Incretin mimetics, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonists, have become first-line treatment options for the treatment of type 2 diabetes and obesity. Their therapeutic status is attributed to their high level of efficacy as well as positive impact on related comorbidities, such as sleep apnea and heart failure. Multiple incretin mimetics are currently available with different durations of drug action, dosing frequencies, and delivery devices. Patients may benefit from education on the proper drug administration, anticipated adverse effects, and nutrition considerations with treatment. Practitioners must monitor progress and support the patient to achieve maintenance doses for optimal weight reduction and diabetes-related outcomes. This review aims to present the current literature supporting US Food and Drug Administration-approved indications of incretin mimetics, equip healthcare professionals to optimize care for patients who are prescribed these agents, and provide insights into potential future applications, which may include dual- or triple-mechanism agents that are injected or administered orally. Additional studies are anticipated with existing and future incretin mimetics for the treatment of type 2 diabetes, obesity, and related comorbidities in a rapidly developing therapeutic pipeline.

The presence of excess liver fat secondary to metabolic dysregulation represents the end-organ manifestation of a systemic disease that can progress to steatohepatitis, cirrhosis and its feared complications of clinical decompensation and hepatocellular cancer. Since metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent globally, there is a pressing need to augment lifestyle interventions with pharmacotherapies to ameliorate disease burden and reduce adverse liver-related events.

This review summarises current evidence for the utility of incretin mimetics in the MAFLD/MASH arena.

A literature review that encompassed multiple database searches to inform the evidence base for incretin drugs in MAFLD/MASH.

Incretin mimetics demonstrate multifarious benefits across the metabolic diseases spectrum with mounting evidence for their role in remitting steatohepatitis and liver fibrosis. Weight loss and insulin sensitisation contribute, but additional mechanisms may also be engaged. Gastrointestinal adverse effects are common but for most, can be managed while preserving the hepatic and cardiometabolic benefits.

The literature reveals benefits from incretin-based therapies for MASH, but data on whether they improve long-term hepatic outcomes are awaited to support their future incorporation into routine clinical care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease globally. Based on the 2023 definition, MASLD is characterized by the presence of metabolic dysfunction and limited alcohol consumption (<140 grams/week for women, <210 grams/week for men). Given the significant burden of MASLD in Latin America, this guidance was developed by the Latin American Association for the Study of the Liver (ALEH) Working Group to address key aspects of its clinical assessment and therapeutic strategies. In Latin America, ultrasonography is recommended as the initial screening tool for hepatic steatosis due to its accessibility, while Fibrosis-4 (FIB-4) is preferred for fibrosis risk stratification, with further evaluation using more specific techniques (i.e., vibration-controlled transient elastography or Enhanced Liver Fibrosis [ELF] test). A Mediterranean diet is advised for all MASLD patients, with a target of 7-10% weight loss for those with excess weight. Complete alcohol abstinence is recommended for patients with significant fibrosis, and smoking cessation is encouraged regardless of fibrosis stage. Pharmacological options should be tailored based on the presence of steatohepatitis, liver fibrosis, excess weight, and diabetes, including resmetirom, incretin-based therapies, pioglitazone, and sodium-glucose cotransporter-2 inhibitors. Bariatric surgery may be considered for MASLD patients with obesity unresponsive to lifestyle and medical interventions. Hepatocellular carcinoma screening is advised for all cirrhotic patients, with consideration given to those with advanced fibrosis based on individual risk. Finally, routine cardiovascular risk assessment and proper diabetes prevention and management remain crucial for all patients with MASLD.

This review addresses the role of semaglutide (SMG), a GLP-1 receptor agonist, in the treatment of obesity and its related comorbidities. Originally developed for type 2 diabetes (DM2), SMG has shown significant efficacy in weight reduction, with superior results compared to other treatments in the same class. Its effects include appetite suppression, increased satiety, and improvements in cardiovascular, renal, and metabolic parameters. Studies such as SUSTAIN, PIONEER, and STEP highlight its superiority compared to other GLP-1 receptor agonists and anti-obesity drugs. The oral formulation showed promising initial results, with higher doses (50 mg) showing weight losses comparable to those of subcutaneous administration. Despite its benefits, there are challenges, such as weight regain after cessation of treatment, gastrointestinal adverse effects, and variability of response. Future studies should explore strategies to mitigate these effects, identify predictive factors of efficacy, and expand therapeutic indications to other conditions related to obesity and insulin resistance. The constant innovation in this class of drugs reinforces the potential of SMG to transform treatment protocols for chronic weight-related diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Cardiovascular-Renal-Hepatic-Metabolic diseases are on the rise worldwide, creating major challenges for patient care and clinical research. Although these conditions share common mechanisms and often respond to similar treatments-such as lifestyle changes and newer cardiometabolic drugs (e.g., SGLT2 inhibitors, GLP-1 receptor agonists)-clinical management remains divided among multiple specialties. Recently proposed curricula in Cardiometabolic Medicine and Preventive Cardiology reflect an effort to address this fragmentation. In addition, recent studies reveal that hormonal deficiencies may increase cardiovascular risk and worsen heart failure, with emerging data showing that correcting these imbalances can improve exercise capacity and possibly reduce major cardiac events. To overcome gaps in care, we propose a new sub-specialty: Cardiovascular-Endocrine-Metabolic Medicine. This approach unifies three main pillars: (1) Lifestyle medicine, emphasizing nutrition, physical activity, and smoking cessation; (2) the Integrated Medical Management of obesity, diabetes, hypertension, dyslipidemia, heart failure with preserved ejection fraction, early-stage kidney disease, metabolic-associated liver disease, and related conditions; and (3) hormonal therapies, focused on optimizing sex hormones and other endocrine pathways to benefit cardiometabolic health. By bridging cardiology, endocrinology, and metabolic medicine, this sub-specialty offers a more seamless framework for patient care, speeds up the adoption of new treatments, and sets the stage for innovative research-all critical steps in addressing the escalating cardiometabolic pandemic.

MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron-corrected T1 (cT1) of ≥80 ms and relative reduction in liver fat content (LFC) of 30% reflect histological improvement. We aimed to validate the associations of changes to these non-invasive biomarkers with histological improvement, specifically the resolution of steatohepatitis.

We performed a retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and LFC (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders were assessed.

Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and LFC (-65% vs. -29%) in responders compared to non-responders (p <0.001), respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥80 ms reduction in cT1 were 5-fold more likely to achieve histological response (sensitivity 0.68; specificity 0.70). Those achieving a 30% relative reduction in liver fat were ∼4-fold more likely to achieve a histological response (sensitivity 0.77; specificity 0.53).

These results, from a pooled analysis of three drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and LFC) can predict histological response for steatohepatitis following therapeutic intervention.

We investigated the utility of two MRI-derived non-invasive tests, iron-corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for metabolic dysfunction-associated steatohepatitis. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis on histology. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health.

NCT02443116, NCT03976401, NCT03551522.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease, especially in patients with severe obesity. However, current mouse models for MASLD do not reflect the polygenetic background nor the metabolic changes in this population. Therefore, we investigated two novel mouse models of MASLD with a polygenetic background for the metabolic syndrome.

TALLYHO/JngJ mice and NONcNZO10/LtJ mice were fed a high-fat- high-carbohydrate (HF-HC) diet with a surplus of cholesterol diet. A second group of TH mice was additional treated with empagliflozin.

After sixteen weeks of feeding, both strains developed metabolic syndrome with severe obesity and histological manifestation of steatohepatitis, which was associated with significantly increased intrahepatic CD8+cells, CD4+cells and Tregs, contributing to a significant increase in pro-inflammatory and pro-fibrotic gene activation as well as ER stress and oxidative stress. In comparison with the human transcriptomic signature, we could demonstrate a good metabolic similarity, especially for the TH mouse model. Furthermore, TH mice also developed signs of kidney injury as an extrahepatic comorbidity of MASLD. Additional treatment with empagliflozin in TH mice attenuates hepatic steatosis and improves histological manifestation of MASH.

Overall, we have developed two promising new mouse models that are suitable for preclinical studies of MASLD as they recapitulate most of the key features of MASLD.

No therapy has been shown to reduce the risk of major adverse liver outcomes (MALO) in patients with cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH). The Surgical Procedures Eliminate Compensated Cirrhosis In Advancing Long-term (SPECCIAL) observational study compared the effects of metabolic surgery and nonsurgical treatment in patients with obesity and compensated histologically proven MASH-related cirrhosis. Using a doubly robust estimation methodology to balance key baseline characteristics between groups, the time-to-incident MALO was compared between 62 patients (68% female) who underwent metabolic surgery and 106 nonsurgical controls (71% female), with a mean follow-up of 10.0 ± 4.5 years. The 15 year cumulative incidence of MALO was 20.9% (95% confidence interval (CI), 2.5-35.9%) in the surgical group compared with 46.4% (95% CI, 25.6-61.3%) in the nonsurgical group, with an adjusted hazard ratio of 0.28 (95% CI, 0.12-0.64), P = 0.003. The 15 year cumulative incidence of decompensated cirrhosis was 15.6% (95% CI, 0-31.3%) in the surgical group compared with 30.7% (95% CI, 12.9-44.8%) in the nonsurgical group, with an adjusted hazard ratio of 0.20 (95% CI, 0.06-0.68), P = 0.01. Among patients with compensated MASH-related cirrhosis and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MALO. In the absence of approved medical therapies for compensated MASH-related cirrhosis, metabolic surgery may represent a safe and effective therapeutic option to influence the trajectory of cirrhosis.

To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, separately, compared with dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with a reduced risk of cirrhosis and other adverse liver outcomes among patients with type 2 diabetes.

