HYPOLIPIDEMIC DRUGS

DR REHNUMA URMI
Hyperlipidemia
•Lipids of human plasma are transported
as complexes with proteins, such
macromolecular complexes are termed
lipoproteins; except fatty acids which are
bound to albumin.
•Any metabolic disorders involving the
elevations in plasma concentrations of any
lipoprotein species known as
hyperlipoproteinemias or hyperlipidemias.
What is Hyperlipidemia?
- Hyperlipidemia a broad term, also called
hyperlipoproteinemia,is a common
disorder in developed countries and is the
major cause of coronary heart disease.
-
It results from abnormalities in lipid
metabolism or plasma lipid transport or a
disorder in the synthesis and degradation of
plasma lipoproteins.
HYPERLIPIDEMIA
•Hyperlipidemia refers to increased levels
of lipids (fats) in the blood,including
cholesterol and triglycerides.

•hyperlipidemia significantly increase your

risk of developing
•cardiovascular disease,
•coronary artery disease,
• cerebrovascular disease, and
• peripheral vascular disease.
 Terms for lipid levels
Dyslipidemia: This is the umbrella term for
any type of imbalance in your lipid levels. The
include
(LDL) levels that are too high
(HDL) levels that are too low
•triglyceride levels that are too high
The following are subtypes of dyslipidemia:
Hyperlipidemia: This refers to high counts of
any type of lipid, including:
•high LDL levels
•high triglyceride levels
Hypercholesterolemia: This refers
specifically to LDL levels that are too high. It
does not refer to triglycerides.
Hypolipidemia: This refers to low levels of
lipids in the blood, specifically total
cholesterol that is lower than 120 mg/dL or
LDL below 50 mg/dL.
Hypertriglyceridemia: This refers specifically
to triglyceride levels that are too high.
The major complications are acute
Pancreatitis and Atherosclerosis

Those which contain apolipoprotein (apo)

B100 act as vehicles by which cholesterol
are transported into artery wall.

Those are low-density (LDL), intermediate

density (IDL), very low density (VLDL) and
Lp(a) lipoproteins.
Cellular components in atherosclerotic plaque are
foam cells, derived form macrophages and smooth
muscle cells filled with cholesteryl esters.

•The atheromatous plaque grows over time with

the accumulation of increased no. of foam cells
and of collagen and fibrin.

•High-density lipoproteins (HDL) exert

antiatherogenic effects.
 The biochemistry of Plasma Lipids

What is lipid?
Lipids are the heterogrnous mixture of
fatty acid and alcohol that are present in
the body.
The major lipids in the bloodstream are
Cholesterole and its esters ,
Trigycerides and
Phospgolipids
What are lipoproteins?
Since blood and other body fluids are watery,
so fats need a special transport system to travel
around the body.

They are carried from one place to another

mixing with protein particles, called lipoproteins.

There are SIX types of lipoproteins, each having

very distinct job.
 What are lipoproteins?
• A lipoprotein contains both proteins and lipids,
bound to another proteins which is called
apolipoproteins, which
• allow fats to move through the water inside and
outside cells.
• ** provide structural support
• and stability, binds to receptors
• Lipoprotein structure (chylomicron)
 LIPOPROTEINS
Macromolecular complexes of lipid and proteins
apoproteins
-provide structural stability
-ligands for receptors
-activate enzymes
unesterified cholesterol
core (TG ,cholesteryl esters)
phospholipids
Lipoprotein structure:

Central core of hydrophobic lipid—TG,CE &its esters

Enclosed in a more hydrophilic coat of polar substance
phospholipid
free cholesterol
associated apoprotein
HDL-7-20 n.m diameter
LDL-20-30 n.m diameter
VLDL-30-80 n.m diameter
Chylomicrons—100-1000 n.m diameter
What are the normal functions
of cholesterol in the body?

- It is necessary for new cells to form and

for older cells to repair themselves after
injury.
-Cholesterol is also used
by the adrenal glands to form hormones
such as cortisol,
by the testicles to form testosterone, and
by the ovaries to form estrogen and
progesterone.
What are the normal functions of
triglycerides and Phospholipids in the body?
•Triglycerides supply energy for the body.
Triglycerides either meet immediate energy
needs in muscles or stored as fat for future
energy requirements.

