Efficacy of pemafibrate in metabolic dysfunction associated steatotic liver disease and metabolic dysfunction and alcohol associated steatotic liver disease with dyslipidemia: alanine aminotransferase reduction and predictive factors

Efficacy of pemafibrate in metabolic dysfunction associated steatotic liver disease and metabolic dysfunction and alcohol associated steatotic liver disease with dyslipidemia: alanine aminotransferase reduction and predictive factors | 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 Efficacy of pemafibrate in metabolic dysfunction associated steatotic liver disease and metabolic dysfunction and alcohol associated steatotic liver disease with dyslipidemia: alanine aminotransferase reduction and predictive factors Takako Nomura, Masafumi Ono, Kiyoyuki Kobayashi, Maiko Murakami, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5929636/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 Background: Although pemafibrate has shown promise in treating metabolic dysfunction associated steatotic liver disease (MASLD), reports on its effects on metabolic dysfunction and alcohol associated steatotic liver disease (MetALD) are limited. The aim of this study was to evaluate the efficacy of pemafibrate in both conditions complicated with dyslipidemia, with focus on alanine aminotransferase (ALT) reduction. Predictive factors for treatment response were also identified. Methods: This retrospective, single-center cohort study included 96 patients with MASLDand14 with MetALD treated with pemafibrate for 24 weeks. Changes in liver function tests, lipid profiles, and body mass index were analyzed. Factors predicting ALT reduction were identified using correlation analysis and multivariate regression. Patients were categorized as ALT responders or non-responders based on changes at 24 weeks. Results: After 24 weeks, significant improvements were observed in liver function tests and lipid profiles of patients with MASLD; similar benefits were found in patients with MetALD. The median ALT reduction rate was -24.75%. Higher baseline aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) levels were associated with greater ALT reduction. Baseline AST and GGT levels above the upper limit of normal were significant predictors of ALT reduction. Conclusions: Pemafibrate effectively improved liver function and lipid profiles in patients with MASLD and MetALD complicated by dyslipidemia. Baseline liver enzyme levels, particularly AST and GGT levels above the upper limit of normal, were significant predictors of ALT reduction in response to pemafibrate treatment. Metabolic dysfunction associated steatotic liver disease metabolic dysfunction associated steatohepatitis metabolic dysfunction and alcohol associated steatotic liver disease pemafibrate Figures Figure 1 Figure 2 BACKGROUND Metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) are emerging concepts that have recently replaced non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis, respectively. A new category, metabolic dysfunction and alcohol associated steatotic liver disease (MetALD), describes individuals with MASLD who consume higher amounts of alcohol (140–350 g/week for females and 210–420 g/week for males). This new nomenclature aims to improve awareness and patient identification and reduce the stigma associated with these conditions. 1 – 3 Among the various treatment options for MASLD and MetALD, pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR)α modulator, has shown promising results in improving liver function and lipid profiles in patients with dyslipidemia. 4 Recent studies have demonstrated the efficacy of pemafibrate in reducing alanine aminotransferase (ALT) levels in patients with NAFLD, 5 suggesting its potential as a therapeutic agent for MASLD and MetALD. Pemafibrate significantly decreases low-density lipoprotein cholesterol (LDL-C) levels, increases high-density lipoprotein cholesterol (HDL-C) levels, and markedly reduces triglyceride levels. 6 Moreover, its beneficial effects extend to liver function, with significant reductions observed in aspartate aminotransferase (AST), ALT, gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) levels. 7 Although the efficacy of pemafibrate in MASLD has been increasingly studied, understanding its effects on patients with MetALD remains unclear. Most clinical trials and observational studies have focused on patients with NAFLD or MASLD, often excluding those with substantial alcohol consumption. 8 This exclusion has left a critical knowledge gap regarding the potential benefits and risks of pemafibrate treatment in those with metabolic risk factors and higher alcohol intake. Furthermore, factors predicting treatment response to pemafibrate in either patients with MASLD or MetALD are not well established. Identifying such predictive factors is crucial for optimizing treatment strategies and improving patient outcomes. Given the high prevalence of MASLD, previously known as NAFLD, 9 and MetALD in the general population, as well as their potential progression to severe liver disease, addressing these knowledge gaps is crucial for public health and clinical practice. This study aimed to evaluate the efficacy of pemafibrate in patients with MASLD and MetALD complicated with dyslipidemia, focusing specifically on ALT reduction and identifying predictive factors for treatment response. By including patients with MetALD, we aim to address the critical knowledge gap regarding the effects of pemafibrate in this under-studied population. Our study seeks to determine whether the ALT-lowering effect of pemafibrate observed in patients with MASLD extends to those with MetALD and the extent of such effects. In addition, we aim to identify baseline characteristics that may predict a favorable response to pemafibrate treatment. These findings will contribute to developing more personalized and effective treatment strategies for patients with MASLD and MetALD, potentially improving clinical outcomes and quality of life for this growing patient population. METHODS Study design and patients. This retrospective single-center cohort study included 195 patients with MASLD and MetALD complicated with dyslipidemia, who were treated with pemafibrate at HITO Medical Center between October 2018 and March 2023. All patients met the criteria for MASLD and MetALD. MetALD was diagnosed in patients who met MASLD criteria and reported alcohol consumption of 140–350 g/ week for females or 210–420 g/ week for males. 1 – 3 Alcohol consumption was monitored throughout the study period using standardized questionnaires administered at baseline and follow-up visits. For patients in the MetALD group, only those who maintained their alcohol consumption within the defined MetALD range (140–350 g/week for females and 210–420 g/week for males) throughout the 24-week observation period were included in the final analysis. The inclusion criteria were as follows: (1) hepatic steatosis identified by abdominal ultrasonography, (2) dyslipidemia treated with pemafibrate for at least 24 weeks. The exclusion criteria were as follows: (1) severe chronic kidney disease [serum creatinine (Cr) > 2.5 mg/dl], (2) cirrhosis, hepatocellular carcinoma, gallstones or other chronic liver diseases, such as viral infection and autoimmune hepatitis, (3) alcohol associated/related liver disease (ALD) (alcohol consumption ≥ 420 g/week for males and ≥ 350 g/week for females), (4) patients who stopped receiving pemafibrate within 24 weeks, (5) patients that were newly prescribed or have been prescribed antidiabetic agents, antilipidemic agents, and/or other medications, such as vitamin E within the last 24 weeks. Physical examination and laboratory tests Body weight and height were measured, and the body mass index (BMI) was calculated as weight (kg) divided by height squared (m 2 ). Venous blood samples were taken from all patients following a 12-h overnight fast, and the concentrations of AST, ALT, GGT, HDL-C, LDL-C, triglyceride, hemoglobin A1c (HbA1c), and fasting plasma glucose were measured using standard techniques. Type 2 diabetes mellitus, hypertension, and dyslipidemia were diagnosed based on standard criteria. 