Artigo Lipid-Lowering Agents

8/13/2019 Artigo Lipid-Lowering Agents

1/12

http://cpt.sagepub.com/Therapeutics

Journal of Cardiovascular Pharmacology and

http://cpt.sagepub.com/content/18/5/401Theonline version of this article can be foundat:

DOI: 10.1177/1074248413492906

2013 18: 401 originally published online 27 June 2013J CARDIOVASC PHARMACOL THERMfon Ewang-Emukowhate and Anthony S. Wierzbicki

Lipid-Lowering Agents

Published by:

http://www.sagepublications.com

can be found at:Journal of Cardiovascular Pharmacology and TherapeuticsAdditional services and information for

http://cpt.sagepub.com/cgi/alertsEmail Alerts:

http://cpt.sagepub.com/subscriptionsSubscriptions:

http://www.sagepub.com/journalsReprints.navReprints:

http://www.sagepub.com/journalsPermissions.navPermissions:

What is This?

- Jun 27, 2013OnlineFirst Version of Record

- Aug 12, 2013Version of Record>>

at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from at b-on: 01100 Universidade do Porto on September 27, 2013cpt.sagepub.comDownloaded from
http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/content/18/5/401http://cpt.sagepub.com/content/18/5/401http://cpt.sagepub.com/content/18/5/401http://www.sagepublications.com/http://cpt.sagepub.com/cgi/alertshttp://cpt.sagepub.com/cgi/alertshttp://cpt.sagepub.com/subscriptionshttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsPermissions.navhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://cpt.sagepub.com/content/early/2013/06/26/1074248413492906.full.pdfhttp://cpt.sagepub.com/content/18/5/401.full.pdfhttp://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://cpt.sagepub.com/http://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://cpt.sagepub.com/content/early/2013/06/26/1074248413492906.full.pdfhttp://cpt.sagepub.com/content/18/5/401.full.pdfhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsReprints.navhttp://cpt.sagepub.com/subscriptionshttp://cpt.sagepub.com/cgi/alertshttp://www.sagepublications.com/http://cpt.sagepub.com/content/18/5/401http://cpt.sagepub.com/


2/12

Cardiovascular Pharmacology Core Review

Lipid-Lowering Agents

Mfon Ewang-Emukowhate, MBBS, MRCP, Dip RCPath1

and Anthony S. Wierzbicki, DM, DPhil, FRCPath, FAHA1

Abstract

The role of lipid lowering in reducing the risk of mortality and morbidity from cardiovascular disease (CVD) is well established.Treatment particularly aimed at decreasing low-density lipoprotein cholesterol (LDL-C) is effective in reducing the risk of death

from coronary heart disease and stroke. Statins form the cornerstone of treatment. However, in some individuals with a high riskof CVD who are unable to achieve their target LDL-C due to either intolerance or lack of efficacy, there is the need for alternativetherapies. This review provides an overview of the different classes of currently available lipid-lowering medications includingstatins, fibrates, bile acid sequestrants (resins), and omega-3 fatty acids. Data are presented on their indications, pharmacology,and the relevant end point clinical trial data with these drugs. It also discusses the human trial data on some novel therapeutic

agents that are being developed including those for homozygous familial hypercholesterolemiathe antisense oligonucleotidemipomersen and the microsomal transfer protein inhibitor lomitapide. Data are presented on phase II and III trials on agents with

potentially wider applications, cholesterol ester transfer protein inhibitors and proprotein convertase subtilisin kexin 9 inhibitors.The data on a licensed gene therapy for lipoprotein lipase deficiency are also presented.

