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

New concepts and guidelines in the management of LDL-C and CV Risk: Need for early intervention 1. Need for improvement in managment of cardiovascular risk 2. What do current guidelines propose ? 3. What needs to be explored beyond current guideline recommendations ?

Framingham Heart Study Murabito et al Circulation 1993; 88: Patients (%) Women 0 Men % 46 % First clinical presentation of coronary artery disease is frequently an acute coronary syndrome. i.e. can be the last … Clinical presentation of coronary disease Courtasy of John Deanfield

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

Recommendations regarding risk estimation European Heart Journal 2012;33:1635–1701

Estimated risk as a function of high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular disease risk Eur Heart J 2011;32(14): Atherosclerosis 2011;217(1):3-46

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): Atherosclerosis 2011;217(1):3-46 SCORE charts with HDL-C For use in low risk regions: HDL-C= 1.8 mmol/L (70 mg/dl)

Intervention strategies as a function of total CV risk and LDL-C level Eur Heart J 2011;32(14): Atherosclerosis 2011;217(1):3-46

Recommendations for lipid analyses as treatment target in the prevention of CVD Eur Heart J 2011;32(14): Atherosclerosis 2011;217(1):3-46

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) Eur Heart J 2012;33:

Recommendations for genetic testing European Heart Journal 2012;33:1635–1701

Comparison of different imaging and circulating biomarkers for cardiovascular risk estimation - Multi-Ethnic Study of Atherosclerosis (MESA) analysis - FRS >5%-<20%: 1330 intermediate risk subjects (from 6814 subjects), 7.6 years of follow-up - 6 markers: coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), family history of coronary heart disease (CHD) Conclusions: Coronary artery calcium, ankle-brachial index, high- sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers. Yeboah J et al.; JAMA Aug 22;308(8):788-95

Recommendations on management of hyperlipidaemia European Heart Journal 2012;33:1635–1701

Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet Aug 11; 380(9841): 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.

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

Major vascular events avoided in different cardiovascular risk cohorts categories Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet Aug 11; 380(9841):581-90

Eur Heart J 2011;32(14): Atherosclerosis 2011;217(1):3-46 Recommendations for treatment targets for LDL-C

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

Comparison HPS2-THRIVE and Aim-High trial AIM-HIGH trial (N Engl J Med 2011) HPS2-THRIVE trial HPS2-THRIVE clinical outcome data (presentation expected in 2013) Pre-randomisation phase with ER-niacin (2g)/ laropiprant exclusion: 25.4 % No further adjustment of LDL-C levels after randomization LDL: -20 %; HDL + 17 % Addition of laropiprant (Antagonist of PGD 2 receptor DP 1 ) Randomization (n): vs patients Mean FU - 4 years (? events) Pre-randomisation phase with niacin (1.5/2g) exclusion: 20.1 % Aiming to have similarly low LDL-C in both treatment groups LDL: %, HDL: % More patients on high-dose statin or ezetimibe in control-group Randomization (n): 1718 vs patients Mean FU - 3 years (556 events)

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

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