Abstract

The application of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represents a crucial milestone in the field of lipid-lowering therapy. As the first PCSK9 inhibitor to be approved globally, evolocumab has not only offered an entirely novel therapeutic option for patients with familial hypercholesterolemia but also established a paradigm for the development of subsequent anti-PCSK9 monoclonal antibodies. This narrative review provides an overview of the discovery of PCSK9 and its role in low-density lipoprotein cholesterol metabolism, detailing the developmental trajectory and key clinical trials of evolocumab, and underscoring its central importance and transformative impact on lipid-lowering therapeutics. On this basis, we conduct a comparative analysis of the differences in mechanism of action, clinical efficacy and safety among the marketed PCSK9 inhibitors, and dissect the limitations and unmet needs in current clinical practice. Furthermore, this review explores the pleiotropic effects of PCSK9 beyond lipid metabolism, and comments on its potential application value and latest research advances in diseases such as infection, liver disease, and malignancy. Finally, we prospect the future development directions of PCSK9-targeted therapy, aiming to provide an integrated reference perspective for basic research and clinical practice in this field.

1 Introduction

Cardiovascular disease (CVD) remains the leading cause of death worldwide, resulting in approximately 19.41 million deaths in 2021 (Martin et al., 2025). Dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is a key driver of atherosclerotic CVD (ASCVD) and plays a central role in the initiation and progression of atherosclerosis (Baigent et al., 2010). Substantial evidence indicates that each 1.0 mmol/L reduction in LDL-C is associated with a 20%–25% decrease in cardiovascular event risk (Baigent et al., 2010), underscoring the importance of effective LDL-C lowering in the primary and secondary prevention of ASCVD (Li et al., 2023).

Statins have long been the cornerstone of LDL-C-lowering therapy, effectively reducing circulating LDL-C levels (Li et al., 2023). Beyond their lipid-lowering action, statins exert multiple pleiotropic benefits, including improved endothelial function and vascular tone, anti-inflammatory and antioxidative effects, reduced thrombogenicity, and stabilization of atherosclerotic plaques (German and Liao, 2023). However, statin therapy is also associated with adverse effects such as hepatotoxicity, statin-associated muscle symptom, and an elevated risk of new-onset diabetes (Li et al., 2023). Clinically, muscle-related symptoms affect approximately 10%–30% of patients on statin treatment (Urina-Jassir et al., 2021). Furthermore, even among patients who tolerate statins well, a considerable proportion fail to attain LDL-C targets, leading to persistent residual cardiovascular risk (Mach et al., 2020). Notably, in very-high-risk ASCVD populations, only about 20% achieve the guideline-recommended LDL-C goal of <55 mg/dL (Mach et al., 2020). For patients who are statin-intolerant or unable to reach LDL-C goals with statins alone, additional lipid-lowering strategies are needed—underscoring the demand for novel therapeutic approaches (Lin et al., 2018).

Recent advances in our understanding of atherosclerotic pathogenesis have facilitated the identification of novel therapeutic targets for cholesterol management (Yaghoubi and Sallam, 2025). Among these, proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial regulatory role in cholesterol metabolism and has emerged as a significant target for lipid-lowering interventions (Lin et al., 2018).

Based on a selective literature search of PubMed and Web of Science databases for articles published up to March 2026, using keywords including “PCSK9”, “PCSK9 inhibitor”, “evolocumab”, “alirocumab”, “cardiovascular disease”, “atherosclerosis”, and “clinical trial”, and including peer-reviewed original articles, systematic reviews, meta-analyses, clinical guidelines, and other relevant literature, this narrative review focuses on advances in PCSK9 inhibitors from evolocumab to novel discoveries and discusses their pleiotropic effects and future clinical directions.

