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.

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

Ference BA et al., Eur Heart J. 2017;38(32):2459-2472

LDL-c level increases with age, so does the
risk of atherogenesis

6.0
Fatty streaks T1 Complex plaque T2 Transitioning
pathology

5.0
LDL-c cholesterol (mmol/l)

Familial
Hypercholes-
4.0 terolemia
LDL-c rise with age
Polygenic
hypercholes-
3.0 terolemia
Integrated LDL-c exposure

2.0
71 2 17
3 4 27
5 6 7 8 47
37 9 10 57
11 12 67
13 14
Age (years)

Packard CJ. Trends Cardiovasc Med. 2018 Jul;28(5):348-354

The atherosclerosis disease process changes with time and LDL-c
level, and treatment effect depends on the disease phase

Greater RRR per Lesser RRR Response to initiation

mmol/l reduction Plaque stabilisation of LDL-c lowering
Plaque resolution

6.0
Fatty streaks T1 Complex plaque T2 Transitioning
pathology

5.0
LDL-c cholesterol (mmol/l)

Familial
Hypercholes-
terolemia
4.0
LDLc rise with age
Polygenic
hyperchole
3.0 s-terolemia
Integrated LDL-c exposure

2.0
71 2 17
3 4 27
5 6 7 8 47
37 9 10 57
11 12 67
13 14
Age (years)

Packard CJ. Trends Cardiovasc Med. 2018 Jul;28(5):348-354

 Regression of atherosclerotic plaque is
possible with adequate lipid-lowering therapy
GLAGOV study
Prava- Atorva- Statin Statin +
statin statin monotherapy evolocumab
3 0.2
2.7* 0.05
2.22044604925031E-16
P = NS
-0.2
2

Change in PAV (%)

P=0.02 -0.4
Change in TAV (%)

-0.6
1 -0.8
-0.95
-1 P < 0.0001

0 -1.2
Series1
-0.4 †
-1 Significant †
No significant change No significant Significant
atherosclerotic from baseline; change from atherosclerotic
progression atherosclerotic baseline; regression baseline
from baseline progression stopped

TAV: Total atheroma volume, PAV: percent atheroma volume

Nissen SE et al. JAMA. 2004 Mar 3;291(9):1071-80, Nicholls SJ et al. JAMA. 2016;316:2373-2384.
 Side effects are not the effect of LDL-c
lowering
Data of patients with low LDL-c levels at baseline

1.2 Safety outcomes in non-statin lipid-lowering trials,

Experimental vs. control arm
Baseline LDL-c <1.8 mmol/L
Risk ratio in meta-analysis (95%CI)

0.8

0.6
Any serious Myalgias or Aminotrans- New-onset Hemorrhagic Cancer
adverse event myopathy ferase elevation diabetes stroke

Sabatine MS et al., JAMA Cardiol. 2018;3(9):823-828

 Side effects are not the effect of achieved
LDL-c level
Safety of achieving very low LDL-c with PCSK9 inhibition
(FOURIER trial, evolocumab)
P-trend:
0.30 0.13 0.64 0.72 0.15 0.48 0.43 0.72 0.91 0.73
Achieved LDL-c
Adjusted OR (95%CI)

<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)

Serious Stopping AST / ALT Creatine Neuro- New onset Cataract- New or Haemo Non-CV
adverse study drug >3x ULN kinase cognitive diabetes related progressive rrhagic death
events due to AE >5x ULN events mellitus adverse malignancy stroke
events

Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

 Lowering LDL-c to very low levels is safe
Exploratory analysis in FOURIER trial

Safety outcomes at 4 weeks

N=504, median [IQR] LDL-c: 0.18 [0.13-0.23] mM, 7 [5-9]
HR: 0.94 mg/dL
>2.6 mM
(95%CI: 0.74-1.20)
25 P=0.61 <0.26 mM (<10 mg/dL)

20
Incidence (%)

15

10
HR: 1.08
(95%CI: 0.63-1.85)
5 P=0.78

0
Serious AE Stopping study drug due to AE

Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

 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.
Even below LDL-c target further LDL-c
reduction gives additional CV benefit
A quarter of a century of
200 treating LDL-C
180
High is bad
160