With an active comparator, new-user approach, we conducted a cohort study using the U.K. Clinical Practice Research Datalink linked with hospital and national statistics databases. Cox proportional hazards models using propensity score fine stratification weighting were used to calculate hazard ratios (HRs) and 95% CIs for cirrhosis (primary outcome) and decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality (secondary outcomes).

In the first cohort comparing 25,516 patients starting GLP-1RAs and 186,752 starting DPP-4 inhibitors, GLP-1RAs were not associated with the incidence of cirrhosis (HR 0.90, 95% CI 0.68-1.19) or the secondary outcomes. In a separate cohort comparing 33,161 patients starting SGLT-2 inhibitors and 124,431 starting DPP-4 inhibitors, SGLT-2 inhibitors were associated with a reduced incidence of cirrhosis (HR 0.64, 95% CI 0.46-0.90), as also decompensated cirrhosis (HR 0.74, 95% CI 0.54-1.00), but not with a lower risk of hepatocellular carcinoma or liver-related mortality.

In patients with type 2 diabetes in the U.K., GLP-1RAs were not associated with a lower risk of cirrhosis compared with DPP-4 inhibitors in patients with type 2 diabetes. However, SGLT-2 inhibitors were associated with a lower risk of cirrhosis compared with DPP-4 inhibitors.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) or glucagon receptor agonists have emerged as promising agents to treat metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Although the beneficial effects of GLP-1RAs on glycemic control and weight are well-established, clinicians may be unfamiliar with other potential benefits of this class.

We examined the pleiotropic effects of GLP-1RAs and how they relate to gastroenterologists for MASLD/MASH treatment. Our narrative review of English articles included four GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide, and efpeglenatide), a dual GLP-1/GIP agonist (tirzepatide), a dual GLP-1/glucagon receptor agonist (survodutide), MASLD/MASH, related disorders, clinical management, treatment outcomes and landscape.

In Phase I - III trials, GLP-1RAs are associated with clinically relevant hepatic improvements including MASH resolution, liver fat reduction, and preventing worsening fibrosis. Effects on cardiometabolic parameters align with type 2 diabetes/obesity Phase III data, comprising substantial improvements in glycemic, weight, and cardiovascular outcomes. Promising data also suggest benefits in common comorbidities, including obstructive sleep apnea, polycystic ovary syndrome, chronic kidney disease, and heart failure with preserved ejection fraction.GLP-1RAs represent a valuable pharmacotherapeutic option for gastroenterologists managing individuals with MASLD/MASH and cardiometabolic comorbid conditions.

With a steadily rising prevalence, nonalcoholic fatty liver disease (NAFLD) was a leading global cause of liver-related health problems. In the clinical management of NAFLD, various western pharmaceuticals were widely utilized. This network meta-analysis aimed to evaluate the effectiveness of common western medications for NAFLD patients.

We systematically reviewed and screened articles based on predesigned criterion about western medications for NAFLD, which were from Embase, Cochrane Library, PubMed, CNKI, WanFang, and China Science and Technology Journal Database until August 1, 2024. Eligible studies included randomized controlled trials of patients aged 18 or older with NAFLD, comparing Western medicines to placebos or other Western medicine treatments. The risk of bias assessment tool 2.0 from the Cochrane system was used to assess the quality of the included articles. A Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 with a random-effects model and Markov Chain Monte Carlo methods. Treatment rankings were based on Surface Under the Cumulative Ranking Curve (SUCRA) values, and heterogeneity was assessed with I2 and Q statistics. The outcomes were analyzed in WinBUGS and visualized using Stata 14.0, generating network plots and cumulative probability rankings to compare treatment effects. The systematic review was registered in PROSPERO (CRD42024509176).

Based on 37 included articles involving 7673 patients, pioglitazone demonstrated the most significant effects in resolving nonalcoholic steatohepatitis without worsening fibrosis, increasing high-density lipoprotein cholesterol levels, and achieving a ≥ 2-point reduction in NAFLD activity scores (odds ratio [OR] = 0.09, 95% confidence interval [CI]: 0.01 to 0.81), with a SUCRA probability of 91.4%. Aldafermin showed remarkable effects in improving liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase, with cumulative probabilities of 90% for ALT and 69.8% for AST. Cluster analysis revealed that Resmetirom and Aldafermin were superior options for enhancing liver function, while pioglitazone emerged as the best treatment for the comprehensive improvement of NAFLD.

Pioglitazone outperformed other western medicines in terms of overall efficacy when treating NAFLD, but Aldafermin and Resmetirom showed superior improvement in liver function. This study provided a certain level of support for the use of specific clinical medications.

