Antihyperlipidemics

Absorption of lipids
 Lipoprotein Density Protein Lipids Predominant Lipid
(% total % total (% of total weight)
weight) weight)

Chylomicron <1.006 2 98 Triacylglycerol (85 %)

VLDL 0.950- 10 90 Triacylglycerol (50%)

1.006

IDL 1.006- 12 88 About 40 % Cholesterol

1.019 (30 % esterified and 10 %
free)
LDL 1.019- 25 75 About 50 % Cholesterol
1.063 (40 % esterified + 10%
free)
HDL 1.063- 55 45 Phospholipids (35 %)
1.210

Biochemistry of Lipoproteins
# Very Low Density Lipoproteins (VLDL)
# Intermediate Density Lipoproteins (IDL)
# Low Density Lipoproteins (LDH)
# High Density Liporprotein (HDL)
 Transportation of lipids
Lipids are transported in the plasma as lipoproteins.
Source Destination Functions

Chylomicrons Intestine Many organs Deliver lipids of

dietary origin to
body cell.
VLDLs Liver Many organs Deliver
endogenously
produced
triglycerides to
body cells.
LDLs Intraviscular Blood vessels, Liver Deliver
removal of endogenously
triglycerides from produced
VLDL cholesterol to
various organs.
HDLs Liver and intestine Liver and steroid- Remove and
hormone-producing degrade
glands Cholesterol.
Figure 20-1 Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drugs
affecting lipoprotein metabolism. ACoA, acetyl-coenzyme A; C, cholesterol; CE, cholesteryl ester; HDL, high-
density lipoprotein; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; LDL, low-density
lipoprotein; MVA, mevalonate; TG, triglyceride; VLDL, very low-density lipoprotein.
Acetyl CoA is the source of all carbon atoms in cholesterol
Acetyl CoA
CoA

Acetoacetyl CoA
Acetyl CoA
CoA
β -hydroxy- β- methylglutaryl CoA

HMG-CoA
reductase

Mevalonate Squalene

Cyclization
Farmesyl pyrophosphate
Persons are categorized into one of three levels of risk, to identify
group-specific treatment modalities:
(1) high-risk, established IHD or IHD risk equivalents (diabetes,
noncoronary forms of atherosclerotic disease). The treatment
goals is to have LDL-cholesterol (LDL-C) levels < 100 mg/dl

(2) moderately high-risk, multiple (more than two) risk factors .

The treatment goals is to have LDL-cholesterol (LDL-C) levels <
130 mg/dl

(4) lower-risk, zero to one risk factor. The treatment goals is to

have LDL-cholesterol (LDL-C) levels < 160 mg/dl
(Goal of lipoprotein level for prevention of coronary heart disease)
 Strategy for Controlling Hyperlipidemia

STATINS
Diet Biosynthesis

HMG CoA reductase

Ezetimibe
LDL-R
Serum Cholesterol Cellular Cholesterol

Conversion to
Bile Acids hormones within
cells or storage
Re-absorption as granules
Intestine
Lipoprotein
BILE ACID catabolism
SEQUESTRANTS FIBRATES
Feces
 CLASSIFICATION OF HYPERLIPIDEMIA

Hyperlipidemia may be classified as either familial (also

called primary) caused by specific genetic abnormalities, or
acquired (also called secondary) when resulting from another
underlying disorder that leads to alterations in plasma lipid
and lipoprotein metabolism. Also, hyperlipidemia may be
idiopathic, that is without known cause.
 FAMILIAL (PRIMARY)

According to “fredrickson” classification, there are five types of

hyperlipidaemia

• 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

Acquired (secondary)
Acquired hyperlipidemias (also called secondary
dyslipoproteinemias) may mimic primary forms of
hyperlipidemia and can have similar consequences.
They may result in increased risk of premature
atherosclerosis or, when associated with marked
hypertriglyceridemia, may lead to pancreatitis and other
complications of the chylomicronemia
syndrome.
The most common causes of acquired hyperlipidemia are:
• Diabetes Mellitus
• Use of drugs such as diuretics, beta blockers,
and estrogens
Other conditions leading to acquired hyperlipidemia include:

• Hypothyroidism
• Renal Failure
• Nephrotic Syndrome
• Alcohol
• Some rare endocrine disorders and metabolic
disorders
According to "Greenspan's Basic & Clinical Endocrinology"
by Dr. David Gardner, acquired hyperlipidemia is high fat
and cholesterol in the blood due to other conditions or
medications. Diabetes, low thyroid hormone levels, kidney
disease and some other metabolic disorders cause
hyperlipidemia. Some drugs can also cause hyperlipidemia,
including alcohol, diuretics, estrogens and beta-blockers.
SIGNS AND SYMPTOMS OF
HYPERLIPIDEMIA
Hyperlipidemia usually has no
noticeable symptoms
and tends to be discovered
during routine
examination or evaluation for
atherosclerotic
cardiovascular disease
1. Xanthoma 9. Higher rate of obesity and
2. Xanthelasma of eyelid glucose intolerance
3. Chest Pain 10. Pimple like lesions across
4. Abdominal Pain body
5. Enlarged Spleen 11. Atheromatous plaques in
6. Liver Enlarged the arteries
7. High cholesterol or 12. Arcus senilis
triglyceride levels
8. Heart attacks
Pathophysiology of hyperlipidemia
Decreased clearance of triglyceride-rich lipoproteins due to
inhibition of lipoprotein lipase and triglyceride lipase. Other
factors such as peripheral insulin resistance, carnitine deficiency,
and hyperthyroidism may contribute to lipid abnormalities.
In nephrotic syndrome, decreased effective plasma albumin
circulation results in increased lipoprotein synthesis to maintain
plasma oncotic pressur
HMG CoA reductase inhibitors:

#They are the first-line and more effective treatment for patients
with elevated LDL cholesterol
# Inhibits the first committed enzymatic step of cholesterol
synthesis
# Therapeutic benefits include
plaque stabilization
improvement of coronary endothelial function
inhibition of platelet thrombus formation, and
anti-inflammatory activity.
The value of lowering the level of cholesterol with statin
drugs has now been demonstrated in

1) patients with CHD with or without hyperlipidemia,

2) men with hyperlipidemia but no known CHD, and
3) men and women with average total and LDL
cholesterol levels and no known CHD.
 Current drugs include :
Lovastatin
simvastatin
pravastatin
atorvastatin
fluvastatin
and rosuvastatin
Lovastatin and simvastatin are lactones that are
hydrolyzed to the active drug. Pravastatin
and fluvastatin are active as such.

Order of potency (LDL cholesterol–lowering ) Rosuvastatin atorvastatin simvastatin

pravastatin ovastatin fluvastatin.
Inhibition of HMG CoA reductase by statin drugs
 Mechanism of action

Inhibition of HMG CoA reductase:

Because of their strong affinity for the enzyme, this drug
compete effectively to inhibit HMG CoA reductase, the rate-
limiting step in cholesterol synthesis.
By inhibiting de novo cholesterol synthesis, they deplete the
intracellular supply of cholesterol.

Increase in LDL receptors:

Depletion of intracellular cholesterol causes the cell to increase
the number of specific cell-surface LDL receptors that can bind
and internalize circulating LDLs.
Thus, the end result is a reduction in plasma cholesterol, both
by lowered cholesterol.
They can also increase plasma HDL levels in some patients,
resulting in an additional lowering of risk for CHD.
Decreases in triglyceride also occur.
Therapeutic uses:
# Effective in lowering plasma cholesterol levels in all
types of hyperlipidemias.
# However, patients who are homozygous for familial
hypercholesterolemia lack LDL receptors and, therefore,
benefit much less from treatment with these drugs.
# in spite of the protection afforded by cholesterol
lowering,
about 1/4 of the patients treated with these drugs still
present with coronary events.
Thus, additional strategies, such as diet, exercise, or
additional agents, may be warranted.
Pharmacokinetics:

Pravastatin and fluvastatin are almost completely absorbed

after oral administration; oral doses of lovastatin
and simvastatin are from 30 to 50 percent absorbed.

lovastatin and simvastatin must be hydrolyzed to their acid forms.

Due to first-pass extraction, the primary action of these drugs is
on the liver.
Excretion takes place principally through the bile and feces, but
some urinary elimination also occurs.
Their half-lives range from 1.5 to 2 hours
 •Adverse effects

Liver: Biochemical abnormalities in liver function have

occurred with the HMG CoA reductase inhibitors evaluate
liver function and measure serum transaminase levels
periodically. These return to normal on suspension of the drug.

