HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC TOOL OR JUST A PASSING FANCY?

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HDL CHOLESTEROL REVISITED-- A RELIABLE DIAGNOSTIC
TOOL OR JUST A PASSING FANCY?

• GARY A. LOPEZ, M.D.

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Disclosures

• None

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Atherosclerotic Heart Disease

• Continues to be the foremost cause of mortality
  in the Western world and is rapidly becoming so
  in the developing nations
• Low-density lipoprotein (LDL) reduction using
  statins have been established to reduce the
  number of recurrent cardiovascular events and has
  been the main contributor of CHD reduction
• Residual events still occur despite statin
  treatment

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Coronary Heart Disease according to HDL-C Levels
The Framingham Heart Study
4.0
CHD Risk Ratio
2.0
1.0

• For every 1 mg/dl decrease in HDL, there is a
  corresponding 2 increased risk
• of CHD in men and 3 for women (overall average
  2.5)

Kannel WB, Am J Cardiol, 1983529B-12B
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(22 studies90,000 patients)
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Properties of HDL

• Function
• Reverse cholesterol transport
• (RCT)
• LDL antioxidation
• Endothelial protection
• Antiplatelet activity
• Anticoagulation

• Mechanism
• Cholesterol efflux through ABCA1, ABCG1, ABCG4
• Activation of LCAT
• Inhibition of adhesion molecule expression,
  prevention of monocyte chemotaxis, nitric oxide
  synthase stimulation
• Protection against endothelial injury
• Inhibition of factors Va and VIIa

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HDL Functionality and Reverse Cholesterol
Transport
CE
CETP
TG
PPAR
ACAT
ACAT
LCAT
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Treatment Non-pharmacologic

• Aerobic exercise
• Diet
• Weight loss
• Tobacco cessation
• Alcohol
• ALL MODESTLY INCREASE HDL-C

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Statins

• LDL-C reduction causing decrease in
  atherosclerosis progression and cardiovascular
  events
• Increases HDL-C levels by 5-15 (ave. 9)
• HDL-C effects relatively smaller compared to
  LDL-C
• Promotes formation of more favorable HDL
  subfraction profile by creating more
  cholesterol-rich HDL particles thru reduction of
  cholesterol transfer from HDL

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CTT Meta Analysis
70 69 76 76 84 76 76
44 Percent Residual Cardiovascular Risk
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Low HDL-C is a Predictor of Coronary Events in
Statin-Treated Patients
Statin
Placebo
4S
LIPID
CARE
HPS
35
30
25
20
Coronary Events ()
15
10
5
0
HDL-C (mg/dl)
mmol/L mg/dl
? 1.1 42
lt 0.9 35
? 1.35 52
? 0.99 38
? 1.0 gt39
? 1.0 lt39
? 1.26 44
? 0.75 33
Adapted from Ballantyne CM et al. Circulation
199999736-743.
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Low HDL-C Increases Cardiovascular Disease Risk
Even If LDL-C Levels Are Well-controlled The
Treating to New Targets Study
Patients (n 2661) with LDL-C lt70 mg/dL on a
Statin
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5-Year Risk of Major Cardiovascular Disease
Events ()
HDL-C quintiles (mg/dL)
37 to lt42
42 to lt47
42 to lt55
gt55
lt37
0.85
0.57
0.55
0.61
Hazard Ratio vs. Q1
On-treatment level (3 months statin
therapy) Mean low-density lipoprotein
cholesterol (LDL-C) level 58 mg/dL mean
triglyceride (TG) level 126 mg/dL P.03 for
differences among quintiles of HDL-C
Barter P, et al. N Engl J Med. 20073571301-1310.
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Coronary Lesion Change with HDL-Raising Drug
Treatment Using Niacin
Mean change, minimum lesion diameter
mm
BECAIT
LOCAT
DAIS
CLAS
FATS
HATS
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Coronary Drug Project Long-Term Mortality
Benefit of Niacin in Post-MI Patients (8341 men)
100
90
80
70
Niacin
60
Survival ()
50
Placebo
40
30
P 0.0012
20
10
16
14
10
12
0
4
6
8
2
Years of follow-up
Canner PL et al. J Am Coll Cardiol
1986812451255
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Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/High Triglycerides Impact
on Global Health Outcomes (AIM-HIGH Trial)

