COMMON CLINICAL PROBLEM HYPERLIPIDEMIA: AT GLANCE · Hyperlipidemia is characterized by elevated serum total cholesterol, low-density, and very low-density lipoprotein and decreased

COMMON CLINICAL PROBLEM HYPERLIPIDEMIA: AT GLANCE

Dr. Nishkruti Mehta*, Dr. Pankti Dalwadi & Dr. Pragnesh Patani

Department of Pharmacology, A-One Pharmacy College, Naroda, Ahmedabad.

Email: [email protected]

ABSTRACT:

Hyperlipidemia is a medical condition characterized by an increase in one or more of the

plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids and or

plasma lipoproteins including very low-density lipoprotein and low-density lipoprotein along

with reduced high-density lipoprotein levels. This elevation of plasma lipids is among the

leading risk factors associated with cardiovascular diseases. Hyperlipidemia may basically be

classified as either familial hyperlipidemia or acquired hyperlipidemia. There are two types of

hyperlipidemia; modifiable and non-modifiable risk factors. Management of hyperlipidemia

requires multi-team intervention include medical, nutritional and lifestyle modifications. In

the meantime, statins and fibrates remain the major anti-hyperlipidemic agents for the

treatment of elevated plasma cholesterol and triglycerides respectively, with the price of

severe side effects on the muscles and the liver. The present review focuses mainly on the

types of hyperlipidemias, risk factors, symptoms, diagnosis and treatments of elevated lipid

profile.

KEYWORDS: Hyperlipidemia; elevated lipid levels; cardiovascular disease

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Volume 8, Issue 4, 2020

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http://aegaeum.com/ Page No: 265

INTRODUCTION:

Hyperlipidemia is characterized by elevated serum total cholesterol, low-density, and very

low-density lipoprotein and decreased high density lipoprotein levels. It has been ranked as

one of the greatest risk factors contributing to the prevalence and severity of coronary heart

diseases. Coronary heart disease, stroke, atherosclerosis and Hyperlipidemia are the primary

cause of death. Hyperlipidemia associated lipid disorders are considered to cause

atherosclerotic cardiovascular disease. Among these, Hypercholesterolemia and

hypertriglyceridemia are closely related to ischemic heart disease. 1

The American Heart Association has identified the primary risk factor associated with the

development of atherosclerosis. It is the elevated levels of cholesterol and triglyceride in the

blood. Therefore the clinician considers the treatment of hyperlipidemia to be one of the

major approaches towards decelerating the atherogenic process. Atherosclerosis, referred to

as a “silent killer”, is one of the leading causes of death in the developing countries like India.

In the general population, the cardiovascular risk from increased LDL cholesterol and is

supported by observations that cholesterol-lowering therapy greatly diminishes the clinical

manifestations of atherosclerosis, particularly since the advent of inhibitors of 3-HMG Co A

reductase (i.e., statins) that profoundly lower LDL cholesterol. In contrast to the situation

with LDL cholesterol, the relation between HDL cholesterol and atherosclerosis is an inverse

one.2, 3, 4

Human body needs cholesterol which is involved in building the membrane of the cells and

hormones like estrogen.5 Liver is responsible for controlling the content of cholesterol in the

blood stream. In the body, liver produces approximately 80% of the cholesterol whereas rest

of the cholesterol is obtained from the food like fish, eggs, meat, etc. 6 After having a meal,

cholesterol is digested and absorbed in small intestine then the metabolism and storage

occurred in the liver. The cholesterol may be secreted by the liver whenever the requirement

of cholesterol is needed by the body. 7 Cholesterol is not present in the food which is derived

from the plants. 8 Cholesterol and several other fats together deposit inside the arteries

making them narrower by which blood cannot pass easily through it and the pressure may be

elevated causing high blood pressure. 9 The deposition of cholesterol may lead to blood

clotting and if it breakdown and goes through the blood towards the heart then it may leads to

heart attack and if it enters the brain then it may increase the chances of stroke. The main

etiology of elevated cholesterol in blood is high intake of several saturated fats. 10 Cholesterol

are attached or carried by lipoproteins (lipo=fat) as it cannot travel freely in the blood. 11

