Bases Tto Hiperlipidemias

BASES FARMACOGICAS PARA EL
TRATAMIENTO DE LAS
DISLIPIDEMIAS
Dr. Persio Lpez Contreras
Junio 2011
PUCMM
Tuesday, June 14, 2011
HIPERLIPIDEMIA
Transporte de lpidos de su sitio de absorcin o

produccin a los tejidos
Apolipoprotenas: protenas anpticas

transportadoras en el medio acuoso plasmtico
Hiperlipoproteinemias o hiperlipidemias:
alteraciones metablicas que llevan a incremento
de las lipoprotenas
Hiperlipemia: aumento de triglicridos

Estructura de las principales molculas
lipdicas
Estructura y tamao de las lipoprotenas
FUNCIONES DE LAS APOLIPOPROTEINAS
Ensamblaje y secrecin de la
lipoprotena (apo A-I, apo B100,
apo B48)
Integridad estructural (apo B, apo

E, apo A-I, apo A-II)
Coactivadoras o inhibidoras de
enzimas (apo A-I, A-V, C-I, C-II, C-
III)
Unin o anclaje a receptores

especcos para captacin de la
partcula completa o extraccin
selectiva de componentes lipdicos
(apo A-I, apo B100, apo E)
Otras desconocidas
DIAGRAMA ESQUEMATICO DEL SISTEMA DE
TRANSPORTE LIPIDICO
VIA INTESTINAL: QUILOMICRONES Y
REMANENTES
Absorcin de ac. grasos esenciales
20-40% de las caloras provienen de lpidos
Hidrlisis de lpidos por lipasas, formacin de micelas con

ac. biliares, interaccin con la protena Niemann-Pick C1-
like I y captacin de la micela
Reestericacin de ac. grasos + apoB48 quilomicrones
Interaccin con LPL endotelial msculo y adipocitos

(dependiente de insulina), transporte AGL a hgado VLDL
Integracin de apo E, captacin heptica por receptor apo

B/E
VIA HEPATICA: VLDL A IDL
Sntesis de TG en situaciones de ayuno
VLDLs: ms pequeas que los quilomicrones
LP principal: apo B-100
Interaccin con LPL endotelial, extraccin de TGs, adicin de

apo Cs y apo E por HDLs
Intercambio de TGs por steres colesterol de HDL por la

CETP
Transeren fosfolpidos a las HDLs nacientes por la prot.

transferidora de fosfolpidos (PLTP)
Remanente: IDL, captada en hgado por receptor de apo B/E

o mayor deslipidacin por la lipasa heptica LDL
LIPOPROTEINAS DE BAJA DENSIDAD: LDLs
Composicin: colesterol, slo 4-8% de TGs
Apo B100
En presencia de hipertrigliceridemia: aumento de TGs,

aumento de densidad y reduccin de tamao
Captadas por el receptor de LDL en clulas, saturable.
LDL sntesis (interaccin SCAP [SREPB cholesterol

activated protein] con SREPB [steroid-responsive element binding protein])
Reduccin actividad de la HMG-CoA)
Macrfagos: SR-B, no saturables, induccin clulas

espumosas
LIPOPROTEINAS DE ALTA DENSIDAD Y
TRANSPORTE REVERSO DE COLESTEROL
Relacin inversa entre cifras de

HDL y ECV
Portadoras de apo A-I
Origen heptico del 80%, intestinal

20%
Apo A-I libre ABCA1 HDL

naciente captacin colesterol
esfericidad (HDL3) estericacin
colesterol tamao (HDL2)
ABCG1 colesterol a HDLs

esfricas
Captadas en hgado y tejidos

productores de hormonas por el
SR-B1
Interacin con TRL (QM,

remanenes, VLDL, IDL) por la CETP
EVOLUCION DE LA PLACA
ATEROESCLEROSA
RUPTURA DE LA PLACA ATEROESCLEROSA
UMBRALES DE TRATAMIENTO DE
COLESTEROL LDL CON DIETA Y FARMACOS
(ATP-III)
CATEGORIA DE
RIESGO
LDL META
DIETA
ESTILO VIDA
UMBRAL INICIO
FARMACOS
0-1 factor de
riesgo
< 160 mg > 160 mg
> 190 mg
> 160 opcional
> 2 factores
riesgo
< 130 mg > 130 mg
FRS
10-20%: >130
<10%: >160 mg
EAC o
equivalentes
(Diabetes, ECV en
otros rganos,
aneurisma Ao, FRS
>20%
< 100 mg
< 70 mg
>100 mg > 100 mg
CLASIFICACION FENOTIPICA DE LAS
HIPERLIPIDEMIAS
(FREDRICKSON)
TIPO Fraccin lipdica
I Quilomicrones
IIa LDL (beta)
IIb LDL + VLDL (rel. TG/Col < 5:1)
III Remanentes
IV VLDL (prebeta)
V VLDL + QM (rel. TG/Col > 5: 1)
Clculo LDL (Friedwald): Colesterol total - HDL - VLDL
(TG5, siempre que TG < 400 mg)
HIPERTRIGLICERIDEMIAS PRIMARIAS
Asociadas a incremento de riesgo de ECV
Aumento de VLDL e IDL
Asociadas a LDLs pequeas, densas
TGs > 700: pancreatitis
Asociadas a resistencia a la insulina (no captacin

de TGs por adipocitos): Diabetes Mellitus,
Sndrome Metablico
Frmacos de eleccin: bratos, ac. nicotnico,

omega-3
Asociacin con metformina o pioglitazona

QUILOMICRONEMIA PRIMARIA (TIPO I)
Rara, asociada a deciencia de LPL
TGs 2000-3000 mg. Plasma lechoso, blanco, con nata de quilomicrones

tras reposo en refrigerador
Pancreatitis, xantomas eruptivos, hepatosplenomegalia, hiperesplenismo,

clulas espumosas en MO, hgado, bazo.
Asociada a xerostoma, xeroftalma, trast. conducta.
Agravada por estrgenos o embarazo
HIPERTRIGLICERIDEMIA FAMILIAR (TIPO IV)
Elevacin de VLDL, IDL. LDL y HDL usualmente bajos
TGs en ayuno 200-500 mg, >1000 en post-prandio
Xantomas eruptivos, lipemia retinalis, epigastralgia, pancreatitis. Obesidad

centrpeta, resistencia insulina.
Inuenciada por ingestin alcohol, dieta, obesidad, diabetes, sedentarismo

HIPERLIPOPROTEINEMIA FAMILIAR
COMBINADA (II-B)
Comn (2% adultos), asociada a enf. coronaria. Patrn familiar.
Elevacin de VLDL, LDL o ambas, patrn cambiante por efectos

exgenos.
Muy pocos signos clnicos
Base gentica compleja
DISBETALIPOPROTEINEMIA FAMILIAR (TIPO III)
Remanentes de quilomicrones e IDL, apo E anormal.
Rara
Xantomas tuberosos, estriados palmares

MANEJO DIETETICO DE LAS
HIPERLIPOPROTEINEMIAS
Restriccin de colesterol a < 200 mg da
Restriccin de grasas saturadas y trans
Restriccin de azcares (especialmente sacarosa y

fructuosa), restriccin de alcohol
Restriccin de aceites comestibles (omega 6)
Restriccin de aporte calrico total, reduccin de

peso
Estimular consumo de frutas, granos y vegetales
Estimular consumo de bras viscosas (avena,

nopales, molondrones)
Estimular consumo de aceite de pescados marinos

(omega 3), estimulan los PPAR-
FARMACOS HIPOLIPEMIANTES
ESTATINAS
FIBRATOS
ACIDO NICOTINICO
INHIBIDORES
ABSORCION
INTESTINAL
RESINAS
INHIBIDORES CETP
ESTATINAS
Extradas de hongos Penicillium citrinum, Aspergillus

terreus, semisintticas o sintticas
Inhiben competitivamente la reductasa de la

Hidroximetil-glutaril-CoA, la formacin de
mevalonato y bloqueo de la sntesis de colesterol
desde sus pasos iniciales
Aumento en la expresin de receptores de LDL

hepticos, mayor captacin
Reduccin de colesterol srico reduccin

colesterol en placas reduccin inamacin vascular
Posibles efectos pleiotrpicos: sntesis de

isoprenoides (ubiquinona, dolichol), prenilacin
protenas Rho y Rab
ESTRUCTURA QUIMICA DE LAS ESTATINAS
ESTATINAS
Absorcin de 40-75%, uvastatina 100%
Metabolismo heptico de primer paso extenso
CYP3A4: lovas, simvas, atorvas (bratos, amiodarona,

verapamil, macrlidos, ketoconazol, etc.)
CYP2C9: uvas, rosuvas (metronidazol, ketoconazol,

amiodarona, cimetidina)
Pravas mixta, sulfatacin includa
Excrecin primaria biliar, 5-20% en orina
Vida media 1-3 horas: administracin nocturna

(mxima sntesis de colesterol entre 0:00 hrs y 2:00 AM)
Vida media atorvas 14, rosuvas 19,

administrables a cualquier hora
ESTATINAS
TOXICIDAD
Mialgias, dolor abdominal, anorexia
Elevacin de trans-aminasa (TGP) en 1-3% pacientes
Hepatotoxicidad seria 1 por milln personas/ao
Esteatosis heptica o infeccin por VHC NO son

contraindicacin para su uso
Miopata (rabdomilisis I por milln personas/ao,
Dependiente de dosis, uso concomitante otros

frmacos (gembrozilo), edad avanzada,
alcoholismo, peri-operatorio, disfuncin heptica
o renal, enf. multisistmica
Medir TGP y CPK basal, 4-6 semanas, 6-12 meses

posteriormente
DOSIS DE ESTATINAS REQUERIDAS....
Table 3110
Dose (mg) of Statins Required to Achieve Various Reductions in Low-Density-Lipoprotein
Cholesterol from Baseline
20-25% 26-30% 31-35% 36-40% 41-50% 51-55%
Atorvastatin 10 20 40 80
Fluvastatin 20 40 80
Lovastatin 10 20 40 80
Pitavastatin 1 2 4
Pravastatin 10 20 40
Rosuvastatin 5 10 20, 40
Simvastatin 10 20 40 80

DERIVADOS DEL AC. FIBRICO:
FIBRATOS
Estimulan los peroxisome

proliferator-activated receptors
(PPAR-) expresados en
hgado, tejido adiposo
marrn...msculo esq.,
corazn, rin
Estimulan oxidacin ac.

