New advances in novel pharmacotherapeutic candidates for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) between 2022 and 2024

Resmetirom

The first FDA-approved drug, resmetirom (MGL-3196), which is 28-fold more selective than triiodothyronine (T3) for THR-β over THR-α [20, 21], is based on the encouraging endpoint results of the randomized, double-blind, and placebo-controlled phase III MAESTRO-NASH trial [14]. This trial recruited 966 patients with biopsy-proven MASH and a fibrosis stage of F1B, F2, or F3 and the subjects were randomly distributed to receive once-daily resmetirom 80 mg, 100 mg or placebo in a ratio of 1:1:1 for 52 weeks. Significant effect on MASH resolution without worsening of fibrosis was evident in the 80 mg and 100 mg resmetirom-treated group, marked with the rates of 25.9% and 29.9%, respectively, compared to 9.7% in the placebo group [14]. Additionally, 24.2% and 25.9% response rates of at least one stage of fibrosis reversal were observed in 80 mg and 100 mg resmetirom-treated groups, compared to 14.2% of the placebo group [14]. Thus, the MAESTRO-NASH trial has successfully reached two primary end-points (P < 0.001). Furthermore, the lowering of LDL-C levels (−13.6% in the 80 mg and −16.3% in the 100 mg) was noted in resmetirom-treated groups at week 24 versus 0.1% in the placebo group, thereby leading to the achievement of key secondary endpoint [14]. Other secondary point parameters: ApoB, triglyceride, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF), and FibroScan CAP, exhibited significant improvements in resmetirom-treated subjects versus placebo [14]. Moreover, resmetirom was generally safe as mild or transient episodes of diarrhea and nausea were mostly reported during the initiation of treatment. Consistent with the findings above, the incidence of treatment-emergent adverse events (TEAES) was majorly mild to moderate in severity, with cases of diarrhea (23.5%–31.2% vs. 13.8%) or nausea (11.9%–18.2% vs. 7.9%) being more commonly reported in the resmetirom-treatment arms than the placebo, and there was no significant disparity in the occurrence of TEAES observed between the resmetirom treatment arms (86.1%–88.4%) and the control arm (81.8%) [22]. The trial results above serve as strong evidence to fully support the fast-track approval of resmetirom by the FDA [14].

In order to reduce the inter-personal errors in reading and scoring NAS (NAFLD activity score) or fibrotic stages, additional analyses were conducted by employing artificial intelligence (AI) reading with the help of second harmonic generation (qFibrosis)/two-photon excited fluorescence microscopy on 768 paired biopsy tissue sections from the MAESTRO-NASH trial. A pronounced reduction in the continuous qSteatosis score (tissue area—steatosis area) has been showcased by the percentage change of −36% in 80 mg resmetirom, −46% in 100 mg resmetirom, and −10% in placebo [23]. Likewise, the continuous change in corrected qFibrosis score (calculating the quantifiable collagen fibrillar properties) displayed a decrease in percentage change of −22% in 80 mg resmetirom, and −20% in 100 mg resmetirom, in contrast to 3% in placebo [23]. Moreover, this study has spotlighted the improvement for at least one stage in qFibrosis, which was aligned with, but surpassed, the central evaluation performed by pathologists among the 90% of resmetirom responders in the previous MAESTRO-NASH trial [23]. Therefore, the incorporation of the AI algorithm has provided a clear identification of reduced worsening and improvement in treatment-induced fibrosis diminution as compared to the placebo group. Undoubtfully, the advancement of AI strengthens the confidence level in becoming one of the gold standards to reduce interpersonal errors in semi-quantitative assessment of histological responses in the near future, attributed to its higher sensitivity and its predictability on variable liver-related clinical outcomes.

With the superiority displayed by resmetirom-treated groups over the placebo for the achievement of dual primary endpoints and secondary end-points, the FDA has approved Rezdiffra (resmetirom) due to its likeliness in predicting clinical benefit. Ultimately, this breakthrough provides an option to treat MASH patients with moderate to advanced liver fibrosis (stages F2 to F3), along with lifestyle modifications to address the unmet medical need [2]. Yet, the usage of Rezdiffra is contraindicated in patients with decompensated cirrhosis as its treatment benefit on this target population remains unknown [2]. To avoid any serious outcomes, patients who experience any hepatotoxicity or gallbladder-related adverse reactions, such as cholelithiasis and cholecystitis should discontinue using this drug.

