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`
`
`
`
`
`
`
`
`
`
`- Dr Markus Ruharic, Med. ‘
`twerpunkt Onkologic/Hii»
`Elle der Humbolthnjve-rv
`1558 2ll/2l, Berlin, 10117,
`
`'
`
`'
`
`:. dc
`
`Drugs 2101.134 (30
`
`Medical LipidRegulating Therapy
`Current Evidence, Ongoing Trials and Future Developments
`
`Marc Evans,‘ Aled Roberts,2 Steve Davies2 and Alan Reesz
`
`1 Department of Metabolic Medicine, Diabetes and Endocrinology, University of Wales College
`Of Medicine, Cardiff Wales
`2 Department of Metabolic Medicine, Diabetes and Endocrinology, University Hospital of
`Wales, Cardiff Wales
`
`Contents
`
`Abstract. . ............................................................................‘ ..... ”81
`1. Cholesterol Lowering: Completed Trials and Current Evidence ............................... ”83
`2. Ongoing Clinical Trlals of Hold-Lowering Therapy ......................................... '.
`. NBA
`3. High Density Llpoproteln, Triglyceride and Other Upld Sublractlons: Impact on Cardlovascular
`, Dlsease ................................................................ ,~ ............... 1:85
`4.
`lnflammatlon Coronary Heart Dlséase and Upldlowedng Therapy .......................... 1186 ’
`' 5. TherapeutlcAdvances ln Upld-Lowering Therapy ...................... ..................... ”88
`51 AdvanceslnStatlnTherapy......_ ..................................' ..............’...,llt38
`5.2 Cholesterol Absorption lnhlbltors. ..................................................... use
`5.3 Acleoenzyme AvCholesterol Acyllranslerose Inhibitors ............................. i .. H90
`5.4 Mlcrosomal triglyceride Transfer Protein lnhlbltors .
`.
`.
`,
`.
`.
`.
`.
`.
`.
`; ............... ; ........... H9!
`5.5 CholesterylEsletlronslerProteinlnhiblllon..........................,...,....,.....;.'.'. llOl
`5.6 ATP—Blnding Cassette Transporter Al (Uver X Receptor) Agontsts ......................... “92
`5.7 Elle Add Transport lnhlbltors .......................................................... ll92 ,
`o. Conclusions............r...............,..........‘ ...... , ............................... ‘l392
`
`
`AbSlfGCl
`
`'
`
`
`Coronary heart disease (CHD) is a major cause of morbidity and mortality
`worldwide. Elevated low density lipoprotcimcholcslcrol (LDL—C) and reduced
`high density lipoprotcin-cholcsterol (HDL—C) levels are well recognised CHD risk
`
`factors, with recent evidence supporting thc‘bencfits ol' intcnsivc LDLLC reduc-
`
`(ion on CHD risk. Such obs’crvalions suggest
`that the. most recent National _
`‘
`
`Cholesterol Education Program Adult Treatment Panel Ill guidelines. with
`in under-treatment of a significant
`LDL—C targets ot“2.6 mmol/L,'may result
`
`number of patients and form the basis for the proposed new joint European
`
`Societies treatment targets of 2 and 4 mmol/L. respectively. for LDL and total
`cholesterol. HMGCoA reductase inhibitors (statins) reduce LDL—C by inhibiting
`
`the rate-limiting step in cholesterol biosyuthcsis and reduced CHD event rates in
`primary zind secondary prevention trials. The magnitude of this effect is not fully '
`accounted for by LDL~C reduction alone and may relate to effects on other lipid ~
`' parameters such as HDL-C and apolipoprotcins 'B and Ad, as well as additional
`anti-inflammatory effects. With increasing locus on the benefitx of intensive
`cholesterol jcduction new. more efficacious 31mins are being developed. Rosuvas-
`tatin is a potcnl, hydmphilic cnayntiomcric slatin producing reductions in LDL»C
`of up to 55%, with about 80% of patients reaching European LDL~C treatment
`mrgcrs‘at the 10 lug/day dosage.
`
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` 1182
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`Evans r! 0!,
`awninwmammuWWmmw«W.thMWmWAMMagMMWM‘mWWsza-‘mwg
`
` The Heart Protection Study (llPS) demonstrated that LDL~C reduction to
`
`
`levels as low its L7 mmol/L was associated with significant clinical benefit in a
`wide range of high-risk individuals.
