PPAR agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

PPAR agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article PPAR agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Hilária Saugo Faria, Milene Vitória Sampaio Sobral, Victor Gonçalves Soares, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4369688/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Agonists of the peroxisome proliferator-activated receptor (PPAR) have attracted attention for their potential to treat primary biliary cholangitis (PBC). However, individual trials lack sufficient power to detect significant differences in clinical and laboratory outcomes. Objectives This meta-analysis aims to compare PPAR agonists versus placebo or standard treatment in patients with PBC. Methods We systematically searched PubMed, Embase and Cochrane for studies comparing PPAR agonists with placebo or standard-of-care treatment in PBC. The primary outcomes were pruritus, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total and direct bilirubin levels. We performed statistical analyses using R 4.1.1. Heterogeneity was examined with the Cochran Q test and I 2 statistics. We computed risk ratios (RR), mean differences (MD), and Standardized Mean Differences (SMD), with 95% confidence intervals (CI), using a random-effects model. Results Thirteen randomized controlled trials were included in this meta-analysis, comprising 1,124 patients, of whom 687 (57%) received PPAR agonists plus UDCA. When compared with control, PPAR analogs were significantly associated with a reduction in pruritus (RR 0.63; 95% CI 0.41 to 0.96; p = 0.031; I ²=9%), ALP (MD -130.93; 95% CI -156.44 to -105.42; p < 0.01; I ²=84%), GGT (MD -39.83; 95% CI -78.44 to -1.22; p = 0.04; I ²=94%) and total bilirubin levels (SMD − 0.03; 95% CI -0.06 to -0.01; p < 0.01; I ²=69%). Conclusion The use of PPAR agonists reduced the incidence of pruritus and the levels of ALP, GGT, and total bilirubin in patients with PBC. PPAR agonists ursodeoxycholic acid primary biliary cholangitis meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Primary biliary cholangitis (PBC) is an autoimmune disease characterized by inflammation and destruction of intrahepatic bile ducts. [ 1 ] Global prevalence is approximately 35 to 40 people per 100,000 inhabitants, which varies heterogeneously among countries and is predominantly found in females. [ 2 – 6 ] The increasing number of cases raises a public health alert as it can progress to hepatic fibrosis, cirrhosis, and complications such as portal hypertension and hepatocellular carcinoma. [ 7 ] The only medications approved by the Food and Drug Administration (FDA) are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), as an adjunctive agent to UDCA or monotherapy in UDCA-intolerant patients. [ 8 , 9 ] However, 40% of patients do not respond adequately to UDCA and OCA frequently leads to pruritus and treatment discontinuation. [ 7 , 10 ] On the other hand, PPAR ligands are receiving much interest due to positive results obtained in clinical trials, especially regarding reduction in pruritus. PPARs, nuclear receptors responsible for regulating the transcription of genes involved in inflammation, inhibit the expression and duration of action of pro-inflammatory cytokines, reducing acute and chronic inflammatory processes. [ 7 ] The protective role of PPARs in the regulation of carcinogenesis and metabolic pathways makes them essential molecular targets for cholestatic liver diseases, such as PBC. [ 7 , 11 , 12 ] However, individual trials lack sufficient power to detect significant differences in outcomes, posing significant challenges to the use of PPARs agonists as recommended drugs for PBC treatment. [ 13 ] Previous meta-analyses evaluated the use of fibrates in the treatment of patients with PBC [ 14 – 17 ] and a recent one compared the use of PPAR agonists to UCDA regards alkaline phosphatase levels. [ 18 ] However, no previous meta-analysis has focused on investigating the potential outcomes of fibrates and non-fibrate PPAR agonists in a larger population. Therefore, we aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PPAR agonists versus placebo or standard treatment in patients with PBC. 2. Material and Methods This systematic review and meta-analysis was performed in accordance with the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. [ 19 ] As such, it was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol CRD42024527779. 2.1 Search strategy and data extraction MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to March 2024 with the following search terms: ("Primary Biliary Cholangitis" OR PBC) AND (Bezafibrate OR Fenofibrate OR Saroglitazar OR saroglitazar OR Seladelpar OR Elafibranor OR "PPAR agonist" OR "PPAR agonists"). The references from all included studies were also searched manually for any additional studies. Two authors (B.N. and T.T.) independently extracted the data following predefined search criteria and quality assessment. Disagreements were resolved by consensus between the authors. 2.2 Eligibility criteria Inclusion in this meta-analysis was restricted to studies that met all the following eligibility criteria: (1) RCTs that directly compared PPAR agonists with placebo or standard of care treatment; (2) enrolling patients with PBC. In addition, there was no restriction on follow-up. We excluded studies with (1) no control group; (2) population overlap (i.e. overlapping institutions and recruitment periods); (3) patients without PBC; (4) no outcomes of interest. Conference abstracts, case reports, editorials or reviews were also excluded. The corresponding authors were contacted in case of missing data from individual studies. 2.3 Endpoints and subgroup analyses The endpoints of interest were the incidence of pruritus and the mean change in alkaline phosphatase levels (ALP), gamma-glutamyltransferase (GGT), and total and direct bilirubin levels. We assessed the incidence of nausea, headache, fatigue, myalgia, diarrhea, abdominal pain, normalization of ALP levels, laboratory abnormalities, and serious treatment adverse events. The mean change in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were also analyzed. The definitions of normalization of ALP levels, laboratory abnormalities, and serious treatment adverse events were described respectively as adequate biochemical response rate, as established by the Barcelona, Paris-I, Paris-II and Toronto I criterias, kidney dysfunction, elevated levels of creatine phosphokinase, rapid elevation of serum levels of creatinine, and aminotransferases in grades 1, 2 and 3, in addition to slight changes in total bilirubin and albumin; and serious adverse events that occurred as a result of the experimental treatment. 