raising hdl with drugs - does it work?

Source: International Chair on Cardiometabolic Riskwww.cardiometabolic-risk.org

Ronald M. Krauss, MDChildren’s Hospital Oakland

Research Institute

UC Berkeley and UCSF

Raising HDL With Drugs – Does it Work?


Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictors*

Adapted from Castelli WP Can J Cardiol 1988;4(SupplA):5A-10A

Rel

ativ

e ri

sk o

f C

HD

aft

er 4

yea

rs

LDL cholesterol (mg/dl)

8565

4525

HDL

cholesterol

(mg/dl)

*Data represent men aged 50 – 70 from the Framingham Heart Study


Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol

Adapted from HPS Collaborative Group Lancet 2002; 360: 7-22and Sacks FM et al. Circulation 2000; 102: 1893-900

CV

D e

ven

t ra

te (

%)

CARE: Cholesterol And Recurrent EventsHPS: Heart Protection StudyLIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease

High HDL cholesterol + statin

Low HDL cholesterol + statin


On-Treatment HDL Cholesterol and LDL Cholesterol vs. Cardiovascular Events: Treating to New Targets (TNT) Study

%

Mean LDL cholesterol 73 mg/dl (1.89 mmol/l)

Mean LDL cholesterol 99 mg/dl (2.56 mmol/l)

Adapted from Barter P et al. J Am Coll Cardiol 2006; 47: 298A (abstract 914-203)

On treatmentHDL cholesterol

(mg/dl)

<40>40-50>50-60>60


Pleiotropic Anti-Atherogenic Properties of HDL

Cholesterol efflux and reverse cholesterol transport

Anti-oxidant and anti-inflammatory effects Anti-apoptotic properties Vasodilation (increased eNOS activity) HDL proteomics: anti-thrombotic,

complement activation

eNOS: endothelial nitric oxide synthase


Role of HDL in Reverse Cholesterol Transport

Adapted from Tall AR et al. J Clin Invest 2001; 108: 1273-5

PL FC

LCATCE

CETP

PLTP

FC

Apolipoprotein AI

LDL receptor

ABCA1: ATP-binding cassette transporter A1

CE: cholesteryl ester

CETP: cholesteryl ester transfer protein

FC: free cholesterol

LCAT: lecithin-cholesterol acyltransferase

PC: phosphatidylcholine

PL: phospholipids

PLTP: phospholipid transfer protein

SR-B1: scavenger receptor B1

PL, FC

CE

PL

CE, FC

FC, PC

FC, CE

Cholesterol synthesis

Other peripheral cellsMacrophage

Liver

HDL

VLDL/LDL

HDL

FC

CE


Apolipoprotein AI


ABCG1: ATP-binding cassette transporter G1




LXR/RXR: liver X receptor / retinoid X receptor

FC

FCCE FC

CE

Role of ABCA1 and ABCG1 in Macrophage Cholesterol Efflux

Mature HDL Nascent HDL

Modified lipoproteins

Scavenger receptors

LXR/RXR

Oxysterols

LCAT

LCAT

Macrophage


HDL Therapy

Adapted from Linsel-Nitschke P and Tall AR. Nat Rev Drug Discov 2005; 4: 193-205Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery, Copyright © 2005

ABCA1: ATP-binding cassette transporter A



Apo AI: apolipoprotein AI


LUVs: large unilamellar phopholipid vesicles

LXR: liver X receptor

PPAR-: peroxisome proliferator activated

receptor-

RXR: retinoid X receptor

RAR: retinoid acid receptor-


CETP

Apo AI synthesis increased by fibrates

Infusion of apo AI

Cholesterol phospholipids

Cholesterol

Upregulation of ABCA1 by LXR-agonists, apo AI, RAR/RXR

Upregulation of ABCG1/ABCG4 by LXR-agonists, PPAR- agonists

Infusion of apo AI/ phospholipid complexes, LUVs

Niacin decreases HDL catabolism by unknown mechanism

CETP inhibitors

Bile

Apo AI synthesis

Apo AI

preβHDL HDL3

HDL2

VLDLLDL

Macrophage Macrophage

Liver


Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome

High triglyceride (TG) levels– TG-rich remnant lipoproteins (VLDL)