10 – 12 Abdominal ultrasound protocol and definition of fatty liver Abdominal ultrasound protocol and definition of fatty liver Hepatic steatosis was diagnosed via abdominal ultrasonography. Examinations were performed by sonographers with at least 5 years of experience and trained by gastroenterologists with > 5 years of experience. Technical parameters were adjusted for each patient using standard ultrasonography protocols, as previously reported. 13 , 14 Ultrasonography was performed with a ProSound Alpha 10 system with a 3.5-MHz convex array transducer (Hitachi Aloka Medical, Tokyo, Japan) at HITO Medical Center. Treatment and data collection All patients received oral pemafibrate 0.1 mg twice daily. Demographic data, clinical characteristics, and laboratory results were collected at baseline and 24 weeks post-treatment. A self-administered questionnaire survey was performed to obtain information on the use of drugs for diabetes mellitus, hypertension, and dyslipidemia. Alcohol consumption was quantified using a standardized questionnaire. Outcome measures The primary outcome was a change in ALT levels from baseline at 24 weeks, calculated as follows: ALT 24 weeks – ALT baseline) / ALT baseline × 100%. Secondary outcomes included changes in AST, GGT, and lipid parameters. Patients were categorized as ALT responders (decreased ALT levels at 24 weeks) or non-responders. Statistical analysis Analyses were performed using EZR version 1.68 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). 15 Continuous variables were expressed as median (interquartile ranges [IQR]) and categorical variables as numbers and percentages. We used the Wilcoxon signed-rank test for paired comparisons and Mann–Whitney U test for unpaired continuous variables. Correlations were assessed using Spearman's rank correlation coefficient. Multiple linear regression analysis was used to identify independent predictors of changes in ALT levels. All statistical tests were two-sided and evaluated at the 0.05 level of significance. RESULTS Patient characteristics Of the 195 patients initially screened, 85 were excluded: 46 had no data for hepatic steatosis identified using abdominal ultrasonography, 19 did not receive medication for ≥ 24 weeks, and 20 had ALD. Consequently, 110 patients met the inclusion criteria for the final analysis. Table 1 summarizes the patients’ demographic profiles and laboratory results. The study population comprised 96 patients (87.3%) with MASLD and 14 patients (12.7%) with MetALD. The median age was 63 years (IQR: 54–72), with 76 males (69.1%). The median BMI was 26.9 kg/m² (IQR: 24.7–29.9), and 81 patients (73.6%) had a BMI of ≥ 25 kg/m². Comorbidities were prevalent, with 72 patients (65.4%) having diabetes mellitus and 79 (71.8%) having hypertension. Common concomitant medications included sodium-glucose cotransporter 2 inhibitors (35.5%), dipeptidyl peptidase-4 antagonists (30.9%), and statins (53.6%). The median laboratory values for triglycerides, total cholesterol, HbA1c, ALT, and AST were 262 mg/dL (IQR: 186–437), 193 mg/dL (IQR: 156–230), 6.7% (IQR: 6.0–7.4), 29 U/L (IQR: 21–48), and 26 U/L (IQR: 19–36), respectively. Table 1 Patient characteristics at baseline ( n = 110) Factors n = 110 Age (years) 63 (54–72) Male, n (%) 76 (69.1) Body weight (kg) 71.8 (62.4–83.2) BMI (kg/m 2 ) 26.9 (24.7–29.9) BMI (kg/m 2 ) ≥ 25, n (%) 81 (73.6) Steatotic liver disease, n (%) MASLD 96 (87.3) MetALD 14 (12.7) Comorbidities, n (%) Type 2 diabetes 72 (65.4) Hypertension 79 (71.8) Concomitant medications, n (%) Antidiabetics DPP4 antagonist 34 (30.9) SGLT2 inhibitor 39 (35.5) Metformin 30 (27.3) GLP-1 receptor agonist 17 (15.5) Thiazolidinedione 8 (7.3) Glinide 6 (5.5) Sulfonylurea 7 (6.4) Antilipidemics Statin 59 (53.6) Ezetimibe 24 (21.8) EPA 2 (1.8) EPA/DHA preparation 5 (4.6) Other medications Vitamin E 1 (0.9) Laboratory data Platelets (×10 3 /mm 3 ) 233 (198–272) AST (U/L) 26 (19–36) ALT (U/L) 29 (21–48) GGT (U/L) 41 (26–89) ALP (U/L) 82 (67–102) Serum albumin (g/dL) 4.3 (4.2–4.5) Triglyceride (mg/dL) 262 (186–437) Total cholesterol (mg/dL) 193 (156–230) LDL cholesterol (mg/dL) 93 (76–115) HDL cholesterol (mg/dL) 44 (37–52) HbA1c (%) 6.7 (6.0–7.4) Fasting plasma glucose (mg/dL) 129 (112–185) Note: Data are presented as numbers or medians (interquartile ranges). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DHA, docosahexaenoic acid; DPP4, dipeptidyl peptidase-4; EPA, eicosapentaenoic acid; GGT, gamma-glutamyl transpeptidase; GLP-1, Glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MASLD, metabolic dysfunction associated steatotic liver disease; MetALD, metabolic dysfunction and alcohol-associated steatotic liver disease; SGLT2, sodium-glucose cotransporter 2 DISCUSSION This study presents two key findings regarding the efficacy of pemafibrate in patients with MASLD and MetALD. First, pemafibrate treatment significantly improved liver function tests and lipid profiles in patients with MASLD, and our preliminary findings suggest similar improvements in patients with MetALD. Second, baseline liver enzyme levels, particularly AST and GGT above the ULN, were significant predictors of ALT reduction in response to pemafibrate treatment. These findings address critical knowledge gaps in the treatment of MASLD and MetALD, providing valuable insights into the broader applicability of pemafibrate and factors influencing treatment response. The primary finding of our study demonstrated significant improvement in liver function tests and lipid profiles in patients with MASLD and those with MetALD following pemafibrate treatment. Recent studies showed the efficacy of pemafibrate in patients with MASLD. Hassan et al.'s meta-analysis revealed the ability of pemafibrate to decrease LDL-C and triglyceride levels while increasing HDL-C levels in patients with MASLD. 6 Similarly, Ono et al.'s single-arm prospective study observed significant reductions in liver-related enzymes, such as AST, ALT, and GGT, after 48 weeks of pemafibrate treatment in patients with MASLD. 16 Our study extends these findings by demonstrating similar improvements in patients with MASLD, while also providing preliminary evidence suggesting comparable effects in patients with MetALD. This extension is further supported by the findings of Iwasa et al. in their retrospective study, which examined the efficacy of pemafibrate across patients with MASLD, MetALD, and ALD. 17 They reported significant decreases in ALT, AST, and triglyceride levels in all groups, with no significant differences in the degree of improvement between the groups. This collective evidence suggests that the beneficial effects of pemafibrate may apply to a broader spectrum of metabolic liver disorders than previously established, with preliminary data indicating potential benefits in patients with increased alcohol intake. The second main finding of our study identifies baseline liver enzyme levels, particularly AST and GGT above the ULN, as significant predictors of ALT reduction in response to pemafibrate treatment. This finding aligns with and expands upon recent related studies. Takahashi et al. conducted a retrospective study on patients with NAFLD and dyslipidemia and revealed that baseline GGT levels correlated with improvements in the FibroScan-aspartate aminotransferase (FAST) score following pemafibrate treatment. 