Inclisiran for the Treatment of Hyperlipidemia and for Atherosclerotic Cardiovascular Disease Risk Reduction: A Narrative Review

Abstract

Purpose: Inclisiran is a novel nonstatin therapy providing significant reduction in low-density lipoprotein cholesterol (LDL-C) as well as improvements in other lipid biomarkers. This review summarizes data from postapproval publications regarding the impact of inclisiran on lipids and cardiovascular risk reduction, as well as its tolerability and cost-effectiveness.

Methods: A search of PubMed for inclisiran was used to identify articles published since its approval by the US Food and Drug Administration (FDA). Clinical research studies reporting meta-analysis; pooled patient-level trial analyses; cost-effectiveness analyses; new human data; prespecified, post-hoc, or subgroup trial analyses; and clinical trial extensions were included.

Findings: The search identified 153 citations; 16 studies were included. FDA-approval trials, subsequent pooled patient-level trial analyses, and extension studies found that inclisiran, administered with and without maximally tolerated statin therapy, reduced LDL-C by ≈50%, with the reduction sustained for 4 years. Inclisiran appeared to be well tolerated, even long-term, with injection-site reactions being the most common adverse effect. A patient-level pooled analysis of data from Phase III trials suggested that cardiovascular events were reduced with inclisiran versus placebo (7.1% vs 9.4%; odds ratio = 0.74 [95% CI, 0.58-0.94]). Inclisiran is suggested to be cost-effective based the presumed cardiovascular benefit commensurate with LDL-C reduction.

Implications: The cardiovascular benefit and cost-effectiveness of inclisiran are promising, though not definitive. The results of a large-scale study of the effects of inclisiran on cardiovascular outcomes are expected in 2026; until then, the nonstatin therapies primarily prescribed for LDL-C reduction remain proprotein convertase subtilisin/kexin (PCSK)-9 inhibitors and ezetimibe. However, inclisiran is a reasonable alternative to, PCSK-9 inhibitors, in patients who struggle with the self-injection of or adherence to PCSK-9 inhibitors as inclisiran maintenance therapy is administered twice yearly by a health care professional.

Keywords: Cardiovascular disease; Dyslipidemia; Hyperlipidemia; Nonstatin.