New concepts and guidelines in the management of LDL-c and CV Risk: Need for early intervention

1. New concepts and guidelines in the management of LDL-c and CV Risk: Need for early intervention Prof. Ulf Landmesser University Hospital Zürich Switzerland

2. New concepts and guidelines in the management of LDL-C and CV Risk: Need forearlyintervention • Need forimprovement in managmentofcardiovascularrisk • What do currentguidelinespropose ? • Whatneedstobeexploredbeyondcurrentguidelinerecommendations ?

3. Clinical presentation of coronary disease First clinical presentation of coronary artery disease is frequently an acute coronary syndrome. i.e. can be the last … Men 62 % 46 % Women 0 20 40 60 Patients (%) Framingham Heart Study Murabitoet al Circulation 1993; 88: 2548-54 Courtasy of John Deanfield

4. Frequency and mortality of a first coronary event 28.9 % 9.5 % 61.6 % • 384,597 Individuals with first coronary event (Coronary death or first acute myocardial infarction – population aged 35-84) Dudas K et al.; Circulation 2011; 123: 46-52

5. Recommendationsregarding riskestimation European Heart Journal 2012;33:1635–1701

6. Estimatedriskas a functionofhigh-densitylipoprotein-cholesterol (HDL-C) forwomen in populationsathighcardiovasculardiseaserisk Eur Heart J 2011;32(14):1769-1818 Atherosclerosis 2011;217(1):3-46

7. SCORE charts with HDL-C For use in low risk regions: HDL-C= 1.8 mmol/L (70 mg/dl) SCORE charts with HDL-C For use in low risk regions: HDL-C= 0.8 mmol/L (32 mg/dl) Eur Heart J 2011;32(14):1769-1818 Atherosclerosis 2011;217(1):3-46

8. Intervention strategies as a functionof total CV riskand LDL-C level Eur Heart J 2011;32(14):1769-1818 Atherosclerosis 2011;217(1):3-46

9. Recommendationsforlipidanalysesastreatmenttarget in thepreventionof CVD Eur Heart J 2011;32(14):1769-1818 Atherosclerosis 2011;217(1):3-46

10. European Guidelines on cardiovascular disease prevention in clinicalpractice (version 2012) Eur Heart J 2012;33:1635-1701

11. Recommendationsforgenetictesting European Heart Journal 2012;33:1635–1701

12. Comparisonof different imagingandcirculatingbiomarkersforcardiovascularriskestimation Yeboah J et al.; JAMA. 2012 Aug 22;308(8):788-95 • - Multi-Ethnic Study ofAtherosclerosis (MESA) analysis • FRS >5%-<20%: 1330 intermediate risksubjects (from 6814 subjects), • 7.6 yearsoffollow-up • 6 markers: • coronaryarterycalcium, • carotidintima-mediathickness, • ankle-brachial index, • brachial flow-mediateddilation, • high-sensitivity C-reactiveprotein (CRP), • familyhistoryofcoronaryheartdisease (CHD) • Conclusions: Coronaryarterycalcium, ankle-brachial index, high-sensitivity CRP, andfamilyhistorywereindependentpredictorsofincident CHD/CVD in intermediate-risk individuals. • Coronaryarterycalciumprovidedsuperiordiscriminationandriskreclassificationcomparedwithotherriskmarkers.

13. Recommendations on managementofhyperlipidaemia European Heart Journal 2012;33:1635–1701

14. Is there evidence for a benefit of statin therapy in people at low risk of vascular disease ? Interpretation: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90

15. Is there evidence for a benefit of statin therapy in people at low risk of vascular disease ? Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90

16. Major vasculareventsavoided in different cardiovascularriskcohortscategories Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90

17. Recommendationsfortreatmenttargetsfor LDL-C Eur Heart J 2011;32(14):1769-1818 Atherosclerosis 2011;217(1):3-46

18. JAMA. 2012 Mar 28;307(12):1302-9

19. Comparison HPS2-THRIVE and Aim-High trial HPS2-THRIVE trial AIM-HIGH trial (N Engl J Med 2011) • Pre-randomisation phase with niacin (1.5/2g) exclusion: 20.1 % • Aiming to have similarly low LDL-C in both treatment groups • LDL: - 5.5 %, HDL: + 13.2 % • More patients on high-dose statin • or ezetimibe in control-group • Randomization (n): 1718 vs. 1696 patients • Mean FU - 3 years (556 events) • Pre-randomisation phase with ER-niacin (2g)/ • laropiprantexclusion: 25.4 % • No further adjustment of LDL-C levels after randomization • LDL: -20 %; HDL + 17 % • Addition of laropiprant • (Antagonist of PGD2receptor DP1) • Randomization (n): 12838 vs. 12835 patients • Mean FU - 4 years (? events) HPS2-THRIVE clinical outcome data (presentation expected in 2013)

20. Lipid-targeted Therapies What should be added to statins in patients with high vascular risk ? Statin therapy HDL-C Further LDL-C Combined LDL-C HDL-C • Reconstituted HDLs • ApoA1 modulation • NPC1L1 (Ezetimibe*) • PCSK9 inhibition • (Monoclonal Ab*) • ApoB-100 Antisense oligonucleotides • Niacin/Laropiprant* • CETP inhibition • (Anacetrapib*,Evacetrapib*) *Clinical outcometrialsongoing

21. HDL metabolism – HDL-C canbeincreasedbyseveralmechanisms (2) apoA-I (lipid-free) (3) ABCA-1 expression (4) SR-BI inhibition (1) CETP inhibition Besler C et al. & Landmesser U. EMBO Mol Med 2012; 4(4):251-68