18 They reported that patients with GGT levels of 90 IU/L or higher showed significantly greater improvement in the FAST score. Our study corroborates this finding by extending it to include AST levels. Sugimoto et al.'s study on pemafibrate efficacy in patients with NAFLD showed significant decreases in AST, ALT, and GGT levels, with changes in these enzymes correlating with improvements in liver stiffness. 19 Our study builds upon these findings by specifically identifying higher baseline AST and GGT levels as predictors of greater ALT reduction, demonstrating significant differences in these baseline characteristics between ALT responders and non-responders. The focus of this study on ALT reduction has significant implications for liver disease management, particularly given the complex nature of MASLD and MASH. ALT is a key indicator of liver inflammation, and its persistent elevation is closely associated with the progression of liver fibrosis. 20 Recent studies highlighted that high-to-normal ALT levels are associated with an increased risk of new-onset metabolic dysfunction-associated fatty liver disease, 21 emphasizing the need for vigilant monitoring and early intervention. Our findings suggest that the ability of pemafibrate to reduce ALT levels could have wide-ranging positive effects on liver health and beyond. Honda et al. demonstrated that pemafibrate decreased inflammation-related factors in a rodent model of nonalcoholic steatohepatitis. 5 Recent clinical studies have shown the potential of pemafibrate in improving not only liver function tests but also non-invasive surrogates for liver fibrosis. Morishita et al. and Hatanaka et al. reported significant improvements in liver function tests and fibrosis scores in patients with NAFLD after pemafibrate treatment. 22 , 23 The implications of these findings extend beyond liver health. Recent studies have highlighted the systemic impact of MASLD and MASH, demonstrating their association with cardiovascular mortality, sarcopenia, and chronic kidney disease. 24 Liver fibrosis parameters in patients with MASLD have been linked to cardiovascular disease, emphasizing the importance of comprehensive surveillance. 25 , 26 In this context, the potential of pemafibrate to improve liver function and lipid profiles positions it as a promising therapeutic option that may offer benefits beyond liver health. The efficacy of pemafibrate can be further contextualized by considering the broader role of PPARs in liver disease. Lefere et al. compared the effects of selective PPAR agonists with those of pan-PPAR agonists in NAFLD models, suggesting the potential benefits of combination therapies. 27 Nikam et al.'s study on fenofibrate, another PPARα agonist, demonstrated its ability to prevent PPARα-associated gene downregulation and reduce oxidative stress and inflammation in a murine model. 28 Although our study did not directly assess these markers, these findings provide valuable context for understanding the potential mechanisms underlying the efficacy of pemafibrate. Our study provides compelling evidence for the efficacy of pemafibrate in improving liver function and lipid profiles in patients with MASLD and those with MetALD, extending previous findings in MASLD to include patients with increased alcohol intake. The identification of baseline AST and GGT levels as predictors of treatment response offers valuable insights for personalized medicine approaches in managing these conditions. However, it is important to acknowledge the limitations of our study. First, as a retrospective single-center study, our findings may not be fully generalizable to all patient populations. Second, the relatively small sample size in the MetALD group (n = 14) compared with that in the MASLD group (n = 96) limited our ability to draw definitive conclusions about differences in treatment response between the two groups and may have reduced the statistical power to detect potential group-specific effects. This imbalance in group size reflects the real-world distribution of these conditions in our clinical setting and suggests the need for larger, multicenter studies with more balanced representation of MetALD patients to validate our findings. Third, although we observed improvements in liver function tests and lipid profiles, long-term clinical outcomes, such as progression to cirrhosis or development of hepatocellular carcinoma, were not assessed because of the relatively short follow-up period. Additionally, our study did not include liver biopsies, which could have provided more direct evidence of histological liver changes. Future studies should address these limitations through prospective, multi-center studies with longer follow-up periods and the inclusion of histological liver assessments. Investigating the potential synergistic effects of pemafibrate with other therapeutic agents could provide valuable insights into optimizing treatment strategies for MASLD and MetALD. Finally, elucidating the molecular mechanisms underlying the effects of pemafibrate on liver inflammation and fibrosis could open new avenues for targeted therapies in steatotic liver disease (SLD). CONCLUSIONS In conclusion, this study demonstrates pemafibrate's efficacy in improving liver function and lipid profiles in patients with MASLD, while providing preliminary evidence for similar benefits in patients with MetALD, with baseline liver enzymes serving as potential predictors of treatment response. These findings position pemafibrate as a promising therapeutic agent in SLD management, with potential applications extending to the prevention of advanced liver disease. As the prevalence of MASLD and MetALD continues to rise globally, our study contributes valuable insights that may inform clinical practice and guide future investigations in this critical area of hepatology. Abbreviations ALP alkaline phosphatase ALT alanine aminotransferase AST aspartate aminotransferase BMI body mass index GGT gamma-glutamyl transpeptidase HbA1c hemoglobin A1c HDL high-density lipoprotein LDL low-density lipoprotein MASLD metabolic dysfunction-associated steatotic liver disease MetALD metabolic dysfunction and alcohol-associated steatotic liver disease MASH metabolic dysfunction-associated steatohepatitis NAFLD non-alcoholic fatty liver disease PPAR peroxisome proliferator-activated receptor IQR interquartile range Declarations Ethics approval and consent to participate This study was performed in accordance with the ethical guidelines of the 2013 Declaration of Helsinki and approved by the Ethics Committee of HITO Medical Center (approval number: Rin 20240403001). The need for informed consent was waived because this study retrospectively analyzed anonymous clinical data obtained after each patient agreed to the treatment. In addition, an opt-out approach was used to obtain participants’ informed consent, and personal information was protected during data collection. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Author Contribution T.N. and M.O. conceptualized the study. T.N. wrote the original draft of the manuscript. M.O., K.K., M.M., M.A., T.O., M.O., K.I., and A.M. critically reviewed and edited the manuscript. H.K. supervised the study. All authors made substantial contributions to data interpretation, approved the final version of the manuscript, and agree to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and documented in the literature. Acknowledgement We are grateful to Ms. Hitomi Nagano and Mr. Jun Saiki for their efforts in organizing the database. 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Association between triglyceride-glucose related indices and mortality among individuals with non-alcoholic fatty liver disease or metabolic dysfunction-associated steatotic liver disease. Cardiovasc Diabetol. 2024;23:232. Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages ☆ . J Hepatol. 2020;73:757–70. Nikam A, Patankar JV, Somlapura M, Lahiri P, Sachdev V, Kratky D, et al. The PPARalpha agonist fenofibrate prevents formation of protein aggregates (Mallory-Denk bodies) in a murine model of steatohepatitis-like hepatotoxicity. Sci Rep. 2018;8:12964. Additional Declarations No competing interests reported. 