2 Landscape of PCSK92.1 Discovery of PCSK9

PCSK9 was identified approximately 2 decades ago (Barale et al., 2021). In 2003, Abifadel et al. studied a French cohort of families with autosomal dominant familial hypercholesterolemia (FH), characterized by markedly elevated LDL-C levels. Although two major FH-associated genes were known at the time, no pathogenic variants were detected in these families, prompting the search for an additional causative gene. Genetic analysis later revealed that gain-of-function (GOF) mutations in PCSK9 explained the severe hypercholesterolemia in these patients, establishing PCSK9 as the third gene linked to FH (Abifadel et al., 2003). The following years further elucidated the role of PCSK9 in lipid metabolism. In 2004, mouse studies showed that hepatic overexpression of PCSK9 increased circulating LDL-C and reduced hepatic LDL receptor (LDLR) expression (Maxwell and Breslow, 2004). In 2005, data from the Dallas Heart Study demonstrated that loss-of-function (LOF) mutations in PCSK9 were associated with significantly lower LDL-C levels and a markedly reduced risk of ASCVD. Remarkably, individuals with PCSK9 deficiency exhibited serum LDL-C concentrations as low as 14 mg/dL (Cohen et al., 2006). Together, these findings positioned PCSK9 as a promising therapeutic target for lipid-lowering interventions. The determination of the PCSK9 crystal structure in 2007 provided a structural basis for rational drug design (Piper et al., 2007). Building on these foundational discoveries, the development of PCSK9-targeted therapies has advanced through several key milestones, summarized in Figure 1. This timeline outlines pivotal advances in PCSK9 research and clinical translation from 2003 to 2025.

PCSK9 discovery and time point in its pharmaceutical development process PCSK9, proprotein convertase subtilisin/kexin type 9; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; ASCVD, atherosclerotic cardiovascular disease; mAbs, monoclonal antibodies; EC, European Commission; FDA, U.S. Food and Drug Administration.

2.2 Role of PCSK9 on LDL-C metabolism

PCSK9 is primarily secreted by hepatocytes and modulates circulating LDL-C levels by binding to the LDLR. Expressed on the hepatocyte surface, LDLR captures circulating LDL-C particles to form an LDLR–LDL-C complex. This complex undergoes endocytosis, and the resulting vesicles fuse with endosomes. Within the acidic endosomal environment, LDL-C dissociates from LDLR and is subsequently transported to lysosomes for degradation into free cholesterol, fatty acids, and amino acids. Under normal conditions, LDLR is recycled back to the hepatocyte membrane to facilitate further LDL-C clearance. However, when PCSK9 binds to LDLR, it induces conformational changes that prevent receptor recycling. Instead, the PCSK9–LDLR–LDL-C complex is diverted to lysosomes for degradation. This process reduces the number of LDLRs available on the hepatocyte surface, thereby impairing LDL-C clearance and elevating circulating LDL-C levels. Consequently, pharmacological inhibition of PCSK9 increases surface LDLR expression, enhances hepatic uptake of LDL-C, and effectively lowers plasma LDL-C concentrations (Lagace et al., 2006) (Figure 2).

Mechanism of PCSK9 in regulating of LDL-C metabolism. The physiological degradation of LDL-C and recycling of LDLR (left panel), and the disruption of this recycling by PCSK9 (right panel). LDL-C, Low-density lipoprotein cholesterol; LDLR, LDL receptors; PCSK9, Proprotein convertase subtilisin/kexin type 9.

3 Evolocumab: the first globally approved PCSK9 inhibitor3.1 The development of evolocumab

Following elucidation of the structure and biological function of PCSK9, its inhibition was recognized as a promising strategy for lowering LDL-C levels. Due to the considerable challenge of designing small molecules or peptide mimetics that effectively block the PCSK9–LDLR interaction, monoclonal antibodies targeting circulating PCSK9 emerged as the most clinically feasible approach.

Chan et al. were the first to successfully develop a fully human monoclonal antibody targeting PCSK9 (Chan et al., 2009). This antibody exhibited high affinity for a specific PCSK9 epitope, effectively blocking its interaction with the LDLR and thereby inhibiting PCSK9-mediated lysosomal degradation of LDLR. Preclinical studies demonstrated that the antibody significantly lowered cholesterol levels in both murine and non-human primate models, while showing no lipid-lowering effect in LDLR-knockout mice—confirming that its efficacy depends entirely on the LDLR pathway (Chan et al., 2009). In cynomolgus monkeys, a single administration reduced circulating LDL-C levels by approximately 80% from baseline.