Keywords

cardiovascular disease, lipid lowering, dyslipidemia, statin, fibrate, bile acid sequestrant

Introduction

Dyslipidemia is one of the risk factors for progression of ather-

osclerotic disease which may account for up to 55% of the

cardiovascular disease (CVD) risk after correction for age and

gender.1 Epidemiological and prospective studies have estab-

lished the benefit of reducing low-density lipoprotein choles-

terol (LDL-C), with a 1% reduction associated with a 1%

decrease in CVD events.2 Alternatively, a 40 mg/dL (1

mmol/L) reduction in LDL-C is associated with a 21% reduc-

tion in major CVD events.3 In the Helsinki heart study, a 1%

increase in high-density lipoprotein cholesterol (HDL-C) is

linked with a 3% reduction in cardiovascular events.4 The

effects of high triglycerides (TGs), TG-rich lipoprotein rem-

nants, and very LDLs (VLDLs) are uncertain,5,6 but they are

also associated with increased CVD risk through the effects

on HDL and LDL particle sizes increasing the atherogenicity

of LDL.7,8

There are different guidelines with practical recommenda-

tions on the management of dyslipidemia. Lifestyle modifica-

tion that includes dietary changes, weight reduction, exercise,

decreased alcohol consumption, and smoking cessation is

important in the management of hyperlipidemia.2 However,

in certain patients who have a high risk of CVD, the addition

of drug therapy will be necessary to achieve beneficial effects.

Lipid-lowering agents in current use are generally effective,

but some are limited by their side effects. Statins are the first

choice lipid-lowering drugs given their almost universal

efficacy for CVD.3 However, only 50% of the high-risk

patients attain LDL-C targets with statins,9 and the role of addi-

tional lipid-lowering therapies remains unclear.10 Hence, there

is a need for development of new therapeutic agents aimed atthose who cannot achieve current targets or who are intolerant

to most or all of the existing therapies.

Currently Available Lipid-Lowering

Therapies

Statins

Statins inhibit 2-hydroxyl-methyl-glutaryl coenzyme A (HMG-

CoA) reductase, the rate-limiting step in cholesterol synth-

esis.11,12 This leads to a reduced intracellular cholesterol

concentration and subsequent upregulation of LDL receptors

that encourages the removal of LDL-C from the circulation.

Mevastatin, the first statin produced, was a fungal

1 Department of Chemical Pathology, Guys & St Thomas Hospitals, St Thomas

Hospital Campus, London, England

Manuscript submitted: April 19, 2013; accepted:May 14, 2013.

Corresponding Author:

Mfon Ewang-Emukowhate, Department of Chemical Pathology, Guys & St

Thomas Hospitals, St Thomas Hospital, Lambeth Palace Road, London SE1

7EH, England.

Email: [email protected]

Journal of Cardiovascular

Pharmacology and Therapeutics

18(5) 401-411

The Author(s) 2013

Reprints and permission:

sagepub.com/journalsPermissions.nav

DOI: 10.1177/1074248413492906

cpt.sagepub.com
http://www.sagepub.com/journalsPermissions.navhttp://cpt.sagepub.com/http://cpt.sagepub.com/http://www.sagepub.com/journalsPermissions.nav


3/12


4/12


5/12


6/12


7/12


8/12

Table3.(continued)

Drug

Dosage

Indication

Contraindication

andCaution

AdverseEffects

DrugInteractions

orasmonotherapyif

statinintolerance

av

oidinpregnancyand

br

eastfeeding,insevereliver

disease;caution:acute

co

ronarysyndrome,diabetes

m

ellitus,gout,historyofpeptic

ulcer,renalimpairment,

discontinueifsevere

ab

normalitiesinliverfunction

te

st

pruritus,rash.

Lesscommon

palpitations,headache,

dizziness,hypotension,

syncope,reducedglucose

toler

ance,andmyalgia

O

mega-3-fattyacidcompounds

Omega-3acid

ethylesters

1gtoamaximumof

4gdependingon

preparation

Inhypertriglyceridemia,in

combinationwitha

statininmixed

hyperlipidemiaor

secondaryprevention

notadequately

controlledwithstatin

Con

traindication:avoidin

pr

egnancy,noclear

information;caution:

he

morrhagicdisorders,

an

ticoagulanttreatment

Gastro

intestinaldisturbances,

lessc

ommon,tastedisorder,

hype

rsensitivityreactions,

head

ache,hyperglycemia,

hepa

ticdisorders

Omega-3-marine

TGs

1gtoamaximumof

5gcapsules,5to

10mlofliquid

formulation

dependingon

preparation

Inhypertriglyceridemia,in

combinationwithstatin

insevere

hypertriglyceridemia

Con

traindication:avoidin

pr

egnancy,noclear

information;caution:

he

morrhagicdisorders,

an

ticoagulanttreatment,

as

pirinsensitiveasthma,type2

diabetes

Occasionalnauseaand

belching

407


9/12

Bile Acid Sequestrants

Cholesterol is secreted into the gut through the biliary system

and directly through the action of perilipin in enterocytes in the

ileum.28 Bile acid sequestrants decrease LDL-C by binding to

bile acids in the gut and preventing their reabsorption leading

to decreased enterohepatic concentration of bile acids and cho-

lesterol. The decreased level of bile acids stimulates upregula-

tion of hepatic LDL receptors leading to increased LDL-C

clearance from the circulation. They increase HDL-C by 3%

to 5% and increase TG levels by stimulating hepatic VLDL

production through its action on the liver-X receptor.29 Bile

acid sequestrants also reduce blood glucose through their effect

on the farnesoid-X receptor. Cholestyramine, colestipol, and

colesevelam are currently available therapies, and colesevelam

has been shown to decrease hemoglobin A1cby 0.4% to 0.6%

and is thus also licensed for glycemic control.30 Colesevelam

decreases LDL-C by about 16% to 19%, and combination with

statins produces a greater than 40% decrease.29 Some end point

evidence exists for the use of bile acid sequestrants. In the Lipid

Research Clinics trial, cholestyramine decreased CVD events

by 25% (Table 2).31 The use of these agents is limited by their

frequent gastrointestinal side effects. They interfere with the

absorption of micronutrients such as vitamin A, D, E, K, iron,

folic acid, and magnesium. They also reduce the absorption of

medications such as warfarin and to a lesser extent thiazide

diuretics and digoxin.30

Niacin/Nicotinic Acid

Niacin or vitamin B3 is the oldest lipid-lowering therapy. Itsmode of action is still not entirely clear, but it has favorable

effects on all aspects of an abnormal lipid profile.32,33 It

decreases VLDL and TG synthesis in the liver by inhibiting

diacylglycerol O-acyltransferase 2 (DGAT-2) and hormone-

sensitive lipase activity.33 The LDL-C is decreased by

increased catabolism of apolipoprotein B (apo B) and TG lev-

els are decreased by niacin, leading to increased LDL particle

size and decreased LDL particle number. Niacin increases

HDL-C by promoting production of apolipoprotein A-1 and

reducing its clearance through the ATP synthaseb-chain holo-

particle receptor. Niacin monotherapy reduced the CVD risk by

22% in the Coronary Drug Project (Table 2).34 It, unlike ezeti-

mibe, also leads to significant regression of carotid intima

media thickness when combined with statin therapy as

demonstrated by the Arterial Biology for the Investigation of

the Treatment Effects of Reducing Cholesterol 6-HDL and

LDL Treatment Strategies in Atherosclerosis (ARBITER 6-

HALTS) trial.35 The use of niacin is limited by flushing due

to increased prostaglandin D2 synthesis. Niacin treatment is

also associated with increased rates of new diabetes and dete-

rioration in glycemic control.36,37 End point studies of niacin

combined with statins have been disappointing. In the Athero-

thrombosis Intervention in Metabolic Syndrome with Low

HDL/High Triglycerides: Impact on Global Health Outcomes

(AIM-HIGH) study, patients with established high CVD risk

and dyslipidemia where secondary optimization of LDL-C was

allowed, extended release (ER) of niacin did not reduce CVD

events.38 The Heart Protection Study-2/Treatment of HDL to

Reduce the Incidence of Vascular Events (HPS-2/THRIVE)

study investigated the effect of the combination of niacin and

laropiprant (Tredaptive) with a statin on CVD events in

patients at high risk of CVD after initial optimization ofLDL-C levels.10,37 Niacinlaropiprant failed to show any sig-

nificant reduction in CVD events but showed an increased inci-

dence of nonfatal side effects, and it has since been withdrawn.

