Transcript Hyperlipidemia: What You Need To Know Daniel White, MD, FACC National Stroke Awareness Month May 21, 2013

Hyperlipidemia:
What You Need
To Know
Daniel White, MD, FACC
National Stroke Awareness Month
May 21, 2013
Daniel S. White MD FACC
Hyperlipidemia
Tonight’s Goals
• Understand why lipid management is critically important
– Individual
– Population
• Gain insight into pathophysiology of CVD
• Learn a little about what lipids/cholesterol are and how they behave in
health and disease
• Understand how dyslipidemia was identified as a CRF
• Take a look into the mind of your physician
– Look at you and your RF’s
– Why they want you to change your ways and maybe take medications
Epidemiology of CVD
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Epidemiology of CVD
CVD
CVD
Cancer
Cancer
Acc
Resp
Acc
DM
Alz
Resp
DM
Alz
Epidemiology of CVD
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Epidemiology of CVD
Major causes of Death U.S., 2008
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Epidemiology of CVD
Other, 16.2%
Diseases of the Arteries, 3.4%
Coronary Heart Disease, 49.0%
High Blood Pressure, 7.8%
Heart Failure*, 7.2%
Stroke, 16.4%
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*Not a true underlying cause. With any mention deaths, heart failure accounts for 35 percent of cardiovascular disease deaths. Total may not add to
Epidemiology of CVD
Cost of leading diseases in U.S. 2008
Billions of dollars
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Epidemiology of CVD
Projected total (direct and indirect) costs of total
cardiovascular disease by age (2010 $ in billions).
All Ages
>80 yrs
65-79 yrs
45-64 yrs
18-44 yrs
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Epidemiology of CVD
The Good News
Deaths attributable to cardiovascular disease (United States: 1900–2009).
Framingham
Go A S et al. Circulation 2013;127:e6-e245
Copyright © American Heart Association
Epidemiology of CVD
The Good News
Cardiovascular disease mortality trends for males and females (United States: 1979–2009).
Go A S et al. Circulation 2013;127:e6-e245
Copyright © American Heart Association
Epidemiology of CVD
The Bad News

Dramatic reduction in
CAD RF’s
Concerning trend
recently
HTN

Smoking
HLP
What will this mean for
the future?
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Epidemiology of CVD
• CVD in the U.S.
– Leading cause of death despite huge reduction in
overall mortality rates in last 30-40 yrs
• Will this last
– Leading economic burden on healthcare system
– Second leading cause of years of potential life lost
– Affects both sexes and most racial groups equally
– BIG PROBLEM!!!
– MAY GET BIGGER??? 15
Why Lipids?
• Framingham Heart Study
Thomas R. Dawber MD
Framingham 1949-1966
– Started in 1948, NHLBI/Boston University
– Epidemiologic study of 5209 participants in
Framingham MA
• Men/Women, aged 30-62 yrs without CVD
– Goal was to evaluate the epidemiology of
CV disease
– Landmark program currently on the third
generation of enrollees - over 2300 articles
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Why Lipids?
• Framingham Heart Study- Landmarks
– Developed the term “risk factor”
• 1960- Cigarette smoking
• 1961- Hypertension, Hyperlipidemia
• 1967- Lack of exercise, obesity
• Combined with observational data about
CAD in Mediterranean and Japanese led
to concern about hyperlipidemia
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Framingham Data
Framingham Data
TC at age 40
Framingham Data
TC at age 70
Risk
• Presence of hyperlipidemia:
– Directly correlates with the risk of
developing CVD and future CV events
– Overall increases risk for future CV events
by 3 fold
– Additive to nonlipid CVD risk factors:
cigarette smoking, HTN, DM, low HDL,
electrocardiographic abnormalities
– Is a significant predictor of
morbidity/mortality
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What Are Lipids?
• Chylomicrons transport fats from the
intestinal mucosa to the liver
• In the liver, the chylomicrons release
triglycerides and some cholesterol and
become low-density lipoproteins (LDL).
