Effects of sodium glucose co-transporter-2 inhibitors and glucagon like peptide-1 receptor agonists in diabetic metabolic dysfunction-associated steatotic liver disease management

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition, affecting approximately 30% of the general population. Type 2 diabetes mellitus (T2DM) and MASLD are closely linked, and similar management strategies often apply to both conditions. For example, weight reduction has beneficial effects on both diseases. Sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have transformed the treatment landscape of T2DM. Recent evidence suggests that these agents may also provide benefits in MASLD, as they promote weight loss and reduce hepatic fat content. The aim of this minireview is to provide a detailed overview of current literature from clinical and experimental studies regarding the role of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in the management of MASLD, with a particular focus on their mechanisms of action, therapeutic efficacy, and impact on liver-related and cardiometabolic outcomes in patients with or at risk for T2DM.

Key Words: Metabolic dysfunction associated steatotic liver disease; Type 2 diabetes mellitus; Sodium-glucose co-transporter 2 inhibitor; Glucagon-like peptide-1 receptor agonist; Management

Core Tip: Metabolic dysfunction–associated steatotic liver disease is highly prevalent and closely intertwined with type 2 diabetes mellitus, sharing common pathophysiological mechanisms and therapeutic targets. Emerging evidence indicates that sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, beyond their established glycemic benefits, exert favorable effects on body weight, hepatic steatosis, and cardiometabolic risk. This minireview synthesizes current clinical and experimental data on the role of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatotic liver disease, highlighting their mechanisms of action, therapeutic potential, and implications for integrated management of patients with or at risk for type 2 diabetes mellitus.

INTRODUCTION

Metabolic dysfunction associated steatotic liver disease (MASLD) is a prevalent chronic liver condition affecting approximately 3 out of every 10 adults. MASLD encompasses patients who have hepatic steatosis and have at least one of five cardiometabolic risk factors. It is tightly linked to type 2 diabetes mellitus (T2DM), with a significant overlap in their pathophysiology and clinical manifestations[1]. Metabolic dysfunction associated steatohepatitis (MASH) is an advanced form of MASLD that can lead to chronic inflammation and liver fibrosis.

The prevalence of MASLD among individuals with T2DM is notably high. A meta-analysis involving over 1.8 million patients with T2DM reported a global prevalence of MASLD of approximately 65%. In certain countries, such as Turkey, the prevalence reaches as high as 94.35%. Conversely, individuals with MASLD have a two-fold increased risk of developing T2DM compared with those without MASLD[2,3].

Both MASLD and T2DM are associated with metabolic syndrome and share common pathophysiological mechanisms, including insulin resistance, chronic low-grade inflammation, and dysregulated lipid metabolism. Moreover, MASLD has a more complex pathophysiology including increased glucose production and release of procoagulant factors, dyslipidemia, and dysregulated release of hepatokines and microRNAs[4]. As an important feature of T2DM, insulin resistance contributes to hepatic fat accumulation and leads to MASLD. Conversely, hepatic steatosis and inflammation in MASLD exacerbate insulin resistance, thereby worsening glycemic control in T2DM[5].

The coexistence of MASLD and T2DM corresponds to a high risk of poor outcomes[6]. Individuals affected by both conditions are at an increased risk of developing advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. Additionally, the combination significantly elevates the risk of cardiac and vascular diseases, which remain the most important cause of mortality in this population[2,5,7].

Because of the bidirectional relationship and shared risk factors, a multidisciplinary approach is essential for the effective management of patients with MASLD and T2DM. Lifestyle modifications, including diet and exercise, are foundational. Pharmacological interventions targeting both glycemic control and hepatic steatosis, such as thiazolidinediones, glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have shown promise in improving outcomes[8,9]. The strong association between MASLD and T2DM underscores the need for integrated screening and management strategies to mitigate the progression of liver disease and associated metabolic complications.

SGLT2i and GLP-1RA have transformed the treatment landscape of T2DM, providing therapeutic advantages that go beyond glycemic regulation. These agents not only lower blood glucose levels but also confer significant cardiovascular and renal protection[10]. SGLT2i act by facilitating glucose excretion through urine, thereby improving glycemic control and reducing both weight and blood pressure. Clinical trials have demonstrated that SGLT2i lower the risk of hospitalization for heart failure and delay the progression of chronic kidney disease independent of baseline glycemic levels[11]. Meanwhile, GLP-1RA improve glycemic control and promote weight loss by enhancing glucose-dependent insulin secretion and inhibiting glucagon release. They have been shown to reduce major adverse cardiovascular events, particularly in patients with established atherosclerotic cardiovascular disease. The complementary mechanisms of SGLT2i and GLP-1RA suggest potential additive benefits when used in combination, addressing multiple pathophysiological aspects of T2DM. The combined treatment may deliver greater cardiovascular and renal benefits[12]. Despite their proven efficacy, the utilization of SGLT2i and GLP-1RA remains suboptimal, highlighting the need for increased awareness and implementation of guideline-recommended therapies to improve outcomes for patients with T2DM[13]. SGLT2i and GLP-1RA represent significant advances in T2DM treatment, providing multifaceted benefits that address the complex interplay between glycemic control and cardiovascular and renal health.

