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TOPLINE:

Monotherapy with inclisiran — an injectable small interfering RNA that targets hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) — reduced levels of low-density lipoprotein (LDL) cholesterol more effectively than placebo or ezetimibe in patients at a low-to-borderline risk for atherosclerotic cardiovascular disease who were not receiving any lipid-lowering therapy, with a favorable safety profile.

METHODOLOGY:

• Previous studies have shown the efficacy of inclisiran in lowering the level of LDL cholesterol when used in combination with statins in patients with a high risk for atherosclerosis; however, its efficacy as a monotherapy without statins remains uncertain.
• Researchers conducted a 6-month multinational, randomized, phase 3 study to compare the efficacy and safety of inclisiran with those of placebo or ezetimibe in reducing levels of LDL cholesterol.
• They included 350 participants (mean age, 46.1 years; 62.6% women) with no history of atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia and a fasting LDL cholesterol level of 100-190 mg/dL.
• Participants were randomly assigned to receive subcutaneous inclisiran (n = 174), oral ezetimibe (n = 89), or matching placebo (n = 87), with inclisiran administered on days 1 and 90.
• The primary endpoint was the percentage change in the level of LDL cholesterol from baseline to day 150; several secondary endpoints, including the absolute change in LDL and safety, were assessed.

TAKEAWAY:

• By day 150, participants who received inclisiran showed a 47.9% greater reduction in the level of LDL cholesterol than those who received placebo and a 35.4% greater reduction than those who received ezetimibe (P < .0001 for both).
• The absolute reduction in the level of LDL cholesterol and the percentage reduction in PCSK9 levels were also greater in participants who received inclisiran than in those who received placebo or ezetimibe (P < .0001 for all).
• In the group who received inclisiran, levels of lipoprotein(a) decreased by 25.2% compared with placebo (P = .001) and by 24.3% compared with ezetimibe (P = .0002) by day 150.
• Similar rates of treatment-emergent adverse events were noted across the three groups, with no new safety concerns.

IN PRACTICE:

“There is a significant unmet clinical need for therapies that address both statin intolerance and adherence in primary prevention,” the researchers noted. “Inclisiran is potentially uniquely positioned to meet these challenges owing to its first-in-class mechanism of action, favorable safety profile, and infrequent twice-yearly dosing,” they added.

SOURCE:

This study was led by Pam R. Taub, MD, of the University of California in San Diego. It was published online on June 9, 2025, in Journal of the American College of Cardiology.

LIMITATIONS:

A short follow-up duration and limited sample size prevented the researchers from evaluating the cardiovascular outcomes of lowering the level of LDL cholesterol with inclisiran. The analysis lacked direct comparison with statins, anti-PCSK9 monoclonal antibodies, or bempedoic acid. The response of LDL with ezetimibe was lower than that observed in other studies.

DISCLOSURES:

This study received funding from Novartis Pharma. Two authors reported receiving compensation for serving as principal investigators of this trial, and another author reported serving as a consultant for multiple pharmaceutical companies including the funding agency. Several other authors reported serving as employees of the US or Switzerland wings of the funding agency or being principal investigator, consultants, and/or holding shares in the same.

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