HDL : A Treatment Target? ESC Paris M. John Chapman Ph.D., D.Sc., FESC. President, European Atherosclerosis Society

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1 ESC Paris 2011 HDL : A Treatment Target? M. John Chapman Ph.D., D.Sc., FESC Director, Dyslipidemia and Atherosclerosis Research Unit, INSERM, University Pierre and Marie Curie, Hôpital de la Pitié-Salpetriere, Paris, France President, European Atherosclerosis Society

2 Treatment of CV Disease : Current Status 100 Statins 40% % CV EVENTS LOW HDL-C HIGH TG, TG-rich LPs and Remnants Lp(a) 60% 0

3 HDL-C: Independent Predictor of CHD Risk PROspective Cardiovascular Münster (PROCAM) Study events, 4407 men aged years Incidence, per 1000 in 6 Years <0.9 mmol/l mmol/l >1.4 mmol/l HDL-C Adapted from Assmann G et al. In: Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease: Primary Prevention, Diagnosis, and Therapy Guidelines for General Practice. 2nd ed. Munich: MMV Medizin Verlag. 1993:

Hazard Ratio Coronary Heart Disease and HDL-C 3.5 3.0 2.5 2.0 N = 302,430 1.5 1.0 0.

4 Hazard Ratio Coronary Heart Disease and HDL-C N = 302, HDL-C (mg/dl) The Emerging Risk Factors Collaboration. JAMA 2009;302:

5 Lipid Levels in Patients Hospitalised with Coronary Artery Disease in US HDL-C (mg/dl) <40 (1 mmol/l) >40 (1 mmol/l) 55% HDL-C <40mg/dL (1 mmol/l) HDL-C Levels in 136,905 Patients Hospitalised With CAD: Sachdeva et al, Am Heart J 2009;157:111-7.e2.

6 Patients with low HDL-C are 3x times more likely to die after ACS (heart attack) 12 RR= 0.33, p= % patients P<0.001 High HDL n=452 Low HDL n= Low HDL-C: <40 mg/dl in men <45 mg/dl in women 0-30 days 30 days-1 year Follow up period Wolfram MR et al. Am J Cardiol 2008;98:

7 Estimated hazard ratio Risk Factors for premature CHD in Type 2 Diabetes 2.5 LDL-C HDL-C TG 2.29 P < P < P < UKPDS N= st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd Tertile Tertile Tertile Turner RC et al. BMJ 1998;316:

8 Does statin treatment abrogate CV risk associated with low HDL-C?

14 12 10 8 6 4 2 0 <38 38-42 43-47 48-54 >54

9 MCVE frequency (%) TNT: Frequency of major CV Events as a function of LDL-C and HDL-C levels < >54 HDL-C (mg/dl) > <70 Barter et al, NEJM

10 Relative risk (95% CI) CTT: Relevance of baseline HDL-C to Major Vascular Event risk in randomized trials of statin vs control and of more vs less statin (Lancet 2010) Statin vs control More vs less statin Control Statin Less statin More statin HDL-C (mmol/l) HDL-C (mmol/l) Adjusted for baseline age, sex, history of diabetes, history of vascular disease, smoking status, body mass index, LDL cholesterol, triglycerides, estimated glomerular filtration rate and systolic blood pressure

11 Why do levels of TG-rich lipoproteins appear to be a major determinant of HDL levels, and potentially HDL-associated CV risk?

12 12 Mixed Dyslipidemia HDL-C Apo AI TG-rich LPs Chylos, VLDL + Remnants - Fasting - Nonfasting Chronic Inflammation, Premature Atherosclerosis and CHD Small Dense LDL Apo B

13 Action of CETP in driving the High TG / Low HDL-C Phenotype NY /020131YlsjoLS1 LIVER + TG-rich VLDL-1 CE / TG + TG CETP + CE HDL CE / TG FFA + TG CE + HL ADIPOSE TISSUE + TG LDL TG / CE Small dense HDL t 1/2 HSL FFA HL Small dense LDL + Kidney AI, AII INSULIN Guerin et al., ATVB, 2001, 21 : Chapma Atherosclerosis, 2003, 171 : 1-13

14 Percentage Prevalence of Atherogenic Dyslipidemia in Indian patients undergoing CABG High LDL-C Low HDL-C High TG 0 Entire group Males Females Majority of the patients included in the study were already on statins Kasliwal et al. JAPI VOL. 54 MAY 2006

15 EAS Consensus Panel : Objectives To critically appraise evidence for elevated levels of TG-rich LPs and low levels of HDLcholesterol as CV risk factors To advise on therapeutic strategies for clinical management of this atherogenic lipid phenotype

16 Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management M. John Chapman, Henry N. Ginsberg, Pierre Amarenco, Felicita Andreotti, Jan Borén, Alberico L. Catapano, Olivier S. Descamps, Edward Fisher, Petri T. Kovanen, Jan Albert Kuivenhoven, Philippe Lesnik, Luis Masana, Børge G. Nordestgaard, Kausik K. Ray, Zeljko Reiner, Marja-Riitta Taskinen, Lale Tokgözoglu, Anne Tybjærg European Atherosclerosis Society Consensus Panel Published April 29, Most recent citation: Eur Heart J (2011) 32(11): doi: /eurheartj/ehr112

