Pharmacovigilance analysis of inclisiran:a real-world assessment based on the FAERS database

Background :Inclisiran, a novel small interfering RNA (siRNA) therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), has demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C). While generally well-tolerated, emerging evidence has highlighted safety concerns, particularly joint-related adverse events (AEs), such as arthralgia. atorvastatin, a commonly prescribed lipid-lowering agent, is also associated with joint-related AEs, leading to concerns about the safety of concomitant use. This study utilized the FDA Adverse Event Reporting System (FAERS) to evaluate inclisiran’s safety profile, with a specific focus on its monotherapy and combination therapy with atorvastatin. Methods :A retrospective pharmacovigilance study was conducted using FAERS data from 2004 to 2024.Advanced signal detection algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Bayesian Confidence Propagation Neural Network (BCPNN), were employed to detect significant AEs. Data cleaning and standardization were performed using MedDRA terminology. Analyses included signal detection by System Organ Classes (SOCs), Preferred Terms (PTs), drug-drug interaction (DDI) analysis to detect signal. Result :Among 4269 AE reports related to inclisiran, 48.3% were from females, and 31.4% involved individuals ≥65 years. The United States contributed 84.4% of reports, reflecting higher pharmacovigilance reporting in this region.The SOC signal detection indicates that the most frequently reported SOCs included ”general disorders and administration site conditions” (23.78%) and ”musculoskeletal and connective tissue disorders” (16.88%). The PT signal detection indicates Arthralgia was the most reported PT (512 reports; ROR: 5.84, 95% CI: 5.35–6.39), followed by injection site pain and myalgia. The interaction between inclisiran and atorvastatin indicates that Combination therapy was associated with significant signals for musculoskeletal AEs, with synergistic effects noted in joint-related conditions. Conclusion： This comprehensive pharmacovigilance analysis highlights the safety profile of inclisiran, identifying musculoskeletal and injection site-related AEs as primary concerns. The findings emphasize the need for early monitoring during Inclisiran therapy, particularly in at-risk populations such as females, older adults, and those on combination therapy with atorvastatin. Enhanced pharmacovigilance frameworks and real-world evidence are essential to mitigate AE risks and inform clinical practice. Pharmacovigilance analysis of inclisiran:a real-world assessment based on the FAERS database Name of authors: Changjiang Deng 1 * , Yixin Xu 1 * , Ying Pan 1, Tingting Wu 1, Chao Fan 1, Zhihui Jiang 1, Mingming Lv 1, BingxinBai 1, Zhiyan Du 1, ZhiLong Wang 1, Adilai.Adilijiang 1, Yingying Zheng 1, Xiang xie 1 Affiliations: The First Affiliated Hospital of Xinjiang Medical University, Department of Cardiology No. 137, Liyushan South Road, Urumqi, Xinjiang Uygur Autonomous Region, China First author:Changjiang Deng 1* Co-first author:Yixin Xu 1* *These authors contributed to the work equllly and should be regarded as co-first authors. Corresponding author: Xiang xie 1 The First Affiliated Hospital of Xinjiang Medical University E-mail:[email protected]

Background :Inclisiran, a novel small interfering RNA (siRNA) therapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), has demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C). While generally well-tolerated, emerging evidence has highlighted safety concerns, particularly joint-related adverse events (AEs), such as arthralgia. atorvastatin, a commonly prescribed lipid-lowering agent, is also associated with joint-related AEs, leading to concerns about the safety of concomitant use. This study utilized the FDA Adverse Event Reporting System (FAERS) to evaluate inclisiran’s safety profile, with a specific focus on its monotherapy and combination therapy with atorvastatin.

:A retrospective pharmacovigilance study was conducted using FAERS data from 2004 to 2024.Advanced signal detection algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Bayesian Confidence Propagation Neural Network (BCPNN), were employed to detect significant AEs. Data cleaning and standardization were performed using MedDRA terminology. Analyses included signal detection by System Organ Classes (SOCs), Preferred Terms (PTs), drug-drug interaction (DDI) analysis to detect signal.

:Among 4269 AE reports related to inclisiran, 48.3% were from females, and 31.4% involved individuals ≥65 years. The United States contributed 84.4% of reports, reflecting higher pharmacovigilance reporting in this region.The SOC signal detection indicates that the most frequently reported SOCs included ”general disorders and administration site conditions” (23.78%) and ”musculoskeletal and connective tissue disorders” (16.88%). The PT signal detection indicates Arthralgia was the most reported PT (512 reports; ROR: 5.84, 95% CI: 5.35–6.39), followed by injection site pain and myalgia. The interaction between inclisiran and atorvastatin indicates that Combination therapy was associated with significant signals for musculoskeletal AEs, with synergistic effects noted in joint-related conditions. Conclusion： This comprehensive pharmacovigilance analysis highlights the safety profile of inclisiran, identifying musculoskeletal and injection site-related AEs as primary concerns. The findings emphasize the need for early monitoring during Inclisiran therapy, particularly in at-risk populations such as females, older adults, and those on combination therapy with atorvastatin. Enhanced pharmacovigilance frameworks and real-world evidence are essential to mitigate AE risks and inform clinical practice.

Inclisiran, pharmacovigilance analysis, FAERS, data mining, adverse event Key points: 1.Inclisiran linked to joint pain and injection-site reactions in real-world data. 2.Combining inclisiran with atorvastatin increases muscle/joint side effect risks. 3.Adverse events peak within 30 days; early monitoring critical for safety. 4.Women, older adults, and combination therapy users face higher risks. The Plain Language Summary (PLS) : Inclisiran is a new cholesterol-lowering medication designed to reduce ”bad” cholesterol (LDL-C) with just two injections per year. While effective, concerns have been raised about its safety, particularly related to joint pain. Another commonly used cholesterol drug, atorvastatin (a statin), is also linked to joint issues, prompting questions about the risks of using these drugs together. To better understand Inclisiran’s safety, we analyzed over 8 million reports from the U.S. Food and Drug Administration’s safety database (2004–2024). We found that Inclisiran was most frequently associated with joint pain, injection-site reactions (like pain or redness), and muscle discomfort. These side effects often appeared within the first month of treatment. Combining Inclisiran with atorvastatin increased the risk of muscle and joint problems compared to using either drug alone. Older adults (especially those over 65), women, and people receiving both drugs faced higher risks. While most side effects were not life-threatening, early monitoring is critical to address these issues quickly. Our findings help patients and doctors make informed decisions about cholesterol management, especially for those needing combination therapies. This study highlights the importance of ongoing safety tracking for new medications, ensuring their benefits outweigh potential risks.

