Glucagon

Tirzepatide in Metabolically Dysfunctional-Associated Steatohepatitis (MASH): A Bibliometric and Evidence-Based Review.

Ileana Pantea, Angela Repanovici

Metabolically-dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) and is strongly linked to obesity and type 2 diabetes mellitus (T2D). Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a promising therapeutic option due to its profound metabolic effects and potential hepatic benefits. This study integrates bibliometric mapping with current clinical evidence to evaluate tirzepatide's role in MASLD/MASH.

Impact of Fibrotic Metabolic Dysfunction-Associated Steatohepatitis as a New Indication on Semaglutide Eligibility in the US Adult Population.

Laurens A van Kleef, Maurice Michel, Mesut Savas +9 more

Semaglutide, a glucagon-like peptide-1 receptor agonist, is effective in the treatment of fibrotic (F2-F3) metabolic dysfunction-associated steatohepatitis (MASH) and has recently received accelerated Food and Drug Administration approval. However, the extent to which this new indication expands treatment eligibility beyond existing approvals for type 2 diabetes mellitus (T2DM) and obesity remains unclear.

Research advances in the diagnosis and treatment of MASLD/MASH.

Dekai Wang, Jinxian Miao, Lihua Zhang +1 more

Background: The global increase in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and its progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) pose significant public health challenges. Objective: To review key research advancements in the diagnosis and treatment of MASLD/MASH over the past two decades. Methods: This article synthesizes recent findings on diagnostic and therapeutic strategies for MASLD/MASH, focusing on non-invasive diagnostic tools and emerging pharmacological treatments. Results: Non-invasive diagnostic techniques, including high-resolution CT, MRI, FIB-4 index, and FAST score, have enhanced early detection and diagnostic accuracy. Treatment strategies encompass pharmaceuticals such as THR-β agonists, FXR agonists, PPAR agonists, GLP-1 receptor agonists, and SGLT2 inhibitors, alongside lifestyle interventions like dietary changes, weight management, and exercise. Surgical options, including gastric bypass and liver transplantation, are effective, particularly for obese and advanced MASH patients. However, challenges remain in standardizing treatment protocols, validating long-term efficacy, and addressing patient-specific factors. Conclusion: MASLD/MASH treatment has advanced significantly with new diagnostic tools and therapies. Future research should focus on personalized approaches, long-term treatment outcomes, and multidisciplinary collaboration to improve patient care and treatment efficacy.

Development of NAFLD-Specific Human Liver Organoid Models on a Microengineered Array Chip for Semaglutide Efficacy Evaluation.

Xiao-Yan You, Xiang-Yang Li, Hui Wang +1 more

Progressive non-alcoholic fatty liver disease (NAFLD) may culminate in severe complications, including fibrosis, cirrhosis and hepatocellular carcinoma, yet therapeutic breakthroughs remain elusive, necessitating novel pharmacological strategies. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist clinically approved for type 2 diabetes and obesity management, has demonstrated pleiotropic effects in preclinical NAFLD models. In this study, we investigated semaglutide's therapeutic efficacy and mechanisms in a human liver organoids (hLOs) model of NAFLD. Utilising microengineered array chips, human induced pluripotent stem cells (hiPSCs) were differentiated into hLOs with functional hepatic properties. NAFLD pathology was induced via free fatty acid (FFA) exposure, recapitulating disease hallmarks such as steatosis, inflammatory cytokine elevation and fibrogenic activation. Semaglutide treatment at 50 nM significantly attenuated lipid deposition caused by FFAs and reduced triglyceride levels by 8-fold and cholesterol levels by 1.8-fold. It also inhibited the expression of pro-inflammatory markers (IL-6, IL-8, TNF-α) by about 1.5-2 fold and increased the level of lipolytic genes by about 45%. These findings elucidate the therapeutic potential of semaglutide in attenuating key NAFLD-associated pathologies and establish a robust in vitro platform for preclinical drug evaluation. The study provides critical insights into targeted NAFLD interventions and supports the translation of GLP-1-based therapies into clinical practice, addressing an unmet need in hepatology.

Interplay of childhood metabolic dysfunction-associated steatotic liver disease and obesity in the development of youth-onset type 2 diabetes.