Commonly, absolute levels of LDL cholesterol are not significantly increased, number of LDL particles– Predominantly small, dense LDL particles

Low levels of HDL cholesterol

Adapted from Haffner SM Diabetes Care 2003; 26: S83-6 and Garvey WT et al. Diabetes 2003; 52: 453-62


Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL, Small LDL and Reduction of HDL

SmallerLDL

HL

Apo AI

Renalclearance

LPL

RemnantsLPL/HL

VLDL

TG TG CETP

Cholesterol

HDL

TGTGLDL

Apo AI: apolipoprotein AICETP: cholesteryl ester transfer proteinHL: hepatic lipaseLPL: lipoprotein lipaseTG: triglycerides

TGTG SmallerHDL


Relation of HDL Cholesterol to Aortic Atherosclerosis in Apo E-Deficient Mice Transgenic for Human Apo AI (Model for Increased Apo AI Transport)

Adapted from Plump AS et al. Proc Natl Acad Sci USA 1994; 27: 9607-11 Copyright © 1994 National Academy of Sciences, U.S.A.

0

250000

500000

750000

50 100 1500

Me

an

les

ion

are

a (

µm

2)

HDL cholesterol (mg/dl)

r=0.88, p<0.0001

Apo AI expression

None

Low

High

Apo: apolipoprotein


Statin ± cholesterol absorption inhibitor

Niacin

Fibrate

Thiazolidinedione (type 2 diabetes)

Combination therapy (statin + niacin/fibrate)

Current Options for Pharmacologic Management of Patients With Low HDL Cholesterol


Niacin Extended-Release + Statins: Extended-Release Lovastatin/Niacin

Adapted from Hunninghake DB et al. Clin Cardiol 2003; 26: 112-8

LDL cholesterol HDL cholesterol Triglycerides

Lovastatin/niacin 40 mg/2,000 mg, week 28

Lovastatin 40 mg, week 28C

ha

ng

e f

rom

ba

selin

e (

%)

* *

*

*p<0.05 vs. lovastatin 40 mg


SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia

Reprinted from The American Journal of Cardiology, Vol 95, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 462-8, Copyright © 2005, with permission from Elsevier

**

*

*Simvastatin 20 mg

Simvastatin 20 mg + Fenofibrate 160 mg

n=618*p<0.001 vs. simvastatin


Gemfibrozil, Niacin, and Cholestyramine in Men With Low HDL Cholesterol and Coronary Heart Disease

Triglycerides

Adapted from Whitney EJ et al. Ann Intern Med 2005; 142: 95-104

Drug treatment + lifestyle modification

Lifestyle modification only

*

*

*

LDL cholesterol HDL cholesterol

*p<0.001 vs. lifestyle only


Cardiovascular Disease Outcomes in Trials of HDL-

Raising Drug Therapies


Niacin Therapy: Angiographic and Outcomes Trials

TG: triglycerides

No. of subjects Lipid changes (treatment group)

TrialTreatment

(mean dose)Treatmen

tPlacebo

Total cholesterol

TGLDL

cholesterolHDL

cholesterolFindings

Stockholm Ischaemic Heart Disease Secondary Prevention Study

Niacin (4.5 g/d) + clofibrate

(1.5 g/d)

279 276 -13% -19% --- --- 36% ischemic heart disease mort. (p<0.01) 26% total mortality

(p<0.05)

Coronary Drug Project

Niacin (3 g/d) 1119 2789 -10% -26% --- --- 27% nonfatal myocardial infarction 11% total mortality

(p=0.0004)

Cholesterol Lowering Atherosclerosis Study

Niacin (4.3 g/d) + colestipol

(30 g/d)

80 82 -26% -21% -43% +37% angiographic regression

no difference in clinical events

Familial Atherosclerosis Treatment Study

Niacin (4 g/d) + colestipol

(30 g/d)


80% clinical events(p<0.01)

