C5
`
`Review
`
`Monthly Focus: Cardiovascular; Renal, Endocrine & Metabolic
`
`Pharmacotherapy for
`dyslipidaemia - current therapies
`and future agents
`
`Harold Bayst & Evan A Stein
`'L-MARC Research Center. 3288 blinolsAvenue, louisvllleKY 40213. USA
`
`Current lipid-altering agents that lower low density lipoprotein cholesterol
`(~Dl~C) primarily through increased hepatic LDL receptor activity include stat(cid:173)
`ins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as
`ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuti~al.s such as
`oat bran, psyllium and soy proteins; those currently in development include
`. newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid_
`transport inhibitors and SREBP cleavage-activating protein (SCAP) activating
`ligands. Other current agents that C'lffect lipid metabolism include nicotinic
`acid (niacin).· acipimox, high-dose fish oils, antioxidants and policosanol, whilst
`those in development include microsomal triglyceride transfer protein (MTP)
`inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAD i~hibitors, gem(cid:173)
`cabene. lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists.
`anti-inflammatory agents (such as lp-PLA2 antagonists and AGl-1067) and
`functional oils. Current agents that affect nuclear. receptors include PPAR-a
`and -y agonists, while in development a~e newer PPAR-a, -y and -0 agonists, as
`well as dual PPAR-a/y and 'pan' PPAR-o:fy/~ agonists. Liver X receptor (LXR), far(cid:173)
`nesoid X receptor (FXR) and sterol-regulatory element binding protein
`(SREBP) are also nuclear receptor large.ts of investigational agents. Agents in
`development also may affect high density lipoprotein cholesterol (HDL-C)
`blood levels or flux and include cholesteryl ester transfer protein (CETP) inhib(cid:173)
`itors (such as torcetrapib), CETP vaccines. various HDL 'therapies' and upregu(cid:173)
`lators of ATP-binding cassette transporter (ABC) A1, lecithin cholest~rol
`acyltransferase (LCAD and scavenger receptor class B Type 1 (SRB1), as well as
`synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination·
`lipid-altering drugs are currently available such as extended-release niacin/lov(cid:173)
`astatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvasta(cid:173)
`tin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin ·
`and pravastati_n/aspirin are under development. Finally. current arid future
`lipid-altering drugs may include anti-obesity agents which could favourably
`affect lipid levels.
`
`Keywords: ABC Al. ACAT, aclpimox, adlposopathy, AGI-!067, CETP. cholesterol, CRP. ezetlmlbe.
`· FM-VP4. FXR. gemcabene. HDL-C, lmplitaplde. JUPITER. large unllamellar vesicles, LCAT.
`LDL-C. ll!lbrol, lipid, Lp-PLA2• LXR. MTP. niacin, PAF-AH. pantethlne. pantothenlc acid,
`phytostanol. PPAR. RXR. squalene synthase, SRB I, SREBP. stanol, sterol, torcetraplb, triglyceride
`
`Expert Opin. Pharmacother. (2003) 4(11):1901-1938 ·
`
`1. Background
`
`Atherosclerosis is by far the single most important pathological process in the
`development of coronary heart disease (CHO), which is the single most common.
`cause of morbidity and mortality in both men and women in developed nations
`
`2003 C> Ashley Publications ltd ISSN 1465'6566
`
`1901
`
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`for reprint ord(ffS, please.
`·
`contact:
`reprints@ashfey"pup.co.m
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`
`Pharmacotherapy for dyslipidaemia - current therapies and future agents
`
`Table 1. lipid-altering efficacy of common lipid-altering agents [JJ.
`
`lipid-altering agent
`
`Change in LDL-C (%)
`
`Change in triglyeride (%)
`
`Change in HDL-C (%)
`
`.J, 7-30
`i 5-15
`.l.18-55
`Statins
`.I. 20- 50
`.I. 5-25
`i 15 - 35
`Nicotinic acid (niacin)
`.I. 20- 50
`.I. 5 - 20·
`i 10-20
`Fibric acids (fibrates)
`.I. 4 . 11
`i2-5
`,j.17 - 22
`Ezetimibe
`i3-5
`.J, 15 - 30
`No changeto increased
`Bile acid sequestrants
`.I. 20- 50
`No change to increased
`No change to increased
`Fish oils1
`No change to increased
`No change to decreased
`.J.10-15
`Ph}'t:osterols/phytostanols
`•fibrates may increase LDL-C blood levels in some patients with hypertrigly<:eridaemia. 'The lipid-altering effects of fish oil listed are with administratlo1lof - 5 - 9 g
`or omega-3 fatty acids per day.
