HDL: A Good Fat Just Got Better Charles J. Lowenstein, MD Division of Cardiology, Department of Medicine The University of Rochester School of Medicine & Dentistry

DISCLOSURES Speaker declared financial support; Pfizer paid honorarium to speak at an Atherosclerosis update forum in 2012

HDL Cholesterol 







Pathophysiology of HDL – HDL Composition and Synthesis – Reverse Cholesterol Transport HDL and Disease – Clinical Observations about HDL – HDL Diseases HDL is Anti-Inflammatory – Anti-Atherosclerosis – Anti-Inflammation – Can HDL be Pro-Inflammatory? HDL as a Therapeutic Target – Clinical Trials and HDL – Treatment of Low HDL

(Rate / 1000)

Coronary Heart Disease

Framingham Study: HDL + CHD Risk 200 150 100

Mean Risk

50 0 0

25

50

75

100

[HDL] (mg/dL)

1 % decrease in HDL associated with 2% increase in coronary heart disease (CHD) risk Gordon Am J Med 1977

Relative Risk of Coronary Heart Disease

Framingham Study: HDL Independent of LDL for CHD Risk 3

2

1

0

100

160

[LDL] (mg/dL)

25 45 65 [HDL] 85 (mg/dL) 220 Franceschini et al. Am J Cardiol 2001

HDL and Risk of CHD  1%

decrease in HDL associated with 2% increase in coronary heart disease (CHD) risk  HDL is an independent risk factor for CHD  HDL is more highly correlated with CHD than LDL

Gordon et al. Circ. 1989

How does HDL protect against atherosclerosis?  HDL

removes cholesterol from cells  HDL inhibits inflammation  HDL decreases oxidant stress

Barter… and Fogelman Circ. Res. 2004 Mineo… and Shaul Circ. Res. 2006

Transport & HDL

HDL Transport Cholesterol  Composition  Synthesis  Metabolism

Lipoproteins  Lipoproteins

carry cholesterol and triglyceride in the plasma.

 Lipoproteins

particles – Lipids – Proteins

are spherical

Lipoprotein Particles 1. 2. 3. 4.

Low density lipoprotein (LDL) High density lipoprotein (HDL) Very low density lipoprotein (VLDL) Chylomicrons

Lipoprotein Particles 1.

Low density lipoprotein (LDL) 1. 2. 3. 4.

2.

Transports cholesterol to tissues 65% serum cholesterol Single apolipoprotein apoB Primary target of cholesterol lowering therapy

High density lipoprotein (HDL) 1. 2. 3. 4.

1.

Transports cholesterol away from tissues 25% serum cholesterol Major apolipoproteins apoA-I and apoA-II Secondary target of therapy

Very low density lipoprotein (VLDL) 1.

2. 3. 4. 2.

Trigylceride carrier synthesized in liver; LDL precursor 10% serum cholesterol Apolipoproteins apoB-100, apoC, apoE Secondary target of therapy

Chylomicrons 1. 2.

Dietary lipid carrier synthesized in intestine Apolipoproteins apoB-48, apoC, apoE

Components of Lipoproteins  Cholesterol

– Free unesterified – Cholesterol ester  Triglycerides  Phospholipids  Apolipoproteins  Other

proteins….

Lipoprotein Particle Lipoprotein Particle

Nonpolar Lipids Triglyceride

NonPolar Lipids

Cholesteryl ester Triglycerides

Cholesterol Apoproteins

O

CH2 O

C (CH2)n CH3 O

CH2 O

C (CH2)n CH3 O

CH2 O

C (CH2)n CH3

Cholesterol ester

O CH3 (CH2)n C O

Components of HDL HDL Particle

Apolipoproteins on HDL apoA-I

Cholesteryl ester Triglycerides NonPolar Lipids

apoA-II apoA-IV, apoC, apoD, apoE

Cholesterol Apoproteins

Other Components of HDL Sphingolipids Estrogen Paroxonase

HDL Synthesis  Early

HDL made by liver and intestine  Early HDL particles have little lipid  HDL particles pick up lipid in the plasma

