Journal of the American Society of Nephrology : JASN · 2026
Inclisiran in Patients with CKD: Post Hoc Pooled Analysis of Three Phase 3 Trials.
Клиническое исследование III фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Landmesser Ulf, Ray Kausik K, Raal Frederick J, Garcia Conde Lorena, Han Jackie, Koenig Wolfgang, Leiter Lawrence A, Schwartz Gregory G, Wright R Scott, on behalf of the ORION Investigators
Аннотация
KEY POINTS: Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD. Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials. Inclisiran showed sustained and effective LDL cholesterol-lowering in patients across various levels of eGFR values, without new safety findings.
BACKGROUND: Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11).
METHODS: Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 . Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated.
RESULTS: Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m 2 . The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 were -49.9% (-53.2 to -46.6), -51.2% (-54.4 to -48.0), -54.7% (-62.5 to -47.0), and -44.7% (-57.6 to -31.8), respectively ( P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were -48.4% (-50.8 to -46.1), -51.8% (-54.2 to -49.4), -55.6% (-61.0 to -50.2), and -50.4% (-59.3 to -41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings.
CONCLUSIONS: Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m 2 , without new safety findings.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, ORION-9 ( NCT03397121 ), ORION-10 ( NCT03399370 ), and ORION-11 ( NCT03400800 ).
BACKGROUND: Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11).
METHODS: Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 . Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated.
RESULTS: Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m 2 . The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 were -49.9% (-53.2 to -46.6), -51.2% (-54.4 to -48.0), -54.7% (-62.5 to -47.0), and -44.7% (-57.6 to -31.8), respectively ( P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were -48.4% (-50.8 to -46.1), -51.8% (-54.2 to -49.4), -55.6% (-61.0 to -50.2), and -50.4% (-59.3 to -41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings.
CONCLUSIONS: Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m 2 , without new safety findings.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, ORION-9 ( NCT03397121 ), ORION-10 ( NCT03399370 ), and ORION-11 ( NCT03400800 ).