Advancing Lipid Management: Saudi Heart Association Position Statement on PCSK9-targeted Therapies in the Primary and Secondary Prevention of Cardiovascular Disease

Abstract

Background

Despite robust evidence for low-density lipoprotein cholesterol (LDL-C) reduction in atherosclerotic cardiovascular disease (ASCVD) prevention, attainment of guideline-recommended targets remains suboptimal in Saudi Arabia, especially among high- and very high-risk patients. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)-targeted therapies, which include monoclonal antibodies (evolocumab, alirocumab) and small interfering RNA (inclisiran), offer potent LDL-C lowering that can help address this gap.

Methods

The Saudi Heart Association (SHA) convened a multidisciplinary panel to review evidence from randomized controlled trials, real-world studies, and economic analyses on PCSK9-targeted therapies. Recommendations were developed through expert consensus, contextualized to the Saudi healthcare environment.

Results and conclusions

PCSK9 inhibitors (evolocumab, alirocumab) lower LDL-C substantially by around 60% and reduce the risk of adverse cardiovascular outcomes when added to maximally tolerated statins. Inclisiran achieves similar LDL-C reductions with biannual dosing, potentially improving adherence, though cardiovascular outcome data are pending. Both drug classes are well tolerated across diverse patient populations, including those with high or very high-risk, familial hypercholesterolemia (FH), recent acute coronary syndrome (ACS), or statin intolerance. The SHA expert panel recommends the early integration of upfront combination treatment including PCSK9-targeted therapies for patients with high risk features unlikely to reach LDL-C goals with statins ± ezetimibe, including recent ACS, FH, established ASCVD, metabolic conditions with end-organ damage, and statin intolerance. For Saudi populations, targeted integration of these agents into combination regimens offers a significant opportunity to close LDL-C treatment gaps and reduce residual ASCVD risk.

1. Introduction

Cardiovascular diseases (CVDs) remain the primary cause of death in the world. In 2022, CVD was responsible for close to 20 million deaths [1,2], accounting for 32% of all global deaths [3]. In Saudi Arabia, CVD is responsible for nearly half of all deaths and age-standardized mortality rates due to CVD exceed the global average [4–7], reflecting a disproportionately high national burden [4,5,8–12]. Projections estimate that by 2035, approximately half a million individuals in the Kingdom will be affected by CVD, and annual costs will nearly triple [5,12]. Notably, the epidemiological profile of CVD in Saudi Arabia differs from that seen in Western populations, characterized by an earlier age of onset and a disproportionately high prevalence of key cardiovascular risk factors, including dyslipidemia [13–18].

Although up to 80% of premature cardiovascular deaths are preventable through optimal control of modifiable risk factors [3], elevated low-density lipoprotein cholesterol (LDL-C) remains the primary causal and modifiable driver of atherosclerotic cardiovascular disease (ASCVD) [2,19,20]. Despite large-scale evidence of cardiovascular risk reduction and disease regression with LDL-C lowering [21,22], attainment of guideline-directed targets remains suboptimal across the world [23–27]. In the Arabian Gulf region, including Saudi Arabia, fewer than one in four patients with high-risk features or established ASCVD achieve recommended LDL-C treatment goals [28–30]. The importance of lipid control also extends beyond secondary prevention, as evidence increasingly demonstrates that prolonged exposure to elevated LDL-C levels beginning in early adulthood significantly increases lifetime cardiovascular risk [31].

The persistent shortfall in LDL-C target attainment, despite the widespread use of statins and ezetimibe, underscores the need for more potent and durable lipid-lowering therapies. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a key regulator of LDL receptor recycling represented a paradigm shift in lipid management [32–34] and led to the development of novel PCSK9-targeted therapies, including the monoclonal antibodies evolocumab and alirocumab, and the small interfering RNA (siRNA) agent inclisiran. These therapies offer substantial LDL-C reduction and cardiovascular risk mitigation, representing a major advancement in lipid management and ASCVD prevention [35,36].

Given the growing burden of CVD and the persistent gaps in LDL-C control in Saudi Arabia, optimizing LDL-C management is an urgent priority. In response, the Saudi Heart Association (SHA) developed this position statement to provide evidence-based guidance on the integration of PCSK9-targeted therapies for both primary and secondary prevention of ASCVD in the Saudi population.

2. Methods

2.1. Expert panel and consensus methodology

A multidisciplinary expert panel representing key specialties involved in lipid management and cardiovascular prevention in Saudi Arabia was convened for the development of this position statement. The panel comprised clinical and interventional cardiologists, cardiac surgeons, an endovascular medicine specialist, an endocrinologist, a family medicine physician, an emergency medicine physician, a clinical pharmacist, and an expert in health policy and pharmacoeconomics.

The expert panel met for two structured virtual meetings to review current evidence on PCSK9-targeted therapies and discuss their applicability within the Saudi healthcare context. The process was informed by a comprehensive, unrestricted literature review covering clinical trials, observational studies, real-world evidence, and relevant guidelines. The objective was to develop contextual, practical, and consensus-driven recommendations for the integration of PCSK9 inhibitors and inclisiran into routine CVD preventive care in Saudi Arabia.

Consensus was achieved through open discussion and moderated real-time deliberation. Areas of disagreement were addressed through clarification of evidence and facilitated dialogue. Recommendations were finalized based on unanimous agreement among panel members, consistent with the established methodological approach of SHA guidance. As per SHA standards, the strength of recommendations was categorized as recommended, should be considered, may be considered, or not recommended, without formal evidence grading.

Draft recommendations and narrative sections were subsequently circulated among all panel members for further review. Feedback was incorporated to ensure accuracy, scientific rigor, and relevance to Saudi practice. Final approval of the position statement was obtained from all experts involved.

2.2. Literature review

A comprehensive literature review was conducted to evaluate the efficacy, safety, clinical outcomes, and practical considerations associated with PCSK9-targeted therapies, including evolocumab, alirocumab, and inclisiran. The search strategy utilized PubMed as the primary database, supplemented by Embase, Scopus, and the Cochrane Library. No restrictions on publication date or language were applied.

Search terms included keywords related to PCSK9 and lipid-lowering therapies (“PCSK9 inhibitors”, “evolocumab”, “alirocumab”, “inclisiran”, “siRNA therapy”, “lipid-lowering agents”), dyslipidemia and ASCVD (“LDL-C”, “atherosclerotic cardiovascular disease”, “familial hypercholesterolemia”, “hypercholesterolemia”), and clinical outcomes (“major adverse cardiovascular events”, “cardiovascular outcomes”, “risk reduction”, “adherence”). Relevant publications were additionally identified through manual review of reference lists from included articles, as well as expert suggestions from panel members familiar with the evolving evidence on PCSK9-targeted therapies.

Priority was given to high-quality evidence from randomized controlled trials, systematic reviews, meta-analyses, and large real-world studies. Observational data, economic evaluations, and international and regional guidelines were also reviewed to ensure a comprehensive and balanced assessment. Particular attention was paid to evidence relevant to the Saudi population, healthcare system structure, treatment availability, and patterns of dyslipidemia and cardiovascular risk.

3. Lipid-lowering therapies: current landscape and unmet needs

3.1. High prevalence of dyslipidemia

Dyslipidemia, particularly elevated LDL-C levels, is a well-established and modifiable driver of ASCVD [2,20]. Its prevalence varies by region, age, sex, and ethnicity, influenced by both genetic and environmental determinants [37]. Global estimates fluctuate, but a meta-analysis of over 200 studies estimated the prevalence of high LDL-C at approximately 19% among adults, with some of the highest rates observed among Middle Eastern populations [38].