The aim of this minireview is to provide a detailed overview of current evidence from clinical and experimental studies regarding the role of SGLT2i and GLP-1RA in the management of MASLD, with a particular focus on their mechanisms of action, therapeutic efficacy, and impact on liver-related and cardiometabolic outcomes in patients with or at risk for T2DM.

SGLT2I IN MANAGEMENT OF MASLD

SGLT2i have emerged as a pivotal class of oral antihyperglycemic agents in the management of T2DM, providing advantages that surpass glucose regulation. SGLT2 inhibitors function by blocking glucose reabsorption within the proximal tubules of the kidney, resulting in enhanced glucose excretion in the urine. This mechanism results in modest reductions in glycated hemoglobin (HbA1c) levels, typically around 0.5%-1.0%, and is associated with additional benefits such as weight loss and lowered blood pressure. Notably, these agents carry a low risk of hypoglycemia when used as monotherapy or in combination with other non-insulin agents[14,15]. Beyond glycemic control, SGLT2i have demonstrated significant cardiovascular and renal benefits. These agents have been shown in clinical trials to reduce hospitalizations for heart failure and delay chronic kidney disease progression in individuals with T2DM, regardless of their baseline glucose levels[16-18]. The multifaceted benefits of SGLT2i have led to their inclusion in treatment guidelines as a preferred option for patients with T2DM, particularly those with established chronic kidney disease, cardiovascular disease, or heart failure. Their insulin-independent mechanism of action and favorable safety profile make them suitable for a broad range of patients[19,20].

Beyond their beneficial effects in the treatment of T2DM and heart failure, SGLT2i have also been used in MASLD. SGLT2i, originally developed for T2DM, have garnered significant attention for their potential role in managing MASLD. Dapagliflozin improved metabolic dysfunction associated steatohepatitis more than placebo in a clinical study[21]. Moreover, authors reported that empagliflozin and dapagliflozin reduced liver fat content, as assessed by magnetic resonance imaging studies[22].

SGLT2i work by preventing glucose reabsorption in the proximal renal tubules, resulting in increased glucose excretion through the urine. This mechanism results in better glycemic control, weight loss, and better control in blood pressure. In the context of MASLD, these effects are particularly beneficial, as insulin resistance and obesity are key contributors to hepatic steatosis. Additionally, SGLT2i may exert direct hepatic benefits by reducing hepatic fat accumulation and inflammation, although the exact mechanisms remain under investigation[23]. Clinical studies have demonstrated that SGLT2i therapy significantly decreases liver enzymes, including alanine and aspartate transaminases (alanine aminotransferase and aspartate aminotransferase), which indicates improved hepatic function. For instance, a study involving empagliflozin showed a significant decrease in hepatic fat content after 24 weeks of treatment. These findings suggest that SGLT2i can effectively reduce hepatic steatosis in patients with MASLD[24]. SGLT2i have also been associated with improvements in liver fibrosis markers. A retrospective case-control analysis involving patients with MASLD and T2DM found that SGLT2i treatment significantly reduced fibrosis-4 (FIB-4) index and aspartate aminotransferase-to-platelet ratio index scores, suggesting a potential anti-fibrotic effect. These improvements were observed over a median treatment duration of 22 months[25,26]. Furthermore, long-term studies have reported sustained histological improvements with SGLT2i therapy. In a 5-year retrospective study, patients with nonalcoholic fatty liver disease and T2DM treated with canagliflozin exhibited histopathological improvements, including decreased nonalcoholic fatty liver disease activity score without worsening of fibrosis. These findings underscore the potential of SGLT2i for long-term management of liver disease progression[27]. Comparative studies have evaluated the efficacy of SGLT2i against other treatments. For example, a study comparing dapagliflozin with vitamin E in patients with MASLD and T2DM found that both treatments reduced liver enzymes, but dapagliflozin also significantly decreased HbA1c, body mass index, and low-density lipoprotein cholesterol. However, a notable reduction in skeletal muscle index (SMI) was reported with dapagliflozin, highlighting the need for monitoring muscle mass during therapy[28].

Multiple randomized trials and meta-analyses show that SGLT-2i improve non-invasive fibrosis scores such as FIB-4 and serologic fibrosis markers, including type 4 collagen 7s. These changes were statistically significant in pooled analyses[29,30]. Imaging-based measures, such as liver stiffness, are modestly reduced, especially with longer duration therapy[29]. These surrogate metrics are influenced by reduced inflammation, steatosis, and improved metabolism, but they are not direct measures of collagen remodeling or fibrosis stage reversal on biopsy[30].

