DISLIPIDEMIA

Dharma Lindarto
Div: Endokrinologi-Metabolik. Departemen Ilmu Penyakit Dalam
FK USU/RSUP. H Adam Malik Medan

Introduction
Dyslipidemia is a general term associated with
high cholesterol and/or high triglyceride (TG)
levels in plasma.
Combined Dyslipidemias is both cholesterol
(>200 mg/dL) and TGs are elevated.
Cholesterol and triglycerides are normally
present in the body and needed for normal cell
function. (steroids, digestion, cell membranes)
Two major clinical sequlae of hyperlipidemia are
acute pancreatitis and atherosclerosis.

Lipoprotein Subclasses
0.95

Density (g/ml)

Chylomicrons

VLDL
1.006

IDL
Chylomicron
Remnants

1.02
LDL
1.06
HDL2

1.10
1.20

Lp(a)

HDL3
5

10

20

40

60

Diameter (nm)

80

1000

Functions of the Plasma

Lipoproteins

ChylomicronTransport of dietary triglyceride

VLDL
Transport of endogenous triglyceride
IDL
-LDL precursor
LDL
Major cholesterol transport lipoprotein (BAD)
HDL
Reverse cholesterol transport (GOOD)

Released into lymph, and reach circulation through thoracic duct

Apolipoproteins
ApoA-I, which is synthesized in the liver and intestine, is
found on virtually all HDL1 particles.
ApoA-II is the second most abundant HDL
apolipoprotein.
ApoB is the major structural protein of chylomicrons,
VLDL2, IDL3, and LDL4; apoB-48 (chylomicrons) or
apoB-100 (VLDL, IDL, or LDL),
ApoE is present in multiple copies on chylomicrons,
VLDL, and IDL and plays a critical role in the metabolism
and clearance of triglyceride-rich particles.
ApoC-series (apoC-I, -II, and -III) also participate in the
metabolism of triglyceride-rich lipoproteins.

Atherosclerosis
Atherosclerosis is the deposit of plaques containing
cholesterol and lipids on the innermost layer of the walls of
arteries.
Atherosclerosis is the leading cause of death for both sexes
in the US. (MI, hypertension,, brain infarct, death)
A key risk factor in the development of atherosclerosis is
high blood cholesterol.
Among non-Hispanic whites age 20 and older, the ageadjusted prevalence of total blood cholesterol levels over 200
mg/dL is 48.9 percent of men and 52.1 percent of women. *
* National Health and Nutrition Examination Survey (NHANES), 1999-2002, Centers for Disease
Control/National Center for Health Statistics.

Pathogenesis of Atherosclerotic Plaques

Endothelial damage
Protective response results in production of
cellular adhesion molecules (ICAM)
Monocytes and T lymphocytes attach to
sticky surface of endothelial cells
Migrate through arterial wall to subendothelial space
Macrophages take up oxidised LDL-C
Lipid-rich foam cells
Fatty streak and plaque

The inflammatory atherosclerotic process

Inflamm
markers,
CRP

Lumen of
blood vessel

sdLDL

endothelium
sdLDL
Artery
wall

Inflamm
cytokines,
IL-6, TNF
NFB
O2 - ROS

PLAQUE
RUPTURE

monocyte
MMP-9

MCP-1
ICAM-1

fatty streak

chemotaxis

Complex
(vulnerable)
plaque

differentiation

ox-LDL
foam cell

Smooth muscle
cells

Lipid Levels in ATP III

Disorder Lipoprotein
metabolisme
1.

Hypertriglyceride
Primary Hypertriglyceridemia
Secondary Hypertriglyceridemia

2.

Primary Familial Hypercholesterolemia

Familial Hypercholesterolemia
Familial combined Hyperlipidemia
Lp (a) hyperlipoproteinemia

3.

Secundary Hypercholesterolemia
Obesity, Diabetes, Hypothyroid, Cushing disease,
renal disease

I. Primary Triglyceridemias
High triglyceride (TG) levels have been epidemiologically
linked with increased risk of coronary disease.
Often linked with elevated VLDL and chylomicron levels.
TG clearance is dependent on lipoprotein lipase.
When plasma levels of TGs reach levels reach 800mg/dl
or higher, lipoprotein lipase becomes saturated,
individuals above that level must be treated to prevent
acute pancreatitis.
Niacin and fibric acid derivatives are effective treatments.

