Transcript HDL REVISITED: A RELIABLE DIAGNOSTIC TOOL OR JUST A

HDL CHOLESTEROL
REVISITED-- A RELIABLE
DIAGNOSTIC TOOL OR
JUST A PASSING FANCY?
GARY A. LOPEZ, M.D.
Disclosures
None
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
Coronary Heart Disease according to HDL-C
Levels: The Framingham Heart Study
CHD Risk Ratio
4.0
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, 1983;52:9B-12B
(22 studies;90,000 patients)
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
HDL Functionality and
Reverse Cholesterol Transport
CE
CETP
TG
PPAR
ACAT
ACAT
LCAT
Treatment: Non-pharmacologic
• Aerobic exercise
• Diet
• Weight loss
• Tobacco cessation
• Alcohol
ALL MODESTLY INCREASE HDL-C
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
CTT Meta
Analysis
70%
69% 76% 76% 84% 76% 76% 44%
Percent Residual Cardiovascular Risk
Low HDL-C is a Predictor of Coronary
Events in Statin-Treated Patients
Coronary Events (%)
Statin
35
30
25
20
15
10
5
0
4S
LIPID
Placebo
CARE
HPS
HDL-C (mg/dl)
mmol/L  1.35  0.99
mg/dl
52
38
 1.0  1.0
>39 <39
Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.
 1.26  0.75
44
33
 1.1 < 0.9
42 35
5-Year Risk of Major
Cardiovascular Disease
Events (%)
Low HDL-C Increases Cardiovascular Disease Risk Even If LDL-C
Levels Are Well-controlled:
The Treating to New Targets Study
10
Patients (n = 2661) with LDL-C <70 mg/dL on a Statin*†
8
+64%
6
4
2
0
HDL-C
quintiles*
(mg/dL)
Q1
Q2
Q3
Q4
Q5
<37
37 to <42
42 to <47
42 to <55
>55
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. 2007;357:1301-1310.
Coronary Lesion Change with HDLRaising Drug Treatment Using Niacin
Mean change, minimum lesion diameter
mm
BECAIT LOCAT
DAIS
CLAS
FATS
HATS
Coronary Drug Project
Survival (%)
Long-Term Mortality Benefit of Niacin in Post-MI
Patients (8341 men)
100
90
80
70
60
50
40
30
20
10
Niacin
Placebo
P = 0.0012
0
2
4 6 8 10 12 14 16
Years of follow-up
Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255
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 <40 and
50 mg/dL, respectively; TG 150–400; and LDL-C <180 mg/dL,
3–5-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
AIM-HIGH Trial: CHD Death, MI, Stroke,
High-Risk ACS Hospitalization
Boden WE et al, New Eng J Med, 2011; 365:2255-67
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 25%
• LDL averaged below 70 in both arms at 3 years
• 25% increase in HDL and 29% trig reduction in Niacin arm
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
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%
Jun M et al, Lancet ,2010; 375: 1875-84
Thiazolidinediones
• Insulin-sensitizers (Pioglitazone,Rosiglitazone)
• FDA-approved for treatment of diabetes
• Noted to modestly increase HDL levels (2.74.6 mg/dl)
• Rosiglitazone pulled out from market;
Pioglitazone has side effect issues
• With current data, generally not used
primarily for HDL modification
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 /
LDL-R
VLDL
C
E
SR-B1
Liver
FC
CETP
CE
LCAT
Bile
FC
X inhibition
HDL
Free Cholesterol (FC)
in Extrahepatic tissues
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
ILLUMINATE Trial
HR 1.25
P=0.001
HR 1.54
P=0.006
5.0
%
1.2
(Primary endpoint)
NEJM 2007; 357:2109-22
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.
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
DEFINE Trial
Cardiovascular Death, MI, Unstable Angina or Stroke
(after 24 weeks / 1623 patients)
%
Cannon CP, et al. N Engl J Med 2010;363:2406-2415
Effects on LDL-C and HDL-C
100
LDL-C
120
100
HDL-C (mg/dL) (SE)
LDL-C (mg/dL) (SE)
80
-39.8% (p<0.001)
60
40
20
0
HDL-C
Anacetrapib
Placebo
BaselineWk 6Wk 12Wk 18Wk 24Wk 30
80
60
40
20
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
+138.1% (p<0.001)
0
Anacetrapib
Placebo
BaselineWk 6Wk 12Wk 18Wk 24Wk 30
Wk 46
Wk 62
Wk 76
Anacetrapib n = 776 757 718 687 647
607
572
543
Placebo n = 766 761 741 744 736
711
691
666
Study Week
•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
Lipid-Modulating Effects of
Evacetrapib, a Novel CETP Inhibitor,
Administered as Monotherapy or
in Combination with the MostCommonly 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
Percent Change HDL-C: Evacetrapib 100 mg
Combined with Statin Therapy
P<0.001
P,0.001
P<0.001
94
86.6
79.9
%
7.3
5.5
1.4
Evacetrapib: Conclusions
• Evacetrapib monotherapy produced a dosedependent 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
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
Other Therapeutic Modalities
rHDL Infusions
A1 Milano Infusions
A1 Peptide Mimetics
A1 Up-regulators
ACAT Inhibitors
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
Large HDL particle size has the most
favourable CHD risk profile
Arsenault BJ et al, Epic-Norfolk Prospective Population Study, Atherosclerosis, Sept,2009
Dysfunctional HDL
• HDL transformed into a pro-inflammatory
and pro-oxidative state
• Inflammation plays a central role in
creating dysfunctional HDL and disrupting
RCT
Cholesterol within
Macrophage Foam Cells
Is Cholesterol Efflux
Capacity
More Reliable Instead
of
HDL Quantity?
p=0.002
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
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
Main Issues
1. 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
Thank You