Lipoprotein Disorders and

Management: 2008 Update

. .

Outline
History of cholesterol and atherosclerosis
(experimental, genetic, and epidemiological
evidence)
Approach to dyslipidemia

N. N. Anitschkow

History of Cholesterol and

Atherosclerosis
Cholesterol feeding in other animals (rats and
dogs) failed to induce lesions
Atherosclerosis was thought to be an inevitable
accompaniment of aging, a chronic slowly
progressive deterioration developing over
decades

Plasma Lipids
Cholesterol
Free (unesterified) cholesterol
Cholesterol ester (cholesterol + fatty acid)
Triglyceride (glycerol + fatty acids)
Phospholipids
Others

Lipoproteins

Lipoproteins
Particles composed of lipids and proteins
Transported in plasma
Different types, classified according to density
after ultracentrifugation
Chylomicron and remnants
Very low density lipoprotein (VLDL) and remnants
Low density lipoprotein (LDL)
High density lipoprotein (HDL)

John W. Gofman

The first person to characterize lipoproteins

successfully
He later showed the correlation between
lipoprotein and risk of coronary heart disease

Tendinous xanthoma in FH

Familial hypercholesterolemia (FH)

autosomal dominant
typically have mutations affecting LDL receptor
The result of these mutations is a high level of serum
cholesterol
Individuals who are homozygous for the disease have
very high levels of cholesterol usually die of heart disease
before age 20
People heterozygous for the disease have higher
cholesterol than normal and are at high risk for heart
attacks in their 30s and 40s

Relationship Between Cholesterol and CHD Risk

Epidemiologic Trials
MRFIT (n=361,662)

150

50

125
100
75
50
25

40
(Deaths/1000)

10-year CHD death rate

CHD indications per 1000

Framingham Study (n=5,209)

30
20
10

0
204

205-234

235-264

265-294

295

Serum cholesterol (mg/dL)

Each 1% increase in total cholesterol level is
associated with a 2% increase in CHD risk

150

200

250

300

Serum cholesterol (mg/dL)

1% reduction in total cholesterol
resulted in a 2% decrease in CHD risk

Castelli WP. Am J Med. 1984;76:4-12, Gotto AM Jr, et al. Circulation. 1990;81:1721-1733

Incidence
per 1,000 (in 6 years)

CHD Risk According to HDL-C Levels

Prospective Cardiovascular Mnster Study
120

110

100

186 events in 4,407 men

(aged 4065 y)

80
60
30

40

21

20
0

< 35

3555
HDL-C (mg/dL)

> 55

Assmann G, ed. Lipid Metabolism Disorders and Coronary Heart Disease. Munich: MMV Medizin Verlag, 1993

LDL and Atherogenesis

Cholesterol efflux

Approaches to Dyslipidemia
1.
2.
3.
4.
5.
6.

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Lipoprotein analysis
To identify the abnormalities of dyslipidemia
1. High cholesterol (high LDL)
2. High triglyceride
3. Low HDL cholesterol
4. Mixed
5. Others

Who should be tested?

1. Patients with atherosclerotic vascular
disease
2. High-risk patients
3. Patients with abnormal physical findings

Who should be tested?

1. Patients with atherosclerotic vascular
disease
1. Coronary artery disease
2. Cerebrovascular disease
3. Peripheral vascular disease

Who should be tested?

2. High-risk patients
1. Age 45 (males), 55 (females)
2. Family history of premature coronary artery
disease: < 55 in males, < 65 in females
3. Diabetes mellitus
4. Hypertension
5. Smoking
6. Obesity
7. Nephrotic syndrome or chronic renal failure

Who should be tested?

3. Patients with abnormal physical findings
1. Corneal arcus
2. Xanthelasma
3. Tendon xanthoma
4. Palmar xanthoma
5. Eruptive xanthoma

What is your diagnosis?

Tendinous xanthoma

Tendinous xanthoma

What is your diagnosis?

Folliculitis

Eruptive xanthoma

Eruptive xanthoma
Small yellowish round papules
Found on the abdomen, back, buttocks, and pressure
areas
Due to accumulation of triglyceride in macrophages
Pathognomonic for severe hypertriglyceridemia

Lipemia retinalis and lipemic serum

Tuberous xanthoma

Planar xanthoma

Who should be tested?