II. Familial Hypercholesterolemia

Is an autosomal dominant trait, a defect in the high
affinity LDL receptor.
Homozygous individuals can have serum cholesterol
levels as high as 1000mg/dl, leading to childhood
development of coronary disease.
Niacin and Atorvastatin are beneficial, but binding
resins have from little to no effect in this disorder,
depending on LDL receptor activity.

III. Familial Ligand-Defective Apolipoprotein B

Defect in ligand region of apo B100 region of LDL
Impairs the endocytosis of LDL, leading to moderately
severe hypercholesterolemias.
Statins have variable effects, since even with
upregulation of LDL receptors, defective LDL still cant
taken up by cells.
Niacin produces beneficial effects by reducing vLDL
plasma levels.

IV. Familial Combined Hyperlipidemia

(The Phenotypic Classification of the Hyperlipoproteinemias based
upon serum electrophoresis are: Types I, IIA, IIB, III, IV and V)
Type I Hyperlipidemia
chylomicrons (triglycerides) results LPL or apo C-II,
Type IIA Hyperlipidemia
LDL.
Type IIB Hyperlipidemia :
of both LDL cholesterol and triglycerides.
Type III Hyperlipidemia
defect in VLDL remnant clearance

 Type IV Hyperlipidemia
- Hypertriglyceridemia 250 and 500 mg/dl.
Type V Hyperlipidemia
- chylomicrons and VLDL.

Coronary event, Eruptive xanthomas and pancreatitis

Symptoms of Hyper Cholesterolemia

High cholesterol rarely causes symptoms.

It is usually detected during a regular blood test
The first symptom of coronary artery disease (CAD)
is often chest pain (angina).
Unless the person has a transient ischemic attack
(TIA), it is rare to have any warning signs of an
oncoming stroke.
Some people with lipid disorders or familial
hypercholesterolemia symptoms such as deposits of
excess cholesterol in the skin or eye tissue, nodules
in tendons in the hands or feet or rarely yellow
streaks in the hands.

Eye signs in Hyperlipidaemia

CORNEAL
ARCUS

XANTHELASMATA

Secundary Hypercholesterolemia
Diabetes Mellitus
(1) LPL
catabolism of chylomicrons, VLDL.
(2) release of FFA from the adipose tissue
(3) FFA synthesis in the liver,
(4) hepatic VLDL production.
Hypothyroid
- hepatic LDL receptor function and clearance of LDL.
Cushing Syndrome
- VLDL synthesis and hypertriglyceridemia.
Regular alcohol consumption
- oxidation FFA

hepatic synthesis VLDL

CHD Risk Factors

Smoking
HTN >140/90 or on HTN Meds
HDL < 40 mg/dl
Family Hx of Premature CHD
1st degree Male < 45 yo
1st degree Female < 55 yo
Age
Men > 45 yo
Women > 55 yo
DM
HDL 60 mg/dl counts as negative Risk Factor

Risk Equivalents

CHD

MI
Angina
Angioplasty
Bypass Surgery

Non-coronary Atherosclerotic Disease

Peripheral Artery Disease
Carotid Artery Disease

DM

TREATMENT OPTIONS FOR

DYSLIPIDEMIA
Lifestyle Changes include:
-reduce CAD risk include smoking cessation,
-dietary changes,
-weight loss,
-and regular physical activity.
Dietary changes include:
- reducing the intake of saturated fats to less than
7% of the diet,
- reducing cholesterol to <200 mg/dL,
- increasing the intake of soluble fiber (10-25 g/d).

Diet Therapy for High Blood

Cholesterol

(Data from National Cholesterol Education Program [NCEP]. Second Report of the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel II]. NIH Publication N. 93-3095. Bethesda, MD; National
Institutes of Health. National Heart, Lung, and Blood Institute, 1993.) * Calories from alcohol not included.

Treatment Paradigm

Lipid Lowering Drugs

Lipoprotein Effects of Lipidmodifying Therapy

Statins

Nicotinic
acid

Fibrates

LDL

18%-55%

5%-25%

5%-20%

HDL

5%-15%

15%-35%

10%-20%

Triglycerides

7%-30%

20%-50%

20%-50%

Small, dense
LDL

No effect

Decrease

Decrease

Effect on
insulin
resistance

None

May increase May increase

Anti-hyperlipidemic Drugs
A. Niacin (Nicotinic Acid)
Treats combined dyslipidemias

Decreases LDL levels and vLDL levels.

Pharmacokinetics
Rapid absorption, Plasma T1/2- (20-40min)
Water soluble Vitamin B3 which is converted in the body into
nicotinamide adenine dinucleotide (NAD).
Excreted unchanged as well as a number of metabolites.