Razieh Parizad, Juniali Hatwal, Ajit Singh Brar +4 more

The global increase in childhood and adolescent obesity has significantly contributed to the rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) - a condition now recognized as a key metabolic complication in youth. MASLD significantly increases the risk of youth-onset type 2 diabetes (T2D), particularly among obese individuals. Its asymptomatic progression presents considerable challenges for timely diagnosis and intervention.

Efsubaglutide Alfa attenuates metabolic dysfunction-associated steatohepatitis in mice with improvements in second harmonic generation-derived fibrosis features.

Yahao Wang, Zhihong Wang, Guirui Yan +4 more

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited effective treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise for metabolic and hepatic benefits. This study evaluated the therapeutic efficacy of Efsubaglutide Alfa, a novel long-acting GLP-1RA, in a mouse model of MASH.

Crosstalk between alcohol use disorder and obesity: two sides of the same coin?

Lorenzo Leggio, Mehdi Farokhnia, Paul J Kenny +2 more

Investigating similarities and differences between alcohol use disorder (AUD) and obesity is important because both AUD and obesity are public health concerns and share neurobiological and periphery-brain mechanisms. Furthermore, AUD and obesity often present with similar medical consequences related to organ damage, including liver and cardiovascular diseases. There is also growing evidence of changes in alcohol drinking in people who undergo bariatric surgery for obesity. In this non-systematic critical review, we identified relevant articles through PubMed searches, previous knowledge, and recursive reference searching. A librarian also used PubMed and Google Scholar for additional relevant articles, using terms such as alcohol, metabolic disorders, obesity, glucagon-like peptide-1 (GLP-1), bariatric surgery, and gut-brain axis. We provide an overview of the neurobiological, pathophysiological, neuroimaging, and clinical features related to the overlap and crosstalk between AUD and obesity. We also provide a summary of the currently approved medications for obesity and those for AUD and note the potential for some of these medications to work for both disorders. Specific to the latter point, we place emphasis on GLP-1 therapies, given their recent approval for weight loss and the growing evidence suggesting their potential efficacy for AUD and other addictions. We further review studies of the relationship between bariatric surgery and AUD and discuss potential mechanisms and future directions. In summary, studying the overlap between obesity and AUD may shed light on the mechanisms underlying the development and maintenance of both diseases. This knowledge, in turn, may help identify new therapeutic targets for AUD, and possibly comorbid obesity and/or other metabolic disorders.

MASH in Type 2 Diabetes: Pathophysiology, Diagnosis, and Therapeutic Management-A Narrative Review.

Adela Gabriela Ştefan, Adina Mitrea, Diana Clenciu +11 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as one of the greatest challenges for the modern public health system and serves as the foundation for the development of advanced stages, such as metabolic dysfunction-associated steatohepatitis (MASH), which may progress to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). MASLD and type 2 diabetes mellitus (T2DM) mutually exacerbate one another. MASLD increases the incidence of T2DM and the risk of complications in patients already affected. T2DM accelerates progression to MASH, which has become the second leading cause of liver transplantation and end-stage liver disease, and is associated with hepatic decompensation, cirrhosis, HCC, chronic kidney disease, and cardiovascular disease. MASLD and MASH are strongly linked to T2DM and obesity, pathogenesis including genetic polymorphisms, environmental factors, and multiple metabolic disturbances: insulin resistance (IR), gut dysbiosis, altered adipokine signaling, such as reduced adiponectin alongside increased pro-inflammatory cytokines. Inflammation plays a central role in the development of HCC in MASH, even in the absence of significant fibrosis. The Fibrosis-4 index (FIB-4) should be used as a first-line noninvasive tool to assess fibrosis risk. Additionally, ultrasound-based transient elastography (FibroScan) supports clinicians in assessing steatosis and fibrosis severity. Histologically, MASH is characterized by steatosis, lobular inflammatory changes, and ballooning degeneration of hepatocytes, with or without associated fibrosis. Accurately diagnosing and stratifying MASLD based on fibrosis risk is crucial to identify patients who may benefit from pharmacological treatment or can be managed only with lifestyle interventions. Patients should attain above 10% weight loss through lifestyle modifications. Resmetirom is recommended in F2/F3 fibrosis stages. For treating T2DM, glucagon-like peptide-1 receptor agonists and coagonists, sodium-glucose cotransporter-2 inhibitors, metformin (if glomerular filtration rate exceeds 30 mL/min), and insulin (in decompensated cirrhosis) are preferred. Clinical insights derived from trials are expected to optimize quality of life and long-term outcomes in patients with MASH.

