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HDL: Still a target for therapy? PaACC Annual Chapter Meeting November 2, 2008

HDL: Still a target for therapy? PaACC Annual Chapter Meeting November 2, 2008. Daniel J. Rader, MD University of Pennsylvania School of Medicine rader@mail.med.upenn.edu. Lipoproteins and Atherosclerosis. Oxidation, modification, aggregation. CE. B. Chol. Chol. Arterial macrophage.

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HDL: Still a target for therapy? PaACC Annual Chapter Meeting November 2, 2008

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  1. HDL: Still a target for therapy?PaACCAnnual Chapter MeetingNovember 2, 2008 Daniel J. Rader, MD University of Pennsylvania School of Medicine rader@mail.med.upenn.edu

  2. Lipoproteins and Atherosclerosis Oxidation, modification, aggregation CE B Chol Chol Arterial macrophage LDL

  3. Previous LDL-C goals New LDL-C goals LDL goals keep going down Moderately High Risk ≥2 risk factors (10-yr risk 10–20%) High Risk CHD or CHD risk equivalents (10-yr risk >20%) Moderate Risk ≥2 risk factors (10-yr risk <10%) Lower Risk <2 risk factors 190 - goal 160 mg/dL 160 - goal 130 mg/dL goal 130 mg/dL LDL-C level 130 - goal 100 mg/dL 100 mg/dL* 100 - 70 mg/dL* 70 - Grundy SM, et al. Circulation. 2004;110:227-239.

  4. 0.15 (HR = 0.78 95% CI 0.69, 0.89) P=0.0002 Relative risk reduction = 22% Atorvastatin 10 mg LDL 100 0.10 Atorvastatin 80 mg LDL 77 Proportion of patients experiencing major cardiovascular event 0.05 0 0 1 2 3 4 5 6 Time (years) TNT: Stable CAD PatientsMajor Cardiovascular Events *CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke LaRosa JC, et al.N Eng J Med. 2005;352

  5. Lipoproteins and Atherosclerosis A-I Oxidation, modification, aggregation CE CE CE B Chol HDL Arterial macrophage LDL

  6. “On-treatment” HDL-C Predicts Cardiovascular Events: TNT Major Cardiovascular Events On treatmentHDL-C (mg/dL) % Mean LDL-C99 mg/dL Mean LDL-C73 mg/dL Barter et al. ACC 2006. Abstract 914-203.

  7. Is HDL causally related to atherosclerosis and CHD risk or simply a very good integrator and biomarker of CHD risk?

  8. Low HDL is often accompanied by other cardiovascular risk factors Insulin resistance Inflammation Hypertension High triglycerides ↓HDL ↑Cardiovascular Disease

  9. Low HDL is often accompanied by other cardiovascular risk factors Insulin resistance Inflammation Hypertension High triglycerides ↓HDL ? ↑Cardiovascular Disease

  10. Hepatic expression of apoA-I reduces and even regresses atherosclerosis in mice Liver AdapoA-I A-I HDL

  11. HDL Metabolism and Reverse Cholesterol Transport Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver

  12. Quantitation of macrophage to feces reverse cholesterol transport in vivo Feces 3H-BA 3H-FC Bile 3H-BA 3H-FC 3H-Chol 3H-BA 3H-FC Plasma 3H-cholesterol, AcLDL 3H-chol

  13. ApoA-I overexpression promotes macrophage to feces reverse cholesterol transport ApoA-I adenovirus Feces 3H-BA 3H-FC Bile 3H-BA 3H-FC 3H-Chol 3H-BA 3H-FC Plasma 3H-cholesterol, AcLDL 3H-chol

  14. HDL-C levels are not a marker of the rate of reverse cholesterol transport Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver SR-BI HDL RCT atherosclerosis SR-BI HDL RCT atherosclerosis Zhang, et al, J Clin Invest, 2004

  15. Targeting HDL metabolism for therapeutic reasons is complex Intestine ABCG1 A-I A-I FC PPARα PPARγ PPARδ LXR BA FC LCAT FC FC FC CE ABCA1 SR-BI HL, EL M Macrophage Liver CETP LDLR PLTP CE B TG Anti-oxidant, anti-inflammatory, anti-thrombotic, other VLDL/LDL

  16. Clinical studies have not definitively confirmed the HDL hypothesis • Niacin: Coronary Drug Project, HATS • Fibrates: VA-HIT, BIP, FIELD • ApoA-I: IVUS studies

  17. Nicotinic Acid (Niacin)

  18. Niacin acts on adipose to reduce FFA release and flux to liver B VLDL apoB MTP TG LDLR B LDL FFA FFA Niacin

  19. Niacin receptor (GPR109A) • Highly expressed in adipose tissue • Mediates the anti-lipolytic effects of niacin

  20. Adipocyte lipolysis generating FFA Adenylate Cyclase ATP cAMP FFA PKA Inactive HSL Active HSL TG FFA

  21. Suppression of lipolysis in adipocytes by niacin activating its receptor GPR109A Niacin GPR109A Gi-GDP Gi-GTP Adenylate Cyclase ATP cAMP FFA PKA Inactive HSL Active HSL TG FFA

  22. B VLDL apoB MTP TG LDLR B LDL FFA FFA Niacin Niacin activates its receptor GPR109A in adipose to reduce FFA release and flux to liver GPR109A

  23. Smooth muscle cell or othercell type EP2 or EP4 PGE2 Dermal macrophages PGD2 DP1 Undesirable effects Nicotinic Acid–Induced Flush Arachidonic acid COX-1 PGD2 PGE2 Mechanism of Niacin-induced Flushing Cutaneousvasodilation andburning sensationon face andupper body Adapted from Pike NB. J Clin Invest. 2005;115:3400-3403.

