NUOVE STRATEGIE NEL
TRATTAMENTO DELLA
DISLIPIDEMIA
Prof. Paolo de Caprariis
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Altered coagulation
And fibrinolysis
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Lipoproteina
2 Sets of Lipoproteins
0.95
Density (g/mL)
ApoA1
Apo B
1.006
1.02
1.06
1.10
1.20
5
MAL
10
20
40
Diameter (nm)
60
80
1000
4
Atherogenic Cholesterol Load
Density (g/ml)
0.95
1.006
1.02
1.06
1.10
1.20
5
10
20
40
60
80
1000
Diameter (nm)
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Two Types of Lipoproteins are Atherogenic in Humans
Apo B100 containing
LDL
Hepatic
Apo B48 containing
Chylomicron Remnants
B100
B48
TG
TG
CE
CE
TG
Intestinal
Apolipoprotein B fragments
Cholesteryl ester
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Atherosclerosis is linked to a Desequilibrium
between Protective and Atherogenic Lipoproteins
Apo B
VLDL - IDL - LDL
Atherogenic Transport
Apo AI
HDL
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Anti Atherogenic Transport
7
FARMACI IMPIEGATI NELLE
DISLIPIDEMIE
 Niacina, 1955
 Resine sequestranti acidi biliari, 1961
 Fibrati, 1967
 Statine (inibitori HMG-CoA
reduttasi), 1987
 Inibitori dell’assorbimento del
Colesterolo (ezetimibe), 2002
 Terapia combinata, 2004-2005
NIACINA o VITAMINA B3 o PP
 Primo farmaco ipolipemizzante introdotto nel
1955.
 COMPLESSO DELLA VITAMINA B
IDROFILO
 Sembra che agisca inibendo la lipolisi nel
tessuto adiposo, con conseguente riduzione
della sintesi epatica di VLDL
 Effetti collaterali: vasodilatazione, prurito al
viso ed alle parti superiori del tronco,
eritema, vampate
 Altri effetti collaterali importanti sono a
carico del fegato, con aumento delle
transaminasi e possibilità di ittero,dolore
epigastrico,nausea,vomito, diarrea
Niacin is Available in a Number of Different Formulations
According to the Speed of Drug Release.
Formulations that Differ in Time of Release
May Have Different Lipid Effects
and Vary in their Adverse Reaction Profiles
Efficacy
Hepatotoxicity
Knopp R. Am J Cardiol 2000;86:51-56
Flushing
 DRUG DESCRIPTION
 NIASPAN (niacin tablet, film-coated extended-release),
contains niacin, which at therapeutic doses is an
antihyperlipidemic agent. Niacin (nicotinic acid, or 3pyridinecarboxylic acid) is a white, crystalline powder, very
soluble in water, with the following structural formula:
 NIASPAN is an unscored, medium-orange, film-coated tablet
for oral administration and is available in three tablet
strengths containing 500, 750, and 1000 mg niacin. NIASPAN
tablets also contain the inactive ingredients hypromellose,
povidone, stearic acid, and polyethylene glycol, and the
following coloring agents: FD&C yellow #6/sunset yellow FCF
Aluminum Lake, synthetic red and yellow iron oxides, and
titanium dioxide.
11
Conjugated Pathway
Non Conjugated Pathway
Comparison of the Effect of Niaspan and Immediate Release Nicotinic Acid
on Plasma Lipids and Lipoproteins
8 weeks
N=223
Carlson L.A. J.Internal Medicine 2005;258:94-114
Mechanisms of Action of Nicotinic Acid
Knopp R. NEJM 1999;341:498-511
Flushing Out the Role of GPR109A (HM74A)
in the Clinical Efficacy of Nicotinic Acid
Pike N. JCI 2005;115:3400-3403
Vit E 800UI
Vit C 1000mg
Beta Carotene 25mg
Selenium 100ug
Simva 10-40mg
Niacor 2000mg
N: 34
39
Brown G.NEJM 2001;345:1583-1592
33
40
Brown G.NEJM 2001;345:1583-1592
Wolfe M. Am.J Cardiology 2001;87:476-489
Simcor
 SIMCOR ® è indicato per ridurre elevate totale-C, C-LDL,
Apo B, non-HDL-C, TG, o di aumentare il colesterolo HDL nei
pazienti con ipercolesterolemia primaria e dislipidemia mista
quando il trattamento con simvastatina in monoterapia o
niacina monoterapia a rilascio prolungato è considerato
inadeguato, e TG nei pazienti con ipertrigliceridemia quando il
trattamento con simvastatina in monoterapia o niacina a
rilascio prolungato in monoterapia è considerata inadeguata.
