the target is ldl, hdl not so much hdl: a riddle wrapped ......plump as, scott cj, breslow jl. pnas...
TRANSCRIPT
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