American Journal of Therapeutics 22, 234–241 (2015)
New and Emerging LDL Cholesterol–Lowering Drugs Constantine E. Kosmas, MD, PhD1 and William H. Frishman, MD2*
The role of low-density lipoprotein cholesterol (LDL-C) in the pathophysiology of atherosclerosis is well recognized, and the use of LDL-C lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins are the standard of care and their use is supported by extensive evidence demonstrating their effectiveness in lowering LDL-C and in reducing the risk for cardiovascular disease. However, many individuals at risk for cardiovascular disease fail to achieve LDL-C goals. In addition, several patients are intolerant to statins due to side effects, mostly myalgia and weakness, especially at high statin doses. However, until recently, the efficacy of other non-statin LDL-C-lowering drugs was modest, not exceeding a LDL-C reduction of 20%. In view of the above, extensive research is being carried out to identify new LDL-C-lowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve our ability to achieve LDL-C goals and reduce cardiovascular risk. This review aims to provide the current evidence regarding the newly approved LDL-C-lowering agents, as well as the clinical and scientific data pertaining to promising new and emerging LDL-C-lowering drugs on the horizon. Keywords: LDL cholesterol, cholesterol-lowering drugs, atherosclerosis
INTRODUCTION The role of low-density lipoprotein cholesterol (LDL-C) in the pathophysiology of atherosclerosis is well known, and the use of LDL-C-lowering medications has led to a significant reduction of cardiovascular risk in both primary1 and secondary2 prevention. Statins are the standard of care (SOC) and their use is supported by extensive evidence demonstrating their effectiveness in lowering LDL-C and in reducing the risk for cardiovascular disease (CVD).3,4 However, many individuals at risk for CVD fail to achieve LDL-C goals,5,6 including patients with familial hypercholesterolemia, and patients with established
1
Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY; and 2 Department of Internal Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, NY. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Medicine, New York Medical College, Valhalla, NY 10595. E-mail: william_frishman@ nymc.edu
coronary artery disease that cannot reach their LDL-C target despite maximum dose statin therapy. In addition, several patients are intolerant to statins due to side effects, mostly myalgia and weakness, especially at high statin doses.7 Other recently identified side effects, such as an increased risk for diabetes,8 particularly at higher doses,9 and reports of statininduced memory loss, has prompted the Food and Drug Administration (FDA) to mandate additional safety-labeling warnings.10 However, until recently, the efficacy of other non-statin LDL-C-lowering drugs was modest, not exceeding an LDL-C reduction of 20%. Specifically, extended-release niacin has been reported to lower LDL-C by up to 17%,11 whereas fenofibrate has been reported to lower LDL-C levels by approximately 20%,12 although it may actually increase LDL-C levels in patients with hypertriglyceridemia. In addition, ezetimibe, an intestinal cholesterol absorption inhibitor, and colesevelam, a bile acid sequestrant, have been reported to lower LDL-C by 18%.13,14 In view of the above, extensive research is being carried out to identify new LDL-C-lowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve
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LDL Cholesterol–Lowering Drugs
our ability to achieve LDL-C goals and potentially reduce cardiovascular risk. This review aims to provide the current evidence regarding the newly approved LDL-C-lowering agents, as well as the clinical and scientific data pertaining to promising new and emerging LDL-C-lowering drugs on the horizon.
MIPOMERSEN—INHIBITION OF THE SYNTHESIS OF APOLIPOPROTEIN B Mipomersen, an antisense inhibitor of apolipoprotein B-100 (apoB) synthesis was recently approved by the FDA for the treatment of homozygous familial hypercholesterolemia (HoFH). ApoB is the main structural and receptor-binding component of all atherogenic lipid particles and is required for the secretion of very LDL from the liver.15 The approval of mipomersen for the treatment of HoFH was based on a randomized, double-blind, placebo-controlled, phase 3 study, which was undertaken in 9 lipid centers in 7 countries.16 Thirty-four patients with HoFH were assigned to mipomersen and 17 patients to placebo. All patients were already being treated with other lipid-lowering drugs, including highdose statins. Mipomersen significantly reduced LDL-C by 24.7% (P 5 0.0003 vs. placebo), apoB by 26.8% (P , 0.0001 vs. placebo), and lipoprotein(a) by 31.1% (P 5 0.0013 vs. placebo). In addition, mipomersen increased high-density lipoprotein-cholesterol (HDL-C) by 15.1% (P 5 0.0326 vs. placebo). The most common adverse effects of mipomersen were injection site reactions (76% vs. 24% of patients in the mipomersen and placebo groups, respectively) and increases in concentrations of alanine aminotransferase (ALT) of $3 times the upper limit of normal (12% vs. 0% of patients in the mipomersen and placebo groups, respectively).16 Thomas et al17 examined the efficacy and safety of mipomersen for reducing the atherogenic lipids/lipoproteins in hypercholesterolemia. The study enrolled 158 patients having a baseline LDL-C $100 mg/dL with, or at high risk for, coronary heart disease, taking maximally tolerated lipid-lowering therapy. The patients received weekly subcutaneous (SC) mipomersen (n 5 105) or placebo (n 5 52) for 26 weeks with a 24week follow-up. Mipomersen significantly reduced LDL-C by 36.9%, apoB by 37.5%, and Lp(a) by 25.6% (P , 0.001 vs. placebo for all comparisons). Common adverse effects included injection site reactions (78.1% vs. 30.8%) and flu-like symptoms (34.3% vs. 21.2%) in the mipomersen and placebo groups, respectively). In addition, mipomersen therapy led to increases in concentrations of ALT of $3 times the upper limit of normal in 9.5% of patients and hepatic steatosis in 10.5% of www.americantherapeutics.com
