Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.
aIf pretreatment LDL-C is near or below LDL-C goal value, then a statin dose sufficient to lower LDL-C by 30-40% should be prescribed. bPatients in this category include those with a 10-year risk of 10-20% and one of the following: age >60 years, three or more risk factors, a severe risk factor, triglycerides >200 mg/dL and HDL-C <40 mg/dL, metabolic syndrome, highly sensitive C-reactive protein (CRP) >3 mg/L, and coronary calcium score (age/gender adjusted) >75th percentile. cPatients include those with any severe single risk factor, multiple major risk factors, 10-year risk >8%.
By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation they also reduce T-cell activation, macrophage infiltration, vascular wall inflammation, and promote plaque stabilization
Dr. Ali Ahmad
Hyperlipidemia is a condition excess
of fatty substances called lipids,
largely cholesterol and triglycerides,
in the blood.
It results from abnormalities in lipid
metabolism or plasma lipid transport
or a disorder in the synthesis and
degradation of plasma lipoproteins.
Serum Lipid Level (mg/dL) and Risk of
CAD and IHD based on NCEP Guidelines
Current cigarette smoking Defined
as smoking within the preceding 30
Age Male >45 years of age or
female >55 years of age
Family history of premature CHD A first-
degree relative (male <55 years of age or
female <65 years of age when the first CHD
clinical event occurs)
Hypertension Blood pressure
140/90 or use of
irrespective of blood pressure
Low HDL-C <40 mg/dL
(consider <50 mg/dL as "low" for
Body mass index >25 kg/m2
and waist circumference >40
inches (men) or >35 inches
Type 2 diabetes mellitus
Primary: due to:
(a) A single gene defect: is familial and
called ‘monogenic’ or genetic
(b) Multiple genetic, dietary and
physical activity related causes:
‘polygenic’ or multifactorial.
Secondary: associated with
Drugs (corticosteroids, oral
contraceptives, β blockers) etc.
Lipids- Hterogenous group of compounds
related to fatty acids, which are insoluble in
fatty acids and are source of energy.
Lipoproteins- Spherical particles of water
soluble proteins, that transport neutral lipids
through body fluids.
• Life style modification.
• Obesity reduction.
• Stop smoking &
• Restrict intake of saturated
Fish intake-oily sea fish.
Eg-Tuna & Mackarel.
• Plenty of fruits &
• TREAT THE UNDERLYING
recommend the drug
therapy to be started along
with lifestyle changes in
patients with IHD or in
patients with having LDL
greater than 130mg/dl.
Lowering LDL cholesterol
Reducing total serum cholesterol
Increasing HDL cholesterol
The goals of treatment are:
Primary prevention involves
management of risk factors to prevent a
first-ever CHD event.
Secondary prevention patients are
those who have had a prior CHD event
and whose risk factors are treated most
Recently, the concept of primordial
prevention has been applied to CHD
The primordial prevention guidelines include
150 minutes/week of moderate-intensity exercise (walking
Dietary recommendations include
reducing total calories from fat to <30% and saturated fat to
<7% to avoid trans fat;
consuming <300 mg of cholesterol/day,
a variety of oily fish twice a week or more often, and
oils/foods rich in -linolenic acid (canola, flaxseed, and
soybean oils; flaxseed; and walnuts);
restricting sugary beverages to <36 oz/week for a person
consuming 2000 Kcal daily
Several different classes of drugs are
used to treat hyperlipidemia. These
classes differ not only in their
mechanism of action but also in the
type of lipid reduction and the
magnitude of the reduction.
Classification of Hypolipidemic
First Line Therapy
1. HMG-CoA reductase inhibitors (Statins): Lovastatin,
Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin,
2. Bile acid sequestrants (Resins):
3. Inhibitors of Intestinal Absorption of
Cholesterol: Stanol Esters, Ezetimibe.
4. CETP Inhibitors: Torcetrapib,
Second Line Therapy
Lipoprotein lipase activators (PPARα
activators, Fibrates): Clofibrate,
Gemfibrozil, Bezafibrate, Fenofibrate
Lipolysis and triglyceride synthesis
inhibitor: Nicotinic acid (Niacin)
Miscellaneous Agents: Gugulipid and
Fish oil Derivatives.
The statins are the most effective and
best-tolerated agents for treating
These drugs are competitive inhibitors of
HMG-CoA reductase, which catalyzes an
early, rate-limiting step in cholesterol
Statins were isolated from a mold,
Penicillium citrinum, and identified
as inhibitors of cholesterol
biosynthesis in 1976 by Endo and
The first statin studied in humans
was compactin, renamed
mevastatin, which demonstrated
the therapeutic potential of this
Alberts and colleagues at Merck
developed the first statin approved for
use in humans, lovastatin (formerly
known as mevinolin), which was
isolated from Aspergillus terreus.
Pravastatin and simvastatin are
chemically modified derivatives of
rosuvastatin, and pitavastatin are
structurally distinct synthetic
They competitively inhibit
conversion of 3-Hydroxy-3-
methyl glutaryl coenzyme A
(HMG-CoA) to mevalonate
(rate limiting step in CH
synthesis) by the enzyme
LDL is also reduced by
enhancing the removal of
precursors of of LDL. Eg;
VLDL and IDL.