`HDL-C: High density lipoproteln-cholesterol; LDl-C: Low density lipoproteln-cholesterol.
`
`13011. Atherosclerosis is a complex disease with multiple risk
`factors. I~ has been reported that 80 - 90% of patients who
`develop significant CHD and > 9S% of patients who experi(cid:173)
`ence fatal CHO have major atherosclerotlc risk factors, such
`as cigarette smoking, diabetes mellitus, hypertension and
`dyslipidaemla Ill - all of which are modifiable through life(cid:173)
`style, diet or therapeutic measures.
`With regard to treatment of dyslipldaemia, numerous well(cid:173)
`_ controlied outcome studies of lipid-altering drug mono(cid:173)
`therapy in > 50,000 subjects have consistently demonstrated a
`relatlye CHO risk reduction (compared to placebo) of only
`- 20 - 40% after - 3 - 6 years of therapy 121. Thus, the major(cid:173)
`ity of patients observed in monotherapy trials of lipid-altering
`drugs have not had their CHO .'prevented'. This suggests that
`further absolute and relative CHO risk will only be achieved
`through extending the duration of. lipid-altering therapy,
`achieving more aggressive lipid treatment goals and treating
`multiple lipid parameters. "It may also be reasonable to con-
`. elude that the best way to further reduce CHO risk is to
`aggressively correct the abnormality or abnormalities which
`contribute most to the atherosclerotic process in the Individ(cid:173)
`ual patient. This may occur through monotherapy. or perhaps
`through a multifactorial approach with the use of a variety of
`anti-atherogenic agents whose mechanisms of actions differ,
`and whose treatment targets· may result in additive and/or
`complementary benefits.
`Towards reaching these goals, authoritative bodies such as
`the National Cholesterol Education Program, Adult Treatment
`Panel III (NCEP ATP III) have established guidelines with the
`primary focus being the achievement of low density Jipoprotein
`cholesterol (LOL-C) treatment targets, which is based upon a
`vast amount of data largely derived from evidenced-based out- .
`comes trials (3J. Thus, a reduction in LOL-C blood levels
`remains the primary target of most current lipid-altering drugs
`{Table 1). However, emerging data has suggested that improve(cid:173)
`ments in other lipoprotein parameters might also be beneficial.
`This has prompted the NCJ;:P ATP III to include additional
`treatment targets, such as non-high density lipoprotein choles(cid:173)
`terol {non-HOL-C) blood levels in patients with hypertrigly-
`
`cerldaemia. Other experts have also suggested that the evidence
`Is compelling enough to recommend HOL-C blood levels as a
`specific treatment target 12.41. Finally, the NCEP ATP III has
`recognised a number of emerging CHO risk factors, such as
`Inflammatory markers and lipoprotein ·particle size, that may
`have prognostic and potential therapeutic implications.
`
`2. Current agents that predominantly increase
`LDL/ ApoB - E receptor activity
`
`2.1 Agents that impair cholesterol synthesis (statins)
`The origin~ of cholesterol in LDL-C are from predominantly
`three -sources: peripheral cholesterol synthesis; hepatic choles(cid:173)
`terol
`synthesis; and
`intestinal
`cholesterol
`absorption
`(Figure 1). The relative contribution of each is likely to be the
`result of genetic predisposition, dietary· factors, physical exer(cid:173)
`cise, lifestyle habits, drug therapy and a complex interplay of
`enzymatic up- and downregulation (5). However, Irrespective
`of. the origin of cholesterol. the liver Is the major regulating
`organ of circulating LOL-C. mainly through the up- and
`downregulation of hepatic LOL receptors (Figure 1).
