lipid-altering agents: the future

Lipid-altering agents: the future

A.S. WIERZBICKI

St. Thomas’ Hospital Campus, Lambeth Palace Road, London, UK

SUMMARY

Lipid-lowering is established as proven intervention to

reduce atherosclerosis and its complications. This article

summarises novel developments in the lipid-altering thera-

pies under development. It also discusses other therapeutic

targets, such as squalene synthase, microsomal transfer

protein, acyl-cholesterol acyl transferase, cholesterol ester

transfer protein, peroxosimal proliferator-activating recep-

tors and lipoprotein (a), for which compounds have been

developed and have at least reached trials in animal models.

Lipid-altering drugs are likely to prove a fast-developing

area for novel treatments, as possible synergies exist

between new and established compounds for the treatment

of atherosclerosis.

Keywords: Cholesterol; risk factor; HDL; LDL; therapy;

treatment

� 2004 Blackwell Publishing Ltd

INTRODUCT ION

The progression of atherosclerosis, which is responsible for cor-

onary heart disease, stroke, carotid and femoral artery stenosis

(peripheral vascular disease), is associated with multiple cardio-

vascular risk factors including hyperlipidaemia. The interaction

of risk factors is complex (Figure 1) and synergistic. While the

role of low-density lipoprotein cholesterol (LDL-C) is well

established in both epidemiological and interventional studies,

the case for raising high-density lipoprotein cholesterol (HDL-

C) is strong with some evidence for the benefit with HDL-

raising therapies in selected groups. Studies show a consistent

relationship of 1% reduction in LDL-C with 1% reduction in

cardiovascular events (1). This concept has been slightly

extended to include data suggesting that a 1% increase in

HDL-C is associated with a 3% reduction in cardiovascular

events. Relationships for other risk factors including triglycerides,

triglyceride-rich remnants or lipoprotein (a) are less clear.

VARIANTS OF EXIST ING DRUG TREATMENTS

Statins are effective and safe drugs that reduce LDL with

parallel reductions in triglyceride and a modest rise in HDL

(2). Their main disadvantage is that dose titration by

doubling only results in a 5–7% extra reduction in LDL but

at the expense of increasing side-effects. Unusual effects that

are seen only at the highest doses include an interaction of

simvastatin with amiodarone, reductions in HDL and apoli-

poprotein A1 and HDL with atorvastatin and proteinuria

with rosuvastatin. Thus, a practical limit of 50–60% LDL

reduction exists for these drugs. Evidence for the use of statins

in both secondary and primary prevention of coronary heart

disease is overwhelming (3,4) (Table 1). Fibrates lower trigly-

cerides and raise HDL-C (5,6). There is evidence that fibrates

reduce cardiovascular events in patients with low HDL and

elevated triglycerides, but effects observed in trials in patients

with raised LDL are generally negative. However, not all

patients tolerate the currently available drugs with side effects,

requiring discontinuation of therapy which is being seen in

about 5% of patients in clinical practice receiving statins or

fibrates and 30% in the case of bile acid sequestrants. Also,

while treatment with currently available statins achieves the

LDL target of 3 mmol/l in about 90% of cases at maximum

dose, evidence from the Post-Coronary Artery Bypass Graft

Study (7) reinforced by the recently published Heart Protec-

tion Study (8) suggests that LDL targets will need to be reset

to lower values of around 2 mmol/l. Thus, new lipid-lowering

agents are required to address the issues of increased efficacy,

other risk factors and improved tolerability (Table 1).

NOVEL L IP ID-ALTER ING COMPOUNDS

There are many compounds in development and these can be

divided into groups based on their principal mechanism of

action (Table 2).

THERAP IES TO REDUCE LDL-CHOLESTEROL

New Statins

There are five currently available agents with simvastatin

and atorvastatin, the most potent which all inhibit

Correspondence to:Dr A. S. Wierzbicki, Department of Chemical Pathology,

St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK

Tel.: 144-020-7188-1256

Fax: 144-020-7928-4226

Email: [email protected]

ª 2004 Blackwell Publishing Ltd Int J Clin Pract, November 2004, 58, 11, 1063–1072

