Incretin-based therapies in hepatology practice

Abstract

Glucagon-like peptide-1 receptor agonists and dual incretin therapies are now encountered routinely in hepatology, well beyond their initial use as glucose-lowering agents. Their relevance to steatotic liver disease is largely indirect. By reducing obesity, insulin resistance, adipose tissue dysfunction, systemic inflammation and cardiometabolic risk, they address several processes underpinning metabolic dysfunction-associated steatotic liver disease and, in some patients, metabolic dysfunction-associated steatohepatitis. Biopsy-based trials have shown improvement in steatohepatitis activity, while recent studies of semaglutide, tirzepatide and glucagon-like peptide-1/glucagon co-agonists have also reported favorable fibrosis-related findings. Real-world cohorts suggest lower rates of progression to cirrhosis, decompensation and hepatocellular carcinoma, although the results are inconsistent and remain open to residual confounding. These observations should be interpreted carefully in clinical practice. Loss of body weight or decreased aminotransferase levels should not be treated as proof of hepatic benefit, nor should incretin therapy be regarded as liver-directed treatment on those grounds alone. A more appropriate approach is to place these agents within a fibrosis-based pathway that includes baseline risk assessment, sequential non-invasive testing, attention to nutritional status and frailty, and continued cirrhosis and hepatocellular carcinoma surveillance in patients with established advanced liver disease. This review examines the available evidence and outlines a practical algorithm for hepatology care.

Key Words: Glucagon-like peptide-1 receptor agonists; Tirzepatide; Dual incretin therapy; Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Steatotic liver disease; Liver fibrosis; Hepatocellular carcinoma; Frailty; Resmetirom

Core Tip: Incretin-based therapies are important in hepatology because they act on the metabolic drivers of steatotic liver disease. Their hepatic benefit should be judged by fibrosis-oriented monitoring rather than by weight loss. Histological and real-world data are encouraging, but whether these drugs prevent decompensation, hepatocellular carcinoma, transplantation or liver-related death is unclear. They are best regarded as partners to liver-directed therapy, not as replacements for standard cirrhosis care and surveillance.

INTRODUCTION

Over a short period of a few years, the treatment of type 2 diabetes, obesity and cardiometabolic disease has reorganized itself around glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, more recently, around dual incretin therapies[1-3]. These new treatments are also relevant to hepatology because metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are no longer considered liver diseases that occur in metabolically unwell patients, but as one organ manifestation of a systemic disorder. Obesity, type 2 diabetes, insulin resistance, a failing adipose compartment, dyslipidemia and chronic low-grade inflammation all feed the same process[4-6].

These changes are already visible in everyday clinics. Many patients referred because of abnormal liver tests, incidental steatosis on ultrasound, metabolic syndrome or suspected MASH are prescribed semaglutide, liraglutide, dulaglutide or tirzepatide, and a smaller number may be receiving newer dual or triple agonists. At the same time, clinicians managing obesity and diabetes are increasingly identifying MASLD, at-risk MASH or even advanced fibrosis in people who have never undergone formal liver assessment. Therefore, the clinically useful question is not whether incretin therapies belong to diabetes care or hepatology; it is how their metabolic effects should be incorporated into liver risk stratification and long-term follow-up.

Within the broader steatotic liver disease framework, fibrosis stage remains the strongest predictor of liver-related outcome in MASLD[4-6]. This has an important implication for interpreting treatment response. Weight may fall, alanine aminotransferase (ALT) may improve, glycemic control may improve and steatosis may appear less marked on ultrasound, yet none of these changes demonstrates regression of clinically significant fibrosis or a decreased risk of future liver events. Therefore, in hepatology practice, incretin therapy should be accompanied by non-invasive fibrosis assessment and repeated risk stratification. Metabolic improvement and improvement in liver prognosis should be evaluated as related but distinct outcomes.

