Current and future trends in the lipid lowering therapy

Pharmacological Reports 68 (2016) 737–747

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Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep

Review article

Current and future trends in the lipid lowering therapy Bogusław Okopien´, Łukasz Bułdak *, Aleksandra Bołdys School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

A R T I C L E I N F O

Article history: Received 14 December 2015 Received in revised form 25 February 2016 Accepted 25 March 2016 Available online 13 April 2016 Keywords: Hyperlipidemia Hypercholesterolemia Hypertriglyceridemia Clinical trial Hypolipidemic therapy

A B S T R A C T

Atherosclerosis is an inflammatory disease that affects arterial wall. It leads to wall thickening and its instability. As a result a reduction in lumen diameter and blood flow is observed. This manifests predominantly as the affectation of vascular bed of coronary (myocardial infarction), cerebral, carotid (ischemic stroke) or peripheral arteries (limb amputation). One of the most important factors that accelerate atherosclerosis is hyperlipidemia. According to current guidelines the main attention should be focused on the treatment of hyperlipidemia (beside the prevention, which includes proper diet, physical activity and risk factors avoidance). Major attention is given to LDL (low-density lipoprotein) cholesterol (LDL-C) level as primary, and triglyceride level as secondary targets of therapy. As a result of recent clinical findings and continuous research in the field of hypolipidemic drugs it seems practical to review recent data and show potential new pathways that may be useful in the treatment of hyperlipidemia. The review is divided into several parts presenting the widely used and well-known hypolipidemic drugs. In the first part a brief review of contemporary drugs affecting LDL cholesterol is shown. The second part contains information regarding currently available drugs reducing triglycerides level. The third part describes several novel and promising groups of drugs that are still on various steps of clinical development. In the last part drugs affecting HDL (high-density lipoprotein) level were presented. ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Currently available drugs in the treatment of hypercholesterolemia . . . . . HMG-CoA reductase inhibitors (statins) . . . . . . . . . . . . . . . . . . . . . . NPC1L1 inhibitors (ezetimibe) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plant sterols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monacolin k (red yeast rice). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bile acid sequestrants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PCSK9 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microsomal transfer proteins (MTP) inhibitors . . . . . . . . . . . . . . . . . Antisense oligonucleotide (ASO) against apoB-100 . . . . . . . . . . . . . . Currently available drugs in the treatment of hypertriglyceridemia . . . . . . PPAR (Peroxisome proliferator-activated receptors) alpha agonists . Omega-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypolipidemic drugs currently in development. . . . . . . . . . . . . . . . . . . . . . CETP (cholesteryl ester transfer protein) inhibitors . . . . . . . . . . . . . Allele specific oligonucleotides – ASO . . . . . . . . . . . . . . . . . . . . . . . . Bempedoic acid (ETC-1002) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diacylglicerol O-acylotransferase 1 (DGAT-1) inhibitors. . . . . . . . . .

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* Corresponding author. E-mail address: [email protected] (Ł. Bułdak). http://dx.doi.org/10.1016/j.pharep.2016.03.016 1734-1140/ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

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Acyl-CoA cholesterol acyltransferase (ACAT) inhibitors . . . . . . . Squalene synthase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other PPAR agonists and selective PPAR modulators (SPPARM). Carboxylase Ac-CoA inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . CAT-2003. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid hormone mimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phospholipase A2 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs mainly affecting high-density lipoprotein (HDL) . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Atherosclerosis is an inflammatory disease that affects arterial wall and leads to the narrowing of the vessels. This manifests predominantly as myocardial infarction (coronary arteries), ischemic stroke (cerebral or carotid arteries) and limb amputation (peripheral arteries). Cardiovascular diseases (CVD) are a leading cause of mortality worldwide. 2 million people die as a result of CVD in European Union [1]. These numbers give rise to intensification of health services’ effort, which should be focused on the dietary habits change, increase of physical activity accompanied by pharmacological support. Currently, despite increasing efforts in the patients’ treatment, we are still observing higher level of CVD in certain populations. This specific risk is called the residual risk [2] and it is thought to be still modifiable with further reduction in the level of currently known risk factors (e.g. LDL-C) [3] or by influence on novel risk factors [e.g. lipoprotein (a)] [4]. One of the most important factors that accelerate atherosclerosis is hyperlipidemia, although one must remember that the background of this condition is multifactorial and the prevention or the reduction of the disease progression may be achieved by a complex therapeutic approach including suitable diet, physical activity and avoidance of certain risk factors (e.g. cigarette smoking). Primary efforts in hypolipidemic therapy should be focused on the lowering of the LDL-C level, while triglycerides (TG) lowering treatment is secondary to LDL-C [2,3], with the exception of extremely elevated TG level >440 mg/dL that is connected with the acute pancreatitis. The reason arises from results of multiple studies clearly showing improved cardiovascular outcomes which correlate with the reduction in LDL-C [5]. TG are also associated with atherosclerosis [2,3], but findings of clinical studies that dealt with the reduction of TG are less convincing. Nevertheless without any doubt highly elevated TG are the cause of potentially fatal acute pancreatitis [6]. Furthermore high TG are commonly connected with poorly controlled type 2 diabetes mellitus and one of the markers of atherogenic dyslipidemia, which is described as low level of HDL cholesterol (HDL-C), high level of TG and moderately increased LDL-C, rich in apo B-100 (i.e. small dense LDL) and leads to accelerated atherosclerosis [7]. Currently available drugs are effective in improving of lipid profile. Unfortunately not all of the patients may benefit from them (e.g. due to side effects excluding drugs from treatment or patient’s genetic background leading to severe hyperlipidemia). Therefore several new pathways are explored to further reduce the lipids level and as a result to improve patients’ outcome. There are several comprehensive guidelines for the treatment of hyperlipidemia [8,9]. They focus mainly on LDL-C level as a main risk factor for accelerated atherosclerosis. Generally speaking all experts agree on the fact that currently the best method to obtain reduction in cardiovascular events is the reduction in LDL-C, both in primary and secondary prevention. According to the European