• Patients 3,414 M/F with vascular disease and
  HDL-C lt40 and 50 mg/dL, respectively TG 150400
  and LDL-C lt180 mg/dL, 35-year follow-up
• Centers 91 centers (36 patients per center) in
  US and Canada (20)
• Therapy Simvastatin vs. Simvastatin
  Extended-release niacin (1500-2000mg)
• Primary Endpoint Coronary heart disease death,
  myocardial infarction, stroke, or high-risk acute
  coronary syndrome hospitalization

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AIM-HIGH Trial CHD Death, MI, Stroke, High-Risk
ACS Hospitalization
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Boden WE et al, New Eng J Med, 2011 3652255-67
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Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/High Triglycerides Impact
on Global Health Outcomes (AIM-HIGH Trial)

• Trial stopped 18 mos. early 5/25/11 by Data
  Monitoring Board
• Niacin failed to reduce CV events in 36 mos.
• Ischemic strokes higher in Niacin arm (1.6 vs.
  0.7)
• Primary endpoint around 16 CV events reduction
  in both arms less frequent than the expected
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• LDL averaged below 70 in both arms at 3 years
• 25 increase in HDL and 29 trig reduction in
  Niacin arm

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Issues Regarding AIM-HIGH

• Placebo group received 50 mg Niacin and had
  modest 10 increase in HDL-C
• High-risk patients such as those recently
  hospitalized for ACS were excluded
• Few women (15) and minorities (8) enrolled

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Fibric acid derivatives (Fibrates)

• Increases HDL-C levels by 10-15 by PPAR-a
  activation, causing up-regulation of ABCA1 and
  hepatic HDL synthesis
• Main effect is to lower triglycerides by 25-45
  and lower LDL-C by 10-20

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Jun M et al, Lancet ,2010 375 1875-84
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Thiazolidinediones

• Insulin-sensitizers (Pioglitazone,Rosiglitazone)
• FDA-approved for treatment of diabetes
• Noted to modestly increase HDL levels (2.7-4.6
  mg/dl)
• Rosiglitazone pulled out from market
  Pioglitazone has side effect issues
• With current data, generally not used primarily
  for HDL modification

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Background CETP inhibition
Cholesteryl ester transfer protein (CETP) is a
plasma protein that catalyzes the transfer of CE
from HDL to apoB-containing lipoproteins (VLDL
and LDL-C) in exchange for Trig.
LDL / VLDL
LDL-R
CE
SR-B1
Liver
CETP
FC
CE
HDL
LCAT
Free Cholesterol (FC) in Extrahepatic tissues
Bile
FC
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The Investigation of Lipid Level Management to
Understand Its Impact in Atherosclerotic Events
(ILLUMINATE Trial)

• 15,067 patients with history of CV disease or
  Type 2 DM receiving atorvastatin
• Randomly assigned to torcetrapib or placebo
• Over 1 year, Torcetrapib group had
• - 72.1 increase in HDL-C
• - 24.9 decrease in LDL-C
• - 9 decrease in triglycerides

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ILLUMINATE Trial
HR 1.25 P0.001
HR 1.54 P0.006
5.0

1.2
(Primary endpoint)
NEJM 2007 3572109-22
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Dalcetrapib dal-OUTCOMES Trial
Primary Endpoint Time to first occurrence Of CHD
death, nonfatal AMI, unstable angina requiring
hospitalization,resuscitated cardiac arrest or
atherosclerotic stroke

• May 7,2012 Trial stopped despite no safety
  signals due to a lack in
• clinically meaningful efficacy in the results.