2.4 Quality assessment Quality assessment of RCTs was performed using the Cochrane Collaboration’s tool for assessing risk of bias in randomized trials (RoB-2), in which studies are scored as high, low, or unclear risk of bias in 5 domains: selection, performance, detection, attrition, and reporting biases. [ 20 ] The risk of bias was performed independently by two authors (M.V.S.S. and O.R.G.). Disagreements were resolved by consensus between authors. Publication bias was assessed with contour-enhanced funnel plot analysis [ 21 ] and Egger’s test [ 22 ] of efficacy endpoints and evaluation for symmetrical distribution of trials with similar weights, using the Pustejovsky and Rodgers [ 23 ] approach when standardized mean difference was used for the outcome of interest. 2.5 Statistical analysis Treatment effects were compared using standardized mean differences (SMD), with 95% confidence intervals (CI), for outcomes for which studies reported different measures of units, and mean differences (MD), with 95% CI, for continuous outcomes. risk ratios (RR), with 95% CI, were used for binary endpoints. Given the expected heterogeneity between studies, we adopted the DerSimonian and Laird random-effects model for all outcomes reported. We used the Cochran Q test and I 2 statistics to assess for heterogeneity; P values inferior to 0.1 and I 2 > 40% were considered significant for heterogeneity. R version 4.1.2 (The R Foundation, 2021) was used for statistical analysis. 2.6 Sensitivity analysis We performed a pre-specified sensitivity analysis for efficacy and primary endpoints with (1) a leave-one-out approach to ensure that results were not dependent on a single study and to evaluate studies that had high contributions to the heterogeneity on efficacy endpoints when I 2 ≥ 40 ; (2) several univariable meta-regression analyses to assess any interactions with some covariates (PPAR agonists’ dosages; time of follow up measured in weeks; mean ALP levels at baseline) for the outcomes reported by at least 10 studies[ 24 ] In addition, for outcomes with high heterogeneity, we performed subgroup analysis according to (1) time of follow up (12 to 35 weeks and 52 to 104 weeks) and (2) type of PPAR agonist (benzafibrate, fenofibrate, seladelpar, and elafibranor). 3. Results 3.1 Study selection and characteristics As detailed in Figure 1 , the initial search yielded 913 results. After the removal of duplicate records and ineligible studies, 36 remained and were fully reviewed based on inclusion criteria. Of these, a total of 13 randomized controlled trials (RCTs) [25–38] were included, comprising 1,124 patients. A total of 687 (61,1%) patients were in the intervention group, of which 27 (3,9%) received saroglitazar, 138 (20,1%) received elafibrinor, 87 (12,6%) received fenofibrate, 331 (48,2%) received seladelpar and 104 (15,1%) received bezafibrate. Study characteristics are reported in Table 1 . The total number of women in the study was 1039 (92,4%). The mean age of participants was 55.6 years. Mean ALP level at baseline was 325.2 units/liter. Thirteen studies administered UDCA or allowed its continuation for both groups. [25–29,31–38] In addition, ten studies included patients with unresponsive or inadequate biochemical responses to UCDA. [25–31,33,34,36] Finally, there was a significant variability of follow-up duration between the studies. ( Table 1 ) 3.2 Pooled analysis of all studies In those patients receiving PPAR agonists, the ALP (MD -130.93, 95% CI -156.44 to -105.42, p<0.01, I ²=84%, Figure 2 ), GGT (MD -39.83, 95% CI -78.44 to -1.22, p=0.04, I ²=94%, Figure 3 ) and total bilirubin levels (SMD -0.03, 95% CI -0.06 to -0.01, p<0.01, I ²=69%, Figure 4 ) were significantly lower when compared to control group. There was no statistically significant difference in terms of direct bilirubin (SMD 0, 95% CI -0.05 to 0.04, p=0.91, I ²=60%, Figure 5 ), AST (MD -1.85, 95% CI -5.72 to 2.02, p=0.35, I ²=64%, Supplementary Figure 2 ) and ALT levels (MD -5.15, 95% CI -12.48 to 2.19, p=0.17, I ²=85%, Supplementary Figure 3 ). PPAR agonists significantly reduced the incidence of pruritus (RR 0.63, 95% CI 0.41 to 0.96, p=0.031, I ²=9%, Figure 6 ) when compared to the control group. The normalization of ALP levels (RR 10.65, 95% CI 2.18 to 52.01, p=0.003, I ²=83%, Supplementary Figure 4 ) was significantly higher when compared to the control group. However, the incidence of abdominal pain (RR 1.91, 95% CI 1.04 to 3.53, p=0.038, I ²=0%, Supplementary Figure 5 ) and laboratory abnormalities (RR 2.15, 95% CI 1.37 to 3.37, p<0.001, I ²=0%, Supplementary Figure 6 ) were significantly higher in the PPAR agonists group. There was no statistically significant difference in terms of nausea (RR 1.65, 95% CI 0.89 to 3.05, p=0.112, I ²=0%, Supplementary Figure 7 ), headache (RR 1.78, 95% CI 0.67 to 4.72, p=0.244, I ²=37%, Supplementary Figure 8 ), fatigue (RR 0.85, 95% CI 0.56 to 1.28, p=0.436, I ²=19%, Supplementary Figure 9 ), myalgia (RR 1.59, 95% CI 0.68 to 3.72, p=0.282, I ²=0%, Supplementary Figure 10 ), and diarrhea (RR 0.68, 95% CI 0.32 to 1.48, p=0.337, I ²=5%, Supplementary Figure 11 ). 3.3 Subgroup analyses in selected populations In a subanalysis restricted to studies with 12 to 35 weeks (MD -152.67, 95% CI -164.99 to -140.35, p<0.01, I ²=36%, Supplementary Figure 12 ) and 52 to 104 weeks (MD -111.20, 95% CI -139.91 to -82.49, p<0.01, I ²=86%, Supplementary Figure 12 ) of follow-up, the change in ALP levels was significantly reduced in the PPAR agonists group compared to the control group. In addition, in a subanalysis restricted to type of PPAR agonist, ALP levels were significantly reduced in the intervention group compared to the control group: seladelpar (MD -104.05, 95% CI -122.63 to -85.47, p<0.01, I ²=0%, Supplementary Figure 13 ), elafibrinor (MD -128.78, 95% CI -161.09 to -96.47, p<0.01, I ²=68%, Supplementary Figure 13 ), bezafibrate (MD -169.11, 95% CI -191.59 to -146.62, p<0.01, I ²=31%, Supplementary Figure 13 ), and fenofibrate (MD -95.34, 95% CI -150.38 to -40.31, p<0.01, I ²=83%, Supplementary Figure 13 ). 3.4 Sensitivity analyses The leave-one-out analysis showed the robustness of the pooled results for the levels of ALP, direct and total bilirubin. Leave-one-out analysis for the normalization of ALP levels was also consistent with the pooled results. For those outcomes, there was no significant variability in effect size with the removal of each study. For the continuous outcomes, it was not possible to identify one single study responsible for the high heterogeneity, so we identified the study that rendered the lowest heterogeneity possible for each outcome. Meta-regression analysis for the outcome of ALP levels showed that the heterogeneity remained high (I 2 ) and the p-value for the test of significance of the model (QMp) was not significant, independently of the chosen predictor. For the outcome of GGT levels, the heterogeneity remained high independently of the chosen predictor. However, the value of ALP at baseline was a statistically significant predictor of GGT levels (QMp = 0.049) and explained 23.8% of the outcome’s variance. For the outcome of total bilirubin levels, the heterogeneity was reduced below the 25% threshold independently of the chosen predictor. The remaining heterogeneity ranged from 17.94% to 0.05%. The time of follow up and the PPAR dosage were statistically significant predictors of total bilirubin levels (QMp = 0.029 and 0.009, respectively) ( Supplementary Table 1) . 