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patients with return toward baseline after treatment cessation. Interestingly, greater reductions were noted in the number of small (2542.5 nmol/L) versus large LDL particles (279.7 nmol/L) in the mipomersen group, whereas no meaningful changes occurred in the placebo group. Also noted was the LDL-lowering effect of mipomersen was greater in women and patients aged .59 years.17 In a randomized, placebo-controlled, double-blind, dose-escalation study, 44 patients with heterozygous FH (HeFH), being treated with conventional lipidlowering therapy, were assigned to different doses of mipomersen (50–300 mg) versus placebo and received 8 SC doses during a 6-week treatment period.18 After 6 weeks, the LDL-C level was reduced by 21% from baseline in the 200 mg/wk dose group (P , 0.05) and 34% in the 300 mg/wk dose group (P , 0.01), with a concomitant reduction in apoB of 23% (P , 0.05) and 33% (P , 0.01), respectively. Again, injection site reactions were the most common adverse event, while increases in concentrations of ALT of $3 times the upper limit of normal occurred in 11% of patients treated with mipomersen.18 Mipomersen has also been tested in statinintolerant patients. In a randomized, double-blind, placebo-controlled study, 33 subjects at high risk for coronary heart disease, not receiving statins due to intolerance, were randomized to receive a weekly SC dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. After 26 weeks of mipomersen administration, LDL-C, apoB, and Lp(a) were reduced by 47%, 46%, and 27%, respectively (P , 0.001 vs. placebo for all comparisons). Persistent increases in concentrations of ALT of $3 times the upper limit of normal were observed in 33% of patients treated with mipomersen. In addition, hepatic steatosis was detected in 85% of patients in the mipomersen group in whom hepatic magnetic resonance imaging was performed.19 As monotherapy, mipomersen has been tested in subjects with mild-to-moderate hyperlipidemia. In a randomized, placebo-controlled, double-blind, doseescalation study, 50 subjects with LDL-C levels between 119 and 266 mg/dL were enrolled into 5 cohorts at a 4:1 randomization ratio of active to placebo.20 Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/wk. Mipomersen produced dose-dependent reductions in all apoB-containing lipoproteins. In the 200 and 300 mg/wk cohorts, mean reductions from baseline in LDL-C were 45 6 10% and 61 6 8%, respectively, corresponding to mean reductions of 46 6 11% and 61 6 7%, respectively, in apoB levels. In addition, Lp(a) levels were lowered with mean reductions up to 42%, and triglyceride levels were also lowered with median reductions up to 53%. American Journal of Therapeutics (2015) 22(3)
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Injection site reactions were the most common adverse event. The 400-mg/wk cohort was discontinued because of significant transaminase elevations.20 In another study, mipomersen 200 and 300 mg/wk reduced total plasma apoC-III by 42% and 38%, respectively, as compared with placebo (P , 0.03).21 Currently, a trial entitled “A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Continuation Period to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol (FOCUS FH)” is ongoing and will randomize approximately 300 patients with severe HeFH (www.clinicaltrials.gov/ct2/show/NCT01475825). The results of this study will shed more light on the efficacy and safety of mipomersen therapy.
LOMITAPIDE—INHIBITION OF THE MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, was recently approved by the FDA for the treatment of HoFH. MTP is found in the endoplasmic reticulum of hepatocytes and enterocytes and is a key protein in the assembly and secretion of apoBcontaining lipoproteins in the liver and intestine.22,23 However, inhibition of MTP results in an increase in the size of intracellular hepatic cholesterol pools and the development of fatty liver and elevated transaminases through an unopposed action of fatty acid synthases.24 Thus, earlier-studied MTP inhibitors, such as implitapide, were abandoned due to concerns related to gastrointestinal side effects and hepatic fat accumulation.25 The approval of lomitapide for the treatment of HoFH was based on a randomized, single-arm, open-label, phase 3 study, which was undertaken in 7 centers in 4 countries. Twenty-nine patients with HoFH were enrolled and placed on lomitapide (dose escalating from 5 to 60 mg/d with a median dose of 40 mg/d) on top of their other lipid-lowering drugs. The primary end point was mean percent change in levels of LDL-C from baseline to week 26, after which patients remained on lomitapide through week 78 for safety assessment. Twenty-three of the 29 patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). Levels of LDL-C and apoB were reduced by 50% and 49%, respectively, from baseline at week 26 and remained reduced by 44% and 45%, respectively, at week 56 and by 38% and 43%, respectively, at week 78 (P , 0.0001 for all comparisons). American Journal of Therapeutics (2015) 22(3)
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Triglycerides were also significantly reduced by 45%, 29%, and 31% at weeks 26, 56, and 78, respectively. On the contrary, although there was an initial reduction in levels of Lp(a), this was totally attenuated by week 78 (P 5 0.5827). Gastrointestinal symptoms were the most common adverse events. Fourteen percent of patients had increases in transaminase concentrations of .5 times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. However, no patient permanently discontinued treatment due to liver abnormalities.26 Currently, a trial entitled “A Phase III, Long Term, Open Label, Follow on Study of Microsomal Triglyceride Transfer Protein (MTP) Inhibitor “Lomitapide” (LOMITAPIDE) in Patients with Homozygous Familial Hypercholesterolemia” (www.clinicaltrials.gov/ct2/ show/NCT00943306) is ongoing and its results will shed more light on the efficacy and safety of lomitapide therapy.
PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 INHIBITORS Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease synthesized primarily in the liver, which binds to the LDL receptors and promotes degradation by reducing recycling and targeting the receptors for lysosomal destruction, thus decreasing the rate of removal of LDL-C from the circulation.27,28 Genetic studies have shown that gain-of-function mutations of PCSK9 in humans result in hypercholesterolemia,29,30 whereas loss-of-function mutations are associated with low LDL-C and diminished cardiovascular risk.31 Ironically, statins upregulate PCSK9 with consequent attenuation of their LDL-C-lowering effect.32 Thus, inhibition of PCSK9 represents an attractive target to enhance the lipid-lowering effect of statins. Hence, at least 5 different human monoclonal antibodies and 3 gene-silencing approaches are under development.33 To date, the 2 most studied antibodies against PCSK9 are alirocumab (REGN727/SAR236553) and evolocumab (AMG 145). In a recent publication, Stein et al34 reported the results of 3 phase 1 trials in which different SC doses of REGN727 were administered on days 1, 29, and 43 to healthy volunteers, patients with HeFH receiving atorvastatin, and patients with non-HeFH receiving atorvastatin. REGN727 doses of 50, 100, and 150 mg reduced LDL-C levels in the combined atorvastatintreated populations by 39.2%, 53.7%, and 61.0%, respectively, from baseline (P , 0.001 vs. placebo for all comparisons). REGN727 had an acceptable side-effect www.americantherapeutics.com
