Investigational therapies for thetreatment of atherosclerosisGerald H Tomkin† & Daphne Owens†Diabetes Institute of Ireland, Beacon Hospital, Dublin, Ireland
Introduction: There is great need for new drugs to reduce cholesterol in those
patients who have not achieved target levels on statins as well as those who
are statin intolerant.
Areas covered: In this review, the authors discuss the new antisense oligotide
inhibitor of apo B synthesis, mipomersen; pro-protein convertase subtilisin/
kexin type 9 (PCSK9) inhibitors and cholesterol ester transport protein
(CETP) inhibitors. Furthermore, the authors discuss cholesterol absorption
and chylomicron synthesis with an emphasis on microsomal triglyceride trans-
fer protein (MTP) inhibitors, which inhibit very-low-density lipoprotein
production in the liver and chylomicron inhibition in the intestine. Finally,
the authors also discuss Apo A1- and adenosine triphosphate-binding cassette
transporter A1 (ABCA1)-promoting drugs. A literature review was performed
through PubMed using the terms atherosclerosis, hypercholesterolemia, Apo
B inhibition, PSCK9, CETP inhibitors, MTP inhibitors, apo A1 mimetics and
ABCA1.
Expert opinion: So far, research suggests that PCSK9 inhibitors will be success-
ful with mipomersen being used for those patients who do not respond well
or who are still not at target. However, it is difficult to see where CETP
inhibitors will fit in except with patients who have very low high-density
lipoprotein. The MTP inhibitor lomitapide is currently only licensed for famil-
ial homozygous hypercholesterolemia but the intestinal inhibitors may have a
future, particularly in familial combined hyperlipidemia. The future will be
most exciting.
Keywords: ABCA1, Apo A1 mimetics, apo B synthesis, atherosclerosis, cholesterol ester
transfer protein, high-density lipoprotein, microsomal triglyceride transfer protein,
mipomersen, pro-protein convertase subtilisin/kexin type 9 inhibitors
Expert Opin. Investig. Drugs [Early Online]
1. Introduction
For many years, statins have had pride of place in our armamentarium to reducecholesterol and prevent myocardial infarction and less effectively cerebrovascularevents. Targets have been set for ideal lipids and the new guidelines of the AmericanCollege of cardiology/American Heart Association [1] have tried to simplify their usewith some controversy. However, although statins are remarkably effective inlowering cholesterol, many people do not get to target and most studies show a30% reduction in cardiovascular events, suggesting that 70% of patients remainunprotected. Recent strategies have resulted in very exciting new drugs that have amajor further cholesterol-lowering effects. There have also been exciting develop-ments in chylomicron and very-low-density lipoprotein synthesis inhibition. Alter-ation of high density lipoprotein (HDL) function through increase in apo A1 anddecrease in cholesterol transport through inhibition of cholesterol ester transportprotein (CETP) remain exciting projects as do apo A1 mimetics. Efforts to increasecholesterol exit from plaque through adenosine triphosphate-binding cassette trans-porter A1 (ABCA1) is a further strategy with exciting prospects. This paper
discusses the more recent studies describing apo B inhibitionand increased recycling of the low-density lipoprotein recep-tor through inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). The importance of new technologywith the development of antisense oligonucleotides ishighlighted. We are excited by the new knowledge of theABC transporters and the regulation of fatty acids and trans-porters with the development of silencing micro-RNAs. Cho-lesterol absorption and the regulation of Niemann PickC1-like 1 (NPC1L1) are discussed. Chylomicron reductionthrough inhibition of microsomal triglyceride transfer protein(MTP) and the possibility of micro-RNA technology torepress lipid synthesis is another exciting platform. The dis-covery of NUR 77, a key transcriptional regulator of glucoseand lipid homeostasis, lipogenesis and inflammation andvascular remodeling raises new horizons in this exciting field.
