C7
`Review
`
`Monthly Focus: Endocrine & Metabolic
`
`New lipid-modifying therapies
`
`Eric Bruckert
`Department of Endocrinology & Metabolism, kistance Publique - HOpitaUK de Paris. University
`HOpital Pitie-SalpMriere, Paris. France
`
`Lipid abnormalities are central among the risk factors for the development of
`cardiovascular disease and their correction remains a major target for the med(cid:173)
`ical community. Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reduct(cid:173)
`ase (statins) are the most widely prescribed and best tolerated of the currently
`available lipid-modifying therapies. Newer agents in this class (e.g., rosuvasta(cid:173)
`tin) have proven to be more effective at lowering levels of low-density lipopro(cid:173)
`tein cholesterol. New formulations of drugs such as nicotinic acid, which
`improve treatment regimens and reduce unpleasant side effects, may result in
`improved patient compliance with this therapy. The development of novel
`drugs such as cholesterol absorption inhibitors (e.g .• ezetimibe) and acyl-coen(cid:173)
`zyme A cholesterol acyltransferase inhibitors (e.g .. avasimibe) will provide clini(cid:173)
`cians with therapeutic options that exploit different pathways to those
`currently being utilised. By combining these ag~nts with statins, greater
`improvements in the lipid profile than those seen to date could be produced.
`In addition, advances in our understanding of the pathophysiology of dyslipi(cid:173)
`daemia have enabled other novel therapeutic targets to be identified and
`studies with experimental drugs underscore the potential of these approaches.
`
`Keywords: cardiovascular disease, cholesterol absorption. combination therapy, low-:density
`lipoproteln. statin
`
`Expert Opin. lnvestlg. /Jrugr (2003) 12(3):325-335
`
`1. Introduction
`
`Epidemiological and prospective studies have Identified a variety of risk factors for.
`the development of atherosclerotlc cardiovascular disease. Of these, elevated levels of
`low-density llpoproteln cholesterol (LDL-C) and reduced levels of high-density llpo(cid:173)
`proteln cholesterol (HDL-C) are among the most notable 11.21. Hypertrlglycerldae(cid:173)
`mla is also associated with an Increased risk of atherosclerotlc disease, although to a
`lesser extent than LDL-C 111. In addition to plasma lipid levels, which represent tar(cid:173)
`gets for current and new drugs, Increasing the resistance of LDL particles to oxida(cid:173)
`tion and modifying the kinetics of circulating lipoprotelns might become new targets·
`of therapy in the near future. Together with drugs affecting lipid metabolism, new
`compounds that act directly on the atherosclerotic process (e.g .. metalloproteinase
`inhibitors, acyl-CoA cholesterol acyltransferase [ACATJ Inhibitors) are being devel(cid:173)
`oped. Novel therapies with a multiplicity of targets may help develop a 'chemother(cid:173)
`apy approach'.to the prevention and treatment ofatherosclerotic lesions In humans.
`Several classes of therapy are currently available for the pharmacological treatment
`of lipid abnonnallties, including fish oils, flbric acid derivatives (flbrates). nlcotinic
`acid, bile acid sequestrants and Inhibitors of 3-hydroxy-3-methyl glutaryl
`coenzyme A (HMG-CoA) reductase, also known as statlns. Of these, statins are the
`most widely prescribed because they are well-tolerated and very effective at lowering
`LDL-C (3]. Despite improvements in treatments for lipid abnorrnalltles, controrof
`dysllpidaemia remains Inadequate; a recent European survey of risk factor manage(cid:173)
`ment In patients with est~blished coronary heart disease (CHO) revealed that only
`half of those receiving lipid-lowering therapy had attained their total cholesterol goal
`
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`14). Although clinicians can help to reduce the number of
`undertreated patients through better use of current treat(cid:173)
`ments, additional therapies are required in order to optimise
`prevention and treatment of cardiovascular disease. This
`review eJiamines new advances in lipid-modifying therapies,
`Including improvements In currently available treatments and
`the development of agents targeting novel therapeutic path(cid:173)
`ways. The development of drugs that directly interfere with
`the formation of atherosclerotlc plaques will not be described.