Mechanism primarily involves the inhibition of vLDL

secretion thereby reducing LDL levels!!. Also
lowers both triglycerides and Lp(a) levels.

Niacin (cont)
Side Effects:
Flushing, tachycardia, atrial arrhythmias, dry skin, nausea,
hyperuricemia, diarrhea, peptic ulcer disease, glucose
intolerance, hepatic dysfunction.

Contraindications
Peptics ulcers, cardiac arrhythmias, liver disease, gout and
diabetes mellitus

Drug Interactions
Works synergistically with ganglionic blockers leading to
orthostatic hypotension.

B. Fibric Acid Derivatives

Gemfibrozil and Fenofibrate
Reduces vLDL levels and increases the activity of

lipoprotein lipase!!!.

Typically used to treat hypertriglyceridemias in which vLDL

predominate and in dysbetalipoproteinemia.

Lowers triglycerides and raises HDL.

Pharmacokinetics
absorbed from the GI tract & undergoes enterohepatic
circulation. Most (70%) is eliminated unchanged through the
kidneys. Half life is 1.5 hrs.

Fibric Acid Derivatives (cont)

Side Effects:
rare cases of rash, GI symptoms, myopathy,
arrhythmias, hypokalemia & high aminotransferase or

alkaline phosphatase levels, risk of cholesterol

gallstones.

Major drug interactions:

fibric acid derivatives increase the anticoagulant effect

of coumarin & indanediones.

Contraindications

patients with hepatic or renal dysfunction, patients with

biliary tract disease

C. Bile Acid Binding Resins

Colestipol and Cholestyramine
Decrease LDL levels, increase HDL and TGs

Mechanism of Action:
Colestipol binds bile acids in the intestine forming a
complex that is excreted in the feces.
This nonsystemic action results in a partial removal of the
bile acids from the enterohepatic circulation, preventing
their reabsorption.
The increased fecal loss of bile acids due to colestipol
hydrochloride administration leads to an increased
oxidation of cholesterol to bile acids.
*** This results in an increase in the number of lowdensity lipoprotein (LDL) receptors, thereby
decreasing serum LDL levels

Bile Acid Binding Resins (cont)

Pharmacokinetics:
Not absorbed!!!

Side Effects
Constipation, may cause an increase in vLDL

necessitating the addition of a 2nd agent such as niacin.

Bad tasting may lead to compliance issues.
Ineffective in homozygous familial cholesteremia due to
lack of LDL receptor.

Drug interactions:
may delay or reduce the absorption of other concomitant oral
medications
Because these resins bind bile acids they may interfere with
normal fat digestion and absorption and thus may prevent
absorption of fat soluble vitamins such as A, D, E, and K.

D. HMG-CoA Reductase Inhibitors

Statins
They are structural analogues of hydroxy-methyl-glutaryl
coenzyme A (HMG-CoA) and are competitive
inhibitors of HMG-CoA reductase!!.
Used primarily for the reduction of LDL levels. Seems to
also have an effect on C-reactive protein (CRP) levels as
well.
Mechanism
HMG-CoA reductase mediates the first committed step in
sterol biosynthesis.
***This leads to an induction of high affinity LDL receptors,
thus lowering serum LDL levels.
Increasing LDL receptors is the impt. part of mechanism!
Due to the high first pass metabolism, the main effect of
these drugs is on the liver.

Statins (cont)
Pharmacokinetics
Lovastatin (Mevacor) and simvastatin (Zocor* ) are
inactive prodrugs and are activated in the GI tract,
all others are active drug.
Absorption varies between 40-75%, with fluvastatin
(Lescol*) being nearly completely absorbed.
High first pass metabolism by Cytochrome P450
(CYP 3A4 or CYP2C9) (grapefruit juice)
Mainly excreted in the bile with 5-20% excreted in
urine.
T1/2 ranges from 1 to 3 hours, except atorvastatin
(Lipitor*) T1/2=14 hrs.

Statins (cont)
Side Effects
Elevations of serum aminotransferase activity up to 3x
commonly occur and generally do not result in
hepatotoxicity.
In ~2% of patients (some of whom have underlying liver
disease or alcohol abuse) may have > 3x elevations in
aminotransferase levels, may indicate severe

hepatotoxicity, statin treatment should

discontinue immediately.
Rare side effect include myositis (muscle pain), marked by
elevated creatine kinase activity. If the drug is not
discontinued, rhabdomyolysis may occur producing
myoglobinemia that may lead to acute renal failure.