3.5 Quality assessment Individual bias assessment is reported in Supplementary Figure 1 . RCTs were evaluated using Rob2. Seven studies lost points in domains related to deviation from intended interventions or outcome measurement. [29–35] A crossover study was assessed using Rob2 for crossover, considered at high risk of bias due to insufficient time for carryover effects to dissipate before outcome assessment in the second period and lack of blinding of participants and assessors. [38] The remaining studies were considered at low risk. Publication bias was investigated for the outcomes of ALP, GGT, and total bilirubin levels, as at least 10 studies were available. Overall, some outcomes showed asymmetry of the funnel plots, but the possibility of small study effect was contradicted by a more profound analysis with the help of the enhanced contour and Egger’s Test ( Supplementary Table 2) in most cases. 4. Discussion In this systematic review and meta-analysis of 13 RCTs, including 1,198 patients, the safety and efficacy of PPAR analogs were compared with placebo plus UDCA or UDCA monotherapy in patients with PBC. The main findings from the combined analysis were: (1) reduction in ALP and GGT levels in patients that received PPAR analogs; (2) PPAR analogs were associated with a lower incidence of pruritus; and (3) there was no difference between the intervention and control groups in fatigue incidence. PBC is a progressive autoimmune disease that primarily affects middle-aged women. [ 39 ] The pathophysiology of the disease is related to injury to the bile ducts by the immune system's attack. Due to epithelium inflammation, bile excretion is impaired, causing bile accumulation in the gallbladder and reflux of substances to the liver. [ 40 ] Among the main substances are bile salts with hepatotoxic potential, which, when returning to the liver, stimulate the synthesis of ALP, reflecting hepatocyte and ductal cell distress. Recent studies demonstrated the benefits of PPAR analogs in laboratory markers by reducing bile acid toxicity and associated lesions. [ 41 ] As observed in a recent RCT, 400 mg of benzafibrate per day for 104 days resulted in a reduction of 20 U/L in ALP levels. [ 27 ] These data corroborate the findings of our meta-analysis, in which the medication was associated with a reduction in ALP. Furthermore, liver damage resulting from the action of bile secretion also leads to increased levels of GGT, a hepatic enzyme marking oxidative stress. Although some findings lacked sufficient statistical power to demonstrate a difference in GGT levels, [ 35 , 38 ] the pooled analysis points to the benefits of PPAR analogs compared to placebo or standard treatment. Benzafibrate, seladelpar, saroglitazar, and elafibrinor act on reducing the production of interleukins and bile acid toxicity in patients with PBC, reducing liver injury and improving the biochemical profile. [ 42 ] Among the studies included in our meta-analysis, a recent RCT showed the greatest change from baseline, with a reduction of 113.64 U/L. In this study, patients received a daily dose of 2 and 4 milligrams of saroglitazar or placebo, with the continued use of UCDA in both groups, for 16 weeks. It is important to note that these results reveal that the change from baseline is not directly dependent on the medication dosage, as 2 milligrams of saroglitazar are associated with a greater reduction in GGT than the dosage of 4 milligrams. [ 37 ] Although the data are promising, it is essential to address potential side effects before considering these medications as adjunctive treatment to UCDA in PBC patients. Overall, PPAR analogs were considered safe. Regarding pruritus, this meta-analysis revealed an incidence in 8.9% of PPAR analog users, whereas among those who received placebo or standard treatment, the incidence was 12.9%. In this sense, it is important to highlight that recent studies reveal the potential of PPAR signaling in improving pruritus, an important symptom of PBC, due to the control of cytokine release and consequently immunological balance. This data reveals the potential of PPAR analogs not only in improving the biochemical and clinical profile of patients but also as an alternative to reducing medication side effects. Regarding fatigue, no significant differences were found between the two groups. [ 27 ] This study has some limitations. First, the follow-up period of the included studies ranged between 3 to 478 weeks. To explore this heterogeneity, subgroup analysis was performed, stratifying studies by periods of 12 to 35 weeks and 52 to 104 weeks. Meta-regression analyses also showed no relation between the follow-up period and the observed results for ALP, GGT and direct bilirubin. Second, we utilized data only from the first part of Itakura et al. trial since there was not a washout period. This could introduce a potential unit-of-analysis error to this meta-analysis. This type of error results in losses of the information collected. In addition, if the data are available, they are likely to represent a biased subset of trials. [ 43 ] Third, patients with different baseline characteristics were pooled together. Therefore, we performed meta-regressions addressing the influence of PPAR agonists’ dosage, ALP and GGT levels on the primary endpoints that had at least 10 trials. [ 24 ] 5. Conclusion In summary, the use of PPAR analogs plus UDCA was associated with a greater reduction in serum levels of ALP, GGT, and total bilirubin in patients with PBC. Additionally, there was a greater normalization of ALP levels, as well as a lower incidence of pruritus as an adverse event. These findings suggest that PPAR analogs should be considered as an adjuvant therapy to UDCA for the PBC treatment. Abbreviations PBC Primary Biliary Cholangitis UDCA Ursodeoxycholic Acid ALP alkaline phosphatase GGT gamma-glutamyltransferase AST aspartate aminotransferase ALT alanine aminotransferase Declarations Disclosures : All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation Fundings : This study received no fundings. Author Contribution HSF conceived and designed the study. 