Liver fat is associated with cardiometabolic disease, cerebrovascular disease, and dementia. Cerebrovascular disease, most often cerebral small vessel disease, identified by magnetic resonance imaging as white matter hyperintensities (WMHs) often contributes to dementia. However, liver fat's role in the relationship between cardiometabolic risk, WMHs, and cognitive performance is unclear.

In the UK Biobank cohort (N = 32,461, 52.6% female; mean age 64.2 ± 7.7 years; n = 23,354 in the cognitive performance subsample), we used linear regression to investigate associations between cardiometabolic factors measured at baseline and liver fat, WMHs, and cognitive performance measured at follow-up, which was 9.3 ± 2.0 years later on average. We used structural equation modeling to investigate whether liver fat mediated associations between cardiometabolic factors and WMHs and whether WMHs mediated associations between liver fat and cognitive performance.

Nearly all cardiometabolic factors were significantly associated with liver fat (|r| range = 0.03-0.41, p = 3.4 × 10-8 to 0) and WMHs (|r| = 0.04-0.15, p = 5.8 × 10-13 to 7.0 × 10-159) in regression models. Liver fat was associated with WMHs (r = 0.11, p = 4.3 × 10-82) and cognitive performance (r = -0.03, p = 1.6 × 10-7). Liver fat mediated the associations between cardiometabolic factors and WMHs (|βmediation| = 0.003-0.027, p mediation = 1.9 × 10-8 to 0), and WMHs mediated the associations between liver fat and cognitive performance (βmediation = -0.01, p mediation = 0).

Our findings indicate that liver fat mediates associations between cardiometabolic factors and WMHs and that WMHs mediate the association between liver fat and cognitive performance. This suggests that liver fat may be important for understanding the effects of cardiometabolic factors on cerebrovascular disease and cognitive function. Experimental studies are warranted to determine relevant targets for preventing vascular-driven cognitive impairment.

Cardiovascular, kidney and metabolic (CKM) conditions are interrelated, significantly contributing to morbidity, mortality and healthcare burden. Despite therapeutic advances, traditional disease-specific approaches often fail to address their complex interplay. Key therapeutic agents-including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dual GLP-1/glucose-dependent insulinotropic polypeptide RAs, sodium glucose co-transporter inhibitors and the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone-offer multi-organ benefits. Emerging therapies, such as triple receptor agonists and second-generation MRAs, target new pathways further expanding treatment options for CKM conditions. A holistic CKM management approach must address and recognise that conditions such as metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, obstructive sleep apnoea and obesity are part of the CKM spectrum. Frailty assessment is also important alongside CKM conditions, warranting comprehensive geriatric assessment and deprescribing when appropriate. Multidisciplinary care-including lifestyle interventions, pathway redesign, pharmacological advances and novel technologies-is essential for improving outcomes. As the CKM landscape evolves, future strategies should prioritise early intervention, personalised treatment and addressing unmet needs in high-risk populations. This review advocates for an integrated CKM framework, exploring treatment strategies, emerging therapies and technological innovations. It also examines the role of artificial intelligence and digital health tools in risk stratification, early diagnosis and long-term condition management, alongside ethical and regulatory considerations.

This Obesity Medicine Association (OMA) Expert Joint Perspective examines steatotic liver disease (SLD), which is composed of metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) in children with obesity. The prevalence of obesity is increasing, rates have tripled since 1963 from 5 % to now 19 % of US children affected in 2018. MASLD, is the most common liver disease seen in children, can be a precursor to the development of Type 2 Diabetes (T2DM) and is the primary reason for liver transplant listing in young adults. We must be vigilant in prevention and treatment of MASLD in childhood to prevent further progression.

This joint clinical perspective is based upon scientific evidence, peer and clinical expertise. The medical literature was reviewed via PubMed search and appropriate articles were included in this review. This work was formulated from the collaboration of eight hepatologists/gastroenterologists with MASLD expertise and two physicians from the OMA.

The authors who are experts in the field, determined sentinel questions often asked by clinicians regarding MASLD in children with obesity. They created a consensus and clinical guideline for clinicians on the screening, diagnosis, and treatment of MASLD associated with obesity in children.