In Saudi Arabia, dyslipidemia is highly prevalent in the general adult population. The Kingdom’s World Health Survey (2019–2021) reported elevated total cholesterol in 43% of adults [39], and national cohort data such as the Prospective Urban Rural Epidemiology (PURE) study confirm this burden, with dyslipidemia observed in 32.1% of adults [40]. Among patients with established CVD, rates remain high and may reach up to 52% [13–17,41]. Observed differences in dyslipidemia prevalence likely reflect methodological heterogeneity, including variations in age eligibility criteria, lipid thresholds, and sampling design.

Notably, the early manifestation of dyslipidemia was also evident in Saudi Arabia, with 25% of adolescents in the Jeeluna study and nearly one-third of schoolchildren in Riyadh having abnormal lipid profiles [42,43]. Familial hypercholesterolemia (FH), a genetic condition characterized by persistently elevated LDL-C levels, is also disproportionately common in the Arabian Gulf (1 in 112 people), nearly threefold higher than the global average (1 in 313 people) [44,45]. Further compounding the high prevalence of this condition is the dismal rates of LDL-C target attainment, reported at only 12% and 3% among patients at high and very high ASCVD risk, respectively [44].

Although prevalence estimates vary across studies, the collective evidence consistently indicates a high baseline risk and burden related to dyslipidemia and a pressing need to optimize detection, prevention and management strategies to reduce lifetime cardiovascular risk in Saudi Arabia.

3.2. Achievement of LDL-C targets: global and Saudi Arabian perspectives

Despite clear guideline recommendations from international and local bodies, LDL-C treatment goals are frequently unmet, even in high-risk populations receiving lipid-lowering therapy [23–30]. As shown in Fig. 1, this treatment gap is evident both globally and regionally. The Centralized pan- Middle East Survey on the undertreatment of hypercholesterolemia (CEPHEUS) study, which included over 35,000 patients worldwide, reported that approximately 80% of those at very high risk failed to achieve LDL-C targets [23]. Similar trends have been observed in Europe and North America, where registry-based data underscore the challenge of translating guideline-directed therapy into clinical practice, as reflected in poor risk-based LDL-C goal attainment [25,27,46].

Fig. 1.

Current Landscape of Cardiovascular Diseases and Dyslipidemia in Saudi Arabia Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; CVD: cardiovascular disease; LDL-C: low-density lipoprotein cholesterol. * Data from Saudi Arabia only. Dyslipidemia and LDL-C target attainment data derived from studies with differing age inclusion criteria and definitions of dyslipidemia [13,14,23–36,28–30,40].

Although some improvements have been observed in the context of acute coronary syndromes (ACS) that are attributable to structured care models and training initiatives, these gains remain limited [27]. Data from the Arabian Gulf region, including Saudi Arabia, show that only 25% of patients with established ASCVD, ACS or high-risk profiles achieve LDL-C goals [28–30]. The most recent regional data comes from the Gulf Achievement of Cholesterol Targets in Out-Patients (GULF ACTION) registry, which recently confirmed that the vast majority (92%) of patients with dyslipidemia in the Arabian Gulf region are at high or very high ASCVD risk, but less than a quarter of them achieve their LDL-C target [47]. This is likely due to the suboptimal utilization of combination lipid-lowering therapy. Alarmingly, a national survey of Saudis conducted in 2013 highlighted substantial gaps in dyslipidemia screening and management, with around 70% remaining undiagnosed or undertreated [48].

Even among those receiving therapy, treatment regimens are often inadequate. Combination therapies such as statin plus ezetimibe are underutilized, and add-on therapy remains rare, even in ACS settings where intensive management is essential [49]. Consistently, LDL-C target level attainment is very poor among CVD patients, reported at approximately 25% in stable coronary artery disease (CAD) and 11% in high-risk patients with ACS [30]. These findings point to systemic gaps in screening, risk stratification, and therapeutic intensification in Saudi Arabia [50,51]. Addressing these challenges is critical, especially in light of evidence that nearly 40% of incident cardiovascular events occur in individuals without established CVD [52]. This underscores the importance of supplementing secondary prevention efforts with comprehensive primary prevention strategies to achieve optimal cardiovascular outcomes in local populations.

3.3. Barriers to achieving LDL-C targets with conventional lipid-lowering therapy

Conventional lipid-lowering therapies, particularly statins and ezetimibe, remain the cornerstone of LDL-C management. This long-standing preference is driven more by historical precedence, cost-effectiveness, and accessibility than by demonstrable superiority over newer non-statin therapies. In fact, the ability of maximally tolerated statins and ezetimibe to achieve guideline-recommended LDL-C targets is often limited [53], reflecting barriers at drug-, patient-, physician-, and system-levels. Many patients remain untreated, undertreated, or non-adherent, leaving LDL-C above guideline targets and exposing them to ongoing residual risk and high rates of major adverse cardiovascular events (MACE) [54–60].

Nonetheless, statins are capable of producing substantial reductions in LDL-C that may exceed 50%, particularly when used in combination with agents such as ezetimibe [61,62]. In addition to their lipid-lowering efficacy, intensive statin therapy has been shown to significantly reduce long-term cardiovascular risk and the incidence of MACE, with the greatest absolute benefit observed among patients with higher baseline LDL-C levels [63–65]. However, in cases requiring more intensive LDL-C lowering, such as patients with markedly elevated baseline levels or those with statin intolerance, statin monotherapy often fails to achieve therapeutic targets, reinforcing the clinical rationale for combination therapy [66,67]. This is particularly evident in patients with high- and very-high-risk for whom dual targets are recommended, with the Statin Therapy Assessment and Real-world Treatment (START) registry showing that only 3.2% of patients achieve both [68]. Moreover, the efficacy and tolerability of statin monotherapy show marked interindividual variability, influenced by pharmacokinetic and metabolic factors, genetic determinants, comorbidities, hepatic function, and concomitant medications [21,69,70]. Notably, some statins may modestly increase lipoprotein(a) and upregulate PCSK9, which limits LDL-C reductions achieved with monotherapy and possibly leads to disease exacerbation [71–75].

Despite relative reductions of 50% or higher (particularly with high intensity statins), multiple meta-analyses and clinical trials have demonstrated that relative LDL-C reduction alone may be insufficient to optimize cardiovascular outcomes. Rather, achieving specific absolute LDL-C targets is critical to maximizing benefit, especially in patients at high or very high cardiovascular risk [76,77]. Supporting this, target-driven strategies have recently demonstrated equivalent outcomes to using high-intensity statins alone when LDL-C concentrations were brought to levels in the range of 50–70 mg/dL [78,79].

Real-world adherence to long-term statin therapy, particularly high-intensity regimens, remains suboptimal and generally inferior to that of PCSK9-targeted therapies [80]. Factors contributing to this include dose-dependent side effects (whether biologically confirmed or nocebo-related), the burden of polypharmacy in patients with multiple comorbidities, and persistent therapeutic inertia [81–83]. In particular, statin intolerance manifesting primarily as statin-associated muscle symptoms (SAMS) remains a major barrier, and is reported in up to 30% of patients [84–86]. Although statin intolerance is often driven by patient perception (nocebo effect) rather than pharmacologic action, true statin intolerance, defined as adverse effects that resolve or improve upon dose reduction or discontinuation, can still occur in around 5–9% of patients [86]. It may be complete (inability to tolerate any statin) or partial (inability to tolerate doses required to achieve LDL-C targets), and diagnosis necessitates trial of ≥2 statins, including one at the lowest approved dose [85]. Patient nonadherence further limits LDL-C control with statins [81,82,87,88], with fewer than 25% remain on statins at five years in real-world practice [88–90]. System-level barriers, including cost, limited specialist access, and lack of standardized LDL-C monitoring, compound these gaps [87].