Semaglutide

As a GLP-1 receptor agonist, semaglutide is currently approved for the treatment of type 2 diabetes mellitus (T2DM) to lower HbA1c and cardiovascular risk in diabetic patients, and for chronic weight management in individuals with obesity by the FDA [29–38]. Given its effects on multiple organs, adherence to GLP-1 receptor agonist therapy over time may lower the risk of major adverse liver outcomes (MALO) in patients with chronic metabolic disorders, such as diabetes, metabolic syndrome and MASLD. Based on a trial in diabetic subjects with MASLD receiving GLP-1 receptor agonists through inverse-probability weighted marginal structure model, the 10-year risk of MALO was 49% lower in the intention-to-treat group than the non-intention-to-treat group in the per-protocol analysis [39]. In brief, the findings from this study suggest that GLP-1 receptor agonists represent as promising medications to slow down the progression of chronic liver disease in patients with comorbidities of type 2 diabetes.

A previous phase II trial demonstrated that daily subcutaneous injection of semaglutide at 0.4 mg for 72 weeks was effective in MASH resolution, but did not affect fibrosis in MASH significantly [40]. A post-hoc exploratory analysis of this trial (NCT02970942), evaluating the antifibrotic effect by digital image quantification of the collagen proportionate area (CPA), has revealed that both standard CPA (total biopsy area) and fat-free CPA (non-steatotic biopsy area) were numerically decreased in subjects receiving semaglutide treatment versus placebo [41]. Particularly, fat-free CPA demonstrated high accuracy in assessing fibrotic regression because the changes in liver volume were corrected along with the changes in hepatic fat to prevent overestimation of fibrotic level due to collagen condensation. Yet, additional studies are warranted to further validate the value of the fat-free CPA method, including the establishment of its direct correlations with changes in liver volume.

Subsequently, in a double-blind, placebo-controlled phase II trial, 71 patients with biopsy-confirmed MASH-related cirrhosis and body-mass index (BMI) of 27 kg/m² or above were randomly assigned to semaglutide (2.4 mg)-treated or placebo groups in a ratio of 2:1 for 48 weeks [42]. Surprisingly, no profound differences in liver fibrotic regression (11% vs. 29%), as well as MASH resolution (34% vs. 21%) were demonstrated between the semaglutide-treated and the placebo groups, although significant reductions in ALT, AST, GGT, CRP, liver steatosis, and Pro-C3 concentration levels were documented in the semaglutide-treated group compared to the placebo [42]. Positive outcomes such as reduced HbA1c levels in patients with type 2 diabetes and massive improvement in body weight were observed in the semaglutide-treated group [42]. No new safety concerns arose as the percentages of reported adverse events (89% of semaglutide-treated vs. 79% of placebo-treated patients) and serious adverse events (13% vs. 8%) were fairly equivalent [42]. Thus, it seems to be too late for the use of semaglutide to treat MASH with compensated cirrhosis even though there were improvements in aminotransferase and metabolic parameters. Despite yielding inconclusive results in compensated cirrhotic patients, a phase III ESSENCE trial that covers a much larger population and spans a longer treatment period is currently underway (NCT04822181).

Dual receptor co-agonists (efinopegdutide and tirzepatide)

Efinopegdutide (MK-6024) is a synthetic dual GLP-1/glucagon receptor agonist that mimics the peptide of oxyntomodulin, with a relative potency of 2:1 on the GLP-1 receptor:glucagon receptor [43]. A phase IIa active-comparator-controlled study has displayed notable reduction of liver fat content from the baseline, evidenced by a 30.4% difference in response rate between the 10 mg efinopegdutide group and the 1 mg semaglutide group (72.7% vs. 42.3%) [43]. Moreover, the percentage reduction in body weight from baseline at week 24 was 8.5% for efinopegdutide and 7.1% for semaglutide [43]. Although efinopegdutide exhibited a generally tolerable safety profile, it reported slightly higher incidences of gastrointestinal imbalance events than semaglutide. At present, a phase IIb clinical trial is ongoing to evaluate the efficacy and safety profile of efinopegdutide in comparison to placebo among adults with pre-cirrhotic MASH (NCT05877547).

