Cardiovascular diseases (CVDs) constitute a major global public health challenge. According to the World Health Organization (WHO), CVDs remain the leading cause of death worldwide, with approximately 58% of CVD-related mortality occurring in Asia [1]. Among these conditions, atherosclerotic cardiovascular disease (ASCVD) and its major complications myocardial infarction (MI) and ischemic stroke are the predominant contributors to cardiovascular morbidity and mortality. Substantial evidence indicates that inadequate control of low-density lipoprotein cholesterol (LDL-C) plays a critical role in the development of ASCVD [2]. LDL-C is a well-established and independent risk factor for ASCVD [3]. Elevated LDL-C levels promote atherosclerotic plaque formation, leading to endothelial dysfunction and vascular inflammation, which ultimately precipitate adverse cardiovascular events such as MI and stroke [4]. This pathogenic process is particularly pronounced in individuals with diabetes. ASCVD is the leading cause of death and disability among patients with diabetes or prediabetes, who face a markedly increased risk of stroke, coronary heart disease, and myocardial infarction compared with individuals with normoglycemia [5]. In addition to its clinical impact, CVD imposes a substantial economic burden, with combined direct and indirect costs amounting to hundreds of billions of dollars annually. Consequently, effective preventive and therapeutic strategies are essential to mitigate the growing public health burden of cardiovascular disease. Statins are currently the cornerstone of LDL-C-lowering therapy in clinical practice [6]. However, their limited tolerability in some patients and the occurrence of adverse effects underscore the need for alternative lipid-lowering approaches. Inclisiran (Leqvio®) is a novel small interfering RNA (siRNA)-based therapy that targets proprotein convertase subtilisin/kexin type 9 (PCSK9). By inhibiting PCSK9 expression through the endogenous RNA interference (RNAi) pathway, inclisiran effectively reduces circulating LDL-C levels [7, 8]. Beginning in 2017, the ORION series of randomized controlled trials (RCTs) established the clinical efficacy of inclisiran. These studies demonstrated that inclisiran achieved approximately a 50% reduction in LDL-C over a follow-up period of up to 540 days. Among them, the three pivotal Phase III trials ORION-9, ORION-10, and ORION-11 (hereafter collectively referred to as “RCT data”) provided the primary evidence supporting its clinical use [9]. In 2021, inclisiran received approval from the U.S. Food and Drug Administration for use in routine clinical practice. Since then, it has been formally adopted in several European countries, where accumulating real-world clinical data further support its effectiveness and safety. By 2024, approximately 500,000 doses of inclisiran had been administered in real-world settings [10]. RCTs are widely regarded as the gold standard for evaluating the efficacy and safety of novel therapeutic interventions. Under controlled conditions, they provide high-quality evidence that enables rigorous assessment of treatment effects. However, because RCTs typically enroll highly selected patient populations under strict inclusion and exclusion criteria, their findings may not fully reflect outcomes observed in routine clinical practice [11, 12]. RWE, derived from observational studies and everyday clinical care, complements RCT data by capturing treatment performance in broader and more heterogeneous patient populations. In addition, RWE offers valuable insights into medication adherence, long-term outcomes, and real-world cost-effectiveness. Consistency between RCTs and RWE is therefore crucial for validating the clinical utility of novel therapies and supporting evidence-based decision-making in practice [13]. In this review, we aim to evaluate the concordance of inclisiran’s LDL-C-lowering efficacy and safety profiles between RCTs and RWE, with the goal of informing clinical treatment strategies and therapeutic decision-making.

This review, based on a qualitative analysis of RCTs and RWE, demonstrates that inclisiran has highly consistent efficacy in lowering LDL-C across both study types. Integrated analysis of RCTs and RWE further confirms that inclisiran achieves stable and durable LDL-C-lowering effects in high-risk patients with hypercholesterolemia, with efficacy consistently observed across different age groups and comorbidity subgroups. Notably, all patients included in this study received stable-dose statin therapy, with some patients co-administered ezetimibe. The potential influence of concomitant lipid-lowering drugs on efficacy was further assessed through evidence-based literature: the effect of concomitant lipid-lowering therapy on treatment outcomes has been supported by evidence-based studies [26] (CHOLINET: https://clinicaltrials.gov/study/NCT03399370), which did not significantly affect the main conclusions. This finding aligns with the established mechanism of action of inclisiran lowers LDL-C by specifically inhibiting PCSK9 synthesis, and its efficacy is not substantially influenced by baseline statin monotherapy or combination therapy with ezetimibe. Among the five included RWE studies, four showed complete overlap in confidence intervals with their corresponding RCTs, while one showed only partial overlap. This variation is within an acceptable range and may be attributed to higher medication adherence in RCT populations compared with RWE settings, likely due to closer monitoring, more frequent follow-ups, and higher baseline adherence levels [27, 28]. Furthermore, weighted regression analysis demonstrated a significant positive correlation between LDL-C reduction rates in RWE and RCTs, indicating that RCT data can reliably predict real-world outcomes and further supporting the consistency between the two types of studies. This finding shows that inclisiran not only performs effectively in strictly controlled clinical trial settings but also maintains stable efficacy in real-world clinical practice. Compared with patients enrolled in the ORION study protocols, inclisiran is applied to a broader population in real-world settings, including patients with statin intolerance and those receiving concomitant therapy with ezetimibe, fenofibrate, or lipoprotein apheresis [22]. These observations provide strong support for the broader clinical application of inclisiran in daily practice. Diabetic patients are at high risk of cardiovascular disease; therefore, controlling LDL-C levels in this population is crucial for the prevention of cardiovascular events. Subgroup analysis in diabetic patients revealed that inclisiran significantly reduced LDL-C levels compared with the overall study population. Consistency analyses further showed that the efficacy difference between RWE and RCTs was within 5%, indicating good agreement. These results suggest that inclisiran may have a more favorable efficacy profile in diabetic patients, offering a new therapeutic option for cholesterol management, particularly when standard statin therapy is ineffective or poorly tolerated. However, given the small sample size of this subgroup, these findings require validation in larger-scale studies.

