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New agents for hypercholesterolemia
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www.elsevier.es/medicinaclinica
Review
New agents for hypercholesterolemia夽 Xavier Pintó a,b,∗ , María Carmen García Gómez c a
Unidad de Lípidos y Riesgo Vascular, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Universidad de Barcelona, Barcelona, Spain c Servicio de Reumatología, Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 5 November 2014 Accepted 14 January 2015 Available online xxx Keywords: Hypercholesterolemia treatment Arteriosclerosis Lipid metabolism Hypolipidemic drugs
a b s t r a c t An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians’ inappropriate or insufficient use of cholesterol lowering medications or to patients’ bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. ˜ S.L.U. All rights reserved. © 2015 Elsevier Espana,
Nuevos tratamientos para la hipercolesterolemia r e s u m e n Palabras clave: Tratamiento de la hipercolesterolemia Arteriosclerosis Metabolismo de los lípidos Fármacos hipolipidemiantes
Una alta proporción de pacientes de alto riesgo cardiovascular no alcanzan los objetivos terapéuticos del c-LDL. Ello se debe a un uso inadecuado o insuficiente de los fármacos hipolipidemiantes por parte de los facultativos, y también a una mala tolerancia o al incumplimiento terapéutico por parte de los pacientes. Sin embargo, otra causa de esta situación es la potencia insuficiente de los fármacos actuales para disminuir el colesterol, incluyendo las estatinas y la ezetimiba. Entre los nuevos agentes hipocolesteremiantes, los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 se están mostrando como unos agentes seguros y con una alta eficacia para disminuir el c-LDL en los numerosos ensayos clínicos que se han realizado o están en curso, y nos permitirán lograr el control óptimo de la hipercolesterolemia en la gran mayoría de los pacientes. Los fármacos que inhiben la síntesis de apolipoproteína B y los inhibidores de la proteína microsómica transferidora son otros fármacos que aportan un nuevo potencial de disminuir el colesterol en los pacientes con hipercolesterolemias graves y, en particular, en la hipercolesterolemia familiar homocigótica. Por último, los inhibidores de la proteína transferidora de esteres de colesterol han mostrado potentes efectos sobre el c-HDL y el c-LDL, pero su eficacia en prevención cardiovascular y su seguridad aún no han sido probadas. En este artículo se sintetizan las principales características de los fármacos para el tratamiento de la hipercolesterolemia que han sido recientemente aprobados o que están en fase avanzada de investigación. ˜ S.L.U. Todos los derechos reservados. © 2015 Elsevier Espana,
夽 Please cite this article as: Pintó X, García Gómez MC. Nuevos tratamientos para la hipercolesterolemia. Med Clin (Barc). 2016. http://dx.doi.org/10.1016/j.medcli.2015.01.016 ∗ Corresponding author. E-mail address: [email protected] (X. Pintó). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
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Excess LDL cholesterol (LDL-C) is responsible for 60% of coronary heart disease cases and 40% of ischaemic strokes.1 The treatment of hypercholesterolemia directly reduces risk of cardiovascular disease, proportional to the decrease of LDL-C, a concept that is based on the results of a wide range of randomised trials.2 Therefore, a decrease of LDL-C is considered the primary therapeutic action to prevent early episodes and recurrences of cardiovascular disease (CVD), and increasingly strict therapeutic goals for LDL-C have been established, particularly in patients with high or very high cardiovascular risk.3 Statins are the most effective medication to lower cholesterol and have shown the greatest preventive effect against CVD. In a large meta-analysis of the studies conducted with these medications, it was observed that a decrease of 2–3 mmol/l (78–117 mg/dl) could prevent 40–50% of CVD occurrences.4 In this meta-analysis a threshold value of LDL-C was not detected from which the relationship with cardiovascular risk begins or disappears. Despite the foregoing, between half and two thirds of patients do not reach LDL-C goals.5,6 This situation of therapeutic deficiency is of great clinical relevance, since it is associated with high cardiovascular morbidity and mortality. Its causes (Table 1) include intolerance and resistance to statins. Intolerance is the inability to follow a treatment with these medications at any dose or at a dose that is sufficient for the occurrence of adverse effects; this occurs in 5–20% of patients,4 mainly because of liver or more importantly, muscle conditions ranging from mild myalgia to severe rhabdomyolysis. Although myotoxicity of statin is usually selflimiting and improves by withdrawing the medication, in some cases an autoimmune necrotising myopathy can develop, arising from the over-expression of the major histocompatibility complex type 1 and with the presence of Anti-HMG-CoA reductase antibodies (Ab), which unlike other forms of muscle involvement, do not improve with the interruption of statins and require immunosuppressive treatment.7 Resistance to statins is the lack of achievement of goals despite the use of potent statins at high doses8 and may be due to a wide range of genetic polymorphisms associated with lipid metabolism, environmental factors or the coexistence of certain infectious, metabolic or inflammatory diseases.9 Finally, poor compliance with treatment, also known as statin pseudo-resistance is a very common cause of treatment failure.10 In patients who, despite treatment with potent statins at high doses, do not achieve LDL-C goals, the best alternative is to associate a cholesterol absorption inhibitor, such as Resincolestiramina or ezetimibe, as it increases by more than 2 the possibility of achieving those goals compared to monotherapy.11 However – and particularly in ischaemic patients and those suffering from severe genetic
Table 1 Causes of failure in achieving cholesterol goals linked to low density lipoproteins in patients treated with statins. Use of statin with insufficient potency Use of statin with inadequate doses Lack of association of lipid-lowering medications Intolerance due to muscle, liver or other side effects Resistance to statins due to genetic factors (polymorphisms of HMG-CoA reductase, ABCB1, ABCB2, OATP1B1, OATP2B1, NPC1L1, apoE, PCSK9, LDLR and Lp(a), among others) Resistance to statins due to environmental factors or the coexistence of other inflammatory, infectious or metabolic diseases Therapeutic failure ABCB1: ATP-binding cassette B1; ABCB2: ATP-binding cassette B2; apoE: apolipoprotein E; HMG-CoA reductase: hidroximetilglutaril-coenzyme A reducatase; Lp(a): lipoprotein (a); NPC1L1: Niemann-Pick C1-like L1; OATP1B1: organic anion transporter protein 1B1; OATP2B1: organic anion transporter 2B1 protein; PCSK9: proprotein convertase subtilisin/kexin type 9; LDLR: low-density lipoprotein receptor.