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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-5929636","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":409062641,"identity":"38cce2c1-8efd-4416-8d38-3f0513c4703a","order_by":0,"name":"Takako Nomura","email":"data:image/png;base64,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","orcid":"","institution":"HITO Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Takako","middleName":"","lastName":"Nomura","suffix":""},{"id":409062642,"identity":"732757f1-74a8-4a4e-8a9b-e88809d7315a","order_by":1,"name":"Masafumi Ono","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Masafumi","middleName":"","lastName":"Ono","suffix":""},{"id":409062643,"identity":"b4bb941c-faf7-47bf-adee-48f6d4d0e855","order_by":2,"name":"Kiyoyuki Kobayashi","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kiyoyuki","middleName":"","lastName":"Kobayashi","suffix":""},{"id":409062645,"identity":"a47d3349-3655-4343-864a-2a12b0f89f1b","order_by":3,"name":"Maiko Murakami","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maiko","middleName":"","lastName":"Murakami","suffix":""},{"id":409062647,"identity":"20a82e8b-0ac0-4047-af49-aeab05c5c7e4","order_by":4,"name":"Maki Ayaki","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Ayaki","suffix":""},{"id":409062649,"identity":"bff1611c-d4ed-4f87-9240-3461d523dc5e","order_by":5,"name":"Tomohiro Ogi","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Ogi","suffix":""},{"id":409062651,"identity":"a292dd46-b68d-4492-9d15-0cd21df8a53d","order_by":6,"name":"Maki Ogi","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Ogi","suffix":""},{"id":409062653,"identity":"ddfbe69d-5cc1-47b0-a02a-e7a9238fc34d","order_by":7,"name":"Kayo Ishikawa","email":"","orcid":"","institution":"HITO Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kayo","middleName":"","lastName":"Ishikawa","suffix":""},{"id":409062655,"identity":"2f080794-0357-4408-a90d-97c8bff150f9","order_by":8,"name":"Asahiro Morishita","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Asahiro","middleName":"","lastName":"Morishita","suffix":""},{"id":409062656,"identity":"f13be57c-83c8-426a-8491-0743c9633925","order_by":9,"name":"Hideki Kobara","email":"","orcid":"","institution":"Kagawa University","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Kobara","suffix":""}],"badges":[],"createdAt":"2025-01-30 10:53:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5929636/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5929636/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75314627,"identity":"b945d039-88e0-4d77-8b7f-6d40f39e9fe7","added_by":"auto","created_at":"2025-02-03 09:32:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1142752,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between alanine aminotransferase (ALT) level reduction rate at 24 weeks and various baseline parameters\u003c/p\u003e\n\u003cp\u003eScatter plots showing the relationship between the ALT reduction rate at 24 weeks and (a) aspartate aminotransferase(AST), (b) gamma-glutamyl transpeptidase(GGT), (c) alkaline phosphatase (ALP), (d) body mass index (BMI), (e) triglyceride, (f) high-density lipoprotein (HDL) cholesterol, (g) low-density lipoprotein (LDL) cholesterol, and (h) hemoglobin (Hb) A1c levels at baseline. Each point represents an individual patient. The line in each plot represents the linear regression line.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5929636/v1/96d5032d1f843e0d976f3734.png"},{"id":75314626,"identity":"a5e3e4d9-52b4-4a2a-a1d3-655e0e1bc085","added_by":"auto","created_at":"2025-02-03 09:32:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":380700,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of baseline characteristics between alanine aminotransferase (ALT) responders and non-responders\u003c/p\u003e\n\u003cp\u003eBox plots comparing baseline levels of (a) aspartate aminotransferase (AST), (b) gamma-glutamyl transpeptidase (GGT), (c) alkaline phosphatase (ALP), (d) body mass index (BMI), (e) triglyceride, (f) high-density lipoprotein (HDL) cholesterol, (g) low-density lipoprotein (LDL) cholesterol, and (h) hemoglobin (Hb) A1c between ALT responders (R) and non-responders (N). The boxes represent the interquartile range, with the median indicated by the horizontal line. Whiskers extend to the minimum and maximum values, excluding outliers. Outliers are represented as individual points.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5929636/v1/8c8afbba20448de4c8c74bd4.png"},{"id":107518202,"identity":"02291b3d-10a1-41d5-aafa-bdf0aace036f","added_by":"auto","created_at":"2026-04-22 08:43:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1566564,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5929636/v1/8542fcb1-f375-433d-b0b1-2eaa2aaff450.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of pemafibrate in metabolic dysfunction associated steatotic liver disease and metabolic dysfunction and alcohol associated steatotic liver disease with dyslipidemia: alanine aminotransferase reduction and predictive factors","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eMetabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) are emerging concepts that have recently replaced non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis, respectively. A new category, metabolic dysfunction and alcohol associated steatotic liver disease (MetALD), describes individuals with MASLD who consume higher amounts of alcohol (140\u0026ndash;350 g/week for females and 210\u0026ndash;420 g/week for males). This new nomenclature aims to improve awareness and patient identification and reduce the stigma associated with these conditions.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAmong the various treatment options for MASLD and MetALD, pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR)α modulator, has shown promising results in improving liver function and lipid profiles in patients with dyslipidemia.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Recent studies have demonstrated the efficacy of pemafibrate in reducing alanine aminotransferase (ALT) levels in patients with NAFLD,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e suggesting its potential as a therapeutic agent for MASLD and MetALD. Pemafibrate significantly decreases low-density lipoprotein cholesterol (LDL-C) levels, increases high-density lipoprotein cholesterol (HDL-C) levels, and markedly reduces triglyceride levels.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Moreover, its beneficial effects extend to liver function, with significant reductions observed in aspartate aminotransferase (AST), ALT, gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) levels.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough the efficacy of pemafibrate in MASLD has been increasingly studied, understanding its effects on patients with MetALD remains unclear. Most clinical trials and observational studies have focused on patients with NAFLD or MASLD, often excluding those with substantial alcohol consumption.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e This exclusion has left a critical knowledge gap regarding the potential benefits and risks of pemafibrate treatment in those with metabolic risk factors and higher alcohol intake. Furthermore, factors predicting treatment response to pemafibrate in either patients with MASLD or MetALD are not well established. Identifying such predictive factors is crucial for optimizing treatment strategies and improving patient outcomes. Given the high prevalence of MASLD, previously known as NAFLD,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and MetALD in the general population, as well as their potential progression to severe liver disease, addressing these knowledge gaps is crucial for public health and clinical practice.