Metabolic-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition associated with significant morbidity and mortality. Effective pharmacological interventions targeting liver steatosis and fibrosis are essential to improving patient outcomes. This study aims to systematically compare the efficacy and safety of various pharmacologic therapies for MASLD over 24 weeks using a comprehensive network meta-analysis.

A systematic review and network meta-analysis were conducted on randomized controlled trials (RCTs) evaluating pharmacologic treatments for MASLD. The primary outcomes were changes in liver steatosis (measured by magnetic resonance imaging proton density fat fraction) and fibrosis (measured by magnetic resonance elastography-derived liver stiffness measurement), with safety assessed through adverse events. A Bayesian framework was employed to integrate and compare data across treatments, generating rankings for efficacy and safety.

A systematic search was conducted across databases, identifying 23 RCTs from 10 144 initial records. For steatosis reduction, resmetirom showed the most significant improvement (mean difference: -3.86, 95% confidence interval [CI]: -7.33 to -0.39) compared with placebo. In terms of fibrosis improvement, pegozafermin demonstrated the greatest effect (-4.85, 95% CI: -5.50 to -4.19). Most treatments showed acceptable safety profiles, with efruxifermin showing slightly higher adverse events (0.32, 95% CI: 0.06-0.70) compared with placebo.

This comprehensive network meta-analysis demonstrates the varying efficacy of pharmacologic interventions for MASLD, with resmetirom and pegozafermin emerging as particularly promising treatments for steatosis and fibrosis, respectively. While most treatments exhibited favourable safety profiles, careful monitoring is warranted, particularly with efruxifermin due to its slightly elevated adverse event profile. These findings provide valuable evidence to guide clinical decision-making in MASLD management, though longer-term studies are needed to confirm the durability of these therapeutic effects and further establish safety profiles.

Obesity is associated with an increased cardiovascular risk. Drugs with glucagon-like peptide-1 receptor agonist (arGLP-1) action for overweight/obesity, such as liraglutide, semaglutide, and tirzepatide, have shown improvements in weight and body composition, as well as in parameters related to glucose metabolism, hypertension, dyslipidemia (reduction of triglycerides and increase in HDL cholesterol), and metabolic dysfunction-associated steatotic liver disease. Additionally, semaglutide 2.4mg sc has shown a reduction in cardiovascular mortality, non-fatal myocardial infarction or stroke, and symptoms of heart failure, while tirzepatide has demonstrated a reduction in cardiovascular mortality and heart failure symptoms in patients with obesity and heart failure. The availability of these new drugs with arGLP-1 action represents a paradigm shift in the treatment of obesity, as they achieve greater weight loss and improvements in cardiometabolic comorbidities.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated long-term liver benefits in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). However, no direct comparison between these therapies has been conducted. This study aimed to compare major adverse liver outcomes (MALOs) between GLP-1 RAs and SGLT2is in patients with MASLD and T2D.

Using the TriNetX Research Network, a multinational and multi-institutional database, we identified adults with MASLD and T2D who received their first prescription for either a GLP-1 RA or an SGLT2i between January 2010 and June 2023. We conducted a propensity score-matched (PSM) cohort study comparing new users of GLP-1 RAs and SGLT2is. The primary outcome was the risk of MALOs, a composite endpoint consisting of decompensated cirrhosis events, hepatocellular carcinoma, and liver transplantation. Secondary outcomes included all-cause mortality and individual components of the primary outcome.

This study included 15,176 pairs of patients treated with either a GLP-1 RA or a SGLT2i. The adjusted hazard ratio (HR) for MALO associated with GLP-1 RAs relative to SGLT2is was 0.84 (95% confidence interval [CI]: 0.73-0.97; incidence rate: 88.9 versus 105.3 events per 10,000 person-years), primarily driven by reduction in decompensated cirrhosis events (adjusted HR: 0.83, 95% CI: 0.71-0.96). GLP-1 RAs were associated with lower all-cause mortality (adjusted HR: 0.84, 95% CI: 0.75-0.94).

GLP-1 RAs are associated with better long-term liver outcomes compared to SGLT2is in patients with MASLD and T2D.

Quantitative magnetic resonance imaging metrics iron-corrected T1 (cT1) and liver fat from proton density fat-fraction (PDFF) are both commonly used as noninvasive biomarkers for metabolic dysfunction-associated steatohepatitis (MASH); however, their repeatability in this population has rarely been characterized.