http://www.drugs.com
19
 Simcor Dosage and Administration
Simcor should be taken as a single daily dose at bedtime, with a low fat snack.
Patients not currently on niacin extended-release and patients currently on
niacin products other than niacin extended-release should start Simcor at a
single 500/20 mg tablet daily at bedtime. Patients already taking
simvastatin 20-40 mg who need additional management of their lipid levels
may be started on a Simcor dose of 500/40 mg once daily at bedtime.
The dose of niacin extended-release should not be increased by more than 500
mg daily every 4 weeks. The recommended maintenance dose for Simcor is
1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on
patient tolerability and lipid levels.
The efficacy and safety of doses of Simcor greater than 2000/40 mg daily have
not been studied and are therefore not recommended. If Simcor therapy is
discontinued for an extended period of time (> 7 days), re-titration as
tolerated is recommended. Simcor tablets should be taken whole and should
not be broken, crushed, or chewed before swallowing.
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RESINE LEGANTI I SALI BILIARI
Sono disponibili due molecole:
 COLESTIRAMINA
 COLESTIPOLO CLORIDRATO
 Dal punto di vista chimico sono
resine che legano anioni
 Meccanismo d’azione:
Le resine legano gli acidi biliari
scambiando ioni Cl- con cariche negative
 Effetti collaterali: stipsi, nausea
 Interazioni farmacologiche:
diverse classi di vitamine
anticoagulanti orali
glicosidi cardioattivi
diuretici
β-bloccanti
antibiotici
Colesevelam
 Colesevelam is a bile acid sequestrant administered orally. It is developed
by Genzyme and marketed in the US by Daiichi Sankyo under the brand
name WelChol and elsewhere by Genzyme under the tradename
Cholestagel.
 Clinical use
Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated
low-density lipoprotein cholesterol (LDL-C) in patients with primary
hyperlipidemia as monotherapy and to improve glycemic control in adults
with type 2 diabetes mellitus, including in combination with a statin.
 Colesevelam is one of the bile-acid sequestrants, which along with niacin
and the statins are the three main types of cholesterol-lowering agents. The
statins are considered the first-line agents. This is because of side effects
from the other two types, including bloating and constipation (bile-acid
sequestrants) and skin flushing (niacin). These side effects often lead to low
patient compliance.
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Constituents
The compounds which constitute the polymer
colesevelam are:
N-prop-2-enyldecan-1-amine; trimethyl-[6-(prop-2-enylamino)hexyl]azanium; prop-2-en-1-amine;
2-(chloromethyl)oxirane; hydrogen chloride; chloride.
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How it works
Colesevelam is part of a class of drugs known as bile acid sequestrants. Colesevelam
hydrochloride, the active pharmaceutical ingredient in Welchol, is a non-absorbed,
lipid-lowering polymer that binds bile acids in the intestine, impeding their
reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol
7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile
acids. This causes an increased demand for cholesterol in the liver cells, resulting in
the dual effect of increasing transcription and activity of the cholesterol biosynthetic
enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors.
These compensatory effects result in increased clearance of LDL-C from the blood,
resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain
unchanged.
It is not yet known how Colesevelam works to help control blood sugar in people with
type 2 diabetes. However, it is clear that the drug works within the digestive tract,
since it is not absorbed into the rest of the body.

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 Cholesterol
Since Colesevelam can lower total and LDL cholesterol levels
(along with raising HDL -- cholesterol), a person can decrease
his or her risk of developing certain health problems in the
future by taking it.
