New Approaches to Lipoproteins for the Prevention of Cardiovascular Events

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, and recent research has underscored the critical role of lipoproteins in modulating cardiovascular (CV) risk. Elevated low-density lipoprotein cholesterol (LDL-C) levels have been linked to increased CV events, and while numerous trials have confirmed the efficacy of lipid-lowering therapies (LLT), significant gaps remain between recommended LDL-C targets and real-world clinical practice. This review addresses care gaps in LLT, emphasizing the necessity for innovative approaches that extend beyond LDL-C management. It explores combination therapy approaches such as statins combined with ezetimibe or PCSK9 inhibitors, which have shown promise in enhancing LDL-C reduction and improving outcomes in high-risk patients. Additionally, this review discusses new approaches in lipid modification strategies, including bempedoic acid, inclisiran, and drugs that lower Lp(a), highlighting their potential for CV risk reduction. Furthermore, it emphasizes the potential of polygenic risk scores to guide LLT and lifestyle changes despite challenges in implementation and genetic testing ethics. This article discusses the current guidelines and proposes innovative approaches for optimizing lipoprotein management, ultimately contributing to improved patient outcomes in ASCVD prevention.

Abbreviations: ACC: American College of Cardiology, ACS: acute coronary syndrome, AHA: American Heart Association, AMI: acute myocardial infarction, apoA-I: apolipoprotein A-I, ASCVD: atherosclerotic cardiovascular disease, ASO: antisense oligonucleotides, CAD: coronary artery disease, CV: cardiovascular, EAS: European Atherosclerosis Society, ESC: European Society of Cardiology, FH: familial hypercholesterolemia, JAS: Japan Atherosclerosis Society, LDL-C: low-density lipoprotein cholesterol, LLT: lipid-lowering therapy, Lp(a): lipoprotein(a), MI: myocardial infarction, NSTEMI: non-ST-elevation myocardial infarction, PCI: percutaneous coronary intervention, PCSK9: proprotein convertase subtilisin/kexin type 9, PRS: Polygene risk scores, siRNA: small interfering RNA, STEMI: ST-elevation myocardial infarction, TG: triglycerides

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death worldwide ^{1 , 2)} . Since the Framingham Study revealed the detrimental impact of elevated total cholesterol on cardiovascular (CV) events ³⁾ , numerous trials have demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) levels through pharmacological interventions, including statins, effectively reduces the risk of CV events ^{4 , 5)} . Clinical practice guidelines have been developed based on this evidence, but it has been reported that there is a gap between target LDL-C levels and their achievement in real-world clinical practice ^{6 - 8)} . However, it remains unclear whether pharmacological interventions targeting lipids other than LDL-C can prevent CV events. Consequently, various new approaches are being evaluated to determine how and with which drugs LDL-C should be achieved as well as potential interventions targeting factors beyond LDL-C.

This review investigates gaps in lipid-lowering therapy (LLT) and tactics to address them. It further discusses how and with which drugs LDL-C should be lowered, the need for interventions targeting lipid profiles beyond LDL-C, and the importance of personalized medicine. This article aims to question the current state of the guidelines and contribute to the development of more effective treatment strategies.

Care Gaps in Lipid-lowering Therapy

The care gap refers to the difference between the recommended care indicated by clinical practice guidelines derived from high-quality evidence-based randomized clinical trials and the care actually provided in everyday practice ⁶⁾ . Table 1 presents guidelines and statements for lipid management in various countries and regions. The DA VINCI study ⁷⁾ is a cross-sectional observational study conducted in 18 European countries that investigated patients prescribed LLT for primary and secondary prevention. Based on data collected between June 2017 and November 2018, the study evaluated the LDL-C target achievement rate according to the 2019 guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) ⁴⁾ and found that 33% of the patients achieved the LDL-C goal. The use of high-intensity statin monotherapy in very high-risk patients was low, with only 17% achieving the 2019 goals for primary prevention, and 22% for secondary prevention. One in three patients achieved the LDL-C goal, whereas in Poland, Central Europe, and Eastern Europe, only one in four patients met the goal. The results of the SANTORINI study conducted in Europe between 2020 and 2021 also indicate that the situation has not improved ⁹⁾ . The EXPLORE-J study was a two-year multicenter observational study involving 1,944 Japanese patients with acute coronary syndrome (ACS) (mean age 66 years, 80.3% male) that assessed the current state of lipid management ⁸⁾ . In patients with ACS, the average LDL-C level decreased from 121.3 mg/dL at baseline measurement to 79.8 mg/dL after two years. However, the proportion of patients reaching the target LDL-C level of less than 70 mg/dL, as recommended by the Japan Atherosclerosis Society (JAS), increased only from 14.4% to 34.6% ¹⁰⁾ . In a Canadian study investigating CV events after percutaneous coronary intervention (PCI) ¹¹⁾ , only 57% of patients achieved LDL-C levels below the recommended target of less than 70 mg/dL, as outlined by the Canadian Cardiovascular Society (CCS) guidelines ¹²⁾ . Nelson et al. analyzed a cohort of 601,934 patients with ASCVD in the United States, revealing that 49.9% did not use statins, 22.5% were on high-intensity statins, and 27.6% were using other low-to moderate-intensity statins, highlighting significant gaps in care ¹³⁾ . Furthermore, in an analysis of primary and secondary prevention of ASCVD within the National Analysis of the Veterans Health Administration, low levels of LDL-C control have been demonstrated ¹⁴⁾ . The study concluded with a call for “the need for updated performance measures in ASCVD prevention to achieve LDL-C control.” Nonetheless, the current achievement rates for LDL-C targets, which are recommended in many countries, still remain insufficient and present an urgent issue.