•Phospholipids are compounds that are

used to make cell membranes, generate
second messengers, and store fatty acids for
the use in generation of prostaglandins
Pathophysiology of hyperlipoproteinemia
• Major lipoproteins are:
1. Cholesteryl esters and
2. Triglycerides
•A monolayer of unesterified cholesterol and phospholipids
surrounds the hydrophobic core of above lipoproteins.
•Specific proteins (apolipoproteins) are located on the
surface.
•Also certain lipoproteins contain large mol. wt
apolipoproteins(B lipoproteins) which don’t migrate like
smaller ones.
• Subtypes of B apolipoproteins:
– B-48 formed in intestine with chylomicrons
–B100 synthesized in liver and found in VLDL, VLDL
remnants,LDL and the Lp(a) lipoproteins.
LIPID METABOLISM
Lipid transport
LDL is the primary carrier of cholesterol while
VLDL is of triglycerides. There are different
pathways for the transport of endogenous
and exogenous lipids .
In the exogenous pathway, cholesterol and
triglycerides absorbed from the gut are
transported as chylomicrons. They are
hydrolysed to chylomicron remnants by the
action of lipoprotein lipase (LPL) and free
fatty acids are released which are taken up
by muscle and adipose tissue. The
chylomicron remnants are transported to
the liver.
In the endogenous pathway, cholesterol and
triglycerides from the liver are carried as
VLDL to the muscle and adipose tissue. Here
the triglycerides in VLDL are hydrolysed and
free fatty acids released. Thus intermediate
density lipoprotein (IDL) and then LDL are
formed by the action of lipoprotein lipase.
Cells have LDL receptors and LDL is taken up
into the cell. When the LDL plasma levels
rise, LDL is taken up by the scavenger
macrophages. In this process, they are
oxidised and such LDL is atherogenic
Excess cholesterol from the cells is transported
to the liver for excretion by reverse cholesterol
transport. High density lipoproteins (HDL) take
part in this process. They also antagonise
atherogenesis by other mechanisms including
antiplatelet—aggregatory effect,
anticoagulant and other effects. High density
lipoproteins decrease the risk of coronary
heart disease, are called protective
lipoproteins and higher plasma levels of HDL
are thus desirable.
RISK FACTORS FOR HYPERLIPIDEMIA
• Family history of early heart disease (father before the age
of 55 years and mother before the age of 55 years)
➢ Cigarette smoking
• High blood pressure
• Age (men older than 45 years and women older than 55
years)
• Low HDL levels
• Obesity
• Diabetes
• etc
Normally EDRF(Endothelium –derived relaxing
factors), nitric oxide are responsible for vessels
regulation but it is impaired in hyperlipidemia.
So natural antioxidants such as tocopherol and
ascorbic acid can reduce such impairment.
 DIAGNOSIS OF HYPERLIPIDEMIA
Diagnosis is typically based on medical history, physical examination
and blood test done after overnight fasting
Chylomicrons:
– Lagest type;formed in intestine and carry dietary lipids
triglycerides which are unesterified cholesterol
&cholesterol esters.
– Responsible for transport of lipids

• Very low density lipoproteins (VLDL) :

–Secreted by liver; means for transporting triglycerides
to peripheral tissues
–Hydrolyzed by lipoprotein lipase yielding free fatty
acids for oxidation and storage.
–Intermediate particles called IDL are formed after the
VLDL is depleted of triglycerides.
Low density lipoproteins:
– Further removal of triglycerides by hepatic
Lipase results in its formation.
– Hepatocytes play a major role for its catabolic activity.
• Lp(a) lipoprotein:
– Formed form an LDL-like moiety
–The Lp(a) lipoprotein complex can be found in
atherosclerotic plaques and contribute to
coronary disease by inhibiting thrombolysis.
High density lipoproteins:
– Secreted by the liver and intestine
–Comes from surface of chylomicrons and VLDL
during lipolysis.
Atherosclerosis: It is a disease which affects large
and medium size arteries, and a leading cause of
death.
•consists of localized plaque in the intima, and is
composed of cholesterol esters, proliferation of
smooth muscle, deposition of fibrous proteins and
calcifications.
• Effects:
– Narrowing of the arterial lumen
–Ulceration of arterial lumen and thrombosis of
artery and embolization.
– Weakens arterial wall , formation of aneurysms.
 Management of hyperlipidemia

Management of hyperlipidemia start with

therapeutic life changes(TLC) which includes;
• a cholesterol-lowering diet (TLC diet),
• physical activity,
• quitting smoking (if applicable),
• weight management,
• and antihyperlipidemia drugs
What is the classification of Hyperlipidemia?
Hyperlipidemias are classified according to the
Fredrickson classification which is based on the
pattern of lipoproteins on electrophoresis or
ultracentrifugation. It was later adopted by the
World Health Organization (WHO). It does not
directly account for HDL, and it does not
distinguish among the different genes that may
be partially responsible for some of these
conditions.
 GROUPS OF
HYPERLIPIDEMIA
• Primary or familial hyperlipoproteinaemia
• Secondary hyperlipoproteinaemia

The current classification of hyperlipidemias is

based on the pattern of lipid abnormality in the
blood.
TYPES
 Primary familial
hyperlipoproteinaemia
• Subclassified into six phenotypes
I , IIa , IIb, III, IV, and V based on lipoproteins
and lipids were elevated.