Adults over 20 years of age (NCEP-ATP III)
In normal population, recommend
screening those in urban areas over the
age of 35 (RCPT)

Recommendations for lipoprotein analysis

Complete lipoprotein profile preferred
Fasting total cholesterol, HDL cholesterol, and triglycerides

Calculate LDL cholesterol using Friedewalds formula:

LDL cholesterol = TC HDL-C TG/5

Secondary option
Non-fasting total cholesterol and HDL
Proceed to lipoprotein profile if total cholesterol 200 mg/dL
or HDL <40 mg/dL

Lipid and Lipoprotein Classification

Total Cholesterol (mg/dL)

< 200
200239
240

Desirable
Borderline high
High

Lipid and Lipoprotein Classification

LDL Cholesterol (mg/dL)
< 100
100129
130159
160189
190

Optimal
Near optimal/above optimal
Borderline high
High
Very high

Lipid and Lipoprotein Classification

HDL Cholesterol (mg/dL)
< 40
60

Low
High

Elevated Triglycerides
Classification of Serum Triglycerides

Normal
Borderline high
High
Very high

< 150 mg/dL

150 199 mg/dL
200 499 mg/dL
500 mg/dL

Approaches to Dyslipidemia

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Secondary Causes of Dyslipidemia

Diabetes mellitus
Hypothyroidism
Obstructive liver disease/cholestasis
Chronic renal failure/nephrotic syndrome
Lipodystrophies
Drugs

clinical lab

Secondary Causes of Dyslipidemia

Drugs:
Steroids
Ethanol
Estrogen, progestins
Testosterone
Thiazides
Retinoids
HIV protease inhibitors

Approaches to Dyslipidemia

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Three Categories of Risk that Modify

LDL-Cholesterol Goals
Risk Category

LDL Goal (mg/dL)

CHD and CHD risk

equivalents

< 100

Multiple (2+) risk factors

< 130

Zero to one risk factor

< 160

CHD Risk Equivalents

Other clinical forms of atherosclerotic disease
peripheral arterial disease
abdominal aortic aneurysm
symptomatic carotid artery disease

Diabetes
(Multiple risk factors that confer a 10-year risk
for CHD >20%)

Major Risk Factors

Cigarette smoking
Hypertension (BP 140/90 mmHg or on
antihypertensive medication)
Low HDL cholesterol (< 40 mg/dL)
Family history of premature CHD
CHD in male first degree relative < 55 yrs
CHD in female first degree relative < 65 yrs
Age (men 45 yrs; women 55 yrs)

HDL cholesterol 60 mg/dL counts as a negative risk factor; its

presence removes one risk factor from the total count.

LDL Cholesterol Goals and Cutpoints in

Different Risk Categories

Risk Category

CHD or CHD Risk

Equivalents

2+ Risk Factors

01 Risk Factor

LDL Level at
Which to Initiate
Therapeutic
Lifestyle Changes
(TLC) (mg/dL)

LDL Level at
Which
to Consider
Drug Therapy
(mg/dL)

< 100

100

130
(100129: drug
optional)

< 130

130

160

< 160

160

190

LDL Goal
(mg/dL)

ATP III Risk Categories

High
High Risk
Risk

CHD, PAD, carotid

disease, diabetes, 2+
RF
(10-year risk > 20%)
LDL-C goal
< 100 mg/dL

Moderately
Moderately High
High Risk
Risk

2+ RF
(10-yr risk 1020%)
LDL-C goal
< 130 mg/dL

Moderate
Moderate Risk
Risk

2+ RF
(10-yr risk < 10%)
LDL-C goal
< 130 mg/dL

Lower
Lower Risk
Risk

01 RF
LDL-C goal
< 160 mg/dL
Slide Source
LipidsOnline
www.lipidsonline.org

Implications of Recent
LDL-Lowering Trials
High-risk patients with various LDL-C levels
Patients with diabetes
Older patients
Acute coronary syndromes
Moderately high risk patients
Grundy, et al. Circulation 2004;110:227-39

Implications of Recent
LDL-Lowering Trials
High-risk patients with various LDL-C levels
LDL-C 130 mg/dL: drug + diet
LDL-C 100129: LDL-lowering drug preferred (over

other options)
LDL-C < 100 mg/dL
Very high risk patients: LDL-C goal < 70
Other high-risk patients: optional therapies including

statins, fibrates, nicotinic acid

Candidates for Very Low LDL-C Goal of

<70 mg/dL
Very high risk patients
Established atherosclerotic CVD
+ multiple risk factors (esp. diabetes)
+ severe and poorly controlled risk factors (e.g.,

cigarette smoking)
+ metabolic syndrome (high TG, low HDL-C)
+ acute coronary syndromes (PROVE IT)

Whats New for High-Risk Patients?

