New Trends in Dyslipidemia Treatment

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Advance Publication

Circulation Journal REVIEW doi: 10.1253/circj.CJ-20-1037

Albert Youngwoo Jang, MD; Soo Lim, MD, PhD; Sang-Ho Jo, MD, PhD; Seung Hwan Han, MD, PhD; Kwang Kon Koh, MD, PhD

Dyslipidemia is one of the most important risk factors for cardiovascular (CV) disease. Statin therapy has dramatically improved CV outcomes and is the backbone of current lipid-lowering therapy, but despite well-controlled low-density lipoprotein cholesterol (LDL-C) levels through statin administration, up to 40% patients still experience CV disease. New therapeutic agents to tackle such residual cholesterol risk by lowering not only LDL-C but triglycerides (TG), TG-rich lipoproteins (TRL), or lipoprotein(a) (Lp(a)) are being introduced. Ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, PCSK9 small interference RNA (siRNA), and bempedoic acid added to statin therapy have shown additional improvement to CV outcomes. Recent trials administering eicosapentaenoic acid to patients with high TG despite statin therapy have also demonstrated significant CV benefit. Antisense oligonucleotide (ASO) therapies with hepatocyte-specific targeting modifications are now being newly introduced with promising lipid-lowering effects. ASOs targeting TG/TRL, such as angiopoietin-like 3 or 4 (ANGPTL3 or ANGPTL4), apolipoprotein C-III (APOC3), or Lp(a) have effectively lowered the corresponding lipid profiles without requiring high or frequent doses. Clinical outcomes from these novel therapeutics are yet to be proven. Here, we review current and emerging therapeutics targeting LDL-C, TG, TRL, and Lp(a) to reduce the residual CV risk.

Key Words: Cardiovascular disease; Dyslipidemia; Residual risk; Treatments

yslipidemia is one of the major risk factors for have demonstrated the role of statin in lowering LDL-C cardiovascular (CV) disease. Many investigators levels and the associated CV benefit Table( 1).11–13 The D have demonstrated the beneficial effects of statins Scandinavian Simvastatin Survival Study (4S) study showed lowering of low-density lipoprotein cholesterol (LDL-C) on that simvastatin 20–40 mg daily dose reduced all-cause the risk of coronary artery disease (CAD) events in patients death by 30% through lowering LDL-C up to 68 mg/dL with or without CV disease (CVD).1–4 Despite significant over a 5.4-year period.11 In the West of Scotland Coronary improvement in CV outcomes since the advent of statins, Prevention Study (WOSCOPS) study, daily pravastatin up to 40% of statin-treated patients continue to suffer from 40 mg treatment attenuated a composite of all-cause death life-threatening CV events even when the LDL-C target is and CAD death by 31% over 4.9 years.12 These landmark achieved by intensive statin treatment; this is termed the trials and subsequent studies have consistently demon- ‘residual risk’.5–7 Here, we review current and emerging strated a marked CV benefit, revolutionizing the treatment therapeutics targeting LDL-C, triglyceride (TG), TG-rich of CVD. Today, statins are the backbone of all CVD lipoproteins (TRL), and lipoprotein(a) (Lp(a)) in order to therapy.7,8 reduce the residual cholesterol risk. Statin-Related Side Effects Statin Therapy for LDL-C Lowering The use of statins, however, is often associated with adverse effects such as insulin resistance or myopathy. Among the various lipoproteins, LDL-C is known for its Statins dose-dependently worsen insulin sensitivity by atherosclerotic traits through accumulating and inducing reducing plasma levels of adiponectin and thus increase the inflammation in the subendothelial layer.7,8 Statins have a risk of type 2 diabetes (T2DM) in humans.14–17 Whether pleiotropic protective effect against atherosclerotic CVD the reduced insulin sensitivity is caused by on-target or (ASCVD) through vasodilation, anti-inflammatory, anti- off-target effects of statins is unclear, but genetic studies oxidant, antithrombotic, and plaque-stabilizing effects.9,10 have demonstrated that those with LDL-C lowering genetic Major landmark randomized controlled trials (RCTs) variants have a higher risk of T2DM despite a reduction of

Received October 8, 2020; accepted October 8, 2020; J-STAGE Advance Publication released online November 12, 2020 Division of Cardiovascular Disease, Gachon University Gil Hospital and Gachon Cardiovascular Research Institute, Incheon (A.Y.J., S.H.H., K.K.K.); Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam (S.L.); and Cardiovascular Center, Hallym University Sacred Heart Hospital, Anyang-si (S.-H.J.), Korea Mailing address: Kwang Kon Koh, MD, PhD, FACC, Professor of Medicine, Director, Cardiometabolic Syndrome Unit, Division of Cardiology, Gachon University Gil Hospital, 774 Beongil 21, Namdongdaero, Namdong-Gu, Incheon 21565, Korea. E-mail: [email protected] All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] ISSN-1346-9843 Advance Publication 2 JANG AY et al.