`
`2. Agents that predominantly decrease plasma
`levels of low-density lipoprotein cholesterol
`
`z.1 New statins
`Stalins act by competitively Inhibiting HMG-CoA reductase,
`the enzyme that catalyses the rate-limiting step In cholesterol
`biosynthesls (3). This results In a reduction In hepatocyte cho(cid:173)
`lesterol concentration, stimulating increased expression of
`hepatic LDL receptors {LDL-Rs). which clear LDL-C from
`the circulation. While this effect Is considered the primary
`mechanism of LDL-C lowering, It has also been suggested
`that statlns can Inhibit the synthesis of some lipoprotelns,
`since they can lower LDL-C In patients without functional
`LDL- Rs 13). Several landmark clinical trials with statlns have
`demonstrated their efficacy In lowering LDL-C as well as their
`benefits in reducing CHD and total mortality 15-9). Large
`Intervention trials are now underway to test whether larger
`reduction In LDL-C yields greater benefit. In patients with
`hypercholesterolaemla, currently available agents can lower
`LDL-C by 24 - 60%, reduce triglyceride levels by 10 - 29%
`and modestly increase HDL-C levels by 6 - 12% llOJ.
`In addition to their ability to lower LDL-C, it Is generally
`recognised that statlns have cholesterol-independent or 'plei(cid:173)
`otropic' effects. Inhibition of mevalonate synthesis by HMG(cid:173)
`CoA reductase can also prevent the production of isoprenoid
`Intermediates that may modulate cellular events through the
`post-transcriptional modification of G proteins fill. The
`inhibition of these · 1soprenolds may be responsible for the
`ability of statins to modulate Inflammation and thrombogen(cid:173)
`·esls, Improve endothelial function and stabilise atheroscle(cid:173)
`rotic plaque 1111. While the clinical Importance of these
`plelotroplc effects Is not easily established, since they are dif(cid:173)
`ficult to differentiate from the benefits of lipid lowering, it
`may be that they contribute to the ability of statlns to reduce
`cardiovascular events.
`In general, statln monotherapy Is well-tolerated and adverse
`events are rare 13). The most serious adverse effect associated
`with statln treatment Is myopathy and rhabdomyolysis may
`develop If the condition Is not recognised and treatment Is
`discontinued. The withdrawal of cerivastatln from clinical use
`has heightened awareness of these effects, although there Is
`now extensive data available to indicate that the increased
`incidence of rhabdomyolysis with cerivastatin was specific to
`that agent 1121. Several factors can influence whether a statin
`may Induce an adverse event. For example, it has been sug-
`
`gested that the lipophilicity of a statln determines whether it
`can enter Into muscular tissues and induce myopathy 113).
`Hydrophilic statins require an active uptake mechanism to
`enter Into the liver and they do not easily penetrate into
`peripheral tissues 114.151. Therefore, hydrophilic statlns may be
`less likely to provoke an adverse event than llpophlllc agents.
`Indeed, there is evidence to suggest that pravastatln, a
`hydrophilic agent, may be less myotoxic than more llpophilic
`statlns 113). Drug interactionS are another mechanism by
`which adverse effects can occur, often as a result of shared
`metabolic pathways. The cytochrome P450 3A4 lsoenzyme
`metabolises the greatest number of drugs in humans and,
`therefore, statlns utilising this pathway may have a higher
`potential for adverse drug Interactions !16).
`Newer agents In the.statln c-lass Include rosuvastatln, recently
`approved for use in Europe over the dose range 10 - 40 mg,
`and pltavastatln, currently
`in development.
`In hyper(cid:173)
`cholesterolaeinlc ·patients, rosuvastatln has been shown to
`reduce LDL-C by up to 63% 1111. Data from comparative stud(cid:173)
`ies have shown that rosuvastatln Is more effective than atorvas(cid:173)
`tatln, simvastatln and pravastatin at reducing LDL-C, as well as
`raising HDL-C 118-20). In patients with primary hypercholester(cid:173)
`olaemla, LDL-C levels were reduced by 47% with rosuvastatln
`IO mg/day compared with 36% for atorvastatln IO mg/day
`(20). In similar studies, rosuvastatln IO mg/day lowered LDL-C
`by 48%, compared with 36% for slmvastatin 20 mg/day 1191
`and 27% for pravastatln 20 mg/day 118). In addition, greater
`efficacy of rosuvastatln compared with atorvastatin has been
`demonstrated In patients with heterozygous familial hypercho(cid:173)
`lesterolaemla 121), and rosuvastatln also significantly reduces
`LDL-C In patients with homozygous familial hypercholestero(cid:173)
`laemia 1221: Clinical trials with rosuvastatln Indicate that It is
`well-tolerated 1231, possibly because It is relatively hydrophilic
`and does not undergo significant metabolism, being predomi(cid:173)
`nantly excreted unchanged (15J.