grasos, expresin de LPL
Aumentan expresin apoA-I

y apoA-II
Reducen apoC-III (inhibidor

liplisis)
Reduccin QM y VLDL,
reduccin LDL en grados
variables, aumento HDL
FIBRATOS
Absorcin > 90%
VM 1.1 horas gembrozilo, 20

horas fenobrato
Contraindicados:
Nios, embarazadas
Insuciencia renal
Insuciencia heptica
Efectos secundarios:
5-10% pacientes, leves
Molestias gastrointestinales
Urticaria, cada pelo, mialgias, fatiga,

cefalea, impotencia, anemia
Incrementos trans-aminasas
Posible miopata o rabdomilisis

al asociarlos con estatinas: ojo
con gembrozilo
Bilis litognica
Aumento efecto warfarina

FIBRATOS: DOSIS
Gembrozilo
600 mg cada 12 horas
Fenobrato
Sal de colina (Trilipix) 45-135 mg
Dimetil-ester (Tricor) 48-145 mg
Local: 160 mg y 250 mg

(Controlip, Normolip)
Ciprobrato
100 mg diarios con la cena
Bezabrato
Clobrato
NIACINA (ACIDO NICOTINICO)
Vitamina B3, efectos hipolipemiantes a dosis altas
Inhibe liplisis de TGs en adipocitos (a travs de

receptor GPCR) y estimular la va Gi-adenilciclasa,
reduce liberacin de ac, grasos libres y reduce su sntesis
heptica: menos secrecin de VLDL y LDL
Aumenta aclaramiento QMs y VLDL va LPL
Reduce TGs 35-45% (tan efectiva como bratos, ms

efectiva que estatinas)
Reduce niveles de bringeno, aumenta activador tisular

del plasmingeno
Aumenta cifras HDL 35-40% reduciendo captacin

apoA-1, aumenta la extraccin de steres de colesterol
Aumenta actividad del ABCA-1 y eujo de colesterol en

macrfagos
Unico frmaco que reduce Lp(a) efectivamente

NIACINA:
Hipertrigliceridemia, HDL bajo
Vida media 60 min. Niveles sricos mx. 30-60 min
Dosicacin tres veces al da
Induce rubor (ushing) y dispepsia.
Iniciar tratamiento con dosis bajas (100 mg, 500 mg de

SR) ingeridas con alimentos; la aspirina e ibuprofn
reducen este efecto. Tomar la SR al acostarse con un
poco de fruta, evitar caf, t, etanol en la noche
Tolerancia a estos efectos con el paso de los das, no

olvidar dosis
Hiperglucemia, hiperuricemia, prurito, acantosis

nigricans. Disfuncin heptica (menos comn con SR).
Trastornos visuales
Arritmias atriales ocasionales
Contraindicada en embarazo
EZETIMIBE
Reduce la absorcin colesterol enterocitos yeyuno
Inhibe la protena Niemann-Pick C1-like (NPC1-

L1)
Reduce colesterol 15-20%, adyuvante estatinas

potenciando su efecto
Tiene circulacin enteroheptica
Dosis de 5-20 mg
Faltan estudios a largo plazo. Combinacin efectiva

en pacientes con falla renal (SHARP).
RESINAS: SECUESTRO DE ACIDOS BILIARES
No se absorben
Aumentan excrecin ac. biliares 10

veces
reducen contenido heptico de

colesterol, aumentan receptores LDL
Utiles en elevacin aislada LDL,

reducciones de hasta 25%
Dispepsia, distensin abdominal,

constipacin, frecuentes
Polvos o grnulos para ser diluidos,

colesevelam en tabletas
Ingerirlas con los alimentos
Malabsorcin diversos
medicamentos, administrarlos una
hora antes o dos horas despus
INHIBIDORES DE CETP
trapib.
1
Similarly, in mice that normally lack CETP activity,
overexpression of simian or human CETP increases athero-
sclerosis.
1
These observations are tempered by contradictory
findings in other studies, however. In the presence of pro-
longed hyperlipidemia, dalcetrapib failed to reduce athero-
sclerosis in rabbits, despite marked increases in HDL-C.
1
Similarly, CETP overexpression was shown to reduce athero-
sclerosis in hypertriglyceridemic mice overexpressing apoli-
poprotein CIII and in SRB-1deficient mice.
1
Torcetrapib
was recently shown to create a proinflammatory phenotype of
atherosclerotic lesions and not to reduce atherosclerosis
beyond atorvastatin in CETP-overexpressing mice.
17
Torce-
trapib was the first CETP inhibitor to advance to large-scale
human trials. All human trials of torcetrapib were terminated
in December 2006 when an interim analysis of the Investi-
gation of Lipid Level Management to Understand its Impact
in Atherosclerotic Events (ILLUMINATE) trial by the Data
Safety Monitoring Board showed that torcetrapib added to
atorvastatin, compared with atorvastatin alone, significantly
increased cardiovascular and noncardiovascular (infection
and cancer) adverse events, including death, despite a 72%
increase in HDL-C and 25% reduction in LDL cholesterol.
18
Similarly, imaging trials failed to show a beneficial effect of
torcetrapib on carotid and coronary atherosclerosis.
1921
Fail-
ure of torcetrapib has been attributed, at least in part, to
non-CETPdependent molecule-specific off-target effects,
which include an increase in arterial pressure attributed to
adrenal activation and increased aldosterone levels.
1,2,2224
One of the unexplained and interesting findings from the
ILLUMINATE trial was an excess of deaths from cancer (24
versus 14) and infection (9 versus 0) in the torcetrapib arm,
raising concerns about whether torcetrapib or CETP inhibi-
tion could interfere with innate immunity.
1
Aside from the
molecule-specific off-target toxicity of torcetrapib, it has also
been suggested that cholesteryl esterrich large HDL parti-
cles resulting from CETP inhibition are poor acceptors of free
cholesterol from arterial wall macrophages because the
ABCA-1 transporter selectively effluxes cholesterol to lipid-
poor nascent apolipoprotein A-Icontaining particles.
1
This
notion has been challenged by studies showing that macro-
phage ABCG-1, an alternative transporter, can effectively
efflux cholesterol to large HDL particles and that HDL
particles from human carriers of loss-of-function CETP
mutation promote macrophage cholesterol efflux.
1
The con-
cept that HDL composition may influence HDL function is
currently a topic of great interest, and several studies have
suggested that an acute-phase response, hyperglycemia, ex-
posure to mast cellderived tryptase, or macrophage-derived
myeloperoxidase may modify HDL composition, rendering it
less functional or actually dysfunctional.
1
Whether torce-
trapib failed because it produced nonfunctional or dysfunc-
tional HDL remains an intriguing but yet unproven possibil-
ity. At this time, therefore, it remains uncertain whether
CETP has a net proatherogenic or atheroprotective role in
humans. Ultimately, this question may be answered only
when ongoing event-based randomized trials of alternative
clean CETP inhibitors such as dalcetrapib and anacetrapib,
which to date appear to not have off-target adverse effects on
blood pressure, aldosterone, or other aspects of adrenal
function, are completed.
1,25
It is conceivable that a potent
inhibitor of CETP could produce large increases in HDL
levels, which may produce atheroprotective effects if the
beneficial vascular effects of HDL increase are not neutral-
ized by adverse off-target effects. Historical precedent sug-
gests that failure of a first-in-class drug does not always
sound a death knell for the entire class.
Disclosures
The author is a member of the Steering Committee for the dal-
Outcomes study, which is a randomized double-blind, placebo-
controlled clinical trial investigating the effects of dalcetrapib on
cardiovascular events in patients after an acute coronary syndrome.
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Figure. This schematic illustrates how
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KEY WORDS: Editorials atherosclerosis cholesterol ester transfer proteins
cholesterol, high-density lipoprotein lipoproteins prevention
2410 Circulation December 15, 2009
RELEVENCIA CLINICA DE ESTOS FARMACOS
Jupiter
PROVE-IT

The New England

Journal

of

Medicine

Copyr i ght 2001 by t he Massachus et t s Medi cal Soci et y

VOLUME 345

N

OVEMBER

29, 2001

NUMBER 22

N Engl J Med, Vol. 345, No. 22

November 29, 2001

www.nejm.org

1583

SIMVASTATIN AND NIACIN, ANTIOXIDANT VITAMINS, OR THE COMBINATION
FOR THE PREVENTION OF CORONARY DISEASE

B. G

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LAN

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HAIT

, M.D., L

LOYD

D. F

ISHER

, P

H

.D.,
M

ARIAN

C. C

HEUNG

, P

H

.D., J

OSH

S. M

ORSE

, B.S., A

LICE

A. D

OWDY

, R.D., E

MILY

K. M

ARINO

, M.S.,
E

DWARD

L. B

OLSON

, M.S., P

ETAR

A

LAUPOVIC

, P

H

.D., J

IRI

F

ROHLICH

, M.D.,

AND

J

OHN

J. A

LBERS

, P

H

.D.

A

BSTRACT

Background

Both lipid-modifying therapy and an-
tioxidant vitamins are thought to have benefit in pa-
tients with coronary disease. We studied simvastat-
inniacin and antioxidant-vitamin therapy, alone and
together, for cardiovascular protection in patients with
coronary disease and low plasma levels of high-den-
sity lipoprotein (HDL) cholesterol.

Methods

In a three-year, double-blind trial, 160 pa-
tients with coronary disease, low HDL cholesterol
levels, and normal low-density lipoprotein (LDL) cho-
lesterol levels were randomly assigned to receive
one of four regimens: simvastatin plus niacin, antiox-
idants, simvastatinniacin plus antioxidants, or pla-
cebos. The end points were arteriographic evidence
of a change in coronary stenosis and the occurrence
of a first cardiovascular event (death, myocardial in-
farction, stroke, or revascularization).

Results

The mean levels of LDL and HDL choles-
terol were unaltered in the antioxidant group and the
placebo group; these levels changed substantially (by
42 percent and +26 percent, respectively) in the sim-
vastatinniacin group. The protective increase in HDL2
with simvastatin plus niacin was attenuated by con-
current therapy with antioxidants. The average steno-
sis progressed by 3.9 percent with placebos, 1.8 per-
cent with antioxidants (P=0.16 for the comparison with
the placebo group), and 0.7 percent with simvastatin
niacin plus antioxidants (P=0.004) and regressed by
0.4 percent with simvastatinniacin alone (P<0.001).
The frequency of the clinical end point was 24 per-
cent with placebos, 3 percent with simvastatinniacin
alone, 21 percent in the antioxidant-therapy group, and
14 percent in the group given simvastatinniacin plus
antioxidants.

Conclusions

Simvastatin plus niacin provides
marked clinical and angiographically measurable ben-
efits in patients with coronary disease and low HDL
levels. The use of antioxidant vitamins in this setting
must be questioned. (N Engl J Med 2001;345:1583-92.)

Copyright 2001 Massachusetts Medical Society.