Inclisiran, marketed as Leqvio, employs a novel mechanism of action as a small interfering RNA (siRNA) that targets the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, resulting in reduced LDL cholesterol levels [1] . While it is primarily prescribed for managing hyperlipidemia, recent reports have highlighted joint-related adverse events associated with its use, notably arthralgia, which is characterized by joint painii, leading to significant discomfort and may deter patients from adhering to their lipid-lowering therapy [2] . Although these adverse effects are not widely prevalent, they have raised concerns among healthcare professionals and patients regarding the overall safety profile of inclisiran. Atorvastatin, a widely prescribed statin, works by inhibiting HMG-CoA reductase to decrease cholesterol synthesis [3] . Reports indicate that atorvastatin is associated with arthralgia, affecting approximately 6.9% of users, and patients have expressed concerns regarding debilitating joint pain during treatment [4, 5] . The combined use of these medications offers potential benefits for patients struggling to achieve adequate cholesterol reduction, particularly those experiencing side effects from statin therapy alone [6] . Given its implications for patient safety and management of adverse events, the interaction between inclisiran and atorvastatin have garnered considerable interest [7, 8] . The exploration of these drug interactions is vital for optimizing cholesterol management while minimizing the potential for adverse events in patients. Existing evidence indicates that inclisiran does not exacerbate the joint pain associated with atorvastatin [9] . However, most current studies rely on small samples or single-center data, limiting the generalizability and representativeness of their findings. While the FDA Adverse Event Reporting System(FAERS) data have been utilized, some studies lack robust signal detection algorithms, increasing the risk of false-positive or false-negative results. Thus, further studies are necessary to definitively establish the safety and efficacy of their combined use, especially in populations at risk for joint-related issues. Especially, more comprehensive and real-world studies leveraging large pharmacovigilance databases like FAERS are essential to uncover hidden signals and assess the safety profile of Inclisiran-Atorvastatin combination therapy. In response, this study aims to assess the safety profile of inclisiran-atorvastatin combination therapy, with a particular focus on joint-related adverse events, utilizing comprehensive FAERS data and robust signal detection algorithms to provide real-world evidence for clinical decision-making. 2 Methods 2.1 Study design and data source This study utilized a retrospective pharmacovigilance analysis based on data from the FDA Adverse Event Reporting System(FAERS) database focusing on adverse event signals associated with inclisiran. The FDA’s post-marketing safety surveillance program for drug and therapeutic biologic products is supported by voluntary reports that are incorporated in the FAERS database from a variety of sources, including patients, pharmacists, healthcare professionals, and pharmaceutical corporations. It includes a variety of data, such as patient demographics, drug utilization, adverse reaction information, reporting sources, duration of therapy, drug indications, and patient outcomes. There are seven different types of data documents in the FAERS data files: DRUG (drug information), OUTC (patient outcomes), RPSR (report sources), THER (therapy start and end dates for reported drugs), INDI (indications for drug administration), and DEMO (demographic and administrative information). In the FAERS database architecture, these files were linked together by unique identifying numbers like PRIMARYID (Unique number for identifying a FAERS report). 2.2 Data mining Data mining was conducted on the FAERS database, encompassing adverse event reports submitted between the first quarter of 2004 and the fourth quarter of 2024. The MedDRA score is divided into five levels from low to high, which are the lowest term (LLT), the preferred term (PT), the advanced term (HLT), the advanced group term (HLGT) and the system organ category (SOC). Extraction processes targeted records associated with Inclisiran and, where applicable, its combination with atorvastatin.The Medical Dictionary of Regulatory activities (MedDRA; version 26.0) was used for all adverse reactions, and the PTs was assigned according to the SOC. Duplicate entries were eliminated using unique case identifiers to ensure data accuracy. Data were standardized according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, facilitating uniform classification of SOCs and PTs [10] . 2.3 Data analysis In this study, we used descriptive statistics to present AE reports related to inclisiran. Reports with incomplete or ambiguous data, such as missing drug or reaction information, were excluded to maintain dataset reliability. The disproportionality analysis, focusing on reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and empirical bayes geometric mean (EBGM), was applied to detect significant adverse event signals [11, 12] . For valid signal generation using the ROR method, events must have a lower 95% CI limit > 1 and at least three reports. In the PRR method, a valid signal is indicated by a PRR ≥ 2 and X2 ≥ 4. In the BCNPP method, an IC025 > 0 qualifies as a valid signal. In the EBGM method, valid signal was defined as an EBGM05 > 2. Larger values in the calculated results signify stronger signal strength, suggesting a more robust association between the drug and the AE. The equation of the four methods are shown in Table 1 . 3 Results 3.1 Descriptive results for the total population The FAERS database contained 8, 327, 605 records, reduced to 7, 133, 678 after removing 1, 193, 927 duplicates. A total of 4269 reports identified Inclisiran as the primary suspect (PS), including 576 reports of arthralgia, which underwent clinical, signal detection, stratification, and time-to-onset analyses.