Incretin-based therapies in MASLD/MASH: from GLP-1 receptor agonists to dual and triple agonists - mechanisms, clinical evidence, and therapeutic perspectives

GLP-1 receptor signaling

Intestinal L-cells serve as the primary source of GLP-1 synthesis, which operates via G-protein coupled receptors present in pancreatic beta cells, gastrointestinal and central neural systems, cardiac tissues, and kidneys^[26]. GLP-1 originates from the cleavage of preproglucagon, a 160-amino acid precursor whose expression, driven by the GCG gene, occurs in pancreatic α-cells and intestinal cells. Its metabolic journey is a prime example of tissue-specific post-translational processing, where the same precursor is cleaved into different bioactive peptides depending on the enzymes present in the cell^[27] [Figure 2].

Figure 2. Tissue specific processing of preproglucagon. This image was created by us with Canva. SP: Signal peptide; GRPP: glicentin-related pancreatic polypeptide; IP-1: intervening peptide 1; GLP-1: glucagon-like peptide-1; IP-2: intervening peptide 2; GLP-2: glucagon-like peptide-2. MPGF: major proglucagon fragment.

Preproglucagon is a 160-amino acid precursor encoded by the GCG gene and expressed in pancreatic α-cells, intestinal cells. The same precursor is differentially cleaved by two prohormone convertases depending on the tissue context. In pancreatic α-cells, PC2 cleaves proglucagon to yield mature glucagon (29 aa), glicentin-related pancreatic polypeptide (GRPP) and the major proglucagon fragment (MPGF). Glucagon promotes hepatic glucose output and is secreted primarily during fasting. In intestinal L-cells - concentrated in the distal ileum and colon - PC1/3 processes proglucagon into GLP-1, GLP-2, glicentin, and oxyntomodulin. GLP-1 acts as a potent incretin, stimulating glucose-dependent insulin secretion postprandially.

While GLP-1 receptor expression is absent in hepatocytes, GLP-1 receptor agonism exerts profound hepatic benefits through multiple indirect mechanisms. The primary pathway involves amplification of glucose-triggered insulin production by pancreatic beta cells, which enhances adipose tissue nutrient uptake and reduces circulating free fatty acid flux to the liver^[28]. This insulin-mediated improvement in systemic insulin sensitivity reduces hepatic lipid accumulation from peripheral sources.

Additionally, GLP-1 receptor activation indirectly suppresses hepatic de novo lipogenesis through downregulation of lipogenic transcription factors and enzymes, independent of weight loss^[29]. GLP-1 also reduces hepatic VLDL release and decreases enterocyte chylomicron production, further limiting hepatic triglyceride delivery^[30]. These coordinated actions on lipid metabolism contribute to steatosis resolution. Furthermore, GLP-1 RAs exhibit anti-inflammatory effects, lowering circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6, while promoting anti-inflammatory mediator production^[26]. Although precise hepatic anti-inflammatory mechanisms remain incompletely defined, proposed pathways include reduction of lipotoxicity-induced cellular stress, modulation of hepatic macrophage activity, and direct effects on inflammatory signaling cascades^[26].

Regarding fibrosis, while direct anti-fibrotic mechanisms are less established, preclinical studies indicate that GLP-1 RAs could suppress fibrogenic cell activation and reduce expression of pro-fibrotic genes encoding extracellular matrix proteins, potentially facilitating fibrosis regression in conjunction with improvements in steatosis and inflammation^[29-32]. In a recent study, Jara et al. evaluated the molecular mechanisms through which semaglutide mediated resolution of MASH^[17]. They showed that semaglutide enhanced histological parameters of fibrosis and inflammation while decreasing hepatic expression of genes associated with fibrotic and inflammatory cascade: through proteomic profiling of serum from MASH patients treated with semaglutide, they detected 72 proteins linked to disease resolution and validated these findings in preclinical mouse models and an independent patient cohort^[28].

Preclinical studies in accelerated mouse models of diet-induced steatohepatitis have demonstrated that retatrutide improves steatohepatitis through mechanisms involving enhanced hepatic fat oxidation, reduced lipogenesis, decreased inflammation, and attenuation of fibrosis markers, supporting the rationale for clinical development in MASH^[33]. Combined activation of GLP-1, GIP, and GCG systems theoretically provides complementary mechanisms: GLP-1-mediated insulin sensitization and satiety promotion, GIP-mediated enhancement of insulin secretion and adipose lipid buffering, and glucagon-mediated direct hepatic lipid oxidation and energy expenditure augmentation.