Obesity and the comorbidity of MASLD is increasing in children, and this is a medical problem that needs to be addressed urgently. It is well known that children with metabolic associated chronic disease often continue to have these chronic diseases as adults, which leads to reduced life expectancy, quality of life, and increasing healthcare needs and financial burden. The authors of this paper recommend healthy weight reduction not only through lifestyle modification but through obesity pharmacotherapy and bariatric surgery. Therefore, this guidance reviews available therapies to achieve healthy weight reduction and reverse MASLD to prevent progressive liver fibrosis, and metabolic disease.

Metabolic dysfunction-associated steatohepatitis (MASH), the progressed period of metabolic dysfunction-associated steatotic liver disease (MASLD), is a multifaceted liver disease characterised by inflammation and fibrosis that develops from simple steatosis, even contributing to hepatocellular carcinoma and death. MASH involves several immune cell-mediated inflammation and fibrosis, where T cells play a crucial role through the release of pro-inflammatory cytokines and pro-fibrotic factors. This review discusses the complex role of various T cell subsets in the pathogenesis of MASH and highlights the progress of ongoing clinical trials involving T cell-targeted MASH therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent among people with HIV (PWH) and increasingly recognized as a major contributor to morbidity and mortality. The field of MASLD is rapidly evolving with adoption of a new nomenclature and approval of the first FDA-approved therapy within the past year. These developments underscore the need to consider the current state of the science specifically in the context of HIV.

MASLD in PWH (MASLD-HIV) follows a more aggressive clinical course compared to HIV-negative individuals. While MASLD-HIV shares common pathogenic mechanisms with MASLD in the general population, HIV-specific factors - including altered body composition, chronic immune activation, enhanced gut permeability, and antiretroviral therapy - exacerbate disease progression. Despite an expanding pipeline of MASLD therapies, a critical gap remains in evaluating these interventions specifically among PWH. Nonetheless, dedicated studies of glucagon-like peptide-1 receptor agonists and the growth hormone-releasing hormone analog tesamorelin have shown promise in MASLD-HIV.

MASLD is a key contributor to liver-related and cardiovascular-morbidity in PWH. While there have been exciting advances to improve diagnosis and management of MASLD in the general population, differences in MASLD pathophysiology demonstrate the need to tailor our approach specifically for PWH.

The THR-β agonist resmetirom is the first treatment approved for metabolic dysfunction-associated steatohepatitis (MASH) in the US so far. It can be prescribed given MASH and F2/F3-fibrosis ("at-risk MASH").We analyzed how many patients qualify for resmetirom in a recently recruited Steatotic Liver Disease-cohort involving both tertiary and secondary care centers, the German SLD-Registry.Indication for resmetirom was assessed by three different approaches: (i) biopsy-proven MASH with F2/3 fibrosis and NAS-score ≥ 4; (ii) FibroScan-AST (FAST) score ≥ 0.67 and vibration controlled transient elastography (VCTE) < 15 kPa; (iii) US expert recommendations with VCTE 10-15 kPa and platelets ≥ 140×109/L or VCTE 8-15 kPa.1113 patients were recruited across 8 tertiary and 12 secondary care centers. NAS grading and staging were available for 180 cases (16%) with 179/180 conducted at tertiary care level. Of these, 61 (34%) qualified for resmetirom. FAST score without histologic assessment was available for 638 cases (57.3%), of which 612 (87%) were from tertiary and 26 (11%) from secondary care centers. Based on approach (ii), 41 (6%) of these individuals qualified for resmetirom compared to 117 (18.3%) using approach (iii). Combining approach (iii) with FAST ≥ 0.67 leads to 191 (30.0%) eligible patients. Using VCTE 8-15 kPa results in 182 (28.5%) eligible patients.Eligibility for resmetirom treatment depends on the available method used to identify "at-risk MASH". Availability of VCTE was highest among different levels of care.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rising among reproductive-aged individuals and in pregnancy. MASLD in pregnancy does increase such risks as gestational diabetes, preeclampsia, and preterm birth. Although routine screening for MASLD has not been established in pregnancy, individuals with metabolic comorbidities, such as type 2 diabetes mellitus, should be evaluated by liver imaging and liver panel. Preconception counseling should address potential risks as well as need for optimized metabolic health before and during pregnancy. Fibrosis assessment should ideally be completed before pregnancy, to identify cases of cirrhosis that may warrant additional preconception management, such as variceal screening, as well as comanagement with maternal-fetal medicine specialists. In patients with MASLD, aspirin is advised at 12 weeks of gestational age to lower preeclampsia risk. In the absence of cirrhosis, no additional blood test monitoring is needed. In the general population, breastfeeding has beneficial effects on metabolic health in birthing parents and offspring and thus should be encouraged in the setting of MASLD, including access to enhanced lactation support. Research needs include evaluation of the long-term risks of MASLD in pregnancy on metabolic health in birthing parents and infants, as well as safety data for MASLD-directed therapies during pregnancy and lactation.

