Treatment

of Hyperlipidemias

Pharmacology Team
Ansam Sawalha, Adham Abu Taha, Suhaib Hattab,
Naim Kittana and Waleed Sweileh

An-Najah National University

Faculty of Medicine and Health Sciences
Department of Biomedical Sciences
Risk factors for coronary heart disease (CHD):

1. High LDL cholesterol and TG

2. low HDL cholesterol.
3. cigarette smoking
4. Hypertension
5. Obesity
6. diabetes
• Elevated cholesterol can be due to:

1. Lifestyle: lack of exercise and consumption of a diet

containing excess saturated fatty acids
2. a single inherited gene defect in lipoprotein metabolism
3. combination of genetic and lifestyle factors.
 TREATMENT GOALS
• The primary goal: Reduction of the LDL level

• Recommendations for the reduction of LDL cholesterol to

specific target levels are influenced by
– Coexistence of CHD
– number of other cardiac risk factors

• The higher the overall risk of heart disease, the more

aggressive the recommended LDL-lowering therapy.
 ATHEROSCLEROSIS

A. Significance: Major cause of death in the U.S. (heart attacks

and strokes)

B. Risk Factors: Hypertension, age, obesity, diabetes, high fat

diet, smoking, stress, low HDL, lack of exercise, family history
and high plasma lipoproteins (VLDL, IDL and LDL).
 ATHEROSCLEROSIS

C. Pathogenesis:
- Elevated plasma lipoproteins such as VLDL, IDL and LDL are a
major risk factor in atherosclerosis

- Endothelium of blood vessel is injured and blood components

(LDL and platelets) infiltrate injured area.

- Growth factors cause proliferation of cells and plaque starts to

form at site of injury.
 ATHEROSCLEROSIS

C. Pathogenesis: (Continue)
- Cells internalize LDL (oxidized) and form foam cells (saturated
with fat).

- Cells die and plaque is formed.

- Narrowed vessel gets clogged by blood clot and stroke or heart

attack is the consequence.
 ATHEROSCLEROSIS

D. Rationale of treatment: Studies have clearly demonstrated

that appropriate diet and drugs reduces atherosclerosis-
induced mortality 20 to 40%.
Lipoprotein Structure
 Classification of Lipoproteins

1. Chylomicrons - carry triacylglycerol from the intestines to

the liver and adipose tissue.

2. Very low density lipoproteins (VLDL) - carry triacylglycerol

from the liver to adipose tissue.

3. Low density lipoprotein (LDL) - carry cholesterol from the

liver to the tissues. “Bad cholesterol“

4. High density lipoprotein (HDL) - collects cholesterol from

the tissues, and transport it back to the liver. “Good
cholesterol“
Classification of Lipoproteins
Composition of Lipoproteins
 Hyperlipoproteinemia

Lipoproteins Normal Values mg/dl

Total Cholesterol < 200

LDL 100

HDL 40-50

Triglycerides 150
Hyperlipoproteinemia
Fredrickson Classification of Hyperlipoproteinemia
Type Serum Lipoprotein
Disease Main cause
elevation elevation
I Familal Triglycerides Lipoprotein lipase Chylomicrons
hyperchylomicronemia deficiency
IIa Familal Cholesterol Defect in LDL receptors LDL
hypercholesterolemia
IIb Familal mixed Cholesterol and Overproduction of VLDL LDL, VLDL
hyperlipidemia triglycerides by liver
III Familal Cholesterol and Overproduction or IDL
dysbetalipoproteinemia triglycerides underutilization of IDL
(mutant apolipoprotien E)
IV Familal Triglycerides Overproduction or VLDL
hypertriglyceridemia decrease removal of
serum VLDL & TG
V Familal mixed Cholesterol and Overproduction or VLDL,
hypertriglyceridemia triglycerides decrease clearance of chylomicrons
VLDL & chylomicrons
Lipoprotein metabolism
LCAT: lecithin:cholesterol acyl transferase, CETP: cholesteryl ester transfer protein
FFA: free fatty acid
A. Treatment options for hypercholesterolemia

• Moderate hyperlipidemia:

– Lifestyle changes, such as diet, exercise, and weight

reduction, can lead to modest decreases in LDL levels and
increases in HDL levels.

