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5 June 2025

Current and Emerging Treatments for Metabolic Associated Steatotic Liver Disease and Diabetes: A Narrative Review

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Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA
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Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Wisconsin, Madison, WI 53706, USA
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Pikeville Medical Center, Pikeville, KY 41501, USA
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VCU Health Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA
Endocrines2025, 6(2), 27;https://doi.org/10.3390/endocrines6020027
This article belongs to the Special Issue Feature Papers in Endocrines: 2024
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Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent chronic liver condition strongly linked to Type 2 Diabetes Mellitus (T2DM) and obesity. Globally, MASLD is the most common cause of chronic liver disease. The bidirectional relationship between MASLD and T2DM underscores the pivotal role of insulin resistance in disease progression, which contributes to hepatic steatosis, oxidative stress, and inflammation, forming a vicious cycle. MASLD is also associated with heightened risks of cardiovascular and chronic kidney diseases, necessitating comprehensive treatment approaches. While lifestyle interventions and weight loss remain the cornerstone of management, their sustainability is challenging. This review highlights the evolving pharmacological landscape targeting MASLD and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Currently, Resmetirom is the only FDA-approved drug for MASH. Current and investigational therapies, including insulin-sensitizing agents like peroxisome proliferator-activated receptor (PPAR) agonists, glucose-lowering drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), drugs that target intermediary metabolism such as Vitamin E, de novo lipogenesis inhibitors, and emerging agents targeting the gut-liver axis and oxidative stress, are explored. These therapies demonstrate promising effects on hepatic steatosis, inflammation, and fibrosis, providing new avenues to address the multifaceted pathophysiology of MASLD.

1. Introduction

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD), is a significant health concern, especially in individuals with Type 2 Diabetes Mellitus (T2DM). MASLD refers to fatty liver disease due to metabolic dysfunction, characterized by hepatic steatosis (>5% fat) and at least one cardiometabolic risk factor, such as dyslipidemia or obesity, with minimal or no alcohol consumption (<20 g daily for females and <30 g daily for males) [1].
MASLD is the most common cause of chronic liver disease globally, affecting about 30% of the population. Metabolic Dysfunction-Associated Steatohepatitis (MASH) is a more advanced stage within the MASLD spectrum. It is characterized by the presence of hepatic steatosis along with inflammation and hepatocyte injury (ballooning), with or without fibrosis. This stage is associated with a higher risk of progression to advanced liver disease, including cirrhosis and hepatocellular carcinoma [2]. MASLD is more prevalent in males (40%) than females (26%) and affects up to 70% of T2DM patients, adding to their health burden [3,4,5]. The bidirectional relationship between MASLD and T2DM involves insulin resistance, which promotes liver fat accumulation and oxidative stress, while MASLD worsens insulin resistance. This interplay complicates clinical management and can lead to severe liver conditions like steatohepatitis, cirrhosis, and hepatocellular carcinoma. Additionally, MASLD increases the risk of cardiovascular and chronic kidney diseases in diabetes patients, emphasizing the need for early diagnosis and treatment to address both liver health and associated risks [6].
Management of diabetes and MASLD focuses primarily on lifestyle modifications, with weight loss through diet and exercise improving liver histology and reducing liver fat [7]. Pharmacological treatments like pioglitazone and GLP-1 receptor agonists have shown promise for MASLD. Other medications such as SGLT2 inhibitors, DPP-4 inhibitors, and dual GIP/GLP-1 receptor agonists have also been studied. In March 2024, the FDA approved Resmetirom, a THR-β (thyroid hormone receptor β) agonist, for treating MASH in patients with fibrosis stages 2 or 3. Emerging therapies target specific pathways in MASLD pathogenesis, including de novo lipogenesis (DNL) inhibitors, fibroblast growth factors (FGFs), Farsenoid X receptor (FXR) agonists, gut–liver axis drugs (probiotics, symbiotics), and antioxidants. We review these various therapeutic options below.

2. Pathophysiology of MASLD/MASH

The pathophysiology of MASLD and later progression to MASH is complex, continues to be investigated, and involves multiple stressors. Excess intrahepatic lipid accumulation results from an imbalance between fat influx and disposal. Fat influx is linked to excess dietary fat, increased lipolysis in adipose tissue, and de novo lipogenesis (DNL) in the liver, while lipid clearance occurs through very-low-density lipoproteins (VLDL) assembly and mitochondrial beta-oxidation [8,9,10].
Insulin resistance is crucial in MASLD, affecting the liver, muscle, and adipose tissue. In adipose tissue, it increases lipolysis, raising plasma free fatty acids (FFAs) and hepatocyte uptake. In skeletal muscle, reduced glucose uptake also boosts hepatocyte lipid uptake [11]. Insulin resistance enhances hepatic DNL, regulated by transcription factors like sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP), leading to toxic lipid production such as ceramides and diacylglycerols, which further increases hepatic insulin resistance [12]. DNL is notably higher in MASLD patients [13].
These mechanisms promote steatosis and increase hepatic mitochondrial reactive oxygen species (ROS) production, overwhelming the liver’s oxidative capacity and leading to oxidative stress, mitochondrial dysfunction, impaired β-oxidation, and endoplasmic reticulum stress [14,15], and this hepatocyte stress initiates the inflammatory response. ROS activate hepatic stellate cells which lead to development of fibrosis, and also activate Kupffer cells and cytokine release, leading to progressive inflammation [16,17]. Cytokines and adipokines are key to MASH inflammation; adipose tissue in obesity and metabolic syndrome produces pro-inflammatory cytokines (TNF-α, IL-6) and adipokines (leptin, resistin, retinol-binding protein 4, chemerin), promoting insulin resistance and hepatic inflammation, while anti-inflammatory adipokines like adiponectin decrease, furthering inflammation and fibrogenesis [18,19,20].
Genetic factors also influence MASH susceptibility and progression. Variants in genes like PNPLA3, TM6SF2, and MBOAT7 are linked to increased hepatic fat, inflammation, and fibrosis, while a loss-of-function variant in HSD17B13 reduces MASH risk. These genetic polymorphisms affect lipid metabolism pathways, leading to toxic lipid accumulation, oxidative stress, and lipotoxicity, which drive hepatocyte injury and inflammation [21,22,23,24]. The gut-liver axis also plays a role in MASH development, as dysbiosis and increased intestinal permeability allow microbial metabolites and endotoxins, like lipopolysaccharide, into the portal circulation, triggering immune responses and promoting liver inflammation and fibrosis [25]. Bile acids, which aid in lipid digestion and are influenced by gut microbiota, are altered in MASLD and MASH. This alters FXR and bile acid receptor pathways, leading to inflammation and fibrosis [26]. The agents discussed in this review target various aspects of the pathophysiological process in MASLD (Figure 1).
Figure 1. Mechanisms of therapeutic approaches to MASLD/MASH in patients with T2DM. Abbreviations: PPAR = peroxisome proliferator-activated receptor gamma; THR-β agonist = thyroid hormone receptor β agonist; TRE = thyroid hormone response element RXR = retinoid X receptor; FXR = farnesoid X receptor; FGF = fibroblast growth factor; DPP4-i = dipeptidyl peptidase 4 inhibitor; GLP-1 RA = glucagon-like peptide 1 receptor agonist; SGLT2i = sodium-glucose transport protein 2 inhibitor; ACC = Acetyl-CoA carboxylase; FAS = fatty acid synthase; SCD1 = stearoyl-coA desaturase 1; DCAT = diacylglycerol acyltransferase; ROS = reactive oxygen species.