REVIEW d o i : 1 0 . 1 1 1 1 / j . 1 3 6 8 - 5 0 3 1 . 2 0 0 4 . 0 0 0 8 7 . x

hydroxy-methyl-glutaryl CoA reductase. Rosuvastatin is a long

half-life (19 h) statin that has been shown to reduce LDL by

57% at 40 mg, with a reasonable safety profile in initial

studies (9–11). Rosuvastatin does not cause the degree of

myalgia and side effects that was observed in trials of

simvastatin at 120 mg despite achieving a superior LDL

reduction (12). One curious side effect of rosuvastatin that

has yet to be fully explored is a transient tubular proteinuria

that was noted in patients with normal renal function,

and this may represent an inhibition of the renal proximal

convoluted tubule cell isoprenoid-regulated (i.e. cholesterol

synthetic pathway dependent) proteins which are involved in

endocytosis. There are less data on (P)itavastatin (13).

CHOLESTEROL SYNTHES IS PATHWAY

INHIB ITORS

While early and the final stages of cholesterol synthesis occur

in peroxisomes, one of the limiting stages of cholesterol

synthesis occurs in the endoplasmic reticulum and is catalysed

by squalene synthase (Figure 2). Inhibition of squalene

synthase is likely to lead to a reduction in cholesterol synthesis

without affecting synthesis of compounds derived from

geranyl pyrophosphate including dolichols and ubiquinone

(coenzyme Q10) or affect the control of protein function

through farnesylation (14,15). As the mechanism of myalgia

associated with statin therapy may be associated with deple-

tion of mitochondrial ubiquinone levels (16), squalene

synthase inhibitors offer the possibility of reducing cholesterol

without causing unpredictable effects on protein regulation or

myalgia (17). Initial studies with zaragozic acid produced

reductions in LDL up to 70–80% at minimal doses (18).

Unfortunately, such a degree of cholesterol synthesis inhib-

ition caused functional abetalipoproteinaemia and resulted in

retinopathy, ataxia and polyneuropathy through secondary

deficiencies in the fat-soluble vitamins A and E (18). Newer

compounds in the field have lesser effects on cholesterol

synthesis, resulting in a 20% reduction in LDL and do not

seem to cause abetalipoproteinaemia in cell culture, animal and

human studies (17,19,20). They remain under investigation as

possible additive agents for statin therapy or as monotherapy.

Clotting

(Unsaturated FAs) PAI-1 PDGF (Apoptosis)

PAF-H Lp (a) Factor VII

TAGs Fibrinogen

Lipids LDL Atheroma Clonal

(HDL) OxLDL CRP ICAMs;selectins proliferation

(Vit E, C) apoE IL-6 IL-2

Oxidation Angiotensin II

Inflammation

vWF

Hcy

(TGF-β)

NFκ-B, p21ras IL-1

Figure 1 A schematic placing of biochemical risk factors and

protective factors and their interactions in causing or protecting against

atheroma. PAI-1, plasminogen activator inhibitor-1; PDGF, platelet-

derived growth factor; Lp (a), lipoprotein (a); TAGs, triglycerides;

oxLDL, oxidised LDL-cholesterol; CRP, C-reactive protein; ICAMs,

intercellular adhesion molecules; Hcy, homocysteine; Il, interleukin;

vWF, von Willebrand factor; NFk-B, nuclear factor-kappa-B; PAF-H,

platelet-activating factor hydrolase; p21ras, ras oncogene product;

TGF-b, transforming growth factor-beta

Table 1 Summary of major end-point trials

Number Starting (mmol/l) Reduction (%) Events

Primary Treatment Men Women LDL TG LDL TG PTCA/CABG MI Death

LRC Colestyramine 10627 – 5.3 1.70 8 13 – 25 20

WHO Clofibrate 3806 – �5 – 9 – – 19 19

HHS Gemfibrozil 4081 – 5.37 2.01 11 35 – 34 37

VA-HIT Gemfibrozil 2531 – 2.90 1.81 0 25 9 22 22

4S Simvastatin 3617 827 4.87 1.51 35 10 37 34 42

CARE Pravastatin 3583 576 3.60 1.00 28 14 27 27 24

LIPID Pravastatin 7498 1516 3.89 1.56 25 11 20 29 22

WOSCOPS Pravastatin 6595 – 5.00 1.70 26 12 37 31 32

AF/TexCAPS Lovastatin 5608 997 3.89 1.78 25 15 33 40 N/A

Post-CABG Lovastatin6 colestyramine 1243 108 3.98 1.76 14/38 – 29 12.5 10

HPS Simvastatin 15454 5082 3.5 2.0 31 23 24 26 13

GREACE Atorvastatin 1256 344 4.65 2.08 46 31 51 59(non–fatal) 43

ASCOT Atorvastatin 8437 1956 3.40 1.70 35 17 21 29 13

NB Lovastatin is not licensed in the UK. LRC, Lipid research clinics primary prevention trial (35, 74); WHO, WHO clofibrate study (75); HHS, Helsinki heart

