub ahead of print.
Placebo
13,779
13,251
13,151
12,954
12,596
12,311
10,812
6926
3352
790
Evolocumab
13,784
13,288
13,144
12,964
12,645
12,359
10,902
6958
3323
768
Absolute difference (mg/
dL)
54
58
57
56
55
54
52
53
50
Percentage difference
57
61
61
59
5857555654P-value
<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001No. at Risk
Slide48Summary of Effects of
PCSK9i Evolocumab
0
2
0
4
0
6
0
8
0
100
LD
L
Cho
l
es
t
e
r
o
l
(
m
g
/
d
l)
0 24 48 72 96 1
2
0
1
4
4
1
68
Weeks
after
randomization
An
Academic Research Organization
of
Brigham and Women’s Hospital and Harvard Medical
School
LDL-C by 59% down to a
median
of 30
mg/dl
CV outcomes
in
patients on
statin
Safe and well-toleratedEvolocumab(median 30 mg/dl, IQR 19-46 mg/dl)Placebo59% reduction P<0.00001Absolute 56 mg/dl14.69.912.67.9051015KM R
ate (%) at 3 YearsHR 0.85 (0.79-0.92) P<0.0001
HR
0.80 (0.73-0.88) P<0.0001
CVD, MI, stroke UA, cor
revasc
CVD, MI,
strokeSabatine MS
et al. NEJM
2017;376:1713-22
Slide49FOURIER: CV Outcomes
FOURIER: CV OutcomeSabatine MS, et al . NEJM. [published online ahead of print March 17, 2017].
Slide50FOURIER Evolocumab Study Endpoints
Abbreviations: FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; MI, myocardial infarction.Sabatine MS, et al. NEJM. 2017; epub ahead of print.
Cumulative event rates for the primary efficacy endpoint (Composite of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization
)
Cumulative rates for the key secondary efficacy endpoint (Composite of cardiovascular death, MI, or stroke)
Slide51FOURIER: LDL CholesterolIn patients with baseline LDL-C≤70 mg/dL
FOURIER: LDL
Cholestrol
In patients with baseline LDL-C ≤ 70 mg/
dL
FOURIER
subanalysis
in several thousand patients who had baseline LDL-C
≤ 70 mg/
dL
or non-HDL
≤
100 mg/
dL
Courtesy of Marc S.
Sabatine
, MD, MPH- National Lipid Association Conference 2017.
Slide52FOURIER: Clinical OutcomesIn patients with baseline LDL-C<70 mg/dL
FOURIER: LDL
Cholestrol
In patients with baseline LDL-C ≤ 70 mg/
dL
Courtesy of Marc S.
Sabatine
, MD, MPH- National Lipid Association Conference 2017.
Slide53FOURIER Primary and Secondary Endpoints
At 26 months, extremely tight lipid control with evolocumab led to 15% decrease in risk for the primary composite endpoint 20% decrease in risk for a secondary composite endpoint
Beyond the second year of follow-up, the risk reduction increased to 20
% for the primary endpoint
25
% for the secondary endpoint
Abbreviations:
FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol
;
MI, myocardial infarction.
Sabatine MS, et al.
NEJM.
2017; epub ahead of print.
Slide54FOURIER Primary and Secondary Endpoints
For singular endpoints at 26 months, very tight lipid control reduced the risk of MI by 27% stroke by 21
% coronary revascularization by 22%
Abbreviations:
FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial; LDL-C, low-density lipoprotein cholesterol
;
MI, myocardial infarction.
Sabatine MS, et al.
NEJM.
2017; epub ahead of print.
Slide55PCSK9 inhibitor changes levels and sizes of lipoprotein particles
Slide56Evolocumab was associated with reductions in the mean total concentration of VLDL-p/chylomicron, medium VLDL-p, small VLDL-p, and IDL-p
, and non-significantly increased the concentration of large VLDL-p/chylomicron.
All 95%Ci’s were quite wide and included 0.
Main
results Cont..
Slide57The
results were consistent in patients with type 2 diabetes, those with metabolic syndrome, and in individuals with IFG and regardless of concordance status of LDL-c/LDL-p levels at baseline (discordance defined as LDL-c and LDL-p values differing by >14 percentile units).Main
results Cont..
Slide58Size
of LDL-p was decreased in the evolocumab group compared to placebo (% change: -1.7 to 1.4 P<0.0001) size of HDL and VLDL particles was increased with evolocumab compared to placebo
HDL: 1.1,
vs
. -0.02,
P<0.001
VLDL
: 8.7,
vs
. 0.9,
P<0.0001.
Main
results Cont..