Muscle: Myopathy and rhabdomyolysis (disintegration or

dissolution of muscle) have been reported only rarely. In most
of these cases, patients usually suffered from renal
insufficiency or were taking drugs such as cyclosporine,
itraconazole, erythromycin, gemfibrozil, or niacin. Plasma
creatine kinase levels should be determined regularly.
Bile acid sequestrant resins
a. Mechanism of action.
# These insoluble, nonabsorbable
anion-exchange resins bind bile acids within
the intestines.
# Bile acids are synthesized from
cholesterol.
# Lowering the bile acid concentration
causes hepatocytes to
increase conversion of cholesterol to bile
acids,
# Consequently the intracellular
cholesterol concentration
decreases, which activates an increased
hepatic uptake
of cholesterol-containing LDL particles
leading to a fall in plasma LDL.
b. Indications. These agents have been shown to be safe
and effective in lowering LDL-C especially in patients
with modestly elevated levels, in primary prevention,
in young adult men, and postmenopausal women.
They are effective in combination with other agents.

c. Currently available agents include the following:

(1) Cholestyramine : 2-8 g by mouth in two daily doses
(2) Colestipol : 2-16 g by mouth in one or two daily doses
(3) Colesevelam : 6-7 tablets (625 mg/tablet) by mouth in
one daily dose
d. Precautions

(1) These resins are taken just before meals and

present palatability problems in patients.
(2) Gastrointestinal (GI) intolerance, especially constipation
flatulence, and dyspepsia are frequent.
(3) Absorption of many other drugs can be affected.
Other drugs should be taken 1 hr before or 4-6 hr after
resins.
 Ezetimibe

• Action: inhibits dietary cholesterol uptake by

jejunal enterocytes by binding to a key
mediator of cholesterol absorption – Neimnn-
Pick C1-Like1 (NPC1L1).
Results: 1) reduction of cholesterol incorporation into
chylomicrons and delivery to hepatocytes; 2) increased synthesis
of cholesterol and LDL receptors in hepatocytes; 3) decreased
serum LDL and cholesterol levels.

Advantages: clinically safe; effective; used as monotherapy in

statin-intolerant patients; also used in combination with statins in
statin-tolerant patients for further reduction of serum LDL and
cholesterol.

Disadvantages: no effect on TG absorption; a new class of

anti-atherosclerotic drug – long term effect not known.
NPC1L1 protein recycles between the plasma cell membrane and endocytic recycling
compartment. When the extracellular cholesterol concentration is high, cholesterol is
incorporated into the cell membrane and is sensed by cell surface–localized NPC1L1.
NPC1L1 and cholesterol are then internalized together through clathrin/AP2-mediated
endocytosis and transported along microfilaments to the ERC in vesicles. The ERC is where
cholesterol and NPC1L1 are stored. When the intracellular cholesterol level is low, ERC-
localized NPC1L1 moves back to the PM along microfilaments in order to absorb cholesterol.
Ezetimibe hinders the interaction of the NPC1L1/cholesterol complex with the AP2-clathrin
complex
 Niacin (nicotinic acid)

• Action: Acts through a Gi-coupled GPCR to decrease

cAMP levels. Inhibits hormone-sensitive lipase
involved in lipolysis in adipose tissue and decreases
free fatty acid (FFA) transfer to the liver for synthesis
of triglycerides.
Results: 1) decreased production and release of VLDL by
liver; 2) decreased serum levels of VLDL as well as LDL and
TG; 3) reduced clearance of HDL or increased serum level of
HDL; 4) increased HDL/LDL ratio.

Advantages: long clinical experience; effective; least

expensive.

Disadvantages: evokes flushing, itchiness, dyspepsia and GI

discomfort, contraindicated for diabetic patients and pregnant
women; adverse effects in hepatic diseases and reactivation of
gout.
Metabolic effects of nicotinic acid at pharmacological doses.