study (76); VA-HIT, veterans affairs HDL-intervention trial (77); 4S, Scandinavian simvastatin survival study (78); CARE, cholesterol and recurrent events (79);

LIPID, long-term intervention with pravastatin in ischaemic disease (80); WOSCOPS, West of Scotland coronary prevention study (81); AF/TexCAPS, Air force

texas coronary atherosclerosis prevention study (82); Post-CABG, Post-coronary artery bypass graft study (2 · 2 design with coumarin) (83); HPS, Heart

protection study (2· 2 design with anti-oxidants) (8); GREACE, The Greek atorvastatin and coronary-heart disease evaluation (84); ASCOT, AngloScandi-

navian coronary outcomes study (85). Conversion factors mmol/l!md/dl cholesterol· 38.61; triglycerides· 88.5.

1064 NEW AGENTS FOR LIPIDS


A number of other compounds probably act through inhib-

ition at the stage of isoprenoid formation during cholesterol

synthesis. Imidazoles including drugs such as metronidazole

lower LDL by 10–20%, but little work has been performed

on derivatives to elucidate whether they would be useful

additions to statin therapy (21).

INHIB ITORS OF CHOLESTEROL PART ICLE

SYNTHES IS

Assembly of apolipoprotein-B containing lipoproteins is

dependent on a cholesterol sensor (the sterol regulatory

element-activating protein, SCAP) (Figure 3) in the endo-

plasmic reticulum, which regulates apoB gene expression

through cleavage and liberation of sterol regulatory element-

binding protein 2 (SREBP-2). This complex pathway offers

many opportunities for inhibition of particle assembly or for

increasing degradation.

ACYL -CHOLESTEROL ACYL TRANSFERASE

INHIB ITORS

One of the critical steps in atherosclerosis and in cholesterol

uptake is the esterification of cholesterol. In macrophages, this

process promotes foam cell formation, and while in hepato-

cytes or enterocytes, it is required for lipoprotein synthesis

(22). The esterification reaction is catalysed by acyl-

cholesterol acyl transferase (ACAT), which exists in two

forms, one of which is universally expressed (ACAT-1) and

another which is expressed mostly in the liver and intestine

(ACAT-2) (23). ACAT inhibitors include azasimibe which

has been shown to reduce foam-cell formation and to reduce

atherosclerotic lesion size in hypercholesterolaemic rabbit

models but to have little effect on plasma lipid profiles

(24,25). They are additive to statins in reducing lesion

formation in rabbits (26). Avasimibe has reached phase 3

clinical trials in humans (27–29).