Table 1. Summary of Clinical Trials Targeting the Lowering of LDL-C LDL-C Sample Duration Primary Outcome Trial name Drug and dose Inclusion reduction size (years) endpoint (95% CI) (mg/dL) 4S11 (statin) Simvastatin n=4,444 Hypercholesterolemia, 5.4 All-cause death 68 RR: 0.70 20–40 mg daily angina, or previous MI (0.58–0.85) WOSCOPS 12 Pravastatin 40 mg n=6,595 Men with 4.9 CAD death or 41 HR: 0.69 (statin) daily hypercholesterolemia nonfatal MI (0.57–0.83) JUPITER 13 Rosuvastatin 20 mg n=17,802 Healthy subjects 5 MI, stroke, arterial 50 HR: 0.56 (statin) daily revascularization, (0.46–0.69) hospitalization for unstable angina, or CV death IMPROVE-IT26 Ezetimibe 10 mg + n=18,144 ACS 6 Composite 40.6 HR: 0.94 (ezetimibe) simvastatin 40 mg vs. endpoint (0.89–0.99) simvastatin 40 mg SHARP30 Ezetimibe 10 mg + n=9,270 CKD 4.9 Composite 30 HR: 0.83 (ezetimibe) simvastatin 20 mg vs. endpoint (0.74–0.94) placebo FOURIER33 Evolocumab 140 mg n=27,574 CAD, elevated LDL-C 2.2 Composite 56 HR: 0.85 (PCSK9 mAb) every 2 weeks or endpoint (0.79–0.92) 420 mg monthly ODYSSEY 34 Alirocumab 75 mg n=18,924 Recent ACS, elevated 2.8 Composite 48 HR: 0.85 (PCSK9 mAb) every 2 weeks LDL-C, non-HDL-C or endpoint (0.78–0.93) apoB ORION-941 Inclisiran 284 mg SC n=482 FH patients on 1.5 1. Percent change 58.7 58.7+ (PCSK9 siRNA) injection on days 1, maximal statin dose from baseline 37.7%++ 90, 270, and 450 with or without LDL-C at day 510 ezetimibe 2. Time-adjusted percent change from baseline LDL-C between days 90 and 540 ORION-10 and Inclisiran 284 mg SC n=3,172 Elevated LDL-C 1.5 1. Percent change 56.2/50.9 52.3/49.9%+ ORION-1142 injection on days 1, despite maximal statin from baseline 53.8%/49.2%++ (PCSK9 siRNA) 90, 270, and 450 dose LDL-C at day 510 2. Time-adjusted percent change from baseline LDL-C between days 90 and 540 CLEAR43 Bempedoic acid n=2,230 CV disease and 1.0 Safety at 1 year 19.2 Higher incidence Harmony 180 mg once daily heterozygous FH on of drug maximal statin dose discontinuation due to adverse events. Higher incidence of gout (1.2% vs. 0.3%) +Outcomes for primary endpoint 1. ++Outcomes for primary endpoint 2. 4S, Scandinavian Simvastatin Survival Study; ACS, acute coronary syndrome; CAD, coronary artery disease; CI, confidence interval; CKD, chronic kidney disease; CLEAR, The Cholesterol Lowering via Bempedoic Acid and ACL‐Inhibiting Regimen; CV, cardiovascular; FH, familial hypercholesterolemia; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; HDL-C, high-density lipoprotein cholesterol; HPS, Heart Protection Study; IMPROVE-IT, The Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; ODYSSEY, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; ORION, Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol; RR, relative risk; SHARP, Study of Heart and Renal Protection; WOSCOPS, West of Scotland Coronary Prevention Study.

CVD.18,19 Statin-induced myalgia is reported in 1.5–3.0% cholesterol (HDL-C) and atherogenic lipoproteins (LDL-C of subjects enrolled for RCTs and 10–13% of participants and TRL cholesterol (TRL-C)) which contain the apolipo- in prospective studies.20 protein B100 molecule (apoB) (Figure 1). Among LDL-C, small dense LDL is characterized as cholesterol-depleted Residual Cholesterol Risk Despite Statin Therapy LDL particles. Lp(a) consists of an LDL-like particle and Although statins have already significantly improved CV apolipoprotein (a) (apo(a)), of which apo(a) specifically outcomes, patients with LDL-C target levels achieved by binds covalently to the apoB of the LDL-like particle. intense statin therapy still have significant remaining CV Because the level of TG significantly correlates with the risk. Therefore, managing the unresolved residual risk is amount of remnant cholesterol in TRLs, the amount of TG the ultimate purpose of treating atherosclerosis and even- may represent the level of remnant cholesterol. Therefore, tually CVD. the level of TG is a biomarker for circulating TRLs and Total cholesterol is composed of high-density lipoprotein their metabolic remnants.6,7 Despite high-intensity statin Advance Publication New Lipid-Lowering Therapies 3