3. Therapeutic Options for MASLD/MASH Under Investigation

This review will include studies available on PubMed with primary and/or secondary endpoints of assessment and response to treatment of hepatic steatosis and/or fibrosis in MASLD/MASH. The reference standard for grading and staging of MASLD/MASH is liver biopsy. Scoring systems using histologic evaluation include the NAFLD Activity Score (NAS), which can range from 0 to 8, is a composite score of steatosis (0–3), hepatocyte ballooning (0–2), and lobular inflammation (0–3), and is used in the NASH Clinical Research Network (CRN) scoring system along with fibrosis staging (0–4) [27]. Another scoring system is the SAF (Steatosis, Activity, and Fibrosis) score, which grades steatosis, hepatocellular ballooning, and lobular inflammation and determines activity using ballooning and inflammation only [28]. Due to limitations in feasibility of liver biopsies in many studies, accurate noninvasive methods of liver fat quantification by MRI-derived proton density fat fraction (MRI-PDFF) or magnetic resonance spectroscopy (MRS), and with controlled attenuation parameter (CAP) measured by vibration-controlled transient elastography (VCTE), were included. Studies that reported liver fibrosis as measured by the liver stiffness measurement (LSM) derived from VCTE, or as measured by magnetic resonance elastography (MRE), were also included [29].

3.1. Glucose Lowering Medications

3.1.1. Peroxisome Proliferator-Activated Receptors (PPAR) Agonists

Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-activated transcription factors regulating glucose and lipid metabolism, inflammation, and fibrogenesis [30]. The PPAR family includes PPAR-α, PPAR-β/δ, and PPAR-γ, each playing roles in lipid signaling and serving as therapeutic targets. PPAR-γ, targeted by insulin-sensitizing thiazolidinediones (TZDs) like pioglitazone for T2DM, is crucial for lipogenesis, insulin sensitivity in the liver, and various functions in adipose tissue, including fatty acid storage, adipocyte differentiation, and increased glucose uptake [31]. PPAR-α, targeted by fibrates for hyperlipidemia, is expressed in liver and muscle and regulates fatty acid oxidation and metabolic responses during fasting [32,33]. PPAR-β is involved in fatty acid oxidation and energy uncoupling in skeletal muscle and adipose tissue. PPARs also exhibit anti-inflammatory effects by repressing pro-inflammatory cytokines [31,34]. Given the link between insulin resistance and MASLD, both single and combination PPAR agonists have been studied in patients with T2DM and MASH.
Pioglitazone
Pioglitazone, a thiazolidinedione and PPAR-γ agonist, has shown significant histologic improvements in MASLD and MASH. In a randomized, double-blind, placebo-controlled trial (RDBPCT) involving 55 patients with impaired glucose tolerance (IGT) or T2DM and biopsy-confirmed MASH, groups treated with pioglitazone when compared to placebo had histologic improvement in steatosis (65% vs. 38%, p = 0.003), ballooning necrosis (54% vs. 24%; p = 0.02), inflammation (65% vs. 29%; p = 0.008), and necroinflammation (85% vs. 35%; p = 0.001). However, there was no significant difference in reduction in fibrosis from baseline between groups, though there was a significant improvement in fibrosis in the pioglitazone group from its baseline (p = 0.002). Hepatic fat content decreased significantly (54% vs. unchanged; p < 0.001), with increased plasma adiponectin (r = −0.60; p < 0.001), alongside improved glycemic control but with notable weight gain [35].
In a single-center, parallel-group randomized controlled trial (RCT) with prediabetes or T2DM patients (51.5%) and biopsy-proven MASH, pioglitazone showed significant improvement in ≥2 point NAS reduction without fibrosis worsening (58% vs. 17%; p < 0.001) and MASH resolution (51% vs. 19%, p < 0.001) after 18 months. These effects persisted at 36 months, with 69% achieving the primary outcome and 59% MASH resolution. Histologic improvements in steatosis (71% vs. 26%, p < 0.001), inflammation (49% vs. 22%; p = 0.004), and ballooning (51% vs. 24%; p = 0.004) were observed, though fibrosis improvement was modest (p = 0.039) [36].
In a prospective trial with biopsy-proven MASH patients treated with pioglitazone 30 mg daily, primary outcomes of NAS reduction were achieved in T2DM (48%) and prediabetes (46%) groups, with significant MASH resolution in T2DM patients (60% vs. 16%, p = 0.002). Fibrosis reduction was significant only in T2DM patients (p = 0.042). Improvements in adipose tissue insulin sensitivity (p < 0.001) and intrahepatic triglyceride content (11% in T2DM and 9% in prediabetes groups) were observed [37].
In a multicenter phase 2 RDBPCT in Taiwan with 90 biopsy-confirmed MASH patients (23% with T2DM), pioglitazone improved MASLD activity score (p < 0.0001), steatosis (p < 0.0001), and lobular inflammation (p = 0.002), though ballooning changes were not significant (p = 0.17). Improvement in MASH without fibrosis worsening was greater in the pioglitazone group (46.7% vs. 11.1%; p = 0.002), but MASH resolution was not significantly different (26.7% vs. 11.1%; p = 0.103). Significant reductions in liver fat content, ALT, AST, HbA1c, and FPG were also observed (p < 0.0001) [38].
Saroglitazar
Saroglitazar, a dual PPAR-α/γ agonist, is approved in India for treating diabetic dyslipidemia and hypertriglyceridemia. It has shown noninferiority to pioglitazone in improving glycemic management (HbA1c and FPG) and significantly improving lipid profile [39]. In experimental models, saroglitazar improved histologic features of MASH, prevented hepatic fibrosis, and decreased transaminase levels and biomarkers of inflammation and fibrosis [40]. A phase 2A trial in post-liver transplantation patients with MASLD showed it reduced liver fat (MRI-PDFF) [41]. Saroglitazar is now also approved in India for use in MASH [42].
In a multicenter RDBPCT, patients treated with saroglitazar (2 mg or 4 mg) for 24 weeks exhibited trends toward NAS improvement, with significant reductions in steatosis and hepatocellular ballooning, although MASH resolution was not observed in the placebo group [43]. A phase 2 RDBPCT demonstrated dose-dependent ALT reductions and significant liver fat reduction in the 4 mg group (−19.7% vs. +4.1%; p = 0.004), with improved insulin resistance (HOMA-IR), adiponectin levels, and dyslipidemia [44]. Additionally, a prospective open-label study in India found that saroglitazar 4 mg significantly reduced fibrosis stages (17% at 24 weeks and 22% at 52 weeks) and improved CAP values, ALT, AST, TG, TC, and LDL-C [45].
Lanifibranor
Lanifibranor, a pan-PPAR agonist, showed promising results in the phase 2B NATIVE trial, a multicenter RDBPCT in patients with highly active MASH (SAF-Activity score ≥3) without F4 fibrosis. The 1200 mg dose significantly reduced SAF-Activity scores by ≥2 points without fibrosis worsening (55% vs. 33%; p = 0.007) and improved fibrosis by at least one stage. Both 1200 mg and 800 mg doses led to greater MASH resolution and fibrosis improvement compared to placebo, with similar results in patients with and without T2DM [46].
Other PPAR Agonists
In a multicenter open-label trial in South Korea, lobetaglitazone, a novel thiazolidinedione, significantly reduced CAP in 65.1% of T2DM patients but did not significantly change liver fibrosis as measured by LSM by VCTE [47]. Lobetaglitazone is not currently approved for use by the FDA or EMA.
Elafibranor, a dual PPAR-α and PPAR-β/δ agonist, was studied as a treatment for MASH, but phase 3 trials failed to meet the primary endpoint of MASH improvement without worsening fibrosis, leading to the trial’s discontinuation in 2022 (NCT02704403).
Summary: PPAR agonists, such as pioglitazone and saroglitazar, improve steatosis, inflammation, and insulin sensitivity in MASLD. Pros include established glycemic control and lipid profile improvements. Cons are weight gain and mixed results on fibrosis resolution. Side effects: fluid retention, weight gain, and rare risks of heart failure.