( Figure 1 ). Among 4269 AE reports associated with inclisiran( Table 2 ), 48.3% were from female patients and 35.4% from males, with 16.3% missing sex data. Most reports (55.6%) involved patients aged 18-64, and 31.4% were from those aged 65 years or older. Weight data was missing for 89.8%, and only 2.1% exceeded 100 kg. Geographically, 84.4% of reports were submitted from the United States, followed by China (1.1%) and Canada (2.4%). Healthcare professionals contributed 22.2% of reports. No statistically significant differences were reported in demographic variables. The yearly distribution of AE reports associated with inclisiran in the FAERS database showed a significant increase over time. Among the 4269 reports, the largest number was recorded in 2023 (2105, 49.3%), followed by 2024 (1457, 34.2%) and 2022 (706, 16.5%). Only one report was submitted in 2021. This increasing trend indicates a growing awareness of inclisiran-related safety issues. The time to onset of inclisiran-associated AEs shows the highest number of reports within 0-30 days (232 cases, 38.8%), followed by 91-120 days (94 cases, 15.7%), and 31-60 days or 61-90 days (71 cases each, 11.7%). Events reported beyond 360 days accounted for 34 cases (5.7%). This suggests that most AEs occur within the first month of drug administration, requiring early monitoring. Among the 4269 reported AEs associated with inclisiran, 73.6% (3143 cases) resolved without long-term effects. Fatal outcomes (DE) accounted for 2.4% (103 cases), while life-threatening events (LT) were 0.8% (33 cases). Serious outcomes such as hospitalization (HO) and disability (DS) were reported in 4.4% (188 cases) and 1.0% (43 cases), respectively. Other outcomes (OT) comprised 17.7% (754 cases), while recovery issues (RI) were rare (0.1%, 5 cases). These findings highlight a majority of non-severe outcomes, but serious cases warrant further investigation. 3.2 mining of adverse signals 3.2.1 system organ class disproportionality analysis Signal detection of adverse drug reactions associated with inclisiran by SOC Classification The results highlight the adverse drug reaction (ADR) signals associated with inclisiran, categorized by SOC( Table3 ). Notable findings include five AEs under ”cardiac disorders, ” such as myocardial infarction (ROR: 5.37; 95% CI: 2.46–11.73) and angina pectoris (ROR: 6.15; 95% CI: 3.17–11.94), both exceeding the ROR threshold for signal detection (lower limit >1). In ”investigations, ” low-density lipoprotein increased was significant, with an ROR of 2.32 (95% CI: 1.97–2.73) and IC025 of 0.84, suggesting its association with the drug. musculoskeletal and connective tissue disorders, including arthralgia (ROR: 3.01; 95% CI: 2.32–3.92), also showed robust signals. These indicators suggest a potential drug-AE association. Meanwhile, we have prepared forest plots to summarize the signal intensities of adverse events classified as SOC by inclisiran( Figure2 ). The forest plot indicates the strongest signal was observed for ”Musculoskeletal and Connective Tissue Disorders” (ROR=3.72, 95% CI: 3.54–3.9), with a significant reporting odds ratio (p<0.001). Other notable signals include ”Investigations” (ROR=2.08, 95% CI: 1.96–2.2) and ”Ear and Labyrinth Disorders” (ROR=2.01, 95% CI: 1.64–2.46). Categories such as ”Surgical and Medical Procedures” (ROR=0.01, 95% CI: 0.0–0.04) and ”Congenital, Familial, and Genetic Disorders” (ROR=0.1, 95% CI: 0.03–0.31) displayed minimal signal strength. ROR (Reporting Odds Ratio) values and their 95% confidence intervals (CI) provide insight into the disproportionality of adverse events, with a reference value of ROR=1 indicating no association. 3.2.2 Preferred terms disproportionality analysis The signal analysis of inclisiran monotherapy identified arthralgia as the most prominent adverse event PT, with 512 reports and a significant disproportionality: ROR=5.84 (95% CI: 5.35–6.39), PRR=5.63. Other PTs, including injection Site Pain (N=462, ROR=5.72) and Myalgia (N=445, ROR=5.91), showed strong signals. The IC and EBGM indicators corroborated these findings, confirming the robustness of the associations. Notably, musculoskeletal-related and injection site-related adverse events accounted for the majority of significant signals( Table4 ) . These results suggest the necessity for monitoring such adverse events in patients treated with Inclisiran. The forest plot presents the top 50 PTs of adverse events associated with inclisiran(Figure3). Among these, injection site pain (ROR=7.06, 95% CI: 6.09-8.49) and arthralgia (ROR=5.84, 95% CI: 5.35-6.39) exhibited the strongest signals, indicating significant disproportionality (p<0.001). Other notable signals included myalgia (ROR=3.74, 95% CI: 2.96-4.73) and pain in extremity (ROR=3.63, 95% CI: 3.26-4.01). Each PT is classified under its corresponding SOC, with musculoskeletal and connective tissue disorders showing the most frequent reports. ROR represents the disproportionality of adverse events, with values above 1 indicating a higher-than-expected Sreporting frequency. This analysis, based on FAERS data, provides insights into the safety profile of Inclisiran, highlighting its potential to cause localized and musculoskeletal adverse effects. 3.2.3 The Venn diagram The Venn diagram visualizes the intersections of adverse event (AE) signals detected by four algorithms: ROR, PRR, EBGM, and BCPNN( Figure 4 ). Among the 415 signals, 103 (24.8%) were identified by all four algorithms, representing the strongest and most consistent signals. Additionally, EBGM and BCPNN independently contributed the largest sets of signals, identifying 133 (32.0%) and 109 (26.2%) events, respectively. Notably, 43 signals (10.3%) were shared by ROR, PRR, and EBGM, while only 4 (1.0%) were detected by PRR and BCPNN exclusively. These findings indicate the complementary strengths of each algorithm for signal detection. 3.3 analysis of combined medications 3.3.1 FFUN analysis of inclisiran and atorvastatin concomitant use on adverse event signals. The FFUN analysis of concomitant use of Inclisiran and Atorvastatin identified several significant adverse event signals. Myocardial infarction showed the strongest signal with ROR (95% CI) = 9.66 (6.21–15.03) and PRR = 9.66 (p < 0.001). Similarly, ”Low Density Lipoprotein Decreased” demonstrated notable signals with ROR (95% CI) = 8.11 (5.89–11.69) and PRR = 8.09 (p 2) and BCPNN (IC025>0), consistently confirmed these findings. These results suggest potential risks for specific adverse events with combined therapy, necessitating further investigation( Table5 ). 3.3.2. drug-drug interaction (DDI) analysis of inclisiran and atorvastatin on joint adverse The DDI analysis between Inclisiran and Atorvastatin revealed significant signals for joint adverse events( Table6 ). For the combination involving ”a-targetpt, ” the ROR (95% CI) was 3.42 (3.16–3.7), and PRR (X2) was 3.28 (1064.28), both indicating positive signals. Additionally, EBGM (EBGM05>2) and BCPNN (IC025>0) also confirmed the signals. In contrast, ”a-b-targetpt” did not show significant interaction with an ROR of 1.1 (0.52–2.33). These results highlight significant adverse event risks in specific combinations. 