\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate the efficacy of pemafibrate in patients with MASLD and MetALD complicated with dyslipidemia, focusing specifically on ALT reduction and identifying predictive factors for treatment response. By including patients with MetALD, we aim to address the critical knowledge gap regarding the effects of pemafibrate in this under-studied population. Our study seeks to determine whether the ALT-lowering effect of pemafibrate observed in patients with MASLD extends to those with MetALD and the extent of such effects. In addition, we aim to identify baseline characteristics that may predict a favorable response to pemafibrate treatment. These findings will contribute to developing more personalized and effective treatment strategies for patients with MASLD and MetALD, potentially improving clinical outcomes and quality of life for this growing patient population.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e \u003cb\u003eStudy design and patients.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis retrospective single-center cohort study included 195 patients with MASLD and MetALD complicated with dyslipidemia, who were treated with pemafibrate at HITO Medical Center between October 2018 and March 2023. All patients met the criteria for MASLD and MetALD. MetALD was diagnosed in patients who met MASLD criteria and reported alcohol consumption of 140\u0026ndash;350 g/ week for females or 210\u0026ndash;420 g/ week for males.\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Alcohol consumption was monitored throughout the study period using standardized questionnaires administered at baseline and follow-up visits. For patients in the MetALD group, only those who maintained their alcohol consumption within the defined MetALD range (140\u0026ndash;350 g/week for females and 210\u0026ndash;420 g/week for males) throughout the 24-week observation period were included in the final analysis. The inclusion criteria were as follows: (1) hepatic steatosis identified by abdominal ultrasonography, (2) dyslipidemia treated with pemafibrate for at least 24 weeks. The exclusion criteria were as follows: (1) severe chronic kidney disease [serum creatinine (Cr)\u0026thinsp;\u0026gt;\u0026thinsp;2.5 mg/dl], (2) cirrhosis, hepatocellular carcinoma, gallstones or other chronic liver diseases, such as viral infection and autoimmune hepatitis, (3) alcohol associated/related liver disease (ALD) (alcohol consumption\u0026thinsp;\u0026ge;\u0026thinsp;420 g/week for males and \u0026ge;\u0026thinsp;350 g/week for females), (4) patients who stopped receiving pemafibrate within 24 weeks, (5) patients that were newly prescribed or have been prescribed antidiabetic agents, antilipidemic agents, and/or other medications, such as vitamin E within the last 24 weeks.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePhysical examination and laboratory tests\u003c/h2\u003e \u003cp\u003eBody weight and height were measured, and the body mass index (BMI) was calculated as weight (kg) divided by height squared (m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). Venous blood samples were taken from all patients following a 12-h overnight fast, and the concentrations of AST, ALT, GGT, HDL-C, LDL-C, triglyceride, hemoglobin A1c (HbA1c), and fasting plasma glucose were measured using standard techniques. Type 2 diabetes mellitus, hypertension, and dyslipidemia were diagnosed based on standard criteria.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAbdominal ultrasound protocol and definition of fatty liver\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eAbdominal ultrasound protocol and definition of fatty liver\u003c/div\u003e \u003cp\u003eHepatic steatosis was diagnosed via abdominal ultrasonography. Examinations were performed by sonographers with at least 5 years of experience and trained by gastroenterologists with \u0026gt;\u0026thinsp;5 years of experience. Technical parameters were adjusted for each patient using standard ultrasonography protocols, as previously reported.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Ultrasonography was performed with a ProSound Alpha 10 system with a 3.5-MHz convex array transducer (Hitachi Aloka Medical, Tokyo, Japan) at HITO Medical Center.\u003c/p\u003e\n\u003ch3\u003eTreatment and data collection\u003c/h3\u003e\n\u003cp\u003e All patients received oral pemafibrate 0.1 mg twice daily. Demographic data, clinical characteristics, and laboratory results were collected at baseline and 24 weeks post-treatment. A self-administered questionnaire survey was performed to obtain information on the use of drugs for diabetes mellitus, hypertension, and dyslipidemia. Alcohol consumption was quantified using a standardized questionnaire.\u003c/p\u003e\n\u003ch3\u003eOutcome measures\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was a change in ALT levels from baseline at 24 weeks, calculated as follows:\u003c/p\u003e \u003cp\u003eALT 24 weeks \u0026ndash; ALT baseline) / ALT baseline \u0026times; 100%.\u003c/p\u003e \u003cp\u003eSecondary outcomes included changes in AST, GGT, and lipid parameters. Patients were categorized as ALT responders (decreased ALT levels at 24 weeks) or non-responders.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAnalyses were performed using EZR version 1.68 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Continuous variables were expressed as median (interquartile ranges [IQR]) and categorical variables as numbers and percentages. We used the Wilcoxon signed-rank test for paired comparisons and Mann\u0026ndash;Whitney U test for unpaired continuous variables. Correlations were assessed using Spearman's rank correlation coefficient. Multiple linear regression analysis was used to identify independent predictors of changes in ALT levels. All statistical tests were two-sided and evaluated at the 0.05 level of significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eOf the 195 patients initially screened, 85 were excluded: 46 had no data for hepatic steatosis identified using abdominal ultrasonography, 19 did not receive medication for \u0026ge;\u0026thinsp;24 weeks, and 20 had ALD. Consequently, 110 patients met the inclusion criteria for the final analysis. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the patients\u0026rsquo; demographic profiles and laboratory results. The study population comprised 96 patients (87.3%) with MASLD and 14 patients (12.7%) with MetALD. The median age was 63 years (IQR: 54\u0026ndash;72), with 76 males (69.1%). The median BMI was 26.9 kg/m\u0026sup2; (IQR: 24.7\u0026ndash;29.9), and 81 patients (73.6%) had a BMI of \u0026ge;\u0026thinsp;25 kg/m\u0026sup2;. Comorbidities were prevalent, with 72 patients (65.4%) having diabetes mellitus and 79 (71.8%) having hypertension. Common concomitant medications included sodium-glucose cotransporter 2 inhibitors (35.5%), dipeptidyl peptidase-4 antagonists (30.9%), and statins (53.6%). The median laboratory values for triglycerides, total cholesterol, HbA1c, ALT, and AST were 262 mg/dL (IQR: 186\u0026ndash;437), 193 mg/dL (IQR: 156\u0026ndash;230), 6.7% (IQR: 6.0\u0026ndash;7.4), 29 U/L (IQR: 21\u0026ndash;48), and 26 U/L (IQR: 19\u0026ndash;36), respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics at baseline (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;110)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;110\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (54\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (69.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.8 (62.4\u0026ndash;83.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.9 (24.7\u0026ndash;29.