140
Average is not good
mg/dL

120
TNT
100

80
Lower is better
60 Even lower is even better
40

20
Lowest is best
0
1994 1996-2002 2004-2005 2015 2017
 Even below LDL-c target further LDL-c
reduction gives additional CV benefit
Risk for Major CV Events by Achieved on-Trial LDL-C levels

1
1,00
0.8
adjusted HR (95%CI)*

(Ref.)
0.71
0.6 (0,56-0,89) 0.64
(0,53-0,79)
0.58 0.56
(0,48-0,69) (0,46-0,67)
0.51
0.4 (0,42-0,62) 0.44
(0,35-0,55)

0.2

0
mg/dL >175 150 - 175 125 - 150 100 - 125 75 - 100 50 - 75 < 50
mmol/L > 4.52 3.88 - 4.52 3.23 - 3.88 2.58 - 3.23 1.94 - 2.58 1.29 - 1.94 < 1.29

* Adjusted for sex, age, smoking status, presence of DM, SBP, HDL-C and trial

Boekholdt et al. JACC 2014; 64: 485-494

 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
Efficacy outcomes at 4 weeks
N=504, median [IQR] LDL-c: 0.18 [0.13-0.23] mM, 7 [5-9]
mg/dL
HR: 0,69 >2.6 mM

14 (95%CI: 0.49-0.79) <0.26 mM (<10 mg/dL)

P=0.03
12
HR: 0,59
10 (95%CI: 0.37-0.92)
P=0.02
Incidence (%)

0
CV death, MI, stroke, UA, coron. CV death, MI, stroke
Revasc

Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

 Greatest risk reduction can be achieved in
the highest risk groups
5-year number needed to treat 5-year number needed to treat
(NNT) (NNT)
Max. statin therapy + Max. statin therapy + PCSK9
ezetimibe: 20% LDL-c mAb: 50% LDL-c reduction
300 reduction 300

250 250

200 200
NNT

NNT
150 150

100 100

50 50

0 0
70 100 130 160 190 70 100 130 160 190
mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL
Very high risk (>30% 10-yr ASCVD risk) Very high risk (>30% 10-yr ASCVD risk)
High risk (20% -30% 10-yr ASCVD risk) High risk (20% -30% 10-yr ASCVD risk)
Moderate risk (10% -20% 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

 Statin therapy is remarkably safe
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.

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

Mach F et al., Eur Heart J. 2018;39(27):2526-2539, Collins R et al., Lancet. 2016; 388(10059):2532-2561
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.

Cumulative incidence (%)

Myocardial infarction: 10 years after statin initiation
After 10 years: 9.9 vs. 8.0%, 12
adjusted HR: 1.26 (95%CI: 1.21-1.30) 10
8
6
Death from CV disease: 4
After 10 years: 10.6 vs. 9.5%, 2
adjusted HR: 1.18 (95%CI: 1.14-1.23) 0
MI CV death

Discontinuation Continued use

Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37(11):908-916

 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
All-cause mortality in survivors of
the index hospitalization
9
Crude Kaplan-Meier 1-year mortal

OMT vs. no-OMT

-

8 No OMT at discharge
7 OMT at discharge Unadjusted HR : 0.35, 95%CI: 0.28-0.44
6 Adjusted HR: 0.66, 95%CI: 0.46-0.93
ity rates (%)

5 (Adjusted for age, gender, diagnosis STEMI,

4 preadmission medication, diabetes, hypertension,
3 previous MI, previous stroke, shock during acute phase,
2 eGFR <60 mL/min/1.73 m2, PCI during hospitalization,
1 OAC at discharge, SBP at discharge, and heart rate at
0 discharge.)
Series1

, 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
 LDL-c lowering treatment impacts disease
progression before clinical manifestation
Life course trajectory of atherosclerotic progression for different CV risk
categories and the hypothesized effects of intensive LDL-c lowering.

Robinson JG et al., J Am Heart Assoc. 2018 Oct 16;7(20):e009778

 Screening for familial hypercholesterolemia
after ACS pays off
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.

Risks of recurrent events after ACS,

Per Dutch Lipid Clinic Definition Category
10
No FH
Possible FH
Adjusted HR (95%CI)

8
Probable/definite FH

0
Coronary Cardiovascular
events events

Nanchen D et al., Circulation. 2016;134(10):698-709