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one-fourth of the global adult population and is the leading cause of liver disease worldwide. To address this, the Asian Pacific Association for the Study of the Liver (APASL) has created clinical practice guidelines focused on MAFLD. The guidelines cover various aspects of the disease, such as its epidemiology, diagnosis, screening, assessment, and treatment. The guidelines aim to advance clinical practice, knowledge, and research on MAFLD, particularly in special groups. The guidelines are designed to advance clinical practice, to provide evidence-based recommendations to assist healthcare stakeholders in decision-making and to improve patient care and disease awareness. The guidelines take into account the burden of clinical management for the healthcare sector.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing global health problem linked to obesity, insulin resistance, and dyslipidemia. MASLD often leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, therapeutic options are limited, emphasizing the need for novel, targeted pharmacological interventions. Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, offers a promising approach by specifically enhancing hepatic metabolism while minimizing systemic effects. Clinical trials have demonstrated its capacity to reduce hepatic triglyceride accumulation and improve lipid profiles. Early- and advanced-phase studies, including the MAESTRO program, highlight significant reductions in hepatic fat content and favorable impacts on noninvasive biomarkers of fibrosis with minimal side effects. This review highlights evidence from pivotal studies, explores resmetirom's mechanism of action, and compares its efficacy and safety with other emerging therapeutic agents. While resmetirom marks a breakthrough in non-cirrhotic MASH management, further long-term studies are essential to fully evaluate its clinical benefits and potential regulatory approval for broader use in MASLD and MASH.

Semaglutide is highly effective for decreasing weight. Concomitant loss of muscle mass often accompanies weight loss and may have consequences on muscle function.

This is a secondary analysis from the SLIM LIVER (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, ACTG A5371) study, a single-arm study of semaglutide in people with human immunodeficiency virus (HIV, PWH) with metabolic dysfunction-associated steatotic liver diseases (MASLD). Participants received subcutaneous semaglutide for 24 weeks (titrated to 1 mg/week by week 4). Psoas volume and fat fraction were assessed from liver magnetic resonance imaging, and physical function was assessed by 10-time chair rise test and 4 m gait speed. Mean change from baseline to week 24 was estimated with linear regression modeling.

Fifty-one PWH were enrolled (muscle measures n = 46). The mean age was 50 years (standard deviation, 11), body mass index was 35.5 kg/m2 (5.6), 43% were women, 33% Black, and 39% Hispanic/Latino. Psoas muscle volume decreased by 9.3% (95% confidence interval [CI]: -13.4 to -5.2; P < .001) over 24 weeks, but psoas muscle fat did not significantly change (-0.42%; 95% CI: -1.00 to .17; P = .16). Chair rise and gait speed showed nonsignificant improvements of 1.27 seconds (95% CI: -2.7 to .10) and 0.05 m/sec (95% CI: -.01 to .10), respectively (both P > .07). The prevalence of slow gait speed (<1 m/sec) decreased from 63% to 46% (P = .029).

In PWH receiving semaglutide for MASLD, despite decreased psoas muscle volume, there was no significant change in physical function, suggesting function was maintained despite significant loss of muscle.

NCT04216589.

Metabolic dysfunction-associated steatotic liver disease, a prevalent chronic liver condition, can cause severe complications like hepatitis, cirrhosis, and hepatocellular carcinoma. In recent years, glucagon-like peptide-1 receptor agonists (GLP - 1RA) have shown unique therapeutic advantages and may become a preferred treatment for it. This meta-analysis aims to systematically examine GLP-1RA associated adverse events, providing a basis for guiding patient clinical management.

We conducted a search for randomized controlled trials (RCTs) investigating the therapeutic effects of GLP-1RA in the treatment of metabolic dysfunction-associated steatotic liver disease across four databases: PubMed, Embase, Web of Science, and Cochrane Library. The search period extended from the inception of each database until December 2023. Information pertaining to various adverse events was collected as outcome measures. Statistical analysis of the results and assessment of bias risk were conducted utilizing Review Manager (version 5.4.1) software.

An analysis of 10 studies encompassing 960 participants revealed a significantly higher overall incidence of adverse events in the GLP-1RA group compared to the control group (OR: 2.40 [1.10, 5.26], P = 0.03). Subgroup analysis based on treatment duration demonstrated a higher rate of adverse events in the GLP-1RA group during follow-ups of less than 30 weeks (P = 0.0005, OR: 3.58 [1.75, 7.32]), but no statistical difference was observed between the two groups in follow-ups exceeding 30 weeks. There was no statistically significant difference between the two groups in adverse events leading to discontinuation (P = 0.29, OR: 1.47 [0.72, 2.98]). However, a notable difference was observed in gastrointestinal adverse events (P < 0.00001, OR: 4.83 [3.36, 6.95]).

GLP-1RA exhibits an overall higher incidence of adverse events in the treatment of metabolic dysfunction-associated steatotic liver disease, particularly in the gastrointestinal domain. Short-term use of GLP-1RA may be associated with a greater occurrence of adverse events, underscoring the importance of educating patients on preventive measures and establishing tolerance. However, there was no statistically significant difference between the two groups in severe adverse events and adverse events leading to discontinuation, confirming the safety profile of GLP-1RA application.

