Remnant cholesterol in chronic obstructive pulmonary disease—phenotypes and pharmacotherapy matter

We read with interest the Mendelian randomization study by Feng et al. (1) linking remnant cholesterol (RC) to chronic obstructive pulmonary disease (COPD) risk [inverse variance weighted (IVW) odds ratio (OR) =1.222, 95% confidence interval (CI): 1.092–1.368]. Although their analysis robustly demonstrates causality, key clinical and mechanistic dimensions warrant attention. First, COPD encompasses distinct phenotypes, emphysema-dominant and chronic bronchitis, with divergent inflammatory drivers (2). RC may preferentially exacerbate airway-predominant disease via neutrophilic inflammation, whereas its role in emphysema (driven by protease-mediated destruction) remains speculative. Stratifying future analyses by phenotype using genome-wide association study (GWAS) subgroups could clarify subtype-specific RC effects.

Second, the authors advocate lifestyle modifications to lower RC but overlook emerging pharmacotherapies. Fibrates reduce RC by 35–40% and suppress interleukin-6 production (3), while proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower RC independent of low-density lipoprotein cholesterol (LDL-C) (4). Both agents merit evaluation in COPD, particularly given their pleiotropic anti-inflammatory effects. Notably, the completed PROMINENT trial (NCT03071692) investigated pemafibrate’s impact on cardiovascular outcomes (5). Although it did not focus on respiratory outcomes, its design offers insights that Feng et al. (1) could consider for future studies.

Lastly, RC’s lung-specific actions are unexplored. Triglyceride-rich lipoproteins in RC may impair surfactant function or induce lipid-laden macrophages in alveoli, amplifying oxidative stress (6). Validating these mechanisms requires correlating RC levels with bronchoalveolar lavage lipidomics in COPD cohorts. We commend the authors’ work and urge future studies to address these gaps, enhancing translational relevance.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergone external peer review.

Funding: This study was supported by “Nanchang Hongdu Hospital of Traditional Chinese Medicine”.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1676/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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