Ezetimibe

Ezetimibe inhibits cholesterol absorption through inhibition of

the duodenal Niemann-Pick C1-like protein.39 In combination

with statin therapy, it decreases LDL-C although its effect in

reducing cardiovascular events is controversial. Studies of add-

ing ezetimibe to statins in familial hypercholesterolemia (FH)

such as ezetimibe and Simvastatin in HypercholesterolaemiaEnhances Artherosclerosis Regression (ENHANCE) of carotid

intima-media thickness40 and of combination therapy on CVD

events in the underpowered Simvastatin and Ezetimibe in

Aortic Stenosis (SEAS)41 have not shown any beneficial effect.

Recently, in the Study of Heart And Renal Protection (SHARP)

combination therapy with statin reduced CVD events by 27%

in patients with advanced renal failure.42 Some small studies

have suggested ezetimibe may improve hepatic steatosis.39

Ezetimibe is generally well tolerated but can cause nausea or

bloating. The outcome data on the effect of ezetimibe and sim-

vastatin combination therapy in reducing the risk of CVD in

patients with acute coronary syndrome in the IMProved Reduc-tion of Outcomes: Vytorin Efficacy International Trial

(IMPROVE-IT) study are still awaited.10

Omega-3 Fatty Acids

Omega-3 fatty acids that include docosahexaenoic acid and

eicosapentaenoic acid (EPA) have been shown to decrease

CVD events in monotherapy in patients with CVD or at high

risk of developing CVD.43,44 However, individual studies

examining the CVD effect of omega-3 fatty acids have shown

conflicting results with early studies being positive and later

studies negative. Meta-analyses of omega-3 fatty acids added

to optimal statin therapy suggest they give no added

benefit.45 Their mechanism of action is complex and not fully

understood, but it may involve the regulation of genes involved

in lipid metabolism. They are known to reduce TGs in a dose-

dependent manner. In the Multi-center plAcebo-controlled

Randomised double-blINd 12-week study with an open label

extension (MARINE; AMR-101; Amarin Pharmaceuticals,

Dublin, Eire), an EPA preparation has been shown in patients

with high TGs (>750 mg/dL; 8.5 mmol/L) to reduce TGs by

33% to 45%.46 The suggested mechanism for TG reduction

includes suppression of lipogenesis, decreased TG synthesis

through inhibition of DGAT-2 and increased beta-oxidation

in the mitochondria.44 They are well tolerated with mild

408 Journal of Cardiovascular Pharmacology and Therapeutics 18(5)


10/12

gastrointestinal disturbance being the most commonly reported

adverse symptom.46

New Therapies for Dyslipidemia

Statins remain the cornerstone of drug-based lipid managementallied with lifestyle changes such as dietary modification,

weight reduction, and exercise. However, if the desired level

of LDL-C is not achieved with statins even after titration to the

highest tolerable dose, then other treatment options may need

to be considered. A considerable number of new therapies for

dyslipidemia are in development (Table 4).47,48 New lipid-

lowering therapies can be classified based on their role, either

as LDL-C reducing agents or as drugs that target other lipids

such as HDL-C or TGs.

LDL-cholesterol-Lowering Therapies

Patients with heterozygous FH respond to statin and ezetimibe

therapy, but statins show reduced or absent efficacy in patients

with homozygous FH who do not have functioning LDL recep-

tors. Novel treatments to reduce LDL-C include drugs with a

primary license indication for orphan disorders such as homo-

zygous FH and drugs that interfere with the production of

VLDL and hence LDL either through disruption of apoB synth-

esis or through interference with transfer factors involved in

loading lipids onto the nascent particle. Mipomersen is an anti-

sense oligonucleotide to apoB which reduces LDL-C by 25% in

homozygous FH but is limited by injection site reactions and

hepatic steatosis.49 Lomitapide is a microsomal transfer protein

inhibitor50 which reduces LDL-C by 50% but causes hepatic

steatosis.51 The side effects of these drugs restrict them at the

moment to orphan indications.

