New Trends in Dyslipidemia Treatment

Abstract

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.

Dyslipidemia is one of the major risk factors for cardiovascular (CV) disease. Many investigators have demonstrated the beneficial effects of statins lowering of low-density lipoprotein cholesterol (LDL-C) on the risk of coronary artery disease (CAD) events in patients with or without CV disease (CVD).^1–4 Despite significant improvement in CV outcomes since the advent of statins, up to 40% of statin-treated patients continue to suffer from life-threatening CV events even when the LDL-C target is achieved by intensive statin treatment; this is termed the ‘residual risk’.^5–7 Here, we review current and emerging therapeutics targeting LDL-C, triglyceride (TG), TG-rich lipoproteins (TRL), and lipoprotein(a) (Lp(a)) in order to reduce the residual cholesterol risk.

Statin Therapy for LDL-C Lowering

Among the various lipoproteins, LDL-C is known for its atherosclerotic traits through accumulating and inducing inflammation in the subendothelial layer.^7,8 Statins have a pleiotropic protective effect against atherosclerotic CVD (ASCVD) through vasodilation, anti-inflammatory, antioxidant, antithrombotic, and plaque-stabilizing effects.^9,10 Major landmark randomized controlled trials (RCTs) have demonstrated the role of statin in lowering LDL-C levels and the associated CV benefit (Table 1).^11–13 The Scandinavian Simvastatin Survival Study (4S) study showed that simvastatin 20–40 mg daily dose reduced all-cause death by 30% through lowering LDL-C up to 68 mg/dL over a 5.4-year period.¹¹ In the West of Scotland Coronary Prevention Study (WOSCOPS) study, daily pravastatin 40 mg treatment attenuated a composite of all-cause death and CAD death by 31% over 4.9 years.¹² These landmark trials and subsequent studies have consistently demonstrated a marked CV benefit, revolutionizing the treatment of CVD. Today, statins are the backbone of all CVD therapy.^7,8

Table 1. Summary of Clinical Trials Targeting the Lowering of LDL-C

Trial name	Drug and dose	Sample size	Inclusion	Duration (years)	Primary endpoint	LDL-C reduction (mg/dL)	Outcome (95% CI)
4S11 (statin)	Simvastatin 20–40 mg daily	n=4,444	Hypercholesterolemia, angina, or previous MI	5.4	All-cause death	68	RR: 0.70 (0.58–0.85)
WOSCOPS12 (statin)	Pravastatin 40 mg daily	n=6,595	Men with hypercholesterolemia	4.9	CAD death or nonfatal MI	41	HR: 0.69 (0.57–0.83)
JUPITER13 (statin)	Rosuvastatin 20 mg daily	n=17,802	Healthy subjects	5	MI, stroke, arterial revascularization, hospitalization for unstable angina, or CV death	50	HR: 0.56 (0.46–0.69)
IMPROVE-IT26 (ezetimibe)	Ezetimibe 10 mg + simvastatin 40 mg vs. simvastatin 40 mg	n=18,144	ACS	6	Composite endpoint	40.6	HR: 0.94 (0.89–0.99)
SHARP30 (ezetimibe)	Ezetimibe 10 mg + simvastatin 20 mg vs. placebo	n=9,270	CKD	4.9	Composite endpoint	30	HR: 0.83 (0.74–0.94)
FOURIER33 (PCSK9 mAb)	Evolocumab 140 mg every 2 weeks or 420 mg monthly	n=27,574	CAD, elevated LDL-C	2.2	Composite endpoint	56	HR: 0.85 (0.79–0.92)
ODYSSEY34 (PCSK9 mAb)	Alirocumab 75 mg every 2 weeks	n=18,924	Recent ACS, elevated LDL-C, non-HDL-C or apoB	2.8	Composite endpoint	48	HR: 0.85 (0.78–0.93)
ORION-941 (PCSK9 siRNA)	Inclisiran 284 mg SC injection on days 1, 90, 270, and 450	n=482	FH patients on maximal statin dose with or without ezetimibe	1.5	1. Percent change from baseline LDL-C at day 510 2. Time-adjusted percent change from baseline LDL-C between days 90 and 540	58.7	58.7+ 37.7%++
ORION-10 and ORION-1142 (PCSK9 siRNA)	Inclisiran 284 mg SC injection on days 1, 90, 270, and 450	n=3,172	Elevated LDL-C despite maximal statin dose	1.5	1. Percent change from baseline LDL-C at day 510 2. Time-adjusted percent change from baseline LDL-C between days 90 and 540	56.2/50.9	52.3/49.9%+ 53.8%/49.2%++
CLEAR43 Harmony	Bempedoic acid 180 mg once daily	n=2,230	CV disease and heterozygous FH on maximal statin dose	1.0	Safety at 1 year	19.2	Higher incidence of drug 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.