Most SGLT-2i randomized controlled trials do not report systematic liver biopsy outcomes, and meta-analyses emphasize improvements in surrogate markers rather than robust histologic staging[29]. Some systematic reviews note histologic improvement in a minority of smaller studies, but these are not consistently reproducible and often lack statistical power[31]. The current literature suggests that SGLT-2i have modest effects on fibrosis markers and no definitive proof of reproducible fibrosis regression on histology.

Large cardiovascular and renal outcome studies with SGLT-2i demonstrate major benefits (heart failure, renal progression) in diabetic and chronic kidney disease populations but do not include liver-specific hard endpoints, such as cirrhosis decompensation and liver-related mortality. Observational data suggests an association with reduced risk of incident MASLD/MASH, but these analyses do not establish causality or fibrosis regression as a mechanism[32]. Surrogate improvements are reproducible, histologic fibrosis regression is weak/inconclusive, and hard liver outcomes remain unproven.

Interestingly, SGLT2i drugs have also been reported to be useful for cardiovascular and cerebrovascular conditions. Liu et al[26] studied 283 patients with MASLD and found that in addition to lowering aspartate aminotransferase-to-platelet ratio index and FIB-4 scores, SGLT2i drugs were associated with reduced risk of cardiovascular and cerebrovascular events. Similarly, a randomized controlled study evaluated dapagliflozin’s effects in patient with both MASLD and T2DM and revealed that SGLT2i reduced body fat and liver enzymes in this population[28]. Moreover, a meta-analysis of randomized controlled trials on patients with MASLD demonstrated that SGLT2i treatment significantly reduced liver stiffness in patients with significant fibrosis[33]. A recent study from Japan compared SGLT2i and pioglitazone in 8408 patients with T2DM plus MASLD and reported that after 6 months of follow-up, SGLT2i were superior to pioglitazone in improving hepatic inflammation and fibrosis indices[34]. These data were confirmed by a meta-analysis[35], which suggested that SGLT2i were more beneficial than pioglitazone in improving liver fibrosis, blood lipids, liver fat, and body composition in patients with MASLD. These data suggests that SGLT2i should be considered in the treatment of patients with MASLD, especially in those with significant fibrosis.

SGLT2i represent a promising pharmacological option for the treatment of MASLD, particularly in patients with coexisting T2DM. Their multifaceted benefits, including improvements in hepatic steatosis, liver enzyme levels, fibrosis markers, and systemic metabolic parameters, position them as valuable agents in a comprehensive treatment strategy. Ongoing research and long-term studies will further elucidate their role and optimize their use in clinical practice[23,33,34,36].

Beyond lowering glucose and aiding weight loss, SGLT2i induce a mild ketogenic state by promoting adipose lipolysis and hepatic fatty-acid oxidation, leading to increased circulating ketone bodies. In humans, this ketogenic shift is well documented in metabolic and cardiovascular outcome trials; however, direct evidence linking SGLT2i-induced ketone signaling to histologic improvement in MASH remains limited. The proposed anti-oxidative and anti-inflammatory signaling effects of ketone bodies are largely extrapolated from mechanistic and translational studies rather than biopsy-controlled liver trials. In animal models of MASH, SGLT2i-associated ketogenesis has been reported to attenuate hepatic inflammation and fibrosis, including modulation of intrahepatic immune responses (e.g., reduced pathogenic CD8+ T-cell activation). These preclinical findings provide biologically plausible pathways by which SGLT2i could influence fibrogenesis; however, such immune-modulatory effects have not yet been conclusively demonstrated in human liver tissue[37,38].

Similarly, alterations in the gut-liver axis represent another proposed mechanism. In rodent models, SGLT2 inhibition has been associated with shifts in gut microbiota composition and changes in microbial metabolites such as short-chain fatty acids, which in turn may influence hepatic lipid handling and inflammatory pathways. Limited human studies also report microbiome compositional changes during SGLT2i therapy. However, these clinical data are heterogeneous, based on small cohorts, and do not establish a direct causal relationship between microbiome modulation and histologic liver improvement. Taken together, ketone-mediated signaling, immune modulation, and alterations in gut microbiota represent complementary and biologically plausible mechanisms that may contribute to the observed reductions in hepatic steatosis and inflammatory marker expression with SGLT2i therapy. Nevertheless, current human evidence directly linking these mechanistic pathways to biopsy-proven fibrosis regression remains preliminary. Accordingly, these pathways should be regarded as hypothesis-generating rather than definitive explanations of antifibrotic benefit[39,40]. Effects of GLP-1RAs and SGLT2i on MASLD are summarized in Figure 1. Table 1 lists the effects of SGLT2i in MASLD.

Figure 1 Effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors on metabolic dysfunction-associated steatotic liver disease. MASLD: Metabolic dysfunction-associated steatotic liver disease; RCT: Randomized clinical trial; CVD: Cardiovascular disease; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 1 Summary of the effects of sodium-glucose co-transporter 2 inhibitor in metabolic dysfunction-associated steatotic liver disease.