From the Department of Medicine, Division of Cardiology (B.G.B.,
X.-Q.Z., J.S.M., E.L.B.), the Division of Metabolism, Endocrinology, and
Nutrition (A.C., M.C.C., A.A.D., J.J.A.), and the Department of Biostatis-
tics (L.D.F., E.K.M.), University of Washington School of Medicine, Se-
attle; the Oklahoma Medical Research Foundation, Oklahoma City (P.A.);
and the Department of Pathology and Laboratory Medicine, University of
British Columbia, Vancouver, Canada (J.F.). Address reprint requests to Dr.
Brown at the Division of Cardiology, Box 356422, Health Sciences Bldg.,
Rm. A509, University of Washington, 1959 N.E. Pacific St., Seattle, WA
98195.
Other authors were Leny Serafini, B.S., Ellen Huss-Frechette, B.S., and
Shari Wang, B.S. (Department of Medicine, University of Washington School
of Medicine, Seattle); and Debbie DeAngelis, R.T., and Arthur Dodek,
M.D. (Department of Pathology and Laboratory Medicine, University of
British Columbia, Vancouver, Canada).

N the basis of epidemiologic data, it has
been predicted

1,2

that each 1 percent reduc-
tion in the level of low-density lipoprotein
(LDL) cholesterol results in a reduction of
1.0 to 1.5 percent in the risk of major cardiovascular
events. In trials of LDL-lowering strategies, a reduc-
tion of 12 to 38 percent in the LDL level has resulted
in a relative reduction in risk of 19 to 35 percent.

3,4

Similarly, in an insightful epidemiologic analysis

5

of
risk related to high-density lipoprotein (HDL) choles-
terol, an increment of 1 mg per deciliter (0.03 mmol
per liter or about 2 to 3 percent) in the HDL level has
been associated with a reduction of 2 to 4 percent in
the risk of cardiac events that is independent of the
LDL level. If the benefits of raising the HDL level
and lowering the LDL level are independent and of
similar magnitude, as the results of several trials im-
ply,

6-8

then simultaneous therapeutic alterations of 30
to 40 percent in the levels of these lipoproteins should
theoretically reduce the risk of events by 60 to 80 per-
cent. Furthermore, a low HDL level may reflect an an-
tioxidant deficiency

9

; therefore, supplemental antioxi-
dants may also reduce risk.

10

We undertook a trial to
test the hypothesis that lipid-altering and antioxidant
therapy provide independent and additive benefits for
patients with coronary artery disease and low HDL
levels.
O
Copyright 2001 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org by PERSIO J. LOPEZ CONTRERAS MD on September 24, 2009 .
1590 N Engl J Med, Vol. 345, No. 22 November 29, 2001 www.nejm.org
The New Engl and Jour nal of Medi ci ne
These findings concur with the results of four large
negative trials of vitamins.
29-32
The clinical and angiographically measurable ben-
efits of simvastatin plus niacin were greater than those
that would be expected from statins alone. We found
regression of stenosis, rather than slowed progression,
3
and a reduction of 60 to 90 percent, instead of 24 to
34 percent, in the rate of events.
3,4
These results were
not entirely unexpected. They are consistent with the
epidemiologic projection of a 1 percent reduction in
cardiovascular risk for each 1 percent increase in the
HDL cholesterol level and, independently, a 1 percent
reduction in risk for each 1 percent decrease in the
LDL cholesterol level.
1
For this study, the approximate
risk reduction, by this simplified estimate, would be
68 percent (corresponding to a 26 percent increase in
the HDL cholesterol level plus a 42 percent decrease
in the LDL cholesterol level). Similarly, in another tri-
al, the risk of the same composite end point was re-
duced by 80 percent with the use of niacin plus co-
lestipol, which led to a 43 percent increase in the HDL
cholesterol level and a 32 percent decrease in the LDL
cholesterol level.
7
The greater-than-expected clinical
and angiographically measurable benefits of simva-
statin plus niacin may, in part, be due to a proposed
33
dual therapeutic pathway: statins principally reduce the
number of LDL particles; niacin principally increases
HDL2 levels and the buoyancy of LDL particles by di-
minishing hepatic lipase activity,
33
one determinant of
low HDL2 levels.
34,35
Surprisingly, when antioxidants were combined with
simvastatin and niacin, arterial and clinical benefits
tended to diminish as compared with those achieved
with simvastatin and niacin alone. The adverse interac-
tion between these two therapeutic strategies was sig-
nificant (P=0.02) in terms of the angiographic end
Figure 2. KaplanMeier Curves for the Time to the First of the Components of the Composite Primary Clinical End Point (Death
from Coronary Causes, Nonfatal Myocardial Infarction, Confirmed Stroke, or Revascularization for Worsening Ischemia).
Panel A shows the curves for the 38 patients in the simvastatinniacin group and for the 38 in the placebo group; the relative risk
(RR) of an event was 0.10 (95 percent confidence interval, 0.01 to 0.81). Panel B shows the curves for the 42 patients assigned to
receive simvastatinniacin and antioxidants and for the 42 in the antioxidant group. Panel C shows the curves for all 80 patients
who were assigned to receive simvastatin plus niacin and for the 80 who were not. Panel D shows the curves for the 84 patients who
were assigned to receive antioxidants and for the 76 who were not.
0
100
C
0 3
70
80
90
2 1
Years
Simvastatinniacin
No simvastatinniacin
78%
91%
RR=0.40
P=0.02
P
a
t
i
e
n
t
s

