Verhoging van HDL cholesterol: welke opties zijn er binnenkort beschikbaar?

Transcription

1 HDL en LDL cholesterol state of the art Verhoging van HDL cholesterol: welke opties zijn er binnenkort beschikbaar? Prof. dr. E.S.G. Stroes - internist Academisch Medisch Centrum Amsterdam

2 Increasing HDL as a Target in Cardiovascular Prevention in 2013 Fact of Failure? ERIK STROES Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands

3 Current situation for HDLc increasing strategies: Life was never meant to be easy, but Light may as yet be revealed Torcetrapib discontinuation

4 Percent Is There a Therapeutic Need Beyond LDL Lowering? HPS 1-27 WOSCOPS S 3-34 ASCOT-LLA 4 CARDS 5 * Reduction in major coronary events vs placebo (%) Potential for further risk reduction 1. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; 2. Shepherd J et al. N Engl J Med. 1995;333: ; 3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: ; 4. Sever PS et al. Lancet. 2003;361: ; 5. Colhoun HM et al. Lancet. 2004;364:

5 Hazard Ratio Selecting promising candidates Based on Epidemiology 3.0 N = 302, HDL-C (mg/dl) The Emerging Risk Factors Collaboration. JAMA 2009;302:

6 Shape Complexity of HDL(-c) Cholesterol concentration versus particle Electrophoretic mobility Discoidal HDL Spherical HDL Pre-β-2 Pre-β-3 Density and size α1 HDL2b HDL2a HDL3a HDL3b HDL3c HDL2 HDL Density (g/ml) 1.21 Diameter (nm) α2 α3 α4 Apolipoprotein composition Pre-β-1 LpA-I LpA-I:A-II Origin Pre-β α migration migration Camont L, et al. Trends Mol Med. 2011;17(10):

7 Production Intestine Lipid-free A-I Complexity of HDL-c Cholesterol concentration versus flux ABCA1 FC HDL3 CE PLTP HL EL Peripheral cell FC, PL Maturation LCAT LCAT FC HDL2 CE ABCG1 CE TG CETP CE A-I TG Pre-β-HDL VLDL VLDL-R IDL LDL Remodeling Hepatocyte SR-BI HDL-R Clearance LDL-R FC, CE Kontush A, Nature CPCM 2008

8 Outline HDL-c and CV-protection Protective mechanisms Epidemiology versus Genetics Lessons learnt from HDL-c increasing trials The future for interventions targeting HDL-c

9 Quantity versus Quality Reverse cholesterol transport cholesterol carrier Other effects carrier platform QUANTITY HDL-C / Apo AI QUALITY Particle structure Functionality Chapman MJ. Pharmacol Rev

10 Intestinal Excretion mg/day HDL Increases Cholesterol Flux: Whole-body and Vascular 400 Bile Acids Neutral Sterols Before Infusion HDL-C (mg/dl) 41±7 After Infusion 35% peak Increase SG GG LM IN Eriksson, Circ 1999 Shaw, Circ Res 2008

11 Static versus Dynamic 13 C-cholesterol Tracer Dilution Flux Control Carrier of APOA1 De Goma, Rader, JACC 2008

12 Tissue cholesterol efflux (mg/kg/hr) Tissue Cholesterol Efflux Reduced in low apoai states 6 4 p = 0.03** * * ApoAI - 50% TCE - 20% carriers vs. controls 2 0 APOA1 or ABCA1 def. n = 7 controls n = 7 mean HDL-c: 13 mg/dl (SD 13) mean HDL-c: 55 mg/dl (SD 11) Holleboom, Stroes, JLR 2012

13 HDL protection beyond RCT HDL increase Endothelial Function (Endothelial cell NO production) Vascular protection Anti-thrombotic effects Anti-oxidant effects (Endothelial cell superoxide production) REVERSE CHOLESTEROL TRANSPORT Anti-inflammatory effects (Endothelial cell inflammatory activation)