Table 1. Guidelines or consensus statements for the management of blood cholesterol.

Guideline	Year	Tactics	Target goal of LDL-C levels	First-line therapy	Patient population
ACC/AHA 15)	2013	Minimal follow-up required	not applicable	High-intensity statin	≤ 75 years of age who have clinical ASCVD
Multisociety 5)	2018	Treat-to-target	＜70 mg/dL	High-intensity statin	Very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions
ESC/EAS 4)	2019	Treat-to-target	＜55 mg/dL	High-intensity statin	Very-high-risk includes a history of ASCVD or FH
		Treat-to-target	＜40 mg/dL	High-intensity statin	≥ 2 events within 2 years
CCS 12)	2021	Treat-to-target	＜70 mg/dL	High-intensity statin	Clinical ASCVD
ACC 97)	2022	Treat-to-target	＜55 mg/dL	High-intensity statin	Very-high-risk: same as 2018 5)
ACVC/EAPC 18)	2022	Strike early and strike strong	not applicable	Combination therapy with statin and ezetimibe (polypill if possible)	Patients with ACS
ESC 17)	2023	Treat-to-target	＜55 mg/dL	High-intensity statin	Patients with ACS
JAS 10)	2024	Treat-to-target	＜70 mg/dL	High-intensity statin	Patients with ACS, FH, DM, or CAD combined with atherothrombotic cerebral infarction.

ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CCS, Canadian Cardiovascular Society; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; FH, familial hypercholesterolemia; JAS, Japanese Atherosclerosis Society; DM, diabetes mellitus; CAD, coronary artery disease; ACS, acute coronary syndrome; ACVC, Asian Congress of Vascular Disease; EAPC, European Association of Preventive Cardiology.

“Minimal Follow-up Required” and “Treat-to-target”

The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines on the treatment of blood cholesterol to reduce CV risk ¹⁵⁾ recommends that “high-intensity statin therapy should be initiated or continued as first-line therapy for those with clinical ASCVD.” This guideline was based on trials comparing statins of varying intensities, and did not establish specific targets for LDL-C, which may be reasonable. This “minimal follow-up required” tactic, known as “fire-and-forget,” which involves minimal follow-up after initiating treatment, allowing for simplicity and potentially improved patient compliance. However, because the treatment responses and side effects can vary, periodic monitoring may still be necessary, and not all patients may achieve optimal lipid control with this tactic, necessitating careful patient selection. Conversely, the “treat-to-target” tactic for LLT involves setting specific treatment goals and adjusting therapy accordingly. This tactic may more effectively suppress atherosclerosis progression and allow flexible treatment tailored to the patient’s risk profile, making it particularly beneficial for high-risk patients. The latest ESC/EAS and ACC/AHA guidelines have adopted a “treat-to-target” tactic ( Table 1 ) . The ESC/EAS guidelines ⁴⁾ recommend that for secondary prevention in very high-risk patients, an LDL-C reduction of ≥ 50% from baseline, along with an LDL-C goal of ＜55 mg/dL, should be achieved.

The LODESTAR trial was presented at the 2023 ACC Annual Scientific Session, randomizing patients with coronary artery disease (CAD) into these two tactics with 4,400 participants ¹⁶⁾ . The primary outcome of major adverse CV and cerebrovascular events, which included all-cause death, myocardial infarction (MI), stroke, and any coronary revascularization, at the 3-year follow-up showed rates of 8.1% in the treat-to-target group compared with 8.7% in the high-intensity statin group (p＜0.001 for non-inferiority). Notably, only 60% of patients in the treat-to-target group in this trial achieved the LDL-C target level, highlighting the need for more robust LLT in treat-to-target tactics. Building on the recommendations of the 2019 guidelines ⁴⁾ , which advocated a stepwise approach for LLT in secondary prevention, starting with high-intensity statins, followed by the addition of ezetimibe after 4 to 6 weeks if the LDL-C target is not reached, and escalation to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors if treatment goals remain unmet after another 4 to 6 weeks, the 2023 guidelines for the treatment of ACS continue to endorse this stepwise approach (Class I) ¹⁷⁾ .

Combination Therapy for High-risk Patients

The 2022 Clinical Consensus Statement from the Association for Acute Cardiovascular Care introduced a new treatment strategy termed “strike early and strike strong” ¹⁸⁾ . Compared with statin monotherapy, the combination therapy of statins with either ezetimibe ¹⁹⁾ or PCSK9 inhibitors ²⁰⁾ reduces LDL-C levels and improves outcomes in preventing CV events. The HUYGENS trial demonstrated that plaque stabilization and regression were achieved through combination therapy with evolocumab in statin-treated patients following non-ST-elevation myocardial infarction (NSTEMI) ²¹⁾ . An increasing number of reports suggest that combination therapy in post-ACS patients can “strike early, strike strong,” and achieve rapid and significant reductions in LDL-C levels ^{22 - 26)} . Makhmudova U et al. achieved the recommended LDL-C targets in all patients with ST-elevation myocardial infarction (STEMI) ²⁷⁾ . Early combination therapy with high-dose atorvastatin and ezetimibe was initiated. The follow-up treatment was escalated with bempedoic acid and PCSK9 to achieve the recommended LDL-C targets. The study showed that 80% of the patients reached the LDL-C target with the initial combination therapy, and by adding either bempedoic acid or PCSK9 inhibitors, all patients achieved LDL-C levels below 55 mg/dL. The EVOPACS trial evaluated the feasibility, safety, and LDL-C lowering effect of evolocumab initiated during the inpatient phase of ACS ²⁸⁾ . In 308 patients with ACS, the administration of evolocumab in the hospital demonstrated the efficacy of PCSK9 inhibitors in achieving the recommended target levels after 8 weeks. Patients treated with evolocumab added to high-intensity statins achieved the target levels compared to the placebo group, ((LDL-C ＜70 mg/dL: 95.7% vs. 37.6%, p＜0.001; LDL-C ＜55 mg/dL: 90.1% vs. 10.7%, p=NA) with no concerns regarding adverse events between the two groups.