Μetabolic dysfunction-associated steatotic liver disease (MASLD) comprises a heterogeneous condition in the presence of steatotic liver. There can be a hierarchy of metabolic risk factors contributing to the severity of metabolic dysfunction and, thereby, the associated risk of both liver and extrahepatic outcomes, but the precise ranking and combination of metabolic syndrome (MetS) traits that convey the highest risk of major adverse liver outcomes and extrahepatic disease complications remains uncertain. Insulin resistance, low-grade inflammation, atherogenic dyslipidaemia and hypertension are key to the mechanisms of liver and extrahepatic complications. The liver is pivotal in MetS progression as it regulates lipoprotein metabolism and secretes substances that affect insulin sensitivity and inflammation. MASLD affects the kidneys, heart and the vascular system, contributing to hypertension and oxidative stress. To address the global health burden of MASLD, intensified by obesity and type 2 diabetes mellitus epidemics, a holistic, multidisciplinary approach is essential. This approach should focus on both liver disease management and cardiometabolic risk factors. This Review examines the link between metabolic dysfunction and liver dysfunction and extrahepatic disease outcomes, the diverse mechanisms in MASLD due to metabolic dysfunction, and a comprehensive, personalized management model for patients with MASLD.

Semaglutide exerts metabolic effects and cardiovascular protection in type 2 diabetes (T2D), also acting on hepatic steatosis and inflammation. No data are, so far, available on the effect of semaglutide on oxidative stress, neither a comparison of injective (InjS) and oral (OrS) formulations has been performed in subjects with T2D and liver steatosis.

In a real-life, open label, prospective study we compared standard doses of InjS and OrS in targeting liver inflammation and fibrosis and systemic markers of inflammation and oxidative stress by consecutively prescribing InjS or OrS formulation in a 2:1 ratio to sixty T2D + MASLD subjects (T0), observing them for 6 months (T1). Anthropometry, biochemistry and transient elastography (TE) data were collected; hormones, inflammatory cytokines and peroxidation products were measured.

At baseline, InjS and OrS subjects were similar, except for waist circumference, liver enzymes and Controlled Attenuation Parameter (CAP), a measure of liver steatosis (InjS > OrS, all p < 0.05). Differences emerged in T0-T1 variation between the formulations in HbA1c, lipid profile, blood pressure. CAP significantly decreased only in InjS. GLP-1 quite similarly increased; insulin, glucagon and GIP did not vary. InjS and OrS did not modify TNFα, IL-10 (an anti-inflammatory cytokine) and MCP-1, while IL-18 was reduced only by InjS. When exploring oxidative stress, AGEs were unaffected, Thiobarbituric acid reactive substances decreased in InjS, 4-Hydroxynonenal was reduced in OrS.

In T2D + MASLD subjects, InjS, better than OrS, improves metabolic control; a significant reduction of IL-18 by InjS, and a mild anti-oxidative effect of both formulations are reported for the first time.

Obesity and type 2 diabetes mellitus (T2DM) are significant global health challenges, closely linked to metabolic dysfunction-associated steatotic liver disease (MASLD). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in treating T2DM and obesity, but their potential for managing MASLD is still being explored. This review aims to examine the current progress in using GLP-1RAs for MASLD treatment and evaluate emerging dual and triple hormonal agonists as future therapeutic options.

GLP-1RAs have been effective in controlling blood sugar levels, promoting weight loss, and improving cardiovascular and kidney function. Furthermore, they have shown potential benefits for liver function in patients with MASLD. GLP-1, a key incretin hormone, influences glucose metabolism, appetite, and insulin sensitivity while affecting gastric emptying and potentially reducing fat deposition in the liver. Recent developments in GLP-1RAs include various formulations with different administration and dosing options, expanding their therapeutic use.

GLP-1RAs have become central to the management of T2DM, obesity, and possibly MASLD due to their ability to lower HbA1c, aid in weight reduction, and provide cardiovascular protection. As research continues, dual and triple hormonal agonists are emerging as the next evolution of incretin-based therapies, offering promising new strategies for addressing MASLD in the future.

This systematic review and meta-analysis evaluated the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on hepatocellular carcinoma (HCC) and liver decompensation in patients with type 2 diabetes. Analysing over 641,377 patients, GLP-1RA use was associated with a significant 58% reduction in HCC risk, particularly in patients with cirrhotis. While a trend towards reduced liver decompensation risk was observed, it was not statistically significant. These findings suggest a potential role for GLP-1RAs in HCC risk stratification and prevention strategies.