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ABOUT LIPOPROTEINS 12,13,14

In the post absorptive state, after the removal of all chylomicrons from the blood, more than

95% of all the lipids in the plasma are in the form of lipoprotein, which are macromolecular

complexes of lipids with protein, containing TG, cholesterol, phospholipids, and fat-soluble

vitamins. They transport lipids through body fluids (plasma, interstitial fluid, and lymph) to

and from tissues. The total concentration of lipoproteins in the plasma averages about 700

mg per 100 ml of plasma with Cholesterol 180 mg/dl, Phospholipids 160mg/dl, Triglycerides

160mg/dl and Protein 200mg/dl.

Based on their relative densities and separation by electrophoresis they are classified as

Chylomicrons: They are synthesized in the small intestine in the course of fat absorption &

in liver and transport dietary TAG to various tissues. They consist of highest (99%) quantity

of lipid mostly TAG besides about 9% phospholipids, 3% cholesterol & lowest concentration

(1%) of protein Apoprotein B - 48. They have least density and is largest in size. Nascent

chylomicron with Apo C II & Apo E derived from HDL forms chylomicron. Chylomicron

formation fluctuates with the load of TG absorbed.

Very low density lipoproteins (VLDL): They contain high concentrations of TAG and

moderate concentrations of both cholesterol and phospholipids are produced in liver &

intestine. It helps transport of endogenously synthesised TAG. Nascent VLDL with Apo B

100 rich in TAG & cholesterol, with Apo CII & Apo E donated by circulating HDL forms

VLDL.

Intermediate-density lipoproteins (IDL): They are VLDL, from which a part of the TG

has been removed, so that the concentrations of cholesterol and phospholipids are

increased.

Low-density lipoprotein (LDL): They are derived from IDL in the course of VLDL

metabolism, by the removal of almost all the TG, leaving an especially high concentration

of cholesterol and a moderately high concentration of phospholipids. Apo E is returned to

HDL. Thereby LDL contains high cholesterol & less TAG. It transports cholesterol from

liver to other tissues. The key function of LDL is to supply cholesterol to extrahepatic

tissues by binding to the specific receptor pits on cell membrane which is recognized by

Apo B 100. Defect in LDL receptor causes elevation of plasma LDL & hence plasma

cholesterol.

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High-density lipoproteins (HDL): They contain a high concentration of protein

(about50%) but much smaller concentrations of cholesterol and phospholipids. Mostly

synthesized in liver, it transports cholesterol from peripheral tissues to liver. Free nacsent

HDL is synthesized in liver which contain free cholesterol, phospholipid & Apoprotein.

HDL accepts free cholesterol from other lipoprotein in circulation & cell membrane of

peripheral tissue which undergoes LCAT catalysed esterification.

FA complexed with albumin Each lipoprotein class comprises a family of particles that

vary slightly in density, size, migration during electrophoresis, and protein composition. The

density of a lipoprotein is determined by the amount of lipid and protein per particle. HDL

is the smallest and most dense lipoprotein, whereas chylomicrons and VLDL are the largest

and least dense lipoprotein particles Most TG is transported in chylomicrons or VLDL, and

most cholesterol is carried as cholesteryl esters in LDL and HDL .They function as transport

vehicles for lipids in blood plasma & deliver the lipid components to various tissue for

utilization. VLDL transport TG synthesized in the liver mainly to the adipose tissue,

whereas the other lipoproteins are especially important in the different stages of

phospholipid and cholesterol transport from the liver to the peripheral tissues or from the

periphery back to the liver.13

Low Density Lipoproteins (LDL) is thought to be as the ‘bad’ cholesterol due to higher ratio

of cholesterol content to protein and this elevated level may increase the risk of causing heart

disease, stroke, etc.15 Sometime plaque buildup or deposits along the walls of arteries due to

which artery become narrow and the flow of blood decreased in the body. 16 Blood flow may

obstruct by plaque rupture as it may cause a clotting of blood which may lead to heart attack

or myocardial infarction. 17 High Density Lipoprotein (HDL) may be protective against heart

disease, stroke, etc. and thus thought to be “good” cholesterol. 18 The lower level of

cholesterol and higher level of protein may leads to HDL. Very Low Density Lipoproteins