In terms of safety, existing data indicate that the incidence of AEs associated with inclisiran shows a generally consistent pattern between RCTs and RWE. Injection-site reactions are the most common AEs, which are mostly mild and reversible [29], and this finding is largely consistent with the safety profile reported in RCTs. Additionally, our analysis of the latest pharmacovigilance data from FAERS [14] not only confirms injection-site reactions as the primary safety signal but also quantifies and highlights the occurrence of musculoskeletal events, including myalgia and arthralgia. This underscores the importance of proactively identifying and interpreting potential causal relationships among emerging adverse reactions in real-world clinical settings. However, the safety analysis in this study has several limitations. First, only one of the included RWE studies considered safety as the primary endpoint, resulting in relatively limited data support. Second, FAERS data have inherent limitations, including susceptibility to reporting bias, duplicate records, and the absence of denominators for exposed populations, which introduces uncertainty in data interpretation. Therefore, caution should be exercised regarding the current conclusion of “consistent safety”, and overinterpretation should be avoided. Existing evidence can only tentatively suggest that the benefit-risk profile of inclisiran is generally manageable, while its long-term safety requires verification in more targeted studies. At the same time, a potential limitation of inclisiran should be acknowledged: due to its long-acting effect of up to six months, any adverse reactions occurring after long-term treatment may be difficult to reverse [26, 30]. This further emphasizes the need for long-term follow-up studies with safety as the primary endpoint.

The evidence base of this study also has limitations. The included RWE dataset is relatively small, comprising five cohorts with a total of 805 patients, and most study populations are from high-income regions, including Italy, Germany, the UK, the US, and the Middle East. Data from low- and middle-income regions and from broader ethnic or racial populations are lacking, which may limit the external validity and generalizability of the findings [31, 32]. Although RWE has, to some extent, expanded the extrapolation of traditional RCTs and addressed certain limitations of clinical trials, practical factors in real-world settings such as variations in patient adherence, treatment cost burdens, medical insurance coverage, and complex comorbidities may still influence the final outcomes of cholesterol management. Even in the era of PCSK9 inhibitors, the rate of achieving lipid-control targets in clinical practice remains suboptimal [33]. These observations suggest that future studies should expand sample sizes, include more diverse regions and populations, and conduct multicenter, long-term follow-up RWE studies. Such efforts would not only validate the efficacy and safety of inclisiran in broader populations but also help identify effective strategies to optimize lipid management in clinical practice, thereby improving the rate of achieving lipid-control targets.

In conclusion, this study, based on integrated RCT and RWE data, confirms that inclisiran demonstrates highly consistent efficacy in lowering LDL-C among high-risk patients with hypercholesterolemia. This efficacy is not significantly affected by baseline statin monotherapy or ezetimibe combination therapy, providing evidence-based support for its clinical use. Subgroup analysis indicates that inclisiran also achieves stable LDL-C reduction in patients with diabetes complicated by hypercholesterolemia, offering an alternative option for those with statin intolerance or poor response. However, the analysis focused solely on LDL-C-lowering efficacy as a single endpoint, and the limited sample size restricts a comprehensive evaluation of inclisiran’s overall therapeutic benefits. Additionally, a formal risk of bias assessment has been conducted, but the sample size was small, which may affect the internal validity of the results. Future research should expand sample sizes, extend follow-up periods, include populations from low- and middle-income regions and diverse ethnic groups, and incorporate risk assessments and cost-effectiveness analyses to verify the long-term efficacy and safety of inclisiran across diverse populations.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

YL and HY designed and performed the research study. ZL and HW participate in the design of the article and provide suggestions. YL analyzed the data and drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflicts of interest.

During the preparation of this work, the authors used DeepSeek and QuillBot for the purposes of language translation and polishing. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM48272.