Identification of exendin-4 (a glucagon-like peptide 1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases. One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes. We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a progressive liver disease frequently associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity, has the potential to progress symptomatically to liver cirrhosis and, in some cases, hepatocellular carcinoma. Hence, an urgent need arises to identify and approve new therapeutic options to improve patient outcomes. Research efforts have focused on either developing dedicated molecules or repurposing drugs already approved for other conditions, such as metabolic diseases. Among the latter, antidiabetic and anti-obesity agents have received the most extensive attention, with pivotal trial results anticipated shortly. However, the primary focus underlying successful regulatory approvals is demonstrating a substantial efficacy in improving liver fibrosis and preventing or ameliorating cirrhosis, the key advanced outcomes within MASLD progression. Besides liver steatosis, the ideal therapeutic candidate should reduce inflammation and fibrosis effectively. Although some agents have shown promise in lowering MASLD-related parameters, evidence of their impact on fibrosis and cirrhosis remains limited. This review aims to evaluate whether antidiabetic and anti-obesity drugs can be safely and effectively used in MASLD-related advanced fibrosis or cirrhosis in patients with T2DM. Our paper discusses the molecules closest to regulatory approval and the expectation that they can address the unmet needs of this increasingly prevalent disease.

Clinically effective pharmacological treatment(s) for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) represent a largely unmet need in medicine. Since glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been licensed for the treatment of type 2 diabetes mellitus and obesity, they were one of the first drug classes to be examined in individuals with MASLD/MASH. Successful phase 2 randomised clinical trials with these agents have resulted in progression to phase 3 clinical trials (principally testing the long-term efficacy of subcutaneous semaglutide). Over the last few years, in addition to GLP-1RAs, newer agents with glucose-dependent insulinotropic peptide and/or glucagon receptor agonist functions have been tested, with increasing evidence from phase 2 randomised clinical trials of histological improvements in MASLD/MASH, as well as benefits on MASLD-related extrahepatic complications. Based on this background of evidence, single, dual or triple incretin receptor agonists are becoming an attractive and promising treatment option for MASLD or MASH, particularly in individuals with coexisting obesity or type 2 diabetes mellitus. In this narrative review, we examine the rapidly expanding body of clinical evidence supporting a role of incretin-based pharmacotherapies in delaying or reversing MASH progression. We also discuss the biology of incretins and the putative hepatoprotective mechanisms of incretin-based pharmacotherapies for managing MASLD or MASH.

The prognosis of patients with decompensated cirrhosis is poor, with significantly increased liver-related mortality rates. With the rising tide of decompensated cirrhosis associated with metabolic dysfunction-associated steatotic liver disease (MASLD), the role of metabolic bariatric surgery (MBS) in achieving hepatic recompensation is garnering increasing attention. However, the complexity of preoperative assessment, the risk of postoperative disease recurrence, and the potential for patients to experience surgical complications of the MBS present challenges. In this opinion article we analyze the potential of MBS to induce recompensation in MASLD-related cirrhosis, discuss the mechanisms by which MBS may affect recompensation, and compare the characteristics of different MBS procedures; we highlight the therapeutic potential of MBS in MASLD-related cirrhosis recompensation and advocate for research in this complex area.

Weight loss mediated by glucagon-like peptide-1 (GLP-1) analogues is lower in patients with type 2 diabetes versus those without. Type 2 diabetes and obesity are risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD) and associated steatohepatitis (MASH). We evaluated weight changes in adults with MASLD/MASH with or without type 2 diabetes receiving the GLP-1 analogue semaglutide.

This was a post hoc analysis of data from three 48-72-week randomised trials investigating the effect of semaglutide versus placebo in adults with MASLD (NCT03357380) or biopsy-confirmed MASH (NCT02970942 and NCT03987451). Pooled data for semaglutide (0.4 mg once daily and 2.4 mg once weekly [n = 163]) and placebo (n = 137) were analysed at 1 year. Weight changes were analysed by type 2 diabetes status (type 2 diabetes [n = 209], pre-type 2 diabetes [n = 51] and no diabetes [n = 40]) and by other cardiometabolic risk parameters using analysis of covariance and Spearman's rank correlations.

The overall mean weight change was -11.1 kg (-11.7%) and -0.7 kg (-0.6%) with semaglutide and placebo, respectively. While numerically higher for people without type 2 diabetes, estimated treatment differences with semaglutide versus placebo were similar overall for people with type 2 diabetes (-10.2 kg; -10.8%), pre-type 2 diabetes (-9.8 kg; -10.2%) and no diabetes (-11.6 kg; -13.1%). Differences between groups were not statistically significant (p > 0.50 for all). Baseline fasting plasma glucose, glycated haemoglobin, insulin levels, insulin resistance and lipids did not correlate with weight change.

People with MASLD/MASH had similar semaglutide-mediated weight loss regardless of type 2 diabetes status and other cardiometabolic risk parameters.