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Li et al. , ‘A randomized, controlled trial on fenofibrate in primary biliary cholangitis patients with incomplete response to ursodeoxycholic acid’, Ther Adv Chronic Dis, vol. 13, p. 204062232211141, Jan. 2022, doi: 10.1177/20406223221114198 . E. N. Liberopoulos, M. Florentin, M. S. Elisaf, D. P. Mikhailidis, and E. Tsianos, ‘Fenofibrate in Primary Biliary Cirrhosis: A Pilot Study’, Open Cardiovasc Med J , vol. 4, no. 1, pp. 120–126, Apr. 2010, doi: 10.2174/1874192401004010120 . Y. Liu et al. , ‘Effectiveness of Fenofibrate in Treatment-Naive Patients With Primary Biliary Cholangitis: A Randomized Clinical Trial’, American Journal of Gastroenterology , vol. 118, no. 11, pp. 1973–1979, Nov. 2023, doi: 10.14309/ajg.0000000000002238 . J. M. Schattenberg et al. , ‘A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA’, J Hepatol, vol. 74, no. 6, pp. 1344–1354, Jun. 2021, doi: 10.1016/j.jhep.2021.01.013 . R. Vuppalanchi et al. , ‘Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis’, J Hepatol, vol. 76, no. 1, pp. 75–85, Jan. 2022, doi: 10.1016/j.jhep.2021.08.025 . J. ITAKURA, ‘Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis’, Hepatology Research , vol. 29, no. 4, pp. 216–222, Aug. 2004, doi: 10.1016/j.hepres.2004.04.001 . I. M. Iljinsky and O. M. Tsirulnikova, ‘Primary biliary cholangitis’, Russian Journal of Transplantology and Artificial Organs , vol. 23, no. 1, pp. 162–170, Apr. 2021, doi: 10.15825/1995-1191-2021-1-162-170 . A. F. Gulamhusein and G. M. Hirschfield, ‘Primary biliary cholangitis: pathogenesis and therapeutic opportunities’, Nat Rev Gastroenterol Hepatol, vol. 17, no. 2, pp. 93–110, Feb. 2020, doi: 10.1038/s41575-019-0226-7 . N. S. Ghonem et al. , ‘Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol’, Clin Pharmacol Ther , vol. 108, no. 6, pp. 1213–1223, Dec. 2020, doi: 10.1002/cpt.1930 . A. E. Kremer et al. , ‘Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis’, Hepatology, Dec. 2023, doi: 10.1097/HEP.0000000000000728 . D. R. Elbourne, D. G. Altman, J. P. Higgins, F. Curtin, H. V Worthington, and A. Vail, ‘Meta-analyses involving cross-over trials: methodological issues’, Int J Epidemiol , vol. 31, no. 1, pp. 140–149, Feb. 2002, doi: 10.1093/ije/31.1.140 . Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABLE1.docx SUPPLEMENTARYMATERIAL.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4369688","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301402131,"identity":"bff9998e-ac60-4351-8885-a040fe1848a5","order_by":0,"name":"Hilária Saugo Faria","email":"","orcid":"","institution":"Federal University of Santa Maria","correspondingAuthor":false,"prefix":"","firstName":"Hilária","middleName":"Saugo","lastName":"Faria","suffix":""},{"id":301402132,"identity":"6e8c5a10-da2d-4a8a-9d83-df169c33b9b9","order_by":1,"name":"Milene Vitória Sampaio Sobral","email":"","orcid":"","institution":"University of Western São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Milene","middleName":"Vitória Sampaio","lastName":"Sobral","suffix":""},{"id":301402133,"identity":"541d4216-8174-4024-aa93-708f63f0c939","order_by":2,"name":"Victor Gonçalves Soares","email":"","orcid":"","institution":"Federal University of Vales do Jequitinhonha e Mucuri","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"Gonçalves","lastName":"Soares","suffix":""},{"id":301402134,"identity":"fc04c451-e44c-4963-bc53-65d16d886494","order_by":3,"name":"Thainá Torres Cavalheiro","email":"","orcid":"","institution":"Federal University of Santa Maria","correspondingAuthor":false,"prefix":"","firstName":"Thainá","middleName":"Torres","lastName":"Cavalheiro","suffix":""},{"id":301402135,"identity":"984e9803-1af1-44d9-82a9-24a845ed91b8","order_by":4,"name":"Beatriz Nishimoto","email":"","orcid":"","institution":"University of Western São 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Piauí","correspondingAuthor":false,"prefix":"","firstName":"Ocílio","middleName":"Ribeiro","lastName":"Gonçalves","suffix":""},{"id":301402139,"identity":"1fafad4e-592a-4416-a19d-7955d114da3e","order_by":8,"name":"Daniela Gomez Costa","email":"","orcid":"","institution":"Federal University of Santa Maria","correspondingAuthor":false,"prefix":"","firstName":"Daniela","middleName":"Gomez","lastName":"Costa","suffix":""},{"id":301402140,"identity":"ec3e38c9-63fc-44b7-baf6-0175e68347d2","order_by":9,"name":"Eduardo Buzatti Souto","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYFCCBCBmg3EqGPiRuQS1MDYwnGGQbCBNC2MbEVr42XMMP1eU2TDIt/eYP/g477CE/LQDbI8r8GiR7HljLHnmXBqDwZkzho0ztx2WMLidwG54Bo8Wgxs5BpKNbYcZDCRyDJt5tx2uM5BOYAO5Diewv5Fj/BOkRX4GSMscoMNmE9ACNNwMbAvDDZCWhsMSDLcJaJE486zMsuFcGo/BmWOFM2ccSwf6JbHdEJ8W/vbkzTcbymzk5NubN3z4UGMNdFjysYf4tMAADxKbkRgNo2AUjIJRMArwAQDnaUwhXKrYYAAAAABJRU5ErkJggg==","orcid":"","institution":"Federal University of Santa Maria","correspondingAuthor":true,"prefix":"","firstName":"Eduardo","middleName":"Buzatti","lastName":"Souto","suffix":""}],"badges":[],"createdAt":"2024-05-04 20:39:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4369688/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4369688/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56478467,"identity":"dd65caba-133c-46f1-bcb2-b546df55de0a","added_by":"auto","created_at":"2024-05-14 17:51:56","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74573,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow of included studies.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/87ea6868ed8198c97fc6e5c7.jpeg"},{"id":56478525,"identity":"ba9c5e35-bce2-476b-a769-3d76e9578dd7","added_by":"auto","created_at":"2024-05-14 17:51:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21981,"visible":true,"origin":"","legend":"\u003cp\u003ePPAR agonists\u003cstrong\u003e \u003c/strong\u003esignificantly reduced the levels of ALP compared with the control group.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/12d9c50d0ee44a0e634960b1.png"},{"id":56478464,"identity":"44f80a4c-97ee-41b9-9f63-7a430a0bb99f","added_by":"auto","created_at":"2024-05-14 17:51:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19490,"visible":true,"origin":"","legend":"\u003cp\u003ePPAR agonists\u003cstrong\u003e \u003c/strong\u003esignificantly reduced the levels of GGT compared with the control group.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/9bf7ab469e6d898d41e572d1.png"},{"id":56478527,"identity":"071dab4e-16e1-405a-95f9-65acaa0510ee","added_by":"auto","created_at":"2024-05-14 17:51:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":18299,"visible":true,"origin":"","legend":"\u003cp\u003ePPAR agonists\u003cstrong\u003e \u003c/strong\u003esignificantly reduced the levels of total bilirubin compared with the control group.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/6fe10bd0c82a1a4b30e6796d.png"},{"id":56478526,"identity":"d19bfbb7-df44-4441-9a84-21ae183904ed","added_by":"auto","created_at":"2024-05-14 17:51:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":11874,"visible":true,"origin":"","legend":"\u003cp\u003eThere was no statistically significant difference in terms of direct bilirubin levels\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/544408634173b1e45d93ab13.png"},{"id":56478470,"identity":"60af1bc8-8897-4639-a4cf-9c3d1eb14ef7","added_by":"auto","created_at":"2024-05-14 17:51:56","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":18888,"visible":true,"origin":"","legend":"\u003cp\u003ePPAR agonists\u003cstrong\u003e \u003c/strong\u003esignificantly reduced the incidence of pruritus compared \u0026nbsp;with the control group.\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/52089590064fa258c5868245.png"},{"id":56479437,"identity":"aada897c-2465-4798-b51f-aa413c34699e","added_by":"auto","created_at":"2024-05-14 18:00:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":799258,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/344bf14b-54d5-4ee0-9573-3a07578a35ed.pdf"},{"id":56478505,"identity":"0c1c88bf-2629-41ed-8dcd-cc04fd10e77b","added_by":"auto","created_at":"2024-05-14 17:51:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":144123,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/d1dbb3c20c3f323bdcabedf8.docx"},{"id":56478528,"identity":"b218f77f-8d36-4bbf-b407-a6a350f16197","added_by":"auto","created_at":"2024-05-14 17:51:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":616649,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYMATERIAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-4369688/v1/79ef153626cd96e3e0dbec93.