NonPolar Lipids

HDL Particles Apoproteins

apoA-I Lipid Poor

Apoproteins Apoproteins Apoproteins Apoproteins Cholesterol + PL Cholesterol + PL Cholesterol + PL Cholesterol + PL Cholesterol Ester Cholesterol Ester Cholesterol Ester

pre-BetaHDL

NonPolar Lipids

NonPolar Lipids

NonPolar Lipids

HDL3

HDL2

HDL1

HDL Role: Transport  Mature

HDL shuttles lipid between cells  HDL picks up free cholesterol from cells – LCAT converts free cholesterol into cholesterol esters  HDL

delivers cholesterol esters to other cells

– Liver for excretion – Tissues that make steroids and hormones

Monty Krieger Ann Rev Biochem 1999

Forward Cholesterol Transport Exogenous Pathway Endogenous Pathway Dietary Fat

Liver Sterols

Small Intestine

Peripheral Cells

Forward Cholesterol Transport Exogenous Pathway

Endogenous Pathway

Dietary Fat Chylo Rem

Chylo

LP Lipase Sterols

LDL Receptor

Peripheral Cells

Liver

FFA VLDL LP Lipase FFA

Small Intestine

LDL

Adipose Tissue And Muscle

Adipose Tissue And Muscle

IDL

Arterial Wall

Reverse Cholesterol Transport Dietary Fat

Liver Sterols

Small Intestine

Peripheral Cells

J. Glomset J Lipid Res 1968

Reverse Cholesterol Transport Dietary Fat

Sterols

Small Intestine

ABCG5 ABCG8 Bile Sterols and Cholesterol

Peripheral Cells

Liver

ABC1

LCAT Scavenger Receptor B1

HDL

HDL Macrophages

LCAT converts free cholesterol to cholesteryl CETP transfers cholesteryl to other lipoproteins

Reverse Cholesterol Transport Dietary Fat LDL Receptor

Sterols

Small Intestine

ABCG5 ABCG8 Bile Sterols and Cholesterol

Liver

VLDL LDL

CETP

HDL

Peripheral Cells ABC1

LCAT Scavenger Receptor B1

Scavenger Receptor A

HDL Macrophages

LCAT converts free cholesterol to cholesteryl CETP transfers cholesteryl to other lipoproteins

Cholesterol Transport Dietary Fat

Liver Sterols

Small Intestine

Peripheral Cells

Clinical Observations of HDL

HDL and Risk of CHD 1

% decrease in HDL associated with 2% increase in coronary heart disease (CHD) risk  HDL is an independent risk factor for CHD  HDL is more highly correlated with CHD than LDL

Gordon et al. Circ. 1989

Classification of HDL  Low

HDL < 40 mg/dL  High HDL > 60 mg/dL

National Cholesterol Education Program JAMA 2001

Why is high HDL good?  If

HDL carries cholesterol out of the body, then high cholesterol can mean many different things:  High cholesterol = lots of reverse transport?  High cholesterol = transport is blocked so HDL builds up?

Transport & HDL

Reverse Cholesterol Transport & HDL

Khera AV et al. N Engl J Med 2011;364:127-135

Classification of HDL For Metabolic Syndrome:  Low HDL < 40 mg/dL for men  Low HDL < 50 mg/dL for women

National Cholesterol Education Program JAMA 2001

Sources of Variation in HDL  50

% genetic  50% acquired

Cohen et al. JCI 1994

Primary Causes of Low HDL 

ApoA-I



– Transfers cholesterol from peripheral cells to HDL – Tangier disease

– Major apolipoprotein on HDL – Complete apoA-I deficiency – ApoA-I mutations (e.g., ApoAIMilano) 

» Homozygous » Heterozygous

LCAT – Converts free cholesterol to cholesteryl – Complete LCAT deficiency – Partial LCAT deficiency (fish-eye disease)

ABC1

– Familial hypoalphalipoproteinemia (some families) 

Unknown genetic etiology – Familial hypoalphalipoproteinemia (most families) – Familial combined hyperlipidemia with low HDL-C – Metabolic syndrome

Low HDL: Tangier Disease        

Genetic disorder of cholesterol transport First identified in a five-year old boy on Tangier Island, VA Dentist noticed orange tonsils, contacted Donald Fredrickson at NIH Low HDL and apoA-I Cholesterol accumulates in tissues (tonsils, liver, spleen…) Premature atherosclerosis Normally ABCA1 transfers cholesterol from peripheral cells to HDL ABCA1 mutation – Heterozygotes – Homozygotes

