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Lipid, lipid-lowering drugs, and bleedings: A Mendelian randomization and retrospective study

Shaohua Guo1,2, Sutao Hu3, Hui Chen1,2

  • 1Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Science Progress
|October 21, 2025
PubMed

Insights

This study investigated the causal link between low-density lipoprotein cholesterol (LDL-C) and bleeding risks. Findings suggest LDL-C may causally increase bleeding, especially with HMGCR inhibitor use in coronary artery disease patients.

Area of Science:

  • Cardiovascular Medicine
  • Pharmacogenomics
  • Epidemiology

Background:

  • Cholesterol metabolism, particularly low-density lipoprotein cholesterol (LDL-C), is increasingly linked to various health outcomes.
  • The precise causal relationship between LDL-C levels and bleeding events remains incompletely understood.
  • Lipid-lowering drugs are widely used, necessitating a clear understanding of their potential impact on bleeding risk.

Purpose of the Study:

  • To investigate the causal effect of LDL-C levels on bleeding outcomes.
  • To evaluate the causal association between lipid-lowering drugs and bleeding events.
  • To re-examine the LDL-C and bleeding relationship in a real-world clinical setting.

Main Methods:

  • Two-sample Mendelian randomization (MR) analyses were performed to assess LDL-C and drug target associations with bleeding.
  • Drug target MR included HMGCR, PCSK9, and NPC1L1 inhibitors.
  • A retrospective cohort study of coronary artery disease (CAD) patients was conducted for validation.

Main Results:

  • MR analyses did not find a causal association between LDL-C levels and intracerebral hemorrhage (ICH), gastrointestinal bleeding (GIbleeding), or hemorrhage from respiratory passages (HRP).
  • No causal relationship was identified between lipid-lowering drugs and the studied bleeding outcomes via MR.
  • Genetic variants mimicking statin effects (HMGCR) suggested an elevated ICH risk, independent of lipid lowering.
  • In the CAD cohort, elevated LDL-C was significantly associated with increased risk of severe bleeding (BARC 3-5) and trended towards increased ICH risk.

Conclusions:

  • Findings suggest a potential causal relationship between LDL-C levels and bleeding outcomes.
  • This association appears particularly relevant in patients treated with HMGCR inhibitors.
  • Further investigation is warranted to elucidate the mechanisms underlying LDL-C's impact on bleeding risk.

Keywords:
ICHLDL-CMendelian randomizationbleeding outcomecoronary artery disease cohort

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