Table 2 New medications for treating hypercholesterolemia. PCSK-9 inhibitors Alirocumab Bococizumab Evolocumab apoB synthesis inhibitors Mipomersen MTP inhibitors Lomitapida CETP inhibitors Anacetrapib Evacetaprib apoB: apolipoprotein B; CETP: cholesteryl ester transfer protein; MTP: microsomal transfer protein; PCSK9: proproteína convertasa subtilisina/kexina type 9.
hyperlipidaemia, including heterozygous familial hypercholesterolaemia and familial combined hyperlipidaemia–the therapeutic goals are frequently not achieved, even when these patients are treated in specialised lipid units.12,13 For these reasons, the need for new medications to improve the effectiveness of hypercholesterolaemia treatment seems obvious, especially in patients at high cardiovascular risk. Among the new medications (Table 2) described in this review, a new family of highly effective agents for treating hypercholesterolaemia are currently in the advanced stages of research; they neutralise the activities of proprotein convertase subtilisin/kexin type 9 (PCSK9)14 and cholesteryl ester transfer protein (CETP) inhibitors: anacetrapib and evacetrapib.15 In addition two new agents have recently been commercialised in some countries which act against hypercholesterolaemia, an inhibitor of the synthesis of apolipoprotein B (apoB): mipomersen, and an inhibitor of microsomal transfer protein (MTP): lomitapida.16 The first has not been authorised in Europe.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors The PCSK9 protein is secreted by the liver into the bloodstream, where it binds to the LDL receptor on the surface of hepatocytes, resulting in its internalisation and subsequent degradation in the lysosomes.17 This protein is intended to regulate the entry of cholesterol into cells, such that when these have a low cholesterol level the sterol regulatory element-binding protein 2 (SREBP-2) is activated which in turn stimulates the expression of LDL receptors in the cell membrane and therefore, the entry of LDL which delivers the cholesterol that the cells contain. SREBP-2 simultaneously stimulates the production of PCSK9, which is involved in the degradation of LDL receptors (Fig. 1). Thus a precise regulation between synthesis and destruction of them is achieved and consequently, the entry of cholesterol into cells. Both the PCSK9 gene mutations that represent a loss and those that suppose a gain of function very markedly influence the concentrations of LDL-C and the risk of CVD. In individuals with a lower PCSK9 activity, the degradation of LDL receptors to the level of lysosomes is lower, so there is greater expression of them in the cell membrane and LDLs are removed from the plasma at a faster rate, which leads to a decrease of cholesterolaemia and also the risk of CVD.18,19 Conversely, mutations that occur with an increase of PCSK9 function are associated with hypercholesterolaemia and an increased cardiovascular risk.20 In fact, gain-of-function mutations in PCSK9 have been described which are presented with autosomal dominant inheritance and occur with severe hypercholesterolaemia, which have been included in the group of mutations causing familial hypercholesterolaemia.21
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Anti-PCSK9 antibodies LDL
LDL receptor
LDL receptor recycling
PCSK9
LDL receptor degradation
A B SREBP-2
Core Endoplasmic reticulum
PCSK9
Golgi apparatus
Fig. 1. Mechanism of action of medications proprotein convertase subtilisin/kexin type 9. When the cholesterol content decreases in cells, the SREBP-2 protein is activated, which induces the co-expression of the LDL receptor and the PCSK9 protein. LDL receptors increase the cellular uptake of LDL plasma and thus, the contribution of cholesterol into the cell. Furthermore, the PCSK9 secreted into the bloodstream binds to the LDL receptor, and when the complex LDL receptor bound to PCSK9 enters the cell, degradation of the LDL receptor is produced without the recycling that normally occurs when PCSK9 does not intervene (see text). LDL: low density lipoproteins; PCSK9: proprotein convertase subtilisin/kexin type 9; SREBP-2: sterol regulatory element-binding protein 2.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition Inhibiting the PCSK9 protein has been conducted with different agents, but those that have been most studied in humans through extensive clinical research programmes are monoclonal Ab. They include, evolocumab (Amgen Thousand Oaks, CA, USA. NCT01764633) and alirocumab alirocumab (Sanofi/Regeneron, París, France, and Tarrytown, NY, USA. NCT01663402), which are at the most advanced stages of research, followed by bococizumab (Pfizer, New York, NY, USA. NCT01975376). Various research programmes using anti-PCSK9 Ab and which plan to include over 60,000 patients are currently under-way.16 In regard to the metabolism of anti-PCSK9 Ab, the fact that these are metabolised in the mononuclear phagocyte system and degraded into small peptides and amino acids has been acknowledged.22 Safety analysis indicates that the most common side effects are local reactions at the injection site. There have been isolated cases of itching due to a hypersensitivity reaction, an increase of CK and, in one case, leukocytoclastic vasculitis.23 When monoclonal Ab are used as medications for the treatment of certain disorders, there is a possibility that the patient develops Ab against monoclonal Ab. In the case of using anti-PCSK9 Ab, Ab formation responses were detected, but at very low levels, and when they have appeared they have not led to a reduction in systemic exposure of the anti-PCSK9 Ab, nor an occurrence of adverse effects.22,24
statins, these agents can be considered one of the main therapeutic advances for clinical relevance in the past 30 years.25,26 In phase 2 clinical trials evolocumab has proven to be effective in lowering cholesterol–whether or not they are associated with other lipidlowering agents such as monotherapy27 –both in patients with familial and non-familial hypercholesterolaemia and in those with intolerance to statins.28,29 In these clinical studies, subcutaneous administration of evolocumab decreased LDL-C by between 41 and 66% and allowed the majority of patients to reach the therapeutic goals,30 both with an average dose of 140 mg administered every 2 weeks and with doses of 280–420 mg administered every 4 weeks. Alirocumab has also been studied in Phase 2 clinical trials conducted in patients with varying types and degrees of hypercholesterolaemia, both in monotherapy as an addition to associated statins, or not, to ezetimibe. This drug, administered at doses of 75–300 mg subcutaneously every 2–4 weeks, decreased LDL-C by between 30 and 75%.31,32 As for the effect of anti-PCSK9 Ab on other areas of lipid metabolism, in Phase 2 studies a moderate and variable decrease in triglycerides and an average increase of HDL-C and apolipoprotein A1 higher than 8 and 5% respectively have been observed, changes were significant compared to a placebo.33 The anti-PCSK9 Ab decreases the lipoprotein (a) [Lp (a)],34 a lipoprotein with high atherogenic potential, by approximately 30%,35,36 and the response is greater in patients with baseline levels of Lp(a) within the reference values than in those who have higher values.