Statin-Related Side Effects

The use of statins, however, is often associated with adverse effects such as insulin resistance or myopathy. Statins dose-dependently worsen insulin sensitivity by reducing plasma levels of adiponectin and thus increase the risk of type 2 diabetes (T2DM) in humans.^14–17 Whether the reduced insulin sensitivity is caused by on-target or off-target effects of statins is unclear, but genetic studies have demonstrated that those with LDL-C lowering genetic variants have a higher risk of T2DM despite a reduction of CVD.^18,19 Statin-induced myalgia is reported in 1.5–3.0% of subjects enrolled for RCTs and 10–13% of participants in prospective studies.²⁰

Residual Cholesterol Risk Despite Statin Therapy

Although statins have already significantly improved CV outcomes, patients with LDL-C target levels achieved by intense statin therapy still have significant remaining CV risk. Therefore, managing the unresolved residual risk is the ultimate purpose of treating atherosclerosis and eventually CVD.

Total cholesterol is composed of high-density lipoprotein cholesterol (HDL-C) and atherogenic lipoproteins (LDL-C and TRL cholesterol (TRL-C)) which contain the apolipoprotein B100 molecule (apoB) (Figure 1). Among LDL-C, small dense LDL is characterized as cholesterol-depleted LDL particles. Lp(a) consists of an LDL-like particle and apolipoprotein (a) (apo(a)), of which apo(a) specifically binds covalently to the apoB of the LDL-like particle.

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

Because the level of TG significantly correlates with the amount of remnant cholesterol in TRLs, the amount of TG may represent the level of remnant cholesterol. Therefore, the level of TG is a biomarker for circulating TRLs and their metabolic remnants.^6,7 Despite high-intensity statin therapy to lower LDL-C, and more recently, statins with ezetimibe or proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to further decrease LDL-C levels, a significant residual risk of CVD still persists.^2,4 TRL-C may account, at least in part, for this residual cholesterol risk. Recently, increased TRL-C levels were found to be associated with increased CV risk.^21–23 Mendelian randomization (MR) studies demonstrated that genetic variants that mimic LDL-C-lowering therapies and TG-lowering therapies were associated with the same reduction in ASCVD risk for the same change in apoB concentration, despite being associated with markedly different changes in plasma LDL-C or TG concentrations.⁴ In RCTs, TG-lowering has been associated with a lower risk of major vascular events, even after adjustment for LDL-C-lowering.² These data strongly suggest that the risk of ASCVD is determined by the total concentration of circulating apoB particles regardless of their lipid content, and therefore the clinical benefit of any lipid-lowering therapy should be proportional to the absolute achieved reduction in apoB concentration regardless of the corresponding changes in LDL-C or TGs. Of note, targeting TRL-C and non-HDL-C rather than lowering LDL-C to very low concentrations to reduce residual CV risk is closely associated with cardiometabolic risk factors.^7,8,24,25

Emerging LDL-C-Lowering Therapies

Ezetimibe

Ezetimibe is the most prescribed LDL-C-lowering agent in patients with high CV risk or statin intolerance. Ezetimibe targets the Niemann-Pick C1-like 1 protein, which plays a key role in the absorption of cholesterol from the intestines. When co-administered with statins, ezetimibe reduces high-sensitivity C-reactive protein (CRP) and LDL-C levels up to 3-fold, compared with statin monotherapy. Thus, the combination therapy potentiates LDL-C-lowering efficacy while avoiding the adverse effects of high-dose statins.