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profile as compared with placebo, and among subjects receiving REGN727, there were no discontinuations due to adverse events and no subject had a transaminase elevation to .3 times the upper limit of normal.34 In a recent phase 2 randomized, double-blind, placebo-controlled trial, which was performed at 16 lipid clinics in the United States and Canada, 77 patients with HeFH being treated with high-dose statins, with or without ezetimibe, were randomly assigned to 4 different SC dose regimens of REGN727 or placebo.35 REGN727 caused significant dose-dependent reductions in mean LDL-C from baseline to week 12 ranging from 28.9% in the 150 mg every 4-week regimen (P 5 0.0113) to 67.9% in the 150 mg every 2-week regimen (P , 0.0001). The most common adverse event was injection site reaction. There were no increases of .3 times the upper limit of normal reported for hepatic transaminases or creatinine kinase.35 The safety and efficacy of SAR236553/REGN727 has also been studied in patients with primary hypercholesterolemia. In a double-blind, parallel-group, placebo-controlled, multicenter trial, which included 183 patients with LDL-C $100 mg/dL receiving ongoing stable atorvastatin therapy, SAR236553 again demonstrated a clear dose–response relationship with respect to LDL-C lowering, causing LDL-C reductions from baseline to week 12 ranging from 39.6% in the 50 mg every 2-week regimen to 72.4% in the 150 mg every 2-week regimen (P , 0.0001 vs. placebo for all comparisons).36 SAR236553 also substantially reduced the levels of apoB and Lp(a). SAR236553 was generally well tolerated and only 1 patient experienced a serious adverse event of leukocytoclastic vasculitis. In a phase 2 randomized, double-blind, parallelgroup, placebo-controlled study, 92 patients with LDL-C $100 mg/dL were randomly assigned to receive 8 weeks of treatment with 80 mg/d atorvastatin plus SAR236553 (150 mg SC every 2 weeks), 10 mg/d atorvastatin plus SAR236553, or 80 mg/d atorvastatin plus placebo SC every 2 weeks.37 LDL-C was reduced from baseline by 73.2 6 3.5% with 80 mg of atorvastatin plus SAR236553, as compared with 17.3 6 3.5% with 80 mg of atorvastatin plus placebo (P , 0.001) and 66.2 6 3.5% with 10 mg of atorvastatin plus SAR236553. Similar significant reductions in levels of apoB were also noted with SAR236553. Median Lp(a) levels were substantially reduced by 1.9% in patients receiving 80 mg of atorvastatin plus SAR236553, as compared with a reduction of only 2.7% in the group receiving 80 mg of atorvastatin plus placebo. Overall, the percentages of patients who reported at least 1 adverse event were similar in the 2 groups assigned to 80 mg of atorvastatin and were lower in the group assigned to 10 mg of atorvastatin plus SAR236553.37 www.americantherapeutics.com
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The preliminary results of a study entitled “Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Ezetimibe in Patients with Hypercholesterolemia (ODYSSEY MONO)” (www.clinicaltrials.gov/ct2/ show/NCT01644474) were recently announced. ODYSSEY MONO was a randomized, double-blind, active-controlled, parallel-group study to evaluate the efficacy and safety of alirocumab over 24 weeks in patients with primary hypercholesterolemia and moderate cardiovascular risk. One hundred three patients were randomized to receive monotherapy with either ezetimibe 10 mg daily or alirocumab. Alirocumab was initiated at a dose of 75 mg SC every 2 weeks, and the dose was increased to 150 mg every 2 weeks if the LDL-C level at week 8 was .70 mg/dL. The mean LDL-C reduction from baseline to week 24 was 47.2% with alirocumab versus 15.6% with ezetimibe (P , 0.0001). The percentage of patients who reported treatment emergent adverse events was 69.2% in the alirocumab group and 78.4% in the ezetimibe group. The most common adverse events reported were infections (42.3% with alirocumab vs. 39.2% with ezetimibe), including nasopharyngitis, influenza, and upper respiratory tract infections. Injection site reactions occurred in ,2% of patients in both groups. Muscle-related adverse events occurred in 3.8% of the alirocumab group versus 3.9% of the ezetimibe group. The detailed results of this trial will be presented in the near future.38 Finally, the results of a large trial evaluating the efficacy and safety of another PCSK9 inhibitor, evolocumab (AMG 145) were recently published. Patients (n 5 1104) with hypercholesterolemia were randomly assigned (2:1) to receive either open-label SC evolocumab 420 mg every 4 weeks with SOC therapy or SOC therapy alone. The follow-up period was 52 weeks.39 In the group of patients who received evolocumab plus SOC therapy, there were mean reductions in LDL-C, apoB 52.1%, and 42.5%, respectively, versus 2.5% and 3.7%, respectively, in the group that received SOC therapy alone (P , 0.0001). Moreover, in the evolocumab plus SOC therapy group, as compared with the SOC therapy–only group, there was a significant reduction in Lp(a) levels (30.1% vs. 9.3%, P , 0.0001), as well as a significant increase in HDL-C and apoA1 levels (9.0% vs. 3.6% and 4.6% vs. 0.3%, respectively, P , 0.0001 for both comparisons). The 5 most commonly reported adverse events in the 2 groups were nasopharyngitis, upper respiratory tract infections, influenza arthralgia, and back pain. Investigators considered only 5.6% of all adverse events as possibly related to evolocumab. Transaminase elevations of .3 times the upper limit of normal were reported in 1.8% of patients who received evolocumab and in American Journal of Therapeutics (2015) 22(3)
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1.6% of the patients who received SOC therapy alone.39 Ongoing outcome trials will further define the clinical role of PCSK9 inhibitors in the treatment of hypercholesterolemia.
ETC-1002—DUAL MODULATION OF ADENOSINE TRIPHOSPHATECITRATE LYASE AND ADENOSINE MONOPHOSPHATE–ACTIVATED PROTEIN KINASE ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism. More specifically, ETC-1002 modulates 2 distinct and complementary molecular targets, adenosine triphosphate–citrate lyase (ACL) and adenosine monophosphate–activated protein kinase (AMPK). Inhibition of ACL reduces the levels of acetyl coenzyme A, the final common pathway for both fatty acid and sterol synthesis, at a level well upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the molecular target of statins. However, in a manner complementary to its effects on ACL, ETC1002 activates AMPK, leading to an inhibitory phosphorylation of acetyl coenzyme A carboxylase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase.40,41 The efficacy and safety of ETC-1002 was examined in a multicenter, randomized, double-blind, placebocontrolled, parallel group trial, which evaluated 177 patients with hypercholesterolemia (LDL-C 5 130– 220 mg/dL), who were stratified by baseline triglycerides [not elevated (,150 mg/dL) or elevated (150 to ,400 mg/dL)] and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. ETC-1002 lowered mean LDL-C, apoB, and LDL particle number in a dose-dependent manner. ETC-1002 doses of 40, 80, and 120 mg caused reductions in levels of LDL-C by 17.9 6 2.2%, 25.0 6 2.1%, and 26.6 6 2.2%, respectively, reduction in levels of apoB by 14.6 6 1.8%, 18.4 6 1.8%, and 22.1 6 1.8%, respectively, and reductions in LDL particle number by 14.8 6 2.3%, 16.3 6 2.2%, and 20.7 6 2.3%, respectively (P , 0.0001 vs. placebo for all comparisons). LDL-C lowering was similar between the subgroups of nonelevated and elevated triglycerides. HDL-C and triglyceride levels remained relatively unchanged. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments.41 The above results suggest that ETC-1002 may represent a novel LDL-lowering therapeutic modality, and American Journal of Therapeutics (2015) 22(3)
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future outcome trials may further define its role in the treatment of hypercholesterolemia.
CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS The role of the cholesteryl ester transfer protein (CETP) is to promote the transfer of CEs from HDL to other lipoproteins. Therefore, CETP inhibition raises HDL-C levels and decreases LDL-C levels. Torcetrapib was the first CETP inhibitor studied in the “Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE)” trial, which was designed to assess the hypothesis that torcetrapib would decrease cardiovascular events in high-risk populations.42 Despite a 72.1% increase in HDL-cholesterol and a 24.9% decrease in LDL-cholesterol, the study was prematurely terminated because of a 25% increase in cardiovascular events and a 58% increase in deaths from any cause.43 Of note, torcetrapib was also associated with a mean 5.4 mm Hg increase in systolic blood pressure, as well as lower potassium levels, which were attributed to off-target hyperaldosteronism. The ILLUMINATE investigators suggested that the high aldosterone state might account at least partly for the increased mortality.42,44 The CETP inhibitor dalcetrapib had with no effect on aldosterone levels but also failed to reduce the risk of recurrent cardiovascular events in patients with recent acute coronary syndrome despite a 31%–40% increase in HDL-cholesterol levels.44,45 It is important to point out although that dalcetrapib therapy did not have any meaningful effect on LDL levels.45 Currently, 2 large randomized trials are in the recruitment phase and aim to evaluate the efficacy, safety, and cardiovascular outcomes of treatment with 2 other CETP inhibitors, anacetrapib and evacetrapib. Anacetrapib has been shown to raise HDL-C by up to 138.1% and lower LDL-C by up to 39.8%.46 Evacetrapib has been shown to raise HDL-C by up to 128.8% and lower LDL-C by up to 35.9%.47 Both drugs were well tolerated, with no adverse effects on blood pressure or mineralocorticoid activity.46,47 Anacetrapib will be evaluated in the “Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL)” trial (estimated enrollment of 30,000 patients—estimated follow-up of 4 years), which aims to determine whether lipid modification with anacetrapib 100 mg daily can reduce the risk of major coronary events in patients with established vascular disease (www. clinicaltrials.gov/ct2/show/NCT01252953). Evacetrapib will be evaluated in a trial entitled “A Study www.americantherapeutics.com
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LDL Cholesterol–Lowering Drugs
of Evacetrapib in High-Risk Vascular Disease (ACCELERATE)” (estimated enrollment of 12,000 patients—estimated follow-up of 4 years), which aims to evaluate the clinical efficacy and safety of evacetrapib in patients with high-risk vascular disease (www. clinicaltrials.gov/ct2/show/NCT01687998). The results of these trials will shed more light on the role of CETP inhibitors in CVD.
WAY-252623—ACTIVATION OF THE b-ISOFORM OF THE LIVER X RECEPTORS Liver X receptors (LXR) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis.48 LXRa is the predominant subtype expressed in the liver and seems to be responsible for observed increases in hepatic lipogenesis.49,50 However, it has been shown that selective LXRb activation reverses atherosclerosis in a murine model lacking apoE and LXRa.51 WAY-252623 is a highly selective and orally bioavailable synthetic LXRb agonist. In an experimental study in nonhuman primates with normal lipid levels, WAY-252623 was shown to significantly reduce total cholesterol (50%–55%) and LDL-C (70%–77%) in a time- and dose-dependent manner.52 LXRb agonists have not been studied in humans yet, but this class my hold promise for LDL lowering.
CONCLUSIONS The role of LDL-C in the pathophysiology of atherosclerosis is well recognized, and the use of statins has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. However, many individuals at risk for CVD are intolerant to statins, whereas others fail to achieve LDL-C goals despite maximum statin doses. Until recently, the efficacy of non-statin LDL-lowering drugs was modest, not exceeding a LDL-C reduction of 20%. Thus, extensive research is being carried out to identify new LDLlowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve our ability to achieve LDL-C goals and reduce cardiovascular risk. Inhibitors of apoB synthesis, MTP inhibitors, PCSK9 inhibitors, modulators of ACL and AMPK, and CETP inhibitors are new classes of promising LDL-lowering agents discussed in this article. Ongoing and future outcome studies will shed more light on the clinical efficacy of these agents in patients with hypercholesterolemia. www.americantherapeutics.com
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Kosmas and Frishman familial hypercholesterolaemia: a randomised, doubleblind, placebo-controlled trial. Lancet. 2010;375:998–1006. Thomas GS, Cromwell WC, Ali S, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013;62:2178–2184. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on lowdensity lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol. 2010;105:1413–1419. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2012;33:1142–1149. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-tomoderate hyperlipidaemia. Eur Heart J. 2011;32:2650–2659. Furtado JD, Wedel MK, Sacks FM. Antisense inhibition of apoB synthesis with mipomersen reduces plasma apoC-III and apoC-III-containing lipoproteins. J Lipid Res. 2012;53:784–791. Wetterau JR, Lin MC, Jamil H. Microsomal triglyceride transfer protein. Biochim Biophys Acta. 1997;1345:136–150. Calandra S, Tarugi P, Speedy HE, et al. Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. J Lipid Res. 2011;52: 1885–1926. Wierzbicki AS, Viljoen A, Hardman TC, et al. New therapies to reduce low-density lipoprotein cholesterol. Curr Opin Cardiol. 2013;28:452–457. Wilkinson MJ, Davidson MH. Recent developments in the treatment of familial hypercholesterolemia: a review of several new drug classes. Curr Treat Options Cardiovasc Med. 2013;15:696–705. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381:40–46. Qian YW, Schmidt RJ, Zhang Y, et al. Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J Lipid Res. 2007;48: 1488–1498. Weinreich M, Frishman WH. Antihyperlipidemic therapies targeting PCSK9. Cardiol Rev. 2014;22:140–146. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156. Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65:419–422. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272.