F
r
e
e

o
f

E
v
e
n
t
s

(
%
)
0
100
D
0 3
70
80
90
2 1
Antioxidants
No antioxidants
82%
87%
RR=1.38
P=0.38
0
100
A
0 3
70
80
90
2 1
Simvastatinniacin
All placebos
76%
97%
RR=0.10
P=0.03
0
100
B
0 3
70
80
90
2 1
Antioxidants
Simvastatinniacin
plus antioxidants
79%
86%
RR=0.64
P=0.40
Downloaded from www.nejm.org by PERSIO J. LOPEZ CONTRERAS MD on September 24, 2009 .
n engl j med 361;22 nejm.org november 26, 2009 2113
The new england
journal of medicine
established in 1812 november 26, 2009 vol. 361 no. 22
Extended-Release Niacin or Ezetimibe and Carotid
IntimaMedia Thickness
Allen J. Taylor, M.D., Todd C. Villines, M.D., Eric J. Stanek, Pharm.D., Patrick J. Devine, M.D., Len Griffen, M.D.,
Michael Miller, M.D., Neil J. Weissman, M.D., and Mark Turco, M.D.
Abstract
From the Cardiology Service, Walter Reed
Army Medical Center (A.J.T., T.C.V., P.J.D.,
M.M.); and Medstar Research Institute,
Washington Hospital Center (A.J.T., N.J.W.)
both in Washington, DC; Medco Health
Solutions, Franklin Lakes, NJ (E.J.S.); Car-
diac Associates, Rockville, MD (L.G.); Uni-
versity of Maryland Medical Center, Balti-
more (M.M.); and Washington Adventist
Hospital, Takoma Park, MD (M.T.). Ad-
dress reprint requests to Dr. Taylor at the
Department of Medicine (Cardiology),
Medstar Research Institute, Washington
Hospital Center, 110 Irving St. NW, Rm.
1E12, Washington, DC 20010, or at allen.
taylor@medstar.net.
This article (10.1056/NEJMoa0907569)
was published on November 16, 2009, at
NEJM.org.
N Engl J Med 2009;361:2113-22.
Background
Treatment added to statin monotherapy to further modify the lipid profile may in-
clude combination therapy to either raise the high-density lipoprotein (HDL) choles-
terol level or further lower the low-density lipoprotein (LDL) cholesterol level.
Methods
We enrolled patients who had coronary heart disease or a coronary heart disease risk
equivalent, who were receiving long-term statin therapy, and in whom an LDL choles-
terol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level
under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol
per liter, respectively) had been achieved. The patients were randomly assigned to
receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg
per day). The primary end point was the between-group difference in the change
from baseline in the mean common carotid intimamedia thickness after 14 months.
The trial was terminated early, on the basis of efficacy, according to a prespecified
analysis conducted after 208 patients had completed the trial.
Results
The mean HDL cholesterol level in the niacin group increased by 18.4% over the
14-month study period, to 50 mg per deciliter (P<0.001), and the mean LDL choles-
terol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7
mmol per liter) (P<0.001). Niacin therapy significantly reduced LDL cholesterol and
triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As
compared with ezetimibe, niacin had greater efficacy regarding the change in
mean carotid intimamedia thickness over 14 months (P = 0.003), leading to sig-
nificant reduction of both mean (P = 0.001) and maximal carotid intimamedia
thickness (P0.001 for all comparisons). Paradoxically, greater reductions in the
LDL cholesterol level in association with ezetimibe were significantly associated with
an increase in the carotid intimamedia thickness (R = 0.31, P<0.001). The inci-
dence of major cardiovascular events was lower in the niacin group than in the
ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test).
Conclusions
This comparative-effectiveness trial shows that the use of extended-release niacin
causes a significant regression of carotid intimamedia thickness when com-
bined with a statin and that niacin is superior to ezetimibe. (ClinicalTrials.gov
number, NCT00397657.)
The New England Journal of Medicine
Downloaded from nejm.org by PERSIO LOPEZ CONTRERAS on May 2, 2011. For personal use only. No other uses without permission.
Extended-Release Niacin or Ezetimibe and Carotid IntimaMedia Thickness
square test was used to evaluate categorical vari-
ables. A general linear model was used to analyze
repeated measures of carotid intimamedia thick-
ness for the comparison of effects between the two
groups. KaplanMeier survival analysis was per-
formed with the use of the log-rank test. All sta-
tistical analyses were performed with SPSS soft-
ware (version 16). Values are reported as means
and standard deviations or standard errors or, for
non-normal distributions, as medians and inter-
quartile ranges. A two-sided P value of 0.05 or less
was considered to indicate statistical significance.
The study design prespecified the performance
of a blinded, interim analysis, according to the
conservative method of OBrien and Fleming, with
an alpha spending function.
14
This analysis was
conducted after 180 patients (60% of the planned
sample size) had completed the study (in March
2009). On June 4, 2009, an independent data ad-
visory committee evaluated the end-point data
without knowledge of the treatment assignments.
No formal, a priori stopping boundaries were set
for the trial. On the basis of efficacy as measured
in terms of the primary end point the consis-
tency of findings at 8 and 14 months in both mean
and maximum carotid intimamedia thicknesses,
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P<0.001
Niacin
Ezetimibe P
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30
0 2 4 6 8 10 14 12
8 LDL Cho|estero|
Months
P=0.01
Niacin
Ezetimibe
P
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P=0.01
Niacin
Ezetimibe
P
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5
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D 1rig|ycerides
Months
P=0.001
Niacin
Ezetimibe
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Figure 1. Mean Percent Changes in Cholesterol and Triglyceride Levels over the 14-Month Study Period
among the 208 Patients Who Completed the Study, According to Treatment Group.
P values are given for the comparison between the two treatment groups at 14 months. The vertical bars indicate
the standard errors. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein.
The new engl and journal o f medicine
results of sensitivity analyses regarding the sta-
tistical stability of the findings, and other sec-
ondary analyses showing potentially paradoxical
effects of ezetimibe the committee unanimous-
ly recommended that the trial should be termi-
nated. After termination, final visits were con-
ducted, which resulted in 208 patients having
14-month end-point data. These data are described
herein.
Results
The baseline characteristics of the 208 patients who
had completed the trial at the time of its termi-
nation were similar between the two treatment
groups (Table 1). In the study population, a total
of 80% of patients were male, the mean (SD) age
was 6511 years, and all patients had received a
statin simvastatin or atorvastatin in 95% of pa-
tients at a mean dose of 4225 mg for 65
years. The baseline level of total cholesterol was
146.123.6 mg per deciliter (3.80.7 mmol per li-
ter); LDL cholesterol, 82.123.1 mg per deciliter
(2.10.6 mmol per liter); HDL cholesterol, 42.48.5
mg per deciliter (1.10.2 mmol per liter); and tri-
glycerides, 13767 mg per deciliter (21 mmol per
liter). The mean and maximum carotid intima
media thicknesses at baseline were 0.89780.1516
mm and 1.00780.1653 mm, respectively.
The final change in LDL cholesterol level in
the ezetimibe group was 17.620.1 mg per deci-
liter (0.50.5 mmol per liter), as compared with
10.024.5 mg per deciliter (0.30.6 mmol per li-
ter) in the niacin group (P = 0.01) (Fig. 1, and Ta-
ble 2 in the Supplementary Appendix). The final
change in HDL cholesterol level in the ezetimibe
group was 2.85.7 mg per deciliter (0.10.1 mmol
per liter), as compared with 7.59.2 mg per deci-
liter (0.20.2 mmol per liter) in the niacin group
(P<0.001). Significant reductions in the triglycer-
ide level were observed in both groups.
Niacin showed superior efficacy to ezetimibe
regarding the change in the mean carotid intima
media thickness at both 8 and 14 months (Fig. 2),
with similar findings for the maximal thickness
(Table 2, and Fig. 3 in the Supplementary Appen-
dix). The change from baseline to 14 months in
the mean carotid intimamedia thickness was
significantly different between the niacin group
and the ezetimibe group (P = 0.003 for the re-
peated-measures analysis). Niacin therapy caused
a significant reduction in the mean and maximal
carotid intimamedia thicknesses at both 8 and
14 months. Significant reduction of the mean ca-
rotid intimamedia thickness was observed in the
niacin group between 8 and 14 months (P = 0.02).
No significant net changes in the carotid intima
media thickness were seen with ezetimibe.
In a post hoc analysis, we explored the bivari-
ate relationships between changes in LDL choles-
terol levels and mean carotid intimamedia thick-
ness. There was a significant inverse relationship
between the changes in LDL cholesterol level and
the carotid intimamedia thickness in the ezeti-
mibe group (R = 0.31, P<0.001), such that a para-
doxical increase in the carotid intimamedia thick-
ness was seen in patients with greater reductions
in LDL cholesterol. Such a relationship was not
observed in the niacin group (R = 0.01, P = 0.92)
(Fig. 4 in the Supplementary Appendix).
Major adverse cardiovascular events occurred at
a significantly higher incidence in the ezeti mibe
group (9 of 165 patients [5%]) than in the niacin
group (2 of 160 patients [1%]) (P = 0.04 by the chi-
square test) (Fig. 3, and Table 3 in the Supplemen-
tary Appendix). The effects of niacin on the mean
carotid intimamedia thickness were consistent
across the prespecified subgroups: those stratified
according to sex, presence or absence of diabetes,
quartile of baseline HDL cholesterol level, and me-
3 col
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(
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0.006
0.002
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0.000
0.002
0.006
0.008
0.012
0.004
0.010
0.020
0.018
0.016
0.014
0 8 14
Months
P=0.003
Ezetimibe
Niacin
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Figure 2. Changes in the Mean Carotid IntimaMedia
Thickness over the 14-Month Study Period, According to
Treatment Group.
The carotid intimamedia thickness is the thickness of
the far wall of the bilateral distal common carotid arter-
ies, measured in millimeters. The P value is given for
the comparison of repeated measures of the carotid in-
timamedia thickness over the 14-month period. The
vertical bars indicate the standard errors.
of HDL cholesterol, with cholesterol-transport pro-
teins such as ATP-binding cassette transporters
A1 and G1 and scavenger receptor B1.
20,21
The clinical use of niacin extends over 50 years,
with trial data, beginning with data from the
Coronary Drug Project,
22
suggesting favorable
clinical outcomes. The use of niacin, characterized
by the National Cholesterol Education Program
as the most potent therapy for favorably altering
all lipoprotein abnormalities of the atherogenic
dyslipidemic profile,
23
increases the HDL choles-
terol level through a diverse mechanism of action
including the induction of apolipoprotein A-I pro-
duction.
24,25
Traditionally, a low HDL cholesterol
level has been defined as less than 40 mg per deci-
liter (1.0 mmol per liter), with recent guidelines
for women citing an increase in this threshold to
less than 50 mg per deciliter.
26
Our trial, through
enrollment of men and women with an HDL cho-
lesterol level of less than 50 or 55 mg per decili-
ter, respectively (the values approximating popu-
lation means for men and women in the United
States),
27
suggests that an even higher treatment
threshold of low HDL cholesterol one that
is above the current guideline recommendations
may be warranted.
Ezetimibe was licensed by the Food and Drug
Administration in 2002 exclusively on the basis of
its ability to reduce the LDL cholesterol level while
having an acceptable short-term side-effect profile.
An understanding of ezetimibes mechanism of
action has subsequently evolved and appears to be
increasingly more complex than the purported
simple inhibition of cholesterol absorption at the
enterocyte and than can be inferred from murine
and other animal models.
28
The drug, systemi-
cally absorbed and enterohepatically recirculated
in a potent glucuronidated form,
29
inhibits mul-
tiple, key cholesterol-transport proteins including
the primarily intracellular lipid cholesterol trans-
port receptor, NiemannPick C1-L1.
30
In addition,
ezetimibe has been reported to have diverse ac-
tions including mild inhibition of acyl-coenzyme
A:cholesterol acyltransferase,
30
a mechanism of ac-
tion shown to potentially worsen atherosclerosis
and clinical cardiovascular events.
31-33
Ezetimibe
can inhibit scavenger receptor B1, the high-affin-
ity HDL receptor that may be responsible for up to
50% of HDL binding.
20
This effect, which includes
inhibition of the in vitro uptake of cholesterol
by means of scavenger receptor B1
34,35
and tran-
scriptional down-regulation of this and other key
cholesterol-transport proteins,
36
may disrupt the
process of HDL-mediated, reverse transport of
cholesterol. Thus, we hypothesize that the seem-
ingly paradoxical association of greater ezetimibe-
induced reduction of LDL cholesterol level with
a greater increase in carotid intimamedia thick-
ness is biologically plausible if it is associated with
the unintended disruption of reverse cholesterol
transport.
If viewed properly, this hypothesis-generating
finding is not an indictment of the overall impor-
tance of reducing LDL cholesterol for the pur-
pose of preventing cardiovascular events, as illus-
trated by therapies based on statins or nonstatins
(e.g., bile acid sequestrants).
37
Rather, this adverse
relationship may be attributable to the net effect
of ezetimibe, a drug with diverse actions, not all
of which are measured through its effects on in-
testinal cholesterol absorption and LDL choles-
terol level. Taken together with a preexisting
concern regarding the clinical effectiveness of
ezeti mibe,
38-40
our findings challenge the useful-
ness of LDL cholesterol reduction as a guaranteed
surrogate of clinical efficacy, particularly reduc-
tion achieved through the use of novel clinical
compounds. For ezetimibe, our results indicate a
disconnect between reductions in the LDL cho-
lesterol level and increases in the carotid intima
media thickness in patients with dyslipidemia who
are receiving statin therapy. Thus, we believe that
prudent clinical practice currently favors the avoid-
ance of ezetimibe, with consideration of further
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(
%
j
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80
90
70
60
40
30
10
50
20
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0 2 4 6 8 10 14 12
Months
P=0.047
Ezetimibe
Niacin
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No. at Risk
Ezetimibe
Niacin
176
187
174
185
171
171
167
163
160
160
154
152
146
138
143
132
139
130
132
116
126
106
121
104
118
101
113
97
111
97
7
6
4
3
1
5
2
0
0 2 4 6 8 10 14 12
Ezetimibe
Niacin
Figure 3. KaplanMeier Estimates of the Incidence of a Major Cardiovascu-
lar Event among the 363 Study Patients, According to Treatment Group.
The P value, calculated with the use of the log-rank test, is given for the
comparison between the two treatment groups at 14 months. The inset
shows the same data on a magnified scale.
n engl j med 358;14 www.nejm.org april 3, 2008 1431
Simvastatin with or without Ezetimibe
in Familial Hypercholesterolemia
John J.P. Kastelein, M.D., Ph.D., Fatima Akdim, M.D., Erik S.G. Stroes, M.D., Ph.D., Aeilko H. Zwinderman, Ph.D.,
Michiel L. Bots, M.D., Ph.D., Anton F.H. Stalenhoef, M.D., Ph.D., F.R.C.P., Frank L.J. Visseren, M.D., Ph.D.,
Eric J.G. Sijbrands, M.D., Ph.D., Mieke D. Trip, M.D., Ph.D., Evan A. Stein, M.D., Ph.D., Daniel Gaudet, M.D., Ph.D.,
Raphael Duivenvoorden, M.D., Enrico P. Veltri, M.D., A. David Marais, M.D., Ph.D., and Eric de Groot, M.D., Ph.D.,
for the ENHANCE Investigators*
Abstract
From the Academic Medical Center, Am-
sterdam (J.J.P.K., F.A., E.S.G.S., A.H.Z.,
M.D.T., R.D., E.G.); the University Medi-
cal Center, Utrecht (M.L.B., F.L.J.V.); Rad-
boud University Nijmegen Medical Cen-
ter, Nijmegen (A.F.H.S.); and Erasmus
Medical Center, Rotterdam (E.J.G.S.)
all in the Netherlands; the Metabolic and
Atherosclerosis Research Center, Cincin-
nati (E.A.S.); Department of Medicine,
Montreal University, Montreal, QC, Can-
ada (D.G.); Schering-Plough Research
Institute, Kenilworth, NJ (E.P.V.); and
Cape Heart Center, Cape Town, South
Africa (A.D.M.). Address reprint requests
to Dr. Kastelein at the Department of
Vascular Medicine, Academic Medical
Center, Meibergdreef 9, P.O. Box 22660,
1100 DD Amsterdam, the Netherlands,
or at j.j.kastelein@amc.uva.nl.
*Investigators in the Ezetimibe and Simva-
statin in Hypercholesterolemia Enhances
Atherosclerosis Regression (ENHANCE)
trial are listed in the Appendix.
This article (10.1056/NEJMoa0800742) was
published at www.nejm.org on March 30,
2008.
N Engl J Med 2008;358:1431-43.
Background
Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipopro-
tein (LDL) cholesterol when added to statin treatment. However, the effect of ezet-
imibe on the progression of atherosclerosis remains unknown.
Methods
We conducted a double-blind, randomized, 24-month trial comparing the effects
of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of
ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent
B-mode ultrasonography to assess the intimamedia thickness of the walls of the
carotid and femoral arteries. The primary outcome measure was the change in the
mean carotid-artery intimamedia thickness, which was defined as the average of
the means of the far-wall intimamedia thickness of the right and left common
carotid arteries, carotid bulbs, and internal carotid arteries.
Results
The primary outcome, the mean (SE) change in the carotid-artery intimamedia
thickness, was 0.00580.0037 mm in the simvastatin-only group and 0.01110.0038
mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary
outcomes (consisting of other variables regarding the intimamedia thickness of the
carotid and femoral arteries) did not differ significantly between the two groups. At
the end of the study, the mean (SD) LDL cholesterol level was 192.760.3 mg per deci-
liter (4.981.56 mmol per liter) in the simvastatin group and 141.352.6 mg per deciliter
(3.651.36 mmol per liter) in the combined-therapy group (a between-group difference
of 16.5%, P<0.01). The differences between the two groups in reductions in levels of
triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater
reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect
and safety profiles were similar in the two groups.
Conclusions
In patients with familial hypercholesterolemia, combined therapy with ezetimibe and
simvastatin did not result in a significant difference in changes in intimamedia thick-
ness, as compared with simvastatin alone, despite decreases in levels of LDL choles-
terol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.)
The new england
journal of medicine
established in 1812 april 3, 2008 vol. 358 no. 14
The new engl and j ournal o f medicine
n engl j med 358;14 www.nejm.org april 3, 2008 1438
patients (4.7%) in the combined-therapy group
(P = 0.20). No significant change was observed in
the mean maximum carotid-artery intimamedia
thickness, an increase of 0.01030.0049 mm in
the simvastatin-only group and 0.01750.0049 mm
in the combined-therapy group (P = 0.27). Finally,
no significant changes were observed between
study groups regarding mean measures of the
intimamedia thickness of the common carotid
artery (P = 0.93), the carotid bulb (P = 0.37), the
internal carotid artery (P = 0.21), and the femoral
artery (P = 0.16), nor in the average of the mean
values for intimamedia thickness in the carotid
and femoral arteries (P = 0.15) (Table 3).
Adverse Events
Adverse events that were considered to be related
to treatment were similar in the two groups and
occurred in 107 of 363 patients (29.5%) in the sim-
vastatin-only group and in 122 of 357 patients
(34.2%) in the combined-therapy group (P = 0.18).
Likewise, the rates of discontinuation owing to
adverse events were similar: 34 of 363 patients
(9.4%) in the simvastatin-only group and 29 of 357
36p6
10
P
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C
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a
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e
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0
20
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60
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70
0 1 3 6 9 12 15 18 21 24
Simvastatin
Simvastatin plus
ezetimibe
Months
A LDL Cho|estero| 8 HDL Cho|estero|
AUTHOR:
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16
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Months
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C 1ota| Cho|estero|
10
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ezetimibe
10
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C
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20
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Months
Figure 2. Effects of Simvastatin and Combined Therapy with Simvastatin plus Ezetimibe on Levels of Cholesterol and Triglycerides.
All measures of cholesterol low-density lipoprotein (LDL) cholesterol (Panel A), high-density lipoprotein (HDL) cholesterol (Panel B),
and total cholesterol (Panel C) were calculated with the use of analysis for variance for each time point. The I bars represent standard
errors. An analysis for covariance on rank-transformed data for each time point was used for the triglyceride curve (Panel D).
n engl j med 358;14 www.nejm.org april 3, 2008
1440
was one case of possible hepatitis in the simva-
statin-only group. Furthermore, 8 of 360 patients
(2.2%) in the simvastatin-only group and 4 of 356
patients (1.1%) in the combined-therapy group
had an increase in the level of creatine kinase of
more than 10 times the ULN (P = 0.25). Myopathy
(which was defined as a creatine kinase level 10
times the ULN, with associated muscle symptoms)
occurred in one patient in the simvastatin-only
group and in two patients in the combined-ther-
apy group. In all patients, increased levels of ala-
nine aminotransferase, aspartate aminotransfer-
ase, or both and elevations in creatine kinase
levels were transient. No clinically important treat-
ment-related changes were observed for vital signs
or measures on electrocardiography.
Investigator-reported cardiovascular events were
noted in 7 patients in the simvastatin group
(including 1 death from a cardiovascular cause,
2 nonfatal myocardial infarctions, 1 nonfatal
stroke, and 5 coronary revascularization proce-
dures) and in 10 patients in the combined-therapy
group (including 2 deaths from cardiovascular
causes, 3 nonfatal myocardial infarctions, 1 non-
fatal stroke, and 6 coronary revascularizations).
Discussion
The results of our study showed that the addition
of ezetimibe to the highest recommended dose
of simvastatin did not reduce the intimamedia
thickness of the carotid-artery wall in this cohort
of patients with familial hypercholesterolemia, de-
spite significant incremental reductions in levels
of both LDL cholesterol and C-reactive protein. The
primary outcome, the change in the mean intima
media thickness, did not differ significantly be-
tween the two study groups, nor did the second-
ary outcome measures.
There are at least three possible explanations
for the absence of an incremental reduction in the
intimamedia thickness in patients receiving ezet-
imibe: the lack of vascular benefit conferred by
ezetimibe despite the observed reduction in LDL
cholesterol level, the inability of the measurement
technique to accurately reflect changes in athero-
sclerotic burden, and the possibility that the study
population had too low a risk, which would limit
our ability to detect a differential response to the
two interventions.
The first explanation to consider is that the
lowering of LDL cholesterol levels by a drug other
than a statin might be ineffective for slowing ath-
erosclerosis. Thus, the fact that ezetimibe-induced
lowering of LDL cholesterol levels was not associ-
ated with an incremental effect on carotid-artery
intimamedia thickness could be due to the differ-
ent mechanisms of action of ezetimibe, as com-
pared with those of statins. In addition to the ca-
pacity of statins to lower LDL cholesterol levels,
the inhibition of 3-hydroxy-3-methylglutaryl co-
enzyme A (HMG-CoA) reductase also leads to a
plethora of lipid-independent effects involving an-
tiinflammatory action and improvement in endo-
thelial function.
15
A direct comparison between
ezetimibe and statins revealed differential effects
on endothelial function favoring statin therapy
despite similar reductions in LDL cholesterol,
16,17