2. Mipomersen
Low-density lipoprotein cholesterol is the major particleinvolved in cholesterol transport around the body and the sol-ubilizing protein is Apoprotein B 100. Mipomersen is an anti-sense oligonucleotide inhibitor of apo B synthesis (Figures 1and 2). It binds to messenger RNA encoding Apo B preventingits synthesis and secretion of apo B-containing lipoproteins [2].A recent interim report of a randomized placebo-controlledtrial in patients with severe hypercholesterolemia receivingmaximally tolerated lipid-lowering therapy has been reported[3]. The drug is given by weekly injections. Mipomersenreduced LDL cholesterol by another 36% (10 patients had agreater than 50% reduction in LDL cholesterol). This wasassociated with a statistically significant reduction in Apo Band Lp(a). The patients were evaluated in an intention-to-treatbasis. Of the 39 patients randomized to receive treatment,27 completed the 26 weeks of treatment. After treatment,lipids were measured 2 weeks after the last dose. All patientsreceiving the drug had at least one adverse event. The mostcommon side effect was a mild to moderate injection-site reac-tion and one patient had a severe reaction. Mild to moderate
flu-like symptoms occurred in 46% of patients, but also in26% of placebo-treated patients. Six patients withdrewbecause of liver function changes even though only two metprotocol-defined stopping rules. Anti-mipomersen antibodiesoccurred in 14 patients but this did not seem to impair thefunction of the drug. A two-year study in patients with familialhypercholesterolemia has been reported. There was no reduc-tion in efficacy of the drug over this period with mean reduc-tion in LDL of 28% and Apo B of 31%. Side effects weresimilar to the above trial and other shorter trials. Interestingly,the liver fat accumulation that has been described and presum-ably is the cause of the abnormal liver function tests increasedin the first year but then seemed to somewhat diminish [4].Another trial over 26 weeks of patients who had baselineLDL of 100 mg/dl or more in spite of maximally toleratedother lipid-lowering therapy and who were at high risk oralready had coronary heart disease has been reported. Onehundred and five patients entered the treatment arm of thedouble-blind study and 60 completed the trial. Reduction inLDL cholesterol of 36.9% was found as compared to anincrease of 4.5% in the placebo group. Side effects were asreported in the other trials [5].
A 26-week trial in patients with heterozygous familialhypercholesterolemia was published in 2012 [6]. Eighty-threepatients had the active drug and 73 completed the trial. Therewas a reduction in LDL of 28% and Lp (a) was reduced by21%. Injection-site problems, flu-like symptoms and abnor-mal liver function tests were the main adverse events. Liverfat increased by 4.9%. Six percent of patients had raisedalanine aminotransferase levels on two occasions above threetimes normal. Other earlier trials have been very consistentwith the more recent trials. Outcome data in reduction inmortality and myocardial events are anxiously awaited butin the high-risk case, whether familial or nonfamilial hyper-cholesterolemia, most patients I would think, like the oppor-tunity to try the drug if cholesterol levels are not close to goalposts. The drug has been approved for use in the USA for useas an orphan drug in familial hypercholesterolemia butrefused by the European agency because there is still noevidence that it will influence cardiovascular outcome. For areview see Siouke and Balak [7].
3. Proprotein convertase subtilisin/kexintype-9
There is another alternative, PCSK9, which seems perhaps evenmore exciting (Figure 3) and is primarily expressed and secretedfrom the liver with lesser amounts from the kidney and intestineand brain [8]. PCSK9 degrades the LDL receptor and thereforereduces the ability of the LDL receptor to take up and degradethe LDL particle. The LDL receptor is upregulated by statinsand this upregulation increases the efficacy of statin therapy inlowering LDL (Table 1). However, PCSK9 is also upregulatedwith statin therapy, reducing the efficacy of statins. Gain-of-function mutation of the PCSK9 has been described in patients
Article highlights.
. Prevention of atherosclerosis needs new treatments.
. Low-density lipoprotein reduction is a major target.
. Mipomersen is on the market in the USA but so farlicence has not been granted in Europe.
. Pro-protein convertase subtilisin/kexin type 9 inhibitorsare the most exciting of the new drugs.
. Cholesterol ester transport protein inhibitors got off to abad start but may have a place in patients with lowhigh-density lipoprotein.
. Intestinal microsomal triglyceride transfer proteininhibitors may become the most useful new drug forfamilial combined hyperlipidemia.
This box summarizes key points contained in the article.
with autosomal dominant hypercholesterolemia [9-11]. Loss-of-function mutations have also been described and are associatedwith low LDL cholesterol and protection from coronary heartdisease [12,13]. Recently, new information on the mechanismof action, and in particular why fibroblasts respond less wellthan hepatocytes to PKSC9, has been published [14]. It wouldseem that the degradation process is diminished, and may bethe reason why some patients do not respond well to PCSK9therapy.AMG 145 is a monoclonal antibody active against PCSK 9.