Traditional Chinese Medicine (TCM) has recently emerged as a beacon for the treatment of diabetes and its complications. Many TCMs that are commonly used, have the potentially demonstrated significant anti-diabetic effects. The mechanisms of these effects have been extensively discussed using modern techniques, such as genomics, mass spectrometry, and network pharmacology. Studies have demonstrated that TCM can influence glucose metabolism and pancreatic function via a diverse array of mechanisms including PI3K/AKT and AMPK pathways. TCM not only exhibits potential in the treatment of diabetes but also reduces the risk of diabetic complications. It is effective in the treatment of diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DPN), diabetic cardiomyopathy, and peripheral angiopathy. Research has demonstrated that prescriptions, Chinese herbal medicines, and their extracts play a role in a variety of molecular mechanisms such as antioxidation, apoptosis regulation, hypoxia improvement, autophagy, and promotion of glucose and lipid metabolism. The antioxidant properties of TCM have received considerable attention. Recent studies have demonstrated that they are capable of effectively eliminating free radicals from the body and reducing damage to cells caused by oxidative stress. Consequently, they are crucial in the treatment of diabetes and its associated complications. This review summarizes the ever-expanding scope of TCM applicability in the field of diabetes, providing crucial support and innovative ideas for modern healthcare. TCMs could help seek more effective pharmacological targets in basic study and as well serve as the complement to the strategy of diabetic prevention and treatment benefiting the patients. More and more large series of RCT and clinical investigations will eventually examine the efficacy of specific TCM formulas on the therapeutic effect of DM and its complication where currently treatments could not be satisfied.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily managed through diet and lifestyle modifications. However, these behavioural interventions alone may not achieve disease regression or remission, and maintaining long-term adherence is challenging. Incretin mimetics and other gastrointestinal hormones targeting the pleiotropic pathophysiological pathways underlying MASLD have now emerged as promising disease-modifying therapies.

This is a comprehensive review summarising the role of glucagon-like peptide-1 (GLP-1) receptor agonists and glucagon/glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor dual or triple agonists in the treatment of metabolic dysfunction-associated steatohepatitis (MASH).

Only clinical trials with endpoints assessed by liver histology were included for a robust evaluation of therapeutic efficacy.

Recent evidence from phase 2 clinical trials for MASH demonstrated that pharmacological agents based on GLP-1 receptor agonism are effective in improving disease activity. Additionally, tirzepatide and survodutide showed potential clinical benefits in reducing fibrosis. Other cardiometabolic benefits observed include weight loss and improvements in glycaemic control and lipid profile. Adherence to treatment may be limited by gastrointestinal side effects, though they were found to be generally mild to moderate in severity. An interim analysis of the semaglutide phase 3 trial confirmed its efficacy in improving steatohepatitis and demonstrated its potential to improve fibrosis.

GLP-1 receptor agonists, alone or in combination with GIP and/or glucagon receptor agonists, represent promising, effective pharmacotherapies for the treatment of MASLD/MASH. Larger and longer-duration clinical trials are needed to further evaluate the efficacy and safety of GIP receptor and glucagon receptor agonism.