although this finding has not been consistent in
all studies.
18
Also, dose intensification of statins
in patients with familial hypercholesterolemia re-
sulted in a further reduction in the progression of
intimamedia thickness in the carotid artery.
19

Thus, it can be argued that certain lipid-indepen-
dent effects of statins that are not shared by ezeti-
mibe are involved in the production of a vascular
benefit.
However, several facts argue against the con-
cept that ezetimibe-induced lowering of LDL cho-
lesterol levels does not produce additional vascu-
lar benefit beyond that of statins. First, a recent
regression meta-analysis showed that the lipid-
AUTHOR:
FIGURE:
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4-C
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EMail
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Revised
REG F
Enon
1st
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3rd
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3 of 3
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ARTIST: ts
35814 ISSUE:
0.80
M
e
a
n

C
a
r
o
t
i
d

I
n
t
i
m
a
~
M
e
d
i
a

1
h
i
c
k
n
e
s
s

(
m
m
j
0.70
0.75
0.65
0.60
0.00
0 6 12 18 24
Months
Simvastatin
Simvastatin plus
ezetimibe
Figure 3. Mean (SE) IntimaMedia Thickness of the
Carotid Artery during 24 Months of Therapy.
Antecedentes: Ausencia de efectos bencos de

hipolipemiantes en pacientes con IRC
(atorvastatina, rosuvas, uvas)
9270 pacientes con Cr > 1.7 mg, Simvas/eze 20/10
Reduccin colesterol LDL 33 mg%
25% reduccin AVC no hemorrgico
27% reduccin revascularizacin

10.1056/nejmoa1001282 nejm.org 6
tary Appendix 1). An elevation in alanine amin-
otransferase of more than three times the upper
limit of the normal range occurred in 52 patients
(1.9%) in the fenofibrate group and 40 (1.5%) in
the placebo group.
As noted in other fenofibrate trials,
11,22
mean
serum creatinine levels increased from 0.93 to
1.10 mg per deciliter (82 to 97 mol per liter) in
the fenofibrate group within the first year and
remained relatively stable thereafter. In the pla-
cebo group, mean serum creatinine levels in-
creased from 0.93 to 1.04 mg per deciliter (82 to
92 mol per liter) during the course of the trial
(see Section 15 in Supplementary Appendix 1).
The study drug was discontinued by 66 patients
(2.4%) in the fenofibrate group and 30 (1.1%) in
the placebo group because of a decrease in the
estimated GFR. At the last clinic visit, 440 pa-
tients (15.9%) in the fenofibrate group and 194
(7.0%) in the placebo group were receiving a re-
duced dose of either fibrate or placebo because
of a decreased estimated GFR. There was no sig-
7 col
36p6
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a
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1
o
t
a
|

C
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o
|
e
s
t
e
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o
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(
m
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[
d
|
j 180
160
140
120
0
0 1 2 3 4 5 6 7
Years
A 1ota| Cho|estero|
Fenofibrate
Placebo
No. oF Patients
Fenofibrate
Placebo
2747
2735
2593
2591
2505
2484
2361
2364
2417
2375
1478
1480
796
801
248
243
M
e
a
n

L
D
L

C
h
o
|
e
s
t
e
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o
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(
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[
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j 120
100
80
60
0
0 1 2 3 4 5 6 7
Years
8 LDL Cho|estero|
Fenofibrate
Placebo
No. oF Patients
Fenofibrate
Placebo
2747
2735
2593
2591
2505
2484
2361
2364
2417
2375
1477
1480
796
801
248
243
M
e
a
n

H
D
L

C
h
o
|
e
s
t
e
r
o
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(
m
g
[
d
|
j
43
42
39
40
41
37
38
0
0 1 2 3 4 5 6 7
Years
C HDL Cho|estero|
Fenofibrate
Placebo
No. oF Patients
Fenofibrate
Placebo
2747
2736
2593
2591
2505
2484
2361
2364
2417
2375
1477
1480
796
801
248
243
M
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d
i
a
n