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) showed that administering ezetimibe to high-risk patients with maximally dosed statin had additional LDL-C lowering effects leading to significant CV benefit (Table 1).²⁶ In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with T2DM.²⁷ Administering ezetimibe on statin significantly decreased CRP and insulin levels, increased adiponectin levels and insulin sensitivity, and reduced visceral fat and blood pressure in patients with hypercholesterolemia, compared with statin alone.²⁸ A recent LDL-C-lowering therapy trial with ezetimibe alone prevented CV events in individuals aged ≥75 years with elevated LDL-C. Nonetheless, given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution.²⁹ Reduction of LDL-C with the combination of statin and ezetimibe safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.³⁰ The combination of statin and ezetimibe showed greater coronary plaque regression in patients who underwent percutaneous coronary intervention compared with statin monotherapy.³¹

PCSK9 Monoclonal Antibody and siRNA

Potent LDL-C-lowering agents such as PCSK9 monoclonal antibody (mAb) have been recently introduced (Table 1). PCSK9 mAb or PCSK9 small interference RNA (siRNA) decreases atherogenic lipoproteins levels, particularly LDL-C, through attenuating the degradation of LDL-C receptors.³² The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) trials assessed the CV outcomes of PCSK9 mAb, evolocumab and alirocumab, respectively, added to optimal statin therapy, and showed that PCSK9 mAb effectively reduced LDL-C to extremely low levels.^33,34 Both trials also successfully demonstrated that additive LDL-C lowering translated into significantly augmented CV benefit without differences in drug-related side effects compared with the statin alone group.^33–35 The efficacy and safety of alirocumab was reported with similar results even in Orientals.^36,37 In patients with a recent acute coronary syndrome event while on optimal statin therapy, alirocumab improved CV outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dL but less economic value for those with LDL-C <100 mg/dL.³⁸

Inclisiran is a recently developed drug using siRNA technology that inhibits the production of PCSK9 through neutralizing the messenger RNA of PCSK9 (Table 1).³⁹ In inclisiran, siRNAs are conjugated to a substance called triantennary N-acetylgalactosamine (GalNAc), designed to deliver the drug specifically to liver cells, the main site of PCSK9 production. The GalNAc technology maximizes drug efficacy and reduces side effects. Thus GalNAc confers another strength and durability.⁴⁰ The effect of the drug persisted for at least 180 days after initiation of treatment, which enables inclisiran to be administration every 3 or 6 months, compared with PCSK9 mAbs, which are injected every 2 or 4 weeks, although the LDL-C lowering effects are similar. Inclisiran successfully lowered LDL-C levels by 40–50% over a 1.5-year period in subjects with either familial hypercholesterolemia (FH)⁴¹ or elevated LDL-C levels without the presence of FH.⁴² Phase 3 outcome studies are currently underway (ClinicalTrials.gov NCT03705234).

Bempedoic Acid

Bempedoic acid, an ATP citrate lyase inhibitor, reduces LDL-C levels. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial, enrolled 2,230 patients with underlying CVD or heterozygous FH who were being treated with maximal statin therapy (Table 1).⁴³ Although bempedoic acid had proven safety throughout a previous study, the uric acid levels and the incidence of gout were higher in subjects treated with bempedoic acid.^43–45 As MR analysis of those with lifelong genetic variants of the ATP citrate lyases, which mimics the effect of bempedoic acid, do not show an association between genetic variation and gout, these adverse effects are thought to be off-target effects of bempedoic acid.⁴⁵ Further investigation is warranted to delineate the underlying mechanism of such findings.