Slide59Effect of evolocumab on lipoprotein particles
Total LDL-p
Total HDL-p
Total VLDL-p/ chylomicron
IDL-p
Evolocumab
(N=294)
-44.1 (-47.2 to -40.9)
9.4 (7.5-11.4)
-15.3 (-39.3 to 15.4)
-36.2 (-69.8 to 22.0)
Placebo
(N=236)
6.4 (2.9
– 9,9)
-0.1 (-1.6 to 1.4)
-0.3 (-26.3 to 31.7)
0 (-47.4 to 87.5)
P value
P <0.0001
P <0.0001
P <0.001
P <0.0001
Mean % change from baseline to week 52 (95%CI)
Toth
PP, et al. Am J
Cardiol 2018;121:308–314
CI: confidence interval; QM: once every month; LDL-p: low-density lipoprotein particle concentration; HDL-p: high-density lipoprotein particle concentration; VLDL-p: very low-density lipoprotein particle concentration; IDL-p: intermediate-density lipoprotein particle concentration;
Slide60Conclusion
Evolocumab significantly changes lipoprotein particle number and size. Treatment with the PCSK9 inhibitor was associated with lower concentrations of total LDL-c, small LDL-p and large LDL-p. These findings may help guide therapeutic decisions in patients with hyperlipidemia.
Slide61EBBINGHAUS:
Evaluating PCSK9 Binding Antibody Influence on
Cog
nitive
H
e
a
lth in High Cardiovasc
u
lar Risk
S
ubjects
EBBINGHAUS is the first prospectively
designed study to evaluate the relationship between PCSK9 inhibition and
changes in cognition, including memory, attention, and reaction time
The mean change in the primary endpoint of executive function, as measured by the Spatial Working Memory strategy index (from the Cambridge Neuropsychological Test Automated Battery), was -0.29 with placebo and -0.21 with evolocumab (
P
<0.0001 for
noninferiority
)
All secondary outcomes were similar for placebo and evolocumab, including patient self-reports and investigator-reported cognitive adverse events
N=1,974 patients from FOURIER Study, followed for 96 weeks
https://clinicaltrials.gov/ct2/show/NCT02207634;
http://www.acc.org/latest-in-cardiology/articles/2017/03/13/17/44/sat-8am-ebbinghaus-cognitive-study-of-patients-enrolled-in-fourier-acc-2017?w_nav=LC;
https://challengesincardiology.com/ebbinghaus-a-cognitive-study-of-patients-enrolled-in-the-fourier-trial/.
Abbreviations:
FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial;
PCSK9,
proprotein
convertase subtilisin/kexin type 9.
Slide62PCSK9 IVUS Trial
62
Slide6363
Slide64GLAGOV: Mean On-Treatment LDL-C vs.
Change in Percent Atheroma VolumeAchieved On-Treatment LDL-C (mg/dL).
The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment 5/2013 to 1/2015) conducted at 197 academic and community hospitals in 6 continents, enrolling
968 patients
(mean age 59.8 years, 27.8% female) with CAD
Patients with angiographic CAD were randomized to receive monthly evolocumab (420 mg) (n=484) or placebo (n=484) SQ for 76 weeks, in addition to statins
Locally weighted polynomial regression (LOESS) plot demonstrates a linear continuous relationship between achieved LDL-C level and PAV progression/ regression for levels of LDL-C ranging from 110 mg/dL
to as low as 20 mg/dL
Abbreviations:
CAD, coronary artery disease
;
GLAGOV,
Global Assessment of Plaque Regression With a PCSK9 Antibody ;
LDL-C, low-density lipoprotein
cholesterol; SQ, subcutaneous.
Nicholls SJ.
JAMA
. 2016;316(22):2373-2384.
Change In Percent Atheroma Volume (%)
Slide6565
Slide66GLAGOV: Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound
Nominal change in percent atheroma volume at 78 weeks: -0.95% in the evolocumab group vs. 0.05% in the placebo group (
P
<0.001 for between-group comparison)
Patients with plaque regression:
64.3% with evolocumab vs. 47.3% with placebo (
P
<0.001)
Major adverse cardiac events: 12.2% with evolocumab vs. 15.3% with placebo
Trial design:
Patients with CAD and elevated LDL-C on statin therapy were randomized to SQ evolocumab (n=484) vs SQ placebo (n=486).
Results
Conclusions
Among patients with angiographic evidence of CAD on chronic statin therapy, the PCSK9 inhibitor evolocumab resulted in a greater change in percent atheroma volume and a greater proportion of patients with plaque regression
Abbreviations:
CAD, coronary artery disease
;
LDL-C, low-density lipoprotein cholesterol; PCSK9,
proprotein
convertase subtilisin/kexin type 9; SQ, subcutaneous.
Nicholls SJ, et al.
JAMA.
2016;316:2373-2384.
Slide6767
Slide6868
Slide69Slide70Evolution of Lipid Guidelines (cont)
Evolution of Lipid Guideline (cont.)