4 Discussion This study utilized a retrospective pharmacovigilance analysis based on data from the FAERS database to evaluate the safety profile of inclisiran. The study specifically analyzed the demographic and geographic distribution of reports, yearly trends, SOC classifications, PTs, and DDI. The main findings indicate that inclisiran is associated with significant musculoskeletal-related AEs, such as arthralgia and injection site pain, with the strongest signals occurring within the first 30 days of administration. This study highlights the importance of early monitoring and targeted pharmacovigilance efforts for patients on inclisiran therapy, especially those receiving combination treatment with atorvastatin. Further research is warranted to validate these findings. The strong signals observed for musculoskeletal and connective tissue disorders, particularly arthralgia, imply a potential localized inflammatory response, which may be attributed to inclisiran’s mechanism of action as a siRNA targeting PCSK9 [13] . Additionally, the time-to-onset analysis, showing the highest reporting within 30 days, highlights an early phase of heightened AE risk, emphasizing the necessity for close monitoring during this period. Gender-specific differences in adverse event reporting suggest a possible influence of sex-specific factors such as hormonal or metabolic variations. While stratified age analysis highlights the elderly as particularly vulnerable to specific PTs, such as myalgia. Furthermore, the joint-related AE signals detected in the combination therapy with atorvastatin point to possible synergistic effects between the two drugs, necessitating cautious use in patients already at risk for musculoskeletal AEs. Together, these insights underline the complexity of Inclisiran’s safety profile. Our analysis revealed a higher proportion of reports from older age groups, which contrasts with previous studies focusing on broader populations, including younger cohorts [14] . This may reflect demographic characteristics specific to Inclisiran’s targeted use in individuals with comorbidities, such as hypercholesterolemia and cardiovascular disease, which are more prevalent in older populations. Geographically, the concentration of AE reports from the United States in our study mirrors findings in prior FAERS-based analyses [15] . However, lower reporting from regions such as Europe and Asia diverges from studies leveraging local pharmacovigilance databases, where Inclisiran is more widely available [16] . This discrepancy may arise from regional differences in Inclisiran’s market adoption, healthcare access, and underreporting due to regulatory or cultural barriers. These findings underscore the need for harmonized global pharmacovigilance systems and additional region-specific investigations to better capture AE patterns, ensuring comprehensive safety monitoring and addressing potential disparities. The findings from this study indicate a progressive increase in yearly reporting of Inclisiran-related adverse events (AEs) in the FAERS database, which differs from the relatively plateaued trends observed in previous studies such as He et al [16] . While earlier research attributed reporting stability to limited geographic access and delayed global market penetration, this study reflects Inclisiran’s expanded availability in diverse regions and growing clinical adoption, particularly after approvals in multiple jurisdictions in recent years [17] . Another reason for the disparity is the potential variability in pharmacovigilance systems and reporting behaviors over time. This study identified a sharp increase in reports coinciding with inclisiran’s broader post-marketing surveillance campaigns and growing patient awareness of adverse event reporting channels. Previous studies, such as those by Agnello et al [18], suggested underreporting due to limited exposure during the initial post-approval phases, whereas this study captures data from a broader timeline where reporting systems have matured. Mechanistically, the differences could also reflect delayed-onset AEs unique to Inclisiran’s twice-yearly dosing regimen, which may result in cumulative adverse effects becoming apparent later in the therapy timeline. Additionally, increased scrutiny and scientific interest in RNA-based therapies may have incentivized more comprehensive reporting. The analysis of adverse drug reactions (ADRs) associated with Inclisiran by SOC classification in this study revealed significant proportions of general disorders and injection-site reactions, consistent with findings from prior investigations [16] . However, this study detected a higher relative frequency of hepatobiliary disorders and immune system-related ADRs, which diverges from earlier reports that emphasized primarily local injection-site reactions and musculoskeletal complaints [14] . These differences may be attributed to variations in patient populations, pharmacovigilance systems, and study designs. For instance, this study utilized the FAERS database, which aggregates real-world reports and captures diverse demographics, while prior studies relied on controlled clinical trial data, potentially underrepresenting rare or systemic ADRs. Mechanistically, the higher prevalence of hepatobiliary signals could reflect inclisiran’s primary hepatic uptake GalNAc-conjugated delivery and its role in PCSK9 modulation [19] . Immune system-related signals, potentially exacerbated by genetic predispositions or environmental factors in this study’s population, suggest an immunomodulatory component of siRNA-based therapies [20] . Disparities underscore the need for population-specific pharmacovigilance and further investigation into Inclisiran’s systemic effects under varying real-world conditions. the analysis of adverse event PTs identified key Inclisiran-associated safety signals. Injection-site reactions emerged as the predominant signal, aligning with earlier reports [14] ; however, their frequency was higher here, likely reflecting increased reporting sensitivity or expanded post-marketing surveillance.The discrepancies between this study and prior analyses may stem from differences in data sources, such as FAERS’ real-world reporting, which captures a broader patient population and diverse clinical settings. Furthermore, algorithmic variability in signal detection (e.g., ROR vs. PRR) underscores methodological influences on reported outcomes, emphasizing the need for harmonized approaches in pharmacovigilance research. The observed interaction between Inclisiran and atorvastatin in enhancing or mitigating AE signals highlights potential synergistic or compensatory mechanisms. Atorvastatin’s upregulation of LDL receptor expression may amplify inclisiran’s RNA interference mechanism targeting PCSK9 mRNA, leading to enhanced LDL-C reduction but potentially increased risk of musculoskeletal and hepatobiliary AEs due to overlapping metabolic pathways[21]. Furthermore, co-administration could influence Inclisiran’s