Statins increase hepatic LDL receptor expression, and

hence, enhance plasma clearance of LDL. There are also

some data to suggest that they have an effect on reducing

the synthesis of very low-density lipoprotein (VLDL) through

reducing the size of the cholesterol subcompartment in endo-

plasmic reticulum necessary for stabilising apolipoprotein

B100. The direct link between this putative pool and the

endoplasmic reticulum is provided by microsomal transfer

protein (MTP) (30). Specific inhibitors of MTP have been

developed and reached phase 1 clinical trials. Though they

have been shown to deliver LDL reductions of 70–80% with

a reduction in triglycerides of 30–40%, no compound as yet

Table 2 Novel lipid-modulating compounds in development

Compound Class Company Phase

(P)itavastatin Statin Nissan/Novartis 3

Rosuvastatin Statin Astra Zeneca 4

Simvastatin-ezetimibe Statin/absorption inhibitor Merck; Schering-Plough 3

Atorvastatin-amlodipine Statin/CCB Pfizer 3

Implitapide MTP inhibitor Bayer 3/discontinued

BMS-201038 MTP inhibitor BMS 2

TAK-475 Squalene synthase inhibitor Takeda 3

BIBB-1464 Squalene cyclase Boehringer Ingelheim 2

CETi-1 Anti-CETP vaccine AVANT Human

JTT-705 CETP inhibitor Japan Tobacco/Pfizer 3

CP-529/414 (torcetrapib) CETP inhibitor Pfizer 1

ETC-588 ApoA1-HDL mimetic Esperion 3

ETC-216 ApoA1-HDL mimetic Esperion 2

Avasimibe ACAT inhibitor Pfizer 3

CS-505 ACAT inhibitor Sankyo 2

NO-1886 Fibrate Otsuka/TAP 1

SB-480848 PLA2 inhibitor GSK Animal

Ezetimibe Absorption inhibitor (NPC1-L1 antagonist) Merck/Schering-Plough 4

Pamaqueside Absorption inhibitor (stanol derivative) Pfizer 1

FM-VP4 Absorption inhibitor Forbes Medi-tech 1

GT-102–279 Absorption inhibitor Gel Tex 3

HBS-107 Bile acid sequestrant Hisamitsu/Banyu 2

S-8921 IBAT inhibitor Shionogi Animal

BARI-1453 IBAT inhibitor Aventis Animal

KRP-297 (MK-767) PPAR-(a1 g) agonist Kyorin/Banyu/Merck 3/withdrawn

Tesaglitazar PPAR-(a1 g) agonist Astra-Zeneca 1

AGI-1067 Vascular protectant Atherogenics 3

BMS, Bristol-Myers-Squibb; GSK, GlaxoSmithKline. Licenced compounds are in bold.

NEW AGENTS FOR LIPIDS 1065


has proceeded to full-scale studies (31,32). Unfortunately, it

seems that inhibition of MTP function results in an increase

in the size of hepatic cholesterol pools and the development of

fatty liver (non-alcoholic steatitic hepatitis) and elevated

transaminases. This has led to the abandonment of many of

the drugs in this class although niacin inhibits the fatty acid

synthetase in the pathway (33); coformulation of a MTP

inhibitor with niacin may solve this problem.

INH IB IT ION OF INTEST INAL L IP ID ABSORPT ION

About 25% of cholesterol is derived from intestinal uptake.

Treatment with sitostanol/sitosterol margarines that act as

competitive inhibitors of cholesterol uptake show 8–14%

reduction in LDL, if doses of 20 g/day are consumed (34).

Similarly, the use of bile acid sequestrants is associated with a

10–15% reduction in LDL in large scale studies (35). These

drugs are accepted as synergistic additional therapy on top of

statins, though their use is limited by their gastrointestinal

side effects (30%).

CHOLESTEROL ABSORPT ION INHIB ITORS

However, direct approaches to inhibition of cholesterol

uptake are possible (36). Ezetimibe is a specific cholesterol

uptake inhibitor, which has recently been licensed. The

target of ezetimibe is the Niemann-Pick C1-like protein-1-

annexin 2-caveolin steror transport/sensor complex (37,38).

A single daily dose of 10 mg is additive to all doses of statins,

which has no effect on fat-soluble vitamin uptake and

produces a 14% reduction in monotherapy or combination

therapy. In homozygous familial hypercholesterolaemia,

where statins are generally of limited use with LDL reduc-

tions of maximum 30% being achieved at the top doses, it

produces a 30% reduction in LDL (39). This agent is well

tolerated in initial studies with no excess gastro-intestinal

side effects (37,39). Whether there is any negative interac-

tion with the non-absorbed cholesterol analogue sitostanol

(Benecol) has not been explored. Other agents targeting

this protein are likely to be developed, as ezetimibe only

reduces cholesterol absorption by half that is achieved

by ileal bypass surgery in the programme on surgical

Mitochondrion PEROXISOME Cholesterol

Presqualene pyrophosphate squalene 2,3 epoxide

Farnesol Lanosterol

Other sites

Dolicohols ENDOPLASMIC RETICULUM

Ubiquinone (CoQ10)

Unsaturated fatty acid

Acetyl-CoA Cholesterol

?

HMG-CoA

HMG-CoA reductase Multiple steps

Mevalonate

Isopentenyl pyrophosphate ?