The AMUNDSEN trial (ClinicalTrials.gov Identifier: NCT04951856) is an ongoing trial that randomizes 2,166 patients diagnosed with STEMI or NSTEMI who are eligible for PCI to receive evolocumab prior to the procedure, with the aim of evaluating LDL-C reduction at 12 months as the primary endpoint and CV events as the secondary endpoint, with a completion target set for 2027. Additionally, the EVOLVE-MI trial (NCT05284747) will test the effect of adding evolocumab to the standard treatment for major CV events in 6,000 hospitalized patients after AMI, with a planned completion in 2027.

Recent Advances in Lipid Modification to Prevent Cardiovascular Events

The ESC/EAS 2019 guidelines refer to new approaches ⁴⁾ , with anticipated clinical trial results recently reported. We describe clinical research evidence to date, particularly focusing on drugs with promising recent reports ²⁹⁾ .

Drugs Lowering LDL-C

As a treatment that has demonstrated the ability to lower both LDL-C and the risk of CV events, bempedoic acid has recently established its causal relationship through the CLEAR Outcomes trial, which enrolled patients with statin intolerance ³⁰⁾ , which enrolled patients with statin intolerance. Furthermore, although it has not been conclusively shown to reduce the risk of CV events, this section reviews new therapies aimed at lowering LDL-C levels.

Bempedoic Acid

Bempedoic acid is a small oral molecule that inhibits cholesterol synthesis by blocking the action of ATP citrate lyase, a cytosolic enzyme, upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase. After confirming the safety of benzoic acid in 2019 ³¹⁾ , it became available in some countries, and the CLEAR Outcomes trial was presented in the 2023 ACC Annual Scientific Session ³⁰⁾ . This study was conducted as a double-blind, randomized controlled trial targeting patients who were statin-intolerant (those unable or unwilling to take statins owing to side effects). These patients had ASCVD or were at high risk for ASCVD, and 13,970 patients received either 180 mg/day bempedoic acid or placebo. The baseline mean LDL-C level was 139.0 mg/dL in both groups. At 6 months, the bempedoic acid group showed a greater reduction in LDL-C compared to the placebo group by 29.2 mg/dL, resulting in a relative reduction rate difference of 21.1 percentage points. Over a follow-up period of 40.6 months, the incidence of the primary composite endpoint, which included CV death, non-fatal MI, non-fatal stroke, and coronary revascularization, was significantly lower in the bempedoic acid group (11.7% vs. 13.3%; hazard ratio 0.87, 95% confidence interval 0.79–0.96, p=0.004). In a sub-analysis ³²⁾ , patients without diabetes showed no increase in the incidence of newly diagnosed diabetes or deterioration in HbA1c levels. A meta-analysis identified 11 trials without the CLEAR Outcomes trial, analyzing a total of 4,391 participants ³³⁾ . The use of bempedoic acid was associated with a reduction in the composite CV outcomes (risk ratio 0.75, 95% CI 0.56–0.99). Bempedoic acid significantly lowered LDL-C levels (mean difference [MD] -22.91, 95% CI -27.35 to -18.47) and reduced CRP levels (MD -24.70, 95% CI -32.10 to -17.30). Additionally, bempedoic acid was associated with a decrease in the incidence of new-onset or worsening diabetes (risk ratio 0.65, 95% CI 0.44–0.96). In combination therapy, injectable medications for PCSK9 inhibitors and their costs pose significant barriers. Polypills may improve compliance ³⁴⁾ . Therefore, there is a need for further clinical research on the combination therapy of bempedoic acid and statins ³⁵⁾ .

Inclisiran

Inclisiran uses RNA interference (RNAi) technology to target PCSK9 mRNA, thereby inhibiting the production of PCSK9 protein, which allows the liver to more effectively decrease LDL-C ³⁶⁾ . This mechanism provides sustained effects over a longer period than other therapies, with dosing required only every six months, making it particularly beneficial for patients with adherence difficulties. Inclisiran’s phase I trial was published in 2017 ³⁷⁾ , and subsequent ORION trial series demonstrated significant LDL-C reductions across various patient groups, and long-term safety was also confirmed ( Table 2 ) . In the ORION-9, -10, and -11 trials, LDL-C reductions of over 50% were achieved in patients with familial hypercholesterolemia (FH) or at a high risk of ASCVDs. These effects were sustained over a long period, and a meta-analysis confirmed a reduction in CV risk ³⁸⁾ . The ORION-15 study, a phase 2 clinical trial, included 312 Japanese patients with elevated LDL cholesterol and high CV risk, including individuals with heterozygous FH ³⁹⁾ . The trial demonstrated that inclisiran at doses of 100, 200, and 300 mg led to significant reductions in both LDL-C levels by day 180, with the largest decrease observed in the 300 mg group (LDL-C: 65.3%). More than 86% of the patients treated with inclisiran met the lipid management goals set by the JAS ¹⁰⁾ . Adverse events were comparable between the inclisiran and placebo groups, thus indicating the efficacy of the treatment and good tolerability over the 12-month period.

Table 2. Previous and ongoing trials of inclisiran.