Key components	Details/evidence	Clinical implication
Metabolic effects	Decreased renal glucose reabsorption → glycosuria → improved glycemic control and caloric loss	Weight reduction and improved insulin resistance
Hepatic lipid metabolism	Increased β-oxidation, decreased novo lipogenesis (via AMPK activation, reduced SREBP-1c signaling)	Reduction in hepatic steatosis
Insulin sensitivity	Improved peripheral and hepatic insulin sensitivity	Reduced lipotoxicity and hepatic fat accumulation
Anti-inflammatory effects	Decreased pro-inflammatory cytokines, decreased oxidative stress	Attenuation of steatohepatitis progression
Antifibrotic pathways	Modulation of TGF-β, stellate cell activation, collagen deposition	Potential slowing of fibrosis progression
Autophagy and mitochondrial function	Activation of autophagy and improved mitochondrial efficiency (PubMed)	Reduced hepatocellular injury
Gut-liver axis	Modulation of gut microbiota composition	Emerging contributor to metabolic and inflammatory regulation
Systemic cardiometabolic effects	Weight loss, decreased visceral adiposity, CV and renal protection	Indirect benefit on MASLD progression

SREBP-1c: Sterol regulatory element-binding protein 1c; AMPK: AMP-activated protein kinase; TGF-β: Transforming growth factor-β; CV: Cardiovascular; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Several recent clinical studies report that SGLT2i treatment, particularly dapagliflozin, can reduce overall body weight and fat mass while producing variable effects on skeletal muscle mass or SMI. Some cohorts and short-term studies found no clinically meaningful loss of muscle mass, implying favorable body-composition changes with preserved muscle (e.g., 6-month T2DM studies). However, other reports, including carefully measured cohorts, have documented statistically significant declines in SMI during dapagliflozin treatment, particularly in older or non-obese patients and in certain populations, including chronic kidney disease and some diabetes cohorts. These mixed results appear to depend on baseline patient characteristics, study duration, measurement method (bioelectrical impedance analysis vs dual-energy X-ray absorptiometry/computed tomography), and concomitant changes in hydration[41-43]. Plausible mechanisms for reduced SMI with SGLT2i therapy include: (1) Loss of extracellular water and glycogen stores, which can reduce lean-mass estimates on bioelectrical impedance analysis; (2) Negative energy balance with preferential fat loss but some degree of lean-mass catabolism if caloric/protein intake or resistance activity is inadequate; and (3) Unmasking of pre-existing, subclinical sarcopenia in older or frail patients. The magnitude and clinical relevance of true muscle fiber loss, vs measurement/volume effects, remain incompletely defined[42,44]. Sarcopenia and frailty are common in T2DM and MASLD and independently predict worse liver outcomes and mortality. Even modest losses in muscle mass or function can meaningfully worsen physical function in frail patients and accelerate progression to frailty. Therefore, an agent that reduces SMI or causes measurable declines in lean mass could pose a clinical risk for the subgroup of MASLD patients who are elderly, sarcopenic, or already functionally impaired. Population studies and meta-analyses consistently link sarcopenia to higher prevalence of MASLD and more severe fibrosis, which magnifies the clinical importance of preserving muscle in this population[45,46].

GLP-1RA IN THE MANAGEMENT OF MASLD

GLP-1RAs have become an important choice in the management of T2DM, enabling multifaceted benefits that extend beyond glycemic control. These agents imitate the incretin hormone GLP-1, leading to enhanced insulin secretion in a glucose-dependent manner, reduced glucagon release, slower gastric emptying, and increased satiety; all of which work together to improve metabolic outcomes[47,48]. GLP-1RAs effectively lower HbA1c levels, with reductions typically ranging from 0.5% to 1.5% depending on the specific agent and dosage. Notably, semaglutide has demonstrated superior efficacy in glycemic control compared with other GLP-1RAs. In addition to glycemic benefits, these agents promote weight loss, an essential aspect of T2DM management, especially in overweight or obese individuals. Weight reductions of approximately 2-5 kg have been observed, with higher doses of semaglutide achieving even greater weight loss[49]. Beyond metabolic improvements, GLP-1RAs have significant cardiovascular and renal protective effects. Clinical trials have demonstrated that agents like liraglutide and semaglutide decrease the risk of myocardial infarction and stroke, particularly in subjects with established atherosclerotic cardiovascular disease. Moreover, GLP-1RAs have been associated with slowing the progression of diabetic kidney disease, offering renal benefits independent of their glucose-lowering effects[50]. GLP-1RAs are generally well-tolerated with a low risk of hypoglycemia due to their glucose-dependent mechanism of action. Gastrointestinal effects, such as nausea, vomiting, and diarrhea, are the most common adverse effects, which tend to diminish over time. These agents are contraindicated in individuals with a history of multiple endocrine neoplasia syndrome type 2 or medullary thyroid carcinoma[51].