`Pitavastatln is also effective at lowering LDL-C levels 1241. A
`randomised trial comparing pltavastatin (2 mg/day) and prav(cid:173)
`astatln (IO mg/day) In 240 patients showed a decrease in
`LDL-C of37.6 and 18.4%, respectively (25). These results con(cid:173)
`firmed Initial data In Japanese subjects with primary hypercho(cid:173)
`lesterolaemla showing that pltavastatln 2 mg/day Is more
`effective at reducing LDL-C levels than pravastatln IO mg/day
`(-38 versus -18%) 126) (Table 1). Furthermore, in a trial In dia(cid:173)
`betic patients, pitavastatln treatment reduced LDL-C by
`36. l %, together with a significant reduction of triglycerides
`(28.7%) and remnant particles (30.9%) 1331- Pitavastatln Is a
`relatively lipophlllc agent with an octanollphosphate buffer
`partition coefficient similar to that of atorvastatln and ls only
`minimally metabolised by cytochrome P450 enzymes (34).
`
`2.2 New formulations of current treatments
`Although niacin decreases triglyceride levels and raises HDL(cid:173)
`C in addition to lowering LDL-C. new formulations of this
`compound will be discussed In the section on drugs affecting
`LDL-C levels. The lipid-modifying effects of niacin have
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`Table 1. Summary of clinical data for new lipid-modifying agents.
`
`Treatment
`
`Mechanism of action Dose
`
`N
`
`Therapy
`duration (wks)
`
`% Change from baseline Ref.
`
`LDL-C
`
`HDL-C TG
`
`Mono therapy
`Avasimibe
`JTI-705
`Colesevelam hydrochloride
`Ezetimibe
`
`Rosuvastatin
`
`Pitavastatin
`
`ACAT inhibitor
`CETP inhibitor
`Bile acid sequestrant
`Specific cholesterol
`absorption inhibitor
`HMG-CoA reductase
`inhibitor
`HMG-CoA reductase
`inhibitor
`
`50-500mg 130
`300-900mg 198
`3.75g
`137
`615"
`10mg
`
`8
`4
`6
`12
`
`NS
`-7.7
`-19.1
`-17. 71
`
`NS
`-231
`NS
`+34.5
`+11.2S NS
`+11
`-1.7""
`
`[27l
`
`[281
`
`[29)
`
`130)
`
`10-40mg
`
`206
`
`6
`
`-63 11
`
`+141
`
`-351
`
`[17)
`
`2mg
`
`125
`
`12
`
`-38
`
`+4.2
`
`-23
`
`[26)
`
`Combination therapy
`Extended-release niacin/
`lovastatin
`Colesevelam hydrochloride/
`lovastatin
`"n a 606 for change In. LDL-C from baseline. 1p < 0.05 versus placebo. Sp c 0.006 versus placebo. Ip < 0.01 versus placebo ... p < 0.09 versus placebo. "P < 0.0001
`· versus placebo.
`ACAT: Acyl·CoA cholesterol acyltransferase: CETP: Cholesteryl ester transfer protein; HDL-C: High-density lipoproteln cholesterol; HMG-CoA: Hydroxy-methylglutaryl
`coenzyme A; LDL-C: Low-density llpoproteln cholesterol; NS: No significant change from baseline; TG: Triglyceride.