`including patients with type 2 diabetes
`
`
`mellitus, or peripheral and ccrehmvascular disease. irrespective of baseline cho-
`
`lestcrol levels, with no apparent lower threshold for LDL-C with respect to risk.
`
`
`Various large endpoint trials, including Treating to New Targets (TNT) and Study
`
`
`of Effectiveness of Additional
`reductions in Cholesterol and Homocysteine
`
`
`(SEARCH) will attempt to further address the issue of optimal LDL-C reduction. ‘
`
`
`At low LDl.—C levels. HDL—C becomes an increasingly important risk factor and
`
`
`is the primary lipid abnormality in over half of CHD patients. with the Fettofibrate
`
`
`intervention and Event Lowering in Diabetes (FIELD) study set to assess the
`
`
`effect of raising HDLC on cardiovascular events in patients with low HE)!C and
`
`
`LDL-C levels below 3 mmollL
`
`
`A variety of agents are being developed which ttllcct both LDL-C and HDer
`
`
`metabolism, including inhibitors of acyl—cocn7)mt: A-cholesterol acyl tmnsfemse.
`
`
`microsonml
`transfer protein and cholesterol ester transfer protein. as well as
`
`
`specific receptor agonists. Ezetimibe is a selective} cholesterol absorption inhihi-.
`
`
`tor. which produces reductions in LDL—C of up to 25 and 60% reduction in
`
`
`chylomicmn cholesterol content with a l0 trig/day dosage
`
`
`A 1 mmol/L reduction in LDL~C results in a 25% reduction in cardiovascular
`
`
`risk; independent of baseline LDL-C levels. Growing evidence supports the
`
`
`concept that lower is better for LDL-C and that increasing HDL—C represents an
`
`
`important therapeutic target. Furthermore, there is growing appreciation of the
`
`
`role of inflamrriation in ntherogenesis. Consequently/V increasing numbers of
`
`
`people should receive lipidrregulating therapy with the development of newer
`
`
`agents offering potential mechanisms of optimising lipid profiles and thus risk
`
`
`reductionhln addition, the pleiotmpic anti-inflammatory effects or lipid lowering
`
`
`therapy. inay provide further risk reduction.
`
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`it: find Adla Data lnlormolion BV. All rights IBSO'VLKJ.
`Drugsmmdrtt)
`
`
`Despite major advances in the pharmacologicol
`- and surgical
`treatment of cardiovascular disease.
`coronary heart disease (CHD) remains the leading
`cause of death in thc‘industrialised world,m with the
`global burden of disease continuing to increasu in
`association withthe increasing prevalence of type 2
`diabetes mellitus, obesity and the metabolic syn-
`dr‘orne.‘21 Elevated levels of total cholesterol and low
`density ‘lipoprotein cholesterol (LDL~C) are well
`recognised CHD risk factorsm and the reduction of
`total cholesterol and LDL—C is associated with utt-
`
`rnerous sequelae, which attenuate atherogehesis in-
`clnding improved endothelial function, reduced oxi»
`dative Stress and reduced inflammation,”-” Choles-
`terol reduction is associated with a reduced risk of
`CHDJ‘S‘” with recent‘evidence from the Medical
`Research Council/British Heart Fortndation Heart
`
`Protection Study (HPS) demonstrating that the hen—'
`etits of cholesterol-lowering therapy extend into all
`
`forms ol‘ atherosclerotic vascular disease including
`peripheral vascular disease and cerebrovascular dis-
`easerl
`Observational studies indicaten'continuous and
`positive relationship between plasmir-“cholesteml
`levels and cardiovascular l’lSk‘ with no apparent
`lower threshold level at which there is no increased
`
`risk.l”~'°‘ This relationship is approximately linear
`when plotted on a logarithmic scule, implying that
`the proportional reduction in relative risk is similar
`throughout the range of cholesterol levels.
`Several large randomised trials have shown that
`LDL—C reduction with the HMG~COA reductaSc -
`inhibitors (statins) of 25-35% is associated with a
`24—37% decrease in cardiovascular mortulity.”"’3l
`Furthennore, reductions in coronary death of up to
`24% with a longotenn difference of l mmol/L in
`‘LDL—C levels in individuals with and without diag—
`nosed vascular discasc,
`irrespective of baseline
`
`
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`lltlFS
`Medical Lipid-Regulating Therapy W
`WRWAWMMW’wawww.whwvhvvmwumu\mw«NQWWWMWVW.V~VMvmwtwmvWW9“
`
`reduction beyond which additional cardiovascular
`benefit may not be achieved.