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Atherosclerosis Society and European Association of Cardiology (EAS/ESC) guidelines, the goal of therapy should be established using SCORE (Systematic COronary Risk Evaluation) charts and anamnesis [8]. Hypertriglyceridemia should be treated as a secondary objective and it becomes primary goal of therapy in case of TG level >440 mg/dL, when the risk of acute pancreatitis is significantly elevated. Contrary to European guidelines, the American Heart Association (AHA) issued recommendation for the treatment of hyperlipidemia that focuses on the maximizing statin use in population at risk [9]. These experts reasoned that prior to the publication of their guidelines no other therapy added to statin regimen improved patient outcome, therefore only high dose statin is the option for treatment of hyperlipidemia and intensification of lipid lowering therapy with other drugs is futile. Most potent statins (rosuvastatin and atorvastatin) at high doses reduce the LDL-C level by 55–60%. However in June 2015 results of IMPROVE-IT study were published and showed that further reduction of LDL-C by addition of ezetimibe to simvastatin may improve patients’ outcome [10]. Recent clinical findings and continuous research in the field of hypolipidemic drugs urged authors to perform the review of recent data and show potential new pathways (Fig. 1) that may be useful in the treatment of hyperlipidemia. To simplify the assimilation of the information, review is divided into several parts. The first two present LDL-lowering and TG-lowering drugs that are currently available on the market. In the next part new groups of drugs are described, which are still in development but may become valuable therapeutic option. The last part contains information regarding drugs affecting HDL level.

Currently available drugs in the treatment of hypercholesterolemia HMG-CoA reductase inhibitors (statins) Statins are drugs of choice in the treatment of hyperlipidemia, both in hypercholesterolemia and atherogenic dyslipidemia. Clinical benefits associated to statin treatment lead to significant reductions in LDL-C level and in the cardiovascular risk in various groups of patients [11]. With the most potent statins (rosuvastatin or atorvastatin) LDL-C level may be reduced up to 55–60%, which is accompanied by a 30% decrease in TG level. However since several years, a debate had been started regarding an increase in the incidence of diabetes. According to recent meta-analysis data the risk increase is around 9% [12]. Despite this phenomenon, statins should be used in patients with diabetes for their undeniable benefits and the fact that the increase in diabetes occurrence is of lesser concern than the decrease in CVD risk. However, in people at risk of developing diabetes regular check-ups should be scheduled in order to initiate proper treatment [13].

[(Fig._1)TD$IG]

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Fig. 1. Schematic representation of lipid metabolism. The figure shows major steps in lipid synthesis and circulation including enzymes and transporter systems that are targeted by drugs described in the review. Abbreviations: CoA – coenzyme A; ACL – adenosine triphosphate citrate lyase; AcylCoAS – Acyl-CoA synthase; DGAT1 – diacylglicerol O-acylotransferase 1; MTP – microsomal triglyceride transfer protein; HMGCoAR – hydroxy-methyl-glutaryl-CoA reductase; SqualeneS – squalene synthase; LPL – lipoprotein lipase; Lp-PLA – lipoprotein-bound phospholipase A2; CETP – cholesterol esters transfer protein; PCSK9 – proconvertase subtilisin/kexin 9; NPC1L1 – Niemann-Pick C1 like 1 protein. (modified from [137]).

The benefit of statins is seen also in patients with non-alcoholic fatty liver disease (NAFLD) [14]. NAFLD is intensely widespread among the obese subjects, patients with metabolic syndrome as well as those with type 2 diabetes, which are the risk factors for CVD. Therefore, as there is an increased risk of CVD in patients with NAFLD, the multifactorial intervention is necessary to lower this risk. Statins are a safe treatment option in NAFLD patients despite their known influence on transaminases level and might be drugs of choice in this population for lowering LDL-C and reducing the intrahepatic cholesterol, resulting in decreased transaminase level [14,15]. Furthermore the benefits from the pleiotropic effects of statins actions such an antiinflammatory, immunomodulatory, antioxidative or antithrombotic effect might even lead to improved hepatic outcomes [14,15]. Adverse events of statins are an important safety concern; the National Lipid Association (NLA) assembled the Statin Safety Assessment Task Force of experts publishing periodically findings regarding the benefits and potential risk of statin use. The last results of the symposium findings were published in 2014 [16] and they deal with the six specific statin-related safety issues including the effects of statins on: cognitive functions [17], diabetes risk [13],

liver function [18], muscle symptoms [19], statin–drugs interaction [20], and statin intolerance [21]. NPC1L1 inhibitors (ezetimibe) Ezetimibe is a selective inhibitor of NPC1L1 (N-terminal Niemann-Pick C1-like protein 1) receptor, which is located on the luminal surface of enterocytes and is responsible for cholesterol uptake [22]. Ezetimibe results in a selective lowering of cholesterol absorption and it does not impair the absorption of other nutrients. In monotherapy its efficacy is moderate and leads to reduction of LDL-C level up to 18% with negligible impact on TG and HDL-C [23]. The usefulness of the drug in the reduction of CVD was dubious for a long time, but recently published data from IMPROVE-IT study showed that addition of ezetimibe to statin regimen resulted in the incidence of the major outcome by 6.4% and LDL-C reduction by 16% (10). Similarly to statins, ezetimibe may be a valid option while treating the NAFLD’s patients. Further studies are needed to confirm the influence of ezetimibe on liver fat and liver histology, nevertheless the reduction of CVD risk is

