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

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).

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. Glucose-lowering drugs.

Study (year)	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
PPAR Agonists and experimental PPAR agonists
Pioglitazone [35]	55 patients with T2DM/impaired glucose tolerance (IGT) + liver biopsy confirmed NASH	24 weeks	Hypocaloric diet + pioglitazone (45 mg daily) vs. hypocaloric diet + placebo	Hepatic fat content (MRS): significant reduction from baseline compared to placebo (54% vs. unchanged, p < 0.001) Steatosis: significant improvement in pioglitazone group compared to placebo (65% vs. 38%; p = 0.003) Ballooning necrosis: significant improvement in pioglitazone group compared to placebo (54% vs. 24%; p = 0.02), Lobular inflammation: significant improvement in pioglitazone group compared to placebo (65% vs. 29%; p = 0.008). Necroinflammation: significantly greater reduction in pioglitazone group (85% vs. 35%; p = 0.001) Fibrosis: no significant difference between groups (46% vs. 33%; p = 0.08)	Pioglitazone group showed significantly greater improvement in HbA1c (p = 0.008), FPG (p = 0.011), and fasting plasma insulin (p < 0.001) compared to placebo. Significant weight gain was seen in the pioglitazone group (p = 0.003). Plasma adiponectin increased 2.3-fold in pioglitazone group vs. unchanged in placebo (p < 0.001).
Pioglitazone [36]	101 patients with prediabetes or T2DM and biopsy-proven NASH	36 months total (18 months intervention, 18 month open-label pioglitazone treatment phase)	Hypocaloric diet + pioglitazone 45 mg/day vs. placebo	≥2 point reduction in NAFLD activity score (NAS) in 2 histologic categories without worsening of fibrosis: significantly higher in pioglitazone group than placebo (58% vs. 17%; p < 0.001) NASH resolution: significantly higher in pioglitazone group than placebo (51% vs. 19%; p < 0.001) Steatosis: significant improvement in pioglitazone group compared to placebo (71% vs. 26%; p < 0.001) Hepatocellular ballooning: significant improvement in pioglitazone group compared to placebo (51% vs. 24%; p = 0.004) Lobular inflammation: significant improvement in pioglitazone group compared to placebo (49% vs. 22%; p = 0.004) Fibrosis: no significant difference between groups NAS improvement: significantly higher in pioglitazone group than placebo (66% vs. 21%; p < 0.001) Progression of fibrosis: significantly fewer in pioglitazone group compared to placebo (12% vs. 28%; p = 0.039) Hepatic triglyceride content: significant reduction in pioglitazone (19% to 7%) compared to placebo (15% to 11%); p < 0.001	Pioglitazone group showed significant improvement in hepatic (p = 0.002), muscle (p < 0.001), and adipose tissue insulin sensitivity (p < 0.001) compared to placebo. Plasma adiponectin significantly increased (p < 0.001). In T2DM patients, pioglitazone significantly reduced HbA1c (p = 0.009), FPG (p = 0.020), and fasting plasma insulin (p = 0.041) compared to placebo.
Pioglitazone [37]	101 patients with biopsy-proven NASH and T2DM (n = 52) or prediabetes (n = 49)	18 months	Pioglitazone 30–45 mg po daily vs. placebo	≥2 point reduction in NAFLD activity score without worsening fibrosis: Achieved by 60% of T2DM and 70% of prediabetes groups (p = 0.51). NASH resolution: Significant in T2DM group only compared to placebo (60% vs. 16%, p = 0.002). Histologic scores: Similar response in both groups (T2DM −1.3 ± 1.8 vs. prediabetes −1.2 ± 1.9) Histologic improvements: Both groups improved in steatosis; only T2DM showed significant improvements in inflammation (p = 0.013) and ballooning (p = 0.006). Fibrosis: Similar reduction in both groups; significant in T2DM compared to placebo (p = 0.042). Intrahepatic triglyceride content (MRS): Similar reduction in both groups.	Hepatic and muscle insulin sensitivity: Similar response in both T2DM and prediabetes groups. Adipose insulin sensitivity: Significantly higher in T2DM patients. HbA1c: Significant reduction in T2DM group (p = 0.017); interaction with pioglitazone not significant (p = 0.09). Fasting plasma insulin (FPI): Significant reduction in prediabetes group only (p < 0.001). Adiponectin: Significant increase in both T2DM and prediabetes groups (p < 0.001).
Pioglitazone [38]	90 patients in Taiwan with biopsy-proven NASH with (23%) and without T2DM	24 weeks	Pioglitazone 30 mg po daily vs. placebo	NAFLD activity score: Significant decrease in pioglitazone group (4.27 to 2.53, p < 0.0001). Steatosis: Significant decrease in pioglitazone group (p < 0.0001). Lobular inflammation: Significant decrease in pioglitazone group (p = 0.002). Ballooning: No significant change in either group. Fibrosis reduction ≥1 score: No significant difference between groups. NAS fibrosis score: Increase in placebo group (0.75 to 1.11, p = 0.007). Fibrosis progression: 6.7% (pioglitazone) vs. 33.3% (placebo); p = 0.02. NASH improvement without worsening fibrosis: Greater in pioglitazone group (46.7% vs. 11.1%, p = 0.002). NASH resolution: No significant difference (pioglitazone 26.7%, placebo 11.1%; p = 0.103). Liver fat content (MRI-PDFF): Significant reduction in pioglitazone group (20.2% to 14.3%, p < 0.0001).	HbA1c: significant reduction from baseline in pioglitazone group (p = 0.003) FPG: significant decrease from baseline in pioglitazone group (p = 0.02)
Saroglitazar [43]	16 patients with biopsy-proven NASH and NAS ≥4 with 1 point in each NAS component	24 weeks	Placebo vs saroglitazar 2 mg vs. 4 mg	NAS decrease from baseline: No significant difference in saroglitazar 2 mg (42.9%), 4 mg (66.7%), or placebo (33.3%). NASH resolution: Saroglitazar 2 mg (42.9%), 4 mg (66.7%), placebo (0%). Liver fibrosis improvement: Saroglitazar 2 mg (33.3%), 4 mg (57.1%), placebo (0%). Steatosis: Significant improvement in both saroglitazar groups. Hepatocellular ballooning: Significant improvement in both saroglitazar groups.
Saroglitazar [44]	103 patients with NAFLD (diagnosed by imaging) or NASH (diagnosed by biopsy) with ALT ≥ 50 U/L	16 weeks	Placebo vs saroglitazar 1 mg, 2 mg, and 4 mg	LFC (MRI-PDFF): Significant reduction in saroglitazar 4 mg group (−19.7% vs. +4.1%, p = 0.004). LFC (CAP) and liver stiffness (kPa): No significant difference from baseline at any dose.	Body weight: Non-significant dose-dependent increase. FPG, insulin, HbA1c: No significant difference from baseline at any dose. HOMA-IR: Significant improvement with saroglitazar 4 mg only (p = 0.047). Adiponectin: Significant increase with saroglitazar 1 mg (p = 0.007) and 4 mg (p < 0.001). Lipids: Significant reduction in triglycerides (TG) (p < 0.001) and VLDL (p = 0.017) at saroglitazar 4 mg; in TG (p = 0.001) and VLDL (p = 0.009) at saroglitazar 1 mg
Saroglitazar [45]	63 patients with NAFLD/NASH (diagnosed by imaging or histology) with (n = 29) and without T2DM	24 weeks, 52 weeks	Saroglitazar 4 mg once daily	CAP (VCTE): Significant improvement at 24 and 52 weeks (p < 0.001 both) with a 14% reduction (p < 0.001). LSM (VCTE): Significant improvement at 24 and 52 weeks (p < 0.001 both) with a 17% and 22% reduction in F4 fibrosis (p < 0.001).	Body weight: Nonsignificant increase at 24 and 52 weeks. Cholesterol: −16.5% reduction at 24 weeks, −24.1% at 52 weeks (p < 0.001 for both). Triglycerides: −29.6% reduction at 24 weeks, −40.6% at 52 weeks (p < 0.001 for both). LDL-C: −15.9% reduction at 24 weeks, −25.6% at 52 weeks (p < 0.001 for both).
Lanifibranor [46]	247 patients with noncirrhotic (<stage F4) highly active NASH and with (n = 103) and without T2DM	24 weeks	Placebo vs. Lanifibranor 800 mg vs. Lanifibranor 1200 mg daily	SAF-A score decrease ≥2 points without worsening fibrosis: Significantly higher in Lanifibranor 1200 mg group vs. placebo (55% vs. 33%; RR 1.7; 95% CI 1.2–2.3; p = 0.007); not significant in Lanifibranor 800 mg group vs. placebo (48% vs. 33%; RR 1.5; 95% CI 1.0–2.1; p = 0.07). Improvement in fibrosis stage ≥1 with no worsening of NASH: Higher in Lanifibranor 1200 mg (48%; RR 1.68; 95% CI 1.15–2.46) vs. placebo (29%); not significant in Lanifibranor 800 mg (38%; RR 1.15; 95% CI 0.72–1.85). NASH resolution: Greater in Lanifibranor 1200 mg (49%; RR 2.20; 95% CI 1.49–3.26) and Lanifibranor 800 mg (RR 1.70; 95% CI 1.07–2.71). NASH resolution with fibrosis stage ≥1 improvement: Greater in Lanifibranor 1200 mg (35%; RR 3.95; 95% CI 2.03–7.66) and Lanifibranor 800 mg (25%; RR 2.57; 95% CI 1.20–5.51).	FPG (mmol/l): Lanifibranor 1200 mg (−0.60) vs. 800 mg (−0.78) vs. placebo (0.24) HbA1c (%): Lanifibranor 1200 mg (−0.41%) vs. 800 mg (−0.38%) vs. placebo (0.11%) HOMA-IR: Lanifibranor 1200 mg (−5.46) vs. 800 mg (−5.79) vs. placebo (−1.47) Adiponectin (ug/mL): Lanifibranor 1200 mg (17.12) vs. 800 mg (11.95) vs. placebo (−0.35)
SGLT2 Inhibitors
