普洛扎西兰用于重度高甘油三酯血症及胰腺炎风险
完整摘要 · 中文译文
背景：重度高甘油三酯血症与急性胰腺炎风险增加相关。Plozasiran是一种靶向APOC3信使RNA的小干扰RNA，可降低甘油三酯水平并可能降低急性胰腺炎风险。 方法：在两项双盲、安慰剂对照试验中，757例重度高甘油三酯血症成人按2：1比例随机分配，在基线和第3、6、9个月接受plozasiran（25 mg）或安慰剂。这两项试验的设计、终点和分析计划完全相同。主要终点为从基线至第12个月空腹血浆甘油三酯水平的百分比变化。关键次要终点包括从基线至第10个月空腹甘油三酯水平的百分比变化、空腹甘油三酯水平低于500 mg/dL（5.6 mmol/L）且低于150 mg/dL（1.7 mmol/L）、基线甘油三酯水平≥880 mg/dL的患者第12个月空腹血清甘油三酯水平的百分比变化，以及残粒胆固醇和非HDL胆固醇的变化。一项汇总分析评估了经裁定的急性胰腺炎、发生率及首次事件时间。 结果：在第12个月时，plozasiran组患者的中位甘油三酯水平在两项试验中分别较基线水平降低79%和81%。这些降低对应于plozasiran组与安慰剂组相比的中位差异（安慰剂校正变化）分别为-45个百分点（95%置信区间[CI]，-51至-38）和-47个百分点（95% CI，-54至-39）。在第12个月时，plozasiran组分别有91%和93%的患者报告甘油三酯水平低于每分升500毫克，而安慰剂组分别为51%和50%（P<0.001）。急性胰腺炎发生率在plozasiran组为每100患者年1例，在安慰剂组为每100患者年5例（率比，0.22；P = 0.008）。治疗期间不良事件在合并的plozasiran组和安慰剂组中均发生于73%的患者。 结论：在重度高甘油三酯血症患者中，使用plozasiran在第12个月时较安慰剂带来更低的甘油三酯水平和更低的急性胰腺炎风险。（由Arrowhead Pharmaceuticals资助；SHASTA-3 ClinicalTrials.gov注册号，NCT06347003；SHASTA-4，NCT06347016。）
完整摘要 · 英文原文
BACKGROUND: Severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis. Plozasiran, a small interfering RNA targeting APOC3 messenger RNA, lowers triglyceride levels and potentially mitigates the risk of acute pancreatitis. METHODS: In two double-blind, placebo-controlled trials, 757 adults with severe hypertriglyceridemia were randomly assigned in a 2:1 ratio to receive plozasiran (25 mg) or placebo at baseline and at months 3, 6, and 9. These trials had identical designs, end points, and analytic plans. The primary end point was the percent change in the fasting plasma triglyceride level from baseline to month 12. Key secondary end points were the percent change in the fasting triglyceride level from baseline to month 10, a fasting triglyceride level of less than 500 mg per deciliter (5.6 mmol per liter) and less than 150 mg per deciliter (1.7 mmol per liter), the percent change in the fasting serum triglyceride level at month 12 for patients with a baseline triglyceride level of 880 mg per deciliter or greater, and changes in remnant cholesterol and non-HDL cholesterol. A pooled analysis addressed adjudicated acute pancreatitis, incidence, and first-event timing. RESULTS: At month 12, patients in the plozasiran groups had a median triglyceride level that was lower than the baseline level by 79% and 81% in the two trials. These reductions corresponded to a median difference in the plozasiran groups as compared with the placebo groups (placebo-adjusted change) of -45 percentage points (95% confidence interval [CI], -51 to -38) and -47 percentage points (95% CI, -54 to -39). A triglyceride level of less than 500 mg per deciliter at 12 months was reported in 91% and 93% of the patients in the plozasiran groups and in 51% and 50% of those in the placebo groups (P<0.001). The rates of acute pancreatitis were 1 per 100 patient-years with plozasiran and 5 per 100 patient-years with placebo (rate ratio, 0.22; P = 0.008). Adverse events during treatment occurred in 73% of the patients in both the pooled plozasiran and placebo groups. CONCLUSIONS: Among patients with severe hypertriglyceridemia, the use of plozasiran resulted in lower triglyceride levels and a lower risk of acute pancreatitis than placebo at 12 months. (Funded by Arrowhead Pharmaceuticals; SHASTA-3 ClinicalTrials.gov number, NCT06347003; SHASTA-4, NCT06347016.).