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Home , Atorvastatin, Torcetrapib

After – what’s next?

Charles J. Lowenstein, MD Chief of Cardiology UR Medicine Heart & Vascular

Cholesterol Guidelines

New Prevention Guidelines LDL Statins New Guidelines Therapies – Statins – – – CETP Inhibitors –PCSK9 New Prevention Guidelines In 2013 the ACC & AHA released new guidelines to prevent heart disease and .

Epidemiology of

11 million Americans have (CAD) 1.5 million Americans have (MI) 0.5 million Americans die annually from CAD 2013 ACC AHA Guidelines: 4 Guidelines

1. Diet 2. Exercise 3. Obesity 4. Cholesterol

2013 ACC AHA Guidelines

Lifestyle is the Foundation for Atherosclerotic Cardiovascular Risk Reduction Efforts

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013 2013 ACC AHA Guidelines for Diet

Good foods: fruits, vegetables, whole grains, poultry, fish, nuts Bad foods: red meat, sugary foods and drinks Less salt & saturated fats No trans fats

2013 ACC AHA Guidelines on Lifestyle Management to Reduce Cardiovascular Risk Circulation 2014; 129:S76

2013 ACC AHA Guidelines for Exercise

40 min 3-4 days /week Moderate intensity

2013 ACC AHA Guidelines on Lifestyle Management to Reduce Cardiovascular Risk Circulation 2014; 129:S76 2013 ACC AHA Guidelines for Obesity

BMI – BMI > 30 – BMI > 25 + risk factor Diet: – Decrease calories by 500 – No magic diet Exercise – Move 2.5 h / wk Behavioral strategy Surgery for severe obesity –BMI > 40 – BMI > 35 + risk factor

2013 ACC AHA Guidelines on Lifestyle Management to Reduce Cardiovascular Risk Circulation 2014; 129:S76

2013 ACC AHA Guidelines for Cholesterol Cholesterol Guidelines

New Prevention Guidelines LDL Statins New Cholesterol Guidelines Therapies – Statins – Ezetimibe – Niacin – CETP Inhibitors –PCSK9

Lipoproteins

Lipoproteins carry Lipoproteins are cholesterol and spherical particles in the – Lipids plasma. – Proteins Lipoprotein Particles

1. Low density lipoprotein (LDL) 2. High density lipoprotein (HDL) 3. Very low density lipoprotein (VLDL) 4. Chylomicrons

Lipoprotein Particle Lipoprotein Particle Nonpolar Lipids Triglyceride O

CH2 O C(CH2)n CH3 O

Non- CH2 O C(CH2)n CH3 Polar O

Lipids CH2 O C(CH2)n CH3

Apoproteins Cholesterol ester Cholesterol

O

CH3 (CH2)n C O Forward Cholesterol Transport

Dietary Fat

Liver Peripheral Sterols Cells

Small Intestine

Forward Cholesterol Transport

Chylo Dietary Fat VLDL LDL

Liver Peripheral Sterols Cells

Small Intestine Forward Cholesterol Transport Exogenous Pathway Endogenous Pathway Dietary Fat LDL Chylo Chylo Receptor LDL Rem Liver Peripheral LP Lipase Cells

FFA Sterols VLDL IDL Arterial Wall LP Lipase FFA

Adipose Tissue Small Adipose Tissue And Muscle Intestine And Muscle

Reverse Cholesterol Transport

Dietary Fat

Liver Peripheral Sterols Cells

Small Intestine J. Glomset J Lipid Res 1968 Reverse Cholesterol Transport

Dietary Fat

Liver Peripheral Sterols Cells

Bile Sterols HDL and Cholesterol Small Intestine

Cholesterol Transport

Dietary Fat

Liver Peripheral Sterols Cells

Small Intestine Cholesterol Guidelines

New Prevention Guidelines LDL Statins New Cholesterol Guidelines Therapies – Statins – Ezetimibe – Niacin – CETP Inhibitors –PCSK9

Statins Decrease LDL Cholesterol in 2 Ways Statins Block Cholesterol Production Acetyl Co-A

HMG-CoA HMG-CoA HMG-CoA Reductase Reductase Mevalonate Inhibitors (Statins)

Mevalonate pyrophosphate

Isopentenyl pyrophosphate

Geranyl pyrophosphate

Farnesyl pyrophosphate

Squalene Cholesterol

Statins Boost LDL Clearance

LDL LDL LDL LDL LDL Statins LDL LDL LDL LDLR LDLR

LDL LDL LDL LDL LDL LDL Cholesterol Guidelines

New Guidelines LDL Statins New Cholesterol Guidelines Therapies – Statins – Ezetimibe – Niacin – CETP Inhibitors –PCSK9

