www.consumerlab.com
Policosanol: clinical pharmacology and therapeutic significance
of a new lipid-lowering agent.
Gouni-Berthold I, Berthold HK.
Medical Policlinic, University of Bonn, Bonn, Germany. berthold@unibonn.de
BACKGROUND: Policosanol is a mixture of higher primary aliphatic
alcohols isolated from sugar cane wax, whose main component is octacosanol.
The mixture has been shown to lower cholesterol in animal models, healthy
volunteers, and patients with type II hypercholesterolemia. METHODS: We
reviewed the literature on placebo-controlled lipid-lowering studies using
policosanol published in peer-reviewed journals as well as studies
investigating its mechanism of action and its clinical pharmacology.
RESULTS: At doses of 10 to 20 mg per day, policosanol lowers total
cholesterol by 17% to 21% and low-density lipoprotein (LDL) cholesterol by
21% to 29% and raises high-density lipoprotein cholesterol by 8% to 15%.
Because higher doses have not been tested up to now, it cannot be excluded
that effectiveness may be even greater. Daily doses of 10 mg of policosanol
have been shown to be equally effective in lowering total or LDL cholesterol
as the same dose of simvastatin or pravastatin. Triglyceride levels are not
influenced by policosanol. At dosages of up to 20 mg per day, policosanol is
safe and well tolerated, as studies of >3 years of therapy indicate. There is
evidence from in vitro studies that policosanol may inhibit hepatic cholesterol
synthesis at a step before mevalonate generation, but direct inhibition of the
hydroxy-methylglutaryl-coenzyme A reductase is unlikely. Animal studies
suggest that LDL catabolism may be enhanced, possibly through receptormediated mechanisms, but the precise mechanism of action is not understood
yet. Policosanol has additional beneficial properties such as effects on smooth
muscle cell proliferation, platelet aggregation, and LDL peroxidation. Data on
efficacy determined by clinical end points such as rates of cardiac events or
cardiac mortality are lacking. CONCLUSIONS: Policosanol seems to be a
very promising phytochemical alternative to classic lipid-lowering agents such
as the statins and deserves further evaluation.
Publication Types:

Review
Protective effect of policosanol on atherosclerotic plaque on aortas in
monkeys.
Noa M, Mas R.
Center of Natural Products, National Center for Scientific Research, Havana City,
Cuba. cpn@cnic.edu.cu
BACKGROUND: Policosanol is a cholesterol-lowering drug isolated from sugar cane
wax with concomitant antiplatelet effects. Previous studies have shown that
policosanol prevents lipofundin-induced atherosclerotic lesions in rabbits and rats,
including foam cell formation, as well as the development of foam cells in
carrageenan-induced granulomas in rats. Policosanol also inhibits smooth muscle cells
proliferation induced on rabbit cuffed artery and on forceps-induced arterial wall
damage. Furthermore, policosanol administered long term lowered serum cholesterol
and prevented the development of atherosclerotic lesions in Macaca arctoides
monkeys. The present study was undertaken to determine whether policosanol could
change some characteristic features of atherosclerotic lesions, such as macrophage
number and immunohistochemical localization of apoA-1 and apoB in aortas of M.
arctoides monkeys. METHODS: Fourteen adult male monkeys weighing 6-10 kg and
receiving a low fat, protein-rich diet were randomly distributed in three groups:
control group (six monkeys) and two other groups (four monkeys/group) treated with
policosanol (2.5 and 25 mg/kg) for 54 weeks. Samples of arteries were examined by
light microscopy. Monoclonal antibodies were used to evaluate the presence of
macrophage, apoA-1 and apoB. RESULTS: Policosanol reduced the presence of
macrophages and the occurrence of apoB, whereas increased apoA-1 localization in
aortic atherosclerotic lesions compared with control monkeys. CONCLUSIONS:
These results suggest the policosanol potential benefit on plaque composition and
stability and could explain the protective effects of policosanol on atherosclerosis
development.
Effects of addition of policosanol to omega-3 fatty acid therapy on the
lipid profile of patients with type II hypercholesterolaemia.