Reducing hepatic VLDL
production also leads to
reduction in the level of
LDL. This also reduced the
level of TG.
Therapeutic doses reduce CH synthesis by
20–50%. This results in compensatory
increase in LDL receptor expression on liver
cells → increased receptor mediated uptake
and catabolism of IDL and LDL.
Over long-term, feedback induction of HMG-
CoA reductase tends to increase CH
synthesis, but a steady-state is finally attained
with a dose-dependent lowering of LDL-CH
Effect on Lipid Levels
Effect of TG:
• Significant reduction in TG Level (35-45%)
if the TG > 250mg/dl.
• If TG <250 mg/dl – maximum reduction is
• LDL is also reduced.
Effect on LDL-C
• Depending upon the statin its dose the degree
of reduction in the level of LDL ranges from
20-55%Statins Dose Range
Fluvastatin 20-80mg 20 35
Pravastatin 10-40mg 20 35
Lovastatin 10-80mg 20 40
Cervistatin 0.2-0.8mg 20 40
Simvastatin 10-80mg 26 50
Atorvastatin 10-80mg 31 55
Rosuvastatin 5-40mg 36 55
Percentage Reduction in LDL-C in
Min Dose Max Dose
Effect on HDL-C
• Increased irrespective of the dose and statins
used but if the HDL-C <35mg/dl- the effect
may be variable.
• Simvastatin produces greater increase in HDL-
C and apoA-1 level than Atorvastatin and
Level of Lp(a) is not affected by the Statins.
Direct Cardioprotective Effects
Effect on Endothelium
Hypercholestroleamia depresses the
acetylcholine induced vasodilatation in coronary arteries.
Statins increase the synthesis of endothelial NO by stabilization of
endothelial synthase mRNA.
Endothelial dysfunction is also reversed by statins.
Effect on Plaque Stability
Inhibits the infilteration of monocytes in
Inhibits the secretion of metalloproteinases secreted
The metalloproteinases degrade matrix and weaken
the fibrous cap of atherosclerotic plaque.
Statins also appear to modulate the cellularity of the
artery wall by inhibiting proliferation of smooth muscle
cells and enhancing apoptosis.
Reduced proliferation of smooth muscle cells and
enhanced apoptosis- retard initial hyperplasia and
Effect on Inflammation
C- Reactive Protein – marker for high risk
Statins Reduces the baseline CRP.
Effect on Lipoprotein Oxidation
Oxidative changes in LDL
occurs and important in
the uptake of lipoprotein
cytotoxicity with lesions.
Statins inhibits the
oxidative changes and
thus subsequent effect.
Effect on Coagulation
Statins decrease platelet
aggregation and also reduce the
level of fibrinogen.
Increased level of fibrinogen may
be involved in increased incidence
This newer and most popular statin is more
potent and appears to have the highest LDL-CH
lowering efficacy at maximal daily dose of 80 mg.
At this dose a greater reduction in TGs is noted if
the same was raised at baseline.
Atorvastatin has a much longer plasma t½ of 18–
24 hr than other statins, and has additional
This is another newer, commonly used and
potent statin (10 mg rosuvastatin ~ 20 mg
atorvastatin), with a plasma t½ of 18–24 hours.
Greater LDL-CH reduction can be obtained in
severe hypercholesterolaemia; partly due to its
longer persistence in the plasma.
In patients with raised TG levels, rosuvastatin
raises HDL-CH by 15–20% (greater rise than
Potency of Statins
Potency Order for reduction in LDL-C:
Rosuva > Atorva > Simva > Lova > Prava >
Potency Order for reduction in TG:
Atorva >Prava > Rosuva > Simva > Lova
Potency Order for increase in HDL-C:
Prava >Simva > Rosuva = Fluva = Lova >
HMG-CoA reductase activity is
maximum at midnight, so all statins are
administered at bed time to obtain
However, this is not necessary for
atorvastatin and rosuvastatin, which
have long plasma t½.
All statins, except rosuvastatin are
metabolized primarily by CYP3A4.
Hepatotoxicity- Rise in
Myopathy- Rise in CPK
Lupus Like Syndrome
Enzyme inducers (Phenytoin, Rifampicin,
Reduces the plasma concentration of statins
metabolized by CYP3A4 (Lovastatin,
Simulataneous consumption of grape or its juice
Increases the plasma levels of statins.
Primary hyperlipidaemias with raised LDL and
total CH levels, with or without raised TG
levels (Type IIa, IIb, V),
Secondary hypercholesterolaemia- (diabetes,
Bile Acid Sequestrants
Mechanism of Action
Bile acid sequestrants are polymeric compounds
that serve as ion-exchange resins.
Bile acid sequestrants exchange anions such
as chloride ions for bile acids.
By doing so, they bind bile acids and sequester
them from the enterohepatic circulation.
The liver then produces more bile acids to
replace those that have been lost.
Because the body uses cholesterol to make bile
acids, this reduces the amount of LDL
cholesterol circulating in the blood.