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"PPAR agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePrimary biliary cholangitis (PBC) is an autoimmune disease characterized by inflammation and destruction of intrahepatic bile ducts. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Global prevalence is approximately 35 to 40 people per 100,000 inhabitants, which varies heterogeneously among countries and is predominantly found in females. [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] The increasing number of cases raises a public health alert as it can progress to hepatic fibrosis, cirrhosis, and complications such as portal hypertension and hepatocellular carcinoma. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The only medications approved by the Food and Drug Administration (FDA) are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), as an adjunctive agent to UDCA or monotherapy in UDCA-intolerant patients. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] However, 40% of patients do not respond adequately to UDCA and OCA frequently leads to pruritus and treatment discontinuation. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOn the other hand, PPAR ligands are receiving much interest due to positive results obtained in clinical trials, especially regarding reduction in pruritus. PPARs, nuclear receptors responsible for regulating the transcription of genes involved in inflammation, inhibit the expression and duration of action of pro-inflammatory cytokines, reducing acute and chronic inflammatory processes. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The protective role of PPARs in the regulation of carcinogenesis and metabolic pathways makes them essential molecular targets for cholestatic liver diseases, such as PBC. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] However, individual trials lack sufficient power to detect significant differences in outcomes, posing significant challenges to the use of PPARs agonists as recommended drugs for PBC treatment. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePrevious meta-analyses evaluated the use of fibrates in the treatment of patients with PBC [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and a recent one compared the use of PPAR agonists to UCDA regards alkaline phosphatase levels. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] However, no previous meta-analysis has focused on investigating the potential outcomes of fibrates and non-fibrate PPAR agonists in a larger population. Therefore, we aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing PPAR agonists versus placebo or standard treatment in patients with PBC.\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cp\u003e This systematic review and meta-analysis was performed in accordance with the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] As such, it was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol CRD42024527779.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy and data extraction\u003c/h2\u003e \u003cp\u003eMEDLINE, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to March 2024 with the following search terms: (\"Primary Biliary Cholangitis\" OR PBC) AND (Bezafibrate OR Fenofibrate OR Saroglitazar OR saroglitazar OR Seladelpar OR Elafibranor OR \"PPAR agonist\" OR \"PPAR agonists\"). The references from all included studies were also searched manually for any additional studies. Two authors (B.N. and T.T.) independently extracted the data following predefined search criteria and quality assessment. Disagreements were resolved by consensus between the authors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Eligibility criteria\u003c/h2\u003e \u003cp\u003eInclusion in this meta-analysis was restricted to studies that met all the following eligibility criteria: (1) RCTs that directly compared PPAR agonists with placebo or standard of care treatment; (2) enrolling patients with PBC. In addition, there was no restriction on follow-up. We excluded studies with (1) no control group; (2) population overlap (i.e. overlapping institutions and recruitment periods); (3) patients without PBC; (4) no outcomes of interest. Conference abstracts, case reports, editorials or reviews were also excluded. The corresponding authors were contacted in case of missing data from individual studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Endpoints and subgroup analyses\u003c/h2\u003e \u003cp\u003eThe endpoints of interest were the incidence of pruritus and the mean change in alkaline phosphatase levels (ALP), gamma-glutamyltransferase (GGT), and total and direct bilirubin levels. We assessed the incidence of nausea, headache, fatigue, myalgia, diarrhea, abdominal pain, normalization of ALP levels, laboratory abnormalities, and serious treatment adverse events. The mean change in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were also analyzed. The definitions of normalization of ALP levels, laboratory abnormalities, and serious treatment adverse events were described respectively as adequate biochemical response rate, as established by the Barcelona, Paris-I, Paris-II and Toronto I criterias, kidney dysfunction, elevated levels of creatine phosphokinase, rapid elevation of serum levels of creatinine, and aminotransferases in grades 1, 2 and 3, in addition to slight changes in total bilirubin and albumin; and serious adverse events that occurred as a result of the experimental treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Quality assessment\u003c/h2\u003e \u003cp\u003eQuality assessment of RCTs was performed using the Cochrane Collaboration\u0026rsquo;s tool for assessing risk of bias in randomized trials (RoB-2), in which studies are scored as high, low, or unclear risk of bias in 5 domains: selection, performance, detection, attrition, and reporting biases. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] The risk of bias was performed independently by two authors (M.V.S.S. and O.R.G.). Disagreements were resolved by consensus between authors. Publication bias was assessed with contour-enhanced funnel plot analysis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and Egger\u0026rsquo;s test [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] of efficacy endpoints and evaluation for symmetrical distribution of trials with similar weights, using the Pustejovsky and Rodgers [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] approach when standardized mean difference was used for the outcome of interest.