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HDL: Where are we and
  where are we going?

    Annabelle Rodriguez, MD
Johns Hopkins School of Medicine
    Division of ...
CAD Risk as a Function of LDL-C and
HDL-C in Men (Ages 50 to 70 Years
Old): Framingham Heart Study
Coronary Artery Disease...
HDL Metabolism
Nascent HDL (lipid-poor apolipoprotein A1 [Apo A1]) is produced
by the liver and intestine
                ...
Potential Targets to Modify HDL
 Increase apolipoprotein A1 (apo A1) production

 Increase anti-inflammatory effect of h...
Pharmacologic Therapy to Promote
Reverse Cholesterol Transport


     Bile               Feces

                          ...
Normal Apo A1 and Apo A1 Milano Dimer
                                        Lipid Binding In
                           ...
HDL Metabolism as a Therapeutic
Target: Potential Strategies
 Acute (parenteral) therapies

    – Apo A1 Milano/phospholi...
ETC-216 Initial POC Trial:
Secondary Efficacy Parameters
                0
  Mean
               -5       −2.9
Change in
 ...
ERASE Trial: Primary Endpoint
                         Percent Change in Atheroma Volume from
                            ...
Mechanisms Other Than
Reverse Cholesterol Transport by which
HDL May Be Anti-atherogenic

 Anti-oxidant effects

 Anti-i...
Conversion of Anti-Inflammatory
and Pro-Inflammatory HDL
                                Myeloperoxidase
HDL=high-density ...
Regulation of Cholesterol Efflux
in the Macrophage by LXR


            A1


         CE
                          ABCG1
 ...
Pharmacologic Manipulation of
ABCA1 and Macrophage Cholesterol
Efflux
                                                   F...
FIELD Study: Primary Endpoint
Nonfatal MI or CHD death at 5 years
                            5.9%
6%                     ...
Total CVD in Subgroups
                               Feno-         Favors             Favors             HR
 Interaction ...
PROactive Trial: Significant
Reduction in Secondary Outcome
All-cause mortality, nonfatal MI*, stroke

            25
    ...
CHICAGO: Mean Change in CIMT
                               0.020                   p=0.017
LS Mean Change from Baseline

...
HDL Cholesterol Changes
                                  8
                                       Glimepiride     Pioglit...
HDL Metabolism: Role of CETP

  Bile

                      A1
FC                                        A1               ...
CETP Deficiency is Associated with
Markedly Increased HDL-C Levels

     Bile                       A1


 FC              ...
Torcetrapib: Pharmacodynamic
Effect on HDL-C in Phase 1
Phase I Summary of Lipid and Lipoprotein Changes
           100   ...
Torcetrapib (Study A3071007)
Consistent HDL-C Raising by Gender and
Baseline HDL-C
Mean % Change:       58%           55% ...
ILLUSTRATE Trial: Primary Endpoint
Percent change in atheroma volume from baseline

                            0.3       ...
Nicotinic Acid Receptor HM74A
      GPR109A           Nicotinic Acid                                   Smooth muscle
   (P...
Coronary Drug Project:
 Clinical Outcomes*
                 35      −14

                 30                             ...
ARBITER 3:
  Changes in CIMT – Pooled, 12-Month Data
   CIMT=carotid intima-media thickness; ERN=extended-release niacin
 ...
MK-0524 (laropiprant)
Suppresses Niacin-Induced Increases in Skin
Blood Flow
                         1.4
                ...
Summary
 LDL-C remains the primary goal of lipid-treatment but novel
  therapies that affect reverse cholesterol transpor...
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HDL: Where are we and where are we going?

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Transcript of "HDL: Where are we and where are we going?"