Evolocumab was the first PCSK9 inhibitor to receive regulatory approval for clinical use worldwide (approved by the EU in 17 July 2015). It was generated using the Amgen XenoMouse® platform, which introduces human immunoglobulin genes into mice, thereby enabling the production of fully human, mature monoclonal antibodies. This technology accelerated antibody development, reduced immunogenicity, and enhanced both safety and therapeutic efficacy (Mendez et al., 1997; Yang et al., 2001). However, related research, development, and production processes require substantial financial investment and advanced technical support.

Moreover, evolocumab’s rational molecular design was critical: it employs an IgG2 isotype whose Fc region has low affinity for Fcγ receptors, thereby minimizing unwanted effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). This supports IgG2 as the preferred isotype for PCSK9-targeted antibody design. Furthermore, its fully human nature contributed to exceptionally low immunogenicity, with only 0.3% of patients (48 of 17,992) developing anti-drug antibodies in large clinical trials, and no neutralizing antibodies detected (European Medicines Agency, 2015). Collectively, the success of evolocumab thus established a practical and transferable model that has informed the design and optimization of subsequent PCSK9 monoclonal antibodies.

3.2 Key clinical trials of evolocumab3.2.1 The pioneering first-in-human study of PCSK9 inhibitor

In 2010, evolocumab entered its first phase 1 clinical trial (NCT01133522) to evaluate the pharmacokinetics, efficacy, and safety of this PCSK9 inhibitor in humans. The results were published in 2012 and confirmed that evolocumab significantly reduced circulating free PCSK9 and lowered LDL-C in a dose-dependent manner. A single subcutaneous dose of 420 mg lowered LDL-C by up to 67% from baseline, while repeated weekly administration achieved reductions of up to 81%. The reduction in LDL-C was directly correlated with a dose-dependent decrease in free PCSK9 levels and a corresponding increase in hepatic LDL receptor levels. This precisely confirmed the intended mechanism of action in humans: inhibiting PCSK9 prevents LDL receptor degradation, leading to enhanced clearance of LDL-C from the blood. The incidence of adverse events was comparable to placebo, and no serious safety concerns emerged (Dias et al., 2012). This trial marked the successful translation of PCSK9 biology into human therapeutics, validating PCSK9 inhibition as a clinically viable strategy and providing the foundational rationale for subsequent PCSK9 inhibitor development.

3.2.2 GLAGOV: the first to confirm coronary plaque regression by PCSK9 inhibitor

The GLAGOV trial (Nicholls et al., 2016) was the first imaging-based clinical trial to assess the effects of a PCSK9 inhibitor on coronary atherosclerotic plaque burden. In this multicenter, double-blind, placebo-controlled study, 968 patients with prior coronary angiography were randomized (1:1) to receive subcutaneous evolocumab 420 mg monthly or placebo for 76 weeks. The primary endpoint was the change in percent atheroma volume (PAV), measured by serial intravascular ultrasound (IVUS), from baseline to week 78.

The results demonstrated that adding evolocumab to intensive statin therapy significantly promoted plaque regression (Nicholls et al., 2016). PAV decreased by 0.95% in the evolocumab group, whereas it increased by 0.05% in the placebo group (P<0.001). The proportion of patients achieving plaque regression was also significantly higher in the evolocumab group (64.3% vs. 47.3%, P<0.001 for PAV).

3.2.3 FOURIER: the first to confirm cardiovascular event reduction with PCSK9 inhibitor

Evolocumab was the first PCSK9 inhibitor to demonstrate cardiovascular outcome benefits in a large-scale clinical trial. The FOURIER trial (Sabatine et al., 2017a) was a landmark, double-blind, randomized, placebo-controlled, multicenter Phase 3 study. The trial enrolled 27,564 patients with established ASCVD. Key inclusion criteria required that patients have a LDL-C level of ≥70 mg/dL or a non-high-density lipoprotein cholesterol (non-HDL-C) level of ≥100 mg/dL, while concurrently receiving an optimized background lipid-lowering regimen. The primary composite endpoint included cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary composite endpoint included cardiovascular death, MI, or stroke.

