1) Multiple lines of evidence from meta-analyses, prospective cohort studies, and randomized controlled trials establish that LDL causes atherosclerotic cardiovascular disease (ASCVD). 2) The risk of atherosclerosis and need for treatment depends on LDL levels and increases with age from childhood through older age. Lowering LDL, including to very low levels, reduces ASCVD risk and can regress atherosclerotic plaques. 3) Intensive LDL lowering through combination therapy such as statins plus ezetimibe or PCSK9 inhibitors provides additional cardiovascular benefit beyond statin therapy alone, including in those already at very low LDL levels. The greatest risk reduction occurs in high-risk groups.

1. LDL is causal of atherosclerosis
Evidence from meta-analyses of Mendelian randomization studies,
prospective cohort studies, and randomized controlled trials unequivocally
establishes that LDL causes ASCVD.
Ference BA et al., Eur Heart J. 2017;38(32):2459-2472
Mendelian randomization studies
Median follow-up: 52 years
N=194,427
Prospective cohort studies
Median follow-up: 12 years
N=403,501
Randomized controlled trials
Median follow-up: 5 years
N=196,552

2. LDL-c level increases with age, so does the
risk of atherogenesis
2.0
3.0
4.0
5.0
6.0
1 3 5 7 9 11 13
LDL-c
cholesterol
(mmol/l)
7 17 27 37 47 57 67
Age (years)
LDL-c rise with age
Polygenic
hypercholes-
terolemia
Familial
Hypercholes-
terolemia
Integrated LDL-c exposure
Fatty streaks Complex plaque
T1 T2 Transitioning
pathology
Packard CJ. Trends Cardiovasc Med. 2018 Jul;28(5):348-354

3. The atherosclerosis disease process changes with time and LDL-c
level, and treatment effect depends on the disease phase
2.0
3.0
4.0
5.0
6.0
1 3 5 7 9 11 13
LDL-c
cholesterol
(mmol/l)
7 17 27 37 47 57 67
Age (years)
LDLc rise with age
Polygenic
hyperchole
s-terolemia
Familial
Hypercholes-
terolemia
Integrated LDL-c exposure
Response to initiation
of LDL-c lowering
Greater RRR per
mmol/l reduction
Plaque resolution
Lesser RRR
Plaque stabilisation
Fatty streaks Complex plaque
T1 T2 Transitioning
pathology
Packard CJ. Trends Cardiovasc Med. 2018 Jul;28(5):348-354

4. Regression of atherosclerotic plaque is
possible with adequate lipid-lowering therapy
No significant
change from
baseline;
TAV: Total atheroma volume, PAV: percent atheroma volume
2.7*
Prava-
statin
Significant
atherosclerotic
progression
from baseline
-0.4 †
†
Atorva-
statin
No significant change
from baseline;
atherosclerotic
progression stopped
Change
in
TAV
(%)
-1
0
1
2
3
P=0.02
Nissen SE et al. JAMA. 2004 Mar 3;291(9):1071-80, Nicholls SJ et al. JAMA. 2016;316:2373-2384.
.
Statin
monotherapy
Statin +
evolocumab
Significant
atherosclerotic
regression baseline
GLAGOV study
0.05
-0.95
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
Change
in
PAV
(%)
P < 0.0001
P = NS

5. Side effects are not the effect of LDL-c
lowering
Data of patients with low LDL-c levels at baseline
0.6
0.8
1
1.2
1.4
1.6
Risk
ratio
in
meta-analysis
(95%CI)
Safety outcomes in non-statin lipid-lowering trials,
Experimental vs. control arm
Baseline LDL-c <1.8 mmol/L
Sabatine MS et al., JAMA Cardiol. 2018;3(9):823-828
Any serious
adverse event
Aminotrans-
ferase elevation
New-onset
diabetes
Hemorrhagic
stroke
Myalgias or
myopathy
Cancer

6. Side effects are not the effect of achieved
LDL-c level
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Adjusted
OR
(95%CI)
Safety of achieving very low LDL-c with PCSK9 inhibition
(FOURIER trial, evolocumab)
<0.5 mmol/L
0.5 - <1.3 mmol/L
1.3 - <1.8 mmol/L
1.8 to <2.6 mmol/L
>2.6 mmol/L (reference)
P-trend:
0.30 0.13 0.64 0.72 0.15 0.48 0.43 0.72 0.91 0.73
Giuliano RP et al., Lancet. 2017;390(10106):1962-1971
Serious
adverse
events
New or
progressive
malignancy
Cataract-
related
adverse
events
New onset
diabetes
mellitus
Stopping
study drug
due to AE
Neuro-
cognitive
events
AST / ALT
>3x ULN
Creatine
kinase
>5x ULN
Haemo
rrhagic
stroke
Non-CV
death
Achieved LDL-c