17 EAS Consensus Panel «The Panel contends, on the basis of the available evidence, that elevated TRL and their remnants combined with low HDL-C may play a causal role in premature atherosclerosis» Five types of evidence should favour causality: Human epidemiology; Mechanistic studies (pathophysiology); Animal models; Human genetics; Human intervention studies

18 «The Panel believes that there is insufficient evidence to define targets for TG or HDL-C in high risk patients. Instead, treatment should be tailored to the individual to achieve desirable levels» Desirable lipid levels in patients at high risk of CVD, according to recent European guidelines Triglycerides <1.7 mmol/l (150 mg/dl) HDL-C >1.0 mmol/l (40 mg/dl) in men; >1.2 mmol/l (45 mg/dl) in women Eur Heart J (2011) 32(11): doi: /eurheartj/ehr112

19 Low HDL-C / High TG increases MI risk irrespective of LDL-C Event Free Survival According to HDL-C and TG Survival without MI (%) 100 LDL-C 147 mg/dl Diabetes 5.9% HDL-C 35 mg/dl + TG < 200 mg/dl LDL-C 142 mg/dl Diabetes 16.8% HDL-C < 35 mg/dl + TG 200 mg/dl Time (years) PROCAM

20 Percentage Prevalence of Atherogenic Dyslipidemia in Indian patients undergoing CABG High LDL-C Low HDL-C High TG 0 Entire group Males Females Majority of the patients included in the study were already on statins Kasliwal et al. JAPI VOL. 54 MAY 2006

21 Recommendations for lipid analyses for screening for CVD risk Recommendations Class a Level b TC is recommended to be used for the estimation of total CV risk by means of the SCORE system. LDL-C is recommended to be used as the primary lipid analysis for screening and risk estimation. TG adds information on risk and is indicated for risk estimation. I C HDL-C is a strong risk factor and is recommended to be used for risk estimation. Non HDL-C should be considered as an alternative risk marker, especially in combined hyperlipidaemias, diabetes, the MetS or CKD Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature CVD. Apo B should be considered as an alternative risk marker, especially in combined hyperlipiaemias, diabetes, the MetS or CKD. The ratio apo B/apo AI combines the risk information of apo B an apo AI and may be recommended as an alternative analysis for risk screening. The ratio non-hdl-c/hdl-c may be recommended as an alternative analysis for risk screening. a Class of recommendation, b Level of evidence. Apo = apolipoprotein; CKD = chronic kidney disease; CVD = cardiovascular disease; HDL-C = high density lipoprotein-cholesterol, LDL-C = low-density lipoprotein-cholesterol; Lp = lipoprotein; MetS = metabolic syndrome; TC = total cholesterol; TG = triglyceride. Reiner Z et al. Eur Heart J 2011;32: I I I IIa IIa IIa IIb IIb C C C C C C C C

22 Recommendations for lipid analyses for characterisation of dyslipiaemias before treatment Recommendations Class a Level b LDL-C is recommended to be used as the primary lipid analysis. I C TG adds information to risk and is indicated for diagnosis and choice of treatment. HDL-C is recommended to be analysed before initiation of treatment. I C I C Non-HDL-C should be recommended for further characterisation of combined hyperlipidaemias and dyslipaemia in diabetes, the MetS or CKD. IIa C Apo B should be recommended for further characterisation of combined hyperlipidaemias and dyslipaemia in diabetes, the MetS or CKD. IIa C Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature CVD. IIa C TC may be considered but is usually not enough for the characterisation of dyslipidaemia before initiation of the treatment. IIb C a Class of recommendation, b Level of evidence. Apo = apolipoprotein; CKD = chronic kidney disease; CVD = cardiovascular disease; HDL-C = high density lipoprotein-cholesterol, LDL-C = low-density lipoprotein-cholesterol; Lp = lipoprotein; MetS = metabolic syndrome; TC = total cholesterol; TG = triglyceride. Reiner Z et al. Eur Heart J 2011;32:

23 Recommendations for lipid analyses as treatment target in the prevention of CVD Recommendations Class a Level b LDL-C is recommended as target for treatment. I A TC should be considered as treatment target if other analyses are not available. TG should be analysed during the treatment of dyslipidaemias with high TG levels. Non-HDL-C should be considered as a secondary target in combined hyperlipidaemias, diabetes, the MetS or CKD. IIa IIa IIa A B B Apo B should be considered as a secondary treatment target. IIa B HDL-C is not recommended as a target for treatment. III C The ratios apo B/apo AI and non-hdl-c/hdl-c are not recommended as targets for treatment. III C a Class of recommendation, b Level of evidence. Apo = apolipoprotein; CKD = chronic kidney disease; CVD = cardiovascular disease; HDL-C = high density lipoprotein-cholesterol, LDL-C = low-density lipoprotein-cholesterol; Lp = lipoprotein; MetS = metabolic syndrome; TC = total cholesterol; TG = triglyceride. Reiner Z et al. Eur Heart J 2011;32:

24 If we accept that low HDL levels represent an important, independent, strong predictive CV risk factor, and therefore constitute a target for therapy, then what can we expect in terms of clinical benefit from efficacious HDLraising agents?