Physician-related factors, including under-prescribing guideline-recommended lipid lowering therapies and clinical inertia, further hinder LDL-C target achievement [87,88,91]. The Treatment of High and Very High riSk Dyslipidemic pAtients for the PreveNTion of CardiOvasculaR Events in Europe - a MultInatioNal ObservatIonal Study (SANTORINI) registry revealed that approximately 20% of patients at high or very high cardiovascular risk were not receiving any lipid-lowering therapy, and over 50% were prescribed monotherapy alone [25]. Similarly, the EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care (Da VINCI) study highlighted considerable implementation gaps, with combination therapies (statin combined with ezetimibe or PCSK9 inhibitors) underutilized, despite their clear association with higher LDL-C goal attainment [46]. These treatment gaps are also evident across the Arabian Gulf region, including Saudi Arabia, where the uptake of combination lipid-lowering regimens remains low [29,49]. Such gaps contribute significantly to the suboptimal control of dyslipidemia across risk categories and underscore the need for more effective therapeutic strategies to improve lipid management and reduce the burden of cardiovascular disease.

PCSK9-targeted therapies have emerged as a critical advancement in addressing this unmet need. These drugs offer high efficacy, a favorable safety profile, and the potential to close the LDL-C treatment gap as will be discussed in detail in the following section.

4. PCSK9-targeted therapies positioning in CVD management

4.1. Implication of PCSK9 in the pathophysiology of ASCVD

The causal role of LDL-C in the development of ASCVD is well-established, with a robust body of evidence supporting its centrality in the pathogenesis of cardiovascular events [20]. This has led to the widespread integration of lipid-lowering therapies into standard CVD prevention and management strategies. A major breakthrough in the understanding of lipid metabolism occurred in 2003, when Abifadel et al. identified gain-of-function mutations in the PCSK9 gene as a cause of autosomal dominant hypercholesterolemia [33]. Since then, PCSK9 has been firmly established as a pivotal regulator of cholesterol homeostasis and a highly promising therapeutic target in the treatment of dyslipidemia and ASCVD [34,92] (Fig. 2A).

Fig. 2.

PCSK9-Targeted Therapies: Historical Milestones and Mechanisms of Action. A. Timeline of PCSK9 discovery and clinical development of PCSK9-targeted therapies. B. Mechanism of action of commonly used lipid-lowering therapies and PCSK9-targeted therapies. Abbreviations: ASCVD: atherosclerotic cardiovascular disease; CVOT: cardiovascular outcomes trial; CVD: cardiovascular disease; FH: familial hypercholesterolemia; HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A; HoFH: homozygous familial hypercholesterolemia; LDL: low-density lipoprotein; LDL-C: low-density lipoprotein cholesterol; LDLR: low-density lipoprotein receptor; mAbs: monoclonal antibodies; NPC1L1: Niemann-Pick C1-like 1; PCSK9: proprotein convertase subtilisin/kexin type 9.

PCSK9 contributes to atherogenesis primarily by promoting degradation of hepatic LDL receptors, thereby reducing LDL-C clearance and elevating plasma LDL-C levels. In addition to its lipidmodifying effects, PCSK9 has been implicated in several pro-atherogenic pathways, including vascular inflammation, endothelial dysfunction, and plaque instability [92], reinforcing its role in CVD pathophysiology.

These discoveries catalyzed the development of multiple PCSK9-targeted therapeutic approaches, several of which remain under investigation in preclinical and clinical studies. Currently, three PCSK9-targeted agents with two distinct mechanisms of action have been approved for the treatment of primary and refractory hyperlipidemias: the monoclonal antibodies alirocumab and evolocumab, and the siRNA therapy inclisiran (Fig. 2A).

While traditional therapies such as statins inhibit endogenous cholesterol biosynthesis and ezetimibe reduces intestinal cholesterol absorption, PCSK9- targeted therapies intervene directly in the regulation of LDL receptor recycling. Alirocumab and evolocumab function by binding to circulating PCSK9, thereby preventing LDL receptor degradation and enhancing LDL-C clearance. In contrast, inclisiran employs RNA interference to inhibit PCSK9 gene expression, reducing both intracellular and extracellular PCSK9 protein levels, and thereby sustaining LDL receptor availability and lowering plasma LDL-C concentrations (Fig. 2B).

4.2. Clinical efficacy of PCSK9-targeted therapies

4.2.1. LDL-C lowering

All available PCSK9-targeted therapies have demonstrated robust LDL-C-lowering efficacy and favorable safety profiles in clinical trials, particularly among high-risk patients with ASCVD or FH (Supplementary Tables 1–4).

Landmark clinical trials have established the efficacy of PCSK9 inhibitors evolocumab and alirocumab in achieving meaningful LDL-C reductions in high-risk patients with ASCVD or primary hyperlipidemias (Supplementary Tables 1–4). LDL-C levels can be reduced by 60% or more when PCSK9 inhibitors are used in combination with statins, and by 50–60% when used as monotherapy [93–111]. Comparable LDL-C reductions were shown with the siRNA inclisiran, which reduced LDL-C levels in clinical trials by up to 60%, including in the context of primary prevention (VICTORIONMONO) [112–117].

Collectively, studies revealed consistent LDL-C lowering with PCSK9-targeted therapies across various high-risk clinical subgroups [102,117–120], such as patients at high ASCVD risk, patients with statin intolerance, patients with FH, patients with diabetes, and ACS. Importantly, PCSK9-targeted therapies are safe and well tolerated, and provide significant LDL-C reductions that are superior to other therapies such as statins, bempedoic acid, and ezetimibe [36,121,122]. Moreover, there is currently no evidence to support the preference of one PCSK9-targeted therapy over another, as both PCSK9 inhibitors (evolocumab, alirocumab) and siRNA inclisiran provide comparable clinically meaningful improvements in LDL-C levels [36,121].

The recently approved small anti-PCSK9-binding protein lerodalcibep also has demonstrated substantial LDL-C reductions (≈56–65%) across diverse high-risk populations [123,124], consistent with the effects observed for established PCSK9 inhibitors and siRNA therapy. However, lerodalcibep is not yet commercially available and has not yet received SFDA approval. Another emerging therapy, enlicitide decanoate, is an oral PCSK9 inhibitor that has shown LDL-C reductions approaching 60% (≈55–58) in Phase 3 trials among patients with ASCVD, HeFH or elevated cardiovascular risk [125,126]. While these novel agents extend the range of PCSK9-targeted options and offer potential advantages in convenience or dosing, further randomized data and regulatory authorization are required before they can be incorporated into routine clinical practice.