First Author (Year) (Ref #)	Participant number	Population	Development stage	Key findings
Fitzgerald et al. (2017) 37)	69 (a single-ascending- dose phase or a multiple-dose phase, with or without concurrent statin therapy)	Participants without a history of ASCVD or diabetes who had a serum LDLC level of at least 100 mg/dL and a fasting triglyceride level of less than 400 mg/dL	Phase 1	In the single-dose phase, inclisiran doses of 100 mg or more reduced the LDL-C level (up to a LS mean reduction of 50.6% from baseline). Reductions in the level of LDL-C was maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the level of LDL-C (up to a LS mean reduction of 59.7% from baseline to day 84).
Ray et al. (2017) 98)	501 (a single or two dose)	Participants with LDL-C levels of at least 70 mg/dL for those with a history of ASCVD, or at least 100 mg/dL for those without a history of ASCVD	Phase 2	The ORION-1 trial showed the LS mean reductions in LDL-C levels at day 180 were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses. At day 240, LDL-C levels remained significantly lower than at baseline in association with all inclisiran regimens.
Raal et al. (2020) 99)	482	Patients with heterozygous FH	Phase 3	The ORION-9 trial showed that incrysilan reduced LDL-C by an average of 47.9% (95% CI: 50.5% - 45.3%) compared with placebo.
Ray et al. (2020) 100)	1,561 (The ORION- 10), 1,617 (The ORION-11)	The ORION-10 (U.S.) and ORION-11 trial (Europe and South Africa) included adults with ASCVD whose LDL-C levels were more than 70 mg/dL (1.8 nmol/L).	Phase 3	In the ORION-10 and ORION- 11 trial, Lp(a) had median baseline values of 57 and 42 (nmol/L), respectively, and decreased by 21.9% and 18.6%.
Ray et al. (2022) 38)	3660	The ORION-9, -10, and 11 trial pooled.	Phase 3	Inclisiran significantly reduced MACE included non-adjudicated CV death, cardiac arrest, non-fatal MI, and fatal and non-fatal stroke.
Yamashita et al. (2024) 39)	312	Japanese patients with high CV risk and elevated LDL-C (including heterozygous FH)	Phase 2	Inclisiran (100, 200, 300 mg) significantly reduced LDL-C by Day 180 (p＜0.0001). The 300 mg dose showed the greatest reductions (LDL-C: 65.3%). Over 86% of patients on inclisiran achieved the JAS’s 2017 lipid management targets.
Ongoing	16,124 (Inclisiran 300mg sc or a placebo)	Patients with a history of MI, ischemic stroke or PAD as evident by prior lower extremity artery revascularization or aortic aneurysm repair	Phase 3	The ORION-4 trial expected completion in July 2026.
Ongoing	345 (Inclisiran 300mg sc or a placebo)	Asian patients with ASCVD and LDL-C ≥ 70 mg/dL, or ASCVD high risk and LDL-C ≥ 100 mg/ dL)	Phase 3	The ORION-18 trial expected completion in December 2026.

ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CV, cardiovascular; FH, familial hypercholesterolemia; JAS, Japanese Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LS, least squares; MACE, major adverse cardiovascular events; MI, myocardial infarction; PAD, peripheral artery disease.

Inclisiran holds great promise as a novel approach that complements traditional therapies for ASCVD prevention and management. The ongoing ORION-4 trial is currently evaluating its potential in reducing the risk of CV events. This phase 3 trial, which is double-blind, randomized, and placebo-controlled (NCT03705234), aimed to assess the effects of inclisiran on clinical outcomes in patients with ASCVD. The trial began in October 2018 with an estimated primary completion date of July 2026. Conducted at approximately 180 clinical sites in the UK and USA, the study will enroll approximately 16,124 participants with pre-existing ASCVD. Participants will be randomized in a 1:1 ratio to receive either 300 mg of inclisiran or a matching placebo via subcutaneous injection administered on the day of randomization, at 3 months, and then every 6 months. The primary endpoint was a composite of events, including coronary heart disease death, MI, fatal or non-fatal ischemic stroke, or urgent coronary revascularization during the 5-year follow-up period. The VICTORION-INCEPTION trial (NCT04873934) aimed to target patients with persistently high LDL-C levels (＞70 mg/dL) within five weeks post-ACS, despite statin therapy, enrolling 400 patients to assess the efficacy of inclisiran, with completion expected in August 2024. These studies aimed to further elucidate the role of early LDL-C reduction during the acute phase of ACS and will help improve guidelines for lipid risk management in this critical patient population. Given the treat-to-target strategy, there is a strong possibility that combination therapy will be preferred over intensive statin therapy as the initial treatment. Furthermore, ongoing phase 4 studies to achieve early LDL-C targets or coronary imaging to investigate the effects of inclisiran on plaque are currently underway. The VictORION-INCLUSION: Evaluating Inclisiran for Cholesterol Management in Heart Disease (V-INCLUSION) trial (NCT06249165) aims to evaluate the effectiveness of inclisiran in helping close care gaps in historically under-researched and undertreated populations. This will be achieved by systematically identifying individuals at high risk for ASCVD who are already diagnosed, thereby leveraging electronic health records (EHRs) across multiple U.S. healthcare systems (HCS) to achieve LDL-C targets more quickly. The trial plans to enroll 1,440 participants, with completion expected in 2027. The V-ACCELERATE trial (NCT06372925) will enroll 318 patients with ACS scheduled for PCI. The participants had atherosclerotic plaques with stenosis of ≥ 20% and ≤ 50% in non-culprit lesions, as confirmed by coronary angiography. Patients will be randomized to receive either inclisiran or placebo, and plaque volume and phenotype changes will be assessed using intravascular ultrasound and optical coherence tomography at baseline and on day 360. The Aggressive Risk-Prevention Therapies for Coronary Atherosclerotic Plaque (ART-CAP) study (NCT06280976) will enroll 200 participants with moderate or high CAD risk and nonobstructive plaque detected on initial coronary computed tomography angiography. They will be randomized into a standard care group or an aggressive treatment group, which will include inclisiran. Plaque volume and characteristic will be evaluated using coronary computed tomography angiography at baseline and 18 months. These studies are expected to provide deeper insights into the mechanisms by which inclisiran prevents CV events.