14 % change in forearm bloodflow HDL Improves Endothelial Function in ABC-A1 Heterozygotes % change in forearm bloodflow ABCA1 heterozygotes before HDL increase ABCA1 heterozygotes after HDL increase normocholesterolemics before HDL increase normocholesterolemics after HDL increase Controls before rhdl Controls after rhdl DM2 before rhdl DM2 after rhdl DM 7 days after rhdl Restoration of Endothelial Function # p< Dose 5-HT (ng.100 ml FAV -1. min -1 ) Dose 5-HT (ng.100 ml FAV -1. min -1 ) Bisoendial RJ, Stroes El. Circulation 2003 Nieuwdorp, Stroes E, Diabetologia 2008

15 Nitric oxide production AU (changes vs. PBS-treated cells, in %) HDL and NO release Dysfunctional HDL in CAD Arbitrary Units Arbitrary Units P < P < 0.05 n.s Healthy HDL Stable CAD HDL ACS HDL Magnetic field (G) Magnetic field (G) Magnetic field (G) (ESR spectroscopy measurement) Besler C. J Clin Invest 2012

16 Number of GCSF-labeled monocytes per high power field HDL and Inflammation Dysfunctional in CAD? n.s. P < 0.05 P < 0.05 P < Baseline TNFα TNFα + Healthy HDL TNFα + Stable CAD HDL TNFα + ACS HDL Besler C U. J Clin Invest 2012

17 HDL: carrier or carrier- platform? Triglycerids Phospholipids Esterified cholesterol Free cholesterol Cholesterol Ester Apo A1 PON-1 > 1000 different lipids (Phospholipid species, Cholesterol Ester, Trigylcerides, ) 70 different proteins (ApoA1, PON-1, ApoA2, ApoCIII, ApoE, ApoH,.)

18 Summary I protective mechanisms In humans, HDL is both cholesterol acceptor and a carrier of enzymes/proteins HDL can lose its protective effects in (advanced) disease states. How to test and/or need to test HDL quantity remains to be resolved

19 Outline HDL-c and CV-protection Protective mechanisms Epidemiology versus Genetics Lessons learnt from HDL-c increasing trials The future for interventions targeting HDL-c

20 Hazard Ratio HDL in Epidemiology Inverse relation between HDLc and CV-risk 3.0 N = 302, HDL-C (mg/dl) The Emerging Risk Factors Collaboration. JAMA 2009;302:

21 HDL: Impact of confounding factors Confounding factors associated with low HDL: Male gender Smoking Obesity Diabetes Hypertriglyceridemia Systemic inflammation Low socio-economic status Adjustment for apob and TG abolishes the protective capacity of HDLc in EPIC-Norfolk study El Harchaoui, Stroes, Annals Int Med 2009

22 Genetic HDL increase: no relation to MI Observational epidemiology Odds ratio (95% CI) per 0.03 mmol/l (1mg/dL) increase in HDL-c Genetically raised HDLc Odds ratio (95% CI) per 0.03 mmol/l (1mg/dL) increase in HDLc Cohort Atherosclerosis Risk in Communities Study Copenhagen City Heart Study Malmo Diet and Cancer Study, Cardiovascular Cohort Framingham Heart Study Heart Professionals Follow up Study Danish Diet, Cancer, and Health Study 0.97 ( ) 0.98 ( ) 0.97 ( ) 0.96 ( ) - - 7x x x10-6 4x ( ) 1.09 ( ) 0.82 ( ) 1.17 ( ) 1.84 ( ) 1.05 ( ) Meta-analysis of cohort studies Per 0.03 mmol/l (1 mg/dl) increase in plasma HDL-c Per 0.39 mmol/l (15 mg/dl) increase in plasma HDL-c 0.98 ( ) 0.70 ( ) 4x x ( ) 1.28 ( ) Voight, Lancet 2012