– Patients who are unwilling to modify their lifestyle drug

therapy may be required.
Drug therapy:

A. Patients with
– LDL levels >160 mg/dL
– one other major risk factor, such as hypertension,
diabetes, smoking, or a family history of early CHD

B. Aggressive treatment:
– Patients with two or more additional risk factors should be
treated aggressively
– Aim:
• reducing LDL level to less than 100 mg/dL and, in some
patients, to as low as 70 mg/dL.
B. Treatment options for hypertriacylglycerolemia

• Primary modes of treating hypertriacylglycerolemia:

– Diet
– Exercise

• Efficacious drugs in lowering TG:

1. Niacin
2. Fibric acid derivatives
HMG CoA reductase Inhibitors :

• Most efficacious and well tolerated.

• They act by competitive inhibition of HMG CoA reductase

– the rate limiting step in cholesterol synthesis.
HMG CoA reductase Inhibitors
 Statins
Atorvastatin
Fluvastatin
Lovastatin
Mevastatin
Pravastatin
Rosuvastatin
Simvastatin
Simvastatin+Ezetimibe
Lovastatin+Niacin extended-release
Atorvastatin+Amlodipine Besylate
Simvastatin+Niacin extended-release
HMG CoA reductase Inhibitors:

1. Reduced cholesterol synthesis results in a compensatory

increase in the hepatic uptake of plasma cholesterol
mediated by an increase in the number of LDL receptors.

2. Hepatic synthesis of VLDL is reduced

3. There is an increase in HDL levels

HMG CoA reductase Inhibition
 HMG CoA reductase Inhibitors

• Lovastatin and Simvastatin:

– Prodrugs, have to be hydrolyzed to be activated.
– Cross the BBB and can cause sleep disturbances

• Fluvastatin – Less myopathy

• Atorvastatin and rosuvastatin are long acting

– Rosuvastatin, Pitavastatin, & Atorvastatin are the most
potent in decreasing LDL cholesterol.
– Atorvastatin (Lipitor) – antioxidant effect
 Pharmacokinetics:

• Absorption after oral administration:

– Pravastatin and fuvastatin: complete
– Lovastatin and simvastatin: 30 -50%

• Pravastatin and fuvastatin are active as such

• Lovastatin and simvastatin must be hydrolyzed to their acid

(active) forms.
 Pharmacokinetics:

• All are metabolized in the liver and excreted through bile and
feces, but there is also some urinary elimination

• Their half-lives range from 1.5 to 2 hours.

Comparison of some pharmacokinetic parameters for
some HMG-CoA reductase inhibitors
 Therapeutic uses of HMG-CoA reductase inhibitors :

• Lowering plasma cholesterol levels in all types of hyperlipidemias

• Patients who are homozygous for familial hypercholesterolemia

lack LDL receptors and, therefore, benefit much less from
treatment with these drugs.
Adverse effects of HMG CoA reductase Inhibitors:

• Headache
• Sleep disturbances
• Hepatotoxicity
• Myopathy (muscle tenderness) and rhabdomyolysis
Drug interactions:
– May increase Warfarin levels

Contraindications:
• During pregnancy and in nursing mothers.
• In children or teenagers.
 Bile acid–binding resins

Ø Cholestyramine
Ø Colestipol
Ø Colesevelam

• These are bile acid binding resins

• They are neither digested nor absorbed in

the gut

• These interrupt enterohepatic circulation of

bile salts and increase fecal excretion of bile
salts and cholesterol

• Increase in LDL receptor in the liver

Effect of bile-acid binding resins
 Effect of bile-acid binding resins

• Compensatory increase in the activity of HMG CoA reductase

results in increased cholesterol synthesis and thus increased
VLDL secretion – blunting the long term effectiveness of
monotherapy

• Mild increase in triglycerides can be seen.

Therapeutic uses of bile-acid binding resins:

• These are the drugs of choice (often in combination with diet

or niacin) in treating Type IIA and Type IIB hyperlipidemias

• [Note: In those rare individuals who are homozygous for Type

IIA, that is, for whom functional LDL receptors are totally
lacking, these drugs have little effect on plasma LDL levels]

• Cholestyramine can also relieve pruritus caused by

accumulation of bile acids in patients with biliary obstruction

• It is also used to treat diarrhea

Adverse effects

• GI disturbances, such as constipation, nausea, and

flatulence.

• Colesevelam has fewer GI side effects than other bile

acid sequestrants.