To quantify the variability of cT1 and liver fat fraction from PDFF in patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH.

Prospective, single center.

Twenty-one participants (female = 11, mean age 53 ± 24 years) with biopsy-confirmed MASLD, including 6 with MASH and fibrosis ≥2.

3 T; T1 and T2* mapping for the generation of cT1 (shMOLLI: CardioMaps and 2D MDE, T1map-FIESTA and LMS MOST: StarMap, 2D Multi-Echo FSPGR) and magnitude-only PDFF sequence for liver fat quantification (LMS IDEAL: StarMap, 2D Multi-Echo FSPGR).

T1 mapping and PDFF scans were performed twice on the same day for all participants (N = 21), with an additional scan 2-4 weeks later for MASH patients with fibrosis ≥2 (N = 6). Whole liver segmentation masks were generated semi-automatically and average pixel counts within these masks were used for the calculation of cT1 and liver fat fraction.

Bland-Altman analysis for repeatability coefficient (RC) and 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC).

Same-day RC was 32.1 msec (95% LOA: -36.6 to 24.2 msec) for cT1 and 0.6% (95% LOA: -0.5% to 0.7%) for liver fat fraction; the ICCs were 0.98 (0.96-0.99) and 1.0, respectively. Short-term RC was 65.2 msec (95% LOA: -63.8 to 76.5 msec) for cT1 and 2.6% (95% LOA: -2.8% to 3.1%) for liver fat fraction.

In participants with MASLD and MASH, cT1 and liver fat fraction measurements show excellent test-retest repeatability, supporting their use in monitoring MASLD and MASH.

2 TECHNICAL EFFICACY: Stage 2.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease that is heterogenous in nature with various drivers and modifiers such as metabolic dysfunction and genetic factors. MASLD and the progressive subtype, metabolic dysfunction-associated steatohepatitis (MASH) represent the most rapidly increasing cause of liver-related mortality. There are limited treatment options for patients living with MASLD and MASH, various treatments with an array of different targets are under investigation and one therapeutic has been approved since the initiation of this study. Clinical trials investigating treatments for MASLD and MASH are associated with a high screen failure rate, driven largely by the regulatory required histological inclusion criteria for clinical trial eligibility. Other available clinically utilized biomarkers, typically referred to as non-invasive tests (NITs), can assess both the presence of steatosis and the severity of liver fibrosis in patients with MASLD and MASH in the clinic but are not yet approved over histological changes as endpoints for pivotal trials. However, the use of NITs have been demonstrated to increase the likelihood of meeting clinical trial entry criteria. All-Liver Interventional Global Network (ALIGN) is the first described multi-centre global observational screening study aimed at identifying individuals with a high likelihood of MASLD/MASH interested in participating in therapeutic clinical trials using non-invasive methodologies and genetic testing. This study represents a valuable prototype for industry and academic groups looking to evaluate large populations for MASH eligibility and interest in clinical trial participation.

Non-alcoholic fatty liver disease (NAFLD) is common, can progress to cirrhosis and hepatic decompensation, and has no approved medical therapy in Canada.

We conducted a systematic review on whether glucagon-like peptide-1 receptor agonists (GLP-1RA) improve non-alcoholic steatohepatitis (NASH) compared to standard care in NAFLD.

We searched Medline Ovid, EMBASE(Elsevier), Cochrane CENTRAL, Clinical Trials.gov, and the World Health Organization International Clinical Trials Registry Platform in November 2023 for randomized controlled trials. Inclusion criteria included patients ≥13 years with NAFLD receiving GLP-1RA for ≥6 months compared to standard care/placebo. Cochrane risk-of-bias 2.0 tool was used for each outcome. After screening results in duplicate, we performed meta-analysis and reported odds ratios (OR) for dichotomous and mean difference of change score for continuous outcomes.

Six studies with 478 patients met inclusion criteria; 3 studies reported on the primary endpoint resolution of NASH. GLP-1RA likely leads to resolution of NASH (OR 4.45 (95% CI 1.92, 10.3)) and reduction in liver steatosis on imaging (-5.09% (95% CI -7.49, -2.69), but little to no reduction in liver stiffness on imaging (mean difference -0.17 kPa (95% CI -0.34, 0)).

Treatment with GLP-1RA in NAFLD patients for ≥6 months can probably lead to improvement in NASH on liver biopsy and reduce liver steatosis on imaging. Whether improvements in steatosis on biopsy or imaging results in clinically significant outcomes need to be elucidated as the effects of GLP-1RA on liver fibrosis are unclear; larger ongoing trials may provide more definitive answers. Protocol Registration: PROSPERO-CRD42023472186.