Other novel agents reduce LDL-C by inhibiting pro-protein

convertase subtilisin kexin 9 (PCSK-9), a plasma and hepato-

cellular protein that controls LDL receptor expression.52 Anti-

bodies to PCSK-9 deliver up to 70% reduction in LDL-C whenadded to other therapies or in statin-intolerant patients and may

have a large potential application in patients with CVD. Large-

scale CVD end point trials of adding these agents to optimal

LDL-C-lowering strategies are just beginning.

HDL-C Raising Drugs

Statins do not address all lipid-related CVD risk. Epidemiolo-

gical studies show that higher HDL-C is associated with a bet-

ter prognosis even after statin treatment. Some of this residual

risk is ascribed to HDL.7,53 The newest agents that raise HDL-

C are cholesterol ester transfer protein (CETP) inhibitors.

48

These can raise HDL-C by 30% to 100% and reduce LDL-C

by 0% to 40%. The original compound in the class torcetrapib

was highly effective in improving lipid profiles but increased

CVD events by 30%, possibly by raising blood pressure.54 Dal-

cetrapib raised HDL-C by 30%but had no effect on LDL-C and

in reducing CVD events.55 Two other CETP inhibitors

anacetrapib and evacetrapibthat raise HDL-C and also

reduce LDL-C by 40% remain in development.

Gene Therapy for Lipid Disorders

Initial attempts at gene therapy for homozygous FH were

unsuccessful. More recently, the development of adeno-

Table 4. Summary of Major Trials on Novel Cholesterol-Lowering Therapies.

DrugStudyType Participants

Dose and Routeof Administration

Effects on Lipid Profile (%)

Adverse EffectsT CHOL LDL-C HDL-C TG

ApoB 100 inhibitorsMipomersen Phase III 51 (M 22,

F 29)

200 mg

weekly, SC

21 25 2 17 Injection site reactions, raised

ALT 3ULN in 4 patientsPCSK-9 inhibitors

AMG 145 Phase II 157 (M 57,F 100)

280-420 mg, SC (30-44) (41-63) (6-7) Myalgia. Otherwisewell-tolerated

SAR236553/REGN727 Phase II 183 (M 87,F 96)

50-300 mg, SC (23-45) (40-72) (4-9) (6-19) Mild injection site reactions,1 case of leukocytoclasticvasculitis

MTP inhibitorsLomitapide Phase III 29 (M 16,

F 13)5-60 mg, PO 46 50 12 45 Raised ALT 3 ULN in 10

patients,increased hepatic fatCETP inhibitors

Anacetrapib Phase II 1 623 (M 1247,F 376)

100 mg, PO 44 146 7 Compared to placebo nochange in BP, electrolytesor aldosterone

Evacetrapib Phase II 156 (M 76,F 86 30-500 mg, PO (14-36) (54-129) (3-11) Well tolerated, no rise in BP,or changes inglucocorticoid ormineralocorticoid activity

Abbreviation: ALT, alanine transaminases; AMG, alpha 2-macroglobulin; ApoB, apolipoprotein B; BP, blood pressure; CETP, cholesterol ester transfer protein;F, female; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; M, male; MTP, microsomal transfer protein; PCSK-9,pro-protein convertase subtilisin kexin 9; PO, perioral; SC, subcutaneous; T CHOL, total cholesterol; TG, triglyceride; ULN, upper limit of the normal range.

Ewang-Emukowhate and Wierzbicki 409


11/12

associated viral vectors has led to the development of a gene

therapy for lipoprotein lipase deficiency (LPLD).56 The LPLD

is associated with severe hypertriglyceridemia and pancreatitis,

and there is no treatment for homozygotes apart from a highly

fat-restricted diet. Treatment with alipogene tiparvovec transi-

ently reduces TGs in patients with LPLD but does reduce the

frequency of pancreatitis by 80%.