• LDL then carries fat and cholesterol to
the body’s cells.
• High-density lipoproteins (HDL) carry fat
and cholesterol back to the liver for
excretion.
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Lipids/Cholesterol are Necessary
• Lipids not present in free form in plasma;
circulate as lipoproteins
• 3 major plasma lipoproteins:
– VLDL carries ~10 to 15 % of total serum cholesterol
– LDL/IDL carries 60 to 70% of total serum cholesterol
– HDL carries 20 to 30% of total serum cholesterol;
reverse transportation of cholesterol
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• Cholesterol: essential for cell membrane
formation & hormone synthesis
Lipid Pathways
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What Are Lipids?
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What Are Lipids?
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What Are Lipids?
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Heart Attack/Angina
Stroke/TIA
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Causes of Hyperlipidemia
•
•
•
•
•
•
•
Genetic
Diet
Hypothyroidism
Nephrotic syndrome
Anorexia nervosa
Obesity
Diabetes mellitus
• Obstructive liver disease
• Acute heptitis
• Systemic lupus
erythematousus
• AIDS (protease
inhibitors)
• Pregnancy
Dietary sources of Cholesterol
Type of Fat
Main Source
Effect on
Cholesterol levels
Monounsaturated
Olives, olive oil, canola oil, peanut oil,
cashews, almonds, peanuts and most
other nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated
Corn, soybean, safflower and cottonseed
oil; fish
Lowers LDL, Raises
HDL
Saturated
Whole milk, butter, cheese, and ice cream;
red meat; chocolate; coconuts, coconut
milk, coconut oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans
Most margarines; vegetable shortening;
partially hydrogenated vegetable oil; deepfried chips; many fast foods; most
commercial baked goods
Raises LDL
When to check lipid panel
• Two different Recommendations
– Adult Treatment Panel (ATP III) of the National Cholesterol Education
Program (NCEP)
– Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile
consisting of total cholesterol, LDL, HDL and triglycerides
– Repeat testing every 5 years for acceptable values
– United States Preventative Services Task Force
– Women aged 45 years and older, and men ages 35 years and older undergo
screening with a total and HDL cholesterol every 5 years.
– If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained
– Cholesterol screening should begin at 20 years in patients with a history of
multiple cardiovascular risk factors, diabetes, or family history of either
elevated cholesterol levels or premature cardiovascular disease.
Determining Cholesterol Goal
• But Doc my cholesterol has always been good!
• LDL goals vary depending on estimate CV risk
• CHD and CHD Risk Equivalents (highest risk):
– Known CAD- MI, Revasc, CAC, pos stress test
– Peripheral Vascular Disease- low ABI
– Cerebral Vascular Accident
– Diabetes Mellitus
Determining Cholesterol Goal
- ATP III Risk Factors
–
–
–
–
Cigarette smoking
Hypertension (BP ≥140/90 or on anti-hypertensives)
Low HDL cholesterol (< 40 mg/dL)
Family History of premature coronary heart disease (CHD)
(CHD in first-degree male relative <55 or CHD in firstdegree female relative < 65)
– Age (men ≥ 45, women ≥ 55)
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 2001;285:2486-2497.
HDL-C
(mg/dL)
³60
Points
-1
HDL-C
(mg/dL)
³60
Points
-1
50-59
0
50-59
0
40-49
1
40-49
1
<40
2
<40
2
Note: HDL-C and TC values should be the average of at least two
fasting lipoprotein measurements.
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. JAMA. 2001;285:2486-2497.
Risk Category
100 mg/dL‡
130 mg/dL
(100–129 mg/dL:
consider drug
options)
Grundy SM et al. Circulation. 2004;110:227-239.
Grundy SM et al. Circulation. 2004;110:227-239.
How Do We Treat?