1
r
i
g
|
y
c
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r
i
d
e
s

(
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[
d
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j
160
140
100
120
0
0 1 2 3 4 5 6 7
Years
D 1rig|ycerides
Fenofibrate
Placebo
No. oF Patients
Fenofibrate
Placebo
2747
2735
2593
2591
2505
2484
2361
2364
2417
2375
1478
1480
796
801
248
243
AUTHOR:
FIGURE:
RETAKE:
SIZE
4-C H/T Line Combo
Revised
1st
2nd
3rd
Ginsberg
1 of 3
ARTIST:
TYPE:
ts
04-29-10 JOB: 36217 ISSUE:
Figure 1. Lipid Values.
Shown are mean plasma levels of total cholesterol (Panel A), low-density lipoprotein (LDL) cholesterol (Panel B), and high-density lipo-
protein (HDL) cholesterol (Panel C) and median levels of triglycerides (Panel D) at baseline, 4 months, 8 months, 1 year, and annually
thereafter. Nominal P values for differences between the study groups at 4 months and at the end of the study were, respectively: total
cholesterol, P<0.001 and P = 0.02; LDL cholesterol, P = 0.11 and P = 0.16; HDL cholesterol, P<0.001 and P=0.01; and triglycerides, P<0.001
for both comparisons with the use of nonparametric tests. End-of-study visits were those that occurred in early 2009 and included fol-
low-up at years 4, 5, 6, and 7. The I bars represent 95% confidence intervals. To convert the values for cholesterol to millimoles per liter,
multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129.
Downloaded from www.nejm.org on March 30, 2010 . Copyright 2010 Massachusetts Medical Society. All rights reserved.
triglyceride levels and low HDL cholesterol levels,
the primary outcome rate was 12.4% in the feno-
fibrate group, versus 17.3% in the placebo group,
whereas such rates were 10.1% in both study
groups for all other patients.
Discussion
In this trial, we tested the hypothesis that the use
of fenofibrate to increase plasma HDL cholesterol
levels and to reduce plasma triglyceride levels in
patients with type 2 diabetes who were already
receiving simvastatin therapy would result in an
additional cardiovascular benefit, as compared
with simvastatin therapy alone. However, the rates
of the primary outcome did not differ significant-
ly between the fenofibrate group and the placebo
group during 4.7 years of treatment and follow-up.
When a study does not support the central hy-
pothesis, it is critical to examine potential reasons
for this outcome. One possibility is that the addi-
tion of fenofibrate to statin therapy benefited only
certain subgroups of patients and that other sub-
groups that did not benefit diluted the overall ef-
fect. Our study was part of a factorial design to
simultaneously test the effects of intensive glyce-
mic control
17,20
and combination lipid therapy on
cardiovascular outcomes. To allow for efficient
7 col
36p6
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o
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i
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w
i
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E
v
e
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(
%
j
100
80
60
20
40
0
100
80
60
20
40
0
0 1 2 3 4 5 6 8 7
Years
A Primary Outcome
Fenofibrate
Placebo
No. at Risk
Fenofibrate
Placebo
2765
2753
2644
2634
2565
2528
1981
1979
2485
2442
1160
1161
412
395
137
131
249
245
8 Expanded Macrovascu|ar Outcome
C Death From Any Cause D Death From Cardiovascu|ar Causes
AUTHOR:
FIGURE:
RETAKE:
SIZE
4-C H/T Line Combo
Revised
1st
2nd
3rd
Ginsberg
2 of 3
ARTIST:
TYPE:
ts
04-29-10 JOB: 36217 ISSUE:
P=0.32
10
20
0
0 1 2 3 4 5 6 8 7
P
r
o
p
o
r
t
i
o
n

w
i
t
h

E
v
e
n
t

(
%
j
0 1 2 3 4 5 6 8 7
Years
Fenofibrate
Placebo
No. at Risk
Fenofibrate
Placebo
2765
2753
2538
2531
2390
2357
1751
1732
2262
2207
999
992
354
316
112
104
211
201
P=0.30
20
40
0
0 1 2 3 4 5 6 8 7
P
r
o
p
o
r
t
i
o
n

w
i
t
h

E
v
e
n
t

(
%
j
100
80
60
20
40
0
0 1 2 3 4 5 6 8 7
Years
Fenofibrate
Placebo
No. at Risk
Fenofibrate
Placebo
2765
2753
2737
2723
2704
2680
2147
2164
2646
2615
1271
1293
469
450
157
157
285
274
P=0.33
10
20
0
0 1 2 3 4 5 6 8 7
P
r
o
p
o
r
t
i
o
n