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u0026thinsp;\u0026ge;\u0026thinsp;25, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (73.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteatotic liver disease, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMASLD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96 (87.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetALD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (12.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType 2 diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (65.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 (71.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant medications, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntidiabetics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDPP4 antagonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (30.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGLT2 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (35.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetformin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLP-1 receptor agonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (15.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThiazolidinedione\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlinide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSulfonylurea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (6.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntilipidemics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (53.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEzetimibe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (21.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEPA/DHA preparation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther medications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (\u0026times;10\u003csup\u003e3\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e233 (198\u0026ndash;272)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (19\u0026ndash;36)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (21\u0026ndash;48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (26\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (67\u0026ndash;102)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 (4.2\u0026ndash;4.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglyceride (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262 (186\u0026ndash;437)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e193 (156\u0026ndash;230)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 (76\u0026ndash;115)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL cholesterol (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (37\u0026ndash;52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.7 (6.0\u0026ndash;7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting plasma glucose (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129 (112\u0026ndash;185)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eNote: Data are presented as numbers or medians (interquartile ranges).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DHA, docosahexaenoic acid; DPP4, dipeptidyl peptidase-4; EPA, eicosapentaenoic acid; GGT, gamma-glutamyl transpeptidase; GLP-1, Glucagon-like peptide-1; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MASLD, metabolic dysfunction associated steatotic liver disease; MetALD, metabolic dysfunction and alcohol-associated steatotic liver disease; SGLT2, sodium-glucose cotransporter 2\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study presents two key findings regarding the efficacy of pemafibrate in patients with MASLD and MetALD. First, pemafibrate treatment significantly improved liver function tests and lipid profiles in patients with MASLD, and our preliminary findings suggest similar improvements in patients with MetALD. Second, baseline liver enzyme levels, particularly AST and GGT above the ULN, were significant predictors of ALT reduction in response to pemafibrate treatment. These findings address critical knowledge gaps in the treatment of MASLD and MetALD, providing valuable insights into the broader applicability of pemafibrate and factors influencing treatment response.\u003c/p\u003e \u003cp\u003eThe primary finding of our study demonstrated significant improvement in liver function tests and lipid profiles in patients with MASLD and those with MetALD following pemafibrate treatment. Recent studies showed the efficacy of pemafibrate in patients with MASLD. Hassan et al.'s meta-analysis revealed the ability of pemafibrate to decrease LDL-C and triglyceride levels while increasing HDL-C levels in patients with MASLD.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Similarly, Ono et al.'s single-arm prospective study observed significant reductions in liver-related enzymes, such as AST, ALT, and GGT, after 48 weeks of pemafibrate treatment in patients with MASLD.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Our study extends these findings by demonstrating similar improvements in patients with MASLD, while also providing preliminary evidence suggesting comparable effects in patients with MetALD. This extension is further supported by the findings of Iwasa et al. in their retrospective study, which examined the efficacy of pemafibrate across patients with MASLD, MetALD, and ALD.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e They reported significant decreases in ALT, AST, and triglyceride levels in all groups, with no significant differences in the degree of improvement between the groups. This collective evidence suggests that the beneficial effects of pemafibrate may apply to a broader spectrum of metabolic liver disorders than previously established, with preliminary data indicating potential benefits in patients with increased alcohol intake.\u003c/p\u003e \u003cp\u003eThe second main finding of our study identifies baseline liver enzyme levels, particularly AST and GGT above the ULN, as significant predictors of ALT reduction in response to pemafibrate treatment. This finding aligns with and expands upon recent related studies. Takahashi et al. conducted a retrospective study on patients with NAFLD and dyslipidemia and revealed that baseline GGT levels correlated with improvements in the FibroScan-aspartate aminotransferase (FAST) score following pemafibrate treatment.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e They reported that patients with GGT levels of 90 IU/L or higher showed significantly greater improvement in the FAST score. Our study corroborates this finding by extending it to include AST levels. Sugimoto et al.'s study on pemafibrate efficacy in patients with NAFLD showed significant decreases in AST, ALT, and GGT levels, with changes in these enzymes correlating with improvements in liver stiffness.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Our study builds upon these findings by specifically identifying higher baseline AST and GGT levels as predictors of greater ALT reduction, demonstrating significant differences in these baseline characteristics between ALT responders and non-responders.\u003c/p\u003e \u003cp\u003eThe focus of this study on ALT reduction has significant implications for liver disease management, particularly given the complex nature of MASLD and MASH. ALT is a key indicator of liver inflammation, and its persistent elevation is closely associated with the progression of liver fibrosis.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Recent studies highlighted that high-to-normal ALT levels are associated with an increased risk of new-onset metabolic dysfunction-associated fatty liver disease,\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e emphasizing the need for vigilant monitoring and early intervention.