Young & Fielding, Nature Genetics 1999

Reverse Cholesterol Transport: Tangier Disease Dietary Fat

Sterols

Small Intestine

ABCG5 ABCG8 Bile Sterols and Cholesterol

Peripheral Cells

Liver

ABC1

LCAT Scavenger Receptor B1

HDL

HDL

LCAT converts free cholesterol to cholesteryl CETP transfers cholesteryl to other lipoproteins

Secondary Causes of Low HDL  Smoking  Obesity  Inactivity  High

carbohydrate / very-low-fat diet  Hypertriglyceridemia  Type 2 Diabetes  Drugs – Beta-blockers – Androgenic steroids – Androgenic progestins

Primary Causes of High HDL  CETP

– CETP deficiency  Hepatic

lipase

– Hepatic lipase deficiency  Unknown

genetic etiology

– Familial hyperalphalipoproteinemia

Reverse Cholesterol Transport: CETP Deficiency Dietary Fat LDL Receptor

Sterols

Small Intestine

ABCG5 ABCG8 Bile Sterols and Cholesterol

Liver

VLDL LDL

CETP

HDL

Peripheral Cells ABC1

LCAT Scavenger Receptor B1

Scavenger Receptor A

HDL Macrophages

CETP transfers cholesteryl to other lipoproteins

CETP Deficiency in Japan 

Japanese cohort:



– Heterozygotes » 40% decrease in CETP » 30% increase HDL » LDL no change

– Homozygotes » 100% decrease in CETP » 100% increase HDL » 40% decrease LDL

Pathophysiology – Increased HDL-2 suggests decreased HDL CE removal



Cinical – Small cross-sectional study showed increased CHD in CETP heterozygotes (RR 1.5) – Other small substudies were unclear.

Brown et al. Nature 1989 Inazu… and Tall NEJM 1990

CETP Deficiency 

Genetics: – Autosomal co-dominant – Mutations in both alleles of CETP gene



Pathophysiology: – Delayed catabolism of HDL cholesteryl ester and apoA-I – HDL particles enlarged and enriched in cholesteryl ester



Labs: – Elevated HDL-C and apoA-I



Natural History: – No evidence of protection against atherosclerosis – Possible increased risk of premature atherosclerotic vascular disease

Secondary Causes of High HDL  Exercise  Diet:

high-fat  Alcohol  Drugs – Phenytoin – Estrogen

HDL Cholesterol 

Pathophysiology of HDL – HDL Composition and Synthesis – Reverse Cholesterol Transport



HDL and Disease – Clinical Observations about HDL – HDL Diseases



HDL is Anti-Inflammatory – Anti-Atherosclerosis – Anti-Inflammation – Can HDL be Pro-Inflammatory?



HDL as a Therapeutic Target – Clinical Trials and HDL – Treatment of Low HDL

Anti-Atherosclerotic Properties of HDL  HDL

removes cholesterol from cells  HDL decreases vascular inflammation

HDL Anti-Atherosclerosis Mechanisms: Reverse Cholesterol Transport  Atherosclerosis

is associated with excess lipids  HDL promotes cholesterol efflux from cells  Animal studies show that HDL decreases atherosclerosis – ApoA-I (apolipoprotein of HDL) – SR-BI (Scavenger Receptor-BI for HDL)

Reverse Cholesterol Transport: ApoA-I helps make HDL Dietary Fat

Sterols

apoA-I

ABCG5 ABCG8 Bile Sterols and Cholesterol

Peripheral Cells

Liver

Scavenger Receptor B1

HDL CETP

Small Intestine

ABC1

LCAT HDL

HDL and Atherosclerosis: apoA-I Tg  Increasing

expression of apoA-I in mice by

genetics – Increases HDL 2-fold – Decreases atherosclerosis

Rubin… and Clift Nature 1991 Paszty … and Rubin JCI 1994

Scavenger Receptor BI is the Receptor for apoA-I on HDL Dietary Fat LDL Receptor

Sterols

ABCG5 ABCG8 Bile Sterols and Cholesterol

Liver

CETP

HDL

Scavenger Receptor A Peripheral Cells ABC1

LCAT

Scavenger Receptor B1 ApoA-I

Small Intestine

VLDL LDL

HDL Macrophages

SR-BI helps liver take up cholesterol from HDL

HDL and Atherosclerosis: SR-BI KO  Scavenger

Receptor-BI (SR-BI)  Expressed on liver and steroidgenic tissues  Binds HDL and takes up cholesterol ester from HDL  Mice lacking SR-BI have – Increased atherosclerosis