`Lipid-altering agents which impair liver cholesterol synthe(cid:173)
`sis, as illustrated by statins, lower LOL-C blood levels through
`the .secondary upregulation and increased activity of .hepatic
`LOL receptors. At therapeutic doses, bl~od levels of all statins
`are measurable in the peripheral circulation. Thus, various
`other non-hepatic tissues which synthesise cholesterol and
`which possess LOL receptors on their cellular membranes, are
`also exposed to statins to some extent. However, the principal
`therapeutic target of statins Is the liver. Thus, the vast major~
`ity of clearance of circulating LOL-C Is specifically through
`hepatic LOL receptors.
`A reduction In the exposure of arterial endothelia to circu(cid:173)
`lating LOL-C reduces the potential for LDL receptor inde(cid:173)
`pendent cholesterol diffusion across the arterial endothelia
`and thus, reduces potential cholesterol uptake by subendothe(cid:173)
`lial macrophages. Reduction in macrophage foam-cell crea(cid:173)
`tion reduces
`the subsequent creation of atherosclerotic
`plaques and inflammatory response (Figure 2), thus reducing
`
`1902
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`. .
`
`. .... "
`
`" .
`
`Arterial lumen
`
`Intestinal eplthellat cell
`
`Biliary
`cholesterol
`
`Dietary
`cholesterol
`
`Atherosclerotic plaque/foam cells
`
`~1
`
`·~
`
`LOlJApo B-E
`receptor
`/
`
`Hepatic cholesterol synthesis
`
`Increased liver low density lipoprotein receptor
`activity decreases circulating low density
`lipoprotein and reduces risk of atheroma
`
`Intestinal cholesterol absorption
`
`Low density llpoprotein
`
`e~e~e.,, ~
`-~---~
`l
`. . . . . .
`
`atherosclerotic plaque
`~
`
`Decreased liver low densitY lipoprotein receptor
`activity increases circulating low density lipoprotein I Diseased artery with Increased plaque
`cholesterol, and increases risk of atheroma
`
`.g'
`~
`-& ;:;·
`J I
`~
`~ .!:!
`~ =
`
`I p~~il'll~r<l1 ~ll~1~st~r~1 5)-r;tll~sisJ
`
`ti (©
`@
`
`Low density lipoprotein
`
`l
`. . . . . . . . . . . .
`. . . . . . . . . . . .
`<::::::>
`-.....
`<!::> ~
`Healthier artery with decreased plaque
`
`Figure 1. A simplified figure of cholesterol origins of LDL-C. Cholesterol may be derived from peripheral and liver synthesis. or intestinal cholesterol absorption. An increase in
`hepatic LDL-C receptor activity (through interventions such as diet and therapeutic agents) may increase clearance of circulating LDL-C, reduce LDL-C levels. reduce atherosclerotic plaque
`formation. and thus reduce CHO risk. A decrease in hepatic LDL-C receptor activity may Increase circulating LDL-C levels, ihcrease the risk of LDL-C diffusion into the intima. increase
`inflammatory cell activity with formation of an atheroma or atherosclerotic plaque. and thus increase CHO risk. Adapted from 1221.
`...
`:g ABC: ATP-binding cassette: ACAT: Acyl-coenzyme A cholesterol acyltransferase; CM: Chytomicrons; HDL: High-densily lipoprotein: LDL·R: Low-density lipoprotein receptor;
`c.o MTP: Microsomal trigtyceride transfer protein; SRBl: Scavenger.receptor dass B Type 1.
`1
`
`m
`I»
`~
`
`12" s s·
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`
`Pharmacotherapy for dyslipidaemia - current therapies and future agents
`
`Monocyte
`
`Vessel lumen
`
`Matrix
`degradation
`
`t
`
`Cell
`proliferation
`
`Figure 2. Inflammatory processes involved in a_therosclerotic lesions. Monocytes attach to the endothelium through adhesion
`molecules, and then may migrate into the subendothelium (intima) through stimulation by MCP-1. During this migration, monocytes
`become activated into macrophages that undergo cell division, produce cytokines, and express scavenger receptors which Internalise
`modified LDL-C resulting in foam cell formation. Macrophages and foam cells may also produce growth factors that may promote cell
`proliferation and metalloproteinases that may promote cell matrix degradation. Adapted from (3071.