Statins for Primary + Secondary Prevention

30 4S-Pl 25 20 4S-Rx

LIPID-Pl 15 LIPID-Rx CARE-Pl CARE-Rx 10

CV Event Rate (%) AFCAPS-TexCAPS-Rx WOSCOPS-Pl 5 WOSCOPS-Rx ASCOT-Pl AFCAPS-TexCAPS-Pl 0 ASCOT-Rx 90 110 130 150 170 190 210 LDL Achieved (mg/dL) Ballantyne et al. AJC 1998; 82: 3 Meta-Analysis of Trials

Cholesterol Treatment Trialists' (CTT) Collaboration Meta-Analysis of 170,000 patients Statins better than control Intensive statin therapy better than less intensive statin therapy Lancet 2010; 376: 1670- 81

Conclusion of statin trials

Statins decrease cardiovascular events “No evidence of any threshold within the cholesterol range studied.”

No evidence for treating to specific LDL targets Cholesterol Guidelines

New Guidelines LDL Statins New Cholesterol Guidelines Therapies – Statins – Ezetimibe – Niacin – CETP Inhibitors –PCSK9

Summary of 2013 Statin Guidelines Give statins to 4 risk groups ACC AHA 2013 Statin Guidelines: 4 risk groups

Use statins for adults in 4 risk groups: 1. History of cardiovascular event 2. LDL > 190 mg/dL 3. 4. Risk > 7.5%

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013

ACC AHA 2013 Statin Guidelines Intensity of Statin Dose

Match statin dose with level of risk ACC AHA 2013 Statin Guidelines Intensity of Statin Dose

Moderate intensity statin: High intensity statin: Moderate intensity for mod risk: High intensity for high risk: ASCVD age > 75 ASCVD age < 75 10 yr risk > 7.5% LDL > 190 Diabetes Diabetes & 10 yr risk > 7.5%

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013

ACC AHA 2013 Statin Guidelines Intensity of Statin Dose

Moderate intensity statin: High intensity statin: 10 Atorvastatin 80 10 Rosuvastatin 20 20 40 40 40

Decrease LDL 30% - 50% Decrease LDL > 50%

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013 Should we add other drugs to statins?

Do other drugs improve survival? Do other drugs decrease cardiovascular events?

Ezetimibe? Ezetimibe blocks cholesterol absorption Exogenous Pathway Endogenous Pathway Dietary Fat LDL Chylo Chylo Receptor LDL Rem Liver Peripheral LP Lipase Cells

FFA Sterols VLDL IDL

LP Lipase Ezetimibe FFA

Small Intestine

Ezetimibe lowers LDL cholesterol

The American Journal of Cardiology, Volume 90, 2002 Ezetimibe doesn’t help: ENHANCE

700 patients with familial Simvastatin vs. Simvastatin + Ezetimibe 2 year trial No change in carotid artery wall thickness

Kastelein et al. NEJM 2008

Ezetimibe might help: IMPROVE-IT

18,000 patients with Simvastatin vs. Simvastatin + Ezetimibe 7 year trial Small change in combined endpoint – 35%  33%

NOT YET PUBLISHED !? PCSK9 Inhibitors?

PCSK9 Degrades LDLR

LDL LDL LDL LDL LDL LDL LDLR PCSK9

LDL PCSK9 Inhibitors Boost LDL Receptors

LDL LDL LDL LDL PCSK9 LDL LDL LDL LDL inhibitors LDLR LDLR

LDL LDL LDL LDL LDL LDL

Forward Cholesterol Transport Exogenous Pathway Endogenous Pathway Dietary Fat LDL Chylo Chylo Receptor LDL Rem Liver Peripheral LP Lipase Cells

FFA Sterols VLDL IDL Arterial Wall LP Lipase FFA

Adipose Tissue Small Adipose Tissue And Muscle Intestine And Muscle PCSK9 Mutants have Low LDL

Cohen JC and Hobbs HH Nature Genetics 2005

PCSK9 Mutants have Low LDL and less CHD

Cohen JC et al. N Engl J Med 2006;354:1264-1272. PCSK9 Inhibitors Increase LDLR and Decrease LDL

Stein et al. N Engl J Med 2012

PCSK9 Inhibitors Decrease LDL

Does an antibody to PCSK9 decrease LDL & events? 4500 patients (mixed group) 1 year decreased LDL and decreased events

Sabatine MS et al. N Engl J Med 2015 PCSK9 Inhibitors Decrease LDL

Sabatine MS et al. N Engl J Med 2015

PCSK9 Inhibitors Might Decrease Events

Sabatine MS et al. N Engl J Med 2015 Niacin?

