Use of lipid-lowering drugs may increase risk of inflammatory bowel disease

The study revealed that inhibition of the lipid-lowering drug-target NPC1L1 (Niemann-Pick C1-like 1) may result in an increased risk of IBD, mainly in the ulcerative colitis (UC) population.

Data from a team of China-based investigators showed that inhibition of NPC1L1, a polytopic transmembrane protein that impacts the absorption of intestinal cholesterol, with lipid-lowering drugs is linked to a more than 2-fold increased risk of IBD development in patients.

Previous observational studies have suggested an association between lipid-lowering drugs and the risk of inflammatory bowel disease. Dongbo Xue, The First Affiliated Hospital of Harbin Medical University, Harbin, China, and colleagues aimed to evaluate the causal influence of lipid-lowering agents on IBD risk using Mendelian randomization analysis.

For this purpose, the researchers identified 55 single-nucleotide polymorphisms in a population of 173,082 individuals of European ancestry, as instrumental variables for six lipid-lowering drug targets (APOB, CETP, LDLR, PCSK9, NPC1LC, and HMGCR).

They obtained summary statistics for the genome-wide association study of ulcerative colitis, IBD, and Crohn's disease (CD) from the FinnGen consortium, UK Biobank, and Program in Complex Trait Genomics. Inverse-variance weighted was employed as the primary MR method, and odds ratios were reported as the results. The team also conducted sensitivity analyses using conventional MR methods to assess result robustness.

The study revealed the following findings:

• Gene-proxied inhibition of Niemann-Pick C1-like 1 was associated with an increased IBD risk (OR 2.31), particularly in UC (OR 2.40), but not in CD. This finding was replicated in the validation cohort.
• Gene-proxied inhibition of low-density lipoprotein receptors was associated with reduced IBD (OR .72) and UC risk (OR .74), although this result was not replicated in the validation cohort.
• Other drug targets did not show significant associations with IBD, UC or CD risk.

"Currently, there is a lack of reliable data from randomized controlled trials (RCTs) to demonstrate the adverse reactions of lipid-lowering drugs, and conducting large-scale RCTs is difficult, time-consuming, and expensive," the researchers concluded.

"Mendelian randomized analysis is a natural RCT, with convenience and accuracy. 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.”

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

Reference:

Liu X, Lv Z, Xie Z, Wang Q, Yao W, Yu J, Jing Q, Meng X, Ma B, Xue D, Hao C. Association between the use of lipid-lowering drugs and the risk of inflammatory bowel disease. Eur J Clin Invest. 2023 Jul 28:e14067. doi: 10.1111/eci.14067. Epub ahead of print. PMID: 37515404.