Slide71Updated Non-statin Therapy Considerations to Achieve Net ASCVD Risk Reduction
Consider adding
ezetimibe as the initial agent and PCSK9 inhibitor as the second agent
Adults ≥ 21 yrs with ASCVD with Comorbidities, on Statin for Secondary
Prevention, Baseline LDL-C 70-189 mg/dL
2016 pathway
2017 Pathway
C
on
s
ider
adding
e
i
t
h
er
e
z
e
t
i
m
ibe
o
r
a
P
C
SK9
i
nhibi
t
or
bas
ed on c
onsiderations of the additional percent LDL-C reduction desired, patient preferences, costs, route of administration, other factorsEither ezetimibe or PCSK9 inhibitor maybe consider as the initial agent adding after maximaly tolerated statine depending on desired reduction in LDL-C and other considerations
PCSK9 inhibitor may be preferredas the initial non-statin agent if patients require > 25% additional lowering of LDL-CConsiderations favoring ezetimibeinclude: requiring < 25% additional lowering of LDL-C, recent ACS < 3 months, cost, ease of use, and patient preferenceComorbidities that predict response to ezetimibe include: heart failure, hypertension, age > 75 years, diabetes, stroke, CABG, PAD, eGFR < 60 ml/min/1.73m 2 , and smoking
Slide72U
lf Landmesser, M. J
ohn Chap
ma
n
, Ja
n
e
K. Stock,
Pi
e
rre
Amar
e
nc
o
,
Ji
l
l J.F.Be
lch, Jan
Boré
n, Mic
hel Farn
ier,
Brian
A. Feren
ce, Stephan
Gielen
, Ian Grah
am, Die
derick
E. Grobb
ee,
G. Kees Ho
vingh,
Thomas
F. Lüscher, Massimo F. Piepoli, Kausik K. Ray, Erik S. Stroes, Olov Wiklund, StephanWindecker, Jose Luis Zamorano, Fausto Pinto, Lale Tokgözoğ
lu, Jeroen J. Bax, and Alberico CatapanoPublication online 16 October 2017Landmesser U, et al. Eur Heart J 2017. doi:1
0.1093/eurheartj
/ehx
549.
Slide73Evolution of Lipid Guidelines (cont)
Evolution of Lipid Guidelines
(cont.)
Slide74ESC/EAS 2017 Task Force Update on Clinical Guidance for PCSK9 Inhibitors:
Patients with Clinical ASCVD*Markers of high risk as determined by CTA include global markers (left main artery disease, proximal left anterior descendin g artery disease, 3-vessel disease) and focal markers (stenosis >50% obstruction, mixed or non-calcified lesion composition)ACS =acute coronary syndrome; CAD = coronary artery disease; CTA = coronary computed tomography angiography; PAD = peripheral artery disease; EAS = European Atherosclerosis Society; ESC = European Society of Cardiology; LDL-C = low-density lipoprotein cholesterolLandmesser U, et al. Eur
Heart J. 2017. doi: 10.1093/eurheartj/ehx549 [epub ahead of print].
Slide75Criti
cality of LD
L-C
in C
H
D
:
S
u
mmary
1. Ross R. N Engl J Med. 1999;340:115-126. 2. Stary HC, et al. Circulation. 1995;92:1355-1374. 3. Pepine CJ. Am J Cardiol. 1998;82:23S-27S. 4. Ference BA, et al. Eur
Heart J. 2017;38:2549-2472. 5. O’Gara PT, et al. Circulation. 2013;127:e362-e425. 6. Ibanez B et al. Eur Heart J. 2017;1–66 (in press). 7. Stone NJ, et al. JACC.
2014;63::3024-3025. 8. Amsterdam EA, et al. JACC. 2014;64:e139-228. 9. Roffi M, et al. Eur Heart J. 2016;34:267-315. 10. Pedersen TR, et al. Lancet. 1994;344:1383-1389. 11. Sacks FM, et al N Engl J Med 1996;335:1001-1009. 12. Cannon CP, et al. for IMPROVE-IT Investigators. N Engl J Med. 2015;372:2387-2397.
High LDL-C is a driving force for atherosclerosis and coronary
Events
1-3
•
Reducing LDL-C leads to a risk reduction in coronary events that is
proportional to the magnitude of LDL-C
reduction
4
•
Treatment of acute MI requires a multifactorial approach, and after
the
acute stage, chronic therapy includes the intensive management
of LDL-C
5-9
•
LDL-C lowering with statins and combination therapy with
ezetimibe
has
been demonstrated to reduce the risk of coronary heart disease
as
well as reduce the risk of CV events in patients with coronary heart
Disease
10-12
Slide76Criti
cality of LD
L-C
in C
H
D
:
S
u
mmary
1. Ross R. N
Engl
J Med. 1999;340:115-126. 2.
Stary
HC, et al. Circulation. 1995;92:1355-1374. 3.
Pepine
CJ. Am J
Cardiol
. 1998;82:23S-27S. 4.
Ference
BA, et al.
Eur
Heart J. 2017;38:2549-2472. 5. O’Gara PT, et al. Circulation. 2013;127:e362-e425. 6. Ibanez B et al.
Eur
Heart J. 2017;1–66 (in press). 7. Stone NJ, et al. JACC. 2014;63::3024-3025. 8. Amsterdam EA, et al. JACC. 2014;64:e139-228. 9.
Roffi M, et al. Eur Heart J. 2016;34:267-315. 10. Pedersen TR, et al. Lancet. 1994;344:1383-1389. 11. Sacks FM, et al N
Engl J Med 1996;335:1001-1009. 12. Cannon CP, et al. for IMPROVE-IT Investigators. N
Engl J Med. 2015;372:2387-2397.