This study reported that in high-risk statin-treated patients, evolocumab reduced LDL-C levels by 59% and lowered the risk of major adverse cardiovascular events (MACE) by 15% (composite endpoint: cardiovascular death, MI, stroke, unstable angina, or coronary revascularization) (Sabatine et al., 2017a). These findings established the role of PCSK9 inhibitors in secondary prevention of ASCVD. Additionally, the FOURIER open-label extension study provided the longest follow-up data available for any PCSK9 inhibitor. Over more than 8 years of follow-up, LDL-C levels remained consistently and markedly low, with early initiation of evolocumab therapy associated with further reduction in long-term cardiovascular risk (Gaba et al., 2023). Furthermore, in patients with ASCVD, achieving sustained very low LDL-C levels below 20 mg/dL (<0.5 mmol/L) with evolocumab was linked to a reduced risk of cardiovascular events, without raising significant safety concerns (Gaba et al., 2023).

3.2.4 VESALIUS-CV: the first to confirm cardiovascular benefit of PCSK9 inhibitor in primary prevention population

The VESALIUS-CV trial is a phase 3, double-blind, randomized, placebo-controlled global study (Bohula et al., 2026). It enrolled 12,257 patients with atherosclerosis or high-risk diabetes mellitus and no history of myocardial infarction or stroke. The study aimed to assess whether evolocumab, through LDL-C lowering, could reduce MACE in a primary prevention population. After a median follow-up of 4.6 years, evolocumab significantly lowered the incidence of 3-point MACE (a composite of death from coronary heart disease, myocardial infarction, or ischemic stroke, 6.2% vs. 8.0%; P < 0.001) and 4-point MACE (a composite of 3-point MACE or ischemia-driven arterial revascularization, 13.4% vs. 16.2%; P < 0.001) compared with placebo, with no significant safety differences. These results demonstrate that evolocumab reduces the risk of first cardiovascular event in this primary prevention cohort. By extending the benefits of potent LDL-C lowering to individuals without prior cardiovascular events, this finding challenges the traditional paradigm that such aggressive lipid-lowering therapy is reserved solely for secondary prevention. It establishes a new benchmark for early intervention, potentially redefining treatment thresholds for high-risk primary prevention patients.

3.2.5 HAUSER-RCT: the first to evaluate cognitive safety with FH of PCSK9 inhibitor

Evolocumab is also the first PCSK9 inhibitor to have its cognitive effects systematically evaluated in pediatric patients with FH. The HAUSER-RCT trial (Santos et al., 2020) was a phase 3, randomized, double-blind, placebo-controlled study conducted in children and adolescents aged 10–17 years with heterozygous FH. Over 24 weeks of treatment, evolocumab significantly reduced LDL-C levels by approximately 38% compared with placebo, with no significant differences observed in cognitive function as assessed by standardized neuropsychological tests. Safety profiles were similar between groups, and no treatment-related adverse effects on neurocognitive development were reported.

Although cognitive function was an exploratory endpoint in this trial, these findings support the cognitive safety of evolocumab in the pediatric FH population and provide important evidence for its use in younger high-risk patients (Santos et al., 2020). Given that atherosclerotic processes begin in childhood for patients with FH, the ability to intervene safely during this developmental window has profound implications for lifelong cardiovascular risk reduction.

4 Comparison of PCSK9 inhibitors in China

China bears a substantial and growing burden of ASCVD all over the world, and the accessibility and affordability of PCSK9 inhibitors in the Chinese healthcare system represent a distinctive clinical scenario that is underrepresented in the English-language literature. Moreover, China has seen the rapid emergence of domestically developed PCSK9 inhibitors, with four novel monoclonal antibodies (tafolecimab by Innovent Biologics, approved in 2023; ebronucimab by Akeso Biopharma, approved in 2024; ongericimab by Junshi Biosciences, approved in 2024; and recaticimab by Hengrui Pharma, approved in 2025) now available alongside the imported agents evolocumab and alirocumab (Sanofi, first approved globally by the FDA in 24 July 2015 and approved in China in 2019, while scheduled for withdrawal from the Chinese market in 2025), as well as the small-interfering RNA (siRNA) agent inclisiran (Novartis, first approved globally by the EU in 2020 and approved for marketing in China in 2023), making China one of the most competitive markets for PCSK9-targeted therapies globally. Across diverse patient populations, these PCSK9 inhibitors have demonstrated potent lipid-lowering efficacy along with favorable safety and tolerability profiles in clinical studies. Data concerning their respective market availability, regulatory status, pharmacokinetic differences, clinical trial comparisons, potential advantages and disadvantages, and strength of outcome evidence are detailed in Table 1.

