HDL: A riddle wrapped in a mystery inside an enigma

Jacques Genest MD

Cardiovascular Research Laboratories

McGill University Health Center

The Target is LDL, HDL not so much

Merck *

Pfizer

Novartis

AMGEN *

Roche *

AstraZeneca

Disclosure J. Genest MD 2013

Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS , CAPREE steering Committees; REVEAL , ACCELERATE, AMG145 Clinical Trials.

Advisory Board, Speaker’s Bureau, Consultant, Grants, Clinical Trials

Sanofi/Regeneron

Lilly

Valeant

Biotech:

Danone

Acasti

Nutrasource

Stock ownership: none;

Off label use: none

* Scientific Advisory

The Case for HDL

Epidemiology and Mendelian randomization

What does HDL actually do?

The Future

Figure 45-2

Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quantiles HDL-C

JAMA 2009;302:1993-2000

PTTH*-1

Association does NOT imply Causality

* Points To Take Home

Human Serum Lipoproteins

Blaha MJ et al., J Clin Lipidol 2008;2:267-273

Figure 3. Hazard Ratios for Coronary Heart Disease Across Fifths of Usual Lipids or

Apolipoproteins

JAMA 2009;302:1993-2000

Copyright restrictions may apply.

HDL and the CVD: Animal Models

Mouse apo AI transgenic

Rabbit apo AI transgenic

Genetically modified animals with increased apo AI production have less atherosclerosis… and less aortic stenosis (Fuster V 2010)

Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Plump AS, Scott CJ, Breslow JL. PNAS 1994;91:9607-1 Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. Pászty C, Maeda N, Verstuyft J, Rubin EM. J Clin Invest. 1994;94:899-903.

Voight BF et al. Lancet 2012;May 17 e-pub

Frikke-Schmidt R et al. Lancet 2008;299(21):2524-2532

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Q1 Q2 Q3 Q4

Placebo

Rosuvastatin 20mg

Inci

de

nce

Rat

e /

10

0 p

ers

on

ye

ars

Quartile of On-Treatment HDLC

Ridker PM et al. JUPITER 2010

HDL as a Predictor of Residual Risk in JUPITER

Clinical study DATA

Fibrates: FIELD; Accord

Niacin: AIM-HIGH; HPS2-THRIVE

Torcetrapib, Dalcetrapib

The rest is Surrogate End Points

FATS, HATS

Apo AIMilano, rHDL

12

Effects of Combination Lipid Therapy on Cardiovascular Events in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial

Henry C. Ginsberg, MD College of Physicians & Surgeons , Columbia University, New York For The ACCORD Study Group

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group Published at www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

Meta-Analysis of Fibrate trials

Jun M, Lancet 2010;375:1875

Comparison of ACCORD subgroup results with

those from prior fibrate studies

Trial

(Drug)

Primary Endpoint:

Entire Cohort

(P-value)

Lipid Subgroup

Criterion

Primary Endpoint:

Subgroup

HHS (Gemfibrozil)

-34% (0.02)

TG > 200 mg/dl

LDL-C/HDL-C > 5.0

-71%

BIP (Bezafibrate)

-7.3% (0.24)

TG > 200 mg/dl

-39.5%

FIELD (Fenofibrate)

-11% (0.16)

TG > 204 mg/dl

HDL-C < 42 mg/dl

-27%

ACCORD (Fenofibrate)

-8% (0.32)

TG > 204 mg/dl

HDL-C < 34 mg/dl

-31%

ACCORD Study www.nejm.org March 14, 2010 (10.1056/NEJMoa1001282)

AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events Age: >45 years, CAD + Dyslipidemia Simvastatin 40mg daily Randomized to: Niacin 2 g/day n=3,300 2005 – 2011 Sponsor: NHLBI

HDL Clinical trials: Niacin

AIM-HIGH: Niacin Plus Statin to Prevent Vascular Events Age: >45 years, CAD + Dyslipidemia Simvastatin 40mg daily Randomized to: Niacin 2 g/day n=3,300 2005 – 2011 Sponsor: NHLBI

HDL Clinical trials: Niacin

AIM-HIGH : Results 50

40

30

20

10

0 0 1 2 3 4

P=0.79 by log-rank best

Niacine plus statine

Placebo plus statine

Années

Po

urc

en

tage

cu

mu

lé d

e p

atie

nts

ave

c d

es

résu

ltat

s p

rim

aire

s

No. à risque

Placebo plus statine 1695 1581 1381 910 436

Niacin plus statine 1718 1606 1366 903 428

HPS-2 THRIVE: Major Findings

• ER niacin/laropiprant to simvastatin (or ezetimibe/simvastatin) did not reduce the risk of MI, strokes and revascularizations

• This result were consistent across study sites • ER niacin/laropiprant did cause side-effects. (skin

irritation, strokes and gastrointestinal bleeding; increase diabetes risk).

• Increased risk of myopathy (among patients in China). • There was no effect on cancer nor risk of death • These results are important because they tell us more

about Niacin. This is disappointing but still matters.

22

Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

Schawartz GG. N Engl J Med. 2012 Nov 5. [Epub ahead of print]

DALcetrapib Outcomes

PTTH-2

The epidemiological association between HDL-C and CVD is strong and coherent.

Animal data is unequivocal: HDL protect against atherosclerosis

Strong biological plausibility for HDL as a therapeutic target

PTTH-2

The epidemiological association between HDL-C and CVD is strong and coherent.