Figure 1. Production of triglyceride-rich lipoproteins (TRLs), remnant cholesterol that induces the formation of atherosclerosis. Because triglyceride (TG) can be degraded by most cells, but cholesterol cannot be degraded by any cell, the cholesterol content of TRLs is more likely to be the cause of atherosclerosis and cardiovascular disease than raised TG concentration per se. Indeed, cholesterol rather than TG accumulates in intimal foam cells and in atherosclerotic plaques, and remnant lipoproteins such as low-density lipoprotein (LDL) can enter the arterial intima. In contrast, chylomicrons are too large to enter. Lipoprotein lipase (LPL) activity at the surface of remnant particles, either at the surface of vascular endothelium or within the intima, leads to liberation of free fatty acids, monoacylglycerols, and other molecules for energy use and storage. Some apoB lipoproteins in LDL and TRLs can become trapped in the artery wall and cause local injury and inflammation. Although other possible mechanisms have been suggested, perhaps the simplest chain of events is that high TG concentrations are a marker for raised TRLs, remnant cholesterol which, upon entering the intima, leads to low-grade inflammation, foam cell formation, atherosclerotic plaques, and ultimately cardiovascular disease and increased mortality. apoB, apolipoprotein B100 molecule; CE, cholesterol ester. CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; VLDL, very low-density lipoprotein. Modified from Han et al and Cho et al.6,7