Trials and mechanistic reviews of GLP-1RAs, dual GIP/GLP-1 receptor agonists and GLP-1/glucagon receptor agonists indicate improved steatohepatitis activity and, in some settings, fibrosis-related endpoints[7-12]. In parallel, a rapidly growing body of real-world work has moved on to the most important outcomes: Progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC) and mortality[13-18]. These cohort studies warrant a skeptical reading, as residual confounding, heterogeneous comparators, treatment selection, coding accuracy, adherence and length of follow-up can each shape the reported association. This review addresses the hepatology-specific questions raised by these data and proposes a working framework for MASLD/MASH care.

SCOPE AND LITERATURE BASIS

This is a narrative review of the roles for GLP-1RA and dual incretin therapy in hepatology practice. It was built around current guideline statements, mechanistic reviews, histology-based MASH trials, real-world liver outcome studies and special populations with practical clinical problems. Topics such as gastrointestinal endoscopy, perioperative aspiration risk, pediatric obesity and non-hepatic pharmacokinetics were screened for relevance but omitted from the main text unless they were directly relevant to liver care.

RELATIONSHIP BETWEEN INCRETIN-BASED THERAPIES AND HEPATOLOGY

Nearly everything that makes these drugs interesting to hepatologists is metabolic. They blunt appetite and energy intake, produce substantial weight loss, improve glycemic control and insulin sensitivity, and appear to act favorably on lipid handling and systemic inflammation[1-3,7]. Therefore, they simultaneously address several of the main drivers of MASLD/MASH.

It is important not to infer a direct hepatic effect. Mechanistic reviews indicate that hepatocytes, Kupffer and hepatic stellate cells do not express canonical GLP-1 receptor, suggesting indirect routes: Weight reduction, adipose tissue remodeling, improved insulin sensitivity, reduced lipotoxic load and modulation of inflammatory signaling[7,8]. Immune-metabolic and anti-inflammatory hypotheses have also been proposed[9-11], and while plausible, receptor signaling has not been demonstrated in the human liver.

One practical corollary follows. Weight loss is a poor proxy for hepatic response. A patient may lose substantial weight and still carry significant liver-related risk because of advanced fibrosis, coexisting sarcopenia, continued alcohol intake or poorly controlled diabetes. The reverse can also be true: A real metabolic improvement may quieten liver disease while aminotransferase levels do not change. Response is best judged by reading metabolic, biochemical, imaging and fibrosis-related information together, not a single parameter.

MECHANISTIC PATHWAYS LINKING INCRETIN THERAPY TO LIVER DISEASE

There are several overlapping mechanisms, none of which operates in isolation. Weight loss is the most obvious. Removing adipose mass decreases hepatic triglyceride content and improves insulin resistance, and sustained weight reduction remains the best documented non-pharmacological route to improve steatosis and steatohepatitis; when the loss is large enough, fibrosis risk may also decrease. Incretin-based drugs deliver weight loss of that magnitude in a substantial proportion of patients, making them important in obesity and metabolic dysfunction-driven liver disease[7-11].

Glycemic control independently contributes. Hyperglycemia feeds de novo hepatic lipogenesis and glucotoxic injury, and type 2 diabetes is among the strongest clinical predictors of MASH, advanced fibrosis and adverse liver-related outcomes. Therefore, an agent that simultaneously lowers glucose and body weight acts on two fronts[4-6].

Adipose tissue is likely to have a central role. As adipose function deteriorates, delivery of free fatty acids to the liver increases, adipokine signaling becomes abnormal, insulin resistance deepens and low-grade inflammation is maintained. Reducing adiposity and improving insulin sensitivity within adipose tissue would therefore be expected to decrease the lipotoxic burden on hepatocytes[7-11].

Dual and triple agonists extend the same logic. Tirzepatide adds GIP agonism to GLP-1 receptor agonism, while glucagon/GLP-1 co-agonists, and triple agonists that also engage GIP receptors, are designed to further enhance weight loss, energy expenditure, insulin sensitivity and hepatic fat reduction[9-11]. Whether this additional pharmacology translates into improved fibrosis outcomes, and at what cost to long-term tolerability, remains unknown.