\u003c/p\u003e \u003cp\u003eOur findings suggest that the ability of pemafibrate to reduce ALT levels could have wide-ranging positive effects on liver health and beyond. Honda et al. demonstrated that pemafibrate decreased inflammation-related factors in a rodent model of nonalcoholic steatohepatitis.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Recent clinical studies have shown the potential of pemafibrate in improving not only liver function tests but also non-invasive surrogates for liver fibrosis. Morishita et al. and Hatanaka et al. reported significant improvements in liver function tests and fibrosis scores in patients with NAFLD after pemafibrate treatment.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe implications of these findings extend beyond liver health. Recent studies have highlighted the systemic impact of MASLD and MASH, demonstrating their association with cardiovascular mortality, sarcopenia, and chronic kidney disease.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Liver fibrosis parameters in patients with MASLD have been linked to cardiovascular disease, emphasizing the importance of comprehensive surveillance.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e In this context, the potential of pemafibrate to improve liver function and lipid profiles positions it as a promising therapeutic option that may offer benefits beyond liver health.\u003c/p\u003e \u003cp\u003eThe efficacy of pemafibrate can be further contextualized by considering the broader role of PPARs in liver disease. Lefere et al. compared the effects of selective PPAR agonists with those of pan-PPAR agonists in NAFLD models, suggesting the potential benefits of combination therapies.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Nikam et al.'s study on fenofibrate, another PPARα agonist, demonstrated its ability to prevent PPARα-associated gene downregulation and reduce oxidative stress and inflammation in a murine model.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Although our study did not directly assess these markers, these findings provide valuable context for understanding the potential mechanisms underlying the efficacy of pemafibrate.\u003c/p\u003e \u003cp\u003eOur study provides compelling evidence for the efficacy of pemafibrate in improving liver function and lipid profiles in patients with MASLD and those with MetALD, extending previous findings in MASLD to include patients with increased alcohol intake. The identification of baseline AST and GGT levels as predictors of treatment response offers valuable insights for personalized medicine approaches in managing these conditions. However, it is important to acknowledge the limitations of our study. First, as a retrospective single-center study, our findings may not be fully generalizable to all patient populations. Second, the relatively small sample size in the MetALD group (n\u0026thinsp;=\u0026thinsp;14) compared with that in the MASLD group (n\u0026thinsp;=\u0026thinsp;96) limited our ability to draw definitive conclusions about differences in treatment response between the two groups and may have reduced the statistical power to detect potential group-specific effects. This imbalance in group size reflects the real-world distribution of these conditions in our clinical setting and suggests the need for larger, multicenter studies with more balanced representation of MetALD patients to validate our findings. Third, although we observed improvements in liver function tests and lipid profiles, long-term clinical outcomes, such as progression to cirrhosis or development of hepatocellular carcinoma, were not assessed because of the relatively short follow-up period. Additionally, our study did not include liver biopsies, which could have provided more direct evidence of histological liver changes.\u003c/p\u003e \u003cp\u003eFuture studies should address these limitations through prospective, multi-center studies with longer follow-up periods and the inclusion of histological liver assessments. Investigating the potential synergistic effects of pemafibrate with other therapeutic agents could provide valuable insights into optimizing treatment strategies for MASLD and MetALD. Finally, elucidating the molecular mechanisms underlying the effects of pemafibrate on liver inflammation and fibrosis could open new avenues for targeted therapies in steatotic liver disease (SLD).\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn conclusion, this study demonstrates pemafibrate's efficacy in improving liver function and lipid profiles in patients with MASLD, while providing preliminary evidence for similar benefits in patients with MetALD, with baseline liver enzymes serving as potential predictors of treatment response. These findings position pemafibrate as a promising therapeutic agent in SLD management, with potential applications extending to the prevention of advanced liver disease. As the prevalence of MASLD and MetALD continues to rise globally, our study contributes valuable insights that may inform clinical practice and guide future investigations in this critical area of hepatology.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\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\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine aminotransferase\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\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\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-glutamyl transpeptidase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHbA1c\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehemoglobin A1c\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh-density lipoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow-density lipoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMASLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetabolic dysfunction-associated steatotic liver disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMetALD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetabolic dysfunction and alcohol-associated steatotic liver disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMASH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetabolic dysfunction-associated steatohepatitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAFLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-alcoholic fatty liver disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperoxisome proliferator-activated receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was performed in accordance with the ethical guidelines of the 2013 Declaration of Helsinki and approved by the Ethics Committee of HITO Medical Center (approval number: Rin 20240403001). The need for informed consent was waived because this study retrospectively analyzed anonymous clinical data obtained after each patient agreed to the treatment. In addition, an opt-out approach was used to obtain participants\u0026rsquo; informed consent, and personal information was protected during data collection.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.N. and M.O. conceptualized the study. T.N. wrote the original draft of the manuscript. M.O., K.K., M.M., M.A., T.O., M.O., K.I., and A.M. critically reviewed and edited the manuscript. H.K. supervised the study. All authors made substantial contributions to data interpretation, approved the final version of the manuscript, and agree to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and documented in the literature.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe are grateful to Ms. Hitomi Nagano and Mr. Jun Saiki for their efforts in organizing the database. We would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Ann Hepatol. 2024;29:101133.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshibashi S, Yamashita S, Arai H, Araki E, Yokote K, Suganami H, et al. Effects of K-877, a novel selective PPARalpha modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHonda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep. 2017;7:42477.