•current literature, however, favour the more

descriptive classifications and subclassification
Classification of anti-hyperlipidemics:

• HMG-CoA reductase inhibitors ( statins)

– Lovastatin
– Atorvastatin
– Simvastatin
– Pravastatin
–Rosuvastatin
(5 to 40mg /day)
• Bile acid sequestrants (resins):
– Cholestyramine
– Colestipol
• lipoprotein lipase inducers (fibric acid derivative)
– Clofibrate
– Gemfibrozil
– Benzafibrate
• Inhibit lipolysis and triglycerides synthesis
– Nicotinic acid ( niacin)
• Inhibit intestinal cholesterol absorption
– Ezetimibe
• Others(LDL oxidation inhibitors)
– Probucol
– gugulipid
 HMG-CoA reductase inhibitors
• Mechanism of action
The de novo synthesis of cholesterol involves a pathway in
which mevalonic acid is formed and by the enzyme
hydroxymethylglutaryl co-enzyme reductase (HMG-Co A
reductase); the statins inhibits this step resulting in decrease
hepatic cholesterol synthesis.
Resultantly synthesis of high affinity LDL receptors on the
liver occurs and increased clearance of plasma LDL.
• Decrease liver cholesterol
• Increase LDL gene expression
• Decrease plasma LDL
• Decrease VLDL synthesis
• Decrease TGLs
Mechanism of action of STATINS
Pharmacokinetics:
well absorbed when given orally and food
enhances their absorption but may undergo
extensive first pass metabolism in the liver.
– Given orally except fluvastatin
– Upto 90% available
–Undergoes first pass metabolism and secreated
in bile
. Statins are metabolised by the enzyme
cytochrome P450.
– 5-10% excreted in urine
Indications:
Therapeutic Uses
Great for all hyperlipidemias involving
increased levels of LDL or cholesterol
Atherosclerosis; stroke prevention
Primary prevention of CAD
Ischemic heart disease of elderly
Major side effect and drug interactions
Side effects
• Headache
• nausea
• sleep disturbance,
-muscle weekness,myalgia , myopathy
•elevations in hepatocellular enzymes and
alkaline phosphatase. CI in hepatic
dysfunction
•Myositis and rhabdomyolysis, primarily when
given with gemfibrozil or
cyclosporine; myositis is also seen with severe
renal insufficiency (CrCl <30 mL/min).
• Contraindicated in pregnancy
Drug interactions :
– Gemfibrogil
– Cyt P450 enzymes

Lovastatin, atorvastatin, rosuvastatin, and

simvastatin potentiate effect of warfarin; this
interaction is not seen with pravastatin,
fluvastatin, or pitavastatin.
Most statins can also affect digoxin metabolism
and levels
Simvastatin is also a prodrug like lovastatin
and is better absorbed, more potent and
more efficacious than lovastatin. Both
simvastatin and atorvastatin raise HDL levels
and may also lower triglycerides.
Fluvastatin is almost completely absorbed;
it is metabolized by microsomal enzymes
(CYP2C9). Microsomal enzyme inhibitors
prolong the action of fluvastatin.
Atorvastatin has good potency and efficacy
and a longer duration of action.
It effectively lowers LDL-CH and to some
extent triglycerides.
It is a popular hypolipidaemic and is a
commonly used drug.
Pravastatin has relatively low efficacy.
It also lowers plasma fibrinogen levels.