Huszar … and Tall ATVB 2000

Cholesterol Transport Dietary Fat

Liver Sterols

Small Intestine

Peripheral Cells

HDL Anti-Atherosclerosis Mechanisms: Anti-Inflammatory  Atherosclerosis

is an inflammatory disease.  LDL is one of the major inflammatory triggers of atherogenesis.  HDL has anti-inflammatory properties

Anti-Inflammatory Properties of HDL  Reverses

cholesterol transport  Decreases oxidant stress  Boosts nitric oxide production  Decreases endothelial inflammation

Anti-Oxidant Properties of HDL  Oxidized

LDL triggers atherosclerosis

– LDL contains lipid hyroperoxides – Enzymes in the injured wall make radicals that further oxidize LDL (cyclo-oygenase, lipoxygenase, myeloperoxidase, NADPH oxidase) LDL

 HDL

O2-, H2O2

oxLDL

is an anti-oxidant

– HDL carries enzymes that reduce oxidized LDL lipids (paraoxonase, glutathione peroxidase, apoA-I) HDL oxLDL

LDL

Paraoxonase in HDL Blocks LDL Oxidation and Decreases Atherosclerosis

Shih … and Lusis, Nature 1998

Anti-Inflammatory Properties of HDL  Reverses

cholesterol transport  Decreases oxidant stress  Boosts nitric oxide production  Decreases endothelial inflammation

HDL Increases Nitric Oxide Levels  Nitric

Oxide (NO) protects the vasculature from atherosclerosis – Lack of NO is associated with atherosclerosis

 HDL

increases NO

– Activates eNOS – Increases eNOS

NO Protects Vessels NO is: a vasodilator an anti-thrombotic an anti-inflammatory

NOS

NO

Platelets

Smooth muscle

Endothelial cell Leukocyte

Lack of NO: less vascular protection Lack of NO: vasoconstriction pro-thrombotic pro-inflammatory

Platelets THROMBOSIS

Smooth muscle PROLIFERATION AND MIGRATION

Dysfunctional Endothelial cell

Leukocyte

VASCULAR INFLAMMATION

HDL Increases Vasodilation

Purified HDL boosts forearm vasodilation during acetylcholine infusion.

Spieker… Luscher, and Noll Circ. 2002

HDL Increases Nitric Oxide Levels

Yuhanna … and Shaul Nat Med 2001

Sphingolipids in HDL Activate eNOS ApoA-I

SR-BI

HDL

S1P3

PI3K / Akt

eNOS

NO

Nofer … and Levkau JCI 2004

Anti-Inflammatory Properties of HDL  Reverses

cholesterol transport  Decreases oxidant stress  Boosts nitric oxide production  Decreases endothelial inflammation

HDL Decreases Adhesion Molecules  Human

endothelial cells  Pre-treated with human HDL  Stimulated with cytokines  HDL inhibits VCAM-1 expression

Cockerill et al. ATVB 1995

HDL blocks endothelial inflammation P-selectin: Leukocyte Adherence IL-8: Leukocyte Activation vWF: Thrombosis

Arterial Lumen

Resting Endothelial Cell

Arterial Wall

HDL

Inflamed Endothelial Cell

ApoA-I decreases endothelial exocytosis [VWF] (U/mL)

3.0 2.5

*

2.0 1.5

*

1.0

*

*

0.5 0.0

Thrombin ApoA-I (mg/mL)

-

+ 0

+ + + + 10-5 10-4 10-3 10-2 Cameron… and Lowenstein 2005

ApoA-I blocks leukocyte adhesion to endothelial cells Phase

FITC 20

Thrombin

Thrombin + ApoA-I

Leukocyte Adhesion

Control

18 16

*

14 12 10 8 6 4 2 0

ApoA-I Cameron… and Lowenstein 2005

Wild-type Baseline

Histamine

ApoA-I -/-

Leukocytes Rolling Velocity (µm/ms)

ApoA-I inhibits leukocyte rolling along vessels in mice 140

Wild Type

ApoA-I-/-

Wild Type + ApoA-I

120 100 80 60 40 20 0

Baseline + - + - + Histamine - + - + - +

A digital camera was used to photograph rhodamine 6G labeled lekocytes as they flowed along mouse venules in vivo, before and after histamine treatment.