  24. Mechanisms of niacin’s HDL raising effects? Niacin A-I A-I CE ? PL TG Liver Kidney

  25. Data are needed proving that adding niacin to a statin reduces CV outcomes to a greater extent than statin alone

  26. AIM-HIGHStudy Overview Simvastatin Atherogenic Dyslipidemia (HDL<40 or 50; TGL>149; LDL<160) CV Death NFMI Stroke ACS 3-5 yr Vascular Dz. Age >45 years Simvastatin + niaspan 2 year enrollment Hypothesis -30% event rate with Simva -23% event rate with simva-nia - 50% relative reduction based on ~46% placebo rate 3300 patients from 60 sites (U.S. and Canada LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)

  27. HPS2-THRIVE: A Randomized Trial of the Long-term Clinical Effects of Raising HDL With Niacin and Laropiprant Does niacin combined with Laropiprant prevent vascular events in high-risk patients receiving intensive LDL-lowering therapy? An international collaboration, with a Central Office in Oxford and 3 Regional Coordinating Centers in the UK, China and Scandinavia, will conduct the trial in about 200 hospitals Patients aged 50-80 years with pre-existing atherosclerotic disease receiving simvastatin 40 mg qd and, if indicated, ezetimibe/simvastatin 10/40 mg qd N=20,000 Randomization Niacin 2 g + Laropiprant 40 mg Placebo Follow-up visits at 3 and 6 months, then every 6 months thereafter THRIVE=Treatment of HDL to Reduce the Incidence of Vascular Events.

  28. CETP inhibition:the definitive test of the HDL hypothesis?

  29. HDL Metabolism: Role of CETP Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver CETP LDLR CE B TG VLDL/LDL

  30. CETP Deficiency is Associated with Markedly Increased HDL-C Levels A-I Bile FC A-I FC CE CE CE LCAT FC FC ABCA1 SR-BI Macrophage Liver X CETP LDLR CE B TG VLDL/LDL

  31. CETP Inhibition as a Novel Strategy to Raise HDL-C Feces Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver X CETP LDLR CETP inhibitor CE B TG VLDL/LDL

  32. Treatment with the CETP inhibitor torcetrapib substantially raiseed HDL-C levels in patients with low HDL Brousseau, et al. NEJM 350:1505-1515; 2004

  33. ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to torcetrapib therapy despite favorable lipid changes HDL 72% LDL 25% Barter P et al. N Engl J Med 2007

  34. Torcetrapib Phase III Imaging Program:Efficacy • One coronary IVUS and two carotid IMT trials • Torcetrapib resulted in increases in HDL-C of 50-63% and decreases in LDL-C of ~ 20% • No significant impact on atherosclerosis progression by carotid IMT or coronary IVUS

  35. Torcetrapib Phase III Imaging Program:Blood pressure • Carotid IMT trial in heterozygous FH patients (RADIANCE 1): Mean BP increase 2.1 mmHg • Carotid IMT trial in mixed hyperlipidemia (RADIANCE 2): Mean BP increase 5.1 mmHg • Coronary IVUS study in CHD patients (ILLUSTRATE): Mean BP increase 4.6 mmHg

  36. Is the BP increasing effect of torcetrapib - a mechanism-based effect of CETP inhibition -or a molecule-specific effect of torcetrapib?

  37. ILLUMINATE: Increased mortality and major cardiovascular events in subjects randomized to torcetrapib therapy Barter P et al. N Engl J Med 2007

  38. Potential Mechanisms of Adverse Outcomes Associated with Torcetrapib Rader D. N Engl J Med 2007

  39. Could CETP inhibition impair reverse cholesterol transport? Feces Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver X CETP LDLR CETP inhibitor CE B TG VLDL/LDL

  40. Potential beneficial effects of CETP inhibition Feces Bile ABCG1 A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver X CETP LDLR CETP inhibitor CE B TG VLDL/LDL

  41. Increasing HDL-C levels is neither adequate nor necessary for predicting cardiovascular benefit of an HDL-targeted therapeutic approachImproving HDL function will be the focus of new therapiesBetter and standardized methods to assess HDL function will be required HDL-targeted therapeutics in the post-torcetrapib era: focus on HDL function

  42. Targeting HDL: Promote Reverse Cholesterol Transport Bile A-I A-I FC CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver

  43. Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux via ABCA1 A-I A-I BA FC LCAT FC FC FC CE ABCA1 SR-BI Macrophage CETP LDLR CE B TG VLDL/LDL

  44. Increasing lipid-poor apoA-I as an acceptor for cholesterol efflux:parenteral approaches • ApoA-I Milano/phospholipid complexes • ApoA-I (wild-type)/PL complexes • ApoA-I mimetic peptides • Large unilamellar vesicles (LUVs) • Delipidated HDL

  45. Increasing endogenous apoA-I production via transcriptional enhancement Liver Intestine A-I HDL

  46. Regulation of Cholesterol Efflux in the Macrophage by LXR A-I CE ABCG1 LXR Chol A-I ABCA1

  47. Pharmacologic Promotion of Macrophage Cholesterol Efflux by Synthetic LXR Agonists A-I CE ABCG1 LXR Chol A-I ABCA1 Agonist

  48. The LXR agonist GW3965 significantly increased macrophage to feces reverse cholesterol transport in vivo 2.5 * 2.0 % CPM Injected 1.5 1.0 0.5 0.0 Control LXR agonist Naik, et al, Circulation 2005

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