3.1.2. Sodium Glucose Transport 2 Inhibitors (SGLT2i)

Given the link between insulin resistance and MASLD, SGLT2 inhibitors have been studied as a treatment. These inhibitors block renal glucose reabsorption, increasing glucosuria and reducing blood glucose levels, leading to weight loss [48]. SGLT2 inhibitors also promote glucagon secretion, enhancing hepatic gluconeogenesis and beta-oxidation, and thereby improving fatty acid metabolism in preclinical mice models [49,50,51].
Dapagliflozin
Dapagliflozin has demonstrated benefits in improving liver steatosis, fibrosis, and metabolic parameters in MASLD and T2DM patients. A randomized open-label trial over 24 weeks showed significant reductions in liver steatosis (CAP values: 316 to 290 dB/m, p = 0.0424) and fibrosis (LSM values: 14.7 to 11.0 kPa, p = 0.0158), alongside decreased visceral fat mass [52]. Similarly, an 8-week RDBPCT revealed significant placebo-corrected reductions in liver PDFF (−3.74%, p < 0.01), liver volume (−0.10 L, p < 0.05), and visceral adipose tissue volume (−0.35 L, p < 0.01), with improved glycemic control (HbA1c change: −0.39%, p < 0.01) [53].
Combination therapy with dapagliflozin and omega-3 carboxylic acids resulted in a −25.4% reduction in liver PDFF and improved glucose control and body weight without increasing oxidative stress biomarkers in a multi-institution RDBPCT [54]. A 52-week multicenter RDBPCT found that dapagliflozin combined with saxagliptin and metformin reduced liver fat by 30% (p = 0.007) and adipose tissue volumes by >10%, showing superior efficacy compared to a glimepiride-based regimen [55]. A 104-week extension of a similar study confirmed sustained metabolic improvements, with significant reductions in liver fat (−4.89%) and adipose tissue volumes and better glycemic control compared to glimepiride [56].
The combination of exenatide and dapagliflozin reduced hepatocellular lipids by −35.6% and −32.5%, respectively, over 24 weeks, alongside modest reductions in subcutaneous and visceral adipose tissues. While these studies highlight dapagliflozin’s potential in MASLD and T2DM management, further research is needed to assess the long-term benefits of combination therapies [57].
Empagliflozin
Empagliflozin has shown promise in improving liver fat content (LFC), fibrosis, and metabolic parameters in MASLD and T2DM patients. In an RCT, adding empagliflozin 10 mg to standard diabetes treatment significantly reduced LFC after 20 weeks (16.2% to 11.3%, p < 0.0001) compared to standard therapy, with no correlation between liver fat reduction and HbA1c or weight changes [58].
A Malaysian open-label trial with biopsy-proven MASH patients treated with empagliflozin 25 mg for 24 weeks showed significant histologic improvements in steatosis (p = 0.014), ballooning (p = 0.034), and fibrosis (p = 0.046), with 44% achieving MASH resolution without fibrosis worsening. Compared to a historical placebo group, empagliflozin yielded higher rates of improvement in steatosis (67% vs. 26%, p = 0.025), ballooning (78% vs. 34%, p = 0.024), and fibrosis (44% vs. 6%, p = 0.008) [59]. In phase 4 and phase 3 RDBPCTs, empagliflozin led to significant LFC reductions measured by MRS (−22%, p = 0.009) and weight loss (p < 0.001), particularly in male patients [60].
The EMPACEF trial in France showed a 27% LFC reduction with empagliflozin 10 mg daily compared to 2% in placebo (p = 0.0005), with modest weight loss correlating with LFC reduction (r = 0.39, p = 0.006) and decreased visceral adipose tissue (p = 0.043) [61]. Additionally, in Iran, RDBPCTs comparing empagliflozin to pioglitazone to placebo showed significant CAP score reduction (−29.6 dB/m, p = 0.05), fibrosis decrease (−0.77 kPa, p = 0.03), and weight loss with empagliflozin, while pioglitazone led to weight gain [62,63].
Canagliflozin
