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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
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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
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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
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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)
8/13/2019 Artigo Lipid-Lowering Agents
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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
8/13/2019 Artigo Lipid-Lowering Agents
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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.
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