In previous clinical research studies, people taking 3,800 mg to
4,500 mg of Colesevelam daily were able to:
Reduce LDL cholesterol by 15 to 18 percent
Reduce total cholesterol by 7 to 10 percent
Raise HDL cholesterol by 3 percent.
 The combination of Colesevelam with a HMG-CoA reductase
inhibitor (known more commonly as a statin) can further
lower cholesterol levels.
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DERIVATI DELL’ACIDO FIBRICO:
CLOFIBRATO E GEMFIBROZIL
• Riduzione dei livelli di VLDL
•Modesto aumento delle HDL
• Effetto variabile sulle LDL
Il clofibrato attiva la lipasi a livello
endoteliale
Farmacocinetica
• Ben assorbiti per os.
•Elevatissimo legame (95%) con
l’albumina plasmatica.
•Generalmente ben tollerati, con scarsi
effetti collaterali gastrointestinali.
ATTENZIONE alla competizione con altri farmaci (es.
anticoagulanti orali) per i siti di legame alle proteine
plasmatiche
Fibrati
Cl
O
O
OiPr
O
FENOFIBRATO
Cl
O
O
OiPr
O
Steiner G. Atherosclerosis 2005;182:199-207
Rate of Rhabdomyolysis
With Fenofibrate + Statin
Versus Gemfibrozil + Statin
Jones P. Am.J. Cardiol. 2005;95:120-122
Fenofibrate Resulted in a 33 Times Lower
Rhabdomyolysis Reporting Rate
than Did Gemfibrozil
O
Cl
O
O
FENOFIBRATE
O
Pri
Jones P. Am.J. Cardiol. 2005;95:120-122
Grundy S. Am.J. Cardiology 2005;95:462-468
Structural Mechanism for Statin
Inhibition of HMG-CoA Reductase
Simvastatin
Type 1
Butyryl group
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Atorvastatin
Type 2
Fluorophenyl group
32
Le statine inibiscono la biosintesi del mevalonato
HMG-CoA
HMG-CoA reduttasi
Mevalonato
STATINE
Geranyl-difosfato
Geranylgeranyl difosfato
Ubiquinone
Farnesyl-difosfato
Squalene
Colesterolo
Dolicolo
Anti-hyperlipidemic Drugs - Statins
HO
R'
O
HO
R
R O
O
O
O
O
CH2CH2
CH3
CH3
R
COONa
R OH
CH2CH2
CH3
CH3
HO
R''
R'
Mevastatin
H
Lovastatin
H
Simvastatin CH3
R''
Pravastatin
H
CH3
CH3
34
Anti-hyperlipidemic Drugs - Statins
_
COO Ca +
HO
HO
OH
COONa
OH
F
OH
F
F
N
H
HO
COONa
CH3
CH3
CH3
CH3
CH3
O
H3C
O
NH
CH3
N
H3C
Atorvastatin
N
CH3
Cerivastatin
Fluvastatin
_
+
COO Ca
HO
_
+
COO Ca
HO
OH
OH
F
CH3
F
CH3
O
H3C
S
N
N
N
N
CH3
O
Rosuvastatin
Pitavastatin
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Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
O
HO
O
HO
COONa
OH
HO
COOH
SCoA
O
For example,
Mevastatin
Lovastatin
Simvastatin
For example,
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
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Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin
Bioavail.
Dosage (mg)
Protein
Binding
Metabolites
Atorvastatin
~14%
10 – 80
>98%
Active
Cerivastatin
~60%
0.2 – 0.3
>99%
Active
Fluvastatin
~24%
10 – 80
98%
Active
Lovastatin
~5%
10 – 80
>95%
Pravastatin
~17%
10 – 40
~50%
Simvastatin
~5%
10 - 80
~95%
Typically all statins possess side effects. The most dominant side effect, cited
in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or
weakening of skeletal muscles.
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MECCANISMO D’AZIONE DELLE STATINE
STATINE
Riduzione attività HMG CoA reduttasi
Deplezione del pool di colesterolo nell’epatocita
Aumento espressione
recettori LDL epatici
Aumento clearance
LDL circolanti
Diminuita produzione
di VLDL
Alterata composizione
delle VLDL
STATINE DI I GENERAZIONE
MEVASTATINA e’ stata la prima
sostanza scoperta, è stato isolata
da colture di specie di Penicillum
LOVASTATINA è un analogo della
mevastatina, con aggiunto un gruppo metile
E’ stato isolato da colture di Aspergillus.
