TOPLINE:

In a pooled post hoc analysis, the administration of subcutaneous inclisiran for 540 days led to significantly greater reductions in low-density lipoprotein (LDL) cholesterol levels than that of placebo in patients with heterozygous familial hypercholesterolaemia and atherosclerotic cardiovascular disease (ASCVD) or its risk equivalent. This effect was observed even in patients with a baseline estimated glomerular filtration rate (eGFR) as low as 15 mL/min/1.73 m².

METHODOLOGY:

• Researchers conducted a post hoc pooled analysis of data from three phase 3 trials to evaluate the efficacy and safety of inclisiran vs placebo in lowering LDL cholesterol levels in 3660 patients with heterozygous familial hypercholesterolaemia, ASCVD or its risk equivalent, and elevated LDL cholesterol levels across chronic kidney disease stages 1-4.
• Patients were categorised on the basis of the baseline eGFR: ≥ 90 (n = 1610), 60 to < 90 (n = 1608), 45 to < 60 (n = 300), and 15 to < 45 mL/min/1.73 m² (n = 142).
• They received either subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days, in addition to maximally tolerated statins with or without oral lipid-lowering therapy.
• Co-primary endpoints were the percentage change in LDL cholesterol levels from baseline at day 510 and the time-adjusted percentage change in LDL cholesterol levels from baseline after day 90 through day 540.
• Safety outcomes of the drug were also evaluated.

TAKEAWAY:

• At day 510, the mean percentage change in LDL cholesterol levels from baseline was significantly greater in the inclisiran group than in the placebo group, with mean placebo-corrected percentage reductions of -49.9%, -51.2%, -54.7%, and -44.7% for the eGFR categories ≥ 90, 60 to < 90, 45 to < 60, and 15 to < 45 mL/min/1.73 m², respectively (P < .001 for all).
• Similarly, mean time-adjusted placebo-corrected percentage reductions in LDL cholesterol levels from baseline after day 90 through day 540 were -48.4%, -51.8%, -55.6%, and -50.4% for the eGFR categories ≥ 90, 60 to < 90, 45 to < 60, and 15 to < 45 mL/min/1.73 m², respectively (P < .001 for all).
• The placebo-corrected percentage changes in levels of total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and remnant cholesterol from baseline to day 510 (day 540 for lipoprotein[a]) were also significantly greater in the inclisiran group vs placebo group, irrespective of the eGFR category.
• Inclisiran was well tolerated, with a safety profile comparable to that of placebo across all eGFR categories, except for a higher incidence of mild or moderate reactions at the injection site in the inclisiran group.

IN PRACTICE:

"Inclisiran, administered twice-yearly (after initial and 3-month doses) with maximum-tolerated statins or other oral lipid-lowering therapies, provide sustained and effective LDL cholesterol lowering with favorable safety for a broad range of patients with atherosclerotic cardiovascular disease including those with advanced CKD [chronic kidney disease]," the authors wrote.

SOURCE:

This study was led by Ulf Landmesser, Deutsches Herzzentrum der Charité, Berlin, Germany. It was published online on January 28, 2026, in the Journal of the American Society of Nephrology.

LIMITATIONS:

This study included very few patients with severe kidney disease. Data on the urinary albumin-to-creatinine ratio or urinary protein-to-creatinine ratio were not collected, limiting the evaluation of kidney damage markers. Additionally, cardiovascular outcome data were not captured in these trials, preventing the assessment of long-term cardiorenal benefits.

DISCLOSURES:

This study was funded by Novartis Pharma AG. Two authors reported being employees of Novartis. Some authors reported receiving consultancy fees, research funding, honoraria, and speaker fees and having other ties with various organisations and pharmaceutical companies, including Novartis.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.