The FOURIER study further demonstrated that the addition of evolocumab
to optimized statin therapy significantly reduces the risk of CV
events, including MI
1
– A progressive and proportion relationship between CV event reduction and intensive
LDL-C reduction achieved with evolocumab continues to very low levels of LDL-C (< 20 mg/
dL [< 0.5 mmol
/L])
• Globally, current dyslipidemia guidelines and recommendations target
LDL-C lowering to reduce the risk of ASCVD, including CHD, with
statins recommended as first-line therapy. Expert consensus and clinical
pathway recommendations incorporate PCSK9 inhibitors and ezetimibe for secondary prevention in high risk patients 3-8• However, a substantial number of patients are unable to achieve LDL-C goals, and residual risk exists in patients receiving statins ± ezetimibe 9,10
Slide77American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia
and Prevention of Cardiovascular Disease
Slide78ASCVD Risk Categories and LDL-C Treatment Goals
Risk category
Risk factors/10-year risk
Treatment goals
LDL-C
(mg/dL)
Non-HDL-C
(mg/dL)
Apo B
(mg/dL)
Extreme risk
–
Progressive ASCVD including unstable angina in individuals after achieving an LDL-C <70 mg/dL
– Established clinical cardiovascular disease in individuals with DM, stage 3 or 4 CKD, or HeFH
– History of premature ASCVD (<55 male, <65 female)
<55
<80
<70
Very high risk
– Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease, 10-year risk >20%
– DM
or
stage 3 or 4 CKD with 1 or more risk factor(s)
– HeFH
<70
<100
<80
High risk
– ≥2 risk factors and 10-year risk 10%-20%
– DM or stage 3 or 4 CKD with no other risk factors
<100
<130
<90
Moderate risk
≤2 risk factors and 10-year risk <10%
<100
<130
<90
Low risk
0 risk factors
<130
<160
NR
Barter PJ, et al.
J Intern Med
. 2006;259:247-258; Boekholdt SM, et al.
J Am Coll Cardiol
. 2014;64(5):485-494; Brunzell JD, et al.
Diabetes Care
. 2008;31:811-822; Cannon CP, et al.
N Engl J Med.
2015;372(25):2387-2397; Grundy SM, et al.
Circulation.
2004;110:227-239; Heart Protection Study Collaborative Group.
Lancet. 2002;360:7-22; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Lloyd-Jones DM, et al. Am J Cardiol. 2004;94:20-24; McClelland RL, et al. J Am Coll Cardiol. 2015;66(15):1643-1653; NHLBI. NIH Publication No. 02-5215. 2002; Ridker PM, J Am Coll Cardiol. 2005;45:1644-1648; Ridker PM, et al. JAMA. 2007;297(6):611-619; Sever PS, et al. Lancet. 2003;361:1149-1158; Shepherd J, et al. Lancet. 2002;360:1623-1630; Smith SC Jr, et al. Circulation. 2006;113:2363-2372; Stevens RJ, et al. Clin Sci. 2001;101(6):671-679; Stone NJ. Am J Med. 1996;101:4A40S-48S; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):1307-1315.Abbreviations: ACS, acute coronary syndrome; apo, apolipoprotein;
ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; HeFH, heterozygous familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NR, not recommended.
Slide79ASCVD Risk Categories
Low risk:No risk factorsModerate risk:2 or fewer risk factors and a calculated 10-year risk of less than 10%High risk:An ASCVD equivalent including diabetes or stage 3 or 4 CKD with no other risk factors, or individuals with 2 or more risk factors and a 10-year risk of 10%-20%Very high risk:Established or recent hospitalization for ACS; coronary, carotid or peripheral vascular disease; diabetes or stage 3 or 4 CKD with 1 or more risk factors; a calculated 10-year risk greater than 20%; or HeFHExtreme risk:Progressive ASCVD, including unstable angina that persists after achieving an LDL-C less than 70 mg/dL, or established clinical ASCVD with diabetes, stage 3 or 4 CKD, and/or HeFH, or in those with a history of premature ASCVD (<55 years of age for males or <65 years of age for females)
This category was added in this CPG based on clinical trial evidence and supported by meta-analyses that further lowering of LDL-C produces better outcomes in individuals with ACS. IMPROVE-IT demonstrated lower rates of cardiovascular events in those with ACS when LDL-C levels were lowered to 53 mg/dL combining ezetimibe with statins. Abbreviations: ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CPG, clinical practice guideline; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; IMPROVE-IT,
Improved Reduction of Outcomes: Vytorin Efficacy International Trial.
AACE/ACE
CPG. 2017;epub ahead of print;
Cannon, CP, et al.
N Engl J Med.
2015;372(25):2387-239;
Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice
. 2017;23(4):479-497.
Slide80Question: For patients with diabetes,
what risk categories does AACE recommend?Recommendations associated with this question:
T1DM is associated with increased ASCVD riskIndividuals with T1DM should be screened annually for dyslipidemia
Individuals with T1DM should be treated aggressively for dyslipidemia according to risk level recommendations
Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice
. 2017;23(4):479-497.