Rosuvastatin is a fluorinated compound,

most potent and longer acting and has
good efficacy.
It raises HDL-cholesterol in patients who
also have raised triglyceride levels.
It is metabolized by microsomal enzymes in
the liver.
Pitavastatin is a recently introduced statin
which binds with high affinity to HMG-CoA
reductase. Its actions are similar to
atorvastatin.
Lovastatin is a prodrug converted to the
active drug in the gut.
It is incompletely absorbedand undergoes
extensive first pass metabolism by CYP3A4.
Pleotropic Effects of Statins
• Antioxidant
• Anti-inflammatory
• Anti-proliferative
What is statin-induced myopathy?
The most common complaint associated with
statins, is myopathy, a muscle disorder
. Statin-induced myopathy brings on muscle-related
symptoms that didn’t exist prior to when you
started taking a statin. Symptoms tend to start soon
after you begin statin therapy.
symptoms of myopathy:
muscle pain
muscle weakness
cramping
tendon problems
fatigue
Why do statins cause myopathy?
Statins may interfere with a protein integral to
your muscle health and growth.
Another theory is that statins cause a reduction
in coenzyme Q10, a substance necessary for
your muscles to have enough energy to work
optimally.
Myopathy is separated into three different types based on
toxicity:
Myalgia. Myalgia refers to generalized pain in your
muscles. There may be a small increase in the creatine
kinase enzyme, which is associated with muscle damage.
If you have an increase in kinase, it can be identified in
your bloodstream through a routine blood test.
Myositis. Myositis presents itself with muscle pain,
tenderness, or weakness and a higher level of creatine
kinase in your bloodstream.
Rhabdomyolysis.
Rhabdomyolysis is an extreme, life-threatening type of
myopathy. It’s brought on by muscle breakdown and
significant creatine kinase elevations, up to 10 times
greater than normal values.
•Bile acid binding resin.
Bile acid sequestrants (resins):
Cholestyramine
Colestipol
Colesevelam
These are basic ion exchange resins supplied in
the chloride form. They are neither digested nor
absorbed in the gut: bind
bile acids in the intestine interrupting their
enterohepatic circulation.
Faecal excretion of bile salts and CH (which
is absorbed with the help of bile salts) is increased.
This indirectly leads to enhanced hepatic
metabolism of CH to bile acids.
More LDL receptors are expressed on liver
cells: clearance of plasma IDL, LDL and indirectly
that of VLDL is increased
Cholestyramine:
• Also known as bile acid binding resin.
•Bile acid binding resins are cholesterol lowering
drugs that are man made resins. They are gritty,
insoluble granules which are available in the form
of a bar that has to be chewed thoroughly or
comes in the form of a powder and needs to be
mixed with a liquid.
•These prevent re-absorption of cholesterol into
the body when they bind with the cholesterol rich
bile acids secreted by the liver.
Resulting in decreased enterohepatic
circulation of causing the liver to increase
production of bile acids utilizing cholesterol
• Decrease LDL levels
• Increase LDL receptor gene expression.
•It significant effect on LDL levels by utilizing the
LDL receptors but no effect on the HDL levels.
Pharmacokinetics:
– Orally (chewed)
– No systemic effects as it is retained in the GI tract
–Usual dose of 12-36g of resin per day in divided
doses with meals.
Major side effect and drug interactions
Side effects
• Constipation
• Flatulence
• Dyspepsia
• Hypertriglyceridemia
• Hyperchloremic acidosis (since they exchange Cl)
•Bind many things (drugs, vitamins, toxins,
anything fat soluble) which limits their
absorption
•Prexisting coagulopathy is a contraindication since
they prevent absorption of vit K
• Drug interactions

Impaired absorption of fat soluble vitamins

and co-administered medications including:
Amiodarone, digoxin, warfarin, thiazides, β-
blockers,levothyroxine, others; interaction can
be minimized by taking other medications at
least 1 hour before or 4 hours after bile acid
sequestrant.
lipoprotein-lipase activators

Fibric acid derivatives

( isobutyric acid derivatives)
Prototype:

•Gemfibrozil (600 mg BID),

•Fenofibrate (Nanocrystal 145 mg/day
•Bezafibrate
•Ciprofibrate,
•Micronized 160 to 200 mg/day0 •
•Others : clofibrate , benzafibrate
Funtion of fibrates:
enhance activity of the enzyme lipoprotein
lipase which degrades VLDL resulting in
lowering of triglycerides by about 40%.
The fibrates activate PPAR alpha receptor
(a nuclear receptor) which in turn increases the
synthesis of lipoprotein lipase.
Fibrates also increase HDL levels by 10–15%.
Oxidation of fatty acids in the liver and muscle is
increased while the lipolysis within the adipocytes
is decreased.
Fibrates inhibit coagulation and promote
thrombolysis which also account for their benefical
effects in coronary heart diseases
Peroxisome proliferator Activated Receptor
Mechanism of action:
Induction of lipoprotein lipase
Activation of the nuclear transcription receptor
“peroxisome proliferator - activated receptor alpha” (PPAR-
α). –mediate effects of insulin
class of intracellular receptors that modulate carbohydrate
and fat metabolism and adipose tissue differentiation.
PPAR-α activation by fibrates results in numerous changes
in lipid metabolism that act together to decrease plasma
triglyceride levels & increase plasma HDL.
Decrease VLDL and IDL
Adverse effects to fibrates include
gastrointestinal upset,
skin rashes, headache,
myositis, muscle cramps and blurred vision.
Fibrates can cause rhabdomyolysis particularly in
patients with renal failure and
When concurrently used with statins, risk of
myopathy gets added up.
Fibrates should be avoided in patients with renal
and hepatic dysfunction.
Fibrate therapy should be discontinued
after 2 months if an adequate lowering of
TG level is not obtained. Combination of a
fibrate with a statin for primary or
secondary prevention of CVD
is also not recommended
Indications:
–Hypertriglyceridemias in which VLDL
predominate & in dysbetalipoproteinemia.
–Treatment of hypertriglyceridemia resulting from
treatment with viral protease inhibitors.
Contraindication:
Hypercholesteremia
Pharmacokinetics:
–absorbed from the GI tract & undergoes
enterohepatic circulation
–most (70%) is eliminated unchanged through the
kidneys
– half life : 1.5 hrs.
:
Side Effects
– rare cases of rash
– GI symptoms
– Gall stones
– Myositis
– Myopathy
– Arrhythmias
– Hypokalemia &
–High aminotransferase or alkaline
phosphatase levels, risk of cholesterol
gallstones.
Lab findings Drugs
Hypercholesteremia Cholestyramine ,
colestipol, ezetimibe
Hypertriglyceridemia Gemfibrozil
Combined hyperlipidemia (Statins
and niacin) + ezetimibe
Gemfibrozil is the drug of choice in patients
with increased TG levels and in type III,
type
IV and type V hyperlipoproteinaemias
Fenofibrate: In addition to lowering TGs, it
also lowers LDL-CH and raises HDL-CH. It
may be used in place of gemfibrozil or in
combination with statins.
Bezafibrate is similar to gemfibrozil and
has greater LDL lowering effects.
Nicotinic acid :
Nicotinic acid :
a B group vitamin, in large doses
inhibits triglyceride synthesis in the liver and
VLDL production resulting in a decrease in
LDL, and increase in HDL-cholesterol.
Nicotinic acid (Niacin)
Examples; Niacin (IR: 1 to 6 g/day or XR 0.5to2g/day)
Mechanism of action
Inhibition of VLDL synthesis( inhibiting
ApoB100 gene expression and resulting in:
•Decreased plasma VLDL
•Decreased plasma LDL
•Increased plasma HDL
•It is a potent inhibitor of lipolysis in adipose tissues
which decreases mobilization of FFAs (major
precursor of TGs) to the liver which in turn decreases
VLDL (after few hours)
• Increases HDL levels
Major side effect and drug interactions
Side effects
• dry skin
• myositis
•Prostaglandin-mediated (PGD2)cutaneous flushing,
warm sensation
• Headache
• Pruritus, Nausea, Vomiting, Dyspepsia,diarrhea
•hyperpigmentation (particularly in intertriginous
regions); acanthosis nigricans;
• Decreased glucose tolerance
• Hepatotoxicity (check AST, ALT levels)-liver dysfuntion
• Rhabdomyolysis
• Hyperuricemia(inhibits tubular secretion of uricacid)
Drug Interaction :
Postural hypotension may occur
in patients on antihypertensives when they take
nicotinic acid.
Risk of myopathy due to statins is increased
USE:Nicotinic acid
Nicotinic acid is highly efficacious in
hypertriglyceridaemia (type III, IV, V) whether
associated with raised CH level or not.
It is mostly used to lower VLDL and raise
HDL levels, but outcome benefits in terms of
ASCVD reduction are uncertain.
The most important indication of niacin is
to control pancreatitis associated with severe
hypertriglyceridaemia, mainly in genetic type
IV and type V disorders
Dose:Nicotinic acid
Start with 100 mg TDS, gradually increase to 2–4
g per day in divided doses. It should be taken just
after food to minimize flushing and itching.
Probucol lowers LDL- and HDL-cholesterol
and has antioxidant properties. It is generally
not preferred