GLP-1 receptor activation exerts profound systemic effects that indirectly benefit hepatic steatosis and MASH through multiple complementary mechanisms. At the systemic level, GLP-1 RAs improve insulin sensitivity in peripheral tissues (muscle, adipose), reduce circulating free fatty acid flux to the liver, suppress hypothalamic appetite circuits to promote weight loss, and lower systemic pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), thereby reducing the hepatic inflammatory milieu indirectly^[7,26,30]. Central nervous system-mediated appetite regulation represents a primary mechanism through which GLP-1 RAs induce weight reduction and subsequently improve hepatic steatosis. Key hypothalamic centers, including the arcuate and paraventricular nuclei, exhibit high GLP-1 receptors expression, which coordinate peripheral metabolic cues to modulate feeding behavior and energy balance^[34]. Through stimulation of pro-opiomelanocortin (POMC) neurons while simultaneously inhibiting neuropeptide Y/agouti-related peptide neurons in the arcuate nucleus, GLP-1 receptor agonism promotes satiety, reduces meal size, and decreases overall caloric intake^[35]. Importantly, GLP-1 appears to attenuate reward-driven food consumption by modulating dopaminergic signaling in the mesolimbic system, potentially reducing preference for high-fat, energy-dense foods^[36]. These central effects translate into substantial weight loss - typically 5%-15% of body weight with current GLP-1 RAs - which directly ameliorates hepatic steatosis by reducing adipose tissue mass, reducing hepatic free fatty acid influx, and improving insulin sensitivity.

Beyond appetite suppression, GLP-1 RAs improve systemic glucose homeostasis through pancreatic and extra-pancreatic mechanisms. Potentiation of glucose-stimulated insulin release from pancreatic beta cells embodies the classic incretin action, reducing postprandial hyperglycemia and chronic hyperinsulinemia^[35,36]. Concomitant suppression of inappropriate glucagon secretion from alpha cells further improves glycemic control by reducing hepatic glucose production during fed states^[36]. These pancreatic effects are complemented by improved peripheral insulin responsiveness in muscle tissue and lipid storage sites, facilitating glucose disposal and reducing systemic insulin resistance - a key driver of hepatic lipid accumulation and MASH progression^[28,31]. Moreover, GLP-1 RAs slow gastric emptying, thereby blunting postprandial glucose and lipid excursions, though diminished tolerance to this effect may develop during prolonged administration of extended-release preparations.

Cardiovascular therapeutic effects of GLP-1 RAs extend beyond traditional cardiometabolic risk factor improvement. Trial data have shown decreases in serious cardiovascular complications, including cardiovascular mortality, nonlethal heart attacks, and nonfatal cerebrovascular accidents, among individuals with type 2 diabetes and pre-existing cardiovascular pathology or high cardiovascular risk^{[3,5,13,14,37]}.

These benefits appear to reflect both improvements in traditional risk factors - weight, blood pressure, lipid profiles, glycemic control - and potentially direct cardioprotective effects mediated by GLP-1 receptors expressed in cardiomyocytes and vascular endothelium. Given the strong association between MASLD and cardiovascular pathology, that represents the primary cause of death in this population, the cardioprotective benefits of GLP-1 RAs provide important additional clinical value beyond hepatic benefits.

Renal protective effects have emerged as another important extra-hepatic benefit^[15].

Collectively, these extra-hepatic effects create a favorable systemic metabolic environment that indirectly but substantially benefits hepatic steatosis and MASH.

GIP receptor signaling

GIP, produced by duodenal K-cells, shares insulinotropic properties with GLP-1 but exhibits distinct receptor expression patterns and physiological effects. GIP receptors are highly expressed in pancreatic beta cells and adipose tissue, but are present at minimal or negligible levels in the liver and skeletal muscle, suggesting tissue-specific mechanisms. The additive insulinotropic effect of GIP combined with GLP-1 results from direct beta-cell stimulation and enhancement of alpha-to-beta cell paracrine communication, with GIP contributing substantially to postprandial insulin secretion^[30,31]. Importantly, GIP receptor sensitivity is impaired in prolonged hyperglycemic states due to receptor downregulation but can be restored upon achieving euglycemia through complementary GLP-1 action^[38,39].

Beyond pancreatic effects, GIP receptor agonism enhances peripheral insulin sensitivity, particularly in adipose tissue, where it promotes healthy white adipose tissue (WAT) expansion, facilitates dietary triglyceride clearance through increased lipoprotein lipase activity and adipose blood flow, and improves lipid buffering capacity^[40]. This enhanced adipose function reduces ectopic lipid deposition in liver and other tissues, indirectly ameliorating hepatic steatosis. Additionally, GIP receptor expression in hypothalamic regions and oligodendrocytes suggests central nervous system actions that may synergize with GLP-1 to reduce appetite and food intake while potentially mitigating GLP-1-associated nausea, thereby improving treatment tolerability^[36,41,42].