Animal data is unequivocal: HDL protect against atherosclerosis

Strong biological plausibility for HDL as a therapeutic target

Mendelian Randomization does not support HDL-Cholesterol as a causal risk factor

HDL-C looses its predictive value if LDL-C is low

The Clinical trial data is neutral

HDL Protects the Vascular System

HDL mediate reverse cholesterol transport

Potent antioxidant effects

Potent anti-inflammatory effects

Improves vascular endothelial function (●NO)

Promotes vascular endothelial progenitor cells

Anti-apoptosis

Anti-thrombotic effects

Anti trypasonomial activity (apo L1 and haptoglobin)

ABCA1 –Mediated Cellular Cholesterol Efflux

LxR/RxR

Campbell S, Genest J, 2012

HDL- Vascular endothelial Cell Interaction

HDL and Endothelial Progenitor Cells

Sorrentino SA et al. Circulation 2010;121;110-122

Points to Take Home -3

HDL particles are complex

Genes involved in HDL biogenesis may make better therapeutic targets than genes involved in HDL remodeling (Lipases, CETP)

New Gene, new pathways

Anacetrapib: Effects on LDL-C and HDL-C

HDL-C

Study Week

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

HD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

120

Anacetrapib

Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

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

LD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

Anacetrapib

Placebo

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)

Conclusions

Modulation of HDL function for the prevention and treatment of CVD shows great promise

Biomarkers of HDL function (and not solely HDL-C mass) are required in pre- and early clinical trials

Outcome-driven clinical trials are absolutely required

The Case for LDL

Clinical Data

Clinical Data

Clinical Data

Some science stuff

It’s the LDL, Stupid

• LDL-C <2.0

mmol/L in high-

risk patients

• No HDL-C

targets, yet

Pres. T. Anderson 2013 Guidelines

On Going Trials of “Statin Add-on”

Landmesser U. Eur Heart J 2013 Feb 26

Medications

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

Absolute effect of statin therapy on MAJOR VASCULAR EVENTS

0 1 2 3 4 5

0

5

10

1

5

20

LDL cholesterol, mmol/L

Fiv

e y

ea

r ri

sk o

f a

ma

jor

va

scu

lar

eve

nt,

%

Control

21% relative risk reduction per mmol/L Statin

15% relative risk reduction per 0.5 mmol/L More statin

Combined evidence:

~33% relative risk reduction

per 1.5 mmol/L

(0.79 x 0.85 = 0.67)

Less statin

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL cholesterol

0.4 0.6 0.8 1 1.2 1.4

No. of events (% pa) Statin/

More statin Contr ol/ Relative risk (CI)

Statin/more statin better

Control/less statin better

Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unspecified

Any coronary revascularisation

Ischaemic stroke

Haemorrhagic stroke

Unknown stroke

Any stroke

Any major vascular event

3485 (1.0)

1887 (0.5)

5105 (1.4)

1453 (0.4)

1767 (0.5)

2133 (0.6)

5353 (1.5)

1427 (0.4)

257 (0.1)

618 (0.2)

2302 (0.6)

10973 (3.2)

4593 (1.3)

2281 (0.6)

6512 (1.9)

1857 (0.5)

2283 (0.7)

2667 (0.8)

6807 (2.0)

1751 (0.5)

220 (0.1)

709 (0.2)

2680 (0.8)

13350 (4.0)

0.73 (0.69 - 0.78)

0.80 (0.74 - 0.87)

0.76 (0.73 - 0.78)

0.75 (0.69 - 0.82)

0.72 (0.65 - 0.80)

0.76 (0.70 - 0.82)

0.75 (0.72 - 0.78)

0.79 (0.72 - 0.87)

1.12 (0.88 - 1.43)

0.88 (0.76 - 1.01)

0.84 (0.79 - 0.89)

0.78 (0.76 - 0.80)

99% or 95% CI

Anacetrapib: Effects on LDL-C and HDL-C

HDL-C

Study Week

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

HD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

120

Anacetrapib

Placebo

Anacetrapib n = 776 757 718 687 647 607 572 543

Placebo n = 766 761 741 744 736 711 691 666

LDL-C

Study Week

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

LD

L-C

(m

g/d

L)

(SE

)

0

20

40

60

80

100

Anacetrapib

Placebo

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)

Medications

Statins

Ezetimibe

Fibrates

Niacin

BAR

CETP inh

MTP inh

ApoB iRNA

PCSK9 mAb

Effects of AMG 145 on LDL-C Over 12 Weeks

Q2

W D

osi

ng

*Data show mean observed values without imputation for missing data BL = baseline

Koren M, et al. Lancet. Epub 2012Nov 6

Q4

W D

osi

ng

Placebo Ezetimibe 280 mg AMG 145 350 mg AMG 145 420 mg AMG 145

Placebo Ezetimibe 70 mg AMG 145 105 mg AMG 145 140 mg AMG 145

-90

-70

-50

-30

-10

10

BL 2 4 6 8 10 12

Mean Percent Change From

Baseline in Calculated LDL-C*

Weeks

-90

-70

-50

-30

-10

10

BL 2 4 6 8 10 12

Mean Percent Change From

Baseline in Calculated LDL-C*

Weeks

Mean Percent Change from Baseline in Low-Density Lipoprotein (LDL) Cholesterol Levels, According to Treatment Group.

Roth EM et al. N Engl J Med 2012;367:1891-1900.

Conclusions

Novel therapeutic avenues targeted at LDL-C lowering.

Little data presently supporting HDL-C increase pharmacologically

On-going clinical trials of CETP inhibitors and PCSK9 inhibitors will alter the therapeutic landscape