HISTOLOGY-BASED EVIDENCE IN MASH

Histology remains the reference point in MASH because neither aminotransferase levels nor liver fat content reliably track with inflammation or fibrosis. Most incretin-based agents have now been through biopsy-controlled trials.

Proof of concept came first from the LEAN trial, in which liraglutide improved non-alcoholic steatohepatitis (NASH) resolution compared with placebo and slowed fibrosis progression[19]. Semaglutide followed, improving NASH resolution in patients with non-cirrhotic disease in an earlier phase 2 study, although its effect on fibrosis was limited[20]. ESSENCE, a phase 3 trial, subsequently met both histological endpoints at week 72 on semaglutide 2.4 mg weekly: Resolution of steatohepatitis without worsening of fibrosis and improvement in fibrosis stage without worsening of steatohepatitis in patients with biopsy-confirmed MASH and stage 2 or 3 fibrosis[21].

Cirrhosis has been a different story. In patients with compensated MASH-related cirrhosis, the same weekly dose improved neither fibrosis nor NASH resolution during the trial period[22]. This finding does not rule out metabolic benefits for individual patients, but it does mark an important boundary. Once architectural distortion, portal hypertension, sarcopenia and the risk of decompensation are established, the disease behaves, and must be managed, differently.

Tirzepatide produced dose-dependent improvements in both endpoints, resolving MASH without worsening fibrosis and reducing fibrosis by at least one stage without worsening MASH in patients with biopsy-confirmed F2 or F3 disease[23]. Survodutide, a dual glucagon and GLP-1 receptor agonist, produced similar histological improvements in MASH and fibrosis-related endpoints[24]. Together, these trials suggest that gut hormone-based therapies may become genuinely disease-modifying in pre-cirrhotic MASH.

Resmetirom has changed how these findings should be interpreted. By acting directly on thyroid hormone receptor beta in the liver, it has demonstrated phase 3 histological efficacy in non-cirrhotic NASH with fibrosis[25] and now occupies the liver-directed therapeutic niche. Incretin-based agents are better positioned as metabolic disease-modifying drugs that may complement liver-directed therapy than as MASH-targeted treatments in their own right.

The caveat is familiar: Histological improvement is a surrogate, and whether these drugs reduce hepatic decompensation, HCC, the need for transplantation, or liver-related mortality remains unknown. HCC brings the uncertainty into sharpest focus, as MASLD-related tumors typically arise in the setting of advanced fibrosis but can develop before cirrhosis is established. Whether metabolic improvement alters that trajectory remains unresolved.

REAL-WORLD LIVER OUTCOMES

Randomized trials establish histological efficacy but are poorly suited to assessing liver-related events, which are uncommon and take years to accrue. Observational studies have begun to fill this gap, with the usual caveats regarding study design, comparator selection, baseline liver disease, and the adequacy of confounding control.

Among veterans with MASLD and diabetes, GLP-1RA use was associated with lower risks of progression to cirrhosis and death, but only in those without cirrhosis at treatment initiation; no such association was observed in those with established cirrhosis[13]. This distinction is clinically instructive and consistent with the trial data: Metabolic intervention appears to be most effective before cirrhosis develops.

A target trial emulation using a large electronic health record network compared tirzepatide, semaglutide, and liraglutide with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and no prior major adverse liver outcomes. Tirzepatide and semaglutide were associated with fewer such outcomes, with a weaker association observed for liraglutide[14]. Among patients with both MASLD cirrhosis and type 2 diabetes, initiation of a GLP-1RA was associated with fewer adverse liver events, including decompensation, HCC and transplantation, subject to the usual limitations of observational studies[15]. A third emulation, again involving adults with both diagnoses, found fewer hepatic and extrahepatic complications with GLP-1RA treatment[16].