GCG signaling

Unlike GLP-1 and GIP receptors, GCG show robust hepatic expression, enabling direct hepatic metabolic effects. Hepatic glucose homeostasis during fasting or hypoglycemia depends critically on GCG signaling, which activates both glycogen breakdown and gluconeogenic pathways to prevent dangerous decreases in circulating glucose levels. GCG activation suppresses endogenous hepatic lipid production by inhibiting lipogenic enzymatic pathways while simultaneously enhancing mitochondrial oxidative lipid catabolism, thereby promoting lipid catabolism and reducing hepatic triglyceride content^[18].

Furthermore, glucagon stimulates the secretion of follistatin, a hepatokine that inhibits hepatic lipid influx and de novo lipogenesis, providing additional hypolipidemic effects^[20]. While the inflammation-reducing and fibrosis-attenuating effects of glucagon agonism are less well-characterized, the reductions in hepatic inflammation parameters and fibrosis observed in preclinical models likely reflect secondary effects consequent to improved steatosis, rather than direct anti-inflammatory actions^[21]. Glucagon also contributes to energy homeostasis by promoting satiety through vagal signaling to brainstem nuclei and by increasing resting energy expenditure through facultative thermogenesis in brown adipose tissue, skeletal muscle, and through promotion of WAT browning^[22]. These effects on energy balance complement incretin-mediated appetite suppression, facilitating greater weight loss.

Boland et al. employed a diet-induced NASH mouse model to compare the efficacy of cotadutide (a dual GLP-1/GCG agonist) against liraglutide (selective GLP-1 receptor agonist) and pair-fed controls. Both cotadutide and liraglutide markedly diminished liver steatosis, inflammatory activity, and fibrosis compared to ad libitum-fed controls. However, cotadutide demonstrated superior performance in decreasing liver triglyceride levels and ameliorating mitochondrial functional markers in the liver compared to liraglutide, despite comparable reductions in body weight and food intake between the two treatments^[43]. Mechanistic analyses revealed that cotadutide’s enhanced hepatic benefits were associated with increased mitochondrial β-oxidation capacity, improved mitochondrial respiratory chain function and more pronounced suppression of de novo lipogenesis enzymes. These findings suggest that the additional GCG agonism in cotadutide provides direct metabolic benefits to hepatocytes beyond those achievable through GLP-1 receptor activation alone, even when caloric restriction is matched^[43].

In summary, the distinct receptor expression patterns and physiological roles of GLP-1, GIP, and glucagon create complementary mechanisms that, when engaged through mono-, dual-, or triple agonist formulations, address multiple pathogenic pathways in MASLD. GLP-1 receptor activation chiefly enhances systemic insulin sensitivity and decreases liver lipid accumulation through indirect mechanisms. GIP receptor agonism amplifies insulinotropic effects, enhances adipose tissue function to prevent ectopic lipid deposition, and may improve treatment tolerability. GCG agonism provides direct hepatic effects by inhibiting lipogenesis and promoting fat oxidation while augmenting energy expenditure. These integrated actions position incretin-based therapies as uniquely suited to address the complex, multifactorial pathophysiology of MASLD^[19].

Liraglutide

Liraglutide, a once-daily GLP-1 receptor agonist with authorized indications for type 2 diabetes and obesity, was evaluated in the LEAN trial (NCT01237119), a phase 2 randomized controlled study enrolling 52 adults with biopsy-proven MASH^[22]. Participants received subcutaneous liraglutide 1.8 mg daily or placebo for a 48 week period. Histological resolution of MASH without fibrosis worsening - the study’s primary outcome - occurred in 39% of liraglutide recipients vs. only 9% of placebo-treated patients, achieving statistical significance (P = 0.019). While liraglutide demonstrated lower rates of fibrosis worsening compared to placebo (9% vs. 36%, P = 0.04), improvement in fibrosis stage did not differ significantly between groups (26% with liraglutide vs. 14% with placebo, P = 0.46)^[44].

Secondary outcomes demonstrated significant improvements in metabolic parameters. Body weight reduction averaged 5.5% in the liraglutide arm compared to 0.7% with placebo (P = 0.003), while glycemic control improved as reflected by a mean HbA1c decrease of 5.7 mmol/mol (P = 0.03). Liraglutide therapy exhibited good safety tolerability, with gastrointestinal symptoms representing the predominant adverse events: nausea affected 46% of liraglutide users vs. 38% receiving placebo, diarrhea occurred in 38% vs. 19%, constipation in 27% vs. 0%, and vomiting in 19% vs. 12%. These gastrointestinal events were predominantly of minor to intermediate severity. Adverse event-related discontinuation rates were 8% among liraglutide-treated patients compared to 4% of placebo recipients^[44].