`to the
`Controversy thus remains with respect
`magnitude of LDL-C reduction required to niax~
`imise clinical benefit. The results of the HPS‘“j
`demonstrated a similar 25% evcnt rate reduction
`with l mmol/L reduction in LDL-C independent of
`pretreatment
`levels. with continuing benefit seen
`with [.13ch reduction to levels as low as 1.7 mmol/
`
`L. These observations suggest that there appears to
`be no baseline threshold for initiation of statin ther-
`apy. and current guidelines such as the National
`Cholesterol Education Program (NCEP) Adult
`Treatment Panel (ATP) ill and the Ztid‘European
`Joint Task Force recommendations!"’1‘” with LDL-
`C goals of 2.6 and 3.0 tnmol/L, respectively, may
`lead to'undervttcntment of at~risk individuals who
`present with LDL-C levels at or near these levels.
`The question that remains is how low these treat-
`ment goals should be, u situation which may be
`addressed, by the new Joint European Societies
`guidelines, which are due to be published in mid
`2004 and are set to define treatment goals of 2 and
`4 mntol/L, respectively, for LDL and total choles-
`terol.
`.
`y
`in BPS the chief determinants of CHD risk were
`preexisting vascular disease (CHD, cerebrovasv
`cular disease, peripheral vascular disease), the pres-
`ence or absence of type 2 diabetes. or some combi-
`nation of these conditions, with significant reduc-
`tions in risk produced by statin therapy irreSpective ,
`of pretreatment LDL—C levels On the basis of such
`observations it appears logical to include peripheral
`vascular disease, cerebrovascular disease and CH0
`in assessing the need to commence statin therapy.
`The benefits of LDL-C reduction in individuals
`
`with LDL-C levels at or near present target values
`was further illustrated‘in a post‘coronary percutane-
`ous intervention study using fiuvastatin,”'1 While the
`benefits ofintensive cholesterol lowering on cardin’
`vascular events are lurther supported by the Myo- __
`onrdial lschemia Reduction with Aggressive Cho-
`lesterol Lowering (MIRACL) trial. l*l The Atorvas-
`tatin
`versus Simvastatin
`on Atherosclerosis
`
`Progression (ASAP) and Arterial Biology tbr the
`investigation of the Treatment Effects of Reducing
`cholesterol (ARBITER) studies‘l’c'“ demonstrated
`the effects of intensive cholesterol reduction on the
`
`
`
`-
`
`Etmns (-t «I.
`mmmvmmw.
`
`LDLvC reduction to
`nt clinical benefit in a
`
`with type 2 diabetes
`:ctive of baseline cho-
`C with respect to risk.
`rgets (TNT) and Study
`)l and Homocysleinc
`mul LDL—C reduction.
`portant risk factor and
`s. with the Fettofibmte
`tudy set to assess the
`sw‘ith low HDL—C and
`
`th LDL—C and HDL-C.
`sterolacyl tmnst‘erase.
`:r protein, as well as
`:rol absorption inhibi—
`md 60% reduction in
`
`:tion in cardiovascular
`:vidence supports the
`HDL-C represents an'
`lg appreciation of the
`icreasing numbers oi"
`levelopment of newer.
`profiles and thus risk
`‘fects of lipid lowering
`
`LDLC levels.in raise questions regarding optimal
`target levels for cholesterol and imply a lower the
`better approach to cholesterol reduction.
`Cutrently there are five main classes of drugs
`available for the treatment of dysiipidaemiu: bile
`acid binding agents (resins); libric acid derivatives
`. (librates): nicotinie acid (niacin); I‘lMG-CoA reduc‘
`tase inhibitors (statins); and ezetimibc and the
`phytostanols and esters, although these are not yet in
`widespread use The statins are the most potent
`LDL‘C-lowering agents. but have van‘able effects
`on high density lipoprotein--cholesterol (HDL--C)
`This'is a potential limitation with respect to optimal
`CHD risk reduction with statin therapy, since low
`.HDL-C is the primary lipid abnormality in approxi»
`matcly hall' of CHD patientsml
`In this article “we review the most recent. evidence
`and guidelines regarding lipid lowering and vascular
`risk reduction and how these may influence the
`design and objectives of future clinical trials In
`addition. with increasing focus on the potential ben—
`bills ofintensive lipid modification, we also discuss
`recent advances in lipiddowering therapy and how
`these may relate to future-treatment strategies.
