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.
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):

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

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

4. Regression of atherosclerotic plaque is possible with adequate lipid-lowering therapy
GLAGOV study
Statin monotherapy
Statin + evolocumab
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 1 2 3
P=0.02
No significant change from baseline;
Significant atherosclerotic regression baseline
TAV: Total atheroma volume, PAV: percent atheroma volume
Nissen SE et al. JAMA Mar 3;291(9): , Nicholls SJ et al. JAMA. 2016;316: .

5. Side effects are not the effect of LDL-c lowering Data of patients with low LDL-c levels at baseline
Any serious adverse event
Myalgias or myopathy
Aminotrans-ferase elevation
New-onset diabetes
Hemorrhagic stroke
Cancer
Sabatine MS et al., JAMA Cardiol. 2018;3(9):

6. Side effects are not the effect of achieved LDL-c level
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
Haemorrhagic stroke
Non-CV death
Giuliano RP et al., Lancet. 2017;390(10106):

7. Lowering LDL-c to very low levels is safe Exploratory analysis in FOURIER trial
Giuliano RP et al., Lancet. 2017;390(10106):

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: (95%CI: ), 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: ), 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: ), P<0.001
Cannon CP et al., N Engl J Med. 2015;372(25): , Sabatine MS et al., New Engl J Med 2017;376:1713, Schwartz et al., N Engl J Med. 2018;379(22):

9. Even below LDL-c target further LDL-c reduction gives additional CV benefit
A quarter of a century of treating LDL-C
High is bad
Average is not good
mg/dL
TNT
Lower is better
Even lower is even better
Lowest is best
1994
2015
2017

10. Risk for Major CV Events by Achieved on-Trial LDL-C levels
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
(Ref.)
(0,56-0,89)
* Adjusted for sex, age, smoking status, presence of DM, SBP, HDL-C and trial
Boekholdt et al. JACC 2014; 64:

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

12. Greatest risk reduction can be achieved in the highest risk groups
Robinson JG et al., J Am Coll Cardiol. 2016;68(22):

13. Statin therapy is remarkably safe
Typically, treating 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 new cases of diabetes 5-10 hemorrhagic strokes (in those with prior stroke) 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): , Collins R et al., Lancet. 2016; 388(10059):

14. When statin therapy is discontinued, the risk of CV events and mortality increases
Danish study: 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
who continued statin were matched 5:1 with who discontinued.
Myocardial infarction:
After 10 years: 9.9 vs. 8.0%,
adjusted HR: 1.26 (95%CI: )
Death from CV disease:
After 10 years: 10.6 vs. 9.5%,
adjusted HR: 1.18 (95%CI: )
Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37(11):

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
OMT vs. no-OMT
Unadjusted HR : 0.35, 95%CI:
Adjusted HR: , 95%CI:
(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.)
, 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):

16. 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 Oct 16;7(20):e009778

17. 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.
Adjusted for traditional cardiovascular risk factors, including age, sex, body mass index, current smoking, hypertension, and diabetes mellitus, as well as high-intensity statins at discharge and attendance at cardiac rehabilitation.
Coronary events
Cardiovascular events
Nanchen D et al., Circulation. 2016;134(10):