Semaglutide

Semaglutide, a weekly-administered GLP-1 receptor agonist with enhanced potency and prolonged half-life, has been extensively evaluated in MASH populations. The phase 2 dose-ranging trial (NCT02970942) included 320 individuals with histologically proven MASH and hepatic fibrosis F1-F3, randomizing them 3:3:3:1:1:1 to daily subcutaneous administration of semaglutide 0.1, 0.2, or 0.4 mg, or placebo for 72 weeks^[18]. The principal outcome - resolution of MASH in absence of fibrosis worsening - occurred in 40%, 36%, and 59% of individuals treated with semaglutide 0.1, 0.2, and 0.4 mg, respectively, vs. 17% in the placebo arm (P < 0.001 for 0.4 mg compared to placebo). However, the secondary outcome of hepatic fibrosis amelioration by at least one stage in the absence of MASH progression did not demonstrate statistical significance (49%, 32%, and 43% for semaglutide 0.1, 0.2, and 0.4 mg vs. 33% for placebo; P = 0.48 for 0.4 mg compared to placebo)^[18].

Metabolic benefits were substantial, including mean weight decrease of 13% in the semaglutide 0.4 mg cohort relative to 1% with placebo. Dose-dependent reductions in HbA1c were observed regardless of diabetes status. Semaglutide 0.4 mg was associated with elevated rates of gastrointestinal side effects as opposed to placebo (nausea 42% vs. 11%; diarrhea 20% vs. 14%; constipation 22% vs. 12%; vomiting 15% vs. 2%), but were generally mild to moderate, leading to discontinuation in only 4% of semaglutide-treated participants. Biliary tract complications demonstrated higher incidence among semaglutide group (6%-7%) vs. placebo (2%), consistent with known GLP-1 RA class effects. No acute pancreatitis events were reported^[18].

Building upon phase 2 findings, the ongoing phase 3 ESSENCE trial (NCT04822181) is assessing weekly subcutaneous semaglutide 2.4 mg compared to placebo in 1197 individuals with biopsy-proven MASH and fibrosis stages F2-F3 over 240 weeks, with primary endpoints of MASH resolution without fibrosis progression, fibrosis improvement in absence of MASH exacerbation, and cirrhosis-free survival^[10]. A scheduled intermediate evaluation at week 72 in the earliest 800 enrollees (534 semaglutide, 266 placebo) demonstrated that among semaglutide-treated patients, 62.9% obtained MASH resolution absent fibrosis deterioration, compared with 34.3% in the placebo group (P < 0.001). Importantly, fibrosis reduction without MASH progression was documented in 36.8% of semaglutide recipients compared to 22.4% of placebo recipients (P < 0.001), representing the first demonstration of significant fibrosis benefit with a GLP-1 receptor agonist in a phase 3 MASH trial^[10]. Subgroup analyses demonstrated that treatment responses with semaglutide were consistent across different patient populations. Specifically, the dual primary outcomes - steatohepatitis resolution without concurrent fibrosis worsening, and fibrosis improvement without concurrent steatohepatitis worsening - remained consistent regardless of age, sex, type 2 diabetes status, or baseline fibrosis severity (stage F2 vs. F3). This consistency suggests that semaglutide’s beneficial effects on liver histology are robust and applicable to a diverse patient population with MASH and intermediate-to-advanced fibrosis. However, semaglutide appeared less effective at reducing fibrosis without MASH worsening in patients with a body mass index (BMI) below 27 kg/m², and showed attenuated efficacy for both histological endpoints in Hispanic patients; these findings merit further exploration and prospective validation. Additionally, an analysis of insulin resistance improvement [measured by homeostatic model assessment for insulin resistance (HOMA-IR)], performed after excluding patients using insulin, suggested that semaglutide reduced insulin resistance to a slightly greater extent in patients with type 2 diabetes than in those without, although both groups demonstrated improvement^[10].

Mean weight loss in the ESSENCE interim analysis was 10.5% with semaglutide vs. 2% with placebo (P < 0.001). Improvements in cardiometabolic parameters included reductions in HbA1c, high-sensitivity C-reactive protein, and lipid profiles. Non-invasive fibrosis markers improved significantly: liver stiffness by transient elastography decreased by 20%, improved hepatic fibrosis index decreased by 0.6 units, and Pro-C3 biomarker decreased by 17% (all P < 0.001). Gastrointestinal complications persisted as the predominant adverse effects (nausea 36.2% vs. 13.2%; diarrhea 26.9% vs. 12.2%; constipation 22.2% vs. 8.4%; vomiting 18.6% vs. 5.6%), although severe manifestations comprised only 13.4%. Treatment withdrawal secondary to adverse events was observed in 3% of both groups. Biliary tract events (2.5% vs. 1.5%) and acute pancreatitis inflammation (< 1%, 3 cases) were infrequent. Long-term outcomes are anticipated in 2028^[10].