Lipid-lowering efficacy Monoclonal anti-PCSK9 Ab lower the cholesterol associated with atherogenic lipoproteins, specifically LDL-C, by over 60%, and in addition, even though to a somewhat lesser percentage, non-HDL cholesterol and ApoB, the principle LDL protein. As they show the capacity to decrease cholesterol to higher levels than
Effects of proprotein convertase subtilisin/kexin type 9 in cardiovascular prevention Currently the effects of evolocumab on the incidence of CVD are being researched in different Phase 3 studies, where the most significant study today, Further Cardiovascular Outcomes Research
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with PCSK9 Inhibition in Subjects With Elevated Risk–FOURIER–is currently in the patient selection stage.37 More than 20,000 patients with stroke or previous myocardial infarction who also present a greater cardiovascular risk factor or 2 less will participate in it, and, despite being treated with the maximum tolerated dose of atorvastatin associated, or not, with ezetimibe, have an LDL-C of ≥70 mg/dl. The preventive efficacy against CVD of Alirocumab is also being researched in an extensive programme of clinical Phase 3 trials with more than 23,000 patients participating in the Odyssey programme, among which the largest is the Odyssey Outcome, in which 18,000 patients who have had a recent acute coronary event are planned to participate and who will be followed for a minimum period of 2 years.22 Data from a preliminary analysis of the Odyssey Long Term Study on the efficacy and tolerance of alirocumab were presented at the European Society of Cardiology 2014 congress, in this programme 2341 high cardiovascular risk patients with an LDL-C at or above 70 mg/dl (1.81 mmol/l)despite following treatment with a statin at the maximum tolerated dose, with or without other lipid-lowering medications. Alirocumab decreased LDL-C by an average of 61%, and what was more remarkable is that in a post hoc analysis of the safety of major CVD events after a follow up after at least 52 weeks, a decrease in CVD risk of 54% was observed (risk ratio = 0.46, 95% CI: 0.26–0.82).38 Since the anti-PCSK9 Ab will predictably have a high economic cost, it is very likely that health authorities will require very accurate definitions of patients who can benefit most from their use and of where its use will have an optimal cost/effectiveness balance for the state’s economic resources. These could be affected by the following conditions: 1. familial hypercholesterolaemia and other forms of severe hypercholesterolaemia or high cardiovascular risk where reducing LDL-C at rates higher to those achieved with statins is necessary, either in monotherapy or associated with medications that inhibit cholesterol absorption. 2. Patients with CVD or who are at a risk equivalent to resistance or have insufficient response to statins in monotherapy or associated with medications that inhibit cholesterol absorption. 3. Patients with high cardiovascular risk with a history of intolerance or toxicity response to statins or a high risk of presenting it. Apolipoprotein B synthesis inhibitors Mipomersen is a modified oligonucleotide 20-mer 2 -Omethoxyethyl complementary and specific apoB 100 messenger RNA, which inhibits the production of apoB and decreases the formation of lipoproteins that contain it. Therefore it decreases the plasma concentrations of the lipoproteins with apoB, particularly the LDL.39 It is administered at a dose of 200 mg per week subcutaneously, from where it passes into the bloodstream and is distributed mainly in the liver, where it mutes the apoB messenger RNA. In an analysis of 6 randomised clinical trials with 444 patients in total and compared to placebo, patients treated with mipomersen showed a decrease of LDL-C by 33%, non-HDL by 32%, apoB by 33% and Lp(a) by 26%. They described lesser decreases of triglycerides, by approximately 10–25%, and no change in HDLC concentrations.40,41 The most significant side effects were local reactions at the injection site, which affect the vast majority of patients, an influenza-like illness that affects between one quarter and half of patients, and an increase in transaminases and fat liver content, which occurs in about 10% of patients. Its main indication is homozygous familial hypercholesterolaemia and severe heterozygous forms in which the LDL-C therapeutic goals are not
achieved despite the use of potent statins at the maximum tolerated doses.42,43 Mipomersen has been approved by the Food and Drug Administration for the treatment of homozygous familial hypercholesterolaemia, with the aim of reducing the need to practice LDL apheresis, but by the European Medicines Agency. Microsomal triglyceride transfer protein inhibitor MTP inhibitors inhibit a protein associated with the endoplasmic reticulum expressed in hepatocytes and enterocytes. The MTP intervenes in the assembly of apoB 100 and apoB 48 with cholesterol esters and hepatic triglycerides synthesis to form the VLDL and the chylomicrons respectively.44 These medications were developed from the observation that mutations associated with reduced function of the MTP were associated with the hypobetalipoproteinaemia, at a lower concentration of LDL-C and a lower risk of CVD. However, abetalipoproteinaemia is a rare autosomal recessive disorder where the MTP is non-functioning, it experiences very low concentrations of serum cholesterol and protection against CVD, but a hepatic steatosis, increase in the transaminases and a deficit of liposoluble vitamins20 occurs. In the same sense, pharmacological inhibition of MTP provokes hepatic steatosis, elevated transaminase levels, steatorrhea and increases stool frequency, which lowers their expectations for clinical use. These effects are reversible by interrupting the inhibition of MTP. Lomitapida is a potent inhibitor of MTP45 that is metabolised by cytochrome P450 3A4 and for that reason has a high potential for pharmacological interactions. It lowers LDL-C by 30–50%, triglycerides by 31–45%, apoB by 43–49%, and Lp (a) by 15–19%. The recommended starting dose is one 5-mg lomitapida capsule per day and the maximum daily dose is 60 mg. Lomitapida has been approved for use in homozygous familial hypercholesterolaemia. Inhibiting cholesterol ester transfer protein CETP catalyses the step of cholesterol ester from HDL to LDL and generally to the rest of apoB containing lipoproteins, i.e., IDL and VLDL, in exchange of triglycerides. The genetic deficiency of CETP is accompanied by an increase in HDL-C and decrease in LDLC, and generally, a decrease of vascular risk, a reason why this group of medications began to be researched.46 Within this group, torcetrapib, the first with which large-scale clinical trials were conducted, was withdrawn because of the appearance of serious side effects and cardiovascular morbidity and mortality and in all causes.47 The second member of the group, dalcetrapib, was withdrawn when its lack of efficacy in cardiovascular prevention was confirmed in the Dal-Outcomes study.48 Anacetrapib is currently being researched in large-scale clinical trials with 30,000 ischaemic patients participating, as is evacetrapib, with 11,000 patients at high-risk of CVD. Both anacetrapib and evacetrapib induce an increase of HDL-C greater than 100% and a decrease of LDL-C by 30–50%. None of the 2 seem to induce increases in blood pressure nor have other side effects in previous group members.49,50 Results from experimental studies found an increased faecal excretion of cholesterol by inhibiting CETP, an index of the effectiveness of reverse cholesterol transport and HDL functionality.51 The future of CETP inhibitors depends on the results of cardiovascular prevention clinical trials which are currently underway. In the event that their therapeutic usefulness is proven, they could be of great interest for ischaemic patients or those at high cardiovascular risk with serious HDL-C deficits and for those with chronic inflammatory disease such as rheumatoid arthritis, which is associated with a high cardiovascular risk and often occurs with low plasma HDL-C levels and alterations of the functionality of HDL particles.52