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32. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24:1454–1459. 33. Norata GD, Ballantyne CM, Catapano AL. New therapeutic principles in dyslipidaemia: focus on LDL and Lp (a) lowering drugs. Eur Heart J. 2013;34:1783–1789. 34. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–1118. 35. Stein EA, Gipe D, Bergeron J, 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. 36. McKenney JM, Koren MJ, Kereiakes DJ, et al. 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;59:2344–2353. 37. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–1900. 38. Regeneron. Sanofi and Regeneron report positive top-line results with alirocumab from first phase 3 study of a PCSK9 inhibitor for LDL-cholesterol reduction [press releases]. 2013. Available at: investor.regeneron.com/releasedetail. cfm?ReleaseID5797732. Accessed October 16, 2013. 39. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of Longer-Term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52Week results from the open-label study of Long-Term Evaluation against LDL-C (OSLER) randomized trial. Circulation. 2013;129:234–243. 40. Pinkosky SL, Filippov S, Srivastava RA, et al. AMPactivated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013;54:134–151. 41. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154–1162. 42. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122. 43. Frishman WH, Barkowski RS. Cholesteryl ester transfer protein inhibition for coronary heart disease prevention: real hope or despair? Am J Med. 2008;121:644–646. 44. Kosmas CE, Christodoulidis G, Cheng JW, et al. Highdensity lipoprotein Functionality in coronary artery disease. Am J Med Sci. 2014;347:504–508. www.americantherapeutics.com
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LDL Cholesterol–Lowering Drugs 45. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–2099. 46. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406–2415. 47. Nicholls SJ, Brewer HB, Kastelein JJ, 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;306:2099–2109. 48. Parikh N, Frishman WH. Liver X receptors: a potential therapeutic target for modulating the atherosclerotic process. Cardiol Rev. 2010;18:269–274.
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241 49. Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–2838. 50. Peet DJ, Turley SD, Ma W, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell. 1998;93:693–704. 51. Bradley MN, Hong C, Chen M, et al. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J Clin Invest. 2007;117:2337–2346. 52. Quinet EM, Basso MD, Halpern AR, et al. LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. J Lipid Res. 2009;50:2358–2370.
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New and Emerging LDL Cholesterol–Lowering Drugs Constantine E. Kosmas, MD, PhD1 and William H. Frishman, MD2*
The role of low-density lipoprotein cholesterol (LDL-C) in the pathophysiology of atherosclerosis is well recognized, and the use of LDL-C lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins are the standard of care and their use is supported by extensive evidence demonstrating their effectiveness in lowering LDL-C and in reducing the risk for cardiovascular disease. However, many individuals at risk for cardiovascular disease fail to achieve LDL-C goals. In addition, several patients are intolerant to statins due to side effects, mostly myalgia and weakness, especially at high statin doses. However, until recently, the efficacy of other non-statin LDL-C-lowering drugs was modest, not exceeding a LDL-C reduction of 20%. In view of the above, extensive research is being carried out to identify new LDL-C-lowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve our ability to achieve LDL-C goals and reduce cardiovascular risk. This review aims to provide the current evidence regarding the newly approved LDL-C-lowering agents, as well as the clinical and scientific data pertaining to promising new and emerging LDL-C-lowering drugs on the horizon. Keywords: LDL cholesterol, cholesterol-lowering drugs, atherosclerosis
INTRODUCTION The role of low-density lipoprotein cholesterol (LDL-C) in the pathophysiology of atherosclerosis is well known, and the use of LDL-C-lowering medications has led to a significant reduction of cardiovascular risk in both primary1 and secondary2 prevention. Statins are the standard of care (SOC) and their use is supported by extensive evidence demonstrating their effectiveness in lowering LDL-C and in reducing the risk for cardiovascular disease (CVD).3,4 However, many individuals at risk for CVD fail to achieve LDL-C goals,5,6 including patients with familial hypercholesterolemia, and patients with established
1
Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY; and 2 Department of Internal Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, NY. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Medicine, New York Medical College, Valhalla, NY 10595. E-mail: william_frishman@ nymc.edu
coronary artery disease that cannot reach their LDL-C target despite maximum dose statin therapy. In addition, several patients are intolerant to statins due to side effects, mostly myalgia and weakness, especially at high statin doses.7 Other recently identified side effects, such as an increased risk for diabetes,8 particularly at higher doses,9 and reports of statininduced memory loss, has prompted the Food and Drug Administration (FDA) to mandate additional safety-labeling warnings.10 However, until recently, the efficacy of other non-statin LDL-C-lowering drugs was modest, not exceeding an LDL-C reduction of 20%. Specifically, extended-release niacin has been reported to lower LDL-C by up to 17%,11 whereas fenofibrate has been reported to lower LDL-C levels by approximately 20%,12 although it may actually increase LDL-C levels in patients with hypertriglyceridemia. In addition, ezetimibe, an intestinal cholesterol absorption inhibitor, and colesevelam, a bile acid sequestrant, have been reported to lower LDL-C by 18%.13,14 In view of the above, extensive research is being carried out to identify new LDL-C-lowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve
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LDL Cholesterol–Lowering Drugs
our ability to achieve LDL-C goals and potentially reduce cardiovascular risk. This review aims to provide the current evidence regarding the newly approved LDL-C-lowering agents, as well as the clinical and scientific data pertaining to promising new and emerging LDL-C-lowering drugs on the horizon.