We assessed the global incidence, mortality, and disability-adjusted life years (DALYs) associated with various liver diseases, including alcohol-related liver disease (ALD), hepatitis B/C virus infections (HBV or HCV), liver cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), and other chronic liver diseases, from the 2019 Global Burden of Disease study. Additionally, we analyzed the global trends in hepatology research and drug development. From 2000 to 2019, prevalence rates increased for ALD, MASLD and other liver diseases, while they decreased for HBV, HCV, and liver cancer. Countries with a high socio-demographic index (SDI) exhibited the lowest mortality rates and DALYs. The burden of liver diseases varied due to factors like sex and region. In nine representative countries, MASLD, along with hepatobiliary cancer, showed highest increase in funding in hepatology research. Globally, the major research categories in hepatology papers from 2000 to 2019 were cancer, pathobiology, and MASLD. The United States (U.S.) was at the forefront of hepatology research, with China gradually increasing its influence over time. Hepatologists worldwide are increasingly focusing on studying the communication between the liver and other organs, while underestimating the research on ALD. Cancer, HCV, and MASLD were the primary diseases targeted for therapeutic development in clinical trials. However, the proportion of new drugs approved for the treatment of liver diseases was relatively low among all newly approved drugs in the U.S., China, Japan, and the European Union. Notably, there were no approved drug for the treatment of ALD in the world.

The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of cardiometabolic diseases, extending their therapeutic applications far beyond glycemic control in type 2 diabetes (T2D) and obesity. This editorial synthesizes key milestones, from the discovery of GLP-1 to recent clinical trials highlighting the pleiotropic effects of GLP-1RAs in addressing the interconnected spectrum of cardiometabolic conditions, with a focus on cardiovascular, renal, and hepatic benefits. In addition, as GLP-1RAs continue to reshape the management of cardiometabolic disease and global public health, we discuss future challenges to better elucidate their mechanisms of cardiometabolic protection and maximize their therapeutic potential.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

Metabolic dysfunction-associated steatotic liver disease (MASLD) covers a broad spectrum of profile from simple fatty liver, evolving to metabolic dysfunction-associated steatohepatitis (MASH), to hepatic fibrosis, further progressing to cirrhosis and hepatocellular carcinoma (HCC). MASLD has become a prevalent disease with 25% in average over the world. MASH is an active stage, and requires pharmacological intervention when there is necroptotic damage with fibrotic progression. Although there is an increased understanding of MASH pathogenesis and newly approved resmetirom, given its complexity and heterogeneous pathophysiology, there is a strong necessity to develop more drug candidates with better therapeutic efficacy and well-tolerated safety profile. With an increased list of pharmaceutical candidates in the pipeline, it is anticipated to witness successful approval of more potential candidates in this fast-evolving field, thereby offering different categories of medications for selective patient populations. In this review, we update the advances in MASH pharmacotherapeutics that have completed phase II or III clinical trials with potential application in clinical practice during the latest 2 years, focusing on effectiveness and safety issues. The overview of fast-evolving status of pharmacotherapeutic candidates for MASH treatment confers deep insights into the key issues, such as molecular targets, endpoint selection and validation, clinical trial design and execution, interaction with drug administration authority, real-world data feedback and further adjustment in clinical application.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, characterized by hepatic steatosis with at least one cardiometabolic risk factor. Patients with MASLD are at increased risk for the occurrence of cardiovascular events. Within this review article, we aimed to provide an update on the pathophysiology of MASLD, its interplay with cardiovascular disease, and current treatment strategies.

Given their high burden of cardiovascular comorbidities, patients with MASLD or MASH should undergo regular cardiovascular risk assessment using established risk models. In the absence of liver-specific therapies, therapeutic strategies should focus on improving cardiometabolic risk factors. Patients require a multimodal and multi-stakeholder treatment approach, including optimization of lifestyle, dysglycemia, obesity, and dyslipidemia. Statin treatment represents a safe and effective but often underused therapy in the management of at-risk patients with MASLD and MASH. Novel promising approaches include the use of GLP-1 receptor agonists, especially in, but not limited to, patients with cardiovascular disease and obesity. Patients with MASLD and MASH are at high cardiovascular risk requiring a multi-modal therapeutic approach including regular cardiovascular risk assessment, as well as lifestyle and pharmacological interventions. Statin therapy represents an inexpensive, safe and effective therapy across the spectrum of non-alcohol related steatotic liver diseases without major safety concerns. More prospective, randomized trials in patients with MASLD and MASH are needed.

Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.

Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To preliminarily explore the molecular mechanisms of tirzepatide on metabolic dysfunction-associated fatty liver disease (MAFLD), liquid chromatography-mass spectrometry (LC-MS) was employed for comprehensive metabolomic, lipidomic, and proteomic analyses in MAFLD mice fed a high-fat diet (HFD). The results demonstrated that tirzepatide significantly reduced serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as hepatic triglycerides (TG) and total cholesterol (TC), indicating its efficacy in treating MAFLD. Further findings revealed that tirzepatide reduced fatty acid uptake by downregulating Cd36 and Fabp2/4, as well as enhance the mitochondrial-lysosomal function by upregulating Lamp1/2. In addition, tirzepatide promoted cholesterol efflux and reduced cholesterol reabsorption by upregulating the expression of Hnf4a, Abcg5, and Abcg8. These results suggest that tirzepatide exerts its therapeutic effects on MAFLD by reducing fatty acid uptake, promoting cholesterol excretion, and enhancing mitochondrial-lysosomal function, providing a theoretical basis for a comprehensive understanding of tirzepatide.