MK-061: Enlicitide

An oral PCSK9 inhibitor, MK-0616 (enlicitide), may soon be available. In a phase 2 trial reported in 2023 involving 380 participants, enlicitide demonstrated a significant reduction in LDL-C from baseline after 8 weeks across all doses (–41.2% at 6 mg, –55.7% at 12 mg, –59.1% at 18 mg, and –60.9% at 30 mg; all p＜0.001) ⁴⁰⁾ . The incidence of adverse events was similar between the enlicitide group (39.5%–43.4%) and the placebo group (44.0%), with discontinuation due to adverse events being two or fewer in any treatment group. A phase 3 trial, the CORALreef study (NCT06008756) is set to enroll 14,000 participants to evaluate the efficacy of enlicitide in increasing major adverse CV events compared to placebo, including coronary heart disease death, ischemic stroke, MI, acute limb ischemia or amputation, and urgent arterial revascularization.

Approaches for Other Lipid Profiles

Statins result in an approximately 30% reduction in LDL-C, which corresponds to a roughly 30% decrease in CV events, highlighting the issue of residual risk that remains unresolved with statin therapy. Mendelian randomization studies that position PCSK9 as a target have revealed that genes associated with high lipoprotein(a) [Lp(a)] and hypertriglyceridemia also contribute to the development of atherosclerosis. Thus, another key to mitigating residual risk lies in intervening in lipid profiles beyond the LDL-C levels.

Lp(a)

Lp(a) is a particle similar to low-density lipoprotein that contains an apolipoprotein(a) component and is recognized as a risk factor for ASCVD ^{41 - 43)} and aortic valve stenosis ⁴⁴⁾ . Lp(a) levels are primarily influenced by genetics and contribute to thrombogenesis, inflammation, and atherogenesis. The 2019 ESC/EAS guidelines recommend assessing Lp(a) at least once during a patient’s lifetime ⁴⁾ , effective therapeutic approaches for managing elevated Lp(a) remain scarce. Traditional treatments, such as statins ^{45 , 46)} and ezetimibe ^{47 , 48)} , have little to no impact on Lp(a) levels and may even lead to an increase in Lp(a). In contrast, PCSK9 inhibitors have demonstrated the ability to reduce Lp(a) levels by 20–30% with associated CV benefits ^{49 , 50)} . Advancements in therapies specifically aimed at targeting Lp(a) have sparked considerable interest. These therapies include antisense oligonucleotides (ASO), small interfering RNA (siRNA), and inhibitors of microsomal transfer proteins ( Table 3 ) ⁵¹⁾ .

Table 3. Ongoing trials of drugs lowering Lp(a).

Drug Name	Expected Enrollment number	Eligibility Criteria	Development stage	Intervention dose	Estimated Completion Date	CT.gov Registration number
SLN360 (siRNA)	180	•Lp(a) ≥ 125 nmol/L •High risk of ASCVD events	Phase 2	N/A by subcutaneous injection	June 2024	NCT05537571
Pelacarsen (ASO)	8,323	•Lp(a) ≥ 70 mg/dL •MI •Ischemic stroke •PAD	Phase 3	80 mg by monthly subcutaneous injection	May 2025	NCT04023552
Olpasiran (siRNA)	7,297	•Lp(a) ≥ 200 nmol/L •ASCVD •MI or prior PCI	Phase 3	N/A by subcutaneous injection once every 12 weeks.	December 2026	NCT05581303
Lepodisiran (siRNA)	12,500	•Lp(a) ≥ 175 nmol/L •At risk for a first CV event who have: CAD, carotid stenosis, or PAD without a history of events or revascularization •Known FH •A combination of high-risk factors	Phase 3	N/A by subcutaneous injection	March 2029	NCT06292013
Muvalaplin (Small Molecule Inhibitor)	233	•Lp(a) ≥ 175 nmol/L •CAD •Stroke •PAD •ASCVD risk equivalents	Phase 2	N/A by oral	March 2024	NCT05563246

The information in this table was searched on the website https://clinicaltrials.gov/ on 5th September 5, 2024.

ASO, antisense oligonucleotide; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CT, clinical trial; CV, cardiovascular; FH, familial hypercholesterolemia; Lp(a), lipoprotein(a); MI, myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; siRNA, small interfering RNA

Gene Silencing Therapies

Mipomersen, one of the first Antisense Oligonucleotides (ASO) targeting apolipoprotein B, reduced Lp(a) levels by 26% in phase III trials ⁵²⁾ . A post-hoc analysis of prospectively collected data showed that mipomersen use was associated with an 85% lower risk of major adverse cardiac events ⁵³⁾ but raised concerns about liver toxicity where hepatic fat accumulation could potentially cause fibrosis or cirrhosis. More promising is pelacarsen, an ASO targeting apolipoprotein (a) synthesis that has shown reductions of up to 80% in Lp(a) levels in phase II ⁵⁴⁾ and III trials ⁵⁵⁾ . The ongoing Phase III Lp(a)HORIZON trial (NCT04023552) will provide insights into its effects on CV events.