The landmark SELECT trial demonstrated that semaglutide decreases cardiovascular event rates in non-diabetic obesity who have prior cardiovascular disease, establishing cardiovascular benefits beyond glycemic effects. In this multicenter, double-masked, randomized, placebo-controlled, event-based superiority study, 17,604 participants were recruited; 8,803 were randomized to semaglutide and 8,801 to placebo. Among participants, 569 of 8,803 (6.5%) receiving semaglutide and 701 of 8,801 (8.0%) receiving placebo experienced a primary cardiovascular endpoint [hazard ratio (HR): 0.80; 95% confidence interval (CI): 0.72 to 0.90; P < 0.001]^[4]. Combined analysis across SELECT, FLOW, STEP-HFpEF (heart failure with preserved ejection fraction), and STEP-HFpEF DM studies confirmed these cardiovascular benefits across diverse patient populations. Across the four investigations, 3,743 participants (16.8%) among 22,282 total presented with established HFpEF (1,914 randomized to semaglutide, 1,829 to placebo). Among HFpEF subset, semaglutide reduced the composite endpoint risk of cardiovascular death or cardiac decompensation cases [103 (5.4%) of 1,914 in semaglutide arm vs. 138 (7.5%) of 1,829 in placebo arm; HR: 0.69 (95%CI: 0.53-0.89); P = 0.0045]. Furthermore, semaglutide decreased the risk of heart failure exacerbation events [54 (2.8%) vs. 86 (4.7%); HR: 0.59 (0.41-0.82); P = 0.0019]. Cardiovascular mortality as an isolated endpoint showed no meaningful effect [59 (3.1%) vs. 67 (3.7%); HR: 0.82 (0.57-1.16)]^[3-5].

The FLOW trial specifically demonstrated semaglutide’s impact on kidney function in subjects with type 2 diabetes, showing renal protective effects^[15]. Proposed mechanisms include hemodynamic effects reducing intraglomerular pressure, anti-inflammatory actions, and metabolic improvements reducing oxidative stress and advanced glycation end-product formation. Since CKD frequently coexists with MASLD as part of the broader metabolic syndrome, renal protection represents a clinically relevant pleiotropic benefit^[15].

A phase 2 trial in MASH-related cirrhosis (NCT03987451) assessed semaglutide 2.4 mg weekly vs. placebo in 71 adults with histologically confirmed cirrhosis for 48 weeks. Despite the primary endpoint of fibrosis improvement without worsening of MASH failing to reach statistical significance, the trial established safety in this advanced population without significant concerns^[46]. However, the limited enrollment in this study precludes drawing definitive conclusions regarding semaglutide 2.4 mg weekly efficacy and safety in patients with MASH-related compensated cirrhosis.

Tirzepatide

Tirzepatide, the first food and drug administration (FDA)-approved dual GLP-1/GIP receptor agonist for type 2 diabetes and obesity, was evaluated in the SYNERGY-NASH trial (NCT04166773), a phase 2, double-masked, dose-finding study in 190 participants with histologically confirmed MASH and fibrosis stages F2-F3^[11]. Participants were randomized 1:1:1:1 to weekly subcutaneous tirzepatide 5, 10, or 15 mg, or placebo for 52 weeks. The primary endpoint - MASH resolution absent fibrosis progression - was documented in 44%, 56%, and 62% of individuals receiving tirzepatide 5, 10, and 15 mg, contrasting with 10% among placebo participants (P < 0.001 for all tirzepatide doses vs. placebo). Notably, the secondary endpoint of fibrosis amelioration by ≥ 1 stage without concurrent MASH deterioration was met in 55%, 51%, and 51% of the 5, 10, and 15 mg cohorts vs. 30% receiving placebo (P < 0.05 for all doses), representing substantial fibrosis benefit^[11].

Non-invasive imaging demonstrated a marked reduction in liver fat fraction and intrahepatic lipid content measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), with absolute reductions spanning 41.3% to 57% among tirzepatide recipients compared to 9.8% in placebo-treated individuals (P < 0.05 for all doses). Iron-corrected T1 (cT1), a biomarker of hepatic inflammation and fibrosis, decreased by 70.7-107.2 msec across tirzepatide groups (P < 0.05). Liver stiffness quantified by vibration-controlled transient elastography decreased by 3.1-3.5 kPa with tirzepatide vs. minimal change with placebo (P < 0.05). Biomarkers of fibrosis including enhanced liver fibrosis score (0.45-0.50 unit reduction) and Pro-C3 (40.1-45.7 μg/L reduction) improved significantly with all tirzepatide doses (P < 0.001)^[11]. Subgroup analysis from the SYNERGY-NASH trial revealed consistent efficacy of tirzepatide across different patient populations. Weight reduction at 52 weeks showed a dose-dependent response in both participants with and without type 2 diabetes mellitus, with mean percentage changes ranging from -10.7% to -15.6% across the three tirzepatide doses compared to -0.8% with placebo. Regarding fibrosis stage, liver fibrosis improvement appeared more pronounced in participants with stage F3 fibrosis relative to stage F2 counterparts, potentially reflecting reduced placebo effect in the more advanced fibrosis group^[47].

