Getting to Goal, and Saving Lives “Cholesterol metabolism, intake, absorption, and synthesis Timothy A. Denton, M.D., F.A.C.C. High Desert Heart Institute.

Getting to Goal,Getting to Goal,and Saving Livesand Saving LivesGetting to Goal,Getting to Goal,and Saving Livesand Saving Lives

““Cholesterol metabolism,Cholesterol metabolism,intake, absorption, and synthesisintake, absorption, and synthesis

Timothy A. Denton, M.D., F.A.C.C.High Desert Heart Institute

Victorville, CA

What are the goals of Medical Care?

1 - Prolong Survival

2 – Improve Quality-of-Life

Atherosclerosis

Copyright ©2001 American Heart Association

Tuzcu, E. M. et al. Circulation 2001;103:2705-2710

Prevalence of coronary atherosclerosis by age with 0.5- and 0.3-mm thresholds for defining atherosclerotic lesions

LDL

3,000,000 daltons3,000,000 daltons22 nm22 nm800 phospholipid molecules800 phospholipid molecules500 free cholesterol molecules500 free cholesterol molecules1 B-100 protein1 B-100 protein1,500 ester molecules1,500 ester molecules

3,000,000 daltons3,000,000 daltons22 nm22 nm800 phospholipid molecules800 phospholipid molecules500 free cholesterol molecules500 free cholesterol molecules1 B-100 protein1 B-100 protein1,500 ester molecules1,500 ester molecules

Framingham- Coronary Heart Disease risk ratiosFramingham- Coronary Heart Disease risk ratiosHDL-cholesterol

0.7

2

1 0.7

2

0

1

2

3

4

5

6

100 150 200 250 300 Serum cholesterol (mg/dL)

CH

D r

isk

ra

tio

Serum Chol

HDL chol

Gordon, Probstfeld, Garrison, et al, Circulation 1989;79:8

25 45 65

1 - Diet2 - Exercise3 - Drugs4 - Partial ileal bypass5 - Portacaval shunting6 - Apheresis

adsorption column (LDL apheresis)plasma exchangedouble membranedextran sulfate precipitationimmunoabsorption

7 - Liver transplantation

Methods for Modifying Cholesterol Levels

What you make(or metabolize)

What you eat

What you absorb

Lowering Cholesterol

What you make(or metabolize)

What you eat

What you absorb

Lowering Cholesterol

Medications

Diet

SurgeryMedications

Cholesterol Outcomes

Pfeffer, M. A. et al. J Am Coll Cardiol 1999;33:125-130

4S

TNTTNT

LaRosa, J. C. et al. N Engl J Med 2005;352:1425-1435

2.2% absolute reduction

0

20

40

60

80

100

0 50 100 150 200 250 300

LDL Cholesterol

Ev

ent

Ra

te

WOSCOPS

AFCAPS

ASCOT

Diet

• Weight loss• Prolong survival• Lower LDL• Low calorie (triglycerides)• Renal• Liver• Diabetic• Gluten-free• Metabolic diseases• and on and on…

What is a “diet”?

Biosphere

•Biosphere 2•“Isolated, confined environment”, 2 years•8 subjects•Green and yellow vegetables•Animal products of 1 egg, 112 g of meat,

500 cc of goat milk per WEEK•All had consistent weight loss for 2 years•Blood samples q 1-2 months

Verdery, et al. Arch Intern Med 1998;158:900

Biosphere2 Dietary Restriction

Change in LDL Cholesterol

105

58

020406080

100120140160180200

Baseline 2 years

LD

L C

ho

lest

ero

l (m

g%

)

Verdery, et al. Arch Intern Med 1998;158:900

Biosphere2 Dietary Restriction

0

5

10

15

20

25

30

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

Serum LDL Cholesterol (mg/dl)

Mean = 58 + 7 mg/dl

LDL after 2 years

NCEP Goal

Verdery, et al. Arch Intern Med 1998;158:900

Biosphere2 Dietary Restriction

100%0%

Shai I et al. N Engl J Med 2008;359:229-241

Randomization

322 PatientsBMI > 27

40-65 years old

Low Fat DietRestricted calorie

Mediterranean DietRestricted calorie

Low Carb DietNon-restricted calorie

Shai I et al. N Engl J Med 2008;359:229-241

Weight Changes during 2 Years According to Diet Group

Shai I et al. N Engl J Med 2008;359:229-241

Changes in Cholesterol and Triglyceride Biomarkers According to Diet Group during the Maximum Weight-Loss Phase (1 to 6 Months) and the Weight-Loss Maintenance Phase (7 to 24 Months) of the 2-

