Hyperlipidaemias

By: Dr. Prasad B. Chinchole
Doctor of Pharmacy
Ass. Professor
SCOP, Almala
@ Dr. Prasad B. Chinchole

INDEX
1. Introduction
2. Definition
3. Epidemiology
4. Etiology
5. Risk factors
6. Pathogenesis
7. Complications
8. Signs and Symptoms
9. Diagnosis
10. Management (Treatment Goals)
11. Non-pharmacological Treatment
12. Pharmacological Treatment
13. Evaluation of Therapeutic Management
14. Conclusion

Introduction
• Cholesterol, triglycerides, and phospholipids are the major lipids in the
body. They are transported as complexes of lipid and proteins known as
lipoproteins.
• Hypercholesterolemia, elevated low-density lipoprotein (LDL) levels, and
low high-density lipoprotein (HDL) levels are unequivocally linked to
increased risk for coronary heart disease and cerebrovascular morbidity and
mortality. LDL is the primary target.
• The three major classes of lipoproteins in serum are low-density
lipoproteins (LDLs), high-density lipoproteins (HDLs), and very-low-
density lipoproteins (VLDLs).
• Abnormalities of plasma lipoproteins can result in a predisposition to
coronary, cerebrovascular, and peripheral vascular arterial disease and
constitutes one of the major risk factors for coronary heart disease (CHD).

• Premature coronary atherosclerosis, leading to the manifestations of
ischemic heart disease, is the most common and significant
consequence of dyslipidemia.

DEFINITION
• Dyslipidemia is defined as elevated total cholesterol, low-density
lipoprotein (LDL) cholesterol, or triglycerides; a low high-density
lipoprotein (HDL) cholesterol; or a combination of these
abnormalities.
• Hyperlipoproteinemia describes an increased concentration of the
lipoprotein macromolecules that transport lipids in the plasma.
• Abnormalities of plasma lipids can result in a predisposition to
coronary, cerebrovascular, and peripheral vascular arterial disease.

• Dyslipidaemia is an abnormal amount of lipids (cholesterol or fat) in the
blood.
 It is a disorder of lipoprotein metabolism, including lipoprotein
overproduction or deficiency.
 In developed countries, most dyslipidemias are hyperlipidemias that is an
elevation of lipids in the blood often due to diet and lifestyle.

Dyslipidemia include either a low High Density Lipoprotein(HDL) or
elevation in lipoprotein particles like Cholesterol, Cholesterol esters and
Triglycerides.
Reducing LDL cholesterol, triglycerides and increasing HDL cholesterol is
the primary focus on treatment.

NCEP ATP III classification (mg/dL)

 Primary cause (genetic predisposition)
 Secondary cause(diet, underlying disease or
medication)
A defect occurs in lipid metabolism or transport in primary hyperlipidemia,
resulting in reduced LDL receptor activity and accumulation of LDL of
cholesterol in the plasma, leading to atherogenesis.
Secondary causes of hyperlipidemia include DM, hypothyroidism, cushing
syndrome, liver disease, nephrotic syndrome, alcoholism.
ETIOLOGY

PRIMARY DYSLIPIDAEMIA
The common genetic disorders can be classified as
Familial Hypercholesterolaemia
 Caused by mutations in the LDL receptor gene that varies from family
to family.
 The patient have plasma levels of LDL 2-3 times higher than the general
population.
 Familial combined Hyperlipidaemia
 Associated with excessive synthesis of LDL levels.
 Increase in triglycerides, LDL, apo B levels.
 Increased risk of atherosclerosis.

Familial type 3 Hyperlipoproteinaemia
 Accumulation of chylomicrons & VLDL remnants.
Triglycerides & total cholesterol are elevated & accompanied by corneal arcus,
xanthelasma, tuberoreuptive xanthomas.
Familial lipoprotein lipase deficiency
 Hypertriglyceridaemia & chylomicronaemia.
 Deficiency of lipoprotein lipase result in the failure of lipolysis & accumulation of
chylomicrons in plasma.
Familial apolipoprotein c-11 deficiency
 Associated with reduced levels of apo c-11, the activator of lipoprotein lipase.