Conclusion

Many therapies that reduce LDL-C have been proven to reduce

CVD risk in monotherapy. Statins remain as first-line treat-

ment, and they are safe. Combination therapy with other cur-

rently used lipid-lowering drugs such as niacin and ezetimibe

has not shown beneficial effects in CVD risk reduction. Despite

the efficacy of statins in LDL-C lowering there still remains a

residual risk of CVD, and it is important that this is addressed.

Newer therapies are being developed to further reduce LDL-C.

Some have been disappointing with respect to their safety and

tolerability profiles. The PCSK-9 inhibitors and CETP inhibi-

tors anacetrapib and evacetrapib appear promising. These

newer agents can be used as alternatives to statins in patients

who are statin intolerant, or they can be used in combination

therapy to help achieve LDL-C targets, especially in high-

risk individuals thereby reducing the risk of CVD. As noted

with torcetrapib, LDL-C lowering is not always associated with

CVD risk reduction. Therefore, these new lipid-lowering thera-

pies should provide evidence of improved CVD outcome.

Safety and efficacy data in large clinical trials will ascertain the

benefits of these agents.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

References

1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifi-

able risk factors associated with myocardial infarction in 52 coun-

tries (the INTERHEART study): case-control study. Lancet.

2004;364(9438):937-952.

2. Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. Executive Summary of the Third

Report of the National Cholesterol Education Program (NCEP)

Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA.

2001;285(19):2486-2497.

3. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of

more intensive lowering of LDL cholesterol: a meta-analysis of

data from 170,000 participants in 26 randomised trials. Lancet.

2010;376(9753):1670-1681.

4. Sacks FM. The role of high-density lipoprotein (HDL) cholesterol

in the prevention and treatment of coronary heart disease: expert

group recommendations. Am J Cardiol. 2002;90(2):139-1343.

5. Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride-mediated

pathways and coronary disease: collaborative analysis of 101

studies.Lancet. 2010;375(9726):1634-1639.

6. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apoli-poproteins, and risk of vascular disease. JAMA. 2009;302(18):

1993-2000.

7. Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich

lipoproteins and high-density lipoprotein cholesterol in patients at

high risk of cardiovascular disease: evidence and guidance for

management.Eur Heart J. 2011;32(11):1345-1361.

8. Mikhailidis DP, Elisaf M, Rizzo M, et al. European panel on low

density lipoprotein (LDL) subclasses: a statement on the patho-

physiology, atherogenicity and clinical significance of LDL sub-

classes.Curr Vasc Pharmacol. 2011;9(5):533-571.

9. Santos RD, Waters DD, Tarasenko L, et al. A comparison of non-

HDL and LDL cholesterol goal attainment in a large, multina-tional patient population: the Lipid Treatment Assessment Project

2.Atherosclerosis. 2012;224(1):150-153.

10. Wierzbicki AS. All at sea: new lipid-lowering drug trials continue

to disappoint. Int J Clin Pract. In press.

11. Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects

of statins. Pharmacol Ther. 2003;99(1):95-112.

12. Steinberg D. Thematic review series: the pathogenesis of athero-

sclerosis. An interpretive history of the cholesterol controversy,

part V: the discovery of the statins and the end of the controversy.

J Lipid Res.2006;47(7):1339-1351.

13. Jones PH, Davidson MH, Stein EA, et al. Comparison of the effi-

cacy and safety of rosuvastatin versus atorvastatin, simvastatin,

and pravastatin across doses (STELLAR* Trial). Am J Cardiol.

2003;92(2):152-160.

14. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose

efficacy study of atorvastatin versus simvastatin, pravastatin,

lovastatin, and fluvastatin in patients with hypercholesterolemia

(the CURVES study).Am J Cardiol. 1998;81(5):582-587.