  1. 1. HDL: Where are we and where are we going? Annabelle Rodriguez, MD Johns Hopkins School of Medicine Division of Endocrinology Slide Source Lipids Online Slide Library www.lipidsonline.org
  2. 2. CAD Risk as a Function of LDL-C and HDL-C in Men (Ages 50 to 70 Years Old): Framingham Heart Study Coronary Artery Disease (CAD) 3 Relative Risk 2 25 0.65 1 45 1.16 65 1.68 0 85 2.2 220 160 100 mg/dL 5.69 4.14 2.58 mmol/L LDL Cholesterol (LDL-C) Slide Source Modified from Castelli WP. Can J Cardiol 1988;4:5A10A. Lipids Online Slide Library www.lipidsonline.org
  3. 3. HDL Metabolism Nascent HDL (lipid-poor apolipoprotein A1 [Apo A1]) is produced by the liver and intestine intestine liver particle LPL uptake TGRL selective uptake apo A1 HDL2 CETP ABC1 SR-BI peripheral cells HL, EL LCAT HDL3 PLTP pre- surface cubilin HDL remnants kidney Slide Source Von Eckardstein A et al. Curr Opin Lipidol 2000;11:627637. Lipids Online Slide Library www.lipidsonline.org
  4. 4. Potential Targets to Modify HDL  Increase apolipoprotein A1 (apo A1) production  Increase anti-inflammatory effect of high-density lipoprotein (HDL)  Infuse apo A1 phospholipid complexes  PPAR alpha, delta and gamma  LXR agonists  Upregulate ABCA1 or ABCG1  Enhance LCAT activity  Inhibit CETP  Modify Hepatic Holoparticle uptake of HDL (niacin receptor agonist) PPAR=peroxisome proliferator-activated receptor; LXR=liver X receptor; ABCA1=ATP-binding cassette transporter A1; ABCG1=ATP-binding cassette transporter G1; LCAT=lecithin Slide Source cholesterol acyltransferase; CETP=cholesteryl ester transfer protein Lipids Online Slide Library www.lipidsonline.org
  5. 5. Pharmacologic Therapy to Promote Reverse Cholesterol Transport Bile Feces A1 A1 CE FC CE LCAT FC FC CE SR-BI Nascent Macrophage HDL Liver Mature HDL CE=cholesterol ester ;FC=free cholesterol; SR-BI=scavenger receptor class-B, type I; A1=apolipoprotein A1; LCAT=lecithin cholesterol acyltransferase; HDL=high-density Slide Source lipoprotein Lipids Online Slide Library www.lipidsonline.org
  6. 6. Normal Apo A1 and Apo A1 Milano Dimer Lipid Binding In Vivo Catabolism 35 143 187 99 243 A1 1 25 209 220 66 121 165 A1=apolipoprotein A1 LCAT Activation Receptor A1m=apolipoprotein A1 Milano Cholesterol Efflux Binding LCAT=lecithin cholesterol acyl- transferase 243 243 A1m/A1m 173 173 1 ss 1 Slide Source Franceschini G. Eur J Clin Invest 1996;26:733746. Lipids Online Slide Library www.lipidsonline.org
  7. 7. HDL Metabolism as a Therapeutic Target: Potential Strategies  Acute (parenteral) therapies – Apo A1 Milano/phospholipid complexes – Apo A1 mimetic peptides – Large unilamellar vesicles (LUVs) – Delipidated HDL – Apo A1 isolated from human plasma and phosphatidylcholine derived from soybean Slide Source HDL=high-density lipoprotein; Apo A1=apolipoprotein A1 Lipids Online Slide Library www.lipidsonline.org
  8. 8. ETC-216 Initial POC Trial: Secondary Efficacy Parameters 0 Mean -5 −2.9 Change in Total -10 Atheroma -15 −12.6 −14.1 Volume −15.1 p=0.007 (mm3) p=0.02 p<0.001 -20 0 -0.01 Mean −0.008 Maximal -0.02 Atheroma -0.03 Thickness -0.04 (mm) −0.039 −0.042 -0.05 −0.044 p=0.02 p=0.03 p<0.001 Placebo ETC-216 ETC-216 ETC-216 (n=11) 15mg/kg 45mg/kg Combined POC=proof-of-concept (n=21) (n=15) (n=36) Slide Source Nissen SE et al. JAMA 2003;290:22922300. Lipids Online Slide Library www.lipidsonline.org