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHassan M, Al-Obaidi H, Karrick M, Merza N, Nawras Y, Saab O, et al. Effect of pemafibrate on the lipid profile, liver function, and liver fibrosis among patients with metabolic dysfunction-associated steatotic liver disease. Gastroenterol Res. 2024;17:159\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIchikawa T, Oba H, Owada M, Watanabe K, Yoshimura T, Fuchigami A, et al. Evaluation of the effects of pemafibrate on metabolic dysfunction-associated steatotic liver disease with hypertriglyceridemia using magnetic resonance elastography combined with fibrosis-4 index and the magnetic resonance imaging-aspartate aminotransferase score. JGH Open. 2023;7:959\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S, et al. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12:173\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYounossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. 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Eur Heart J. 2020;41:111\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2012;47:586\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakahashi H, Ono M, Hyogo H, Tsuji C, Kitajima Y, Ono N, et al. Biphasic effect of alcohol intake on the development of fatty liver disease. J Gastroenterol. 2015;50:1114\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transpl. 2013;48:452\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOno H, Atsukawa M, Tsubota A, Arai T, Suzuki K, Higashi T, et al. Impact of pemafibrate in patients with metabolic dysfunction-associated steatotic liver disease complicated by dyslipidemia: a single-arm prospective study. JGH Open. 2024;8:e13057.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIwasa M, Sugimoto R, Eguchi A, Tamai Y, Shigefuku R, Fujiwara N, et al. Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: The influence of alcohol consumption. Eur J Gastroenterol Hepatol. 2024;36:793\u0026ndash;801.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakahashi Y, Seko Y, Yamaguchi K, Takeuchi K, Yano K, Kataoka S, et al. Gamma-glutamyl transferase predicts pemafibrate treatment response in non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2023;38:1743\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugimoto R, Iwasa M, Eguchi A, Tamai Y, Shigefuku R, Fujiwara N, et al. Effect of pemafibrate on liver enzymes and shear wave velocity in non-alcoholic fatty liver disease patients. Front Med (Lausanne). 2023;10:1073025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112:18\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen JF, Wu ZQ, Liu HS, Yan S, Wang YX, Xing M, et al. Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China. World J Gastroenterol. 2024;30:1346\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorishita A, Oura K, Takuma K, Nakahara M, Tadokoro T, Fujita K, et al. Pemafibrate improves liver dysfunction and non-invasive surrogates for liver fibrosis in patients with non-alcoholic fatty liver disease with hypertriglyceridemia: a multicenter study. Hepatol Int. 2023;17:606\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHatanaka T, Kosone T, Saito N, Takakusagi S, Tojima H, Naganuma A, et al. Effect of 48-week pemafibrate on nonalcoholic fatty liver disease with hypertriglyceridemia, as evaluated by the FibroScan-aspartate aminotransferase score. JGH Open. 2021;5:1183\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandireddy R, Sakthivel S, Gupta P, Behari J, Tripathi M, Singh BK. Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front Cell Dev Biol. 2024;12:1433857.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKubotsu Y, Sakamoto Y, Tago M, Chihara A, Norita M, Inadomi C et al. FIB-4 index and liver stiffness measurement are potential predictors of atherosclerosis in metabolic dysfunction-associated steatotic liver disease. J Atheroscler Thromb 2024 Sep 4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5551/jat.64809\u003c/span\u003e\u003cspan address=\"10.5551/jat.64809\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Online ahead of print.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Q, Hu P, Hou X, Sun Y, Jiao M, Peng L, et al. Association between triglyceride-glucose related indices and mortality among individuals with non-alcoholic fatty liver disease or metabolic dysfunction-associated steatotic liver disease. Cardiovasc Diabetol. 2024;23:232.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages\u003csup\u003e☆\u003c/sup\u003e. J Hepatol. 2020;73:757\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNikam A, Patankar JV, Somlapura M, Lahiri P, Sachdev V, Kratky D, et al. The PPARalpha agonist fenofibrate prevents formation of protein aggregates (Mallory-Denk bodies) in a murine model of steatohepatitis-like hepatotoxicity. Sci Rep. 2018;8:12964.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Metabolic dysfunction associated steatotic liver disease, metabolic dysfunction associated steatohepatitis, metabolic dysfunction and alcohol associated steatotic liver disease, pemafibrate","lastPublishedDoi":"10.21203/rs.3.rs-5929636/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5929636/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAlthough\u003cstrong\u003e \u003c/strong\u003epemafibrate has shown promise in treating metabolic dysfunction associated steatotic liver disease (MASLD), reports on its effects on metabolic dysfunction and alcohol associated steatotic liver disease (MetALD) are limited. The aim of this study was to evaluate the efficacy of pemafibrate in both conditions complicated with dyslipidemia, with focus on alanine aminotransferase (ALT) reduction. Predictive factors for treatment response were also identified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective, single-center cohort study included 96 patients with MASLDand14 with MetALD treated with pemafibrate for 24 weeks. Changes in liver function tests, lipid profiles, and body mass index were analyzed. Factors predicting ALT reduction were identified using correlation analysis and multivariate regression. Patients were categorized as ALT responders or non-responders based on changes at 24 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAfter 24 weeks, significant improvements were observed in liver function tests and lipid profiles of patients with MASLD; similar benefits were found in patients with MetALD. The median ALT reduction rate was -24.75%. Higher baseline aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) levels were associated with greater ALT reduction. Baseline AST and GGT levels above the upper limit of normal were significant predictors of ALT reduction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003ePemafibrate effectively improved liver function and lipid profiles in patients with MASLD and MetALD complicated by dyslipidemia. Baseline liver enzyme levels, particularly AST and GGT levels above the upper limit of normal, were significant predictors of ALT reduction in response to pemafibrate treatment.\u003c/p\u003e","manuscriptTitle":"Efficacy of pemafibrate in metabolic dysfunction associated steatotic liver disease and metabolic dysfunction and alcohol associated steatotic liver disease with dyslipidemia: alanine aminotransferase reduction and predictive factors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-03 09:32:03","doi":"10.21203/rs.3.rs-5929636/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":"d421ded2-34a2-4d08-ba13-b0ae4803f9e4","owner":[],"postedDate":"February 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T08:43:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-03 09:32:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5929636","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5929636","identity":"rs-5929636","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}