`
`600
`
`16
`
`-47
`
`+30
`
`-42
`
`500/10
`- 2000/40mg
`2.3 g/10 mg
`
`135
`
`4
`
`.34tt
`
`NS
`
`NS
`
`[31)
`
`[321
`
`been known for almost 50 years and Its primary mechanism
`of action Is a reduction In the hepatic production of triglycer(cid:173)
`ide-rich llpoprotelns as a result of the mobilisation of free
`fatty acids from peripheral tissues J35). The benefits of niacin
`treatment have been confirmed In a major outcome-based
`clinical trial. A 5-year follow up of the Coronary Drug
`Project, a large secondary prevention study conducted In
`834 l patients, reported that niacin (3 g/day) effectively
`reduced total cholesterol (9.9% from baseline) and·trlglycer(cid:173)
`ldes (26.1 % from baseline) 136]. Niacin treatment was also
`associated with significant reductions In non-fatal myocar(cid:173)
`dial Infarction (MI) and death from CHO and cerebrovascu(cid:173)
`lar disease when compared with placebo (14 and 26%,
`respectively; p < 0.005) (36]. Further evidence that niacin
`reduces CHO events came from the Familial Atherosclerosis
`Treatment Study (FATS). a small trial demonstrating that
`niacin and a bile acid sequestrant in combination were at
`least as effective as lovastatln combined with a bile acid
`sequestrant at reducing clinical events and anglographic dis(cid:173)
`ease progression In coronary arteries (37].
`Immediate-release niacin Is associated with frequent dos(cid:173)
`ing and cutaneous flushing. contributing to poor patient
`compliance [38]. In addition, potentially serious side effects
`such as deterioration of glycaemlc control and increased gly(cid:173)
`cosylatlon of haemoglobin In diabetic patients have also been
`reported l39J. Consequently, new extended-release prepara(cid:173)
`tions of niacin have been developed that are designed to be
`more acceptable to patients. Studies indicate that extended(cid:173)
`release formulations of niacin are generally well-tolerated
`
`and essentially equivalent- to immediate-release niacin with
`respect to efficacy In Increasing HDL-C and reducing trig(cid:173)
`lycerides (40-421.
`It has recently been suggested that, since niacin and statlns
`modify lipid levels and reduce the risk of CHO by different
`mechanisms, their use in combination may have an additive
`effect at reducing coronary events (43]. When used In combina(cid:173)
`tion with a statin, extended-release formulations of niacin have
`also been shown to be effective in Improving lipid parameters
`(44). A combination oflovastatln and extended-release niacin Is
`available in the US and Interim data from a study of 818
`patients with dyslipldaemia have shown that 16 weeks of treat(cid:173)
`ment with the combination (dally dose range: 500 mg niacin/
`lO mg lovastatln to 2000 mg niacln/40 mg lovastatin) reduced
`LDL-C by 47% from baseline and favourably modified HDL(cid:173)
`C and triglyceride levels {311 (Table I}. Flushing. a common
`side effect of niacin treatment, was reported in 7% of patients
`receiving the combination, who subsequently withdrew from
`the study. In the HDL-Atherosclerosls Treatment Study
`(HATS}. a 3-year, double-blind trial, the combination of slm(cid:173)
`vastatln and niacin was found to significantly regress proximal
`coronary stenoses compared with placebo, In parallel with sub(cid:173)
`stantial changes In LDL-C {-42%) and HDL-C (+26%) (45].
`
`2.3 Squalene synthase inhibitors
`The enzyme squalene synthase plays an Important role in the
`cholesterol biosynthetlc pathway. In monkeys. ER-27856, the
`triplvaloyloxymethyl ester prodrug of ER-28448, lowered cho(cid:173)
`lesterol levels more potently than pravastatln, slmvastatln and
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`atorvastatln [46]. In addition, this compound has interesting
`triglyceride-lowering effects both_ in homozygote and heterozy(cid:173)
`gote animal models of familial hypercholesterolaemia (47]. This
`effect was also found with a similar Inhibitor,. YM-53601. In
`hamsters and is explained by a LDL-R~independent mecha(cid:173)
`nism (47.48). A new Inhibitor of squalene synthase (Cj-15, l 83)
`has been identified in the fennentatlon broth of the fungus
`Aspergillus aculateus (49]. However, no data are currently availa(cid:173)
`ble regarding the clinical efficacy of this agent.