Secondary dyslipidaemia
Common disorder that cause secondary dyslipidaemia include
o Anorexia nervosa
oBulimia
o Type 1- diadetes
o Type 2-diadetes
o Hypothyroidism
o Pregnancy
o Inappropriate diet
o Alcohol abuse
oChronic renal failure
o Nephrotic syndrome
o Renal transplantation

Type 1 diabetes
Patient with type I diabetes have 2-3 fold increased risk of developing
coronary heart disease or having stroke in later life.
Type 2 diabetes
Patient with type 2 diabetes have increased triglycerides & decreased HDL-
C and increased levels of highly atherogenic LDL particles.
Individuals with type 1 or type 2 diabetes are candidate for treatment with a
Statin where there is evidence of
 Retinopathy
 Nephropathy
 Poor glycemic control
 Elevated blood pressure
 Metabolic syndrome

Hypothyroidism
Hypothyroidism may elevate LDL because of reduced LDL receptor activity
and it causes hypertriglyceridaemia and an associated reduction in HDL as a
result of reduced lipoprotein lipase activity.
Remnants of chylomicrons and VLDL also accumulate.

Chronic renal failure
The hypertriglyceridaemia that most commonly occurs is
associated with reduced lipoprotein lipase activity.

Nephrotic syndrome
In patients with Nephrotic syndrome dyslipidaemia appears to be caused by an
increased production of apoB-100 and associated VLDL along with increased
hepatic synthesis of LDL & reduction in HDL.
The use of glucocorticoids in patients with nephrotic syndrome may exacerbate
underlying lipoprotein abnormality.

Obesity
excessive intake calories leads to increased concentrations of triglycerides and
reduced HDL.
Alcohol
In the heavy drinker high calorie content of beer and wine may be a cause of
obesity with its associated adverse effect on lipid profile.
Alcohol increases hepatic triglyceride synthesis which in turn produces
hypertriglyceridaemia.
Light to moderate drinkers (1-3 units/day) have lower incidence of coronary heart
disease.
This protective effect is due to an increase in HDL.

DRUGS
 Diuretics
Thiazide and loop diuretics increase VLDL and LDL levels.
 Beta blockers
Effect of beta blocker on lipoprotein metabolism are reflected in an increase in
plasma triglyceride concentrations, a decrease in HDL but no discernible
effect on LDL.
• Acebutolol and Oxprenolol may be useful if a β blocker has to be used in a
patient susceptible to altered lipoprotein metabolism.
• The combined ∞ and β blocking effect of labetalol may be of use since it would
appear to have a negligible effect on the lipid profile.

Oral contraceptives
Oral contraceptives containing an oestrogen and progestron provide most effective
contraceptive preparation for general use.
Oestrogen cause a slight increase in hepatic production of VLDL and HDL and
reduce plasma LDL levels.
Progestogens increase LDL and reduce plasma HDL and VLDL.

Corticosteroids
Administration of glucocorticoid such as prednisolone has been shown to
increase total cholesterol, triglycerides by elevated LDL level.
Ciclosporin
Ciclosporin is used to prevent tissue rejection in recipient of renal, hepatic and
cardiac transplants.
Its use has been associated with increased LDL levels, hypertension and
glucose intolerance.
These adverse effect are exacerbated by the concurrent administration of
glycocorticoids.

Hepatic microsomal enzyme inducer
Drugs such as carbamazepine, phenytoin, phenobarbital, rifampicin and
griseofulvin increase hepatic microsomal enzyme activity and can increase plasma
HDL.
The administration of these drugs leads to slight increase in LDL and VLDL.
The patient treated for epilepsy have been reported to have a decreased incidence of
coronary heart disease.

PATHOPHYSIOLOGY
• Cholesterol, a lipid, is an essential component of cell membranes and is a precursor in
steroid hormone and bile acid metabolism.
• Cholesterol, triglycerides, and other lipid particles are transported throughout the
human body in the form of lipoproteins.
• These spherically shaped lipoproteins may be divided into five main categories:
LDL, composed primarily of cholesterol;
HDL, mostly containing cholesterol;
VLDL, consisting mostly of triglycerides with some
cholesterol esters;
IDLs, composed of triglycerides and cholesterol esters
Chylomicrons.

