A JAK of two trades: beneficial or adverse effects of Janus kinase inhibition for plasma LDL-cholesterol and major adverse cardiovascular events in inflammatory bowel disease patients?

Purpose of review Janus kinase (JAK) inhibitors have emerged as potent anti-inflammatory drugs and are prescribed in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, cardiovascular safety concerns have emerged from RA safety trials, alongside increases in LDL cholesterol (LDL-c). Whether similar lipid changes in IBD translate into clinically meaningful cardiovascular risk remains uncertain. This review focuses on studies and mechanisms increasing LDL-c due to JAK inhibition in IBD. Recent findings JAK inhibitors increase plasma LDL-c levels in IBD patients in a dose-dependent manner. While this has generally been attributed to JAK inhibitors decreasing inflammation, inhibition of JAK signaling also decreases hematopoiesis: the differentiation of hematopoietic stem cells into granulocyte/macrophage progenitors, and subsequently neutrophils, monocytes, and macrophages. Hematopoiesis requires LDL-c uptake, and is associated with elevated plasma LDL-c when inhibited. While statins lower LDL-c, the high prevalence of metabolic syndrome-associated type 2 diabetes in IBD patients may prompt the use of alternative lipid-lowering drugs. Summary JAK inhibitors are associated with increased LDL-c levels in IBD patients which may be due to suppressed inflammation and decreased hematopoiesis. This review summarizes the evidence on lipid changes and cardiovascular outcomes upon JAK inhibition and discusses approaches for LDL-c management in IBD.