`
`2.4 Microsomal transfer protein inhibitors
`Microsomal transfer protein (MTP) facilitates the transloca(cid:173)
`tlon of apollpoproteln B (apoB) and its assembly with trig(cid:173)
`lyceride and cholesterol within the hepatic cells. Absence of
`this protein In the genetic disorder called abetallpoprotelnae(cid:173)
`mla Is associated with almost undetectable levels of very-low(cid:173)
`density llpoproteln (VLDL) and LDL ln plasma. Patients
`also present with a neurological disorder due to abnormal
`vitamin E transport and fat malabsorptlon and steatosis.
`Genetic manipulation of mice to knockout the MTP gene
`can decrease plasma apoB levels by 95% and Increase the
`secretion rate of apoB particles by 7 4%. Thus, the potency of
`MTP lnhlbltlon to decrease atherogenlc llpoproteln concen(cid:173)
`trations must be balanced against potential adverse effects
`due to Inhibition of Intestinal fat absorption and hepatic
`lipid secretion. MTP Inhibitors have been shown to decrease
`LDL-C and VLDL-C in a human liver cell line consequent
`to Inhibition of apoB secretion (SO]. However, the develop(cid:173)
`ment of these compounds has been hampered due to side
`effects, mainly diarrhoea and steatosls with a high Incidence
`of liver enzyme Increase. A series of benzlmldazole-based ana(cid:173)
`logues of the BMS-201038 have been recently described (51).
`Incorporation of an unsubstituted benzlmidazole moiety in
`place of a plperldine group led to increases In po~ency. both
`In a cellular assay of apoB secretion and especially In animal
`models of cholesterol lowering. The most potent compound
`In this series, 3g (BMS-212122), was significantly more
`effective than BMS-201038 In reducing plasma lipids (cho(cid:173)
`lesterol, VLDL/LDL. triglyceride) in both hamsters and
`cynomolgus monkeys 151).
`
`2.s Inhibitors of bile acid absorption from the
`intestine
`The bile acid sequestrants (resins), which have been In clini(cid:173)
`cal use for several decades, act by binding bile acids In the
`intestine, thereby disrupting their reabsorptlon and lowering
`lntrahepatlc cholesterol levels. A subsequent increase in the
`synthesis of LDL-Rs leads to a reduction in the level of
`plasma LDL-C. Despite being effective at reducing choles·
`terol levels, bile acid sequestrants are associated with undesir(cid:173)
`able side effects and, consequently. patient compliance ls
`poor (52]. The development of new bile acid sequestrants may
`help to reduce the sideceffect problems associated with res(cid:173)
`ins. One such bile acid sequestrant ls colesevelam hydrochlo(cid:173)
`ride. a non-absorbed, polymeric cholesterol-lowering agent
`
`that was recently launched in the US. In a placebo-control(cid:173)
`led study, colesevelam 3. 75 g/day was reported. to lower
`LDL-C levels by 19.1% and increase HDL-C by 8.1% com(cid:173)
`pared with baseline (29] (Table I). Constipation, a common
`effect with the older resins, was not apparent with coleseve(cid:173)
`lam treatment in this study. The higher potency of the drug
`might be explained by the greater binding· affinity for glyco(cid:173)
`chollc acid (53). The efficacy and tolerability of colesevelam
`used in combination with a statln has also been demon(cid:173)
`strated (Table I). For example. additional reductions in
`LDL-C of 8 - 16% above that produced by statins alone
`have been reported with combination therapy. Furthermore,
`the overall incidence of adverse effects with colesevelam
`alone and In combination with statlns was similar to that
`observed with placebo 132,54.55).
`Reabsorptlon of bile acids from the Intestine is mediated
`by the Heal Na•/bile acid cotransporter (IBAT) and Inhibi(cid:173)
`tion of this transporter would be expected to produce phar(cid:173)
`macological effects similar to those of bile acid sequestrants.
`Several compounds have been reported to Inhibit IBAT
`in vivo. One of these compounds, the novel IBAT Inhibitor
`S-8921. has shown promising cholesterol-lowering capabili(cid:173)
`ties In preclinical studies (56-58]. Treatment of heterozygous
`Watanabe heritable hyperlipldaemlc rabbits with S-8921
`reduced plasma cholesterol levels by 29 - 37% (581. In the
`same study, treatment with S-8921 Inhibited the accumula(cid:173)
`tion of cholesterol In the aortic arch and reduced the severity
`of coronary atherosclerosis (58].