• At high doses, cholestyramine and colestipol (but not

colesevelam) impair the absorption of the fat-soluble
vitamins (A, D, E, and K).
Drug interactions:

• Cholestyramine and colestipol interfere with the intestinal

absorption of many drugs (for example, tetracycline,
phenobarbital, digoxin, warfarin, pravastatin, fuvastatin,
aspirin, and thiazide diuretics).

• Therefore, drugs should be taken at least 1–2 hours before, or

4–6 hours after, the bile acid–binding resins.
Cholesterol uptake inhibitor: Ezetimibe

• It decrease cholesterol absorption by localizing at the brush

border of the small intestine.

• In addition to this direct effect, decreased cholesterol

absorption leads to an increase in LDL-cholesterol uptake into
cells, thus decreasing levels in the plasma.

• Can be used in combination with Simvastatin (Vytorin®)

 Pharmacokinetics of Ezetimibe

• Ezetimibe is metabolized in the small intestine and liver via

glucuronide conjugation, with subsequent biliary and renal
excretion.

• half-life of approximately 22 hours.

• Patients with moderate to severe hepatic insufficiency should

not be treated with ezetimibe.
 Niacin (nicotinic acid)

• The most rapid effect of nicotinic acid on

lipid metabolism is a decrease in plasma
levels of free fatty acid , which can be
observed within minutes upon
administration of the drug.

• After a few hours, the plasma VLDL and

TG levels are reduced, whereas the LDL
and HDL cholesterol levels are changed
only after several days of treatment.

• It reduces VLDL and TG production

• The most effective in increasing HDL

• Effective in reducing LDL

Therapeutic uses of niacin:

• Niacin lowers both cholesterol and triacylglycerol. So it is

useful in the treatment of familial hyperlipidemias.

• Used in treating severe hypercholesterolemias

• It is the most potent anti-hyperlipidemic agent for raising

plasma HDL levels, which is the most common indication for
its clinical use.
Adverse effects of Niacin

• Cutaneous dilator – flushing, itching

• Liver dysfunction

• Hyperglycemia

• Potentiates gout (decrease uric acid secretion), diabetes and

peptic ulcers
 Fibric acid derivatives

• Drugs:
§ Fenofibrate (a prodrug for the active metabolite fenofibric
acid)
§ Gemfibrozil
§ Clofibrate

• They lower serum triacylglycerol and increase HDL levels

 Mechanism of action of Fibric acid derivatives

• They interact with the peroxisome proliferator activated

receptor alpha (PPARα) which regulates gene expression of
enzymes involved in fatty acid oxidation.

• They increase expression of lipoprotein lipase, which

enhances clearance of triglyceride rich lipoproteins.

• Fibrates also increase the level of HDL cholesterol by

increasing the expression of apo AI and apo AII.
 Therapeutic uses:

• Treatment of hyper triacylglycerolemias, causing a significant

decrease in plasma triacylglycerol levels.

• Treatment of Type III hyperlipidemia (dysbetalipo proteinemia),

in which intermediate-density lipoprotein particles accumulate.

• Patients with hypertriacylglycerolemia (Type IV [elevated VLDL]

or Type V [elevated VLDL plus chylomicron] disease) who do not
respond to diet or other drugs may also benefit from treatment
with these agents.
Adverse effects :

• Gall stones with clofibrate

• Myopathy (Myositis):
- Inflammation of skeletal muscles) causing muscle weakness
and tenderness
- Rhabdomyolysis can occur
- Risk is greatly increased in combination with statins
(contraindicated)
• Nausea
• Skin Rash
Drug interactions:

• Fibrates compete with the coumarin anticoagulants for

binding sites on plasma proteins (monitor INR frequently)

• They may transiently elevate the levels of sulfonylureas.

Drugs for Hyperlipoproteinemia
Drugs for Hyperlipoproteinemia
Drugs Indication Effects On Adverse
Lipid Profile Effects

Cholestyramine Elevated LDL ↓ LDL(20%) GI problems

Colistipol Pregnancy and ↑ TGs (~5%) (bloating,
Colesevelam Children constipation)

Niacin Elevated LDL, ↓ TG (40%) Flushing of face

Low HDL and ↓ LDL (15%) & Pruritus
Elevated TG ↑ HDL (25%) Hyperglycemia

Gemfibrozil Elevated TG ↓ TG (50%) Myositis

↓ LDL (10%) Gall stones
↑ HDL (15%)

HMG-CoA Elevated LDL ↓ LDL (30%) Hepatotoxicity

Reductase ↑ HDL (8%) Myositis
Inhibitors ↓ TG (20%)