(VLDL) are associated with plaque deposits and contain even less protein than LDL. 19

Triglycerides are basically those types of fat which involves the low level of HDL and high

level of LDL with the elevated level of cholesterol.20 The blood test determines the total

cholesterol score by the sum of HDL, LDL and triglycerides. 21 A high score indicates higher

risk of various heart diseases. 22, 23

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CLASSIFICATION OF PRIMARY HYPERLIPIDEMIA:

Hyperlipidemia can be of two types-

1. Primary Type: Due to genetic causes such as mutation in receptor proteins.

2. Secondary Type: Due to underlying causes such as Diabetes, Lipid metabolism

abnormalities, myxoedema, nephritic syndrome, chronic alcoholism, drugs like

corticosteroids, oral contraceptives, β- Blockers etc.

Types of Primary Hyperlipidemia

Type I - Raised cholesterol with high triglyceride levels.

Type II - High cholesterol with normal triglyceride levels

Type III - Raised cholesterol and triglycerides

Type IV - Raised triglycerides, atheroma, and raised uric acid

Type V - Raised triglycerides

Table 1: Classification of primary Hyperlipidemia

Hyperlipo-

proteinemia

Synonyms Defect Increased

Lipoproteins

Serum

Appearance

TYPE I

A Buerger - Gruetz

syndrome, or

Familial Hyper

chylomicronemia

Decreased

lipoprotein

lipase (LPL)

Chylomicrons Creamy top

layer

B Familial Apoprotein

CII deficiency

Altered ApoC2

C - LPL inhibitor

in blood

TYPE II

A Familial

hypercholesterolemia

LDL receptor

deficiency

LDL Clear

B Polygenic

hypercholesterolemia

Decreased

LDL receptor

and increased

Apo B

LDL,

VLDL

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TYPE III

Familial

Dysbetalipoproteinemia

Defect in Apo

E 2

Synthesis

IDL Turbid

TYPE IV

Familial

Hypertriglyceridemia

Increased

VLDL

production and

Decreased

elimination

VLDL Turbid

TYPE V

mixed hyperlipoproteinemia

familial

Increased

VLDL

production and

Decreased LPL

VLDL and

Chylomicrons

Creamy top

layer &

turbid

bottom

Secondary Forms of Hyperlipidemia 24, 25

Table 2: Secondary forms of hyperlipidemia

Type Causes

1

Hypothyroidism.

Anorexia nervosa.

Obstructive liver disease.

Nephritic syndrome.

Acute intermittent porphyria.

Drugs like progestrin, cyclosporine, diuretics,

glucocorticosteroids, β- Blockers, protease

inhibitors, sirolimus, mitrazapine, isotretinone.

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Hypertriglyceridemia

Obesity.

Acute hepatitis.

Diabetes Mellitus.

Lipodystrophy.

Illeal bypass surgery.

Glycogen storage disease.

Systemic lupus eryethrematosus.

Mnoclonal gammopathy: Multiple myolema.

Drugs like Alcohol, estrogen, Β- Blockers,

glucocorticosteroids, bile acids, resins, interferone,

azons, antifungals, anabolic steroids.

Hypocholesterolemia

Malnutrition.

Malabsorption.

Chronic Liver disease.

Chronic Infectitious disease like AIDS.

Myeloproliferative disease.

Low LDL

Malnutrition.