pharmacokinetics by modifying hepatic uptake via shared transporters like OATP1B1 [22] . This interplay suggests the necessity of monitoring AEs during combined lipid-lowering therapy. This study is the first to analyze the impact of the combined use of evipaxin and atorvastatin on adverse event signals. There have been no similar related studies before. The observed joint-related AEs from inclisiran and atorvastatin combination therapy may stem from overlapping and synergistic pharmacodynamic effects. Inclisiran’s interference with PCSK9 production, altering lipid metabolism, combined with atorvastatin’s statin-induced muscle stress, could exacerbate inflammatory responses in joint tissues [23] . Additionally, atorvastatin’s metabolism through CYP3A4 and potential interactions with inclisiran-induced liver uptake pathways might amplify musculoskeletal AEs [24] . Gender-specific variations in AEs observed may reflect hormonal influences on statin pharmacokinetics. These findings highlight the need for individualized dosing strategies in combination therapies to mitigate DDI-associated joint AEs. Furthermore, there has been no other research conducted on the DDI analysis of inclisiran and atorvastatin at present. This study provides critical theoretical insights into the pharmacovigilance of inclisiran by revealing specific patterns in its AE profile, enhancing our understanding of siRNA-based therapies in real-world settings. The identification of joint-related AEs provides actionable data for clinicians to enhance patient monitoring, particularly for those with predisposing conditions or on concomitant therapies such as atorvastatin. The temporal patterns of AE onset suggest that early post-administration periods warrant intensified vigilance, enabling timely interventions and reducing patient morbidity. This study possesses several notable strengths that enhance its robustness and scientific significance. First, it employs a comprehensive pharmacovigilance approach, leveraging the extensive FAERS database to analyze a broad spectrum of inclisiran-associated AEs across multiple demographic, geographic, and temporal dimensions. This breadth enables a more nuanced understanding of safety signals compared to prior studies. Second, the application of multiple advanced signal detection algorithms, including ROR, PRR, EBGM, and BCPNN, minimizes biases inherent to individual methods and provides greater analytical reliability. Furthermore, this study is the first to conduct the FFUN and DDI analyses for inclisiran and atorvastatin. Despite its comprehensive design, this study has limitations that warrant consideration. First, reliance on the FAERS database introduces inherent biases, including underreporting and incomplete data, which may affect the generalizability of findings. Second, the study’s disproportionality analyses detect associations but cannot establish causal relationships between Inclisiran and adverse events. Third, variability in demographic and geographic reporting may obscure certain region or population-specific patterns. Finally, confounding factors such as polypharmacy and comorbidities were not fully accounted for, which may influence the observed signals. To address the limitations identified, future research should leverage multiple pharmacovigilance databases globally to validate these findings and mitigate underreporting bias. Advanced causal inference techniques, such as propensity score matching and machine learning models, could be employed to establish causal relationships between inclisiran and adverse events. Finally, long-term real-world studies and prospective cohort designs should be prioritized to monitor Inclisiran’s safety over extended periods. 5 Conclusions The study provides critical insights into inclisiran’s safety profile, highlighting areas for targeted pharmacovigilance and patient risk management.However, limitations include reliance on spontaneous reporting data with potential underreporting and bias. Future studies should incorporate prospective cohort designs and explore genetic and pharmacokinetic mechanisms underlying these findings. Expanding investigations to diverse populations will further validate and refine safety assessments of inclisiran in real-world settings. Funding This paper was not funded. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. Reviewer disclosure Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Availability of data and material The database used in this study is publicly available on the website of https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Ethics statement Ethical approval was not required for this study because it used the FAERS database, which is a free open-access database. This study was conducted in strict adherence to ethical research principles and guidelines. The analysis utilized publicly available, anonymized data from the FDA Adverse Event Reporting System (FAERS) database, ensuring that no identifiable patient information was included. As the FAERS data is de-identified, ethical approval and informed consent were not required for this study. All data cleaning, processing, and analyses were performed to maintain data integrity and uphold ethical standards in pharmacovigilance research. Acknowledgments This research received no specific grant from any funding agencies in the public, commercial, or nonprofit sectors. Author contribution statement All authors were involved in the conception and design, or analysis and interpretation of the data as well as the drafting and revising of the paper. All authors agree to be accountable for all aspects of the work.

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Lancet. 2022;400(10355):832–845. doi: 10.1016/s0140-6736(22)01545-8 Table1. The equations of the four methods. | Algorithms | Equation | Equation | | ROR | ROR = ad / b / c | lower limit of 95% CI > 1, N ≥ 3 | | 95%CI = e ln(ROR) ± 1.96(1/a+1/b+1/c+1/d)∧0.5 | || | PRR | PRR = a( c + d ) / c / ( a + b ) | PRR≥2, X 2 ≥ 4, N ≥ 3 | | X 2 = [(ad-bc) ∧ 2]（a + b + c + d)/[(a + b)(c + d)(a + c)(b + d)] | || | BCPNN | IC = log 2 (a + b + c + d)(a + c)(a + b) | IC025 > 0 | | 95%CI = E(IC) ± 2V(IC) ∧ 0.5 | || | EBGM | EBGM = a( a + b + c + d) /( a + c)/( a + b) | EBGM05 > 2 | | 95%CI = e ln(EBGM)±1.96(1/a + 1/b + 1/c+ 1/d )∧ 0.5 | Equation: a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reaction of the target drug; c, number of reports containing the target adverse drug reaction ofother drugs; d, number ofreports containing other drugs and other adverse drug reactions. 