`LDL: Low-density lipoprotein: MCP-1: Monocyte chemoattractant protein-1.
`·
`
`Box 1. Examples of potential adverse effects and potential drug interactions of statins.
`
`Potential adverse effects
`• Myalgias with/without elevations in muscle enzymes
`• Elevations in creatine kinase (CK) blood levels with or without myalgias
`• · Myopathy (defined as muscle symptoms and CK elevations > 10 times the upper limits of normal)
`• Rhabdomyolysis
`• Elevations in liver transaminase blood levels
`• Gastritis
`
`Potential drug interactions
`Simvastatin. atorvastatin and lovastatin are metabolised by the hepatic cytochrome P450 (CYP) 3A4 enzyme system. and may
`have drug interactions if taken with drugs that are inhibitors (competitive or otherwise) of this same CYP 3A4 enzyme system.
`such as cyclosporin. macrolide antibiotics. protease inhibitors. nefazodone and azole antifungal agents
`Pravastatin does not undergo significant metabolism through the CYP mixed oxidase system. This results in less potential for drug
`interactions with drugs that are inducers or inhibitors of the CYP enzyme system. However. pravastatin blood levels may increase
`when taken concurrently with cyclosporin
`It is sometimes recommended that some statins be administered in lower doses when used concomitantly with amiodarone.
`verapamil, cyclosporin. fibrates. or niacin. However. the use.of statln in combination with the extended-release niacin formulation
`(as high as niacin 2000 mg and lovastatin 40 mg/day) has been shown to be as safe with regard to liver and musde enzyme
`elevation as higher doses of statin alone (such as atorvastatin 40 mg and simvastatin 40 mg) (BBi
`Fluvastatin blood levels decrease with rifampin. Fluvastatin blood levels Increase with glyburide. phenytoin, cimetidine. ranitidine.
`and omeprazole. Fluvastatin is at least partially metabolised through the CYP 2C9 enzyme system and has the potential to have
`drug interactions with other drugs that interact with this same enzyme system
`Some statins have been suggested to interact with digoxin, and increase the clotting time in patients treated with warfarin
`In general. the use of statins with fibrates has been shown to reduce clearance. and increase circulating levels of all statins
`(except perhaps fruvastatin), increasing the risk of myopathy and possibly rhabdomyolysis. This appears to be particularly true
`when statins are used in combination with gemfibrozil IB7.220.2211
`Rosuvastatin does not undergo metabolism through the CYP 3A4 enzyme system to a clinically significant extent. resulting in less
`potential drug interactions than with statins that are significantly metabolised through this enzyme system (such as atorvastatin.
`simvastatin and lovastatin). Rosuvastatin is not extensively metabolised at all. with only 10% recovered as metabolite formed
`through CYP 2C9. Rosuvastatin absorption may be decreased with concurrent antacids. which does not occur if antacids are
`taken~ 2 h after rosuvastatin. As with other statins. rosuvastatin blood levels may increase when taken concurrently with
`cyclosporin
`
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`Acetyl coenzyme A
`
`3-Hydroxy-3-methylglutaryl coenzyme A
`
`3-Hydroxy-3-methylglutaryl
`coenzyme A reductase•
`.---~~---.
`
`Mevalonate
`
`lsopentenyl tRNA
`Dolichol
`Coenzyme 010
`lsoprenylated proteins
`
`lsopentenyl pyrophosphate
`
`Famesyl pyrophosphate
`
`Squalene synthase
`
`Unesterified (free) cholesterol
`
`Acyl-coenzyme A:
`cholesterol acyl transferase
`.------'-----~
`Esterilied cholesterol
`
`Microsomal. triglyceride
`transfer protein
`
`Cholesterol packaged into ApoB
`containing very low density lipoproteins
`
`Endothelial lipoprotein lipase ·
`
`Intermediate density lipoproteins
`
`Hepatic lipase
`
`Low density lipoprotein cholesterol
`
`Figure 3. Simplified schematic of cholesterol synthesis and
`hepatic ApoB - ·containing lipoprotein assembly (219).
`Animal data suggests that marked inhibition of rnevalonate
`production might occasionally result in elevated liver enzymes.