Non-alcoholic fatty liver disease (NAFLD) is a multisystem metabolic disorder, marked by abnormal lipid accumulation and intricate inter-organ interactions, which contribute to systemic metabolic imbalances. NAFLD may progress through several stages, including simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and potentially liver cancer. This disease is closely associated with metabolic disorders driven by overnutrition, with key pathological processes including lipid dysregulation, impaired lipid autophagy, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and local inflammation. While hepatic lipid metabolism in NAFLD is well-documented, further research into inter-organ communication mechanisms is crucial for a deeper understanding of NAFLD progression. This review delves into intrahepatic networks and tissue-specific signaling mediators involved in NAFLD pathogenesis, emphasizing their impact on distal organs.

The association between hypopituitarism and metabolic dysfunction-associated steatotic liver disease is increasingly recognized, although data about therapies targeting recurrence posttransplant is limited. An 8-year-old with hypopituitarism-associated metabolic dysfunction-associated steatotic liver disease underwent a liver transplant due to rapid progression of metabolic dysfunction-associated steatohepatitis. Hepatosteatosis recurred within weeks. Her therapeutic plan included a glucagon-like peptide-1 agonist and growth hormone replacement. Her transaminases normalized in 2.5 months, and her macrosteatosis significantly improved on the 1-year surveillance biopsy. This case highlights one of the youngest reported children with hypopituitarism to have undergone transplantation for rapidly progressing metabolic dysfunction-associated steatohepatitis and its recurrence post-operatively. We observed that steatosis improved with growth hormone replacement and glucagon-like peptide-1 agonist therapy. If started early, this combination could help delay recurrence of steatosis post-transplantation. Further research is needed to determine long-term effects and establish protocols.

Type 2 diabetes mellitus (T2DM) is intrinsically linked to various etiologies of liver disease, with 69% of patients having concomitant metabolic dysfunction-associated steatotic liver disease (MASLD). Studies suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorating liver disease. With this analysis, we address the gap in knowledge about the effectiveness of these agents in preventing different major adverse liver outcomes (MALOs).

PubMed, Embase, and The Cochrane Central of Trials were searched for articles reporting MALOs in T2DM patients. Publication bias-identifying methods, quality assessment and sensitivity analyses (subgroup analyses, leave-one-out meta-analyses, and meta-regression) were employed. Statistical analyses were performed in R using the "meta" and "metafor" packages.

Nine cohort studies from 535 identified articles encompassing 579 256 T2DM patients were included in the main analyses. GLP-1RA use was associated with reduced risks of hepatocellular carcinoma (HR 0.74, 95% CI 0.56-0.96) and cirrhosis decompensation (HR 0.68, 95% CI 0.65-0.72). Within the latter, variceal bleeding and hepatic encephalopathy prevention were found to be significantly reduced. Egger's test, Begg's test, and funnel-plot analysis yielded no publication bias. No significant differences were observed in preventing cirrhosis or hepatic failure. Meta-regression analysis revealed a positive correlation between hepatocellular carcinoma incidence and both male sex and longer follow-up duration.

This meta-analysis improves our understanding of the hepatoprotective effects of GLP-1RAs in T2DM patients and supports existing research, exhibiting superiority over other antidiabetic medications for hepatoprotection in this subgroup. Additional long-term follow-up studies are necessary to further validate these findings.

Pediatric obesity, characterized by a body mass index (BMI) at or above the 95th percentile for age, affects a substantial number of children and adolescents worldwide. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, represents a prominent hepatic manifestation of obesity and metabolic syndrome, emerging as the most prevalent hepatic disorder among pediatric patients and a significant contributor to liver transplantation in adults. The escalating prevalence of pediatric MASLD mirrors the alarming rise in childhood obesity rates over recent decades. While lifestyle modifications focusing on dietary changes and increased physical activity constitute the cornerstone of MASLD management, achieving and maintaining significant weight reduction remains challenging. Moreover, disease progression often persists despite standard-of-care interventions, warranting exploration into alternative therapeutic strategies. Pharmacological interventions, particularly, glucagon-like peptide-1 receptor agonists (GLP-1RA), have shown promise in addressing pediatric obesity and its associated comorbidities, including MASLD. Recent studies have demonstrated the efficacy of GLP-1RA in inducing weight loss and improving liver enzyme levels, suggesting a potential role in halting disease progression, and reducing the risk of major adverse liver outcomes. This review provides a comprehensive overview of the current pharmacotherapy landscape for pediatric MASLD, with a focus on novel agents such as GLP-1RA. Furthermore, the manuscript proposes a practical algorithm to assist in integrating GLP-1RA into the clinical management of pediatric patients with obesity and MASLD. Despite promising results, further research is warranted to elucidate the long-term efficacy and safety of GLP-1RA in pediatric populations.