`
`ll. Cholesterol towering: Completed
`Trials and Currenl'Evlclence
`
`
`
`. tseular disease including
`and cerebrovascular dis-*
`
`idicate a continuous and
`
`con plasma cholesterol
`risk, with no apparent
`rich there is no increased
`is approximately linear
`mic scale, implying that
`in relative rislt'is similar
`olesterol levels.
`
`:d trialshnve shown that
`c HMO-(70A retluctase
`59" is associated with a
`
`.wascular tnonality.l”'”l
`coronary death of up to
`Terence of l inmol/L in
`
`s with and without diag—
`irrespective of baseline
`
`
`
`
`Despite the clear epidemiological association be-
`tween cholesterol and cardiovascular risk. the ma-
`joritypl' individuals who develop vascular disease
`; do not have particularly elevated cholesterol levels.
`Epidemiological evidence supporting the notion
`that lower LDL-C levels are associated with lower
`
`-
`
`CHD risk comes from, among others. studies of men
`in" rural China, where subjects in the lowest quartile
`’of LDL—C (<3.0 mmol/L) had coronary event rates
`75% lower than those in the highest qtittttile.“5l
`Further evidence in support of this notion comes
`front the Seven Countries study,l"‘l as well as pro-
`spective longitudinal studies such as the Prospective
`Cardiovascular Munster (PROCAM) study and the
`Framingham study.“7~'5’ Every major clinical end
`point trial of statin therapy has demonstrated that
`lower LDL—C levels are associated with a reduced
`.atherosclerotic disease burden!“ Such observations
`suggest that. there may be no threshold for LDl..-C
`
`DmgsZOO-flzbdlll)
`
`Jr» 2004 Adi: Onto lntormotlon BV. All lighl: reserved.
`
`DIupsi‘OOd:ort(ll)
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`limits at rrl,
`\wMMme‘\r-\\W-WMWMVWWI‘mWWhWWmMWWNMvWmy.
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`Table 1. Future studies evaluating the clinical benefits oi more aggressive cholesterol lowering
`
`
` Trial No. of participants Treatment
`Primary endpoint
`Coronary death or nonlatal Ml
`lDEAUNl
`7600
`Atorvastatin 80mg or simvastalin 20—40mg
`Coronary death or noniatal Mt
`SEARCHI‘M
`12 000
`Simvastatln 80 or 20mg 1 vitamin 812 and
`loiic add (2mg)
`Atorvaslatin 80mg orbpravastatin 40mg
`‘ Atorvastatin 80mg or prevestetln 40mg
`
`BELLESW
`~ REVERSALN
`
`’
`
`600
`600
`
`>lO 000
`10000
`
`TN‘W‘"
`Atorvastatln to or 80mg
`HPS ll'f”)
`Slmvasiatln 80 or 20—40mg : vitamin E312
`
`and tells acid (2mg)
`BELLES a Beyond Endorsed Lipid Levels Evaluation Study; 6801 = electron beam computerised tomography; HPS ll = Heart Protection
`Study ll; lDEAL = incremental Decrease in End points through Aggressive cholesterol Lowering: lvus = intravescular ultrasound; Mr :1
`myocardial inlarcilon; BEVERSAL c Reversal oi Atherosclerosis with Lipilor Study: SEARCH :2 Study of the Ettacth’leness ol Additional
`Reductions in Cholesterol and Homocysleine: TNT = Treating to New Targets
`
` 1184
`
`Calcium content 01 coronary arteries by EBCT
`Coronary artery lntlmal medial accumulation at
`lesions as measured by lVUS
`Coronary death“ or noniatel‘Ml
`Major cardiovascutar events
`
`\
`
`(TNT) trial, more than 10 000 puticnts have been
`enrolled to assess the effects. of LDL»C reduction to
`below 2.6 mmol/L in patients aged 35—75 years who
`have had a major coronary event within the previous
`5 years.