The LAPLACE-TIMI 57 trial [15] examined the drug inpatients at high risk of cardiovascular events and who hadnot achieved their cholesterol goals. Ninety percent of patientsachieved their goals with the new treatment. The effect ofAMG 145 in homozygous familial hypercholesterolemia hasbeen reported by Stein et al. [16]. Eight patients with LDLreceptor, negative or defective, or homozygous hypercholes-terolemia on stable drug therapy, were investigated with asubcutaneous dose every 4 weeks for 12 weeks and then every2 weeks for another 12 weeks. With the 2 weeks dosing, thepatients with defective LDL receptors reduced their LDL cho-lesterol by 26% but the receptor-negative patients had noresponse. In 2012, Raal et al. [17] examined the monoclonalantibody in patients with heterozygous familial hypercholes-terolemia diagnosed by The Simon Broome criteria. Onehundred and sixty-seven of 168 patients received the investi-gational drug. Two doses were used. The higher dose of420 mg subcutaneously every 4 weeks resulted in a 55%reduction in LDL cholesterol. Serious adverse events (notconsidered to be due to the drug) occurred in only twopatients.AMG 145 was examined in an open-label study over
52 weeks. The patients had hypercholesterolemia and were
invited to take part in the extension of a 12-week study.The benefit of a 50% reduction in LDL cholesterol continuedat 52 weeks with no new findings on safety and tolerability [18].AMG 145 was tested in 145 patients with statin intolerancedue to muscle-related side effects [19]. Over a 12-week period,patients were divided into various dose groups together withezetimbe. The trial was placebo-controlled using Ezetimbealone. The highest dose (420 mg subcutaneously every4 weeks) resulted in a 51% reduction in LDL cholesterol ascompared to 15% with the ezetimbe placebo group. Myalgiawas the most common treatment-emergent adverse eventoccurring in 20% of the 420 mg dose as compared to 15%in the lowest dose (280 mg) and myalgia occurred in onepatient on placebo (3%). AMG 145 has also been shown toreduce Lp(a) by up to 32% in patients who had hypercholes-terolemia and who were already on statin therapy. Thereduction in Lp(a) correlated with the reduction in LDLcholesterol [20].
The safety and efficacy of ALN-PCS, a small interferingRNA that inhibits PCSK9 synthesis, were examined inhealthy volunteers with raised cholesterol who were not onany lipid-lowering treatment. This was a Phase I dosingexperiment. Adverse events were not different between theactive drug and the controls. Treatment reduced circulatingPCSK9 by 70% and LDL by 40% [21]. This is, the authorssay, the first study to show that an RNA-i drug can affect aclinically validated endpoint.
A PCSK9 antisense oligonucleotide or rather two lockednucleic acid antisense oligotides targeting PCSK9 have beenshown to reduce LDL cholesterol in primates [22]. It is proba-ble that other molecules that interfere with other parts of thePCSK9 molecule will be developed to inhibit its action and soeffectively lower LDL cholesterol. The endpoint trials
Table 1. Major effects of lipid-lowering drugs.
Drug Phase Action Target Effect
Statins Released Inhibition of cholesterol synthesis LDL cholesterol LDL #Ezetimibe Released Inhibition of cholesterol absorption NPC1L1 Chylomicron and VLDL #Mipomersen Released in
USA for FHInhibition of apo B synthesis Apo B VLDL LDL #
Lomatide Releasedfor FH
Inhibition of TRL synthesis MTP (liver and intestine) Chylomicron + VLDL #
SLx-4090 Phase II Intestine-only MTP inhibitor MTP (intestine-onlymouse studies)
LDL #
AMG145 Phase II Monoclonal antibody for PCSK9 LDL receptor LDL #ALNPCS Phase II Interfering mRNA for PCSK9 LDL receptor LDL #Torcetrapib Withdrawn CETP inhibitor HDL cholesterol HDL "Dalcetrapib Phase II CETP inhibition HDL cholesterol HDL "Anacetrapib Phase II CETP inhibition HDL cholesterol HDL "Evacetrapib Phase II CETP inhibition HDL cholesterol HDL "RVX-208 Phase II Promotes cholesterol efflux BET proteins Apo A1 + HDL "FAMP Phase II Apo A1 mimetic HDL HDL "MiRNA-144 Phase II Suppresses ABCA1 expression ABCA1 HDL #
showing cardiovascular events/mortality improvement areawaited with excitement but the large LDL cholesterol-lowering effect suggests that inhibitors of PCSK9 will becomean important treatment to prevent atherosclerosis events.
