Use of bezafibrate alone or combined with ursodeoxycholic acid improves liver biochemistries in patients with primary biliary cholangitis (PBC), according to a study in Digestive Diseases and Sciences.
The systematic review and meta-analysis compared the efficacy of ursodeoxycholic acid monotherapy vs combination therapy (bezafibrate + ursodeoxycholic acid) and ursodeoxycholic acid monotherapy vs bezafibrate alone in patients with PBC.
Researchers searched multiple databases on January 3, 2020 for relevant randomized controlled trials (RCTs) as well as additional observational studies regarding adverse effects of the treatments.
Patient-important outcomes included all-cause mortality, liver-related complications, quality of life, pruritus, and mean change in various biochemical markers. The certainty in the estimates of effect for each outcome was rated based on the Grading of Recommendation, Assessment, Development, and Evaluation approach.
A total of 7 RCTs with 279 participants were included in the meta-analysis. All of the studies were conducted in Japan from 2000 to 2015, except for 1 in France in 2018. Participants’ mean age ranged from 49.8 to 64.0 years.
The effect of bezafibrate and ursodeoxycholic acid combination therapy on mortality was unclear as few deaths were reported in 5 RCTs that included this outcome. The risk ratio (RR) for pruritus in 2 studies was 1.12 (95% CI, 0.5-2.53).
Mean changes in alkaline phosphatase (ALP) in patients treated with combination therapy compared with monotherapy were reported in 6 RCTs. Based on 2 studies that included mean change and standard deviations allowing for pooled results, combination therapy was associated with statistically significant and clinically meaningful decreases in ALP vs ursodeoxycholic acid monotherapy (mean difference [MD], -155.51 U/L; 95% CI, -183.43 to -127.58; I2 = 48% [moderate certainty of evidence]). An MD in serum ALP of 159.04 U/L (95% CI, -186.45 to -131.62) was found in 255 patients across 6 studies with use of imputed data for missing standard deviations.
Combination therapy was associated with a statistically and clinically significant decrease in gamma-glutamyltransferase (GGT) (MD, -106.94 IU/L; 95% CI, -151.99 to -61.89; I2 = 0% [low certainty of evidence]), according to pooled data from 2 studies.
For bezafibrate monotherapy vs UDCA monotherapy, 1 study of 45 patients found a significant reduction in serum ALP of -424.48 (from 764.0±401.3 to 340.4±162.4 IU/L) in the bezafibrate group (n=20) and -296.22 (from 713±577 to 439.2±255.3 IU/L) in the ursodeoxycholic acid group (n=25), although no significant difference occurred between the 2 groups.
In a study of 24 patients, those in the bezafibrate group had greater reductions in ALP at 12 months (% change from baseline: -66.63% vs -38.47% in the ursodeoxycholic acid group), which was clinically and statistically significant. Patients in the bezafibrate group also had greater reductions in GGT, alanine aminotransferase, and immunoglobulin M compared with pretreatment levels.
In 1 observational study, among 5 incomplete responders, 1 patient died of advanced liver disease. In another observational study of 37 patients, 1 patient who received ursodeoxycholic acid monotherapy died of pneumonia.
Study limitations include the small number of trials and limited number of patients, which made it challenging to detect statistically significant differences. Also, insufficient information was available for patient-relevant clinical outcomes, including mortality, quality of life, progression to cirrhosis, liver transplantation rates, and histologic improvement. Furthermore, obtaining the raw data from the selected studies was not always possible.
“The treatment landscape for PBC is changing as new treatment targets are being investigated,” the study authors noted. “BZF [bezafibrate] is among the most promising new therapies, with several studies suggesting it improves surrogate endpoints and clinical outcomes in PBC. Our meta-analysis supports the beneficial effect on surrogate endpoints, although further studies with longer follow-up and larger sample sizes are clearly needed to evaluate whether combination therapy improves quality of life, liver-related mortality, all-cause mortality, and long-term transplant-free survival in PBC.”
Disclosure: One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures.
Khakoo NS, Sultan S, Reynolds JM, Levy C. Efficacy and safety of bezafibrate alone or in combination with ursodeoxycholic acid in primary biliary cholangitis: systematic review and meta‑analysis. Dig Dis Sci. Published online September 30, 2022. doi: 10.1007/s10620-022-07704-4