MIPOMERSEN—INHIBITION OF THE SYNTHESIS OF APOLIPOPROTEIN B Mipomersen, an antisense inhibitor of apolipoprotein B-100 (apoB) synthesis was recently approved by the FDA for the treatment of homozygous familial hypercholesterolemia (HoFH). ApoB is the main structural and receptor-binding component of all atherogenic lipid particles and is required for the secretion of very LDL from the liver.15 The approval of mipomersen for the treatment of HoFH was based on a randomized, double-blind, placebo-controlled, phase 3 study, which was undertaken in 9 lipid centers in 7 countries.16 Thirty-four patients with HoFH were assigned to mipomersen and 17 patients to placebo. All patients were already being treated with other lipid-lowering drugs, including highdose statins. Mipomersen significantly reduced LDL-C by 24.7% (P 5 0.0003 vs. placebo), apoB by 26.8% (P , 0.0001 vs. placebo), and lipoprotein(a) by 31.1% (P 5 0.0013 vs. placebo). In addition, mipomersen increased high-density lipoprotein-cholesterol (HDL-C) by 15.1% (P 5 0.0326 vs. placebo). The most common adverse effects of mipomersen were injection site reactions (76% vs. 24% of patients in the mipomersen and placebo groups, respectively) and increases in concentrations of alanine aminotransferase (ALT) of $3 times the upper limit of normal (12% vs. 0% of patients in the mipomersen and placebo groups, respectively).16 Thomas et al17 examined the efficacy and safety of mipomersen for reducing the atherogenic lipids/lipoproteins in hypercholesterolemia. The study enrolled 158 patients having a baseline LDL-C $100 mg/dL with, or at high risk for, coronary heart disease, taking maximally tolerated lipid-lowering therapy. The patients received weekly subcutaneous (SC) mipomersen (n 5 105) or placebo (n 5 52) for 26 weeks with a 24week follow-up. Mipomersen significantly reduced LDL-C by 36.9%, apoB by 37.5%, and Lp(a) by 25.6% (P , 0.001 vs. placebo for all comparisons). Common adverse effects included injection site reactions (78.1% vs. 30.8%) and flu-like symptoms (34.3% vs. 21.2%) in the mipomersen and placebo groups, respectively). In addition, mipomersen therapy led to increases in concentrations of ALT of $3 times the upper limit of normal in 9.5% of patients and hepatic steatosis in 10.5% of www.americantherapeutics.com
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patients with return toward baseline after treatment cessation. Interestingly, greater reductions were noted in the number of small (2542.5 nmol/L) versus large LDL particles (279.7 nmol/L) in the mipomersen group, whereas no meaningful changes occurred in the placebo group. Also noted was the LDL-lowering effect of mipomersen was greater in women and patients aged .59 years.17 In a randomized, placebo-controlled, double-blind, dose-escalation study, 44 patients with heterozygous FH (HeFH), being treated with conventional lipidlowering therapy, were assigned to different doses of mipomersen (50–300 mg) versus placebo and received 8 SC doses during a 6-week treatment period.18 After 6 weeks, the LDL-C level was reduced by 21% from baseline in the 200 mg/wk dose group (P , 0.05) and 34% in the 300 mg/wk dose group (P , 0.01), with a concomitant reduction in apoB of 23% (P , 0.05) and 33% (P , 0.01), respectively. Again, injection site reactions were the most common adverse event, while increases in concentrations of ALT of $3 times the upper limit of normal occurred in 11% of patients treated with mipomersen.18 Mipomersen has also been tested in statinintolerant patients. In a randomized, double-blind, placebo-controlled study, 33 subjects at high risk for coronary heart disease, not receiving statins due to intolerance, were randomized to receive a weekly SC dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. After 26 weeks of mipomersen administration, LDL-C, apoB, and Lp(a) were reduced by 47%, 46%, and 27%, respectively (P , 0.001 vs. placebo for all comparisons). Persistent increases in concentrations of ALT of $3 times the upper limit of normal were observed in 33% of patients treated with mipomersen. In addition, hepatic steatosis was detected in 85% of patients in the mipomersen group in whom hepatic magnetic resonance imaging was performed.19 As monotherapy, mipomersen has been tested in subjects with mild-to-moderate hyperlipidemia. In a randomized, placebo-controlled, double-blind, doseescalation study, 50 subjects with LDL-C levels between 119 and 266 mg/dL were enrolled into 5 cohorts at a 4:1 randomization ratio of active to placebo.20 Two 13-week dose regimens were evaluated at doses ranging from 50 to 400 mg/wk. Mipomersen produced dose-dependent reductions in all apoB-containing lipoproteins. In the 200 and 300 mg/wk cohorts, mean reductions from baseline in LDL-C were 45 6 10% and 61 6 8%, respectively, corresponding to mean reductions of 46 6 11% and 61 6 7%, respectively, in apoB levels. In addition, Lp(a) levels were lowered with mean reductions up to 42%, and triglyceride levels were also lowered with median reductions up to 53%. American Journal of Therapeutics (2015) 22(3)
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Injection site reactions were the most common adverse event. The 400-mg/wk cohort was discontinued because of significant transaminase elevations.20 In another study, mipomersen 200 and 300 mg/wk reduced total plasma apoC-III by 42% and 38%, respectively, as compared with placebo (P , 0.03).21 Currently, a trial entitled “A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Continuation Period to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol (FOCUS FH)” is ongoing and will randomize approximately 300 patients with severe HeFH (www.clinicaltrials.gov/ct2/show/NCT01475825). The results of this study will shed more light on the efficacy and safety of mipomersen therapy.
LOMITAPIDE—INHIBITION OF THE MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, was recently approved by the FDA for the treatment of HoFH. MTP is found in the endoplasmic reticulum of hepatocytes and enterocytes and is a key protein in the assembly and secretion of apoBcontaining lipoproteins in the liver and intestine.22,23 However, inhibition of MTP results in an increase in the size of intracellular hepatic cholesterol pools and the development of fatty liver and elevated transaminases through an unopposed action of fatty acid synthases.24 Thus, earlier-studied MTP inhibitors, such as implitapide, were abandoned due to concerns related to gastrointestinal side effects and hepatic fat accumulation.25 The approval of lomitapide for the treatment of HoFH was based on a randomized, single-arm, open-label, phase 3 study, which was undertaken in 7 centers in 4 countries. Twenty-nine patients with HoFH were enrolled and placed on lomitapide (dose escalating from 5 to 60 mg/d with a median dose of 40 mg/d) on top of their other lipid-lowering drugs. The primary end point was mean percent change in levels of LDL-C from baseline to week 26, after which patients remained on lomitapide through week 78 for safety assessment. Twenty-three of the 29 patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). Levels of LDL-C and apoB were reduced by 50% and 49%, respectively, from baseline at week 26 and remained reduced by 44% and 45%, respectively, at week 56 and by 38% and 43%, respectively, at week 78 (P , 0.0001 for all comparisons). American Journal of Therapeutics (2015) 22(3)
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Triglycerides were also significantly reduced by 45%, 29%, and 31% at weeks 26, 56, and 78, respectively. On the contrary, although there was an initial reduction in levels of Lp(a), this was totally attenuated by week 78 (P 5 0.5827). Gastrointestinal symptoms were the most common adverse events. Fourteen percent of patients had increases in transaminase concentrations of .5 times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. However, no patient permanently discontinued treatment due to liver abnormalities.26 Currently, a trial entitled “A Phase III, Long Term, Open Label, Follow on Study of Microsomal Triglyceride Transfer Protein (MTP) Inhibitor “Lomitapide” (LOMITAPIDE) in Patients with Homozygous Familial Hypercholesterolemia” (www.clinicaltrials.gov/ct2/ show/NCT00943306) is ongoing and its results will shed more light on the efficacy and safety of lomitapide therapy.
PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 INHIBITORS Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease synthesized primarily in the liver, which binds to the LDL receptors and promotes degradation by reducing recycling and targeting the receptors for lysosomal destruction, thus decreasing the rate of removal of LDL-C from the circulation.27,28 Genetic studies have shown that gain-of-function mutations of PCSK9 in humans result in hypercholesterolemia,29,30 whereas loss-of-function mutations are associated with low LDL-C and diminished cardiovascular risk.31 Ironically, statins upregulate PCSK9 with consequent attenuation of their LDL-C-lowering effect.32 Thus, inhibition of PCSK9 represents an attractive target to enhance the lipid-lowering effect of statins. Hence, at least 5 different human monoclonal antibodies and 3 gene-silencing approaches are under development.33 To date, the 2 most studied antibodies against PCSK9 are alirocumab (REGN727/SAR236553) and evolocumab (AMG 145). In a recent publication, Stein et al34 reported the results of 3 phase 1 trials in which different SC doses of REGN727 were administered on days 1, 29, and 43 to healthy volunteers, patients with HeFH receiving atorvastatin, and patients with non-HeFH receiving atorvastatin. REGN727 doses of 50, 100, and 150 mg reduced LDL-C levels in the combined atorvastatintreated populations by 39.2%, 53.7%, and 61.0%, respectively, from baseline (P , 0.001 vs. placebo for all comparisons). REGN727 had an acceptable side-effect www.americantherapeutics.com
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LDL Cholesterol–Lowering Drugs
profile as compared with placebo, and among subjects receiving REGN727, there were no discontinuations due to adverse events and no subject had a transaminase elevation to .3 times the upper limit of normal.34 In a recent phase 2 randomized, double-blind, placebo-controlled trial, which was performed at 16 lipid clinics in the United States and Canada, 77 patients with HeFH being treated with high-dose statins, with or without ezetimibe, were randomly assigned to 4 different SC dose regimens of REGN727 or placebo.35 REGN727 caused significant dose-dependent reductions in mean LDL-C from baseline to week 12 ranging from 28.9% in the 150 mg every 4-week regimen (P 5 0.0113) to 67.9% in the 150 mg every 2-week regimen (P , 0.0001). The most common adverse event was injection site reaction. There were no increases of .3 times the upper limit of normal reported for hepatic transaminases or creatinine kinase.35 The safety and efficacy of SAR236553/REGN727 has also been studied in patients with primary hypercholesterolemia. In a double-blind, parallel-group, placebo-controlled, multicenter trial, which included 183 patients with LDL-C $100 mg/dL receiving ongoing stable atorvastatin therapy, SAR236553 again demonstrated a clear dose–response relationship with respect to LDL-C lowering, causing LDL-C reductions from baseline to week 12 ranging from 39.6% in the 50 mg every 2-week regimen to 72.4% in the 150 mg every 2-week regimen (P , 0.0001 vs. placebo for all comparisons).36 SAR236553 also substantially reduced the levels of apoB and Lp(a). SAR236553 was generally well tolerated and only 1 patient experienced a serious adverse event of leukocytoclastic vasculitis. In a phase 2 randomized, double-blind, parallelgroup, placebo-controlled study, 92 patients with LDL-C $100 mg/dL were randomly assigned to receive 8 weeks of treatment with 80 mg/d atorvastatin plus SAR236553 (150 mg SC every 2 weeks), 10 mg/d atorvastatin plus SAR236553, or 80 mg/d atorvastatin plus placebo SC every 2 weeks.37 LDL-C was reduced from baseline by 73.2 6 3.5% with 80 mg of atorvastatin plus SAR236553, as compared with 17.3 6 3.5% with 80 mg of atorvastatin plus placebo (P , 0.001) and 66.2 6 3.5% with 10 mg of atorvastatin plus SAR236553. Similar significant reductions in levels of apoB were also noted with SAR236553. Median Lp(a) levels were substantially reduced by 1.9% in patients receiving 80 mg of atorvastatin plus SAR236553, as compared with a reduction of only 2.7% in the group receiving 80 mg of atorvastatin plus placebo. Overall, the percentages of patients who reported at least 1 adverse event were similar in the 2 groups assigned to 80 mg of atorvastatin and were lower in the group assigned to 10 mg of atorvastatin plus SAR236553.37 www.americantherapeutics.com
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The preliminary results of a study entitled “Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Ezetimibe in Patients with Hypercholesterolemia (ODYSSEY MONO)” (www.clinicaltrials.gov/ct2/ show/NCT01644474) were recently announced. ODYSSEY MONO was a randomized, double-blind, active-controlled, parallel-group study to evaluate the efficacy and safety of alirocumab over 24 weeks in patients with primary hypercholesterolemia and moderate cardiovascular risk. One hundred three patients were randomized to receive monotherapy with either ezetimibe 10 mg daily or alirocumab. Alirocumab was initiated at a dose of 75 mg SC every 2 weeks, and the dose was increased to 150 mg every 2 weeks if the LDL-C level at week 8 was .70 mg/dL. The mean LDL-C reduction from baseline to week 24 was 47.2% with alirocumab versus 15.6% with ezetimibe (P , 0.0001). The percentage of patients who reported treatment emergent adverse events was 69.2% in the alirocumab group and 78.4% in the ezetimibe group. The most common adverse events reported were infections (42.3% with alirocumab vs. 39.2% with ezetimibe), including nasopharyngitis, influenza, and upper respiratory tract infections. Injection site reactions occurred in ,2% of patients in both groups. Muscle-related adverse events occurred in 3.8% of the alirocumab group versus 3.9% of the ezetimibe group. The detailed results of this trial will be presented in the near future.38 Finally, the results of a large trial evaluating the efficacy and safety of another PCSK9 inhibitor, evolocumab (AMG 145) were recently published. Patients (n 5 1104) with hypercholesterolemia were randomly assigned (2:1) to receive either open-label SC evolocumab 420 mg every 4 weeks with SOC therapy or SOC therapy alone. The follow-up period was 52 weeks.39 In the group of patients who received evolocumab plus SOC therapy, there were mean reductions in LDL-C, apoB 52.1%, and 42.5%, respectively, versus 2.5% and 3.7%, respectively, in the group that received SOC therapy alone (P , 0.0001). Moreover, in the evolocumab plus SOC therapy group, as compared with the SOC therapy–only group, there was a significant reduction in Lp(a) levels (30.1% vs. 9.3%, P , 0.0001), as well as a significant increase in HDL-C and apoA1 levels (9.0% vs. 3.6% and 4.6% vs. 0.3%, respectively, P , 0.0001 for both comparisons). The 5 most commonly reported adverse events in the 2 groups were nasopharyngitis, upper respiratory tract infections, influenza arthralgia, and back pain. Investigators considered only 5.6% of all adverse events as possibly related to evolocumab. Transaminase elevations of .3 times the upper limit of normal were reported in 1.8% of patients who received evolocumab and in American Journal of Therapeutics (2015) 22(3)
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1.6% of the patients who received SOC therapy alone.39 Ongoing outcome trials will further define the clinical role of PCSK9 inhibitors in the treatment of hypercholesterolemia.
