Inclisiran fails to find place in AACE 2025 Dyslipidemia Guidelines

Ohio: Once pegged as a blockbuster medicine for lowering LDL, long-acting small interfering RNA, Inclisiran failed to find any place in the recently released American Association of Clinical Endocrinology guideline

A recent American Association of Clinical Endocrinology guideline on the pharmacologic management of dyslipidemia in adults 2025 proposed that the current evidence is insufficient to establish a definitive recommendation for or against the use of Inclisiran to reduce the risk of atherosclerotic cardiovascular disease (ASCVD).

The guidelines published in the Endocrine Practice highlighted that only a few clinical trials have been conducted, and the available data on cardiovascular events is too limited to determine whether inclisiran provides significant benefits or poses any risks when added to standard care.

Inclisiran, a small interfering RNA therapy, has demonstrated a significant reduction in low-density lipoprotein cholesterol (LDL-C) levels and has been approved by the USFDA since 2021 and by the Indian CDSCO since 2023. Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol. 

However, its impact on cardiovascular outcomes remains uncertain due to lack of well-powered, long-term studies. While all evaluated lipid-lowering medications effectively reduce LDL-C, their impact on mortality and cardiovascular events remains unclear. Consequently, the guidelines issue conditional recommendations for the use of alirocumab, evolocumab, and bempedoic acid in adults with or at increased risk for ASCVD.

Ongoing large-scale clinical trials, including ORION-4 (NCT03705234) and VICTORION-2 PREVENT (NCT05030428), are expected to provide additional insights upon completion in 2026 and 2027, respectively. These trials aim to evaluate inclisiran’s effects on urgent coronary revascularization and all-cause mortality, with VICTORION-2 PREVENT also assessing major limb adverse events—a clinically significant factor in treatment decision-making.

A systematic review of randomized controlled trials (RCTs) evaluating the efficacy of inclisiran in adults with dyslipidemia indicates that the drug does not provide a statistically significant reduction in major cardiovascular events over a follow-up period of 30 to 77 weeks. Across a sample size ranging from 3,655 to 3,739 participants, inclisiran demonstrated no clinically meaningful effect on all-cause mortality (OR 1.01, 95% CI 0.59-1.71), cardiovascular-related mortality (OR 1.11, 95% CI 0.56-2.23), stroke (OR 0.69, 95% CI 0.11-4.21), or myocardial infarction (OR 0.85, 95% CI 0.36-1.98). Additionally, the likelihood of treatment discontinuation due to adverse events was slightly higher in the inclisiran cohort (OR 1.21, 95% CI 0.77-1.88), though this finding was not statistically significant. The certainty of evidence for all reported outcomes was rated as low, highlighting potential bias and imprecision in effect estimates. Furthermore, data on coronary revascularization and peripheral vascular disease (PVD) events were unavailable in the reviewed studies.

The guidelines do not demonstrate clinically meaningful benefits of inclisiran in reducing mortality or cardiovascular events when added to usual care. While minor absolute risk reductions were observed—such as three fewer strokes and myocardial infarctions per 1,000 participants—these effects fall within confidence intervals that include potential harms. Similarly, no significant difference was observed in all-cause and cardiovascular-related mortality rates. Adverse events, primarily injection site reactions and bronchitis, led to a small number of treatment discontinuations, though these were considered trivial. Given these findings, inclisiran’s net clinical benefit remains uncertain, with its effects deemed marginal by expert reviewers.

Due to limited clinical evidence, it remains unclear whether inclisiran’s potential cardiovascular and mortality benefits outweigh possible risks when used alongside usual care. To address these uncertainties, robust, long-term cardiovascular outcomes trials are needed to assess its efficacy in reducing cardiovascular events, its impact on mortality, and its long-term safety profile.

A discussion published in the Endocrinology and Metabolism Institute noted that inclisiran was not included in the 2017 AACE guidelines (like not FDA approved then) and, as of 2025, remains without a recommendation due to insufficient evidence for relevant clinical outcomes of interest.

The guidelines also recommend pharmacotherapy to reduce the risk of atherosclerotic cardiovascular disease events. It highlights several effective and safe treatment options for adults with dyslipidemia, particularly those with ASCVDor at increased risk, who require additional lipid-lowering medications.

Reference:

Patel SB, Wyne KL, Afreen S, Belalcazar LM, Bird MD, Coles S, Marrs JC, Peng CC, Pulipati VP, Sultan S, Zilbermint M. American Association of Clinical Endocrinology Clinical Practice Guideline on Pharmacologic Management of Adults With Dyslipidemia. Endocr Pract. 2025 Feb;31(2):236-262. 

Correa R. Highlights of the 2025 American Association of Clinical Endocrinology Clinical Practice Guideline on Pharmacologic Management of Adults With Dyslipidemia. Endocr Pract. 2024 Dec 18:S1530-891X(24)00831-0. doi: 10.1016/j.eprac.2024.11.006. Epub ahead of print. PMID: 39918518.

Inclisiran, International Innovator Prescribing Information, Leqvia, Last Revised June,2024: URL: https://www.leqviohcp.com/dosing-and-administration