Obesity.

Β- Blockers, steroids, probcol, Progestrin.

RISK FACTORS OF HYPERLIPIDEMIA 26

The major risk factors that modify LDL goals are:

Cigarette smoking

Hypertension (BP ≥140/90 mmHg or on antihypertensive medication)

Low HDL cholesterol [<1.0 mmol /L (<40 mg/dL)]

Diabetes mellitus

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Family history of premature CHD

CHD in male first-degree relative < 55 years

CHD in female first-degree relative < 65 years

Age (men ≥ 45 years; women ≥55 years)

Lifestyle risk factors

Obesity (BMI ≥ 30 kg/m2)

Physical inactivity

Atherogenic diet

Emerging risk factors

Lipoprotein(a)

Homocysteine

Prothrombotic factors

Proinflammatory factors

Impaired fasting glucose

Subclinical atherogenesis

SYMPTOMS OF HYPERLIPIDEMIA 27

Hyperlipidemia usually has no noticeable symptoms and tends to be discovered

during routine examination for atherosclerotic cardiovascular disease.

Deposits of cholesterol (known as xanthomas) may form under the skin

(especially around the eyes or along the Achilles tendon) in individuals with

familial forms of the disorder or in those with very high levels of cholesterol in

the blood.

Individuals with hypertriglyceridemia may develop numerous pimple-like lesions

across their body, severe inflammation of the pancreas and enlargement of spleen.

High cholesterol or triglyceride levels during lipid profile estimation.

Higher rate of obesity and glucose intolerance.

Heart attacks, chest pain and abdominal pain may occur.

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COMPLICATIONS OF HYPERLIPIDEMIA: 28,29

1. Pancreatitis

The pancreas is responsible for breaking down carbohydrates, fats and

proteins in the body. When hyperlipidemia occurs, an excess amount of

triglycerides can build up and cause infection known as pancreatitis

which can result in the eventual shut down of the pancreas entirely.

2. Premature Coronary Artery Disease

Hyperlipidemia occurs when the blood vessels, which bring blood and

oxygen to heart, begin to narrow and the heart has to work overtime to

pump blood through the body. Eventually, the vessels become so

narrow that the blood cannot be pumped through to the heart. Early

symptoms are chest pain and difficulty in breathing, and eventually can

cause a heart attack.

3. Heart Attack

A heart attack can be a result of coronary artery disease, occurs when

blood vessels which brings blood to the heart become completely

blocked. When this occurs, heart muscle begins to slowly die off,

creating permanent damage. Heart attacks are a serious occurrence and

can result in death if not treated quickly enough.

4. Stroke

Hyperlipidemia has been linked with increased stroke risk because

plaque build up which can loosen and cause an ischemic stroke and its

most common. The plaque lodges in the brain and prevent blood from

flowing to the brain, resulting in cell death.

5. Atherosclerosis

High lipid levels due to a build up of plaque can increase the rate at

which sticky, fatty deposits known as plaque build up in the body. In

addition to reducing the blood flow through the arteries, plaque also

causes the arteries to harden, making them less flexible, known as

atherosclerosis and can contribute to heart disease and possibly heart

attack.

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DIAGNOSIS OF HYPERLIPIDEMIA 30, 31, 32

Table 3: Ideal range of various lipoproteins

Lipoproteins Desirable Borderline High Remarks

Total cholesterol <200 200-239 >240 > 240 mg/dL

Hyper-

cholesterolemia

Total cholesterol

for Children

<180 > 180 mg/dL may

lead to premature

Atherosclerosis

Low density

lipoprotein

cholesterol

(LDL-C)

<130 130-159 160-189 >190 mg/dl is very

high level increase

CHD risk

High density

lipoprotein

cholesterol

(HDL-C)