Cardiovascular disease and metabolic dysfunction-associated steatotic liver disease are common conditions associated with high mortality and morbidity, yet opportunities for integrated prevention are underinvestigated. We explored the association between impairment in the liver (defined by increased iron-corrected T1 (cT1) time) and/or heart (reduced left ventricular ejection fraction ≤ 50) and risk of experiencing cardiovascular- or liver-related events or all-cause mortality among 28,841 UK Biobank participants who underwent magnetic resonance imaging. Using Cox proportional hazard models, adjusted for age, sex, body mass index, type 2 diabetes and dyslipidaemia, we observed that cardiac impairment was associated with increased incidence of cardiovascular events (hazard ratio (HR) 2.3 (1.9-2.7)) and hospitalization (HR 2.1 (1.8-2.4)). Liver impairment was associated with incident cardiovascular hospitalization (cT1 ≥ 800 ms, HR 1.3 (1.1-1.5)), liver events (cT1 ≥ 875 ms, HR 9.2 (3.2-26) and hospitalization (cT1 ≥ 875 ms, HR 5.5 (3.2-9.3). Associations between cT1 and liver events were maintained in participants with metabolic dysfunction-associated steatotic liver disease (N = 6,223). Reduced left ventricular ejection fraction (≤50) combined with elevated cT1 (≥800 ms) were associated with earlier cardiovascular events (time to event 0.8 versus 2.4 years; P < 0.05). Cardiac and liver impairment are independently, or in combination, associated with cardiovascular or liver events, suggesting a dual role for magnetic resonance imaging in integrated prevention pathways.

Obesity rates have surged since 1990 worldwide. This rise is paralleled by increases in pathological processes affecting organs such as the heart, liver, and kidneys, here termed systemic metabolic disorders (SMDs). For clinical management of SMD, the European Atherosclerosis Society proposes a pathophysiology-based system comprising three stages: Stage 1, where metabolic abnormalities such as dysfunctional adiposity and dyslipidaemia occur without detectable organ damage; Stage 2, which involves early organ damage manifested as Type 2 diabetes, asymptomatic diastolic dysfunction, metabolic-associated steatohepatitis (MASH), and chronic kidney disease (CKD); and Stage 3, characterized by more advanced organ damage affecting multiple organs. Various forms of high-risk obesity, driven by maintained positive energy balance, are the most common cause of SMD, leading to ectopic lipid accumulation and insulin resistance. This progression affects various organs, promoting comorbidities such as hypertension and atherogenic dyslipidaemia. Genetic factors influence SMD susceptibility, and ethnic disparities in SMD are attributable to genetic and socioeconomic factors. Key SMD features include insulin resistance, inflammation, pre-diabetes, Type 2 diabetes, MASH, hypertension, CKD, atherogenic dyslipidaemia, and heart failure. Management strategies involve lifestyle changes, pharmacotherapy, and metabolic surgery in severe cases, with emerging treatments focusing on genetic approaches. The staging system provides a structured approach to understanding and addressing the multi-faceted nature of SMD, which is crucial for improving health outcomes. Categorization of SMD abnormalities by presence and progression is aimed to improve awareness of a multi-system trait and encourage a tailored and global approach to treatment, ultimately aiming to reduce the burden of obesity-related comorbidities.

Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common chronic liver disorder in the world. Most patients with MASLD are undiagnosed, untreated and unreferred. Treatment depends on diagnosis and accurate staging of fibrosis risk, and therefore screening at the primary care setting coupled with consistent, timely, evidence-based, widely accessible, and testable management processes is critical. Randomized controlled trials of methods for screening, diagnosis, severity stratification, and referral are lacking. We previously validated the MASLD clinical care pathway (MCCP), a multistep algorithmic process geared to support primary care settings in screening, diagnosis, risk stratification, and suggested referral and treatment of patients with MASLD. We will evaluate the effectiveness of the MCCP intervention compared to usual care in improving MASLD care process and patient outcomes.