Dapagliflozin [52]	57 patients with T2DM and NAFLD	24 weeks	Dapagliflozin 5 mg/day	LSM was positively correlated with markers of liver fibrosis including decrease in CAP from 314 ± 61 to 290 ± 73 dB/m (p = 0.0424). LSM also decreased significantly from 14.7 ± 5.7 to 11.0 ± 7.3 kPa (p = 0.0158).	Alanine aminotransferase, gamma-glutalytranspeptidase, and visceral fat mass also decreased in the experimental group
Dapagliflozin [53]	32 patients with T2DM with A1c 6.5–10.5 and >3 months stable of metformin, dipeptidyl peptidase 4 inhibitor, or their combination	8 weeks	Dapagliflozin 10 mg or placebo daily for 8 weeks	Significant placebo-corrected decrease in liver PDFF (−3.74%, p < 0.01), liver volume (−0.10 L, p < 0.05) Tissue specific insulin stimulated glucose uptake was unchanged in the liver.	Significant reductions were also seen in visceral adipose tissue volume (−0.35 L, p < 0.01), IL-6 (−1.87 pg/mL, p < 0.05), and N-terminal prohormone of BNP (−96 ng/L, p = 0.03).
Dapagliflozin and N-3 carboxylic acids [54]	84 participants with T2DM and NAFLD	12 weeks	Dapagliflozin 10 mg vs. OM-3CA 4 g vs. combination of both vs. placebo	All treatments reduced liver PDFF: OM-3CA −15%; dapagliflozin −13%; OM-3CA + dapagliflozin −21%. Combination therapy reduced liver PDFF (p = 0.046). Total liver fat was reduced by −24%, p = 0.037.	Dapagliflozin monotherapy and combination therapy with OM-3CA showed improvements with glucose control, reduction in body weight, and abdominal fat.
Dapagliflozin plus saxagliptin add on to Metformin [55]	82 patients with T2DM (HbA1c 7.5–10.5%) on >1500 mg/day	52 weeks	Dapagliflozin 10 mg/day plus saxagliptin 5 mg/day vs. titrated glimepiride 1–6 mg	>30% reduction in liver fat by MRI-PDFF from baseline (p = 0.007) was seen with dapagliflozin plus saxagliptin plus metformin at week 52	>10% reduction in adipose tissue volumes (p < 0.01), as well as reduction in body weight, serum ALT and ALT with dapagliflozin plus saxagliptin plus metformin at 52 weeks
Combined exenatide (EXE) and dapagliflozin (DAPA) [57]	30 patients age 18–75 with BMI > 25 kg/m2 and metformin > 1000 mg	24 weeks	Weekly EXE and daily DAPA versus weekly placebo and daily DAPA	HCLs reduced by −35.6% in EXE-DAPA group and −32.5% in PLAC + DAPA group. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) mean differences: −0.66 (CI −1.02 to 0.82) and −0.10 (−2.53 to 1.21), respectively.	Subcutaneous and visceral adipose tissue were reduced in both treatment groups. HbA1c and fasting glucose were reduced in the EXE + DAPA group. Body weight was reduced in both therapy groups.
Dapagliflozin (DAPA) plus saxagliptin (SAXA) vs. glimepiride (GLIM) [56]	338 patients with T2DM on background metformin (MET)therapy	156 weeks	DAPA + SAXA 10/5 mg plus placebo versus GLIM (1–6 mg) plus placebo once daily	DAPA + SAXA + MET reduced baseline liver fat, VAT by −4.89%, −0.41 L, and SAT by −0.44 L compared to GLIM + MET at week 122.	VAT and SAT reduced with DAPA + SAXA + MET at week 122. Therapeutic glycemic control was achieved by 21.4% of DAPA + SAXA + MET versus 11.7% of GLIM + MET at week 156.
Empagliflozin [58]	50 patients with T2DM (HbA1c 7.0–10.0%) and NAFLD by MRI-PDFF > 6%)	20 weeks	Empagliflozin 10 mg daily + standard T2DM treatment vs. standard treatment only	Liver fat by MRI-PDFF: significant reduction in empagliflozin group compared to control (mean difference –4.0%, p < 0.0001) and compared to baseline (16.2% to 11.3%, p < 0.0001)	FPG: both groups had significant decrease from baseline (p < 0.0001 for both), no significant between groups HbA1c: both groups had significant decrease from baseline (p < 0.0001), no significant between groups
Empagliflozin [60]	84 patients with T2DM (HbA1c 6.0–8.0%) not on current antihyperglycemic management with (79%) and without NAFLD by MRS	24 weeks	Empagliflozin 25 mg daily vs. placebo	LFC (MRS): significant reduction in empagliflozin group compared to placebo (placebo-corrected absolute reduction –1.8%, p = 0.02; placebo-corrected relative reduction –22%, p = 0.009)	Weight loss: empagliflozin group had placebo-corrected reduction (−2.5 kg, p < 0.001) Tissue-specific insulin sensitivity: no placebo-corrected change in skeletal muscle and hepatic insulin sensitivity FPG: significant placebo-corrected reduction in empagliflozin group (p = 0.01) HbA1c: no significant placebo-corrected change
Empagliflozin [59]	9 patients with T2DM and biopsy-proven NASH	24 weeks	Empagliflozin 25 mg daily (single arm)	Liver fat fraction (MRI): significant median reduction (−7.8%; p = 0.017). Steatosis grade: significant median reduction (p = 0.014). Ballooning grade: significant median reduction (p = 0.034). Inflammation grade: nonsignificant trend toward reduction (p = 0.157). Fibrosis stage: significant median reduction (p = 0.046). NASH resolution without worsening fibrosis: 44% of patients. Progression to cirrhosis: none.	FPG: significant median reduction from baseline (p = 0.008) HbA1c: no significant median reduction from baseline
Empagliflozin [61]	56 patients with T2DM (HbA1c 7–10%) with (96%) or without NAFLD by imaging	12 weeks	Empagliflozin 10 mg daily vs. placebo	Liver fat content by MRS: significant reduction in empagliflozin group compared to placebo (27% vs. 2%, p = 0.0005). Significant reduction from baseline in empagliflozin group only (p < 0.0001)	VAT: significant reduction from baseline in empagliflozin group (p = 0.04) and compared to placebo (p = 0.04) SAT: significant reduction from baseline in empagliflozin group (p < 0.001), but not compared to placebo Epicardial fat volume, myocardial fat content and pancreatic fat content: no significant change from baseline in either group and no difference between groups Weight loss: significant reduction in empagliflozin group compared to placebo (p = 0.0047) and compared to baseline (p < 0.0001) FPG: significant reduction in empagliflozin group compared to placebo (p = 0.0063) HbA1c: significant reduction compared to placebo (p = 0.0033)
Empagliflozin [62]	106 patients with T2DM (HbA1c 7–10%) and NAFLD by CAP ≥ 238 dB/m	24 weeks	Empagliflozin 10 mg daily vs. pioglitazone 30 mg daily vs. placebo	LFC (CAP): Empagliflozin showed borderline significant improvement vs. placebo (mean difference: −29.6 dB/m vs. −16.4 dB/m, p = 0.05); pioglitazone did not (p = 0.08). LSM (VCTE): Empagliflozin significantly reduced LSM (−0.77 kPa, p = 0.02); pioglitazone did not (0.01 kPa, p = 0.98); between groups p = 0.03. NAFLD fibrosis score, FIB-4 index: No significant changes	HbA1c: Significant decrease in empagliflozin (p = 0.001) and pioglitazone (p < 0.001); greater decrease in pioglitazone vs. empagliflozin (p = 0.01). FPG: Significant decrease in pioglitazone group (p < 0.001). Fasting insulin: Significant decrease in pioglitazone group (p = 0.008). HOMA-IR: Significant decrease in pioglitazone group (p < 0.001). HOMA2-IR: Significant decrease in pioglitazone group (p < 0.001). Body weight: Significant reduction in empagliflozin group (p < 0.001); significant increase in pioglitazone group (p = 0.007). VAT: Significant increase in pioglitazone (p = 0.006) and placebo (p = 0.005); significant difference in empagliflozin vs. pioglitazone (p = 0.01).
Empagliflozin and pioglitazone [63]	60 patients with T2DM (HbA1c 7.0–10.0%) and NAFLD (≥F1 on VCTE with CAP > 238)	24 weeks	Metformin + empagliflozin 10 mg daily vs. metformin + pioglitazone 30 mg daily	NAFLD grade (US): Significant reduction in both groups (p < 0.001), no significant difference between groups (p = 0.34). Liver fibrosis grade (VCTE): Significant reduction in both groups (p < 0.001), no significant difference between groups (p = 0.48). LSM (kPa): Significant reduction in both groups (p < 0.001), no significant difference between groups (p = 0.14).	HbA1c: Significant reduction in both groups (p < 0.001), no significant difference between groups. FPG: Significant reduction in both groups (p < 0.001), no significant difference between groups. Weight: Significant reduction in empagliflozin group (p < 0.001); significant increase in pioglitazone group (p = 0.01); significant difference between groups (p < 0.001).
