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 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. 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 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. 2018 Jul;28(5):348-354

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. 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 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):823-828

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):1962-1971

Lowering LDL-c to very low levels is safe Exploratory analysis in FOURIER trial 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 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 1996-2002 2004-2005 2015 2017

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

Greatest risk reduction can be achieved in the highest risk groups 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. 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

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: 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.) , 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. 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):698-709