LDL-C's Role in Atherosclerosis Progression

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

2. LDL-c level increases with age, so does the risk of atherogenesis Transitioning pathology T1 Fatty streaks Complex plaque T2 Familial Hypercholes-terolemia LDL-c cholesterol (mmol/l) LDL-c rise with age Polygenic hypercholes-terolemia Integrated LDL-c exposure 17 27 37 47 57 67 7 Age (years) 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 Response to initiation of LDL-c lowering Lesser RRR Plaque stabilisation Greater RRR per mmol/l reduction Plaque resolution T1 T2 Fatty streaks Complex plaque Transitioning pathology Familial Hypercholes-terolemia LDLc rise with age LDL-c cholesterol (mmol/l) Polygenic hypercholes-terolemia Integrated LDL-c exposure 17 27 37 47 57 67 7 Age (years) Packard CJ. Trends Cardiovasc Med. 2018 Jul;28(5):348-354

4. Regression of atherosclerotic plaque is possible with adequate lipid-lowering therapy GLAGOV study Statinmonotherapy Statin + evolocumab Prava-statin Atorva-statin 3 2.7* 2 P=0.02 1 Change in TAV (%) 0 -0.4†† Significant atheroscleroticprogression from baseline No significant change from baseline; atheroscleroticprogression stopped -1 No significant change from baseline; Significant atheroscleroticregression 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. .

5. Side effects are not the effect of LDL-c lowering Data of patients with low LDL-c levels at baseline Aminotrans-feraseelevation Cancer Anyserious adverse event Myalgias or myopathy New-onset diabetes Hemorrhagicstroke Sabatine MS et al., JAMA Cardiol. 2018;3(9):823-828

6. Side effects are not the effect of achieved LDL-c level Achieved LDL-c Stopping study drug dueto AE Creatine kinase >5x ULN Neuro- cognitive events AST / ALT >3x ULN Cataract-related adverse events Serious adverse events New onset diabetes mellitus New or progressivemalignancy Haemorrhagicstroke Non-CV death Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

7. Lowering LDL-c to very low levels is safeExploratory analysis in FOURIER trial 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 • Primaryendpoint: CV death, MI, unstable angina requiringhospitalization, coronaryrevascularization (≥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 statintherapyafter 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-intensitystatintherapy, after ACS • Primaryendpoint: 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 High is bad Average is not good mg/dL TNT Lower is better Even lower is even better Lowest is best 1996-2002 2004-2005 2015 2017 1994

10. 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 Boekholdtet al. JACC 2014; 64: 485-494

11. Even below LDL-c target further LDL-c reduction gives additional CV benefitExploratory analysis in FOURIER trial in thosewithvery low LDL-c Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

12. Greatest risk reduction can be achieved in the highest risk groups Robinson JG et al., J Am Coll Cardiol. 2016;68(22):2412-2421

13. Statin therapy is remarkably safe • Typically, treating 10.000 patientsfor 5 yearswith a standard statinregimen, is expected • toprevent: • 1000 major vascular events (secondary prevention) • 500 major vascular events (primary prevention) • tocause: • 5 cases of myopathy • 50-100 new cases of diabetes • 5-10 hemorrhagicstrokes (in thosewith prior stroke) • 50-100 patientsmayexperiencesymptomatic adverse events such as musclepain or weakness. Placebo-controlledrandomized trials show thatalmostall of these cases are misattributed. NO evidenceto support adverse effects of statins on: Cognitivefunction, clinically significant renaldeterioration, risk of cataract and risk of haemorrhagicstroke in patients without prior stroke Mach F et al., EurHeart J. 2018;39(27):2526-2539, Collins R et al., Lancet. 2016; 388(10059):2532-2561

14. When statin therapy is discontinued, the risk of CV events and mortality increases • Danishstudy: 2.176.361 person-years (median FU: 4.3 years, range: 0-14) • Cumulativeincidence of events from 6 monthsafterinitiation of statintherapy in individualswithearlystatindiscontinuationvs. thosewithcontinueduse • Discontinuation: no second dispense in first 6 monthsafterinitiation • 424.000 whocontinuedstatinwerematched 5:1 with 84.800 whodiscontinued. • Myocardialinfarction: • After 10 years: 9.9 vs. 8.0%, • adjustedHR: 1.26 (95%CI: 1.21-1.30) • Deathfrom CV disease: • After 10 years: 10.6 vs. 9.5%, • adjustedHR: 1.18 (95%CI: 1.14-1.23) Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37(11):908-916

15. After an event, initiate the right treatment in hospital • EUROASPIRE IV data showedthata 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 (Adjustedforage, gender, diagnosis STEMI, preadmissionmedication, diabetes, hypertension, previous MI, previousstroke, shock during acute phase, eGFR <60 mL/min/1.73 m2, PCI duringhospitalization, OAC at discharge, SBP at discharge, andheartrate at discharge.) , Kotseva K et al., Eur J PrevCardiol. 2016;23(6):636-48, Hoedemaker NPG et al., EurHeart J CardiovascPharmacother. 2018;4(2):102-110

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. 2018 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. Coronary events Cardiovascular events Nanchen D et al., Circulation. 2016;134(10):698-709