  9. 9. ERASE Trial: Primary Endpoint Percent Change in Atheroma Volume from Baseline to 6 weeks Change in Atheroma Volume (%) 1%  The primary endpoint CSL-111 Placebo of percent change in 0% atheroma volume from baseline to 6 weeks did -1% not differ between treatment groups -2% −1.6% (−3.4% in the CSL-111 group vs. -3% p = 0.48 −1.6% in the placebo −3.4% group, p=0.48) -4% Slide Source Tardif JC et al. JAMA 2007;297:16751682. Lipids Online Slide Library www.lipidsonline.org
  10. 10. Mechanisms Other Than Reverse Cholesterol Transport by which HDL May Be Anti-atherogenic  Anti-oxidant effects  Anti-inflammatory effects  Anti-coagulant effects  Improve endothelial function Slide Source HDL=high-density lipoprotein Lipids Online Slide Library www.lipidsonline.org
  11. 11. Conversion of Anti-Inflammatory and Pro-Inflammatory HDL Myeloperoxidase HDL=high-density lipoprotein Nitrotyrosine Chlortyrosine  Apo A1  Paraoxonase, other factors Apo A1  Pro-inflammatory factors, other factors Anti-inflammatory Pro-inflammatory Modified from Ansell BJ et al. J Am Coll Cardiol 2005;46:1792 Slide Source 1798. Lipids Online Slide Library www.lipidsonline.org
  12. 12. Regulation of Cholesterol Efflux in the Macrophage by LXR A1 CE ABCG1 LXR Chol A1 ABCA1 LXR=liver X receptor; CE=cholesterol ester;A1=apolipoprotein A1; ABCA1=ATP-binding Slide Source cassette transporter A1; ABCG1=ATP-binding cassette transporter G1 Lipids Online Slide Library www.lipidsonline.org
  13. 13. Pharmacologic Manipulation of ABCA1 and Macrophage Cholesterol Efflux Fibrates, TZDs, dual PPARs, new agents PPAR PPAR PPAR A1 FC LXR/RXR ABCA1 New agents ?New ABCA1=ATP-binding cassette transporter A1; A1=apolipoprotein A1; FC=free agents cholesterol; LXR=liver X receptor; RXR=retinoid X receptor; PPAR= peroxisome proliferator-activated Slide Source receptor; TZD=thiazolidinedione Lipids Online Slide Library www.lipidsonline.org
  14. 14. FIELD Study: Primary Endpoint Nonfatal MI or CHD death at 5 years 5.9% 6%  Full study cohort: 5.2% – Fenofibrate (n=4895) – Placebo (n=4900) 5%  The primary end point of nonfatal MI or CHD death was 4% not significantly lower in the fenofibrate group compared with the placebo group 3% P = .16  Nonfatal MI and revascularization were significantly lower in the 2% fenofibrate group compared with the placebo group  Patients in the placebo group 1% were treated more frequently with lipid-lowering therapy 0% Fenofibrate Placebo MI=myocardial infarction CHD=coronary heart disease (n=256) (n=288) Slide Source Keech A et al. Lancet 2005;366:18491861. Lipids Online Slide Library www.lipidsonline.org
  15. 15. Total CVD in Subgroups Feno- Favors Favors HR Interaction Placebo fibrate Fenofibrate Placebo (95% CI) P HDL-C P % % 15.1 Low (ATPIII) 13.0 0.02 0.3 2.1% 12.3 High 11.8 0.6 0.5% Triglycerides 15.4 >1.7 mM 13.6 0.07 0.8 2.8% 12.4 <1.7 11.3 0.2 1.1% Dyslipidemia (low HDL-C + high TG) 16.3 Yes 14.0 0.06 0.6 2.3% 12.6 No 11.6 0.2 1.0% CVD=cardiovascular disease 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 Slide Source Keech A et al. Lancet 2005;366:1849-1861. Lipids Online Slide Library www.lipidsonline.org