Meta-analyses generally point in the same direction but do not resolve the uncertainty. In pooled cohort data from patients with type 2 diabetes, HCC and hepatic decompensation occurred less often among GLP-1RA users, whereas associations with incident cirrhosis and hepatic failure were less consistent[17]. Another meta-analysis examining HCC and hepatic decompensation also favored GLP-1RAs but emphasized that the included studies were heterogeneous and predominantly observational[18].

The overall signal is therefore promising but not definitive. Target trial emulation and active-comparator, new-user designs represent substantial improvements over conventional observational analyses. Even so, they cannot fully account for residual confounding, misclassification of liver disease severity, variation in adherence or treatment duration, or healthy-user bias. These studies are valuable for generating hypotheses and informing clinical pathways, but randomized outcome trials are needed before causal conclusions can be drawn.

HCC AND CANCER-RELATED CONSIDERATIONS

HCC warrants particular caution. In a large real-world analysis of patients with type 2 diabetes, GLP-1RA use was associated with lower risks of HCC and hepatic decompensation than several other antidiabetic treatments[26]. A nationwide target trial emulation likewise found lower risks of cirrhosis and HCC compared with long-acting insulin[27]. These findings are biologically plausible because incretin therapies improve obesity, diabetes, hepatic steatosis and systemic inflammation, all of which contribute to modifiable HCC risk.

Not all evidence is consistent. In a propensity-matched cohort of veterans comparing initiation of GLP-1RAs with DPP-4 inhibitors, newly diagnosed HCC was modestly more common in the GLP-1RA group[28]. This finding conflicts with most other observational reports and should not be interpreted as evidence of causation, but it underscores the need for long-term, cancer-specific safety surveillance. For now, GLP-1RAs should not be considered chemopreventive agents; their effect on HCC risk remains uncertain, and surveillance should continue to be guided by fibrosis stage and cirrhosis status.

ALCOHOL-RELATED LIVER DISEASE AND METABOLIC AND ALCOHOL-ASSOCIATED LIVER DISEASE

The effects of incretin therapy in alcohol-related liver disease remain unclear. In patients with harmful alcohol use, one target trial emulation found GLP-1RA exposure to be associated with a lower risk of the composite liver endpoint and all-cause mortality, as well as lower odds of a positive follow-up alcohol screen[29]. By contrast, a cohort study of veterans with both alcohol use disorder and diabetes found no differences in progression to cirrhosis or hospitalization for an alcohol-related cause compared with DPP-4 inhibitor initiation[30].

The two studies differed in population, comparator, definition of alcohol exposure, endpoints and duration of follow-up, any of which could account for the divergent results without implying a true difference in drug effect. The practical position remains unchanged: GLP-1RA therapy may have a role in metabolic and alcohol-associated liver disease, including in patients with both metabolic and alcohol-related risk factors, but it is not a treatment for alcohol use disorder and does not replace cessation support or standard chronic liver disease care.

NON-INVASIVE RISK STRATIFICATION AND MONITORING

Fibrosis stage should guide the clinical pathway. Current recommendations support active case-finding in patients with cardiometabolic risk factors, unexplained aminotransferase elevations, or steatosis detected on imaging, with particular attention to those with obesity or type 2 diabetes[4,6]. Assessment generally proceeds in stages: A simple blood-based score such as the Fibrosis-4 Index (FIB-4) is used first, followed, when indicated, by transient elastography or another measure of liver stiffness to help rule in or rule out advanced fibrosis[4,6].

This assessment should be performed before incretin therapy begins or shortly thereafter. A practical baseline evaluation includes alcohol history, weight and body mass index or waist circumference, blood pressure, diabetes status, glycated hemoglobin (HbA1c), lipid profile, ALT, aspartate aminotransferase (AST), platelet count, and FIB-4, together with any available imaging evidence of steatosis, prior elastography results and features suggestive of portal hypertension.