therapy to lower LDL-C, and more recently, statins with LDL-C or TGs. Of note, targeting TRL-C and non-HDL-C ezetimibe or proprotein convertase subtilisin-kexin type 9 rather than lowering LDL-C to very low concentrations to (PCSK9) inhibitors to further decrease LDL-C levels, a reduce residual CV risk is closely associated with cardio- significant residual risk of CVD still persists.2,4 TRL-C metabolic risk factors.7,8,24,25 may account, at least in part, for this residual cholesterol risk. Recently, increased TRL-C levels were found to be Emerging LDL-C-Lowering Therapies associated with increased CV risk.21–23 Mendelian randomization (MR) studies demonstrated that genetic variants Ezetimibe that mimic LDL-C-lowering therapies and TG-lowering Ezetimibe is the most prescribed LDL-C-lowering agent in therapies were associated with the same reduction in patients with high CV risk or statin intolerance. Ezetimibe ASCVD risk for the same change in apoB concentration, targets the Niemann-Pick C1-like 1 protein, which plays a despite being associated with markedly different changes key role in the absorption of cholesterol from the intestines. in plasma LDL-C or TG concentrations.4 In RCTs, TG- When co-administered with statins, ezetimibe reduces lowering has been associated with a lower risk of major high-sensitivity C-reactive protein (CRP) and LDL-C levels vascular events, even after adjustment for LDL-C-lowering.2 up to 3-fold, compared with statin monotherapy. Thus, the These data strongly suggest that the risk of ASCVD is combination therapy potentiates LDL-C-lowering efficacy determined by the total concentration of circulating apoB while avoiding the adverse effects of high-dose statins. particles regardless of their lipid content, and therefore the The Improved Reduction of Outcomes: Vytorin Efficacy clinical benefit of any lipid-lowering therapy should be International Trial (IMPROVE-IT) showed that adminis- proportional to the absolute achieved reduction in apoB tering ezetimibe to high-risk patients with maximally dosed concentration regardless of the corresponding changes in statin had additional LDL-C lowering effects leading to Advance Publication 4 JANG AY et al. significant CV benefit (Table 1).26 In IMPROVE-IT, the Bempedoic Acid benefit of adding ezetimibe to statin was enhanced in Bempedoic acid, an ATP citrate lyase inhibitor, reduces patients with T2DM.27 Administering ezetimibe on statin LDL-C levels. The Cholesterol Lowering via Bempedoic significantly decreased CRP and insulin levels, increased Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony adiponectin levels and insulin sensitivity, and reduced trial, enrolled 2,230 patients with underlying CVD or visceral fat and blood pressure in patients with hypercho- heterozygous FH who were being treated with maximal lesterolemia, compared with statin alone.28 A recent LDL- statin therapy (Table 1).43 Although bempedoic acid had C-lowering therapy trial with ezetimibe alone prevented proven safety throughout a previous study, the uric acid CV events in individuals aged ≥75 years with elevated levels and the incidence of gout were higher in subjects LDL-C. Nonetheless, given the open-label nature of the treated with bempedoic acid.43–45 As MR analysis of those trial, its premature termination and issues with follow-up, with lifelong genetic variants of the ATP citrate lyases, the magnitude of benefit observed should be interpreted which mimics the effect of bempedoic acid, do not show an with caution.29 Reduction of LDL-C with the combination association between genetic variation and gout, these of statin and ezetimibe safely reduced the incidence of adverse effects are thought to be off-target effects of major atherosclerotic events in a wide range of patients bempedoic acid.45 Further investigation is warranted to with advanced chronic kidney disease.30 The combination delineate the underlying mechanism of such findings. of statin and ezetimibe showed greater coronary plaque regression in patients who underwent percutaneous coro- Emerging Hypertriglyceridemia (TG, TRL-C, 31 nary intervention compared with statin monotherapy. and Non-HDL-C)-Lowering Therapies PCSK9 Monoclonal Antibody and siRNA Peroxisome Proliferator-Activated Receptor α (PPARα) Potent LDL-C-lowering agents such as PCSK9 monoclonal Agonist antibody (mAb) have been recently introduced (Table 1). High TG levels contribute to CVD even when LDL-C is PCSK9 mAb or PCSK9 small interference RNA (siRNA) well controlled.46 Worldwide efforts to abrogate CV events decreases atherogenic lipoproteins levels, particularly in such patients, namely, those with residual CV risk, have LDL-C, through attenuating the degradation of LDL-C been made by modulating non-LDL-C such as TGs, receptors.32 The Further Cardiovascular Outcomes TRL-C or Lp(a).6,7,47,48 Research with PCSK9 Inhibition in Subjects with Elevated The level of TGs significantly correlates with the amount Risk (FOURIER) and Evaluation of Cardiovascular of TRL and remnant cholesterol, which are strongly asso- Outcomes After an Acute Coronary Syndrome During ciated with the risk of CVD.6,7,49 Accordingly, TG- or Treatment With Alirocumab (ODYSSEY OUTCOMES) TRL-lowering strategies have been substantially tested for trials assessed the CV outcomes of PCSK9 mAb, evo- CVD reduction. Although fenofibrates failed to show locumab and alirocumab, respectively, added to optimal significant benefit in those with T2DM in the Fenofibrate statin therapy, and showed that PCSK9 mAb effectively Intervention and Event Lowering in Diabetes (FIELD) reduced LDL-C to extremely low levels.33,34 Both trials also and Action to Control Cardiovascular Risk in Diabetes successfully demonstrated that additive LDL-C lowering (ACCORD) trials, patients with T2DM and high TG translated into significantly augmented CV benefit without showed improved CV outcomes in the post-hoc analysis differences in drug-related side effects compared with the (Table 2).50,51 When fairly reviewed, it is important to statin alone group.33–35 The efficacy and safety of alirocumab acknowledge that none of these trials, selected on the was reported with similar results even in Orientals.36,37 In basis of hypertriglyceridemia and, in each of these trials, patients with a recent acute coronary syndrome event subgroup analyses in patients with hypertriglyceridemia or while on optimal statin therapy, alirocumab improved CV mixed dyslipidemia (high TG and low HDL-C), consistently outcomes at costs considered intermediate value, with showed benefits. The Pemafibrate to Reduce Cardiovascular good value in patients with baseline LDL-C ≥100 mg/dL but Outcomes by Reducing Triglycerides in Patients With less economic value for those with LDL-C <100 mg/dL.38 Diabetes (PROMINENT) study will test pemafibrate, a Inclisiran is a recently developed drug using siRNA potent selective PPARα modulator, as one means to technology that inhibits the production of PCSK9 through resolve this issue.52 neutralizing the messenger RNA of PCSK9 (Table 1).39 In inclisiran, siRNAs are conjugated to a substance called Omega-3 Fatty Acids triantennary N-acetylgalactosamine (GalNAc), designed Clinical trials evaluating the effect of omega-3 fatty acids to deliver the drug specifically to liver cells, the main site of supplements have shown conflicting results among the PCSK9 production. The GalNAc technology maximizes different regimens and doses (Table 2). The first large-scale drug efficacy and reduces side effects. Thus GalNAc clinical trial using omega-3 fatty acids was the Japan confers another strength and durability.40 The effect of the Eicosapentaenoic acid Lipid Intervention Study (JELIS) drug persisted for at least 180 days after initiation of trial. Those randomized to the omega-3 fatty acids group treatment, which enables inclisiran to be administration were given 1,800 mg of eicosapentaenoic acid (EPA) every 3 or 6 months, compared with PCSK9 mAbs, which daily.53 The treatment group showed 19% decrease in are injected every 2 or 4 weeks, although the LDL-C lowering composite CV endpoints, although the results of this trial effects are similar. Inclisiran successfully lowered LDL-C were criticized because the study was open-labelled. levels by 40–50% over a 1.5-year period in subjects with Subsequent RCTs, the Outcome Reduction with an Initial either familial hypercholesterolemia (FH)41 or elevated Glargine Intervention (ORIGIN),54 A Study of Cardio- LDL-C levels without the presence of FH.42 Phase 3 vascular Events in Diabetes (ASCEND),55 and Vitamin D outcome studies are currently underway (ClinicalTrials. and Omega-3 Trial (VITAL) trial,56 administering low gov NCT03705234). doses of EPA and docosahexaenoic acid (DHA), showed conflicting results compared with the JELIS trial. All 3 Advance Publication New Lipid-Lowering Therapies 5