ATP III LDL-C goal: < 100 mg/dL
For very high risk: optional goal < 70 mg/dL
For LDL-C 100 mg/dL, start LDL-lowering drug

simultaneously with lifestyle changes

For LDL-C < 100 mg/dL, LDL-lowering drug is a

therapeutic option
For high TG/low HDL-C, consider fibrate or nicotinic acid

in combination with LDL- lowering drug

Implications of Recent
LDL-Lowering Trials
Patients with diabetes
HPS supports ATP IIIs high-risk status
Benefit of statin therapy (HPS, CARDS)
Older patients
Benefit of LDL lowering (HPS, PROSPER, ASCOT-

LLA ALLHAT-LLT)
Acute coronary syndromes
Consider LDL-C goal < 70 mg/dL (PROVE IT)
Grundy, et al. Circulation 2004;110:227-39

NCEP ATP III: LDL

-C Goals
LDL-C
(2004 proposed modifications)
High Risk

190 -

CHD or CHD risk 2 risk factors

equivalents
(10-yr risk 10(10-yr risk >20%)
20%)

LDL-C level

160 -

130 -

Moderately
High Risk

goal
130
mg/dL

goal
100
mg/dL

Moderate Risk

Lower Risk

2 risk factors

< 2 risk
factors

(10-yr risk
<10%)

goal
160
mg/dL

goal
130
mg/dL

or
optional
100 mg/dL

100 or
optional
70 mg/dL

Existing LDL-C goals

Proposed LDL-C goals

70 Grundy SM, et al. Circulation 2004;110:22739.

Elevated Triglycerides
Primary target of therapy: LDL
cholesterol
Secondary target: Non HDL cholesterol
Achieve LDL goal before treating nonHDL cholesterol

Non HDL cholesterol

Non-HDL cholesterol = VLDL + LDL cholesterol
= (Total Cholesterol HDL cholesterol)
VLDL cholesterol: denotes atherogenic
remnant lipoproteins
Non-HDL cholesterol: secondary target of
therapy when serum triglycerides are 200
mg/dL (esp. 200499 mg/dL)
Non-HDL cholesterol goal:
LDL-cholesterol goal + 30 mg/dL

Comparison of LDL Cholesterol and

Non-HDL Cholesterol Goals for
Three Risk Categories

Risk Category

LDL-C Goal
(mg/dL)

Non-HDL-C
Goal (mg/dL)

CHD and CHD Risk Equivalent

< 100

< 130

Multiple (2+) Risk Factors

< 130

< 160

< 160

< 190

01 Risk Factor

SCORE

Approaches to Dyslipidemia

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Therapeutic Lifestyle Changes (TLC) in

LDL-Lowering Therapy
TLC Diet
Reduced intake of cholesterol-raising nutrients
Saturated fats < 7% of total calories
Dietary cholesterol < 200 mg per day
LDL-lowering therapeutic options
Plant stanols/sterols (2 g per day)
Viscous (soluble) fiber (1025 g per day)

Weight reduction
Increased physical activity

Approaches to Dyslipidemia

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Drugs for Dyslipidemia

1. HMG CoA Reductase Inhibitors (Statins)
2. Fibric Acid Derivatives (Fibrates)
3. Nicotinic Acid (Niacin)
4. Bile Acid Binding Resins (Resins)
5. Others

HMG CoA Reductase Inhibitors

(Statins)

Fluvastatin
Pravastatin
Simvastatin
(Lovastatin
Atorvastatin
Rosuvastatin
Pitavastatin

20-80 mg/d
10-40 mg/d
5-80 mg/d
10-40 mg/d)
10-80 mg/d
5-40 mg/d
1-8 mg/d

Cholesterol Biosynthetic Pathway

Squalene
synthase

HMG-CoA
reductase
Acetyl
CoA

HMGCoA

Mevalonate

Farnesyl
pyrophosphate

Dolichol

Squalene

Cholesterol

Farnesyltransferase
E,E,E-Geranylgeranyl
pyrophosphate
Farnesylated
proteins
Geranylgeranylated
proteins