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.

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is increasing at an alarming rate. To date, only one therapy has been provisionally approved for the treatment of MASH and liver fibrosis, and novel strategies are urgently needed. In addition, the frequent coexistence of MASH and type 2 diabetes has further intensified interest in devising comprehensive therapies to simultaneously tackle both diseases. We have recently shown that increasing hepatic and/or circulating levels of hexosaminidase A (HEXA), a lysosomal enzyme that remodels GM2 to GM3 gangliosides within lipid rafts, offers therapeutic benefits for metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Taking advantage of the MUP-uPA mouse model of MASH, including both wild-type (WT) mice with mild MASH and MUP-uPA mice with severe MASH and fibrosis, we show that biweekly treatment with a long-lasting HEXA-FC analog improves features of MASLD, including hepatic steatosis and hepatocyte ballooning, in mice with mild MASH, as well as glycemic control across both mouse models. Mechanistically, HEXA-FC enhances hepatic fatty acid oxidation and peripheral glucose disposal while not impacting endogenous glucose production. Together, these outcomes suggest that while HEXA-FC treatment may offer therapeutic benefits in mild MASH and insulin resistance, it is ineffective against severe MASH and liver fibrosis.NEW & NOTEWORTHY The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes is increasing. Here, we show that chronic FC-HEXA recombinant protein treatment reduces hepatic lipid accumulation and improves blood glucose control in mice with mild MASH and insulin resistance.

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.

GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes.

This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration.

The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.

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.

Deep learning for body composition analysis (BCA) is gaining traction in clinical research, offering rapid and automated ways to measure body features like muscle or fat volume. However, most current methods prioritize computed tomography (CT) over magnetic resonance imaging (MRI). This study presents a deep learning approach for automatic BCA using MR T2-weighted sequences.

Initial BCA segmentations (10 body regions and 4 body parts) were generated by mapping CT segmentations from body and organ analysis (BOA) model to synthetic MR images created using an in-house trained CycleGAN. In total, 30 synthetic data pairs were used to train an initial nnU-Net V2 in 3D, and this preliminary model was then applied to segment 120 real T2-weighted MRI sequences from 120 patients (46% female) with a median age of 56 (interquartile range, 17.75), generating early segmentation proposals. These proposals were refined by human annotators, and nnU-Net V2 2D and 3D models were trained using 5-fold cross-validation on this optimized dataset of real MR images. Performance was evaluated using Sørensen-Dice, Surface Dice, and Hausdorff Distance metrics including 95% confidence intervals for cross-validation and ensemble models.

The 3D ensemble segmentation model achieved the highest Dice scores for the body region classes: bone 0.926 (95% confidence interval [CI], 0.914-0.937), muscle 0.968 (95% CI, 0.961-0.975), subcutaneous fat 0.98 (95% CI, 0.971-0.986), nervous system 0.973 (95% CI, 0.965-0.98), thoracic cavity 0.978 (95% CI, 0.969-0.984), abdominal cavity 0.989 (95% CI, 0.986-0.991), mediastinum 0.92 (95% CI, 0.901-0.936), pericardium 0.945 (95% CI, 0.924-0.96), brain 0.966 (95% CI, 0.927-0.989), and glands 0.905 (95% CI, 0.886-0.921). Furthermore, body part 2D ensemble model reached the highest Dice scores for all labels: arms 0.952 (95% CI, 0.937-0.965), head + neck 0.965 (95% CI, 0.953-0.976), legs 0.978 (95% CI, 0.968-0.988), and torso 0.99 (95% CI, 0.988-0.991). The overall average Dice across body parts (2D = 0.971, 3D = 0.969, P = ns) and body regions (2D = 0.935, 3D = 0.955, P < 0.001) ensemble models indicates stable performance across all classes.

The presented approach facilitates efficient and automated extraction of BCA parameters from T2-weighted MRI sequences, providing precise and detailed body composition information across various regions and body parts.

Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia, elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).

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.

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.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD.