Bile acid sequestrants are large polymeric
structures, and they are not significantly
absorbed from the gut into the bloodstream.
Thus, bile acid sequestrants, along with any
bile acids bound to the drug, are excreted
via the feces after passage through the
colestipol bind and interfere
with the absorption of many
They reduce the absorption
a- Increase TG
Mechanism of Action
Fibrates reduce TG- activate a nuclear receptor-
Stimulates beta oxidation of Fatty Acids
Increase LPL synthesis
Reduce production of Apo C3
Inhibits Lipolysis and receptor mediated clearance.
VLDL clearance is enhanced
Fibrate-mediated increases in HDL-C are due to
PPAR stimulation of apoA-I and apoA-II
expression, which increases HDL levels.
PPARα may also mediate enhanced LDL
receptor expression in liver seen particularly with
second generation fibrates like bezafibrate,
Fibrates decrease hepatic TG synthesis as well.
All of the fibrate drugs are absorbed rapidly and
efficiently (>90%) when given with a meal but
less efficiently when taken on an empty
The ester bond is hydrolyzed rapidly.
Peak plasma concentrations -within 1-4 hours.
The t1/2 ranges from 1.1 hours (gemfibrozil) to
20 hours (fenofibrate).
The fibrate drugs are excreted predominantly
as glucuronide conjugates; 60-90% of an oral
dose is excreted in the urine.
Increse in serum
transaminases and ALP
Water soluble vitamin B
One of the oldest drug used in
the treatment of dyslipidemia
LIPOLYSIS AND TRIGLYCERIDE
SYNTHESIS INHIBITOR (Niacin)
Mechanism of Action
In adipose tissue, niacin inhibits the lipolysis of
triglycerides by hormone-sensitive lipase- reduces
transport of free fatty acids to the liver and
decreases hepatic triglyceride synthesis.
Acting on GPR109A, niacin stimulates the Gi–
adenylyl cyclase pathway in adipocytes, inhibiting
cyclic AMP production and decreasing hormone-
sensitive lipase activity, triglyceride lipolysis, and
release of free fatty acids.
Niacin also may inhibit a rate-limiting enzyme of
triglyceride synthesis, diacylglycerol
In the liver, niacin reduces triglyceride synthesis
by inhibiting both the synthesis and
esterification of fatty acids, effects that increase
Reduction of triglyceride synthesis reduces
hepatic VLDL production-reduced LDL levels.
Niacin also enhances LPL activity-promotes
clearance of chylomicrons and VLDL
Niacin 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-apoA-I, but not of cholesteryl
esters, thereby increasing the apoA-I content of
plasma and augmenting reverse cholesterol
Postural hypotension may occur in patients on
antihypertensives when they take nicotinic acid.
Risk of myopathy due to statins is increased.
It is a novel drug that acts by inhibiting
intestinal absorption of cholesterol and
( Cholesterol Absorption Inhibitor)
Mechanism of action
Lowers plasma cholesterol levels by inhibiting the
absorption from intestine
This cause a decrease in the cholesterol delivery to
the liver which in turn clears more cholesterol from
Selective action (( not interfere with TGs, lipid-
soluble vitamins absorption))
• Monotherapy or in combination with HMGRI for
reduction of elevated total cholesterol.
Should not be given
Should not be given in
LDL oxidation inhibitor:
Acts by inhibiting the synthesis of sterols.
Inhibits atherogenesis- Antioxidant action
Reduces LDL as well as HDL.
Used in patients of severe atherosclerosis with
HDL-C is decresed.
Guggul is made from the sap (gum resin) of the
Commiphora mukul tree, which is native to India.
Reduces the sectretion and enhances the
excretion of cholesterol.
VLDL,LDL,TG are reduced.
HDL is incresed
Used is type 2b and Type 4 hyperlipidemia.
The cholesteryl ester transfer protein (CETP)
facilitates exchange of CHEs with TGs
between HDL particles and chylomicrons,
VLDL, LDL, etc.
It plays an important role in the disposal of
Inhibitors of this protein, torcetrapib,
anacetrapib, etc. markedly raise HDLCH and
They were presumed to have
However, during a large randomized clinical
trial, torcetrapib was found to increase
cardiovascular events like angina, MI, heart
failure and death.
The trial and further development of the drug
was stopped in 2007.
Whether other CETP inhibitors will have
therapeutic value is being investigated, but
Statin + Niacin- Type 2a and 2b
Can be used for incresed LDL and decreased
Statins + Ezetimibe- Synergistic combination for
Primary Hypercholestrolemia and Type2a
Statins + Fibrates- High risk patients on Statin
therapy having increased TG levels as their main
Patient treted with this combination must be
observed for Myopathy.
Bile Acid Binding Resin + Fibrates- Type 2b.
Increased risk of Cholelithiasis.
Bile Acid Binding Resin + Niacin- Type 2a and
Resin has neutralizing action which
reduces gastric irritation caused by niacin.
Resin + Statins- Reduces LDl-C in Type 2a
Statins should be given one hour before or
four hours after the resin to ensure proper
Resin+ Statin +Niacin- Used in severe disorders
due to increased levels of LDL- Type 2a and