Burden of obesity-associated metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to under the umbrella of non-alcoholic fatty liver disease (NAFLD), is now recognized as the most prevalent chronic liver disease condition globally, closely linked to the rising rates of obesity [1, 2]. At the core of MASLD is hepatic steatosis, an excessive accumulation of fat in liver cells that can progress to more severe conditions like liver inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. Obesity increases these risks by causing insulin resistance (IR), increasing the influx of free fatty acids into the liver, and promoting chronic low-grade inflammation [3]. The impact on the quality of life for affected individuals is substantial, as MASLD is also associated with metabolic comorbidities like type 2 diabetes mellitus (T2DM), dyslipidemia, and hypertension. From a public health perspective, the increase in healthcare expenses associated with MASLD and its complications is significant, underscoring the urgent need for effective treatment strategies that tackle both the liver-specific issues and the broader metabolic risks faced by affected individuals [2].

Presentation of tirzepatide

Tirzepatide is a synthetic dual incretin receptor agonist (molecular mass ∼4.8 kDa, water-soluble) that has recently emerged as a novel therapeutic strategy for metabolic disorders by targeting both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors (GLP-1R), leading to marked improvements in glycemic control and body weight in clinical trials for T2DM [4] (Table 1, Figure 1).

Display full size

Figure 1. Tirzepatide structure and function. (A) Tirzepatide is a synthetic peptide of 39 amino acids carrying a C20 fatty di-acid moiety that is connected via a linker to lysine at position 20. The peptide contains two non-natural amino acids (α-amino isobutyric acids, Aib) at positions 2 and 13; (B) chemical structure of tirzepatide showing the peptide sequence and the location of the C20 fatty-di-acid moiety. The structure coordinates were taken from the PubChem database (PubChem CID: 172874756, https://pubchem.ncbi.nlm.nih.gov/compound/172874756#section=2D-Structure) [7] and the image was generated with Jmol (version 14.2.15_2015.07.09); (C) 3D representation of the structure of the GLP-1R/tirzepatide complex. Tirzepatide binds to the extracellular domain of GLP-1R, leading to recruitment of different G-proteins; (D) rough depiction of the binding sites of tirzepatide within the extracellular domain of the GLP-1R. The structure coordinates of the receptor-drug complex were taken from the RCSB Protein Data Bank (PDB ID: 7RBT DOI Citation: B. Sun, B.K. Kobilka, K.W. Sloop, D. Feng, T.S. Kobilka, cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to tirzepatide (2022) https://doi.org/10.2210/pdb7rbt/pdb) [8] and the image was generated with Ribbons (Ribbons XP Version 3.0). Details about the structure are given elsewhere [9]. GLP-1R: glucagon-like peptide-1 receptor.

This dual agonism of tirzepatide represents a promising approach to obesogenic and metabolic pathways. As interest in addressing the multifaceted pathophysiology of MASLD expands, the potential of tirzepatide to improve insulin sensitivity, promote weight loss, and modify hepatic inflammation makes it an attractive candidate for further investigation. Recent experimental studies, first case reports, and clinical trials suggest that these benefits may extend to ameliorating hepatic fat accumulation, reducing fibrosis, and modulating gut microbiota may hold promise to mitigate the progression of MASLD and its more rapidly evolutive variant metabolic dysfunction-associated steatohepatitis (MASH) [10–12].

Aims of the review

This review aims to clarify the relationship between tirzepatide and MASLD, focusing on its mechanistic basis and preliminary data on clinical outcomes. First, we will provide a comprehensive overview of the mechanism by which tirzepatide exerts its metabolic effects, exploring its dual receptor activity and downstream signaling pathways. We will then discuss the current evidence, detailing how the ability of tirzepatide to reduce weight, improve insulin sensitivity, and potentially possess anti-inflammatory properties could lead to therapeutic benefits for MASLD. Finally, we will identify gaps in the existing literature and emphasize the need for further clinical trials to understand the long-term impact of tirzepatide on MASLD disease progression and outcomes in various patient populations.