95%CI, 95% confidence interval; N, the number ofreports; X2, chi-squared; IC, information component; IC025, the lower limit of95% CI, ofthe IC; E(IC), the IC, expectations; V(IC), the variance ofIC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM. Table2. Demographic and geographic distribution of inclisiran-associated adverse event reports. | Characteristics | N | % | | | Overall | 4269 | || | Gender | ||| | Female | 2061 | 48.3% | | | Male | 1511 | 35.4% | | | Missing | 697 | 16.3% | | | Weight | ||| | ＜50 kg | 13 | 0.3% | | | ＞100 kg | 75 | 1.8% | | | 50～100 kg | 348 | 8.2% | | | Missing | 3833 | 89.8% | | | Age | ||| | <18 | 1 | 85 | 38 | 0.9% | | | 18～64.9 | 515 | 12.1% | | | 65～85 | 1341 | 31.4% | | | Missing | 2374 | 55.6% | | | Occupation Code | ||| | CN | 2246 | 52.6% | | | HP | 948 | 22.2% | | | MD | 965 | 22.6% | | | PH | 104 | 2.4% | | | Missing | 6 | 0.1% | | | Country of Reporter | ||| | ARGENTINA | 2 | <0.1% | | | AUSTRALIA | 26 | 0.6% | | | AUSTRIA | 15 | 0.4% | | | BAHRAIN | 1 | <0.1% | | | BELARUS | 1 | (0.0%) | | | BELGIUM | 42 | <0.1% | | | BRAZIL | 5 | 0.1% | | | BULGARIA | 14 | 0.3% | | | CANADA | 102 | 2.4% | | | CHINA | 48 | 1.1% | | | COLOMBIA | 1 | <0.1% | | | CROATIA | 7 | 0.2% | | | CYPRUS | 2 | <0.1% | | | CZECHIA | 12 | 0.3% | | | DOMINICAN REPUBLIC | 2 | <0.1% | | | EGYPT | 33 | 0.8% | | | ESTONIA | 1 | <0.1% | | | FINLAND | 3 | 0.1% | | | GERMANY | 96 | 2.2% | | | GHANA | 1 | <0.1% | | | GREECE | 8 | 0.2% | | | HONG KONG | 1 | <0.1% | | | HUNGARY | 4 | 0.1% | | | INDIA | 2 | <0.1% | | | INDONESIA | 1 | <0.1% | | | ISRAEL | 10 | 0.2% | | | ITALY | 14 | 0.3% | | | JAPAN | 17 | 0.4% | | | KOREA, SOUTH | 1 | <0.1% | | | LATVIA | 1 | <0.1% | | | LITHUANIA | 1 | <0.1% | | | LUXEMBOURG | 2 | <0.1% | | | MALAYSIA | 12 | 0.3% | | | MEXICO | 5 | 0.1% | | | NETHERLANDS | 40 | 0.9% | | | NEW ZEALAND | 1 | <0.1% | | | PAKISTAN | 1 | <0.1% | | | PHILIPPINES | 2 | <0.1% | | | POLAND | 12 | 0.3% | | | PORTUGAL | 1 | <0.1% | | | RUSSIA | 21 | 0.5% | | | SAUDI ARABIA | 10 | 0.2% | | | SINGAPORE | 2 | <0.1% | | | SLOVAKIA | 7 | 0.2% | | | SLOVENIA | 13 | 0.3% | | | SOUTH AFRICA | 1 | <0.1% | | | SPAIN | 4 | 0.1% | | | SWEDEN | 1 | <0.1% | | | SWITZERLAND | 8 | 0.2% | | | UKRAINE | 2 | <0.1% | | | UNITED ARAB EMIRATES | 3 | 0.1% | | | UNITED KINGDOM | 41 | 1.0% | | | UNITED STATES | 3605 | 84.4% | | | URUGUAY | 1 | <0.1% | | | Data Collection Year | ||| | 2021 | 1 | || | 2022 | 706 | || | 2023 | 2105 | || | 2024 | 1457 | || | Time to Onset Group | ||| | 0-30 days | 232 | || | 121-150 days | 20 | || | 151-180 days | 15 | || | 181-360 days | 66 | || | 31-60 days | 71 | || | 61-90 days | 71 | || | 91-120 days | 94 | || | >360 days | 34 | || | Outcome Code | ||| | 3143 | 73.6% | || | DE | 103 | 2.4% | | | DS | 43 | 1.0% | | | HO | 188 | 4.4% | | | LT | 33 | 0.8% | | | OT | 754 | 17.7% | | | RI | 5 | 0.1% | Table3. signal detection of adverse drug reactions associated with inclisiran by SOC Classification. | SOC | PT | N | ROR(95%CI 2 ) | IC(IC 025 ) | PRR( X 2 ) | EBGM(EBGM 05 ) | | Cardiac Disorders | Myocardial Infarction | 53 | 3.45(2.64-4.53) | 1.78(1.39) | 3.44(91.71) | 3.44(2.74) | | Acute Myocardial Infarction | 18 | 5.53(3.48-8.79) | 2.46(1.8) | 5.53(66.42) | 5.5(3.74) | | | Angina Pectonis | 17 | 4.7(2.92-757) | 2.23(155) | 4.7(493) | 4.68(3.14) | | | Coronary Artery Occlusion | 10 | 8.15(4.38-15.19) | 3.02(2.14) | 8.15(62.28) | 8.1(4.81) | | | Angina Unstable | 9 | 1927(997-3725) | 4.25(332) | 19.26(153.31) | 18.97(10.93) | | | Ear And Labyrinth Disorders | Hypoacusis | 41 | 3.89(2.86-5.29) | 1.95(1.51) | 3.88(87.58) | 3.87(3) | | Vertigo | 22 | 2.45(1.61-3.73) | 1.29(0.69) | 2.45(18.87) | 2.45(1.72) | | | Deafness | 10 | 2.17(1.17-4.04) | 1.12(024) | 2.17(629) | 2.17(1.29) | | | Sudden Heaning Loss | 3 | 10.16(3.26-31.67) | 3.33(1.88) | 10.16(24.57) | 10.08(3.9) | | | Endocrine Disorders | Hyperthyroidism | 6 | 2.25(1.01-5.01) | 1.17(0.08) | 2.25(4.15) | 2.25(1.15) | | Gastrointestinal Disorders | Diarrhoea | 258 | 2.07(1.83-2.34) | 1.03(0.85) | 2.05(13953) | 2.05(1.84) | | Abdominal Discomfort | 62 | 1.83(1.43-2.35) | 0.87(0.51) | 1.83(23.33) | 1.83(1.48) | | | Abdominal Pain Upper | 56 | 1.6(123-2.08) | 0.67(029) | 139(12.37) | 1.59(1.28) | | | Pancreatitis | 17 | 2.53(1.57-4.08) | 1.34(0.66) | 2.53(15.73) | 2.53(1.7) | | | Swollen Tongue | 10 | 2.51(135-4.67) | 1.33(0.46) | 2.51(9.08) | 251(1.49) | | | General Disorders And Administration Site CondiionsAdministration Site Condiions | njection Site Pain | 408 | 7.69(696-8.49) | 2.89(2.74) | 7.46(2277) | 7.42(6.83) | | Pain | 254 | 1.75(155-1.98) | 0.79(0.61) | 1.74(80.1) | 1.73(1.56) | | | Fatigue | 248 | 1.6(1.41-1.82) | 0.67(0.48) | 1.59(55.14) | 1.59(1.43) | | | Injection Site Reaction | 110 | 12.37(10.24-14.94) | 3.6(3.33) | 12.27(1127.44) | 12.15(10.38) | | | njection Site Erythemz | 90 | 5.46(4.44-6.72) | 2.43(2.13) | 5.43(324) | 5.41(4.54) | | | Hepatobilary Disorders | Hepatic Fibrosis | 3 | 3.34(1.78-17.23) | 2.46(1.02) | 5.54(11.11) | 552(2.14) | | mmune System Disorders | Hypersensitivity | 53 | 1.66(1.27-2.18) | 0.73(034) | 1.66(13.93) | 1.66(1.32) | | nfections And Infestations | Uninary Iract Infection | 127 | 3.81(32-4.54) | 1.91(1.66) | 3.78(259.45) | 3.77(3.26) | | Nasopharyngitis | 81 | 2.09(1.68-2.6) | 1.05(0.73) | 2.08(45.45) | 2.08(1.73) | | | Bronchitis | 68 | 5.95(4.69-7.56) | 2.56(221) | 5.92(277.16) | 5.9(4.83) | | | Lower Respiratory Tract Infection | 39 | 4.16(3.03-5.7) | 2.05(1.59) | 4.15(92.85) | 4.14(3.18) | | | Cystitis | 10 | 1.87(1.01-3.48) | 0.9(0.03) | 1.87(4.06) | 1.87(1.11) | | | njury,Poisoning And Procedural Complications | Product Storage Error | 103 | 3.02(2.49-3.67) | 1.59(13) | 3.01(138.01) | 3(2.55) | | Incorrect Route Of Produet Administration | 14 | 2.62(1.55-4.42) | 1.38(0.64) | 2.61(13.93) | 2.61(1.68) | | | Muscle Rupture | 3 | 4.28(1.38-13.3) | 2.09(0.65) | 4.28(751) | 4.27(1.65) | | | nvestigations | Low Density Lipoprotein Increased | 233 | 237(205.71-273.06) | 7.6(7.4) | 2323(44873.91) | 194.4(172.68) | | Blood Cholesterol Increased | 106 | 13.46(111-1631) | 3.72(3.44) | 13.34(1197.73) | 13.21(1124) | | | Blood Tniglycerides Increased | 86 | 44.78(36.08-55.58) | 5.42(5.11) | 44.46(3522.1) | 42.89(35.8) | | | Weight Decreased | 71 | 136(1.07-1.71) | 044(01) | 135(6.6) | 135(1.11) | | | Blood Cholesterol Decreased | 56 | 202.13(152.18-268.48) | 7.43(7.02) | 201.17(9535.79) | 172.13(135.74) | | | Metabolism And Nutrition Disorders | Diabetes Metlitus | 48 | 4.27(321-5.67) | 2.08(1.67) | 4.25(119.11) | 424(3.34) | | Gout | 11 | 3.52(1.95-6.36) | 1.81(0.98) | 3.51(19.73) | 3.51(2.14) | | | Diabetes Mellitus Inadequate Contro | 6 | 2.38(1.07-5.31) | 1.25(0.16) | 2.38(48) | 238(122) | | | Ghucose Tolerance Impaired | 5 | 4.68(1.94-11.26) | 2.22(1.04) | 4.68(14.4) | 4.66(2.24) | | | Overweight | 4 | 3.62(1.36-9.66) | 1.85(0.56) | 3.62(7.56) | 3.61(1.59) | | | Musculoskeletal AndConnective Tissue Disorders | Arthralgia | 512 | 5.84(535-6.39) | 2.49(2.36) | 5.63(1956.77) | 5.61(5.21) | | Myalgia | 345 | 13.76(12.35-1532) | 3.73(3.57) | 13.38(3916.73) | 13.24(12.1) | | | Pain In Extremity | 308 | 6.34(5.66-7.1) | 2.63(2.46) | 6.2(1341.42) | 6.17(5.61) | | | Muscle Spasms | 149 | 5.15(438-6.05) | 2.34(2.11) | 5.09(489.32) | 5.08(4.43) | | | Back Pain | 115 | 2.87(2.39-3.45) | 1.51(124) | 2.85(138.55) | 2.85(2.44) | | | Neoplasms Benign,Malignant And Unspecified (Incl Cysts And Polyps) | Lipoma | 3 | 7.04(226-21.92) | 2.81(136) | 7.04(15.46) | 7.01(2.71) | | Nervous System Disorders | Headache | 174 | 1.66(1.43-1.93) | 0.72(0.5) | 1.65(45.03) | 1.65(1.46) | | Dizziness | 119 | 1.48(1.23-1.77) | 0.56(029) | 1.47(18.02) | 1.47(1.26) | | | Memory Impairment | 53 | 2.12(1.62-2.78) | 1.08(0.69) | 2.12(31.18) | 2.11(1.69) | | | CerebrovascularAcciden | 40 | 1.94(1.42-2.65) | 0.95(0.5) | 1.94(18.17) | 1.94(1.49) | | | Buming Sensation | 30 | 2.75(1.92-3.94) | 1.46(0.94) | 2.75(33.29) | 2.74(2.03) | | | Product Issues | Product Temperature Excursion Issue | 16 | 751(4.59-12.27) | 29(22) | 7.5(89.54) | 7.46(4.94) | | Psychiatric Disorders | Middle Insomnia | 9 | 2.59(1.35-4.98) | 1.37(0.46) | 2.59(8.75) | 2.58(1.49) | | Renal And Urinary Disorders | Pollakiuria | 26 | 3.94(2.68-5.79) | 1.97(1.41) | 3.93(56.7) | 3.92(2.84) | | Dysuria | 20 | 3.56(23-5.53) | 1.83(12) | 3.56(36.72) | 3.55(2.46) | | | Renal Pain | 6 | 3.15(1.42-7.03) | 1.65(0.56) | 3.15(8.8) | 3.15(1.61) | | | Bladder Discomfort | 4 | 17.63(6.57-47.33) | 4.12(2.82) | 17.63(61.82) | 17.38(7.61) | | | Bladder Pain | 3 | 5.69(1.83-17.7) | 2.5(1.06) | 5.69(11.54) | 5.67(2.19) | | | Respiratory,Thoracic And Mediastinal Disorders | Dyspnoe2 | 210 | 2.22(1.94-2.55) | 1.13(0.93) | 2.2(138.03) | 2.2(196) | | Cough | 119 | 2.03(1.69-2.43) | 1.01(0.75) | 2.02(61.46) | 2.02(1.73) | | | Rhinorhoea | 39 | 2.83(2.06-3.87) | 1.49(1.04) | 2.82(45.83) | 2.82(2.17) | | | Oropharyngeal Pain | 33 | 1.72(1.22-2.43) | 0.78(029) | 1.72(998) | 1.72(1.29) | | | NasalCongestion | 26 | 2(136-2.93) | 0.99(0.44) | 1.99(12.86) | 1.99(1.44) | | | Skin And Subcutaneous Tissue Disorders | Rash | 149 | 1.85(157-2.17) | 0.88(0.64) | 1.84(57.33) | 1.84(1.61) | | Pruritus | 101 | 1.34(1.1-1.63) | 0.42(0.13) | 1.34(8.55) | 1.33(1.13) | | | Urticania | 47 | 1.71(128-2.27) | 0.77(0.35) | 1.7(13.71) | 1.7(134) | | | Vascular Disorders | Arteriosclerosis | 10 | 738(3.96-13.74) | 2.87(2) | 7.37(54.74) | 7.33(4.36) | | Artenial Occlusive Disease | 6 | 6.35(2.85-14.18) | 2.66(157) | 6.35(26.91) | 6.32(3.23) | | | Vasculitis | 6 | 2.58(1.16-5.75) | 1.37(0.27) | 2.58(5.8) | 2.58(1.32) | | | Infarction | 4 | 4.83(1.81-12.9) | 2.27(0.97) | 4.83(12.09) | 4.81(2.12) | | | Aortic Aneurysm | 3 | 3.26(1.05-10.13) | 1.7(0.26) | 3.26(4.69) | 3.25(1.26) | Table4. top 50 adverse event PTs signal analysis for inclisiran monotherapy. | PT | N | ROR(95%CI) | PRR(X 2 ) | EBGM(EBGMO5) | Ic(IC025) | | ARTHRALGIA | 512 | 5.84(5.35-6.39) | 5.63(1956.77) | 5.61(5.21) | 2.49(2.36) | | INJECTION SITE PAIN | 408 | 7.69(6.96-8.49) | 7.46(2277) | 7.42(6.83) | 2.89(2.74) | | MYALGIA | 345 | 13.76(12.35-15.32) | 3.38(3916.73) | 13.24(12. 1) | 3.73(3.57) | | PAIN IN EXTREMITY | 308 | 6.34(5.66-7. 1) | 6.2(1341.42) | 6. 17(5.61) | 2.63(2.46) | | DIARRHOEA | 258 | 2.07(1.83-234) | 2.05(139.53) | 2.05(1.84) | 1.03(0.85) | | PAIN | 254 | 1.75(1.55-1.98) | 1.74(80. 1) | 1.73(1.56) | 0.79(0.61) | | FATIGUE | 248 | 1.6(1.41-1.82) | 1.59(55. 14) | 1.59(1.43) | 0.67(0.48) | | LOW DENSITYLIPOPROTEIN INCREASED | 233 | 237(205.71-273.06) | 232.3(44873.91) | 194.4(172.68) | 7.6(7.4) | | DYSPNOEA | 210 | 2.22(1.94-2.55) | 2.2(138.03) | 2.2(1.96) | 1. 13(0.93) | | DRUG INEFFECTIVE | 209 | 0.86(0.75-0.99) | 0.86(4.74) | 0.86(0.77) | -0.21（-0.42） | | HEADACHE | 174 | 1.66(1.43-1.93) | 1.65(45.03) | 1.65(1.46) | 0.72(0.5) | | RASH | 149 | 1.85(1.57-2. 17) | 1.84(57.33) | 1.84(1.61) | 0.88(0.64) | | MUSCLE SPASMS | 149 | 5. 15(4.38-6.05) | 5.09(489.32) | 5.08(4.43) | 2.34(2. 11) | | URINARY TRACT INFECTION | 127 | 3.81(3.2-4.54) | 3.78(259.45) | 3.77(3.26) | 1.91(1.66) | | COUGH | 119 | 2.03(1.69-2.43) | 2.02(61.46) | 2.02(1.73) | 1.01(0.75) | | DIZZINESS | 119 | 1.48(1.23-1.77) | 1.47(18.02) | 1.47(1.26) | 0.56(0.29) | | NAUSEA | 119 | 0.91(0.76-1.08) | 0.91(1. 16) | 0.91(0.78) | 0. 14(-0.41) | | BACK PAIN | 115 | 2.87(2.39-3.45) | 2.85(138.55) | 2.85(2.44) | 1.51(1.24) | | INJECTION SITE REACTION | 110 | 12.37(10.24-14.94) | 12.27(1127.44) | 12. 15(10.38) | 3.6(3.33) | | BLOOD CHOLESTEROL INCREASED | 106 | 13.46(11. 1-16.31) | 13.34(1197.73) | 3.21(11.24) | 3.72(3.44) | | PRODUCT STORAGE ERROR | 103 | 3.02(2.49-3.67) | 3.01(138.01) | 3(2.55) | 1.59(1.3) | | PRURITUS | 101 | 1.34(1. 1-1.63) | 1.34(8.55) | 1.33(1. 13) | 0.42(0. 13) | | INJECTION SITE ERYTHEMA | 90 | 5.46(4.44-6.72) | 5.43(324) | 5.41(4.54) | 2.43(2. 13) | | BLOOD TRIGLYCERIDES INCREASED | 86 | 44.78(36.08-55.58) | 44.46(3522. 1) | 42.89(35.8) | 5.42(5. 11) | | ASTHENA | 84 | 1.31(1.05-1.62) | 13(5.97) | 1.3(1.09) | 0.38(0.07) | | INJECTION SITE RASH | 82 | 15.45(12.42-19.23) | 15.35(1086.62) | 15. 17(12.63) | 3.92(3.6) | | NASOPHARYNGITIS | 81 | 2.09(1.68-2.6) | 2.08(45.45) | 2.08(1.73) | 1.05(0.73) | | GENERAL PHYSICAL HEALTH | 79 | 3.36(2.69-4.2) | 3.35(129.87) | 3.34(2.77) | 1.74(1.42) | | MALAISE | 76 | 1. 11(0.89-1.39) | 1. 11(0.84) | 1. 11(0.92) | 0. 15(-0. 18) | | CHEST PAIN | 73 | 2.81(2.23-3.54) | 2.8(84.42) | 2.8(2.31) | 1.48(1. 15) | | cOVID-19 | 72 | 0.66(0.53-0.84) | 0.67(12. 19) | 0.67(0.55) | -0.59(-0.93) | | WEIGHT DECREASED | 71 | 1.36(1.07-1.71) | 1.35(6.6) | 1.35(1. 11) | 0.44(0. 1) | | DpONCHITIS | 68 | 5.95(4.69-7.56) | 5.92(277. 16) | 5.9(4.83) | 2.56(2.21) | | INJECTION SITE PRURITUS | 67 | 6.88(5.41-8.76) | 6.85(333.09) | 6.82(5.57) | 2.77(2.42) | | DEATH | 66 | 0.41(0.33-0.53) | 0.42(54.33) | 0.42(0.34) | -1.26(-1.61) | | FEELING ABNORMAL | 65 | 1.75(1.37-2.23) | 1.75(20.72) | 1.74(1.42) | 0.8(0.45) | | GAITDISTURBANCE | 64 | 1.95(1.53-2.5) | 1.95(29.54) | 1.95(1.58) | 0.96(0.6) | | ARTHRITIS | 63 | 3.94(3.08-5.05) | 3.93(137.24) | 3.92(3. 18) | 1.97(1.61) | | ABDOMINAL DISCOMFORT | 62 | 1.83(1.43-2.35) | 1.83(23.33) | 1.83(1.48) | 0.87(0.51) | | MUSCULAR WEAKNESS | 58 | 3. 17(2.45-4. 11) | 3. 16(85.55) | 3. 15(2.54) | 1.66(1.28) | | BLOOD CHOLESTEROL DECREASED | 56 | 202. 13(152. 18-268.48) | 201. 17(9535.79) | 172. 13(135.74) | 7.43(7.02) | | LOW DENSITY LIPOPROTEIN DECREASED | 56 | 262.61(196.52-350.93) | 261.36(11900.87) | 214.33(168. 16) | 7.74(7.33) | | ABDOMINAL PAIN UPPER | 56 | 1.6(1.23-2.08) | 1.59(12.37) | 1.59(1.28) | 0.67(0.29) | | PERIPHERAL SWELLING | 56 | 1.58(1.21-2.05) | 1.58(11.79) | 1.57(1.26) | 0.66(0.27) | | ILLNESS | 55 | 1.2(0.92-1.56) | 1. 19(1.75) | 1. 19(0.96) | 0.26(-0. 13) | | BLOOD GLUCOSE INCREASED | 54 | 2. 16(1.66-2.83) | 2. 16(33.55) | 2. 16(1.72) | 1. 