15. Betteridge J. Pitavastatinresults from phase III & IV. Atheros-

cler Suppl. 2010;11(3):8-14.

16. Law MR, Wald NJ, Thompson SG. By how much and how

quickly does reduction in serum cholesterol concentration lower

risk of ischaemic heart disease?BMJ. 1994;308(6925):367-372.

17. Stein EA, Lane M, Laskarzewski P. Comparison of statins in

hypertriglyceridemia.Am J Cardiol. 1998;81(4A):66B-69B.

18. Armitage J. The safety of statins in clinical practice.Lancet. 2007;

370(9601):1781-1790.

19. Joy TR, Hegele RA. Narrative review: statin-related myopathy.

Ann Intern Med. 2009;150(12):858-868.

20. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident

diabetes: a collaborative meta-analysis of randomised statin trials.

Lancet. 2010;375(9716):735-742.

21. Lalloyer F, Staels B. Fibrates, glitazones, and peroxisome

proliferator-activated receptors. Arterioscler Thromb Vasc Biol.

2010;30(5):894-899.

22. Wierzbicki AS. FIELDS of dreams, fields of tears: a perspective

on the fibrate trials. Int J Clin Pract. 2006;60(4):442-449.

410 Journal of Cardiovascular Pharmacology and Therapeutics 18(5)


12/12

23. Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of

fibrates in the prevention of cardiovascular diseasea pooled

meta-analysis of long-term randomized placebo-controlled clini-

cal trials. Am Heart J. 2007;154(5):943-953.

24. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular

outcomes: a systematic review and meta-analysis. Lancet. 2010;

375(9729):1875-1884.25. Idzior-Walus B, Sieradzki J, Rostworowski W, et al. Effects of

comicronised fenofibrate on lipid and insulin sensitivity in

patients with polymetabolic syndrome X. Eur J Clin Invest.

2000;30(10):871-878.

26. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination

lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;

362(17):1563-1574.

27. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination

statin-fibrate therapy: safety aspects. Diabetes Obes Metab.

2009;11(2):89-94.

28. Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis.

Physiol Rev. 2012;92(3):1061-1085.29. Manghat P, Wierzbicki AS. Colesevelama specifically engi-

neered bile acid sequestrant.Future Lipidol. 2008;3(3):237-255.

30. Jialal I, Abby SL, Misir S, Nagendran S. Concomitant reduction

in low-density lipoprotein cholesterol and glycated hemoglobin

with colesevelam hydrochloride in patients with type 2 diabetes:

a pooled analysis. Metab Syndr Relat Disord. 2009;7(3):

255-258.

31. The Lipid Research Clinics (LRC) Coronary Primary Prevention

Trial Investigators. The Lipid Research Clinics Coronary Primary

Prevention Trial results. I. Reduction in incidence of coronary

heart disease. JAMA. 1984;251(3):351-364.

32. Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th

anniversary review. J Intern Med. 2005;258(2):94-114.

33. Wierzbicki AS. Niacin: the only vitamin that reduces cardiovas-

cular events. Int J Clin Pract. 2011;65(4):379-385.

34. The Coronary Drug Project Research Group. Clofibrate and nia-

cin in coronary heart disease.JAMA. 1975;231(4):360-381.

35. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin

or ezetimibe and carotid intima-media thickness. N Engl J Med.

2009;361(22):2113-2122.

36. Sazonov V, Maccubbin D, McCrary Sisk C, Canner PL. Effects of

niacin on the incidence of new onset diabetes and cardiovascular

events in patients with normoglycemia and impaired fasting glu-

cose.Int J Clin Pract. 2013;67(4): 297-302.

37. Micheal ORiordan If not dead, not healthy: Niacin full results

in HPS2-THRIVE aired at ACC; 2013. http://www.theheart.org/

article/1515533.do. Accessed March 11, 2013.

38. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients

with low HDL cholesterol levels receiving intensive statin ther-

apy.N Engl J Med. 2011;365(24):2255-2267.