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Safety of Anacetrapib in Patients with or at Risk
for Coronary Heart Disease

• Christopher P. Cannon, MD, Sukrut Shah, PhD, RPh,
  Hayes M. Dansky, MD, Michael Davidson, MD, Eliot
  A. Brinton, MD, Antonio M. Gotto, Jr., MD, DPhil,
  Michael Stepanavage, MS, Sherry Xueyu Liu, MS,
  Patrice Gibbons, MS, Tanya B. Ashraf, BA,
  Jennifer Zafarino, MS, Yale Mitchel, MD, Philip
  Barter, MD, PhD, for the DEFINE Investigators

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DEFINE TrialCardiovascular Death, MI, Unstable
Angina or Stroke(after 24 weeks / 1623
patients)

Cannon CP, et al. N Engl J Med 20103632406-2415
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Effects on LDL-C and HDL-C
LDL-C
-39.8 (plt0.001)
138.1 (plt0.001)
LDL-C (mg/dL) (SE)
Baseline
Wk 6
Wk 12
Wk 18
Wk 24
Wk 30
Wk 46
Wk 62
Wk 76
Anacetrapib n
804
771
716
687
646
604
568
540
Placebo n
803
759
741
743
735
711
691
666
Study Week
35

• 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
• Scheduled follow-up in 4 years
• Primary outcome coronary death, myocardial
  infarction or coronary revascularization

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Lipid-Modulating Effects of Evacetrapib, a Novel
CETP Inhibitor, Administered as Monotherapy or in
Combination with the Most-Commonly Used Statins

• SJ Nicholls, HB Brewer, JJP Kastelein,KA Krueger,
  MD Wang, K Wolski , E McErlean, SE Nissen
• 
  Presented at AHA Scientific Sessions,
  Orlando, Nov, 2011

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Percent Change HDL-C Evacetrapib 100 mg Combined
with Statin Therapy
Plt0.001
P,0.001
Plt0.001
86.6
94
79.9

7.3
5.5
1.4
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Evacetrapib Conclusions

• Evacetrapib monotherapy produced a dose-dependent
  increase in HDL-C up to 128.8 and decrease in
  LDL-C up to 35.9
• Evacetrapib was well-tolerated with no adverse
  blood pressure or mineralocorticoid effects
• The impact of evacetrapib on cardiovascular
  events remains to be determined

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Summary of CETP Inhibition Trials

• The state of CETP inhibition remains strong with
  ongoing studies testing the hypothesis that
  raising HDL through CETP inhibition will be
  beneficial for RCT and modulation of
  cardiovascular disease

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Other Therapeutic Modalities
rHDL Infusions A1 Milano Infusions A1 Peptide
Mimetics A1 Up-regulators
ACAT Inhibitors
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Association of an HDL-C Genetic Variant (LIPG
Ans396Ser) With Myocardial Infarction in 116,320
Participants From 20 Studies (PROCARDIS
Consortium)
Voight BF et al, Lancet,17 May, 2012
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Large HDL particle size has the most favourable
CHD risk profile
Arsenault BJ et al, Epic-Norfolk Prospective
Population Study, Atherosclerosis, Sept,2009
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Dysfunctional HDL

• HDL transformed into a pro-inflammatory and
  pro-oxidative state
• Inflammation plays a central role in creating
  dysfunctional HDL and disrupting RCT

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Cholesterol within Macrophage Foam Cells
Is Cholesterol Efflux Capacity More Reliable
Instead of HDL Quantity?
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p0.002
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Conclusion

• There is overwhelming evidence that high levels
  of HDL-C is associated with lower risk of
  coronary HD
• HDL-C has evolved as one of the risk factor to
  predict risk of incident Coronary HD
• Lifestyle interventions are safe but only
  modestly increase HDL-C
• Best treatment currently are the niacin
  derivatives particularly for atherogenic
  dyslipidemia and metabolic syndrome with high
  cardiometabolic risk

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Conclusion (2)

• Newer agents such as CETP inhibitors hold much
  promise.
• Other possible points to target include
• -efflux or cycling of HDL instead of HDL
  level
• -raising specific HDL subclasses instead of
  HDL itself

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Main Issues

• Could we accept HDL as a significant risk
• factor in the progression of
  Atherosclerotic
• Vascular Disease?
• YES
• 2. Is HDL a reliable therapeutic target in
  Atherosclerotic Vascular Disease?
• NO
• 3. Can we completely disregard HDL in monitoring
  lipids and simply label it as a passing fancy?
• NO

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Thank You