Men > 40

Women >60

In general, HDL

levels < 40 mg/dL

increases risk for

CHD. Women

with levels < 47

mg/dL and men

<37 mg/dL have

increased risk

Triglycerides (TG) <150 150-199 >200 500 mg/dL or

above is Very

High

TREATMENT OF HYPERLIPIDEMIA

A. Non Pharmacologic Treatment 33, 34

1. Diet: Dietary modification is an important component in the management of

hyperlipidemia. Dietary saturated fat and cholesterol should be restricted in the

hypercholesterolemic patient. For patients who are hypertriglyceridemic, the

intake of simple sugars should also be prohibited. For severe hypertriglyceridemia

[>11.3 mmol/L (>1000 mg/dL)], restriction of total fat intake is critical. The most

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widely used diet to lower the LDL-C level is the “Step 1 diet” developed by the

American Heart Association. Most patients have a relatively modest (<10%)

decrease in plasma levels of LDL-C on a step I diet in the absence of any

associated weight loss. Almost all persons experience a decrease in plasma HDL-

C levels with a reduction in the amount of total and saturated fat in their diet.

2. Foods and Additives: Certain foods and dietary additives are associated with

modest reductions in plasma cholesterol levels. Plant stanol and sterol esters are

available in a variety of foods such as spreads, salad dressings, and snack bars

which interferes with cholesterol absorption and reduce plasma LDL-C levels by

10 to 15% when taken three times per day. The addition to the diet of psyllium,

soy protein, or Chinese red yeast rice (which contains lovastatin) having modest

cholesterol-lowering effects. Other herbal approaches like guggulipid require

further study to assess their effectiveness.

3. Weight Loss and Exercise: The treatment of obesity, if present, a favorable

impact on plasma lipid levels and should be actively encouraged. Plasma

triglyceride and LDL-C levels tend to fall and HDLC levels tend to increase in

obese persons who lose weight. Aerobic exercise has a very modest elevating

effect on plasma levels of HDLC in most individuals but has cardiovascular

benefits extended beyond the effects on plasma lipid levels.

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B. Pharmacologic Treatment: 35, 36, 37

1. STATINS:

It includes drugs like Atorvastatin, Pravastatin, simvastatin, fluvastatin,

rosuvastatin etc. Statins are the most effective and best-tolerated agents for

treatment of dyslipidemia. These drugs are competitive inhibitors of 3 - HMG Co

A reductase, which catalyzes an early, rate-limiting step in cholesterol

biosynthesis. Higher doses of the more potent statins (e.g., atorvastatin and

simvastatin) also reduce triglyceride levels caused by elevated VLDL levels. Some

statins also are indicated for raising HDL-C levels.

Mechanism:

Statins exert their major effect via reduction of LDL levels through a mevalonic

acid-like moiety that competitively inhibits HMG-CoA reductase.

By reducing the conversion of HMG-CoA to mevalonate, statins inhibit an early

and rate-limiting step in cholesterol biosynthesis.

Statins affect blood cholesterol levels by inhibiting hepatic cholesterol synthesis,

which results in increased expression of the LDL receptor gene.

In response to the reduced free cholesterol content within hepatocytes, membrane-

bound SREBPs are cleaved by a protease and translocated to the nucleus.

The transcription factors then bind the sterol-responsive element of the LDL

receptor gene, enhance transcription and increase the synthesis of LDL receptors.

Degradation of LDL receptors are also reduced. The number of LDL receptors on

the surface of hepatocytes results in increased removal of LDL from the blood,

thereby lowering LDL-C levels.

Some studies suggest that statins also can reduce LDL levels by enhancing the

removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL

production.

Since VLDL remnants and IDL are enriched in ApoE, a statin-induced increase in

the number of LDL receptors, which recognize both ApoB-100 and ApoE,

enhances the clearance of these LDL precursors.

The reduction in hepatic VLDL production induced by statins is thought to be

mediated by reduced synthesis of cholesterol, a required component of VLDL.

