Department of Medicine, Lincoln Medical Center, New York, NY, USA.
Cebu Institute of Medicine, Cebu City, Philippines.
Curr Med Res Opin. 2024 Jul;40(7):1103-1121. doi: 10.1080/03007995.2024.2363971. Epub 2024 Jun 11.
BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.
背景：阿利西尤单抗和依洛尤单抗的使用通常是安全且耐受良好的。然而，人们仍然对其长期安全性表示担忧，尤其是新发或恶化的糖尿病（DM）。我们旨在评估阿利西尤单抗和依洛尤单抗与对照药物相比的安全性。
方法：检索了比较 PCSK9i 与对照药物（安慰剂或他汀类药物，加或不加依折麦布）安全性的研究。主要结局是导致死亡的不良事件。次要结局包括严重不良事件、新发糖尿病（DM）、DM 恶化、神经认知功能障碍、肌酸激酶（CK）升高、肝酶升高和局部注射部位反应。通过荟萃回归分析确定与治疗效果相关的因素。进行亚组分析，以根据 PCSK9i 类型和治疗持续时间探索潜在的治疗效果差异。
结果：我们确定了 56 项研究，涉及 85123 名成年人（29.14%为女性）。PCSK9i 与导致死亡的不良事件无关（OR 0.94，95%CI 0.84 至 1.04， = 0.22）。在两种 PCSK9i 中，阿利西尤单抗降低了导致死亡的不良事件（OR 0.79，95%CI，0.67 至 0.94， = 0.008）。与对照药物相比，PCSK9i 与较少的严重事件相关（OR 0.93，95%CI 0.89 至 0.98， < 0.001）。这种减少主要归因于阿利西尤单抗（OR 0.89，95%CI，0.85 至 0.93， < 0.001）。依洛尤单抗加重 DM（OR 2.3，95%CI 1.26 至 4.2， = 0.041）。亚组分析显示，在治疗的前 24 周内，DM 恶化，在前 12 周内治疗的可能性最高（<12 周：OR 3.82，95%CI 1.13 至 12.99， = 0.03；12-24 周：OR 2.12，95%CI 1.20 至 3.73， = 0.01。另一方面，治疗持续时间>24 周可降低 DM 恶化的可能性（OR 0.89，95%CI 0.79 至 0.99， = 0.04）。PCSK9i 不会增加认知功能障碍（OR 1.02，95%CI 0.88 至 1.18， = 0.76）、肝酶升高（OR 0.91，95%CI 0.81 至 1.03， = 0.14）或 CK 升高（OR 0.82，95%CI 0.65 至 1.04， = 0.10）。然而，PCSK9i 与局部注射部位反应相关（OR 1.54，95%CI 1.37 至 1.73， < 0.01）。
结论：阿利西尤单抗降低了导致死亡的不良事件。阿利西尤单抗和依洛尤单抗均降低了严重不良事件。PCSK9i 不会增加新发 DM，但是依洛尤单抗在治疗的前 24 周内加重 DM。PCSK9i 不会增加神经认知功能障碍，也不会升高肝酶和 CK，但与局部注射部位反应相关。
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