Feng Zhen, Li Xiaoye, Tong Wai Kei, He Qingfeng, Zhu Xiao, Xiang Xiaoqiang, Tang Zhijia
Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.
Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
Front Pharmacol. 2022 Nov 24;13:894685. doi: 10.3389/fphar.2022.894685. eCollection 2022.
We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe. We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively. Compared with all other drugs, both alirocumab and evolocumab had a significant signal in "musculoskeletal and connective tissue disorders" (ROR = 2.626, 95% CI 2.552-2.702; ROR2 = 2.575, 95% CI 2.538-2.613). The highest ROR value of 2.311 (95% CI 2.272-2.351) was for "injury, poisoning and procedural complications" and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were "general disorders and administration site conditions" and "musculoskeletal and connective tissue disorders" for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC "nervous system disorders", "psychiatric disorders" and "metabolism and nutrition disorders" (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4-95.3) and xanthoma (ROR = 9.3, 95% CI 3.4-25.5), were also reported. Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.
我们旨在评估在真实世界中，与所有其他药物相比，阿利西尤单抗和依洛尤单抗相关的不良事件（AE），包括总体情况以及按性别和年龄亚组分析；我们还旨在比较它们与各种他汀类药物和依折麦布相比，发生认知障碍、肌肉骨骼疾病和糖尿病的风险。我们回顾性地从美国食品药品监督管理局不良事件报告系统（FAERS）数据库中提取了2015年7月至2021年6月期间的AE报告。分别使用报告比值比（ROR）进行不成比例分析，以检测阿利西尤单抗和依洛尤单抗在总体人群以及不同年龄和性别亚组中的AE信号。与所有其他药物相比，阿利西尤单抗和依洛尤单抗在“肌肉骨骼和结缔组织疾病”方面均有显著信号（ROR = 2.626，95% CI 2.552 - 2.702；ROR2 = 2.575，95% CI 2.538 - 2.613）。依洛尤单抗治疗的≥65岁患者中，“损伤、中毒及操作并发症”的ROR值最高，为2.311（95% CI 2.272 - 2.351）。所有亚组中最常见的AE是“全身性疾病和给药部位状况”以及“肌肉骨骼和结缔组织疾病”。在首选术语层面，总体及各亚组中，阿利西尤单抗最常见的AE信号是肌痛，依洛尤单抗是注射部位疼痛。与他汀类药物/依折麦布相比，前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂在与“神经系统疾病”“精神疾病”和“代谢及营养疾病”相关的不良事件方面的ROR值较低（所有ROR均<1），但在肌肉骨骼疾病方面结果不一。与所有其他药物相比，还报告了一些未记录的AE，如急性心脏事件（ROR = 30.0，95% CI 9.4 - 95.3）和黄瘤（ROR = 9.3，95% CI 3.4 - 25.5）。真实世界证据表明，PCSK9抑制剂与肌肉骨骼和结缔组织疾病以及全身性疾病和给药部位状况的风险增加相关，总体及各亚组均如此。肌肉毒性、注射部位反应和流感样疾病是显著的AE信号。与各种他汀类药物和依折麦布相比，PCSK9抑制剂在肌肉相关事件、认知障碍和糖尿病方面显示出良好的安全性。还报告了一些未记录的AE信号。由于自发报告数据库的局限性，仍需要进一步研究来确定因果关系并验证我们的结果。