CharacteristicPCSK9 monoclonal antibodysiRNAReferenceEvolocumabAlirocumabRecaticimabEbronucimabOngericimabTafolecimabInclisiranFirst global approval2015/07/1 (EC)2015/07/24 (FDA)————2020/12/9 (EC)​Approval in China2018/07/312019/12/26 (The supply has been discontinued in August 2025)2025/01/102024/09/262024/10/112023/08/162023/8/22​Antibody typeFully human IgG2 monoclonal antibodyFully human IgG1 monoclonal antibodyFully human IgG1 monoclonal antibodyFully human IgG1 monoclonal antibodyFully human IgG4 monoclonal antibodyFully human IgG2 monoclonal antibody—​Dosage regimen140 mg Q2W or 420 mg Q4W75 mg or 150 mg
Q2W150 mg Q4W or 300 mg Q8W150 mg Q2W or 450 mg Q4W150 mg Q2W or 300 mg Q4W
or 450 mg Q4W150 mg Q2W or 450 mg Q4W
or 600 mg Q6W284 mg Q6M (After the first dose, it is administered again at 3 months and then every 6 months)​Half-life (t1/2)11–17 days17–20 days22–27 days11.8–14.2 days4.5–6.5 days26 days9 hAkeso Biopharma (2024); Innovent Biologics (2024); Jiang et al. (2024), Junshi Biosciences (2024); Amgen Inc (2025); Jiangsu Hengrui (2025); Novartis, 2025a; Sanofi (2025)Bioavailability72%85%70%—36.0%–55.5%58%85%Time to peak drug concentration3–4 days3–7 days7–9 days5 days3–7 days5–7 days4 hClearance0.3—0.254–0.2710.6170.53–1.090.162—Volume of distribution (L)3.32.8–3.58.28–8.649.65–19.43.69–7.065.7500ADA incidence0.3%5.5%14.1%9.4%5.8%10.9%4.9%Key phase 3 trialFOURIERODYSSEYREMAIN-2AK102-301JS002-007CREDIT-1ORION​LDL-C reduction59.2%–75%44.5%–63.3%53.4%–62.2%59.13%–60.43%66.2%57.3%–65%51.5%–57.0%(Huo et al., 2023; Sun et al., 2024; Wilkinson et al., 2024; Zhang et al., 2024; Amgen Inc, 2025; Sanofi, 2025; Shao et al., 2025)Decreased percent of atheroma volume1.0% (78w)1.21% (52w)—————(Nicholls et al., 2016; Räber et al., 2022)MACE reduction15%15%————26%(Nicholls et al., 2016; Schwartz et al., 2018)Injection-site reactions3.2%6.1%3.8%10.8%3.6%–5.1%7.3%5.0%(Huo et al., 2023; Akeso Biopharma, 2024; Innovent Biologics, 2024; Junshi Biosciences, 2024; Amgen Inc, 2025; Jiangsu Hengrui, 2025; Novartis, 2025a; Sanofi, 2025)

Approved PCSK9 inhibitors in China.

PCSK9, Proprotein convertase subtilisin/kexin type 9; siRNA, small interfering RNA; EC, European commission; FDA, food and drug administration; ADA, anti-drug antibody; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular event.