Statins (cont)
Major drug interactions:
Drugs that inhibit or compete for CYP 3A4 or
CYP2C9 will increase the plasma concentrations of
statins.
Drugs that induce CYP will reduce plasma statin
levels (see below).
Concomitant use of amiodarone or verapamil
causes an increased risk of myopathy.

Contraindications
Pregnancy due to potential teratogenicity

E. EZETIMIBE (Zetia*)
Prodrug (liverglucuronide)
Decreases GI Uptake of cholesterol
Both dietary and biliary secreted cholesterol
Reduces tightly regulated cholesterol pool in liver
resulting in increased synthesis of high affinity LDL
receptors and subsequent removal of LDL from blood
LOWERS SERUM LDL and TRIGLYCERIDES!!
INDICATIONS: hypercholesterolemia
TOXICITY: Well tolerated, but may increase hepatic
toxicity with HMG CoA reductase inhibitors

Dyslipidemia Treatment Guideline

This algorithm is useful once a confirmatory 9-12 hour fasting lipoprotein
profile is available and secondary dyslipidemia has been ruled out.
NCEP ATP III JAMA. 2001;285:2486-2497

Visit 2 TLC ONLY

(6 weeks later)

Visit 3 (6 weeks later)

Check LDL response

Intensify TLC
Consider ordering labs for next visit

Check LDL response

Intensify TLC
Consider drug therapy
(Go to VISIT 2, TLC & Rx)

HDL 40
TG < 200
HDL < 40
and CHD or
equivalent

Visit 1
Rule out secondary dyslipidemia*
Assess CHD risk
Identify CHD risk equivalents
(DM, AAA, ASPVD, symptomatic carotid disease)
Calculate 10-year risk -- see Framingham Risk Scoring
Identify major risk factors (RF) (see reverse)
If TG 400 treat to < 400$
Set LDL goal$ (Consider ordering labs for next visit now)
Determine initial treatment plan$
(TLC alone or TLC + Rx)
Begin Therapeutic Lifestyle Changes (TLC) if LDL > goal

Meet LDL goal

consider secondary
treatment goals

TLC and Rx HDL

(see reverse)

TG 200-499
Visit 2 TLC AND Rx

Visit 3 (6 weeks later)

(6 weeks later)
Check LDL response
Intensify TLC
Initiate LDL drug therapy if LDL
exceeds levels shown below.
Consider ordering labs for next visit

*Secondary Dyslipidemia
Diabetes
Hypothyroidism
Obstructive liver disease
Chronic renal failure
Drugs that LDL
Progestins
Anabolic steroids
Corticosteroids

Isolated low-HDL

Check LDL response

Maintain/Intensify TLC
Intensify current med
or initiate combination
therapy as needed

Primary Treatment Goals (mg/dL)

When TG 400, lab cant calculate LDL
Treat: TG-specific TLC + Niacin/Fibrate
When TG < 400; set LDL goals
Framingham
LDL Goal
Consider
10-yr Risk
(TLC if LDL above goal)
Add Meds
< 10% (0-1 RF)
< 160
160
< 10% (2+ RF)
< 130
160
10-20%
< 130
130

Follow up Visit
(q 4-6 mos.)
Monitor treatment
response
Maintain TLC
Monitor for drug
side effects

Metabolic Syndrome 3 of 5
Waist Circumference
Men
> 40
Women
> 35
Triglycerides
150
HDL
Men
< 40
Women
< 50
Fasting glucose 110
Blood Pressure 130 / 85

Secondary Treatment Goals

If TG 200 mg/dL non-HDL is 2 target
Usually seen with metabolic syndrome
LDL + VLDL = non-HDL-C = Total cholesterol HDL
Normal VLDL = 30 mg/dL, therefore
10-yr Risk
LDL Goal non-HDL Goal
< 10% (0-1 RF) < 160
< 190
< 10% (2+ RF) < 130
< 160
10-20%
< 130
< 160
> 20%
< 100
< 130

Initial Approach
Major Risk Factors (RF)
Age/Gender
Male 45 years
Female 55 years
BP 140/90 mm Hg or BP meds
Cigarette smoking
FH of CHD in 1 relative
Male < 55 years
Female < 65 years
HDL < 40 mg/dL

