Proprotein Convertase Subtilisin/Kexin Type 9抑制劑作為高膽固醇血症患者的Statin輔助治療之效果及安全性評估: 系統性回顧與網絡統合分析研究

Abstract

背景與目的 許多研究指出有部份高膽固醇血症的患者使用第一線用藥statin，未能有效地降低血中低密度脂蛋白膽固醇，進而提高罹患心血管疾病的風險。準則建議此族群的患者，應採用statin加上輔助性治療，例如: proprotein convertase subtilisin/kexin type 9 (PCSK9)抑製劑。不過，目前針對不同種類與劑量的PCSK9抑製劑作為statin輔助治療，用於高膽固醇血症患者的相對療效、安全性尚未確定。因此，本研究將進行系統性回顧與網絡統合分析，用以比較高膽固醇血症患者接受不同PCSK9抑製劑作為statin輔助治療的血脂改變、不良反應與心血管疾病事件的發生率。 研究方法 本研究透過搜尋MEDLINE/PubMed, Embase、Cochrane CENTRAL、Web of Science、LILACS 和 ClinicalTrials.gov資料庫，針對2017年3月24日以前發表的文獻，進行系統性文獻回顧，找出PCSK9抑製劑作為statin輔助治療的隨機分派臨床試驗，運用網絡統合分析比較不同種類與劑量的PCSK9抑製劑降低低密度脂蛋白膽固醇、脂蛋白元B和血清脂蛋白(a)的百分比改變量，以及比較不同種類與劑量的PCSK9抑製劑不良反應、包括鼻咽炎，注射部位反應和神經系統不良反應，以及嚴重不良反應的勝算比。 結果 本研究納入包含了58,641位患者的25個隨機分派臨床試驗。與安慰劑組相比，低劑量evolocumab(-69.0％，[95％CI：-73.8％至-64.1％])、高劑量evolocumab(-59.8％[-63.8％至-55.7％])、低劑量bococizumab(-56.5％ [-66.8％至-46.2％])顯著地降低低密度脂蛋白膽固醇。低劑量evolocumab(-55.3％ [-60.2％至-50.5％])、高劑量evolocumab(-49.7％[-54.3％至-45.1％])、低劑量bococizumab(-47.4％ [-57.6％至-37.2％])顯著地降低血中脂蛋白元B。而低劑量evolocumab(-37.0％ [-42.7％至-31.2％])與高劑量evolocumab(-30.4％ [-35.8％至-25.1％])降低脂蛋白(a)的效果也顯著地較安慰劑多。PCSK9抑製劑與安慰劑相比，沒有顯著增加不良反應的發生率，包括鼻咽炎，神經系統不良反應和嚴重不良反應。不過，高劑量或低劑量的bococizumab和LY3015014和低劑量alirocumab發生注射部位不良反應的風險較高。 結論 PCSK9抑製劑對低密度脂蛋白膽固醇和脂蛋白元B濃度有顯著降低效果。低劑量evolocumab為高膽固醇血症患者之輔助性治療的首要選擇。

IMPORTANCE: The relative efficacy and optimal doses of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as an add-on statins therapy for hypercholesterolemia patients remained inconclusive. OBJECTIVE: To compare the efficacy and safety of different PCSK9 inhibitors in the treatment of hypercholesterolemia. DATA SOURCES: MEDLINE/PubMed, Embase, Cochrane CENTRAL, Web of Science, LILACS and ClinicalTrials.gov were searched for publications up to March, 2017. STUDY SELECTION: Randomized control trials that compared PCSK9 inhibitors in patients with hypercholesterolemia, and reported percentage change in low-density lipoprotein (LDL) cholesterol, apolipoprotein B, and lipoprotein(a) levels, and the numbers of adverse events and major adverse cardiac events. DATA EXTRACTION AND SYNTHSIS: Random-effect network meta-analysis was undertaken to compare the differences in the percent reduction in lipid levels and the risk of adverse events between different PCSK9 inhibitors. Ranking of efficacy and safety for each treatment was evaluated by simulation. MAIN OUTCOMES AND MEASURES: We calculated the mean differences for the percentage change in lipid and odds ratios for the incidence of adverse events and major adverse cardiac events. RESULTS: Twenty-five trials with 58,641 patients were included in our systematic review. Compared with placebo, low-dose evolocumab (-69.0%, [95% CI: -73.8% to -64.1%]), high-dose evolocumab (-59.8% [-63.8% to -55.7%]) , low-dose bococizumab (-56.5% [-66.8% to -46.2%]) attained significantly greater reductions in LDL cholesterol. Low-dose evolocumab (-55.3% [-60.2% to -50.5%]), high-dose evolocumab (-49.7% [-54.3% to -45.1%]), low-dose bococizumab (-47.4% [-57.6% to -37.2%]) also achieved a greater decrease in apolipoprotein B than placebo. A significantly greater reduction in lipoprotein(a) was found in patients treated with low-dose evolocumab (-37.0% [-42.7% to -31.2%]) or high-dose evolocumab (-30.4% [-35.8% to -25.1%]) compared with placebo. Low-dose evolocumab was ranked the best among all treatments. PCSK9 inhibitors did not significantly increase the incidence of adverse event, including nasopharyngitis, neurological event, and serious adverse event, but high or low dose bococizumab and LY3015014 and low-dose alirocumab showed a significant increase in the risk of injection-site reaction. CONCLUSIONS AND RELEVANCE: PCSK9 inhibitors consistently showed a significant effect on the reduction in LDL cholesterol and apolipoprotein B levels. Low-dose evolocumab may be the first add-on statin therapy choice for patients with hypercholesterolemia.