4. High-density lipoprotein
The association of low HDL with atherosclerosis has stimu-lated the search for treatments that raise HDL with thepresumption that if low is bad high must be good (Figure 4).Niacin has been shown in many studies to raise HDL andhad been used in the presumption that it would preventatherosclerosis. Previous trials had mostly been positive butperhaps underpowered. The most recent definitive trial wasthe HPS2-THRIVE study [23], which set out to show thatniacin with laropiprant to prevent the flushing that so oftendiscouraged patients from continuing the drug was ineffectiveand did not show benefit. The trial was therefore stopped andthe enthusiasm for nicotinic acid treatment has waned eventhough it raises HDL. One of the problems is that HDL ismade up of many proteins, which have many actions includ-ing reverse cholesterol transport. HDL also has an effect oninsulin sensitivity in muscle and insulin secretion. Antioxi-dant/anti-thrombotic and anti-inflammatory actions mayalso promote the reduction in the burden of atherosclerosisas may the effect on endothelial repair. All these functionsshould be anti-atherosclerosis and, in theory, increasingHDL should be beneficial. This indeed has been the casewith infusion of Apo A Milano, a genetic variant of HDLthat is associated with prevention of atherosclerosis. HDLfunction can change, for example HDL may even change toproinflammatory in chronic inflammatory disease [24] and in
acute coronary syndrome HDL changed to a dysfunctionalHDL [25].
4.1 Cholesterol ester transport protein inhibitorsCETP has been a target for cholesterol lowering for someyears. A downregulation of the transfer of HDL cholesterolto the liver via VLDL and LDL seemed a promising therapeu-tic ploy and in animal studies these inhibitors not onlylowered VLDL and LDL cholesterol but also increasedHDL. CETP inhibitors have also been shown to reduce ApoB 48 production (the solubilising protein for the chylomi-cron), an effect that was not apparent in patients already onatorvastatin [26]. Alteration of the HDL particle might haveadverse effects on its many beneficial functions. Bellangeret al. [27] found that in fact CETP inhibition improvedHDL cholesterol ester delivery to hepatic cells and maintainedan efficient direct return of cholesterol esters to the liver dur-ing postprandial lipemia. However, a trial of torcetrapib, aCETP inhibitor, was stopped in 2006 [28,29] as, alas, therewas an increase in cardiovascular events and the drug waswithdrawn. This surprising result was perhaps due to a slightincrease in blood pressure caused by the drug. Newer-generation inhibitors have now been trialed. These drugs donot have a hypertensive side effect and in animal studiesthey seem to be effective.
Anacetrapib increased HDL by 129% at the highest doseand reduced LDL cholesterol by up to 38% without a risein blood pressure [30]. Phase III trials are now under way look-ing at cardiovascular outcome. Anacetrapib more recently wasfound to lower LDL cholesterol by 26% and Apo B by 29%and to raise HDL by 82% but a worry was the finding thatalthough VLDL and large, medium and small LDL decreased
very small and dense LDL increased, small dense LDL beingparticularly atherogenic [31].One of the fears about the CETP inhibitors is that
alteration to HDL might diminish its anti-inflammatoryproperties. Han et al. [32] found no evidence using anacetra-pib. Dalcetrapib is another CETP inhibitor that has receiveda lot of attention. More than 15,000 patients were investi-gated with the drug or placebo by the dal-OUTCOMESinvestigators [33]. The patients had a recent acute coronarysyndrome. HDL increased by 31 -- 40% in the treatedpatients with little effect on LDL. Alas, the drug did notdecrease the risk of recurrent cardiovascular events. The effectof dalcetrapib on endothelial function, blood pressure andinflammatory markers was examined in the dal-Vessel ran-domized trial [34]. No effect was observed but Lp-PLA(2)mass levels increased by 17%, which may turn out to be aworry. The divergence between increasing HDL and improv-ing function is clearly shown in a recent trial of the CETPinhibitor dalcetrapib trial. HDL cholesterol was raised by37% but Apo A1 by only 11.8%. Total cholesterol effluxonly increased by 9.5%, again demonstrating the divergencebetween HDL composition and function [35].Evacetrapib is another CETP inhibitor. A randomized