HDL-Atherosclerosis Treatment Study

Niacin (2.4 g/d) + simvastatin

(13 mg/d)


60% clinical events(p=0.02)


Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastatin + Niacin vs. Placebo

Adapted from Brown BG et al. N Engl J Med 2001; 345: 1583-92

Placebo

Mea

n c

han

ge

in s

ten

osi

s (%

)

*p<0.001 vs. placebo‡p=0.04 vs. placebo

Coronary death, myocardial infarction, stroke or

revascularization

Simvastatin + Niacin

Co

mp

osite even

t rate (%)

3.923.7

-0.4

2.6*‡

89% reduction

-0.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Nine proximal lesions

25

20

15

10

5

0


ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d Primary Endpoint – Carotid Intima-Media Thickness (CIMT) Change

Statin + Placebo(n=71)

Statin + Extended release niacin

(n=78)

Bas

elin

e C

IMT

(m

m)

Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7

Ch

ang

e in

CIM

T (

mm

)Statin + Extended

release niacin(n=78)

p=0.23*

Statin + Placebo(n=71)

p<0.001*

*Within-group comparisons

Baseline CIMT after 1 year


AIM-HIGH: Study Overview

Vascular diseaseAge >45 years

Atherogenic dyslipidemia (HDL<40♂ or 50♀ mg/dl; TG>149 mg/dl; LDL<160 mg/dl)

Simvastatin

Simvastatin + Niaspan

3-5 years

3,300 patients from 60 sites (U.S. and Canada)

Cardiovascular death Nonfatal myocardial infarction Stroke Acute coronary syndrome

LDL cholesterol target <80 mg/dl both groups (may add ezetimibe if needed)

Hypothesis

- 30% event rate with simvastatin- 23% event rate with simvastatin + niacin- 50% relative reduction based on ~46% placebo rate

2-year enrollment

TG: Triglycerides


VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids

Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-8

LDL cholesterol TG

HDL cholesterolPrimary endpoint occurrence*†

Ch

ang

e fr

om

bas

elin

e (%

)

%

Placebo Gemfibrozil

TG: Triglycerides

*Nonfatal myocardial infarction or death from coronary causes†22% relative risk reduction (95% CI: 7%–35%, p=0.006)


VA-HIT: LDL and HDL Particle Subclasses

Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63

IDL: intermediate-density lipoproteinB: baseline

IDL Large HDL Large LDL Medium HDL Small LDL Small HDL

Placebo Fibrate

5% reduction

13641463

1352 1290*

LD

L p

arti

cle

nu

mb

er (

nm

ol/l

)

B 7 months B 7 months

20

% d

ec

rea

se

36

% i

nc

rea

se

*

*

HD

L p

arti

cle

nu

mb

er (m

ol/l

) 25.2 25.126.6 27.6*

Placebo Fibrate

B 7 months B 7 months

21

% i

nc

rea

se

*

*

10% increase

*p≤0.0005 vs. placebo at 7 months


Rel

ativ

e o

dd

s ra

tio

†

LDL particle number

HDL particle number

VA-HIT: LDL and HDL Particle Numbers in Prediction of New Coronary Heart Disease Events

Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63

**

**

†Calculated for a 1-SD increment of each lipoprotein particle in separate logistic regression models adjusted for treatment group, age, hypertension, smoking, body mass index, and diabetes

*p<0.01

Baseline

7 Months


FIELD: End of Study Lipid Results

Adapted from Keech A et al. Lancet 2005; 366: 1849-61

Placebo (P)Fenofibrate (F)

113

LDLcholesterol

HDLcholesterol

Triglycerides

Baseline (mg/dl)

117 43 43 164 167

119

LDLcholesterol

HDLcholesterol

Triglycerides

Baseline (mg/dl)

119 43 43 171 173

128

LDLcholesterol

HDLcholesterol

Baseline (mg/dl)

125 42 40 184 197

Triglycerides

Did not start other lipid-lowering therapyn= 3,124 (P) 3,951 (F)

Total population

Started other lipid-lowering therapyn= 1,776 (P) 944 (F)