4.1 Mechanistic differences

Currently, two classes of PCSK9 inhibitors are clinically available: fully human monoclonal antibodies and siRNA-based therapeutics. While both effectively reduce PCSK9 activity, their mechanisms of action differ. Monoclonal antibodies, such as evolocumab, alirocumab, bind to circulating PCSK9 in the plasma and block its interaction with the LDLR on hepatocytes. This prevents PCSK9-mediated LDLR degradation, allowing more receptors to recycle to the cell surface and thereby enhancing hepatic uptake and clearance of LDL-C (Seidah and Prat, 2022). Clinically, evolocumab has been shown to achieve maximum suppression of free PCSK9 within 4 h of administration (Kasichayanula et al., 2018). The reductions of unbound PCSK9 levels at 1 week after evolocumab treatment were consistently around 90% regardless of background therapy (Blom et al., 2014).

In contrast, siRNA-based therapeutics such as inclisiran act intracellularly. Inclisiran is a double-stranded non-coding RNA that enters hepatocytes and is incorporated into the RNA-induced silencing complex (RISC). The RISC then uses the guide strand to bind and degrade PCSK9 mRNA, thereby reducing PCSK9 protein synthesis (Carthew and Sontheimer, 2009). This “upstream” mode of inhibition enables sustained LDL-C lowering, with a single dose capable of suppressing PCSK9 levels over an extended period. However, factors such as intracellular delivery efficiency and saturation of the RISC complex limit the ability of siRNA therapy to completely silence PCSK9 expression (Gavrilov and Saltzman, 2012). At optimal doses and dosing intervals, inclisiran can inhibit approximately 80% of PCSK9 production (Ray et al., 2023).

4.2 Lipid-lowering and cardiovascular efficacy

The lipid-lowering efficacy of PCSK9 inhibitors has been consistently demonstrated in pivotal clinical trials, though the degree of LDL-C reduction varies across agents. Early studies including FOURIER and LAPLACE reported that evolocumab lowered LDL-C by approximately 59%–75% from baseline (Robinson et al., 2014; Sabatine et al., 2017a). The HUA TUO study further showed that evolocumab also improved other lipid parameters in Chinese dyslipidemia patients, such as total cholesterol and apolipoprotein B (apoB) (Tan et al., 2023). In the ODYSSE EAST trial, alirocumab reduced LDL-C by 56.0% from baseline to week 24 (Han et al., 2020). The CREDIT-1 study demonstrated that tafolecimab decreased LDL-C by 57.3%–65% (Huo et al., 2023). Similarly, in the AK102-301 trial, ebronucimab (150 mg Q2W) achieved a 60.43% reduction in LDL-C after 12 weeks (Zhang et al., 2024). The JS002-007 trial (2023) reported that ongericimab lowered LDL-C by 62.7% at week 12, with effects sustained through week 52 (Shao et al., 2025). Most recently, the REMAIN-2 study showed that all dosing regimens of recaticimab significantly reduced LDL-C; the 150 mg Q4W regimen yielded a 62.2% decrease, accompanied by meaningful improvements in non-HDL-C, apoB, and lipoprotein(a) (Sun et al., 2024). For siRNA-based therapy, the ORION program indicated that inclisiran—administered twice yearly (300 mg) after initial loading doses—maintained a persistent LDL-C reduction of approximately 50% (Wilkinson et al., 2024).

In addition to their potent LDL-C-lowering effects, certain PCSK9 inhibitors, such as evolocumab and alirocumab, have demonstrated clear cardiovascular benefits. Evolocumab currently possesses the most extensive cardiovascular outcomes evidence across both primary and secondary prevention settings. The FOURIER and FOURIER-OLE studies showed that evolocumab reduced the risk of MACE—including myocardial infarction, stroke, and coronary revascularization—by approximately 15% in patients with ASCVD, with a particularly pronounced reduction in myocardial infarction risk (approximately 27%) (Sabatine et al., 2017a). The VESALIUS-CV trial further confirmed these benefits in a high-risk primary prevention population (Bohula et al., 2026). For alirocumab, the ODYSSEY OUTCOMES trial demonstrated that in patients with recent acute coronary syndrome, treatment not only lowered MACE risk but also significantly reduced all-cause mortality (Schwartz et al., 2018). However, large-scale primary prevention cardiovascular outcomes data for alirocumab have not yet been published. The siRNA agent inclisiran has initiated cardiovascular outcomes programs including VICTORION-INITIATE (Novartis, 2025b) and VICTORION-2 PREVENT (Novartis, 2025c), both of which focus on patients with established ASCVD; results for cardiovascular endpoints are still pending. A primary prevention study, VICTORION-1 PREVENT, is ongoing in high-risk individuals without prior ASCVD and is expected to be completed in 2029 (Novartis, 2025d). For other PCSK9 inhibitors currently available in China, comprehensive cardiovascular outcomes data remain limited, and their long-term cardiovascular benefits require further validation in future studies.