`V
`in Endpoints
`In
`the
`incremental Decrease
`through Aggressive Lipid lowering (IDEAL) tn‘al,
`7600'patients with a history of myocardial infarction
`will be randomised to atorvustatin 80 mg/day or
`simvastatin 20 trig/day, titrated to 40mg/duy if total
`cholesterol remains >5 mmol/L. A follow-up period
`of 5.5 years is planned and a large segment of
`elderly patients will he studied.
`The Study of the Effectiveness of Additional
`Reductions
`in Cholesterol
`and Homocystcinc
`(SEARCH).is a secondary-prevention trial of 12 000
`patients with a 2 x 2 factorial design to simvastatin
`80 mg/day or simvastatin 20 mg/day with or without
`folatc (2 mg/dayyvitamin B12. Other studies using
`electron beam computerised tomography or
`in-
`travascular ultrasound to evaluate changes in ana~
`tomic features of atherosclerosis are also under way.
`in the Beyond Endorsed Lipid Levels Evaluation
`Study (BELLES) and the Reversal of Atherosclero—
`sis with Lipitor (REVERSAL) study, the effects of
`high~dosc (80 trig/day) ntorvastatin and pravastutin
`40 rug/day on coronary atherosclerosis willhc stud-
`ied over 12- and 18-month periods, respectively.
`The Pt‘avaslatin or Atorvastatin Evaluation and
`
`infection Therapy (PROVE-1T) study has a 2x2
`factorial design and will compare the effects of
`atorvastntln 80 lug/day and pravasmu’n 40 mg/day
`on major cardiovascular events. The second limb
`
`early structural changes of atherosclerosis in the
`form of reduction in carotid intima media thickness.
`The Antihypertensivc and Lipid—Lowering Treat-
`ment
`to prevent Heart Attack Tn’ul
`(ALLHAT—
`LLT), in which more than 10000 moderately hyper
`.cholcsterolaemic, hypertensive individuals were
`randomised to-reccive either usual care or pravnstn-
`tin 40 mg/day. demonstrated no significant. differ-
`ence in CHD mortality between both groitps.‘m
`Because of the' use of non-trial statins and'cross-
`oven; in the usual-cure group, there were only mod—
`csl differences in total cholesterol (9.6%) and LDL
`C (16.7%) between the two groups, This observe“
`tion;
`that
`less cholesterol lowering produces less
`clinical benefit, provides further indirect support for
`the hypothesis that robust LDL-C reduction is re-
`quircd'to prtxiucé significant outcome benefits. The
`results of ALLHAT~LLT also suggest that choles—
`lcroi lowaring remains central to the benefits pro-
`duced by statin therapy for CHD prevention and that
`the reported pleiotropic effects do not appear to
`significantly contribute to the therapeutic benefits of
`Statins.
`‘
`
`is
`therefore,
`The pertinent clinical question.
`whether larger reductions in LDL-C may produce
`greater risk reductions, an issue that is the subject of
`various ongoing randomised trials.
`
`2. Ongoing Clinical Trials of
`tipidoLowerlng Therapy
`
`A number of clinical trials assessing the potential,
`benefits of aggressive cholesterol
`lowering arc
`under way (table 1). in the Treating to New Targets
`
`O 2% Add Doro tnlormon'on 8V. All riglils reserved.
`
`02139520040401)
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`-Wm—‘—WM—Nmw.. ~M‘Movavh‘II‘2M.saw
`
`3185
`WW“
`Medical LipidRegulntutg Therapy
`mWmmmawvwmmw«WWWWWWMm§vaAMWWWWm
`
`
`
`includes evaluating the effects of gatifloxncin. n
`fluoroquinolone, against. placebo on cardiovascular
`events and will provide the first major endpoint
`evidence relating to the importance of addtessing
`low—grade infection on cardiovascular risk. ‘
`- it has been recently suggested that at low LDL-C,
`elevated plasma triglyceride and low HDL-C levels
`-,becomc increasingly important with respect to de—
`termining, vascular risk.”” Future studies will he
`
`.mquircd to specifically address the potential addi-
`tional cardiovascular benefits of treating hypertrig—
`
`lyceridaemiu and low HDLoc in patients with low
`LDL-C levels, particularly in view of the incneasing
`focus on lower LDL—C treatment targets. Indeed, a
`'clinical trial
`is already under way to evaluate the
`‘ hcnelits of raising i-lDL»C and lowering triglyceride
`levels in patients with type 2 diabetes and modest
`LDLC levels The Fcnot'tbrate Intervention and
`
`'
`
`Evans at 0!.WWW
`
`Jr nonfatal Mi
`)1 nonfatal Ml
`
`ol coronary arteries by EBCT
`nllmal medial accumuletlon oi
`ired by lVUS
`>r nonlatal Ml
`=ulat events
`
`iph'y; HPS it = Heart Protection
`lntravascmar ultrasound: Mt a
`the Ellectlvenéss o! Aodltlonat
`
`
`000 patients have been
`5 of LDL‘C reduction to
`
`ts aged 35—75 years‘who
`vent within the previous
`
`in Endpoints
`lecrease
`owering (lDEAL)'trinl.