Emerging Hypertriglyceridemia (TG, TRL-C, and Non-HDL-C)-Lowering Therapies

Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist

High TG levels contribute to CVD even when LDL-C is well controlled.⁴⁶ Worldwide efforts to abrogate CV events in such patients, namely, those with residual CV risk, have been made by modulating non-LDL-C such as TGs, TRL-C or Lp(a).^6,7,47,48

The level of TGs significantly correlates with the amount of TRL and remnant cholesterol, which are strongly associated with the risk of CVD.^6,7,49 Accordingly, TG- or TRL-lowering strategies have been substantially tested for CVD reduction. Although fenofibrates failed to show significant benefit in those with T2DM in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials, patients with T2DM and high TG showed improved CV outcomes in the post-hoc analysis (Table 2).^50,51 When fairly reviewed, it is important to acknowledge that none of these trials, selected on the basis of hypertriglyceridemia and, in each of these trials, subgroup analyses in patients with hypertriglyceridemia or mixed dyslipidemia (high TG and low HDL-C), consistently showed benefits. The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes (PROMINENT) study will test pemafibrate, a potent selective PPARα modulator, as one means to resolve this issue.⁵²

Table 2. Summary of Clinical Trials Targeting the Lowering of TG or TG-Rich Lipoproteins

Trial name (phase)	Type of drug	Dose	Sample size	Inclusion	Follow-up duration (years)	Primary endpoint	Outcome HR (95% CI)
FIELD50 (phase 3)	Fenofibrate	Fenofibrate 200 mg daily vs. placebo	n=9,795	T2DM/CVD	5	Nonfatal MI or CAD death	0.89 (0.75–1.05)
ACCORD51 (phase 3)	Fenofibrate	Fenofibrate 160 mg daily + simvastatin vs. placebo + simvastatin	n=5,518	T2DM/CVD	4.7	MI stroke or CV death	0.92 (0.79–1.08)
JELIS53 (phase 3)	EPA	EPA, 1,800 mg/day	n=18,645	Men aged 40–75 years and postmenopausal women aged up to 75 years	4.6	Composite endpoint	0.81 (0.69–0.95)
ORIGIN54 (phase 3)	Ethyl ester	Ethyl esters of n-3 fatty acids, 900 mg (≥90% ethyl esters)	n=12,536	At high risk for CV events and had impaired fasting glucose, impaired glucose tolerance, or diabetes	6.2	CVD death	0.98 (0.87–1.10)
ASCEND55 (phase 3)	EPA+DHA	840 mg of marine n-3 fatty acids, 460 mg of EPA + 380 mg of DHA	n=15,480	Men and women ≥40 years both. Diabetes but without evidence of CVD	7.4	Composite endpoint	0.97 (0.87–1.08)
VITAL56 (phase 3)	EPA+DHA	EPA+DHA, 840 mg; 460 mg of EPA+380 mg of DHA	n=25,871	Healthy, no cancer, no CVD, men ≥50 years, women ≥55 years	5.3	Composite endpoint	0.92 (0.80–1.06)
REDUCE-IT57 (phase 3)	Icosapent- ethyl	Icosapent-ethyl, 4 g	n=8,179	Diabetes or established CVD, on statin with high TG	4.9	Composite endpoint	0.75 (0.68–0.83)
N/A63 (phase 1)	ANGPTL3 mAb	SAD: evinacumab SC at 75/150/250 mg, or IV at 5/10/20 mg/kg; MAD: SC 150/300/450 mg once weekly, 300/450 mg every 2 weeks, or IV at 20 mg/kg once a month	n=83 for SAD study; n=56 for MAD study	TG >150 but ≤450 mg/dL and LDL ≥100 mg/dL	0.5	Incidence and severity of treatment- emergency adverse events	Evinacumab was well-tolerated. Lipid changes in TG were similar to those observed with ANGPTL3 loss-of-function mutations
N/A61 (phase 1)	ANGPTL3 ASO	IONIS-ANGPTL3-LRx 10, 20, 40, or 60 mg single or multiple SC injection per week for 6 weeks	n=44	TG >90 mg/dL	6 weeks	Lipid markers, safety, and others	TG, LDL-C, VLDL reduction
N/A64 (phase 2)	ANGPTL3 ASO	Vupanorsen (AKCEA- ANGPTL3-LRx)	n=105	T2DM patients with hepatic steatosis, and fasting TG levels >150 mg/dL	0.5	Was mean percentage change in fasting TG from baseline to 6 months	40 mg Q4W group: 36% 80 mg Q4W group: 53% 20 mg QW group: 47%
N/A66 (phase 3)	APOC3 ASO	Volanesorsen (ISIS304801) 300 mg weekly or placebo	n=66	Familial chylomicronemia syndrome	0.72 (52 weeks)	Percentage change in fasting TG at 3 months	77% mean TG decrease
N/A67 (phase 2)	APOC3 ASO	GalNAc-conjugated volanesorsen, 10 mg Q4W, 15 mg Q2W, 10 mg QW, 50 mg Q4W	n=114	Established CVD or at high risk for CVD with fasting TG levels between ≥200 and ≤500 mg/dL	0.5	Mean percentage change in fasting TG levels from baseline to 6 months	10 mg Q4W group: 23% 15 mg Q2W: 56% 10 mg QW: 60% 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.