w
i
t
h

E
v
e
n
t

(
%
j
100
80
60
20
40
0
0 1 2 3 4 5 6 8 7
Years
Fenofibrate
Placebo
No. at Risk
Fenofibrate
Placebo
2765
2753
2700
2689
2660
2633
2114
2128
2606
2574
1255
1270
457
437
155
153
285
271
P=0.26
10
20
0
0 1 2 3 4 5 6 8 7
Figure 2. KaplanMeier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death.
Shown are the cumulative incidence of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascu-
lar causes) (Panel A), the expanded macrovascular outcome (a combination of the primary outcome plus revascularization or hospital-
ization for congestive heart failure) (Panel B), and death from any cause (Panel C) or from cardiovascular causes (Panel D) during fol-
low-up. The insets show close-up versions of the graphs in each panel.
original article
Effects of Combination Lipid Therapy
in Type 2 Diabetes Mellitus
The ACCORD Study Group*
The members of the Writing Committee
(Henry N. Ginsberg, M.D., Marshall B.
Elam, M.D., Laura C. Lovato, M.S., John
R. Crouse III, M.D., Lawrence A. Leiter,
M.D., Peter Linz, M.D., William T. Friede-
wald, M.D., John B. Buse, M.D., Ph.D.,
Hertzel C. Gerstein, M.D., Jeffrey Probst-
field, M.D., Richard H. Grimm, M.D.,
Ph.D., Faramarz Ismail-Beigi, M.D.,
Ph.D., J. Thomas Bigger, M.D., David C.
Goff, Jr., M.D., Ph.D., William C. Cush-
man, M.D., Denise G. Simons-Morton,
M.D., Ph.D., and Robert P. Byington,
Ph.D.) assume responsibility for the in-
tegrity of the article. Address reprint re-
quests to Dr. Ginsberg at the Department
of Medicine, Columbia University Col-
lege of Physicians and Surgeons, Rm. PH
10-305, New York, NY 10032, or at hng1@
columbia.edu.
*The members of the Action to Control
Cardiovascular Risk in Diabetes (ACCORD)
Study Group are listed in Section 20 in
Supplementary Appendix 1, available
with the full text of this article at NEJM
.org. The affiliations of members of the
Writing Committee are listed in the Ap-
pendix.
published on March 14, 2010, and updated
on March 18, 2010, at NEJM.org.
N Engl J Med 2010.
Abstract
Background
We investigated whether combination therapy with a statin plus a fibrate, as com-
pared with statin monotherapy, would reduce the risk of cardiovascular disease in
patients with type 2 diabetes mellitus who were at high risk for cardiovascular
disease.
Methods
We randomly assigned 5518 patients with type 2 diabetes who were being treated
with open-label simvastatin to receive either masked fenofibrate or placebo. The pri-
mary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal
stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
Results
The annual rate of the primary outcome was 2.2% in the fenofibrate group and
2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confi-
dence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences
between the two study groups with respect to any secondary outcome. Annual rates
of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard
ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested
heterogeneity in treatment effect according to sex, with a benefit for men and pos-
sible harm for women (P = 0.01 for interaction), and a possible interaction according
to lipid subgroup, with a possible benefit for patients with both a high baseline
triglyceride level and a low baseline level of high-density lipoprotein cholesterol
(P = 0.057 for interaction).
Conclusions
The combination of fenofibrate and simvastatin did not reduce the rate of fatal
cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as com-
pared with simvastatin alone. These results do not support the routine use of com-
bination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in
the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number,
NCT00000620.)
original article
Effects of Combination Lipid Therapy
in Type 2 Diabetes Mellitus
The ACCORD Study Group*
The members of the Writing Committee
(Henry N. Ginsberg, M.D., Marshall B.
Elam, M.D., Laura C. Lovato, M.S., John
R. Crouse III, M.D., Lawrence A. Leiter,
M.D., Peter Linz, M.D., William T. Friede-
wald, M.D., John B. Buse, M.D., Ph.D.,
Hertzel C. Gerstein, M.D., Jeffrey Probst-
field, M.D., Richard H. Grimm, M.D.,
Ph.D., Faramarz Ismail-Beigi, M.D.,
Ph.D., J. Thomas Bigger, M.D., David C.
Goff, Jr., M.D., Ph.D., William C. Cush-
man, M.D., Denise G. Simons-Morton,
M.D., Ph.D., and Robert P. Byington,
Ph.D.) assume responsibility for the in-
tegrity of the article. Address reprint re-
quests to Dr. Ginsberg at the Department
of Medicine, Columbia University Col-
lege of Physicians and Surgeons, Rm. PH
10-305, New York, NY 10032, or at hng1@
columbia.edu.
*The members of the Action to Control
Cardiovascular Risk in Diabetes (ACCORD)
Study Group are listed in Section 20 in
Supplementary Appendix 1, available
with the full text of this article at NEJM
.org. The affiliations of members of the
Writing Committee are listed in the Ap-
pendix.
published on March 14, 2010, and updated
on March 18, 2010, at NEJM.org.
N Engl J Med 2010.
Abstract
Background
We investigated whether combination therapy with a statin plus a fibrate, as com-
pared with statin monotherapy, would reduce the risk of cardiovascular disease in
patients with type 2 diabetes mellitus who were at high risk for cardiovascular
disease.
Methods
We randomly assigned 5518 patients with type 2 diabetes who were being treated
with open-label simvastatin to receive either masked fenofibrate or placebo. The pri-
mary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal
stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
Results
The annual rate of the primary outcome was 2.2% in the fenofibrate group and
2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confi-
dence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences
between the two study groups with respect to any secondary outcome. Annual rates
of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard
ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested
heterogeneity in treatment effect according to sex, with a benefit for men and pos-
sible harm for women (P = 0.01 for interaction), and a possible interaction according
to lipid subgroup, with a possible benefit for patients with both a high baseline
triglyceride level and a low baseline level of high-density lipoprotein cholesterol
(P = 0.057 for interaction).
Conclusions
The combination of fenofibrate and simvastatin did not reduce the rate of fatal
cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as com-
pared with simvastatin alone. These results do not support the routine use of com-
bination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in
the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number,
NCT00000620.)
n engl j med 356;13 www.nejm.org march 29, 2007 1314
a single agent in the class, particularly an agent
with adverse effects on blood pressure.
The results of our study also have important
implications for the use of imaging methods in
the development of novel antiatherosclerotic ther-
apies. Intravascular ultrasonography has been in-
creasingly proposed as one of several imaging
methods for determining the potential of new
agents.
33
Our results would have predicted nei-
ther benefit nor harm from the administration
of torcetrapib. Although this finding may appear
to be incongruent with the failed clinical out-
Figure 3. Schematic Representation of the Metabolism of HDL Cholesterol.
Apolipoprotein A-I (ApoA-I) is secreted by the liver as a discoidal particle containing protein and phospholipid. This lipid-poor protein
interacts with ATP-binding cassette transporter A1 (ABCA1) in macrophages, removing intracellular free cholesterol. When these lipid-
poor HDL particles accept additional cholesterol, they mature into larger, spheroidal particles that do not actively interact with the ABCA1
transporter. However, the mature HDL particle can participate in reverse cholesterol transport through uptake in the liver by the scaven-
ger receptor class B1 (SR-B1), potentially regenerating lipid-poor discoidal HDL cholesterol. Alternatively, mature HDL particles can also
accept additional free cholesterol through the ATP-binding cassette transporter G1 (ABCG1). Mature HDL particles can also efflux free
cholesterol from macrophages through the SR-B1 receptor. Cholesteryl ester transfer protein (CETP) inhibitors increase concentrations
of the larger, mature alpha-HDL particles by blocking transfer of cholesteryl ester to particles of very-low-density lipoprotein (VLDL) and
low-density lipoprotein (LDL) cholesterol. Pathways shown in blue represent the potentially beneficial effects of CETP inhibition, those
shown in green may remain relatively unaffected, and those shown with dashed lines have potentially reduced activity after CETP inhibi-
tion. FC denotes free cholesterol, PL phospholipids, CE cholesteryl ester, and LPL lipoprotein lipase.
Downloaded from nejm.org on May 2, 2011. For personal use only. No other uses without permission.
original article
Effect of Torcetrapib on the Progression
of Coronary Atherosclerosis
Steven E. Nissen, M.D., Jean-Claude Tardif, M.D.,
Stephen J. Nicholls, M.B., B.S., Ph.D., James H. Revkin, M.D.,
Charles L. Shear, Dr.P.H., William T. Duggan, Ph.D., Witold Ruzyllo, M.D.,
William B. Bachinsky, M.D., Gabriel P. Lasala, M.D., and E. Murat Tuzcu, M.D.,
for the ILLUSTRATE Investigators*
From the Cleveland Clinic, Cleveland
(S.E.N., S.J.N., E.M.T.); Montreal Heart
Institute, Montreal (J.-C.T.); Pfizer, New
London, CT (J.H.R., C.L.S., W.T.D.); Insty-
tut Kardiologii, Warsaw, Poland (W.R.);
Pinnacle Health at Harrisburg Hospital,
Harrisburg, PA (W.B.B.); and Tchefuncte
Cardiovascular Associates, Covington, LA
(G.P.L.). Address reprint requests to Dr.
Nissen at the Department of Cardiovas-
cular Medicine, Cleveland Clinic, 9500
Euclid Ave., Cleveland, OH 44195, or at
nissens@ccf.org.
* Investigators and committees of the In-
vestigation of Lipid Level Management
Using Coronary Ultrasound to Assess
Reduction of Atherosclerosis by CETP In-
hibition and HDL Elevation (ILLUSTRATE)
trial are listed in the Supplementary Ap-
pendix, available with the full text of this
article at www.nejm.org.
N Engl J Med 2007;356:1304-16.
Abstract
Background
Levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardio-
vascular risk. Torcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor,
increases HDL cholesterol levels, but the functional effects associated with this
mechanism remain uncertain.
Methods
A total of 1188 patients with coronary disease underwent intravascular ultrasonog-
raphy. After treatment with atorvastatin to reduce levels of low-density lipoprotein
(LDL) cholesterol to less than 100 mg per deciliter (2.59 mmol per liter), patients
were randomly assigned to receive either atorvastatin monotherapy or atorvastatin
plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured
by repeated intravascular ultrasonography in 910 patients (77%).
Results
After 24 months, as compared with atorvastatin monotherapy, the effect of torcet-
rapibatorvastatin therapy was an approximate 61% relative increase in HDL cho-
lesterol and a 20% relative decrease in LDL cholesterol, reaching a ratio of LDL
cholesterol to HDL cholesterol of less than 1.0. Torcetrapib was also associated with
an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume
(the primary efficacy measure) increased by 0.19% in the atorvastatin-only group
and by 0.12% in the torcetrapibatorvastatin group (P = 0.72). A secondary mea-
sure, the change in normalized atheroma volume, showed a small favorable effect
for torcetrapib (P = 0.02), but there was no significant difference in the change in ath-
eroma volume for the most diseased vessel segment.
Conclusions
The CETP inhibitor torcetrapib was associated with a substantial increase in HDL
cholesterol and decrease in LDL cholesterol. It was also associated with an increase
in blood pressure, and there was no significant decrease in the progression of
coronary atherosclerosis. The lack of efficacy may be related to the mechanism of
action of this drug class or to molecule-specific adverse effects. (ClinicalTrials.gov
number, NCT00134173.)
Effect of Torcetrapib on the Progression of Coronary Atherosclerosis
Table 2. Primary and Secondary Study End Points as Evaluated on Intravascular Ultrasonography at Baseline
and at 24-Month Follow-up with Changes from Baseline.
Variable
Atorvastatin Only
(N = 446)
Atorvastatin
plus Torcetrapib
(N = 464) P Value
Baseline
Percent atheroma volume* 0.88
Mean SD 37.18.5 37.0 8.6
Median 36.5 36.8
Interquartile range 31.242.7 31.3 42.8
Normalized total atheroma volume (mm
3
) 0.66
Mean SD 198.786.2 196.190.8
Median 185.1 177.3
Interquartile range 134.8252.2 133.9238.2
Atheroma volume of most diseased 10-mm segment (mm
3
) 0.46
Mean SD 58.225.7 56.828.7
Median 55.8 54.0
Interquartile range (39.574.2) (35.972.6)
Follow-up at 24 months
Percent atheroma volume 0.78
Mean SD 37.38.8 37.18.6
Median 36.3 37.0
3
) 0.32
Mean SD 192.485.7 186.787.6
Median 176.4 169.7
3
) 0.22
Mean SD 54.924.7 52.726.5
Median 53.4 50.5
Change from baseline
Percent atheroma volume 0.72
Mean SD 0.192.83 0.122.99
Least-square mean SE 0.190.14 0.120.13
3
) 0.02
Mean SD 6.322.2 9.421.0
3
) 0.12
Mean SD 3.39.1 4.18.6
* This variable was the primary efficacy measure.
This variable was a secondary efficacy measure.
original article
n engl j med 363;25 nejm.org december 16, 2010 2406
Safety of Anacetrapib in Patients with
or at High Risk for Coronary Heart Disease
Christopher P. Cannon, M.D., Sukrut Shah, Ph.D., R.Ph., Hayes M. Dansky, M.D.,
Michael Davidson, M.D., Eliot A. Brinton, M.D., Antonio M. Gotto, Jr., M.D., D.Phil.,
Michael Stepanavage, M.S., Sherry Xueyu Liu, M.S., Patrice Gibbons, M.S.,
Tanya B. Ashraf, B.A., Jennifer Zafarino, M.S., Yale Mitchel, M.D.,
and Philip Barter, M.D., Ph.D., for the DEFINE Investigators*
From the TIMI Study Group, Cardiovascu-
lar Division, Brigham and Womens Hos-
pital, Boston (C.P.C.); Merck Research
Laboratories, Rahway, NJ (S.S., H.M.D.,
M.S., S.X.L., P.G., T.B.A., J.Z., Y.M.); Radi-
ant Research, Chicago (M.D.); University
of Utah School of Medicine, Salt Lake
City (E.A.B.); Weill Cornell Medical Col-
lege, New York (A.M.G.); and the Heart
Research Institute, Sydney (P.B.). Address
reprint requests to Dr. Cannon at the
TIMI Study Group, Cardiovascular Divi-
sion, Brigham and Womens Hospital,
350 Longwood Ave., 1st Fl., Boston, MA
02115, or at cpcannon@partners.org.
*The Determining the Efficacy and Toler-
ability of CETP Inhibition with Anacetra-
pib (DEFINE) study investigators and
committee members are listed in the
Supplementary Appendix, available at
NEJM.org.
published on November 17, 2010, at NEJM
.org.
N Engl J Med 2010;363:2406-15.
ABSTRACT
BACKGROUND
Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density
lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial to assess the ef-
ficacy and safety profile of anacetrapib in patients with coronary heart disease or at
high risk for coronary heart disease. Eligible patients who were taking a statin and
who had an LDL cholesterol level that was consistent with that recommended in
guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18
months. The primary end points were the percent change from baseline in LDL cho-
lesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety
and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and
deaths were prospectively adjudicated.
RESULTS
A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol
level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per
deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction
from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per
liter) in the placebo group (P<0.001) a 39.8% reduction with anacetrapib beyond
that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg
per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the
anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol
per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)
a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76
weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels
with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular
events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiv-
ing placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this
event distribution provided a predictive probability (confidence) of 94% that anacetra-
pib would not be associated with a 25% increase in cardiovascular events, as seen
with torcetrapib.
CONCLUSIONS
Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an
acceptable side-effect profile, and, within the limits of the power of this study, did
not result in the adverse cardiovascular effects observed with torcetrapib. (Funded
by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.)
original article
Safety of Anacetrapib in Patients with
or at High Risk for Coronary Heart Disease
Christopher P. Cannon, M.D., Sukrut Shah, Ph.D., R.Ph., Hayes M. Dansky, M.D.,
Michael Davidson, M.D., Eliot A. Brinton, M.D., Antonio M. Gotto, Jr., M.D., D.Phil.,
Michael Stepanavage, M.S., Sherry Xueyu Liu, M.S., Patrice Gibbons, M.S.,
Tanya B. Ashraf, B.A., Jennifer Zafarino, M.S., Yale Mitchel, M.D.,
and Philip Barter, M.D., Ph.D., for the DEFINE Investigators*
From the TIMI Study Group, Cardiovascu-
lar Division, Brigham and Womens Hos-
pital, Boston (C.P.C.); Merck Research
Laboratories, Rahway, NJ (S.S., H.M.D.,
M.S., S.X.L., P.G., T.B.A., J.Z., Y.M.); Radi-
ant Research, Chicago (M.D.); University
of Utah School of Medicine, Salt Lake
City (E.A.B.); Weill Cornell Medical Col-
lege, New York (A.M.G.); and the Heart
Research Institute, Sydney (P.B.). Address
reprint requests to Dr. Cannon at the
TIMI Study Group, Cardiovascular Divi-
sion, Brigham and Womens Hospital,
350 Longwood Ave., 1st Fl., Boston, MA
02115, or at cpcannon@partners.org.
*The Determining the Efficacy and Toler-
ability of CETP Inhibition with Anacetra-
pib (DEFINE) study investigators and
committee members are listed in the
Supplementary Appendix, available at
NEJM.org.
published on November 17, 2010, at NEJM
.org.
N Engl J Med 2010;363:2406-15.
ABSTRACT
BACKGROUND
Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density
lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial to assess the ef-
ficacy and safety profile of anacetrapib in patients with coronary heart disease or at
high risk for coronary heart disease. Eligible patients who were taking a statin and
who had an LDL cholesterol level that was consistent with that recommended in
guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18
months. The primary end points were the percent change from baseline in LDL cho-
lesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety
and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and
deaths were prospectively adjudicated.
RESULTS
A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol
level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per
deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction
from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per
liter) in the placebo group (P<0.001) a 39.8% reduction with anacetrapib beyond
that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg
per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the
anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol
per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)
a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76
weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels
with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular
events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiv-
ing placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this
event distribution provided a predictive probability (confidence) of 94% that anacetra-
pib would not be associated with a 25% increase in cardiovascular events, as seen
with torcetrapib.
CONCLUSIONS
Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an
acceptable side-effect profile, and, within the limits of the power of this study, did
not result in the adverse cardiovascular effects observed with torcetrapib. (Funded
by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.)
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Figure 1. Changes in Cholesterol Levels and Blood Pressure during the Study Period.
Panel A shows low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in the anacetrapib and placebo groups from baseline to week 76. Horizontal bars
indicate standard errors. To convert the values for LDL and HDL cholesterol to millimoles per liter, multiply by 0.02586. Panel B shows systolic and diastolic blood pressure from
baseline to week 76. Boxes indicate the interquartile ranges; the lines within the boxes are medians. The vertical lines represent 1.5 times the interquartile range (above the upper
end of the range and below the lower end of the range); the short horizontal lines indicate the last data points that fall within 1.5 times the interquartile range. The dots beyond
those lines indicate outliers.
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study drug, there was 1 death in the anacetrapib
group and there were 4 deaths in the placebo
group (Table 3 in the Supplementary Appendix);
thus, there were 12 deaths in each group through
week 88.
DISCUSSION
This moderate-size safety study shows that ana-
cetrapib, when used concomitantly with statin
therapy, had substantial effects on plasma lipid
levels. Treatment with anacetrapib, as compared
with placebo, increased HDL cholesterol levels by
138.1%, decreased LDL cholesterol levels by 39.8%,
and decreased non-HDL cholesterol levels by 31.7%
effects that are two to four times as large as
those with other CETP inhibitors that have been
tested to date.
5,8
The effects of anacetrapib ther-
apy on apolipoprotein A-I and apolipoprotein B
levels paralleled the effects on HDL cholesterol
levels and LDL cholesterol levels, respectively, and,
as compared with placebo, resulted in a substan-
tial (36.4%) reduction in levels of lipoprotein(a),
another atherogenic lipid particle that is relative-
ly unaffected by statin therapy. The ratio of LDL
cholesterol to HDL cholesterol was reduced from
2.1 at baseline to just 0.5 at both 24 and 76 weeks
among patients treated with the combination of
a statin and anacetrapib a level that, to our
knowledge, has not been achieved previously.
Treatment with anacetrapib had an accept-
able side-effect profile and was not associated
with an increase in liver enzyme levels or with
myalgia, both of which are well-known side ef-
fects of statins.
1
Concern about the safety of
inhibiting CETP was expressed when the results
of the ILLUMINATE trial showed that treatment
with the CETP inhibitor torcetrapib was associ-
ated with an excess of both cardiovascular events
and deaths from any cause.
6
In addition, torcet-
rapib increased blood pressure, altered serum
electrolyte levels, and increased serum aldoste-
r one levels, which may have accounted for the
adverse clinical outcomes.
6
It was subsequently
shown that torcetrapib induces synthesis of both
aldosterone and cortisol in adrenal cortical
cells.
7,14
In contrast, in the current study, anacet-
rapib treatment did not alter blood pressure,
electrolyte levels, or serum aldosterone levels,
and the distribution of cardiovascular events be-
tween the two treatment groups provided a 94%
predictive probability (confidence) that treatment
with anacetrapib is not associated with the rate
of adverse cardiovascular effects reported with
torcetrapib.
6
These findings have opened the door
to retesting the hypothesis that inhibition of
CETP is cardioprotective.
One question that has been raised, however,
is whether the HDL particles generated by the
inhibition of CETP retain their atheroprotective
function. Given the complex biologic character-
istics of HDL and the role it plays in reverse
cholesterol transport, the exact role of CETP in-
hibition has been debated. Inhibition of CETP
increases the concentration of apolipoprotein A-I,
the major HDL protein, and increases the size of
HDL particles. However, concerns about the func-
tionality of HDL particles isolated from patients
who are taking CETP inhibitors has been largely
defused by recent investigations. In vitro studies
have shown that HDL particles isolated from pa-
tients treated with torcetrapib
15
and from patients
treated with anacetrapib
16
have a normal or even
an enhanced ability to promote the efflux of
cholesterol from macrophages in vitro.
16
Further-
more, the enhanced functionality of HDL parti-
cles in patients treated with anacetrapib is greater
at higher HDL cholesterol concentrations.
16
Questions have also been raised about thera-
pies that increase HDL cholesterol levels because
of the conflicting results of epidemiologic stud-
ies examining the relationship between CETP
activity and cardiovascular outcomes.
17,18
How-
ever, a recent meta-analysis of 92 studies involving
113,833 participants concluded that the CETP
Table 4. Cardiovascular Events during the Treatment Phase of the Study.*
Event
Anacetrapib
(N = 808)
Placebo
(N = 804)
number (percent)
Prespecified, adjudicated cardiovascular
safety end point
16 (2.0) 21 (2.6)
Death from cardiovascular causes 4 (0.5) 1 (0.1)
Nonfatal myocardial infarction 6 (0.7) 9 (1.1)
Hospitalization for unstable angina 1 (0.1) 6 (0.7)
Nonfatal stroke 5 (0.6) 5 (0.6)
Death from any cause 11 (1.4) 8 (1.0)
Heart failure 3 (0.4) 4 (0.5)
Revascularization 8 (1.0) 28 (3.5)
PCI 6 (0.7) 25 (3.1)
CABG 2 (0.2) 3 (0.4)
* The duration of the treatment phase of the study was 76 weeks. CABG
denotes coronary-artery bypass grafting, and PCI percutaneous coronary
intervention.
CONCLUSIONES
El objetivo farmacolgico primario en el