There is a new awareness of the widespread nature of metabolic dysfunction-associated steatotic liver disease (MASLD) and its connection to cardiovascular disease (CVD). This has catalyzed collaboration between cardiologists, hepatologists, endocrinologists, and the wider multidisciplinary team to address the need for earlier identification of those with MASLD who are at increased risk for CVD. The overlap in the pathophysiologic processes and parallel prevalence of CVD, metabolic syndrome, and MASLD highlight the multisystem consequences of poor cardiovascular-liver-metabolic health. Metabolic dysfunction and associated insulin resistance, together with the predilection for ectopic fat deposition in the liver and surrounding tissues, are associated with elevated risk of endothelial dysfunction, systemic inflammatory response, and ectopic fat deposition in the epicardium. This complex pathophysiology can accelerate atherogenic dyslipidemia, atherogenesis, diastolic dysfunction, valvular calcification, and cardiac arrhythmias. Despite the mounting evidence of mechanistic pathways underpinning MASLD and CVD, current recommendations have not clearly focused upon MASLD as a risk factor or target for intervention in CVD. We have brought together a diverse range of international experts committed to promoting cardiovascular-liver-metabolic health and related outcomes across the globe. The overarching goal of this document is to offer a construct for clinicians in the cardiovascular field with regards to (1) diagnosis and screening of MASLD through the use of noninvasive serum and imaging tests; (2) screening for CVD in all individuals with MASLD regardless of established atherosclerotic risk factors; and (3) the approach to management of MASLD with respect to prevention of CVD through lifestyle, as well as pharmacologic and surgical strategies. To achieve this, the modified Delphi method was applied and a series of evidence-based quality standard recommendations have been identified.

This was a randomized, double-blind, placebo-controlled study to assess the effects of pemvidutide, a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist, on liver fat content (LFC) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).

Patients with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus. The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment.

Ninety-four patients were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of patients had type 2 diabetes mellitus. At week 12, relative reductions in LFC from baseline were 46.6% (95% CI -63.7 to -29.6), 68.5% (95% CI -84.4 to -52.5), and 57.1% (95% CI -76.1 to -38.1) for the pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg groups, respectively, vs. 4.4% (95% CI -20.2 to 11.3) for the placebo group (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of patients achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events.

In patients with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.

Metabolic dysfunction-associated steatotic liver disease, and its progressive form steatohepatitis, are strongly associated with overweight/obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/glucagon receptor agonist, to significantly reduce liver fat content, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both metabolic dysfunction-associated steatohepatitis and obesity.

NCT05006885.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA.

Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters.

Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss.

The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin.

gov, Number: NCT05039450.

As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar effects to GLP-1 but are less prone to degradation, and they are widely used in the treatment of type 2 diabetes and obesity. In recent years, different beneficial effects of GLP-1R agonists were discovered, such as reducing ischemia-reperfusion injury, improving the function of various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, and prolonging graft survival. Therefore, GLP-1R agonists have great potential for clinical application in various diseases. Here, we briefly summarized the beneficial effects of GLP-1R agonists other than the anti-diabetic and anti-obesity effects.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health concern, affecting over 30 % of adults. It is a principal driver in the development of cirrhosis and hepatocellular carcinoma. The complex pathogenesis of MASLD involves an excessive accumulation of lipids, subsequently disrupting lipid metabolism and prompting inflammation within the liver. This review synthesizes the recent research progress in understanding the mechanisms contributing to MASLD progression, with particular emphasis on metabolic disorders and interorgan crosstalk. We highlight the molecular mechanisms linked to these factors and explore their potential as novel targets for pharmacological intervention. The insights gleaned from this article have important implications for both the prevention and therapeutic management of MASLD.

To compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).

A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight.

Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-β agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism.

These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.

Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis.

This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored.

In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment.

Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis.

Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted.

NCT05296733.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic-Dysfunction Associated Steatohepatitis (MASH) are linked to obesity, type 2 diabetes, and metabolic syndrome, increasing liver-related morbidity and cardiovascular risk. Recent therapies, including Resmetirom, FGF21 analogs, and GLP-1 agonists, have shown promise. This network meta-analysis evaluates their comparative efficacy and safety.

A literature search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library. Included clinical trials addressed MASLD or MASH with Resmetirom, FGF21 analogs, or GLP-1 agonists. Statistical analyses used a random-effects model, calculating mean differences (MD) and relative risks (RR), with heterogeneity assessed using τ2, I2, and Q statistics.