Abbreviations:
A1C, glycated hemoglobin;
AACE, American Association of Clinical Endocrinologists;
ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV,
cerebrovascular; T1DM, type 1 diabetes mellitus;
T2DM, type 2 diabetes mellitus.
Slide81Factors That May Increase Risk for Ischemic ASCVD in Patients With T1DM
Albuminuria1Late-onset T1DM (>30 years of age) without nephropathy, but with: Initiation of intensive control more than 5 years after diagnosis2,3 Duration of disease greater than 15 years4-8
Previous history of MI or poorly controlled A1C4Insulin resistance or MetS9
and an hsCRP concentration
>3.0 mg/L
10
Individuals with T1DM for >15 years or with ≥2 CV risk factors should be treated as if they had T2DM. Given the risks associated with T1DM, dyslipidemia in this population must not be overlooked and should be treated aggressively
1. Borch-Johnsen K, Kreiner S
. Br Med J (Clin Res Ed)
. 1987;294:1651-1654. 2.
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group, Nathan DM, et al.
N Engl J Med
. 2005;353:2643-2653.
3. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group.
JAMA
. 2003;290:2159-2167. 4.
Lehto S, et al.
Arterioscler Thromb Vasc Biol. 1999;19:1014-1019.
5.
Pambianco G, et al.
Diabetes
. 2006;55:1463-1469. 6. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group, Nathan DM, et al.
Arch Intern Med.
2009;169:1307-1316. 7. Secrest AM, et al.
Diabetes
. 2010;59:3216-3222. 8. de Ferranti SD, et al.
Diabetes Care
. 2014;37:2843-2863. 9.
Alexander CM, et al.
Diabetes
.
2003;52:1210-1214. 10. Mackness B, et al.
Atherosclerosis
.
2006;186:396-401.
Abbreviations:
A1C, glycated hemoglobin;
ASCVD, atherosclerotic cardiovascular disease; CV, cerebrovascular;
hsCRP, highly sensitive C-reactive protein; MetS, metabolic syndrome; MI, myocardial infarction; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Slide82Systematic Review, Summary of Event Rates in Trial Participants With Diabetes, Stratified by Absence or Presence of Baseline Proteinuria
Preiss D, et al. Am Heart J. 2011;161:210-219.
~6-fold higher
~15-fold higher
~13-fold higher
~12-fold higher
Abbreviations:
CVD, cardiovascular disease;
MI, myocardial infarction.
Randomized controlled trials (N=29), 116,790 patients with diabetes,
~518,611 patient-years of follow-up
Slide83Slide84Question: Who should be screened for ASCVD risk and when?
Recommendations associated with this question: Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice
. 2017;23(4):479-497. Abbreviations:
ASCVD, atherosclerotic cardiovascular disease; FH,
familial hypercholesterolemia;
HDL, high-density lipoprotein; LDL, low-density lipoprotein;
MI, myocardial infarction;
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Slide85Familial Hypercholesterolemia: Diagnosis
FH diagnostic criteria include lipid levels and family history, physical symptoms (if any), and genetic analysis (if available)1Three clinical diagnostic tools:2-3 Simon Broome Register Diagnostic CriteriaDutch Lipid Clinic Network Diagnostic CriteriaU.S. MEDPED
Factors that lead to an FH diagnosis include: Premature ASCVD, fasting LDL-C >190 mg/dL, the presence of tendon xanthomas, full corneal arcus in individuals <40 years of age, or a family history of high cholesterol and/or premature ASCVD1
While genetic testing may identify FH, it is not commonly used in the United States due to cost and lack of payer coverage
1
Abbreviations:
ASCVD, atherosclerotic cardiovascular disease;
FH, familial hypercholesterolemia;
LDL-C, low-density lipoprotein cholesterol; MEDPED
,
Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria.
1.
Bouhairie VE, et al.
Cardiol Clin
. 2015;33:169-179; 2. Haralambos K, et al.
Curr Opin Lipidol
. 2016;27:367-374; 3. Turgeon RD, et al.
Can Fam Physician
. 2016;62:32-37.
Slide86Familial Hypercholesterolemia: Prevalence and Risk
FH is caused by genetic mutations passed on by:One parent (heterozygous, HeFH)1Both parents (homozygous, HoFH)1HoFH prevalence ranges from 1 in 160,000 to 1 in 250,0002,3Individuals with HoFH have extremely high LDL-C levels (>500 mg/dL) and premature CV risk
4Many with HoFH experience their first coronary event in childhood or adolescence
4
HeFH prevalence ranges from 1 in 200 to 1 in 250
3
Individuals with HeFH can present with LDL-C levels 90 to 500 mg/dL and have premature CV risk
4
On average, individuals with HeFH experience their first coronary event at age 42 (about 20 years younger than the general population)
4
Early treatment is recommended for all individuals with FH, with a
goal of reducing LDL-C levels by 50% from baseline
3
Abbreviations:
CV, cerebrovascular;
FH, familial hypercholesterolemia;
HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia;
LDL-C, low-density lipoprotein cholesterol.