11(0.72) | | MYOCARDIALINFARCTION | 53 | 3.45(2.64-4.53) | 3.44(91.71) | 3.44(2.74) | 1.78(1.39) | | HYPERSENSITIVITY | 53 | 1.66(1.27-2. 18) | 1.66(13.93) | 1.66(1.32) | 0.73(0.34) | | MEMORY IMPAIRMENT | 53 | 2. 12(1.62-2.78) | 2. 12(31. 18) | 2. 11(1.69) | 1.08(0.69) | | INSOMNIA | 51 | 1.27(0.96-1.67) | 1.27(2.87) | 1.27(1.01) | 0.34(-0.06) | Table5. FFUN analysis of inclisiran and atorvastatin concomitant use on adverse event signals. | PT | a | b | c | d | ROR(95%CI) | PRR(X 2 ) | EBGM(EBGM05) | IC(IC025) | | MYOCARDIAL INFARCTION | 8 | 259 | 164986 | 53038148 | 9.93(4.91-20.07) | 9.66(62.31) | 9.66(5.36) | 3.27(2.29) | | BLOOD CHOLESTEROLIN CREASED | 7 | 260 | 40969 | 53162165 | 34.94(16.49-74.02) | 34.05(224.66) | 34.04(18.16) | 5.09(4.05) | | LOWDENSITY LIPOPROTEIN DECREASED | 5 | 262 | 1227 | 53201907 | 827.47(340.95-2008.21) | 811.99(4033.62) | 808.7(385.12) | 9.66(8.47) | | LOW DENSITYLIPOPROTEIN INCREASED | 5 | 262 | 6581 | 53196553 | 154.26(63.65-373.85) | 151.39(746.52) | 151.28(72.13) | 7.24(6.05) | | FATIGUE | 5 | 262 | 684898 | 52518236 | 1.46(0.6-3.55) | 1.45(0.72) | 1.45(0.69) | 0.54(-0.65) | | CHEST PAIN | 5 | 262 | 167664 | 53035470 | 6.04(2.49-14.62) | 5.94(20.62) | 5.94(2.83) | 2.57(1.38) | | ARTHRALGIA | 4 | 263 | 362627 | 52840507 | 2.22(0.83-5.95) | 2.2(2.63) | 2.2(0.96) | 1.14(-0.17) | | SYNCOPE | 4 | 263 | 90091 | 53113043 | 8.97(3.34-24.07) | 8.85(27.89) | 8.85(3.87) | 3.15(1.84) | | DRUG INEFFECTIVE | 4 | 263 | 1165783 | 52037351 | 0.68(0.25-1.82) | 0.68(0.6) | 0.68(0.3) | -0.55(-1.85) | | MYALGLA | 4 | 263 | 151644 | 53051490 | 5.32(1.98-14.28) | 5.26(13.82) | 5.26(2.3) | 2.39(1.09) | | GAIT DISTURBANCE | 4 | 263 | 173553 | 53029581 | 4.65(1.73-12.47) | 4.59(11.28) | 4.59(2.01) | 2.2(0.9) | | URTICARIA | 3 | 264 | 142586 | 53060548 | 4.23(1.36-13.2) | 4.19(7.31) | 4.19(1.62) | 2.07(0.61) | | BACK PAIN | 3 | 264 | 208359 | 52994775 | 2.89(0.93-9.02) | 2.87(3.67) | 2.87(1.11) | 1.52(0.07) | | PAIN | 3 | 264 | 556318 | 52646816 | 1.08(0.34-3.36) | 1.07(0.02) | 1.07(0.41) | 0.1(-1.35) | | BLOOD TRIGLYCERIDES INCREASED | 3 | 264 | 16009 | 53187125 | 37.75(12.1-117.83) | 37.34(106.11) | 37.33(14.41) | 5.22(3.77) | | PAIN IN EXTREMITY | 3 | 264 | 268749 | 52934385 | 2.24(0.72-6.98) | 2.22(2.03) | 2.22(0.86) | 1.15(-0.3) | | CARDIAC DISORDER | 3 | 264 | 84958 | 53118176 | 7.1(2.28-22.17) | 7.04(15.56) | 7.04(2.72) | 2.81(1.36) | | PERIPHERAL SWELLING | 3 | 264 | 133723 | 53069411 | 4.51(1.45-14.07) | 4.47(8.1) | 4.47(1.72) | 2.16(0.71) | | DEATH | 3 | 264 | 752967 | 52450167 | 0.79(0.25-2.47) | 0.79(0.16) | 0.79(0.31) | -0.33(-1.79) | | HEADACHE | 3 | 264 | 558225 | 52644909 | 1.07(0.34-3.34) | 1.07(0.01) | 1.07(0.41) | 0.1(-1.35) | | ANGINAUNSTABLE | 3 | 264 | 6364 | 53196770 | 94.99(30.43-296.5) | 93.93(275.73) | 93.89(36.22) | 6.55(5.1) | | ABDOMINAL DISTENSION | 3 | 264 | 90677 | 53112457 | 6.66(2.13-20.77) | 6.59(14.26) | 6.59(2.54) | 2.72(1.27) | | DRUG INTOLERANCE | 3 | 264 | 83594 | 53119540 | 7.22(2.31-22.53) | 7.15(15.9) | 7.15(2.76) | 2.84(1.38) | | DYSPNOEA | 3 | 264 | 502330 | 52700804 | 1.19(0.38-3.72) | 1.19(0.09) | 1.19(0.46) | 0.25(-1.2) | | DIZZINESS | 3 | 264 | 442615 | 52760519 | 1.35(0.43-4.23) | 1.35(0.28) | 1.35(0.52) | 0.43(-1.02) | | PRURITUS | 3 | 264 | 310941 | 52892193 | 1.93(0.62-6.03) | 1.92(1.34) | 1.92(0.74) | 0.94(-0.51) | | PRODUCT DOSE OMISSION ISSUE | 3 | 264 | 196807 | 53006327 | 3.06(0.98-9.55) | 3.04(4.12) | 3.04(1.17) | 1.6(0.15) | | ACUTEMYOCARDLAL INFARCTION | 3 | 264 | 27466 | 53175668 | 22(7.05-68.66) | 21.76(59.46) | 21.76(8.4) | 4.44(2.99) | | ERYTHEMA | 3 | 264 | 182051 | 53021083 | 3.31(1.06-10.33) | 3.28(4.78) | 3.28(1.27) | 1.72(0.26) | | INSOMNIA | 2 | 265 | 240226 | 52962908 | 1.66(0.41-6.69) | 1.66(0.53) | 1.66(0.52) | 0.73(-0.94) | | ABDOMINAL PAIN UPPER | 2 | 265 | 179821 | 53023313 | 2.23(0.55-8.95) | 2.22(1.34) | 2.22(0.69) | 1.15(-0.53) | | DIARRHOEA | 2 | 265 | 561954 | 52641180 | 0.71(0.18-2.84) | 0.71(0.24) | 0.71(0.22) | -0.5(-2.17) | | GENERAL PHYSICAL HEALTH | 2 | 265 | 96077 | 53107057 | 4.17(1.04-16.77) | 4.15(4.79) | 4.15(1.3) | 2.05(0.38) | | GASTROINTESTINAL DISORDER | 2 | 265 | 71986 | 53131148 | 5.57(1.39-22.39) | 5.54(7.44) | 5.54(1.73) | 2.47(0.79) | | INJECTION SITE PAIN | 2 | 265 | 252870 | 52950264 | 1.58(0.39-6.35) | 1.58(0.42) | 1.58(0.49) | 0.66(-1.02) | | ANGINA PECTORIS | 2 | 265 | 26623 | 53176511 | 15.07(3.75-60.6) | 14.97(26.08) | 14.97(4.67) | 3.9(2.23) | | ANAPHYLACTICREACTION | 2 | 265 | 46400 | 53156734 | 8.65(2.15-34.75) | 8.59(13.42) | 8.59(2.68) | 3.1(1.43) | | MUSCLE SPASMS | 2 | 265 | 164488 | 53038646 | 2.43(0.61-9.78) | 2.42(1.68) | 2.42(0.76) | 1.28(-0.4) | | CHESTDISCOMFORT | 2 | 265 | 89056 | 53114078 | 4.5(1.12-18.09) | 4.47(5.41) | 4.47(1.4) | 2.16(0.49) | | TREMOR | 2 | 265 | 149914 | 53053220 | 2.67(0.66-10.74) | 2.66(2.07) | 2.66(0.83) | 1.41(-0.26) | | PARAESTHESIA | 2 | 265 | 142905 | 53060229 | 2.8(0.7-11.26) | 2.79(2.3) | 2.79(0.87) | 1.48(-0.2) | | ASTHENIA | 2 | 265 | 334664 | 52868470 | 1.19(0.3-4.79) | 1.19(0.06) | 1.19(0.37) | 0.25(-1.42) | | CEREBROVASCULARACCIDENT | 2 | 265 | 155136 | 53047998 | 2.58(0.64-10.37) | 2.57(1.92) | 2.57(0.8) | 1.36(-0.31) | | CORONARY ARTERYDISEASE | 2 | 265 | 29327 | 53173807 | 13.68(3.4-55.01) | 13.59(23.34) | 13.59(4.24) | 3.76(2.09) | | TRANSIENT ISCHAEMICATTACK | 2 | 265 | 31042 | 53172092 | 12.93(3.22-51.96) | 12.84(21.84) | 12.84(4.01) | 3.68(2.01) | | ABDOMINAL DISCOMFORT | 2 | 265 | 146339 | 53056795 | 2.74(0.68-11) | 2.72(2.19) | 2.72(0.85) | 1.45(-0.23) | | OFF LABELUSE | 2 | 265 | 712405 | 52490729 | 0.56(0.14-2.24) | 0.56(0.7) | 0.56(0.17) | -0.84(-2.51) | | HYPOAESTHESIA | 2 | 265 | 134843 | 53068291 | 2.97(0.74-11.94) | 2.96(2.59) | 2.96(0.92) | 1.56(-0.11) | | WOUND | 2 | 265 | 23287 | 53179847 | 17.24(4.29-69.28) | 17.11(30.35) | 17.11(5.34) | 4.1(2.42) | | BLOOD CREATINE PHOSPHOKINASE | 2 | 265 | 27333 | 53175801 | 14.68(3.65-59.02) | 14.58(25.31) | 4.58(4.55) | 3.87(2.19) | Table6. DDI analysis of inclisiran and atorvastatin on joint adverse | PT | a | b | c | d | ROR(95%C1) | PRR(X 2 ) | EBGM(EBGM05) | IC（IC025) | | a-b-Langclpl | 7 | 354 | 244518 | 13638992 | 1.10.52-2.33) | 1.1(0.07) | 1.1(0.59-2.06) | (0.59-2.06) | | a–targetpt | 662 | 10824 | 243863 | 13628522 | 3.42(3.16-3.7) | 3.28(1064.28) | 3.27(3.06-3.49 | (3.06-3.49) | | b–targetp | 787 | 37108 | 243738 | 13602238 | 1.18(1.1-1.27 | 1.18(21.87) | 1.18(1.11-1.25 | (1.11 -125) | Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 464views 177downloads Citations Download citation Changjiang Deng, Yixin Xu, Ying Pan, et al. Pharmacovigilance analysis of inclisiran:a real-world assessment based on the FAERS database. Authorea. 06 March 2025. DOI: https://doi.org/10.22541/au.174127529.93210053/v1 DOI: https://doi.org/10.22541/au.174127529.93210053/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.