GLP-1RAs, initially developed for T2DM, have attracted attention for their potential role in managing MASLD. Emerging evidence from clinical trials and observational studies suggests that GLP-1RAs may offer multifaceted benefits in MASLD, including improvements in liver histology, metabolic parameters, and cardiovascular outcomes. GLP-1RAs exert their effects through several mechanisms pertinent to MASLD. One of these mechanisms is improved glycemic control. By enhancing glucose-dependent insulin secretion and suppressing glucagon release, GLP-1RAs improve glycemic control, thereby mitigating insulin resistance, which is a key driver of hepatic steatosis. Another possible mechanism is weight reduction. GLP-1RAs promote satiety and reduce caloric intake, leading to significant weight loss. Weight reduction is associated with decreased hepatic fat accumulation and inflammation. The third mechanism is through the drug’s anti-inflammatory effects. MASLD is associated with significant chronic inflammatory burden[52,53]. GLP-1RAs may exert anti-inflammatory effects, reducing hepatic inflammation and potentially slowing the progression of liver fibrosis.

Clinical trials have demonstrated that GLP-1RAs can lead to histological improvements in subjects with MASLD. In a randomized, clinical trial involving 800 patients with metabolic dysfunction-associated steatohepatitis, semaglutide treatment for 72 weeks resulted in 62.9% of patients experiencing reduced liver fat and inflammation without worsening fibrosis. Additionally, 33% showed improvements in liver fibrosis[54,55]. Tirzepatide, another GLP-1RA agent, has also been used to treat MASLD. As a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1RA, tirzepatide exerted higher efficacy in resolving MASH without worsening fibrosis compared with placebo over a 52-week period[56].

Observational studies reported that GLP-1RA treatment was associated with a reduced risk of progression to cirrhosis and related complications[57]. A cohort study comparing GLP-1RA users to those on dipeptidyl peptidase-4 inhibitors found a reduced incidence of cirrhosis (hazard ratio, 0.86) and mortality (hazard ratio, 0.89) among GLP-1RA users[58]. When compared with other therapeutic agents, GLP-1RAs have shown better long-term liver outcomes than SGLT2is in individuals with MASLD and T2DM, primarily due to a reduction in decompensated cirrhosis events[59].

A randomized controlled trial compared the effects of lifestyle intervention, including weight loss, and liraglutide in patients with MASLD and found that both strategies have similar effects on hepatic steatosis but that GLP-1RA treatment also had metabolic benefits on serum lipids and serum glucose[60]. Another interventional study revealed that GLP-1RA treatment reduced FIB-4 score in patients with MASLD and T2DM[61]. These suggests the beneficial use of GLP-1RA drugs in treating MASLD, especially those patients with T2DM. In addition, the ESSNCE trial showed that semaglutide improved liver histology in patients with MASH[45].

Preclinical studies support the presence of functional GLP-1Rs on hepatocytes and show that GLP-1/GLP-1RA exposure increases intracellular cAMP and activates AMP-activated protein kinase, leading to down-regulation of lipogenic enzymes and up-regulation of fatty-acid β-oxidation pathways with resultant reductions in hepatocellular triglyceride accumulation. These direct hepatic effects plausibly complement systemic benefits (weight loss, improved insulin sensitivity) to reduce steatosis. Nevertheless, hepatic GLP-1R expression and the magnitude of direct hepatocyte signaling are contested across species and human datasets; differences in receptor detection methods, tissue sampling and disease state likely contribute to inconsistent findings. Consequently, while preclinical supports a direct anti-lipogenic mechanism, translation to humans requires further confirmation with rigorously controlled tissue-level studies[62,63]. Pharmacological effects of GLP-1RAs and SGLT2is are summarized in Figure 2.

Figure 2 Pharmacological effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors. MASLD: Metabolic dysfunction-associated steatotic liver disease; GLP-1RA: Glucagon-like peptide-1 receptor agonist; SGLT2: Sodium-glucose co-transporter 2.