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This mechanism accounts for the triglyceride-lowering effect of statins and for the

reduction (~25%) of LDL-C levels in patients with homozygous familial

hypercholesterolemia treated with 80 mg of atorvastatin or simvastatin.

Side Effects: 38

Potential side effects include dyspepsia, headaches, fatigue, and muscle or joint

pains, hepatitis.

Severe myopathy and rhabdomyolysis are very rare.

2. BILE ACID SEQUESTRANTS:

The two established bile-acid sequestrants or resins (cholestyramine and

colestipol) are the oldest of the hypolipidemic drugs. They are probably the safest,

since they are not absorbed from the intestine. These resins are also recommended

for patients 11 to 20 years of age. Because statins are as effective as monotherapy,

the resins are used as second agents if statin therapy does not lower LDL-C levels

sufficiently. Statins, cholestyramine and colestipol usually are prescribed at

submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are

associated with unacceptable gastrointestinal side effects (bloating and

constipation) which limit compliance. Bile acid sequestrants are not systemically

absorbed and are very safe. They are the cholesterol-lowering drug of choice in

children and women of childbearing age who are lactating, pregnant, or could

become pregnant. These drugs can also be useful in young, well-motivated

patients with moderate hypercholesterolemia who wish to avoid systemic drug

therapy

Mechanism:

The bile-acid sequestrants are highly positively charged and bind negatively

charged bile acids but because of their large size, the resins are not absorbed, and

the bound bile acids are excreted in the stool.

Since over 95% of bile acids are normally reabsorbed, interruption of this process

depletes the pool of bile acids, and hepatic bile-acid synthesis increases.

As a result, hepatic cholesterol content declines, stimulating the production of

LDL receptors, similar to that of statins.

The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-

C levels, but partially offset the enhanced cholesterol synthesis caused by up

regulation of HMG-CoA reductase.

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3. FIBRIC ACID DERIVATIVES (FIBRATES):

It includes Clofibrate, Benzafibrate, Gemfibrozil etc. This are the drugs of choice

in patients with severe hypertriglyceridemia [11.3 mmol/L (>1000 mg/dL)] and

reasonably considered in patients with moderate hypertriglyceridemia [4.5 to 11.3

mmol/L (400 to 1000 mg/dL)].

Mechanism:

Effects of these compounds on blood lipids are mediated by their interaction with

peroxisome proliferator activated receptors (PPARs), which regulate gene

transcription.

Three PPAR isotypes (a, b, and g) have been identified. Fibrates bind to PPARa,

which is expressed primarily in the liver brown adipose tissue and to a lesser

extent in kidney, heart, and skeletal muscle.

Fibrates reduce triglycerides through PPARa-mediated stimulation of fatty acid

oxidation, increased LPL synthesis, and reduced expression of ApoC-III. An

increase in LPL enhances the clearance of triglyceride-rich lipoproteins.

A reduction in hepatic production of ApoC-III, serves as an inhibitor of lipolytic

processing and receptor-mediated clearance, would enhance the clearance of

VLDL.

Fibrate-mediated increases in HDL-C are due to PPARa stimulation of ApoA-I

and ApoA-II expression, which increases HDL levels

Side Effects:

Fibrates compounds usually are well tolerated. Side effects may occur in 5% to

10% of patients but most often are not sufficient to cause discontinuation of the

drug.

Gastrointestinal side effects occur in up to 5% of patients.

Other includes rash, urticaria, hair loss, myalgias, fatigue, headache, impotence,

and anemia.

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4. NICOTINIC ACID (NIACIN) 38

Nicotinic acid, or niacin, is a B-complex vitamin which reduces plasma

triglyceride and LDL-C levels, increase the plasma HDL-C (Table 335-6) in high

doses. Niacin is the only currently available lipid-lowering drug which

significantly reduces plasma levels of Lp(a). If properly prescribed and monitored,

niacin is a safe and effective lipid-lowering agent.