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undeniable. Ezetimibe is considered safe in patients with NAFLD while used alone or in combination with statins [14,15,24]. Plant sterols Plants sterols, like sitosterol or campesterol, are present in normal diet at doses reaching 0.5 g per day. It was shown that the increase in the dietary intake of these substances (1.8–2.0 g per day) [25,26] might reduce LDL-C by even 10%. The mechanism of action relies predominantly on the competition with cholesterol in the intestinal uptake [27]. Plant sterols were shown to be effective in lowering non-HDL cholesterol level (by around 8%), but the data on the subject are not superfluous [25,26]. Unfortunately there is no hard scientific evidence to support the idea of reduction in cardiovascular events [28]. One might speculate that it should be comparable to the achieved LDL-C reduction. The therapy with plant sterols pose no imminent threat to subjects and is currently recommended as adjunct therapy or in statin intolerant patients [29]. Monacolin k (red yeast rice) Monacolin k is a naturally occurring substance in a specific yeast species (Monascus purpureus) [30]. The compound has moderate lipid lowering potential, which stems from structural similarity to lovastatin. LDL-C lowering potential may reach 33%, but we are lacking evidence from clinical trials to support the notion for reduced cardiovascular (CV) risk. Monacolin k is available on the market as an over-the counter (OTC) drug and sometimes it is used in patients who do not tolerate statin therapy. Precise data on side effects are lacking, but as a result of similarity to statin it should posses similar safety profile. One must remember that this notion is attributable to monacolin k as a compound, and it is not valid in dietary supplements that contain non-standardized ingredients [30].

with PCSK9 binding to LDL receptors on cell surface a significant increase in the density of LDL receptor is obtained. The drawback of currently available compounds is their method of acquisition – these drugs are monoclonal antibodies, which leads to certain issues (e.g. availability, pricing). The lack of small molecules as inhibitors of PCSK9 results from relatively flat surface of the protein active center, which would ease inter-particle linkage (SXPCK9 is an ongoing program to develop such compounds) [36]. On the bright side, the subcutaneous injections are not often (once to four times a month). Other methods of reduction in PCSK9 level are also explored and include antisense oligonucleotides. Nevertheless the progress is less advanced and we need to wait for more detailed results (SPC-5001 and ALN-PCS02 both in phase I clinical trials) [37,38]. The efficacy of PCSK9 inhibitors is spectacular and reaches 60% LDL-C reduction – even in patients treated concurrently with statins [39–41]. Such a high activity in people on statin regimen might be a sequel of PCSK9 augmentation, which was described previously [42]. Interestingly, both European (European Medicines Agency – EMA) and American (Food and Drug Administration – FDA) regulatory authorities approved two PCSK9 inhibitors (evolocumab and alirocumab) for use in certain group of patients (2015), despite the lack of results of large scale trials focused on CV outcomes, which are currently ongoing (ODYSSEY Outcomes and FOURIER) [43]. Until recently there are no indications of severe side effects associated to the treatment with PCSK9 inhibitors [41]. Most commonly injection side reactions or flu-like syndromes were reported. Additionally a slight increase in creatine kinase level [41] and uric acid were noted but did not lead to the cessation of therapy [44]. The results of three long-term studies (ODYSSEY LONG TERM and OSLER-1 and 2) also did not show excessive adverse effects of PCSK9 inhibitors (alirocumab, evolocumab). Beyond the already mention injection side reactions they reported the myalgia, ophthalmological and neurocognitive events [39–41,45].

Bile acid sequestrants Microsomal transfer proteins (MTP) inhibitors Resins (e.g. cholestyramine, colesevelam) are a group of drugs that inhibit entero-hepatic bile acid circulation [31]. In normal conditions 95% of bile acids excreted with bile is absorbed in intestines. Resins exchange their ionic chloride with anionic bile salts. Afterwards insoluble complexes are excreted with the stool. In order to ensure proper amount of bile acids in the GI tract liver synthesizes more bile acid from the cholesterol and that leads to a reduction in serum cholesterol level up to 15–30% [32]. Unfortunately, the treatment is cumbersome, which results from the relatively high dose of the drug, gastrointestinal side effects and decreased availability of other nutrients (e.g. lipid soluble vitamins). What-is-more these compounds may increase TG level and therefore are contraindicated in the hypertriglyceridemia. Nevertheless the best results are obtained with colesevelam, which stems from the fact that the drug is given at lower doses than other resins and in more convenient tablet formulation. Additionally colesevelam improves glucose tolerance and becomes a valid option in the treatment of type 2 diabetes mellitus [33,34]. PCSK9 inhibitors PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are new players in the therapy of hyperlipidemia. The novelty of the mechanism of action is based on the fact that these drugs mimic naturally occurring loss-of-function mutation of PCSK9, which is connected with low LDL-C level. In humans PCSK9 is a particle that tags LDL receptor for degradation and prevents the receptor from reappearance on cell surface [35]. By interfering