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Conclusions Despite the high efficacy in lowering LDL-C of statins associated or not to inhibitors of cholesterol absorption, the failure to reach LDL-C therapeutic goals is also due to the fact that current medications do not have the sufficient capacity to lower cholesterol to achieve the goals in a high percentage of complex cases, especially in familial hypercholesterolaemia. Inhibitors of the PCSK9 protein are being defined as agents of high efficacy in lowering LDL-C and with a good safety profile, which will allow us to achieve optimal control of hypercholesterolaemia in the vast majority of patients, which cannot be controlled with current medications. Medications that inhibit the synthesis of apoB and MTP inhibitors are also new medications that bring a new potential to lowering cholesterol in patients with severe hypercholesterolaemia and in particular, in homozygous familial hypercholesterolaemia or in severe heterozygous forms. Finally, CETP inhibitors are promising because of their potent effects on HDL-C and LDL-C. However, negative or neutral effects of the first members of this family on CVD mean the results of clinical trials of cardiovascular prevention that are currently underway are needed before its clinical utility is defined. Conflict of interest The authors declare no conflict of interest. Xavier Pintó has intervened as a member of the expert committee on alirocumab in Sanofi and as a member of the expert committee on evolocumab at Amgen. References 1. European Society of Cardiology. European cardiovascular disease statistics. 2012 ed; 2012 [accessed 04.09.14]. Available from: www.escardio.org/ Search/results.aspx/Results.aspx?k=European%20Cardiovascular%20disease% 20Statistics%202012%20Edition 2. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57:1666–75. 3. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818. 4. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trial. Lancet. 2010;376:1670–81. 5. Gitt AK, Drexel H, Feely J, Ferrières J, Gonzalez-Juanatey JR, Thomsen KK, et al. Persistent lipid abnormalities in statin-treated patients and predictors of LDLcholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prev Cardiol. 2012;19:221–30. 6. Karalis DG, Subramanya RD, Hessen SE, Liu L, Victor MF. Achieving optimal lipid goals in patients with coronary artery disease. Am J Cardiol. 2011;107:886–90. 7. Mohassel P, Mammen AL. The spectrum of statin myopathy. Curr Opin Rheumatol. 2013;25:747–52. 8. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24:1057–66. 9. Chen Y, Ku H, Zhao L, Wheeler DC, Li LC, Li Q, et al. Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation. Arterioscler Thromb Vasc Biol. 2014;34:365–76. 10. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21. 11. Mikhailidis DP, Lawson RW, McCormick AL, Sibbring GC, Tershakovec AM, Davies GM, et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. Curr Med Res Opin. 2011;27:1191–210. 12. Lahoz C, Mostaza JM, Pintó X, de la Cruz JJ, Banegas JR, Pedro-Botet J, et al. LDL-cholesterol control in patients with genetic dyslipidemia followed up by Lipid and Vascular Risk Units of the Spanish Society of Arteriosclerosis [Spanish]. Clin Investig Arterioscler. 2015;27:1–8, http://dx.doi.org/10.1016/ j.arteri.2014.04.001. 13. Pedro-Botet J, Mostaza JM, Pintó X, Banegas JR, en nombre del Grupo de Investigadores EDICONDIS-ULISEA. Achievement of low-density lipoprotein cholesterol therapeutic goal in lipid and vascular risk units of the Spanish Arteriosclerosis Society. Clin Investig Arterioscler. 2013;25:155–63. 14. Hooper AJ, Burnett JR. Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opin Biol Ther. 2013;13:429–35.
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Drug Des Devel Ther. 2013;7:1135–48. 27. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995–2006. 28. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408–17. 29. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–506. 30. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, doseranging phase 2 study. Lancet. 2012;380:2007–17. 31. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29–36. 32. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–53. 33. Koren MJ, Stein E, Roth EM. Efficacy, safety and tolerability of alirocumab 150 mg Q2W, a full human PCSK9 monoclonal antibody: a pooled analysis of 352 patients from Phase 2. In: Presented at National Lipid Association Scientific Session. 2013. 34. Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, Zhou J, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: An analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation. 2013;128:962–9. 35. Gaudet D, Kereiakes D, McKenney J, Roth E, Hanotin C, Gipe D, et al. Alirocumab, a fully human monoclonal antibody to PCSK9, reduces high plasma Lp(a) concentration: pooled analysis of 352 patients from Phase 2. In: Presented at National Lipid Association Scientific Session. 2003. 36. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1300 patients in 4 phase ii trials. J Am Coll Cardiol. 2014;63:1278–88. 37. Stawowy P, Just IA, Kaschina E. Inhibition of PCSK9: a novel approach for the treatment of dyslipidemia. Coron Artery Dis. 2014;25:353–9. 38. Robinson JG, Farnier M, Krempf M. Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2341 patients. In: Presented at the Congreso de la Sociedad Europea de Cardiología. 2014. 39. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia:
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a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375: 998–1006. Li N, Li Q, Tian XQ, Qian HY, Yang YJ. Mipomersen is a promising therapy in the management of hypercholesterolemia: a meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs. 2014;14:367–76. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–32. Akdim F, Stroes ES, Sijbrands EJ, Tribble DL, Trip MD, Jukema JW, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol. 2010;55:1611–8. Parhofer KG. Mipomersen: Evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia. Core Evid. 2012;7:29–38. Joy TR. Novel therapeutic agents for lowering low density lipoprotein cholesterol. Pharmacol Ther. 2012;135:31–43. Stefanutti C, Morozzi C, di Giacomo S. New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia. Curr Med Chem. 2012;19: 4861–8.
46. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future therapies. J Am Coll Cardiol. 2010;55:1283–99. 47. Wiviott SD. ILLUMINATE sheds more light. Circulation. 2011;124:536–7. 48. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99. 49. Shinkai H. Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases. Vasc Health Risk Manag. 2012;8:323–31. 50. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306:2099–109. 51. Niesor EJ, Magg C, Ogawa N, Okamoto H, von der Mark E, Matile H, et al. Modulating cholesteryl ester transfer protein activity maintains efficient prebeta-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51:3443–54. 52. García-Gómez C, Bianchi M, de la Fuente D, Badimon L, Padró T, Corbella E, et al. Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: a qualitative relationship? World J Orthop. 2014;5:304–11.
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www.elsevier.es/medicinaclinica
Review
New agents for hypercholesterolemia夽 Xavier Pintó a,b,∗ , María Carmen García Gómez c a
Unidad de Lípidos y Riesgo Vascular, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Universidad de Barcelona, Barcelona, Spain c Servicio de Reumatología, Consorci Sanitari de Terrassa, Terrassa, Barcelona, Spain b
a r t i c l e
i n f o
Article history: Received 5 November 2014 Accepted 14 January 2015 Available online xxx Keywords: Hypercholesterolemia treatment Arteriosclerosis Lipid metabolism Hypolipidemic drugs
a b s t r a c t An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians’ inappropriate or insufficient use of cholesterol lowering medications or to patients’ bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. ˜ S.L.U. All rights reserved. © 2015 Elsevier Espana,
Nuevos tratamientos para la hipercolesterolemia r e s u m e n Palabras clave: Tratamiento de la hipercolesterolemia Arteriosclerosis Metabolismo de los lípidos Fármacos hipolipidemiantes
Una alta proporción de pacientes de alto riesgo cardiovascular no alcanzan los objetivos terapéuticos del c-LDL. Ello se debe a un uso inadecuado o insuficiente de los fármacos hipolipidemiantes por parte de los facultativos, y también a una mala tolerancia o al incumplimiento terapéutico por parte de los pacientes. Sin embargo, otra causa de esta situación es la potencia insuficiente de los fármacos actuales para disminuir el colesterol, incluyendo las estatinas y la ezetimiba. Entre los nuevos agentes hipocolesteremiantes, los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 se están mostrando como unos agentes seguros y con una alta eficacia para disminuir el c-LDL en los numerosos ensayos clínicos que se han realizado o están en curso, y nos permitirán lograr el control óptimo de la hipercolesterolemia en la gran mayoría de los pacientes. Los fármacos que inhiben la síntesis de apolipoproteína B y los inhibidores de la proteína microsómica transferidora son otros fármacos que aportan un nuevo potencial de disminuir el colesterol en los pacientes con hipercolesterolemias graves y, en particular, en la hipercolesterolemia familiar homocigótica. Por último, los inhibidores de la proteína transferidora de esteres de colesterol han mostrado potentes efectos sobre el c-HDL y el c-LDL, pero su eficacia en prevención cardiovascular y su seguridad aún no han sido probadas. En este artículo se sintetizan las principales características de los fármacos para el tratamiento de la hipercolesterolemia que han sido recientemente aprobados o que están en fase avanzada de investigación. ˜ S.L.U. Todos los derechos reservados. © 2015 Elsevier Espana,
夽 Please cite this article as: Pintó X, García Gómez MC. Nuevos tratamientos para la hipercolesterolemia. Med Clin (Barc). 2016. http://dx.doi.org/10.1016/j.medcli.2015.01.016 ∗ Corresponding author. E-mail address: [email protected] (X. Pintó). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
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Excess LDL cholesterol (LDL-C) is responsible for 60% of coronary heart disease cases and 40% of ischaemic strokes.1 The treatment of hypercholesterolemia directly reduces risk of cardiovascular disease, proportional to the decrease of LDL-C, a concept that is based on the results of a wide range of randomised trials.2 Therefore, a decrease of LDL-C is considered the primary therapeutic action to prevent early episodes and recurrences of cardiovascular disease (CVD), and increasingly strict therapeutic goals for LDL-C have been established, particularly in patients with high or very high cardiovascular risk.3 Statins are the most effective medication to lower cholesterol and have shown the greatest preventive effect against CVD. In a large meta-analysis of the studies conducted with these medications, it was observed that a decrease of 2–3 mmol/l (78–117 mg/dl) could prevent 40–50% of CVD occurrences.4 In this meta-analysis a threshold value of LDL-C was not detected from which the relationship with cardiovascular risk begins or disappears. Despite the foregoing, between half and two thirds of patients do not reach LDL-C goals.5,6 This situation of therapeutic deficiency is of great clinical relevance, since it is associated with high cardiovascular morbidity and mortality. Its causes (Table 1) include intolerance and resistance to statins. Intolerance is the inability to follow a treatment with these medications at any dose or at a dose that is sufficient for the occurrence of adverse effects; this occurs in 5–20% of patients,4 mainly because of liver or more importantly, muscle conditions ranging from mild myalgia to severe rhabdomyolysis. Although myotoxicity of statin is usually selflimiting and improves by withdrawing the medication, in some cases an autoimmune necrotising myopathy can develop, arising from the over-expression of the major histocompatibility complex type 1 and with the presence of Anti-HMG-CoA reductase antibodies (Ab), which unlike other forms of muscle involvement, do not improve with the interruption of statins and require immunosuppressive treatment.7 Resistance to statins is the lack of achievement of goals despite the use of potent statins at high doses8 and may be due to a wide range of genetic polymorphisms associated with lipid metabolism, environmental factors or the coexistence of certain infectious, metabolic or inflammatory diseases.9 Finally, poor compliance with treatment, also known as statin pseudo-resistance is a very common cause of treatment failure.10 In patients who, despite treatment with potent statins at high doses, do not achieve LDL-C goals, the best alternative is to associate a cholesterol absorption inhibitor, such as Resincolestiramina or ezetimibe, as it increases by more than 2 the possibility of achieving those goals compared to monotherapy.11 However – and particularly in ischaemic patients and those suffering from severe genetic
Table 1 Causes of failure in achieving cholesterol goals linked to low density lipoproteins in patients treated with statins. Use of statin with insufficient potency Use of statin with inadequate doses Lack of association of lipid-lowering medications Intolerance due to muscle, liver or other side effects Resistance to statins due to genetic factors (polymorphisms of HMG-CoA reductase, ABCB1, ABCB2, OATP1B1, OATP2B1, NPC1L1, apoE, PCSK9, LDLR and Lp(a), among others) Resistance to statins due to environmental factors or the coexistence of other inflammatory, infectious or metabolic diseases Therapeutic failure ABCB1: ATP-binding cassette B1; ABCB2: ATP-binding cassette B2; apoE: apolipoprotein E; HMG-CoA reductase: hidroximetilglutaril-coenzyme A reducatase; Lp(a): lipoprotein (a); NPC1L1: Niemann-Pick C1-like L1; OATP1B1: organic anion transporter protein 1B1; OATP2B1: organic anion transporter 2B1 protein; PCSK9: proprotein convertase subtilisin/kexin type 9; LDLR: low-density lipoprotein receptor.