Mechanism:

Niacin inhibits the lipolysis of triglycerides by hormone-sensitive lipase, which

reduces transport of free fatty acids to the liver and decreases hepatic triglyceride

synthesis.

These agents may exert their effects on lipolysis by inhibiting adipocyte adenylyl

cyclase (AC).

A GPCR for niacin has been identified and designated as HM74A; its mRNA is

highly expressed in the adipose tissue and spleen, sites of high-affinity nicotinic

acid binding.

Niacin stimulates the HM74A (HM74b)- Gi-adenylyl cyclase pathway in

adipocytes, which inhibits c AMP production and decreasing hormone-sensitive

lipase activity, triglyceride lipolysis, and release of free fatty acids.

Niacin may also inhibit a rate-limiting enzyme of triglyceride synthesis,

diacylglycerol Acetyltransferase 2.

Niacin reduces triglyceride synthesis by inhibiting both the synthesis and

esterification of fatty acids, effects that increase ApoB degradation in liver.

Reduction of triglyceride synthesis reduces hepatic VLDL production, which

accounts for the reduced LDL levels.

Niacin also enhances LPL activity, which promotes the clearance of chylomicrons

and VLDL triglycerides, it also raises HDL-C levels by decreasing the fractional

clearance of ApoA-I in HDL rather than by enhancing HDL synthesis.

This effect is due to a reduction in the hepatic clearance of HDL-Apo A-I, but not

of cholesteryl esters, thereby increasing the Apo A-I content of plasma and

augmenting reverse cholesterol transport.

In macrophages, niacin stimulates expression of the scavenger receptor CD36 and

the cholesterol exporter ABCA1. The net effect of niacin on monocytic cells

("foam cells") is HDL-mediated reduction of cellular cholesterol content

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Side Effect:

The most frequent is cutaneous flushing which may be reduced with aspirin pre

treatment.

5. EZETIMIBE:38

Ezetimibe inhibits the absorption of dietary and biliary cholesterol from the

intestinal lumen.

It reduces LDL-C cholesterol levels by 18% as monotherapy or in combination

with a statin.

These agents are particularly useful in combination with a statin in patients unable

to reach their LDL-C goal on statin monotherapy.

The consequence of inhibiting intestinal cholesterol absorption is a reduction in

the incorporation of cholesterol into chylomicrons, reduced cholesterol content of

chylomicrons diminishes the delivery of cholesterol to the liver by chylomicron

remnants.

The diminished remnant cholesterol content may decrease atherogenesis directly,

as chylomicron remnants are very atherogenic lipoproteins.

Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants

stimulates expression of the hepatic genes regulating LDL receptor expression and

cholesterol biosynthesis.

The greater expression of hepatic LDL receptors enhances LDL-C clearance from

the plasma by 15% to 20%.

6. OMEGA-3 FATTY ACIDS (FISH OILS)38

N-3 polyunsaturated fatty acids (PUFAs) are present in high concentration in fish

and in flax seeds. The most widely used n-3 PUFAs for the treatment of

hyperlipidemia are the two active molecules in fish oil, eicosapentanoic acid

(EPA) and decohexanoic acid (DHA).

Side effects:

Burning

Fishy taste

Dyspepsia.

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C. Drug Combination 39

Combined drug therapy is useful

i. Significant increase in VLDL levels during treatment of hypercholesterolemia

with a resin;

ii. Initial rise in both LDL & VLDL levels.

iii. when LDL or VLDL levels are not normalized with a single agent

iv. when an elevated level of Lp(a) or an HDL deficiency coexists with other

hyperlipidemia.

1. FIBRIC ACID DERIVATIVES AND BILE ACID BINDING RESINS

Useful in treating patients with familial combined hyperlipidemia who shows

intolerance of niacin or statins. However, it may increase the risk of cholelithiasis.

2. HMG-COA REDUCTASE INHIBITORS & BILE ACID-BINDING RESINS

Combination is useful in the treatment of familial hypercholesterolemia but may

not control of VLDL in some patients with familial combined

hyperlipoproteinemia. Statins should be given at least 1 hour before or 4 hours

after the resin to ensure their absorption.