Year Intervention

Sjostrom L et al. N Engl J Med 2007;357:741-752Bariatric Surgery and Long Term Mortality in Swedish Obese Subjects

Unadjusted Cumulative Mortalityafter Bariatric Surgery

Exercise

Effect of Fitness on Survival

24.6

7.83.1

20.3

7.34.7

64

26.3

20.3

0

10

20

30

40

50

60

70

Unfit Mod Fit Very Fit

Dea

th R

ate

/ 10

,000

CHDCancerAll Cause

Blair JAMA 1989;262:2395

Copyright ©2008 American Heart Association

Kokkinos, P. et al. Circulation 2008;117:614-622

Cumulative survival and exercise capacity for the entire cohort

Effect of Exercise on Lipids

Kokkinos Arch Int Med 1995:155:415

2906 menage 30-64 yearsexercise treadmill test to exhaustionclassified into 6 groups based on

average miles run per week

Effect of Exercise on Lipids

Kokkinos Arch Int Med 1995:155:415

HDL, LDL versus miles per week

40

45

50

55

60

0-2 mi 3-6 mi 7-10 mi 11-14 mi 15-20 mi 21-60 mi

Miles Run per Week

HD

L m

g%

0

20

40

60

80

100

120

140

LD

L m

g%

Y2

HDLLDL

Inhibition of Inhibition of Cholesterol AbsorptionCholesterol Absorption

Inhibition of Inhibition of Cholesterol AbsorptionCholesterol Absorption

Decrease in Absorption•Plan stanols/sterols Benecol Take Control•Bile acid sequestrants Colestipol (colestid) Cholestyramine (Questran) Colesevelam (Welchol)•Fat absorption blocker Orlistat (Xenecal)•Cholesterol uptake blocker Ezetimibe

Monotherapy Dose-Ranging Study: Efficacy at Week 8

Mea

n %

ch

ang

e in

LD

L-C

fr

om

bas

elin

e at

wk

8

Placebo(n=17)

-40

-30

-20

-10

0

+10

Ezetimibe 1 mg

(n=17)

Ezetimibe 5 mg(n=20)

Ezetimibe 10 mg(n=16)

Ezetimibe 20 mg(n=16)

Ezetimibe 40 mg(n=18)

Lovastatin 40 mg(n=16)

-14.6 -15.7 -16.4 -17.9 -20.0

-31.8

+3.8

* p<0.05 vs placebo

Ezetimibe Phase II Efficacy Results

Bays et al. Atherosclerosis. 2000;151:133. Abstract.

EzetimibeEzetimibe Reduces Carotid Artery Reduces Carotid Artery Atherosclerosis in apo E Knockout Mice*Atherosclerosis in apo E Knockout Mice*

EzetimibeEzetimibe Reduces Carotid Artery Reduces Carotid Artery Atherosclerosis in apo E Knockout Mice*Atherosclerosis in apo E Knockout Mice*

Control Ezetimibe 5 mg/kg/d

Davis et al. Atherosclerosis. 2000;151:133. Abstract.

* Mice fed 0.15% cholesterol diet for 6 months.

What you make(or metabolize)

What you eat

What you absorb

Lowering Cholesterol

Medications

Diet

SurgeryMedications

Statins and Other Meds

Medications for Modifying MetabolismMedications for Modifying Metabolism

•Small molecules Ethyl alcohol Niacin•Statins Fluvastatin Pravastatin Lovastatin Simvastatin Atrovastatin Rosuvastatin Simvastatin + ezetimibe• Fibrates Fenofibrate Gemfibrozil

Cholesterol Outcomes

Pfeffer, M. A. et al. J Am Coll Cardiol 1999;33:125-130

4S

TNTTNT

LaRosa, J. C. et al. N Engl J Med 2005;352:1425-1435

2.2% absolute reduction

0

20

40

60

80

100

0 50 100 150 200 250 300

LDL Cholesterol

Ev

ent

Ra

te

WOSCOPS

AFCAPS

ASCOT

A Comment from “The Press”

Is Vytorin a failure?

So how could such a drug be approved in the first place?

Time – January 15, 2008

What are the goals ofResearch in Medical Care?