Table 2. Summary of Clinical Trials Targeting the Lowering of TG or TG-Rich Lipoproteins Follow-up Trial name Type of Sample Primary Outcome HR Dose Inclusion duration (phase) drug size endpoint (95% CI) (years) FIELD50 Fenofibrate Fenofibrate 200 mg n=9,795 T2DM/CVD 5 Nonfatal MI or 0.89 (0.75–1.05) (phase 3) daily vs. placebo CAD death ACCORD 51 Fenofibrate Fenofibrate 160 mg n=5,518 T2DM/CVD 4.7 MI stroke or CV 0.92 (0.79–1.08) (phase 3) daily + simvastatin vs. death placebo + simvastatin JELIS53 EPA EPA, 1,800 mg/day n=18,645 Men aged 40–75 4.6 Composite 0.81 (0.69–0.95) (phase 3) years and endpoint postmenopausal women aged up to 75 years ORIGIN54 Ethyl ester Ethyl esters of n-3 n=12,536 At high risk for CV 6.2 CVD death 0.98 (0.87–1.10) (phase 3) fatty acids, 900 mg events and had (≥90% ethyl esters) impaired fasting glucose, impaired glucose tolerance, or diabetes ASCEND55 EPA+DHA 840 mg of marine n-3 n=15,480 Men and women ≥40 7.4 Composite 0.97 (0.87–1.08) (phase 3) fatty acids, 460 mg of years both. Diabetes endpoint EPA + 380 mg of DHA but without evidence of CVD VITAL56 EPA+DHA EPA+DHA, 840 mg; n=25,871 Healthy, no cancer, 5.3 Composite 0.92 (0.80–1.06) (phase 3) 460 mg of EPA+380 mg no CVD, men ≥50 endpoint of DHA years, women ≥55 years REDUCE-IT57 Icosapent- Icosapent-ethyl, 4 g n=8,179 Diabetes or 4.9 Composite 0.75 (0.68–0.83) (phase 3) ethyl established CVD, on endpoint statin with high TG N/A63 ANGPTL3 SAD: evinacumab SC n=83 for TG >150 but 0.5 Incidence and Evinacumab was (phase 1) mAb at 75/150/250 mg, or SAD ≤450 mg/dL and LDL severity of well-tolerated. IV at 5/10/20 mg/kg; study; ≥100 mg/dL treatment- Lipid changes in MAD: SC n=56 for emergency TG were similar to 150/300/450 mg once MAD adverse events those observed weekly, 300/450 mg study with ANGPTL3 every 2 weeks, or IV loss-of-function at 20 mg/kg once a mutations month

N/A61 ANGPTL3 IONIS-ANGPTL3-LRx n=44 TG >90 mg/dL 6 weeks Lipid markers, TG, LDL-C, VLDL (phase 1) ASO 10, 20, 40, or 60 mg safety, and others reduction single or multiple SC injection per week for 6 weeks N/A64 ANGPTL3 Vupanorsen (AKCEA- n=105 T2DM patients with 0.5 Was mean 40 mg Q4W group: (phase 2) ASO ANGPTL3-LRx) hepatic steatosis, percentage change 36% and fasting TG levels in fasting TG from 80 mg Q4W group: >150 mg/dL baseline to 6 53% months 20 mg QW group: 47% N/A 66 APOC3 Volanesorsen n=66 Familial 0.72 Percentage 77% mean TG (phase 3) ASO (ISIS304801) 300 mg chylomicronemia (52 weeks) change in fasting decrease weekly or placebo syndrome TG at 3 months N/A67 APOC3 GalNAc-conjugated n=114 Established CVD or 0.5 Mean percentage 10 mg Q4W group: (phase 2) ASO volanesorsen, 10 mg at high risk for CVD change in fasting 23% Q4W, 15 mg Q2W, with fasting TG levels TG levels from 15 mg Q2W: 56% 10 mg QW, 50 mg between ≥200 and baseline to 6 10 mg QW: 60% Q4W ≤500 mg/dL months 50 mg Q4W: 60% ACCORD, Action to Control Cardiovascular Risk in Diabetes; ANGPTL3, angiopoietin-like 3; ANGPTL4, angiopoietin-like 4; APOC3, apolipoprotein C-III; ASCEND, A Study of Cardiovascular Events in Diabetes; ASO, antisense oligonucleotide; CVD, cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; GalNAc, triantennary N-acetylgalactosamine; JELIS, Japan Eicosapentaenoic acid Lipid Intervention Study; mAb, monoclonal antibody; MAD, multiple ascending dose; NA, not available; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; SAD, single ascending dose; SC, subcutaneous; T2DM, type 2 diabetes mellitus; TG, triglyceride; VITAL, Vitamin D and Omega-3 Trial; VLDL, very low-density lipoprotein. Other abbreviations as listed in Table 1. Advance Publication 6 JANG AY et al.