`of myocardial infarction
`rvastatin 80 trig/day or
`nod to 40mg/day if total
`)l/L. A follow-up period
`nd a large segment of
`iied,
`'
`:tiveness of Additional
`)l
`and Homocysteine
`rcvention lrialof l2 000
`al design to simvastatin
`lmg/day with or without
`$12. Other studies using
`ed tomography or
`in‘
`valuatc changes in amp
`rosis are also under way.
`..ipid Levels Evaluation
`:vcrsal of Atherosclero~
`tL) study. the etfeets of
`vastatin and pmvastatin
`rosclerosis will betstud-
`periods, respectively.
`vastatin Evaluation and
`
`i-I'I‘) study has a 2x 2
`:ompare the effects of
`pravastatin 40 mg/day
`lents. The second limb
`
`DmgsZOMHSAIH)
`
`
`
`
`
`
`
`
`
`"Event Loweringin Diabetes (FlELD) trialis due to
`report in 2005.133
`The clinical significance of the pleiotropic effects
`of statin therapyis controversial. However. a recent
`post hoc analysis of the Westof Scotland Coronary
`Prevention Study (WOSCOPS) data suggested that
`.pravastatin therapy may acnially reduce incident
`.typc 2 diabetesfm The insulin resistance Or meta-
`bolic syndrome is a recognised risk factor for both
`cardiovascular disease and the development of type
`Z‘diahctes,'and is estimated to affect up to 30% of
`the US population.mi Indeed. the recent NCEP ATP
`. Ill guidelines provide definitive criteria forthe diag— _
`nosis of the metabolic syndrome?" Future trials
`may thus focus on the therapeutic effects of statins.
`fibrntes and other agents in individuals with the
`metabolic syndrome, from the perspective of both
`cardiovascular risk and the development of type ’2
`diabetes.
`
`3. High Density tipoproteln, Triglyceride
`and Other Lipid Subtroctions: impact on
`Cardiovascular Disease
`
`Although high LDL-C is undoubtedly a causal
`risk factor for CHD. LDL—C alone is insufficient to
`fully evaluate cardiovascular risk.‘351 The role of
`triglyceride (TG) and HDL-C levels in determining
`vascular risk has been demonstrated by the PRO-
`CAM and Veterans Affairs High—density lipoprotein
`intervention Trial (VA-HIT) studies‘lm“ Within
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`{2 2C0: Adi; Dole Inl'orrnollon BV, All dgnls reserved.
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`each LDL—C subgroup. the risk of myocardial in‘
`{motion increased with increasing TG levels and
`reduced HDL-C levels, an effect
`that was most
`pronounced in individuals with lower LDL«C levels.
`The Air Force/Texas Coronary Atherosclerosis
`Pievention Study (AFCAPS/l‘exCAPS) further il—
`lustrated the importance of HDL-C in predicting
`CHD risk in individuals with average LDL-C levels.
`in this study, individuals with low HDbC and aver~
`age LDL-C levels disproportionately benefited from
`statin therapy!” HDL apolipoprotein (apolA-l
`kinetic studies have shown that statin treatment can
`increase apoA-l production but, the evidence is not
`conclusiveJ-“l with cholesterol depletion in hepato-
`cyles resulting in selective uprcgulation of the SRB~
`l receptor, facilitating the removal of HDL‘Z, which
`may account for the ovurcalabolism. Oversynthesis
`may be related to an effect on petoxisome prolifer-
`slur-activated receptor or (PPARrx) and increased
`apoA-l synthesis“) Statins have also been shown to
`produce modest "reductions
`in cholesteryl ester
`transfer protein (CETP) activitydd‘” since reduced
`CE’I‘P activity may be associated with increased
`HDL levels!“) this effect may partly account for the
`modest effects of statins on increasing HDL. How-
`ever.
