Adjunctive therapy with lipid-lowering agents in COVID-19: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Many commonly used drugs were evaluated as repurposed treatment options since the emergence of the COVID-19 pandemic. The benefit of lipid-lowering agents has been controversial in this regard. In this systematic review, we assessed the effect of these medications as adjunctive therapy in COVID-19 by the inclusion of randomized controlled trials (RCTs). Methods We searched four international databases including PubMed, the Web of Science, Scopus, and Embase for RCTs in April 2023. The primary outcome was mortality, while other efficacy indices were considered secondary outcomes. In order to estimate the pooled effect size of the outcomes, considering the odds ratio (OR) or standardized mean difference (SMD) and 95% confidence interval (CI), random-effect meta-analyses was conducted. Results Ten studies involving 2,167 COVID-19 patients using statins, omega-3 fatty acids, fenofibrate, PCSK9 inhibitors, and nicotinamide as intervention compared to control or placebo, were included. No significant difference was found in terms of mortality (OR 0.96, 95% CI 0.58 to 1.59, p-value = 0.86, I2 = 20.4%) or length of hospital stay (SMD -0.10, 95% CI -0.78 to 0.59, p-value = 0.78, I2 = 92.4%) by adding a statin to the standard of care. The trend was similar for fenofibrate and nicotinamide. PCSK9 inhibition, however, led to decreased mortality and an overall better prognosis. Omega-3 supplementation showed contradicting results in two trials, suggesting the need for further evaluation. Conclusion Although some observational studies found improved outcomes in patients using lipid-lowering agents, our study found no benefit in adding statins, fenofibrate, or nicotinamide to COVID-19 treatment. On the other hand, PCSK9 inhibitors can be a good candidate for further assessment. Finally, there are major limitations in the use of omega-3 supplements in treating COVID-19 and more trials are warranted to evaluate this efficacy.

背景 自新型冠状病毒肺炎（COVID-19）大流行暴发以来，众多临床常用药物被评估为老药新用的治疗候选方案。其中，降脂药物的应用价值仍存在较大争议。本项系统综述纳入随机对照试验（randomized controlled trials, RCTs），旨在评估此类药物作为COVID-19辅助治疗手段的临床疗效。
方法 本研究于2023年4月检索PubMed、Web of Science、Scopus及Embase四大国际数据库，筛选相关RCTs。本研究的主要结局指标为死亡率，其余疗效相关指标设为次要结局指标。为合并估算各结局的效应量，我们采用比值比（odds ratio, OR）、标准化均差（standardized mean difference, SMD）及95%置信区间（confidence interval, CI），并开展随机效应Meta分析。
结果 本研究共纳入10项研究，涉及2167例COVID-19患者，干预组分别使用他汀类药物、ω-3脂肪酸、非诺贝特、前蛋白转化酶枯草溶菌素9抑制剂（PCSK9抑制剂）及烟酰胺，对照组采用常规治疗或安慰剂。在标准治疗方案基础上加用他汀类药物，患者死亡率（OR=0.96，95%CI：0.58~1.59，P=0.86，I²=20.4%）与住院时长（SMD=-0.10，95%CI：-0.78~0.59，P=0.78，I²=92.4%）均未出现显著改善。非诺贝特与烟酰胺的研究结果趋势与之相似。而PCSK9抑制剂可降低患者死亡率，整体预后更佳。两项试验中ω-3脂肪酸补充治疗的结果存在矛盾，提示需开展进一步研究以明确其疗效。
结论 尽管部分观察性研究显示使用降脂药物的COVID-19患者临床结局有所改善，但本研究证实，在标准治疗基础上加用他汀类药物、非诺贝特或烟酰胺并未使患者获益。另一方面，PCSK9抑制剂可作为后续临床评估的优质候选药物。最后，当前关于ω-3补充剂治疗COVID-19的研究存在显著局限性，需开展更多临床试验以评估其实际疗效。