Mechanistic insights and biological pathways

Incretin hormones such as GIP and GLP-1 are secreted by enteroendocrine cells in response to oral nutrient intake. The 42-amino acid peptide hormone GIP is primarily released by K-cells in the duodenum and proximal jejunum, while GLP-1 is secreted by L-cells located predominantly in the distal ileum and colon [14, 15]. Both hormones play critical roles in glucose homeostasis, affecting insulin secretion, suppressing glucagon, regulating gastric emptying, and controlling appetite through central nervous system signals. There are two clinically important incretin receptors, the GIPR and the GLP-1R [16, 17]. The GIPR is a G-protein-coupled receptor (GPCR) that, upon binding GIP, initiates a signaling cascade predominantly through the stimulatory G-protein [16]. Activation of adenylate cyclase leads to increased cyclic adenosine monophosphate (cAMP) levels, which in turn activate protein kinase A (PKA) and downstream targets [16]. The overall effect promotes glucose-dependent insulin secretion in pancreatic β-cells and may have additional effects on lipolysis and adipocyte function. Like the GIPR, GLP-1R is also a GPCR primarily coupled to Gs, leading to elevated cAMP levels and PKA-mediated signaling. The downstream effects in pancreatic β-cells include enhanced insulin synthesis and secretion, while in α-cells, GLP-1R activation reduces glucagon secretion. Peripheral actions include delayed gastric emptying, reduced appetite, and a variety of cardioprotective and anti-atherogenic effects [16].

Tirzepatide is specifically designed with structural elements to bind to both GIPR and GLP-1R. While many existing drugs for T2DM and obesity target the GLP-1R alone, the ability of tirzepatide to act on both incretin receptors seems to provide synergistic or at least additive benefits [18]. This is in terms of enhanced insulin secretion by stimulating both GIPR and GLP-1R on β-cells. Tirzepatide augments insulin release in a glucose-dependent manner, reducing the risk of hypoglycemia commonly associated with non-glucose-dependent insulin secretagogues, such as sulfonylureas and meglitinides [19]. Furthermore, in states of hyperglycemia, activation of GLP-1R in α-cells due to tirzepatide helps curb excessive glucagon secretion, further improving glycemic control. Therefore, the net effect of tirzepatide in T2DM is a reduction in inappropriately high glucagon levels, likely due to the predominant GLP-1R-mediated suppression. Moreover, tirzepatide can lead to a mean reduction in body weight, as both GIP and GLP-1 play roles in modulating appetite and satiety [20]. However, GLP-1R agonism is most famously associated with central appetite suppression and delayed gastric emptying, and the effects of tirzepatide on weight reduction are multifactorial. These encompass central appetite regulation, changes in gut motility, and improved insulin sensitivity [21].

Upon binding to their respective GPCRs, GIP and GLP-1 trigger a cascade of intracellular events. In the first step, there is a Gs-mediated increase in cAMP, leading to PKA-dependent phosphorylation of key transcription factors such as cAMP response element-binding protein (CREB) [22]. This process subsequently simulates regulatory genes responsible for β-cell growth, insulin biosynthesis, and mitochondrial function in various tissues. Additionally, increased cAMP also modulates the flow of intracellular calcium through secondary messenger systems, which is a prerequisite for insulin granule exocytosis in β-cells. By facilitating calcium-dependent vesicle release, tirzepatide can enhance insulin output in T2DM. In addition to the cAMP axis, incretin hormone receptor activation can engage the extracellular signal-regulated kinase (ERK1/2) and phosphoinositide 3-kinase (PI3K)/Akt routes, pathways integral to cell survival, proliferation, and receptor cross-talk [22], further potentiating the beneficial effects of incretin agonists on β-cell health and peripheral insulin sensitivity.

The pancreas is perhaps the most direct target of the dual agonism of tirzepatide, affecting both endocrine and, to a lesser extent, exocrine function. Chronic exposure to GLP-1R agonists (GLP-1RAs) can promote β-cell proliferation and protect cells from apoptosis, possibly mediated by anti-inflammatory signals and an improved metabolic environment [23]. GIP has also been implicated in β-cell maintenance, although debates remain regarding its long-term effects. The combined effect of tirzepatide therapy may support better β-cell mass maintenance over time. Its glucose-dependent effect on insulin release implies a reduction of the risk of hypoglycemia with tirzepatide, while providing more robust glycemic control with reductions in glycated hemoglobin (HbA1c) levels compared to traditional secretagogues [24, 25]. Moreover, the potent effects of tirzepatide on GLP-1R activity in hyperglycemic states also contribute to preventing hyperglycemic surges postprandially through fine-tuning of glucagon levels.