Cameron… and Lowenstein 2005

Baseline Control

ApoA-I

Histamine

Adherent Platelets/mm2

ApoA-I inhibits platelet adhesion to blood vessels in mice Histamine ApoA-I + Histamine Vehicle

350 300

* *

250 200

**

150 100

* *

* *

*

*

50 0

0

1

2

3 4 5

6

7 8

9

10

Time after Histamine (mins)

HDL blocks endothelial inflammation P-selectin: Leukocyte Adherence IL-8: Leukocyte Activation vWF: Thrombosis

Arterial Lumen

Resting Endothelial Cell

Arterial Wall

HDL

Inflamed Endothelial Cell

Pro-Inflammatory Properties of HDL  Dysfunctional

HDL  HDL in patients with metabolic diseases contains fewer anti-inflammatory proteins and more pro-inflammatory proteins.

Anti and Pro Inflammatory HDL Particles Anti-Inflammatory Proteins Apoproteins Cholesterol + PL Cholesterol Ester

NonPolar Lipids

Good HDL

Pro-Inflammatory Proteins Apoproteins Cholesterol + PL Cholesterol Ester

Diabetes Htn

NonPolar Lipids

Bad HDL

HDL as a Therapeutic Target  Strategies  Trials

& Treatments of Low HDL  Guidelines for HDL

Overview of Trials to Increase HDL  Clinical

studies suggest that HDL is inversely correlated with the risk for CHD.  However, drugs that change HDL do not affect mortality.  We don’t know the right way to raise HDL  We are aiming at the wrong target – We have been trying to change HDL – We should be trying to change reverse cholesterol transport

Strategies to Raise HDL  Lifestyle

– Exercise (3-9%) – Smoking Cessation – Weight Loss (0.3 mg/dL/kg) – Alcohol (4 mg/dL for 1 oz EtOH) – Dietary Fat Intake (complex issue)

 Medications

– – – –

Fibrates Niacin Statins Emerging Therapies

Strategies to Boost HDL and Reverse Cholesterol Transport Dietary Fat

Sterols

ApoA-I

Fibrates apoA-I

ABCG5 ABCG8 Bile Sterols and Cholesterol

Peripheral Cells

Liver

ABC1

LCAT Scavenger Receptor B1

HDL

HDL

CETP

Niacin Small Intestine

CETP Inhibitors

LXR agonists apoA-I RAR/RXR

Treatment of Low HDL: Drugs 

 Fibrates  Nicotinic

acid (niacin)

Peroxisome proliferator activated receptor (PPAR) agonists – PPAR-alpha agonists – PPAR-gamma agonists

   

CETP Inhibitors Apolipoproteins LXR Activators Lipase Inhibitors – Endothelial – Hepatic

Treatment of Low HDL: Drugs Medication

HDL Increase

Mechanism

Agents

Side Effects Flushing, pruritis, nausea, vomiting, elefvated LFT, hyperglycemia Elevated LFT and CK, nausea, back pain, constipation

Niacin

20-35%

GPCR agonist Blocks uptake of apoA-I

Niacin XR Niacin Niacin SR

Fibrates

10-25%

PPAR-a agonist Increases apoA-I synthesis

Gemfibrozil Fenofibrate

Statins

5-15%

HMG-CoA inhibitor Increases apoA-I synthesis

Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Rosuvastatin

Myalgias,,elevate d LFT and CK,

Ashen and Blumenthal NEJM 2005

Treatment of Low HDL: Fibrates  Fibrates

are PPAR-alpha activators  Weak, non-selective, indirect activation of PPAR-alpha!  Mechanisms – Increase production: apoA-I, enhancing formation of new HDL – Decrease destruction: hepatic SR-BI, increasing HDL levels  Increase

HDL, decrease TG

Trials of Fibrates for Low HDL  Primary

Prevention (CHD Endpoint)

– WHO Trial – Helsinki Heart Study  Secondary

– – – – – –

Prevention (CHD Endpoint)

