Lipid-Lowering Drug Target Linked to Increased IBD Risk

Certain lipid-lowering drugs available on the US market may be associated with greater risk for developing irritable bowel disease (IBD) based on their treatment target, according to new research.¹

In data from a team of China-based investigators, inhibition of the Niemann-Pick C1-like 1 (NPC1L1), a polytopic transmembrane protein that influences the absorption of intestinal cholesterol,² with lipid-lowering drugs is associated with a more than 2-fold increased risk of developing IBD in patients.

The findings implicate gastric disease risk associated with NPC1L1-targeting cholesterol drugs including ezetimibe (Zetia), while also providing more prescribing guidance for primary care physicians and cardiometabolic specialists.

A team of investigators led by Xuxu Liu and Zhenyi Lv, of The First Affiliated Hospital of Harbin Medical University, sought to assess the causal influence of lipid-lowering drugs on the risk of IBD development. Prior research has shown IBD is linked to increased incidence of cardiovascular diseases and stroke, which investigators believe is due to blood lipid abnormalities linked to the gastric condition.

“Nowadays, various lipid-lowering drugs have been developed based on the process of lipid metabolism to regulate lipid homeostasis, with different targets of action,” Liu, Lv and colleagues wrote. “Therefore, the association between different types of lipid-lowering drugs and IBD deserves further exploration.”

Investigators conducted a Mendelian randomization analysis using a population of 173,082 individuals of European ancestry to identify what totaled 55 single-nucleotide polymorphisms. These components were key variables for 6 targets of lipid-lowering drugs:

• 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)
• Proprotein convertase subtilisin-kexin type 9 (PCSK9)
• Cholesteryl ester transfer protein (CETP)
• Apolipoprotein B (APOB)
• Low-density lipoprotein receptor (LDLR)
• NPC1LC

The team then collected summary statistics for the genome-wide association assessment of IBD, ulcerative colitis, and Crohn’s disease from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. The primary method for Mendelian randomization included inverse-variance weighted scoring; results were conveyed as odds ratios (ORs) with 95% CI.

Indeed, investigators observed that inhibition of NPC1L1 was linked to a doubled risk of IBD (OR, 2.31; 95% CI, 1.38 – 3.85; P = .001). More particularly, risk of ulcerative colitis was significantly increased among patients who experienced NPC1L1 inhibition (OR, 2.40; 95% CI, 1.21 – 4.74; P =. 012); the correlation was not significant for risk of Crohn’s disease, however.

Interestingly, investigators additionally observed that gene-proxied inhibition of LDLR was associated with a 28% reduced risk of IBD development (OR, 0.72; 95% CI, 0.60 – 0.87; P <.001). Risk of ulcerative colitis was similarly decreased among patients with LDLR inhibition (OR, 0.74; 95% CI, 0.59 – 0.92; P = .006). However, the latter outcome was not replicated in the investigators’ validation cohort.

None of the other 4 lipid-lowering drug targets were associated with significantly increased nor decreased IBD risk among patients. The team noted more research is needed to confirm the impact of LDLR inhibition on IBD risk—but the same findings could inform strategies like avoiding NPC1L1 inhibitors like ezetimibe in high-patients including those with ulcerative colitis.

“Currently, there is a lack of reliable randomized controlled trial data to demonstrate the adverse reactions of lipid-lowering drugs, and conducting large-scale randomized controlled trials is difficult, expensive and time-consuming,” investigators concluded. “Mendelian randomized analysis is a natural randomized controlled trial, with accuracy and convenience. Our study provides evidence suggesting that NPC1L1 inhibition increases the risk of IBD (mainly ulcerative colitis) and provides a reference for people using lipid-lowering drugs.”

References

1. ^{Liu X, Lv Z, Xie Z, et al. Association between the use of lipid-lowering drugs and the risk of inflammatory bowel disease [published online ahead of print, 2023 Jul 28]. Eur J Clin Invest. 2023;e14067. doi:10.1111/eci.14067}
2. ^{Jia L, Betters JL, Yu L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu Rev Physiol. 2011;73:239-259. doi:10.1146/annurev-physiol-012110-142233}