• Combination of multiple modalities
– Therapeutic lifestyle modification
– Natural supplements
– Statin therapy
– Niacin
– Bile acid sequestrants
– Fibric Acid Derivatives
– Brush Border Inhibitor- Zetia
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Lifestyle Modification
• Initial treatment for dyslipidemia is
(Therapeutic Lifestyle Changes)
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– restricted total fats, saturated fats, cholesterol
intake
– modest increase in polyunsaturated fat
– increased soluble fiber intake
– exercise: moderate intensity 30 min/day most
days
– weight reduction (initial goal of 10%) if needed
– smoking cessation
– treat HTN
TLC Dietary Recommendations
Componenta
Recommended Intake
Total fat
25% to 35% of total calories
Saturated fat
Less than 7% of total calories
Polyunsaturated fat
Up to 10% of total calories
Monounsaturated fat
Up to 20% of total calories
Carbohydratesb
50% to 60% of total calories
Cholesterol
< 200 mg/day
Dietary fiber
20 to 30 g/day
Plant sterols
2 g/day
Protein
~15% of total calories
Total calories
To achieve & maintain desirable body weight
aCalories
from alcohol not included.
bComplex carbohydrates (whole grains, fruits, vegetables).
DiPiro46JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
Treatment
• Most patients should receive 3 to 6 month TLC
trial before initiating pharmacologic therapy
unless very high risk
• If patient unable to reach goals with TLC alone
consider statin therapy
• Combination therapy may be necessary
– monitor closely: increased risk of drug
interactions, adverse effects
• For secondary prevention statin therapy
Proof of the Cholesterol Hypothesis
Surgical Treatment
Proof of the Cholesterol Hypothesis
Surgical Treatment
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Proof of the Cholesterol Hypothesis
Surgery, Diet and Non-Statin Therapy
Targets of Therapy
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Drug
Mechanism of Effects on
Action
Lipids
Effects on Comment
Lipoprotein
s
↓Cholestero ↓ LDL
Problem with compliance; binds
l
↓ VLDL
many coadministered acidic drugs
Cholestyramine, ↑ LDL
colestipol,
catabolism
colesevelam
↓ Cholesterol
absorption
Niacin
↓ LDL and
↓
↓ VLDL
VLDL synthesis Triglyceride ↓ LDL
↓Cholesterol ↑ HDL
Gemfibrozil,
fenofibrate,
clofibrate
↑ VLDL
clearance
↓ VLDL
synthesis
↓
↓ VLDL
Triglyceride ↓ LDL
↓Cholesterol ↑ HDL
Lovastatin,
pravastatin,
simvastatin,
fluvastatin,
atorvastatin,
rosuvastatin
Ezetimibe
↑ LDL
catabolism;
inhibit LDL
synthesis
↓Cholesterol ↓ LDL
Blocks
cholesterol
absorption
across the
intestinal
border
↓Cholesterol ↓ LDL
Problems with patient acceptance;
good in combination with bile acid
resins; ER niacin causes less
flushing and is less hepatotoxic
than SR form
Clofibrate causes cholesterol
gallstones; modest LDL lowering;
raises HDL; gemfibrozil inhibits
glucuronidation of simvastatin,
lovastatin, atorvastatin
Highly effective in
heterozygous familial
hypercholesterolemia and in
combination with other agents
Few adverse effects; effects additive
to other drugs; ENHANCE trial – no
change in carotid intima media
thickness (CIMT) compared to
simvastatin monotherapy in
patients with familial
hypercholesterolemia
Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Eng J Med 2008;358:1431-1443.