Randomized controlled trials and meta-analyses demonstrate that potent GLP-1RA, particularly liraglutide and semaglutide, produce consistent improvements in steatosis and higher rates of nonalcoholic steatohepatitis (NASH) resolution compared with placebo; semaglutide and liraglutide trials reported histologic NASH resolution in phase-2 trials. These findings support a plausible anti-fibrotic trajectory mediated indirectly through weight loss, improved insulin resistance and anti-inflammatory effects[64,65]. Sample size and statistical power is a concern, especially for fibrosis endpoints. Several landmark trials that showed NASH resolution were phase-2 studies with modest sample sizes or had histology endpoints assessed in only a subset of randomized participants. For example, the LEAN/Liraglutide program and the semaglutide phase-2 trial had limited numbers of evaluable biopsy pairs for fibrosis staging, and the semaglutide trial, while large, failed to meet the secondary endpoint for fibrosis improvement despite NASH resolution, suggesting insufficient duration or power to detect fibrosis change. Smaller sample sizes reduce power to detect fibrosis regression, which is a slower and more difficult endpoint to achieve than NASH resolution[64,65]. Heterogeneity in trial design and endpoints is another issue. Trials differ in agent (liraglutide vs semaglutide vs other GLP-1RAs), dosing, duration (48-72+ weeks), entry criteria (presence/absence of diabetes, body mass index ranges), and fibrosis stage included (F1-F3 vs F2-F3 vs compensated cirrhosis). Some studies use biopsy-proven histology, while others rely on imaging (magnetic resonance imaging-proton density fat fraction) or surrogate serum/fibrosis scores. This heterogeneity complicates pooling results and limits the ability to generalize anti-fibrotic claims across all GLP-1RAs or all MASLD phenotypes[65,66]. Duration of follow-up is also important because fibrosis may require longer treatment. Fibrosis remodeling is slow; many positive histology signals reflect steatohepatitis resolution at 48-72 weeks, whereas fibrosis stage improvement may require longer treatment or follow-up to emerge. The null fibrosis outcome in some trials could reflect insufficient exposure time rather than lack of biological effect[67].

GLP-1RAs consistently reduce alanine aminotransferase/aspartate aminotransferase, magnetic resonance imaging-measured hepatic fat, and conventional non-invasive fibrosis biomarkers in multiple meta-analyses[68]. Improvements in insulin resistance and body weight, which are key metabolic drivers of fibrosis, are robustly replicated[68]. These surrogate effects are biologically plausible steps toward reduced fibrogenesis but do not by themselves equate to histologic fibrosis regression. In the LEAN trial, liraglutide was associated with increased MASH resolution and fewer fibrosis progressors vs placebo; however, direct fibrosis regression (≥ 1 stage) was not a primary outcome and statistical significance for fibrosis change was borderline[69]. In biopsy-based phase 2 trials, semaglutide significantly increased steatohepatitis resolution without worsening fibrosis, but the secondary endpoint of fibrosis stage regression was not statistically significant in initial analyses[70]. Meta-analyses of GLP-1RAs show a significant pooled effect on fibrosis improvement (including at least one stage reduction) compared with placebo[71]. Trials including semaglutide and liraglutide show pooled effects favoring GLP-1RA over placebo for fibrosis regression and NASH resolution with no worsening of fibrosis, though heterogeneity and duration limit certainty[71]. GLP-1RAs improve histologic steatohepatitis and show signs of less fibrosis progression or modest regression, particularly in meta-analyses that aggregate multiple biopsy-controlled trials. However, individual randomized controlled trials often lack power or sufficient follow-up for conclusive fibrosis regression. There are no dedicated GLP-1RA trials with primary liver-related endpoints such as cirrhosis events, liver transplant, and liver-related mortality. Cardiometabolic outcome trials primarily designed for cardiovascular endpoints show metabolic and weight benefits but are not informative for liver disease progression. Some retrospective cohort data suggests slowed progression in non-invasive fibrosis scores with GLP-1RA treatment, but these are not definitive clinical outcomes[72]. Surrogate benefits are consistent; biopsy data indicates stronger signals of histologic steatohepatitis resolution and modest fibrosis improvement, but confirmatory evidence and direct hard clinical liver outcomes remain limited or underpowered.