Omega-3 Fatty Acids

Clinical trials evaluating the effect of omega-3 fatty acids supplements have shown conflicting results among the different regimens and doses (Table 2). The first large-scale clinical trial using omega-3 fatty acids was the Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS) trial. Those randomized to the omega-3 fatty acids group were given 1,800 mg of eicosapentaenoic acid (EPA) daily.⁵³ The treatment group showed 19% decrease in composite CV endpoints, although the results of this trial were criticized because the study was open-labelled. Subsequent RCTs, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN),⁵⁴ A Study of Cardiovascular Events in Diabetes (ASCEND),⁵⁵ and Vitamin D and Omega-3 Trial (VITAL) trial,⁵⁶ administering low doses of EPA and docosahexaenoic acid (DHA), showed conflicting results compared with the JELIS trial. All 3 trials failed to prove benefits in the primary endpoints.

Recently, the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that high doses (4 g/day) of EPA, icosapent ethyl, was associated with CV benefit (Table 2). REDUCE-IT studied a total of 8,179 participants with high CV risk among whom 71% had established CVD, 29% comprised a primary prevention cohort, and 58% had T2DM (Table 2).⁵⁷ Baseline LDL-C levels were well controlled with statins (median value, 75.0 mg/dL), although TG levels were moderately elevated (median value, 216.0 mg/dL). The primary endpoint occurred in 17.2% and 22% in the EPA and placebo groups, respectively, while the event rate was significantly reduced by 25%. Interestingly, the benefit was consistent irrespective of initial TG or LDL-C levels and regardless of statin use. Additionally, target TG attainment of 150 mg/dL did not affect the efficacy of EPA. The recently announced analysis of the REDUCE-IT data suggests that the benefit may not have been mediated by the reduction of TG levels, but rather the increased EPA levels after the administration of omega-3 fatty acids (https://www.acc.org/latest-in-cardiology/articles/2020/03/24/16/41/mon-1045-eicosapentaenoic-acid-levels-in-reduce-it-acc-2020).