Current evidence suggests that evolocumab, alirocumab, and inclisiran may exert beneficial effects on atherosclerotic plaque burden and stability. In the GLAGOV study (Nicholls et al., 2016), evolocumab treatment resulted in a significantly greater reduction in PAV compared with control therapy, with a higher proportion of patients achieving plaque regression. The PACMAN-AMI trial (Biccirè et al., 2023) showed that adding alirocumab to high-intensity statin therapy in patients with acute myocardial infarction produced “triple regression”—reduced PAV, decreased lipid content, and increased fibrous-cap thickness—in approximately one-third of participants, indicating substantial improvements in plaque composition. A recent single-center prospective pilot study of inclisiran in 35 patients with coronary artery disease (Trusinskis et al., 2025) reported a 46.7% reduction in the maximum lipid-core burden index (maxLCBI4 mm) after 15 months of treatment, supporting a potential plaque-stabilizing effect. The VICTORION-PLAQUE study (Revaiah et al., 2026) is aiming to evaluate the efficacy of inclisiran, when compared with placebo, on top of maximally tolerated statin therapy with or without other lipid-lowering therapy in reducing total coronary atheroma volume and atheroma compositional changes assessed by CCTA in patients diagnosed with nonobstructive coronary artery disease (NOCAD). The enrollment has been completed for the VICTORION-PLAQUE study, while the study itself remains ongoing with clinical results not yet available. To date, clinical evidence demonstrating plaque regression effects for other marketed PCSK9 inhibitors remains limited.

4.3 Safety and immunogenicity

Although currently marketed PCSK9 monoclonal antibodies are fully human antibodies, the incidence of anti-drug antibodies (ADAs) varies across agents. Available data indicate that the incidence of ADAs is relatively low with evolocumab (0.3%) (Amgen Inc, 2025), while higher rates have been reported for alirocumab (5.5%) (Sanofi, 2025), recaticimab (14.1%) (Jiangsu Hengrui, 2025), ebronucimab (9.4%) (Akeso Biopharma, 2024), ongericimab (5.8%) (Junshi Biosciences, 2024), and tafolecimab (10.9%) (Innovent Biologics, 2024).

Inclisiran, a chemically synthesized siRNA therapeutic, exhibits inherently low immunogenicity. Clinical data indicate that the incidence of ADAs with inclisiran is approximately 4.9% (Novartis, 2025a), and these antibodies are typically low-titer, transient, and do not significantly impact clinical efficacy (Ray et al., 2020).

Overall, PCSK9 inhibitors exhibit a favorable safety profile and good tolerability, although potential adverse reactions should still be monitored in clinical practice (Chaudhary et al., 2017). Injection-site reactions represent the most commonly reported adverse event for both monoclonal antibodies and siRNA-based agents, typically presenting as localized pain, erythema, or swelling. These reactions are generally mild to moderate, transient, and self-limiting (Kosmas et al., 2020). Other frequently observed adverse events include nasopharyngitis and upper respiratory tract infections.

