Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation. For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90–540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo. Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) placebo (n = 1264) were 2.66 mmol/L 2.60 mmol/L and 24.9% 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was −1.32 mmol/L (95% CI −1.37 to −1.26; < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran 24.7% with placebo (absolute difference [95% CI], −6.99% [−7.33 to −6.66]; < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60–<80% risk), 52,142 to 22,665 (40–<60% risk), 197,752 to 141,014 (20–<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518. Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins.

中文翻译：

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通过每年两次基于 siRNA 的方法，评估改善人群对 LDL 胆固醇水平控制的潜在心血管健康益处：卫生系统水平干预的模拟研究

Inclisiran 是一种 siRNA 疗法，每年给药两次，可持续降低低密度脂蛋白胆固醇 (LDL-C)。通过模拟评估了在人群水平上实施 inclisiran 与他汀类药物相结合的潜在心血管益处。对于比较 inclisiran 与安慰剂的 ORION-10 和 ORION-11 试验中的每位参与者，使用 SMART 方程估计基线 10 年心血管风险。假设基线后 90-540 天观察到的经时间调整的 LDL-C 与基线的差异持续存在，并用于估计 10 年心血管风险的潜在降低。使用蒙特卡罗模拟了对 500,000 名类似 ORION 个体的影响。随机接受 inclisiran (n = 1288) 安慰剂 (n = 1264) 的患者的平均基线 LDL-C 和预测 10 年主要血管风险分别为 2.66 mmol/L、2.60 mmol/L 和 24.9% 和 24.6%。安慰剂校正时间调整的 inclisiran LDL-C 绝对降低值为 -1.32 mmol/L（95% CI -1.37 至 -1.26；< 0.001），这预测使用 inclisiran 的 10 年心血管风险为 18.1%，而使用 inclisiran 则为 24.7%安慰剂（绝对差异 [95% CI]，−6.99% [−7.33 至 −6.66]；< 0.001） NNT 15。外推到 500,000 名接受 inclisiran 治疗的个体，该模型预测大量人群会转向风险较低的五分位数，而剩下的人数较少高风险类别； 3350 至 471（≥80% 风险）、11,793 至 3332（60–<80% 风险）、52,142 至 22,665（40–<60% 风险）、197,752 至 141,014（20–<40% 风险）以及更多进入最低风险类别（<20%）从 234,963 增至 332,518。通过实施大规模的方法，能够在 10 年内实现人口健康方面的有意义的进展，这些方法能够大幅、持续地降低 LDL-C，超出他汀类药物所能达到的水平。