`myopathy, and inhibition of renal tubular reabsorption of protein.
`*Rate limiting step in cholesterol biosynthesis.
`Coenzyme A a Ubiquinone 10.
`
`the potential for plaque rupture, which might otherwise man(cid:173)
`ifest as myocardial infarction, peripheral arterial occlusion or
`stroke. In this way, the reduction of circulating LDL-C
`reduces CHO event risk.
`Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase
`inhibitors; HMG CoA reductase inhibitors) inhibit the rate
`limiting step of cholesterol synthesis where HMG CoA is
`converted to mevalonate (Figure 3). In general, statins are
`both efficacious and well-tolerated in reducing LDL-C blood
`levels {Table I). It is the lipid-altering effects of statins. prima(cid:173)
`rily the reduction in LDL-C blood levels, that are thought to
`account for their benefits in reducing atherosclerosis (such as
`improved endothelial function and plaque stabilisation) that
`
`Bays & Stein
`
`lead to a reduction in CHO. Stalins niay also have other
`favourable effects that may be independent of modification
`of blood lipids. However, while these 'pleiotropic' effects are
`of eriormous scientific interest, they have yet to be proven to
`be of definitive clinical relevance (6).
`Therapeutically, statins have been shown In large, well-con(cid:173)
`trolled trials to safely lower LDL-C blood levels by> 50% 171,
`reduce CHO morbidity (8-131 and reduce overall mortality in
`clinical outcomes trials (141. Due to their proven safety and
`efficacy, statins are currently the most prescribed lipid-altering
`drug (Box 1).
`The most recently approved statin, rosuvastatln, has bee!'l
`shown to have greater LDL-C blood !eve! lowering effects com(cid:173)
`pared both on a mg/mg basis, and across Its entire dose range
`than all other approved statins.(Table 2) (7.15). (Rosuvastatin has
`not, as yet~ proven to have beneficial CHO outcomes, as has
`been the case with all statlns upon Initial approval). Potential
`efficacy benefits above that of other previously approved statlns
`. include increased efficacy in LDL-C lowering. Another poten(cid:173)
`tial benefit is that rosuvastatln may result in higher HDL-C
`blood levels at its higher doses [21 compared to atorvastatln at
`its higher doses 17.15). (Atorvastatin demonstrates an attenuated
`HDL raising effect as the dose is increased to the 80 mg dose;
`however, the actual clinical outcomes implications of this find(cid:173)
`ing have not been established (91)).
`Rosuvastatin is not metabolised through the cytochrome
`P450 (CYP) 3A4 enzyme system to a clinically significant
`extent (16.17), resulting in less potential drug interactions than
`with statins that are significantly metabolised through this
`enzyme system (such as atorvastatln, simvastatin and lovasta(cid:173)
`tin). In fact, rosuvastatin is not extensively metabolised at all,
`with only 10% recovered as metabolite,· which is formed
`through CYP 2C9. Consequently, clinically significant drug
`interactions do not occur when. used with concomitant drugs
`metabolised through CYP 3A4 such as erythromycin and the
`azole antifungal agents. Although warfarin plasma concentra(cid:173)
`tions may not be·altered, the International Normalised Ratio
`(INR) may be increased by coadministration with rosuvastatin
`and therefore, should be frequently monitored both before and
`after initiation or change of dose of rosuvastatin. When taken
`together with antacids, rosuvastatin ·levels may be decreased.
`although this does not occur if these two agents are taken 2 h
`apart. Oestrogens and progestin levels may be increased, whilst
`. digoxin levels are unaffected by rosuvastatin. As. with other
`statins, the administration of cyclosporin and gemfibrozil may
`increase rosuvastatin concentrations. Although neither rosuv(cid:173)
`astatin nor fenofibrate levels are altered by concomitant
`administration, reports of increased risk of myopathy and
`rhabdomyolysis with other statins used with fibrates have led
`to the recommendation that the use of fenofibrate plus rosuv(cid:173)
`astatin combination therapy should only occur if the potential
`benefits outweigh the potential risks. The combination ther(cid:173)
`apy of rosuvastatin and gemfibrozil generally should be
`avoided (17). Rosuvastatin is marketed at 5 - 40 mg doses. The
`incidence of creatinine kinase elevations > ] 0 times the upper
`
`Expert Opin. Pharmacother. (2003) 4(11)
`
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`Pharmacotherapy for dyslipidaemia - current therapies and future agents
`
`Table 2. Lipid-altering effects of selected statins in a direct comparative study (STELLAR trial) at similar doses.