Tirzepatide is another dual agonist of the GIP (insulinotropic polypeptide) and GLP-1 receptor, that exhibits outstanding therapeutic efficacy in inducing extensive weight loss among T2DM and/or obese individuals [44–46]. Its exceptional therapeutic performance in both primary and secondary endpoints has been shown in the participants with MASH and stage F2/F3 fibrosis as well, with a dose-dependent MASH resolution without worsening of fibrosis seen in the 5 mg tirzepatide group (44%), 10 mg tirzepatide group (56%), and 15 mg of tirzepatide group (62%), versus 10% for placebo [47]. Besides, over 50% of the participants in each tirzepatide-treatment arm, demonstrated reduction in at least 2 points of the NAS at week 52 [47]. However, the improvement in fibrosis is not conclusive and needs a larger sample size to determine [47]. The tolerability profile of tirzepatide is similar to the previous phase III clinical trials among the T2DM and/or obesity population, with mild to moderate gastrointestinal events being mostly encountered [44–46].

To summarize, the positive outcome generated in both clinical trials mentioned above suggested that MASLD/MASH are likely to occur owing to the underlying cause of metabolic dysfunction, such as obesity and insulin resistance. Therefore, efinopegdutide and tirzepatide may be promising drug candidates in treating MASLD/MASH due to the complementary strength of GLP-1 and GIP or glucagon receptor agonism in terms of reducing lipogenesis and caloric intake, oxidizing fatty acids, aiding in weight loss, and stimulating energy expenditure [44–46, 48], as well as its comparable tolerability profile with semaglutide [43, 49].

Triple-hormone-receptor agonist (retatrutide)

Retatrutide (RETA; LY3437943) is a once-weekly, injectable, fatty acid acylated single peptide that possesses novel triple agonist activity at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor, and glucagon-like peptide-1 receptor (GLP-1R) [50]. In a randomized, double-blind phase II trial, 98 out of 338 MASH subjects were randomly assigned to receive either 1, 4, 8, or 12 mg of retatrutide or placebo for 48 weeks. Based on the parameters of primary and key secondary endpoints, more than 80% of participants who received higher dosages (8 and 12 mg) of retatrutide achieved substantial reduction in liver fat content from baseline at week 24 and week 48; whilst hepatic steatosis resolution (liver fat content <5%) was observed in over 85% of MASLD subjects at week 48 [50]. Additionally, a strong correlation was found between liver fat reductions and body weight loss, and the linear improvements in insulin sensitivity and lipid metabolism were observed [50]. Of note, retatrutide exerted a positive dose-dependent effect on the heart rate, peaking at week 24, and subsequently declining [51]. Hence, the refinement of the dosage scheme should be considered in future studies. Overall, it is obvious that the current pilot data on the efficacy of retatrutide in treating MASLD/MASH subjects is significantly valuable to support its further assessment, given its superior metabolic outcomes by enhancing energy expenditure, improving glycemic control, and promoting weight loss [52].

Adverse effects

Unsurprisingly, the use of GLP-1 receptor agonists for weight loss was associated with increased risks of gastrointestinal adverse events in a meta-analysis study [53]. Based on the PharMetrics Plus database (IQVIA) from 2006 to 2020, patients who received GLP-1 receptor agonists (either semaglutide or liraglutide) were 9.09, 4.22, and 3.67 times more likely to experience pancreatitis, bowel obstruction, and gastroparesis, respectively, than the bupropion-naltrexone (weight loss agent) group after adjusting for the hazard ratios (HR) [53]. Despite the rare occurrence of reported adverse effects, the risks of GLP-1 receptor agonists should not be underestimated. Although semaglutide is widely recognized for its sustained reduction in weight loss, individuals who contemplate using this type of medication to lose weight are advised to seek professional advice prior to the use because the risk-benefit profile may differ from the outcome used in diabetic patients.

Aldafermin

Aldafermin is an engineered analog of FGF19 that targets both FGFR1c-KLB and FGFR4-KLB receptor complexes [55]. Activation of these two receptor complexes leads to improvements in both liver steatosis and insulin sensitivity, and suppression of the rate-limiting enzyme, CYP7A1, in bile acid metabolism [55–57]. A 24-week randomized, double-blind, placebo-controlled phase IIb (ALPINE 2/3) trial has greatly increased the challenges for future studies as aldafermin failed to meet the primary dosage response in the fibrosis regression among 171 patients with biopsy-confirmed MASH with fibrosis F2/F3 stages. 31%, 15%, and 30% of 0.3 mg, 1 mg, and 3 mg respectively for the aldafermin-treated subjects showed fibrosis improvement without worsening of MASH in contrast to 19% of patients in the placebo group [58]. Nonetheless, statistical significances in multiple non-invasive measures were noticed in a dose-dependent manner [58].