Patients with a low FIB-4 and no other concerning features can continue metabolic treatment with periodic reassessment. An indeterminate or high FIB-4, persistently elevated aminotransferases, thrombocytopenia, splenomegaly, suggestive imaging findings, or physical signs of chronic liver disease should prompt second-line testing with transient elastography or the Enhanced Liver Fibrosis (ELF) test, or referral to hepatology[4,6]. When at-risk MASH or significant fibrosis is suspected, treatment discussions should address both liver-directed and metabolic therapies.

Monitoring during treatment should not be reduced to ALT alone. Normalization of aminotransferase levels is encouraging but provides limited information about fibrosis, just as weight loss alone does not define liver-related risk. Metabolic response, tolerability, liver enzymes, platelet count, FIB-4 trajectory, elastography when indicated, and assessment for complications of cirrhosis in patients with advanced disease should all be reviewed together. Table 1 summarizes the hepatology-relevant effects and associated uncertainties.

Table 1 Hepatology-relevant effects of glucagon-like peptide-1 receptor agonist and dual incretin therapy.

Pathology	Potential benefit	Clinical uncertainty	Practical hepatology action
Obesity	Reduced hepatic fat and metabolic stress	Lean mass loss and frailty risk, particularly with rapid or unstructured caloric restriction	Monitor body composition risk; encourage protein intake and resistance exercise
Glycemic control	Reduced glucotoxicity and insulin resistance	Effect on fibrosis outcomes varies across agents and populations	Combine metabolic and fibrosis-based monitoring; do not rely on HbA1c alone
Steatohepatitis	Improved disease activity in histology-based trials	Durability and long-term clinical outcomes remain uncertain	Interpret histological and non-invasive test responses cautiously
Fibrosis	Signals of improvement with semaglutide, tirzepatide, and survodutide in selected non-cirrhotic populations	Fibrosis regression is less consistent than steatohepatitis resolution and may depend on disease stage	Use FIB-4 and elastography-based longitudinal follow-up
Cirrhosis	Possible metabolic benefit in selected patients	Limited histological efficacy in established compensated MASH cirrhosis	Continue standard cirrhosis care, HCC surveillance, and decompensation monitoring
HCC risk	Observational studies suggest possible risk reduction in some diabetic and MASLD populations	Findings are inconsistent and not sufficient to support chemoprevention claims	Maintain guideline-based HCC surveillance; treat HCC risk as unresolved
MASH pharmacotherapy	Potential complement to liver-directed drugs such as resmetirom	Optimal sequencing and combination therapy remain uncertain	Individualize according to fibrosis stage, metabolic indication, and local approval

MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; MASLD: Metabolic dysfunction-associated steatotic liver disease; FIB-4: Fibrosis-4 index; HbA1c: Glycated hemoglobin.

Because GLP-1 receptor agonists slow gastric emptying, they can alter the rate and extent of absorption of co-administered oral medications. This is particularly relevant in patients with chronic liver disease who receive drugs with a narrow therapeutic index or that require careful titration, including immunosuppressants in liver transplant recipients, oral anticoagulants, and diuretics used to manage ascites. Closer monitoring is advisable when incretin therapy is initiated or up-titrated.

THERAPEUTIC SEQUENCING WITH MASH-DIRECTED DRUGS

The therapeutic landscape is being redrawn. Resmetirom provides a liver-directed pharmacological option, whereas GLP-1RAs and dual or triple agonists target the metabolic environment that drives liver injury[4,12,25]. In principle, these approaches are complementary rather than competing.

In patients with obesity or type 2 diabetes and MASLD/MASH, incretin therapy can be justified on metabolic grounds alone, regardless of whether liver-directed treatment is indicated. In non-cirrhotic MASH with significant fibrosis, liver-directed therapy may be added where approved and clinically appropriate, while incretin therapy continues to address obesity, diabetes and cardiometabolic risk[4,12,25].