39. Wierzbicki AS. The ezetimibe Jonah: the trials and tribulations of

an unlucky drug. Int J Clin Pract. 2011;65(12):1207-1208.

40. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or with-

out ezetimibe in familial hypercholesterolemia. N Engl J Med.

2008;358(14):1431-1443.

41. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lower-

ing with simvastatin and ezetimibe in aortic stenosis. N Engl J

Med. 2008;359(13):1343-1356.

42. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL

cholesterol with simvastatin plus ezetimibe in patients with chronic

kidney disease (Study of Heart and Renal Protection): a randomised

placebo-controlled trial.Lancet. 2011;377(9784):2181-2192.43. Wierzbicki AS. A fishy business: omega-3 fatty acids and cardi-

ovascular disease.Int J Clin Pract. 2008;62(8):1142-1146.

44. Harris WS, Miller M, Tighe AP, Davidson MH, Schaefer EJ.

Omega-3 fatty acids and coronary heart disease risk: clinical and

mechanistic perspectives. Atherosclerosis. 2008;197(1):12-24.

45. Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3

fatty acid supplements (eicosapentaenoic acid and docosahexae-

noic acid) in the secondary prevention of cardiovascular disease:

a meta-analysis of randomized, double-blind, placebo-controlled

trials. Arch Intern Med. 2012;172(9):686-694.

46. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman

RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) ther-apy in patients with very high triglyceride levels (from the Multi-

center, plAcebo-controlled, Randomized, double-blINd, 12-week

study with an open-label Extension MARINE. trial). Am J Car-

diol. 2011;108(5):682-690.

47. Wierzbicki AS. Lipid-altering agents: the future.Int J Clin Pract.

2004;58(11):1063-1072.

48. Wierzbicki AS, Hardman TC, Viljoen A. New lipid-lowering

drugs: an update. Int J Clin Pract. 2012;66(3):270-280.

49. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipopro-

tein B synthesis inhibitor, for lowering of LDL cholesterol

concentrations in patients with homozygous familial hypercholes-

terolaemia: a randomised, double-blind, placebo-controlled trial.

Lancet. 2010;375(9719):998-1006.

50. Wierzbicki AS, Hardman T, Prince WT. Future challenges for

microsomal transport protein inhibitors.Curr Vasc Pharmacol.

2009;7(3):277-286.

51. Cuchel M, Meagher EA, du Toit Theron H, et al.Efficacy and safety

of a microsomal triglyceride transfer protein inhibitor in patients

with homozygous familial hypercholesterolaemia: a single-arm,

open-label, phase 3 study.Lancet. 2013;381(9860):40-46.

52. Wierzbicki AS, Hardman TC, Viljoen A. Inhibition of pro-protein

convertase subtilisin kexin 9 (PCSK9) as a treatment for hyperli-

pidaemia. Expert Opin Investig Drugs. 2012;21(5):667-676.

53. FruchartJC, Sacks F, HermansMP, et al.The residual risk reduction

initiative: a call to action to reduce residual vascular risk in patients

with dyslipidemia.Am J Cardiol. 2008;102(10 suppl):1K-34K.

54. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in

patients at high risk for coronary events. N Engl J Med. 2007;

357(21):2109-2122.

55. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in

patients with a recent acute coronary syndrome.N Engl J Med.

2012;367(22):2089-2099.

56. Wierzbicki AS, Viljoen A. Alipogene tiparvovec: gene therapy

for lipoprotein lipase deficiency. Expert Opin Biol Ther. 2013;

13(1):7-10.

Ewang-Emukowhate and Wierzbicki 411
http://www.theheart.org/article/1515533.dohttp://www.theheart.org/article/1515533.dohttp://www.theheart.org/article/1515533.dohttp://www.theheart.org/article/1515533.do

Date post:	04-Jun-2018
Category:	Documents
Upload:	jorge-daniel
View:	222 times
Download:	0 times

Artigo Lipid-Lowering Agents

Documents