1.
Zimmerman MP.
Am Health Drug Benefits
. 2015;8:436-442; 2.
Goldstein J, et al.
The Metabolic and Molecular Bases of Inherited Disease
.
7th ed. New York, NY: McGraw-Hill; 1995: 1981-2030; 3.
Bouhairie VE, et al.
Cardiol Clin
. 2015;33:169-179; 4. Turgeon RD, et al.
Can Fam Physician. 2016;62:32-37.
Slide87Familial Hypercholesterolemia: Prevalence and Risk
FH is caused by genetic mutations passed on by:One parent (heterozygous, HeFH)1Both parents (homozygous, HoFH)1HoFH prevalence ranges from 1 in 160,000 to 1 in 250,0002,3Individuals with HoFH have extremely high LDL-C levels (>500 mg/dL) and premature CV risk
4Many with HoFH experience their first coronary event in childhood or adolescence
4
HeFH prevalence ranges from 1 in 200 to 1 in 250
3
Individuals with HeFH can present with LDL-C levels 90 to 500 mg/dL and have premature CV risk
4
On average, individuals with HeFH experience their first coronary event at age 42 (about 20 years younger than the general population)
4
Early treatment is recommended for all individuals with FH, with a
goal of reducing LDL-C levels by 50% from baseline
3
Abbreviations:
CV, cerebrovascular;
FH, familial hypercholesterolemia;
HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia;
LDL-C, low-density lipoprotein cholesterol.
1.
Zimmerman MP.
Am Health Drug Benefits
. 2015;8:436-442; 2.
Goldstein J, et al.
The Metabolic and Molecular Bases of Inherited Disease
.
7th ed. New York, NY: McGraw-Hill; 1995: 1981-2030; 3.
Bouhairie VE, et al.
Cardiol Clin
. 2015;33:169-179; 4. Turgeon RD, et al.
Can Fam Physician. 2016;62:32-37.
Slide88Lipid Goals for Individuals at Risk for ASCVD
Lipid parameter
Goal (mg/dL)
TC
<200
LDL-C
<130 (low risk)
<100 (moderate risk)
<100 (high risk)
<70 (very high risk)
<55 (extreme risk)
Non
–
HDL-C
30 above LDL-C goal; 25 above LDL-C goal (extreme risk individuals)
TG
<150
Apo B
<90 (individuals at high risk of ASCVD, including those with diabetes)
<80 (individuals at very high risk with established ASCVD or diabetes plus ≥1 additional risk factor)
<70 (individuals at extreme risk)
Abbreviations: apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.
AACE/ACE 2017;epub ahead of print; Baigent C, et al. Lancet. 2010;376:1670-1681; Boekholdt SM, et al.
J Am Coll Cardiol
. 2014;64(5):485-494;
Brunzell JD, et al.
Diabetes Care
. 2008;31:811-822; Cannon CP, et al.
N Engl J Med.
2015;372(25):2387-2397; Heart Protection Study Collaborative
Group.
Lancet
. 2002;360:7-22;
Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice
. 2017;23(4):479-497;
Ridker PM,
J Am Coll Cardiol
. 2005;45:1644-1648; Sever PS, et al.
Lancet
. 2003;361:1149-1158; Shepherd J, et al.
Lancet. 2002;360:1623-1630; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):1307-1315.
Slide89Classification of LDL-C Levels in Children and Adolescents
Category
LDL-C (mg/dL)
Acceptable
<100
Borderline
100-129
High
≥130
A body of evidence indicates that atherosclerosis begins early in life and that elevated lipid levels in adolescence predict elevated lipid levels well into adulthood. Dyslipidemia in childhood and adolescence should be diagnosed and managed as early as possible.
AAP NCEP
Pediatrics.
1992;89:525-584; Daniels SR, et al. EPIGCVHRRCAFR, 2012;
Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice
. 2017;23(4):479-497
.
Some pediatric lipid guidelines have an “Acceptable” LDL-C target of <110 mg/dL
Abbreviation: LDL-C, low-density lipoprotein cholesterol.
Slide90Recommendations associated with this question:
Question: How are different drugs used to treat dyslipidemia? PCSK9 inhibitors, cholesterol absorption inhibitors, niacinJellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice. 2017;23(4):479-497.
Slide91Question: How does treatment of dyslipidemia affect ASCVD risk?
Recommendations associated with this question: Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice. 2017;23(4):479-497. Abbreviations:
ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.
Slide92Lipid-Lowering Drug Therapies, Starting Dosages, and Dosage RangesPCSK9 Inhibitors
AgentUsual recommended
starting daily dosageDosage range
Method of
administration
PCSK9 inhibitors
Alirocumab
75 mg every 2 weeks
75-150 mg every 2 weeks
SQ
Evolocumab
140 mg every 2 weeks or 420 mg once monthly
Not applicable
SQ
Metabolic Effects:
↓LDL-C 48%-71%, ↓ non-HDL-C 49%-58%, ↓TC 36%-42%, ↓Apo B 42%-55% by inhibiting PCSK9 binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C levels
Main Considerations:
Require subcutaneous self-injection; refrigeration generally needed
Overall levels of adverse reactions and discontinuation very low
Adverse reactions with significantly different rates between drug and placebo were: local injection site reactions and influenza
The most common adverse reactions with similar rates for drug vs. placebo were:
Alirocumab
: nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia
Evolocumab
: nasopharyngitis, back pain,
and upper respiratory tract infection
Jellinger P, Handelsman Y, Rosenblit P, et al.