The results of these trials bring in to question why EPA-only regimens had positive results but EPA+DHA regimens did not. The STRENGTH trial (A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia (https://clinicaltrials.gov/ct2/show/NCT02104817) was planned as a randomized double-blind, placebo-controlled trial to test 4 g omega-3 carboxylic acid (EPANOVA, 75% concentration of EPA and DHA) daily therapy as an add-on to statin in high-risk patients with high TG levels and low HDL-C levels. The trial was expected to provide insight to 2 important questions: low vs. high dosage and EPA vs. EPA+DHA combination. Unfortunately, the trial was terminated in January 2020, due to futility (https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html). The results may suggest that CV benefits are mediated by EPA but not DHA. Experimental studies have shown that EPA does not raise LDL-C, reduces hsCRP, enhances endothelial function, inhibits oxidation of apoB particles, and has effects on membrane stability and cholesterol organization, including crystal formation, unlike DHA.⁵⁸ The EVAPORATE study assessed the effects of EPA on plaque progression over 9–18 months compared with placebo, using serial computerized tomographic angiography of statin-treated patients with elevated TG levels. Treatment with EPA 4 g once daily significantly reduced the plaque quantity of multiple plaque components, including low-attenuation plaque, compared with placebo.⁵⁹

Emerging New Therapies for TG Lowering

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are promising targets for CVD reduction. The ANGPTLs inhibit lipoprotein lipase (LPL), which mediates lipolysis of TGs in TRLs (Figure 2).⁶⁰ Dysfunction of ANGPTLs may translate into higher levels of TGs, thereby leading to higher risk of CVD. Accordingly, heterozygous carriers of ANGPTL3 and ANGPTL4 loss-of-function mutations show a 34% and 19% reduction, respectively, in CAD incidence (Table 2).^61,62 Pharmacological inhibition of these ANGPTLs, including an ANGPTL3 mAb, called evinacumab,⁶³ or ANGPTL3 antisense oligonucleotides (ASOs),^61,64 showed similar reduction of TG, LDL-C and very low-density lipoprotein levels compared with genetic variants without safety issues. In patients with homozygous FH receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL-C level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49% points at 24 weeks.⁶³ Drugs targeting ANGPTL4 may also be a promising candidate for CVD reduction, because inactivating mutations of ANGPTL4 resulted in lower TG levels and the risk of CAD than did noncarriers.⁶²

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.

Another key regulating protein for TRL metabolism is apolipoprotein C-III (APOC3), a glycoprotein mainly synthesized in the liver. APOC3 regulates TG levels through inhibition of LPL activity and hepatic TRL uptake (Figure 2).⁶⁵ ASO therapy targeting APOC3 has shown promising results (Table 2). An APOC3 ASO named volanesorsen was administered to 66 subjects with familial chylomicronemia syndrome.⁶⁶ Through a 52-week period, APOC3 levels decreased by 84%, with a concurrent 77% decrease in TG levels. However, 61% of patients who received volanesorsen had injection-site reactions that may have been caused by the high doses and short intervals.⁶⁵ As APOC3 is mainly synthesized in the liver, GalNAc enabled the drug to be delivered with lower doses. GalNAc-conjugated volanesorsen was administered to established/high-risk CV patients with high TG levels at lower doses and with longer intervals, and effectively lowered TG levels without apparently increased injection-site side effects.⁶⁷ These data provide evidence for a causal relationship between APOC3 and TG metabolism. Whether reducing APOC3 or TG translates to better outcomes is to be decided.

Atherothrombotic and Proinflammatory Traits of Lp(a)

Lp(a) consists of apoB covalently bound to apo(a). Lp(a) thus simultaneously inherits the atherogenic properties of apoB within LDL-C, and the thrombotic and proinflammatory characteristics of apo(a).⁴⁸ Because Lp(a) is not an enzyme or a receptor, small molecules are not able to inactivate its function. Also, Lp(a)-neutralizing mAbs would be needed in massive amounts because Lp(a) exists in high concentrations. Such high doses would be cumbersome and cause adverse drug-related reactions.⁶⁸

Difficulty in Reducing CVD by Modest Lowering of Lp(a)