4.2.2. Cardiovascular risk reduction

In addition to their LDL-C lowering effect, PCSK9 inhibitors significantly reduce cardiovascular risk as demonstrated in dedicated cardiovascular outcome trials. When used in addition to maximally tolerated statins, both evolocumab and alirocumab were associated with significant reductions in the risk of MACE among patients with established ASCVD and recent ACS, respectively [108,127,128]. Extended follow-up confirmed further cardiovascular risk reduction with continued use of PCSK9 inhibitors, without any increase in long-term adverse events [127,129]. Evolocumab has also recently been demonstrated to be beneficial for primary prevention of cardiovascular events in patients with atherosclerosis or diabetes who had not previously experiences a myocardial infarction or stroke [130]. Preliminary, non-conclusive evidence showed that siRNA inclisiran may also potentially reduce cardiovascular risk [36,131,132], a benefit that is expected to be confirmed by ongoing cardiovascular outcome trials (NCT03705234, NCT05030428, and NCT05739383).

4.2.3. Reduction of plaque burden

Beyond LDL-C lowering and cardioprotective benefits, direct imaging studies have revealed the potential of PCSK9-targeted therapies to reduce atherosclerotic plaque burden. While evidence with inclisiran is still pending (VICTORION-PLAQUE Phase IV trial ongoing), evolocumab and alirocumab have evident benefit in terms of plaque regression and stabilization [122], extending their role beyond LDL-C lowering into atherosclerosis reversal.

4.3. Real-world effectiveness and adherence of PCSK9- targeted therapy

Randomized clinical trials are crucial for the investigation and demonstration of a therapy’s safety and efficacy, but real-world practice does not always reflect the same results as those seen in controlled clinical settings. Notably, several studies have reported that the benefit of PCSK9-targeted therapies in real-world practice is consistent with, albeit slightly lower than, that reported in pivotal clinical trials in terms of LDL-C lowering. For example, evolocumab, alirocumab and inclisiran have all been shown to be safe and effective in routine practice, achieving significant reductions in LDL-C levels among patients with hyperlipidemia, established CVD and FH, including patients who were reportedly statin intolerant [133–142]. In the context of Saudi Arabia, published real-world evidence remains scarce but notable data are emerging. Reports on the use of evolocumab [143–145] and inclisiran (Preliminary results from the RADICAL study; unpublished data, 2025) indicate that these medications can significantly lower LDL-C levels in Saudi patients with hyperlipidemia and/or FH who have not achieved their lipid targets through conventional therapy.

Although limited, there are real-world data showing that PCSK9 inhibitors evolocumab and alirocumab result in clinically equivalent reductions in LDL-C, and can be used interchangeably [136,146]. In the absence of head-to-head trials between PCSK9-targeted therapies, the choice between Evolocumab, alirocumab and inclisiran will remain largely dependent on availability and accessibility of these therapies. Although long-term safety is still unknown for both drug classes, patient- related considerations might favor one drug class over another particularly in case of adherence issues. Compared to PCSK9 inhibitors which are administered once or twice a month, inclisiran has a more favorable dosing regimen with biannual HCP-led administration that might improve therapeutic adherence significantly [147,148]. Improving patient compliance is important considering the high rate of lipid-lowering treatment discontinuation reported in real-world settings, including with PCSK9 inhibitors [80,149–151]. Inclisiran offers long-lasting effect due to intracellular action and hepatic uptake and significant LDL-C lowering. While its LDL-C benefit is comparable to PCSK9 inhibitors, its cardiovascular benefit is not yet fully established as cardiovascular outcome trials are still ongoing, with positive results expected based on preliminary evidence [36,131,132]. This further supports inclisiran and PCSK9 inhibitors being comparable therapeutic options for patients failing to achieve LDL-C targets on conventional therapy, or with very high baseline LDL-C levels requiring potent therapy.

4.4. Cost-effectiveness of PCSK9 targeted therapy

Drug accessibility remains a major challenge in the implementation of PCSK9 targeted therapies and is predominately driven by cost-effectiveness considerations. While the LDL-C lowering efficacy of PCSK9-targeted therapies is well-established, their real-life impact on cardiovascular outcomes and death remains less certain outside the controlled setting of clinical trials. More importantly, their high acquisition costs limit widespread uptake. Consequently, within most healthcare systems, the cost-effectiveness of PCSK9-targeted therapies is primarily driven by their use in higherrisk patient populations, while broader implementation is influenced by reductions in acquisition costs and evolving reimbursement structures.

In this context, both the National Institute for Health and Care Excellence (NICE; UK) and Canadian Agency for Drugs and Technologies in Health (CADTH; Canada) recommend the PCSK9 inhibitors evolocumab and alirocumab for patients with heterozygous familial hypercholesterolemia who fail to achieve LDL-C targets despite optimized standard therapy. However, these recommendations are contingent upon the application of significant, typically confidential, discounts that can approach 50% of list prices to achieve acceptable cost-effectiveness, particularly in patients treated for primary hypercholesterolemia or mixed dyslipidemia with high or very high cardiovascular risk [152–155]. Similarly, analyses in Saudi Arabia suggest that evolocumab offers good value for patients with familial hypercholesterolemia but is less cost-effective for broader ASCVD populations unless prices are significantly reduced or outcomebased agreements are implemented [156–158]. For example, while the traditional threshold for costeffectiveness in Saudi Arabia is higher, recent health economic benchmarks indicate that most ASCVD patients would not meet cost-effectiveness targets without targeted pricing strategies [156,157].

Comparable concerns extend to inclisiran, especially in the absence of published data from dedicated cardiovascular outcome trials [131,159]. While inclisiran demonstrates robust and sustained LDL-C lowering, health technology assessment bodies have highlighted ongoing uncertainties regarding its long-term impact on cardiovascular morbidity and mortality, pending results from large outcomes trial such as ORION-4 [160,161]. Consequently, both NICE and CADTH currently position inclisiran as a stepwise intensification therapy rather than an upfront combination option, restricting reimbursement to patients who remain above LDL-C targets despite maximum tolerated statin therapy [160,161], consistent with recommendations for PCSK9 inhibitors. From an economic perspective, health technology assessment frameworks such as NICE and CADTH suggest that inclisiran may require price reductions of up to 32% to ensure long-term sustainability. However, these assessments also recognize that, over extended treatment durations exceeding two years, inclisiran’s infrequent dosing schedule may offset cumulative costs, effectively eliminating the need for additional price reductions when compared with the public list prices of the PCSK9 inhibitors [160,161].

The high cost of PCSK9-targeted therapies must therefore be addressed by national healthcare authorities through strategic price negotiations and value-based agreements to ensure equitable access and maximize population-level benefit. In the meantime, and until more outcome data or less costly treatments are available, PCSK9-targeted therapies should be reserved for patients most likely to benefit, with a focus on maximizing clinical impact while ensuring responsible healthcare spending.

5. PCSK9-targeted therapies in the primary and secondary prevention of cardiovascular disease: SHA recommendations

5.1. Overarching principles: maximizing lifetime cardiovascular protection

As previously mentioned, LDL-C is a causal driver, not merely a marker, of ASCVD [19,20]. Randomized clinical trials and meta-analyses have established a consistent, log-linear relationship between the magnitude of LDL-C reduction and the risk of major adverse events that is consistent across diverse patient populations and treatment modalities, including statins, ezetimibe, and PCSK9 targeted therapy; each 1 mmol/L (~39 mg/dL) reduction in LDL-C lowers the relative risk of MACE by approximately 20%–25% [65,76,162–165]. Notably, cardiovascular benefits persist even at baseline LDL-C ≤70 mg/dL, where each 1 mmol/L reduction confers an additional 21% reduction in MACE [65,166,167], and among lower-risk populations [168,169]. Importantly, achieving very low LDL-C levels (15–25 mg/dL) confers maximal cardiovascular protection without safety concerns [127,166,167,170–173]. Meta-analyses also show that starting LDL-C–lowering therapy earlier in life produces the greatest cardiovascular benefit per mmol/L reduction, independent of baseline LDL-C or overall risk profile [19,174].