23 Epidemiology versus Genetics LDL vs HDL LDL-c HDL-c OR per SD increase in plasma lipid Observational epidemiology* 1.54 ( ) 0.62 ( ) OR per SD increase in plasma lipid Genetic score** 2.13 ( ) p=2x ( ), p=0.63 We confirm that genetically raised plasma HDL cholesterol is not associated with risk of myocardial infarction. A genetic score consisting of these 14 variants was not associated with risk of myocardial infarction. These results show that some ways of raising HDL cholesterol might not reduce risk of myocardial infarction in human beings. Observational epidemiology estimates derived from more than individuals from prospective cohort studies as shown in the appendix p 22. ** LDL genetic score consisting of 13 single necleotide polymorphisms (SNPs) as shown in the appendix p 27; HDL genetic score consisting of 14 SNPs as shown in the appendix p 28. Voight, Lancet 2012

24 6 of 15 variants altering HDL-C, do affect MI risk Voight, Lancet 2012

25 Separate case for extremes? Carriers of LCAT Gene Mutations Carriers (n=45) Controls (n=45) P Adj. P Adj. P CVD excl. 3.0 Tesla MRI Plaque components (n, %) 37 (4.1%) 12 (1.3%) < Total PC volume (mm 3 ) Duivenvoorden, Stroes, JACC 2012

26 Separate case for extremes? carriers of in ABCA-1 mutations Bochem, Stroes, JLR

27 Summary II Epidemiology vs Genetics Overall, genetic HDL-c changes not related to risk: 6 HDL-related variants do associate with risk Extreme genetic HDL-phenotypes associate with risk Whereas the impact of HDLc on risk is evident, the effect of raising HDLc might not invariably reduce risk of MI

28 Outline HDL-c and CV-protection Protective mechanisms Epidemiology versus Genetics Lessons learnt from HDL-c increasing trials The future for interventions targeting HDL-c

29 AIM-HIGH Raising HDL Human Studies ACCORD ERASE Joy, Hegele, Nature Reviews 2008 Aim-High invest, N Engl J Med 2011 Ginsberg, N Engl J Med 2010 Tardiff, JAMA 2007.

30 Major negative HDLc trials AIM-HIGH: ILLUMINATE: Niacin Torcetrapib dal-outcomes: Dalcetrapib

31 AIM HIGH: Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes 3300 patients Men and women Aged 45 years Established vascular disease and atherogenic dyslipidemia (low HDL-C and high triglycerides) Primary End Point Composite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk ACS with objective evidence of ischemia Simvastatin 40 mg + ER niacin 2 g Simvastatin 40 mg 4-year follow-up Key Secondary End Points Composite of CHD death, nonfatal MI, or ischemic stroke clinicaltrials.gov/ct/show/nct

32 AIM-HIGH Event driven trial powered to detect a 25% reduction in cardiovascular events (target 800 primary events) LDL-c in placebo group titrated to <1.8mmol/l Study terminated (futility) after 550 primary events On-treatment difference in HDL-C between groups: 4 mg/dl (~ 4% event reduction) Boden et al. N Eng J Med 2011; 356:2255

33 Event Free (%) ILLUMINATE: Primary Endpoint: Time to First MCVE*: Kaplan-Meier Plot Hazard Ratio 1.25 P= Atorvastatin (A) events = 373 Torcetrapib/Atorvastatin (T/A) events = Days from Randomization *Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina Barter et al, NEJM 2007;357:2109

34 Reasons for adverse outcome with torcetrapib in ILLUMINATE? Inhibiting CETP is pro-atherogenic Inhibiting CETP generates dysfunctional HDL Torcetrapib has an adverse off-target pharmacology unrelated to CETP

35 Off-target effects of torcetrapib unrelated to CETP inhibition Torcetrapib: - induces synthesis/secretion of aldosterone and cortisol from human adrenal cells - increases blood pressure Torcetrapib: - reduces expression of enos, - increases expression of ET-1 - induces endothelial dysfunction (in animals) Other CETP inhibitors do not have these off-target effects Forrest et al. Br J Pharmacol. 2008;154: ). Hu et al. Endocrinology 2009;150: Capponi et al. Circulation 2008;118:S:452. Connelly et al. J Cardiovasc Pharmacol 2010; 55:459.