More targeted siRNA therapies, such as olpasiran ⁵⁶⁾ and SLN360 ⁵⁷⁾ have achieved nearly complete suppression of Lp(a) synthesis, with reductions of up to 97%. The OCEAN(a)-DOSE trial n ⁵⁶⁾ was a phase II study that enrolled 281 participants with ASCVD and elevated Lp(a) levels (＞150 nmol/L). Participants were assigned to receive olpasiran at doses of 10, 75, or 225 mg every 12 weeks, or a single 225 mg subcutaneous injection every 24 weeks. The 75 mg Q12W dose resulted in adjusted mean percentage changes in Lp(a) from baseline of -76.2%, -53.0%, -44.0%, and -27.9% at weeks 60, 72, 84, and 96, respectively (all p＜0.001). For the 225 mg Q12W dose, the changes were -84.4%, -61.6%, -52.2%, and -36.4% (all p＜0.001). Notably, Lp(a) levels were reduced by approximately 40% to 50% nearly one year after the last dose ⁵⁸⁾ . Phase III trials such as OCEAN(a)-Outcome (NCT05581303) using olpasiran and ACCLAIM-Lp(a) (NCT06292013) using lepodisiran are currently underway to evaluate the long-term CV benefits of these drugs. These trials are expected to enroll more than 7,000 and 12,000 patients, respectively.

Small Molecule Inhibitor: Muvalaplin

Muvalaplin is a novel small-molecule inhibitor targeting the apolipoprotein (a)–apolipoprotein B interaction, offering a promising oral treatment option. Early phase I trials demonstrated a 65% reduction in Lp(a) levels, without significant safety concerns ⁵⁹⁾ . The Phase II trial enrolled 233 participants with Lp(a) levels ≥ 175 nmol/L and a history of CAD, stroke, peripheral artery disease, or other ASCVD risk equivalents. Participants received either muvalaplin or placebo (specific dosage not disclosed). Additionally, the ongoing KRAKEN trial (NCT05537571) aims to further evaluate the efficacy of the drug in patients with ASCVD.

Triglycerides

Hypertriglyceridemia contributes to residual risk, even when low LDL-C levels are achieved through intensive statin therapy ⁶⁰⁾ . Mendelian randomization studies have demonstrated that genetic polymorphisms affecting factors regulating triglyceride-rich lipoprotein (TRL) metabolism are associated with CV risk, further supporting the causal relationship between TRLs and atherosclerosis ⁶¹⁾ .

Fibrates

Fibrates serve as pharmacological agonists of peroxisome proliferator-activated receptor-α and have been utilized in lipid-modifying therapy for over 50 years. According to the 2019 ESC guidelines, the use of fibrates is currently recommended for managing hypertriglyceridemia in patients taking statins with triglyceride (TG) levels exceeding 200 mg/dL, particularly for primary prevention or in high-risk populations (Class IIb) ⁴⁾ . The PROMINENT trial ⁶²⁾ , a multinational randomized controlled study involving 10,497 patients with type 2 diabetes, hypertriglyceridemia (200-499 mg/dL), and low high-density lipoprotein cholesterol (HDL-C) (≤ 40 mg/dL), compared the effects of pemafibrate and placebo. After four months, pemafibrate resulted in a 26.2% reduction in TG, 25.8% reduction in VLDL, 25.6% decrease in remnant cholesterol, and 27.6% decrease in apolipoprotein C-III (ApoC3). After a median follow-up of 3.4 years, no significant difference in CV events was noted (HR, 1.03; 95% CI, 0.91–1.15). Pemafibrate did not lower apolipoprotein B levels, which may underscore its benefits. Pemafibrate was associated with an increased incidence of renal events and venous thromboembolism but a decreased incidence of nonalcoholic fatty liver disease. The 2022 JAS guidelines recommend the addition of fibrates to statin therapy for the prevention of ASCVD in patients with concurrent hypertriglyceridemia and low HDL cholesterol (Class II) ¹⁰⁾ .

Omega-3 Fatty Acids

The ASCEND trial, which included 15,480 patients with diabetes, found that a daily dose of 1 g g omega-3 fatty acids did not lead to a reduction in CV events ⁶³⁾ . Similarly, the VITAL trial, which enrolled 25,871 participants for primary prevention, showed no significant impact on the major CV composite endpoints with the administration of 1 g of marine omega-3 fatty acids per day ⁶⁴⁾ . However, a secondary outcome in the VITAL trial showed a 28% reduction in the incidence of MI, although the clinical significance of this finding remains unclear. On the other hand, trials involving high doses of omega-3 fatty acids have yielded encouraging results. In the open-label JELIS trial, which included 18,645 Japanese statin-treated patients, daily administration of 1.8 g of EPA led to a modest reduction in TGs but resulted in a 19% decrease in coronary events ⁶⁵⁾ . Notably, patients with higher plasma EPA concentrations had the lowest event rates, which contributed to the increased use of EPA for CV prevention in Japan. The REDUCE-IT trial further supported these findings by demonstrating a 25% reduction in CV events among high-risk patients with hypertriglyceridemia who received 4 g of pure EPA daily ⁶⁶⁾ . However, the evidence linking TG reduction directly to clinical benefits remains inconclusive. As a result of these findings, the 2019 ESC guidelines recommend 4 g/day of n-3 polyunsaturated fatty acids for high-risk patients with TG levels between 135 and 499 mg/dL who are on statin therapy (Class IIa) ⁴⁾ . In contrast, the STRENGTH trial, which compared EPA and docosahexaenoic acid (DHA) carboxylic acids (4 g/day) to corn oil in 13,078 high-risk patients receiving statins, was terminated early because of a lack of benefit ⁶⁷⁾ . The primary endpoint, comprising CV death, non-fatal MI, stroke, revascularization, or unstable angina, occurred at a rate of 12.0% in the omega-3 group versus 12.2% in the corn oil group (HR 0.99, p=0.84). Gastrointestinal side effects were more common in the omega-3 diet group. The differing outcomes between REDUCE-IT and STRENGTH are thought to be primarily due to the oils used as comparators (mineral oil vs. corn oil) rather than differences in their active ingredients (EPA vs. EPA + DHA). The additional 13% reduction in risk observed in REDUCE-IT may be attributable to other actions of EPA or the use of mineral oil as a placebo.