3. NIACIN & BILE ACID BINDING RESINS

This combination effectively controls VLDL levels during resin therapy for

familial combined hyperlipoproteinemia and other disorders involving both

increased VLDL and LDL levels. When VLDL and LDL levels are both initially

increased, doses of niacin as low as 1-3 g/d may be sufficient in combination with

a resin. The niacin-resin combination is effective for treating heterozygous

familial hypercholesterolemia.

Both the agents can be administered simultaneously, because niacin does not bind

to the resins. LDL levels in patients with heterozygous familial

hypercholesterolemia require daily doses of up to 6 g of niacin with 24-30 g of

resin.

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4. NIACIN & REDUCTASE INHIBITORS

This regimen is more effective than either agent alone in treating

hypercholesterolemia. Experience indicates that it is an efficacious and practical

combination for treatment of familial combined hyperlipoproteinemia.

5. REDUCTASEINHIBITORS AND EZETIMIBE

This combination is highly synergistic in treating primary hypercholesterolemia

and has some use in the treatment of patients with homozygous familial

hypercholesterolemia.

6. REDUCTASEINHIBITORS AND FIBRATES

Fenofibrate appears to be complementary with rosuvastatin or pravastatin in the

treatment of familial combined hyperlipoproteinemia and other conditions

involving elevations of both LDL and VLDL. The combination of fenofibrate with

rosuvastatin is particularly effective. Other statins may interact unfavourably due

to effects on cytochrome P450 metabolism.

7. TERNARY COMBINATION OF RESINS, EZETIMIBE, NIACIN

& REDUCTASE INHIBITORS

These agents act in a complementary fashion to normalize cholesterol in patients

with severe disorders involving elevated LDL and gives sustain effects with little

compound toxicity. Effective doses of the individual drugs may be lower than

when each is used alone eg, as little as 1-2 g of niacin may substantially increase

the effects of the other agents.

D. Newer Drugs 40

AdvicorR a once daily combination of Niaspan (extended release niacin) and

lovastatin lowers LDL and TGs to a greater extent than lovastatin alone and

can raise HDL by as much as 40%.

In December 2008, FDA approved, Trillipix (fenofibric acid) to treat

dyslipedemia, Hypertriglyceridemia and hyperlipidemia.

Livalo (pitavastatin) was approved by FDA in August 2009, for treat,ment of

primary hyperlipidemia and mixed dyslipidemia

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In December 2012, FDA approved Juxtapid(lmitapide) to reduce LDL-C, TC,

Apolipoprotein B, and non HDL-C in patients with Homozygous Familial

Hypercholesterolemia (HoHF).

Vascepa ( Icosapent ethyl) was approved in july 2012, by FDA for treatment

of Hypertriglyceridemia

Recently, in January 2013, FDA approved Kynamro injection (Mipomersen

Sodium) as an addition to Lipid lowering medications and diet to treat patients

with rare type of High cholesterol called Homozygous Familial

Hypercholesterolemia (HoHF). The addition of kynamro helps to reduce LDL-

C, Apolopoprotein B, non HDL-C.(Given once a week with other

medications).Adverse effects: Serious risks of Liver toxicity as it is associated

with Liver enzyme abnormalities and accumulations of fat in liver, which

leads to Progressive liver disease with chronic use. Also caused injection site

reactions, flu-like symptoms, nausea, headache and elevation in liver enzymes

(serum transaminases).

Liptruzet (Ezetimibe and Atorvastatin) was approved by FDA in May 2013,

for treatment of high cholesterol and high TG levels. It also increases HDL

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Documents

COMMON CLINICAL PROBLEM HYPERLIPIDEMIA: AT GLANCE · Hyperlipidemia is characterized by elevated serum total cholesterol, low-density, and very low-density lipoprotein and decreased