`
`Sta tin
`
`Total cholesterol (%)
`
`LDL-C (%)
`
`Triglyceride
`
`HDL-C (%)
`
`-45.8
`-36.8*
`-28.3*
`-20.1 *
`
`-52.4
`-42.61
`-35.Q*I
`-24.4 *I
`
`-55.0
`-47.81§
`-38.8* 1§
`-29.7* 1§
`
`-19.8
`-20.0
`-11.9
`-8.2*
`
`-23.7
`-22.6
`-17.6
`-7.7*1
`
`-26.1
`-26.8
`-14.81§
`-13.2 1§
`
`+7.7
`+5.7
`+5.3
`+3.2*
`
`+9.5
`+4.8 1
`+6.0
`+4.4'
`
`+9.6
`+4.41§
`+5.2 1§
`+5.6 1§
`
`-32.9
`-21.1 •
`-20.3*
`-14.7*
`
`-37.6
`-31.81
`-25.7* 1
`-17.2*1
`
`-40.2
`-35.8§
`-27.9* 1§
`-21.S*I§
`
`10mgdoses
`Rosuvastatin
`Atorvastatin
`Simvastatin
`Pravastatin
`20mgdoses
`Rosuvastatin
`Atorvastatin
`Simvastatin
`Pravastatin
`40mgdoses
`Rosuvastatin
`Atorvastatin
`Simvastatin
`Pravastatin
`BO mg doses
`NA
`NA
`NA
`NA
`Rosuvastatin
`Atorvastatin
`+2.1 1§
`-51.1
`-38.9
`-28.2
`Simvastatin
`-45.8 1§
`-32.9 1§
`-18.2
`+6.8
`NA
`NA
`NA
`NA
`Pravastatin
`'Significantly different versus rosuvastatin 10 mg. 'Significantly different versus rosuvastalln 20 mg. ssignlficantly different versus rosuvastatin 40 mg
`(p values < 0.002 are statistically significant).
`Adapted from [7].
`HDL-C: High-density lipoprotein-choJesteroJ: LOL-C: Low-density llpoprotein-chc>lesteroJ: NA: Not available.
`
`limits of normal in clinical trials of rosuvastatin 5 - 40 mg has
`been found to be between 0.2 - 0.4%, which is similar to rates
`seen with other currently approved statins. Clinical trials have
`shown that myopathy {defined as muscle aches or muscle
`weakness in conjunction with increases in creatine kinase
`> ] 0 times the upper limit of normal) was reported in up to
`0.1 % of patients taking rosuvastatin doses up to 40 mg/day.
`Statins have been associated with liver transaminase eleva(cid:173)
`tions and, albeit rarely, hepatitis and liver failure. Liver
`transaminase elevation in - 1.5 - 2.5% of patients has most
`often been described with administration of statins at the
`highest doses [19[. Clinical trials of rosuvastatin have shown a
`frequency of hepatic transaminase elevations similar to that
`seen in currently approved statlns and no cases of irreversible
`liver disease or liver failure have been reported (18j.
`Patients receiving rosuvastatin have been shown to have an
`increased rate of developing proteinuria with the 40 mg dose
`compared to lower doses of rosuvastatin or comparator statins.
`These urinary findings were generally transient, not associated
`with a deterioration in renal function and were only slightly
`more frequent than found with other statins or before adminis(cid:173)
`tration of any statin. The clinical significance of this finding ls
`unclear and the cause of these urine findings with statlns is cur(cid:173)
`rently unknown. It ls possible that the overall increased rate of
`abnormal urine findings among all statins during rosuvastatin
`comparative trials was due to the unique lack of an upper age
`limit as an exclusion criterion in the clinical trial programme
`and because subjects with mild-to-moderate renal insufficiency
`were often allowed in these studies. The manufacturer of
`
`rosuvastatin has also proposed that because protelnuria has
`been found with all statins, these findings may be a class effect
`and caused by the inhibition of HMG CoA reductase in proxi(cid:173)
`mal tubular cells, as demonstrated Jn an opossum kidney cell
`model. If proven, this would suggest that the proteinuria may
`be due to impaired reabsorption of protein in the renal tubule
`cells as opposed to tubular or glomerular toxicity {18]. Finally,
`kinetic trials have shown that after intravenous administration,
`- 30% of rosuvastatln is excreted through the kidneys 1111.