Geranyl pyrophosphate Lanosterol

Farnesyl pyrophosphate

Saturatedfatty acid

Acetyl CoA

Presqualene pyrophosphate Squalene 2,3 epoxide

Squalene synthase ?Lanosterol

Squalene ?Cholesterol

Figure 2 Compartmentation and

simplified biochemistry of cholesterol

synthesis. Drug targets are shown in bold

italics



correction of hyperlipidemia (40). This could reflect either

its low affinity for the receptor or the presence of alter-

native cholesterol uptake channels not blocked by this

specific compound.

I LEAL B ILE AC ID TRANSPORT INHIB ITORS

The long-established drug class of bile acid sequestrants has

shown the utility of interference with bile acid-mediated

cholesterol transport. However, these drugs are known to be

associated with a high incidence of gastro-intestinal side

effects, probably due to the increased amount of colonic bile

acid exposure. Another drug target in this pathway is the

specific ileal bile acid transporter (IBAT) that resorbs bile

acids into the enterohepatic circulation. Depletion of the

hepatic portal vein bile acids is likely to lead to an increase

in bile acid synthesis from cholesterol by up-regulation of

7-a-hydroxylase through action at the farnesoid-X-receptor

(41). The enterohepatic circulation includes cholesterol and

some drugs, e.g. statins and ezetimibe, but it is unclear

whether these are resorbed through IBAT, organic anion

transporters or by other mechanisms. Some studies show

success with potential inhibitors in animals (42).

INCREASE IN REVERSE CHOLESTEROL

TRANSPORT

While approaches to reduce LDL-cholesterol and this choles-

terol import to tissue are well established, the importance of

increasing reverse cholesterol transport by HDL has been

shown in epidemiological studies and in some fibrate trials

(5,43,44).

COMBINED PEROXISOMAL PROL IFERATOR-

ACT IVAT ING RECEPTOR ALPHA–GAMMA

AGONISTS

Fibrates are activators of peroxisomal proliferator-activating

receptor alpha (PPAR-a) (45). High dose fibrates can reduce

triglycerides by 70%, raise HDL by 20% and reduce LDL by

10–25%. All of these actions are anti-atherogenic. Glitazones

are PPAR-g agonists and increase insulin receptor expression

in muscle, and hence, insulin sensitivity. In practice, as oral

hypoglycaemic drugs, they deliver a 0.5–1% reduction in

HbA1c, 5–15% decrease in triglycerides and an increase in

HDL of 0–4%. Though there are anecdotal reports of the

combination therapy with fibrates and glitazones, no large-

scale studies have been performed. The reports to date suggest

a synergy of action. Thus, as PPARs share structural hom-

ology, it has proved possible to synthesise PPAR a-g coagonists

Nucleus

SREBP-2

mRNA

ER Amino acids

SREBP-2

SCAP AAAA

Ubiquitin

ApoB-protein

ApoB-cholesterol-ester Nascent-VLDL

MTP-cholesterol ester MTP-triglyceride

MTP-I NA

Cholesterol-ester Fatty acid synthetase

ACAT ACAT-inhibitor

Cholesterol

Proteasome

Figure 3 Assembly of apolipoprotein-

B containing lipoproteins. Intracellular

cholesterol depletion activates (SREBP)-

activating protein (SCAP) to cleave

sterol regulatory element-binding

protein 2 (SREBP-2) resulting in

nuclear apoB mRNA synthesis. ApoB

mRNA traffics to the endoplasmic

reticulum where the protein is

synthesised. If not stabilised by the

addition of cholesterol from microsomal

transfer protein (MTP), apoB is

ubiquitinated and degraded by the

proteasome. If it is stabilised then more

cholesterol and triglyceride is added and

nascent very low density lipoprotein

(VLDL) is formed and exported via

the Golgi apparatus. MTP-I, MTP-

inhibitor; NA, nicotinic acid; ACAT,

acyl-cholesterol acyl transferase



with the requisite effects in cell culture studies. Some have

reached clinical trials in man as benefits have been shown on

both lipid and glycaemic profiles in obese and diabetic rodent

models (46–50). In human trials PPAR-a compounds are

lithogenic, while PPAR-g cause transaminase elevations and

fluid retention but all PPAR-a-g agonists investigated to date

seem to be associated with multiple side-effects including

tumour promotion which may be a PPAR-d effect.