controlled trial was reported in 2011. At the highest dose,monotherapy increased HDL by 128% and decreased LDLby 35%. No adverse effects were reported. The authorsconcluded that the effects on cardiovascular outcomes requirefurther investigation [36].The Illuminate trial using torcetrapib, which as explained
above was stopped due to an increase in mortality and cardio-vascular events, showed an improvement in diabetes control,suggesting that raising HDL might have an effect on insulinrelease [37]. A CETP inhibitor under development byHofmann La Roche rg7232 has been shown to increase post-prandial insulin and promote ex vivo insulin release from thepancreatic B cells.Another way of improving HDL function in cholesterol
transport away from the plaque to the liver is to increaseHDL. Niacin has not proved useful in protecting againstcardiovascular events even though it raised HDL [38] butApo A1 Milano, when infused, has proven beneficial [39].Since then efforts have been made to synthesize small HDL-like peptides that might have the same effect but be able tobe given orally [40]. Recently, an apo A1 mimetic proteinELK-2A2K2E has been shown in Apoe-/- mice on a high-fatdiet to increase HDL, increase the proportion of smallerHDL particles and to reduce atherosclerosis [41].Dialysis of HDL by removal of lipid from HDL and then
returning the lipid-poor HDL, which now resembles thereconstituted HDL mentioned above, has been shown in asmall clinical trial to perhaps decrease atheroma volume [42].RVX-208 is a small molecule that has been found to
increase apo A1 expression in liver cells and promote choles-terol efflux in monkeys [43]. In early clinical trials it has beenshown to increase apo A1 and HDL. A recent study has
shown that the target of the molecule is BET proteins, whichregulate Apo A1 expression through an epigenetic mecha-nism [44]. Fukouka ApoA1 mimetic protein is another ApoA1 mimetic, which has also been shown in mice to reduceaortic plaque formation [45]. The story of HDL and ApoA1 as a useful treatment in cardiovascular protection is in itsinfancy but causing a lot of interest and excitement particularlyas it seems to have antioxidant and anti-inflammatory effects.
Several ABC transporters including ABCA1 are involved inregulating efflux of cholesterol from macrophages. ABCA1together with ABCG1 act in sequence to lipidate nascentHDL. In the liver ABCA1 plays a critical role in the biogenesisof HDL. Ramirez CM et al. [46] have recently demonstratedthat MiRNA-144 can regulate cholesterol metabolism bysuppressing ABCA1 expression and conversely, silencing ofmiR-144 in mice increased ABCA1 expression and increasedHDL, perhaps a future therapy for atherosclerosis.
The sterol response element-binding protein (SREBP)regulates the synthesis of fatty acids and cholesterol. Micro-RNA-33 a and b have been found to be negative regulatorsof, and repress, a number of genes that are involved in regulat-ing cellular cholesterol export and fatty acid oxidation [47,48].Rotllan et al. [49] have shown that therapeutic silencing ofmicro-RNA-33 inhibits the progression of atherosclerosis inLdlr-/- mice. It is of interest that the mice treated with anti-miR-33 oligonucleotides had increased HDL only if treatedwith a chow diet. The authors showed that the isolatedHDL had an increased cholesterol efflux capacity.
5. Cholesterol absorption
The process of cholesterol absorption (Figure 1) regulationand the synthesis of lipoproteins have been unraveled at leastto a large extent. The discovery of NPC1L1 particle and itsrole in cholesterol absorption in the gut and its role in livertransport of Apo B-containing particles has resulted in newtargets to reduce serum cholesterol. Ezetimbe is now in useand reduces cholesterol by around 15%. NPC1L1 is increasedby statins and results in an increase in cholesterol absorption,which negated the effect of statins to some degree. The use ofEzetimbe with statins results in an increase in the effectivenessof statins and reduces LDL cholesterol by55% [50]. ABC G5/8acts as heterodimers to excrete cholesterol from the intestineand this knowledge may in the future result in a drug toreduce serum cholesterol levels.
