Rheumatoid arthritis drugs face-off: tofacitinib linked to higher dyslipidemia risk

A real-world study involving over 7,500 newly diagnosed rheumatoid arthritis (RA) patients found that those treated with the Janus kinase (JAK) inhibitor tofacitinib exhibited a higher risk of developing dyslipidemia compared to those receiving the tumor necrosis factor (TNF) inhibitor adalimumab. These findings underscore the necessity of monitoring lipid levels in RA patients undergoing tofacitinib therapy. 

This retrospective cohort study, published in Frontiers in Pharmacology, analyzed data from the TriNetX US Collaborative Network, tracking adult RA patients treated with either tofacitinib or adalimumab over a three-year period from 2018 to 2020. Employing propensity scoring to match patient characteristics, the researchers determined that the tofacitinib group had a 25% increased risk of developing dyslipidemia. Despite this increased risk, the study found no significant difference in the incidence of major adverse cardiac events (MACE) and all-cause mortality between the two drug cohorts during the study period. 

Tofacitinib is a JAK inhibitor that interferes with the signaling pathways of various inflammatory cytokines, thereby modulating the immune response and reducing inflammation. By inhibiting JAK enzymes, tofacitinib prevents the phosphorylation and activation of signal transducers and activators of transcription (STAT) proteins, which are critical for the expression of pro-inflammatory genes. In contrast, adalimumab is an injectable biologic monoclonal antibody that specifically binds to tumor necrosis factor-alpha (TNF-α). This binding neutralizes TNF-α, a key cytokine in the inflammatory process, thereby directly targeting and reducing the activity of inflammatory cells and cytokines. This dual approach highlights the distinct mechanisms of action of these two therapies in managing RA. 

Previous studies present somewhat conflicting results regarding the differential impact of tofacitinib and adalimumab on blood lipid levels. Some systematic reviews and meta-analyses have linked tofacitinib treatment to increase in serum cholesterol, low-density lipoprotein, and high-density lipoprotein levels, regardless of dosage. Conversely, TNF-α antagonists like adalimumab have shown no significant effects on lipid levels. However, randomized controlled trials have reported no adverse changes in lipid profiles following up to 24 months of tofacitinib treatment. Tofacitinib’s action by blocking specific pathways involved in the inflammatory process can alter lipid metabolism, potentially leading to an increase in lipid levels. Additionally, JAK inhibitors may influence hepatic lipid synthesis and clearance, contributing to dyslipidemia. Studies on other JAK inhibitors (like baricitinib and upadacitinib) also report similar concerns regarding lipid profile changes, suggesting a class effect that warrants attention. 

While previous clinical trials reported no adverse lipid changes with tofacitinib, this large real-world analysis suggests a potential link between the JAK inhibitor and dyslipidemia development in RA patients. As dyslipidemia increases risks for heart disease and stroke over the long-term, the study underscores the importance of proactive lipid monitoring and management strategies, especially for RA patients prescribed tofacitinib who may be at greater dyslipidemia risk based on demographics or other cardiovascular risk factors. 

Reference 

Ma XN, Shi MF, Wang SI, et al. Risk of dyslipidemia and major adverse cardiac events with tofacitinib versus adalimumab in rheumatoid arthritis: a real-world cohort study from 7580 patients. Frontiers in Pharmacology. 2024;15:1370661. 

Enhance your expertise on tofacitinib by tuning into our webinar series, “Tofacitinib in Rheumatology” at https://rheumatv.com/category/tofacitinib-in-rheumatology/ 

 

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