Castano G, Fernandez L, Mas R, Illnait J, Gamez R, Mendoza S, Mesa M,
Fernandez J.
Surgical Medical Research Center, Havana City, Cuba.
BACKGROUND: Policosanol is a mixture of higher aliphatic primary alcohols
purified from sugar-cane wax. The mixture has cholesterol-lowering efficacy, its
specific effects being to reduce serum total (TC) and low-density lipoprotein
cholesterol (LDL-C), and to increase high-density lipoprotein cholesterol (HDL-C).
The effects of policosanol on triglycerides (TG) are modest and inconsistent. Omega3 fatty acids (FA) from fish oil protect against coronary disease, mainly through
antiarrhythmic and antiplatelet effects. Omega-3 FA also have lipid-modifying
effects, mostly relating to TG reduction. Thus, potential benefits could be expected
from combined therapy with omega-3 FA and policosanol. OBJECTIVE: To
investigate whether combined therapy with omega-3 FA + policosanol offers benefits
compared with omega-3 FA + placebo with respect to the lipid profile of patients with
type II hypercholesterolaemia. METHODS: This randomised, double-blind study was
conducted in 90 patients with type II hypercholesterolaemia. After 5 weeks on a
cholesterol-lowering diet, patients were randomised to omega-3 FA + placebo,
omega-3 FA + policosanol 5 mg/day or omega-3 FA + policosanol 10 mg/day for 8
weeks. Omega-3 FA was supplied as 1g capsules (two per day); placebo and
policosanol were provided in tablet form. Physical signs and laboratory markers were
assessed at baseline and after 4 and 8 weeks on therapy. Drug compliance and adverse
experiences (AEs) were assessed at weeks 4 and 8. The primary efficacy variable was
LDL-C reduction; other lipid profile markers were secondary variables. RESULTS:
After 8 weeks, omega-3 FA + policosanol 5 and 10 mg/day, but not omega-3 FA +
placebo, significantly reduced LDL-C by 21.1% and 24.4%, respectively (both p <
0.0001). Omega-3 FA + policosanol 5 mg/day also significantly lowered TC (12.7%;
p < 0.01) and TG (13.6%; p < 0.05), and significantly increased HDL-C (+14.4%; p <
0.001). Omega-3 FA + policosanol 10 mg/day significantly decreased TC (15.3%; p <
0.001) and TG (14.7%; p < 0.01), and significantly increased HDL-C (+15.5%; p <
0.0001). Omega-3 FA + placebo significantly reduced TG (14.2%; p < 0.05) but had
no significant effect on other lipid profile variables. The proportion of randomised
patients in the omega-3 FA + policosanol 5 or 10 mg/day groups that achieved LDLC targets or reductions 15% was significantly greater than in the omega-3 FA +
placebo group (p < 0.001). Combined therapy with omega-3 FA + policosanol 5 or 10
mg/day resulted in significantly greater changes in LDL-C, TC and HDL-C than
treatment with omega-3 FA + placebo, but did not modify the TG response compared
with the omega-3 FA + placebo group. Four patients (two in the omega-3 FA +
placebo group and two in the omega-3 FA + policosanol 10 mg/day group) withdrew
from the study; none of these withdrawals was due to AEs. Two patients reported
mild AEs, namely nausea/headache (one in the omega-3 FA + placebo group) and
heartburn (one in the omega-3 FA + policosanol 5 mg/day group). CONCLUSIONS:
Policosanol 5 or 10 mg/day administered concomitantly with omega-3 FA 1 g/day
improved LDL-C, TC and HDL-C, maintained the reduction in TG attributable to
omega-3 FA monotherapy, and was well tolerated. Treatment with omega-3 FA +
policosanol could be useful for regulating lipid profile in patients with type II
hypercholesterolaemia, but further studies involving larger sample sizes are needed
before definitive conclusions can be drawn.
PMID: 16050054 [PubMed - in process]
!!!!!!!!!!!!!!!!!!!!!!‫מחקר מעניין‬
An ezetimibe-policosanol combination has the potential to be an OTC
agent that could dramatically lower LDL cholesterol without side
effects.