Ch

ang

e fr

om

bas

elin

e at

24

wee

ks (

mg

/dl)

Lipid Effects of Pioglitazone and Rosiglitazone

Adapted from Goldberg RB et al. Diabetes Care 2005; 28: 1547-54

†

†

†‡

-12

15

4

1916

23

15 8

Triglycerides HDL cholesterol

Non-HDL cholesterol

LDL cholesterol

Pioglitazone

Rosiglitazone

†Between-group comparison for change from baseline: p<0.001 (mg/dl, %)‡Between-group comparison for change from baseline: p<0.001 (mg/dl), p=0.002 (%) Values in bars = percent change from baseline at 24-week endpoint


Age-Adjusted 6-Year Coronary Heart Disease (CHD) Rates for Elderly Japanese American Men With and Without CETP Mutations

Adapted from Curb JD et al. J Lipid Res 2004; 45: 948-53 Reproduced with permission


CH

D i

nci

den

ce (

rate

/1,0

00 p

erso

n-y

ears

)

HDL cholesterol <60 mg/dl

HDL cholesterol 60 mg/dl

171/1,713*

31/509†

5/76

2/42

*Number of CHD events/men at risk†Significantly lower risk compared to men with HDL cholesterol <60 mg/dl (1.55 mmol/l) and without a CETP mutation (p<0.05)

CETP mutationAbsentPresent


Raising HDL Cholesterol With CETP Inhibition

LCAT

CETG

CETP

Apo B

Apolipoprotein AI


Apo B: apolipoprotein B





LDLR: low-density lipoprotein receptor


TG: triglycerides

CE

FC

CEFC

Bile Macrophage

Liver

CE FC

Mature HDL

Nascent HDL

FC

VLDL/LDL


Torcetrapib Slows Apolipoprotein AI Turnover Rate

Adapted from Brousseau ME et al. Arterioscler Thromb Vasc Biol 2005; 25: 1057-64

Atorvastatin+Torcetrapib

Torcetrapib 120 mg bid

Torcetrapib 120 mg qd

% c

han

ge

vs

. pla

ceb

o

*

(n=19)*p<0.01 vs. placebo


446 atorvastatin patients 464 torcetrapib patients

24-month follow-up intravascular ultrasound of originally imaged “target” vessel (n=910)

4 to 10-week run-in atorvastatin 10-80 mgto achieve LDL cholesterol of 100±15 mg/dl

Intravascular ultrasound with 40 MHz transducerMotorized pullback at 0.5 mm/sec through >40 mm segment

1,188 patients from 137 centres in North America and Europe Symptomatic coronary artery disease, coronary angiography with >20% stenosis

Atorvastatinmonotherapy

Torcetrapib 60 mg+atorvastatin

24-monthtreatment

135 patients withdrew140 patients withdrew

ILLUSTRATE

Adapted from Nissen SE et al. N Engl J Med 2007; 356: 1304-16


Time Course: Change in HDL Cholesterol Levels

Adapted from Barter et al. New Engl J Med 2007; 357, 2109-22

20

30

40

50

60

70

80

90

0 1 3 6 9 12 15 18 21 24Time (months)

HD

L c

ho

lest

ero

l le

vel

(m

g/d

l)

Difference 60.8%

Atorvastatin monotherapy

Torcetrapib+Atorvastatin


ILLUSTRATE: Primary Efficacy ParameterChange in Percent Atheroma Volume


†p value from ANCOVA*LS mean change

p=0.72†


ILLUSTRATE: Secondary Intravascular Ultrasound Efficacy Parameters


p=0.023† p=0.12†

Change in normalizedatheroma volume (mm3)*

Change in 10 mm mostdiseased segment (mm3)*

†p value from ANCOVA*LS mean change

Atorvastatin+Torcetrapib


Blood Pressure Related Adverse Events

Blood pressure>140/90 mmHg

Systolic blood pressureincrease >15 mmHg

Atorvastatin


+Torcetrapib


ILLUSTRATE Adverse Events: Safety Population

Atorvastatinmonotherapy

(n=597)