In the latest phase IIb study (ALPINE-4), 160 patients with compensated MASH cirrhosis were randomly assigned to receive 0.3 mg, 1 mg, and 3 mg of aldafermin or placebo, respectively for 48 weeks. The primary goal of a notable decrease in enhanced liver fibrosis score has been achieved, with a least-square (LS) mean difference of −0.1 in the 1 mg aldafermin group and −0.5 in the 3 mg aldafermin group when compared to the placebo [59]. In addition, aldafermin demonstrated a dose-dependent trend in fibrosis improvement by at least one stage, with the achievement of 15%, 21%, and 23% among the patients in the placebo, 1 mg, and 3 mg aldafermin groups, respectively [59]. Parallel to the 24-week phase II study (NCT02443116) and the ALPINE 2/3 study, rosuvastatin was employed to manage the aldafermin-associated elevations in LDL-C at week 2, which was aligned with the on-target inhibition of the conversion of cholesterol to bile acids [55, 58, 59]. The administration of aldafermin for up to 1 year seemed to be well-tolerated as most of the adverse events were relatively mild and moderate in severity. In summary, the compelling evidence of dose-dependent benefits shown by aldafermin in most at-risk compensated MASH cirrhosis populations instilled optimism for the promising development of this potential drug. However, more comprehensive studies on aldafermin are required to establish its longer-term therapeutic effects. Future studies should address possible aldafermin-related cardiovascular risks, even though LDL-C levels were effectively managed with the commitment use of statin [55, 58, 59].

Efruxifermin (EFX)

HARMONY is a 96 weeks, double-blind, placebo-controlled phase IIb trial, which involves 128 patients with biopsy-confirmed F2-F3 MASH being randomly assigned to 28 mg, 50 mg EFX, or placebo in a ratio of 1:1:1. In the first liver biopsy at week 24, fibrosis regression for at least one stage without worsening of MASH was notably higher in the subjects of EFX groups (39% for 28 mg EFX and 41% for 50 mg EFX) than the placebo (20%) [63]. Longer exposure to EFX for 96 weeks has ultimately led to the achievement of the primary endpoint, showcasing an increase in response rates to 46% and 75% in the 28 mg EFX and 50 mg EFX groups, respectively, in comparison with 24% for placebo [64]. Meaningful histology endpoint on ≥1 stage improvement in fibrosis without worsening of MASH at week 96 was attained [64]. EFX treatment was also found to be associated with a decrease in triglyceride markers (triglyceride, non-HDL cholesterol, and LDL-C) and enhancement of glucose metabolism, thereby reflecting an establishment of a balanced whole-body metabolic environment based on its pharmacological effect [63]. Regarding its safety profile, most of the patients reported experiencing mild to moderate drug-related symptoms and the serious adverse events were relatively balanced across the groups [64].

Different from HARMONY, the SYMMETRY study evaluates the effects of EFX on cirrhotic patients, compensated MASH, which lasts for 96 weeks. In the 36-week analysis, it revealed a trend of at least one-stage fibrosis improvement in 22% of 28 mg EFX-treated patients and 24% of 50 mg EFX-treated patients, compared to 14% for placebo [65, 66]. This eventually drew a setback for EFX’s profile as no distinct differences were observed across the groups, thereby failing to meet its primary endpoint. Yet, there were 4% of patients experienced ≥2 stages of fibrosis reversal without any worsening of MASH in each EFX-treated group, as opposed to none in the placebo [65]. Apart from that, significant MASH resolution rates were observed among 67% and 60% of patients in the 28 mg and 50 mg EFX groups, respectively, compared to 26% for placebo [65, 66]. In addition, several key secondary efficacy endpoints, such as anti-fibrotic effects, improved insulin sensitivity, and enhanced lipid metabolism assessed via histopathology or non-invasive markers could be observed at this early time point as well [65].