DiPiro52JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
Trials of Statin Therapy in Primary Prevention
Trial (yr)
Duratio
n
Medication
Comp
Pts
Age
LDL chng
MG/DL
MCE
CHD Mort
WOSCOP
1995
4.8
PRAVA 40
PLAC
6,596
45-64
-41
0.685
0.683
AFCAPS
1998
5.3
LOVA 20-40
PLAC
6,605
45-73
-36
0.629
0.679
ALLHAT LLT
2002
4.8
PRAVA 40
PLAC
10,355
>55
-20
0.905
0.986
PROSPER
2002
3.2
PRAVA 40
PLAC
5,804
70-82
-40
0.826
0.866
ALERT
2003
5.1
FLUVA 40
PLAC
2,102
30-75
-32
0.754
0.906
ASCOT LLA
2003
3.2
ATOVA 10
PLAC
10,305
40-79
-41
0.6
0.898
ALLIANCE
2004
4.3
ATORVA 1080
UC
2,442
31-78
-15
0.617
0.710
MEGA
2006
5.3
PRAVA 1020
PLAC
3,966
MEAN 58
-27
0.539
0.627
JUPITER
2008
1.9
ROSUVA 20
PLAC
17,802
MEAN 66
-47
0.538
0.838
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Trials of Statin Therapy in Secondary Prevention
Trial (yr)
Duratio
n
Medication
Comp
Pts
Age
LDL chng
MCE
CHD Mort
4S
1994
5.2
SIMVA 2040
PLAC
4,444
35-70
-68
0.657
0.658
CARE
1994
4.8
PRAVA 40
PLAC
4,159
21-75
-40
0.773
0.847
LIPID
1998
5.6
PRAVA 40
PLAC
9,014
31-75
-40
0.778
0.763
GISSI
2000
1.9
PRAVA 20
PLAC
4,271
19-90
-14
0.841
0.769
A-Z
2004 (ACS)
2.0
SIMVA 80
LDL=63
SIMVA 20
LDL=77
4,497
42-69
-14
0.862
0.757
PROVE-IT
2004 (ACS)
2.0
ATORVA 80
PRAVA 40
4,162
MEAN 58
-31
0.843
0.774
TNT
2005
4.9
ATORVA 80
LDL=77
ATORVA 10
LDL=101
10,001
29-76
-25
0.790
0.781
IDEAL
2005
4.0
ATORVA 80
SIMVA 20-40
8,888
30-80
-23
0.882
0.972
LDL=81
LDL=104
SPARCL
2006 (CVA)
4.9
ATORVA 80
PLAC
4731
MEAN 63
-61
0.675
0.800
LDL=62
LDL=95
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CHD Event Rates in Secondary
Prevention and ACS Trials
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y = 0.1629x · 4.6776
R² = 0.9029
p < 0.0001
CHD Events (%)
25
4S-P
20
HPS-P
4S-S
15
LIPID-P
HPS-S
A2Z 20
CARE-P
A2Z 80
TNT 10 LIPID-S
IDEAL S20/40
PROVE-IT-AT TNT 80
CARE-S
IDEAL
A80
PROVE-IT-PR
10
5
0
30
50
70
90
110 130 150 170 190 210
LDL Cholesterol (mg/dl)
Updated from - O’Keefe, J. et al., J Am Coll Cardiol
ASTEROID Trial: Principal Findings
LDL/HDL mg/dL
Mean LDL level decrement and HDL
level increment (mg/dL)
132
130.4
110
88
66
60.8
43.1
44
49.0
22
0
LDL Levels
Baseline
HDL Levels
Mean Normalized Total atheroma volume (mm3)
240
210
180
150
120
90
60
30
0
212.2
Baseline
197.5
Follow-up
Follow-up
Presented at ACC 2006
Recent Coronary IVUS Progression Trials
Relationship between LDL-C and Progression Rate
1.8
CAMELOT
placebo
1.2
Median 0.6
Change
In Percent
0
Atheroma
Volume
(%)
-0.6
REVERSAL
pravastatin
ACTIVATE
placebo
REVERSAL
atorvastatin
A-Plus
placebo
ASTEROID
rosuvastatin
-1.2
50
60
70
80
90
100
110
120
Mean Low-Density Lipoprotein Cholesterol (mg/dL) r2= 0.95
Nissen S. JAMA 2006
p<0.001
Conclusions
• CVD is the leading cause of
morbidity/mortality in US today
• Enormous economic burden
• Identification/alterations of RF’s has had
a major impact on CVD incidence
• Lipid hypothesis has been proven
• TLC is the cornerstone of therapy
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