Discovery and Preclinical Evaluation of TPM003: A Novel GLP-1/GIP/Glucagon Triple Hormone Receptor Agonist with Robust Efficacy in Obesity and NASH.

Nan Zheng, Longfang Tu, Pu Xu +9 more

Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential.

Multi-target incretin-based therapeutics: The rise of dual and triple agonists for metabolic disorders.

Seyed Ebrahim Alavi, Reza Boshrouyeh, Aun Raza +1 more

Dual and triple incretin-based therapies are transforming treatment for type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. By targeting glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors, these agents enhance glycemic control, reduce body weight, and improve liver outcomes. Drugs like tirzepatide and retatrutide have shown unprecedented efficacy and tolerability. This review summarizes their mechanisms, clinical progress, and limitations, highlighting how dual and triple incretin agonists may extend or refine the therapeutic benefits established by current GLP-1-based therapies. While challenges remain in safety, accessibility, and long-term use, multi-target agonists represent a promising future in metabolic disease management.

Effects of glucagon-like peptide-1 receptor agonists on patients with metabolic dysfunction-associated steatohepatitis: protocol for a systematic review and sequential meta-analysis.

Mei-Jun Wang, Yu-Nuo Jiang, Pei-Pei Li +1 more

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive subtype of steatotic liver disease, imposes a substantial global health burden due to its association with obesity and metabolic syndrome. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate therapeutic potential through pleiotropic mechanisms, including appetite regulation, metabolic enhancement, and anti-inflammatory activity. However, clinical evidence remains limited by methodological heterogeneity and insufficient long-term efficacy data, necessitating a rigorous systematic evaluation.

Advances in Incretin-Based Therapies for MAFLD: Mechanisms and Clinical Evidence.

Wenqi Dong, Haiming Zhang, Shaowei Mu +3 more

The global prevalence and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), are steadily rising, making them the most common chronic liver diseases worldwide. However, therapeutic options for MAFLD are currently limited. Glucolipid dysregulation drives MAFLD pathogenesis through intertwined glucose metabolic imbalance and lipid accumulation. Patients with type 2 diabetes mellitus (T2DM) are particularly prone to developing MASH and are at a higher risk of progressing to cirrhosis and hepatocellular carcinoma. The coexistence of MAFLD and T2DM correlates with clinical prognosis and elevates the risk of extrahepatic complications. Given the close association between MAFLD and T2DM, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been approved for the treatment of T2DM and obesity, were the first to be investigated in patients with MAFLD/MASH. Recently, beyond GLP-1RAs, novel combination agents integrating glucose-dependent insulinotropic peptide receptor (GIPR) and/or glucagon receptor (GCR) agonists have also been explored. A large number of phase II randomized clinical trials have demonstrated significant improvements in body weight, insulin resistance, and liver parameters. Thus, GLP-1RAs and dual/triple agonists are promising for MAFLD/MASH, especially in those with obesity or T2DM. This study explores mechanisms and clinical evidence of incretin-based therapies for MAFLD by targeting its core pathogenesis-glucolipid disorders. With growing evidence, it also forecasts the broad clinical prospects on MAFLD treatment.

Multidisciplinary care of pediatric obesity and its impact on sleep: a review.

Ravali Inja, Christopher Cielo

Pediatric obesity has emerged as a significant global health issue with multifaceted consequences, including its impact on sleep health. Obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) are among the serious sleep-related comorbidities in obese children, contributing to impaired quality of life, cognitive deficits, and cardiovascular risks. These conditions frequently coexist with other obesity-related complications such as insulin resistance, type 2 diabetes, hypertension, and non-alcoholic fatty liver disease (NAFLD). This review explores the importance of multidisciplinary care in addressing pediatric obesity, emphasizing early diagnosis, nutritional counseling, physical activity interventions, psychological support, and pharmacologic therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists. The role of global trends, academic performance, and wellbeing clinics are also discussed. Although promising, the use of GLP-1s and surgical interventions in pediatrics remains constrained by limited data, particularly concerning their impact on sleep disorders. Further research is essential to clarify the long-term effects of GLP-1 receptor agonists and bariatric surgery not only on obesity and sleep-related comorbidities such as OSA and OHS, but also on cognitive function, psychosocial wellbeing, and overall health outcomes-thereby informing evidence-based, multidisciplinary approaches to pediatric obesity management.

The Triple-Agonist Revolution: Retatrutide and the Paradigm Shift in Multi-Hormonal Pharmacotherapy for Obesity and Cardiometabolic Comorbidities.

Nila Ganamurali, Sarvesh Sabarathinam

Obesity has emerged as a global health crisis requiring innovative therapeutic strategies beyond conventional approaches. While glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists have redefined pharmacological management, their limitations necessitate further innovation. Retatrutide (LY3437943), a novel triple agonist targeting GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors, represents a transformative advance in obesity pharmacotherapy. Phase 2 trials report unprecedented weight reductions, comparable to bariatric surgery, with additional benefits for metabolic comorbidities such as NASH and cardiovascular disease. Retatrutide exemplifies rational multi-agonist peptide engineering and signals a paradigm shift in systems pharmacology. This perspective underscores the urgent need for scientific engagement, equity considerations, and policy preparedness, positioning retatrutide as a watershed in obesity treatment and a blueprint for future poly-agonist therapies.

Effect of glucagon-like peptide-1 receptor agonists on histologic MASH: A meta-analysis of randomized controlled trials.

Noppachai Siranart, Christopher C Thompson, Pichamol Jirapinyo

Metabolic dysfunction-associated steatohepatitis (MASH) is the most common chronic liver disease worldwide, with a particularly high incidence among individuals with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as effective weight loss agents, with growing evidence suggesting potential benefits in MASH. This study aimed to evaluate the efficacy and safety of GLP-1RAs in improving the histologic features of MASH.

Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review.

Herbert Tilg, Salvatore Petta, Norbert Stefan +1 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) includes a range of liver conditions, progressing from isolated steatosis (characterized by fat accumulation in the liver without inflammation) to metabolic dysfunction-associated steatohepatitis (MASH), which involves fat accumulation and inflammation in the liver. The presence of MASLD is associated with increased morbidity and mortality due to liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers.

Hypothalamic regulation of obesity: Revealing the therapeutic potential of a novel anti-obesity peptide.

Yi Ning Choo, Ram Narayanan, Vetriselvan Subramaniyan

Obesity is a chronic, complex condition defined by excessive fat buildup due to an imbalance between caloric consumption and energy expenditure. The significant global rise in prevalence of obesity is associated with numerous comorbidities, such as cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. Conventional management approaches, including diet, exercise, pharmacotherapy, and bariatric surgery, may demonstrate restricted long-term effectiveness owing to inadequate adherence and physiological adjustments. Recent advancements in neuroscience underscore the hypothalamus as a pivotal regulator of energy balance via essential nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and ventromedial nucleus (VMN). This review examines the therapeutic potential of a new anti-obesity peptide that targets hypothalamic signalling pathways. Preclinical and clinical evidence endorses the utilization of glucagon-like peptide-1 receptor (GLP-1R) agonists and novel multi-receptor drugs such as AMG 133, which integrate GLP-1R activation with glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism. These therapies exhibit improved weight reduction and metabolic enhancement. Moreover, the integration of hypothalamic peptide therapy with lifestyle modifications or post-bariatric care provides synergistic advantages. Notwithstanding favorable results, peptide therapy encounters obstacles such as administration methods, sustained effectiveness, and expense. Overcoming these obstacles is crucial for the effective implementation of peptide-based treatments in sustained clinical obesity control.

GLP-1-based therapies for obesity: Impact on comorbidities or obesity-related diseases.

Nuria Vilarrasa, Silvia Pellitero

Agents targeting the glucagon-like peptide-1 receptor (GLP-1R) are effective in managing metabolic conditions associated with obesity, such as obstructive sleep apnea (OSA), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic kidney disease (CKD). In OSA, studies with first generation GLP-1R agonists (ArGLP-1) and co-agonists (GLP-1/GIP) have demonstrated significant improvements in the apnea-hypopnea index and weight reduction. In MASLD, GLP-1RAs and co-agonists (GLP-1/GIP or GLP-1/glucagon) have shown efficacy in reducing hepatic fat, improving fibrosis, and resolving steatohepatitis, with promising results from trials such as ESSENCE and SYNERGY-NASH. In CKD, semaglutide has been associated with a reduction in renal events and slower disease progression. Beyond their metabolic and cardiovascular benefits, these agents represent a comprehensive approach to treating obesity and its complications, with ongoing research exploring their potential indications in chronic inflammatory diseases such as psoriasis and hidradenitis suppurativa.

Glucagon, the Alpha Cell, and Potential Targets for Diabetes Treatment.

Savita Dhanvantari, E Danielle Dean

Glucagon is a 29-amino acid hormone synthesized and secreted by the pancreatic alpha cell in the islets of Langerhans. It is the primary glucose counter-regulatory hormone, secreted by the alpha cell to maintain euglycemia by stimulating hepatic gluconeogenesis and glycogenolysis. In addition to glucose, the alpha cell senses and responds to a number of inputs, such as paracrine factors, neurotransmitters, and other nutrients, including amino acids, to regulate the secretion of glucagon. Disruption of this fine regulation results in excessive glucagon secretion (hyperglucagonemia) and contributes to the pathogenesis of diabetes. In this mini-review, we summarize the current understanding of glucagon biosynthesis and intracellular trafficking, and we discuss emerging concepts in amino acid sensing and signaling that underpin the biology of the alpha cell and that may provide clues to the control of the hyperglucagonemia of diabetes.

The Proteomic Analysis of Intermittent Fasting Alone or with GLP-1RA in NAFLD Rats.

Yimin Shao, Shengya Xu, Yuanyuan Ma +4 more

Intermittent fasting (IF) and glucagon-like peptide-1 receptor agonists (GLP-1RA) offer effective therapeutic options for nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of alternate-day fasting (ADF) alone and with liraglutide, and to explore the mechanisms behind each treatment.

Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, metabolic dysfunction-associated steatotic liver disease, and other cardio-kidney-metabolic conditions.

Guy W Neff

Glucagon is a pancreatic peptide hormone whose receptor (GCGR) is expressed in the liver, kidney, and, to a lesser extent, various other tissues. Glucagon is well known as the counterpart to insulin in glucose homeostasis. However, recent evidence has revealed other potential roles of glucagon, which include the regulation of amino acid metabolism via a liver-pancreatic alpha cell axis, stimulation of lipolysis and mitochondrial fat oxidation in the liver (and possibly in other tissues), reduction of caloric intake, and an increase in energy expenditure (at least in animal models). These advances in basic science-together with clinical trials that found GCGR antagonists increased body weight, hepatic fat, and serum lipids in people with type 2 diabetes-are driving the development of GCGR-based agonists for the treatment of obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and other cardio-kidney-metabolic diseases. Due to the hyperglycaemic effects of glucagon, these unimolecular compounds also incorporate moieties that activate the glucagon-like peptide-1 (GLP-1) receptor, which stimulates insulin secretion to lower blood glucose levels. In early clinical trials, several GCGR-based multi-agonists (mazdutide, survodutide [being developed by the sponsor of this review], retatrutide) demonstrated substantial efficacy for eliciting weight loss in people with obesity while improving liver health in those with MASLD. However, the physiological and molecular pathways modulated by chronic pharmacological activation of the GCGR in humans remain to be delineated, as do its potential risks. Thus, there is great interest in the ongoing phase 3 clinical trials of these compounds. As data for their safety and efficacy emerge, glucagon's role in energy regulation and lipid metabolism will become clearer, along with warranting a potential new therapeutic option for obesity and MASLD.

A synergic GLP-1/Acylethanolamide-based combined therapy for MAFLD: Studies in rat models.

Marialuisa de Ceglia, Rubén Tovar, Miguel Rodríguez-Pozo +6 more

Obesity remains a major epidemic in developed countries, with metabolic-associated fatty liver disease (MAFLD) as one of its main hepatic consequences. Pharmacological treatments for MAFLD are limited, but modulation of glucagon-like peptide-1 (GLP-1) or acylethanolamide signalling offers promising therapeutic potential, while exerting anti-obesity effects. This study evaluated the effects of a combined therapy using a dual ligand targeting peroxisome proliferator-activated receptor alpha (PPARα) and peripheral cannabinoid receptor 1 (CB1) (OLHHA, acting as a PPARα agonist and CB1 antagonist) in combination with the GLP-1 receptor agonist liraglutide. Our aim was to assess their potential as a multitarget therapy to ameliorate liver dysfunction in an obesity animal model. In Wistar rats, we evaluated the effects of administering 3 mg/kg OLHHA and 25  µg/kg liraglutide, both acutely and chronically (daily for 42 days), in the context of exposure to a high-fat/high-fructose diet. Although both OLHHA and liraglutide individually ameliorated certain hepatic alterations induced by MAFLD, our findings demonstrate that their combined administration was significantly more effective in promoting body weight loss, improving lipid profiles and transaminase levels, and exerting robust antisteatotic effects in obese rats. This enhanced efficacy was evidenced by a marked reduction in hepatic fat content, downregulation of lipogenesis-related enzymes, and upregulation of proteins involved in lipid oxidation. Moreover, OLHHA, either alone or in combination with liraglutide, efficiently restored redox balance disrupted by MAFLD in obese rats. Collectively, these results highlight the potential of this multitarget therapeutic strategy for the treatment of obesity, MAFLD, and their associated comorbidities.

Liraglutide for adults living with obesity.

Nicolás Meza, Javier Bracchiglione, Camila Micaela Escobar Liquitay +13 more

Obesity is a complex chronic condition linked to various comorbidities, such as hypertension, diabetes, and dyslipidaemia, with a significant global burden. Standard treatments, such as diet modifications and physical activity, often have limited effects and poor compliance. Pharmacological options, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), show promise for individuals with obesity. This is one of three reviews investigating GLP-1RAs for adults living with obesity.

Current and Future Implications of Weight Loss Drugs on Liver Disease.

Arvind Bussetty, Nishali Shah, Toni Marie Chandler +2 more

The disease burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represents an unmet need for pharmacotherapies to halt progression or reverse fibrosis. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) are the first to be approved for chronic obesity management and diabetes to be examined in individuals with MASLD/MASH. Successful phase 2 and phase 3 randomized control trials have shown indirect improvements in liver fat, histology, and biomarkers. Over the last few years, newer agents with glucose-dependent insulinotropic peptide agonism and/or glucagon receptor agonism have shown considerable improvements in liver fat content and histology in phase 2 studies. Based on the mounting evidence, single, dual, and triple incretin receptor agonists are promising agents in the treatment of MASLD. In this narrative review, we evaluate weight loss pharmacotherapy for MASLD and then explore the potential for a "positive" disruption that these agents will bring to the existing management of MASLD in patients with obesity.

Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review.

Marcio J Concepción-Zavaleta, Jenyfer M Fuentes-Mendoza, Jhean G Gonzáles-Yovera +7 more

Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). As the global prevalence of obesity continues to rise, the burden of MASLD/MASH is increasing, posing significant challenges to healthcare systems. The use of anti-obesity medications (AOMs) in this population is complex due to altered hepatic metabolism, safety concerns, and potential hepatotoxicity. Recent advances in pharmacologic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), dual GLP-1/glucose-gastric inhibitory polypeptide (GIP) agonists, and triple GLP-1/GIP/glucagon agonists, have shown promising metabolic effects in the general population. Among these, GLP-1 RAs (e.g., liraglutide and semaglutide) consistently demonstrate hepatic benefits, including reductions in hepatic steatosis, improvements in liver enzyme profiles, and attenuation of fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, has shown superior weight loss effects compared to GLP-1 receptor agonist monotherapy, with emerging but still limited data on hepatic outcomes in MASLD/MASH. Retatrutide, a triple agonist, has produced the most pronounced metabolic effects to date, although its impact on liver histology remains underexplored. Other AOMs, such as bupropion-naltrexone and phentermine-topiramate, require cautious use due to potential hepatotoxicity. Importantly, advanced MASLD may alter drug pharmacokinetics, underscoring the need for individualized therapy and close monitoring. This review provides an updated synthesis of the efficacy and safety of current and emerging AOMs in patients with MASLD/MASH and highlights the urgent need for further research to define optimal pharmacological strategies in this high-risk population.