The mechanism of action of MTP inhibitors is based on the disruption of the lipoprotein synthesis in the intestines and liver. As a consequence the substantial reduction in the lipoproteins in blood stream is seen, which leads to approximate 50% reduction in LDL-C and up to 65% reduction in TG level [46]. EMA and FDA approved lomitapide (the first MTP inhibitor) to the treatment of homozygous hypercholesterolemia (2013 and 2012). However the pattern of lipid profile change also seems very promising in patients with atherogenic dyslipidemia [47]. Lomitapide is administered orally, which is very convenient, but the side effects remain a serious issue in the therapy. Due to severe diarrheas patient need to maintain specific low lipid diet, which reduces the symptoms [46]. The drug must be also slowly uptitrated, because side effects are dose dependent and tolerance to the drug is variable among patients. Additionally, a liver damage accompanied by liver steatosis was seen in clinical trials and in post-marketing surveillance, which may precipitate further problems with cirrhosis, but till now there are no such indications [48]. In order to reduce potential issues with liver damage a JTT130 and SLx-4090 compound were conceived. This drug blocks lipoprotein synthesis in intestines only thus should not cause hepatotoxicity [49]. According to preclinical data SLx-4090 significantly and dose dependently reduced TG, total and LDL cholesterol level with a concurrent rise in HDL, in an animal model of hypertriglyceridemia [50]. Moreover, no significant toxicity was noted. The phase II clinical study on the efficacy of SLx-4090 in chylomicronemia is pending [51].

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Antisense oligonucleotide (ASO) against apoB-100 Mipomersen is the first drug in class that relies on the inhibition of protein translation at the mRNA level [52]. Oligonucleotides matching the sequence of apo-B100 in mRNA mark it for digestion and prevent protein synthesis. Mipomersen has additional unique features of the mechanism of action. Firstly, it reduces the synthesis of apoB-100 that is a major constituent of LDL particles at the level prior to protein synthesis. Secondly, the efficacy is not reliant on the expression of LDL receptor, which may be deficient or defunct in familial hypercholesterolemias. Mipomersen therapy is associated with a reduction in LDL-C by up to 40% [53]. So far only FDA approved this drug to the treatment of homozygous hypercholesterolemia (2013). EMA has rejected the application twice due to safety concern related to hepatotoxicity and increased CV risk [54]. The greatest concern is connected with a potential risk of liver damage, which in several people was described as steatohepatitis with fibrosis [55]. This condition may lead in future to liver cirrhosis. Topical complications are a minor problem. Additionally, there are indications of increased CV event rate during the treatment – despite the clear hypolipidemic effect [53]. The orphan drug status will be maintained for the compound until new data regarding safety and impact on clinical outcomes will be published. Recently FOCUS FH trial (patients with familial hypercholesterolemia) was completed but results are not yet available [56]. Currently available drugs in the treatment of hypertriglyceridemia PPAR (Peroxisome proliferator-activated receptors) alpha agonists Fibrates are well-known and one of the oldest drugs to treat hyperlipidemia, especially atherogenic dyslipidemia and hypertriglyceridemia [57]. The mechanism of action relies on activation of intracellular receptors (PPAR alpha) in the liver, adipose tissue and several other metabolically active organs (e.g. heart), which leads to significant changes in the synthesis of proteins associated with lipoprotein (apo CIII, apo AI, apo AII, SR-BI, lipoprotein lipase) and triglycerides metabolism (beta oxidation) [57]. Additionally, during treatment a reduction in proinflammatory proteins and attenuation of atherosclerosis was observed [58]. As a result fibrates reduce TG level up to 50%, LDL-C by up to 20% and may slightly elevate the HDLC level by 10–20%. Furthermore fenofibrate might be useful in patients with mixed dyslipidemia. Post hoc analysis of ACCORD Lipid trial [59] (in patients with TG level >200 mg/dL and HDL <35 mg/dL) showed that fibrates may be considered as a valuable add-on in the combined therapy or as a second-line monotherapy in cases of statin intolerance [57,59]. One must remember about slight differences between fibrates. Fenofibrate is a full PPAR alpha agonist, which effectively elevates HDL-C, whereas gemfibrozil is only a partial agonist of PPAR alpha and is devoid of action on HDL-C. On the other hand bezafibrate is a pan PPAR agonist (acting on all isoforms of PPAR), which improves glucose tolerance [60]. Nevertheless, most clinical trials show only modest improvement in secondary prevention of CV events, especially if clofibrate (withdrawn from the market in 2002) was not taken into account [61]. Fibrates are relatively safe drugs, but an increase in liver aminotransferases is sometimes seen. The CK elevation is also not uncommon, but the rhabdomyoslysis in patients with normal kidney function is a rarity. Finally, due to increased propensity of gall stones formations fibrates are contraindicated in that comorbidity [62]. Omega-3 fatty acids Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are effective in the treatment of hypertriglyceridemia reducing TG