McCarty MF.
NutriGuard Research, 1051 Hermes Avenue, Encinitas, CA 92024, USA.
mccarty@pantox.com
Although many risk factors influence atherogenesis, LDL appears to play a primary
role in this process. In prospective epidemiology, coronary risk increases as LDL
cholesterol increases, throughout the entire range of concentrations encountered in
healthy humans. Coronary risk is minimal in individuals and populations whose
serum cholesterol remains quite low throughout life. Thus, practical strategies for
achieving large reductions of LDL cholesterol in the general population could have a
dramatic impact on coronary mortality rates. Dietary measures have limited potential
in this regard; modest restriction of saturated fat has a rather trivial effect on LDL
cholesterol, and the very-low-fat quasi-vegan diets that do have a notable effect in this
regard currently have little appeal to the majority of the population. With respect to
pharmacotherapy, most available hypolipidemic agents with reasonably potent
activity entail side effects or compliance difficulties that would render their use too
expensive or impractical for population-wide application. However, two agents may
have great potential in this regard: policosanol and ezetimibe. The former, a mixture
of long-chain alcohols derived from sugar cane wax, has effects on serum lipids
comparable to those of statins, and may work by down-regulating expression of
HMG-CoA reductase. However, unlike statins, policosanol appears to be devoid of
side effects or risks. Ezetimibe is a newly approved drug that is a potent and highly
specific inhibitor of an intestinal sterol permease; in daily doses as low as 10 mg, it
suppresses intestinal absorption of cholesterol and decreases serum LDL cholesterol
by approximately 18%. No side effects have been seen in clinical doses, and the fact
that its hypolipidemic activity is additive to that of statins has generated considerable
interest. Both policosanol and ezetimibe can be administered once daily. Future
studies should determine whether policosanol, like statins, interacts additively with
ezetimibe. If so, it may be feasible someday to produce a tablet combining
policosanol and ezetimibe that could reduce LDL cholesterol by about 40%, without
side effects, and that could be recommended to virtually anyone whose LDL
cholesterol levels were not already ideal.
Role of policosanols in the prevention and treatment of cardiovascular
disease.
Varady KA, Wang Y, Jones PJ.
School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue,
Quebec, Canada.
Policosanols are a mixture of aliphatic alcohols derived from purified sugar cane.
When administered at 5 to 20 mg/day, policosanols have been shown to decrease the
risk of atheroma formation by reducing platelet aggregation, endothelial damage, and
foam cell formation in animals. Additionally, policosanols have been shown to lower
total and low-density lipoprotein (LDL) cholesterol levels by 13 to 23% and 19 to
31%, respectively, while increasing high-density lipoprotein (HDL) cholesterol from
8 to 29%. Policosanols are thought to improve lipid profiles by reducing hepatic
cholesterol biosynthesis while enhancing LDL clearance. When compared with
statins, policosanols exhibit comparable cholesterol-lowering effects at much smaller
doses. The mixture is well tolerated when administered to animals; however, a more
precise safety profile is needed for humans. In summary, policosanols are a promising
resource in the prevention and therapy of cardiovascular disease (CVD), but these
results need to be confirmed in independent laboratories.
A 6-Month Study on the Toxicity of High Doses of Policosanol Orally
Administered to Sprague-Dawley Rats.
Gamez R, Aleman CL, Mas R, Noa M, Rodeiro I, Garcia H, Hernandez C,
Menendez R, Aguilar C.
Center of Natural Products, National Center for Scientific Research, Cubanacan,
Havana, Cuba.