`which may contribute to Impaired tubular protein reabsorp(cid:173)
`tion and thus also contribute to the < 1.5% Incidence of shift
`from none or trace proteinuria to <:: 2 plus dipstick protelnuria
`at last study visit in the clinical trials of rosuvastatin 40 mg
`doses [201. Nonetheless, from a practical point of view, a dose
`reduction should be considered for patients on rosuvastatin
`40 mg {or any statin) with unexplained persistent proteinura
`during routine urinalysis testing 117].
`
`z.z Agents that affect enterohepatic bile acid
`metabolism- bile acid sequestrant resins and polymers
`Bile acids are amphipathic, polar derivatives of cholesterol
`that are necessary for the digestion and absorption of choles(cid:173)
`terol, fats and fat-soluble vitamins,. The liver excretes bile
`acids to the intestine where ..;. 95% of bile acids are then reab(cid:173)
`sorbed In the terminal ileum and returned to the liver for
`enterohepatic recirculation. If bile acids are no longer availa(cid:173)
`ble for transport back to the liver (through intestinal bile acid
`binding or through transport inhibition), they are lost in the
`faeces. As a result, there is an upregulation of hepatic enzymes
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`Box 2. Examples of potential adverse affects and drug interactions with bile acid sequestrants.
`
`Potential adverse effects
`• The bile acid resins. cholestyramine and colestipol. have a high potential for gastrointestinal effects such as dyspepsia. nausea
`and constipation '- especially at higher doses
`• Compliance with bile acid resins may be impaired by the administration of an insoluble powder that requires mixing into a
`suspension with fluids or mixing with foods
`• Colestipol may also be administered In tablet form, but still has a risk of gastrointestinal side effects and potential drug
`interactions that have not been shown to differ from the powder form
`• Compliance with bile acid resins may also be impaired by the general recommendation that concurrent drugs be administered at
`least 1 h before. or 2 - 4 h afterwards
`• Bile acid resins may interfere with the absorption of fat soluble vitamins such as A. D. E. and Kat extremely high doses
`• May cause moderate increases in triglyceride blood levels
`• Clinical trials have described mild liver ·enzyme blood level elevations in some patients
`• The bile acid polymer. colesevelam; is significantly better tolerated than the bile acid resin cholesyramine and colestipol
`
`Potential drug interactions
`• The bile acid resins cholestyrarriine and colestipol have been described to potentially impair the absorption of many common.
`concomitant drugs - particularly anionic. acidic materials. Specifically. cholestyramine has been described to potentially impair the
`absorption of phenylbutazone. warfarin. thiazide diuretics. propranolol. tetracycline, penicillin G. phenobarbital, phosphate
`supplements. hydrocortisone. oestrogens and progesterones. thyroid and thyroxine preparations and digitalis. Colestipol has
`been described to potentially impair the absorption of propranolol, thiazide diuretics. digoxin. oral phosphate supplements and
`hydrocortisone
`• May interfere with the pharmacokinetics of concurrent drugs that undergo enterohepatic circulation such as oestrogens and
`ezetimibe
`• The bile acid polymer colesevelam has much less potential for drug interactions than the bile acid resens cholestyramine and
`colestipol. However. the potential drug interactions with an concurrent drugs has not been reported (such as with levothyroxine).
`Therefore. colesevelam should also be taken 1 h before. or 2 - 4 h after a concurrent drug if a potential drug interaction is
`suspected
`
`such as cholesterol 7-a-hydroxylase, which is the rate-limiting
`enzyme in bile acid biosynthesis, with diversion of hepatic
`cholesterol for bile acid production. To compensate, the
`enzyme HMG CoA reductase is upregulated to increase
`endogenous cholesterol production. Hepatic LDL receptors
`are upregulated as well. The net result is increased clearance of
`circulating LDL-C. The increase in cholesterol synthesis often
`results in an increase In very low density lipoprotein (VLDL)
`secretion, which results in a variable increase in triglyceride
`(TG) blood levels often found with agents that impair bile
`acid return to the liver (fable 1).