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013

Strategies to Boost HDL and Reverse Cholesterol Transport

Fibrates Apo-I Dietary Fat Apo A-I

Liver Peripheral ABCG5 Cells Sterols ABCG8 LCAT ABC1 HDL HDL Scavenger Receptor B1 Apo a-I CETP RAR/RXR LXR Niacin CETP Inhibitors Small Intestine Treatment of Low HDL: Niacin

Niacin increases HDL, decrease TG Toxicity: prostaglandins & flushing, impaired glucose tolerance, liver toxicity, infections

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 Niacin increased adverse events

AIM-HIGH NEJM 2011 Niacin for low HDL: HPS2 THRIVE

Does niacin help patients already on a statin? 25,000 patients with vascular disease Statin ± Niacin + Niacin had no clinical benefit – LDL down & HDL up – No mortality benefit – More adverse outcomes

HPS THRIVE NEJM 2014

Niacin for low HDL: HPS2 THRIVE

Adverse Niacin & Placebo Rate Ratio Absolute P Event Laropiprant Excess

GI 620 491 1.3 1.0 % < 0.001

Musculosk 481 385 1.3 0.7 % < 0.001

Skin 86 51 1.7 0.3 % 0.003

Infection 1031 833 1.2 1.4 % < 0.001

Bleeding 326 238 1.4 0.7 % < 0.001

Diabetes 494 376 1.3 1.3 % < 0.001

Distrbd DM 460 311 1.6 3.7 % < 0.001 CETP Inhibitors?

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013

Strategies to Boost HDL and Reverse Cholesterol Transport

Fibrates Apo-I Dietary Fat Apo A-I

Liver Peripheral ABCG5 Cells Sterols ABCG8 Bile LCAT ABC1 HDL HDL Scavenger Receptor B1 Apo a-I CETP RAR/RXR LXR Niacin CETP Inhibitors Small Intestine Treatment of Low HDL: CETP Inhibitors

CETP transfers cholesteryl esters from HDL to VLDL Mutations in CETP gene increase HDL in humans CETP inhibitors might increase HDL, decrease CAD?

Brousseau … and Rader NEJM 2004

Torcetrapib for Low HDL

90 80 70 60 50 40 30 [HDL] (mg/dL) 20 10 0 Placebo Torcetrapib (120 QD) (120 BID)

Brousseau … and Rader NEJM 2004 ’s Torcetrapib Trial

Phase III Trial: ILLUMINATE – 15,000 high risk subjects with DM or CAD – Randomized: atorvastatin vs. atorvastatin + torcetrapib Stopped by DSM for excess death – 82 people taking torcetrapib died vs. 51 placebo – Torcetrapib group had excess Mortality, CHF, Angina, Revascularization Tall et al. ATVB 2007

Use your judgment! Consequences

New guidelines will increase US adults receiving statins from 43 M to 56 M Most new subjects are older adults without coronary artery disease – 30%  87% men age 60-75 – 20%  54% women age 60-75

Conclusions: 4 Statin Benefit Groups

1. ASCVD 2. High LDL > 190 3. Diabetes 4. High risk > 7.5% Conclusions

Fix lifestyle Treat risks Give statins Use judgment

Cholesterol Guidelines

New Guidelines LDL Statins New Cholesterol Guidelines Therapies – Statins – Ezetimibe – Niacin – CETP Inhibitors –PCSK9 Appendix

Summary Many novel genes affect HDL & risk of coronary artery disease. Future therapy for dyslipidemic patient may involve combinations of drugs: – Statins to block cholesterol synthesis and increase clearance of LDL – Ezetimibe to block cholesterol absorption – New drug to raise HDL cholesterol efflux Monitoring Statin Therapy

Baseline fasting lipid profile Determine effects 1-3 months after statin Monitor every year

Summary Many novel genes affect HDL & risk of coronary artery disease. Future therapy for dyslipidemic patient may involve combinations of drugs: – Statins to block cholesterol synthesis and increase clearance of LDL – Ezetimibe to block cholesterol absorption – New drug to raise HDL cholesterol efflux ACC AHA 2013 Statin Guidelines 4 risk groups

1. History of clinical cardiovascular event – heart attack, stroke, stable or , peripheral artery disease, transient ischemic attack, or coronary or other arterial revascularization 2. Adult with LDL > 190 mg/dL – age > 20 3. Adult with diabetes – T1DM or T2DM – ages 40-75 – 70 < LDL < 190 4. Adult with risk > 7.5% – 10 year risk – ages 40-75 – 70 < LDL < 190 5. Others who are at high risk – Use your own judgment !

2013 ACC AHA Guidelines on Treatment of Blood Cholesterol Circulation 2013

Strategies to Boost HDL and Reverse Cholesterol Transport

Fibrates Apo-I Dietary Fat Apo A-I

Liver Peripheral ABCG5 Cells Sterols ABCG8 Bile LCAT ABC1 HDL HDL Scavenger Receptor B1 Apo a-I CETP RAR/RXR LXR Niacin CETP Inhibitors Small Intestine