It is undeniable that the missing hit of the primary endpoint in the SYMMETRY study dented optimism and hampered the further development of EFX. Nonetheless, sustained and gradual fibrosis improvement seen over time in the 96-week analysis of the HARMONY study suggested that EFX may reverse the failure among the most difficult-to-treat population of cirrhotic MASH patients at a later readout after undergoing a longer treatment duration. Hopefully, positive outcomes will prevail. Providing the multiple improvements of key parameters discussed above, a phase III SYNCHRONY trial program was initiated, in which SYNCHRONY Histology (NCT06215716), SYNCHRONY Real-World (NCT06161571), and SYNCHRONY Outcomes (NCT06528314) are under active recruitment.

Pegozafermin

Pegozafermin is a long-acting pegylated recombinant FGF21 analog that is useful for the treatment of MASH and severe hypertriglyceridemia [67]. In an ENLIVEN phase IIb trial, non-cirrhotic patients with fibrotic stage F2-F3 or NAS ≥4 were randomly distributed to receive either pegozafermin or placebo over a period of 24 weeks. It was found that 22% for weekly 15 mg dose, 26% for weekly 30 mg dose, 27% for the every-2-week 44 mg dose of pegozafermin had at least one-stage fibrosis improvement without worsening MASH and were remarkably greater than the placebo group (7%) [67]. In addition, noteworthy changes in MASH resolution were also seen in 37% of the weekly 15 mg dose, 23% of the weekly 30 mg dose, and 26% of the every-2-week 44 mg dose, respectively, compared to 2% of the placebo, but without statistical significance [67]. In the post-hoc analysis of the ENLIVEN study, among the small subset of patients with compensated cirrhosis of stage F4, 82% of pegozafermin-treated patients showed more than one stage in fibrosis improvement and 45% of them displayed fibrosis reversal without worsening of MASH, in contrast to none in the placebo group [68]. These results were strongly correlated with the reductions in liver fat contents, iron-corrected T1, non-invasive biomarkers of fibrogenesis and inflammation, as well as decrease in liver and spleen volumes, thereby suggesting the beneficial effects of pegozafermin therapy on both MASH resolution and fibrotic regression [67]. Most of the patients experienced nausea, diarrhea, and injection-site erythema. While no significant safety-related concerns such as reduced bone-mass density or fractures occurred; however, there was a pegozafermin treatment-related acute pancreatitis being reported in a single patient [67]. Despite the favorable safety profile presented in the ENLIVEN study, the effects on bone turnover must be fully evaluated in future studies, given that cases have been previously reported [69, 70]. Of note, pegozafermin was well-tolerated in patients with stage F4 fibrosis, corresponding to those with stage F2/F3 fibrosis, further bolstering the additional indication for MASH patients with compensated cirrhosis.

The encouraging results from ENLIVEN trial have shown the possibility of pegozafermin as one of the mainstay treatments for MASH with compensated cirrhosis. This is because of the potential of pegozafermin being able to be administered either once weekly or once every other week, which may greatly increase patient compliance with the treatment. Thus, it has further driven to develop phase III ENLIGHTEN-Fibrosis (NCT06318169) and ENLIGHTEN-Cirrhosis (NCT06419374) trials in evaluating the efficacy of pegozafermin on non-cirrhotic MASH subjects with fibrosis stage F2–F3 and MASH subjects with compensated cirrhosis, respectively.

Obeticholic acid

Obeticholic acid (OCA) is one of the potent FXR agonists that improves key histological features of MASH and glucose disposal after short-term administration [73]. A consensus panel analysis of the phase III REGENERATE trial was established from a reassessment of the primary 18-month liver biopsy analysis (NCT02548351), including a more robust database that yielded more than 8000 total patient-years of drug exposure from nearly 1000 MASH participants with stage F2-F3 fibrosis [74]. In the 25 mg OCA treatment arm, 22.4% of patients achieved the primary endpoint of having at least one stage of fibrosis improvement without worsening of MASH, compared to 9.6% in placebo group [74]. Although a numerically higher proportion of subjects in the 25 mg OCA treatment arm displayed MASH resolution than the placebo (6.5% vs. 3.5%), this result did not reach statistical significance [74]. An increase in LDL-C level was related to OCA treatment in 17% of subjects, but it gradually returned to baseline values by month 18, suggesting possible safety concerns on cardiovascular events [73]. Approximately 51% of subjects receiving OCA 25 mg experienced severe pruritus and this led to discontinuation of treatment in 9% of subjects [73]. Besides, the relative risk for dyslipidemia and gallstone-related events should not be neglected in the 25 mg OCA group [74]. Therefore, on June 22, 2023, Intercept decided to discontinue all MASH-related investments after the rejection of New Drug Application (NDA) for OCA by the FDA due to lack of the benefit over risk profile. Regardless of several years of research challenges, it is evident that the previously released topline results have catalyzed the field of MASH, elevating it to an advanced stage.