Ubiquinones

Statins
Molecular mechanisms of action
SREBP feedback control

LDL

Key statin trials and

spectrum of risk

CHD/high cholesterol
4S1
CHD/average to high cholesterol
2
LIPID
Increasing
PROVE-IT3 CHD/low to average cholesterol
absolute CHD
4
MI/low to average cholesterol
CARE
risk
MI/low to average cholesterol
IDEAL5
CHD or diabetes/low to average cholesterol
HPS6
CHD/low to average cholesterol
TNT7
Diabetes and 1 other risk factor/low to average cholesterol
CARDS8
CHD or risk factors/average cholesterol
PROSPER9
no MI/high cholesterol
WOSCOPS10
ALLHAT-LLT11
some CHD/average cholesterol
ASCOT-LLA12
>3 risk factors/low to average cholesterol
AFCAPS/TexCAPS13
no CHD/average cholesterol

Benefits of cholesterol lowering

Meta-analysis of 38 primary and secondary intervention trials
-0.0

Mortality log odds ratio

-0.2

-0.4

-0.6

Total mortality (P = 0.004)

CHD mortality (P = 0.012)

-0.8

-1.0

12

16

20

24

28

32

36

40

% in cholesterol reduction
Gould AL, et al. Circulation 1998;97:94652.

Meta-analysis of statins

Fibric Acid Derivatives (Fibrates)

Gemfibrozil
Fenofibrate
Bezafibrate

Fibric Acid Derivatives (Fibrates)

Decrease triglyceride 25-55% by decreasing
VLDL production and enhancing clearance
Increase fatty acid oxidation and increase
lipoprotein lipolysis
Increase HDL cholesterol 6-35%
Activates PPAR- (Peroxisome proliferator
activated receptor-)

Niacin (Nicotinic acid)

Decreases LDL cholesterol by 20-30%,
decreases triglyceride by 30-50%, and
increases HDL cholesterol by 15-30%
Decreases VLDL production by inhibiting
lipolysis from the adipose tissue
Increases HDL by decreasing clearance of
apo A-I

Niacin
50 mg tab, 375 mg tab and 500 mg tab
Dose: 1.5-3.0 g/d, Maximum dose: up to 6
g/d
Side effects:
Flushing
GI symptoms
Insulin resistance
Hyperuricemia
Hepatitis

Bile acid-binding resins

Bind bile acids and inhibit enterohepatic
recirculation, resulting in increased hepatic
LDL receptor and increased LDL clearance
Cholestyramine and Colestipol
Decrease LDL cholesterol by 10-30%
May increase triglyceride levels
GI side effects

Cholesterol absorption inhibitor

Inhibits cholesterol absorption in the gut
Compensatory increase in hepatic cholesterol
synthesis, hepatic LDL receptor and LDL
clearance
Ezetimibe (10 mg/tab) OD
Can be combined with a statin
Decreases LDL cholesterol by 12-18%
Contraindicated in active liver disease

Effect of Drugs on LDL-C Levels

% Reduction
HMG CoA RI

20-50%

Bile acid resins

15-25%

Nicotinic acid

15-30%

Gemfibrozil

10-15%

Fenofibrate

10-25%

Ezetimibe

12-18%

Dose dependent

Fixed dose

Effect of Drugs on Triglyceride

and HDL-C Levels
HDL-C

Triglyceride

Nicotinic acid

10-30%

20-50%

Fibrates

10-25%

20-50%

HMG CoA RI

5-10%

10-25%

Bile acid resins

3-5%
1-4%

0-20%

Ezetimibe

15-20%

Which Drug(s) to Use?

High LDL

Statin, Niacin, Resin

High Triglyceride

Fibrate, Niacin, Statin

Low HDL

Niacin, Fibrate, Statin

Mixed

Niacin, Statin

Approaches to Dyslipidemia

Complete Fasting Lipoprotein Analysis

Rule Out Secondary Causes
Assess Other CHD Risk Factors and Goals
Therapeutic Lifestyle Changes
Drug Therapy
Monitoring

Statin-associated myopathy
Who is at risk?
1. elderly thin female
2. multiple medical problems
- renal insufficiency
- hepatic dysfunction
- hypothyroidism
3. Polypharmacy

Drugs that increase risk of

statin-associated myopathy
Fibrates, esp. Gemfibrozil
Niacin
Macrolide antibiotics
Azole antifungals
Cyclosporine
HIV protease inhibitors
Amiodarone, verapamil, diltiazem, digoxin, grapefruit juice

Conclusion
Dyslipidemia is a major risk factor for
atherosclerosis
Management requires therapeutic lifestyle changes
medications
Benefits of statins in high-risk patients have been
demonstrated