`the precise mechanisms by which statins
`modify HDL-C and how individual statins may. dif-
`fer in this regard are still uncertain.
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`Although evidence accumulates to support plas-
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`the _cffects,,9f..TG
`ma TC as n CED t‘isklactor.
`reduction on C HD outcome are unclear. Indeed. the
`
`NCEP ATP lll guidelines recommend that corrcc— 5
`tion of hyperhiglyceridaemia (>l .6 mrnol/L) should
`be considered only following the treatment of
`(LDL-C and HDL—C to targetntl
`The influence of statins on CHD risk reduction in
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`hypenriglyceridaemic patients also remains conten-
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`tious. Statins exert ’l‘G-lowcn'ng effects via several
`
`different mechanisms: (i). by increasing expression
`of LDL receptors; (ii) increasing the clearance of
`TG-containing lipoprotcins: and (iii) inducing acti-
`vation of PPAROt, which may decrease hepatic ll‘illl-
`scription of apolipoprotein C—lll, thus altering the
`composition of TG-containing lipoproteins such that.
`their cataholism is enhanced“) These effects may
`be particularly important in the management ot’dys-
`lipidaemia in patients with type 2 diabetes, where
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`the primary defect is excess generation of TG-rlch
`lipoprotein particles."‘3’
`A focus on LDL-C alone may incompletely iden-
`tify patients at risk and it is also conceivable that
`some" patients may benefit from therapy that does
`- not have LDL—C reduction as aprimary effect. Both
`the VA~HIT and Bezafibratc infarction Prevention
`
`indicate that hypertn'glycer—
`(BIPW‘LM studies
`idaemic patients with low HDL-C may benefit from
`librate thcrtipy. In VA—HlT, a' 22% reduction in
`coronoty events over 5 years was seen in men with
`coronary disease. and baseline levels of LDL-C
`<3.6 mmol/L, plasma TG <33 mmol/L andHDch
`<l mntol/L. This risk reduction was associated with
`no change in LDL~C and, avcrage reduction in T6
`of 3l% and increase in HDL—C of 6%. Furthermore,
`in the Diabetes Atherosclerosis Intervention Study
`(DAIS), of 73l patients with type 2 diabetes. a 29%
`reduction in plasma TG and a 6% increase in
`HDL-C following therapy were associated with'a
`significant reduction in'atlterosclcrotic disease pio-
`gressionfl‘m The ongoing FIELD study will attempt
`to address the issues of treating HDL-C and plasma
`TC in patients with type 2 diabetes. This is a 4~year
`primary prevention study using microniscd fe-
`not‘tbmte in patients with type 2 diabetes and LDL-C
`inclusion criterion of <3 tmnol/b and primary end-
`point of cardiovascular eventsm
`.
`The NCEP ATP lll guidelines recommend the
`use of no‘n—HDL-C as a secondary goal of lipid
`lowering after achieving target LDL~C levels.“9"
`Because of its simple Calculation, non—HDL-C mea~
`surement is readily available in clinical practice with
`no additional cost. Since it circumvean TG mea-
`surement. it avoids the potential limitations of TG as
`u CHD risk marker and directly reflects the choles-
`terol content of all proatherogcnic lipoprotein par—_
`ticles, that is, very low density lipoprotein (VLDL).
`intermediate density lipoprotein (lDL). LDL and
`even lipoprotcin (a). Fttrthennote, since its deriva-
`tion does not require a fasting sample,
`it avoids
`potential interindividual variability due to postpran-
`dial
`lipid changes. A routine calculated LDL—C
`_ could not circumvent many of these limitations,
`since its accurate estimation via the Friedwald equa-
`tion requires plasma TG <45 mmol/LL, Indeed, the
`results of the strong heart study, supported by data
`from the Systolic Hypertension in the Elderly Pro—
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`1: 2011 Add Dole lnlormotlon BV. All rights reserved.
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` Evans t)! al.
`”www.mm
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`grant (SHBP) and Lipid Research Clinics (LRC)
`studies.i"°'4sl support the utility of non-HDL-C as a
`superior predictor of CHD risk both in diabetic and
`nondiabetic individuals.