Mean weight loss was dose-dependent: 10.7%, 13.3%, and 15.6% in the 5, 10, and 15 mg groups, respectively, vs. 0.8% with placebo (P < 0.001 for all doses). Even participants with type 2 diabetes achieved substantial weight reduction reaching 13.7% among the maximum dose cohort. Gastrointestinal adverse events were more frequent with tirzepatide (nausea 44% vs. 12%; diarrhea 27% vs. 23%; constipation 15% vs. 6%; vomiting 15% vs. 2%) though generally mild or moderate (> 90%). Treatment withdrawal secondary to adverse events was observed in 4% of participants across both treatment arms. Cirrhotic progression was documented in 3% and 4% of tirzepatide and placebo cohorts, respectively. No events of hepatic decompensation, drug-induced liver injury, or acute pancreatitis were reported. Gallbladder-related events (3% vs. 2%) were infrequent^[11]. Tirzepatide demonstrates significant extrahepatic benefits beyond its well-established hepatic effects, particularly in the cardiovascular and metabolic domains. The SUMMIT trial, involving 731 individuals with HFpEF and obesity followed for a median of 104 weeks, revealed a 38% decrease in the composite endpoint of cardiovascular mortality or heart-failure deterioration events (HR: 0.62, 95%CI: 0.41-0.95, P = 0.026), driven primarily by fewer worsening heart-failure events (8.0% vs. 14.2%, HR: 0.54). These cardiovascular benefits were accompanied by substantial metabolic improvements including 13.9% weight reduction, a 34.9 percentage point greater decrease in high-sensitivity C-reactive protein levels reflecting potent anti-inflammatory effects (P < 0.001), and a 4.7 mm Hg reduction in systolic blood pressure^[48].

Survodutide

Survodutide, a weekly dual GLP-1/GCG agonist, was assessed in a phase 2 dose-finding trial (NCT04771273) including 293 individuals with histologically confirmed MASH and fibrosis stages F1-F3^[46]. Patients were randomized 1:1:1:1 to survodutide 2.4, 4.8, or 6 mg weekly, or placebo for 48 weeks. The primary endpoint - MASH improvement absent fibrosis progression - was observed in 47%, 62%, and 43% of the 2.4, 4.8, and 6 mg groups, respectively, vs. 14% with placebo (P < 0.001 for all doses). The secondary endpoint of fibrosis reduction by at least one stage was documented in 34%, 36%, and 34% of participants receiving survodutide compared to 22% of placebo, demonstrating potential anti-fibrotic benefit^[23].

MRI-PDFF fat fraction assessment revealed marked hepatic fat decreases of 57%-67% among survodutide recipients vs. 14% in placebo-treated individuals. Absolute body weight reductions measured 10.2, 12.9, and 13.1 kg across the 2.4, 4.8, and 6 mg cohorts respectively vs. 0.6 kg with placebo. Of note, glycemic control improved with HbA1c reductions reaching 0.8% with survodutide therapy, indicating preserved glycemic benefits despite GCG agonism, likely reflecting the predominant GLP-1 receptor activity ratio. Gastrointestinal side effects demonstrated higher incidence compared to GLP-1 monotherapy (nausea 66% vs. 23%; diarrhea 49% vs. 23%; constipation 21% vs. 15%; vomiting 41% vs. 4%), leading to therapy interruption in 16% of survodutide recipients vs. 1.4% of placebo, highlighting tolerability challenges that may require optimization of dosing strategies or formulations^[23].

Pemvidutide

Pemvidutide, another weekly GLP-1/glucagon dual agonist, is under evaluation in the ongoing phase 2 IMPACT trial (NCT05989711) in 190 individuals with histologically confirmed MASH and fibrosis stages F2-F3^[47]. Patients are randomized to pemvidutide 1.2 or 1.8 mg weekly, or placebo for 24 weeks, with primary endpoints of MASH resolution without fibrosis progression and fibrosis amelioration without MASH deterioration. Preliminary data from a phase 1b extension study (NCT05292911) involving 64 individuals with MRI-PDFF ≥ 10% and BMI ≥ 28 kg/m² demonstrated that 50%, 44%, and 60% of participants presenting baseline alanine aminotransferase (ALT) ≥ 30 IU/L reached combined MRI-PDFF reduction ≥ 30% and ALT reduction ≥ 17 IU/L at pemvidutide doses of 1.2, 1.8, and 2.4 mg, respectively, vs. 0% with placebo, suggesting promising early efficacy signals^[49].

In the IMPACT trial, pemvidutide achieved mean weight losses of 4.8% and 5.8% with 1.2 and 1.8 mg doses respectively at 24 weeks, compared to 0.5% with placebo, with weight loss curves showing no evidence of plateauing, suggesting continued benefit with longer treatment^[49-51].