5 Association of PCSK9 with other diseases5.1 PCSK9 and diabetes: a complex bidirectional relationship

Beyond its well-established role in lipid metabolism, PCSK9 exhibits a bidirectional and intricate relationship with diabetes that extends beyond simple LDL-C–mediated pathways. At the mechanistic level, PCSK9 influences insulin secretion by modulating LDLR expression on pancreatic β-cell surfaces, and circulating PCSK9 levels correlate positively with fasting blood glucose, glycated hemoglobin (HbA1c), and insulin resistance in patients with type 2 diabetes mellitus (T2DM) (Momtazi et al., 2017) (Figure 3). Notably, genetic evidence reveals a potential trade-off between lipid and glucose homeostasis: LOF mutations in PCSK9 may carry a modestly increased risk of diabetes, whereas GOF mutations might confer reduced risk (Schmidt et al., 2017), suggesting that PCSK9 activity may influence glucose regulation through pathways yet to be fully elucidated. Clinically, this genetic complexity raises important therapeutic considerations. However, large-scale randomized controlled trials have provided reassuring evidence that PCSK9 inhibitors, such as evolocumab, exert no adverse effects on glycemic control and do not increase the risk of new-onset diabetes (Sabatine et al., 2017b). Furthermore, PCSK9 inhibitors significantly reduce the risk of MACE, including myocardial infarction, stroke, and cardiovascular death, in diabetic patients with established ASCVD (Sabatine et al., 2017b). Moreover, it’s reported that PCSK9 also accelerates both macrovascular and microvascular complications in diabetic patients through non-LDL-C-dependent pathways involving inflammation, thrombosis, and endothelial dysfunction (Punch et al., 2022; Gao et al., 2024). Together, these findings position PCSK9 as both a metabolic regulator and a therapeutic target in diabetes management, with PCSK9 inhibitors offering cardiovascular benefit without compromising glycemic safety.

Extra-lipid-lowering effects of PCSK9 PCSK9, Proprotein convertase subtilisin/kexin type 9; HCV, Hepatitis C virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; HIV, Human immunodeficiency virus; NASH, Non-alcoholic steatohepatitis; NAFLD, Non-alcoholic fatty liver disease.

5.2 PCSK9 in infectious diseases: from viral pathogens to sepsis

PCSK9 has emerged as a host factor that modulates susceptibility and outcomes across diverse infectious diseases, largely through its regulation of LDLR family members exploited by pathogens for cellular entry and the interaction between PCSK9 and innate immune signaling.

5.2.1 Viral infections5.2.1.1 Hepatitis C virus (HCV)

In vitro experiment demonstrated that LDLR serves as a host entry factor for HCV infection of hepatocytes (Molina et al., 2007). In patients with HCV infection, serum PCSK9 levels are elevated and show a positive correlation with viral load, yet no correlation is observed with LDL-C levels, suggesting that PCSK9 may modulate HCV infection through mechanisms independent of lipid metabolism (Grimm et al., 2021) (Figure 3). Clinical studies reported that plasma PCSK9 levels rise significantly in HCV patients following treatment with direct-acting antivirals (Ichikawa et al., 2019), likely due to upregulation of LDLR after viral clearance. Therefore, caution is warranted when considering PCSK9 inhibitors in patients combined with active HCV infection, to avoid excessive LDLR upregulation that may theoretically facilitate viral particle assembly or cellular entry.

5.2.1.2 SARS-CoV-2

Cholesterol-rich membrane microdomains facilitate the interaction between the SARS-CoV spike protein and angiotensin-converting enzyme 2 (Ren et al., 2006). Observational studies showed that plasma PCSK9 levels were elevated in sepsis patients with SARS-CoV-2 infection compared with non-COVID-19 sepsis patients (Mester et al., 2023) (Figure 3). Experimental evidence suggests that PCSK9 inhibition could reduce inflammatory cytokine levels, attenuate activation of the inflammatory cascade, and lessen lung injury and inflammation (Arsh et al., 2024), thereby may be helpful for preventing the development of acute respiratory distress syndrome. Furthermore, a double-blind, placebo-controlled, multicenter pilot trial (IMPACT-SIRIO 5) demonstrated that PCSK9 inhibition reduced the primary composite endpoint of death or intubation, as well as IL-6 levels, in severe COVID-19 patients compared with placebo (Navarese et al., 2023). In light of these findings, the administration of a single dose of a PCSK9 inhibitor might be considered upon confirmation of COVID-19 infection or observation of disease progression. However, more clinical evidence is needed to support this indication for PCSK9 inhibitor in future.

5.2.1.3 Human immunodeficiency virus (HIV)