Torcetrapib +Atorvastatin

(n=591)

Death 6 (1.0%) 8 (1.4%)

Coronary heart disease (CHD) death 1 (0.2%) 1 (0.2%)

Nonfatal myocardial infarction (MI) 16 (2.7 %) 13 (2.2%)

Fatal or nonfatal stroke 8 (1.3%) 2 (0.3%)

Hospitalization for unstable angina 34 (5.7%) 47 (8.0%)

Coronary revascularization 95 (15.9%) 114 (19.3%)

Peripheral vascular disease 13 (2.2%) 10 (1.7%)

Hospitalization for congestive heart failure 4 (0.7%) 9 (1.5%)

Composite: CHD death, MI, stroke, and unstable angina

57 (9.5%) 62 (10.5%)

Composite: CHD death, MI, stroke, unstable angina, and revascularization

117 (19.6%) 124 (21.0%)



RADIANCE 1: Heterozygous Familial Hypercholesterolemia

Adapted from Kastelein JJ et al. N Engl J Med 2007; 356: 1620-30 Copyright © 2007 Massachusetts Medical Society. All rights reserved

0.0

0.5

1.0

1.5

2.0

Treatment period (months)

Slope (mm/year)95% CIp value

-0.0006(-0.0084, 0.0072)

0.8737

Baseline 6 12 18 24

Torcetrapib+Atorvastatin (T/A)

Atorvastatin (A)

1.126 1.1321.133 1.1481.134

1.1631.149 1.1621.1501.152

T/A vs. A


RADIANCE 2: Mixed Dyslipidemia

Reprinted from The Lancet, Vol 370, Bots ML et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial, 153-60, Copyright © 2007, with permission from Elsevier

1.3210 1.35921.3150 1.36341.3260

1.36801.3319 1.34691.30791.3002

0.60

0.80

1.00

1.20

1.40

1.60

1.80

Slope (mm/year)95% CIp value

-0.0049(-0.0180, 0.0082)

0.4621

Treatment period (months)

Baseline 6 12 18 24

T/A vs. A

Torcetrapib+Atorvastatin (T/A)

Atorvastatin (A)


ILLUSTRATE and RADIANCE

No change in atherosclerotic burden in coronary or carotid beds

Secondary endpoints suggest modest regression of atheroma in coronaries and progression in carotids

Imaging studies do not parallel clinical outcomes and do not explain toxicity

Carotids more sensitive to blood pressure (BP) related toxicity than coronaries

If other cholesteryl ester transfer protein inhibitors have not caused an increased BP, should they be evaluated in further clinical studies?


Recombinant Apo AI Milano: Change in Atheroma Volume as Measured by Intravascular Ultrasound

Adapted from Nissen SE et al. JAMA 2003; 290: 2292-300

Placebo(n=11) p=0.97

ETC-21615 mg/kg

(n=21) p=0.03

ETC-21645 mg/kg

(n=15) p=0.45

Combined treatment group*

(n=36) p=0.02

*Primary efficacy endpoint

ETC-216: intravenous recombinant Apo AI Milano/phospholipid complexes


ERASE: CSL-111 (Reconstituted HDL)

GroupChange in atheroma

volume (%)p vs. placebo p vs. baseline

Placebo (n=47)

-1.62 — 0.07

CSL-111 (n=89)

-3.41 0.48 <0.001

Adapted from Tardif JC et al. JAMA 2007; 297: 1675-82

Intravascular ultrasound results


Conclusions/Discussion Raising HDL: Does it Work?

Multiple mechanisms for raising HDL No conclusive evidence as yet in humans for

independent benefit of HDL increase on cardiovascular disease

Best evidence to date, from animals and to a limited extent in humans, is for reduced atherosclerosis severity with increased apolipoprotein AI transport


www.cardiometabolic-risk.org

raising hdl with drugs - does it work?

Health & Medicine

relation of hdl cholesterol

mean ldl cholesterol

statin low hdl cholesterol

hdl cholesterol mgdl

hdl therapy

role of hdl

ce cholesterol synthesis

hdl catabolism