Figure 2. Lipoprotein lipase (LPL) is central to metabolism of TRLs formation. Angiopoietin-like 3 (ANGPTL3) or 4 (ANGPTL4) is a promising target because ANGPTLs inhibit LPL, which mediates lipolysis of triglycerides in triglyceride-rich lipoproteins (TRLs). Another key regulating protein for TRL metabolism is apolipoprotein C-III (APOC3), a glycoprotein mainly synthesized in the liver. APOC3 regulates TG levels through inhibiting LPL activity and hepatic TRL uptake. GPIHBP1, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1.

trials failed to prove benefits in the primary endpoints. acid (EPANOVA, 75% concentration of EPA and DHA) Recently, the Reduction of Cardiovascular Events with daily therapy as an add-on to statin in high-risk patients Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed with high TG levels and low HDL-C levels. The trial was that high doses (4 g/day) of EPA, icosapent ethyl, was expected to provide insight to 2 important questions: low associated with CV benefit (Table 2). REDUCE-IT studied vs. high dosage and EPA vs. EPA+DHA combination. a total of 8,179 participants with high CV risk among Unfortunately, the trial was terminated in January 2020, whom 71% had established CVD, 29% comprised a primary due to futility (https://www.astrazeneca.com/media-centre/ prevention cohort, and 58% had T2DM (Table 2).57 Base- press-releases/2020/update-on-phase-iii-strength-trial-for- line LDL-C levels were well controlled with statins (median epanova-in-mixed-dyslipidaemia-13012020.html). The value, 75.0 mg/dL), although TG levels were moderately results may suggest that CV benefits are mediated by EPA elevated (median value, 216.0 mg/dL). The primary end- but not DHA. Experimental studies have shown that point occurred in 17.2% and 22% in the EPA and placebo EPA does not raise LDL-C, reduces hsCRP, enhances groups, respectively, while the event rate was significantly endothelial function, inhibits oxidation of apoB particles, reduced by 25%. Interestingly, the benefit was consistent and has effects on membrane stability and cholesterol irrespective of initial TG or LDL-C levels and regardless organization, including crystal formation, unlike DHA.58 of statin use. Additionally, target TG attainment of The EVAPORATE study assessed the effects of EPA on 150 mg/dL did not affect the efficacy of EPA. The recently plaque progression over 9–18 months compared with announced analysis of the REDUCE-IT data suggests that placebo, using serial computerized tomographic angiography the benefit may not have been mediated by the reduction of statin-treated patients with elevated TG levels. Treatment of TG levels, but rather the increased EPA levels after the with EPA 4 g once daily significantly reduced the plaque administration of omega-3 fatty acids (https://www.acc. quantity of multiple plaque components, including low- org/latest-in-cardiology/articles/2020/03/24/16/41/mon- attenuation plaque, compared with placebo.59 1045-eicosapentaenoic-acid-levels-in-reduce-it-acc-2020). The results of these trials bring in to question why Emerging New Therapies for TG Lowering EPA-only regimens had positive results but EPA+DHA regimens did not. The STRENGTH trial (A Long-Term Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are Outcomes Study to Assess STatin Residual Risk Reduction promising targets for CVD reduction. The ANGPTLs With EpaNova in HiGh Cardiovascular Risk PatienTs inhibit lipoprotein lipase (LPL), which mediates lipolysis With Hypertriglyceridemia (https://clinicaltrials.gov/ct2/ of TGs in TRLs (Figure 2).60 Dysfunction of ANGPTLs show/NCT02104817) was planned as a randomized double- may translate into higher levels of TGs, thereby leading to blind, placebo-controlled trial to test 4 g omega-3 carboxylic higher risk of CVD. Accordingly, heterozygous carriers of Advance Publication New Lipid-Lowering Therapies 7

Table 3. Summary of Clinical Trials Targeting the Lowering of Lp(a) Type of Baseline Lp(a) Lp(a) % Type of trial Sample Outcome Intervention concentration reduction Randomized to FOURIER trial: n=27,654 37 nmol/L (median) 26.9% Patients with higher evolocumab (PCSK9 randomized, double- (patients with established baseline Lp(a) had mAb) or placebo SC blind, placebo-controlled CVD, aged 40–85 years) greater absolute injection every 2 or 4 trial (post-hoc analysis) reductions of Lp(a) weeks69 and coronary benefit Randomized to ORION 1 trial: n=501 32.0–47.0 nmol/L 14–26% Interindividual inclisiran (PCSK9 randomized, double- (patients with established (medians of each (not statistically response variability siRNA conjugated to blind, placebo-controlled CV disease or risk dose) significant) of Lp(a) reduction GalNAc) or placebo70 trial, phase 2 trial equivalents, receiving maximal tolerated statin dose) Randomized to IONIS- Randomized, double- n=64 Cohort A Cohort A: 62.8% NA APO(a)Rx [ASO blind, placebo-controlled, (cohort A: Lp(a) of (>80th percentile): vs. placebo targeting apo(a)] or dose-titration, phase 2 125–437 nmol/L, cohort 261.4 nmol/L Cohort B: 67.7% placebo72 trial B: Lp(a) >438 nmol/L) Cohort B vs. placebo (>99th percentile): 457.6 nmol/L Randomized to IONIS- Randomized, double- n=286 224.3 nmol/L 20-mg monthly NA PO(a)-LRx [ASO blind, placebo-controlled, (patients with established (median of pool dose: 35 targeting apo(a) bound dose-ranging phase 2 CVD with Lp(a) population) 20-mg weekly to GalNAc] or placebo73 trial >60 mg/dL [150 nmol/L]) dose: 80 Control: 6 Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9. Other abbreviations as in Tables 1,2.