Canagliflozin [64]	56 patients with T2DM (HbA1c 7.0–9.5%) with (n = 37) and without NALFD	24 weeks	Canagliflozin 300 mg once daily vs. placebo	Intrahepatic triglyceride content (IHTG): Significant reduction from baseline in canagliflozin group (−4.6%, p = 0.05); greater but not statistically significant reduction compared to placebo (−38% vs. −20%, p = 0.09). For baseline IHTG ≥10%, reduction was greater in canagliflozin group (−39% vs. −20%, p = 0.08). Relative decrease in IHTG correlated significantly with body weight % decrease (r = 0.58, p < 0.001); for NAFLD patients (r = 0.69, p < 0.001). Weight loss ≥5% with ≥30% relative reduction in IHTG was significantly greater in canagliflozin group (38%) vs. placebo (7%), p = 0.009. Hepatic insulin sensitivity: Significant improvement in canagliflozin compared with placebo (p < 0.01).	Body weight: Significant reduction in canagliflozin group (−5.5%) vs. placebo (−2.1%), p = 0.001. FPG: Significant reduction in canagliflozin group (−26) vs. placebo (4), p = 0.002. HbA1c: Significant reduction in canagliflozin group (−0.7%) vs. placebo (0.1%), p < 0.001. Fasting plasma insulin: Significant reduction in canagliflozin group (−4) vs. placebo (0.1), p < 0.001. Fasting FFA: Significant increase in canagliflozin group (0.07) vs. placebo (−0.04), p = 0.04. Insulin secretion rate: Significant increase in canagliflozin vs. placebo, p = 0.005. Beta-cell glucose sensitivity: Significant increase in canagliflozin vs. placebo, p = 0.04. Insulin clearance: Significant increase in canagliflozin vs. placebo, p < 0.001.
Meta-analysis of SGLT2i [71]	10 studies (n = 555), patients with T2DM and NAFLD	24 weeks to 3+ years	SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin) vs. TZD/incretins/metformin/non-SGLT2i	Hepatic fat content: MRI-PDFF: Significant reduction with SGLT2i (SMD: −0.789, CI: −1.404 to −0.175, p = 0.012) vs. control (standardized mean difference (SMD): −0.923, CI: −1.562 to −0.285, p = 0.005) L/S attenuation ratio (CT): Significant improvement with SGLT2i (SMD: 0.456, CI: 0.142 to 0.771, p = 0.004) vs. insulin (SMD: 0.614, CI: 0.116 to 1.112, p = 0.016) or metformin (SMD: 1.957, CI: 1.105 to 2.809, p < 0.001) CAP scores: Significant reduction with SGLT2i (SMD: −1.376, CI: −2.540 to −0.213, p = 0.02) vs. control FIB-4, liver stiffness (transient elastography), NAFLD fibrosis score: Nonsignificant change. NAFIC score: Significant reduction from baseline (SMD: −0.569, CI: −1.062 to −0.077, p = 0.023).	Weight: Significant reduction with SGLT2i vs. control (SMD: −2.317, CI: −3.576 to −1.057, p < 0.001), TZD (SMD: −4.817, CI: −9.201 to −0.433, p = 0.031), incretins (SMD: −0.589, CI: −0.986 to −0.192, p = 0.004), and insulin therapies (SMD: −2.074, CI: −2.681 to −1.468, p < 0.001). BMI: Significant reduction with SGLT2i vs. control (SMD: −1.092, CI: −2.032 to −0.153, p = 0.023) and vs. metformin (SMD: −1.120, CI: −1.869 to −0.371, p = 0.003). VAT: Significant reduction with SGLT2i vs. control (SMD: −2.247, CI: −3.586 to −0.907, p = 0.001), vs. insulin therapies (SMD: −1.179, CI: −1.707 to −0.651, p < 0.001), and vs. metformin (SMD: −1.145, CI: −1.896 to −0.394, p = 0.003). SAT: Significant reduction with SGLT2i vs. TZDs (SMD: −6.347, CI: −7.547 to −5.146, p < 0.001). FPG: Significant reduction with SGLT2i vs. incretins (SMD: −0.841, CI: −1.321 to −0.360, p = 0.001). HbA1c: Significant reduction with SGLT2i vs. metformin (SMD: −0.825, CI: −1.548 to −0.101, p = 0.026). Triglycerides: Significant reduction with SGLT2i vs. control (SMD: −0.336, CI: −0.597 to −0.076, p = 0.011). Total cholesterol: Significant reduction with SGLT2i vs. TZD (SMD: −1.545, CI: −2.096 to −0.993, p < 0.001). HDL: Significantly higher with SGLT2i vs. insulin (SMD: 0.861, CI: 0.352 to 1.370, p = 0.001). Fasting insulin, HOMA-IR, CPR, adipo-IR, CPR index, HOMA-B, LDL: Non-significant compared to other glucose-lowering agents. Adiponectin: Increase with SGLT2i treatment (SMD: 0.301, CI: 0.005 to 0.596, p = 0.046); no differences compared to incretins or insulin.
Meta-analysis of SGLT2i [72]	9 studies (n = 11,369 patients with T2DM and NAFLD)	12 to 28 weeks	SGLT2i vs. control arm (agent not documented to influence hepatic outcomes)	Liver fat (MRI-PDFF): significant reduction with SGLT2i (SDM, −0.98, 95% CI, −1.53 to −0.44, p < 0.01)	HbA1c: significant change from baseline with SGLT2i vs. control (SDM, −0.37, 95% CI, −0.60 to −0.14, p <0.01) Weight: significant change from baseline with SGLT2i (SDM, −0.58, 95% CI, −0.93 to −0.23, p < 0.01)
Meta-analysis of SGLT2i [73]	20 studies (n = 3850 patients with T2DM and with or without NAFLD)	8 weeks to 52 weeks	SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin) vs. control	Hepatic steatosis (MRI-PDFF): significant improvement with SGLT2i vs. placebo (−3.39% [ 6.01, 0.77], p < 0.0.1, I2 = 89%)	Significantly lower HbA1c, triglyceride levels in SGLT2i compared to control Significantly greater HDL with SGLT2i compared to control No significant difference in LDL, total cholesterol
Meta-analysis of SGLT2i [74]	10 studies (n = 573 patients with T2DM and NAFLD)	12 weeks to 52 weeks	SGLT2i (empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin) vs. control (metformin, pioglitazone, sitagliptin, glimepiride)	FIB-4: significant reduction with SGLT2i compared to controls (weighted mean difference (WMD) −0.06 [95% CI: −0.10, −0.02], p = 0.0010). No heterogeneity (p = 0.88, I2 = 0%) Hepatic steatosis (MRI-PDFF): significant reduction with SGLT2i compared to controls (WMD −2.20 [95% CI: −3.67, −0.74], p = 0.003). No heterogeneity (p = 0.44, I2 = 0%)	HbA1c: nonsignificant reduction with SGLT2i compared to controls FPG: nonsignificant reduction with SGLT2i compared to controls HOMA-IR: no significant reduction with SGLT2i compared with controls VFA: significant reduction with SGLT2i vs. controls (WMD −23.83 [95% CI: −28.72, −18.95], p < 0.00001). Significant heterogeneity (p < 0.0001, I2 = 82%) SFA: significant reduction with SGLT2i vs. control (WMD −14.68 [95% CI: −26.96, −2.40], p = 0.02). Significant heterogeneity (p < 0.00001, I2 = 95%) Body weight: significant reduction with SGLT2i vs. controls (WMD −3.02 [95% CI: −4.57, −1.47], p = 0.0001). Significant heterogeneity (p < 0.00001, I2 = 98%)
Meta-analysis of SGLT2i [75]	16 studies (patients with T2DM and NAFLD)	12 weeks to 48 weeks	SGLT2i (empagliflozin, dapagliflozin, ipragliflozin, tofogliflozin) vs. control (standard treatment, placebo, pioglitazone, glimepiride, teneligliptin, metformin + pioglitazone)	LSM: significant reduction with SGLT2i compared to control (SMD = 0.50, 95% CI [0.99, 0.01], p = 0.002) CAP: significant reduction with SGLT2i compared to control (SMD = 0.74, 95% CI [1.21, 0.27], p = 0.005) FIB-4 index: significant reduction with SGLT2i compared to control (SMD = 0.37, 95% CI [0. 74, 0.01], p = 0.03)	Triglycerides: significant reduction with SGLT2i (SMD = 0.81, 95% CI [1.49, 0.12], p < 0.00001) HOMA-IR: significant reduction with SGLT2i (SMD = 0.70, 95% CI [1.36, 0.04], p < 0.00001) BMI: significant reduction with SGLT2i compared to control (SMD = 1.42, 95% CI [2.21, 0.62], p < 0.00001) VAT area: significant reduction with SGLT2i compared to control (SMD = 2.90, 95% CI [4.65, 1.16], p < 0.00001)
Meta-analysis: SGLT2i vs. TZD [76]	5 studies (n = 311 patients with NAFLD and with or without T2DM)	24 weeks to 28 weeks	SGLT2i (dapagliflozin, empagliflozin, ipragliflozin, tofogliflozin) vs. TZD	LSM: no significant difference in degree of reduction in SGLT2i vs. TZD (n = 2 RCTs; pooled WMD: 0.17 kPa, 95% CI 0.75 to 1.08 kPa; I2 = 71%, p = 0.72) L/S ratio: no significant difference in degree of reduction in SGLT2i vs. TZD (n = 2 RCTs; pooled WMD: −0.01; 95%CI −0.04 to 0.03; I2 = 11%, p = 0.72)	Body weight: significant reduction in SGLT2i vs. TZD (n = 4 RCTs; pooled WMD: 4.22 kg, 95% CI 2.47 to 5.98 kg; I2 = 83%, p < 0.00001) HbA1c, FPG, HOMA-IR: decrease from baseline in both TZD and SGLT2i but no significant difference between groups LDL, total cholesterol, triglycerides: no significant difference between TZD and SGLT2i
DPP-4 Inhibitors
Sitagliptin [77]	50 patients with pre-diabetes or controlled T2DM (HbA1c 5.7–8.0%) and NAFLD ( ≥ 5% on MRI-PDFF)	24 weeks	Sitagliptin po 100 mg daily vs. placebo	Liver fat (MRI-PDFF): No significant difference between sitagliptin and placebo group (mean difference −1.3%, p = 0.4096) or compared to baseline in each group MRE for hepatic fibrosis: no significant difference between groups (mean difference –0.2, p = 0.2631) or compared to baseline in each group FIBROSpect for hepatic fibrosis: no significant difference between groups (p = 0.3057); significant increase from baseline in score (p = 0.0306) in control only	HOMA-IR: no significant difference between groups (difference 0.8; p = 0.5560) LDL: no significant difference between groups (difference 0.0; p = 0.7984)
Sitagliptin [78]	12 patients with T2DM (HbA1c 7.1–8.9%) and biopsy-confirmed NASH	24 weeks	Sitagliptin po 100 mg daily vs. placebo	Liver fibrosis: no significant difference between groups (mean difference 0.40, 95% CI −0.98 to 1.78, p = 0.82) NAS: no significant difference between groups (mean difference 0.2, p = 1.00); steatosis (mean difference 0, p = 0.91); hepatocyte ballooning (mean difference 0.40, p = 0.23); lobular inflammation (mean difference 0.60, p = 0.12). Hepatic fat % by MRI IDEAL technique: no significant difference between groups	HbA1c: no significant difference between groups (mean difference –0.7, p = 0.19) Adiponectin: nonsignificant trend toward improvement (p = 0.06)