Exogenous pathway
• When dietary cholesterol and triglycerides are absorbed from intestine they are
transported in the intestinal lymphatics as chylomicrons, 80% of the lipid core are
triglycerides.
• The chylomicrons pass through blood capillaries in adipose tissue and skeletal muscle
where the lipoprotein lipase is located.
• Lipoprotein lipase is activated by apoprotein C- II on the surface of chylomicrons.

• Lipase catalyses the breakdown of triglycerides in the chylomicron to free
acids and glycerol, then enter adipose tissue and muscles.
• The cholesterol rich chylomicrons remnant is taken up by receptors on
hepatocyte membranes, and dietary cholesterol is delivered to liver and
cleared from circulation.

ENDOGENOUS PATHWAY
• VLDL is formed in the liver and transport triglycerides which makes 80% of its
lipid core, to the periphery.
• The triglyceride content of VLDL is removed by lipoprotein lipase and forms IDL
particles.
• The core of IDL particles is 50% triglycerides and 50% cholesterol esters acquired
from HDL in the influence of the enzyme lecithin cholesterol
acyltransferase.(LCAT)
• 50% of body’s IDL particles are cleared from plasma by liver.
• The other 50% of IDL are hydrolysed and modified to form LDL particles.
• LDL is the major cholesterol carrying particle in plasma.

• LDL provides cholesterol, an essential component of cell membranes.
• LDL is modified by oxidation and arterial endothelium become
permeable to the lipoprotein.
• Monocyte migrate through permeable endothelium and engulf
lipoprotein to form lipid-laden macrophages that have key role in the
development of atherosclerosis.
• In patients with metabolic syndrome or type 2 diabetes, LDL particles
become more denser that is more readily oxidized and more easily
penetrates the vascular endothelium.
• Small, dense LDL particles have been associated with a higher risk for
cardiovascular disease

• The aim of treatment in dyslipidaemia is to reduce concentration of LDL
and total cholesterol.
• HDL is called good cholesterol because it is involved in reverse
cholesterol transport; that is, HDL accepts free cholesterol from
peripheral tissues, including the vasculature, for transportation to the liver
and kidney for metabolism and removal.

CLINICAL PRESENTATION
GENERAL
• Most patients are asymptomatic for many years prior to clinically evident
disease.
• Patients with the metabolic syndrome may have three or more of the
following:
Abdominal obesity,
Atherogenic dyslipidemia,
Raised blood pressure,
Insulin resistance with or without glucose intolerance,
prothrombotic state,
proinflammatory state.

SYMPTOMS
None to chest pain, palpitations, sweating, anxiety, shortness of breath, loss of
consciousness or difficulty with speech or movement, abdominal pain, and
sudden death.
SIGNS
None to pancreatitis, eruptive xanthomas, peripheral polyneuropathy, high blood
pressure, body mass index greater than 30 kg/m2, or waist size greater than 40
inches in men (35 inches in women).

LABORATORY TESTS
• Elevations in total cholesterol, LDL, triglycerides, apolipoprotein B, and
C-reactive protein.
• low HDL
OTHER DIAGNOSTIC TESTS
• Lipoprotein(a), homocysteine, serum amyloid A, and small, dense LDL
(pattern B).
• Various screening tests for manifestations of vascular disease (ankle-
brachial index, exercise testing, magnetic resonance imaging) and
diabetes (fasting glucose, oral glucose tolerance test).

Increased serum cholesterol and LDL cholesterol levels are directly
linked to the risk of CHD.
The lowering of serum cholesterol levels is associated with reduced
morbidity and mortality.
For every 1% reduction in total serum cholesterol, there is a 2% to 3%
decrease in the risk of CHD.
A high triglyceride level usually result in low HDL level which is a risk
factor for CHD.

A triglyceride level above 500mg/dL poses an immediate risk for
pancreatitis.
LDL cholesterol levels can be calculated from measured total cholesterol,
HDL, and triglycerides by the Friedwald formula;
LDL=Total cholesterol – HDL –(Triglycerides/5)

RISK ASSESSMENT
Primary prevention
Factors that need to be taken into account at screening include following
Age : In individuals <40 years and >70 years the appropriate clinical
judgement should be used to determine if there is a need for
treatment.
Smoking history : an estimate of lifetime exposure to tobacco is required.