ANGPTL3 and ANGPTL4 loss-of-function mutations Atherothrombotic and Proinflammatory show a 34% and 19% reduction, respectively, in CAD Traits of Lp(a) incidence (Table 2).61,62 Pharmacological inhibition of these ANGPTLs, including an ANGPTL3 mAb, called Lp(a) consists of apoB covalently bound to apo(a). Lp(a) evinacumab,63 or ANGPTL3 antisense oligonucleotides thus simultaneously inherits the atherogenic properties of (ASOs),61,64 showed similar reduction of TG, LDL-C and apoB within LDL-C, and the thrombotic and proinflam- very low-density lipoprotein levels compared with genetic matory characteristics of apo(a).48 Because Lp(a) is not variants without safety issues. In patients with homozygous an enzyme or a receptor, small molecules are not able to FH receiving maximum doses of lipid-lowering therapy, inactivate its function. Also, Lp(a)-neutralizing mAbs the reduction from baseline in the LDL-C level in the would be needed in massive amounts because Lp(a) exists evinacumab group, as compared with the small increase in in high concentrations. Such high doses would be cumber- the placebo group, resulted in a between-group difference some and cause adverse drug-related reactions.68 of 49% points at 24 weeks.63 Drugs targeting ANGPTL4 may also be a promising candidate for CVD reduction, Difficulty in Reducing CVD by Modest Lowering of Lp(a) because inactivating mutations of ANGPTL4 resulted in Studies evaluating the effect of modulating PCSK9 activity lower TG levels and the risk of CAD than did noncarriers.62 showed modest Lp(a) lowering effects (Table 3). In the Another key regulating protein for TRL metabolism is FOURIER trial, evolocumab reduced Lp(a) by 26.9% apolipoprotein C-III (APOC3), a glycoprotein mainly independently of the baseline LDL-C levels with modest synthesized in the liver. APOC3 regulates TG levels coronary benefit.69 Inclisiran failed to non-significantly through inhibition of LPL activity and hepatic TRL uptake lower Lp(a) concentrations by 14–26% in the Inclisiran for (Figure 2).65 ASO therapy targeting APOC3 has shown Subjects With ASCVD or ASCVD-Risk Equivalents and promising results (Table 2). An APOC3 ASO named Elevated Low-density Lipoprotein Cholesterol (ORION) volanesorsen was administered to 66 subjects with familial 1 trial.70 Other trials with cholesteryl ester transfer protein chylomicronemia syndrome.66 Through a 52-week period, inhibitors, niacins, or ASO targeting apoB protein have APOC3 levels decreased by 84%, with a concurrent 77% also failed to reduce Lp(a) more than 40% without proven decrease in TG levels. However, 61% of patients who CV benefit.48 In order to achieve a clinically relevant extent received volanesorsen had injection-site reactions that may of CVD improvement, a much larger degree of Lp(a) have been caused by the high doses and short intervals.65 reduction may be necessary. MR analyses suggest that As APOC3 is mainly synthesized in the liver, GalNAc clinical benefit may be proportional to the absolute enabled the drug to be delivered with lower doses. reduction in Lp(a) concentration. Reduction of Lp(a) by GalNAc-conjugated volanesorsen was administered to 50 mg/dL and 99 mg/dL had a 20% and 40% decrease of established/high-risk CV patients with high TG levels at CVD, respectively.71 These results warrant development of lower doses and with longer intervals, and effectively novel therapeutics that reduce Lp(a) by 60–100 mg/dL with lowered TG levels without apparently increased injection- proven CVD reduction in contemporary RCTs.48 site side effects.67 These data provide evidence for a causal relationship between APOC3 and TG metabolism. Whether Emerging ASO Therapies for Lp(a) Lowering reducing APOC3 or TG translates to better outcomes is to Recently, 2 clinical trials that used ASO technology for be decided. directly inhibiting apo(a) synthesis reported promising Advance Publication 8 JANG AY et al. results.72 The first trial examined the safety and efficacy of analysis of randomized controlled trials. Circulation 2019; 140: the ASO IONIS-APO(a)Rx (previously ISIS-APO(a)Rx) in 1308 – 1317. subjects with high Lp(a) levels. Subcutaneous injections of 3. Orkaby AR, Driver JA, Ho YL, Lu B, Costa L, Honerlaw J, et al. Association of statin use with all-cause and cardiovascular 100 mg, 200 mg and 300 mg of IONIS-APO(a)Rx were given mortality in US veterans 75 years and older. JAMA 2020; 324: once weekly for 4 weeks at each dose sequentially. Subjects 68 – 78. with 125–437 nmol/L and ≥438 nmol/L showed a 62.8% 4. Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman and 67.7% decrease, respectively, in Lp(a) concentrations MJ, Packard CJ, et al. Association of triglyceride-lowering LPL 72 variants and LDL-C-lowering LDLR variants with risk of compared with the placebo group. coronary heart disease. JAMA 2019; 321: 364 – 373. Despite the Lp(a) lowering by IONIS-APO(a)Rx, frequent 5. Lim S, Park YM, Sakuma I, Koh KK. How to control residual injections and high cumulative doses were necessary for cardiovascular risk despite statin treatment: Focusing on delivering the drug into the hepatocytes where apo(a) HDL-cholesterol. Int J Cardiol 2013; 166: 8 – 14. 6. Han SH, Nicholls SJ, Sakuma I, Zhao D, Koh KK. Hypertri- production mainly occurs. GalNAc-conjugated IONIS- glyceridemia and cardiovascular diseases: Revisited. Korean Circ J APO(a)Rx, named IONIS-APO(a)Rx-LRx, solved this problem. 2016; 46: 135 – 144. The GalNAc-conjugation enhanced the potency by 30-fold 7. Cho KI, Yu J, Hayashi T, Han SH, Koh KK. Strategies to with a mean of 92.49% reduction in Lp(a) concentrations.72 overcome residual risk during statins era. Circ J 2019; 83: 1973 – 1979. Tolerability was also improved, as no adverse reactions 8. Cho KI, Sakuma I, Sohn IS, Hayashi T, Shimada K, Koh KK. were observed. A subsequent randomized, double-blind, Best treatment strategies with statins to maximize the cardio- placebo-controlled, dose-ranging trial was published metabolic benefits. Circ J 2018; 82: 937 – 943. recently, investigating the reduction of Lp(a) levels at 9. Koh KK. Effects of statins on vascular wall: Vasomotor function, 73 inflammation, and plaque stability. Cardiovasc Res 2000; 47: Rx rx different doses and intervals of IONIS-APO(a) -L . 648 – 657. Results showed that Lp(a) levels were reduced in a dose- 10. Koh KK. Effects of HMG-CoA reductase inhibitor on hemostasis. dependent manner, with all tested doses achieving a Int J Cardiol 2000; 76: 23 – 32. significant reduction. The highest cumulative dose (20 mg 11. Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, weekly) reduced Lp(a) by a mean 80%. These trials are the Faergeman G, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian first to target lowering of Lp(a). The ASOs covalently Simvastatin Survival Study (4S). 1994. Atheroscler Suppl 2004; 5: bound to GalNAc enabled the drug to effectively lower 81 – 87. Lp(a) by up to 99% within a tolerable dose. The phase 3 12. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, outcome trials with these agents are currently in progress Macfarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med (ClinicalTrials.gov NCT04023552). 1995; 333: 1301 – 1308. 13. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in Perspectives and Conclusion men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195 – 2207. New therapeutic agents for lowering not only LDL-C but 14. Koh KK, Quon MJ, Han SH, Lee Y, Ahn JY, Kim SJ, et al. TG, TRL, or Lp(a) have shown promising results. Novel Simvastatin improves flow-mediated dilation but reduces adipo- siRNA and ASO technology have opened new doors to nectin levels and insulin sensitivity in hypercholesterolemic effectively reducing the expression of target genes. The patients. Diabetes Care 2008; 31: 776 – 782. 15. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorv- introduction of GalNAc into ASOs has pushed the bound- astatin causes insulin resistance and increases ambient glycemia aries even further for reducing cumulative drug doses by in hypercholesterolemic patients. J Am Coll Cardiol 2010; 55: specifically delivering the drugs to hepatic cells, where the 1209 – 1216. majority of lipid metabolism occurs. Drugs that substan- 16. Cederberg H, Stancakova A, Yaluri N, Modi S, Kuusisto J, tially decrease the LDL-C, TG/TRLs, or Lp(a) profiles Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: using technology such as inclisiran (PCSK9 siRNA), A 6 year follow-up study of the METSIM cohort. Diabetologia GalNAc-conjugated ASO therapies for ANGPTL3 or 4, 2015; 58: 1109 – 1117. APOC3, or Lp(a) may potentially revolutionize the para- 17. Labos C, Brophy JM, Smith GD, Sniderman AD, Thanassoulis digm of lipid-lowering therapy. A breakthrough in tackling G. Evaluation of the pleiotropic effects of statins: A reanalysis of the randomized trial evidence using Egger regression-brief report. the residual cholesterol risk may be imminent. Arterioscler Thromb Vasc Biol 2018; 38: 262 – 265. 18. Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Sources of Funding Willems SM, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: This work was supported by a grant from the Korean Society of A meta-analysis. 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