Fenofibrate, a PPARα agonist commonly used to manage hypercholesterolemia and hypertriglyceridemia, has shown promise as an adjunct therapy for mild to moderate ulcerative colitis (UC). A recent study investigated the effects of fenofibrate in combination with mesalamine on clinical outcomes and inflammatory markers in UC patients.
The double-blind, randomized, controlled clinical trial, involving 70 patients diagnosed with mild to moderate UC, was conducted between March 2023 and April 2024. Patients were randomly assigned to either a mesalamine group (control) or a fenofibrate + mesalamine group. The primary outcome was the change in the Partial Mayo Score (PMS), while secondary outcomes included changes in Inflammatory Bowel Disease Questionnaire (IBDQ-32) scores, serum levels of NOD-like receptor protein 3 (NLRP3), Sirtuin 1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK), and fecal calprotectin levels.
Study Design and Methods
The study, registered at ClinicalTrials.gov (NCT05781698), randomized patients into two groups (n = 35 each). The mesalamine group received 1 g mesalamine tablets three times daily plus placebo, while the fenofibrate group received 160 mg of fenofibrate tablets once daily plus 1 g of mesalamine tablets three times daily. The treatment duration was six months.
Inclusion criteria included patients aged 18 to 60 years with mild to moderate UC based on the PMS index. Exclusion criteria encompassed patients receiving systemic or rectal steroids, immunosuppressive medications, or having severe UC, renal or hepatic issues, a history of colorectal cancer, musculoskeletal diseases, hyperlipidemia, pregnancy, or breastfeeding.
Key Findings
The results indicated a significant reduction in the median PMS index in both groups after treatment (p < 0.0001). However, the fenofibrate group demonstrated statistically significant changes in the PMS index compared to the control group (p = 0.044). The response rate for PMS in the control group was 68.57%, with a remission rate of 31.42%, while the fenofibrate group had a response rate of 74.28% and a remission rate of 42.85%.
Regarding secondary outcomes, the fenofibrate group showed a statistically significant reduction in the levels of NLRP3 (p = 0.041) and calprotectin (p = 0.035), along with a significant increase in SIRT1 (p = 0.002) and AMPK (p = 0.0003) levels compared to the control group.
Impact on Quality of Life
Both groups experienced a significant increase in IBDQ scores and its subscales after treatment (p < 0.05). However, there were no statistically significant changes in the IBDQ total score between the groups (p > 0.05), except for a statistically significant difference in the digestive domain (p = 0.023).
Mechanistic Insights
The anti-inflammatory properties of fenofibrate, both directly and indirectly, may explain the positive outcomes observed in this study. Fenofibrate enhances the expression of high-density lipoprotein (HDL) while reducing low-density lipoprotein (LDL) levels. By decreasing cholesterol accumulation, fenofibrate alleviates inflammation and slows the progression of various inflammatory diseases. Furthermore, fenofibrate may increase very-long-chain sphingolipids, contributing to its anti-inflammatory effects.
Fenofibrate directly reduces inflammation primarily by activating PPAR-α, which plays a crucial role in lipid metabolism and inflammatory processes, independent of its cholesterol-lowering effects. Upon activation of PPAR-α, fenofibrate diminishes inflammatory signaling pathways involving AMPK, toll-like receptor 4 (TLR4), SIRT1, and nuclear factor kappa-B (NF-κB). Moreover, fenofibrate directly inhibits the expression of genes associated with inflammation.
Adverse Effects
The study reported no significant differences in side effects such as nausea, heartburn, muscle pain, skin rash, and fatigue between the two groups.
Conclusion
The trial suggests that fenofibrate combination therapy with mesalamine significantly improved digestive domains, reduced inflammatory markers, and upregulated SIRT1 and AMPK. The authors conclude that fenofibrate combination therapy with mesalamine is a safe and tolerable option for further investigation in the treatment of patients with mild to moderate UC. Further multicenter, long-term trials are recommended to evaluate these effects.