ApoA-I

Cholesterol efflux is the initial step in reverse cholesterol transport, a process through which excess cholesterol (such as that found in atherosclerotic plaques) is removed from peripheral tissues and transported to the liver for excretion into the bile. This process is primarily mediated by apolipoprotein A-I (apoA-I), the main component of high-density lipoproteins. Patients with ACS often exhibit impaired cholesterol efflux capacity ⁶⁸⁾ . The MILANO-PILOT study ⁶⁹⁾ examined the effects of MDCO-216, a high-density lipoprotein mimetic containing apoA-I Milano ⁷⁰⁾ , on the progression of coronary atherosclerosis in patients with ACS receiving contemporary statin therapy. This double-blind, randomized clinical trial involved 126 participants who were randomly assigned to receive either MDCO-216 (20 mg/kg once weekly for 5 weeks) or a placebo. The primary outcome, assessed by intravascular ultrasound on day 36, showed a 0.94% reduction in percent atheroma volume in the placebo group and a 0.21% reduction in the MDCO-216 group, with a difference of 0.73% between the two groups (p=0.07), thus indicating no statistically significant difference. The AEGIS-II trial tested the hypothesis that the intravenous administration of CSL112, which is derived from human apoA-I and forms discoidal particles with phosphatidylcholine, promotes cholesterol efflux, stabilizes atherosclerotic plaques, and reduces the incidence of adverse CV events following acute myocardial infarction (AMI) ⁷¹⁾ . A total of 18,219 patients with AMI, multivessel CAD, and additional CV risk factors were randomly assigned to receive either 6 g of CSL112 or placebo administered four times weekly. After 90 days of follow-up, there was no significant difference in the composite endpoint of MI, stroke, or CV death between the two groups (4.8% vs. 5.2%; HR 0.93, 95% CI 0.81–1.05, p=0.24). Among patients with baseline plasma LDL-C levels of ≥ 100 mg/dL, CSL112 administration was associated with significant reductions in the primary endpoint at 90, 180, and 365 days. However, no significant difference was observed in patients with baseline plasma LDL-C levels ＜100 mg/dL. A pre-specified exploratory analysis of this study investigated the effect of CSL112 on the total burden of non-fatal ischemic events and CV death ⁷²⁾ . The total incidence of CV death, MI, and stroke was reported as follows: on day 90, the CSL112 group had 503 events compared to 545 events in the placebo group (risk ratio [RR]: 0.88; 95% CI: 0.76-1.03; p=0.11); on day 180, there were 745 events in the CSL112 group and 821 in the placebo group (RR: 0.87; 95% CI: 0.77-0.99; p=0.04); and on day 365, the CSL112 group recorded 1,120 events, while the placebo group had 1,211 events (RR: 0.89; 95% CI: 0.80-0.99; p=0.04). These findings indicate a significant reduction in the overall burden of CV events, raising expectations for further studies involving apoA-Is.

Small Interfering RNA for ApoC3: Plozasiran

Plazosiran (formerly ARO-APOC3) is an siRNA designed to target and inhibit the production of ApoC3, a key regulator of TG metabolism. By reducing ApoC3 levels, plazosiran lowers TG levels, making it a potential treatment for conditions such as severe hypertriglyceridemia and familial chylomicronemia syndrome (FCS). In 2024, numerous reports emerged on the promising findings for prozasilan. These include phase 2 clinical trials targeting different patient populations, such as the SHASTA trial for patients with severe hypertriglyceridemia ⁷³⁾ , MUIR trial for patients with mixed dyslipidemia ⁷⁴⁾ , and PALISADE trial focusing on patients with FCS ⁷⁵⁾ . These encouraging results stem from the broader SUMMIT program that evaluates prozasilan in various lipid disorders. The PALISADE trial ⁷⁵⁾ , presented at ESC Congress 2024, evaluated plazosiran in 75 patients with FCS, regardless of genetic diagnosis. The participants were randomized to receive subcutaneous plazosiran at doses of 25 mg (n=26), 50 mg (n=24), or placebo (n=25) every three months for 12 months. At baseline, the median TG level was 2,044 mg/dL. Genetic testing confirmed FCS in 44 patients (59%), whereas 31 patients (41%) were clinically diagnosed based on persistent chylomicronemia. At 10 months, the median fasting TG reductions from baseline were -80% in the 25 mg group, -78% in the 50 mg group, and -17% in the placebo group (p＜0.001). The ApoC3 levels also decreased significantly, by -93%, -96%, and -1% in the 25, 50, and placebo group, respectively (p＜0.001).

Acute pancreatitis occurred in 2 of the 50 plazosiran group (4%) compared to 5 of the 25 placebo group (20%) (odds ratio 0.17, p=0.03). Plazosiran holds promising potential for lipid management, particularly in patients with limited treatment options for severe hypertriglyceridemia.