Given that cardiovascular benefit is determined not only by the magnitude of LDL-C lowering, but also by its timing and duration, lipid management strategies began following three major guiding principles: the lower, the earlier, and the longer, the better. In alignment with these principles, international guidelines have progressively lowered LDL-C targets, particularly for patients at high- and very high-risk, recommending a stepwise approach to achieve LDL-C targets. However, the limitations of stepwise approach and statin monotherapy, particularly evident in persistent gaps in LDL-C target achievement (see Section 3.3), have driven a paradigm shift to high-intensity therapy combining moderate- to high-intensity statins plus PCSK9- targeted agents, with or without ezetimibe.

Clinical evidence supports the early implementation of combination therapy including PCSK9-targeted therapies after failure to achieve LDL-C despite maximally tolerated statins [111,175–186]. Notably, LDL-C reductions of up to 85% can be achieved with the combination of maximally-tolerated statins, ezetimibe, and PCSK9 targeted therapies [187,188]. The use of statins in combination with PCSK9 inhibitors or inclisiran consistently results in the highest reductions of LDL-C and major cardiovascular events compared to other nonstatin therapies [53]. The cardiovascular benefit of LDL-C lowering increases with duration of treatment and with additional LDL-C reduction achieved, as each 1 mmol/L lower LDL-C is associated with around 24% lower risk [189]. For example, patients with persistent hyperlipidemia on maximum statin doses who received inclisiran immediately in the VICTORION-INITIATE trial had substantially higher LDL-C lowering compared to usual care (60% vs 6%). Importantly, this approach did not impact statin use or raise any new safety concerns, further supporting the applicability of early PCSK9-targeted therapy use [115]. Moreover, the adoption of an upfront combination strategy without escalation to high-intensity statins is supported by the non-inferiority of moderate-intensity statin + ezetimibe to high-intensity statin in terms of LDL-C lowering [190] and the comparable LDL-C outcomes achieved on both moderate-and high-intensity statin backgrounds in the Evolocumab (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk [FOURIER]), alirocumab (ODYSSEY OUTCOMES) and inclisiran (ORION-9/10/11) trials.

However, it is important to note that the absolute benefit for intensification of lipid-lowering therapy with PCSK9-targeted therapies will be achieved by a subset of patients with established CVD and high or very high risk. The addition of PCSK9-targeted therapy, with or without ezetimibe, is therefore recommended to achieve optimal LDL-C reductions and cardiovascular outcomes for these subsets, which include patients with recent ACS, and patients with ASCVD and concomitant risk enhancers (e.g. diabetes mellitus, metabolic syndrome, PAD, MI, CAD, FH, etc.) [128,191–200]. For example, randomized and observational studies have shown that early LDL-C targets can be achieved in at least 90% of patients with ACS with the early initiation of PCSK9-targeted therapy during hospitalization [111,184–186,201–206].

There are limited but positive data supporting the use of PCSK9 inhibitors (Evolocumab, alirocumab) as alternative therapies for patients with statin intolerance, where significantly higher LDL-C reductions were achieved compared to ezetimibe, with a marked reduction in muscle symptoms [94,107,207]. Substantial and durable LDL-C lowering (45.8% at 16.8 months) has also been reported in a subgroup analysis of statin intolerant patients from the ORION-10 and 11 trials, with similarly acceptable adverse event profile, supporting inclisiran’s potential as a therapeutic option for these patients [208]. For patients with confirmed statin intolerance, upfront combination therapy including a PCSK9-targeted therapy is recommended to improve LDL-C and cardiovascular outcomes and avoid statin-related side effects.

While PCSK9-targeted therapies are effective for LDL-C lowering in patients with FH, there are limited cardiovascular outcome data from these populations [97,105,112,113]. Regardless, FH patients are considered to be at very high risk of premature CVD, which can be alleviated with proper treatment [209,210]. Therefore, upfront combination therapy is also recommended for patients with a clinical diagnosis of FH. The efficacy of PCSK9 inhibitors (evolocumab, alirocumab) and inclisiran is well established in heterozygous FH, whereas their LDL-C–lowering benefit in homozygous FH is less potent, as it depends on the presence of residual LDL receptor activity [114,211,212].

5.2. Recommended LDL-C management approach

The SHA endorses adherence to the principles of “the lower, the earlier, and the longer, the better” through the implementation of high-intensity combination lipid-lowering therapy in eligible patients to achieve durable cardiovascular risk reduction. The SHA also recognizes that PCSK9- targeted therapy as part of combination therapy represents effective strategy for addressing key gaps in LDL-C control and persistent unmet needs in cardiovascular prevention. By further reducing LDL-C and other atherogenic lipids beyond what is achievable with statins and ezetimibe, PCSK9-targeted therapy enables most patients to reach guideline-recommended targets while also improving their adherence, promoting plaque stabilization and regression, and reducing adverse events while demonstrating excellent safety and tolerability.

On the basis of the presented evidence, early use of combination therapy including moderate- to high-intensity statin, ezetimibe and PCSK9-targeted therapies (evolocumab, alirocumab, inclisiran) is strongly recommended in patients who would benefit most, which are those at high, very high or extremely high cardiovascular risk (Table 1) who are unlikely to achieve LDL-C lowering with statins as monotherapy or combined with ezetimibe alone. This includes individuals with established or recurrent ASCVD, recent ACS, polyvascular or multivessel disease, familial hypercholesterolemia, diabetes with target organ damage, chronic kidney disease, metabolic syndrome, and those with statin intolerance. Early, high-intensity combination therapy is recommended in these populations as it provides the greatest absolute LDL-C reductions and cardiovascular risk mitigation.

Table 1.

Cardiovascular risk categories and corresponding LDL-C targets.

Risk Category	Criteria	LDL-C Targets
Low Risk	Calculated SCORE2 or SCORE2-OP <2% for 10-year risk of fatal or non-fatal CVD.	<3 mmol/L (<116 mg/dL)
Moderate Risk	People with any of the following: Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors. Calculated SCORE2 or SCORE2-OP ≥2% and <10% for 10-year risk of fatal or non-fatal CVD.	<2.6 mmol/L (<100 mg/dL)
High Risk	People with any of the following: Markedly elevated single risk factors, in particular TC >8 mmol/L(>310 mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP ≥180/110 mmHg. Patients with FH without other major risk factors. Patients with DM without target organ damage, with DM duration ≥10 years, or with another additional risk factor. Moderate CKD (eGFR 30–59 mL/min/1.73 m2). A calculated SCORE2 or SCORE2-OP ≥10% and <20% for 10-year risk of fatal or non-fatal CVD.	<1.8 mmol/L (<70 mg/dL) And > 50% reduction
Very High Risk	People with any of the following: Documented ASCVD a, either clinical or unequivocal on imaging b. FH with ASCVD or with another major risk factor. DM with target organ damage c, or at least three major risk factors, or early onset of T1DM of long duration (>20 years). Severe CKD (eGFR <30 mL/min/1.73m2}). A calculated SCORE2 or SCORE2-OP ≥20% for the 10-year risk of fatal or non-fatal CVD.	<1.4 mmol/L (<55 mg/dL) And > 50% reduction
Extremely High Risk	Recurrent ASCVD events Polyvascular disease (coronary, peripheral arterial disease, including cerebral vascular disease) Post-ACS status with any of the following: Another vascular event within the preceding 2 years Peripheral artery disease or polyvascular disease Multivessel coronary artery disease Familial hypercholesterolemia	<1 mmol/L (<40 mg/dL) And > 50% reduction

^aDocumented ASCVD includes previous ACS (MI or unstable angina), chronic coronary syndromes, coronary revascularization (PCI, CABG, and other arterial revascularization procedures), stroke and TIA, and peripheral arterial disease.

^bUnequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events, such as significant plaque (≥50%) on coronary angiography or CT scan, or on carotid or femoral ultrasound, or markedly elevated CAC score (>300) by CT.

^cTarget organ damage is defined as microalbuminuria, retinopathy, or neuropathy.

Abbreviations: ASCVD: atherosclerotic cardiovascular disease; BP: blood pressure; CKD: chronic kidney disease; DM: diabetes mellitus; eGFR: estimated glomerular filtration rate; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; SCORE2: Systematic Coronary Risk Evaluation 2; SCORE2-OP: Systematic Coronary Risk Evaluation 2-Older Persons; T1DM: type 1 DM; T2DM: type 2 DM; TC: total cholesterol.

In patients for whom upfront combination therapy is indicated but who have borderline LDL-C levels based on their respective target, the decision to escalate lipid lowering therapy is left to the discretion of the treating physician to be made based on clinical judgment. Otherwise, a stepwise approach is recommended starting with low or moderate dose statins, and escalated as appropriate with statin dose increase or addition of a non-statin therapy as available and accessible, such as a PCSK9 inhibitor (evolocumab, alirocumab), the siRNA inclisiran, and ezetimibe.

Treatment initiation should be preceded by assessment of clinical history and risk factors, in addition to SCORE2-based risk assessment and related risk enhancers (see Mach et al. for more details on SCORE 2, SCORE 2-OP and related risk enhancers [214]). Once baseline LDL-C levels and cardiovascular risk categories are determined, LDL-C targets can be established (Table 1). Based on this, the appropriate treatment can be initiated taking into consideration expected LDL-C reduction with available lipid-lowering therapies (Table 2).

Table 2.

Comparative LDL-C reduction with available therapies [21,22,94,102,103,107,213–218]

Drug/Class	LDL-C Reduction
Statins
Low-intensity statin	<30%
Moderate-intensity statin	30–50%
High-intensity statin	50–60%
Ezetimibe	15–20%
PCSK9-targeted therapy a
PCSK9 mAbs (Alirocumab/Evolocumab)	50–70%
Inclisiran (siRNA)	43–60%
Combination therapies
Low-intensity statin + ezetimibe	~44%
Moderate-intensity statin + ezetimibe	45–50%
High-intensity statin + ezetimibe	60–65%
PCSK9-targeted therapy + ezetimibe	~70%
PCSK9-targeted therapy + low- to moderate-intensity statin	72–76%
PCSK9-targeted therapy + high-intensity statin	80%
PCSK9-targeted therapy + ezetimibe + low- to moderate-intensity statin	78–80%
PCSK9-targeted therapy + ezetimibe + high intensity statin	85%

Abbreviations: LDL-C: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9; siRNA: small interfering ribonucleic acid.

^aPCSK9-targeted therapy includes both PCSK9 inhibitors, evolocumab and alirocumab, as well as siRNA-based Inclisiran.

LDL-C management should rely on baseline cardiovascular risk category, as outlined in the algorithm presented in Fig. 3. Lifestyle interventions form the first-line approach for low and moderate risk individuals, aiming for an LDL-C target of <3 mmol/L (<116 mg/dL) and <2.6 mmol/L (<100 mg/dL), respectively. If this goal is not met within 6–12 weeks, low to moderate-intensity statin therapy should be initiated, reassessed at 4- to 6- week intervals. Addition of ezetimibe can also be considered if targets remain unmet. Physicians should be aware that the presence of risk enhancers such as elevated lipoprotein(a), high-sensitivity C-reactive protein, or increased coronary artery calcium score may warrant further risk refinement and could result in reclassification of low- and moderate- risk individuals to a higher risk category, thereby influencing treatment intensity. For example, healthy individuals with low-moderate risk but very high LDL-C levels (>4.9 mmol/L) are considered to be at least high-risk and should be managed accordingly.

Fig. 3.

Saudi Heart Association consensus algorithm for the integration of PCSK9-targeted therapies in clinical practice for the prevention of CVD through effective LDL-C lowering. a: PCSK9-targeted therapy includes both PCSK9 inhibitors evolocumab and alirocumab, as well as siRNA inclisiran. b: if complete statin intolerance, consider upfront combination of ezetimibe and PCSK9-targeted therapy omitting statin. Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; PCSK9: proprotein convertase subtilisin/kexin type 9; siRNA: small interfering ribonucleic acid.

Dual treatment targets should be achieved for high-, very high- and extremely high-risk patients (<1.8 mmol/L (<70 mg/dL), <1.4 mmol/L (<55 mg/dL), and <1 mmol/L (40 mg/dl)) respectively, with a >50% reduction from baseline. For high-risk patients, upfront triple combination therapy should be initiated when indicated. Otherwise, dual therapy with a moderate- to high-intensity statin plus ezetimibe is recommended regardless of baseline LDL-C. For very high- and extremely high-risk patients, upfront triple combination therapy is recommended regardless of baseline LDL-C levels. Patients with partial statin intolerance should be considered for upfront combination of maximally tolerated statins with ezetimibe, while those with complete statin intolerance may benefit from upfront combination of ezetimibe and PCSK9-targeted therapy.

The role of bempedoic acid, which is not currently available in the Kingdom, is beyond the scope of this document.

After therapy initiation, LDL-C levels should be reassessed after 4–6 weeks to determine treatment efficacy and the need for escalation. For ACS, LDL-C levels should be assessed within 12 h of hospitalization.

6. Conclusion

PCSK9-targeted therapies represent a major advance in lipid management, enabling profound and sustained LDL-C lowering in high- and very high-risk patients who fail to achieve targets with conventional therapy. Evolocumab and alirocumab have demonstrated not only ~60% reductions in LDL-C but also significant reductions in major adverse cardiovascular events. Inclisiran offers comparable LDL-C lowering with a twice-yearly dosing regimen, which may improve long-term adherence, although definitive cardiovascular outcome data are pending. For Saudi patients, where dyslipidemia prevalence, premature ASCVD onset, and suboptimal LDL-C goal attainment are common, early and targeted use of upfront combination therapy including PCSK9 inhibitors or inclisiran in patients with persistently elevated LDL-C despite optimal statin and ezetimibe and high-risk features (ACS, FH, established ASCVD, metabolic conditions with end-organ damage, statin-intolerance) has the potential to markedly reduce cardiovascular risk. Implementation should balance clinical benefit with cost-effectiveness, prioritizing those most likely to achieve substantial absolute risk reduction. To ensure equitable access and maximize population-level benefit, relevant Saudi health authorities must also address the high cost of PCSK9-targeted therapies through strategic price negotiations and value-based agreements. Addressing pricing barriers is crucial, as the integration of these agents into combination lipid-lowering strategies is essential to close the treatment gap and improve long-term cardiovascular outcomes in Saudi Arabia.

Supplementary Data

Supplementary Table 1.

LDL-C reduction with evolocumab: Results from pivotal Phase 3 randomized controlled trials.