Therapeutic sequencing remains unsettled, and a pragmatic approach is to identify the dominant clinical problem. Severe obesity or poorly controlled diabetes favors starting with incretin therapy. Biopsy-confirmed at-risk MASH with significant fibrosis, or a reliable non-invasive equivalent, favors liver-directed treatment, guided by current recommendations, local approval, contraindications, tolerability and patient preferences. Combining the two approaches is biologically attractive but remains untested.

ADVANCED FIBROSIS, CIRRHOSIS, AND HCC SURVEILLANCE

Cirrhosis calls for restraint. In the phase 2 trial of patients with cirrhosis, semaglutide improved neither fibrosis nor NASH resolution[22], and current guidance does not extend MASH-targeted pharmacotherapy to cirrhotic disease as it does to non-cirrhotic MASH with significant fibrosis[4]. Incretin therapy may still be appropriate for treating diabetes or obesity in these patients, but it does not replace cirrhosis care.

That care remains unchanged: HCC surveillance, assessment of portal hypertension, variceal screening when indicated, management of ascites or encephalopathy, vaccination, nutritional assessment, and timely consideration of transplantation[6]. In patients with advanced fibrosis or cirrhosis, weight loss during incretin therapy can create a misleading impression of improvement. Surveillance should remain guided by fibrosis stage and standard cirrhosis care, not by weight or ALT alone.

HCC warrants particular emphasis. MASLD-related HCC is strongly associated with advanced fibrosis and cirrhosis, and metabolic improvement does not eliminate previously accumulated carcinogenic risk. Observational findings suggesting a lower incidence of HCC with GLP-1RAs remain hypothesis-generating, and the discordant results underscore the need for longer follow-up and cancer-specific endpoints[17,18,26-28].

OLDER ADULTS, FRAILTY, AND NUTRITIONAL RISK

Older adults require particular consideration because MASLD/MASH in this population commonly coexists with diabetes, cardiovascular disease, chronic kidney disease, sarcopenia and polypharmacy. GLP-1RAs may be beneficial because they carry a low intrinsic risk of hypoglycemia and can address several comorbidities, potentially simplifying the medication regimen[31]. However, these patients may be particularly vulnerable to dehydration, reduced food intake, gastrointestinal adverse effects, falls, and loss of muscle mass, all of which may increase the likelihood of treatment discontinuation.

In MASLD/MASH, weight reduction is beneficial, but the composition of the weight lost matters. Incretin-based therapies can reduce lean mass as well as fat mass, which is clinically relevant in older adults, patients with chronic liver disease, and anyone already at risk of sarcopenia[32,33]. Without appropriate monitoring, a patient may improve metabolically while losing strength and functional reserve.

For this reason, nutritional status should be assessed before treatment and monitored during follow-up in patients with advanced fibrosis or cirrhosis, older adults, and those with frailty. Management should include adequate protein intake, resistance exercise, medication review, and periodic assessment for sarcopenia. In patients with cirrhosis, nutritional targets should be individualized, and prolonged fasting, severe calorie restriction, and rapid muscle loss should be avoided.

RENAL IMPAIRMENT AND CARDIORENAL CONTEXT

Cardiovascular risk is integral to the hepatological management of MASLD/MASH, as these patients have a substantial burden of atherosclerotic disease and cardiovascular events remain a leading cause of death. Dedicated cardiovascular outcome trials have established that GLP-1 receptor agonists reduce major adverse cardiovascular events. Liraglutide in LEADER and once-weekly semaglutide in SUSTAIN-6 reduced cardiovascular events in patients with type 2 diabetes at high cardiovascular risk[34,35]. SELECT extended this benefit to patients with overweight or obesity and established cardiovascular disease but without diabetes, demonstrating a 20% reduction in the primary composite endpoint[36]. For hepatologists, these findings reinforce that incretin therapies target shared cardiometabolic drivers and that treatment decisions in MASLD/MASH should consider hepatic and cardiovascular outcomes together rather than liver-related outcomes in isolation.