Abbreviations: ALT (Alanine Aminotransferase), BMI (Body Mass Index), CAP (Controlled Attenuation Parameter), CI (Confidence Interval), CRP (C-Reactive Protein), DPP-4 (Dipeptidyl Peptidase-4), ETR (Estimated Treatment Ratios), FIB-4 (Fibrosis-4 Index), FPG (Fasting Plasma Glucose), GLIM (Glimepiride), HbA1c (Hemoglobin A1c), HDL (High-Density Lipoprotein), HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), IGT (Impaired Glucose Tolerance), IL-6 (Interleukin 6), LDL (Low-Density Lipoprotein), LFC (Liver Fat Content), LSM (Liver Stiffness Measurement), MRE (Magnetic Resonance Elastography), MRI-PDFF (Magnetic Resonance Imaging—Proton Density Fat Fraction), NAS (Non-Alcoholic Fatty Liver Disease Activity Score), NAFLD (Non-Alcoholic Fatty Liver Disease), NASH (Non-Alcoholic Steatohepatitis), OR (Odds Ratio), PPAR (Peroxisome Proliferator-Activated Receptor), QUICKI (Quantitative Insulin Sensitivity Check Index), RCTs (Randomized Controlled Trials), SAF-A (Steatosis, Activity, Fibrosis Algorithm), SAT (Subcutaneous Adipose Tissue), SFA (Subcutaneous Fat Area), SGLT2i (Sodium-Glucose Co-Transporter 2 Inhibitors), T2DM (Type 2 Diabetes Mellitus), TG (Triglycerides), TZD (Thiazolidinediones), VAT (Visceral Adipose Tissue), VCTE (Vibration-Controlled Transient Elastography), and VLDL (Very Low-Density Lipoprotein).