L IVER -X -RECEPTOR AGONISTS

The liver-X-receptor (LXR) exists as two isoforms – alpha and

beta, with different tissue expression profile, which are

involved in regulation of intracellular cholesterol levels. In

humans, LXR controls expression of the cholesterol trans-

porter ABC-A1 and also ABC-G1 as well as cholesterol ester

transfer protein (CETP). In mice, it mostly regulates

ABC-A1. LXR agonists raise HDL levels but also activate

fatty acid synthesis, hence, raising triglyceride levels through

an effect attributed to the LXR-b receptor. Certain cyto-

chrome P450 3A4 inducing anti-convulsants (phenobarbital

and carbamazepine) elevate levels of 4-b-hyroxycholesterol,

which is a strong LXR ligand. These drugs raise HDL and

triglycerides in some studies. Conversely, (n-3) fatty acids

which are LXR antagonists lower triglycerides but have

little effect or lower HDL due to their inhibitory action on

ABC-A1 expression. Thus, potentially, these drugs may raise

reverse cholesterol transport though increased cholesterol exit

to HDL, but on the other hand the GISSI-P study shows

that (n-3) fatty acids reduce sudden cardiac death (51,52),

and hence, the effects of LXR agonists may be difficult

to predict. As yet, none of these compounds have reached

human trials.

CHOLESTEROL ESTER TRANSFER PROTE IN

INHIB ITORS

Cholesterol esters are transferred in exchange for triglycerides

in plasma by CETP. Inhibition of the action of CETP is one

of the actions of alcohol, and moderate alcohol intake is

associated with increased levels of HDL and reduced rates of

atherosclerosis. Thus, CETP inhibition has a potential role in

increasing HDL levels and reverse cholesterol transport (53).

Inhibition of CETP in animal models of angioplasty is

associated with reduced rates of restenosis and atherosclerosis

(55). Two CETP inhibitors (jTT-705 and torcetrapib) have

reached phase 3 clinical trials in man where they produce 35–

105% rises in HDL without significant side-effects (56,57).

Another possible strategy to inhibit CETP is to make use of

its immunogenic properties. An anti-CETP vaccine, CETi-1,

has been devised, and phase I safety data is available. Vaccina-

tion reduced CETP levels by 50% and had small and variable

effects on HDL levels (57). However, the efficacy of CETP

inhibition as a method of inhibiting atherosclerosis remains to

be proven, as data from CETP deficient patients show con-

flicting results on relatives rates of coronary heart disease

compared with control populations (57).

HDL-DER IVED PROTE INS AND PEPT IDES

Point mutations in apolipoprotein–A1, the principal protein

component of HDL, are associated with a wide variety of

clinical phenotypes including amyloidosis, neuropathy and

both increased and decreased rates of atherosclerosis (58,59).

Cysteine–arginine mutations at position 151 and 173 in the

a-helices of apoA-1 (apo-A-1 Paris and Milano genotypes)

reduce HDL levels but paradoxically protect against athero-

sclerosis in man and animal models (60,61). Infusion of

purified apoA-1 protein shows no benefit, as it is degraded

in the kidneys. However, recently, it has been proved possible

to synthesis pre-HDL discs containing apoA1-Milano and

phospholipid, which are functional and are not instantly

cleared (59). These are protective against atherosclerosis in

animal models and in phase 3 clinical trials in man (62). It

has been noticed that infusion of these pre-HDL discs is

associated with a rapid thrombolyic effect in animal models

of acute coronary syndromes, possibly reflecting the key role

that HDL and its associated proteins play in the modulation

of coagulation.

HDL-ASSOCIATED ENZYMES

HDL is associated with 20–30 proteins, many of which have

been shown to be cardiovascular risk factors. One of the best

characterised is platelet-activating factor hydrolase (PAF-H

also known as phospholipase A2), which is anti-atherogenic

when associated with HDL but pro-atherogenic when asso-

ciated with LDL through its ability to oxidise phosphatidyl-

choline to lyso-phosphatody-choline (63). Phospholipase A2

(PLA2) is associated primarily with LDL, released by activated

macrophages (foam cells). It is one of the few specific markers

associated with small dense LDL, and levels are also asso-

ciated with the risk of coronary heart disease in statin trials

(64). PAF-H/PLA2 is therefore a good candidate for inhibi-

tion, and a few compounds have entered early clinical trials

after showing benefits in animal models of atherosclerosis

(65).