Family history : risk increase when coronary heart disease has
occurred in a first degree relative (parent, offspring, sibling) when
a number of members have developed coronary heart disease and
the younger the age of those affected.
Body weight and height : body mass index (BMI) should be
calculated. A BMI>25 kg/m2
indicates overweight and >30kg/m2 obesity.
Waist circumference : central obesity is present where the waist
circumference >102cm in men or >80 cm in women

Blood pressure : target blood pressure in a non diabetic individual should
be <140/90mm Hg
Non- fasting lipids: total cholesterol <4mmol/L and LDL <2mmol/L.
Non fasting blood glucose: if non- fasting glucose>6.1mmol/L, individual
should be assessed for impaired glucose regulation or diabetes.
To predict the risk of developing cardiovascular disease over the next 10
years, knowledge of age, gender, smoking history, systolic blood pressure
and ratio of non fasting total cholesterol to HDL is all that is required.

SECONDARY PREVENTION
Patient with coronary heart disease and levels of total cholesterol >4mmol/L and
LDL >2mmol/L are the ones most likely to benefit from treatment with lipid
lowering agents.

LIFESTYLE MODIFICATION
 Body weight and waist measurement
The overweight patient is increased risk of atherosclerotic
disease and elevated levels of triglycerides, raised LDL, low
HDL.
BMI <18.5- underweight
BMI 18.5 to 24.9 –ideal
BMI 25 to 29.9 –overweight
BMI 30 to 40 –obese
BMI>40 obese(high health risk)

Measurement of waist circumference is the indicator of central
obesity.
In Asians,<90 cm in men and <80cm in females.
 Fish
Regular consumption of long chain omega 3 fatty
acids(ecosapentaenoic acid, docosahexaenoic acid) has linked to
low levels of coronary heart disease.
Decrease triglyceride level.
Reduce blood pressure and heart rate.
Increase insulin sensitivity.
Decrease platelet aggregation

 Do not smoke
 Maintain ideal body weight(BMI 20-25 kg/m2)
 Avoid central obesity.
 Reduce total dietary intake of fat to ≤30% of total energy
intake.
 Reduce intake of saturated fats to ≤10% of total fat intake.
 Reduce intake of dietary cholesterol to<300mg/day.
 Replace saturated fats by an increased intake of
monounsturated fats.

• Increase intake of fresh fruit and vegetables to atleast five
portions per day.
• Regularly eat fish and other sources of omega 3 fatty acids.
• Limit alcohol intake to<21units/week for men and
<14units/week for women.
• Restrict intake of salt to <100mmol day.
• Undertake regular aerobic exercise of atleast 30 mins per
day.

Therapeutic lifestyle modification algorithm.

Recommended Diet Modifications to Lower
Blood Cholesterol

LIPID LOWERING THERAPY
Statins
Fibrates
Bile acid binding agents
Cholesterol absorption inhibitors
Nicotinic acid and derivatives.

STATINS
• The statins bind to and inhibit the enzyme HMG-CoA reductase, the rate-
limiting step in cholesterol biosynthesis.
• The inhibition of HMG-CoA reductase activity results in a drop in intracellular
cholesterol production, thus activating primarily hepatic LDL receptors and
increasing the clearance of LDL from the bloodstream.
• Reduction in total cholesterol, LDL, VLDL, triglycerides with increase in HDL.

Pharmacologic actions of statins include improvements in
endothelial function, inhibition of prothrombotic forces,
immunosuppression, atherosclerotic plaque stabilization, and an
anti-inflammatory effect.
Other uses of statin include multiple sclerosis, colorectal
cancer, osteoporosis and bone fractures, sepsis, and dementia.

Statins
• Inhibit 3-hydroxy-3-methylglutaryl Co-A reductase (HMG-CoA reductase)
• Reduction in cholesterol level.
• Increase in hepatic LDL receptor activity.
• Enhanced receptor mediated catabolism.
• Clearance of LDL from plasma.
• Production of VLDL, precursor of LDL reduced
• Reduction in total cholesterol, LDL, VLDL, triglycerides with increase in HDL.