The mechanism of control of Neimenn Pick C1L1 is beingslowly unraveled. Pharmacological blockade of cholesterolabsorption in the enterocyte is associated with an increase incholesterol synthesis through activation of sterol regulatoryelement-binding protein 2 [51,52]. McFarlane et al. [51] haverecently shown that 2 closely related proteins Insig 1 and Insig2 that are required for the feedback inhibition of SREBP andHMG CoA reductase when deleted cause an 11-fold increasein sterol synthesis in the small intestine. The intestine derivedaccumulation in plasma and liver resulted in secondary
feedback inhibition of hepatic SREBP 2 activity. Li et al. [53]have shown that the clatherin adaptor Numb is a pivotalprotein for intestinal cholesterol absorption. The authors sug-gest that Numb may become a therapeutic target to reducecholesterol.
6. Microsomal transfer protein inhibitors
MTP (Figure 1) acts to assemble the chylomicron particle bybinding Apo B 48 with triglyceride and cholesterol in theintestine and in the liver to form VLDL particles [54]. Inhibi-tors of MTP have been described [55,56]. Although a goodresponse to reduction in VLDL and LDL has been shown,hepatic steatosis has limited their use (Figure 2). The MTPinhibitor lomitapide has very recently been released onthe market for use in familial hypercholesterolemia. A sin-gle-arm open-label study has been reported [57], in which29 men and women who had homozygous familial hypercho-lesterolemia were treated with lomitapide for 78 weeks. Therewas a 38% reduction in LDL cholesterol. Six patients with-drew during the study. No patient permanently discontinuedthe drug because of liver problems. Gastrointestinal adverseeffects were the most common problem. From the abovestudy it would seem that with this drug, reducing the dose ifhepatic enzymes rise, or stopping the drug and re-starting ata lower dose, can obviate the hepatic problem. It will be inter-esting to see whether with more experience the drug might beused in other causes of hypercholesterolemia. Intestinal MTPinhibitors that are not absorbed and therefore do not promotehepatic steatosis have been investigated with very good resultsin terms of lowering triglycerides and Apo B 48, and are nowbeing trialed. In 2005, a new molecule that inhibited MTPactivity that was confined to the intestine was shown to reduceLDL cholesterol by 25% and trig by 30% in guinea pigs withno hepatic lipid accumulation [58]. Hata et al. [59] describedfood suppression and delayed gastric emptying in rats givenJTT-1309 (an intestinal MTP inhibitor) and a high-fat diet.This effect was not present in a low-fat diet. The reductionin food intake was associated with a reduction in PYY andGLP-1; thus, there is interest in the drug as an aid to weightreduction. Another intestine-specific MTP inhibitor SLx-4090 has also been described [60]. A recent paper in NatureMedicine reporting micro-RNA-3c as a potent repressor ofMTP demonstrated reduction in MTP activity and in apo Bsecretion in mice with a decrease in atherosclerosis [61]. Themolecule also represses lipid synthesis through direct targetingof lysophosphatidylglycerol acyltransferase 1 and spares theliver steatosis while reducing Apo B-containing particles [62].MTP inhibition is particularly exciting since the synthesis ofthe chylomicron starts the lipid cascade and reduction in thechylomicron by itself would be considered anti-atherogenicbut because a reduction influences both VLDL and LDL,further reduction of the potential atherogenic effect of theselipoproteins would be expected [63].
Inflammation plays a central role in atherosclerosis devel-opment. Nur 77 is a nuclear hormone receptor gene, whichinfluences differentiation proliferation and apoptosis. It is akey transcriptional regulator of glucose and lipid homeostasisadipogenesis and inflammation and vascular remodeling. HuYan-Wei et al. [64] have shown that in apoE-/- mice fed ahigh-fat diet, increased expression of Nur 77 caused a reduc-tion in foam cell formation and lipid deposition in the liver.A downregulation of genes associated with inflammation,adhesion molecules and intestinal lipid absorption as well asa decrease in atherosclerotic plaque formation.
The ultimate goal in lipid research is to prevent the damageto the endothelium that is the start of the atheroscleroticplaque formation and failing this to stimulate repair of theendothelial fatty streak before it becomes an unrepairableplaque. Should this not be possible then the next step wouldbe to stabilize the plaque and stop rupture. Present treatmentis quite good at this stage but the hope is that more powerfulreduction in Apo B-containing lipoproteins would help thisprocess further; increasing the level and function of HDL isanother way to improve the transfer of cholesterol awayfrom the plaque to the liver. Our best buy for the future, inthe short term, is the PCSK9 inhibitors with the micro-RNA inhibition being the winner in the long run. Perhaps,a risky bet at this time and in the longer term is an inhibitorof APO B production that will have a lower side-effect profilethan mipomersen. Apo A1 mimetics may become an excitingfield. ABCA1 stimulation, in an effort to increase CETPactivity, may also prove useful in the future. Further intothe future, the reduction of the obesity booms with oral treat-ment that matches bariatric bypass surgery in the treatment ofobesity. Crystal ball gazing is a dangerous occupation!