A two-arm, parallel, cluster-randomized trial will assess the effect of the MCCP intervention comprised of an e-trigger and structured provider education on screening, diagnosis, referral, and treatment for MASLD. Clusters are Veterans Affairs (VA) patient-centered primary care clinics, called Patient Aligned Care Teams (PACTs). This 4-year study will include three phases: (1) formative assessment to explore barriers to feasibility and acceptability of intervention among providers and patients and adapt MCCP for utilization by VA PACTs, (2) cluster-randomized trial to examine the effectiveness of the MCCP compared to usual care, and (3) summative evaluation to identify patient and provider characteristics associated with effectiveness of MCCP and plan for future implementation. The primary outcome will be a composite dichotomous variable for making a new MASLD diagnosis and completing severity risk stratification of MASLD. Secondary outcomes include referral and receipt of hepatology specialty care for patients with MASLD and advanced fibrosis.

Our randomized controlled trial will be the first to systematically implement the MCCP using strategies that are clinically relevant, adaptable and scalable. If successful, the MCCP will improve outcomes for patients with MASLD through early detection, accurate risk stratification, and timely treatment within primary care settings.

This trial has been registered on clinicaltrails.gov (# NCT06671886), registration date: 10-31-2024.

The 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5-6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20-21, 2025 ( http://www.cvot.org ).

Over the last few years, the approach to clinical recognition and risk stratification of advanced liver disease has changed substantially, and liver cirrhosis has been increasingly conceptualized as a clinical rather than a histopathologic condition. In this Clinical Insight, we summarize the latest developments on recognition and management of 'clinically' advanced chronic liver disease.

The recent conditional approval by the Food and Drug Administration of resmetirom for treating metabolic dysfunction-associated steatohepatitis (MASH) with significant or advanced fibrosis represents a pivotal milestone in the history of metabolic dysfunction-associated steatotic liver disease (MASLD) treatment. As the first liver-directed pharmacological therapy option for MASLD, resmetirom offers a novel approach that specifically targets liver pathology, marking a transformative step forward in managing this widespread and challenging condition. For initiating therapy with resmetirom, a liver biopsy is not required. Consequently, accurately excluding patients with less severe liver histology or cirrhosis using noninvasive tests (NITs) is essential. In addition, monitoring the therapy response should be conducted using NITs. Given the recent approval, our current clinical understanding of resmetirom is primarily informed by phase 3 clinical trials. The long-term effects of the drug should be evaluated in further studies by encouraging the use of the drug in eligible patients. This review highlights key aspects of clinical resmetirom use, including identifying the target population, monitoring therapeutic response, determining appropriate discontinuation criteria, and strategies to prevent unnecessary treatment interruptions.

Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).

Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD). Multiple mechanisms may be important including weight loss, improved glycaemic control and putative direct tissue-specific actions. Following cessation of GLP1-RA therapy, weight regain is common. To dissect the mechanisms underpinning their benefits, we conducted a prospective, randomised, experimental medicine study in people with MASLD, comparing GLP-1RA treatment (liraglutide) to matched lifestyle-induced weight loss and assessed the impact of treatment withdrawal.

Twenty-nine participants with MASLD, without type 2 diabetes underwent metabolic phenotyping including measurement de novo lipogenesis (DNL), liver magnetic resonance imaging, body composition, adipose tissue RNA sequencing, circulating proteome, and stool microbiome analysis. Participants were randomised to lifestyle (∼500 kcal energy deficit) or GLP1-RA treatment for 12 weeks, after which investigations were repeated, and treatment stopped; investigations were also repeated 12 weeks after treatment withdrawal.

Matched weight loss was achieved in both arms. Body composition changes, reductions in alanine aminotransferase, liver steatosis, and disease activity were similar following both treatments. GLP-1RA treatment, but not lifestyle, improved glucose handling, fasting lipids, and significantly deceased DNL. The subcutaneous adipose transcriptome, circulating proteome profile and stool microbiome were not different between groups after treatment. However, 12 weeks after GLP1-RA (but not lifestyle) withdrawal, circulating MMP-10, IL10RB, FGF-23, and Flt3L were elevated, alongside dysregulated adipose gene expression.