MASH resolution was significantly higher for FGF21 (RR 4.84, 95% CI: 2.59 to 9.03), Resmetirom showed the most significant reduction in MRI-PDFF (MD -18.41, 95% CI: -23.60 to -13.22) and >30% fat reduction (RR 3.56, 95% CI: 2.41 to 5.26). Resmetirom significantly reduced ALT (MD -15.71, 95% CI: -23.30 to -8.13), AST (MD -12.28, 95% CI: -21.07 to -3.49), and GGT (MD -19.56, 95% CI: -34.68 to -4.44). FGF21 and GLP-1 also reduced these markers. Adverse events were significantly higher with Resmetirom (RR 1.47, 95% CI: 1.24 to 1.74), while GLP-1 and FGF21 showed non-significant trends towards increased risk.

Resmetirom and FGF21 show promise in treating MASLD and MASH, with Resmetirom particularly effective in reducing liver fat and improving liver enzymes. GLP-1 agonists also show benefits but to a lesser extent. Further long-term studies are needed to validate these findings and assess cost-effectiveness.

Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a major global health challenge. glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential therapeutic benefits for MASLD patients, including improvements in liver function, inflammation, and fibrosis. This study aims to systematically review and meta-analyze randomized controlled trials (RCTs) to evaluate the efficacy and safety of GLP-1RAs in MASLD patients, focusing on hepatic outcomes, cardiovascular outcomes, anthropometric measurements, and mortality. Following PRISMA guidelines, a comprehensive database search was conducted to include RCTs assessing GLP-1RAs' effects on MASLD. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool. Our meta-analysis used a random-effects model, calculating standardized mean differences for continuous outcomes to determine the agents' efficacy and safety. Additionally, funnel plots were generated to assess publication bias, ensuring the integrity of our meta-analytical findings. The review included 27 trials, revealing GLP-1RAs significantly improved hepatic function markers (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and liver fat content) and cardiovascular risk factors (fasting blood sugar, HbA1c levels, lipid profiles). Additionally, GLP-1RAs were associated with significant reductions in body weight, BMI, subcutaneous fat, and waist circumference. GLP-1RAs demonstrate a promising therapeutic role in managing MASLD, offering benefits that extend to improving liver function, mitigating cardiovascular risk, and promoting weight loss. Further research is needed to confirm these findings and optimize GLP-1RAs' usage in MASLD treatment.

Nonalcoholic fatty liver disease (NAFLD), the most common chronic hepatic disease, has become a leading health problem worldwide. The present review summarized the methods and mechanisms to treat NAFLD, including the Mediterranean diet, physical activity and exercise, bariatric surgery and specific therapeutic agents, including statins, peroxisome proliferator‑activated receptor agonists, cenicriviroc and farnesoid X receptor agonists. Biologically active substances, such as peptides, alkaloids, polyphenolic compounds, silymarin, antibiotics, fatty acids, vitamins, probiotics, synbiotics and lamiaceae have also demonstrated actions that combat NAFLD. Considering their different mechanisms of action, combining some of them may prove an efficacious treatment for NAFLD. In this light, the present review describes recent progress and future prospects in treating NAFLD.

This review discusses the quantitative assessment of tissue composition in the human body (body composition, BC) using radiological methods. Such analyses are gaining importance, in particular, for oncological and metabolic problems. The aim is to present the different methods and definitions in this field to a radiological readership in order to facilitate application and dissemination of BC methods. The main focus is on radiological cross-sectional imaging.

The review is based on a recent literature search in the US National Library of Medicine catalog (pubmed.gov) using appropriate search terms (body composition, obesity, sarcopenia, osteopenia in conjunction with imaging and radiology, respectively), as well as our own work and experience, particularly with MRI- and CT-based analyses of abdominal fat compartments and muscle groups.

Key post-processing methods such as segmentation of tomographic datasets are now well established and used in numerous clinical disciplines, including bariatric surgery. Validated reference values are required for a reliable assessment of radiological measures, such as fatty liver or muscle. Artificial intelligence approaches (deep learning) already enable the automated segmentation of different tissues and compartments so that the extensive datasets can be processed in a time-efficient manner - in the case of so-called opportunistic screening, even retrospectively from diagnostic examinations. The availability of analysis tools and suitable datasets for AI training is considered a limitation.

· Radiological imaging methods are increasingly used to determine body composition (BC).. · BC parameters are usually quantitative and well reproducible.. · CT image data from routine clinical examinations can be used retrospectively for BC analysis.. · Prospectively, MRI examinations can be used to determine organ-specific BC parameters.. · Automated and in-depth analysis methods (deep learning or radiomics) appear to become important in the future..