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e \u003cp\u003eTreatment effects were compared using standardized mean differences (SMD), with 95% confidence intervals (CI), for outcomes for which studies reported different measures of units, and mean differences (MD), with 95% CI, for continuous outcomes. risk ratios (RR), with 95% CI, were used for binary endpoints. Given the expected heterogeneity between studies, we adopted the DerSimonian and Laird random-effects model for all outcomes reported. We used the Cochran Q test and I\u003csup\u003e2\u003c/sup\u003e statistics to assess for heterogeneity; P values inferior to 0.1 and I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;40% were considered significant for heterogeneity. R version 4.1.2 (The R Foundation, 2021) was used for statistical analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Sensitivity analysis\u003c/h2\u003e \u003cp\u003eWe performed a pre-specified sensitivity analysis for efficacy and primary endpoints with (1) a leave-one-out approach to ensure that results were not dependent on a single study and to evaluate studies that had high contributions to the heterogeneity on efficacy endpoints when I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;40 ; (2) several univariable meta-regression analyses to assess any interactions with some covariates (PPAR agonists\u0026rsquo; dosages; time of follow up measured in weeks; mean ALP levels at baseline) for the outcomes reported by at least 10 studies[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] In addition, for outcomes with high heterogeneity, we performed subgroup analysis according to (1) time of follow up (12 to 35 weeks and 52 to 104 weeks) and (2) type of PPAR agonist (benzafibrate, fenofibrate, seladelpar, and elafibranor).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Study selection and characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;As detailed in \u003cstrong\u003eFigure 1\u003c/strong\u003e, the initial search yielded 913 results. After the removal of duplicate records and ineligible studies, 36 remained and were fully reviewed based on inclusion criteria. Of these, a total of 13 randomized controlled trials (RCTs) [25\u0026ndash;38] were included, comprising 1,124 patients. A total of 687 (61,1%) patients were in the intervention group, of which 27 (3,9%) received saroglitazar, 138 (20,1%) received elafibrinor, 87 (12,6%) received fenofibrate, 331 (48,2%) received seladelpar and 104 (15,1%) received bezafibrate. Study characteristics are reported in \u003cstrong\u003eTable 1\u003c/strong\u003e. The total number of women in the study was 1039 (92,4%). The mean age of participants was 55.6 years. Mean ALP level at baseline was 325.2 units/liter. Thirteen studies administered UDCA or allowed its continuation for both groups. [25\u0026ndash;29,31\u0026ndash;38] In addition, ten studies included patients with unresponsive or inadequate biochemical responses to UCDA. [25\u0026ndash;31,33,34,36] Finally, there was a significant variability of follow-up duration between the studies. (\u003cstrong\u003eTable 1\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Pooled analysis of all studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn those patients receiving PPAR agonists, the ALP (MD -130.93, 95% CI -156.44 to -105.42, p\u0026lt;0.01, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=84%, \u003cstrong\u003eFigure 2\u003c/strong\u003e), GGT (MD -39.83, 95% CI -78.44 to -1.22, p=0.04, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=94%, \u003cstrong\u003eFigure 3\u003c/strong\u003e) and total bilirubin levels (SMD -0.03, 95% CI -0.06 to -0.01, p\u0026lt;0.01, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=69%, \u003cstrong\u003eFigure 4\u003c/strong\u003e) were significantly lower when compared to control group. There was no statistically significant difference in terms of direct bilirubin (SMD 0, 95% CI -0.05 to 0.04, p=0.91, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=60%, \u003cstrong\u003eFigure 5\u003c/strong\u003e), AST (MD -1.85, 95% CI -5.72 to 2.02, p=0.35, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=64%, \u003cstrong\u003eSupplementary Figure 2\u003c/strong\u003e) and ALT levels (MD -5.15, 95% CI -12.48 to 2.19, p=0.17, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=85%, \u003cstrong\u003eSupplementary Figure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003ePPAR agonists significantly reduced the incidence of pruritus (RR 0.63, 95% CI 0.41 to 0.96, p=0.031, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=9%, \u003cstrong\u003eFigure 6\u003c/strong\u003e) when compared to the control group. The normalization of ALP levels (RR 10.65, 95% CI 2.18 to 52.01, p=0.003,\u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=83%, \u003cstrong\u003eSupplementary Figure 4\u003c/strong\u003e) was significantly higher when compared to the control group. However, the incidence of abdominal pain (RR 1.91, 95% CI 1.04 to 3.53, p=0.038,\u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=0%, \u003cstrong\u003eSupplementary Figure 5\u003c/strong\u003e) and laboratory abnormalities (RR 2.15, 95% CI 1.37 to 3.37, p\u0026lt;0.001, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=0%, \u003cstrong\u003eSupplementary Figure 6\u003c/strong\u003e) \u0026nbsp;were significantly higher in the PPAR agonists group.\u003c/p\u003e\n\u003cp\u003eThere was no statistically significant difference in terms of nausea (RR 1.65, 95% CI 0.89 to 3.05, p=0.112, \u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=0%, \u003cstrong\u003eSupplementary Figure 7\u003c/strong\u003e), headache (RR 1.78, 95% CI 0.67 to 4.72, p=0.244, \u0026nbsp;\u003cem\u003eI\u003c/em\u003e\u0026sup2;=37%, \u003cstrong\u003eSupplementary Figure 8\u003c/strong\u003e), fatigue (RR 0.85, 95% CI 0.56 to 1.28, p=0.436, \u0026nbsp;\u003cem\u003eI\u003c/em\u003e\u0026sup2;=19%, \u003cstrong\u003eSupplementary Figure 9\u003c/strong\u003e), myalgia (RR 1.59, 95% CI 0.68 to 3.72, p=0.282, \u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=0%, \u003cstrong\u003eSupplementary Figure 10\u003c/strong\u003e), and diarrhea (RR 0.68, 95% CI 0.32 to 1.48, p=0.337, \u0026nbsp;\u003cem\u003eI\u003c/em\u003e\u0026sup2;=5%, \u003cstrong\u003eSupplementary Figure 11\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Subgroup analyses in selected populations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a subanalysis restricted to studies with 12 to 35 weeks (MD -152.67, 95% CI -164.99 to -140.35, p\u0026lt;0.01, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=36%, \u003cstrong\u003eSupplementary Figure 12\u003c/strong\u003e) and 52 to 104 weeks (MD -111.20, 95% CI -139.91 to -82.49, p\u0026lt;0.01,\u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=86%,\u003cstrong\u003e\u0026nbsp;Supplementary Figure 12\u003c/strong\u003e) of follow-up, the change in ALP levels was significantly reduced in the PPAR agonists group compared to the control group. In addition, in a subanalysis restricted to type of PPAR agonist, \u0026nbsp;ALP levels were significantly reduced in the intervention group compared to the control group: seladelpar (MD -104.05, 95% CI -122.63 to -85.47, p\u0026lt;0.01,\u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=0%, \u003cstrong\u003eSupplementary Figure 13\u003c/strong\u003e), elafibrinor (MD -128.78, 95% CI -161.09 