7. Lowering LDL-c to very low levels is safe
Exploratory analysis in FOURIER trial
0
5
10
15
20
25
Serious AE Stopping study drug due to AE
Incidence
(%)
Safety outcomes at 4 weeks
N=504, median [IQR] LDL-c: 0.18 [0.13-0.23] mM, 7 [5-9] mg/dL
>2.6 mM
<0.26 mM (<10 mg/dL)
HR: 0.94
(95%CI: 0.74-1.20)
P=0.61
HR: 1.08
(95%CI: 0.63-1.85)
P=0.78
Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

8. Use combination therapy for additive LDL-c
lowering effect to reduce CV risk
IMPROVE-IT: ezetimibe + simvastatin vs. simvastatin, after ACS
Primary endpoint: CV death, MI, unstable angina requiring hospitalization,
coronary revascularization (≥30 days), stroke. Median follow-up: 6 years
HR: 0.936 (95%CI: 0.89-0.99), P=0.016
FOURIER trial: evolocumab vs. placebo, plus background statin therapy
after ACS
Primary endpoint: CV death, MI, stroke, hospitalization for unstable angina, or
coronary revascularization. Median follow-up: 2.2 years
HR: 0.85 (95%CI: 0.79-0.99), P<0.001
ODYSSEY OUTCOMES trial: alirocumab vs placebo, on top of high-intensity
statin therapy, after ACS
Primary endpoint: death from coronary heart disease, nonfatal MI, fatal or
nonfatal ischemic stroke, or unstable angina requiring hospitalization. Median
follow-up: 2.8 years
HR: 0.85 (95%CI: 0.78-0.93), P<0.001
Cannon CP et al., N Engl J Med. 2015;372(25):2387-97, Sabatine MS et al., New Engl J Med
2017;376:1713, Schwartz et al., N Engl J Med. 2018;379(22):2097-2107.

9. Even below LDL-c target further LDL-c
reduction gives additional CV benefit
A quarter of a century of
treating LDL-C
0
20
40
60
80
100
120
140
160
180
200
High is bad
Average is not good
Lower is better
Even lower is even better
Lowest is best
1994 1996-2002 2004-2005 2015 2017
TNT
mg/dL

10. Even below LDL-c target further LDL-c
reduction gives additional CV benefit
1,00
0.71
0.64
0.58 0.56
0.51
0.44
0
0.2
0.4
0.6
0.8
1
>175 150 - 175 125 - 150 100 - 125 75 - 100 50 - 75 < 50
adjusted
HR
(95%CI)*
> 4.52 3.88 - 4.52 3.23 - 3.88 2.58 - 3.23 1.94 - 2.58 1.29 - 1.94 < 1.29
(0,53-0,79)
(0,48-0,69) (0,46-0,67)
(0,42-0,62)
(0,35-0,55)
mg/dL
mmol/L
(Ref.)
(0,56-0,89)
Risk for Major CV Events by Achieved on-Trial LDL-C levels
Boekholdt et al. JACC 2014; 64: 485-494
* Adjusted for sex, age, smoking status, presence of DM, SBP, HDL-C and trial

11. Even below LDL-c target further LDL-c
reduction gives additional CV benefit
Exploratory analysis in FOURIER trial in those with very low LDL-c
0
2
4
6
8
10
12
14
CV death, MI, stroke, UA, coron. Revasc CV death, MI, stroke
Incidence
(%)
Efficacy outcomes at 4 weeks
N=504, median [IQR] LDL-c: 0.18 [0.13-0.23] mM, 7 [5-9] mg/dL
>2.6 mM
<0.26 mM (<10 mg/dL)
HR: 0,69
(95%CI: 0.49-0.79)
P=0.03
HR: 0,59
(95%CI: 0.37-0.92)
P=0.02
Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