`
`2.6 Inhibitors of cholesterol absorption from the
`intestine
`Plasma cholesterol levels are Influenced not only by de novo
`biosynthesis but also by the absorption of dietary and biliary
`cholesterol from the intestine and the removal of cholesterol
`from the blood 159]. Interrupting the absorption of choles(cid:173)
`terol has therefore become an Important target for lowering
`serum cholesterol levels. Since the 1950s, ll has been recog(cid:173)
`nised that plant sterols and stanols (produced by hydrogenat(cid:173)
`ing sterols) can reduce serum cholesterol. As a result of
`structural similarities with cholesterol, plant sterols and
`. stanols can compete for the limited space available In mixed
`micelles, the packages in the Intestinal lumen that deliver lip(cid:173)
`ids for absorption Into mucosa! cells and thereby inhibit the
`absorption of cholesterol from the Intestine. Esterified plant
`sterols or stanols can be incorporated into foods and several
`products enriched with plant sterol and stanol esters have
`become available, such as margarine and yoghurt.
`Studies have consistently demonstrated that 1.6 - 2.5 g/
`day of plant sterols reduced LDL-C levels by IO - 15%. A
`recent analysis of 14 randomised trials of dietary sterols and
`stanols reported that 2 g of plant sterols or stanols added to
`an average dally portion of margarine can reduce LDL-C by
`0.33 - 0.54 mmol/J (60). Interestingly, the efficacy of plant
`sterols appears to be additive to or even synergistic with,
`other lipid-modifying agents (611.
`
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`Recent evidence supports the presence of a specific trans(cid:173)
`porter that facilitates the movement of cholesterol from bile
`acid micelles Into the brush border membranes of enterocytes
`[62). This pathway for cholesterol transport has been exploited
`as a therapeutic target with the development of ezetlmlbe, an
`azetldlnone derivative. Ezetimlbe is a selective Inhibitor of
`cholesterol absorption that reduces the delivery of cholesterol
`to the llver and thereby promotes the synthesis of LDL-Rs,
`resulting In a reduction of plasma LDL-C [30.63). Pooled data
`from Phase II studies have shown that 22% of patients receiv(cid:173)
`ing ezetimlbe 10 mg/day achieved reductions in plasma
`LDL-C of > 25% (30). Recent Phase III study results indicate
`that ezetimlbe 10 mg/day lowers LDL-C by - 17% in patients
`with primary hypercholesterolaemla and has favourable effects
`on other lipid parameters 163) (Table 1). Several studies have
`also demonstrated additive lipid-lowering effects of ezetlmlbe
`when combined with statln therapy 164-67). Indeed, additional
`reductions In LDL-C of 12 - 14% have been reported In
`hypercholesterolaemlc patients receiving ezetlmlbe in combi(cid:173)
`nation with atorvastatln (671, lovastatin (65), pravastatln (661 or
`slmvastatin (64) compared with Individuals treated with statin
`monotherapy. Addition of ezetlmlbe to ongoing open-label
`statln therapy has also been shown to reduce LDL-C levels by
`a further 21% compared with statin monotherapy in patients
`with· primary hypercholesterolaemia
`Interestingly,
`(68J.
`ezetlmibe in combination with atorvastatln or slmvastatln, was
`recently shown to decrease LDL-C .In patients with the
`homozygous form of familial hypercholesterolaemia (69).
`
`2.1 Sterol regulatory element-binding protein
`cleavage-activating protein ligands
`LDL-R pathway is a key component in the maintenance of
`cholesterol homeostasis, and upregulation of LDL-R expres(cid:173)
`sion Is a new therapeutic target for reducing LDL-C. Regula(cid:173)
`tion of LDL-R expression by cholesterol Involves the sterol
`regulatory element-binding protein (SREBP) transcription
`factors as well as SREBP cleavage-activating protein (SCAP).
`A new class of drugs that act directly on SCAP has been iden(cid:173)
`tified 1101. These drugs upregulate the expression of LDL-R
`even when the cells are loaded with sterols. The magnitude of
`the upregulation of the LDL-R ls greater than that obtained
`with statlns. Such results represent a promising approach for
`decreasing both VLDL and LDL levels.