In a RDBPCT, T2DM patients inadequately controlled with metformin or metformin/DPP-4 inhibitor were randomized to canagliflozin 300 mg daily or placebo for 24 weeks. The canagliflozin group showed a non-significant decrease in intrahepatic triglyceride content (IHTG) compared to placebo (−4.6% vs. −2.4%, p = 0.09), with a greater effect in MASLD patients (−6.9% vs. −3.8%, p = 0.05). The canagliflozin group experienced significant weight reduction (p = 0.001), which correlated with IHTG reduction (r = 0.58, p < 0.001). More canagliflozin patients met the ≥5% weight loss threshold impacting hepatic steatosis [64].
Other SGLT2 Inhibitors
Other SGLT2 inhibitors studied in Japan and South Korea but not FDA- or EMA-approved include luseogliflozin, ipragliflozin, and tofogliflozin. Luseogliflozin improved the liver-to-spleen (L/S) ratio more than metformin [65]. Ipragliflozin showed similar L/S ratio improvements to pioglitazone with nonsignificant CAP reductions when added to metformin and pioglitazone [66], but led to greater histologic improvements in ballooning and fibrosis than control in another study [67]. Tofogliflozin reduced hepatic steatosis compared to pioglitazone but did not significantly improve fibrosis unless combined with pioglitazone [68,69]. Compared to glimepiride, tofogliflozin significantly improved liver fibrosis and other histologic categories [70].
SGLT2 Inhibitor Meta-Analysis
Meta-analyses have demonstrated the efficacy of SGLT2 inhibitors in improving hepatic and metabolic parameters in MASLD and T2DM patients. A meta-analysis of 10 studies with 555 patients showed significant improvements in hepatic steatosis (MRI-PDFF, CAP, L/S ratio), AST, and ALT, though fibrosis markers like FIB-4 and MASLD fibrosis score showed no significant changes except for a reduction in the NAFIC score. SGLT2 inhibitors also significantly reduced visceral adipose tissue (VAT) compared to controls, insulin, and metformin, and subcutaneous adipose tissue (SAT) compared to TZDs, with notable weight loss [71].
Another meta-analysis of nine studies (11,369 patients) confirmed improvements in AST, ALT, hepatic steatosis, weight, and HbA1c [72], while a meta-analysis of 20 studies (3859 patients) found consistent benefits across different SGLT2 inhibitors and treatment durations [73]. Further analyses supported these findings: a meta-analysis of 10 studies (573 patients) showed reductions in hepatic steatosis, FIB-4, AST, ALT, body weight, VAT, and SAT compared to other antidiabetic agents [74], and a meta-analysis of 16 RCTs (699 participants) reported decreases in liver stiffness measurement (LSM), CAP, and FIB-4 index [75]. Comparatively, SGLT2 inhibitors outperformed TZDs in reducing body weight and visceral fat area (VFA) but showed no significant differences in hepatic outcomes or glucose metabolism [76]
Summary: SGLT2 inhibitors reduce liver fat, visceral adiposity, and improve metabolic and cardiovascular outcomes in MASLD. Pros: weight loss and cardiometabolic benefits. Cons: limited fibrosis improvement and variable efficacy across subgroups. Side effects: urinary tract and genital infections, rare diabetic ketoacidosis.

3.1.3. Dipeptidyl Peptidase-4 (DPP-4) Inhibitors—Sitagliptin

DPP-4 inhibitors, which inhibit GIP and GLP-1 degradation, have been studied in T2DM and MASLD/MASH patients. In a 2016 multicenter RDBPCT, sitagliptin 100 mg daily for 24 weeks showed no significant improvements in liver fat content (LFC) by MRI-PDFF, liver fibrosis by MRE, FIBROSpect scores, or metabolic markers like glucose, insulin, HbA1c, HOMA-IR, LDL, AST, and ALT compared to placebo [77]. A follow-up RDBPCT with 12 patients and biopsy-confirmed MASH also found no significant histologic or metabolic improvements with sitagliptin, including MASLD activity score, hepatic fat, liver enzymes, VAT, SAT, and weight changes, though HbA1c improved non-significantly compared to placebo [78] (Table 1).
Table 1. Glucose-lowering drugs.
Summary: DPP-4 inhibitors offer mild glycemic benefits but limited efficacy in MASLD. Pros: favorable safety and ease of use. Cons: minimal impact on liver outcomes. Side effects: mild gastrointestinal discomfort and rare hypersensitivity reactions.