Table 2 New medications for treating hypercholesterolemia. PCSK-9 inhibitors Alirocumab Bococizumab Evolocumab apoB synthesis inhibitors Mipomersen MTP inhibitors Lomitapida CETP inhibitors Anacetrapib Evacetaprib apoB: apolipoprotein B; CETP: cholesteryl ester transfer protein; MTP: microsomal transfer protein; PCSK9: proproteína convertasa subtilisina/kexina type 9.
hyperlipidaemia, including heterozygous familial hypercholesterolaemia and familial combined hyperlipidaemia–the therapeutic goals are frequently not achieved, even when these patients are treated in specialised lipid units.12,13 For these reasons, the need for new medications to improve the effectiveness of hypercholesterolaemia treatment seems obvious, especially in patients at high cardiovascular risk. Among the new medications (Table 2) described in this review, a new family of highly effective agents for treating hypercholesterolaemia are currently in the advanced stages of research; they neutralise the activities of proprotein convertase subtilisin/kexin type 9 (PCSK9)14 and cholesteryl ester transfer protein (CETP) inhibitors: anacetrapib and evacetrapib.15 In addition two new agents have recently been commercialised in some countries which act against hypercholesterolaemia, an inhibitor of the synthesis of apolipoprotein B (apoB): mipomersen, and an inhibitor of microsomal transfer protein (MTP): lomitapida.16 The first has not been authorised in Europe.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors The PCSK9 protein is secreted by the liver into the bloodstream, where it binds to the LDL receptor on the surface of hepatocytes, resulting in its internalisation and subsequent degradation in the lysosomes.17 This protein is intended to regulate the entry of cholesterol into cells, such that when these have a low cholesterol level the sterol regulatory element-binding protein 2 (SREBP-2) is activated which in turn stimulates the expression of LDL receptors in the cell membrane and therefore, the entry of LDL which delivers the cholesterol that the cells contain. SREBP-2 simultaneously stimulates the production of PCSK9, which is involved in the degradation of LDL receptors (Fig. 1). Thus a precise regulation between synthesis and destruction of them is achieved and consequently, the entry of cholesterol into cells. Both the PCSK9 gene mutations that represent a loss and those that suppose a gain of function very markedly influence the concentrations of LDL-C and the risk of CVD. In individuals with a lower PCSK9 activity, the degradation of LDL receptors to the level of lysosomes is lower, so there is greater expression of them in the cell membrane and LDLs are removed from the plasma at a faster rate, which leads to a decrease of cholesterolaemia and also the risk of CVD.18,19 Conversely, mutations that occur with an increase of PCSK9 function are associated with hypercholesterolaemia and an increased cardiovascular risk.20 In fact, gain-of-function mutations in PCSK9 have been described which are presented with autosomal dominant inheritance and occur with severe hypercholesterolaemia, which have been included in the group of mutations causing familial hypercholesterolaemia.21
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3
Anti-PCSK9 antibodies LDL
LDL receptor
LDL receptor recycling
PCSK9
LDL receptor degradation
A B SREBP-2
Core Endoplasmic reticulum
PCSK9
Golgi apparatus
Fig. 1. Mechanism of action of medications proprotein convertase subtilisin/kexin type 9. When the cholesterol content decreases in cells, the SREBP-2 protein is activated, which induces the co-expression of the LDL receptor and the PCSK9 protein. LDL receptors increase the cellular uptake of LDL plasma and thus, the contribution of cholesterol into the cell. Furthermore, the PCSK9 secreted into the bloodstream binds to the LDL receptor, and when the complex LDL receptor bound to PCSK9 enters the cell, degradation of the LDL receptor is produced without the recycling that normally occurs when PCSK9 does not intervene (see text). LDL: low density lipoproteins; PCSK9: proprotein convertase subtilisin/kexin type 9; SREBP-2: sterol regulatory element-binding protein 2.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition Inhibiting the PCSK9 protein has been conducted with different agents, but those that have been most studied in humans through extensive clinical research programmes are monoclonal Ab. They include, evolocumab (Amgen Thousand Oaks, CA, USA. NCT01764633) and alirocumab alirocumab (Sanofi/Regeneron, París, France, and Tarrytown, NY, USA. NCT01663402), which are at the most advanced stages of research, followed by bococizumab (Pfizer, New York, NY, USA. NCT01975376). Various research programmes using anti-PCSK9 Ab and which plan to include over 60,000 patients are currently under-way.16 In regard to the metabolism of anti-PCSK9 Ab, the fact that these are metabolised in the mononuclear phagocyte system and degraded into small peptides and amino acids has been acknowledged.22 Safety analysis indicates that the most common side effects are local reactions at the injection site. There have been isolated cases of itching due to a hypersensitivity reaction, an increase of CK and, in one case, leukocytoclastic vasculitis.23 When monoclonal Ab are used as medications for the treatment of certain disorders, there is a possibility that the patient develops Ab against monoclonal Ab. In the case of using anti-PCSK9 Ab, Ab formation responses were detected, but at very low levels, and when they have appeared they have not led to a reduction in systemic exposure of the anti-PCSK9 Ab, nor an occurrence of adverse effects.22,24
statins, these agents can be considered one of the main therapeutic advances for clinical relevance in the past 30 years.25,26 In phase 2 clinical trials evolocumab has proven to be effective in lowering cholesterol–whether or not they are associated with other lipidlowering agents such as monotherapy27 –both in patients with familial and non-familial hypercholesterolaemia and in those with intolerance to statins.28,29 In these clinical studies, subcutaneous administration of evolocumab decreased LDL-C by between 41 and 66% and allowed the majority of patients to reach the therapeutic goals,30 both with an average dose of 140 mg administered every 2 weeks and with doses of 280–420 mg administered every 4 weeks. Alirocumab has also been studied in Phase 2 clinical trials conducted in patients with varying types and degrees of hypercholesterolaemia, both in monotherapy as an addition to associated statins, or not, to ezetimibe. This drug, administered at doses of 75–300 mg subcutaneously every 2–4 weeks, decreased LDL-C by between 30 and 75%.31,32 As for the effect of anti-PCSK9 Ab on other areas of lipid metabolism, in Phase 2 studies a moderate and variable decrease in triglycerides and an average increase of HDL-C and apolipoprotein A1 higher than 8 and 5% respectively have been observed, changes were significant compared to a placebo.33 The anti-PCSK9 Ab decreases the lipoprotein (a) [Lp (a)],34 a lipoprotein with high atherogenic potential, by approximately 30%,35,36 and the response is greater in patients with baseline levels of Lp(a) within the reference values than in those who have higher values.