Efinopegdutide

Emerging data on novel agents continue to expand the evidence base. Studies of efinopegdutide, another dual GLP-1/GCGR agonist, have shown preliminary efficacy. In a phase IIa, randomized, open-label study with an active comparator, efinopegdutide was compared with semaglutide over 24 weeks in individuals with elevated liver fat content (LFC). A total of 145 participants (33.1% with type 2 diabetes) were randomly assigned to once weekly efinopegdutide 10 mg or semaglutide 1 mg following dose titration. Efinopegdutide administered once weekly at 10 mg produced a greater hepatic fat decrease than semaglutide 1 mg in patients with NAFLD (LS mean -72.7% vs. -42.3%; P < 0.001). The safety profile showed modestly elevated rates of overall side effects and drug-attributable side effect in the efinopegdutide cohort relative to semaglutide, attributable predominantly to a higher frequency of gastrointestinal manifestations^[52].

Retatrutide

Retatrutide represents the most advanced triple agonist aiming GLP-1, GIP, and GCG simultaneously. A phase 2 trial in 338 adults with obesity showed remarkable 24.2% mean weight loss (vs. -2.1% in the placebo group) at 48 weeks, the highest pharmacologic weight loss reported to date^[24]. Enrollees underwent random allocation in a 2:1:1:1:1:2:2 distribution to receive weekly subcutaneous retatrutide at doses of 1, 4 mg (starting dose 2 mg), 4 mg (starting dose 4 mg), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg), vs. placebo for a 48-week period.

A MASLD substudy within the phase 2 obesity trial of retatrutide provided compelling evidence of hepatic benefits. Ninety-eight patients with obesity and MASLD (defined as ≥ 10% liver fat by MRI-PDFF) were contained in this substudy. After 24 weeks, retatrutide achieved mean relative reductions in liver fat of 42.9% (1 mg), 57.0% (4 mg), 81.4% (8 mg), and 82.4% (12 mg), compared to 0.3% increase with placebo (all P < 0.001 vs. placebo). At 48 weeks, the liver fat reductions were even more pronounced, with approximately 90% of individuals receiving maximum dose levels achieving normalization of liver fat^[25].

Compensated cirrhosis

Patients with MASH-related compensated cirrhosis (Child-Pugh A) represent a clinically important subgroup given the risk of hepatic decompensation and HCC. A phase 2 trial of semaglutide 2.4 mg in 71 cirrhotic patients confirmed an acceptable safety profile without significant decompensation events, although the primary histological endpoint was not met, possibly due to the limited ability of antifibrotic remodeling to achieve biopsy-detectable fibrosis stage improvement in established cirrhosis over 48 weeks^[46]. Real-world evidence from observational studies consistently shows that GLP-1 RA use is associated with reduced risk of hepatic decompensation even in patients with established cirrhosis, supporting cautious use in this population. GLP-1 RAs are not renally cleared and do not require dose adjustment for hepatic impairment per se; however, close monitoring for gastrointestinal adverse events is warranted in cirrhotic patients, who may have reduced tolerance. Dual and triple agonists have not been formally evaluated in compensated cirrhosis in dedicated trials, and their use in this setting should await further evidence.

Renal impairment

GLP-1 RAs are generally safe in patients with CKD and have demonstrated nephroprotective effects in the FLOW trial, where semaglutide significantly reduced the composite renal endpoint (hospitalization for acute kidney injury, sustained ≥ 50% decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, or renal death) in patients with type 2 diabetes and CKD^[15]. Semaglutide and liraglutide are not renally excreted and can be used across eGFR categories without dose adjustment, though caution is advised in severe CKD (eGFR < 15 mL/min/1.73m²) due to limited data. Gastrointestinal side effects (nausea, vomiting) may exacerbate dehydration and prerenal acute kidney injury in susceptible patients, requiring hydration counseling. Tirzepatide’s renal outcomes trial is ongoing. Given the high prevalence of CKD in MASLD patients and the shared pathophysiology, GLP-1-based therapies are particularly attractive in this comorbid population^[15].

Cardiovascular disease

Patients with established cardiovascular disease represent a population that derives both hepatic and cardiovascular benefit from GLP-1 RAs. The SELECT trial demonstrated a 20% reduction in major adverse cardiovascular events (MACE) with semaglutide in non-diabetic patients with obesity and prior cardiovascular events^[4,5]. In patients with HFpEF and obesity, both semaglutide (STEP-HFpEF) and tirzepatide (SUMMIT) significantly reduced cardiovascular death and worsening heart failure events, with concomitant improvements in quality of life and functional capacity^[3,47]. Importantly, hemodynamic effects - modest reductions in heart rate (+2-4 bpm) and blood pressure decreases - are generally well tolerated and beneficial in this population. GLP-1 RAs are not contraindicated in patients with prior atrial fibrillation, although the modest heart rate increase warrants monitoring. In patients with MASLD and established CVD, GLP-1-based therapies are strongly supported as a cornerstone treatment addressing both hepatic and cardiometabolic disease burden simultaneously.