Policosanol is a cholesterol-lowering drug purified from sugar cane. Previous
toxicological studies have not demonstrated any policosanol-related toxicity, even
with long-term oral administration at 500 mg/kg, a dose 1,724 times larger than the
maximal therapeutic dose (20 mg/day) recommended to date. The present study was
undertaken to investigate the oral toxicity of policosanol administered for 6 months in
doses up to 5,000 mg/kg to Sprague-Dawley rats. Animals were randomly distributed
in five groups (15 animals per dose per sex): a control and four groups given oral
policosanol (50, 500, 2,500, or 5,000 mg/kg). Eight treated rats (6 males, 2 females)
died during the study, five of them (4 males, 1 female) from among those receiving
the highest dose (5,000 mg/kg). According to necropsy, all deaths were related to
gavage manipulation of higher doses. Although the differences were not significant,
body weight gain and food consumption in the groups receiving 2,500 or 5,000 mg/kg
tended to be lower than in the control group. Nevertheless, no drug-related toxicity
symptoms were detected. Analysis of blood biochemistry, hematology, organ weight
ratios, and histopathological findings did not show significant differences compared
with controls, nor any tendency with the dose. Therefore, the present study did not
show any new evidence of oral toxicity of policosanol, and the findings observed
were a consequence of long-term administration by gastric gavage of the highly
concentrated suspensions needed to reach the higher doses. It is concluded that
policosanol chronically administered by the oral route is safe and that no drug-related
toxicity was demonstrated.
Efficacy of over-the-counter nutritional supplements.
Davidson MH, Geohas CT.
Department of Preventive Cardiology, Rush-Presbyterian-St. Luke's Medical Center,
1725 West Harrison Street, Suite 1159, Chicago, IL 60612, USA.
mdavidson@protocare.com
More than 100 million people in the United States report using nutritional
supplements. Most people are under the impression that nutritional supplements offer
health benefits and are closely regulated to ensure safety and efficacy. Unfortunately,
the Dietary Supplement Health and Education Act of 1994 allows for the promotion
of nutritional supplements without review by the United States Food and Drug
Administration; therefore, it is important to evaluate the efficacy and safety of these
supplements. There is strong scientific evidence supporting the use of plant
sterols/stanols, omega-3 fatty acids, niacin, folate, vitamin B(6)/B(12), and tree nuts.
There is potential evidence for the health benefits of soy protein, tea extracts,
policosanol, guggulipids, coenzyme Q10, and L-arginine. There has been a lack of
evidence for the health benefits of garlic and antioxidants.
Comparison of the efficacy, safety and tolerability of original
policosanol versus other mixtures of higher aliphatic primary alcohols
in patients with type II hypercholesterolemia.
Castano G, Fernandez L, Mas R, Illnait J, Fernandez J, Mesa M, Alvarez E,
Lezcay M.
Medical and Surgical Research Center, National Center for Scientific Research,
Havana, Cuba.
This randomized, double-blind study was undertaken to compare the efficacy and
tolerability of policosanol and Octa-60 in patients with type II hypercholesterolemia.
After 4 weeks on a diet, 110 patients were randomized to policosanol or Octa-60 5 mg
tablets once a day for 5 weeks. The dose was then doubled to 10 mg/day for the next 5
weeks. Policosanol 5 and 10 mg/day significantly lowered low-density lipoproteincholesterol (LDL-C) (p<0.0001 and p<0.00001), the main efficacy variable, by 18.6%
and 30.2%, while Octa-60 significantly reduced (p<0.05) LDL-C by 10.0% at study
completion only. The frequency of policosanol patients reaching reductions of LDL-C
> or = 15% after 5 mg/day (37/55; 67.3%) and 10 mg/day (47/55; 88.7%) was greater
(p<0.01 and p<0.01) than in the Octa-60 group, which was 5/55 (9.1%) and 20/55
(36.4%). Likewise, the frequency of patients reaching LDL-C values of <3.4 mmol/l
at study completion was greater (p<0.001) in the policosanol group (39/55, 70.9%)
than in the Octa-60 group (6/55, 10.9%). Policosanol 5 and 10 mg/day significantly
lowered (p<0.00001) total cholesterol (TC) (13.4% and 20.4%), LDL-C/high-density
lipoprotein-cholesterol (HDL-C) (22.1% and 37.0%) and TC/HDL-C (17.2% and
28.2%). Octa-60 at 10 mg/day lowered (p<0.05) TC (8.7%), LDL-C/HDL-C (12.6%)
and TC/HDL-C (9.4%). HDL-C was increased (p<0.001 and 0.0001) by policosanol 5
and 10 mg/day (5.6% and 12.5%) but was unchanged by Octa-60. In both groups,
triglycerides remained unchanged. Both treatments were safe and well tolerated. Octa60, but not policosanol, significantly increased glucose and alanine aminotransferase,
but individual values were within the normal range. Four patients (two from each
group) discontinued the trial, but only one (in the Octa-60 group) did so because of an
adverse event (AE) (skin rash). Overall, three patients (all from the Octa-60 group)
reported AEs. In conclusion, original policosanol at 5 and 10 mg/day, but not Octa 60,
was effective in patients with type II hypercholesterolemia. Thus, policosanol reached
the efficacy criterion for LDL-C reduction in both steps, while Octa-60 failed to reach
this goal. In addition, policosanol was better tolerated than Octa-60.