ETC-1002—DUAL MODULATION OF ADENOSINE TRIPHOSPHATECITRATE LYASE AND ADENOSINE MONOPHOSPHATE–ACTIVATED PROTEIN KINASE ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism. More specifically, ETC-1002 modulates 2 distinct and complementary molecular targets, adenosine triphosphate–citrate lyase (ACL) and adenosine monophosphate–activated protein kinase (AMPK). Inhibition of ACL reduces the levels of acetyl coenzyme A, the final common pathway for both fatty acid and sterol synthesis, at a level well upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the molecular target of statins. However, in a manner complementary to its effects on ACL, ETC1002 activates AMPK, leading to an inhibitory phosphorylation of acetyl coenzyme A carboxylase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase.40,41 The efficacy and safety of ETC-1002 was examined in a multicenter, randomized, double-blind, placebocontrolled, parallel group trial, which evaluated 177 patients with hypercholesterolemia (LDL-C 5 130– 220 mg/dL), who were stratified by baseline triglycerides [not elevated (,150 mg/dL) or elevated (150 to ,400 mg/dL)] and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. ETC-1002 lowered mean LDL-C, apoB, and LDL particle number in a dose-dependent manner. ETC-1002 doses of 40, 80, and 120 mg caused reductions in levels of LDL-C by 17.9 6 2.2%, 25.0 6 2.1%, and 26.6 6 2.2%, respectively, reduction in levels of apoB by 14.6 6 1.8%, 18.4 6 1.8%, and 22.1 6 1.8%, respectively, and reductions in LDL particle number by 14.8 6 2.3%, 16.3 6 2.2%, and 20.7 6 2.3%, respectively (P , 0.0001 vs. placebo for all comparisons). LDL-C lowering was similar between the subgroups of nonelevated and elevated triglycerides. HDL-C and triglyceride levels remained relatively unchanged. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments.41 The above results suggest that ETC-1002 may represent a novel LDL-lowering therapeutic modality, and American Journal of Therapeutics (2015) 22(3)
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future outcome trials may further define its role in the treatment of hypercholesterolemia.
CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS The role of the cholesteryl ester transfer protein (CETP) is to promote the transfer of CEs from HDL to other lipoproteins. Therefore, CETP inhibition raises HDL-C levels and decreases LDL-C levels. Torcetrapib was the first CETP inhibitor studied in the “Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE)” trial, which was designed to assess the hypothesis that torcetrapib would decrease cardiovascular events in high-risk populations.42 Despite a 72.1% increase in HDL-cholesterol and a 24.9% decrease in LDL-cholesterol, the study was prematurely terminated because of a 25% increase in cardiovascular events and a 58% increase in deaths from any cause.43 Of note, torcetrapib was also associated with a mean 5.4 mm Hg increase in systolic blood pressure, as well as lower potassium levels, which were attributed to off-target hyperaldosteronism. The ILLUMINATE investigators suggested that the high aldosterone state might account at least partly for the increased mortality.42,44 The CETP inhibitor dalcetrapib had with no effect on aldosterone levels but also failed to reduce the risk of recurrent cardiovascular events in patients with recent acute coronary syndrome despite a 31%–40% increase in HDL-cholesterol levels.44,45 It is important to point out although that dalcetrapib therapy did not have any meaningful effect on LDL levels.45 Currently, 2 large randomized trials are in the recruitment phase and aim to evaluate the efficacy, safety, and cardiovascular outcomes of treatment with 2 other CETP inhibitors, anacetrapib and evacetrapib. Anacetrapib has been shown to raise HDL-C by up to 138.1% and lower LDL-C by up to 39.8%.46 Evacetrapib has been shown to raise HDL-C by up to 128.8% and lower LDL-C by up to 35.9%.47 Both drugs were well tolerated, with no adverse effects on blood pressure or mineralocorticoid activity.46,47 Anacetrapib will be evaluated in the “Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL)” trial (estimated enrollment of 30,000 patients—estimated follow-up of 4 years), which aims to determine whether lipid modification with anacetrapib 100 mg daily can reduce the risk of major coronary events in patients with established vascular disease (www. clinicaltrials.gov/ct2/show/NCT01252953). Evacetrapib will be evaluated in a trial entitled “A Study www.americantherapeutics.com
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of Evacetrapib in High-Risk Vascular Disease (ACCELERATE)” (estimated enrollment of 12,000 patients—estimated follow-up of 4 years), which aims to evaluate the clinical efficacy and safety of evacetrapib in patients with high-risk vascular disease (www. clinicaltrials.gov/ct2/show/NCT01687998). The results of these trials will shed more light on the role of CETP inhibitors in CVD.
WAY-252623—ACTIVATION OF THE b-ISOFORM OF THE LIVER X RECEPTORS Liver X receptors (LXR) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis.48 LXRa is the predominant subtype expressed in the liver and seems to be responsible for observed increases in hepatic lipogenesis.49,50 However, it has been shown that selective LXRb activation reverses atherosclerosis in a murine model lacking apoE and LXRa.51 WAY-252623 is a highly selective and orally bioavailable synthetic LXRb agonist. In an experimental study in nonhuman primates with normal lipid levels, WAY-252623 was shown to significantly reduce total cholesterol (50%–55%) and LDL-C (70%–77%) in a time- and dose-dependent manner.52 LXRb agonists have not been studied in humans yet, but this class my hold promise for LDL lowering.
CONCLUSIONS The role of LDL-C in the pathophysiology of atherosclerosis is well recognized, and the use of statins has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. However, many individuals at risk for CVD are intolerant to statins, whereas others fail to achieve LDL-C goals despite maximum statin doses. Until recently, the efficacy of non-statin LDL-lowering drugs was modest, not exceeding a LDL-C reduction of 20%. Thus, extensive research is being carried out to identify new LDLlowering agents with an acceptable side effect profile, which, used alone or in combination with statins, would improve our ability to achieve LDL-C goals and reduce cardiovascular risk. Inhibitors of apoB synthesis, MTP inhibitors, PCSK9 inhibitors, modulators of ACL and AMPK, and CETP inhibitors are new classes of promising LDL-lowering agents discussed in this article. Ongoing and future outcome studies will shed more light on the clinical efficacy of these agents in patients with hypercholesterolemia. www.americantherapeutics.com
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