New concepts and guidelines in the management of LDL-c and CV Risk:

Need for early intervention

Prof. Ulf LandmesserUniversity 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 StudyMurabito et al Circulation 1993; 88: 2548-54

Patients (%)

Women

0

Men

20 40 60

62 %

46 %

First clinical presentation of coronary artery disease is frequently

an acute coronary syndrome. i.e. can be the last …

Clinical presentation ofcoronary disease

Courtasy of John Deanfield

Dudas K et al.; Circulation 2011; 123: 46-52

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 ofa first coronary event

Recommendations regardingrisk 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):1769-1818Atherosclerosis 2011;217(1):3-46

SCORE charts with HDL-CFor use in low risk regions: HDL-C= 0.8 mmol/L (32 mg/dl)

Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46

SCORE charts with HDL-CFor 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):1769-1818Atherosclerosis 2011;217(1):3-46

Recommendations for lipid analyses as treatment target in the prevention of CVD

Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012)

Eur Heart J 2012;33:1635-1701

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. 2012 Aug 22;308(8):788-95

Recommendations on management of hyperlipidaemia

European Heart Journal 2012;33:1635–1701

Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90

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 inLDL 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. 2012 Aug 11; 380(9841):581-90

Major vascular events avoided in different cardiovascular risk cohortscategories

Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90

Eur Heart J 2011;32(14):1769-1818Atherosclerosis 2011;217(1):3-46

Recommendations for treatment targets for LDL-C

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

Comparison HPS2-THRIVEand 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 PGD2 receptor DP1)

• Randomization (n): 12838 vs. 12835 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: - 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)

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-CHDL-C

HDL-C

*Clinical outcome trials ongoing

• PCSK9 inhibition (Monoclonal Ab*)

• ApoB-100 Antisense oligonucleotides

• Niacin/Laropiprant*

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