`
`3. Drugs that affect intracellular metabolism
`of lipid
`
`3.1 Inhibitors of acyl-CoA cholesterol acyltransferase
`An Important process In the pathogenesis of atherosclerosis Is
`the accumulation of cholesteryl ester (CE) In macrophages
`and smooth muscle cells of the arterial wall. The ACAT
`enzyme, which Is responsible for the esterificatlon and there(cid:173)
`fore the storage of cholesterol, 1s central to this process. Limit(cid:173)
`ing the esterificatlon of cholesterol by inhibiting ACAT may
`prevent its storage by macrophages and therefore inhibit the
`
`formation of arterial plaques. Several potehtially useful agents
`have been Identified.
`Avasimlbe is an ACAT inhibitor that is currently In early
`clinical development. It has been shown to reduce atheroscle(cid:173)
`rotlc lesion size in a cholesterol-fed rabbit model (71]. Further(cid:173)
`more, by limiting macrophage accumulation and reducing the
`expression of matrix metalloproteinases (MMPs), enzymes
`involved In vascular matrix remodelllng. avasimibe could
`potentially stabilise atherosclerotlc lesions and prevent plaque
`rupture [711. The availability of clinical data are currently lim(cid:173)
`ited, but a placebo-controlled study in 130 men and women
`with combined hyperlipidaemla and hypoalphallpoprotelnae(cid:173)
`mla has produced some promising results (Table l) 127). Dose(cid:173)
`independent reductions In total triglycerides and VLDL of 23
`and 30%. respectively (p <. 0.05 versus placebo), have been
`reported with avasimibe (dose range 50- 500 mg/day). How(cid:173)
`ever,
`total cholesterol, LDL-C and HDL-C
`remained
`unchanged from baseline following avaslmlbe treatment.
`Other ACAT Inhibitors have been identified, including
`NTE-122 and F 12511 (72.73]. Preclinical studies have shown
`that NTE-122 reduces serum and hepatic cholesterol levels In
`cholesterol-fed rabbits and rats 1721 and that F 12511 ls capa(cid:173)
`ble of reducing serum cholesterol levels In rabbits with endog(cid:173)
`enous hypercholesterolaemia f73J. Furthermore, a combination
`of F 12511 and atorvastatin reduced plasma total cholesterol
`and apoB-100-contalnlng lipoproteins in this model to a
`greater extent than either agent alone 1731.
`
`4. High-density lipoprotein as a new target for
`therapeutic intervention
`·
`
`Although elevated plasma LDL-C levels have been the tradi(cid:173)
`tional focus of the medical community, epidemiological data
`have shown that low levels of HDL-C can also play an Impor(cid:173)
`tant role in the development of cardiovascular disease 174). As
`previously discussed, several of the currently established
`agents, Including niacin, fibrates and statlns, are effective at
`increasing HDL-C. In the Veterans Affairs Hlgh~denslty lipo(cid:173)
`protein cholesterol Intervention Trial (VA-HIT). gemflbrozil
`treatment was shown to increase HDL-C and reduce the rela(cid:173)
`tive risk of CHO death and non-fatal MI by 22% In patients
`with low HDL-C and LDL-C levels [751. Nevertheless, It ·
`remains uncertain ·whether the Increase In HDL-C observed
`with the other lipid-modifying compounds translates Into a
`substantial decrease In cardiovascular morbidity and mortality.
`The increasing prevalence of the so-called plurimetabollc syn(cid:173)
`drome ls associated with an increased prevalence of low
`HDL-C in the population. Thus, HDL-C as a target for Inter(cid:173)
`vention represents one of the most challenging issues in the
`field, with a huge potential benefit but also a need to prove the
`concept that increasing HDL-C is indeed beneficial.