Lipid-lowering efficacy Monoclonal anti-PCSK9 Ab lower the cholesterol associated with atherogenic lipoproteins, specifically LDL-C, by over 60%, and in addition, even though to a somewhat lesser percentage, non-HDL cholesterol and ApoB, the principle LDL protein. As they show the capacity to decrease cholesterol to higher levels than
Effects of proprotein convertase subtilisin/kexin type 9 in cardiovascular prevention Currently the effects of evolocumab on the incidence of CVD are being researched in different Phase 3 studies, where the most significant study today, Further Cardiovascular Outcomes Research
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with PCSK9 Inhibition in Subjects With Elevated Risk–FOURIER–is currently in the patient selection stage.37 More than 20,000 patients with stroke or previous myocardial infarction who also present a greater cardiovascular risk factor or 2 less will participate in it, and, despite being treated with the maximum tolerated dose of atorvastatin associated, or not, with ezetimibe, have an LDL-C of ≥70 mg/dl. The preventive efficacy against CVD of Alirocumab is also being researched in an extensive programme of clinical Phase 3 trials with more than 23,000 patients participating in the Odyssey programme, among which the largest is the Odyssey Outcome, in which 18,000 patients who have had a recent acute coronary event are planned to participate and who will be followed for a minimum period of 2 years.22 Data from a preliminary analysis of the Odyssey Long Term Study on the efficacy and tolerance of alirocumab were presented at the European Society of Cardiology 2014 congress, in this programme 2341 high cardiovascular risk patients with an LDL-C at or above 70 mg/dl (1.81 mmol/l)despite following treatment with a statin at the maximum tolerated dose, with or without other lipid-lowering medications. Alirocumab decreased LDL-C by an average of 61%, and what was more remarkable is that in a post hoc analysis of the safety of major CVD events after a follow up after at least 52 weeks, a decrease in CVD risk of 54% was observed (risk ratio = 0.46, 95% CI: 0.26–0.82).38 Since the anti-PCSK9 Ab will predictably have a high economic cost, it is very likely that health authorities will require very accurate definitions of patients who can benefit most from their use and of where its use will have an optimal cost/effectiveness balance for the state’s economic resources. These could be affected by the following conditions: 1. familial hypercholesterolaemia and other forms of severe hypercholesterolaemia or high cardiovascular risk where reducing LDL-C at rates higher to those achieved with statins is necessary, either in monotherapy or associated with medications that inhibit cholesterol absorption. 2. Patients with CVD or who are at a risk equivalent to resistance or have insufficient response to statins in monotherapy or associated with medications that inhibit cholesterol absorption. 3. Patients with high cardiovascular risk with a history of intolerance or toxicity response to statins or a high risk of presenting it. Apolipoprotein B synthesis inhibitors Mipomersen is a modified oligonucleotide 20-mer 2 -Omethoxyethyl complementary and specific apoB 100 messenger RNA, which inhibits the production of apoB and decreases the formation of lipoproteins that contain it. Therefore it decreases the plasma concentrations of the lipoproteins with apoB, particularly the LDL.39 It is administered at a dose of 200 mg per week subcutaneously, from where it passes into the bloodstream and is distributed mainly in the liver, where it mutes the apoB messenger RNA. In an analysis of 6 randomised clinical trials with 444 patients in total and compared to placebo, patients treated with mipomersen showed a decrease of LDL-C by 33%, non-HDL by 32%, apoB by 33% and Lp(a) by 26%. They described lesser decreases of triglycerides, by approximately 10–25%, and no change in HDLC concentrations.40,41 The most significant side effects were local reactions at the injection site, which affect the vast majority of patients, an influenza-like illness that affects between one quarter and half of patients, and an increase in transaminases and fat liver content, which occurs in about 10% of patients. Its main indication is homozygous familial hypercholesterolaemia and severe heterozygous forms in which the LDL-C therapeutic goals are not
achieved despite the use of potent statins at the maximum tolerated doses.42,43 Mipomersen has been approved by the Food and Drug Administration for the treatment of homozygous familial hypercholesterolaemia, with the aim of reducing the need to practice LDL apheresis, but by the European Medicines Agency. Microsomal triglyceride transfer protein inhibitor MTP inhibitors inhibit a protein associated with the endoplasmic reticulum expressed in hepatocytes and enterocytes. The MTP intervenes in the assembly of apoB 100 and apoB 48 with cholesterol esters and hepatic triglycerides synthesis to form the VLDL and the chylomicrons respectively.44 These medications were developed from the observation that mutations associated with reduced function of the MTP were associated with the hypobetalipoproteinaemia, at a lower concentration of LDL-C and a lower risk of CVD. However, abetalipoproteinaemia is a rare autosomal recessive disorder where the MTP is non-functioning, it experiences very low concentrations of serum cholesterol and protection against CVD, but a hepatic steatosis, increase in the transaminases and a deficit of liposoluble vitamins20 occurs. In the same sense, pharmacological inhibition of MTP provokes hepatic steatosis, elevated transaminase levels, steatorrhea and increases stool frequency, which lowers their expectations for clinical use. These effects are reversible by interrupting the inhibition of MTP. Lomitapida is a potent inhibitor of MTP45 that is metabolised by cytochrome P450 3A4 and for that reason has a high potential for pharmacological