Appetite suppression and reduced food intake are primarily driven by GLP-1RAs through three synergistic mechanisms. Firstly, the hypothalamus integrates peripheral signals of nutrient status. Incretin hormones that cross or signal through the blood-brain barrier can impact neuron populations that regulate feeding behavior, such as the pro-opiomelanocortin (POMC) neurons and the neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons [26, 27]. Secondly, incretin-based therapies may influence dopaminergic reward pathways, leading to a reduction in food-related cravings [28], which is particularly relevant for managing obesity. Thirdly, by slowing gastric emptying, tirzepatide promotes an earlier sense of fullness and sustained release of nutrients into the intestines, further enhancing satiety and improving postprandial glucose control [21].

An intriguing biological aspect of tirzepatide activity is its potential influence on adipose tissue metabolism. GIP signaling in adipocytes has historically been linked to both anabolic and catabolic pathways, making the net effect somewhat context dependent. Under certain metabolic states, GIP can promote fat storage by enhancing insulin-mediated lipogenesis in adipocytes [29]. Paradoxically, in an environment where metabolic dysfunction is being actively corrected (e.g., through improved insulin sensitivity, reduced inflammation, or calorie deficit), the net effect of improved glucose handling might facilitate more efficient fuel partitioning, thereby reducing ectopic fat accumulation in the liver. However, some animal studies regarding GIP analogs and GLP-1RAs have hinted at possible “browning” of white adipose tissue, increasing energy expenditure and thermogenesis [30]. Although this mechanism is not fully elucidated in humans, the interplay between GIP and GLP-1 in tirzepatide could theoretically promote a metabolically healthier adipose tissue phenotype. Other studies have shown that incretin therapies may influence the profile of adipokines (e.g., leptin, adiponectin) that modulate steatogenesis, insulin sensitivity, and inflammation [31].

Clinical and pathophysiological context

MASLD is characterized by hepatic steatosis, which results from an imbalance between the influx of free fatty acids, hepatic de novo lipogenesis, and export of triglycerides [1, 2, 32]. Tirzepatide may help correct this imbalance through several interconnected mechanisms. First, by improving glycemic control and insulin sensitivity, tirzepatide addresses key contributors to hepatic lipid accumulation. Chronically elevated insulin levels upregulate lipogenesis while IR in peripheral tissues increases circulating free fatty acids [33]. Through its glucose-dependent insulin-stimulating effects and its capacity to enhance peripheral insulin responsiveness, tirzepatide reduces the hepatic fat load. Second, by promoting weight reduction, tirzepatide alleviates the systemic inflammation and excessive free fatty acid flux that accompany excess adiposity, giving the liver an opportunity to reduce ectopic fat deposition [10]. Third, although direct anti-inflammatory effects of tirzepatide have not been as extensively documented as those observed with GLP-1 agonists alone, its dual incretin receptor activation is widely hypothesized to modulate generation of reactive oxygen species pro-inflammatory cytokine production [21]. Finally, tirzepatide may influence key transcription factors involved in lipid metabolism, such as SREBP-1c and PPAR-α/γ, and by improving systemic insulin sensitivity and promoting weight loss, it could push hepatocytes toward a less lipogenic gene expression profile [34]. Collectively, these direct and indirect effects on the liver position tirzepatide as a promising therapy for mitigating the development and progression of MASLD.

Although not a direct hepatic mechanism, improvements in cardiovascular and renal function under tirzepatide therapy can promote better overall metabolic homeostasis, offering additional benefits for MASLD. On the cardiovascular front, evidence from GLP-1RAs suggests a reduction in major adverse cardiovascular events, particularly in patients with T2DM at high cardiovascular risk [35]. By addressing cardiac dysfunction and atherosclerosis, tirzepatide may indirectly benefit the liver by enhancing nutrient utilization and oxygen delivery to peripheral tissues. Regarding renal protection, the ability of tirzepatide to lower blood pressure, reduce inflammation, and improve glycemic control helps in preserving kidney function [36]. A healthier renal profile allows for more efficient excretion of metabolic byproducts, contributing to a stable internal environment that reduces the risk factors exacerbating hepatic steatosis and inflammation. This cardiovascular and renal crosstalk is crucial for the broader improvements in metabolic health that could ultimately support liver function in patients with MASLD.

While the mechanistic rationale for tirzepatide in MASLD is compelling, several limitations and uncertainties remain. One consideration is the variable patient response to GIP, given the complex involvement of GIPRs in metabolic processes that can sometimes promote anabolic pathways in adipose tissue. The net effect on hepatic steatosis may thus depend on an individual’s metabolic milieu and genetic predisposition. Additionally, although tirzepatide has shown robust benefits for glycemic control and weight management, most clinical evidence has been derived from T2DM-focused studies with relatively limited long-term data on direct hepatoprotective outcomes, such as inflammation, fibrosis markers, or histological changes in the liver. Lastly, common side effects of incretin-based therapies, including nausea, vomiting, or diarrhea, could theoretically affect nutrient absorption and hepatic metabolism, and require more thorough investigation to elucidate their implications for liver health in diverse patient populations.

Given the overlap in pathophysiology among T2DM, obesity, and MASLD, it is logical that a treatment with proven efficacy in glycemic control and weight reduction would be explored for hepatic benefits. Future research is likely to include head-to-head comparisons of tirzepatide with established GLP-1RAs, focusing on liver-specific outcomes, such as MRI-PDFF measurements or histological findings from liver biopsies. Investigations into combination therapies will also be key, as MASLD encompasses lipotoxicity, oxidative stress, inflammation, and fibrosis; pairing tirzepatide with other agents targeting these pathways may offer complementary or synergistic effects. Another priority will be the development of reliable non-invasive biomarkers to track changes in liver fat content and fibrosis, which could include circulating markers like cytokeratin-18 fragments or scoring systems like fibrosis-4 (FIB-4) score and enhanced liver fibrosis (ELF) test, in addition to imaging-based assessments in patients with MASLD [37, 38]. These endeavors will help clinicians better personalize tirzepatide-based treatments and more accurately monitor their impact on disease progression.

MASLD results from a confluence of metabolic derangements that drive lipid overaccumulation and hepatic injury. The capacity of tirzepatide to address IR, obesity, and dysregulated nutrient handling makes tirzepatide particularly pertinent. Its dual incretin receptor agonism confers significant weight and glycemic improvements, targeting two main factors that hasten MASLD progression. Additionally, while direct evidence regarding tirzepatide’s anti-inflammatory and hepatoprotective actions is emerging, the broader metabolic benefits and known anti-inflammatory potential of incretin-based therapies suggest a plausible mechanism by which tirzepatide might reduce hepatic injury and fibrosis. This is especially relevant to patients with MASLD who frequently present with coexisting T2DM or prediabetes. By simultaneously addressing both glycemic control and hepatic steatosis, tirzepatide therapy may reduce the need for multiple medications, simplifying disease management and improving overall patient outcomes.

Efficacy

Given the multifaceted biological, epidemiological, and clinical association of MASLD and MASH with obesity and diabetes, which has been extensively reviewed elsewhere [1, 39, 40], studies have assessed the efficacy profile of tirzepatide on MASLD and MASH. The number of such original and meta-analytical studies is limited so far, as shown in Table 2 [10, 40–47].

Regardless of how it is achieved, whether through lifestyle changes, endoscopic procedures, or metabolic/bariatric surgery, weight loss provides clear benefits on MASH histology [48]. For patients with “diabesity”, the introduction of GLP-1RAs has marked a shift in treatment approaches. The advantages of using GLP-1RAs go beyond their anti-obesity and glucose-lowering effects, encompassing a reduced risk of major adverse cardio-nephro-vascular and hepatic outcomes by lowering arterial hypertension and overall improving metabolic function [49, 50]. Early placebo-controlled randomized controlled trials (RCTs) of GLP-1RAs in patients with obesity and T2DM indirectly indicated positive effects on the liver, as evidenced by improvements in surrogate indices, particularly liver enzymes [51]. Tirzepatide differs from GLP-1RAs in that, in addition to agonizing the GLP-1R, this drug also acts as a GIPR agonist, providing direct effects on white adipose tissue that may further benefit MASH histology beyond glycemic control and weight loss [52].

In this context, the seminal SYNERGY-NASH trial has shown that, by week 52, tirzepatide administration was more effective than placebo in achieving histologic MASH improvement without exacerbating fibrosis, an endpoint supported by the Food and Drug Administration [10]. Among individuals with biopsy-proven MASH and F2 or F3 liver fibrosis, subcutaneous weekly tirzepatide administration was superior to placebo in terms of MASH resolution without worsening liver fibrosis [10]. Additionally, the use of tirzepatide was linked to reductions in body weight, improved liver enzymes, and decreased intrahepatic fat content, hepatitis, and liver fibrosis as assessed noninvasively [10]. Overall, tirzepatide was found to be safe and well-tolerated, with only minor reports of gastrointestinal adverse effects [10]. Interestingly, serious events and adverse events resulting in trial discontinuation were similar across all four study arms, including the placebo arm.

It is reasonable to speculate that MASH resolution could lead to regression of liver fibrosis, a significant factor in major adverse liver outcomes (MALO) such as ascites, hepatic encephalopathy, variceal bleeding, liver transplantation or liver-related mortality. However, current studies have not extended the trial duration long enough to evaluate the effect of tirzepatide on MALO and lack sufficient power to detect any differences in liver fibrosis improvement compared to placebo administration [10]. The trial authors acknowledge that assessing fibrosis improvement will likely require studies longer than 52 weeks. Additionally, it remains to be seen if there is a limit to the amount of fibrosis regression achievable with GLP-1RAs (or weight loss alone). Patients with F4 fibrosis (cirrhosis) and those without fibrosis or with early-stage liver fibrosis (F0 and F1, respectively) were excluded by study design, suggesting the need for further studies. With these limitations in mind, the meta-analytic review by Wang et al. [47] based on 25 RCTs found that GLP-1RAs treatment induced significant histological improvements in steatosis, hepatocellular ballooning, and lobular inflammation but non-significantly improved fibrosis, with the evidence for tirzepatide being more robust than that for semaglutide and liraglutide. Clearly, additional sufficiently sized and long-term studies are requested incorporating not only robust histological endpoints but also clinically significant outcomes.

Methodological concerns and safety profile

It has been noted that there is a lack of placebo-controlled randomized trials with liver histology outcomes. This is because studies have mainly focused on extra-hepatic outcomes, such as body weight loss and metabolic compensation of T2DM. As a result, some studies have assessed liver health using surrogate biomarkers like liver enzymes or imaging techniques to measure intrahepatic liver fat content. Importantly, given the sexually dimorphic nature of MASLD [53] that could potentially affect therapy response [54–56], there have been no male-to-female comparative studies conducted to determine if one sex responds better to tirzepatide. Most studies on tirzepatide have been designed and conducted by the manufacturer, while independent investigations conducted in “real-world” scenarios by investigators are often underpowered due to low enrollment numbers. Regarding safety, a systematic assessment of tirzepatide has found limited side effects, mostly related to the gastrointestinal tract and of mild-to-moderate severity. However, there have been reports of liver toxicity [57, 58] that highlight the need for additional studies in the post-marketing period as more individuals are exposed to the drug, increasing the likelihood of identifying liver safety concerns.

Tirzepatide, marketed as Mounjaro for T2DM, was first approved in the USA in May 2022 for use in adult patients as an adjunct to diet and exercise [59]. In November 2023, it was approved for chronic weight management in adults with obesity or overweight and weight-related conditions under the brand name Zepbound [59]. However, tirzepatide is not yet approved for the treatment of MASH and clinical trials to evaluate its efficacy and safety for MASH are underway, and the manufacturer is collaborating with regulatory authorities regarding potential future approval for this indication of use. This implies that the true safety profile of tirzepatide among MASLD subjects is incompletely characterized, even though individuals living with obesity, overweight or T2DM often have MASLD. A recent pharmacovigilance study based on the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database offers an accurate analysis based on real-world data [60]. These authors analyzed adverse drug events (ADEs) reports from the 2nd quarter of 2022 to the 4th quarter of 2023 using the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods. Importantly, this study specifically addressed sex-specific differences and reporting biases. Data have shown that among 25,212 tirzepatide-related ADE reports, common ADEs included nausea and vomiting while previously unreported ADEs included eructation, gastroesophageal reflux disease, hemorrhage at the site of drug injection, and hyperglycemia. Women reported more injection-site reactions, while men experienced more gastrointestinal complaints [60].

In this regard, alarming reports of drug-induced liver injury due to tirzepatide [57, 58] and major changes in thiopurine metabolites in tirzepatide-treated subjects with inflammatory bowel disease [61] are of specific significance for gastroenterological practice. These reports fully support the notion that close monitoring and further research are needed to ensure the safe use of tirzepatide, particularly among MASLD and MASH subjects.