25 Relative risk for incident CHD Low HDL-C Levels Are Associated With High CHD Risk BUT: Elevated HDL-C Levels Are Cardioprotective 1,2 1,0 Men 1,2 1,0 Women 0,8 0,8 ARIC 0,6 0,6 0,4 0,4 0,2 0,2 0,0 0,0 HDL-C mmol/l mg/dl Adjusted for age and race, 10-year follow-up; N=12,339. Sharrett AR et al. Circulation

26 CHOLESTEROL HOMEOSTASIS: NORMOCHOLESTEROLEMIA NY /020131YlsjoLS1 WHOLE BODY Peripheral Tissue Cholesterol Pool Dietary Cholesterol NPC1L1 Biliary Cholesterol Intestine NPC1L1 Cholesterol Pool Synthesis CM Liver Cholesterol Pool Synthesis VLDL nascent HDL LDL HDL Synthesis Skin Cholesterol Pool Synthesis Endocrine Glands Cholesterol Pool Excretion Skin Sterols 85 mg/j Steroïd Hormones 50 mg/j Synthesis Biliary Cholesterol 600 mg/j Bile Acids 400 mg/j

Anti- Infectious Activity Atheroprotective and

Cholesterol Transport Cellular Cholesterol Efflux

Activity Anti- Apoptotic Activity Kontush A, Chapman

Assmann G, Nofer JR. Ann Rev Med. 2003;53: 321-41.

27 Anti- Infectious Activity Atheroprotective and Vasculoprotective Functions of HDL Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti- Thrombotic Activity HDL Anti- Inflammatory Activity Anti- Apoptotic Activity Kontush A, Chapman MJ. Pharmacol Rev. 2006;58: Assmann G, Nofer JR. Ann Rev Med. 2003;53: Anti- Oxidative Activity Antiproteolytic Activity Endothelial Repair Vasodilatory Activity

28 Reverse cholesterol transport Liver CE SR-B1 LDL-R (3) CE FC SR-B1 (2) (3) CETP VLDL/LDL Bile (1) HDL apoai CE LCAT FC Extrahepatic tissues Arterial wall FC ABCA1, ABCG1, SR-B1

29 Cholesterol efflux capacity, HDL Function and Atherosclerosis Khera et al, NEJM 2011, 364: «Cholesterol efflux capacity from macrophages has a strong inverse association with both carotid IMT and the likelihood of angiographic CAD, independently of HDLcholesterol»

31 Diversity of HDL Functionality : Unifying hypothesis Macrophage foam cells Platelets Pancreatic β-cells HDL Endothelial cells Gordon SM et al Trends Endocrinol Metab. 2011;22:

32 Atherogenic Lipid profile VLDL VLDL-R IDL LDL Lp(a) Circulating monocytes Hypertension Influx M-CSF Low Shear Stress Arterial Wall ENDOTHELIAL DYSFUNCTION INTIMAL LIPOPROTEIN CHOLESTEROL ACCUMULATION Modified / Oxidised Proinflammatory LDL Arterial macrophage Smoking Fatty Streak Lesions Diabetes (Glucose/AGE) NY /020131YlsjoLS1 Oxidative stress Proteolysis Lipolysis Aggregation Proinflammatory Macrophage Foam cell T-Lymphocytes Lipid-rich, Immuno- Inflammatory, Prothrombogenic Plaque Plaque fragilisation/rupture Thrombus Formation Clinical Event

33 Action of CETP in driving the High TG / Low HDL-C Phenotype NY /020131YlsjoLS1 LIVER + TG-rich VLDL-1 CE / TG + TG CETP + CE HDL CE / TG FFA + TG CE + HL ADIPOSE TISSUE + TG LDL TG / CE Small dense HDL t 1/2 HSL FFA HL Small dense LDL + Kidney AI, AII INSULIN Guerin et al., ATVB, 2001, 21 : Chapma Atherosclerosis, 2003, 171 : 1-13

Reconstituted apoai/hdl ; HDL delipidation pre-β HDL ApoAI ApoAI upregulation

34 NY /020131YlsjoLS1 Emerging HDL Therapeutics : Acute and Chronic therapies Reconstituted apoai/hdl ; HDL delipidation pre-β HDL ApoAI ApoAI upregulation ApoAI mimetics ApoAI mimetics PPAR agonists hypertgemia Omega 3s ApoCIII HDL ABCA1 induction/ LXR agonists Niacin analogues ApoAII ApoE spla2 HL EL LCAT SR-B1 receptor

Prof. John Chapman, MD, PhD, DSc

Prof. John Chapman, MD, PhD, DSc Director of the Dyslipidemia and Atherosclerosis Research Unit of the National Institute for Health and Medical Research (INSERM) at the Pitié-Salpétrière Hospital in Paris