Endocr Practice
. 2017;23(4):479-497;
Praluent (alirocumab) [PI] 2015; Repatha (evolocumab) [PI]; 2016.
Abbreviations:
apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol
;
LDLR, low-density lipoprotein receptor;
PCSK9,
proprotein
convertase subtilisin/kexin type 9
;
SQ, subcutaneous injection; TC, total cholesterol.
Slide93Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes
2018
Lipid Management: Recommendations
Slide94Ongoing Therapy and Monitoring with Lipid Panel
In adults not taking statins or other lipid-lowering therapy, it is reasonable to obtain a lipid profile at the time of diabetes diagnosis, at an initial medical evaluation, and every 5 years thereafter if under the age of 40 years, or more frequently if indicated. Obtain a lipid profile at initiation of statins or other lipid-lowering therapy, 4-12 weeks after initiation or a change in dose, and annually thereafter as it may help to monitor the response to therapy and inform adherence.
Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes - 2018
.
Diabetes Care
2018; 41 (Suppl. 1): S86-S104
Lipid Management: Recommendations (2)
Slide95Statin Treatment
For patients of all ages with diabetes and ASCVD, high-intensity statin therapy should be added to lifestyle therapy. For patients with diabetes aged <40 years with additional ASCVD risk factors, the patient and provider should consider using moderate-intensity statin in addition to lifestyle therapy.
Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes - 2018
.
Diabetes Care
2018; 41 (Suppl. 1): S86-S104
Lipid Management: Recommendations (3)
Slide96Statin
TreatmentFor patients with diabetes aged 40-75 years and >75 years without ASCVD, use moderate-intensity statin in addition to lifestyle therapy.
In clinical practice, providers may need to adjust the intensity of statin therapy based on individual patient response to medication (e.g., side effects, tolerability, LDL levels, or percent LDL reduction on statin therapy). For patients who do not tolerate the intended intensity of statin, the maximally tolerated statin dose should be used.
Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes - 2018
.
Diabetes Care
2018; 41 (Suppl. 1): S86-S104
Lipid Management: Recommendations (4)
Slide97Slide98Statin Treatment
For patients with diabetes and ASCVD, if LDL –C is ≥70 md/dL on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor) after evaluating the potential for further ASCVD risk reduction, drug-specific adverse effects, and patient preferences.
Ezetimibe may be preferred due to lower cost.
Cardiovascular Disease and Risk Management:
Standards of Medical Care in Diabetes - 2018
.
Diabetes Care
2018; 41 (Suppl. 1): S86-S104
Lipid Management: Recommendations (5)
Slide99recommendation for PCSK9
inhibitors for patients with stable ASCVD Recommendation 1 PCSK9 inhibitor therapy should be considered for ASCVD risk reduction in patients
with stable ASCVD, particularly in those with
additional ASCVD
risk factors, on maximally-tolerated
statin therapy
±
ezetimibe
, with on-treatment
LDL-C
>70
mg/
dLor
non–HDL-C>100
mg/
dL
. Strength A, Quality: High.
99
Slide100recommendation for
PCSK9 inhibitors for patients with progressive ASCVD Recommendation 2PCSK9 inhibitor therapy may be
considered to further reduce LDL-C in patients with progressive ASCVD on maximally-tolerated
statin therapy
±
ezetimibe
, and on-treatment
LDL-C
>70
mg/
dL
or non–HDL-C
>100
mg/
dL
. Strength B,
Quality: Moderate
.
100
Slide101Recommendation 3a
PCSK9 inhibitor therapy may be considered to further reduce LDL-C in patients aged 40 to 79 years with LDL-C>190 mg/
dL, no uncontrolled ASCVD risk factors, or other key additional-high
risk markers
, and
on-treatment LDL-C
>100
mg/
dL
or non–HDL-C >130
mg/
dL
on maximally-tolerated
statin therapy
±
ezetimibe
. Strength B, Quality: Moderate
101
Slide102Recommendation 3b
PCSK9 inhibitor therapy may be considered to further reduce LDL-C in patients aged 40 to 79 years with LDL-C>190 mg/
dL, and the presence of either
uncontrolled ASCVD risk factors
, key
additional high-risk
markers, or
genetic confirmation of
FH
, and
on-treatment LDL-C
>70
mg/
dL
or
non–HDL-C >100
mg/
dL
on maximally-tolerated statin ±
ezetimibe
. Strength
: B, Quality: Moderate
102
Slide103Recommendation 3c
PCSK9 inhibitor therapy may be considered to further reduce LDL-C in patients aged 18 to 39 years with LDL-C > 190
mg/dL and the
presence
of either uncontrolled ASCVD risk
factors
, key
additional high-risk markers or
genetic
confirmation of
FH
and
on-treatment LDL-C
>100
mg/
dL
or non–HDL-C >
130 mg/
dL
on
maximally-tolerated statin
±
ezetimibe
. Strength: E, Quality: Low.