Gugulipid obtained from ‘gum guggul’

lowers plasma cholesterol and triglycerides.
It is well tolerated but can cause diarrhoea.
Ezetimibe
Ezetimibe is a drug which selectively inhibits the
absorption of cholesterol and other phytosterols by
enterocytes.
Ezetimibe and its metabolite concentrate in the
brush border of the small intestine and interfere
with the absorption of cholesterol by inhibiting a
specific transport protein NPC1L1 which takes up
cholesterol from the intestinal lumen.
As a result, there is a decrease in hepatic
cholesterol leading to increased clearance of
cholesterol from the plasma.
Ezetimibe also blocks the reabsorption of
cholesterol that is excreted in the bile.
The effects are synergisitc with statins and the
combination can bring about a significant (up
to 60%) decrease in LDL-CH levels
Ezetimibe undergoes glucuronide conjugation,
enterohepatic circulation and is largely excreted
through the gut.
It is well tolerated and with available data, can
occasionally cause reversible hepatic
dysfunction and myositis.
It has a long halflife—given 10 mg once daily
Ezetimibe may be used as monotherapy in
patients with mild hypercholesterolaemia or
in combination with a low dose of statins in
patients who have not had adequate response
with statins alone.
It may also be used in patients with
phytosterolaemia.
However, it is not preferred now
Some new drugs that have been introduced are:
1. MTP (microsomal triglyceride transferase
protein) inhibitor—lomitapide.
2. CETP (cholesteryl ester transfer protein)
inhibitors like anacetrapib which
prevent exchange of cholesteryl esters
and triglycerides between HDL and
lipoproteins.
3. DAGT1 (diacylglycerol transferase)
inhibitor—pradigastat.
4. Antisense oligonucleotide against apo
B100 for familial hypercholesterolaemia—
mipomersen
 PCSK9 inhibitors
• Examples; Alirocumab (75 to 150 mg 2/7 w),Evolocumab
(140 mg 2/7 w or 420 mg 1/12 m)
•Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine
protease
produced predominantly in the liver that leads to the
degradation of
hepatocyte LDL receptors and increased LDL-C levels
• This category of lipid lowering therapy appears
promising in a range of
clinical situations.
• They are given subcutaneously
• The major side effect is injectin site reaction
DRUG THERAPY
• If no improvement within 6 weeks with a single drug
therapy, the dose should be increased.
If no improvement after 3 months change
the drug or consider combination therapy:
• Bile acid resins can be safely combined with statins or
nicotinic acid
(↓ LDL, VLDL cholesterol levels respectively).
• Ezetimibe + statins → synergistic effects.
• Fibrates and statins are CI because of myopathy.
• Nicotinic acid and statins (must be cautiously used)
because of myopathy.
EFFECTS OF ANTIHYPERLIPIDEMIC
DRUGS
Summary guidelines on the use of
hypolipidaemic drugs
↑CH is a major risk factor for (CAD) and stroke.
This dug lowers the risk of mortality and
morbidity
Prophylactic use reduces the risk of CVD.
Lifestyle modification :
➢ such as low fat,
➢ low cholesterol diet,
➢ limitation of saturated and
➢ trans-fats,
➢ regular exercise,
➢ body weight control,
➢ smoking cessation,
➢ restriction of alcohol
are the primary approach, whether drugs
are used or not.
All patients who are at risk of CAD or
thrombotic stroke should be put on low
dose aspirin prophylaxis unless it is
contraindicated.
The decision to prescribe hypolipidaemic
drugs depends not only on the LDL-CH level
and the type of lipid abnormality, but also
on associated CAD risk factor(s) or existing
CAD or its equivalent like diabetes,
peripheral/cerebral vascular disease, etc. in
an individual patient
➢ Treatment of high plasma LDL-CH
➢ Treatment of low HDL-CH level
➢ Treatment of raised TG level:
Treatment of high plasma LDL-CH
Raised LDL: Drug therapy and the goal for
LDL levels are guided by the presence of
other risk factors in a given patient. In
patients with raised LDL-CH and total-CH,
statins are the first-line drugs.
Monitoring is carried out every 6 weeks.
Dose may be increased every 6 weeks if
needed till the maximum therapeutic dose.
If the control is not adequate despite the
optimum dose, ezetimibe may be added.
Treatment of low HDL-CH level
HDL-CH levels <40 mg/dl is considered low.
The ratio of total CH:HDL CH should be
ideally <3.5.
If it raises above 4.5, the risk is high and most
such subjects also have metabolic syndrome.
Lifestyle changes largely correct the HDL
deficiency.
Nicotinic acid and fibrates raise HDL levels
but drugs are not indicated only to raise HDL
unless other components also need
treatment.
Treatment of Raised TG Levels:
➢ Lifestyle modification,
➢ treatment of the cause like diabetes,
➢ Renal failure,
➢ high carbohydrate diet,
➢ alcohol,
➢ glucocorticoids and
➢ βblockers can reduce
➢ triglyceride levels.
Treatment of Raised TG Levels:
Reducing LDL and VLDL
levels with a statin may also lower TGs.
If response is not statisfactory, a fibrate or
nicotinic acid may be added.
Presence of very high TG levels, i.e. >500
mg/dl, is associated with a risk of
pancreatitis and needs drastic measures
including lifestyle changes and drugs.
Alcohol should be totally stopped.
Obesity:
➢ Obesity is a common problem in the
Developed countries but is now also
increasing in developing countries.
➢ It is largely due to sedentary lifestyle and
excessive or high calorie food intake.
➢ Obesity is recognised as a risk factor for
several diseases include cardiac diseases
and metabolic syndrome.
Overweight and obesity are defined as abnormal
or excessive fat accumulation that presents a risk
to health.
A body mass index (BMI) over 25 is considered
overweight, and over 30 is obese.
Overweight and obesity are major risk factors for
a number of chronic diseases, including
cardiovascular diseases such as heart disease and
stroke, which are the leading causes of death
worldwide.
In treating obesity,
Emphasis should be on
➢ low calorie diet and
➢ adequate physical activity.
If these fail to control the body weight,
drugs may be used but the drugs can be
used only for a short period as none of
them is proved to be safe for long-term use.
The most commonly used medications
approved by the U.S. Food and Drug
Administration (FDA) for the treatment of
obesity include:

Bupropion-naltrexone (Contrave).
Liraglutide (Saxenda).
Orlistat (Xenical).
Phentermine-topiramate (Qsymia).
Semaglutide (Ozempic, Rybelsus, Wegovy).
Orlistat: Orlistat acts by irreversibly inhibiting
the enzymes gastric and pancreatic lipases—
because of which it prevents the breakdown
of dietary fat to fatty acids and glycerol.
Therefore, it decreases the absorption of
lipids.On prolonged administration, orlistat
brings about a significant reduction in the
body weight.
The patient should also receive a low calorie
diet and an exercise programme. Orlistat is
poorly absorbed from the gut and is mostly
Adverse effects are limited to the gut with
abdominal cramps,
faecal urgency,
Faecal incontinence,
oily faeces and
flatulence.
It interferes with the absorption of
vitamins—
hence supplementation is needed. There is
also a decreased absorption of oral
contraceptives and ciclosporin
Uses: Orlistat
Orlistat is approved for use in obese
individuals.
It is also found to be useful in
patients with type II diabetes mellitus.
In a study
where orlistat was given for 4 years in insulin
resistant obese diabetics—a 37% reduction in
the progression of diabetes was noted
Sibutramine the uptake of NA and serotonin
(5-HT), reduces food intake and also enhances
the expenditure of energy by an increase in
the metabolic rate.
However, sibutramine can cause, hypertension
and an increased incidence of death
due to cardiovascular diseases. Sibutramine
is, therefore, withdrawn from the market.
Amphetamine, dexfenfluramine and
fenfluramine have anorexiant effects but are
banned due to toxicity and potential for
abuse.
Rimonabant: Rimonabant, a cannabinoid
CB1 receptor antagonist, inhibits
lipogenesis,
promotes satiety and reduces food intake.
Because it can cause depression and other
neuropsychiatric side effects, it is not
approved for use in obesity
SUMMARY
Structurally lovastatin and simvastatin are
inactive lactone prodrugs,
pravastatin has active lactone ring whereas
atorvastatin, fluvastatin and rosuvastatin are
fluorine-containing congeners.
➢ All statins can be absorbed orally
(maximum fluvastatin).
➢ Food increases absorption of all drugs
except pravastatin.
➢ Lovastatin and simvastatin undergo
extensive first pass metabolism and are
administered as prodrugs.
➢ Pravastatin, fluvastatin, atorvastatin and
rosuvastatin are administered as active
drugs.
➢ All drugs except pravastatin are
metabolized extensively by hepatic
microsomal enzymes.
➢ Pravastatin is metabolized by sulfation
(non-microsomal) and thus has least
chances of drug interactions.
➢ Rosuvastatin is longest acting whereas
pitavastatin is most potent statin
Major adverse effect of these drugs is
myopathy and hepatotoxicity.
Chances of myopathy increases if these are
co-administered with fibrates (maximum
with gemfibrozil) or niacin.
➢ Myopathy can proceed to rhabdomyolysis
with resultant renal shutdown.
➢ Pravastatin remains confined to the liver
and is safer in this regard.
These agents should be avoided in pregnancy
and lactation.
•Statins are the first line drugs for type IIa,
type IIb and secondary hyperlipoproteinemia
(in these conditions, cholesterol level is raised
more than TG).
• In children with heterozygous familial
hypercholesterolemia, pravastatin is
approved for children ≥ 8 years whereas
other statins are approved for children
≥ 10 years.
Pitavastatin has not been studied for this
indication.
BILE ACID BINDING RESINS
These drugs bind to bile acids in the
intestinal lumen and decrease its
reabsorption (resulting in more excretion