Elderly patients and other special populations

Older adults (≥ 65 years) with MASLD may experience greater gastrointestinal intolerance and dehydration risk; slower dose titration and increased monitoring are advisable. Muscle mass preservation is an important consideration given the risk of sarcopenic obesity: weight loss with GLP-1 RAs includes a lean mass component (approximately 25%-40% of total weight loss), though the clinical significance in MASLD patients without sarcopenia is uncertain. Patients with very low body mass index (< 27 kg/m²) showed attenuated histological responses in the ESSENCE trial subgroup analysis, and the benefit-risk profile in non-obese MASLD warrants further evaluation^[10]. In patients with type 2 diabetes receiving insulin, GLP-1 RA initiation may require insulin dose reduction to minimize hypoglycemia risk. Drug-drug interactions are minimal given predominant non-renal, non-hepatic elimination pathways, though delayed gastric emptying may affect absorption of oral medications with narrow therapeutic windows. Overall, the benefit-risk profile supports broad use of GLP-1-based therapies in MASLD across most patient subgroups, with individualized monitoring plans for high-risk populations.

Durability of histological response and rebound effects

A critical unresolved question concerns the durability of histological improvement following treatment interruption or dose reduction. Available evidence from diabetes and obesity trials demonstrates substantial weight regain after discontinuation of GLP-1 RAs, reaching pre-treatment levels in some cohorts within 12-18 months of cessation, with accompanying deterioration in cardiometabolic parameters^[72]. In the context of MASLD/MASH, analogous rebound phenomena would be expected: regression of achieved steatosis resolution and potential re-emergence of inflammatory activity and fibrogenic stimuli upon drug withdrawal. Dedicated histological reassessment studies after GLP-1 RA discontinuation in MASH patients are currently lacking, representing a major evidence gap. The ESSENCE trial will provide valuable data on the maintenance of histological benefits over 240 weeks of continuous treatment, but long-term extension studies and off-treatment follow-up protocols are needed to characterize rebound kinetics. Until durability data are available, chronic maintenance therapy analogous to treatment paradigms for other chronic liver conditions is likely required to sustain hepatic benefits. This has important implications for patient counseling, treatment planning, and cost-effectiveness analyses.

Future perspectives and outstanding questions

Despite substantial progress, several unmet needs and key questions require investigation to fully realize the therapeutic potential of GLP-1-based therapies in MASLD/MASH. First, optimal patient selection criteria remain poorly defined. Although current evidence supports broad applicability across BMI, diabetes status, and fibrosis stages F2-F3, subgroup analyses suggest attenuated responses in non-obese patients and in certain ethnic groups (Hispanic patients in ESSENCE), emphasizing the need for precision medicine approaches incorporating anthropometric, genetic (e.g., PNPLA3, HSD17B13), and metabolic profiling. Second, head-to-head comparative trials between GLP-1 RA monotherapy, dual agonists, and triple agonists in MASH populations with histological endpoints are entirely lacking: current selection among agents relies on indirect comparisons across trials with different inclusion criteria and follow-up periods. Such trials are essential to guide evidence-based prescribing. Third, the optimal positioning and sequencing of GLP-1-based therapies relative to resmetirom and other emerging MASH agents (e.g., lanifibranor, pegozafermin, semaglutide combination regimens) requires dedicated combination trials, of which preliminary data from the MAESTRO-NASH secondary analysis are encouraging. Fourth, long-term clinical outcomes data - cirrhosis incidence, HCC rates, liver transplantation, and liver-related mortality assessed as primary endpoints in randomized trials - are not yet available and are urgently needed to move beyond surrogate histological endpoints. The ESSENCE trial 240-week readout in 2028 will be a landmark, but longer follow-up and adequately powered studies in higher-risk populations (F3-F4 fibrosis) remain priorities. Fifth, cost-effectiveness analyses are critical given the high price of current GLP-1 RAs and the large potential treatment population: preliminary health-economic models suggest acceptable cost-effectiveness ratios in high-fibrosis patients with comorbid type 2 diabetes and cardiovascular disease, but robust data in broader MASLD populations are lacking. Finally, the biology of non-response and therapeutic resistance - including the role of gut microbiome composition, adipose tissue dysfunction phenotypes, and genetic determinants of drug metabolism - represents a frontier for translational investigation to improve patient outcomes.

Longer-duration randomized controlled trials with hard clinical endpoints including liver-related morbidity and mortality are essential to definitively establish the clinical value of incretin-based therapies in MASH. Nevertheless, current evidence supports GLP-1 RAs and multi-agonist formulations as highly promising pharmacotherapies that address the complex, multifactorial pathophysiology of MASLD while simultaneously improving cardiometabolic comorbidities, positioning them as cornerstone treatments in the evolving therapeutic landscape for this prevalent and burdensome disease.