36 Future 30,000 patients with occlusive arterial disease in North America, Europe and Asia Background LDL-lowering with atorvastatin Randomized to anacetrapib 100 mg vs. placebo Primary outcome: Coronary death, myocardial infarction or coronary revascularization

37 dal-outcomes Trial 15,600 patients 4-12 weeks after an index ACS event Statin therapy to optimal LDL-C level Dalcetrapib 600 mg Placebo 2.5-year follow-up Primary End Point CHD death, non-fatal MI, atherothrombotic stroke, unstable angina requiring hospitalization or resuscitated cardiac arrest Schwartz et al. Am Heart J. 2009;158:896.

38 dal-outcomes Trial May 2012: dal-outcomes trial terminated on the basis of futility. DSMB: further continuation of the study has virtually no chance of a positive result.

39 Why did dalcetrapib fail to reduce CV events? Possible explanations: (i) Increase in HDLc by dalcetrapib induces dysfunctional HDL (ii) Inhibiting CETP with a weak inhibitor not sufficient to have an impact on CV events (iii)cetp inhibition itself is pro-atherogenic (iv)inverse relationship between HDL-C and CV-risk is an epiphenomenon

40 CETP-Inhibitors in comparison Changes of lipid-parameters in % Total chol Torcetrapib* 60 mg/d Pfizer* + 4 Dalcetrapib* 600 mg/d Roche + 8 Anacetrapib 100 mg/d MSD + 16 Evacetrapib 500 mg/d Lilly + 11 LDL-c Triglycerides Apo B HDL-c ApoA Lp(a) Halted Toxicity Halted Futility Ongoing Reveal * Clinical development program of Torcetrapib & Dalcetrapib stopped Cannon C, JAMA 2011;306:2153

41 Summary III Lessons HDLc-increasing trials Trials to date haven t solved the question whether HDL should be a therapeutic target Important lessons: Power adequately with realistic benefit address adverse effects before embarking on a large clinical endpoint trial. Test the compound, not the mechanism

42 Outline HDL-c and CV-protection Protective mechanisms Epidemiology versus Genetics Lessons learnt from HDL-c increasing trials The future for interventions targeting HDL-c

43 Therapies on the Horizon CETP Inhibitors ApoAI upregulation Reconstituted apoai/hdl ; HDL delipidation pre-β HDL PPAR agonists apociii hypertgemia Omega-3 FAs HDL ApoAI upregulation ApoAI mimetics ABCA1 induction / LXR agonists apoaii apoe spla2 HL EL LCAT SR-B1 Niacin analogues

44 Increasing ApoA-I RVX-208 rhdl CER001 HDL Cholesterol Phospholipids ApoA-I Protein Target ApoA-I mrna Cytoplasm Hepatocyte ApoA-I Gene Nucleus 7

45 Reverse cholesterol efflux following apoai infusion A. Murphy and A. Tall, Columbia U. Unpublished obs.

46 Indications for apo-ai/hdl infusables Re-events after ACS Therapeutic gap after ACS Lipid-rich core depletion Days cholesterol Anti-inflammatory Targeted delivery

47 EAS/ESC Guidelines on HDLc in risk stratification and therapy

48 Take Home: For now, measure HDLc Treat LDLc more vigorous in case of low HDLc If HDLc is low in (very)high risk, consider adding nicotinic acid If HDL-c is a valid therapeutic target, will be revealed in the next 3-4 years Key issues to be resolved: HDL concentration vs HDL quality HDL concentration vs Tissue chol efflux Target AI-production, maturation, remodeling or clearance Quantify vascular benefit (PET/MRI)