`Historically, bile acid sequestrants (resins) were among the
`first lipid-altering drug treatments demonstrated in clinical tri(cid:173)
`als to reduce the risk of CHD. Specifically, The Lipid Research
`Clinics Coronary Primary Prevention Trial (LRC-CPPT) was
`among the first landmark trials that. demonstrated that lower(cid:173)
`ing cholesterol blood levels, in this case with cholestyramine,
`reduced CHD events compared to placebo (21). Unfortunately,
`the clinical use of bile acid resins has been limited due to.their
`high incidence of gastrointestinal adverse effects and their
`impaired absorption of many commonly used drugs (Box 2).
`However, low dose administration may be well tolerated in
`many patients, and moderately effective.
`Colesevelam is a bile acid sequestrant that has a unique bio(cid:173)
`chemical polymer structure compared to the bile acid resins
`(cholestyramine and colestipol) 122). As with the bile acid
`
`resins, the bile acid polymer, colesevelam, has been shown to
`significantly lower LDL-C blood levels. Colesevelam also
`favourably affects HDL-C levels in monotherapy and in com(cid:173)
`bination therapy with statins. The effects upon TG blood lev(cid:173)
`els are variable )22). Largely due to its unique polymer structure.
`colesevelam is better tolerated and has less potential drug Inter(cid:173)
`actions than with bile acid resins (Box 2). When added to stat(cid:173)
`Ins, colesevelam further reduces LDL-C blood levels, which
`may be needed for patients who do not sufficiently achieve
`lipid treatme.nt goals with statins alone (22). Finally. because of
`its non-SYStemic nature, colesevelam may be an alternative
`lipid-altering drug for patients with true or perceived intoler(cid:173)
`ance to statin therapy. as well as· for many patients with mild(cid:173)
`to-moderate hypercholesterolaemia who may be at potential
`risk for systemic exposure to alternative lipid-altering drugs
`(such as young children and fertile women).
`
`2.3 Agents that impair cholesterol absorption
`2.3. 1 Ezetimibe
`The cholesterol absorption ·Inhibitor, ezetimlbe, represents
`the first member of the first new class of lipid-altering drugs
`approved in the US in the 15 years prior to its approval in
`2002 (Box 3). Ezetimibe is predominantly an LDL-C lower·
`ing drug that has consistently been shown to reduce LDL-C
`blood levels by about 17 - 22% in both monotherapy )231
`therapy with statins (Table 1) 124.25).
`and combination
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`Pharmacotherapy for dyslipidaemia - current therapies and future agents
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`Table 3. Examples of major ATP binding cassette transporters (ABC)• related to cholesterol metabolism.
`
`Transporter Location
`
`Function
`
`ABCA1
`
`Plasma membrane of multiple body
`tissues induding macrophages,
`liver. placenta. adipose, and spleen
`
`ABCG5
`
`luminal surface of enterocyte
`liver
`
`Transports phospholipids and cholesterol and is
`believed to be a rate-limiting step in
`cholesterol transport from peripheral tissues to
`the liver
`Transports intestinally-absorbed cholesterol
`and plant sterols/stanols from the enterocyte
`back to the lumen of the intestine
`
`Disease or disorder caused by
`dysfunction of transporter
`
`Tangier disease1
`Familial HDL deficiency
`
`Sitosterolaemia§
`
`ABC GS
`
`lumirial surface of entero.cyte
`liver
`
`Transports intestinally-absorbed cholesterol
`and plant sterols/stanols from the enterocyte
`back to the lumen of the intestine
`·
`•ABC transporters function to translocate or 'pump· various compounas (such as sugars. amino acids. metal ions. peptides. and proteins. and a large number of
`hydrophobic compounds and metabolites) across the membranes of cells and tissues. The ABC transporter superfamily is the largest transporter gene family. and is
`typically classified into subf