1. December 19 th, 2023
prof. Elisabetta Cerbai, prof. Pierangelo Geppetti
Dr. Raffaele Coppini
Ricercatore Dip. NeuroFarBa
Antidyslipidemic drugs
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Deaths attributed to 19 leading risk factors,by
country incomelevel (2004)
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
INTRODUCTION
• Plasma lipids are transported in complexes called
lipoproteins.
• Metabolic disorders that involve elevations in any
lipoprotein species are termed hyperlipoproteinemias or
hyperlipidemias.
• Major clinical sequela of hyperlipidemias is
ATHEROSCLEROSIS, the leading cause of death for both
genders in the USA and other Western countries.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Free cholesterol
Phospholipids Triglycerides
Cholesterol esthers
Apolipoproteins
Structure of lipoproteins
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
1. Chylomicrons
2. Very low density lipoproteins (VLDL)
3. Intermediate density lipoproteins (IDL)
4. Low density lipoproteins (LDL)
5. High density lipoproteins (HDL)
Classification of lipoproteins
according to their density
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Bile acids and sterols
(700 mg/die)
Extra-hepatic
tissues
*and extra-hepatic
From Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of
Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In
Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl
2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss,
2002:1082-1150; Bays H Expert Opin Investig Drugs 2002;11:1587-1604.
Biliary cholesterol
(~1000 mg/die)
Uptake
(~600-800 mg/die)
Hepatic
synthesis *
(~900 mg/die)
Gut
Cholesterol from food
(~300-700 mg/die)
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
STRATEGY…
• High-density lipoproteins (HDL) exert several antiatherogenic
effects. They participate in retrieval of cholesterol from the artery wall
and inhibit the oxidation of atherogenic lipoproteins. Low levels of
HDL (hypoalphalipoproteinemia) are an independent risk factor for
atherosclerotic disease and thus are a target for intervention.
• Because atherogenesis is multifactorial, therapy should be directed
toward all modifiable risk factors.
• Atherogenesis is a dynamic process. Quantitative angiographic trials
have demonstrated net regression of plaques during aggressive
lipid-lowering therapy. Primary and secondary prevention trials have
shown significant reduction in mortality from new coronary events and
in all-cause mortality.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
LIPOPROTEINDISORDERS
• Lipoprotein disorders are detected by measuring lipids in serum after
a 10-hour fast.
• Risk of heart disease increases with concentrations of the
atherogenic lipoproteins, is inversely related to levels of HDL, and is
modified by other risk factors.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
BASIC& CLINICALPHARMACOLOGYOF DRUGSUSED
INHYPERLIPIDEMIA
• The decision to use drug therapy for hyperlipidemia is based on the
specific metabolic defect:
1. COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE: REDUCTASE
INHIBITORS “STATINS”
2. NIACIN (NICOTINIC ACID)
3. FIBRIC ACID DERIVATIVES (FIBRATES)
4. BILE ACID-BINDING RESINS
5. INHIBITORS OF INTESTINAL STEROLABSORPTION
6. OMEGA-3 FATTYACIDS (OMEGA-3 FAs)
7. CHOLESTERYL ESTER TRANSFER PROTEIN (CEPT) INHIBITORS
8. PROPROTREIN CONVERTASE SUBTILISIN/KEXIN-TYPE 9 (PPCSKT9)
INHIBITORS
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
HMG-CoA
Mevalonate
HMG-CoA reductase STATINS
Squalene
STATINS inhibit the synthesis of mevalonate and its products
Depletion of cholestorol pool in
the hepatocyte
Increased clearance
of LDL
Activation of SREBP
(sterol regulatory element
binding protein)
Activation of gene
transcription
LDL
Receptors
HEPATOCYTE
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
STATINS
These compounds are structural analogs of HMG-CoA (3-hydroxy-
3-methylglutaryl-coenzyme A, fig.).
Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin,
rosuvastatin, and pitavastatin belong to this class.
They are most effective in reducing LDL. Other effects include: decreased
oxidative stress and vascular inflammation with increased stability of
atherosclerotic lesions.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
PHARMACOKINETICS
• Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed
in the gastrointestinal tract to the active β-hydroxyl derivatives, whereas
pravastatin has an open, active lactone ring.
• Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners
that are active as given.
• Absorption of the ingested doses of the reductase inhibitors varies from 40%
to 75% with the exception of fluvastatin, which is almost completely absorbed.
•
• All have high first-pass extraction by the liver. Most of the absorbed dose
is excreted in the bile; 5–20% is excreted in the urine. Plasma halflives of
these drugs range from 1 to 3 hours except for atorvastatin (14 hours),
pitavastatin (12 hours), and rosuvastatin (19 hours).
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
MECHANISM OFACTION
• HMG-CoA reductase mediates the first committed step in
sterol biosynthesis. The active forms of the reductase
inhibitors are structural analogs of the HMG-CoA
intermediate that is formed by HMG-CoA reductase in the
synthesis of mevalonate.
• These analogs cause partial inhibition of the enzyme and
thus may impair the synthesis of isoprenoids such as
ubiquinone and dolichol and the prenylation of proteins. It is
not known whether this has biologic significance.
• This effect increases both the fractional catabolic rate of
LDL and the liver’s extraction of LDL precursors (VLDL
remnants) from the blood, thus reducing LDL. Because of
marked first pass hepatic extraction, the major effect
is on the liver.
27. STATINS
derivate da funghi sintetiche
ritirata dal commercio nell’agosto 2001
Natural (from fungi) Synthetic
28. *P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
Statins & inhibition of HMG-CoA Reductase:
different potency
Three determinations, IC
50
(nM) with 95% confidence limits
Rosuva
5.4
100
10
Ceriva *
10.0
Atorva
8.2
Fluva ***
27.6
Simva *
11.2
Prava
***
44.1
IC50
(nM)
(log scale)
McTaggart et al., Am J Cardiol 2001, 87: 28B-32B
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
THERAPEUTICUSES& DOSAGE
• Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of
LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should
not be given these agents. Use in children is restricted to selected patients with familial
hypercholesterolemia or familial combined hyperlipidemia.
• Because cholesterol synthesis occurs predominantly at night, reductase inhibitors - except
atorvastatin and rosuvastatin - should be given in the evening if a single daily dose is used.
• Absorption generally (with the exception of pravastatin) is enhanced by food.
• Daily doses:
Lovastatin vary from 10 to 80 mg.
Pravastatin has a maximum recommended daily dose of 80 mg.
Simvastatin is given in doses of 5–80 mg daily. Because of increased risk of myopathy with the 80 mg/day
dose, the FDA issued labelling for scaled dosing of simvastatin and Vytorin in June 2011.
Fluvastatin is given in doses of 10–80 mg daily.
Atorvastatin is given in doses of 10–80 mg/d.
Rosuvastatin, the most efficacious agent for severe hypercholesterolemia, at 5–40 mg/d.
The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage
range in patients with moderate to severe hypercholesterolemia.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
TOXICITY
Elevations of serum aminotransferase activity (up to three times normal) occur in
some patients. This is often intermittent and usually not associated with other evidence
of hepatic toxicity. Therapy may be continued in such patients in the absence of
symptoms if aminotransferase levels are monitored and stable.
Minor increases in creatine kinase (CK) activity in plasma are observed in some
patients receiving reductase inhibitors, frequently associated with heavy physical
activity. Rarely, patients may have marked elevations in CK activity, often accompanied
by generalized discomfort or weakness in skeletal muscles. If the drug is not
discontinued, myoglobinuria can occur, leading to renal injury.
Myopathy may occur with monotherapy, but there is an increased incidence in patients
also receiving certain other drugs. Genetic variation in an anion transporter (OATP1B1)
is associated with severe myopathy and rhabdomyolysis induced by statins.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
MYOPATHY
, CKANDNONCKASSOCIATED
• Statin-induced myalgia is a very frequent phenomenon encountered in daily
practice.
• The true nature of muscle pain remains often unclear, and the vast majority of
patients with statin-induced myalgia have normal CK levels, thus a novel
sensitive biomarker would be greatly appreciated both by patients and
physicians.
