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 Associate European Editor of Arteriosclerosis, Thrombosis and Vascular Biology and of Pharmacology and Therapeutics President of the European Atherosclerosis Society
CVS-European Postgraduate School in Cardiology Prague 2011 WHAT NEXT IN CVD PREVENTION? 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
INTERHEART : RF for first MI Exercise 8 Alcohol Intake 9 Apo B / Apo AI 1 1 High Global CV Risk Smoking 2 Diabetes Vegetable and Fruit Consumption Daily 7 Psychosocial Stress 6 Accelerated Atherosclerosis and CVD Abdominal Obesity 5 Hypertension 4 3 Yusuf S et al. Lancet. 2004. 3
On-treatment LDL-C & CHD Events in Statin Trials 30 NCEP 2004 NCEP 2001 ESC/EAS 2003 4S - PBO Secondary Prevention 20 4S - Rx 10 0 LIPID - Rx CARE - Rx TNT - ATV10 TNT - ATV80 HPS - Rx PROVE-IT - PRA AFCAPS - PBO PROVE-IT - ATV80 AFCAPS - Rx 40 (1.0) 60 70 80 (1.6)(1.8)(2.1) ASCOT - Rx 100 (2.6) 120 (3.1) HPS - PBO CARE - PBO ASCOT - PBO 140 (3.6) LIPID - PBO Primary Prevention WOSCOPS - PBO WOSCOPS - Rx 160 (4.1) LDL-C achieved mg/dl (mmol/l) 180 (4.7) 200 (5.2) Adapted from Rosensen, Exp Opin Emerg Drugs 2004;9:269; LaRosa J et al, N Engl J Med, 2005;352:1425
Change in PAV (%) Lowering LDL-C:HDL-C Ratio to approx 1:1 stops Atherosclerosis progression IVUS Trials: REVERSAL, CAMELOT, ACTIVATE, ASTEROID 2 1 0-1 -2 0 1 2 3 LDL-C:HDL-C during treatment Nicholls S, et al. JAMA. 2007;297:499-508.
BUT 6
Residual Cardiovascular Risk in Prospective Intervention Trials Chapman et al, Pharmacol Therap, 2010
BUT 8
Obésité: fléau mondial En France: 1 personne sur 3 en surpoids ou obèse 20 Millions en surpoids 6 Millions d obèses Obépi 2009
NY-160626.038/020131YlsjoLS1 WHO Prediction of Worldwide Prevalence of TYPE 2 DIABETES in 2025 Le Monde, 2001
Pathophysiology of Type 2 Diabetes, Metabolic Syndrome and Premature Vascular Disease Adipose Fat accumulation Positive Energy Balance Adipose Fat accumulation NY-160626.038/020131YlsjoLS1 Portal FFA Glucose AGE IL6, IL8 TNFa PAI-1 Angio II Leptin Adiponectin VLDL production Insulin resistance Mixed Dyslipidemia Hyperglycemia Hypertension Inflammation Oxidative Stress Microangiopathy Atherosclerosis
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
Factors Contributing to Elevated Triglyceride Levels High Triglyceride Risk Factors Obesity/overweight Physical inactivity Cigarette smoking Excess alcohol intake High carbohydrate diet Type 2 diabetes, renal failure, underactive thyroid Certain drugs Genetic factors NCEP III=National Cholesterol Education Program Adult Treatment Panel III Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486 2497; De Backer G et al. Eur J Cardiovasc Prev Rehabil. 2003;10(suppl 1):S1 S78; Pejic RN et al. J Am Board Fam Med. 2006;19:310 316. 13
NY-160626.038/020131YlsjoLS1 Metabolic Basis of low HDL-C in Type 2 Diabetes and Metabolic Syndrome with insulinoresistance 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
Cardiovascular Disease Prevention : The Unmet Need 100 Statins 35% LOW HDL-C % CV EVENTS 0 HIGH TG, TG-rich LPs and Remnants Lp(a) - Metabolic disease - CHD patients - Mixed hyperlipidemia - Hypercholesterolemia (FH) - Renal Disease 65%
16 Unmet Therapeutic Needs in Atherogenic Dyslipidemia Statin intolerance; pharmacogenomicallydetermined hyporesponse (OATP1B1) to statins Responses : 1) anti-pcsk9 biologics 2) new potent statins, poorly metabolised, low dose, polypharmacy 3) MTP inhibitors, low dose, combination therapy 4) Anti-sense oligonucleotides (apo(a) ; apob )