  16. 16. PROactive Trial: Significant Reduction in Secondary Outcome All-cause mortality, nonfatal MI*, stroke 25 *Excluding silent myocardial infarction (MI) 20 Placebo 16% RRR 358 events Events, % 15 HR 0.84 (0.720.98) P = 0.027 10 Pioglitazone 301 events 5 0 0 6 12 18 24 30 36 Time from randomization (months) Slide Source Dormandy JA et al. Lancet 2005;366:12791289. Lipids Online Slide Library www.lipidsonline.org
  17. 17. CHICAGO: Mean Change in CIMT 0.020 p=0.017 LS Mean Change from Baseline 0.015 Glimepiride Posterior Wall CIMT (mm) 0.010 0.012 Pioglitazone 0.005 0.000 -0.005 −0.001 -0.010 Baseline CIMT GLM (N=186) PIO (N=175) Treatment group difference, LS Mean (SE) 0.779 (0.0085) mm 0.771 (0.0085) mm Final Visit −0.013 (95% CI: −0.024,−0.002) CIMT=carotid intima-media thickness Slide Source Adapted from Mazzone T et al. JAMA 2006;296:25722581. Lipids Online Slide Library www.lipidsonline.org
  18. 18. HDL Cholesterol Changes 8 Glimepiride Pioglitazone LS Mean Change from Baseline, 6 HDL-C (mg/dL) 12.8% 4 2 −1.1% *p<0.0001 0 -2 Baseline 24 48 72 No. of Observations Week Glimepiride 206 203 206 206 Pioglitazone 201 198 201 201 Slide Source Mazzone T et al. JAMA 2006;296:2572−2581. Lipids Online Slide Library www.lipidsonline.org
  19. 19. HDL Metabolism: Role of CETP Bile A1 FC A1 CE CE FC LCAT FC FC CE ABCA1 SR-BI Macrophage Liver CETP LDLR A1=apolipoprotein A1 ABCA1=ATP-binding cassette transporter A1 CE=cholesterol ester CETP=cholesterol ester transfer protein CE FC=free cholesterol B TG LCAT=lecithin cholesterol acyltransferase LDL=low-density lipoprotein LDLR=LDL receptor SR-BI=scavenger receptor class-B, type I TG=triglyceride VLDL/LDL VLDL=very low density lipoprotein Slide Source Lipids Online Slide Library www.lipidsonline.org
  20. 20. CETP Deficiency is Associated with Markedly Increased HDL-C Levels Bile A1 FC FC A1 CE CE LCAT CE FC FC SR-BI ABCA1 Macrophage Liver LDLR X CETP A1=apolipoprotein A1 ABCA1=ATP-binding cassette transporter A1 CE=cholesterol ester CETP=cholesterol ester transfer protein FC=free cholesterol CE LCAT=lecithin cholesterol acyltransferase B TG LDL=low-density lipoprotein LDLR=LDL receptor SR-BI=scavenger receptor class-B, type I TG=triglyceride VLDL/LDL VLDL=very low density lipoprotein Slide Source Lipids Online Slide Library HDL-C=high-density lipoprotein cholesterol www.lipidsonline.org
  21. 21. Torcetrapib: Pharmacodynamic Effect on HDL-C in Phase 1 Phase I Summary of Lipid and Lipoprotein Changes 100 91 70 80 Base HDL-C 73 60 Base HDL-C (mg/dL) 50 60 62 % Change % HDL-C 40 40 % Apo A1 28 27 27 24 30 16 20 11 12 20 0 10 −3 −2 -20 0 PBO 10 30 60 120 240 (bid) Daily Dose Changes are following 2 weeks of treatment; n=6 per active dose group; n=9 placebo (PBO) Created from Clark RW et al. Arterioscler Thromb Vasc Biol 2004; Slide Source Lipids Online Slide Library 24:490497. www.lipidsonline.org
  22. 22. Torcetrapib (Study A3071007) Consistent HDL-C Raising by Gender and Baseline HDL-C Mean % Change: 58% 55% 45% 42% Torcetrapib 120 mg qd 140 130 Male Female 120 110 100 HDL-C 90 (mg/dL) 80 70 60 50 40 30 20 Week: 0 8 0 8 0 8 0 8 Baseline HDL-C: Low High Low High Slide Source Created from Bamberger MJ et al. Circulation 2005;112:II-179. Lipids Online Slide Library www.lipidsonline.org
  23. 23. ILLUSTRATE Trial: Primary Endpoint Percent change in atheroma volume from baseline 0.3 p=0.72 Change in Atheroma Volume  The percent change in from Baseline (%) 0.19% 0.2 atheroma volume did not differ 0.12% between 0.1 treatment groups 0 Torcetrapib Placebo N = 591 N = 597 Slide Source Nissen SE et al. N Engl J Med 2007;356:13041316. Lipids Online Slide Library www.lipidsonline.org