• However, CK activity should be measured in patients receiving potentially
interacting drug combinations and, in all patients, CK should be measured
at baseline. If muscle pain, tenderness, or weakness appears, CK should be
measured immediately and the drug discontinued if activity is elevated
significantly* over baseline. The myopathy usually reverses promptly upon
cessation of therapy.
• *Usually, if the CK level is five times the upper limit of normal or more.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
INTERACTIONS
• Catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through
CYP3A4.
The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that
inhibit or compete for the 3A4 cytochrome (macrolide, antibiotics, cyclosporine, ketoconazole and its
congeners, some HIV protease inhibitors, tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine,
and others). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an
increased risk of myopathy. Conversely, drugs such as phenytoin, griseofulvin, barbiturates,
rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma
concentrations of the 3A4-dependent reductase inhibitors.
• Whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin,
is mediated by CYP2C9.
Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone,
amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Pravastatin
and rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group
of antifungal agents, macrolides, and cyclosporine. Doses should be kept low and the patient
monitored frequently.
• Pravastatin is catabolized through other pathways, including sulfation.
41. Clinically Relevant Drug Interactions with
Statins
+ = interaction reported; - = no interaction reported; n.a. = no data available
From published data.
Adapted from Corsini et al. 1999 Pharmacol Ther 84: 413-428
Drug Atorva Ceriva Fluva Lova Prava Simva
Warfarin - - + + - +
Digoxin - n.a. - - - +
Nicotinic acid n.a. - - + - -
Erythromycin - - - + - +
Cyclosporine A + + - + + +
Fibrates + + - + + +
42. Clinically Relevant Drug Interactions with
Statins
European
Heart
Journal,
ehz455,
https://doi.org/10.1093/eurheartj/ehz455
The
content
of
this
slide
may
be
subject
to
copyright:
please
see
the
slide
notes
for
details.
43. European Heart Journal, ehz455, https://doi.org/10.1093/eurheartj/ehz455
The content of this slide may be subject to copyright: please see the slide notes for details.
Red yeast rice (RYR) is a source of fermented pigment that has been
used in China as a food colorant and flavour enhancer for centuries.
Hypocholesterolaemic effects of RYR are related to a statin-like
mechanism—inhibition of hydroxymethylglutaryl-coenzyme A (HMG-
CoA) reductase—of monacolins, which represent the bioactive
ingredient. Different commercial preparations of RYR have different
concentrations of monacolins, and lower TC and LDL-C levels to
variable extents, but the consumer is not able to make that
distinction.144,185 Moreover, the long-term safety of the regular
consumption of these products has not been fully documented and
safety issues due to the possible presence of contaminants in some
preparations have been raised. Side effects like those observed with
statins have also been reported.
Monacolin and red yeast rice
45. Main “pleiotropic” effects of statins
Platelet aggregation
Adhesion
eNOS, TXA2
Membrane cholesterol
thrombi
Endothelial function
eNOS ; t-PA;
ET-1; ROS
Smooth muscle cells
Migration, proliferation
NAD(P)H-ossidasi
STATINS
Lymphocyte function
Activation, proliferation
Macrophage function
metalloproteases
Cholesterol ester accumulation
LDL oxydation
Direct effects on myocardium
NAD(P)H-oxidase
46. Inhibition of macrophage function:
Inhibition of proteolytic enzymes (metalloproteases)
Inhibition of chemokines and chemoattractive factors for monocytes
Reduced cholesterol ester accumulation
Statins & plaque
stabilization
47. Possible mechanisms of antiarrhythmic effects of statins against atrial fibrillation
Kostapanos, Cardiovasc Res 2007
However,, no prevention against perioperative AF was demostrated
(N Engl J Med. 2016 May 5;374(18):1744-53)
48. Statine: safety reports
Dati da studi clinici randomizzati, segnalazioni di farmacovigilanza, e case reports pubblicati
No statistically significant evidence of renal disease (increased proteinuria or
decreased glomerulal filtration)
Very low risk of hepathic disease (<=placebo)
Hepathic failure: 1 / 1.000.000 pts/year
Myopathy: 11 / 100.000 pts/year
Rhabdomyolisis (all statins but cerivastatin):
3,4 / 100.000 pts/year (10% with fatal events)
Incidence 10-times higher if associated with gemfibrozil
Higher incidence with statins metabolized by CYP 3A4 (erythromycin, azole
antimycotic drugs)
Law M. & Rudnika AR - Am J Cardiol. 97: 52c-60c, 2006
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
MECHANISM OFACTION
Fibrates function as ligands for the
nuclear transcription receptor, PPAR-α.
They transcriptionally up-regulate LPL,
apo A-I and apo A-II, and down-regulate
apo C-III, an inhibitor of lipolysis. A major
effect is an increase in oxidation of
fatty acids in liver and striated muscle.
They increase lipolysis of lipoprotein
triglyceride via LPL. Intracellular lipolysis
in adipose tissue is decreased. Levels of
VLDL decrease, in part as a result of
decreased secretion by the liver. Only
modest reductions of LDL
occur in most patients.
53. • of LPL expression
• of apoA-1 and apoA-2 expression
• inhibition of ApoCIII expression
• ABCA1 (= cholesterol cellular efflux)
PEROXISOME-PROLIFERATOR-ACTIVATED RECEPTORS
Glitazones
Fibrates
PP Responsive Element
54. 1. Fibrates Stimulate lipoprotein lipases (TG hydrolysisi)
Fibrates enhance the oxidation of fatty acids (FA) in liver and muscle and reduce the rate of lipogenesis in
the liver, thereby reducing hepatic secretion of VLDL triglycerides (TG). The increased uptake of FA in
muscle cells results from an in lipoprotein lipase (LPL) activity in adjacent capillaries and a in the
apolipoprotein CIII (Apo CIII-inhibitor of LPL) concentration mediated transcriptionally by peroxisome
proliferator-activated receptor a (PPARa). The enhanced catabolism of VLDL generates surface
remnants, which are transferred to HDL which concentrations are further augmented by an increase in
PPARa-mediated transcription of apolipoprotein AI (Apo AI) and apolipoprotein AII (Apo AII). Ultimately,
the rate of HDL-mediated reverse cholesterol transport may increase.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
FIBRICACID DERIVATIVES
• Fibrates decrease levels of VLDL and, in some patients, LDL as well.
• Gemfibrozil is absorbed quantitatively from the intestine and is tightly
bound to plasma proteins. It undergoes enterohepatic circulation and
readily passes the placenta. The plasma half-life is 1.5 hours.
Seventy percent is eliminated through the kidneys, mostly unmodified.
The liver modifies some of the drug to hydroxymethyl, carboxyl, or
quinol derivatives.
• Fenofibrate is an isopropyl ester that is hydrolyzed completely in the
intestine. Its plasma half-life is 20 hours. Sixty percent is excreted in
the urine as the glucuronide, and about 25% in feces.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
THERAPEUTIC USES & DOSAGE
• Fibrates are useful drugs in hypertriglyceridemias in which VLDL
predominate and in dysbetalipoproteinemia.
•
• They also may be of benefit in treating the hypertriglyceridemia that
results from treatment with viral protease inhibitors.
•
• The usual dose of gemfibrozil is 600 mg orally once or twice daily.
Absorption of the drug is better when it is taken with food.
• The dosage of fenofibrate is one to three 48 mg tablets (or a single
145 mg tablet) daily.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
TOXICITY
• Rare adverse effects of fibrates include: rashes, gastrointestinal
symptoms, myopathy (risk of myopathy increases when fibrates are
given with reductase inhibitors), arrhythmias, hypokalemia, and high
blood levels of aminotransferases or alkaline phosphatase.A few
patients show decreases in white blood count or hematocrit.
• Both agents potentiate the action of coumarin and indanedione
anticoagulants.
• There appears to be a modest increase in the risk of cholesterol
gallstones, reflecting an increase in the cholesterol content of bile.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
NIACIN
• Niacin (vitamin B3) decreases VLDL and LDL levels, and Lp(a) in most
patients. It often increases HDL levels significantly.
• Its action is due in part to its action on hydroxycarboxylic acid receptor
2 (HCA2)and hydroxycarboxylic acid receptor 3 (HCA3),
• Is converted in the body to the amide, which is incorporated into niacinamide
adenine dinucleotide (NAD). It is excreted in the urine unmodified and as
several metabolites.
• Niacin inhibits VLDL secretion, in turn decreasing production of LDL.
Increased clearance of VLDL via the LPL pathway contributes to reduction of
triglycerides. Niacin has no effect on bile acid production. Excretion of neutral
sterols in the stool is increased acutely as cholesterol is mobilized from tissue
pools and a new steady state is reached. The catabolic rate for HDL is
decreased. Niacin inhibits the intracellular lipase of adipose tissue via
receptor-mediated signaling, possibly reducing VLDL production by
decreasing the flux of free fatty acids to the liver.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
THERAPEUTIC USES & DOSAGE
• In combination with a resin or reductase inhibitor, niacin normalizes LDL in
most patients with heterozygous familial hypercholesterolemia and other
forms of hypercholesterolemia.
• In severe mixed lipemia that is incompletely responsive to diet, niacin often
produces marked reduction of triglycerides, an effect enhanced by marine
omega-3 fatty acids.
• It is clearly the most effective agent for increasing HDL and the only agent
that may reduce Lp(a).
For treatment of heterozygous familial hypercholesterolemia, most patients
require 2–6 g of niacin daily.
For other types of hypercholesterolemia and for hypertriglyceridemia,1.5–3.5 g
daily is often sufficient.
Crystalline niacin should be given in divided doses with meals, starting with 100
mg two or three times daily and increasing gradually.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
TOXICITY
• Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose
when niacin is started or the dose increased. Taking aspirin or ibuprofen one half hour before blunts this
prostaglandin-mediated effect.
• Some patients experience nausea and abdominal discomfort. Niacin should be avoided in most
patients with severe peptic disease.
• Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with
liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals. Rarely,
true hepatotoxicity may occur.
• Carbohydrate tolerance may be moderately impaired, especially in obese patients, but this is usually
reversible except in some patients with latent diabetes. Niacin may be given to diabetics who are receiving
insulin and to some receiving oral agents. Niacin may increase insulin resistance in some patients. This can
often be addressed by increasing the dose of insulin or the oral agents.
• Other:
• Hyperuricemia
• Red cell macrocytosis
• Significant platelet deficiency
• Arrhythmias, mostly atrial
• Macular edema
• May potentiate the action of antihypertensive agents
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
[..] The free cholesterol (unesterified cholesterol) is then transferred from the micelles to the surface of the brush border membrane of the
enterocyte, where NPC1L1 plays a critical role for the uptake of cholesterol and phytosterols, and is the target of the cholesterol
absorption inhibitor ezetimibe. Free cholesterol enters the cytoplasmic compartment and moves to the endoplasmic reticulum where it
may be esterified by ACAT2 to form cholesteryl esters. Free cholesterol and cholesteryl esters are packaged into chylomicrons, which are
then secreted into the mesenteric lymph. Once in the circulation, chylomicrons and their remnants are rapidly cleared by the liver.
BBA, 1791: 679, 2009
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
SterolAbsorption Inhibitor
is the first member of a group of drugs that
inhibit intestinal absorption of phytosterols and
cholesterol.
Its primary clinical effect is reduction of LDL levels.
A transport protein, NPC1L1, appears to be the target of the
drug. It is effective even in the absence of dietary cholesterol
because it inhibits reabsorption of cholesterol excreted in the
bile.
The effect of ezetimibe on cholesterol absorption is constant
over the dosage range of 5–20 mg/d.
Therefore, a single daily dose of 10 mg is used.Average
reduction in LDL cholesterol with ezetimibe alone in patients
with primary hypercholesterolemia is about 18%, with minimal
increases in HDL cholesterol.
Ezetimibe is synergistic with reductase inhibitors,
producing decrements as great as 25% in LDL cholesterol
beyond that achieved with the reductase inhibitor alone.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Ezetimibe — Mechanism of action
Potent selective inhibitor of inhibits intestinal uptake of dietary and biliary cholesterol
• Acting at the level of the brush border of the intestine
• interacting with the Niemann-Pick C1-like protein 1 (NPC1L1)
• without affecting the absorption of fat-soluble nutrients.
The mechanism differs from that of resins or vegetal sterols, as well statins or fibrates
• By inhibiting cholesterol absorption, ezetimibe reduces the amount of cholesterol
delivered to the liver.
• Ezetimibe added to ongoing statin therapy reduces LDL-C levels by an additional 21-
27% compared with placebo in patients with hypercholesterolaemia with or without
established CHD.
Tratto da Catapano A Eur Heart J Suppl 2001;3(suppl E):E6-E10; van Heek M et al Br J Pharmacol
2000;129:1748-1754; Worldwide Product Circular (ezetimibe), MSP; Miettinen TA Int J Clin Pract 2001;55:710-
716; Bays H Expert Opin Investig Drugs 2002;11:1587-1604.
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Absorbed and re-secreted with bile in the intestine; low metabolism by
CYP450.
It undergoes extensive first-pass metabolism to form its active glucuronide
metabolite
Half-life 22 hrs; monotherapy at 10 mg/day
50% cholesterol uptake 15-20% LDL-C
Excreted in the faeces (about 78%) predominantly as ezetimibe
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
EZETIMIBE + S RATIONAL
as second-line therapy in association
with statins when the therapeutic goal is
not achieved at the maximal tolerated
statin dose,
or in cases where a statin cannot be
prescribed
Lower risk of dose-
related ADR with
high dose statins
Improved efficacy
73. 73
Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Combination therapy: ezetimibe plus atorvastatin
versus atorvastatin monotherapy.
Ballantyne et al.
Circulation. 2003 May
20;107(19):2409-15.
TOT 628 patients primary
hypercholesterolemia: LDL-c of
145 to 250 mg/dL, and triglyceride
levels 350 mg/dL
255= ator + ezet
248= ator
65= ezet
60= placebo
76. 76
Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
Spettro antidislipidemico di diverse famiglie di farmaci
Current recommendations for LDL-cholesterol targets
Drexel, Fund Clin Pharmacol 23,687,2009
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Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
OMEGA-3 FAs
• Omega-3 Fas:
• eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)
• marine sources, and their metabolic precursor, α-
linolenic acid (ALA), is from vegetable sources.
• The mechanism of action of omega-3 FAs likely
involves hepatic inhibition of triglycerides
synthesis, decreased LDL-C (VLDL-C) production
and secretion, and increased VLDL-C
metabolism.
A 2018 meta-analysis found no support that
daily intake of one gram of omega-3 fatty acid in
individuals with a history of Coronary Heart
Disease or stroke
91. 91
Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
CETPINHIBITORS
• CET (cholesterylester transfer protein) is a protein
produced by the liver and macrophages that
facilitates transfer of cholesterol esters from HDL-C
to larger lipoproteins. This shift CE mass from HDL-C
to apolipoprotein B-containing proteins, thereby
reducing HDL-C, which in turn may increase
atherogenicity. Therefore, inhibition of CEPT raises
HDL-C levels.
• Currently, 4 CEPT inhibitors have
been studied in clinical trials:
1. Torcetrapib
2. Dalcetrapib
3. Anacetrapib
4. Evacetrapib.
But have failed to reduce
cardiovascular
events.
92. 92
Antidyslipidemic drugs 19 December 2023 Dr. Raffaele Coppini
PCSK9 INHIBITORS
• PCSK9 (Proprotein convertase
subtilisin/kexin type 9) is a
human proteinase expressed in
the liver, kidney, intestine and
central nervous system.
• PCSK9 is a regulator of serum
LDL-C by post-translational
reduction of the LDL-receptor.
• Current PCSK9 inhibitors(mAbs)
approved for familial
hypercholesterolemia include:
• Alirocumab
• Evolocumab