• Simvastatin was the first member group followed by
Pravastatin, Fluvastatin, Atorvastatin, Cerivastatin,
Rosuvastatin.
• Cerivastatin withdrawn from market due to fatal
rhabdomyolysis.
• Newest member of the group Rosuvastatin, launched in march
2003.

Adverse effect
• Gastrointestinal symptoms, altered liver fuction test, muscle
aches, hepatitis, rash, headache, insomnia, nightmares, vivid
dreaming, difficulty in concentrating. Memory loss, peripheral
neuropathy
• Myopathy leading to myoglobulinuria secondary to
rhabdomyolysis.
• Low dose (10mg) simvastatin used to treat individuals at
moderate cardiovascular risk.
• Simvastatin cannot take individuals having diabetes, familial
dyslipidaemia, cvs disease,other lipid lowering agents.

Drug interaction involving statins &
Cytochrome P450 enzyme
CYP450 Isoenzyme Inducers Inhibitors
Cyp3a4 Phenytoin Ketoconazole
Lovastatin Rifampicin Erythromycin
Simvastatin Barbiturate Ciclosporin
Atorvastatin Omeprazole Corticosteroids
Carbamazepine Amiodarone
Tricyclic Antidepressants
Verapamil
Cyp2c9 Rifampicin Ketoconazole
Fluvastatin Phenytoin Fluconazole
Phenobarbitone Sulfaphenazole

• Avoid Simvastatin with potent inhibitors of CYP3A4 include
azole, antifungals, erythromycin, HIV protease inhibitors.
Do not exceed the following doses;
• Simvastatin 10mg daily with ciclosporin, gemfibrozil or
niacin.
• Simvastatin 20mg daily with verapamil, or amiodarone
• Simvastatin 40mg daily with diltiazem.
• Avoid grapefruit juice when taking simvastatin or
atorvastatin.

Formulary drugs
• Atorvastatin
Storvas tablet 5 mg, 10 mg, 20 mg
Atocor 10 mg ,20 mg tablet
Modlip 10 mg tablet
Avas tablet 40mg
Simvastatin
Simvotin tablet 5mg, 10mg, 20mg
Rosuvastatin
Rozucor Tablet 10mg, 5mg

Fibrates
Fibrates principally lower triglycerides by increasing the
activity of lipoprotein lipase, the enzyme involved in
hydrolysis of triglycerides from VLDL and IDL particles.
This effect is mediated through stimulation of peroxisome
proliferator-activated receptors (PPAR) of the α subtype.
Fibrates may also decrease the formation of VLDL and
thereby have modest effects on lowering LDL cholesterol.
Fibric acid derivatives generally provide a triglyceride
reduction of 20% to 30%, decrease LDL by up to 20%, and
increase HDL by 10% to 20%

FIBRATES
• Bezafibrate, ciprofibrate, fenofibrate, gemfibrozil
• Fenofibrate and ciprofibrate are potent members of the group.
• Fibrates are considered first-line therapy for patients with elevated triglycerides
• Beneficial effect on fibrinolytic and clotting mechanism.

Adverse effect
• Nausea, diarrhoea, abdominal pain
• Muscle pain, unusual tiredness, weakness
• myositis

Drug interaction
Drug Interacting Drug Comment
fibrates
Antidiabetic drug Improvement in glucose tolerance
ciclosporin Increase risk of renal impairment
Bile acid binding agent Reduce bioavailability of fibrates
statin Increased risk of myopathy
warfarin Increased anticoagulant effect

Formulary drugs
Fenofibrate
Lotgl 200 mg tablet
Gemfibrozil
Lopid Capsules 300 mg
Triglyd 300mg tablet

Bile acid resins
• Bile acid resins exchange an anion, usually sodium, for bile acids in the
intestinal tract.
• This interrupts the recycling of bile acid through entero-hepatic circulation,
causing hepatic cells to be stimulated to convert more cholesterol into bile
acids.
• This process up-regulates the LDL receptors and enhances LDL clearance
from the plasma.
• Therefore, bile acids resins exert their primary effect on LDL cholesterol.