COMBINATION OF SGLT2I AND GLP-1RA IN MASLD

Combining SGLT2i and GLP-1RA targets complementary pathophysiologic pathways relevant to MASLD. GLP-1RAs reduce appetite, body weight and hepatic de novo lipogenesis and improve insulin sensitivity; SGLT2is produce glycosuria that improves glycemia, reduces visceral adiposity, and may reduce hepatic steatosis via substrate shifts and improved metabolic profile. Therefore, the combination may have additive or synergistic effects on weight, glycemic control, cardiometabolic risk and, by extension, hepatic fat and inflammation. Several reviews and preclinical/clinical summaries describe these complementary mechanisms and additive metabolic effects[73,74]. Most direct randomized data in MASLD studies are still limited; however, large diabetes trials and multiple observational/retrospective studies show the combination improves glycemic, weight loss and cardiometabolic endpoints more than either class alone, outcomes that are strongly linked to MASLD improvement[75]. Emerging clinical data specifically examining liver outcomes are encouraging but still evolving. Recent retrospective analyses and 2023-2025 observational studies have reported improved liver function tests, reduced fibrosis indices (e.g., FIB-4 progression) and lower MASLD-related clinical events with combined GLP-1RA + SGLT2i compared with SGLT2i alone; comparisons vs GLP-1RA monotherapy are mixed and may show less additional benefit beyond what GLP-1RAs provide[76]. The most compelling MASLD-specific randomized evidence to date relates to incretin-based agents, particularly tirzepatide, rather than classic GLP-1RA + SGLT2i combinations. Tirzepatide is promising treatment option in T2DM[77] and is also studied in MASLD. The SYNERGY-NASH program (phase 2/2b) showed that tirzepatide produced meaningful rates of MASH (NASH) resolution and improvements in histology vs placebo after 52 weeks; these results strengthen the concept that powerful incretin-mediated weight loss and metabolic effects can translate into histologic liver benefit. However, SYNERGY-NASH evaluated tirzepatide as a single agent (GIP/GLP-1), not a GLP-1RA + SGLT2i pairing[78]. Safety profiles of combination therapy reflect those of each class and are as follows:.GLP-1RAs have adverse gastrointestinal effects (nausea, vomiting), potential gallbladder events with large weight loss; SGLT2i have genitourinary infections, euglycemic ketoacidosis in prone patients, and volume depletion. Published reviews and real-world analyses report that combination therapy is generally tolerated and is not associated with unexpected hepatic safety signals, but long-term, liver-histology-focused safety data are limited. Clinicians should monitor renal function, ketone status in insulin-deficient states, and manage GI side effects that may limit adherence[79]. Important non-efficacy factors that will influence the adoption of combination therapy for MASLD include cost and reimbursement, access and healthcare pathways, regulatory labeling and guideline endorsement, and adverse-effect management and patient acceptability. Both GLP-1RAs and SGLT2i, including newer agents like tirzepatide, are expensive and reimbursement for MASLD, as opposed to diabetes or obesity, is inconsistent across regions and payers. This strongly constrains broad adoption in routine hepatology practice. MASLD patients are often managed by primary care, endocrinology or hepatology practices, and fragmentation can hamper coordinated combination therapy initiation and follow-up. Most agents are approved for T2DM or obesity; specific MASLD/MASH indications are limited, which affects payer coverage and clinician comfort. GI side effects from GLP-1RAs and genitourinary issues from SGLT2i can reduce adherence. These barriers are highlighted in recent reviews and implementation-focused papers[74,79].

Management of MASLD in patients with T2DM should be individualized according to fibrosis stage and comorbidities. Current guidelines from the American Association for the Study of Liver Diseases (2023) and European Association for the Study of the Liver-European Association for the Study of Diabetes-European Association for the Study of Obesity (2024) recommend targeted case finding and noninvasive fibrosis assessment to identify those (F2-F3) most likely to benefit from pharmacologic therapy. SGLT2i and GLP-1RAs offer metabolic, hepatic, and cardioprotective benefits, but sarcopenia and dehydration risks warrant close monitoring in elderly or frail patients. In patients with chronic kidney disease, dosing should follow epidermal growth factor receptor-based thresholds. Emerging dual and triple incretin agonists such as tirzepatide and retatrutide demonstrate marked reductions in liver fat and weight, offering a promising next step in MASLD therapy, though long-term histologic and safety data remain limited. A precision medicine approach integrating fibrosis stage, comorbidity, and patient frailty will optimize outcomes and future guideline implementation[80-83].

Tirzepatide, a dual agonist for GLP1 and GIP receptors, has the most robust clinical evidence among dual incretin therapies. In phase II/III trials, once-weekly tirzepatide produced substantial and sustained weight loss in adults with overweight/obesity, with dose-dependent reductions over 72 weeks[84]. Compared with placebo, tirzepatide also significantly reduced HbA1c and fasting glucose, reflecting potent glycemic control in T2DM[85]. A systematic review and network metaanalysis suggests tirzepatide has among the strongest effects on both weight loss and glucose lowering vs other incretin agonists, although adverse events, especially gastrointestinal, were more frequent than with GLP-1-only therapies[85]. These findings have helped establish dual GLP-1/GIP agonism as a next-generation therapeutic approach beyond single-receptor GLP-1RAs.

The dual activation of GLP-1 and glucagon receptors is another strategy aimed at combining improved glycemic control, appetite suppression, and increased energy expenditure. Cotadutide, a GLP-1R/glucagon receptor agonist, showed improved postprandial glucose control and body weight reduction in patients with T2DM compared with placebo[86]. In phase 2b trials, cotadutide also significantly reduced urinary albumin-to-creatinine ratio, suggesting potential kidney benefits in diabetic patients[87]. Meta-analyses of dual GLP-1/glucagon agonists, including survodutide, indicate weight loss of approximately 7%-9% from baseline across several trials, with favorable metabolic effects[88]. Mazdutide (GLP-1 + glucagon agonist) has shown clinically relevant weight reductions in phase III studies and is being evaluated further[89]. These agents demonstrate that dual incretin agonism extending to glucagon pathways may further enhance energy balance and body weight reduction beyond GLP-1 alone, with potential relevance to metabolic liver disease.