12. Greatest risk reduction can be achieved in
the highest risk groups
0
50
100
150
200
250
300
70
mg/dL
100
mg/dL
130
mg/dL
160
mg/dL
190
mg/dL
NNT
5-year number needed to treat
(NNT)
Max. statin therapy + ezetimibe:
20% LDL-c reduction
Very high risk (>30% 10-yr ASCVD risk)
High risk (20% -30% 10-yr ASCVD risk)
Moderate risk (10% -20% 10-yr ASCVD risk)
Robinson JG et al., J Am Coll Cardiol. 2016;68(22):2412-2421
0
50
100
150
200
250
300
70
mg/dL
100
mg/dL
130
mg/dL
160
mg/dL
190
mg/dL
NNT
5-year number needed to treat
(NNT)
Max. statin therapy + PCSK9 mAb:
50% LDL-c reduction
Very high risk (>30% 10-yr ASCVD risk)
High risk (20% -30% 10-yr ASCVD risk)
Moderate risk (10% -20% 10-yr ASCVD risk)

13. Statin therapy is remarkably safe
Mach F et al., Eur Heart J. 2018;39(27):2526-2539, Collins R et al., Lancet. 2016; 388(10059):2532-2561
NO evidence to support adverse effects of statins on:
Cognitive function, clinically significant renal deterioration, risk of cataract and risk of
haemorrhagic stroke in patients without prior stroke
Typically, treating 10.000 patients for 5 years with a standard statin
regimen, is expected
to prevent:
1000 major vascular events (secondary prevention)
500 major vascular events (primary prevention)
to cause:
5 cases of myopathy
50-100 new cases of diabetes
5-10 hemorrhagic strokes (in those with prior stroke)
50-100 patients may experience symptomatic adverse events such as muscle
pain or weakness. Placebo-controlled randomized trials show that almost all of
these cases are misattributed.

14. When statin therapy is discontinued, the risk
of CV events and mortality increases
Danish study: 2.176.361 person-years (median FU: 4.3 years, range: 0-14)
Cumulative incidence of events from 6 months after initiation of statin therapy in
individuals with early statin discontinuation vs. those with continued use
Discontinuation: no second dispense in first 6 months after initiation
424.000 who continued statin were matched 5:1 with 84.800 who discontinued.
Myocardial infarction:
After 10 years: 9.9 vs. 8.0%,
adjusted HR: 1.26 (95%CI: 1.21-1.30)
Death from CV disease:
After 10 years: 10.6 vs. 9.5%,
adjusted HR: 1.18 (95%CI: 1.14-1.23)
Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37(11):908-916
0
2
4
6
8
10
12
MI CV death
Cumulative incidence (%)
10 years after statin initiation
Discontinuation Continued use

15. After an event, initiate the right treatment in
hospital
EUROASPIRE IV data showed that a large majority of coronary patients do not
achieve the guideline standards for secondary prevention, regarding lifestyle, risk
factor and therapeutic management.
Dutch single-center observational registry (>9000 patients with ACS)
studied ACS care between 2006 and 2014
Optimal medical therapy (OMT): aspirin, P2Y12 inhibitors, statin, beta-blockers,
and ACEi/ARB
, Kotseva K et al., Eur J Prev Cardiol. 2016;23(6):636-48, Hoedemaker NPG et al., Eur Heart J Cardiovasc
Pharmacother. 2018;4(2):102-110
0
2
4
6
8
10
Crude
Kaplan-Meier
1-year
mortality
rates
(%)
All-cause mortality in survivors of
the index hospitalization
No OMT at discharge
OMT at discharge
OMT vs. no-OMT
Unadjusted HR : 0.35, 95%CI: 0.28-0.44
Adjusted HR: 0.66, 95%CI: 0.46-0.93
(Adjusted for age, gender, diagnosis STEMI,
preadmission medication, diabetes, hypertension,
previous MI, previous stroke, shock during acute phase,
eGFR <60 mL/min/1.73 m2, PCI during hospitalization,
OAC at discharge, SBP at discharge, and heart rate at
discharge.)

16. LDL-c lowering treatment impacts disease
progression before clinical manifestation
Robinson JG et al., J Am Heart Assoc. 2018 Oct 16;7(20):e009778
Life course trajectory of atherosclerotic progression for different CV risk
categories and the hypothesized effects of intensive LDL-c lowering.

17. Screening for familial hypercholesterolemia
after ACS pays off
0
2
4
6
8
10
Adjusted
HR
(95%CI)
Risks of recurrent events after ACS,
Per Dutch Lipid Clinic Definition Category
No FH
Possible FH
Probable/definite FH
Coronary
events
Cardiovascular
events
Nanchen D et al., Circulation. 2016;134(10):698-709
Patients with FH and ACS have a >2-fold adjusted risk of coronary event
recurrence within the first year after discharge, as compared with those without FH.