• Colestipol, Cholestyramine lower total cholesterol and LDL
levels by 15% to 30%.
• HDL may be increased moderately by 3% to 5%.
• Triglycerides can be increased by 7% acutely, and 2% to 3%
after prolonged therapy in patients with normal triglyceride
levels.
• Clinicians should use resins with caution in patients with mild
to moderate triglyceride elevations because the increase in
triglycerides may be pronounced in these patients and may
precipitate pancreatitis.
• Bile acid resins can decrease the risk of CHD, are safe, and
have no long-term risks

• These agents are ideal for younger patients, including women
considering pregnancy.
• The most common side effects involve the GI tract and
include constipation, abdominal pain, belching, bloating, gas,
heartburn, and nausea.
• Constipation occurs in about 20% of patients and can be
reduced with stool softeners and increased intake of soluble
fiber.
• Patients should take other medications at least 1 hour before
or 4 hours after the resin.
• Dosing is usually initiated at 4 g for cholestyramine, 5 g for
colestipol, with maximum amounts of 24 g, 30 g,
respectively, generally given in two to four divided dose.

Drug interaction
Drug Interacting Drug Comment
Bile Acid Resins
Digoxin Absorption Reduced
Diuretics Absorption Reduced
Levothyroxin Absorption Reduced
Paracetamol Absorption Reduced
Statin Absorption Reduced By Up To
50%
Warfarin Increased Anticoagulant Effect
Valproate Absorption Reduced

Cholesterol absorption inhibitors
• Ezetimibe acts at the brush border of the small intestines by binding
to the receptor that is responsible for cholesterol uptake and
therefore blocks intestinal cholesterol absorption.
• Adverse effects are GI in nature, such as diarrhea and abdominal
pain, fatigue, back pain, and arthralgia.
• Dose of Ezetimibe is 10 mg a day taken with or without food.
• Ezetimibe is also commercially available in combination with
simvastatin.

Formulary drugs
• Ezetimibe
Ezedoc tablet 10mg
• Atorvastatin+ Ezetimibe
Avas-EZ Tablet (10+10 mg)
Atocor E Tablet (10+10 mg)
Tonact EZ Tablet (20+10 mg)

Niacin
• Niacin is a water-soluble Vitamin B that exerts its lipid-lowering effect by
inhibiting the production of VLDL particles in the liver.
• This results in a decrease in triglycerides and LDL.
• Niacin may also increase HDL levels by reducing its catabolism.
• Niacin is an ideal agent for patients who have elevated LDL and triglyceride
levels and a normal or low HDL level
• Nialip tablet 500 mg, Nicotinic acid tablet 50mg

• The most common symptoms include flushing, tingling, itching, rash, and
headaches, which are thought to be a result of prostaglandin-mediated
vasodilation.
• Patients are instructed to take niacin with food to reduce GI side effects
• Niacin can cause abdominal pain and discomfort,hepatic dysfunction.
• Niacin is contraindicated in patients with chronic liver disease and active
Peptic ulcer disease.
• adverse effects include elevations in liver function test results, uric acid
levels, and blood glucose levels. For these reasons, niacin should be used
with caution in patients with gout or diabetes

Fish oils
 Long-chain polyunsaturated fatty acids (PUFAs) are
found in oily fish and fish oils and appear to protect
against cardiovascular disease.
 The benefits include a 25% to 30% reduction in
triglyceride concentrations, decrease in platelet
aggregation, and reductions in arrhythmias and sudden
death (doses of approximately 1 g/day).
 The most common adverse effect of fish oil capsules is the
fishy aftertaste, reduced by storing the capsules in a
refrigerator prior to consumption.
 excessive ingestion of fatty fishes may increase the
exposure to toxins such as mercury. The supplements are
essentially free of mercury.

Soluble fibre
• Ispaghula husk
• Reduce lipid levels.
• Fibre bind to bile acids in gut and increase the conversion of cholesterol to bile
acids in the liver.
• Reduce total cholesterol and LDL.

Hyperlipidaemias

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Hyperlipidaemias

Similar to Hyperlipidaemias (20)

More from Dr. Prasad Chinchole

More from Dr. Prasad Chinchole (11)

Recently uploaded

Recently uploaded (20)

Hyperlipidaemias