Antiplatelet effects of policosanol (20 and 40 mg/day) in healthy
volunteers and dyslipidaemic patients.
Arruzazabala ML, Molina V, Mas R, Fernandez L, Carbajal D, Valdes S,
Castano G.
Center of Natural Products, National Center for Scientific Research Cubanacan,
Havana City, Cuba.
1. The present study was undertaken to compare the effects of a higher dose of
policosanol, a cholesterol-lowering drug, (40 mg/day) with the effects of 20 mg/day
policosanol on platelet aggregation in healthy volunteers and type II
hypercholesterolaemic patients. 2. Study subjects were randomized to receive, under
double-blind conditions, placebo or policosanol (20 or 40 mg/day) for 30 days once a
day. Blood sampling was performed at baseline and after 30 days on therapy. 3.
Platelet aggregation was induced with three aggregating agents: arachidonic acid
(AA), collagen and low doses of ADP. 4. Policosanol (20 and 40 mg/day) moderately
yet significantly reduced platelet aggregation, but no differences were observed in the
effects produced by either dose of policosanol. In healthy volunteers, policosanol at
20 and 40 mg/day inhibited aggregation induced by 2 mmol/L AA (28.2 and 24.9%,
respectively), 1 micro g/mL collagen (21.1 and 20.2%) and 1 micro mol/L ADP (30.9
and 29.1%). Changes that occurred following the administration of placebo were not
significant, although an upward trend for collagen- and ADP-induced aggregation
occurred in normal and hypercholesterolaemic subjects, respectively, thus partially
masking the effects of policosanol on these responses. 5. The antiplatelet effects of
policosanol at 20 and 40 mg/day in hypercholesterolaemic patients were also similar,
so that both doses inhibited aggregation induced by 1.5 mmol/L AA (20.1 and 33.0%,
respectively), 0.5 micro g/mL collagen (22.7 and 21.1%) and 1 micro mol/L ADP
(40.5 and 34.7%). 6. In addition, after 30 days of therapy, 20 and 40 mg/day
policosanol significantly (P < 0.01) reduced low-density lipoprotein-cholesterol (15.9
and 17.0%, respectively) and total cholesterol (12.4 and 12.3%, respectively; P <
0.05), yet increased high-density lipoprotein-cholesterol values by 5% in both groups
(P < 0.05). 7. Triglycerides were decreased compared with baseline, but not with
respect to the placebo. 8. We conclude that the antiplatelet effects induced by 40
mg/day policosanol administered for 30 days to healthy volunteers and to
hypercholesterolaemic patients were similar to the effects induced by 20 mg/day
policosanol. Thus, no enhancement of the response was achieved with the use of a
higher dose of policosanol in study patients.
Publication Types:
Pharmacotherapy for dyslipidaemia--current therapies and future
agents.
Bays H, Stein EA.
L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA.