interactions. It lowers LDL-C by 30–50%, triglycerides by 31–45%, apoB by 43–49%, and Lp (a) by 15–19%. The recommended starting dose is one 5-mg lomitapida capsule per day and the maximum daily dose is 60 mg. Lomitapida has been approved for use in homozygous familial hypercholesterolaemia. Inhibiting cholesterol ester transfer protein CETP catalyses the step of cholesterol ester from HDL to LDL and generally to the rest of apoB containing lipoproteins, i.e., IDL and VLDL, in exchange of triglycerides. The genetic deficiency of CETP is accompanied by an increase in HDL-C and decrease in LDLC, and generally, a decrease of vascular risk, a reason why this group of medications began to be researched.46 Within this group, torcetrapib, the first with which large-scale clinical trials were conducted, was withdrawn because of the appearance of serious side effects and cardiovascular morbidity and mortality and in all causes.47 The second member of the group, dalcetrapib, was withdrawn when its lack of efficacy in cardiovascular prevention was confirmed in the Dal-Outcomes study.48 Anacetrapib is currently being researched in large-scale clinical trials with 30,000 ischaemic patients participating, as is evacetrapib, with 11,000 patients at high-risk of CVD. Both anacetrapib and evacetrapib induce an increase of HDL-C greater than 100% and a decrease of LDL-C by 30–50%. None of the 2 seem to induce increases in blood pressure nor have other side effects in previous group members.49,50 Results from experimental studies found an increased faecal excretion of cholesterol by inhibiting CETP, an index of the effectiveness of reverse cholesterol transport and HDL functionality.51 The future of CETP inhibitors depends on the results of cardiovascular prevention clinical trials which are currently underway. In the event that their therapeutic usefulness is proven, they could be of great interest for ischaemic patients or those at high cardiovascular risk with serious HDL-C deficits and for those with chronic inflammatory disease such as rheumatoid arthritis, which is associated with a high cardiovascular risk and often occurs with low plasma HDL-C levels and alterations of the functionality of HDL particles.52
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Conclusions Despite the high efficacy in lowering LDL-C of statins associated or not to inhibitors of cholesterol absorption, the failure to reach LDL-C therapeutic goals is also due to the fact that current medications do not have the sufficient capacity to lower cholesterol to achieve the goals in a high percentage of complex cases, especially in familial hypercholesterolaemia. Inhibitors of the PCSK9 protein are being defined as agents of high efficacy in lowering LDL-C and with a good safety profile, which will allow us to achieve optimal control of hypercholesterolaemia in the vast majority of patients, which cannot be controlled with current medications. Medications that inhibit the synthesis of apoB and MTP inhibitors are also new medications that bring a new potential to lowering cholesterol in patients with severe hypercholesterolaemia and in particular, in homozygous familial hypercholesterolaemia or in severe heterozygous forms. Finally, CETP inhibitors are promising because of their potent effects on HDL-C and LDL-C. However, negative or neutral effects of the first members of this family on CVD mean the results of clinical trials of cardiovascular prevention that are currently underway are needed before its clinical utility is defined. Conflict of interest The authors declare no conflict of interest. Xavier Pintó has intervened as a member of the expert committee on alirocumab in Sanofi and as a member of the expert committee on evolocumab at Amgen. References 1. European Society of Cardiology. European cardiovascular disease statistics. 2012 ed; 2012 [accessed 04.09.14]. Available from: www.escardio.org/ Search/results.aspx/Results.aspx?k=European%20Cardiovascular%20disease% 20Statistics%202012%20Edition 2. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57:1666–75. 3. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818. 4. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trial. Lancet. 2010;376:1670–81. 5. Gitt AK, Drexel H, Feely J, Ferrières J, Gonzalez-Juanatey JR, Thomsen KK, et al. Persistent lipid abnormalities in statin-treated patients and predictors of LDLcholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prev Cardiol. 2012;19:221–30. 6. Karalis DG, Subramanya RD, Hessen SE, Liu L, Victor MF. Achieving optimal lipid goals in patients with coronary artery disease. Am J Cardiol. 2011;107:886–90. 7. Mohassel P, Mammen AL. The spectrum of statin myopathy. Curr Opin Rheumatol. 2013;25:747–52. 8. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24:1057–66. 9. Chen Y, Ku H, Zhao L, Wheeler DC, Li LC, Li Q, et al. Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation. Arterioscler Thromb Vasc Biol. 2014;34:365–76. 10. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21. 11. Mikhailidis DP, Lawson RW, McCormick AL, Sibbring GC, Tershakovec AM, Davies GM, et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. Curr Med Res Opin. 2011;27:1191–210. 12. Lahoz C, Mostaza JM, Pintó X, de la Cruz JJ, Banegas JR, Pedro-Botet J, et al. LDL-cholesterol control in patients with genetic dyslipidemia followed up by Lipid and Vascular Risk Units of the Spanish Society of Arteriosclerosis [Spanish]. Clin Investig Arterioscler. 2015;27:1–8, http://dx.doi.org/10.1016/ j.arteri.2014.04.001. 13. Pedro-Botet J, Mostaza JM, Pintó X, Banegas JR, en nombre del Grupo de Investigadores EDICONDIS-ULISEA. Achievement of low-density lipoprotein cholesterol therapeutic goal in lipid and vascular risk units of the Spanish Arteriosclerosis Society. Clin Investig Arterioscler. 2013;25:155–63. 14. Hooper AJ, Burnett JR. Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opin Biol Ther. 2013;13:429–35.
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