).

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. Drugs promoting weight loss with or without glucose lowering.

Study (year)	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
Orlistat
Orlistat [105]	50 patients with (n = 4) and without diabetes and NASH diagnosis	36 weeks	Orlistat 120 mg TID + vitamin E 800 IU daily vs. vitamin E 800 IU daily	NAFLD activity score: no significant difference between groups Fibrosis score: no significant difference between groups	FPG, insulin, quantitative insulin sensitivity check index (QUICKI): no significant difference from baseline in either group or between groups Adiponectin: significant increase in orlistat (p = 0.04); no significant difference between groups Body weight: significant loss in orlistat (8.3%, p < 0.001) and control (6.0%, p = 0.01); no significant difference between groups
GLP-1 Receptor Agonists
Semaglutide [81]	320 patients with (62%) and without T2DM with biopsy-confirmed NASH and fibrosis (stage F1, F2, or F3)	72 weeks	Semaglutide 0.1 mg, 0.2 mg, or 0.4 mg once daily subcutaneous injection vs. placebo	NASH resolution without worsening of fibrosis: significantly higher in semaglutide 0.4 mg group (59% vs. 17% placebo; OR 6.87 [95% CI 2.60 to 17.63], p < 0.001). Improvement of at least one fibrosis stage without worsening of NASH: no significant difference between semaglutide 0.4 mg and placebo (43% vs. 33%; OR 1.42 [95% CI 0.62 to 3.28], p = 0.48).	Body weight: semaglutide 0.4 mg group (mean percent loss −12.51% in 0.4 mg group) vs. placebo (–0.61%) HbA1c (mean % change): semaglutide 0.4 mg group (−1.15%) vs. placebo (–0.01%)
Semaglutide [83]	67 patients with (73%) or without T2DM and NAFLD (MRI-PDFF ≥10)	72 weeks	Semaglutide once daily subcutaneous injection 0.4 mg vs. placebo	Significant reduction in liver steatosis by MRI-PDFF (estimated treatment ratios (ETR): 24 weeks, 0.70 [95% CI 0.59, 0.84], p = 0.0002; 48 weeks 0.47 [95% CI 0.36, 0.60], p < 0.0001; and 72 weeks 0.50 [95% CI 0.39, 0.66], p < 0.0001) No significant difference in liver stiffness by MRE (24 weeks ETR 1.02 (0.95, 1.10); p = 0.5406, 48 weeks ETR 0.96 (0.89, 1.03); p = 0.2798, 72 weeks ETR 0.96 (0.89, 1.03); p = 0.2437) Significant difference in reduction in ≥30% of liver steatosis in the semaglutide group compared to placebo (week 24 64.7 vs. 21.2; p = 0.0006; week 48 76.5 vs. 30.3; p = 0.0001; week 72 73.5 vs. 33.3; p = 0.0006)	Semaglutide group: significant reduction in body weight (at week 72 ETD –9.68%, p < 0.0001)
Semaglutide [84]	71 patients with (75%) and without T2DM and biopsy-confirmed NASH-related cirrhosis	48 weeks	Semaglutide 2.4 mg once weekly subcutaneous injection vs. placebo	Liver fibrosis improvement (≥1 stage) without worsening of NASH: no significant difference between semaglutide and placebo (11% vs. 29%, OR 0.28; 95% CI 0.06–1.24; p = 0.087) NASH resolution: no significant difference (34% vs. 21%; OR 1.97 [95% CI 0.56–7.91]; p = 0.29) Liver stiffness (MRE): no significant difference (ETR 0.93 [95% CI 0.80–1.07]; p = 0.30) Liver steatosis (MRI-PDFF): significant improvement with semaglutide (ETR 0.67; p = 0.0042) 30% reduction in steatosis: significantly greater in semaglutide group (49% vs. 13%, OR 6.58; p = 0.0037) NAS: no significant difference	Body weight: Significant reduction from baseline in body weight in semaglutide group compared to placebo (−8.83% vs. −0.09%) with significant difference between the two (ETD: –8.75; p < 0.0001) HbA1c (in T2DM): significant reduction in semaglutide group compared to placebo group (ETD: −1.63, p < 0.0001)
Liraglutide [85]	26 patients with (65%) and without T2DM and NASH	48 weeks	Liraglutide 1.8 mg once daily subcutaneous injection vs. placebo	NASH resolution without worsening of fibrosis: significantly greater in the liraglutide group (39% vs. 9%, RR 4.3 [95% CI 1.0–17.7], p = 0.019); similar outcomes in T2DM (38%) and non-T2DM patients (40%) Worsening liver fibrosis: fewer cases in the liraglutide group (9% vs. 36%; RR 0.2 [95% CI 0.1–1.0], p = 0.04) Total NAFLD activity score: no significant changes (RR −0.5 [95% CI −1.3 to 0.3], p = 0.24)	HbA1c: significant improvement in liraglutide group (mean change −5.18 [95% CI −9.91 to −0.44], p = 0.03) Weight reduction: significant in liraglutide group (mean change −4.24 [95% CI −6.9 to −1.53], p = 0.003) BMI: significant decrease in liraglutide group (mean change −1.59 [95% CI −2.66 to −0.51], p = 0.005) HOMA-IR, ADIPO-IR, insulin, waist circumference: no significant improvement (HOMA-IR, p = 0.23; ADIPO-IR, p = 0.15; insulin, p = 0.91; waist circumference, p = 0.29)
Liraglutide [86]	27 patients with T2DM and biopsy-proven NAFLD/NASH; 19 patients in liraglutide group	24 weeks, 96 weeks	Liraglutide 0.9 mg daily vs. lifestyle modification	Liraglutide group had significantly greater reductions in AST (p < 0.01), ALT (p < 0.01), and L/S ratio (p < 0.01). In the group that continued therapy for 96 weeks, 7/10 patients had improvement histologic inflammation, 6/10 had improvement in liver fibrosis, and 8/10 had improved NAS.	Significant reduction in BMI (p < 0.001), visceral fat accumulation (p < 0.05), HbA1c (p < 0.001), FPG (p < 0.001) No significant difference in total cholesterol, triglycerides, HDL, LDL, insulin, HOMA-IR, QUICKI, platelet count, ferritin, or FIB-4 index
Liraglutide [87]	35 patients with T2DM	12 weeks	Liraglutide 1.8 mg daily vs. insulin glargine	Liver fat content (MRS): nonsignificant reduction from baseline in insulin glargine group only (12.6% to 9.9%; p = 0.06), no significant difference between groups Liver fat content (MRI-PDFF): significant reduction from baseline in insulin glargine group only (13.8% to 10.6%; p = 0.005); no significant difference between groups Liver volume: significant reduction in insulin glargine group (p = 0.01); no significant difference between groups.	HbA1c: significant reduction from baseline in insulin glargine group (p = 0.001) and liraglutide group (p < 0.001); however no significant difference between groups FPG: significant improvement in insulin glargine group (p = 0.001) and liraglutide group (p < 0.001) Weight: significant reduction from baseline in liraglutide group only (p = 0.005); liraglutide had significantly greater changes from baseline compared to insulin glargine (p = 0.03)
Liraglutide [88]	52 patients with T2DM (HbA1c 7.5–9%) with (n = 46) and without NAFLD	12 weeks	Liraglutide 1.8 mg daily vs. sitagliptin 100 mg daily vs. placebo	Hepatic fat content (MRS): no significant difference between liraglutide and placebo (−10% vs. −9.5%; p = 0.98) or sitagliptin and placebo (−12.1% vs. −9.5%; p = 0.98) NAFLD fibrosis score: no significant difference in both liraglutide and sitagliptin when compared with placebo FIB-4 score: no significant difference with liraglutide or sitagliptin compared to placebo.	HbA1c: significant reduction in both liraglutide and sitagliptin groups when compared to placebo (p < 0.001 both) FPG: significant reduction in both liraglutide and sitagliptin groups when compared to placebo (p < 0.001 both) Weight: nonsignificant reduction in liraglutide group compared to placebo (p = 0.06)