ATGL, adipocyte triglyceride lipase

 α
GTP

ATP cAMP
β γ
Activation of the nicotinic acid receptor GPR109A on adipocytes induces
a Gi-mediated inhibition of adenylyl cyclase (AC) activity resulting in a
decrease of cAMP levels. This leads to a decrease in lipolysis, as cAMP
is the main intracellular mediator of prolipolytic stimuli, such as
sympathetic stimuli acting through theβ-adrenoceptor (β-AR). cAMP
activates protein kinase A (PKA), which increases lipolysis by
phosphorylation of various proteins, including perilipin and hormone-
sensitive lipase (HSL). The decrease in free fatty acid (FFA) levels
induced by nicotinic acid results in a substrate shortage for hepatic
triglyceride (TG) synthesis. Consequently, less triglycerides and less
VLDL are produced by the liver, and as a result, triglyceride and VLDL
as well as LDL plasma levels drop.
The mechanism of the nicotinic acid–induced increase in HDL
cholesterol levels is less clear.
Most likely, the decrease in triglyceride levels in ApoB-
containing lipoproteins (LDL/VLDL) results in a decreased
exchange between cholesterol esters carried by HDL particles
and triglycerides in VLDL and LDL particles mediated by CETP,
resulting in an increase in HDL cholesterol plasma
concentrations.
.
Potential mechanisms underlying lipid-independent
antiatherogenic effects of nicotinic acid.
Evidence has been provided that nicotinic acid can reduce the
progression of atherosclerosis by direct lipid-independent effects on
endothelial and immune cells. Shown is a simplified model of the
recruitment of monocytes into atherosclerotic lesions of the arterial
wall and formation of foam cells. Nicotinic acid has been suggested to
affect this process via different mechanisms.

(i) Nicotinic acid can reduce the expression of endothelial adhesion

molecules involved in the binding and recruitment of immune
cells.

(ii) Via activation of HCA2 on monocytes/macrophages, nicotinic

acid inhibits the homing of cells to atherosclerotic lesions (e.g.
through interaction with chemokine expression and/or signaling).

(iii) Through activation of HCA2 on macrophages, nicotinic acid

increases the efflux of free cholesterol (FC) via cholesterol
transporters onto HDL particles
Potential mechanism of
nicotinic acid–induced
flushing.
 Nicotinic acid induces the cutaneous flushing reaction by
activation of GPR109A on cutaneous immune cells, most likely
epidermal Langerhans cells.

Activation of GPR109A on Langerhans cells results in an

activation ofβ-isoforms of phospholipase C (PLCβ) via Gβγ-
subunits. The consecutive inositol-1,4,5-trisphosphate (IP3)-
mediated release of intracellularly stored Ca 2+ induces an
activation of phospholipase A2(PLA2) and the formation of
arachidonic acid (AA).
AA is then further metabolized via cyclooxygenase-1(COX-1) to
prostaglandin G2and prostaglandin H2(PGG2/H2) and subsequently
via prostaglandin D2 and prostaglandin E2synthases to the
vasodilatory prostanoids prostaglandin D2(PGD2) and prostaglandin
E2(PGE2). PGD2and PGE2 are then acting on subepidermal blood
vessels to induce a vasodilation via activation of DP1and
EP2/EP4receptors.
These receptors have in common that they couple to
Gs and lead to a stimulation of adenylyl cyclase
(AC) activity and an increase in intracellular cAMP,
which relaxes vascular smooth muscle.
 Fibrates (prototype: clofibrate
US: gemfibrozil; Europe: fenofibrate)
• Action: acts through peroxisome proliferator
activated receptors (PPARs) to stimulate gene
transcription of lipoprotein lipase; increases the
clearance of VLDL and reduce plasma TG levels;
decreases VLDL synthesis and lowers LDL levels
moderately; increases plasma HDL by increased
synthesis and/or decreased clearance.
Results: decreased serum TG and cholesterol; increased
HDL/LDL ratio.
Advantages: recent clinical data support safety and
efficacy; well-tolerated, potential anti-thrombotic effect.
Disadvantages: more effective in reducing TG than
LDL; increased LDL levels in some patients; displaces
anticoagulant from albumin; contraindicated in patients
with renal failure. Clofibrate has toxic effect.
 Combined Drug Therapy
• Advantages: Synergistic approaches utilizes
complementary mechanisms of drug actions; reduces
effective doses of single drug to prevent side effects.

• Hypercholesterol without hypertriglycerides:

Bile acid sequestrant plus lovastatin

Ezetimibe plus lovastatin
Bile acid sequestrant plus lovastatin plus ezetimibe
Bile acid sequestrant plus nicotinic acid
Bile acid sequestrant plus gemfibrozil (less common)
• Hypercholesterol with hypertriglycerides:

Nicotinic acid plus lovastatin

Lovastatin plus gemfibrozil
Nicotinic acid plus lovastatin plus bile acid sequestrant
 Probucol (lipophilic antioxidant)

• Action: Taken up by LDL particles and endothelial

cells. Inhibits oxidation of LDL and prevents
ingestion by macrophage foam cells. Decreases HDL
production.