Study (First Author, Year)	Population (N)	Intervention	Primary Endpoint(s)	% LDL-C Reduction
DESCARTES (Blom, 2014) [101]	Hyperlipidemia on background lipid-lowering therapy (N = 901)	Evolocumab 420 mg QM vs. placebo	% LDL-C change at week 52	57%
GAUSS-2 (Stroes, 2014) [102]	Statin-intolerant patients with hypercholesterolemia (N = 307)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo or ezetimibe (10 mg)	% LDL-C change at the mean of weeks 10 and 12, and at week 12	From baseline: 53–56%; 37–39% greater reduction vs. ezetimibe
MENDEL-2 (Koren, 2014) [103]	Hypercholesterolemia and framingham risk scores ≤10% (N = 614)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo or ezetimibe	% LDL-C change at the mean of weeks 10 and 12, and at week 12	From baseline: 55%–57% vs placebo; 38%–40% greater reduction vs. ezetimibe
LAPLACE-2 (Robinson, 2014) [104]	Primary hypercholesterolemia and mixed dyslipidemia (N = 2067)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo or ezetimibe	% LDL-C change at the mean of weeks 10 and 12, and at week 12	66%–75% every 2 weeks; 63%–75% monthly vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups
RUTHERFORD-2 (Raal, 2015) [105]	Heterozygous FH (N = 331)	Evolocumab 140 mg SC every 2 weeks or 420 mg QMvs. placebo	LDL-C % change at 12 weeks	Evolocumab 140 mg Q2W: −59.2% Evolocumab 420 mg QM −61.3%
YUKAWA-2 (Kiyosue, 2016) [106]	Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk on statins (N = 404)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo	% LDL-C change at the mean of weeks 10 and 12, and at week 12	At week 12: 67%–76% vs placebo
GAUSS-3 (Nissen, 2016) [107]	Confirmed muscle-related statin intolerance (N = 218)	Evolocumab 420 mg QM vs. ezetimibe	% change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels.	Mean of weeks 22 and 24: 54.5% with evolocumab; 37.8% greater reduction vs. ezetimibe Week 24: 52.8% with evolocumab; 36.1% greater reduction vs. ezetimibe
FOURIER (Sabatine, 2017) [108]	ASCVD patients and LDL-C≥70 mg/dl on statins (N = 27,564)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo	MACE	59% vs placebo at 48 weeks
BANTING (Rosenson, 2019) [109]	Type 2 diabetes with hypercholesterolemia or mixed dyslipidemia on maximum-tolerated statins of at least moderate intensity (N = 421)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo	% LDL-C change at the mean of weeks 10 and 12, and at week 12	54.3% at week 12 65.0% at the mean of weeks 10 and 12
BERSON (Lorenzatti, 2019) [110]	Type 2 diabetes with hyperlipidemia or mixed dyslipidemia on atorvastatin (N = 981)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo	% LDL-C change at the mean of weeks 10 and 12, and at week 12	71.8 % (Q2W) and 74.9% (QM) at week 12 70.3% (Q2W) and 70.0% at the mean of weeks 10 and 12
EVOPACS (Koskinas, 2019) [111]	ACS patients with elevated LDL-C levels (≥1.8 mmol/l on high-intensity statin for at least 4 weeks; ≥2.3 mmol/l on low- or moderate-intensity statin; or ≥3.2 mmol/l on no stable dose of statin). (N = 308)	Evolocumab 420 mg QM initiated during hospitalization vs placebo	% LDL-C change at week 8	40.7% with evolocumab vs placebo
GAUSS-4 (Koba, 2020) [219]	Japanese statin-intolerant patients with hyperlipidemia (N = 61)	Evolocumab 140 mg Q2W or 420 mg QM vs. ezetimibe/placebo	% LDL-C change at the mean of weeks 10 and 12, and at week 12	40.1% at week 12 39.4% at the mean of weeks 10 and 12
FOURIER-OLE (O’Donoghue, 2022) [127]	ASCVD patients and LDL-C≥70 mg/dl on statins (N = 6635)	Evolocumab 140 mg Q2W or 420 mg QM vs. placebo	Incidence of treatment-emergent adverse events	58.4% at 12 weeks from baseline of FOURIER-OLE
VESALIUS-CV (Bohula, 2025) [130]	Patients with ASCVD or diabetes without previous myocardial infarction or stroke (N = 12,257)	Evolocumab 140 mg Q2W vs. placebo	Composite of death from coronary heart disease, myocardial infarction, or ischemic stroke (3-point MACE) Composite of 3-point MACE or ischemia-driven arterial revascularization (4-point MACE).	55% at 48 weeks vs. placebo

Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; MACE: major adverse cardiovascular events; OLE: Open-Label Extension; QM: once monthly; Q2W: every two weeks; SC: subcutaneous.

Supplementary Table 2.

LDL-C reduction with alirocumab: Results from pivotal Phase 3 randomized controlled trials.

Study (First Author, Year)	Population (N)	Intervention	Primary Endpoint(s)	% LDL-C Reduction
ODYSSEY MONO (Roth, 2014) [93]	Hypercholesterolemia, low cardiovascular risk (N = 103)	Alirocumab 75 mg Q2W (up-titrated to 150 mg if needed) vs. placebo/ezetimibe	% LDL-C change at weeks 12 & 24	Week 24: 47%–54% Week 12 before uptitration: 53%
ODYSSEY ALTERNATIVE (Moriarty, 2015) [94]	Patients with hypercholesterolemia at moderate to high cardiovascular risk with statin intolerance (N = 314)	Alirocumab 75 mg Q2W (up-titrated to 150 mg if needed) vs. ezetimibe 10 mg daily	% change in LDL-C from baseline to week 24	−45%; 30.4% greater reduction vs ezetimibe
ODYSSEY OPTIONS I (Bays, 2015) [95]	Patients with very high or high cardiovascular risk patients on atorvastatin 20 or 40 mg (N = 355)	Adding alirocumab vs. adding ezetimibe or increasing statin dose	% change in LDL-C at week 24	Alirocumab addition: −44.1% (atorvastatin 20 mg), −54.0% (atorvastatin 40 mg)
ODYSSEY COMBO I (Kereiakes, 2015) [96]	Patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. (N = 316)	Alirocumab 75 mg Q2W (up-titrated to 150 mg if needed) vs. placebo	% change in LDL-C at week 24	−48.2%
ODYSSEY COMBO II (Cannon, 2015) [98]	Patients with high cardiovascular risk and elevated LDL-C despite maximal doses of statins (N = 720)	Alirocumab 75 mg Q2W (up-titrated to 150 mg if needed) vs. ezetimibe 10 mg daily	% change in LDL-C at week 24	−50.6%; 29.8% greater reduction vs ezetimibe
ODYSSEY FH I and II (Kastelein, 2015) [97]	Patients with heterozygous familial hypercholesterolemia on maximally tolerated statins (ODYSSEY FH I, N = 486; FH II, N = 249)	Alirocumab 75 mg Q2W (up-titrated to 150 mg if needed) vs. placebo	% change in LDL-C at week 24	Week 24: 57.8% vs placebo in FH I and 51.4% vs placebo in FH II Week 78: 51.8% vs placebo in FH I and 52.1% vs placebo in FH II
ODYSSEY LONG TERM (Robinson, 2015) [99]	High cardiovascular risk patients with hypercholesterolemia not controlled by current therapy (maximally tolerated statins with or without other lipid-lowering therapy (N = 2341))	Alirocumab 150 mg Q2W vs. placebo	% change in LDL-C at week 24	Week 24: 62% Week 78: 52.4%
ODYSSEY OPTIONS II (Farnier, 2016) [100]	Patients on baseline rosuvastatin 10 or 20 mg with established CVD and ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L) (N = 305)	Adding alirocumab vs. adding ezetimibe or doubling statin dose	% change in LDL-C at week 24	Alirocumab addition: −50.6% (rosuvastatin 10 mg), −36.3% (rosuvastatin 20 mg)
ODYSSEY OUTCOMES (Schwartz, 2018) [128]	Patients who had an acute coronary syndrome 1–12 months before enrollment, and LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL or apolipoprotein B ≥ 80 mg/dL on maximally tolerated statin (N = 18,924)	Alirocumab 75 mg Q2W vs. placebo	Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization	4 months: 62.7% 12 months: 61% 48 months: 54,7%

Abbreviations: CVD: cardiovascular disease; CV: cardiovascular; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; Q2W: every two weeks.