1. Prolong Survival2. Improve quality of life

decrease MI, angina, CVA3. Lower LDL4. Decrease atherosclerosis

Carotid intimal thickness

Did you hear about this trial?Randomized controlled trial - carotid intimal thickness

399 womenAge <70

Drug group192 (182)

IMT difference = 13.5% IMT change = 2.9

Placebo group205 (187)

IMT difference = 11.4% IMT change = 2.5

P = 0.287

Placebo vs atorvastatin (CASHMERE study)www.clinicaltrials.gov/ct2/show/record/NCT00163163

Kastelein J et al. N Engl J Med 2008;358:1431-1443

Enrollment and Outcomes

Another Carotid Intimal Thickness Trial (ENHANCE)

1180 FH – Heterozygotes were screened772 started run-in period

720 Randomized

357 assigned simvastatin/ezetimibe356 received the drugs29 adverse events2 lost to follow-up1 non-compliant6 withdrew consent3 other reasons322 included in primary analysis

363 assigned simvastatin/placebo361 received the drugs34 adverse events2 lost to follow-up2 non-compliant26 withdrew consent

320 included in primary analysis

Kastelein J et al. N Engl J Med 2008;358:1431-1443

Effects of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides

Kastelein J et al. N Engl J Med 2008;358:1431-1443

Mean ({+/-}SE) Intima-Media Thickness of the Carotid Artery during 24 Months of Therapy

2,010 Patients with AS were screenedAnd started run-in period

1,873 Randomized

944 assigned simvastatin/ezetimibe943 received the drugs198 discontinued0 lost to follow-up5 other reasons105 died944 included in primary analysis

929 assigned placebo929 received the drug170 discontinued2 lost to follow-up9 other reasons100 died929 included in primary analysis

Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic StenosisSEAS Trial

Rossebo A et al. N Engl J Med 2008;10.1056

Rossebo A et al. N Engl J Med 2008;10.1056/NEJMoa0804602

Serum Low-Density Lipoprotein (LDL) Cholesterol Levels (Panel A) and the Change from Baseline in Peak Aortic-Jet Velocity (Panel B)

Rossebo A et al. N Engl J Med 2008;10.1056/NEJMoa0804602

Kaplan-Meier Curves for Primary and Secondary Outcomes and Death

SEAS trial and Cancer

• Increase in CA – p = 0.05• Not a pre-defined endpoint

• No evidence of cancer in meta-analysis“Conclusions The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer.

Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.”

Peto R, et al. NEJM www.nejm.org September 2, 2008 (10.1056/NEJMsa0806603)

Ezetimibe 10 mg Co-Administered With Ezetimibe 10 mg Co-Administered With

Simvastatin Provides AdditionalSimvastatin Provides Additional 16–18% LDL-C Reduction16–18% LDL-C Reduction

Ezetimibe 10 mg Co-Administered With Ezetimibe 10 mg Co-Administered With

Simvastatin Provides AdditionalSimvastatin Provides Additional 16–18% LDL-C Reduction16–18% LDL-C Reduction

Kosoglou et al. Atherosclerosis. 2000:151:135. Abstract.

Mea

n %

Ch

ang

e in

LD

L-C

fr

om

Bas

elin

e

-30

-20

-10

0

Placebo(n=11)

Simvastatin 10 mg(n=12)

Simvastatin 10 mg+Ezetimibe 10 mg

(n=11)

-3.2*

-34.9*

-51.9*†

-40

-50

-60

PK/PD Co-Administration Study

17%

* p<0.01 vs. placebo

† p<0.01 vs simvastatin 10 mg

How to make a choice between drugs:How to make a choice between drugs:

• Medical literature• Distance to goal• Side effects• Formulary• Copay /cost• Familiarity

How How NOTNOT to make a choice between drugs: to make a choice between drugs:

• Time Magazine• Wall Street Journal• LA Times• National Enquirer

SummarySummary

• Role of diet / exercise• Drug overview• Statin• Statin combinations• Goals of therapy

Effects of Various Cardiac TherapiesEffects of Various Cardiac Therapies

Therapy Survival QOL MI Admits

Rx A 0

Rx B 0

Rx C

Rx D

Effects of Various Cardiac TherapiesEffects of Various Cardiac Therapies

Therapy Survival QOL MI AdmitsPTCA (non-MI) 0

CABG (3v, nl EF, CCS I, II) 0

ASA

Lipid lowering therapy

The END