Although matched weight loss through lifestyle or GLP-1RA have comparable effects on hepatic steatosis, GLP-1RA treatment had additional metabolic benefits on glucose homeostasis, lipid profiles, and DNL. However, GLP-1RA withdrawal may adversely impact the circulating proteome, adipose tissue gene expression, and the stool microbiome, predisposing to weight regain.

Weight loss, through either lifestyle intervention or pharmacotherapy with GLP-1RA has an equally beneficial impact on the liver, and both strategies should be considered in the management of people with MASLD. GLP-1RA therapy may have additional benefits to improve glucose homeostasis even in the absence of pre-existing type 2 diabetes. Further research is needed to explore the differential impact of treatment withdrawal and the resultant metabolic consequences.

This study is registered at EudraCT (2016-002045-36).

Recent trends in use of tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonist (RA), versus other glucose-lowering medications (GLMs) and weight-lowering medications (WLMs) remain unexplored.

To describe trends in insurance claims for GLMs and WLMs after tirzepatide approval.

Population-based cohort study.

Claims data from a large U.S. commercial database (January 2021 to December 2023).

Adults (aged ≥18 years) with type 2 diabetes (T2D) and without diabetes with dispensations for GLMs and WLMs. Any use was defined as medication dispensation regardless of prior use. Incident use was defined as dispensation without use in the preceding year.

Monthly trends in medication dispensations before and after tirzepatide market entry. Tirzepatide uptake was additionally compared with initial postapproval uptake of other GLMs and WLMs.

Tirzepatide dispensations increased markedly among adults with T2D prescribed GLMs, reaching 12.3% of all GLM dispensations by December 2023. Similar patterns were observed for sodium-glucose cotransporter-2 inhibitors (14.5% to 24.4%) and GLP-1 RAs (19.5% to 28.5%). Dispensations of other GLMs, including metformin, declined. Among adults without diabetes but prescribed WLMs, tirzepatide (0.0% to 40.6%) and semaglutide (2.4 mg) (0.0% to 32.2%) dispensations increased sharply, but semaglutide (2.0 mg) was the most frequently dispensed WLM, increasing from 37.8% to 45.7%. Dispensations of other WLMs declined. Similar trends were observed among incident users. Tirzepatide uptake was more rapid and sustained compared with initial postapproval periods for other medications.

Generalizability to U.S. adults without commercial health insurance is uncertain.

These findings highlight the sharp uptake of tirzepatide after U.S. market entry and enhance understanding of the rapidly shifting landscape of prescribing patterns for GLMs and WLMs.

National Institute of Diabetes and Digestive and Kidney Diseases.

Recent genetic studies have implicated an active role for intrahepatic lipid accumulation in the pathogenesis of both polycystic ovary syndrome (PCOS) and cardiovascular disease. These new insights may provide novel (non)pharmacological opportunities for the prevention and treatment of PCOS and cardiovascular disease at both the societal and clinical level.

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.

Glucose-dependent insulinotropic polypeptide (GIP) was the first incretin identified and plays an essential role in the maintenance of glucose tolerance in healthy humans. Until recently GIP had not been developed as a therapeutic and thus has been overshadowed by the other incretin, glucagon-like peptide 1 (GLP-1), which is the basis for several successful drugs to treat diabetes and obesity. However, there has been a rekindling of interest in GIP biology in recent years, in great part due to pharmacology demonstrating that both GIPR agonism and antagonism may be beneficial in treating obesity and diabetes. This apparent paradox has reinvigorated the field, led to new lines of investigation, and deeper understanding of GIP.

In this review, we provide a detailed overview on the multifaceted nature of GIP biology and discuss the therapeutic implications of GIPR signal modification on various diseases.

Following its classification as an incretin hormone, GIP has emerged as a pleiotropic hormone with a variety of metabolic effects outside the endocrine pancreas. The numerous beneficial effects of GIPR signal modification render the peptide an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, drug-induced nausea and both bone and neurodegenerative disorders.