Supplementary Table 3.

LDL-C reduction with inclisiran: Results from pivotal Phase 3 randomized controlled trials.

Study (First Author, Year)	Population (N)	Intervention	Primary Endpoint(s)	% LDL-C Reduction
ORION-9 (Raal, 2020) [112]	Adults with heterozygous FH and LDL-C ≥100 mg/dL on maximally tolerated statin therapy (±ezetimibe) (N = 482)	Inclisiran 300 mg SC on Day 1, Day 90, 270, 450	% change from baseline in the LDL-C level on day 510 Time-adjusted % change from baseline in the LDL-C level between day 90 and day 540.	% change from baseline in the LDL-C level on day 510: −39.7% (47.9% greater reduction vs. placebo) Time-adjusted % change in LDL-C between day 90 and 540: −38.1% (44.3% greater reduction vs placebo)
ORION-10 (Ray, 2020) [113]	Adults with ASCVD and LDL-C ≥70 mg/dL on maximally tolerated statin therapy (±ezetimibe) (N = 1561)	Inclisiran 284 mg SC on Day 1, Day 90, then Q6M	Placebo-corrected % change in LDL-C level from baseline to day 510 Time-adjusted % change in LDL-C level from baseline after day 90 and up to day 540.	Placebo adjusted % change at Day 510: −52.3% Time-adjusted % change in LDL-C between day 90 and 540: −53.8%
ORION-11 (Ray, 2020) [113]	Adults with ASCVD or ASCVD risk equivalents and LDL-C ≥70 mg/dL on maximally tolerated statin therapy (±ezetimibe) (N = 1617)	Inclisiran 284 mg SC on Day 1, Day 90, then Q6M	Placebo-corrected % change in LDL-C level from baseline to day 510 Time-adjusted % change in LDL-C level from baseline after day 90 and up to day 540.	Placebo adjusted % change at Day 510: −49.9% Time-adjusted % change in LDL-C between day 90 and 540: −49.2%
ORION-5 (Raal, 2024) [114]	Patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis (N = 56)	300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo	% change in LDL-C from baseline to day 150	Placebo-corrected % change in LDL-C level from baseline to day 150: −1.68% (not significant)
VICTORION-INITIATE (Koren, 2024) [115]	ASCVD with LDL-C ≥70 mg/dLon maximally tolerated statin therapy (N = 450)	Inclisiran 284 mg SC on Day 0, Day 90, and Day 270	% change in LDL-C from baseline Statin discontinuation rates	60.0% vs usual care
VICTORION-Mono (Taub, 2025) [116]	Adult participants (aged 18–75 years) without prior ASCVD, diabetes, or familial hypercholesterolemia, with a fasting LDL-C of 100–190 mg/dL and 10-year predicted ASCVD risk of <7.5% according to pooled cohort equation, who were not receiving any lipid-lowering therapy (N = 350)	300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or ezetimibe or placebo	% in LDL-C from baseline at 6 months	47.9% vs placebo 35.4% vs ezetimibe
VICTORION-Difference (Landmesser, 2025) [117]	Adults with hypercholesterolemia at high- or very high CV risk (N = 1770)	Inclisiran sodium (300 mg SC injections; equivalent to 284 mg inclisiran) or placebo together with individually optimized lipid-lowering therapy	LDL-C goal achievement at Day 90	84.9% vs. 31.0%

Abbreviations: ASCVD: atherosclerotic cardiovascular disease; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; Q6M: every six months; SC: subcutaneous.

Supplementary Table 4.

LDL-C reduction with emerging PCSK9-targeted therapies: Results from pivotal Phase 3 randomized controlled trials.

Study (First Author, Year)	Population (N)	Intervention	Primary Endpoint(s)	% LDL-C Reduction
LIBerate-HeFH (Raal, 2023) [123]	Adults with HeFH requiring additional LDL-C lowering (N = 478)	Lerodalcibep 300 mg SC monthly vs placebo	% LDL-C change from baseline at week 24 Mean of weeks 22 and 24	58.6% at week 24 & 65.0% mean of weeks 22 and 24
LIBerate-HR (Klug, 2024) [124]	Adults with CVD or at high or very high CVD risk and have uncontrolled LDL-C on maximally tolerated statin therapy (N = 811)	Lerodalcibep 300 mg SC monthly vs placebo	% LDL-C change from baseline at week 52 Mean of weeks 50 and 52	56.2% at week 52 62.7% mean of weeks 50 and 52
LIBerate-HoFH (Raal, 2025) [220]	Patients aged ≥10 years with genetically confirmed HoFH (N = 66)	Lerodalcibep 300 mg SC monthly vs evolocumab 420 mg SC monthly	% LDL-C change from baseline to week 24 for each therapy (crossover design)	4.9% at week 24 with lerodalcibep vs. 10.3% with evolocumab (non-inferior)
CORALreef lipids (Navar, 2026) [126]	Adults with history of major ASCVD event or at risk for first ASCVD event and elevated LDL-C (N = 2909)	Enlicitide decanoate 20 mg once daily vs placebo	Mean % LDL-C change from baseline to week 24	57.1% at week 24
CORALreef HeFH (Ballantyne, 2026) [125]	Adults with HeFH on lipid-lowering therapy with history of major ASCVD event or at risk for first ASCVD event and elevated LDL-C (n≈303)	Enlicitide decanoate 20 mg once daily vs placebo	Mean % LDL-C change at week 24	58.2% at week 24 55.3% at week 52

Abbreviations: ASCVD: atherosclerotic cardiovascular disease; CVD: cardiovascular disease; HeFH: heterozygous familial hypercholesterolemia; HoFH: homozygous familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; SC: subcutaneous.

Abbreviation list

ACS

Acute Coronary Syndrome

ASCVD

Atherosclerotic Cardiovascular Disease

CAD

Coronary Artery Disease

CVD

Cardiovascular Disease

FH

Familial Hypercholesterolemia

LDL

Low-Density Lipoprotein

LDL-C

Low-Density Lipoprotein Cholesterol

MACE

Major Adverse Cardiovascular Events

PAD

Peripheral Artery Disease

PCSK9

Proprotein Convertase Subtilisin/Kexin Type 9

RCT

Randomized Controlled Trial

siRNA

Small Interfering RNA

Funding Statement

There was no financial reward associated with writing the paper. Konoz Retaj (Saudi Arabia) provided editorial assistance for preparing this manuscript based on the Good Publication Practice (GPP 2022) and the ICMJE requirements. This work was funded by Novartis. The views and opinions expressed are those of the authors. Novartis had no role in the decision to publish, or preparation of the manuscript