7. Conclusion
In conclusion, there is a massive need for both alternativetherapy to statins in those patients who cannot tolerate statinsand add-on therapy for those patients who do not reach targetin spite of the present drugs that will lower LDL cholesterol inthe fight against atherosclerosis. The drugs, which the authorshave discussed, all seem to have great potential but the CETPstory, in particular, has made physicians wary of newtreatments until beneficial endpoints have been demonstrated.
8. Expert opinion
The potential ability to reduce the burden of atherosclerosisseems to be growing daily. The new drugs designed to attackatherosclerosis through lipid lowering look very exciting. Theunravelling of mechanisms involved in internalization ofcholesterol through the LDL receptor and the newer technol-ogies, which allow for inhibition of apo B synthesis, and apoB assembly into the chylomicron, VLDL and LDL particles,is very exciting. Second, upregulation of the LDL receptors,increase in their number or decrease in LDL receptor
Investigational therapies for the treatment of atherosclerosis
breakdown as occurs with PCSK9 inhibitors would seem toherald new advances in prevention and treatment of athero-sclerosis. In particular, micro-RNA technology would seemto be a field to watch in the future. The first step in lipidologyhas been taken using this technology to reduce PCSK9 andappears to be the most important technology for the futurein the battle to reduce atherosclerosis. Atherosclerosis is achronic condition and the factors that produce the suddenevent, that is, myocardial infarction or stroke, appear tohave little to do with our present knowledge about the chronicburden of the atherosclerotic plaque development eventhough there is good correlation between the amount ofatherosclerosis and events. Dyslipidaemia competes withhypertension, diabetes and the other risk factors, which makesinvestigation of drugs that reduce the atherosclerotic burdenthrough LDL cholesterol lowering or HDL raising more dif-ficult. It is for this reason that large trials, over a considerableperiod of time, are necessary to show benefit. It is for this rea-son also that cardiovascular events occur in patients whosecholesterol goals have been met. Further research will nodoubt unravel the etiology of atherosclerosis in more detailand new markers will be discovered that may herald the immi-nent fracture of plaque with the disastrous consequences.These are some of the reasons why the evaluation of newdrugs is difficult and explain why it is imperative to have out-come studies completed before being confident that the newdrug, which improves dyslipidaemia, is effective and of coursesafe. Although statins reduce cardiovascular events by around30% it is unlikely that further lowering of cholesterol willmake the same gains in a disease that is so chronic and somultifactorial. It seems that PCSK9 drugs have less side effectsand also a better lipid-lowering effect, at least in patients whocan tolerate statins, but are not to target, than mipomersen.
The early trials with the CETP inhibitor torcetrapip are stillfresh in our minds. We have to wait until the endpoint trialshave been completed to know the answer as to whether thesepowerful drugs will reduce cardiovascular events. The MTPinhibitor lomatide, which has been launched on the marketfor treatment of familial hypercholesterolemia, will probablynot be used in the nonfamilial hypercholesterolemias exceptin exceptional cases due to the fear of hepatic steatosis. Asconfidence with lomatide grows and if by careful monitoringof liver function tests and reduction in dose when liver func-tion tests rise, the drug may find a place in nonfamilial andcombined familial hypercholesterolemias. The cost at presentis prohibitive but that may also change. Intestinal MTP inhib-itors, when they come on the market, look very promising,particularly in familial and nonfamilial combined hypercho-lesterolemia. They may also find a place as an anti-obesitydrug but the consequences of saturating intestinal villae withtriglyceride and cholesterol that cannot be absorbed willhave to be evaluated further. The authors have yet to beconvinced that CETP inhibitors will have a place in the mar-ket place because one would have expected that with the largerise in HDL and the potentially useful reduction in LDL thetorcetrapib trial showed no benefit before it was summarilystopped.
Declaration of interest
The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment,consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.
BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