ATP III Lipid Classification

LDL Cholesterol
< 100
100-129
130-159
169-189
190

Optimal
Above optimal
Borderline high
High
Very high

Specific Dyslipidemias
Therapeutic Lifestyle Changes (TLC)
Smoking cessation as needed
Increase physical activity level
Limit saturated fats, like dairy fats (e.g. butter) and palm and
coconut oil (e.g. baked goods)
Limit high-cholesterol foods, like egg yolks, organ meats (such as
liver) and shellfish
Eat more fruits and vegetables
Eat more broiled or grilled fish and skinless chicken breasts
Choose lean cuts when you eat beef, pork and lamb. Also eat smaller
portions
Eat a variety of fiber-rich foods, like oats, dark breads and apples
Choose low-fat or nonfat dairy products
Avoid fried foods
(Adopted from information found at www.familydoctor.org)

Total cholesterol (TC)

< 200
200-239
240

- Associated with insulin resistance

- Elevated TG
- Overfat
- Physical inactivity
- Type 2 diabetes
- Cigarette smoking
- High-carb diet (> 60% of calories)
- Drugs:
- B-blockers
- Anabolic steroids
- Progestins
Treatment (usually for those with CHD or equivalent)
- Treat LDL then TLC
- HDL < 40 mg/dL + TG 200-499 mg/dL treat TG
- HDL < 40 mg/dL + TG < 200 mg/dL HDL raising
drugs

Generally represents genetic hypercholesterolemia

Important to identify in young adults
Treatment: often requires combination therapy

Low
High

Elevated Triglyceride
Contributory factors

Serum Triglycerides (TG)

< 150
159-199
200-499
500

Contributory factors

Very High LDL (>190 mg/dL)

Desirable
Borderline high
High

HDL cholesterol
< 40
60

Low HDL (< 40 mg/dL)

Normal
Borderline high
High
Very high

Lipid Lowering Medication

Drug Class
Statin

Lipid Effect
LDL 18-55%
HDL 5-15%
TG 7-30%

Side Effects
Myopathy
Increased LFTs

Contraindications
Absolute: liver disease
Relative: concomitant
use of some drugs

DoD Formulary
Simvastatin (Zocor)
start 20-40 mg after evening meal
not approved for flyers

Bile Acid
Sequestrant

LDL 15-30%
HDL 3-5%
TG no effect

GI distress; constipation
Decreased absorption
of other drugs

Absolute: TG > 400 mg/dL

Relative: TG > 200 mg/dL

Colestipol (Colestid)
start 1-2 gms qd-bid
work to 2-16 gms/day

Nicotinic acid

LDL 5-25%
HDL 15-35%
TG 20-50%

Flushing; hyperglycemia
upper GI distress
liver toxic; uric acid

Absolute: Chronic liver dz.

severe gout
Relative: diabetes; PUD

Niacin (Niaspan)
start 250 mg q HS
work to 1-2 gms bid-tid
not approved for flyers

Fibric acid

LDL 5-20%
HDL 10-20%
TG 20-50%

Dyspepsia; gallstones
myopathy; unexplained
non-CHD deaths in studies

Absolute: severe renal dz

severe hepatic dz.

Gemfibrozil (Lopid)
600 mg bid 30 min before meals
not approved for all flyers

- Obesity and overfat

- Physical inactivity
- Cigarette smoking
- Excess alcohol intake
-High-carb diet (> 60% of calories)
- Diseases
- Type 2 diabetes
- Chronic renal failure
- Nephrotic syndrome
- Drugs:
- Corticosteroids
- Estrogens
- Retinoids
Treatment (meet LDL goal, then)
- TG 150-199 mg/dL TLC
- TG 200-499 target non-HDL
- Intensify statin therapy
- Add nicotinic acid or fibrate
- TG 500 lower TG before LDL
- Very low-fat diet ( 15% of calories)
- Fat reduction
- Increased physical activity
- Nicotinic acid or fibrate
- When TG < 500 mg/dL lower LDL

Primary Prevention with Lipoprotein Analysis

(From National Cholesterol Education Program: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel II). National Institutes of Health, NIH Publication No. 93-3095. Bethesda,
MD: National Heart, Lung, and Blood Institute, 1993.)

2004, 2002 Elsevier Inc. All rights reserved.

Primary Prevention in Adults without Evidence of CHD:

Initial Classification Based on Total Cholesterol and
HDL Cholesterol

(From National Cholesterol Education Program: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel II). National Institutes of Health, NIH Publication No. 93-3095. Bethesda,
MD: National Heart, Lung, and Blood Institute, 1993.) HDL = high-density lipoprotein.

2004, 2002 Elsevier Inc. All rights reserved.

Reference
- 1. Basic and Clinical Endocrinology 7th Edition
- 2. 16th Edition HARRISONS PRINCIPLES OF Internal Medicine