  24. 24. Nicotinic Acid Receptor HM74A GPR109A Nicotinic Acid Smooth muscle (PUMA-G in mice) cell or other cell type EP2 or EP4 G1 G1 G1 PGE2 Adipocyte Spleen Dermal Lymphoid Cells Macrophages PGD2 Lung Antilipolytic DP Effects Undesirable Unknown Effects Nicotinic Acid Decreased cAMP level Effects Induced Flush Arachidonic acid Decreased hormone- sensitive TG lipase COX-1 activity PGE2 PGD2 Decreased hydrolysis to TGs and FFAs Antilipolytic Effects: Increased HDL Decreased VLDL and LDL Slide Source Pike NB. J Clin Invest 2005;115:3400−3403. Lipids Online Slide Library www.lipidsonline.org
  25. 25. Coronary Drug Project: Clinical Outcomes* 35 −14 30 Placebo 25 Event Rate (%) Niacin 20 −27 15 −26 10 −47 5 0 Nonfatal MI/ Nonfatal MI Stroke/TIA CV Surgery CHD Death MI=myocardial infarction; CHD=coronary heart disease; TIA=transient ischemic attack; CV=cardiovascular *Total follow-up, adjusted for baseline characteristics, p<0.05, 5-year rate Source Slide Coronary Drug Project Research Group. JAMA 1975;231:360381. Lipids Online Slide Library www.lipidsonline.org
  26. 26. ARBITER 3: Changes in CIMT – Pooled, 12-Month Data CIMT=carotid intima-media thickness; ERN=extended-release niacin  Placebo + statin phase 0.075  n = 61 Overall CIMT regression  Significant CIMT progression Aggregate Change in CIMT for 0.05  Initial 12 months ERN + statin All Drug Periods (mm) ANOVA p<0.001  n = 125 0.025  Pooled ARBITER 2 and 3 −0.027 0.011 results −0.041 0.021 0  Net CIMT regression  −0.027 ± 0.011 mm  p<0.001 vs. -0.025 placebo  24 month ERN + statin effect -0.05  n = 57 Mean ± SEM  Continuous ERN treatment -0.075  CIMT regression Placebo First 12 mos. Total 24 mos.  −0.041 ± 0.021 mm Phase ERN (+ statin) ERN (+ Statin) Treatment Period (+ statin)  p<0.001 vs. placebo Slide Source Taylor AJ et al. Curr Med Res Opin 2006;22:22432250. Lipids Online Slide Library www.lipidsonline.org
  27. 27. MK-0524 (laropiprant) Suppresses Niacin-Induced Increases in Skin Blood Flow 1.4 9 Laser Doppler Perfusion Imaging 1.2 Laropiprant 30mg + ER niacin 1500 mg Placebo-Corrected LDPI 1 Laropiprant 100 mg + ER niacin 1500 mg Measurement (Volt) Laropiprant 300 mg + ER niacin 1500 mg 0.8 Aspirin 325 mg Pretreatment + ER niacin 1500 mg ER niacin 1500 mg 0.6 0.4 0.2 0 2 0 0 30 60 90 120 150 180 210 240 270 300 330 360 ER=extended-release Time (minute, post dose) Slide Source Lai E et al. Clin Pharmacol Ther 2007;81:849-857. Lipids Online Slide Library www.lipidsonline.org
  28. 28. Summary  LDL-C remains the primary goal of lipid-treatment but novel therapies that affect reverse cholesterol transport are on the horizon  Novel strategies to improve reverse cholesterol transport include infusions of synthetic HDL or phospholipids, nuclear receptor agonists to enhance LXR gene regulation, apo A1 peptides to enhance the anti-inflammatory aspects of HDL and DP-1 antagonists in combination with niacin to improve compliance  Even small increases in HDL-C may confer substantial benefit  Intervention to raise HDL-C levels should be considered in high-risk patients Slide Source Lipids Online Slide Library www.lipidsonline.org

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