Liraglutide [89]	68 patients with uncontrolled T2DM with (n = 57) NAFLD (LFC ≥ 5.5%) and without NAFLD	6 months	Liraglutide 1.2 mg daily	Liver fat content (proton spectroscopy): significant reduction from baseline (17.3% to 11.9%; p < 0.0001) Patients with NAFLD at baseline: significant reduction from baseline (20.1% to 13.5%, p < 0.0001); relative reduction of 33% Multivariate analysis: LFC reduction significantly associated with body weight (p < 0.0001), NAFLD at baseline (p = 0.009), reduction in plasma TG level (p = 0.003), and reduction in HbA1c (p = 0.048).	Visceral fat area (VFA) (MRI): significant reduction from baseline (p = 0.005). Subcutaneous fat area (SFA) (MRI): significant reduction from baseline (p = 0.009). HbA1c: significant reduction from baseline (p < 0.0001). Adiponectin: significant increase from baseline (p < 0.0001). Body weight: significant reduction from baseline (p < 0.0001); significant correlation between body weight and reduction in LFC (r = 0.490; p < 0.0001).
Liraglutide [90]	75 patients with T2DM (HbA1c 6.5–10%) inadequately controlled on metformin and NAFLD (MRI-PDFF > 10%)	26 weeks	Add-on to metformin with subcutaneous liraglutide 1.8 mg daily vs. sitagliptin 100 mg daily vs. insulin glargine	Intrahepatic lipid content change (by MRI-PDFF): significant reduction from baseline in both liraglutide (−2.9%, p < 0.001) and sitagliptin (−3.8%, p = 0.001) only; no significant difference between liraglutide and sitagliptin groups. Significantly greater reduction in liraglutide compared to insulin glargine (p = 0.039) and sitagliptin compared to insulin glargine (p = 0.043); remained significant after adjusting for changes in weight	VAT: significant reduction from baseline in liraglutide (p = 0.003) and sitagliptin (p = 0.027); greater change in liraglutide compared to insulin glargine (p = 0.020). SAT: significant decrease from baseline in liraglutide (p = 0.020); greater change in liraglutide compared to insulin glargine (p = 0.003). HbA1c: significant reduction from baseline in all groups; no significant difference between groups. FPG: significant reduction from baseline in liraglutide only (p = 0.001); no significant difference between groups. PPG: significant reduction from baseline in liraglutide (p = 0.001) and sitagliptin (p = 0.005); greater change in liraglutide (p = 0.005) and sitagliptin (p = 0.029) compared to insulin glargine. Weight: significant reduction from baseline in liraglutide (p = 0.005) and sitagliptin (p = 0.005); greater change in liraglutide compared to insulin glargine.
Liraglutide [91]	96 patients with T2DM uncontrolled on metformin and NAFLD	26 weeks	Insulin glargine vs. liraglutide 1.8 mg daily vs. placebo	Intrahepatic content of lipid (MRS): significant reduction from baseline in the liraglutide group (p < 0.05) and compared to placebo (p < 0.05); no significant difference in change compared to insulin group	SAT: significant reduction from baseline in liraglutide group (p < 0.05) and compared to placebo (p < 0.05); significant reduction from baseline in insulin group (p < 0.05) but not compared to placebo; greater change in liraglutide group compared to insulin (p < 0.05) and in insulin group compared to placebo (p < 0.05). VAT: significant reduction from baseline in liraglutide group (p < 0.05) and compared to placebo (p < 0.05); significant reduction from baseline in insulin group (p < 0.05) but not compared to placebo; greater change in liraglutide group compared to insulin (p < 0.05) and in insulin group compared to placebo (p < 0.05). HbA1c: significant reduction from baseline in all groups (p < 0.05 all); no significant difference in change between groups. HOMA-IR: significant reduction from baseline in liraglutide group (p < 0.05); greater improvement compared to insulin or placebo (p < 0.05 for both). Body weight: significant reduction from baseline in liraglutide group only (p < 0.05); greater change compared to insulin and placebo groups (p < 0.05 for both).
Liraglutide [92]	Pre-specified sub-analysis from MAGNA VICTORIA study 49 patients with T2DM (HbA1c 7.0–10.0%)	26 weeks	Liraglutide 1.8 mg daily vs. placebo	Hepatic triacylglycerol content (MRS): no significant difference between liraglutide and placebo (estimated treatment effect: −2.1%, p = 0.17) AST: no significant difference between liraglutide and placebo ALT: no significant difference between liraglutide and placebo	SAT: significant reduction in liraglutide group compared to placebo (estimated treatment effect: −29; p = 0.007) VAT: no significant difference between liraglutide and placebo Epicardial fat, myocardial triacylglycerol content, HbA1c: no significant difference between liraglutide and placebo Body weight (kg): significant reduction in liraglutide group compared with placebo (estimated treatment effect: −4.5 kg; p < 0.001)
Meta-analysis of liraglutide [94]	11 RCTs	12 weeks to 24 months	Liraglutide vs. placebo/pioglitazone/insulin/metformin	Liver fat: decreased compared to pioglitazone group (1 trial, n = 60 patients; MD −2.50; 95% CI −4.30 to −0.70; p = 0.006) AST, ALT: no improvement compared to placebo, pioglitazone, metformin, insulin	BMI: decreased compared to placebo, pioglitazone, metformin, insulin Total cholesterol: decreased compared to placebo, metformin Triglycerides: decreased compared to placebo, insulin Lipoproteins: decreased compared to insulin HbA1c: decreased compared to placebo, insulin
Dulaglutide [95]	64 patients with poorly controlled T2DM (HbA1c >7.0%) and MRI-PDFF based LFC ≥6.0%	24 weeks	Dulaglutide subcutaneous injection 1.5 mg once weekly vs. usual care	LFC: significant reduction in the dulaglutide group (mean difference −26.4%; 95% CI −44.2 to −8.6; p = 0.004). Significant reduction from baseline in dulaglutide group only (17.9% to 12.0%, p < 0.0001) LSM (VCTE): no significant difference between groups. Significant reduction from baseline in dulaglutide group (10.8 kPa to 9.3 kPa, p = 0.016)	Pancreatic fat content: no significant difference between groups. Significant reduction from baseline in dulaglutide group only (9.3% to 7.2%, p = 0.006) Body weight: significant reduction in dulaglutide group compared to placebo (mean difference −2.3 kg; 95% CI −4.1, −0.6; p = 0.01). Significant reduction from baseline in both groups (p < 0.0001) FPG: significant reduction from baseline in both groups (p < 0.0001), no significant difference between groups HbA1c: significant reduction from baseline in both groups (p < 0.0001), no significant difference between groups
Exenatide [96]	21 patients with T2DM on diet/metformin therapy	12 months	Pioglitazone monotherapy 45 mg once daily vs. pioglitazone 45 mg once daily + exenatide 10 ug subcutaneous injection twice daily	LFC (MRS): significant reduction in pioglitazone group (11.0% to 6.5%, p < 0.05) and in pioglitazone + exenatide group (12.1% to 4.7%, p < 0.001). Significant difference between groups (61% change combination group vs. 41% pioglitazone only group, p < 0.05)	Pioglitazone group: significant increase in body weight and BMI (p < 0.05), reduction in HbA1c (p < 0.01), significant reduction in FPG, fasting plasma insulin, fasting plasma FFA, and triglycerides (p < 0.05 all) Pioglitazone + exenatide group: significant reduction in HbA1c, FPG, fasting plasma FFA, and triglycerides (p < 0.01 all), significant reduction in fasting plasma insulin (p < 0.05) Significant difference between groups in triglycerides (p < 0.01) and body weight (p < 0.05) Adiponectin: significant increase in pioglitazone group (86%, p < 0.001) and combination group (193%, p < 0.001), with a significantly greater increase in combination group (p < 0.001 between groups) Body weight: significant increase in pioglitazone monotherapy (+3.7 kg, p < 0.05), no significant increase in combination therapy; significant difference between groups
Exenatide [97]	44 patients with obesity and T2DM	26 weeks	Reference therapy (oral hypoglycemics other than DPP-4 inhibitors and thiazolidinediones, with or without insulin glargine) vs. exenatide 10 ug twice daily subcutaneous injection	Hepatic triglyceride content (HTGC) (MRS): significant reduction in exenatide group (exenatide: −23.8 ± 9.5%, reference treatment: +12.5 ± 9.6%; p = 0.007) Significant association between weight and HTGC (r = 0.47, p = 0.03)	HOMA-IR, fasting plasma glucose, fasting plasma insulin: no significant difference between groups, though these trended down in the exenatide group Weight loss: significant difference in reduction in weight (exenatide: −5.3 ± 1.0% vs. reference treatment: −0.2 ± 0.8%; p = 0.0004)
Exenatide [98]	76 patients with newly diagnosed T2DM with NAFLD and LFC > 10% by MRS	24 weeks	Insulin glargine vs. exenatide 10 ug twice daily subcutaneous injection	LFC: significant reduction from baseline in both groups (exenatide, 42.21% to 24.66%, p < 0.0001 vs. insulin glargine, 35.47% to 24.98%, p < 0.0001), no difference between groups (p = 0.1248) FIB-4: significant reduction from baseline in exenatide group (0.98 ± 0.47 to 0.89 ± 0.39; p = 0.0448), but no difference in change compared to insulin group (p = 0.2149) Independent association with ΔTC (β = 6.059, p = 0.0036) and ΔBMI (β = 3.454, p = 0.0013) with ΔLFC in exenatide group; ΔTG and ΔFFA independently associated with ΔLFC in insulin group	VAT: significant reduction in exenatide group (236.94 cm2 to 193.36 cm2, p < 0.0001) SAT: significant reduction in exenatide group (302.41 cm2 to 273.97 cm2, p = 0.0006) HbA1c: significantly greater reduction in exenatide group (p = 0.0006) Body weight: significantly greater loss in exenatide group compared to insulin (mean difference: −3.75 kg, 95% CI: −5.56 to −1.94, p = 0.0001)
Tirzepatide [101]	296 patients with T2DM (HbA1c 7.0–10.5%) on treatment with metformin/SGLT2i or combination and with fatty liver index ≥ 60	52 weeks	Tirzepatide 5 mg, 10 mg, or 15 mg subcutaneous injection weekly vs. titrated insulin degludec subcutaneous injection daily	LFC (MRI-PDFF): significant reduction from baseline in pooled tirzepatide 10 mg and 15 mg and insulin degludec (p < 0.0001); greater reduction in tirzepatide (−8.09% vs. −3.38%, p < 0.0001) LFC ≤ 10%: significantly greater proportion in tirzepatide group than insulin (60–78% vs. 35%) LFC ≤ 6%: significantly greater proportion in tirzepatide 10 mg group than insulin (48% vs. 21%; p = 0.015) 30% relative decrease in LFC: significantly greater proportion in tirzepatide group than insulin (67–81% vs. 32%)	VAT: significant reduction from baseline in all tirzepatide doses (p < 0.0001), significant increase in insulin group (p = 0.040) Abdominal subcutaneous adipose tissue (ASAT): significant reduction from baseline in all tirzepatide doses (p < 0.0001), significant increase in insulin group (p = 0.0092) VAT:ASAT: significant reduction from baseline in all tirzepatide doses; significant difference between tirzepatide doses and insulin Body weight: significant reduction in all tirzepatide doses HbA1c: significant reduction from baseline in all groups (p < 0.0001); significantly greater reduction in tirzepatide groups compared to insulin (p < 0.0001)
Tirzepatide [102]	190 patients with biopsy-confirmed MASH and stage F2/F3 fibrosis	52 weeks	Tirzepatide 5 mg, 10 mg, 15 mg, or placebo	MASH resolution without worsening of fibrosis: placebo group 10%; 5 mg group 44%, p < 0.001 compared to placebo; 10 mg group 56%, p < 0.001 compared to placebo; 15 mg group 62%, p < 0.001 compared to placebo) Improvement of at least one fibrosis stage without worsening of MASH: placebo group—30%; 5 mg —55%; 10 mg group—51%; 15 mg group—51%	N/A
Cotadutide [104]	30 patients with T2DM and overweight/obesity	35 days (liver steatosis imaging endpoint)	Cotadutide vs. liraglutide vs. placebo	Hepatic steatosis (MRI-PDFF): significant absolute reduction in cotadutide vs. placebo (LS mean absolute change from baseline, −4.1% [90% CI = −6.0 to −2.3]; p = 0.002); and vs. liraglutide (LS mean absolute change from baseline, −1.8% [90% CI = −3.1 to −0.4]; p = 0.044). Relative reduction: 35.1% compared to placebo, 11.7% compared to liraglutide	Weight: no significant difference in weight loss between cotadutide (−2.50 kg (90% CI = −3.34 to −1.66) vs. liraglutide (−2.80 kg (−3.91 to −1.69); p = 0.749)
Meta-analysis (liraglutide, exenatide, dulaglutide, semaglutide) [99]	11 studies (n = 935 overweight/obese patients with NAFLD/NASH, with (72.4%) or without T2DM)	Median 26 weeks	GLP-1 RA (liraglutide, exenatide, dulaglutide, semaglutide) vs. placebo or reference therapy	Absolute % liver fat content (MRI-PDFF): significant reduction with GLP-1 RA compared to controls (pooled WMD: −3.92%, 95% CI −6.27% to −1.56%) Histological resolution of NASH without worsening of fibrosis: significant reduction with GLP-1 RA (liraglutide or semaglutide) vs. placebo (n = 2 RCTs; pooled random-effects OR 4.06, 95% CI 2.52–6.55) % patients with improvement of fibrosis stage without worsening of NASH: no significant difference with liraglutide or semaglutide vs. placebo (pooled random-effects OR 1.50, 95% CI 0.98–2.28; p = 0.06)	Body weight: significant reduction with GLP-1 RA (n = 11 RCTs; pooled WMD: −4.06 kg, 95% CI −5.44 to −2.68 kg; Z-test = −5.76, p < 0.0001) HbA1c: significant reduction with GLP-1 RA (n = 9 RCTs; pooled WMD: −0.45%, 95% CI −0.79 to −0.12; Z-test = −2.65, p = 0.01)
Meta-analysis (liraglutide, exenatide, dulaglutide, semaglutide) [100]	16 RCTs, 2178 patients with NAFLD/NASH	Variable	Variable	Histologic resolution of NASH without worsening of liver fibrosis with once daily liraglutide or semaglutide, n = 2 (pooled random-effects odds ratio 4.08, 95% CI 22.54–6.56; Z-test = 5.82; p < 0.0001; I2 = 0%) No significant improvement in liver fibrosis stage without worsening of NASH (pooled random-effects odds ratio 1.50, 95% CI 0.98 –2.28; Z-test = 1.88, p = 0.06)	Significant reduction in body weight (n = 15 RCTs; WMD: 1.93, 95% CI 3.01 to 0.85; p = 0.0005) Significant reduction in CRP (n = 7 RCTs; WMD: −0.41, 95% CI −0.78 to −0.04, p = 0.002)