3.2. Drugs Promoting Glucose-Lowering and Weight Loss

3.2.1. Glucagon-like Peptide-1 (GLP-1) Receptor Agonists

GLP-1 receptor agonists mimic the actions of endogenous GIP, an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon release, delays gastric emptying, and reduces appetite. These actions contribute to their antihyperglycemic effects and use in T2DM treatment [79,80]. Given the role of insulin resistance in MASLD, these agents are also being investigated for MASLD treatment.
Semaglutide
Semaglutide, a GLP-1 agonist, has shown mixed results in MASLD and MASH patients. In a phase 2 multinational RDBPCT with biopsy-confirmed MASH and F1-F3 fibrosis, semaglutide (0.1 mg, 0.2 mg, 0.4 mg daily) over 72 weeks achieved MASH resolution without fibrosis worsening in up to 59% of patients (vs. 17% placebo), with significant results in the 0.4 mg group (OR 6.87; p < 0.001). Only 5% of the 0.4 mg group had fibrosis progression compared to 19% in placebo, and none progressed to F4 (vs. 4% placebo). However, improvements in fibrosis without MASH worsening were non-significant. Semaglutide dose-dependently reduced AST, ALT, body weight, and HbA1c, with gastrointestinal issues being the most common adverse effects [81], and though there was a higher incidence of neoplasms in the semaglutide groups without a specific pattern or organ affected, and a recent meta-analysis did not find an association with risk of any cancer with semaglutide [82].
In another RDBPCT with MASLD patients (73% T2DM), semaglutide 0.4 mg daily significantly reduced liver steatosis (MRI-PDFF) and body weight but showed no improvement in liver stiffness by MRE or VCTE over 72 weeks. Semaglutide also improved HbA1c and fasting plasma glucose in T2DM patients, though no HOMA-IR changes were noted [83]. A phase 2 RDBPCT in Europe and the U.S. with biopsy-confirmed MASH and cirrhosis found no significant differences in fibrosis improvement or MASH resolution with semaglutide 2.4 mg weekly versus placebo, though liver fat, HbA1c, fasting plasma glucose, and weight were significantly reduced [84].
Liraglutide
In a multicenter phase 2 RDBPC trial in the UK, patients with biopsy-proven MASH (32.7% with T2DM) received liraglutide 1.8 mg daily or placebo for 48 weeks. MASH resolution without fibrosis worsening occurred in 39% of the liraglutide group versus 9% in placebo (RR 4.3; p = 0.019), with improvements in steatosis and hepatocyte ballooning but no significant change in MASLD activity scores. Fewer liraglutide-treated patients experienced fibrosis progression (9% vs. 36%; p = 0.04), and significant reductions in plasma glucose, insulin, and HbA1c were noted, though HOMA-IR remained unchanged [85].
In a trial in Japan, T2DM patients with MASLD/MASH showed that liraglutide 0.9 mg daily for 24 weeks significantly improved BMI, visceral fat, AST, ALT, HbA1c, FPG, and L/S ratio (all p < 0.05). After 96 weeks, patients had reduced histologic inflammation, improved fibrosis, and better NAS [86]. While other studies using noninvasive methods (MRE, MRI-PDFF, VCTE) reported mixed results (Table 1) [87,88,89,90,91,92,93], a meta-analysis of 11 RCTs found liraglutide significantly reduced BMI, HbA1c, cholesterol, and triglycerides, though changes in liver fat, enzymes, and adipose tissue were not statistically significant [94].
Dulaglutide
In the D-LIFT trial in India, a 24-week open-label RCT with T2DM patients and liver fat ≥ 6% by MRI-PDFF, participants received either standard diabetes treatment or added weekly subcutaneous dulaglutide 1.5 mg. The dulaglutide group showed significantly greater liver fat reduction (−32.1% vs. −5.7%, p = 0.004) and body weight loss, with 55.6% achieving ≥5% weight loss compared to 24.0% in controls. Dulaglutide also improved serum GGT, but not ALT or AST. Both groups improved FPG and HbA1c without significant differences, and liver fat reduction was independently associated with body weight, HbA1c, and triacylglycerol levels [95].
Exenatide
In an open-label RCT, T2DM patients treated with pioglitazone 45 mg daily or pioglitazone plus exenatide 5 µg twice daily for 12 months showed significant liver fat reduction (pioglitazone: p < 0.05; combination: p < 0.001), with greater reduction in the combination group (61% vs. 41%, p < 0.05). Both groups improved FPG, HbA1c, and plasma adiponectin, with a larger adiponectin increase in the combination group (193% vs. 85%, p < 0.001). Pioglitazone alone caused weight gain, while the combination did not [96]. In a French trial, exenatide 10 µg twice daily reduced epicardial adipose tissue (EAT) (−8.8% vs. −1.2%; p = 0.003) and hepatic triglyceride content (HTGC) (−23.8% vs. +12.5%; p = 0.007) more than oral hypoglycemics, with weight loss correlating to reductions in EAT and HTGC [97]. A Chinese RCT comparing exenatide and insulin glargine in T2DM with MASLD found similar liver fat reductions, though exenatide led to greater weight loss, VAT and SAT reductions, and FIB-4 improvement, suggesting potential fibrosis benefits [98].
GLP-1 Receptor Agonist Meta-Analysis
A 2021 meta-analysis of 11 RCTs with 935 MASLD/MASH patients (70% with T2DM) treated with GLP-1 receptor agonists (liraglutide, dulaglutide, semaglutide, exenatide) for 26 weeks showed significant benefits over placebo or conventional treatment. These included higher MASH resolution without fibrosis worsening (OR 4.06, 95% CI 2.52–6.55; p < 0.0001) and reduced liver fat percentage (WMD: −3.92%, 95% CI −6.27% to −1.56%, p < 0.0001). ALT levels, HbA1c, and body weight were also significantly reduced. However, no improvement in fibrosis stage without worsening MASH was observed, possibly due to short study durations and advanced baseline fibrosis [99]. A meta-analysis of 16 RCTs with 2178 MASLD/MASH patients found that liraglutide and semaglutide significantly improved MASH resolution without fibrosis worsening (OR 4.08, 95% CI 2.54–6.56, p < 0.0001). While body weight, AST, and ALT were significantly reduced, no significant improvement in fibrosis stage without worsening MASH was noted [100].

3.2.2. Dual Glucose-Dependent Insulinotropic Polypeptide (GIP) and GLP-1 Receptor Agonist: Tirzepatide

Tirzepatide, a dual GIP and GLP-1 receptor agonist, has shown promising results in MASLD/MASH management. In the phase 3 SURPASS-3 RCT substudy, T2DM patients on metformin (±SGLT2i) with fatty liver index ≥60 were randomized to weekly tirzepatide (5 mg, 10 mg, 15 mg) or daily insulin degludec for 52 weeks. Tirzepatide (10 mg/15 mg) led to greater liver fat content (LFC) reduction than insulin (−8.09% vs. −3.38%, p < 0.0001), with all doses showing significant LFC decreases. Tirzepatide also significantly reduced HbA1c, body weight, visceral adipose tissue (VAT), and abdominal subcutaneous adipose tissue (ASAT). LFC reduction was independently associated with baseline LFC (p < 0.0001), body weight change (p = 0.032), and HbA1c change (p = 0.011) [101]. In a phase 2 RDBPCT with 190 biopsy-confirmed MASH patients (F2/F3 fibrosis), tirzepatide achieved MASH resolution without worsening fibrosis in 44% (5 mg), 56% (10 mg), and 62% (15 mg) compared to 10% in the placebo group (p < 0.001) [102].

3.2.3. Dual Glucagon and GLP-1 Receptor Agonist: Cotadutide

Cotadutide, a dual GLP-1 and glucagon receptor agonist, has shown potential for improving liver fibrosis in preclinical models [103]. In a phase 2A trial, cotadutide significantly reduced hepatic fat fraction by MRI-PDFF compared to placebo (p = 0.002) and liraglutide (p = 0.044), with similar weight loss to liraglutide, suggesting direct liver benefits [104] (Table 2).
Table 2. Drugs promoting weight loss with or without glucose lowering.
Summary: GLP-1 receptor agonists and dual GIP, GLP agonists reduce liver fat, improve glycemic control, and promote significant weight loss. Pros: dual efficacy for glycemic and hepatic outcomes. Cons: gastrointestinal intolerance and high cost. Side effects: nausea, vomiting, diarrhea, and rare pancreatitis.

3.3. Drugs Promoting Weight Loss: Lipase Inhibitor: Orlistat

Orlistat, an anti-obesity agent that inhibits pancreatic and gastric lipases, promotes weight loss by reducing fat absorption, potentially improving steatosis and insulin sensitivity in obesity and T2DM patients, making it a possible MASLD therapy. In a U.S. open-label RCT with 50 biopsy-proven MASH patients on a hypocaloric diet and vitamin E (±orlistat 360 mg daily) for 36 weeks, no significant differences were observed between groups in weight loss, glucose homeostasis, insulin resistance, liver enzymes, adipocytokine levels, or histopathology. However, ≥5% body weight loss correlated with improved insulin resistance and steatosis, while ≥9% weight loss led to further improvements in insulin resistance, hepatic steatosis, and histopathology [105] (Table 2).
Summary: Orlistat reduces dietary fat absorption and can help decrease liver fat in MASLD patients. Pros: supports weight loss, reduces liver fat, and improves metabolic parameters. Cons: limited direct impact on liver fibrosis and modest efficacy compared to other agents. Side effects: gastrointestinal issues such as oily stools, flatulence, and potential fat-soluble vitamin deficiencies with long-term use.

3.4. Drugs Affecting Intermediary Metabolism

Antioxidants: Vitamin E

Given oxidative stress’s role in MASH progression, antioxidants like vitamin E are potential treatments. The PIVENS trial, a phase 3 multicenter RDBPCT, compared pioglitazone, vitamin E, and placebo in non-diabetic MASH patients over 96 weeks. Vitamin E significantly improved NAS, ballooning (50% vs. 29% placebo; p = 0.01), and steatosis without worsening fibrosis (43% vs. 19%, p = 0.001, NNT 4.2), while pioglitazone improved steatosis and lobular inflammation but did not improve ballooning, with significant weight gain observed (47% vs. 21%, p < 0.001) [106]. A follow-up RDBPCT in Veterans Affairs patients with T2DM and MASH found that combining vitamin E with pioglitazone significantly improved MASLD activity scores (54% vs. 19%, p = 0.003) and MASH resolution (43% vs. 12%, p = 0.005), while vitamin E alone showed minimal benefit. The combination also improved HbA1c (p = 0.002) but caused significant weight gain (p < 0.001) [107] (Table 3).
Table 3. Drugs affecting intermediary metabolism.
Summary: Antioxidants reduce oxidative stress and inflammation in MASLD leading to histological improvement. Pros: affordability and efficacy, especially in patients without diabetes. Cons: limited effects on fibrosis and long-term safety concerns. Side effects: overall well tolerated.

3.5. Nuclear Receptor Modulators

3.5.1. Thyroid Hormone Receptor Beta (THRβ) Agonists: Resmetirom

Thyroid hormone receptors (THRs), including THR-α and THR-β, regulate gene expression through thyroid hormone response elements (TREs) in DNA. THR-α is predominant in the heart and bone, while THR-β is liver-specific, playing a key role in lipid and cholesterol metabolism [108,109]. Hypothyroidism is associated with MASLD progression due to reduced hepatic T3, which affects mitochondrial turnover and lipid homeostasis via autophagy [110,111,112]. Animal studies show that THR-β activation improves mitochondrial function and beta-oxidation, reducing hepatic steatosis, making it a potential target for MASH treatment [113,114].
Resmetirom (MGL-3196), a THR-β agonist recently FDA-approved for MASH with moderate to advanced fibrosis, significantly reduced hepatic fat by MRI-PDFF (−32.9% vs. −10.4% at 12 weeks; −37.3% vs. −8.5% at 36 weeks, both p < 0.0001), improved ALT, AST, lipids, inflammation, and fibrosis biomarkers, and resolved MASH with mild gastrointestinal side effects in a phase 2 RDBPCT [115]. The MAESTRO MASH phase 3 trial showed that resmetirom (80 mg and 100 mg) improved MASH resolution without fibrosis worsening (25.9–29.9% vs. 9.7% placebo, p < 0.001) and fibrosis by at least 1 stage (24.2–25.9% vs. 14.2% placebo) [116].
While it improved atherogenic dyslipidemia, it had no significant effect on glucose homeostasis or insulin resistance. Nausea and diarrhea were more common adverse effects. Other THR-β agonists under investigation include VK-2809 (NCT04173065), TERN 501 (NCT05415722), and ASC-4 (NCT05118360), with ongoing trials focused on liver fat and fibrosis outcomes (Table 4).
Table 4. Nuclear receptor modulators.
Summary: Resmetirom targets liver fat and improve metabolic markers in MASLD. Pros: targeted mechanism and efficacy in steatosis and fibrosis reduction. Cons: limited long-term safety data. Side effects: mild gastrointestinal symptoms and transient liver enzyme elevation.

3.5.2. Farnesoid X Receptor (FXR) Agonists, Bile Acids, and Synthetic Bile Acids

The farnesoid X receptor (FXR), a nuclear receptor in the intestine and liver, regulates bile acid homeostasis and hepatic lipogenesis, making it a potential MASLD treatment target. This role was established in mice lacking FXR/BAR gene demonstrating elevated hepatic cholesterol and triglycerides [119].
Obeticholic Acid
Steroidal FXR agonist obeticholic acid has shown promising effects on liver histology but has side effects like pruritus, dyslipidemia, and worsening insulin resistance, limiting its use [117,118]. Non-steroidal FXR agonists, including tropifexor, vonafexor, cilofexor, TERN-501, nidufexor, and MET 409, are currently being studied (Table 4).

3.6. De Novo Lipogenesis Inhibitors

3.6.1. Acetyl-CoA Carboxylase (ACC) Inhibitors:

Acetyl-CoA carboxylase (ACC) is an enzyme involved in fatty acid synthesis, converting Acetyl-CoA to Malonyl-CoA and indirectly inhibiting CPT-1, which regulates mitochondrial fatty acid uptake. ACC inhibitors, targeting its liver-expressed isoforms, are potential MASLD treatments by reducing hepatic triglycerides and de novo lipogenesis (DNL) [120,121]. In a phase 2 trial with 126 patients with hepatic steatosis ≥ 8%, GS-0976 (a hepatic ACC inhibitor) led to a ≥30% reduction in MRI-PDFF in 48% (20 mg dose, p = 0.004 vs. placebo), 28% (5 mg dose, p = 0.43), and 15% in the placebo group, significantly reducing hepatic steatosis [122].

3.6.2. Fatty Acid Synthase (FAS) Inhibitors

Fatty Acid Synthase (FAS) catalyzes the conversion of acetyl-CoA and malonyl-CoA to palmitate, and its overexpression in MASLD suggests FAS inhibition could reduce de novo lipogenesis without raising serum triglycerides. A study of FT-4101, a FAS inhibitor, showed dose-dependent inhibition of hepatic DNL. In MASLD patients, a 3 mg dose significantly reduced hepatic steatosis from 20.1 ± 7.0 to 16.7 ± 7.0 after 12 weeks [123].

3.6.3. Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors

Stearoyl-CoA desaturase 1 (SCD1) regulates lipid metabolism by converting saturated to monounsaturated fatty acids and is key in lipogenesis and adipogenesis [124]. SCD1 inhibitors protect against hyperlipidemia, obesity, hepatic steatosis, and insulin resistance [125]. In a phase 2B trial with 247 MASH patients, Aramchol (400 mg, 600 mg) was evaluated over 52 weeks. The 600 mg dose reduced hepatic triglycerides without reaching significance, but MASH resolution occurred in 16.7% of the 600 mg group vs. 5% in placebo (OR = 4.74, 95% CI = 0.99–22.7) [126].

3.6.4. Diacylglycerol Acyltransferase (DGAT) Inhibitors

Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride synthesis, with DGAT-1 in the small intestine reassembling triglycerides and DGAT-2 in the liver, skin, and adipose tissue synthesizing new diglycerides and FFAs. In a phase 2 RDBPCT, DGAT2 inhibition in 44 T2DM and MASLD patients reduced liver fat by −5.2% vs. −0.6% in placebo (p = 0.026), with no impact on lipids, weight, or GI side effects [127]. A phase 2A trial showed that ACC inhibitor monotherapy reduced liver fat by 50–65%, while combination therapy with ACC (15 mg BID) and DGAT2 (300 mg BID) inhibitors reduced liver fat by −44.5% and −35.4% compared to placebo after 6 weeks [120].

3.6.5. Ketohexokinase Inhibitors

Ketohexokinase (KHK), key in fructose metabolism, is a target for MASLD and T2DM treatment. In animal models, KHK inhibitors reduce de novo lipogenesis, steatosis, and early insulin resistance [128]. A phase 2 trial showed that a 300 mg daily dose of a KHK inhibitor significantly reduced liver fat by −18.73% (p = 0.04) over 6 weeks, with no effect at 75 mg, and decreased inflammatory markers [128] (Table 5).
Table 5. Drugs affecting de novo lipogenesis.

3.7. Gut-Liver Axis

Probiotics, Symbiotics

Recent literature suggests that gut microbiome dysregulation in MASLD may be addressed with probiotics, potentially improving liver health [129]. In a 24-week RDBPCT with 39 patients, probiotics containing Lactobacillus and Bifidobacterium were compared to placebo for effects on hepatic steatosis and fibrosis via transient elastography. No significant changes were observed in steatosis (probiotics: −21.70 ± 42.6 dB/m, p = 0.052; placebo: −10.72 ± 46.6 dB/m, p = 0.29) or fibrosis (probiotics: −0.25 ± 1.77 kPa, p = 0.55; placebo: −0.62 ± 2.37 kPa, p = 0.23), concluding probiotics had no significant effects [130].

3.8. Fibroblast Growth Factors

Fibroblast growth factors are involved in the metabolism of lipids, carbohydrates, and bile acids. While several agents are being investigated as potential targets for MASLD, FGF19 and FGF21 analogs have been most studied in humans.

3.8.1. Pegozafermin

Pegozafermin is a FGF21 analog that has been studied in a phase 2 placebo-controlled trial in patients with biopsy-confirmed MASH and stage F2 or F3 fibrosis. Treatment with pegozafermin led to improvements in fibrosis, supporting the advancement of pegozafermin into phase 3 development [131].

3.8.2. Aldafermin

FGF19 analog Aldafermin in its phase 2B RDBPCT was well-tolerated but did not show a significant response in fibrosis improvement in patients with biopsy confirmed MASH and stage 2 or 3 fibrosis [132] (Table 6).
Table 6. Other drugs under investigation.

