ASCVD is one of the leading causes of mortality worldwide, accounting for over one-third of all global deaths (1). Dyslipidemia, characterized by the excessive accumulation of low-density lipoprotein cholesterol (LDL-C) in the vasculature, is recognized as a pivotal risk factor in developing ASCVD (2). Consequently, reducing LDL-C levels is essential for managing ASCVD. Statin therapy had been suggested as the first-line therapy by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines and the European Atherosclerosis Society/European Society of Cardiology (EAS/ESC) guidelines. Despite the widespread use of statin therapy, some patients are unable to tolerate it from the outset (3, 4).A meta-analysis identified the most common reason for statin discontinuation as the development of muscle symptoms, with or without changes in creatine kinase (CK) levels. These symptoms occurred in patients who were on increasing doses of statin therapy or who were using a combination of more than two statins (5). As a result, some new therapies have been developed to enhance LDL-C reduction in high-risk ASCVD patients, including PCSK9i and siRNA therapies (6). Achieving guideline-recommended LDL-C goals in statin-intolerant patients requires the use of personalized lipid-lowering therapies other than statins (7). According to the 2018 AHA/ACC guideline and the 2017 National Lipid Association update, PCSK9 inhibitors were recommended for patients with LDL-C levels ≥70 mg/dl or non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dl after maximally tolerated LDL-lowering therapies (8, 9). The current incidence of statin intolerance is approximately 9.1% and is associated with an increased statin dosage (5).

PCSK9 inhibitors, such as evolocumab, bococizumab, and alirocumab, have demonstrated the ability to bind with PCSK9, effectively inhibiting its interaction with the low-density lipoprotein receptor (LDLR) (10). Common adverse effects of PCSK9 inhibitors include nasopharyngeal pain, headache, and muscle symptoms. Few reports are available comparing the incidence of muscle-related adverse events induced by different types of PCSK9 inhibitors (11). Inclisiran is a siRNA molecule specifically designed to target the mRNA encoding PCSK9, leading to its degradation and the subsequent suppression of PCSK9 protein production (12). The siRNA-mediated degradation of PCSK9 mRNA effectively blocks the synthesis of PCSK9 protein, offering a new therapeutic approach for treating cardiovascular diseases (13, 14). Inclisiran has shown a substantial effect in lowering LDL-C; however, due to the lack of extensive clinical data, its long-term tolerability and safety remain uncertain compared to PCSK9 inhibitors (15). For inclisiran, adverse events at the injection site have been commonly reported. However, the occurrence of muscle symptoms and the elevation of creatine kinase levels have not been thoroughly investigated (16).

For statin-intolerant patients experiencing rhabdomyolysis and requiring alternative therapies, PCSK9i and inclisiran present viable options (17). However, there is no evidence to suggest that these therapies are superior in terms of muscule-related effects. Therefore, we conducted a systematic review and NMA of RCTs to compare the muscle-related adverse effects of these treatments.

This NMA followed the guidelines set by the Cochrane Collaboration and was reported by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis), as outlined in Figure 1 (18). To ensure the originality, dependability and transparency of the research, the research proposal was registered with the Systematic Review Registry (PROSPERO) under the number CRD42023459558.

In this comprehensive NMA, encompassing a substantial cohort of 100,193 patients who either received high-dose statin treatment or reported intolerance to statins, our results indicated that the use of inclisiran and PCSK9i may lead to various adverse effects throughout therapy. Previous reports had suggested that these lipid-lowering therapies could impact the neurocognitive system of patients or even increase the risk of fractures (48, 49). However, the risk of muscular adverse events associated with PCSK9i and inclisiran had not been comprehensively summarized in a complete meta-analysis until now.

The utilization of NMA represented an advancement compared to traditional meta-analyses, as it allows for indirect comparisons of interventions across RCTs by incorporating a joint comparator group. This approach encompassed a broader range of studies, thereby enhancing the credibility of the findings. When evaluating the relative safety profiles of PCSK9i (such as evolocumab, bococizumab, and alirocumab) and inclisiran in patients with hyperlipidemia, head-to-head clinical trials are invaluable. They provide essential insights that guide clinical decision-making.

The comparison of new muscular symptom events demonstrated that evolocumab exhibited the highest level of safety, followed by bococizumab. In contrast, patients treated with alirocumab showed a relatively higher incidence of new muscular symptoms.

Similarly, when comparing events with CK>3ULN, patients treated with bococizumab had a higher risk of elevated creatine kinase compared to those treated with inclisiran (22, 47). In contrast, other PCSK9 inhibitors, such as evolocumab and alirocumab, demonstrated a better safety profile than inclisiran. with evolocumab having the fewest incidents of creatine kinase elevation. However, it is important to note that inclisiran and bococizumab were each included in only one trial, which may impact the results of the NMA. More RCTs are needed in the future to confirm these findings. Notably, bococizumab has been suspended in recent years due to its higher immunogenicity (50).

Adverse drug reactions were observed to be both more severe and more frequent in female subjects compared to their male counterparts. The pharmacological aspects of these reactions have been comparatively understudied. To develop appropriate individualized dosing regimens, gender differences should receive greater attention (51). This may require additional clinical trials to validate this observation. Moreover, an interesting phenomenon was noted, patients with specific genotypes (e.g., SLCO1B1rs4149056) had more difficulty reaching the LDL-C target value, with a notable gender difference in this effect. Future studies should focus on the safety and efficacy of PCSK9 inhibitors in genetically diserve patients to further explore these differences (52).

Through this comprehensive NMA, we provided valuable insights into the relative safety of PCSK9i and inclisiran in patients with hyperlipidemia. These findings have important implications for clinical decision-making and patient outcomes. It is significant to note that clinicians might face challenges in selecting these therapies due to the high cost of PCSK9 inhibitors. A cost-effectiveness analysis of PCSK9 inhibitors and inclisiran would provide a crucial basis to supporting their use in statin-intolerant patients (53).

Our analysis offered significant insights into the safety of muscle adverse events among patients using different lipid-lowering therapies. However, it is imperative to recognize the necessity for additional studies to validate and expand upon our findings. Considering the intricate and diverse nature of individuals with hyperlipidemia, it is crucial to personalize treatment decisions on an individual basis. Patient stratification based on factors such as ethnicity and age may play a vital role in selecting the most suitable lipid-lowering drug for each patient. By tailoring treatment protocols to align with the distinct clinical profiles of individual patients, we can enhance therapeutic outcomes and reduce the incidence of novel muscule symptoms.

Notably, the limitations of these findings stem from the quality of available evidence, including internal bias and heterogeneity. Incomplete reporting, controversial treatment classifications, and potential misclassification also posed constraints. Furthermore, high-impact interventions might be influenced by other factors associated with higher socioeconomic status in the patient population. Therefore, further exploration of these potential limitations is crucial for enhancing our understanding of the safety lipid-lowering therapy in patients with hyperlipidemia.

Based on the results of this NMA, evolocumab demonstrated the lowest likelihood of causing adverse muscle effects compared to other PCSK9 inhibitors (bococizumab, alirocumab) and inclisiran.This makes evolocumab a promising lipid-lowering option for patients with both hyperlipidemia and muscle disease.