HDL: New Perspectives QUANTITY HDL-C / Apo AI QUALITY Particle structure Lipidome, Proteome Functionality Kontush A, Chapman MJ. Pharmacol Rev. 2006. 17
NY-160626.038/020131YlsjoLS1 Abnormal Metabolism and Defective Function of HDL in Diabetic High TG/ Low HDL Dyslipidemia Oxidative stress Hyperglycemia CE VLDL TG Liver A-I SAA (CRP) CE A-I Normal functional HDL PON1 IL-6 A-I HL PON1 Kontush A, Chapman MJ. Pharmacol Rev 2006; Curr. Diabetes Rep. 2008;8:51-59. Chronic low-grade inflammation SAA TG A-I Functionally deficient HDL Cholesterol efflux capacity Antioxidative activity Anti-inflammatory activity Antiapoptotic activity Vasodilatory activity
19 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
Proposed algorithm for management of elevated TG and/or low HDL-C in high-risk patients at LDL-C goal NY-160626.038/020131YlsjoLS1 Patient at LDL-C C goal WITH TG 2.2 1.7 mmol/l and/or HDL-C C <1.0 mmol/l Intensify lifestyle management Address secondary causes Check compliance Insufficient improvement? 2 Consider adding niacin or a fibrate 3 Consider intensifying LDL-C lowering 4 Copyright EAS and Eur Heart J 2011
Atheroprotective & Vasculoprotective Actions of HDL NY-160626.038/020131YlsjoLS1 Anti- Infectious Activity Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti- Thrombotic Activity HDL Anti- Inflammatory Activity Anti- Apoptotic Activity Kontush A, Chapman MJ, Pharmacol Rev 2006, 58:342-74 Assmann G, Nofer JR, Annu Rev Med. 2003,53: 321-41 Anti- Oxidative Activity Antiproteolytic activity Endothelial Repair; Vasodilation Innate immune system
Cholesterol efflux capacity, HDL Function and Atherosclerosis Khera et al, NEJM 2011, 364: 127-135 «Cholesterol efflux capacity from macrophages has a strong inverse association with both carotid IMT and the likelihood of angiographic CAD, independently of HDLcholesterol»
HDL-C Raising Agents Agent Niacin HDL-C 15% 35% LDL-C 5% 25% Triglycerides 20% 40% Fibrates HDL-C 1% 20% LDL-C up to 10% Triglycerides 20% 50% Statins HDL-C 1% 15% LDL-C 18% 55% Triglycerides 7% 30% Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486 2497. Assmann G et al. Circulation. 2004;109(23 suppl 1):III-8 III-14. 23
NY-160626.038/020131YlsjoLS1 Cholesteryl Ester Transfer Protein (CETP) Apo E VLDL or Chylomicron Remnant Cholesteryl Ester TG Apo AI CETP Apo B HDL CE Triglyceride
The dal-heart Program dalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport The dal-heart Program hypothesis: enhancing HDL efficacy through CETP modulation will treat the underlying disease of atherosclerosis and will attenuate CV risk daloutcome S 15,600 patients recently hospita-lized for ACS To evaluate the effect of dalcetrapib on CV outcomes RECRUITMENT COMPLETE dal-vessel 2 450 patients with CHD or CHD risk equivalent To evaluate the effect of dalcetrapib on endothelial function and blood pressure, measured by FMD and ABPM dal-plaque 3 130 patients with CHD To evaluate the effect of dalcetrapib on inflammation, plaque size and burden, measured by PET/CT and MRI dal-plaque2 4 900 patients with CAD To evaluate the effect of dalcetrapib on atherosclerot ic disease progression, assessed by IVUS and carotid B- mode ultrasound
NY-160626.038/020131YlsjoLS1
Cardiovascular Disease Prevention : The Unmet Need 100 Statins 35% LOW HDL-C % CV EVENTS 0 HIGH TG, TG-rich LPs and Remnants Lp(a) - Metabolic disease - CHD patients - Mixed hyperlipidemia - Hypercholesterolemia (FH) - Renal Disease 65%