tratamiento de las hiperlipidemias radica en
reduccin del colesterol LDL.
Las estatinas son los frmacos ms ecaces
Su uso debe ser sostenido, dosis de acuerdo a

objetivos
La reduccin de los triglicridos y la elevacin del

HDL son objetivos secundarios en las dislipidemias
mixtas
La asociacin de estatinas con niacina ofrece

mayor reduccin del riesgo residual...AIM-HIGH...
CONCLUSIONES
La asociacin de estatinas con bratos contribuye

a mejorar metas, dudosamente eventos. Cuidado
con rabdomilisis.
La asociacin de estatinas con ezetimibe

contribuye a mejorar metas, posiblemente eventos
Los bratos son ecaces en el tratamiento de las

hipertrigliceridemias, sus efectos secundarios bajos
La inhibicin de la CETP con resultados todava

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Bases Tto Hiperlipidemias

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Bases Tto Hiperlipidemias

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BASES FARMACOGICAS PARA EL

Transporte de lpidos de su sitio de absorcin o

Apolipoprotenas: protenas anpticas

Hiperlipemia: aumento de triglicridos

Integridad estructural (apo B, apo

Unin o anclaje a receptores

Absorcin de ac. grasos esenciales

20-40% de las caloras provienen de lpidos

Hidrlisis de lpidos por lipasas, formacin de micelas con

Reestericacin de ac. grasos + apoB48 quilomicrones

Interaccin con LPL endotelial msculo y adipocitos

Integracin de apo E, captacin heptica por receptor apo

Sntesis de TG en situaciones de ayuno

VLDLs: ms pequeas que los quilomicrones

LP principal: apo B-100

Interaccin con LPL endotelial, extraccin de TGs, adicin de

Intercambio de TGs por steres colesterol de HDL por la

Transeren fosfolpidos a las HDLs nacientes por la prot.

Remanente: IDL, captada en hgado por receptor de apo B/E

Composicin: colesterol, slo 4-8% de TGs

En presencia de hipertrigliceridemia: aumento de TGs,

Captadas por el receptor de LDL en clulas, saturable.

LDL sntesis (interaccin SCAP [SREPB cholesterol

Reduccin actividad de la HMG-CoA)

Macrfagos: SR-B, no saturables, induccin clulas

Relacin inversa entre cifras de

Portadoras de apo A-I

Origen heptico del 80%, intestinal

Apo A-I libre ABCA1 HDL

ABCG1 colesterol a HDLs

Captadas en hgado y tejidos

Interacin con TRL (QM,

Asociadas a incremento de riesgo de ECV

Aumento de VLDL e IDL

Asociadas a LDLs pequeas, densas

TGs > 700: pancreatitis

Asociadas a resistencia a la insulina (no captacin

Frmacos de eleccin: bratos, ac. nicotnico,

Asociacin con metformina o pioglitazona

QUILOMICRONEMIA PRIMARIA (TIPO I)

Rara, asociada a deciencia de LPL

TGs 2000-3000 mg. Plasma lechoso, blanco, con nata de quilomicrones

Pancreatitis, xantomas eruptivos, hepatosplenomegalia, hiperesplenismo,

Asociada a xerostoma, xeroftalma, trast. conducta.

Agravada por estrgenos o embarazo

HIPERTRIGLICERIDEMIA FAMILIAR (TIPO IV)

Elevacin de VLDL, IDL. LDL y HDL usualmente bajos

TGs en ayuno 200-500 mg, >1000 en post-prandio

Xantomas eruptivos, lipemia retinalis, epigastralgia, pancreatitis. Obesidad

Inuenciada por ingestin alcohol, dieta, obesidad, diabetes, sedentarismo

Comn (2% adultos), asociada a enf. coronaria. Patrn familiar.

Elevacin de VLDL, LDL o ambas, patrn cambiante por efectos

Muy pocos signos clnicos

Base gentica compleja

DISBETALIPOPROTEINEMIA FAMILIAR (TIPO III)

Remanentes de quilomicrones e IDL, apo E anormal.

Xantomas tuberosos, estriados palmares

Restriccin de colesterol a < 200 mg da

Restriccin de grasas saturadas y trans

Restriccin de azcares (especialmente sacarosa y

Restriccin de aceites comestibles (omega 6)

Restriccin de aporte calrico total, reduccin de

Estimular consumo de frutas, granos y vegetales

Estimular consumo de bras viscosas (avena,