HBaysMD@aol.com
Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C)
primarily through increased hepatic LDL receptor activity include statins, bile acid
sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant
stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and
soy proteins; those currently in development include newer statins, phytostanol
analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP
cleavage-activating protein (SCAP) activating ligands. Other current agents that affect
lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils,
antioxidants and policosanol, whilst those in development include microsomal
triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol
acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues,
nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2)
antagonists and AGI1067) and functional oils. Current agents that affect nuclear
receptors include PPAR-alpha and -gamma agonists, while in development are newer
PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and
'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X
receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also
nuclear receptor targets of investigational agents. Agents in development also may
affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include
cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP
vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette
transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger
receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related
peptides. Fixed-dose combination lipid-altering drugs are currently available such as
extended-release niacin/lovastatin, whilst atorvastatin/amlodipine,
ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extendedrelease niacin/simvastatin and pravastatin/aspirin are under development. Finally,
current and future lipid-altering drugs may include anti-obesity agents which could
favourably affect lipid levels.
---------------
Medical lipid-regulating therapy: current evidence, ongoing trials and
future developments.
Evans M, Roberts A, Davies S, Rees A.
Department of Metabolic Medicine, Diabetes and Endocrinology, University of Wales
College of Medicine, Cardiff, Wales. marc.evans2@ntlworld.com
Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide.
Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density
lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with
recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk.
Such observations suggest that the most recent National Cholesterol Education
Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L,
may result in under-treatment of a significant number of patients and form the basis
for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L,
respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins)
reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and
reduced CHD event rates in primary and secondary prevention trials. The magnitude
of this effect is not fully accounted for by LDL-C reduction alone and may relate to
effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as
well as additional anti-inflammatory effects. With increasing focus on the benefits of
intensive cholesterol reduction new, more efficacious statins are being developed.
Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in
LDL-C of up to 55%, with about 80% of patients reaching European LDL-C
treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS)
demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated
with significant clinical benefit in a wide range of high-risk individuals, including
patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease,
irrespective of baseline cholesterol levels, with no apparent lower threshold for LDLC with respect to risk. Various large endpoint trials, including Treating to New
Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and
Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C
reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk
factor and is the primary lipid abnormality in over half of CHD patients, with the
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess
the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and
LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect
both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme Acholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer
protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol
absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60%
reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L
reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of
baseline LDL-C levels. Growing evidence supports the concept that lower is better for
LDL-C and that increasing HDL-C represents an important therapeutic target.
Furthermore, there is growing appreciation of the role of inflammation in
atherogenesis. Consequently, increasing numbers of people should receive lipidregulating therapy with the development of newer agents offering potential
mechanisms of optimising lipid profiles and thus risk reduction. In addition, the
pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further
risk reduction.
Consistency in efficacy and safety of ezetimibe coadministered with
statins for treatment of hypercholesterolemia in women and men.
Bennett S, Sager P, Lipka L, Melani L, Suresh R, Veltri E; Ezetimibe Study
Group.
Cardiology Associates, P.C., Washington, DC, USA.
BACKGROUND: Women are often not treated as aggressively as men to control
levels of low-density lipoprotein cholesterol (LDL-C), despite evidence that women
and men realize comparable cardiovascular benefit from lipid-lowering therapy.
Statins are the most effective drugs currently available for treating
hypercholesterolemia. Despite the impressive cholesterol-lowering capacity of statins,
however, many patients on statin therapy fail to reach established target levels of
LDL-C. The cholesterol absorption inhibitor, ezetimibe, blocks the intestinal
absorption of dietary and biliary cholesterol, a mechanism of action complementary to
that of statins, which inhibit hepatic cholesterol synthesis. Ezetimibe coadministered
with statins produces significant incremental reductions in LDL-C compared with
statin monotherapy. METHODS: Four randomized, double-blind, placebo-controlled,
balanced-parallel group trials compared the efficacy and safety of statin monotherapy
(lovastatin or pravastatin 10, 20, or 40 mg; simvastatin or atorvastatin 10, 20, 40, or
80 mg) vs. ezetimibe 10 mg plus statin (as above). A gender subset analysis (women,
n = 1065; men, n = 796) on data pooled across these four trials was carried out to
determine whether ezetimibe plus statin for the treatment of hypercholesterolemia is
equally efficacious in women and men. RESULTS: Compared with statin
monotherapy, ezetimibe plus statin demonstrated greater efficacy in reducing blood
levels of LDL-C, apolipoprotein B, and triglycerides and raising high-density
lipoprotein cholesterol. The beneficial effects of ezetimibe were comparable in
women and men. The safety profile of subjects receiving ezetimibe plus statin was
similar to that of patients receiving statin monotherapy and similar between the two
sexes. CONCLUSIONS: Ezetimibe plus statin was more effective than statin alone in
improving the lipid profile of patients with hypercholesterolemia and was equally
efficacious in women and men. Ezetimibe plus statin was well tolerated and had a
favorable safety profile in both patient subgroups. Ezetimibe coadministered with
statins, a dual inhibition treatment strategy that targets both cholesterol absorption and
synthesis, is an effective therapeutic option for women with hypercholesterolemia.