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) and alcohol-associated liver disease (ALD) are the major contributors to the liver disease burden globally. The rise in these conditions is linked to obesity, type 2 diabetes, metabolic syndrome and increased alcohol consumption. MASLD and ALD share risk factors, pathophysiology and histological features but differ in their thresholds for alcohol use, and the ALD definition does not require the presence of metabolic dysfunction. A recent multi-society consensus overhauled the nomenclature of liver steatosis and introduced the term MetALD to describe patients with metabolic dysfunction who drink more than those with MASLD and less than those with ALD. This new terminology aims to enhance the understanding and management of liver disease but poses challenges, such as the need to accurately measure alcohol consumption in research and clinical practice settings. Recent studies show that MetALD has significant implications for patient management, as it is associated with increased mortality risks and more severe liver outcomes compared to MASLD alone. MetALD patients face increased risks of liver disease progression, cancer and cardiovascular disease. The diagnosis of MetALD involves the adequate quantification of alcohol use through standardised questionnaires and/or biomarkers as well as proper assessment of liver disease stage and progression risk using non-invasive tools including serologic markers, imaging, elastography techniques and genetic testing. Effective management requires addressing both metabolic and alcohol-related factors to improve outcomes. This review intends to provide a comprehensive overview of MetALD, covering pathogenesis, potential diagnostic approaches, management strategies and emerging therapies.

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, demonstrates promise as a potent medication for obesity. However, the extent to which its weight-reducing effects go beyond suppressing appetite remains unclear. This study aimed to elucidate this by establishing a pair-fed control group, effectively eliminating the influence of reduced caloric intake.

Mice fed on a chow diet or a high-fat diet received single or long-term intracerebroventricular (i.c.v.) injections of tirzepatide or vehicle. The vehicle-treated mice were pair-fed to the tirzepatide-treated group to avoid the impact induced by different caloric intakes. Body weight and food intake were monitored daily. Respiratory exchange ratio (RER) was determined in metabolic cages. Fat utilization was calculated based on RER. Parameters of lipid metabolism were evaluated.

Mice receiving i.c.v. administration of tirzepatide exhibited significant reductions in body weight and fat content compared with pair-fed controls. These effects were mediated by increased lipolytic capacity in white adipose tissue and enhanced thermogenesis in brown and beige adipose tissues, leading to decreased RER and increased lipid utilization. Mechanistic investigations revealed that these effects were primarily mediated by sympathetic nervous system innervation of adipose tissues. This innervation, in turn, might be associated with the neuronal activity changes in the dorsomedial hypothalamus and the nucleus of the solitary tract within the hindbrain.

These findings establish a critical role for tirzepatide in shifting the substrate preference to fat utilization through the central nervous system-adipose tissue axis, promoting weight loss independent of food intake.

A comprehensive update of the S3 guideline for the prevention and treatment of obesity was published in October 2024. In contrast to the former version, the literature search included not only data on weight reduction but also data on patient-reported outcomes and co-morbidity. The new recommendations for nutritional therapy, besides fat and carbohydrate reduction, now also include novel aspects like the Mediterranean diet and intermittent fasting. These will enable individualization and will avoid an unbalanced diet. Pharmacotherapy, especially incretin-based, is recommended in an adjuvant setting, especially since current clinical trials indicate beneficial effects on the heart, liver and kidney in addition to weight reduction. A novel chapter was included regarding eHealth strategies, since these are efficient as supportive measures for multidimensional treatment programs, including nutritional advice, behavioural coaching and exercise training. Finally, a novel aspect was incorporated: discrimination and stigmatization of subjects suffering from obesity. This is important not only for the general environment but also for the medical sector, including the handling of patients as well as the infrastructure of the medical institution (e.g. heavy-duty chairs). Hence, the novel guideline will guarantee high quality in the medical care of subjects suffering from obesity.

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.

Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.

Glucagon-like peptide 1 (GLP-1)-based therapies, such as semaglutide and tirzepatide, represent highly effective treatment options for people with type 2 diabetes and obesity, enabling effective control of glucose and weight loss, while reducing cardiovascular and renal morbidity and mortality. The success of these medicines has spurred development of next-generation GLP-1-based drugs, promising greater weight loss, improved tolerability and additional options for the route and frequency of dosing. This Review profiles established and emerging GLP-1-based medicines, discussing optimization of pharmacokinetics and tolerability, engagement of new therapeutically useful pathways and safety aspects. Structurally unique GLP-1-based medicines that achieve substantially greater and rapid weight loss may impact musculoskeletal health, providing a rationale for therapeutics that more selectively target adipose tissue loss while preserving muscle mass and strength. Ongoing clinical trials in peripheral vascular disease, neuropsychiatric and substance use disorders, metabolic liver disease, arthritis, hypertension and neurodegenerative disorders may broaden indications for GLP-1-based therapeutics.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only type 2 diabetes medications that reduce cardiovascular disease and death, yet their availability in Medicaid is unclear.

