Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: Pathophysiology, diagnosis, and emerging therapeutic strategies

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), the updated terminology for fatty liver disease linked to metabolic dysfunction, is highly prevalent among individuals with type 2 diabetes mellitus (T2DM). MASLD affects a majority of patients with T2DM and markedly increases the risk of fibrosis, cirrhosis, hepatocellular carcinoma, and cardiovascular mortality. The pathogenesis in diabetic populations reflects a convergence of insulin resistance, dyslipidemia, mitochondrial dysfunction, chronic inflammation, and genetic predisposition. Advances in non-invasive diagnostics, including elastography and serum biomarkers, enable earlier identification and staging of disease, though limitations remain in diabetic cohorts. Lifestyle modification is the cornerstone of therapy, yet emerging pharmacotherapies are reshaping the therapeutic landscape. Antidiabetic agents such as glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and pioglitazone show hepatic benefits beyond glycemic control, while novel agents and combination regimens are under active evaluation. This narrative review synthesizes current evidence on epidemiology, mechanisms, diagnostics, and therapeutics of MASLD in T2DM, and highlights future directions in precision medicine. Integration of multidisciplinary care is essential to address this converging epidemic.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Type 2 diabetes mellitus; Insulin resistance; Hepatic fibrosis; Non-invasive diagnostics; Glucagon-like peptide-1 receptor agonists; Sodium-glucose cotransporter-2 inhibitors; Personalized medicine; Fatty liver; Metabolic associated steatohepatitis

Core Tip: Metabolic dysfunction-associated steatotic liver disease is highly prevalent among patients with type 2 diabetes mellitus, amplifying risks of fibrosis, cirrhosis, hepatocellular carcinoma, and cardiovascular disease. The pathogenesis reflects overlapping mechanisms of insulin resistance, dyslipidemia, inflammation, and genetic predisposition. This narrative review integrates updated evidence on epidemiology, diagnostics, and therapeutics, emphasizing the roles of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and emerging agents. A multidisciplinary, personalized approach remains essential to reduce the burden of this increasingly recognized disease spectrum.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major global health challenge, paralleling rising rates of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). Previously classified as non-alcoholic fatty liver disease (NAFLD), the condition was redefined as MASLD to emphasize its metabolic origins rather than the exclusion of alcohol use. This nomenclature shift reflects the central role of insulin resistance, obesity, and cardiometabolic dysfunction in disease development[1-4]. In this review, historical NAFLD/non-alcoholic steatohepatitis (NASH) terminology is retained when referring to earlier studies, as originally reported, while acknowledging that these entities correspond to MASLD/metabolic dysfunction-associated steatohepatitis (MASH) under current definitions.

T2DM and MASLD have a bidirectional, mutually reinforcing relationship. T2DM accelerates MASLD progression through worsening hepatic steatosis, inflammation, and fibrosis, whereas MASLD contributes to worsening insulin resistance, heightened systemic inflammation, and increased cardiovascular risk among individuals with diabetes[5-7].

Epidemiologic data derived from studies using historical NAFLD/NASH criteria conceptually aligned with MASLD/MASH demonstrate that more than 70% of individuals with T2DM exhibit hepatic steatosis, and up to 30% develop steatohepatitis characterized by hepatocellular ballooning, lobular inflammation, and varying degrees of fibrosis. Among these features, fibrosis stage remains the strongest predictor of liver-related morbidity and mortality (Figure 1)[8,9].

Figure 1 Global prevalence of metabolic dysfunction-associated steatotic liver disease in type 2 diabetes mellitus. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than half of individuals with type 2 diabetes mellitus worldwide, with prevalence ranging between 55% and 70% in recent meta-analyses. Estimates vary by region, diagnostic modality, and population studied. MASLD is consistently associated with increased risk of advanced fibrosis, cirrhosis, hepatocellular carcinoma, and cardiovascular outcomes. MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.

The clinical implications of MASLD in T2DM extend well beyond hepatic outcomes. Cardiovascular disease is the leading cause of death in this population, and MASLD consistently associates with elevated cardiovascular risk through shared metabolic mechanisms[7]. Additionally, data from historical NAFLD cohorts demonstrate associations with chronic kidney disease, sarcopenia, and several extrahepatic malignancies, compounding overall morbidity in individuals with diabetes[10-13].

Despite high prevalence, MASLD remains underrecognized and undertreated because the disease often progresses silently and historically lacked standardized screening pathways. Advances in non-invasive assessment including elastography and serum fibrosis scores have improved early detection and risk stratification, though diagnostic accuracy is reduced in individuals with T2DM[14,15].

No pharmacologic therapy is yet approved specifically for MASLD or MASH outside the United States. However, several glucose-lowering agents such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and pioglitazone demonstrate improvements in metabolic parameters and liver-related surrogate markers, though histologic benefit has been inconsistent across trials conducted under historical NAFLD/NASH definitions[4,16-18]. Numerous investigational therapies targeting lipid metabolism, bile acid signaling, and fibrogenesis are advancing through late-phase development.

This review summarizes current understanding of pathophysiology, diagnostic strategies, and established and emerging treatments, with specific attention to considerations unique to individuals with T2DM.

PATHOPHYSIOLOGY

MASLD develops through interrelated disturbances in metabolic regulation, lipid handling, inflammation, and tissue remodeling. These mechanisms are amplified in individuals with T2DM, contributing to accelerated progression to MASH, advanced fibrosis, cirrhosis, and hepatocellular carcinoma[19].

Insulin resistance and hepatic lipid accumulation

Insulin resistance is a central driver of MASLD. Impaired hepatic insulin signaling reduces suppression of gluconeogenesis while maintaining lipogenic activity, resulting in increased de novo lipogenesis, reduced fatty acid oxidation, and triglyceride accumulation within hepatocytes[20]. Concurrent adipose tissue insulin resistance enhances lipolysis and increases free fatty acid delivery to the liver, promoting steatosis[21]. Steatosis alone does not fully explain disease progression, highlighting the importance of downstream lipotoxic and inflammatory mechanisms.

Lipotoxicity, oxidative stress, and early inflammatory activation

Lipotoxicity contributes to hepatocellular injury through the accumulation of diacylglycerols, ceramides, and saturated fatty acids, which impair mitochondrial function, induce endoplasmic reticulum stress, and promote oxidative injury[19,20,22-24]. These disturbances trigger activation of stress-related pathways including c-Jun N-terminal kinase, nuclear factor kappa-B, and the unfolded protein response leading to increased reactive oxygen species, lipid peroxidation, and DNA damage[22-26].

The resulting microenvironment stimulates Kupffer cells and hepatic stellate cells, initiating early inflammatory and fibrogenic cascades[22-26]. Hepatic macrophages and infiltrating immune cells amplify injury by releasing tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, contributing to hepatocyte ballooning and apoptosis histologic features associated with the transition from steatosis to MASH[27,28].

Fibrogenesis and disease progression

Fibrogenesis reflects an imbalance between extracellular matrix production and degradation. Cohort studies consistently show that fibrosis stage is the strongest predictor of liver-related and all-cause mortality in MASLD. Persistent metabolic injury, oxidative stress, and inflammation activate hepatic stellate cells, driving extracellular matrix deposition and progression from simple steatosis to advanced fibrosis and cirrhosis[29-33].

Gut-liver axis and immune activation

Disruption of the gut-liver axis contributes to MASLD pathogenesis. Dysbiosis and increased intestinal permeability permit microbial products such as lipopolysaccharide to reach the portal circulation, activating toll-like receptors on hepatic immune cells and amplifying inflammatory and fibrotic signaling[34-37]. Altered bile acid composition, reduced short-chain fatty acid production, and disturbances in choline metabolism further affect hepatic lipid regulation and immune activation, linking intestinal dysregulation to liver injury[38,39].

Genetic and epigenetic modifiers of disease risk

Genetic variants influence susceptibility and progression. Common polymorphisms in PNPLA3 (I148M), TM6SF2 (E167K), GCKR, and MBOAT7 are associated with increased hepatic steatosis, inflammation, and fibrosis[40-43]. These variants also contribute to interindividual variability in disease severity and therapeutic responsiveness, supporting emerging precision-medicine strategies[44,45].

Epigenetic mechanisms including alterations in DNA methylation and microRNA expression further modify lipid metabolism and inflammatory pathways, adding complexity to MASLD pathogenesis[40-45].

Summary

MASLD arises from interconnected processes involving metabolic dysfunction, lipotoxic stress, immune activation, and fibrogenesis. These mechanisms are more pronounced in individuals with T2DM and vary substantially among patients, producing heterogeneous clinical trajectories. Continued refinement of mechanistic understanding as illustrated in Figure 2 will help inform risk stratification tools and guide development of targeted therapeutic interventions.

Figure 2 Pathophysiology of metabolic dysfunction-associated steatotic liver disease in type 2 diabetes mellitus. The pathogenesis of metabolic dysfunction-associated steatotic liver disease is multifactorial and includes insulin resistance, lipotoxicity, oxidative stress, gut-liver axis alterations, and inflammatory signaling. Hepatic fat accumulation promotes oxidative stress and mitochondrial dysfunction, while adipose tissue dysfunction and systemic inflammation exacerbate steatohepatitis and fibrosis. Genetic predisposition (e.g., PNPLA3, TM6SF2) and environmental factors (diet, sedentary lifestyle) modulate disease progression. ER: Endoplasmic reticulum; ROS: Reactive oxygen species; MASLD: Metabolic dysfunction-associated steatotic liver disease; TLR: Toll-like receptor; TNF: Tumor necrosis factor; IL: Interleukin.

DIAGNOSIS

Diagnosing MASLD in individuals with T2DM is challenging because disease progression is often silent and liver enzyme levels may remain normal. Early recognition is essential, as patients with T2DM carry a disproportionately higher risk for advanced fibrosis and related complications[1].

Initial clinical and laboratory assessment

Evaluation begins with identification of metabolic risk factors, routine laboratory testing, and the calculation of simple non-invasive fibrosis scores. The fibrosis-4 (FIB-4) index is widely used due to its accessibility and cost-effectiveness; however, in T2DM it demonstrates a higher false-negative rate, particularly in individuals under 65 years of age and those with obesity, limiting sensitivity in this population[1,9,46,47]. Other serum-based scores such as the NAFLD fibrosis score and the aspartate aminotransferase-to-platelet ratio index may be used as adjuncts, although their performance varies among diabetic cohorts.

Elastography and imaging-based modalities

Elastography-based techniques markedly improve risk stratification. Transient elastography (FibroScan^®) and magnetic resonance elastography provide excellent negative predictive value for ruling out advanced fibrosis, making them valuable second-line tools following indeterminate or elevated FIB-4 scores. Quantitative imaging biomarkers, including controlled attenuation parameter and magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF), enhance detection of steatosis but have limitations: MRI-PDFF quantifies hepatic fat yet does not reliably predict fibrosis progression, and remains unvalidated as a regulatory surrogate endpoint in MASLD trials[48-54].

Serum biomarkers and emerging diagnostics

Serologic markers such as the enhanced liver fibrosis score, cytokeratin-18 fragments, and emerging metabolomic or proteomic signatures offer additional non-invasive options. However, many require further validation in T2DM-enriched populations, where metabolic abnormalities may alter diagnostic thresholds or reduce accuracy[55-58].

Role of liver biopsy

Liver biopsy remains the reference standard for definitive staging, distinguishing steatosis from MASH, and determining clinical trial eligibility. Limitations include sampling variability, procedural risks, and cost, which restrict its routine use. In clinical practice, biopsy is generally reserved for patients with discordant non-invasive test results or when therapeutic decision-making requires histologic confirmation[59,60].

Screening recommendations and practical implementation

Major societies including the American Diabetes Association (ADA), American Association for the Study of Liver Diseases (AASLD), and European Association for the Study of the Liver (EASL) now recommend structured MASLD screening for all adults with T2DM. A commonly endorsed approach uses FIB-4 as the initial test, followed by elastography for individuals with indeterminate or elevated scores. Real-world implementation remains suboptimal. Embedding these tools into diabetes clinic workflows with electronic health record-based alerts, automated risk calculators, and streamlined referral pathways may significantly improve early detection and timely hepatology referral[15,47].

THERAPEUTICS

Overview

Management of MASLD requires a multifaceted approach that addresses metabolic dysfunction, hepatic inflammation, and fibrosis. Current strategies include lifestyle modification, optimization of metabolic comorbidities, and selective use of pharmacotherapies. Although no agent has been universally approved outside the United States solely for MASLD, several therapies used for T2DM or obesity offer hepatic benefits, and resmetirom has recently become the first Food and Drug Administration (FDA)-approved drug for noncirrhotic MASH with fibrosis. Treatment selection should be individualized based on comorbidities, fibrosis stage, and patient-specific goals (Tables 1 and 2)[61-64].

Table 1 Pharmacologic therapies for metabolic dysfunction-associated steatotic liver disease: Liver fat, cardiometabolic, and fibrosis impact[9,92,160-162].

Drug	Class	Liver effects	CV/metabolic effects	Fibrosis impact	Ref.
Metformin	Biguanide	Unchanged	Improves insulin sensitivity	Neutral	Cusi et al[9]
Pioglitazone	PPAR-γ agonist	Decreased	Improves insulin sensitivity	Improved	Cusi et al[9]
Insulin	Hormone	Decreased	Glucose control	Unknown	Cusi et al[9]
GLP-1 RAs (semaglutide, liraglutide)	GLP-1 RA	Decreased	Weight loss, CV benefit	Improved	Cusi et al[9]; Lin et al[92]
SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin)	SGLT2 inhibitor	Decreased	Weight loss, glycemic control	Effect unknown	Cusi et al[9]
DPP-IV inhibitors (sitagliptin, vildagliptin)	DPP-IV inhibitor	Unchanged (in RCTs)	Modest glucose control	Effect unknown	Cusi et al[9]
Vitamin E	Antioxidant	Not specified	Neutral	Improved (non-diabetics)	Cusi et al[9]
Obeticholic acid	FXR agonist	Not specified	Raises LDL, pruritus	Improved (fibrosis)	Lin et al[92]; Marek and Malhi[161]
Elafibranor	PPAR-α/δ agonist	Not specified	Improves lipids	Improved	Lin et al[160]; Marek and Malhi[161]
Cenicriviroc	CCR2/CCR5 antagonist	Not specified	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Aramchol	SCD1 inhibitor	Not specified	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Selonsertib	ASK1 inhibitor	Not specified	Neutral	Improved	Marek and Malhi[161]
Resmetirom	THR-β agonist	Not specified	Neutral	Improved	Marek and Malhi[161]
Tirzepatide	GLP-1/GIP RA	Decreased	Weight loss, metabolic improvement	Improved	Handu et al[162]
Survodutide	GLP-1/glucagon RA	Not specified	Weight loss	Improved	Handu et al[162]
FGF-21 analogues	FGF-21 mimetic	Decreased	Improves lipid and glucose metabolism	Improved	Lin et al[160]; Marek and Malhi[161]
THR-β agonists	Thyroid hormone receptor-β agonist	Decreased	Neutral	Improved	Lin et al[160]; Marek and Malhi[161]
Pan-PPAR agonists	Pan-PPAR agonist	Decreased	Improves lipids, insulin sensitivity	Improved	Lin et al[160]; Marek and Malhi[161]
Curcumin	Polyphenol	Not specified	Antioxidant effects	Improved	Handu et al[162]
Silymarin	Flavonoid	Not specified	Hepatoprotective	Improved	Handu et al[162]
Resveratrol	Polyphenol	Not specified	Antioxidant/anti-inflammatory	Improved	Handu et al[162]
Coffee	Dietary	Not specified	Anti-inflammatory, antioxidant	Improved	Handu et al[162]
Green tea	Catechin-rich beverage	Not specified	Anti-inflammatory	Improved	Handu et al[162]
Berberine	Plant alkaloid	Not specified	Improves insulin resistance	Improved	Handu et al[162]

This table summarizes pharmacologic agents studied in the management of metabolic dysfunction-associated steatotic liver disease, detailing their effects on hepatic steatosis, cardiometabolic outcomes, and hepatic fibrosis. It includes both antidiabetic and emerging investigational agents. Reference numbers correspond to clinical trials and major reviews. Therapies such as glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor-β agonists demonstrate multifaceted benefits, while others remain investigational or population-specific. CV: Cardiovascular; GLP-1 RA: Glucagon-like peptide-1 receptor agonists; DPP: Diabetes prevention program; SGLT2: Sodium-glucose cotransporter 2; THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; PPAR: Peroxisome proliferator-activated receptor; SCD1: Stearoyl-CoA desaturase 1; FXR: Farnesoid X receptor; ASK1: Apoptosis signal-regulating kinase 1; LDL: Low density lipoprotein; RCT: Randomized clinical trial.

Table 2 Risk factors for metabolic dysfunction-associated steatotic liver disease progression in patients with type 2 diabetes.

Risk factor	Mechanism	Associated outcome
Insulin resistance	Promotes de novo lipogenesis and reduces fatty acid oxidation	Steatosis, progression to MASH
Visceral obesity	Pro-inflammatory adipokine secretion, lipotoxicity	Fibrosis progression, inflammation
Poor glycemic control	Increases oxidative stress, mitochondrial dysfunction	Fibrosis, hepatocellular injury
Dyslipidemia	Elevated triglycerides and LDL lead to hepatocyte stress	Lipotoxicity, NASH progression
Hypertension	Induces endothelial dysfunction and chronic inflammation	Increased risk of fibrosis
Sedentary lifestyle	Reduces insulin sensitivity and promotes weight gain	Increased steatosis and metabolic burden
Genetic variants (e.g., PNPLA3, TM6SF2)	Impaired lipid export and processing	Accelerated fibrosis progression
Gut microbiota dysbiosis	Increased endotoxin (LPS) translocation and inflammation	Worsening hepatic inflammation and fibrosis
Advanced age	Reduced hepatic regeneration capacity, cumulative metabolic injury	Greater risk of advanced fibrosis
Diet high in saturated fats/fructose	Increases hepatic fat accumulation and lipotoxic intermediates	Steatohepatitis and fibrosis
Smoking	Oxidative stress and impaired insulin sensitivity	Fibrosis and cardiovascular risk

This table outlines the key clinical, metabolic, genetic, and lifestyle-related factors that contribute to the progression of metabolic dysfunction-associated steatotic liver disease in individuals with type 2 diabetes. Insulin resistance, visceral adiposity, dyslipidemia, and poor glycemic control are core drivers that promote hepatic steatosis, inflammation, and fibrosis. Additionally, environmental and genetic influences such as sedentary behavior, dietary composition, gut microbiota alterations, and PNPLA3 variants can further accelerate disease severity. Recognizing these risk factors is essential for targeted intervention and prevention of progression to advanced liver disease. LPS: Lipopolysaccharide; LDL: Low density lipoprotein; NASH: Nonalcoholic fatty liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.

Lifestyle modification

Lifestyle intervention remains a foundational element of MASLD therapy across all guidelines (Figure 3). Weight loss of 5%-10% improves steatosis and hepatic inflammation, while losses of ≥ 10% are associated with fibrosis regression[65-68]. Sustained improvement is most consistently achieved with combined dietary caloric restriction, aerobic activity, and resistance training[69-73]. However, adherence remains a major barrier, and multidisciplinary behavioral strategies, structured exercise programs, and dietitian-supported models enhance long-term success[74-79].

Figure 3 Lifestyle intervention in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus. Lifestyle modification remains the cornerstone of metabolic dysfunction-associated steatotic liver disease management. Sustained weight loss of ≥ 7%-10% is associated with steatohepatitis resolution and fibrosis regression. Dietary strategies such as the mediterranean diet and structured exercise programs (aerobic and resistance training) provide durable benefit, although long-term adherence is challenging. THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; PPAR: Peroxisome proliferator-activated receptor; SCD1: Stearoyl-CoA desaturase 1; TG: Triglyceride; ASK1: Apoptosis signal-regulating kinase 1; GCGR: Glucagon receptor; GLP-1R: Glucagon-like peptide-1 receptor; DPP-4: Dipeptidyl peptidase 4; MASH: Metabolic dysfunction-associated steatohepatitis; RCT: Randomized clinical trial; GLP-1 RA: Glucagon-like peptide-1 receptor agonists; AACE: American Association of Clinical Endocrinologists; AASLD: American Association for the Study of Liver Diseases; AGA: American Gastroenterological Association; GI: Gastrointestinal.

GLP-1 receptor agonists

GLP-1 receptor agonists (GLP-1 RAs) improve glycemic control, reduce body weight, and lower hepatic fat content[80]. In the LEAN trial, liraglutide achieved higher rates of NASH (historical term) resolution compared with placebo (39% vs 9%), though fibrosis improvement was not statistically significant[81-83]. Semaglutide demonstrated dose-dependent NASH resolution rates (up to 59%) in a phase 2 trial but did not yield significant improvement in fibrosis stage[84-88].

GLP-1 RAs are FDA-approved for T2DM and obesity, with hepatic effects considered secondary metabolic benefits. They are not approved specifically for MASLD/MASH, and their role remains adjunctive, particularly in patients with T2DM, obesity, or high cardiovascular risk.

SGLT-2i

SGLT-2i reduce hepatic fat content and improve metabolic parameters. Clinical studies demonstrate reductions in aminotransferase levels and MRI-PDFF-quantified steatosis, with consistent glycemic and cardiometabolic benefits[89]. However, histologic evidence remains limited, and no significant antifibrotic effect has been conclusively demonstrated. Their clinical utility in MASLD is therefore tied primarily to management of coexisting T2DM[90-95].

Guidelines from the ADA, AASLD, and EASL recognize SGLT-2i as first-line therapy in T2DM with cardiovascular or renal risk, and their potential hepatic benefits provide an additional rationale for use in MASLD. Ongoing phase 3 studies, including DEAN and DAPA-liver, are expected to clarify their antifibrotic efficacy and establish their role in routine MASLD care[96-98].

Pioglitazone

As a peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone improves insulin sensitivity and has consistently demonstrated histologic benefit in patients with biopsy-proven NASH (historical term), including improvements in steatosis, hepatocellular ballooning, and inflammation. The PIVENS trial showed significant NASH resolution; however, fibrosis improvement was modest. Adverse effects weight gain, edema, and fracture risk limit widespread use. Pioglitazone remains a therapeutic option primarily in patients with concurrent T2DM[99-108].

Metformin

Metformin improves insulin resistance and aminotransferase levels but does not improve histologic features of steatosis, ballooning, inflammation, or fibrosis in MASLD. It should not be used as targeted MASLD therapy but remains appropriate for glycemic management in patients with T2DM[109-116].

Dual and multi-agonist incretin therapies

Dual incretin agonists such as tirzepatide have shown superior reductions in body weight, insulin resistance, and hepatic steatosis compared with GLP-1 monotherapy[117-119]. Early imaging-based data demonstrate robust reductions in liver fat, but no biopsy-based evidence of fibrosis improvement is yet available[120-122]. These agents are not MASLD-specific therapies and require further validation in histologic endpoints.

Resmetirom

Resmetirom, a selective thyroid hormone receptor-β agonist, became the first FDA-approved therapy for noncirrhotic MASH with F2-F3 fibrosis in 2024. In the MAESTRO-NASH trial (conducted under historical NASH definitions), resmetirom achieved: (1) Significantly higher rates of NASH resolution without worsening fibrosis; (2) Significant fibrosis improvement without worsening NASH; and (3) Reductions in low density lipoprotein cholesterol and hepatic fat on MRI-PDFF[123,124].

Common adverse effects include mild gastrointestinal symptoms and transient changes in thyroid function markers. Long-term fibrosis and clinical outcome data remain under investigation. Although approved in the United States for noncirrhotic MASH with fibrosis, its generalizability to broader MASLD populations, particularly those without biopsy-confirmed disease, is still being defined.

Farnesoid X receptor agonists and bile acid-based therapies

Farnesoid X receptor (FXR) agonists, including obeticholic acid, reduce bile acid synthesis and modulate hepatic inflammation and fibrosis pathways. Although early trials demonstrated improvements in fibrosis, pruritus and lipid changes posed safety concerns. Recent studies of newer, more selective FXR agonists aim to improve tolerability while maintaining efficacy[125-128].

Pan-PPAR agonists

Lanifibranor, a pan-PPAR agonist targeting PPAR-α/δ/γ, demonstrated significant improvements across multiple histologic domains, including fibrosis, in its phase 2 trial[129,130]. Phase 3 trials are ongoing to determine long-term and hard-outcome benefits.

Fibroblast growth factor 21 analogs

Fibroblast growth factor (FGF) analogs pegozafermin (FGF21 analog) modulate hepatic lipid metabolism, inflammation, and fibrogenesis. Early trials show meaningful reductions in hepatic fat and improvements in metabolic markers, though fibrosis results remain mixed[131-133].

Stearoyl-CoA desaturase inhibitors

Aramchol reduces de novo lipogenesis and improves hepatic fat metabolism. Early trials demonstrated reductions in liver fat and markers of inflammation, but large-scale fibrosis outcomes remain inconclusive[134-136].

Other emerging agents

Additional agents, including surfodutide and apoptosis signal-regulating kinase 1 inhibitors, are in early-phase development and target pathways involved in inflammation or energy homeostasis[137-139]. Their eventual role will depend on histologic efficacy and long-term safety.

Aldafermin (NGM282) is an analog of FGF19, a regulator of bile acid synthesis and glucose metabolism. It reduces hepatic steatosis and inflammation via FXR-independent pathways. Short-term trials have shown significant reductions in liver fat content and liver enzyme levels, though improvements in fibrosis have been inconsistent[140-143]. Figure 4 highlights the emerging medications with potential benefit in patients with MASLD and T2DM.

Figure 4 Emerging therapies in metabolic dysfunction-associated steatotic liver disease. Several investigational drugs target diverse pathways: Dual incretin agonists (tirzepatide), thyroid hormone receptor-β agonists (resmetirom), farnesoid X receptor agonists (obeticholic acid), pan-peroxisome proliferator-activated receptor agonists (lanifibranor), and fibroblast growth factor analogs (efruxifermin, aldafermin). Most agents demonstrate histologic or imaging benefit in phase 2/3 studies, though none are yet approved. Combination approaches are under evaluation. MASLD: Metabolic dysfunction-associated steatotic liver disease; FA: Fatty acid.

Combination therapies

Given the multifaceted pathophysiology of MASLD spanning steatosis, inflammation, and fibrosis combination therapy is increasingly recognized as a rational and potentially more effective approach. Targeting multiple pathways simultaneously may amplify therapeutic benefits and mitigate the limitations of monotherapy[1,144]. Ongoing trials are evaluating combinations of GLP-1 RAs with FXR agonists, SGLT-2is with PPAR agonists, and metabolic modulators like resmetirom with antifibrotic agents. Such regimens aim to achieve greater histologic improvement while enhancing tolerability and adherence (Table 3)[124,145]. In the context of T2DM, combination therapy must also consider drug-drug interactions, glycemic variability, and patient-specific comorbidities. As precision medicine evolves, tailored combination strategies may become the norm, offering more individualized and effective care[146,147].

Table 3 Timeline of key clinical trials in metabolic dysfunction-associated steatotic liver disease: Drug classes, endpoints, and outcomes[84,117,123,129,133,139,163-166].

Year	Trial	Drug/class	Primary endpoint	Key outcome	Ref.
2015	LEAN	Liraglutide (GLP-1 RA)	NASH resolution without fibrosis worsening	Met endpoint; improved NASH resolution	Armstrong et al[84]
2019	REGENERATE (Interim)	Obeticholic acid (FXR agonist)	Fibrosis improvement without NASH worsening	Improved fibrosis in 23% vs 12% placebo	Ratziu et al[163]
2020	REVERSE	Lanifibranor (pan-PPAR agonist)	Improvement in NAS and fibrosis	Significant histologic improvement	Francque et al[129]
2021	FLINT	Obeticholic acid	NAS improvement ≥ 2 points without fibrosis worsening	Positive results in steatosis and inflammation	Sanyal et al[164]
2022	MAESTRO-NAFLD-1	Resmetirom (THR-β agonist)	Liver fat reduction via MRI-PDFF	Significant reduction in liver fat content	Harrison et al[165]
2022	MAESTRO-NASH	Resmetirom (THR-β agonist)	NASH resolution and fibrosis improvement	Met both primary endpoints	Harrison et al[123]
2022	SYNERGY	Semaglutide + cagrilintide	Liver fat reduction	Significant additive effect on steatosis	Frias et al[166]
2023	SURMOUNT-1	Tirzepatide (GLP-1/GLP RA)	Weight reduction	Robust weight loss and decrease liver fat (MRI)	Loomba et al[117]
2023	ESSENCE	Efruxifermin (FGF-21 analogue)	Histologic NASH resolution and fibrosis improvement	Positive early-phase results	Harrison et al[133]
2023	CENTURION	Survodutide (GLP-1/glucagon RA)	Liver fat reduction	Marked liver fat loss on imaging	Sanyal et al[139]

This table presents a chronological overview of major clinical trials conducted in metabolic dysfunction-associated steatotic liver disease, highlighting the evolving therapeutic landscape. Each trial is listed with its year of publication, pharmacologic class, primary endpoints, and key outcomes. Studies such as LEAN, REGENERATE, and MAESTRO-NASH have laid the foundation for understanding drug efficacy in nonalcoholic fatty liver disease resolution and fibrosis improvement. Newer trials like SURMOUNT-1 and ESSENCE continue to explore novel agents, including dual incretin therapies and fibroblast growth factor-21 analogues, with promising metabolic and histologic effects. This timeline illustrates the progression from early histologic endpoints to robust, non-invasive imaging and metabolic markers. GLP-1 RA: Glucagon-like peptide-1 receptor agonists; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; NASH: Nonalcoholic fatty liver disease; NAS: Nonalcoholic fatty liver disease activity score; MRI: Magnetic resonance imaging; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction.

Summary

Therapeutic options for MASLD are expanding rapidly. Lifestyle modification remains foundational, while pharmacologic therapy is increasingly informed by metabolic comorbidities and fibrosis severity. Resmetirom represents a major step forward as the first approved therapy targeting underlying disease biology. GLP-1 RAs, SGLT-2is, and emerging incretin-based therapies offer metabolic and hepatic benefits but require further validation for fibrosis outcomes. As the therapeutic landscape evolves, integration of noninvasive markers, genetic profiling, and combination approaches may support more individualized and effective treatment strategies. Therapeutic response remains heterogeneous, particularly between individuals with and without T2DM, underscoring the need for individualized risk stratification.

PERSONALIZED MEDICINE IN MASLD

Personalized medicine is increasingly shaping the management of MASLD, particularly in individuals with T2DM, where disease expression, metabolic drivers, and treatment responsiveness vary substantially. Given this heterogeneity, individualized approaches based on genetic, metabolic, phenotypic, and behavioral factors are essential for optimizing outcomes.

Genetic and epigenetic determinants

Genetic polymorphisms strongly influence susceptibility to MASLD and its rate of progression. Variants in PNPLA3 (I148M), TM6SF2 (E167K), MBOAT7, and GCKR are associated with greater hepatic steatosis, inflammation, and fibrosis. PNPLA3 is the most extensively studied and has been linked not only to heightened disease risk but also to reduced responsiveness to lifestyle and pharmacologic interventions. Integration of genotyping into clinical pathways may enhance risk stratification and identify individuals most likely to benefit from early or targeted treatment.

Epigenetic mechanisms such as DNA methylation and non-coding RNA expression further modify disease phenotype and therapeutic response. Biomarkers including miR-122 and miR-34a, along with emerging methylation signatures, show promise for predicting disease activity and may support future precision-based therapeutic strategies[148-152].

Phenotypic and demographic variation

Variation in MASLD severity and progression is also shaped by patient phenotype. Postmenopausal women and men appear to have higher fibrosis risk than premenopausal women, likely due to hormonal and metabolic differences. Ethnic disparities are well recognized; for example, Hispanic individuals have a higher prevalence and more aggressive MASLD phenotypes, partly driven by PNPLA3 prevalence and adipose tissue distribution[153]. These demographic and phenotypic differences underscore the need for tailored clinical approaches rather than uniform management.

Metabolic and molecular profiling

Advances in metabolomics, lipidomics, and proteomics have identified distinct molecular signatures associated with steatosis, inflammation, and fibrosis. Lipid species, bile acid profiles, and inflammatory protein signatures correlate with fibrosis stage and metabolic dysfunction, offering insights into individualized pathophysiology and potential therapeutic targeting[154].

Integration of non-invasive diagnostics

Non-invasive diagnostics including transient elastography, MRI-based techniques, and blood-based fibrosis panels support individualized risk prediction and longitudinal monitoring. Composite algorithms that merge imaging, serologic markers, and genomic data are in active development and may eventually guide the timing and intensity of therapeutic intervention[1,155]. Such tools may reduce unnecessary biopsies and support precision-based follow-up strategies.

Individualized therapeutic selection in MASLD with T2DM

Personalized therapy selection is particularly relevant in MASLD with T2DM. Glucose-lowering medications should be chosen based on comorbidities, cardiovascular and renal risk, obesity status, and patient preference. Examples include: (1) GLP-1 RAs for individuals with obesity and established cardiovascular disease; (2) SGLT-2is for patients with chronic kidney disease or heart failure; and (3) MASLD-targeted agents (e.g., resmetirom) for individuals with biopsy-confirmed disease and fibrosis, where indicated. Response to therapy is known to be heterogeneous, emphasizing the need for flexible, individualized treatment strategies rather than a one-size-fits-all approach.

Digital health and artificial intelligence

Digital health platforms and artificial intelligence (AI) are advancing the ability to personalize MASLD management. Machine-learning models applied to electronic health records, imaging repositories, and wearable sensor data can help identify high-risk individuals, predict fibrosis trajectories, and support clinical decision-making with greater accuracy[156-159].

Personalized medicine represents a critical evolution in MASLD management. Aligning therapeutic decisions with individual genetic, metabolic, phenotypic, and behavioral profiles may improve treatment response, minimize progression, and create a more patient-centered model of care. Continued development of integrated diagnostic algorithms and AI-enhanced tools will further refine precision strategies and improve clinical outcomes (Figure 5).

Figure 5 Personalized medicine framework in metabolic dysfunction-associated steatotic liver disease. Future metabolic dysfunction-associated steatotic liver disease management will integrate genetic risk (e.g., PNPLA3, TM6SF2), metabolic and lifestyle factors, and non-invasive biomarkers with artificial intelligence and electronic health records to enable individualized therapy. Multidisciplinary care involving hepatology, endocrinology, cardiology, and primary care will be essential for optimal outcomes. FDA: Food and Drug Administration.

CONCLUSION

MASLD and T2DM represent intersecting global epidemics with substantial clinical and public health implications. MASLD affects the majority of individuals with T2DM and is associated with accelerated progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and increased cardiovascular mortality. This dual burden underscores the importance of routine liver health assessment within diabetes care and highlights the need for earlier identification of high-risk patients. Advances in non-invasive diagnostics including fibrosis scores, transient elastography, and MRI-based modalities have strengthened risk stratification; however, their accuracy is diminished in T2DM, where false-negative results are more common. Moreover, imaging biomarkers such as MRI-PDFF, although useful for assessing hepatic fat, are not validated surrogate endpoints for predicting fibrosis progression. Despite guideline-supported algorithms from the ADA, AASLD, and EASL, real-world implementation remains inconsistent. Integrating MASLD screening into primary diabetes workflows, supported by electronic health record-based prompts and structured referral pathways, may improve detection and standardization. Lifestyle modification remains a foundational element of therapy, though long-term adherence challenges limit durability. Several glucose-lowering agents including GLP-1 RAs, SGLT-2is, and pioglitazone demonstrate metabolic and hepatic benefits, but most supporting evidence derives from studies conducted under historical NAFLD/NASH definitions and in mixed populations. Resmetirom represents a meaningful advancement as the first FDA-approved therapy for noncirrhotic MASH with fibrosis in the United States, yet its long-term outcomes and applicability across diverse MASLD phenotypes require further study. Emerging agents such as thyroid hormone receptor-β agonists, dual and multi-agonist incretin therapies, FGF analogs, and pan-PPAR modulators show promise, but validation in T2DM-enriched cohorts and across demographic subgroups remains essential. Future efforts should prioritize the validation of non-invasive biomarkers against long-term clinical outcomes, comparative effectiveness studies of pharmacologic agents specifically in T2DM, and integration of MASLD-directed therapy into broader cardiometabolic risk reduction frameworks. Precision medicine approaches incorporating genetic variants (e.g., PNPLA3), metabolomic signatures, and individualized metabolic profiles may refine patient selection and therapeutic strategies. Special populations including children, individuals with type 1 diabetes, and women with gestational diabetes remain significantly understudied and warrant focused investigation. Ultimately, improving MASLD outcomes in T2DM requires reframing the disease as a systemic metabolic disorder rather than a liver-specific condition. Coordinated care involving hepatology, endocrinology, cardiology, and primary care will be essential to translate ongoing advances in diagnostics and therapeutics into meaningful clinical benefit. The coming decade offers the opportunity to shift from under-recognition and fragmented management toward integrated, evidence-based, multidisciplinary care capable of altering the natural history of this increasingly prevalent condition.