Icosabutate (ICO)

FFAs play vital roles in mediating wide-ranging physiological effects on the human body through the ligand binding to a class of G protein-coupled receptors (GPCRs), termed FFARs [81–83]. Icosabutate (ICO) is a structurally engineered and liver-targeted fatty acid that exerts both anti-inflammatory and antifibrotic effects in the liver [84]. By activating multiple targeted pathways, such as FFAR4/FFAR1/PPAR-α pathways and the arachidonic acid (AA) cascade, these synergistic effects aid in lowering metabolic stress, improving glycemic control via the mediation of glucose-stimulated insulin secretion, downregulating inflammatory responses in macrophage through the internalization or formation of FFAR4/β-arrestin 2 complex, and exhibiting anti-proliferative effects on activated hepatic stellate cells [85–87]. Consequently, it leads to a reduction in hepatic oxidative stress, positioning it as an emerging candidate for novel therapeutics in MASH.

ICONA is a phase IIb, placebo-controlled trial that evaluates the safety, tolerability, and efficacy of ICO in 178 MASH patients with F1-F3 fibrosis, either receiving treatment of oral ICO 300 mg, 600 mg, or placebo once daily for 52 weeks. Despite failing to achieve the stringent primary endpoint (without including the NAS score) for not reaching statistical difference across the study cohorts, there was a higher (25.8%) percentage in subjects receiving ICO 600 mg displaying MASH resolution without worsening in fibrosis and a ≥2-point decrease in NAS than the placebo (11.9%) [88]. According to another subgroup analysis that involves patients with T2DM, a greater therapeutic outcome was seen for the same endpoint, with a placebo-adjusted rate of 31.2% for ICO 600 mg, and 10% for ICO 300 mg [88]. Of note, changes in multiple markers of liver injury, inflammation, fibrosis, and glycemic control among T2DM patients were substantially enhanced in a dose-dependent manner after undergoing ICO treatment. Building upon the positive outcomes showcased from this clinical trial, it pushes ICO as a potential therapy in diabetic MASH individuals, with its capability to reduce both cardiovascular and liver-related outcomes. Thus, further investigations in prospective trials are warranted.

Lubiprostone

Lubiprostone is a type of bicyclic fatty acid metabolite of prostaglandin E1. It specifically activates chloride channel-2 on the apical cell membrane of the gastrointestinal tract, promoting intestinal motility by increasing intestinal fluid secretion through the net efflux of chloride and sodium into the lumen [89]. Lately, the relationship between the gut-derived lipopolysaccharide (LPS) and the pathogenesis of MASH or MASLD has been focused in few studies. It was hypothesized that bacterial endotoxin may trigger the signaling pathways of LPS-mediated toll-like receptor 4/nuclear factor-κB and this can subsequently lead to liver inflammation and fibrosis development [90]. The improvement of gut barrier function was demonstrated in the high-dose lubiprostone-treated mice (0.5 mg/kg) by inducing colonic mucin formation and increasing intestine-derived portal HDL to effectively suppress hepatic endotoxin overload [91]. Hence, these findings suggested that blockade of gut-derived bacterial translocation through lubiprostone could be a valuable therapeutic approach for MASH/MASLD.

In the latest phase III randomized-placebo controlled trial of lubiprostone (NCT05768334), a pronounced decline in the fat quantity by MRI-PDFF from baseline was noted in lubiprostone-treated patients with a median (IQR) of −4.17, contrasting to the placebo group with a median (IQR) of −2.32 [92]. Nonetheless, no distinct difference in liver stiffness measured by FibroScan or ALT levels was identified between both groups. Although there were no other serious adverse events or mortality reported, one patient was terminated from lubiprostone treatment due to severe diarrhea [92]. To sum up, lubiprostone therapy has shown beneficial effects among MASLD patients over 48 weeks in liver MRI-PDFF fat content with a tolerable safety profile. However, more extensive and larger-scale trials are necessary to verify its efficacy in MASH/MASLD individuals.