3.9. Other Pathways

CCR2/CCR5 antagonists like Cenicriviroc have been studied for MASH treatment by disrupting the inflammatory responses leading to fibrogenesis. Initial antifibrotic effects were seen in a phase 2B trial, but the AURORA phase 3 study found no significant improvement in liver fibrosis or MASH resolution compared to placebo [133,134]. ASK1, a stress-activated enzyme in the JNK and p38 MAPK pathway, promotes hepatic inflammation and fibrosis. A phase 3 trial evaluated the ASK1 inhibitor Selonsertib in MASH patients with advanced fibrosis, finding dose-dependent reductions in p38 expression but no significant clinical improvements [135]. Gal-3, involved in chronic inflammation and fibrogenesis, was targeted by the inhibitor Belapectin in a phase 2B trial, which found no significant effect on MASLD activity score or liver-related outcomes [136]. LOXL2, which promotes collagen fiber networking in fibrogenesis, was targeted in a phase 2b trial that found the LOXL2 inhibitor Simtuzumab ineffective in reducing fibrosis stage or cirrhosis progression in bridging fibrosis secondary to MASH [137].

4. Conclusions

MASLD is the most common chronic liver disease globally, affecting both the liver and extra-hepatic systems and costing the US over $100 billion annually. Despite this burden, only Resmetirom is FDA approved for moderate to advanced MASH due to the disease’s multifactorial nature and lack of reliable non-invasive biomarkers. Ongoing trials target metabolic pathways like adipose dysfunction, insulin resistance, de novo lipogenesis, lipid export, and energy balance, with a rising interest in combination therapies.
Current treatment guidelines for MASLD emphasize a multidisciplinary approach, including lifestyle modifications like reducing sedentary time, increasing daily movement, minimizing alcohol intake, and adopting dietary changes to promote weight loss. Structured weight loss programs, anti-obesity medications, and bariatric surgery should be considered for patients with obesity. Managing comorbidities such as hypertension and dyslipidemia is crucial, and diabetes treatment should aim to lower hemoglobin A1c to below 6.5%. Medications that reduce liver fat, including pioglitazone, GLP-1 agonists, and SGLT2 inhibitors should be strongly considered. In liver dysfunction, sulfonylureas, meglitinides, metformin, and thiazolidinediones need titration and monitoring to avoid hypoglycemia, risk of lactic acidosis, and fluid accumulation. Precise identification of disease drivers is essential for developing new treatments, with hopes for additional FDA-approved therapeutic options in the near future. Clinicians must stay informed about emerging agents and the need for further research to determine their efficacy, dosage, and treatment duration.

Author Contributions

Conceptualization: R.C. and P.M.; methodology: R.C. and J.V.; data curation: R.C., J.V., A.P., R.R. and P.M.; writing—original draft preparation: R.C., J.V., A.P., R.R., P.M.; writing—review and editing: R.C., J.V., P.M., A.A., M.S.S. and A.M.; visualization: R.C. and J.V.; supervision: P.M., A.A., M.S.S. and A.M. All authors have read and agreed to the published version of the manuscript.

Funding

This study received no external funding.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following includes abbreviations found in the body of the text:
ACCAcetyl-CoA Carboxylase
ALTAlanine Aminotransferase
ASK1Apoptosis Signal-Regulating Kinase 1
ASTAspartate Aminotransferase
BARBile Acid Receptor
BIDTwice Daily Dosing
BMIBody Mass Index
CAPControlled Attenuation Parameter
CIConfidence Interval
CRNClinical Research Network
CRPC-Reactive Protein
DCATDiacylglycerol Acyltransferase
DNLDe Novo Lipogenesis
DPP-4Dipeptidyl Peptidase-4
EMAEuropean Medicines Agency
ETREstimated Treatment Ratios
FASFatty Acid Synthase
FDAFood and Drug Administration
FFAFree Fatty Acids
FIB-4Fibrosis-4 Index
FGFFibroblast Growth Factor
FPGFasting Plasma Glucose
FXRFarnesoid X Receptor
GIPGlucose-Dependent Insulinotropic Polypeptide
GLIMGlimepiride
GLP-1 RAGlucagon-Like Peptide-1 Receptor Agonist
HbA1cHemoglobin A1c
HDLHigh-Density Lipoprotein
HOMA-IRHomeostatic Model Assessment for Insulin Resistance
HSD17B1317β-hydroxysteroid Dehydrogenase Type 13
IGTImpaired Glucose Tolerance
IL-6Interleukin 6
IHTGIntrahepatic Triglyceride
JNKJun N-terminal Kinase
KHKKetohexokinase
LDLLow-Density Lipoprotein
LFCLiver Fat Content
LOXLLysyl Oxidase Like 1
LSMLiver Stiffness Measurement
MAPKMitogen-Activated Protein Kinase
MASHMetabolic Dysfunction-Associated Steatohepatitis
MASLDMetabolic Dysfunction-Associated Steatotic Liver Disease
MBOAT7Membrane-Bound O-Acyltransferase Domain-Containing 7
MREMagnetic Resonance Elastography
MRI-PDFFMagnetic Resonance Imaging - Proton Density Fat Fraction
NASNon-Alcoholic Fatty Liver Disease Activity Score
NAFLDNon-Alcoholic Fatty Liver Disease
NASHNon-Alcoholic Steatohepatitis
NNTNumber Needed to Treat
OCAObeticholic Acid
OROdds Ratio
PNPLA3Patatin-Like Phospholipase Domain-Containing Protein 3
PPARPeroxisome Proliferator-Activated Receptor
QUICKIQuantitative Insulin Sensitivity Check Index
RDBPCTRandomized Double-Blind Placebo-Controlled Trial
RCTsRandomized Controlled Trials
ROSReactive Oxygen Species
RXRRetinoid X Receptor
SAFSteatosis, Activity, Fibrosis
SATSubcutaneous Adipose Tissue
SCD1Stearoyl-CoA Desaturase-1
SFASubcutaneous Fat Area
SGLT2iSodium-Glucose Co-Transporter 2 Inhibitors
T2DMType 2 Diabetes Mellitus
TCTotal Cholesterol
TGTriglycerides
THR-βThyroid Hormone Receptor β
TM6SF2Transmembrane 6 Superfamily Member 2
TREThyroid Hormone Response Element
TZDThiazolidinediones
VATVisceral Adipose Tissue
VCTEVibration-Controlled Transient Elastography
VFAVisceral Fat Area
VLDLVery Low-Density Lipoprotein

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