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level up to 50% [26,63]. But in order to achieve optimal results these compounds must be administered at relatively high doses (4 g per day). Currently, there is a dispute ongoing regarding the best formulation of omega-3 acids. Free fatty omega-3 acids posses the highest bioavailability [63]. Additionally, clinically important differences between EPA and DHA are emerging. DHA, in contrast to EPA, may increase LDL-C [64,65]. Clinical consequences of this phenomenon are currently studied in clinical trials (REDUCE-IT and STRENGTH). Gene therapy Alipogene tiparvovec (brand name Glybera1; AMT-011, AAV1LPLS447X) is the first gene therapy approved by EMA (2012) for use in patients with congenital lipoprotein lipase (LPL) deficiency, resulting in severely elevated TG level, hyperchylomicronemia and subsequent bouts of severe acute pancreatitis [66,67]. The lipoprotein lipase gene is incorporated into viral vector (adenoassociated virus serotype-1) that epigenetically introduces gene into muscle cells and is expressed afterwards. The drug effectively reduces TG up to 60%, but the efficacy drops with passing time due to immune response against viral vector [66]. However, the improvement of postprandial chylomicron metabolism and expression of functional copies of the LPL S477X gene, as well as biologically active LPL in muscles was observed after longer periods of time [67]. Additionally, there were clinically significant reductions in the incidence of pancreatitis and acute abdominal pain noted still after a few years post administration [67]. The drug is overall well-tolerated and reported adverse events included mostly localized, transient, mild to moderate injection-site reactions [67]. However, other issue with this drug is its cumbersome administration, which requires anesthesia and multiple muscle injections. Furthermore, patient must be on immunosuppressive regimen [66]. Hence, currently this drug has an orphan drug status. Hypolipidemic drugs currently in development CETP (cholesteryl ester transfer protein) inhibitors Great expectations were linked to the arrival of that novel group of drugs. The mechanism of action relies on cholesterol ester transfer protein inhibition, which leads to substantial rise in HDL-C accompanied by TG and LDL-C drop [68]. In normal conditions CETP exchanges cholesterol esters for TG between HDL and TG-rich lipoproteins (VLDL – very low density lipoprotein, IDL – intermediate density lipoprotein), leading to a reduction in HDLC level. In people with CETP deficiency a significantly higher levels of HDL-C are observed [69]. The profile of lipid changes seen after CETP inhibitors could be particularly beneficial in people who do not achieve target levels of LDL-C on statin treatment and also in people with atherogenic dyslipidemia. Large-scale trials were initiated, but results of the first (ILLUMINATE) with torcetrapib showed harm compared to placebo [70]. This unfavorable effect was attributed to increased blood pressure and influence on renin angiotensin system. The phase III study with anacetrapib in patients with familial hypercholesterolemia (REALIZE) showed decent toleration of treatment and significant reduction in the LDLC level. No substantial differences in the incidence of adverse effects comparing to placebo were noted, but an increase in cardiovascular events was observed [71]. The third trial (dalOUTCOMES) with dalcetrapib did not show any effect on outcomes, despite the fact that the dug considerably changed the HDL-C level [72]. The fourth study with evacetrapib (ACCELERATE) was recently terminated prematurely due to futility [73]. Therefore at the moment, there is only one large-scale clinical trial with CETP

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inhibitor – REVEAL – with anacetrapib. The impact of the drug on surrogate markers of CVD is substantial. Anacetrapib lowered LDLC by 40% and doubled the HDL-C level [74]. Results are expected this year, but probably during next interim analysis of the study a thorough investigation of benefits will be estimated due to lack of effects of CETP inhibition in previous trials. Despite the above-mentioned drawbacks reverse cholesterol transfer inhibition is still one of the direction in atherosclerosis research. Recently, a Taiwanese research group showed promising results of vaccine against CETP in rabbits. The response to vaccination was good and was accompanied by a significant reduction in atherosclerotic plaques size and improvements in steatohepatitis [75]. Allele specific oligonucleotides – ASO ASO are relatively novel drugs that are currently under development in many therapeutic applications. The method of action of these drugs is based on the loss of function mechanism, which mimics effects of naturally occurring mutations. Mipomersen, which was described previously, belongs to this class of drugs and has already been approved for the treatment of people [52]. But currently, there are numerous research projects to find novel targets for such a therapy. These studies rely on genomewide association scanning (GWAS) and to this moment several promising targets were found. In some cases therapeutic molecules are currently in clinical trials (apo CIII, Lp(a), angiopoietin like protein 3) [76]. The most advanced work is connected with ASO against apo CIII – volanesorsen [77]. The reduction in apo CIII leads to increased activity of LPL that significantly reduces TG level. The drug is currently in phase III clinical trials (COMPASS and APPROACH) in the treatment of hypertriglyceridemia and chylomicronemia. In the phase II clinical trials in these conditions it reduced TG by 71% and 86%, respectively [77,78]. There are also several research projects on other promising pathways that are on less advanced phases of clinical trials. ASOs against Lp(a) (ISIS-APO(a)Rx) and angiopoietin-like protein 3 (ISISANGPTL3RX) successfully completed phase I clinical trials and are currently in phase II clinical trials. Both of these drugs may be found useful in the therapy of hyperlipidemia and high Lp(a) level [79,80]. Currently safety considerations are connected predominantly with injection site reactions (erythema, itching), more detailed data are expected after phase II and phase III clinical trials completion. Bempedoic acid (ETC-1002) ETC-1002 is a compound from a novel group of drugs that simultaneously act on two liver enzymes: it blocks adenosine triphosphate citrate lyase (ACL) and activates adenosine monophosphate-activated protein kinase (AMPK) [81]. As a result a decrease in reduction of fatty acids production and an increase in betaoxidation of FFA are observed. Finally a moderate (30%) reduction in LDL-C, Lp(a) and hsCRP is seen [82]. The advantage of this drug, in contrast to many other recently discovered drugs, is its oral administration once daily and high efficacy in people that do not tolerate statins [83]. Promising results of phase II clinical trials have lead to the phase III clinical studies, which are scheduled to start in fourth quarter of 2015 [84], but till now there are no entries in publicly available clinical trials registries. One may assume that the study is postponed till 2016 [85]. Diacylglicerol O-acylotransferase 1 (DGAT-1) inhibitors DGAT-1 is an enzyme connected with final steps of TG metabolism in the intestines. In people with enzyme deficiency,