!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Inhibition of cholesterol absorption by the combination of dietary plant
sterols and ezetimibe: Effects on plasma lipid levels.
Jakulj L, Trip MD, Sudhop T, von Bergmann K, Kastelein JJ, Vissers MN.
The consumption of plant sterols as well as treatment with ezetimibe both reduce
cholesterol absorption in the intestine. The mechanism of action of both treatment
modalities is not similar and the consequences of combination treatment are unknown.
Therefore, we performed a double-blind placebo controlled cross-over study for the
plant sterol component with open-label ezetimibe treatment to determine the
individual consequences of plant sterol intake and ezetimibe as well as their combined
effects on safety and plasma lipid levels. Forty mildly hypercholesterolemic subjects
were randomized to the following treatments for four weeks each: 10 mg/d ezetimibe
in combination with 25 g/d of control spread; 10 mg/d ezetimibe in combination with
25 g/d of spread containing 2.0 g of plant sterols; 25 g/d of spread containing 2.0 g of
plant sterols; and placebo treatment consisting of 25 g/d of control spread.
Combination treatment of plant sterols and ezetimibe reduced LDL-C by 25.2% or
1.06 mmol/L (p<0.001) as compared to 4.7% or 0.23 mmol/L (p=0.006) by plant
sterols and to 22.2% or 0.94 mmol/L (p<0.001) by ezetimibe monotherapy. LDL-C
reduction conferred by the combination treatment did not differ significantly from
ezetimibe monotherapy (-3.5% or -0.12 mmol/L; p=0.13). In addition, the ratio of the
cholesterol precursor lathosterol to cholesterol increased with all treatments. The
ratios of sitosterol and campesterol to cholesterol increased after plant sterol
treatment, and decreased upon ezetimibe and combination therapy. No differences
were observed for liver transaminases and creatine phosphokinase between
treatments. Our results demonstrate that the combination of plant sterols and
ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with
mild hypercholesterolemia.
‫בטיחות של אזטימיד וסטטינים יחד ולחוד‬
A multicenter, randomized, double-blind, placebo-controlled, factorial
design study to evaluate the lipid-altering efficacy and safety profile of
the ezetimibe/simvastatin tablet compared with ezetimibe and
simvastatin monotherapy in patients with primary
hypercholesterolemia.
Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson-Levonas
AO, Sapre A, Donahue SR; Ezetimibe Study Group.
Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue,
Louisville, KY 40213, USA. HBaysMD@aol.com
OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety
profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to
ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary
hypercholesterolemia. METHODS: This was a randomized, multicenter, doubleblind, placebo-controlled, factorial design study After a 6- to 8-week washout period
and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density
lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350
mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks:
EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10
mg; or placebo. The primary efficacy analysis was mean percent change from
baseline in LDL-C to study end point Secondary end points included percent changes
in other lipid variables and C-reactive protein [CRP]. RESULTS: There were 1528
patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from
54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment
groups were well balanced for baseline demographics. Pooled EZE/SIMVA was
associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P <
0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of
-44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and
TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to
9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like
particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving
EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs
45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile
similar to SIMVA monotherapy There were no significant differences between
EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels >
or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for
SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for
EZE/SIMVA and 02% for SIMVA; P = NS). CONCLUSION: The EZE/SIMVA
tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study
of patients with primary hypercholesterolemia.