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

Objective: Emerging evidence suggests a potential link between cholesterol metabolism and bleeding. We aimed to examine the causal effect of low-density lipoprotein cholesterol (LDL-C) or lipid-lowering drugs on bleeding outcomes. Methods: Two-sample Mendelian randomization (MR) analyses and two types of drug target MR were conducted to evaluate the associations of LDL-C levels with risks for three bleeding outcomes including intracerebral hemorrhage (ICH), gastrointestinal bleeding (GIBleeding), and hemorrhage from respiratory passages (HRP). Furthermore, the association between LDL-C and bleeding outcomes was re-evaluated in a retrospective cohort study involving patients with coronary artery disease (CAD). Results: MR analyses suggest that LDL-C levels are not associated with bleeding outcomes, including ICH, GIbleeding, and HRP. SMR also found no causal relationship between the use of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitor) and bleeding outcomes (ICH, GIbleeding, and HRP). Alleles at or near the HMGCR gene (mimicking the effect of statins) reducing LDL-C level expression levels are intended to elevate the risk of ICH (odds ratio (OR) 1.0018, 95% confidence interval (CI) 1.0001-1.0035, P = 0.043), independent of their lipid-lowering effect. In the CAD cohort with a 2-year follow up, LDL-C levels measured within the last 3 months of follow up were significantly associated with an increased risk of BARC criteria 3 to 5 grade bleeding (P < 0.001) and showed a trend toward an increased risk of ICH (P = 0.051). Conclusions: These findings suggest a potential causal relationship between LDL-C levels and bleeding outcomes, particularly in patients using HMGCR inhibitors.