reduced levels of TG, accompanied by increased insulin sensitivity and protection against diet-induced diabetes are seen. These properties seem exceptionally promising in people suffering from atherogenic dyslipidemia [86]. Pradigastat effectively reduced TG level up to 70% and may be useful in chylomicronemia [87]. However there are no phase III trials in patients with CVD and diabetes, only phase II trials were conducted [88,89]. During 28-day treatment pradigastat was well tolerated with mild side effects consisting of GI tract disturbances (diarrhea, nauseas, vomiting) and headaches [90]. Acyl-CoA cholesterol acyltransferase (ACAT) inhibitors ACAT seems a promising therapeutic target, because it is responsible for cholesterol reestrification in cells and accumulation of cholesterol esters in macrophages, which is a hallmark in the development of atherosclerosis. ACAT-1 is located in macrophages and is connected with foam cells formation, while ACAT-2 inhibition leads to a decrease in VLDL synthesis [91]. Additionally ACAT inhibition was connected with increased expression of collagen in atherosclerotic plaques and diminished activity of matrix metalloproteinase-1 [92]. Both these findings support the idea that ACAT inhibitors may stabilize vulnerable plaques. Avasimibe and eflucimibe showed improvements in lipid profile but were not approved to use in people [93]. Similarly, pactimibe despite significant improvements in lipid profile failed to affect atherosclerotic plaque in the ACTIVATE study, which led to suspension of further clinical trials on this compound [94]. Research projects on other members of this group (e.g. K-604) are still ongoing, but no results have been published so far [95]. Squalene synthase inhibitors Compared to statins, squalene synthase inhibitors affect further step of the endogenous synthesis of cholesterol. In theory it might reduce the adverse event ratio connected with reduced availability of mevalonate (a precursor of isoprenoids) during statin therapy [96]. However studies result with candidate compounds showed other than myopathy potential problems with side effects. Lapaquistat significantly reduced LDL level, but the drug development was stopped due to increased hepatotoxicity without additional benefits compared to currently available drugs [97]. The second compound from this group – AZD7687 – completed phase I clinical trials. During the therapy GI tract side effects were noted (predominantly diarrheas) [98]. Recently another selective inhibitor of squalene synthase was developed (DF-461), but there are no available data whether the compound entered clinical trial phases [99]. Therefore it seems, that currently there are no studies under way to explore hypolipidemic effects of squalene synthase inhibitors. Other PPAR agonists and selective PPAR modulators (SPPARM) PPARs are heterogeneous group of intracellular receptors [100]. PPAR alpha agonists (described above) are used to treat hypertriglyceridemia, while PPAR gamma agonists are used to tackle diabetes. Both these features would be highly valuable in the treatment of atherogenic dyslipidemia, but the failure of dual PPAR alpha/gamma agonists (glitazars) to improve CVD led to increased attraction to other members of PPAR family [101]. A certain amount of attention was given to PPAR beta/delta agonists. PPARs beta/delta are ubiquitously expressed in tissues therefore it is harder to conceive drugs selectively affecting organs associated with lipid synthesis. Additionally effects of PPAR beta/delta stimulation are less delineated, but improvements in lipid profile (connected with apo CIII inhibition and accelerated beta oxidation)