L IPOPROTE IN (A) FORMATION INHIB ITORS

Lipoprotein (a) [Lp (a)] is a lipoprotein associated with excess

cardiovascular risk and known to be present in atherosclerotic

plaques. It comprises of an apolipoproteinB100 containing

LDL particle to which is covalently attached a genetically

polymorphic molecule of apolipoprotein (a) which shares

structural homology with plasminogen. Though the function

of Lp (a) is unknown, it interferes with fibrinolysis in vitro

and is synthesised independently of LDL and cleared through



the VLDL receptor. Elevated levels of Lp (a) are associated

with atherosclerosis, and it shows some acute phase reactant

properties. Therapy for elevated lipoprotein (a) is limited.

Oestrogen-containing hormone replacement therapy (HRT)

reduces Lp (a) up to 30%, and the elevated Lp (a) subgroup

benefited from HRT in the HERS study (66). Similarly, in

males, anabolic steroids or androgens can reduce Lp (a) (67).

The only other therapies to reduce Lp (a) are physical removal

through apheresis and reduction in synthesis by nicotinic

acid. Clinical usage of nicotinic acid and the related com-

pound, acipimox, is limited by facial flushing, and con-

sequently, poor compliance (see above). A number of

specific inhibitors of Lp (a) have been synthesised, but none

have reached clinical trials in man as yet. The most promising

approach seems to be the use of peptides that interfere with

Lp (a) assembly. The peptide apolipoprotein B 4330–4397,

for instance, binds to apolipoprotein (a) and inhibits assembly

of Lp (a) in apo (a) transgenic mice (68).

OXIDANT S IGNAL DISRUPTORS

Oxidised cholesterol is one of the main promoters of athero-

sclerosis but directly through its activation of macrophages

and indirectly through its actions on the oxidised LDL recep-

tors on other cells. The anti-oxidant probucol has been shown

to reduce progression of atherosclerosis both in animals and

to a limited extent in man. However, its mechanism of action

has remained obscure. A derivative of probucol, AGI-1067,

interferes with lipid peroxide signalling in a similar manner to

pyrrolidine dithiocarbamate, which disrupts activation of

intercellular adhesion molecules. In animal models, AGI-

1067 reduces coronary artery disease progression (69), and

in a phase 2 trial in 305 patients, it inhibited restenosis in a

manner similar to some previous studies with probucol

(70,71). The results are being validated in an on-going

phase 3 trial of 4000 patients.

CONCLUS IONS

This review has summarised some of the compounds in

development for treatment of lipid-related risk factors in

cardiovascular disease. One of the major challenges that will

be faced in the development of these agents is the success of

statins. These drugs are increasingly available off-patent and

soon likely to be available over-the-counter either as mono-

therapy or as part of a poly therapeutic package (e.g. the poly

pill) (72). At current doses, statins could deliver a 50–88%

reduction in cardiovascular risk. Similarly, the fibrates and

nicotinic acid are well-established therapies for lowering

triglycerides and raising HDL. Thus, newer agents will have

to show significant advantage in tolerability or efficacy over

existing agents and have the potential to be used in combin-

ation therapy, as is well established for bile acid sequestrants,

nicotinic acid or fibrates and statins. Any new drugs affecting

the principal targets of these agents will also have to be

assessed in clinical endpoint trials against very successful

compounds. Some of the new classes, e.g. ACAT inhibitors,

have modest effects on lipids but large effects on the progres-

sion of atherosclerosis, hence, the accepted surrogate end-

points, e.g. lipid profiles, may not be relevant to these

agents. Other surrogates, e.g. endothelial function, pulse

wave velocity, vascular calcification or direct imaging of

atherosclerotic plaques, will have to be used to monitor

their efficacy.

The data from meta-analyses suggest that the benefits of

LDL-reduction occur independent of the drug type used;

hence, both cholesterol absorption inhibitors and IBATs are

likely to be clinically accepted quickly. Many of the com-

pounds discussed are likely to become adjunctive therapies to

statins, as is already the case for the novel nicotinic acid

preparations (73). Only, the most efficacious will be available

as monotherapies, though some may find small niches

[e.g. reduction of Lp (a)] where they will be of particular

utility.

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Paper received October 2003, accepted October 2003



lipid-altering agents: the future

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