Personalized Medicine Approach

There is substantial variability in individual responses to medications, encompassing both the efficacy and safety profiles. It is estimated that the majority of medications yield therapeutic benefits in ＜10% of patients, consequently exposing the remaining 90% to potential adverse effects without any corresponding therapeutic gain ⁷⁶⁾ . Genetic differences that influence the processes of drug absorption, metabolism, excretion, and mechanisms of action can profoundly impact the effectiveness and safety of pharmacological interventions. Precision medicine is defined as an evolving approach to disease prevention and treatment that incorporates an individual’s genetic, environmental, and lifestyle factors ^{77 , 78)} . In recent years, the field of genetics has rapidly progressed, significantly enhancing diagnostic and therapeutic approaches, with genes increasingly serving as biomarkers ^{79 - 81)} . It is possible that a clinical study drug previously deemed a negative study may experience resurgence by altering its target population. Generally, rare deleterious mutations exhibit a considerable effect size in relation to diseases, whereas high-frequency genetic variants (single nucleotide variants) tend to have a smaller effect size. While our understanding of Mendelian disorders, such as FH, has advanced, the implications of the latter have been elucidated through association analyses involving large sample sizes, given the modest effect size per variant (polymorphism). Guidelines now recommend genetic testing for rare diseases, and in several countries such testing has already been implemented and is reimbursed by insurance.

Polygenic Risk Score

Polygene risk scores (PRS) are a method used to assess individual disease risk based on multiple genetic variants and have been applied to stratify risk for CAD ⁸²⁾ . In 2018, a study by Khera et al. demonstrated that individuals in the top 20% of PRS had a significantly higher risk of developing CAD than the rest of the population (odds ratio 2.55, 95% confidence interval 2.43–2.67) ⁸³⁾ . While genes are a contributing factor in determining the risk of developing CAD, approximately 50% of the disease onset is attributed to lifestyle and environmental factors ^{84 , 85)} . By considering both genetic and environmental factors, it is anticipated that more precise diagnostic and treatment strategies can be developed. In the GENVASC study, adding a polygenic risk score for cardiovascular disease (CVD-PRS) to the clinical risk score increased the proportion of individuals who experienced major CV events by 11.7% in the entire cohort (aged 40–74 years) and by 47.7% in the 40–54 age group ⁸⁶⁾ . In contrast, Elliott et al. in 2020, demonstrated that the improvement in discriminatory power by adding PRS to existing risk factors was minimal (area under the ROC curve: 0.76 vs. 0.78) ⁸⁷⁾ . In this study, the performance of the PRS itself was considered low because of the narrow case definition of genome-wide association studies using population cohorts and the limited sample size, which resulted in no additive effects being observed. This discussion is also reflected in a recent statement by the American Heart Association, which modestly notes that the significance of improving PRS performance is “a matter of debate” ⁸⁸⁾ .

Just as treatment selection based on genetic information has been applied in oncology, LLT based on PRS has the potential to be utilized in the management of atherosclerotic diseases in the future. Individuals with high PRS for CAD can significantly reduce their absolute risk by maintaining a healthy lifestyle ⁸⁹⁾ . Furthermore, it has been reported that individuals informed of their high polygenic risk score (PRS) exhibit a higher rate of favorable behavioral changes than those who are not (odds ratio: 1.53, 95% confidence interval: 1.37–1.72) ⁹⁰⁾ . Thus, PRS may not only serve as a tool for risk stratification but also have the potential to guide lifestyle interventions.

Analysis of trials on primary prevention with statins has demonstrated that patients with a high CAD-PRS derive significantly greater relative and absolute benefits from statin treatment than other patients (46% vs. 26%; P for heterogeneity=0.05) ^{91 , 92)} . Similarly, in PCSK9 inhibitors, patients with a high CAD-PRS showed greater benefits than those with lower scores (37% vs. 13%; P for interaction=0.04) ^{93 , 94)} . These findings were obtained independent of traditional clinical risk factors, suggesting that PRS may play a more significant role in treatment decision-making, particularly in high-risk young adults. Numerous clinical studies utilizing the PRS are expected to be published in the future. The INNOPREV trial is a four-arm randomized controlled trial conducted in Italy that examined the effectiveness of polygenic risk scores and digital technologies in high-risk adults for ASCVD. A total of 1,020 participants aged 40–69 years with a high 10-year CVD risk based on the SCORE 2 chart will be randomly assigned to one of four groups: traditional CV disease risk assessment, genetic testing (CVD-PRS), digital intervention (app and smart band), or a combination of genetic testing and digital intervention. The primary objective is to evaluate the effectiveness of providing CVD-PRS information measured at baseline. The primary outcome of the study is lifestyle change, which will be assessed using Life’s Essential Eight questionnaire. This questionnaire will be administered at the beginning of the study and at two follow-up points to evaluate changes in lifestyle categories (favorable, intermediate, or unfavorable) compared to baseline ⁹⁵⁾ .

Successful implementation of PRS requires robust ethical and legal frameworks. It is evident that the PRS provides information of significant interest to insurance companies. Although the associated costs represent a substantial barrier to implementation, recent trends have indicated a decline in expenses linked to genetic testing. Notably, a recent study demonstrated that the cost-effectiveness of population genomic screening for FH in younger individuals aged 18 to 40 is feasible ⁹⁶⁾ . Therapies based on the PRS are expected to be implemented more widely, positioning them as a crucial approach for the prevention and management of atherosclerotic diseases in the near future.

Conclusions

Significant care gaps persist in the real-world management of LDL-C despite advancements in reducing CV events. Innovative approaches such as combination therapies and novel lipid-modifying agents offer potential solutions. Additionally, integrating polygenic risk scores and personalized medicine could further optimize lipid-lowering strategies, contributing to better patient outcomes for ASCVD prevention. Continued efforts are therefore needed to better align clinical practice with emerging evidence and improve treatment strategies.

Disclosures

M.F. received travel grants from the Policy-based Medical Services Foundation. S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx, and Sanofi-Regeneron, as well as a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Cyclarity, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Vaxxinity, CSL Seqirus, and Novo Nordisk. G.D.G. has no conflicts of interest to declare.