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and insulin sensitivity were noted [102]. Not many results have been published so far. GW501516 showed modest impact on lipid profile [103], while MBX-8025 was much more effective and significantly reduced the number of small dense LDL particles – a feature desirable in atherogenic dyslipidemia [104]. Currently a study on impact of MBX-8025 in patients with homozygous hypercholesterolemia is taking place [105]. Elafibranor (GFT-505) a dual PPAR alpha/delta agonist that may be beneficial in patients with diabetes, liver steatosis and nonalcoholic steatohepatitis (NASH) successfully finished phase II clinical trials [106–108]. In November 2015 a phase III clinical trial in patients with NASH and increased cardiovascular risk was announced [109]. Recently results of GOLDEN 505 study were published showing improvements in the course of non-alcoholic steatohepatitis [110]. Drug was well tolerated during 52-week treatment period, did not show negative cardiovascular adverse effects, but was associated with mild, reversible creatinine level increase. The background for the development of SPPARMs was amplification of the beneficial impact of PPAR agonism, while obtaining simultaneous reduction in the incidence of side effects. K-877 is an SPPARM-alpha and has a thousand-fold higher activity on PPAR alpha than fenofibrate [60]. At doses up to 400 mg per day it significantly reduced the TG level up to 42% in phase I and phase II clinical trials. Additionally improvements in lipoprotein phenotype (reduction in small dense LDL level) and liver damage markers reductions were observed [111]. The drug seems to be safe in studies that were performed so far and may supersede other fibrates, however it must be kept in mind that long-term safety and outcomes studies are warranted. A phase III clinical trial was performed in Japan population with high TG (400 patients), though no clinical findings are published so far [112]. Carboxylase Ac-CoA inhibitors Gemcabene belongs to medium-chain fatty acids. It blocks the acetyl-CoA carboxylase and as a result a significant drop in malonyl-CoA synthesis is observed [113]. Therefore this drug interferes with the very first step of TG synthesis. Additionally TG level is decreased by a concomitant reduction in apo CIII, which leads to improved VLDL clearance. Clinically gemcabene was found to be effective in reducing LDL-C and TG with a concomitant rise in HDL-C in phase II clinical trials [114]. The efficacy of the drug is seen predominantly in people with severe hyperlipidemia and statin intolerant, because it does not provide additional benefit in people already treated with statin [113]. Phase III studies are currently under way [115]. The drug was approved in 2014 to the treatment of homozygous familial hypercholesterolemia as an orphan drug. CAT-2003 This compound belongs to a novel group of concept drugs, which consist of two active drugs that become activated only after entering cells and they are not active prior to the cleavage of a link [116]. This unique technology is called SMART (safety metabolized and rationally targeted) and its benefits include: enhanced activity of compounds due to impact on multiple pathways and improved pharmacokinetic properties, which is accompanied by diminished side effects. CAT-2003 consists of niacin and EPA, both drugs that are used in monotherapies of hyperlipidemias. The drug was in phase II clinical trials in patients with dyslipidemia, chylomicronemia and severe hypertriglyceridemia. It showed significant TG level reduction that reached 90% in postprandial state [102]. However since 2013 the data regarding this compound are scarce.

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Thyroid hormone mimetics Hyperthyroidism (HT) is associated with low levels of LDL-C, but it also lead to numerous complications, including those life threatening. In subjects with HT cholesterol level reduction is associated with a reduction in PCSK9, apo CIII and apo AI levels [117]. Therefore, a focus on compounds that could mimic some features of HT was given. Thyroid hormones mimetics (e.g. eprotirome) are interesting group of drugs that effectively led to weight loss and a reduction in LDL level reaching 32%, without significant adverse effects in a 12-week phase II clinical trial [118]. Furthermore eprotirome led to a reduction in TG and increased bile acid synthesis [117]. Promising results were verified in a phase III study (AKKA) that still showed good lipid lowering results of the drug, but the high incidence of liver damage led to termination of the further drug development. Other drugs from this group (sobetirome and t-0681) are showing promising results, but till now only in animal models of atherosclerosis [119,120]. Phospholipase A2 inhibitors There are several types of phospholipases. Some of them are connected with atherosclerosis. The most important seem to be secretory phospholipase A2 (sPLA2) and lipoprotein-bound phospholipase A2 (Lp-PLA2). Lp-PLA2 is novel marker of cardiovascular diseases. It is synthesized in greater amounts by proinflammatory (M1) macrophages that are associated with the progression of atherosclerosis. It is responsible for synthesis of noxious lipid derivatives (lysoPC – lysophosphatidylcholine and oxidized NEFA – non-esterified fatty acid) in vulnerable plaques, which in consequence lead to their instability [121]. Darapladib, an LpPLA2 inhibitor, showed promising results in numerous short-term studies [122]. Unfortunately, despite its beneficial impact on lipid profile (reduction in LDL) it did not improve the outcome of patients with stable coronary heart disease (STABILITY) [123] and in patients after acute coronary syndromes (SOLID-TIMI 52) [124]. Furthermore phase III trial (VISTA-16) with varespladib not only did not show benefit for patients after acute coronary syndrome but also caused increase in cardiovascular events [125]. Rilapladib that originally was developed as a drug against atherosclerosis [126] is currently studied in patients with Alzheimer disease [127]. Drugs mainly affecting high-density lipoprotein (HDL) Some attention as a therapeutic option is given to HDL-C. Since many years it has been showed that high HDL-C is a marker of metabolic well-being and protection from CVD. Additionally HDLC is a main player in the reverse cholesterol transfer from peripheral deposits (e.g. arterial walls). Therefore, the drugs affecting HDL-C level are also considered as potential targets for therapy. Unfortunately, contrary to drugs affecting LDL metabolism available results are not that promising. Nevertheless the changes in lipid profile might be beneficial for patients with specific forms of hyperlipidemia, like atherogenic dyslipidemia. Currently there are two major methods of achieving an increase in HDL: exogenous administration of apo AI/HDL or administration of drugs increasing endogenous synthesis of apo AI. Apabetalon (RVX-208) is a novel small molecule that selectively inhibits BET (bromodomain and extra-terminal). By this mechanism it epigenetically modulates the expression of various genes associated with hyperlipidemia and diabetes, leading to an increased endogenous synthesis of apo AI. In phase II clinical trials it showed improvements in lipid profile [128] but it failed to affect the area of atherosclerotic plaque during 26-week treatment [129]. A phase III clinical trial (BETonMACE) exploring the impact