`It has been suggested that the protective effects of HDL-C
`are exerted through a number of mechanisms, including the
`promotion of reverse cholesterol transport and pleiotroplc
`effects. The rate of reverse cholesterol transport Is probably
`
`Expert Opin. lnvestig. Drugs (2003) 12(3)
`
`329
`
`5 of 11
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`CFAD V. UPENN
`IPR2015-01835
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`
`New lipid-modifying therapies
`
`not reflected by plasma levels of HDL particles. Indeed,
`patients with Tangier disease or with the apoA-IParis and
`apoA-IMllano mutations display extremely low plasma levels of
`HDL-C and an Increased catabolism of HDL [76.771. In con(cid:173)
`trast, plelotroplc effects Including Inhibition of oxidative
`modification or aggregation of LDL-C (78-801 and modulation
`of inflammatory responses (78J, are more likely to be a direct
`function of the qualitative and quantitative aspects of HDL.
`
`4.1 Recombinant apoA-IM1ano ·
`The protective effects of HDL-C depend on a.number of gene
`products, many of which represent promising targets for the
`development of new therapies. ApoA-I Is the major structural
`protein of HDL and apoA-I deficiency In man predisposes to
`premature atherosclerosis. Studies In animals have shown that
`recombinant apoA-IMilano prevents progression of atheroscle(cid:173)
`rosis and reduces lipid and macrophage content of plaques
`despite severe hypercholesterolaemia (811. It has been suggested
`that these favourable effects may be the direct result of more
`efficlen.t uptake of cellular cholesterol by apoA-IMllano-contaln(cid:173)
`l~g HDL. Cllnlcal studies with recombinant apoA-IMilano are
`currently underway.
`
`4.2 Cholesteryl ester transfer protein inhibitors
`Cholesteryl ester transfer protein (CETP) ts a plasma protein
`that mediates the transfer of CE from HDL to apoB-contaln(cid:173)
`lng llpoprotelns, thereby Increasing the catabollsm of CE asso(cid:173)
`ciated with HDL (82). In humans, deficiency In CETP results
`In Increased plasma levels of HDL-C and apoA-I. suggesting
`that the risk of CHO would be decreased If the action of
`CETP was Inhibited (831. Indeed, It has been suggested that the
`longevity of Japanese kindred is associated with a deficiency In
`CETP (84). However, low CETP activity In hypertrlglyceridae(cid:173)
`mic men has been found to be associated with an Increased risk
`of .CHO [851. Therefore, the effects of CETP on the risk of
`atherosclerosis In humans may be dependent on the lipopro(cid:173)
`teln profile of an Individual. Despite these conflicting data, the
`general consensus is that CETP deficiency Is desirable (811. In
`support of this, data from an animal study demonstrated that
`overexpresslon of a human CETP transgene reduces plasma
`HDL-C levels and leads .to Increased atherosclerosis in mice
`deficient for either apoE or the LDL-R. respectively (861.
`Therefore, CETP Is another potential therapeutic target.
`Several CETP Inhibitors have been developed and their
`potential antlatherosclerotlc properties Investigated. One such
`Inhibitor. JTT-705, has been shown to achieve a 50% Inhibi(cid:173)
`tion of CETP activity In human plasma (871 and to Increase
`levels of HDL-C. decrease non-HDL-C and Inhibit progres(cid:173)
`sion of atherosclerosis In animal models (87.88). The efficacy
`and safety of dally treatment with 300, 600 and 900 mg
`JTT-705 was evaluated In a Phase II trial that Included 198
`subjects with mild hyperllpldaemla (28). A clear dose-depend(cid:173)
`ent decrease In CETP activity was observed, with a maximum
`decrease of 37.2% (p < 0.0001). In parallel, there was a signif(cid:173)
`to 66.8%,
`increase In CETP concentration (up
`icant
`
`p < 0.0001) and HDL-C levels (maximum 34%, p < 0.0001)
`occurred ln the subjects (Table 1).
`
`4.3 Oestrogens and selective oestrogen receptor
`modulators
`Oestrogen therapy generally has favourable effects on the lipid
`profile, particularly HDL-C, and Is associated with lower rates
`of CHO in observational studies 189). However. a randomised,
`placebo-controlled trial of oestrogen plus progestln failed to
`demonstrate any reduction In CHO events with hormone
`therapy, possibly due to adverse effects of progestln and the
`prothrombotic properties of oestrogen 1901. Interest has now
`turned to selective oestrogen receptor modulators (SERMs).
`which lack the prothrombotlc properties of oestrogen and do
`not require concomitant progestin and phytoestrogens, natu(cid:173)
`rally-occurring compounds with oestrogenlc proper