Renal impairment is common among patients with diabetes, obesity, and MASLD and influences hepatology practice through treatment selection, susceptibility to dehydration, and management of cirrhosis-related complications. In randomized trials involving patients with chronic kidney disease, GLP-1RAs have improved composite renal and cardiovascular outcomes and survival[37]. A Cochrane review also found clinically relevant cardiorenal benefits in patients with diabetes and chronic kidney disease, although the certainty of evidence and the magnitude of effect varied by outcome and comparator[38].

Observational renal data are less straightforward. Compared with DPP-4 inhibitors, sulfonylureas, or basal insulin, GLP-1RA initiation has generally been associated with more favorable outcomes. This advantage is less clear when sodium-glucose cotransporter-2 inhibitors are used as the comparator, particularly for some renal endpoints[39]. For hepatologists, the practical goal is not to rank these drug classes in isolation but to consider kidney function, cardiovascular risk, glycemic control, volume status, cirrhosis stage, and concomitant medications together.

REAL-WORLD ADHERENCE, PERSISTENCE, AND ACCESS

Outcomes achieved in clinical trials are not always reproduced in routine care. Patients may discontinue treatment, remain below the target dose, experience adverse effects, encounter drug shortages or financial barriers, or be lost to follow-up. Consequently, real-world weight loss and treatment persistence are generally lower than trial estimates[33,40]. This gap is particularly relevant in MASLD/MASH, as sustained hepatic benefit is likely to depend on durable metabolic improvement.

Treatment persistence is therefore relevant to hepatology as well as obesity medicine. When therapy is discontinued because of nausea, constipation, reflux or cost, the expected cardiometabolic and potential hepatic benefits are interrupted. Practical measures include setting realistic expectations, titrating the dose gradually, discussing potential adverse effects in advance, and managing gastrointestinal symptoms promptly.

Access is the other half of the equation. MASLD/MASH is a population-level disease, whereas incretin-based therapies are expensive and unevenly accessible. If these drugs reach only a fraction of the patients who need them, their public health impact will be substantially smaller than their efficacy in clinical trials would suggest. Affordability, treatment durability, and implementation are therefore clinical concerns rather than merely administrative ones.

PRACTICAL HEPATOLOGY ALGORITHM

Figure 1 summarizes a practical hepatology algorithm. Patients receiving or being considered for GLP-1RA or dual incretin therapy should also be assessed for obesity, type 2 diabetes, elevated liver enzymes, imaging-detected steatosis, harmful alcohol use, and other cardiometabolic risk factors. Baseline assessment should include alcohol intake, metabolic risk factors, weight and body mass index or waist circumference, ALT, AST, platelet count, HbA1c, lipid profile, renal function and FIB-4.

Figure 1 Practical hepatology algorithm for patients receiving or being considered for treatment with a glucagon-like peptide-1 receptor agonist or dual incretin therapy. ¹Red flags include persistently abnormal aminotransferase levels, thrombocytopenia, splenomegaly, and imaging or physical findings suggestive of chronic liver disease or portal hypertension. GLP-1RA: Glucagon-like peptide-1 receptor agonist; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; FIB-4: Fibrosis-4 index; HbA1c: Glycated hemoglobin; ELF: Enhanced Liver Fibrosis test; HCC: Hepatocellular carcinoma; MASH: Metabolic dysfunction-associated steatohepatitis.

When FIB-4 is low and there are no other clinical concerns, metabolic treatment can continue with periodic reassessment of liver risk. When FIB-4 is indeterminate or high, or when liver enzymes, platelet count, imaging findings, or clinical examination suggest significant liver disease, second-line non-invasive assessment with transient elastography or ELF testing should be performed.

When significant fibrosis or at-risk MASH is suspected, consider liver-directed therapy where approved and clinically appropriate, while continuing broader metabolic risk reduction. In patients with advanced fibrosis or cirrhosis, maintain guideline-based HCC surveillance where indicated, assess for portal hypertension, address nutrition and frailty, and monitor for hepatic decompensation.

