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

CH

D R

isk

Rat

io

Kannel WB, Am J Cardiol, 1983;52:9B-12B

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%)

(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

CETP

PPAR

ACATACAT

LCAT

HDL Functionality and Reverse Cholesterol Transport

HDL Functionality and Reverse Cholesterol Transport

CE

TG

Treatment: Non-pharmacologic

• Aerobic exercise• Diet• Weight loss• Tobacco cessation• AlcoholALL 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

70% 69% 76% 76% 84% 76% 76% 44%Percent Residual Cardiovascular Risk

CTT Meta Analysis

CTT Meta Analysis

Low HDL-C is a Predictor of Coronary Low HDL-C is a Predictor of Coronary Events in Statin-Treated PatientsEvents in Statin-Treated Patients

Adapted from Ballantyne CM et al. Circulation 1999;99:736-743Adapted from Ballantyne CM et al. Circulation 1999;99:736-743 ..

Co

ron

ary

Ev

ents

(%

)C

oro

na

ry E

ven

ts (

%)

1.11.14242

< 0.9< 0.93535

1.351.355252

0.990.993838

1.01.0>39>39

1.01.0<39<39

1.261.264444

0.750.753333

mmol/Lmmol/Lmg/dlmg/dl

05

10152025

3035

4S LIPID CARE HPS

HDL-C (mg/dl)

Statin Placebo

Low HDL-C Increases Cardiovascular Disease Risk Even If LDL-C Levels Are Well-controlled:

The Treating to New Targets Study

0

2

4

6

8

10

Q1 Q2 Q3 Q4 Q5

5-Year Risk of Major

Cardiovascular

Disease Events (%)

HDL-C quintiles*(mg/dL)

*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

Patients (n = 2661) with LDL-C <70 mg/dL on a Statin*†

37 to <42 42 to <47 42 to <55 >55<37

0.85 0.57 0.55 0.61Hazard Ratio vs. Q1‡

Barter P, et al. N Engl J Med. 2007;357:1301-1310.

+64%

Coronary Lesion Change with HDL-Raising Drug Treatment Using Niacin

mm

Mean change, minimum lesion diameter

BECAIT LOCAT DAIS CLAS FATS

HATS

Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI

Patients (8341 men)

Niacin

Placebo

P = 0.0012

100908070605040302010

0 2 4 6 8 10 12 14 16

Years of follow-up

Survival (%)

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; 365:2255-67Boden 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- 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 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 (2.7-

4.6 mg/dl)• Rosiglitazone pulled out from market;

Pioglitazone has side effect issues• With current data, generally not used

primarily for HDL modification

Background: CETP inhibition

HDLHDL

LDL / LDL / VLDLVLDL

LiverLiver

BileBile

CECE

LDL-RLDL-R

FCFC

FCFC

LCATLCAT

CETPCETP

CCEESR-B1SR-B1

X X inhibitioninhibition

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.

Free Cholesterol (FC) Free Cholesterol (FC) in Extrahepatic tissuesin 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

5.0

1.2

HR 1.25P=0.001

HR 1.54P=0.006

%

NEJM 2007; 357:2109-22(Primary endpoint)

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

Primary Endpoint: Time to first occurrenceOf CHD death, nonfatal AMI, unstable angina requiring hospitalization,resuscitated cardiac arrest or atherosclerotic stroke

Dalcetrapib : dal-OUTCOMES TrialDalcetrapib : dal-OUTCOMES Trial

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 TrialCardiovascular 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

HDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(m

g/d

L) (

SE

)

0

20

40

60

80

100

120

AnacetrapibPlacebo

Anacetrapib n =Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n =Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (

mg/

dL)

(SE

)

0

20

40

60

80

100

AnacetrapibPlacebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

•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 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

Percent Change HDL-C: Evacetrapib 100 mg Combined with Statin Therapy

P<0.001 P,0.001 P<0.001

7.3

86.6

1.4

79.9

5.5

94

%

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

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

ACAT InhibitorsACAT Inhibitors

rHDL InfusionsA1 Milano InfusionsA1 Peptide Mimetics

A1 Up-regulators

rHDL InfusionsA1 Milano InfusionsA1 Peptide Mimetics

A1 Up-regulators

Other Therapeutic Modalities

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

Arsenault BJ et al, Epic-Norfolk Prospective Population Study, Atherosclerosis, Sept,2009Arsenault BJ et al, Epic-Norfolk Prospective Population Study, Atherosclerosis, Sept,2009

Large HDL particle size has the most favourable CHD risk profile

Dysfunctional HDL

• HDL transformed into a pro-inflammatory and pro-oxidative state

• Inflammation plays a central role in creating dysfunctional HDL and disrupting RCT

Is Cholesterol Efflux Capacity

More Reliable Instead of

HDL Quantity?

Cholesterol withinMacrophage Foam Cells

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 Issues1. Could we accept HDL as a significant risk factor in the progression of Atherosclerotic Vascular Disease? YES2. Is HDL a reliable therapeutic target in

Atherosclerotic Vascular Disease? NO3. Can we completely disregard HDL in monitoring

lipids and simply label it as a passing fancy? NO

Thank YouThank You