· Linder N, Denecke T, Busse H. Body composition analysis by radiological imaging - methods, applications, and prospects. Fortschr Röntgenstr 2024; 196: 1046 - 1054.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism, involving six key processes: increased hepatic fatty acid uptake, enhanced fatty acid synthesis, reduced oxidative degradation of fatty acids, increased cholesterol uptake, elevated cholesterol synthesis, and increased bile acid synthesis. Consequently, maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management. Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD, primarily by inhibiting lipid synthesis and promoting lipid oxidation. In this review, we summarized recent research on MASLD, elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis, and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.

Semaglutide is increasingly used in the management of type 2 diabetes mellitus and obesity. Ensuring the safety of this medication is crucial for its clinical use. This meta-analysis evaluates the safety profile of semaglutide across patient populations and treatment durations.

Randomized controlled trials assessing the safety of semaglutide vs. placebo, with specified treatment durations were identified. The primary outcome was occurrence of any cardiovascular adverse events. Secondary outcomes included sudden cardiac death, adverse events leading to death, adverse events, gastrointestinal side effects, occurrence of hypoglycemia, and new-onset neoplasm.

A total of 23 studies met the inclusion criteria with a combined sample size of 57,911 participants. The meta-analysis revealed that the adverse event associated with semaglutide is gastrointestinal in nature (nausea and vomiting). No significant differences were observed between semaglutide and comparator groups.

Semaglutide appears to have a favorable safety profile across diverse patient populations and treatment durations, supporting its continued use in the management of type 2 diabetes mellitus and obesity. It is generally well-tolerated, with a low incidence of adverse events. Clinicians should be aware of these findings and monitor patients accordingly. Further long-term studies are warranted to assess the safety of semaglutide in clinical practice.

GLP-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control and insulin sensitivity and reduce body weight in obese patients with type 2 diabetes mellitus (T2D). This trial sought to evaluate the therapeutic effect of oral and subcutaneous semaglutide in NAFLD and its sequelae in obesity and/or T2D.

In an open-labelled intervention study, the sample was 180 patients classified into three parallel groups (1:1:1): group I received oral semaglutide, group II patients received injectable semaglutide, and group III received pioglitazone and/or vitamin E. Patients were evaluated at 6 and 12 months.

There was a substantial improvement in lipid profile, liver enzymes, and body mass index, especially in group II. As for HDL, only group II showed a consistent increase at both 6 months (51 ± 4.62 mg/dL) and 12 months (50.08 ± 2.45 mg/dL) compared with baseline (45.6 ± 6.37 mg/dL) (p-value < 0.001). Despite the non-significant difference in NAFLD fibrosis score (NFS) (p-value = 0.45 and 0.63), group II had significantly lower scores of the fibrosis-4 score (FIB-4), liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) at 6 and 12 months (p-value < 0.001). Conclusions: Semaglutide improves lipid profile, liver steatosis, and fibrosis parameters and reduces the BMI in T2D and obese patients with NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.

An increasing amount of research has underscored the significant role of lipoproteins in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). This comprehensive review examines the intricate relationship between lipoprotein abnormalities and the development of MAFLD.

Atherogenic dyslipidemia seen in insulin resistance states play a significant role in initiating and exacerbating hepatic lipid accumulation. There are also specific genetic factors ( PNPLA3 , TM6SF2 , MBOAT7 , HSD17B13 , GCKR- P446L) and transcription factors (SREBP-2, FXR, and LXR9) that increase susceptibility to both lipoprotein disorders and MAFLD. Most monogenic primary lipid disorders do not cause hepatic steatosis unless accompanied by metabolic stress. Hepatic steatosis occurs in the presence of secondary systemic metabolic stress in conjunction with predisposing environmental factors that lead to insulin resistance. Identifying specific aberrant lipoprotein metabolic factors promoting hepatic fat accumulation and subsequently exacerbating steatohepatitis will shed light on potential targets for therapeutic interventions.

The clinical implications of interconnection between genetic factors and an insulin resistant environment that predisposes MAFLD is many fold. Potential therapeutic strategies in preventing or mitigating MAFLD progression include lifestyle modifications, pharmacological interventions, and emerging therapies targeting aberrant lipoprotein metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.

Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism.

Open-label, 48-week randomized trial with a 2 x 2 factorial design.

Multicenter HIV clinics.

Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features).

Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone.

Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF).

Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P  = 0.45]), MET (-0.62 [-1.81 to 0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%.

Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone.