Retatrutide

BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. METHODS: In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA 1c ) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m 2 . Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA 1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. FINDINGS: Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48·8 years (SD 12·1), mean HbA 1c concentration was 7·9% (SD 1·1), mean duration of diabetes was 2·5 years (SD 4·4), and mean BMI was 35·8 kg/m 2 (SD 7·0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA 1c concentration was -1·69% (SE 0·11) with retatrutide 4 mg, -1·86% (0·10) with 9 mg, and -1·94% (0·08) with 12 mg, versus -0·81% (0·12) with placebo, resulting in estimated treatment differences versus placebo of -0·88% (95% CI -1·18 to -0·59) with retatrutide 4 mg, -1·04% (-1·32 to -0·76) with 9 mg, and -1·12% (-1·39 to -0·85) with 12 mg (all p<0·0001). The mean percentage change from baseline in bodyweight was -11·5% (SE 0·7) with retatrutide 4 mg, -13·9% (0·8) with 9 mg, and -15·3% (0·8) with 12 mg, versus -2·6% (0·5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. INTERPRETATION: Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. FUNDING: Eli Lilly and Company.

OBJECTIVES: Functional co- and tri-agonists at the receptors for GLP-1, GIP and glucagon effectively decrease body weight and hyperglycemia but are associated with adverse gastrointestinal effects related to GLP-1R agonism. Here we report the discovery that obesity can be reversed in the absence of a functional GLP-1R. It propelled the identification of a unimolecular GIPR:GCGR co-agonist lacking GLP-1 activity that corrects obesity in obese mice and rats. METHODS: Selective, dual, and triple sustained-action agonists at GIPR, GCGR and GLP-1R were used to assess body weight and glucose management in diet-induced obese (DIO) wildtype (WT) and GLP-1R knock-out (KO) mice. Indirect calorimetry and pair-feeding studies were used to characterize the magnitude of weight lowering specifically to suppression of food intake relative to energy expenditure. RESULTS: When used in physical co-mixture, selective GIPR agonism interacts with selective GCGR agonism to correct obesity and enhance glycemia in DIO mice. Retatrutide a balanced GLP-1R:GIPR:GCGR triagonist normalized body weight in obese GLP-1R KO mice. BWB3054, a fatty acylated GIPR:GCGR co-agonist, was identified as comparably potent as retatrutide to induce cAMP production at the mGIPR, and 4-fold reduced at mGCGR, but notably more than 100-fold diminished at mGLP-1R. Despite minimal relative GLP-1R potency, BWB3054 reduces excess body weight in obese DIO-mice to a similar degree as that observed for retatrutide in obese GLP-1R KO mice. CONCLUSIONS: Correction of obesity and glycemia in mice without employing GLP-1 agonism was demonstrated by three independent methods (GLP-1R KO with retatrutide, GIPR:GCGR physical co-agonism mixture, and GIPR:GCGR covalent co-agonist) which advocate for the prospect that the adverse GI effects commonly associated with its use might be avoided.

Obesity affects over 2 billion adults globally, with projections indicating that nearly two-thirds of adults will be affected by 2050. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity treatment, achieving weight loss previously considered attainable only with bariatric surgery. However, GLP-1-based therapies have revealed important limitations, including weight loss plateaus, substantial inter-individual variability, and weight regain upon discontinuation, underscoring the need for next-generation approaches. Existing reviews have focused predominantly on approved GLP-1RAs, with limited synthesis of emerging multi-receptor agonists, oral formulations, and body composition-targeted agents, while guidance on treatment personalization and sequencing strategies remains limited. This review examines the evolving landscape of obesity pharmacotherapy beyond injectable GLP-1RAs. Oral GLP-1 agonists, including orforglipron, offer comparable efficacy to injectables while potentially improving global accessibility by eliminating cold-chain requirements and simplifying manufacturing. Multi-receptor agonists represent the most transformative developments: triple agonists such as retatrutide achieve weight reductions of 20-24%, while dual GLP-1/glucagon agonists like survodutide and mazdutide show strong efficacy with particular promise for metabolic-associated steatotic liver disease. Maridebart cafraglutide, combining GLP-1 agonism with glucose-dependent insulinotropic polypeptide (GIP) antagonism, enables once-monthly dosing. The amylin pathway has re-emerged through long-acting analogs (cagrilintide, eloralintide) and unimolecular co-agonists (amycretin), achieving weight reductions up to 24% via distinct neuroendocrine circuits. Body composition optimization through agents like bimagrumab addresses lean mass preservation during potent anorectic therapy. Personalized approaches, including setmelanotide for monogenic obesity, exemplify precision pharmacotherapy. Collectively, these advances signal a shift from appetite-centric weight loss toward integrated metabolic, neuroendocrine, and body-composition-focused disease modification. The next epoch of obesity pharmacotherapy will be defined by multi-receptor strategic combinations, targeted approaches to preserve lean mass, and personalized treatment algorithms. Critical priorities include phenotype-stratified trials, long-term safety surveillance, pediatric obesity research, and implementation science to ensure equitable global access. Balancing pharmacologic innovation with sustainable, equitable implementation remains the defining challenge ahead.

OBJECTIVE/METHODS: Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity. RESULTS: In mice, retatrutide strongly reduced body weight by 31% (p < 0.0001 vs. vehicle), both fat and lean mass, and food and water intake during the first days of treatment, while energy expenditure was not altered significantly. Retatrutide markedly reduced the HOMA-IR index of insulin resistance, hepatic steatosis score, fatty acids, triglycerides, and total cholesterol content. In hamsters, retatrutide altered food preference with increased chow diet intake and decreased high fat/cholesterol diet and 10% fructose water intake. The significant weight loss was associated with a reduction in fat and lean mass, but the lean mass was not different after 5 weeks of treatment with no change in mineral bone density. Retatrutide significantly reduced HOMA-IR, plasma triglycerides, and LDL-cholesterol levels. Although retatrutide did not reduce histopathological scoring, there was a 50% reduction in hepatic triglyceride content (p < 0.01). CONCLUSIONS: Retatrutide demonstrates multiple metabolic benefits in both mouse and hamster models. Our preclinical setting will help to assess the efficacy of novel therapies targeting obesity and MASH.

AIMS: Hypertension and obesity frequently coexist and synergistically increase cardiovascular (CV) risk. Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1-RAs), gastric inhibitory polypeptide (GIP)/GLP1-RAs, and glucagon/GIP/GLP-1RAs lead to substantial weight loss. However, their antihypertensive efficacy and safety profile have not been comprehensively quantified. Our study aimed to evaluate the effects of incretin-based therapies on office systolic blood pressure (BP) (SBP), diastolic BP (DBP), all-cause mortality, and key safety outcomes, i.e. hypoglycaemia and pancreatitis episodes, in adults with overweight or obesity. METHODS AND RESULTS: We searched PubMed, EMBASE, and ClinicalTrial.gov from inception to 30 April 2024 for randomized controlled trials (RCTs) comparing incretin-based therapy with placebo and ≥1 month of follow-up. The primary outcome was change in SBP; secondary outcomes were change in DBP, all-cause mortality, hypoglycaemia, and pancreatitis. Random effects meta-analyses generated mean differences (MDs) or risk ratios (RRs) along with 95% confidence intervals (CIs). Heterogeneity was explored with I2 statistics, subgroup analyses, and meta-regression. Eighty-five RCTs encompassing 90 977 participants (median follow-up time 8 months) met the eligibility criteria. GLP1-RAs reduced SBP by 3.4 mmHg (95% CI 2.8-4.0) and DBP by 0.9 mmHg (95% CI 0.5-1.2). A higher weight loss was significantly associated with a greater reduction in BP. The most significant BP reduction was associated with dual (SBP 5.1 mmHg; DBP 1.8 mmHg) and triple (SBP 6.6 mmHg; DBP 2.1 mmHg) receptor agonists. All-cause mortality was reduced by 18% (RR 0.82, 95% CI 0.76-0.90). Incretin-based therapy did not increase the risk of hypoglycaemia (RR 1.05, 95% CI 0.83-1.33) or pancreatitis (RR 0.84, 95% CI 0.61-1.15). CONCLUSION: Incretin-based therapy led to a modest but clinically meaningful BP reduction and lower all-cause mortality in adults with overweight or obesity, without excess in hypoglycaemia or pancreatitis episodes. There was a significant association between weight loss and the reduction in SBP and DBP. Dual and triple agonists exhibited the most pronounced antihypertensive effect. These findings support the use of incretin-based therapies as part of an integrated and multidisciplinary approach to managing obesity and hypertension, with multiple agonists showing particular promise. Our findings also underscore the need for long-term RCTs to clarify weight-independent mechanisms and the durability effect of BP reduction. Incretin-based therapy, now widely used for weight loss, also modestly reduces blood pressure and mortality, providing an additional health benefit to people with obesity or diabetes.Across 85 clinical trials (more than 90 000 adults), incretin-based therapy lowered systolic blood pressure by about 3 mmHg; the most significant falls occurred with the dual and triple agonists, and every kilogram lost made the reduction larger.Incretin-based therapy use was associated with an 18% lower mortality, with no increase in hypoglycaemia or pancreatitis episodes, supporting their safe dual role in weight control and cardiovascular protection.

RATIONALE: Alcohol use disorder (AUD) remains a major public health challenge, yet effective pharmacotherapies are limited. As such, there is growing interest in repurposing medications with novel mechanisms of action. Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for type 2 diabetes, have emerged as promising candidates due to effects on intake regulation and reward processing. GLP-1 receptor agonists, including semaglutide, reduce alcohol intake and relapse-like behaviors in rodent and non-human primate models, and a recent clinical trial found that semaglutide decreased alcohol craving and drinking in adults with AUD. Modulation of the subjective/interoceptive effects of alcohol may contribute to the therapeutic potential of GLP-1 receptor agonists. OBJECTIVES: This study used operant drug discrimination in male and female rats to assess how acute and repeated semaglutide treatment affects alcohol's discriminative stimulus (interoceptive) effects. We hypothesized that GLP-1 receptor activation would disrupt alcohol's interoceptive effects. We also evaluated acute treatment with tirzepatide, a dual GLP-1/gastric inhibitory peptide (GIP) receptor agonist, and retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, to determine whether broader receptor activity would differentially influence alcohol's subjective effects. RESULTS: Acute administration of semaglutide, tirzepatide, and retatrutide each attenuated alcohol discrimination, suggesting modulation of subjective alcohol effects. Repeated semaglutide maintained efficacy across the 15-day treatment period; alcohol discrimination returned to control levels three days after treatment cessation. CONCLUSIONS: Building on prior work with GLP-1 receptor agonists, these results provide important context for interpreting clinical observations of reduced drinking behavior among individuals receiving this class of therapeutics.

BACKGROUND: Retatrutide, a novel GIP, GLP-1, and glucagon receptor triple agonist, exhibits unprecedented weight-reducing efficacy in clinical trials, yet the molecular basis of its systemic metabolic benefits remains unclear. METHODS: Using a high-fat diet–induced obesity mouse model, we investigated the effects of Retatrutide on adipose tissue through integrated physiological, histological, transcriptomic, and metabolomic analyses. RESULTS: Retatrutide markedly reduced body weight and adiposity and improved metabolic parameters including glucose homeostasis and dyslipidemia. Multi-omic profiling revealed a coordinated reprogramming of epididymal white adipose tissue, characterized by suppressed lipogenesis, enhanced fatty acid oxidation and mitochondrial function, restored peroxisomal activity, and downregulated inflammatory/fibrotic pathways while promoting angiogenic/reparative signaling. Metabolomic analysis further demonstrated clearance of lipotoxic intermediates, decreased pro-inflammatory lipids, reduced collagen-derived metabolites, and elevated anti-inflammatory 15-HETE, confirming metabolic restoration at multiple regulatory levels. CONCLUSIONS: Retatrutide transforms dysfunctional white adipose tissue into a metabolically competent organ by simultaneously enhancing lipid oxidation, suppressing inflammation and fibrotic remodeling, and restoring endocrine function. These findings identify adipose tissue as an important therapeutic target of triple incretin agonism and establish tissue quality restoration—rather than mere mass reduction—as a new therapeutic paradigm for obesity and related metabolic disorders.

Incretin-based therapies have revolutionised the management of metabolic disorders, transitioning from DPP-4 inhibitors to advanced GLP-1 receptor agonists (GLP-1RAs) and next-generation dual and triple agonists. This review explores the evolving role of incretin pharmacology in type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD). Literature from PubMed, Scopus, and Google Scholar up to July 2025 was reviewed, emphasising pivotal trials and real-world evidence. While DPP-4 inhibitors offer modest glycaemic benefits, GLP1RAs such as liraglutide and semaglutide have demonstrated significant weight loss and cardiometabolic protection. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide have shown unprecedented efficacy, with up to 24% body weight reduction and improvement in hepatic and inflammatory markers. Agents like cotadutide and efinopegdutide further expand indications to MASLD and metabolic dysfunction associated steatohepatitis (MASH). Despite promising outcomes, challenges persist in terms of cost, accessibility, and the underrepresentation of low- and middle-income countries in major trials. Pharmacogenomic variability may also influence therapeutic response. Incretin-based multi-agonists offer a transformative, multi-system approach to metabolic disease but require tailored implementation. This review provides an updated synthesis of therapeutic developments and outlines priorities for future research, regulatory policy, and equitable global integration as incretin-based therapies have evolved into a versatile class addressing glycaemic control, weight loss, and cardio-metabolic risk.

Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1 RAs such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.

PURPOSE OF REVIEW: Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent among individuals with type 2 diabetes (T2D). This review summarizes current evidence on the pharmacologic treatment of MASLD, with emphasis on agents currently approved for the management of T2D. RECENT FINDINGS: Among glucose-lowering therapies, GLP-1 RAs, dual GIP/GLP-1 RAs, pioglitazone, and SGLT2 inhibitors demonstrate meaningful benefits in steatohepatitis. Semaglutide provides the most robust evidence for fibrosis benefit, while data suggest potential antifibrotic effects of tirzepatide and dapagliflozin. Resmetirom and semaglutide are the only agents specifically approved for MASLD. An expanding pipeline of dual glucagon/GLP-1 and triple GIP/GLP-1/glucagon agonists such as retatrutide has shown marked reductions in liver fat and signals of MASH benefit. Additional therapies, including pan-PPAR agonists, and FGF21 analogues are advancing through phase 3 development. The therapeutic landscape is rapidly evolving toward integrated metabolic, hepatic, and cardiovascular risk reduction in T2D and MASLD.

The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.

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.

Obesity is a chronic and relapsing disease associated with medical complications and mortality. Our improved understanding of the relevance of the gut-brain axis in regulating appetite and body weight has encouraged research into nutrient-stimulated gastroenteropancreatic hormones as a new therapeutic arsenal for the treatment of people living with obesity. Beyond the necessary lifestyle changes, this new era with second-generation drugs has been able to achieve weight loss of 15-25%, close to that of bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists (RA), used as weekly injectable monotherapy or daily oral (semaglutide), achieve weight loss of 15-17%, with a good safety profile. The synergistic combination with other hormones (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, or amylin) will allow to increase weight loss, as well as improve cardiometabolic variables. Tirzepatide (a dual GLP-1/GIP receptor agonist) achieves weight loss of up to 22.5% at the highest doses. In this same range of weight loss, it is expected that it can be achieved with the combination of Cagrisema (cagrilintide 2.4mg plus semaglutide 2.4mg), combinations of GLP-1 RAs - glucagon agonists or with the triple combination of GLP-1 RAs-GIP-Glucagon (Retatrutide). In this review, we will examine the efficacy and safety of the drugs marketed and others under ongoing clinical trials for the treatment of persons with obesity, as well as the main challenges faced by both healthcare professionals and patients in maintaining long-term treatment.

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios.

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.