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Table 1 Antihyperlipidemic drugs and their influence on lipid profile. Group of drugs

Drug name

HMG-CoA reductase inhibitors NPC1L1 inhibitors Plant sterols Red yeast rice Bile acid sequestrants PPAR alpha agonists Omega-3 fatty acids PCSK9 inhibitors MTP inhibitors ASO against apoB-100 LPL substitution CETP inhibitors ACL inhibitor and AMPK activator DGAT-1 inhibitors ACAT inhibitors Squalene synthase inhibitors PPAR delta agonists Carboxylase Ac-CoA inhibitors Selective PPAR modulators SMART Intestinal MTP inhibitors Thyroid hormones mimetics Phospholipase A2 inhibitors

Atorvastatin Ezetimibe Camposterol Monacolin k Colesevelam Fenofibrate Eicosapentaenoic acid Alirocumab Lomitapide Mipomersen Alipogene tiparvovec Anacetrapib ETC-1002 Pradigastat Avasimibe Lapaquistat GW501516 Gemcabene K-877 CAT-2003 SLx-4090 Eprotirome Darapladib

+ = <15% increase; ++ = 15–40% [52,64,71,87,103,104,138–161].

increase;

+++ = >40%

LDL

increase;

TG

TCh

0 +

HDL

Lp (a)

PCSK9

0 0 0 0 + +

+ N/A N/A N/A

++ 0 0 N/A + + N/A

N/A

N/A

0 N/A N/A N/A N/A N/A N/A N/A N/A

N/A N/A N/A N/A N/A N/A N/A N/A N/A

0

N/A

N/A N/A 0

0 + N/A

N/A

N/A N/A N/A

N/A N/A N/A N/A

N/A N/A N/A N/A

N/A N/A N/A N/A

0 <15% decrease;

of the drug on MACE (major adverse cardiac events) in high CV risk patients with low HDL level and concomitant diabetes has recently been launched [130]. In Milan center for atherosclerosis research a mutant apo AI Milano is administered to patients. Apo AI Milano was obtained from subjects with very low cardiovascular risk [131]. But the method, despite its efficacy, requires repeated intravenous infusions, is rather expensive. Other methods with HDL infusions are based on extracorporeal ‘‘purification’’ of autologous HDL-C and then its autologous infusion [132]. In phase II clinical studies there are two novel particles: CER001 (consisting of apo AI and phospholipids) and CSL-112 (reconstituted apo AI) that mimic effects of natural HDL-C [133,134]. The impact on HDL-C level is substantial, but the CV benefit is not clearly outlined [135,136]. Thus further studies on usefulness of HDL elevating strategies are warranted. Conclusions According to the provided data the perspective of hypolipidemic treatment is promising (Table 1). Multiple therapeutic pathways should lead us to the point where we can achieve lipid targets in nearly all patients. Nevertheless, it must be remembered that the outcome trials must be performed to exclude the possibility of futility or even harm associated to these changes. One of the examples is CETP inhibitors, which despite the great impact on surrogate marker, were not approved to use outside of experimental setting. This decision seems reasonable solution until more convincing results of outcome studies are available. On the other hand PCSK9 inhibitors were approved prior to the results of large-scale outcome trials, but currently in a narrow, statinintolerant population of patients. Broader application of these drugs must be postponed till the end of event driven clinical trials. The safety profile of currently approved drugs is relatively wellknown and the usage of lipid lowering drugs is limited predominantly by their propensity to liver damage and GI tract disturbances. Available data on drugs in development are scarce but were gathered here as extensively as possible. We showed several potential pathways that may be affected by drugs

= 15–40%

decrease;

+ 0 0 N/A +++ 0 0 0 N/A +++ N/A N/A N/A N/A 0 0 = >40%

N/A decrease.

N/A N/A = not

available

conceived to reduce lipid levels. However most of the compounds are in Phase I and II clinical trials and probably most of them will not enter into next phases of clinical trials due to side effects or futility compared to currently used drugs. In summary, authors believe that in next several years there will be a significant increase in the availability of novel hypolipidemic drugs acting on various mechanism of lipid metabolism. Similar ‘‘boom’’ has recently been seen in antidiabetic therapy. Hopefully these drugs will effectively improve lipid profile in patients leading to improved patients’ outcome in a safe way. Conflict of interest None. Funding Medical University of Silesia. Grant No. KNW-1-093/N/5/0. References [1] Cardiovascular diseases statistics. Data extracted in October 2015. Available from: http://ec.europa.eu/eurostat/statistics-explained/index.php/ Cardiovascular_diseases_statistics#Deaths_from_cardiovascular_diseases [2] Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012;14(1):1–10. [3] Reiner Zˇ. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr Metab Cardiovasc Dis 2013;23(9):799–807. [4] Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc 2013;88(11):1294–311. [5] LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352(14):1425–35. [6] Ewald N, Hardt PD, Kloer H-U. Severe hypertriglyceridemia and pancreatitis: presentation and management. Curr Opin Lipidol 2009;20(6):497–504. [7] Taskinen M-R, Bore´n J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015;239(2):483–95. [8] Catapano AL, Chapman J, Wiklund O, Taskinen M-R. The new joint EAS/ESC guidelines for the management of dyslipidaemias. Atherosclerosis 2011; 217(1):1. [9] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce

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