`
`It is clear that accurate risk assessment requires
`the assessment of multiple lipid parameters. Optimal
`risk reduction and lipid—regulating therapy may re-
`quire either monothempy or combination therapy,
`thus resulting in the development of a targeted strat-
`egy using a variety of agents. The precedent for such
`an approach has been setin the evolution of pharma-
`cothertipy in hypertension.
`
`4. inflammation, Coronary Heart Disease
`and Lipid-Lowering Therapy
`
`Compelling evidence for the importance of in-
`flammation in atherosclerotic disease has evolved in
`
`parallel from both clinical and experimental stud-
`ies!” Indeed, accumulating data indicate that
`in—
`sights gained from the link between inflammation
`and atherosclerosis may‘yield prognostic informa-
`tion of potential clinical value:
`A varietyof studies have demonstrated that in-
`flammation, as itteasuied by C—reactive protein
`(CRP) levels. may be an important cardiovascular
`risk factorfiml These studies have included elderly as
`well as middle-aged subjects and have shown con-
`sistency for the development of first-ever myo-
`cardial infarction, stroke or symptomatic peripheral
`vascular disease.”()1 indeed, in a recent study of
`27 939 womenfollowed for 8 years for vascular
`events. CRP level was a stronger independent prc~
`dictor of cardiovascular events than [Dual-W Fur-
`thermore. in the Cholesterol and Recurrent Events
`(CARE) study the magnitude of risk reduction at-
`tributable to pravastatin therapy was greater among
`individuals with evidence of enhanced inflamma-
`
`tion?” while lovastatin therapy in the AFCAPS/
`TexCAPS trial produced the greatest benefit in sub-
`jects with elevated CRP levels irrespective of LDL—
`C153)
`
`Various models linking lipid metabolism and in-
`fiammation to atherosclerosis have been developed.
`According to the LDL oxidation hypothesis. LDL—C
`particles retained in the intirna, partly by pmteogly-
`can binding. undergo oxidative modification, pro—
`ducing modified lipoptotcin particles that can in-
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`‘sutmtl’amily, which are widely expressed on a
`variety of tissues including atherosclerotic tissue _
`and inflammatory cells”?-591 To date, three different ,
`PPAR subtypes have been identified: PPAROL.
`PPARlS/B and PPARy. Fibrates
`are synthetic
`PPAROL agonists, whereas
`the thiazolidinedione
`(TZD) clussot’ insulin~sensitising drugs, which also
`have multiple effects on lipid metabolism, are syn-
`thetic PPARY agonistsl‘m Recent data have demon-
`‘strated that
`fenofibrate. via its PPAROL ngonist
`pmperties, may exert unthinflummatory effects'by
`repressing cytokinc—induced activation of a number
`of inflammatory genes such as VCAM ~1 , COX—‘Znnd
`111-6 by negatively interfering with NF-K‘B transcrip
`tional activityme
`.
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`,
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`A variety of studies have established the role for
`PPAR'y in modulating inflammatory responsesJQ-ml
`with data accumulating to support the potential anti—
`inflammatory effects of the TZDs. Both in vitro, and
`animalstudies have demonstrated that T'ZD therapy,
`including 'rosiglitazone, pioglitazone and troglita-
`zone; inhibits tissue factor and inflammatory cyto«
`kine expression as well as macrophage activa—
`doom“)
`
`
`
`.esearch Clinics (LRC)
`lily of non~HDL~C as a
`isk both in diabetic and
`
`isk assessment requires
`pid parameters. Optimal
`nlating therapy may re-
`‘r combination therapy,
`ment of a targeted stntt~
`. The precedent for such
`he evolution of phanna~
`
`mory Heart Disease
`herapy
`
`.' the importance of in-
`c disease has evolved in
`
`and experimental stud»
`33 data indicate that in-
`between inflammation '
`:ld prognostic infomttn
`ue.
`_
`_
`e demonstrated met in-
`.by C—reactive protein
`riportant cardiovascular
`have included elderly as
`as and have shown’con’
`
`etit of fnstoever' myo-
`symptomatic peripheral
`,
`in a recent study of
`)I‘ 8 years for vascular
`'onger independent pre~
`nts than LDL-C.‘-"” Fur—
`l and Recurrent Events
`do of risk reduction at-'
`
`:apy was grenteramong
`3f entranced inflamma-
`empy‘ in .the AFCAPS/