Treatment response should be assessed using combined metabolic, biochemical, renal, nutritional and fibrosis-related parameters rather than weight loss alone. Improvements in body weight, HbA1c, or ALT should not replace fibrosis-based monitoring or cirrhosis surveillance. Table 2 presents a suggested framework for baseline assessment and follow-up in patients with MASLD/MASH receiving incretin-based therapy.

Table 2 Suggested baseline and follow-up assessment.

Clinical scenario	Assessment
Baseline	Alcohol history; metabolic risk factors; body weight, body mass index and/or waist circumference; ALT, AST, platelet count, HbA1c, lipid profile, renal function, and FIB-4
Low FIB-4 and no clinical concerns	Continue metabolic treatment; repeat liver risk assessment periodically according to metabolic risk and local pathway
Indeterminate or high FIB-4	Perform second-line non-invasive testing: Transient elastography, ELF testing, or hepatology referral
During ongoing therapy	Body weight and body mass index; tolerability and gastrointestinal adverse effects; HbA1c and fasting lipids; ALT, AST, platelet count, FIB-4 trajectory; renal function and hydration risk
After meaningful weight loss	Reassess liver enzymes and fibrosis risk markers; avoid concluding that weight loss alone indicates fibrosis regression
Older adult or frailty risk	Assess nutritional intake, muscle strength or function when feasible, fall risk, medication burden, and need for resistance exercise and protein optimization
Advanced fibrosis or cirrhosis	HCC surveillance per guideline; portal hypertension assessment; nutrition and frailty monitoring; decompensation monitoring; transplant consideration when appropriate

FIB-4: Fibrosis-4 index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HbA1c: Glycated hemoglobin; ELF: Enhanced Liver Fibrosis test; HCC: Hepatocellular carcinoma.

FUTURE RESEARCH AGENDA

Several questions remain unanswered. First, does the histological improvement observed with incretin-based therapy translate into fewer clinically meaningful events, including hepatic decompensation, HCC, transplantation and liver-related death? Only long-term outcome trials can answer this question. Second, how should patients be monitored during treatment? The optimal timing and combined use of ALT, AST, FIB-4, liver stiffness measurement, ELF, magnetic resonance imaging-proton density fat fraction, and newer biomarkers have not been prospectively validated.

Third, combination and sequencing strategies will require dedicated trials rather than inference alone. GLP-1RAs, dual incretin therapies, GLP-1/glucagon receptor agonists, triple agonists, resmetirom and future antifibrotic agents may ultimately be used together, but the appropriate populations, timing, and endpoints remain undefined. Fourth, the evidence base is thinnest in the patients who are most clinically complex, including those with advanced fibrosis, compensated cirrhosis, older age, chronic kidney disease, or a high risk of sarcopenia. Finally, implementation research addressing access, adherence, cost and equity is essential, because the population-level impact of these agents will depend at least as much on their durability in routine care as on their efficacy in clinical trials.

CONCLUSION

Hepatology has had to make room for GLP-1 receptor agonists and dual incretin therapies, which target the metabolic drivers of MASLD/MASH. Their benefits should be evaluated within a fibrosis-oriented framework rather than through weight loss alone. Histology-based trials demonstrate clear improvements in steatohepatitis activity and, with newer agents, fibrosis-related endpoints, although long-term data on liver-related outcomes remain limited. In clinical practice, these therapies should be combined with non-invasive fibrosis assessment, individualized metabolic care, attention to nutrition and frailty, cardiorenal assessment, and continuous cirrhosis and HCC surveillance in patients with advanced liver disease. Incretin-based therapy may substantially change the management of MASLD/MASH, but it does not reduce the need for hepatological assessment. Its value will depend on careful patient selection, longitudinal monitoring of liver risk, and thoughtful integration of treatment with liver-directed options.