103
Slide104Recommendation 3d
PCSK9 inhibitor therapy may be considered to further reduce LDL-C in patients with HoFH, either of unknown genotype, or those known to be
LDLR defective, on maximally-tolerated statin therapy ± ezetimibe with
LDL-C
>70
mg/
dL
or
non– HDL-C >100
mg/
dL
. Strength B, Quality: Moderate
104
Slide105Recommendation 4
PCSK9 inhibitor therapy may be considered to further reduce LDL-C in selected very high- risk
patients who meet the definition of statin intolerance
(as
previously defined by the NLA Statin
Expert Panel
) and who require substantial additional
atherogenic cholesterol
lowering, despite the use of other
lipid lowering
therapies
. Strength C, Quality: Low.
105
Slide106Slide107Slide108Slide109American heart Association guideline 2018
Slide110Slide111Slide112Slide113The FOURIER trial evaluated
the PCSK9 inhibitor evolocumab among patients with ASCVD who met at least 1 major or 2 minor criteria. Recruitment was limited to patients who had LDL-C >70 mg/dl (or non–HDL-C >100 mg/dL) on maximal statin + ezetimibe. At a median follow-up of 2.2 years, evolocumab significantly reduced composite ASCVD (15% RRR; 1.5% AAR) without neurocognitive side effects The ODYSSEY OUTCOMES trial, tested alirocumab in patients on maximal statin + ezetimibe with ACS over a median of 2.8 years, observed a 15% RRR (1.6% ARR) in composite ASCVD events.
Slide114Class of recommendation
FOURIER and ODYSSEY OUTCOMES justify a COR of IIa for PCSK9 inhibitors 1-Acknowledging efficacy
2-But at the same time recognizing that there is limited experience with long-term tolerance of expensive monoclonal antibodies
3- Also
inconvenient
because it requires repetitive administration via the
parenteral
route.
Slide115Level of evidence
Because of the statistically significant results in two large RCTS showing reductions in ASCVD events in patients who had very high risk and LDL-C ≥70 mg/dL while on maximally tolerated LDL-C lowering therapy this recommendation warrants an LOE of A.
Slide116Initiation of PCSK9 inhibitors
There are 2 alternative pathways to initiation of PCSK9 inhibitors: a) In patients on maximally tolerated statin +
ezetimibe b) In those on maximally tolerated statin
alone
The strategy of (a) statin + ezetimibe before PCSK9 inhibitor, was graded COR
I.
Second
, strategy (b), excluding ezetimibe, would expose more patients to the inconvenience of antibody therapy and reduce overall cost effectiveness
Slide117LDL <
25mg/dLIf patients develop 2 consecutive LDL<25 mg/dL while on a PCSK9 inhibitor, clinical judgment should be used to determine whether de-intensification of lipid lowering regimen is warranted as long-term safety of such low levels of LDL-C remains unknown
Slide118Price reduction
The cost-effectiveness of using PCSK9 inhibitors for the secondary prevention of ASCVD has been evaluated in 7 published simulation modelsThe reported incremental cost-effectiveness ratios range from $141,700 to $450,000 per added (QALY), with all but 1 model reporting “low value” (>$150,000 per QALY added).
All models agree that the value provided by PCSK9 inhibitors would be significantly improved by price reductions of 70% to 85% from the mid-2018 U.S. list price of roughly $14,000 a year.
Slide119Cost
Evolocumab costs $14,000 per year!Institute for Clinical and Economic Review (ICER) has begun a “New Evidence Update” to incorporate the newly released data, including updated economic analyses and value-based price benchmarks of the PCSK9 inhibitorsAmgen said if insurance companies loosen restrictions on coverage, they will
refund the cost of evolocumab if patients have a heart attack or stroke while taking it
119
Image
available from: https://www.repathahcp.com/
Slide120Slide121Evolocumab (
Repatha®)Indicated as an adjunct to diet and:Maximally tolerated statin therapy for treatment of adults with HeFH
or clinical ASCVD who require additional lowering of low density lipoprotein cholesterol (LDL-C)140 mg subcutaneously every 2 weeks OR 420
mg subcutaneously once monthly
Other LDL-lowering therapies (e.g., statins,
ezetimibe
, LDL apheresis) in patients with
HoFH
who require additional lowering of
LDL-C
420 mg subcutaneously once
monthly
HeFH
: heterozygous familial hypercholesterolemia
HoFH
: homozygous familial hypercholesterolemia
ASCVD: atherosclerotic cardiovascular disease
Repatha
® [package insert]. Thousand Oaks, CA: Amgen; 2015.
Images
available from: https://www.repathahcp.com/
121
Slide122Slide123Slide124Slide125Slide126Slide127Thank You