• Results: 1) decreases atherosclerotic plaque

formation; 2) small reduction in serum LDL-
cholesterol; 3) greater reduction of serum HDL-
cholesterol.
Advantages: may be used in combination therapy
with other drugs that lower serum LDL-cholesterol.
Disadvantages: not effective in single drug
therapy; no long term clinical data.
Newer drugs for the treatment of dyslipidemia

1. PCSK9 INHIBITORS

PCSK9 is a serine protease that plays a central role in cholesterol

metabolism in the liver by enhancing the degradation of LDLRs.
LDLR can be recycled or degraded in the lysosomal process after
internalization. Circulating PCSK9 binds to the LDLRs directing
the LDLRs to the lysosome, enhancing their clearance in the
hepatocyte for degradation, and preventing the recycling of LDLRs
back to the cell surface after internalization [
 1. PCSK9 INHIBITORS
Mechanism of action
By blocking PCSK9, PCSK9 inhibitors can reduce LDLRs
degradation and increase the surface expression of the LDLRs, which
in turn enhances LDLRs recycling and reduces the LDL-C level

Diabetes Metab J 2015;39:87-94

Therapeutic mechanism of pro-protein convertase
subtilisin/kexin type 9 (PCSK9) inhibition. Binding of PCSK9
to the low density lipoprotein (LDL) receptor leads to the
degradation of LDL receptor at lysosome. PCKS9 inhibitor, a
monoclonal antibody against PCKS9, inhibits the binding of
PCSK9 and LDL receptor, which results in the recycling of LDL
receptor and increased expression of LDL receptor at cell
membrane. LDL-C, low density lipoprotein cholesterol.
2. MTP INHIBITOR
Mode of action

MTP is predominantly expressed in hepatocytes and enterocytes,

whose action is required in the synthesis of ApoB-containing
lipoproteins. MTP transfers triglyceride (TG), phospholipids and
cholesteryl esters to the ApoB in endoplasmic reticulum and has a
critical role in the synthesis of very low density lipoprotein (VLDL)
and chylomicrons in liver and intestine. Inhibition of MTP results in
the decreased synthesis and secretion of VLDL in the liver by
inhibiting the lipidation of ApoB. MTP inhibition can reverse the
increased hepatic production and secretion of VLDLs caused by
insulin resistance. Moreover, inhibition of MTP in enterocytes can
contribute to the reduction in plasma TG level by reducing dietary fat
absorption through chylomicron. An orally active small molecule
inhibitor of MTP, lomitapide, was developed and it has been approved
for the treatment of homozygous familial hypercholesterolemia
Therapeutic mechanism of lomitapide and mipomersen. The
assembly of very low density lipoprotein (VLDL) requires the
loading of triglyceride (TG) to the apolipoprotein B (ApoB) in the
liver. The microsomal triglyceride transfer protein (MTP) works
in this proccess and transfers TG to the ApoB. The secreted VLDL
is converted to low density lipoprotein (LDL) in the bloodstream.
The lomitapide inhibits the action of MTP and mipomersen
inhibits the synthesis of ApoB. These two agents eventually
inhibit the assembly of VLDL in the liver, which results in
decreased LDL in the bloodstream. IDL, intermediate-density
lipoprotein.
ANTISENSE OLIGONUCLEOTIDE AGAINST
APOLIPOPROTEIN B
Mode of action
ApoB is the major structural protein of atherogenic lipoproteins
(APO-B containing lipoproteins). It has a key role in the assembly
and secretion of VLDL from the liver . Plasma ApoB concentration
is a reliable index of the total number of atherogenic lipoproteins
such as small dense LDL-C. Mipomersen is a synthetic 20
nucleotide antisense oligonucleotide which can bind to ApoB mRNA
via complementary sequence interactions. Hybridization of
mipomersen to the target ApoB mRNA creates a substrate for RNase
H1, which results in the decrease of the ApoB mRNA level and the
production of ApoB protein .
 APOLIPOPROTEIN A1 MIMETICS

Mode of action
The high serum level of HDL-C is a well-known protective factor of
ASCVD. ApoA1 is the major apolipoprotein component of mature
HDL. ApoA1 took cholesterol from macrophages in atherosclerotic
lesions via ATP-binding cassette A1 (ABCA1), triggering reverse
cholesterol transport. The central role of ApoA1 in comprising
HDL-C makes it as an attractive target for modifying
Atherosclerotic cardiovascular disease ( ASCVD ) risk. ApoA1
mimetics are a class of drugs that is designed to mimic the effect of
ApoA1 and HDL-C to reverse the progression of atherosclerosis