To assess the unrestricted availability of SGLT2is and GLP-1 RAs, using dipeptidyl peptidase-4 inhibitors (DPP4is) as a benchmark.

National cross-sectional study using publicly available data.

All 50 state Medicaid fee-for-service (FFS) plans and 273 nonelderly adult managed care organization (MCO) plans with comprehensive coverage in March 2024.

Medicaid plans and enrollees with diabetes in those plans as of March 2024.

Unrestricted availability was defined as having at least 1 medication in each class listed on the preferred drug list without prior authorization or step therapy.

Of 50 FFS plans (including Washington, DC, and excluding 1 state, which had 5 MCO plans), 40 (80%) had unrestricted availability of SGLT2is, 30 (60%) of GLP-1 RAs, 41 (82%) of either, 29 (58%) of both, and 42 (84%) of DPP4is. Among 273 MCO plans (39 states; median, 6 plans [range, 2 to 24 plans]), 182 (67%) had availability of SGLT2is, 131 (48%) of GLP-1 RAs, 184 (67%) of either, 129 (47%) of both, and 204 (75%) of DPP4is. The proportion of MCO enrollees with availability varied markedly among states (SGLT2i range, 24% to 100%; GLP-1 RA range, 0% to 99%; DPP4i range, 41% to 100%). Primarily because of more MCO restrictions, 1.7 million enrollees (lower to upper bound, 1.33 million to 2.17 million enrollees; 25%) had restricted SGLT2i availability, 2.72 million (lower to upper bound, 2.12 million to 3.45 million; 40%) had restricted GLP-1 RA availability, and 1.5 million (lower to upper bound, 1.17 million to 1.90 million; 22%) had restricted DPP4i availability. Availability increased from 2020 to 2024, especially in FFS, but MCO GLP-1 RA availability has plateaued at below 60% since 2022. Tirzepatide was almost entirely restricted.

Diabetes enrollment was estimated using plan size and state and national prevalence data. The appropriateness of prior authorization restrictions was unknown.

Many Medicaid enrollees have restricted access to cardioprotective medications, particularly in MCO plans for GLP-1 RA medications, with substantial state variation. Formulary coverage is a potential lever to increase availability of these medications while balancing pharmaceutical costs.

University of California, San Francisco, Action Research Center for Health Equity.

Mounting evidence has established metabolic dysfunction-associated steatotic liver disease (MASLD) as an independent risk factor for heart failure (HF), particularly HFpEF. In this narrative review we explore the impact of MASLD on cardiovascular structure and function. We summarize findings from multiple cohort studies demonstrating that MASLD is associated with distinct patterns of adverse cardiac remodeling, including increased left ventricular concentricity and impaired diastolic function. These subclinical changes in cardiac structure and function often precede overt HF development and appear to occur in the context of multiple interconnected pathways involving metabolic dysfunction, systemic inflammation, adipose tissue dysregulation, vascular dysfunction, and altered hepatic hemodynamics. Early identification of cardiac structural and functional abnormalities through systematic screening may enable timely intervention in this high-risk population. Lifestyle modifications remain foundational, but achieving and maintaining significant weight loss is challenging. Recent clinical trials have shown promising results with cardiometabolic agents, particularly glucagon-like protein 1 receptor agonists, which demonstrate significant weight loss and hepatic and cardiovascular benefits. Despite these advances, key knowledge gaps remain regarding optimal screening strategies, mechanisms linking MASLD to HF, and targeted therapeutic approaches. Addressing these gaps will be essential for developing effective prevention and treatment strategies in this high-risk population.

Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.