Molecola lipofila, emivita: 2-3 ore.
PRAVASTATINA è anch’esso un
analogo della mevastatina, con
aggiunto un gruppo idrossilico.
Molecola idrofila, emivita: 1 ora.
STATINE DI II GENERAZIONE
SIMVASTATINA di derivazione
semisintetica.
Molto simile alla lovastatina.
Indicata:
 ipercolesterolemia primaria
 Ipercolesterolemia familiare nella variante eterozigote
 iperlipidemia mista (tipo IIa e IIb)
STATINE DI III GENERAZIONE
FLUVASTATINA è una molecola
sintetizzata chimicamente.
Molecola idrofila, ha una breve emivita.
STATINE DI IV GENERAZIONE
ATORVASTATINA di derivazione sintetica.
Molecola lipofila, con una lunga emivita
(13-16 ore).
Indicata:
- ipercolesterolemia familiare nella variante
omozigote
- ipercolesterolemia primaria
- iperlipidemia mista (tipo IIa IIb)
CERIVASTATINA di derivazione sintetica.
Molecola idrofila, emivita: 2-3 ore. E’ circa 100
volte più potente rispetto alle altre statine.
Ritirata dal commercio perché si sono
manifestati casi di rabdomiolisi mortale per
sovradosaggio o per l’associazione con altri
farmaci ipocolesterolemizzanti.
ROSUVASTATINA
(3R, 5S)
O
HO
•Gruppo polare metan-sulfonico
•La più potente statina: 10-80 mg/dl riduzione LDL-C
da 34%-65% e fino a 90% /2 sett.
•Diminuzione apolipoproteina b e trigliceridi 10-35%
•Aumento HDL da 9-14%
•Basso rischio di interazioni con altri farmaci
Ca
O
OH
F
CH 3
CH 3
N
N
H 3C
S
O
N
O
CH 3 Prostata
Testicoli
Surrene
Tiroide
Cervello
Cervelletto
Occhio
Milza
Ileo
Cuore
Polmone
Rene
Fegato
trasporto attivo per alta affinità
con un sistema organo-specifico
(OATPs :Organic Anion Transport
Proteins)
0,0
0,2
0,4
0,6
CLUptake (mL/min/g tessuto)
0,8
1,0
SINTESI SIMVASTATINA
SINTESI SIMVASTATINA
SINTESI SIMVASTATINA
FARMACOCINETICA
Sono somministrate per os ed hanno un assorbimento
variabile.
 Simvastatina:85% di assorbimento
 Pravastatina:30% assorbimento
 Fluvastatina:assorbita quasi completamente
 Hanno tutte un esteso effetto di primo passaggio che, per la lovastatina
e la simvastatina, serve per dare origine al farmaco attivo.
 Sono strettamente legate alle proteine plasmatiche (50% pravastatina,
95% le altre)
 Escrete quasi completamente per via intestinale.
 Vengono generalmente somministrate in unica dose serale, perché la
sintesi di colesterolo segue un ritmo circadiano, aumentando la notte.
Differenze farmacocinetiche delle statine:
metabolismo epatico
Pravastatina
Rosuvastatin
a
Fluvastatina
Lovastatina
Simvastatina Cerivastatina
Atorvastatina
50 – 80%
<5%
CYP2C9
CYP3A4
CYP2C8
Prodotti di degradazione attivi o inattivi
FDA Approves LIVALO(R) For Primary
Hypercholesterolemia And Combined Dyslipidemia
Pitavastatin
LIVALO(R) (pitavastatin), a potent HMG-CoA reductase inhibitor (statin).
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 Livalo is a fully synthetic and highly potent statin engineered
in Japan. Livalo differs from other, currently available statins
in the U.S. in that it has a unique cyclopropyl group on the
base structure. This cyclopropyl group contributes to a more
effective inhibition of the HMG-CoA reductase enzyme to
inhibit cholesterol production, and potentially affords greater
low-density lipoprotein cholesterol (LDL-C) clearance and
reduction of plasma cholesterol. Importantly, pitavastatin is
only minimally metabolized by the liver through the
cytochrome P450 pathway, through which many other
medications are metabolized.
 In pivotal Phase III trials, Livalo effectively reduced LDL-C
and improved other parameters of lipid metabolism in special
patient populations, including the elderly, patients with
diabetes and patients at higher cardiovascular risk. The
overall safety and tolerability of Livalo are consistent with
other commonly prescribed statins.
 Livalo is expected to launch in the U.S. during Q1 of 2010 and will be available in 3
low dosages (1 mg, 2 mg and 4 mg). After a thorough review of the statin market,
KPA is also seeking a co-promotion partner in order to broaden the reach of KPA's
rapidly growing internal sales force. Partnering with another organization to
expand the sales efforts for this product is aligned with KPA's long-term vision to
become a leader in the cardiometabolic therapeutic arena.
 Since its launch in Japan, South Korea, Thailand and China, Livalo has been
successfully used in these countries to treat primary hypercholesterolemia and
combined dyslipidemia, and has accumulated millions of patient-years of exposure.
It is frequently prescribed in these countries as first-line therapy for a broad range
of patients including the elderly, patients with diabetes and those whose treatment is
complicated by concurrent disease and concomitant medications.
Selected Drugs That May Increase Risk of Myopathy
When Used Concomitantly with Statins
MAL
Adapted from Corsini A. Pharmacol.Ther. 1999;84:413-428
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INTERAZIONI FARMACOLOGICHE CON LE STATINE:
le principali classi di farmaci a rischio
INTERAZIONI FARMACOCINETICHE:
 Inibitori CYP 3A4: Ciclosporina, Eritromicina, Ritonavir, Fluconazolo, fluoxetina,



pompelmo (> la concentrazione plasmatica delle statine)
Induttori CYP 3A4: Barbiturici, Carbamazepina, Fenitoina, Rifampicina (< la
concentrazione plasmatica di statine)
Inibitori CYP 2C9: Amiodarone, Cimetidina, Isoniazide, Chetonazolo
(> concentrazione plasmatica di fluvastatina)
Induttori CYP2C9: Barbiturici,Carbamazepina, Fenitoina, Rifampicina
(< concentrazioni plasmatiche fluvastatina)
Antibiotici macrolidi: Eritromicina, Claritromicina
Antifungini azolici: ketoconazolo


 Calcio-antagonisti
 Acido nicotinico
 Benzodiazepine: Diazepam, Midazolam
 Anticoagulanti cumarinici : warfarin
INTERAZIONI FARMACODINAMICHE:
 Gemfibrozil – fibrati
Altre formulazioni combinate
 Co-somministrazione: statina + niacina
Advicor ( Nicostatin) combinazione di lovastatina e niacina
<LDL del 47%
>HDL del 41%
Aumento glicemia e acido urico con conseguenti anomalie
 Co –somministrazione: statina + resine
Effetti collaterali gastrointestinali: costipazione, gonfiore, flautolenza, dolori addominali
 Co-somministrazione : statina + fibrati
Gemfibrozil > concentrazione statine nel sangue alzando il potenziale di tossicità si sostituì
con il fenofibrato.





Controllo periodico:
Alanina aminotransferasi (ALT)
Aspartato aminotransferasi (AST)
Creatina kinasi (CK)
Usare cautamente un trattamento combinato in pazienti con età superiore a 70
anni
 Se appaiono sintomi muscolari sospendere la terapia
 Non somministrare in pazienti con insufficienza epatica
Whole Body Cholesterol Homeostasis
is Maintained Through 3 Major Pathways
Intestinal
Absorption
LDL-C
de novo Synthesis
MAL
Bays H. Expert Opin. Investig. Drugs 2002; 11: 1587-1604
Biliary Excretion
54
Intestinal Cholesterol Absorption is a Multistep Process
that is Regulated by Multiple Genes
Lumen
Enterocyte
Sterol Influx Transporter
Lammert F. Gastroenterology 2005;129:718-734
Lymph
Complementary Actions of Statins and Selective Cholesterol
Absorption Inhibitors
Assorbimento di Colesterolo nell’Intestino
300–700 mg
1000 mg
Plant stanols
NPC1L1
Ezetimibe: Parametri Farmacocinetici
 Assorbimento
 Rapido,dopo somministrazione
orale
 Picco di concentrazione
plasmatica di metabolita attivo in
1–2 ore
 Metabolismo
 Rapidamente metabolizzato a
metabolita attivo: ezetimibeglucuronide
 Eliminazione
 attraverso le feci
 Emivita
~22 ore / dose giornaliera
Ezetimibe
OH
OH
N
F
O
Glucuronidazione
F
OGluc
OH
N
F
Glucuronide
O
F
Synthesis Ezetimibe
Effetti dell’ Ezetimibe sull’ Assorbimento
del Colesterolo
% Assorbimento
Colesterolo 2 settimane
80
54% Riduzione
dell’assorbimento di
colesterolo con l’ezetimibe
70
60
50
49.8%
40
30
22.7%
20
10
Individuali livelli di assorbimento
Principali livelli di assorbimento
0
Placebo
Ezetimibe
Effetti dell’ Ezetimibe sull’ Aterogenesi
Sezione trasversale dell’arteria coronaria
Control
Nuovi approcci: Ezetimibe
 La associazione di Ezetimibe con statina agisce attraverso la
duplice inibizione della sintesi di colesterolo a livello epatico e
di assorbimento di colesterolo a livello intestinale.
 La associazione di Ezetimibe 10 mg con qualsiasi statina al
dosaggio di 10 o 20 mg produce una riduzione di LDLcolesterolo sovrapponibile a quella ottenibile con il dosaggio
massimo della statina.
 Oltre il 70% dei pazienti che non hanno raggiunto
l’obbiettivo terapeutico in monoterapia con statine, lo
raggiungono se si associa Ezetimibe
Efficacy of LDL-C Lowering with Ezetimibe/Simvastatin
Compared with Simvastatin Alone
In Patients with Primary Hypercholesterolemia
INEGY
Inegy è indicato come terapia aggiuntiva alla dieta in pazienti con ipercolesterolemia
primaria (eterozigote familiare e non-familiare) o con iperlipidemia mista ove sia
indicato l´uso di un prodotto di associazione:

Pazienti non controllati adeguatamente con una statina da sola.

Pazienti già trattati con una statina ed ezetimibe. Inegy contiene ezetimibe e
simvastatina.
E´ stato dimostrato che la simvastatina (20-40 mg) riduce la frequenza degli eventi
cardiovascolari (vedere paragrafo 5.1).
Non sono stati completati gli studi per dimostrare l´efficacia di Inegy o di ezetimibe
nella prevenzione delle complicazioni dell´aterosclerosi. Ipercolesterolemia
familiare omozigote (IF omozigote) Inegy è indicato come terapia aggiuntiva alla
dieta in pazienti con ipercolesterolemia familiare omozigote.
I pazienti possono essere sottoposti anche ad ulteriori misure terapeutiche (per
MALesempio, l´aferesi delle lipoproteine a bassa densità [LDL]).
64
INEGY
 Gruppo farmacoterapeutico: altri ipocolesterolemizzanti ed
ipotrigliceridemizzanti. Codice ATC: C10A
X Inegy (ezetimibe/simvastatina) è un prodotto ipolipemi
zzante che inibisce selettivamente l´assorbimento intestinale
del colesterolo e dei relativi steroli vegetali e inibisce la sintesi
endogena del colesterolo. Meccanismo
d´azione:InegyIl colesterolo plasmatico è derivato dall´assor
bimento intestinale e dalla sintesi endogena. Inegy
contiene ezetimibe e simvastatina, due composti ipolipe
mizzanti con meccanismi d´azione complementari.
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65
Omega-3 Fatty Acids: The Basics
 What are Omega-3 fatty acids?
 What are common dietary sources?
AHA Recommendations
• For patients with documented CHD, about 1g of EPA+DHA per day
– Capsules
Low Potency - 300 mg EPA+DHA/g
(Typical drug
store capsules)
High Potency - 500-700 mg EPA+DHA/g (CardioTabs,
Triomega, OmegaRx)
Pharmaceutical – 850 mg EPA+DHA/g
(Omacor®, Reliant Pharmaceuticals)
– Cod Liver Oil
• 1 tsp (RDA for Vit. D; 2x RDA Vit. A)
OMACOR® (omega-3-acid ethyl esters) reduced triglycerides by a median of 45% while raising
HDL-C by 9% OMACOR reduced non–HDL-C by 14% overall,) The placebo group had no significant
changes from baseline for any of the above lipid parameters
Every attempt should be made to control serum TG levels with appropriate diet, exercise, weight
loss in overweight patients, and control of any medical problems (such as diabetes mellitus and
hypothyroidism) that may be contributing to the patient’s TG abnormalities.
Combination Lipid Therapy Options
Vasudevan A. Curr. Athero. Rep. 2006;8:76-84
While cholesterol is necessary for
many biological functions, too much
of it increases our risk of
cardiovascular diseases. Most of us
have an unfortunate appetite for foods
rich in cholesterol and some of us are
genetically predisposed to handle it
worse than others, so the scientific
community is working hard to help us
control cholesterol levels.
As cholesterol is insoluble in blood, it
must be carried around in the form of
lipoproteins. One particular type of
transporter, HDL (high-density
lipoprotein), has been the focus of
many research groups. HDL carries
cholesterol away from arteries to the
liver, where the cholesterol can be
excreted or reused. Having more HDL
is beneficial to the cardiovascular
system, but raising HDL levels is
difficult.
HDL with surface proteins and cholesterol.
Current drugs that induce our bodies to boost HDL concentration have negative side effects, leading some scientists to
focus on mimicking HDL with synthetic nanoparticles instead. However, creating nanoparticles with the dynamic
activities of HDL is a serious challenge. Scientists at Northwestern University report in an advanced issue of the
Journal of the American Chemical Society that they have solved some of the problems involved in creating a synthetic
HDL.
Their idea was to use gold nanoparticles as the inner cores. The gold nanoparticles act as a scaffold that can be given
the appropriate dimensions to resemble HDL. Apolipoproteins and phospholipids, which are present in natural HDL,
can then be layered onto the nanoparticles to create a surface similar to HDL.
With this in mind, the researchers created synthetic HDL nanoparticles with a diameter of about 18 nm, making them
similar in size to the biological ones
Each nanoparticle contained between 2 and 5 apolipoproteins and 80 to 160 phospholipids; chemical
composition analysis showed that this surface constitution is analogous to natural HDL. The
nanoparticles are also soluble in water, suggesting they can dissolve in blood and move to and from
cells.
To determine how well the synthetic HDL can bind cholesterol, the scientists used a fluorescent
analogue of cholesterol for their studies. When the cholesterol analogues are in water, they are
weakly fluorescent; when they are bound to the synthetic HDL, their fluorescence is increased. Using
the fluorescence signal as an indicator, the authors determined that in a 5 nM solution of synthetic
HDL, the binding affinity to cholesterol has a dissociation constant of 3.8 nM. This is the first time
that a research group has published a value in this range for a synthetic HDL—no value is known for
natural HDL, so it's impossible to make comparisons.
The authors' approach—creating a nanoparticle that mimics the size and functions of biological
HDL—is a good starting point for further investigations. The next steps in this line of research
include determining how well this synthetic HDL transports cholesterol to the liver, testing the
toxicity of the nanoparticles, and finding methods of introducing them inside the body.
MAL
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Anacetrapib
 Anacetrapib (codenamed MK-0859, Merck) is a CETP inhibitor being developed to
treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular
disease. It has been in Phase I clinical trials; preliminary results appear
encouraging, although long-term safety data are lacking.
 At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New
York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study
reported dosage correlated reduction in LDL-C and increases in HDL-C levels with
no corresponding increases in blood pressure in any cohort. The increase in HDL
was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133
percent at doses of 10 mg, 40 mg, 150 mg and 300 mg.
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