to -96.47, p\u0026lt;0.01,\u003cem\u003e\u0026nbsp;I\u003c/em\u003e\u0026sup2;=68%, \u003cstrong\u003eSupplementary Figure 13\u003c/strong\u003e), bezafibrate (MD -169.11, 95% CI -191.59 to -146.62, p\u0026lt;0.01, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=31%, \u003cstrong\u003eSupplementary Figure 13\u003c/strong\u003e), and fenofibrate (MD -95.34, 95% CI -150.38 to -40.31, p\u0026lt;0.01, \u003cem\u003eI\u003c/em\u003e\u0026sup2;=83%, \u003cstrong\u003eSupplementary Figure 13\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Sensitivity analyses\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe leave-one-out analysis showed the robustness of the pooled results for the levels of ALP, direct and total bilirubin. Leave-one-out analysis for the normalization of ALP levels was also consistent with the pooled results. For those outcomes, there was no significant variability in effect size with the removal of each study. For the continuous outcomes, it was not possible to identify one single study responsible for the high heterogeneity, so we identified the study that rendered the lowest heterogeneity possible for each outcome.\u003c/p\u003e\n\u003cp\u003eMeta-regression analysis for the outcome of ALP levels showed that the heterogeneity remained high (I\u003csup\u003e2\u003c/sup\u003e) and the p-value for the test of significance of the model (QMp) was not significant, independently of the chosen predictor. For the outcome of GGT levels, the heterogeneity remained high independently of the chosen predictor. However, the value of ALP at baseline was a statistically significant predictor of GGT levels (QMp = 0.049) and explained 23.8% of the outcome\u0026rsquo;s variance. For the outcome of total bilirubin levels, the heterogeneity was reduced below the 25% threshold independently of the chosen predictor. The remaining heterogeneity ranged from 17.94% to 0.05%. The time of follow up and the PPAR dosage were statistically significant predictors of total bilirubin levels (QMp = 0.029 and 0.009, respectively) (\u003cstrong\u003eSupplementary Table 1)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Quality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIndividual bias assessment is reported in \u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e. RCTs were evaluated using Rob2. Seven studies lost points in domains related to deviation from intended interventions or outcome measurement.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[29\u0026ndash;35] A crossover study was assessed using Rob2 for crossover, considered at high risk of bias due to insufficient time for carryover effects to dissipate before outcome assessment in the second period and lack of blinding of participants and assessors. [38] The remaining studies were considered at low risk.\u003c/p\u003e\n\u003cp\u003ePublication bias was investigated for the outcomes of ALP, GGT, and total bilirubin levels, as at least 10 studies were available. Overall, some outcomes showed asymmetry of the funnel plots, but the possibility of small study effect was contradicted by a more profound analysis with the help of the enhanced contour and Egger\u0026rsquo;s Test (\u003cstrong\u003eSupplementary\u003c/strong\u003e \u003cstrong\u003eTable 2)\u003c/strong\u003e in most cases.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis of 13 RCTs, including 1,198 patients, the safety and efficacy of PPAR analogs were compared with placebo plus UDCA or UDCA monotherapy in patients with PBC. The main findings from the combined analysis were: (1) reduction in ALP and GGT levels in patients that received PPAR analogs; (2) PPAR analogs were associated with a lower incidence of pruritus; and (3) there was no difference between the intervention and control groups in fatigue incidence.\u003c/p\u003e \u003cp\u003ePBC is a progressive autoimmune disease that primarily affects middle-aged women. [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] The pathophysiology of the disease is related to injury to the bile ducts by the immune system's attack. Due to epithelium inflammation, bile excretion is impaired, causing bile accumulation in the gallbladder and reflux of substances to the liver. [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] Among the main substances are bile salts with hepatotoxic potential, which, when returning to the liver, stimulate the synthesis of ALP, reflecting hepatocyte and ductal cell distress. Recent studies demonstrated the benefits of PPAR analogs in laboratory markers by reducing bile acid toxicity and associated lesions. [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] As observed in a recent RCT, 400 mg of benzafibrate per day for 104 days resulted in a reduction of 20 U/L in ALP levels. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] These data corroborate the findings of our meta-analysis, in which the medication was associated with a reduction in ALP.\u003c/p\u003e \u003cp\u003eFurthermore, liver damage resulting from the action of bile secretion also leads to increased levels of GGT, a hepatic enzyme marking oxidative stress. Although some findings lacked sufficient statistical power to demonstrate a difference in GGT levels, [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] the pooled analysis points to the benefits of PPAR analogs compared to placebo or standard treatment. Benzafibrate, seladelpar, saroglitazar, and elafibrinor act on reducing the production of interleukins and bile acid toxicity in patients with PBC, reducing liver injury and improving the biochemical profile. [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] Among the studies included in our meta-analysis, a recent RCT showed the greatest change from baseline, with a reduction of 113.64 U/L. In this study, patients received a daily dose of 2 and 4 milligrams of saroglitazar or placebo, with the continued use of UCDA in both groups, for 16 weeks. It is important to note that these results reveal that the change from baseline is not directly dependent on the medication dosage, as 2 milligrams of saroglitazar are associated with a greater reduction in GGT than the dosage of 4 milligrams. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eAlthough the data are promising, it is essential to address potential side effects before considering these medications as adjunctive treatment to UCDA in PBC patients. Overall, PPAR analogs were considered safe. Regarding pruritus, this meta-analysis revealed an incidence in 8.9% of PPAR analog users, whereas among those who received placebo or standard treatment, the incidence was 12.9%. In this sense, it is important to highlight that recent studies reveal the potential of PPAR signaling in improving pruritus, an important symptom of PBC, due to the control of cytokine release and consequently immunological balance. This data reveals the potential of PPAR analogs not only in improving the biochemical and clinical profile of patients but also as an alternative to reducing medication side effects. Regarding fatigue, no significant differences were found between the two groups. [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, the follow-up period of the included studies ranged between 3 to 478 weeks. To explore this heterogeneity, subgroup analysis was performed, stratifying studies by periods of 12 to 35 weeks and 52 to 104 weeks. Meta-regression analyses also showed no relation between the follow-up period and the observed results for ALP, GGT and direct bilirubin. Second, we utilized data only from the first part of Itakura et al. trial since there was not a washout period. This could introduce a potential unit-of-analysis error to this meta-analysis. This type of error results in losses of the information collected. In addition, if the data are available, they are likely to represent a biased subset of trials. [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] Third, patients with different baseline characteristics were pooled together. Therefore, we performed meta-regressions addressing the influence of PPAR agonists\u0026rsquo; dosage, ALP and GGT levels on the primary endpoints that had at least 10 trials. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn summary, the use of PPAR analogs plus UDCA was associated with a greater reduction in serum levels of ALP, GGT, and total bilirubin in patients with PBC. Additionally, there was a greater normalization of ALP levels, as well as a lower incidence of pruritus as an adverse event. These findings suggest that PPAR analogs should be considered as an adjuvant therapy to UDCA for the PBC treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrimary Biliary Cholangitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUDCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUrsodeoxycholic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealkaline phosphatase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGGT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egamma-glutamyltransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003easpartate aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e: All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFundings\u003c/strong\u003e: This study received no fundings.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eHSF conceived and designed the study. TTC and BN independently assessed the studies for possible inclusion and collected the data. RCP extracted the baseline characteristics. HSF, APS, TTC, BN, MVS and VGS extracted the data. HSF and VGS were responsible for data interpretation. MVS and ORG analyzed the quality assessment of included studies. All authors were responsible for writing the final version. DGC and EBS made general supervision. All authors approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eS. Sarcognato \u003cem\u003eet al.\u003c/em\u003e, \u0026lsquo;Autoimmune biliary diseases: primary biliary cholangitis and primary sclerosing cholangitis\u0026rsquo;, \u003cem\u003ePathologica\u003c/em\u003e, vol. 113, no. 3, pp. 170\u0026ndash;184, Jun. 2021, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.32074/1591-951X-245\u003c/span\u003e\u003cspan address=\"10.32074/1591-951X-245\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA. Wetten, D. E. J. Jones, and J. K. 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Ghonem \u003cem\u003eet al.\u003c/em\u003e, \u0026lsquo;Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol\u0026rsquo;, \u003cem\u003eClin Pharmacol Ther\u003c/em\u003e, vol. 108, no. 6, pp. 1213\u0026ndash;1223, Dec. 2020, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cpt.1930\u003c/span\u003e\u003cspan address=\"10.1002/cpt.1930\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eA. E. Kremer \u003cem\u003eet al.\u003c/em\u003e, \u0026lsquo;Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis\u0026rsquo;, Hepatology, Dec. 2023, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/HEP.0000000000000728\u003c/span\u003e\u003cspan address=\"10.1097/HEP.0000000000000728\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD. R. Elbourne, D. G. Altman, J. P. Higgins, F. Curtin, H. V Worthington, and A. Vail, \u0026lsquo;Meta-analyses involving cross-over trials: methodological issues\u0026rsquo;, \u003cem\u003eInt J Epidemiol\u003c/em\u003e, vol. 31, no. 1, pp. 140\u0026ndash;149, Feb. 2002, doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ije/31.1.140\u003c/span\u003e\u003cspan address=\"10.1093/ije/31.1.140\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PPAR agonists, ursodeoxycholic acid, primary biliary cholangitis, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-4369688/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4369688/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAgonists of the peroxisome proliferator-activated receptor (PPAR) have attracted attention for their potential to treat primary biliary cholangitis (PBC). However, individual trials lack sufficient power to detect significant differences in clinical and laboratory outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis meta-analysis aims to compare PPAR agonists versus placebo or standard treatment in patients with PBC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe systematically searched PubMed, Embase and Cochrane for studies comparing PPAR agonists with placebo or standard-of-care treatment in PBC. The primary outcomes were pruritus, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total and direct bilirubin levels. We performed statistical analyses using R 4.1.1. Heterogeneity was examined with the Cochran Q test and I\u003csup\u003e2\u003c/sup\u003e statistics. We computed risk ratios (RR), mean differences (MD), and Standardized Mean Differences (SMD), with 95% confidence intervals (CI), using a random-effects model.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirteen randomized controlled trials were included in this meta-analysis, comprising 1,124 patients, of whom 687 (57%) received PPAR agonists plus UDCA. When compared with control, PPAR analogs were significantly associated with a reduction in pruritus (RR 0.63; 95% CI 0.41 to 0.96; p = 0.031; \u003cem\u003eI\u003c/em\u003e²=9%), ALP (MD -130.93; 95% CI -156.44 to -105.42; p \u0026lt; 0.01; \u003cem\u003eI\u003c/em\u003e²=84%), GGT (MD -39.83; 95% CI -78.44 to -1.22; p = 0.04; \u003cem\u003eI\u003c/em\u003e²=94%) and total bilirubin levels (SMD − 0.03; 95% CI -0.06 to -0.01; p \u0026lt; 0.01; \u003cem\u003eI\u003c/em\u003e²=69%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of PPAR agonists reduced the incidence of pruritus and the levels of ALP, GGT, and total bilirubin in patients with PBC.\u003c/p\u003e","manuscriptTitle":"PPAR agonists in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-14 17:51:40","doi":"10.21203/rs.3.rs-4369688/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d478b78f-a5b1-49e2-bf52-55f75b223b6a","owner":[],"postedDate":"May 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-14T17:51:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-14 17:51:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4369688","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4369688","identity":"rs-4369688","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}