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.
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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
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
Medications
Diet
SurgeryMedications
• 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 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
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
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
Medications for Modifying MetabolismMedications for Modifying Metabolism
•Small molecules Ethyl alcohol Niacin•Statins Fluvastatin Pravastatin Lovastatin Simvastatin Atrovastatin Rosuvastatin Simvastatin + ezetimibe• Fibrates Fenofibrate Gemfibrozil
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
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
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