Studies evaluating the effect of modulating PCSK9 activity showed modest Lp(a) lowering effects (Table 3). In the FOURIER trial, evolocumab reduced Lp(a) by 26.9% independently of the baseline LDL-C levels with modest coronary benefit.⁶⁹ Inclisiran failed to non-significantly lower Lp(a) concentrations by 14–26% in the Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol (ORION) 1 trial.⁷⁰ Other trials with cholesteryl ester transfer protein inhibitors, niacins, or ASO targeting apoB protein have also failed to reduce Lp(a) more than 40% without proven CV benefit.⁴⁸ In order to achieve a clinically relevant extent of CVD improvement, a much larger degree of Lp(a) reduction may be necessary. MR analyses suggest that clinical benefit may be proportional to the absolute reduction in Lp(a) concentration. Reduction of Lp(a) by 50 mg/dL and 99 mg/dL had a 20% and 40% decrease of CVD, respectively.⁷¹ These results warrant development of novel therapeutics that reduce Lp(a) by 60–100 mg/dL with proven CVD reduction in contemporary RCTs.⁴⁸

Table 3. Summary of Clinical Trials Targeting the Lowering of Lp(a)

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

Lp(a), lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9. Other abbreviations as in Tables 1,2.

Emerging ASO Therapies for Lp(a) Lowering

Recently, 2 clinical trials that used ASO technology for directly inhibiting apo(a) synthesis reported promising results.⁷² The first trial examined the safety and efficacy of the ASO IONIS-APO(a)_Rx (previously ISIS-APO(a)_Rx) in subjects with high Lp(a) levels. Subcutaneous injections of 100 mg, 200 mg and 300 mg of IONIS-APO(a)_Rx were given once weekly for 4 weeks at each dose sequentially. Subjects with 125–437 nmol/L and ≥438 nmol/L showed a 62.8% and 67.7% decrease, respectively, in Lp(a) concentrations compared with the placebo group.⁷²

Despite the Lp(a) lowering by IONIS-APO(a)_Rx, frequent injections and high cumulative doses were necessary for delivering the drug into the hepatocytes where apo(a) production mainly occurs. GalNAc-conjugated IONIS-APO(a)_Rx, named IONIS-APO(a)_Rx-L_Rx, solved this problem. The GalNAc-conjugation enhanced the potency by 30-fold with a mean of 92.49% reduction in Lp(a) concentrations.⁷² Tolerability was also improved, as no adverse reactions were observed. A subsequent randomized, double-blind, placebo-controlled, dose-ranging trial was published recently, investigating the reduction of Lp(a) levels at different doses and intervals of IONIS-APO(a)_Rx-L_rx.⁷³ Results showed that Lp(a) levels were reduced in a dose-dependent manner, with all tested doses achieving a significant reduction. The highest cumulative dose (20 mg weekly) reduced Lp(a) by a mean 80%. These trials are the first to target lowering of Lp(a). The ASOs covalently bound to GalNAc enabled the drug to effectively lower Lp(a) by up to 99% within a tolerable dose. The phase 3 outcome trials with these agents are currently in progress (ClinicalTrials.gov NCT04023552).

Perspectives and Conclusion

New therapeutic agents for lowering not only LDL-C but TG, TRL, or Lp(a) have shown promising results. Novel siRNA and ASO technology have opened new doors to effectively reducing the expression of target genes. The introduction of GalNAc into ASOs has pushed the boundaries even further for reducing cumulative drug doses by specifically delivering the drugs to hepatic cells, where the majority of lipid metabolism occurs. Drugs that substantially decrease the LDL-C, TG/TRLs, or Lp(a) profiles using technology such as inclisiran (PCSK9 siRNA), GalNAc-conjugated ASO therapies for ANGPTL3 or 4, APOC3, or Lp(a) may potentially revolutionize the paradigm of lipid-lowering therapy. A breakthrough in tackling the residual cholesterol risk may be imminent.

Sources of Funding

This work was supported by a grant from the Korean Society of CardioMetabolic Syndrome.

Disclosures

Dr. Koh holds a certificate of patent, 10-1579656 (pravastatin+valsartan), and is an International Associate Editor of Circulation Journal.

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