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Inclisiran in Patients with CKD: Post Hoc Pooled Analysis of Three Phase 3 Trials
Ulf Landmesser1, Kausik K Ray2, Frederick J Raal3
1Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Charité-Universitätsmedizin Berlin, Berlin Institute of Health, DZHK, Partner Site Berlin, Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany.
Insights
Inclisiran effectively lowers LDL cholesterol in patients with atherosclerotic cardiovascular disease and chronic kidney disease. This treatment showed sustained efficacy and a favorable safety profile across all estimated glomerular filtration rate (eGFR) levels.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Pharmacology
Background:
- Lowering low-density lipoprotein cholesterol (LDL cholesterol) is crucial for reducing atherosclerotic cardiovascular disease (ASCVD) risk in patients with chronic kidney disease (CKD).
- The efficacy and safety of inclisiran were evaluated in patients with and without CKD through a post hoc analysis of three Phase 3 trials.
Purpose of the Study:
- To investigate the efficacy and safety of inclisiran in reducing LDL cholesterol in patients with varying degrees of kidney function.
- To assess the effectiveness of inclisiran across different baseline estimated glomerular filtration rate (eGFR) strata.
Main Methods:
- A pooled analysis of three Phase 3 trials (ORION-9, -10, -11) involving patients with heterozygous familial hypercholesterolemia or ASCVD risk.
- Patients received subcutaneous inclisiran or placebo, with stratification based on baseline eGFR (≥90, 60-89, 45-59, and 15-44 mL/min/1.73m²).
- Co-primary endpoints included percentage change in LDL cholesterol at day 510 and time-adjusted percentage change from day 90 to 540; safety was also assessed.
Main Results:
- Inclisiran demonstrated significant placebo-corrected LDL cholesterol reduction across all eGFR groups at day 510 (range: -44.7% to -54.7%) and from day 90 to 540 (range: -48.4% to -55.6%).
- Significant reductions were observed in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, and lipoprotein(a) in all eGFR groups.
- Inclisiran was well tolerated, with no new safety concerns identified across the study population.
Conclusions:
- Inclisiran provides sustained and effective LDL cholesterol reduction in patients at risk for ASCVD, irrespective of their baseline kidney function, including those with eGFR as low as 15 mL/min/1.73m².
- The safety profile of inclisiran remained consistent across all evaluated eGFR levels, supporting its use in patients with CKD.
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 ).
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