through faeces).
Cholesterol pool of liver is depleted because
it is utilized for the formation of bile acids.
Liver acquires cholesterol from the plasma
by increasing LDL receptors. Bile acids inhibit
TG production in the liver and their
deficiency results in elevation of TGs.
Bile acid binding resins are used only for type
IIa disorder(TGs are normal in this condition).
Drugs -cholestyramine, colestipol and
colesevelam.
Cholestyramine and colestipol are available
as sachets.
These are mixed with water, kept for some
time (to increase the palatability) and then
taken with meals. Colesevelam is available as
a tablet and has better patient compliance.
➢ Major adverse effect of these drugs is
constipation.
FIBRIC ACID DERIVATIVES
This drugs acts by activating LPL by activating
a nuclear receptor, PPARα (peroxisome
proliferator activated receptor alpha).
Major effect of the fibrates is to reduce TG
(contained in VLDL) and to increase HDL.
Clofibrate is not used now because it resulted
in increased mortality (due to malignancies
and post cholecystectomy complications) and
did not prevent fatal MI.
Gemfibrozil, fenofibrate and bezafibrate
are currently available.
Fenofibrate is a prodrug
with longest half life.
It has maximum LDL cholesterol lowering
action.
Fibrates also reduce plasma fibrinogen level.
Fibrates are the drugs of choice in
hypertriglyceridemia (type III and IV) and can
be used with other drugs in type IIb
(fenofibrate, as it has maximum LDL ↓action
Fenofibrate is uricosuric and can be used in
the setting of hyperuricemia.
GI distress and ↑ of aminotransferases
are important adverse effects of fibric acid
derivatives.
Risk of myopathy is increased if these are
used with statins except bezafibrate.
NICOTINIC ACID
Niacin (not nicotinamide) is an inexpensive
drug (vitamin B3) that produces decrease in
LDL cholesterol and VLDL triglycerides along
with increase in HDL cholesterol.
It acts by inhibiting lipolysis in the adipose
tissue. Among all hypolipidemic drugs, niacin
has maximum HDL increasing property;
therefore it is useful in patients having
increased risk of CAD. Further, it can also
decrease lipoprotein (a) and fibrinogen. It is
useful for type IIb, III and IV disorders.
Main compliance limiting feature is
cutaneous flushing and pruritis.
These symptoms are due to vasodilatory
action of niacin through release of PGs and
can be prevented by pretreatment with
aspirin. To minimize the side effects, niacin
should be started at low doses. Other
important adverse effects are GI toxicity and
hyperuricemia.
Niacin can also lead to hepatotoxicity which
is manifested by fall in both LDL as well HDL
cholesterol.
MISCELLANEOUS DRUGS
Probucol is useful because of its antioxidant
action. It inhibits oxidation of LDL and causes
reduction in levels of both HDL and LDL
cholesterol.
Gugulipid is the drug developed by
Central Drug Research Institute, Lucknow. It
causes modest decrease in LDL and slight
increase in HDL cholesterol.
Diarrhea is the only adverse effect of this dru
NEW DRUGS
• Avasimibe is an inhibitor of enzyme ACAT-1 (acyl
coenzyme A: cholesterol acyl
transferase-1) which forms cholesterol ester from
cholesterol.
• Torcetrapib and anacetrapib increase HDL
cholesterol by inhibiting the enzyme CETP
(cholesterol ester triglyceride transport protein).
• Lomitapide acts by inhibiting microsomal
triglyceride transfer protein (MTP).
This protein is necessary for VLDL assembly and
secretion in liver
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