Tirzepatide for metabolic dysfunction-associated steatohepatitis: results from phase II clinical trials and perspectives.

Stefano Fiorucci, Ginevra Urbani

Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities.

Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies.

Mohammad Iftekhar Ullah, Sadeka Tamanna

Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5-20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15-25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences.

Safety Choice Drivers of the Coming Treatment Options for Non-Cirrhotic Metabolic Steatohepatitis.

Alessandra Mangia, Luca V C Valenti

Metabolic dysfunction associated steatohepatitis (MASH), formerly known as NASH, represents one of the leading causes of chronic liver disease worldwide. Its high prevalence is driven by insulin resistance, obesity and type 2 diabetes (T2D) and is associated with cardiovascular disease. The main driver of liver damage is fat accumulation in hepatocytes leading to inflammation and fibrosis development. People with MASH and clinically significant fibrosis (stage F2/F3) are 'at risk' of progressing to cirrhosis and hepatocellular carcinoma and are considered in need of treatment. Metabolic drivers of MASH originating outside the liver, for example, from the adipose tissue and the gut, and genetic heterogeneity contribute to making the prevalent pathogenetic factor difficult to dissect at an individual level. In this scenario, the Food and Drug Administration's conditional approval of the liver-directed thyroid hormone receptor beta agonist Resmetirom as the first pharmacological treatment for MASH last March 2024 and the expected extension of the glucagon-like protein-1 receptor agonist Semaglutide indication from diabetes and obesity to MASH mark a key milestone. Both drugs are also under evaluation by the European Medicines Agency. The proven efficacy of these compounds in clinical trials needs to be balanced against safety profiles and patient preferences. To investigate future trajectories and possible uses as mono-therapy or in combination, we examined available results of clinical trials and real-life studies. Despite the need to await the final results of outcome studies to exclude any possible challenges for both compounds, safety profiles and external factors including reimbursement policies or supply limitations may currently guide the individual choice.

MASLD Pharmacotherapy: Current Standards, Emerging Treatments, and Practical Guidance for Indian Physicians.

Ashish Kumar

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a significant public health issue worldwide, with a pronounced impact in India due to the escalating rates of obesity and type 2 diabetes mellitus (T2DM) driving its prevalence. This condition spans a range of hepatic disorders, from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), accompanied by differing levels of hepatic fibrosis, heightening the likelihood of progression to cirrhosis, liver cancer, and cardiovascular complications. While lifestyle modification remains the cornerstone of MASLD management, pharmacologic therapies are increasingly recognized as essential for patients with progressive disease or those at higher risk of complications. Recent insights into the pathogenesis of MASLD have led to the development of innovative therapies targeting key mechanisms such as hepatic steatosis, insulin resistance, inflammation, and hepatic fibrosis. Several pharmacological agents have shown encouraging results in clinical trials, including thyroid hormone receptor-β agonist resmetirom, glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide, peroxisome proliferator-activated receptor (PPAR) agonists such as pioglitazone and saroglitazar, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and vitamin E. Furthermore, emerging therapies, including the dual incretin agonist tirzepatide and fibroblast growth factor (FGF) analogs, hold the potential to transform future treatment strategies. This review provides a comprehensive overview of current and evolving pharmacologic options for MASLD, with a focus on practical recommendations tailored for Indian physicians. A structured treatment algorithm for noncirrhotic MASLD (F0-F3 fibrosis) is presented, incorporating only drugs currently available in India and stratified based on diabetes status and hepatic fibrosis severity. Given India's vast and diverse patient population, ensuring access to cost-effective therapies remains a challenge, necessitating a pragmatic approach that balances efficacy, affordability, and real-world feasibility. This review serves as a practical clinical guide, equipping physicians with evidence-based recommendations to optimize MASLD management in routine practice.