Triple receptor agonists combine GLP-1, GIP, and glucagon receptor stimulation to maximize metabolic benefits, including weight loss, glucose control, and increased energy expenditure. Retatrutide, a GLP-1, GIP, and glucagon receptor triple agonist, has shown substantial reductions in body weight in adults with obesity in clinical trials. In a randomized phase 2 study, retatrutide groups had mean weight reductions up to approximately 17% at 48 weeks, far exceeding placebo effects and highlighting strong metabolic impact[90]. Trials also demonstrated significant improvements in metabolic outcomes compared with comparators, including HbA1c and body fat composition[91]. Phase III development is ongoing, with preliminary data suggesting even more pronounced effects on weight loss and cardiometabolic markers than dual incretin therapies in some cohorts[92].

Current guideline aligned recommendations support systematic risk stratification for advanced fibrosis in all patients with T2DM regardless of aminotransferase levels, given the high prevalence of clinically significant fibrosis in this population. Rather than universal imaging for steatosis, a pragmatic approach endorsed in recent hepatology and diabetes society statements is stepwise non-invasive fibrosis assessment, beginning with a simple serum-based score such as FIB-4 as a first-line triage tool. Patients with low FIB-4 can generally be managed in primary care with metabolic optimization, whereas those with indeterminate or elevated values should undergo second-line assessment with vibration-controlled transient elastography or equivalent elastography-based methods to identify advanced fibrosis and determine the need for hepatology referral. Pharmacotherapy selection should be individualized based on fibrosis risk and cardiometabolic comorbidities: GLP-1RAs may be prioritized in patients with obesity and high atherosclerotic cardiovascular risk where substantial weight reduction is desired, while SGLT2is are particularly attractive in those with heart failure or chronic kidney disease. Importantly, given that biopsy-proven fibrosis regression data remain limited, treatment choice should primarily reflect cardiometabolic benefit rather than assumed antifibrotic efficacy. Key safety considerations include monitoring renal function and volume status with SGLT2i, especially in older or frail patients at risk of dehydration, and vigilance for excessive weight loss, sarcopenia risk, and gastrointestinal intolerance with GLP-1RAs. Table 2 summarizes the treatment of MASLD with SGLT2i.

Table 2 Metabolic dysfunction-associated steatotic liver disease treatment with sodium-glucose co-transporter 2 inhibitor.

Therapeutic strategies	Approach	Details	Clinical positioning
Monotherapy	SGLT2i alone	Effective for metabolic improvement and steatosis reduction	Best suited for MASLD with T2DM
Combination therapy	With GLP-1RA, pioglitazone	Potential synergistic metabolic and hepatic effects (PubMed)	Emerging strategy (not yet standardized)
Patient selection	T2DM + MASLD	Strongest evidence in diabetic populations	First-line metabolic-targeted option
	Non-diabetic MASLD	Less consistent benefit	Consider in selected metabolic phenotype
Treatment duration	Short-term (≤ 24 weeks)	Demonstrates measurable improvement in steatosis	Most RCTs short-term
	Long-term therapy	Needed for fibrosis/hard outcomes	Evidence still limited
Endpoints for monitoring	Imaging (CAP, MRI-PDFF), LSM	Non-invasive monitoring preferred	Surrogate markers widely used
Position in guidelines (emerging)	Adjunct therapy	Not yet MASLD-specific approved therapy	Used based on metabolic indication (T2DM, obesity)

SGLT2i: Sodium-glucose co-transporter 2 inhibitors; GLP-1RA: Glucagon-like peptide-1 receptor agonists; T2DM: Type 2 diabetes mellitus; MASLD: Metabolic dysfunction-associated steatotic liver disease; CAP: Controlled attenuation parameter; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction; LSM: Liver stiffness measurement; RCTs: Randomized controlled trials.

CONCLUSION

The growing burden of MASLD, particularly among individuals with T2DM, underscores the need for effective pharmacological interventions. This minireview highlights the emerging role of GLP-1RAs and SGLT2i as promising therapeutic options in the management of MASLD. Both SGLT2i and GLP-1RA not only provide better glycemic control and promote weight loss, but also demonstrate favorable effects on hepatic steatosis, inflammation, and, in some cases, fibrosis. GLP-1RAs have shown significant potential in improving liver histology and reducing progression to advanced liver disease, likely due to their potent weight-reducing and anti-inflammatory properties. Similarly, SGLT2i offer metabolic, cardiovascular, and renal benefits while also contributing to reductions in hepatic fat content and liver enzyme levels. While neither class is currently approved for MASLD, accumulating clinical evidence supports their utility in patients with coexisting T2DM or metabolic risk factors. Future large-scale, long-term studies are essential to validate their role in liver-specific outcomes and to define optimal therapeutic strategies. As research advances, GLP-1RAs and SGLT2i may become integral components of a comprehensive, multidisciplinary approach to MASLD management.