Coronary Drug Project Newcastle Trial Scottish Trial Stockholm Trial Veterans Administration HDL Intervention Trial (VA-HIT) Bezafibrate Infarction Prevention (BIP)

Trials of Fibrates for Low HDL  Clinical

Trials (Angiographic Endpoint)

– BECAIT – LOCAT – DAIS  Clinical

Trials (Combined with LDL Therapy)

– CLAS (niacin + cloestipol) – FATS (niacin + colestipol) – HATS (niacin + statins)

Fibrates: Helsinki Heart Study  Primary

prevention  4000 men with dyslipidemia (TG + LDL > 200)  Gemfibrozil vs. Placebo  Gemfibrozil – Increased HDL – Decreased CHD events 34% within 2 yrs – Each 5% increase in HDL decreased events 11%

Frick et al. NEJM 1987

Fibrates: VA-HIT  Secondary

prevention  2500 men with CHD, low HDL < 40, mod LDL < 140  Gemfibrozil vs. Placebo x 5 yr  Gemfibrozil – Decreased HDL – Decreased combined event rate 24% – Each 5% increase in HDL lowered CHD events 11%

Rubins et al. NEJM 1999

Fibrates: VA-HIT

Kaplan-Meier Estimates of the Incidence of Death from Coronary Heart Disease and Nonfatal Myocardial Infarction in the Gemfibrozil and Placebo Groups Rubins et al. NEJM 1999

Treatment of Low HDL: Niacin  Niacin

may target a Gi-protein coupled receptor  Mechanism – Increases HDL indirectly – Increase ABC1 indirectly  Increase

HDL, decrease TG  Toxicity: prostaglandins & flushing, impaired glucose tolerance, liver toxicity  (No definitive clinical trials.)

Wise … and Pike JBC 2003

Niacin for low HDL AIM HIGH  Does

niacin help patients already on a statin?  3000 patients with CAD  Statin ± niacin  Niacin had no clinical benefit

AIM-HIGH NEJM 2011

Treatment of HDL in High Risk Patients  Do

fibrates improve survival of high risk diabetics?  Action to Control Cardiovascular Risk in Diabetes (ACCORD)  5500 patients with T2DM received statin ± fenofibrate  HDL increased, TG decreased  No change in outcomes !

ACCORD NEJM 2010

Treatment of Low HDL: CETP Inhibitors  CETP

exchanges cholesteryl esters from HDL to VLDL & chylo  Mutations in CETP gene increase HDL in humans (but don’t affect CAD)  CETP inhibitors might increase HDL, decrease CAD?  Torcetrapib increased HDL by 60% in 10 patients with HDL < 40 mg/dL

Brousseau … and Rader NEJM 2004

Strategies to Boost HDL and Reverse Cholesterol Transport Dietary Fat

Sterols

apoA-I

ABCG5 ABCG8 Bile Sterols and Cholesterol

Peripheral Cells

Liver

ABC1

LCAT Scavenger Receptor B1

HDL

HDL

CETP

Small Intestine

CETP Inhibitors

[HDL] (mg/dL)

Torcetrapib for Low HDL 90 80 70 60 50 40 30 20 10 0 Placebo

Torcetrapib (120 QD)

Torcetrapib (120 BID)

Brousseau … and Rader NEJM 2004

Treatment of Low HDL: CETP Inhibitors 

CETP – Pro-atherogenic: decreases HDL, increases VLDL & LDL – Anti-Atherogenic: boosts reverse cholesterol transport



Are CETP-deficient persons protected from coronary heart disease? Unclear! Torcetrapib decreases atherosclerosis in cholesterol fed rabbits:



Can torcetrapib decrease CHD



– Surrogate endpoints? – Events?

Okamato et al. Nature 2000

Pfizer’s Torcetrapib Trial 

Phase III Trial: ILLUMINATE – 15,000 high risk subjects with DM or CAD – Randomized: atorvastatin (10-80 mg) vs. atorvastatin + torcetrapib (60 mg)



Stopped by DSM for excess death – 82 people taking torcetrapib died vs. 51 – Torcetrapib group had excess: » » » »

Mortality CHF Angina Revascularization

Tall et al. ATVB 2007

Reaction to Failure of Torcetrapib  

Pfizer stock price falls 10% Pfizer, Inc. – 106,000 employees – $50 billion annual sales – $7 billion annual resaerch budget



Pfizer fired 2,000 of 11,000 sales reps



Pfizer’s drug patents expire soon – Lipitor patent ending soon



Pfizer’s new drug pipeline is almost empty

Reaction to Failure of Torcetrapib

Why did Torcetrapib Fail?  Torcetrapib

increases blood pressure

– Phase II Trial 1-2 mm Hg – Phase III Trial 3-4 mm Hg  Perhaps

Torcetrapib increases bad dysfunctional

HDL – During acute phase responses in humans and animals » HDL loses good proteins (paraoxonase, apoA-I) » HDL incorporates bad proteins (ceruloplasm) » HDL can inflame endothelial cells in culture

Ven Lentern et al. JCI 1995

Anacetrapib increases HDL with no Adverse Effects

Cannon CP et al. N Engl J Med 2010;363:2406-2415

Why did Torcetrapib Fail?  Perhaps

we are aiming at the wrong target  Maybe the most important factor is not HDL – (how many garbage trucks are on the road)  Maybe

the most important factor is reverse cholesterol transport – (how fast the garbage trucks are traveling)

Ven Lentern et al. JCI 1995

Treatment of Low HDL: ApoA-I  ApoA-I

is major apolipoprotein on HDL  Transgenic over-expression of apoA-I decreases atherosclerosis in mice  Drugs elevate apoA-I – Fibrates, estrogen, alcohol…  Perhaps

direct infusion of apoA-I is beneficial?  Injecting apoA-I into rabbits decreases atherosclerosis.  If rabbits, why not humans?

Treatment of Low HDL: ApoA-IMilano 





ApoA-IMilano is rare apoA-I mutant first identified in humans in rural Italy Associated with low levels of HDL but not with increased risk of CAD Recombinant ApoA-IMilano infused into patients with ACS decreases atheroma volume over 5 wks by 1%

  

Small size: n = 45 vs 12 Side effects: strokes and cholelithiasis Poor controls: does normal apoA-I have the same effect?

Nissen et al. JAMA 2003

Treatment of Low HDL: ApoA-IMilano

Example of Atheroma Regression in a Patient Who Received High-Dose ETC-216

Nissen et al. JAMA 2003

Is the level of HDL the best target for therapy?     

Mendelian Randomization Compare 20,000 patients with MI and 100,000 patients without Look at genes that raise or lower HDL Some genetic mechanisms that change HDL do not change risk of MI Therefore: raising plasma HDL cholesterol does not always decrease the risk of myocardial infarction !

Kathiresan et al. Lancet 2012

Conclusions  Low

HDL is a risk for CHD

– HDL removes cholesterol – HDL decreases inflammation  Treatment

for HDL 20%



Major risks: – – – –

Age (men > 45, women > 55) Smoking Hypertension (> 140/90 or Rx) Famly History (men < 55, women < 65) – HDL < 40 mg/dL



Negative Risk: – HDL > 60 mg/dL

NCEP ATP III: Estimate Risk 

Classify risk: count risk factors: – Low Risk – Medium Risk – High Risk



0-1 Major Risks 2 or more Major Risks CHD equivalents

Estimate risk: if 2 or more risk factors, estimate 10year risk of cardiovascular events: – Low Risk – Medium Risk – High Risk

< 10% 10% - 20% > 20%

0-1 Major Risks 2 or more Major Risks CHD equivalents

NCEP ATP III: Set LDL Goal  Set

LDL goal

– Low Risk – Medium Risk – High Risk 

LDL < 160 mg/dL LDL < 130 mg/dL or < 100 LDL < 100 mg/dL or 130/80

 Lifestyle

– Diet – Exercise  Drugs

– TG – HDL

– Glucose intolerance » Fasting glucose > 110

Circulation 2004; 110:227-239

NCEP ATP III: Triglycerides 

Classify Triglycerides – – – –



Normal 500

Goal – TG should be less than 150 mg/dL

 Treat

Triglycerides after LDL (unless TG very high) – Diet – Exercise – Drugs (Fibrate or niacin)

 Treat

TG before LDL if TG > 500 – Fibrate or niacin

NCEP ATP III: HDL 1. 2. 3.

First reach LDL goal Second reach triglyceride goal Third reach HDL goal  If HDL < 40 mg/dL  If patient has CHD or CHD equivalent  Consider nicotinic acid or fibrate