Abbreviations: NAFLD (Non-Alcoholic Fatty Liver Disease), NASH (Non-Alcoholic Steatohepatitis), T2DM (Type 2 Diabetes Mellitus), FPG (Fasting Plasma Glucose), QUICKI (Quantitative Insulin Sensitivity Check Index), HbA1c (Hemoglobin A1c), MRI-PDFF (Magnetic Resonance Imaging—Proton Density Fat Fraction), MRE (Magnetic Resonance Elastography), ETR (Estimated Treatment Ratios), NAS (Non-Alcoholic Fatty Liver Disease Activity Score), BMI (Body Mass Index), HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), ADIPO-IR (Adipose Tissue Insulin Resistance), LFC (Liver Fat Content), FIB-4 (Fibrosis-4 Index), SAT (Subcutaneous Adipose Tissue), VAT (Visceral Adipose Tissue), ASAT (Abdominal Subcutaneous Adipose Tissue), CRP (C-Reactive Protein), RCTs (Randomized Controlled Trials), SGLT2i (Sodium-Glucose Co-Transporter 2 Inhibitors), OR (Odds Ratio), CI (Confidence Interval).

).

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. Drugs affecting intermediary metabolism.

Study (year)	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
Vitamin E
Vitamin E and pioglitazone [106]	247 patients with NASH without diabetes	96 weeks	Vitamin E 800 IU daily vs. pioglitazone 30 mg daily vs. placebo	NASH histology (% subjects): Significant improvement with vitamin E therapy only compared to placebo (43% vs. 19%; p = 0.001; NNT 4.2). Pioglitazone compared to placebo did not reach pre-specified significance level of 0.025 (35% vs. 19%, p = 0.04) Hepatic steatosis (% subjects): significant improvement in both groups (vitamin E p = 0.005; pioglitazone p < 0.001) Lobular inflammation (% subjects): significant improvement in both groups (vitamin E p = 0.02; pioglitazone p = 0.004) Fibrosis scores (% subjects): no significant difference compared to placebo in either vitamin E (p = 0.24) or pioglitazone (p = 0.12) Total NAFLD activity score: significant reduction in both groups (p < 0.001 for both) Resolution of NASH (% subjects): significant in pioglitazone only (p = 0.001) Hepatocellular ballooning (%subjects): significant improvement only in vitamin E group (p = 0.01)	Insulin resistance improved only in pioglitazone group compared to placebo (p = 0.03), as did fasting serum glucose (p = 0.006) Weight: significant weight gain in pioglitazone group (p < 0.001) BMI: significant increase in pioglitazone group (p < 0.001), Body composition of % fat: significant increase in pioglitazone group (p < 0.001)
Vitamin E + pioglitazone [107]	105 patients with T2DM and biopsy-proven NASH	18 months	Placebo vs vitamin E 400 IU/day vs. vitamin E 400 IU/day + pioglitazone	Improvement in NAS ≥2 without worsening of fibrosis: significant improvement in combination group only (subjects with improvement 54% vs. 19% in placebo, p = 0.003) NASH resolution: more subjects with improvement in the combination therapy group (43% vs. 12%, p = 0.005) vs. vitamin E monotherapy (33% vs. 12%; p = 0.04) Mean change in score-steatosis: both groups (combination, p < 0.001; vitamin E, p = 0.018), inflammation: combination only (p = 0.018); hepatocellular ballooning: combination only (p = 0.022) SAF score: improved only with combination group (p = 0.011) Fibrosis: No significant changes in fibrosis in either group IHTG: reduction in both groups (combination, p < 0.001; vitamin E, p = 0.03)	HbA1c: significant improvement in combination group only (p = 0.002) FPG: no significant change in either group not in fasting glucose. Fasting plasma insulin: reduction in both groups (combination, p < 0.001; vitamin E, p = 0.03) Weight: significant increase in combination group (p < 0.001)

Abbreviations: IU (International Units), IHTG (Intrahepatic Triglyceride), SAF (Steatosis, Activity, Fibrosis Score), NNT (Number Needed to Treat), NAS (Non-Alcoholic Fatty Liver Disease Activity Score), NASH (Non-Alcoholic Steatohepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease), FPG (Fasting Plasma Glucose), HbA1c (Hemoglobin A1c), and BMI (Body Mass Index).

).

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. Nuclear receptor modulators.

Study	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
Thyroid hormone receptor beta agonists
Resmetirom [115]	125 patients with biopsy-confirmed NASH with fibrosis stage 1–3 and hepatic steatosis ≥10% (MRI-PDFF) with (n = 49) or without T2DM	36 weeks	Resmetirom 80 mg daily vs. placebo	Hepatic fat fraction (MRI-PDFF): significant reduction compared to placebo at week 12 (LSM difference: −23.1%; 95% CI −33.5 to −12.7; p < 0.0001) ≥30% hepatic fat reduction: significantly greater proportion in the resmetirom group than placebo at 12 weeks (60% vs. 18%, p < 0.0001) and 36 weeks (68% vs. 30%, p = 0.0006) 2-point reduction in NAS with at least 1-point reduction in ballooning or inflammation: significantly greater in the resmetirom group than placebo (46% vs. 19%; p = 0.017) at 36 weeks NASH resolution without worsening of fibrosis in patients with <9.5% weight loss: significantly greater proportion in the resmetirom group than placebo (27% vs. 6%, p = 0.018) Liver enzymes: no difference in AST and ALT between groups at 12 weeks; significant difference between groups at 36 weeks (ALT p = 0.0019; AST p = 0.0035)	Body weight: no significant effect from resmetirom Fibrosis biomarkers: significant changes in resmetirom compared to placebo–decreases at 12 and 36 weeks in enhanced liver fibrosis, N-terminal type III, cytokeratin-18, reverse triiodothyronine; increase in adiponectin Lipids: significant reduction in resmetirom compared to placebo in LDL, apolipoprotein B, TG, lipoprotein(a), apolipoprotein CIII
Resmetirom [116]	966 patients with biopsy-confirmed NASH with fibrosis stage F1B to F3 and NAS ≥4, with T2DM (67%) or without T2DM (33%)	52 weeks	Resmetirom 80 mg once daily vs. 100 mg once daily vs. placebo	NASH resolution with no worsening of fibrosis: resmetirom 80 mg (25.9%), 100 mg (29.9%) vs. placebo (9.7%); p < 0.001 for both doses Fibrosis improvement ≥1 stage without worsening of NAFLD activity score: resmetirom 80 mg (24.2%), 100 mg (25.9%) vs. placebo (14.2%); p < 0.001 for both doses Hepatic steatosis (MRI-PDFF): 16 weeks: improvement with resmetirom groups 52 weeks: resmetirom 80 mg vs. placebo (treatment difference −26.7%; 95% CI −32.9 to −20.6); resmetirom 100 mg vs. placebo (treatment difference −37.9%; 95% CI −44.2 to −31.7) Hepatic steatosis (CAP): improvement at 52 weeks with resmetirom groups Liver stiffness (VCTE): greater decrease from baseline in resmetirom groups vs. placebo Liver stiffness (MRE): greater decrease from baseline in resmetirom groups vs. placebo	LDL-c: significant change from baseline at both doses compared to placebo (−13.6% (80 mg resmetirom), −16.3% (100 mg resmetirom), 0.1% (placebo); p < 0.001 for both comparisons) Triglycerides, non-HDL cholesterol, apolipoprotein B, apolipoprotein C-III, lipoprotein(a): greater decrease from baseline in resmetirom vs. placebo at 24 and 52 weeks
Farsenoid X receptor agonists, bile acids and synthetic bile acids
Obeticholic acid [117]	283 participants with histologically proven non-alcoholic steatohepatitis	72 weeks	Obeticholic acid 25 mg once daily versus placebo	45% patients in the Obeticholic acid group had improvement in liver histology vs. 21% in the placebo group (p = 0.0002).	Treatment with Obeticholic acid compared to placebo was associated with weight loss (mean change −2.2, p = 0.008), greater hepatic insulin resistance based on HOMA-IR scores (mean change 13 p = 0.01), higher glycated HbA1c (mean change 0.4, p = 0.71).
Obeticholic acid [118]	931 participants with biopsy-confirmed NASH and NAS ≥ 4, with fibrosis stage 1, 2, or 3, per NASH CRN criteria. Excluded patients with hemoglobin A1c > 9.5%.	>4 years	Placebo, OCA 10 mg, or OCA 25 mg once daily	Improvement in fibrosis was seen in 9.6% in the placebo group versus 14.1% in the OCA 10 mg group versus 22.4% in the OCA 25 mg group. NASH resolution was seen in 3.5% in the placebo group versus 6.1% in the OCA 10 mg group versus 6.5% in the OCA 25 mg group.	Relative risk of hyperglycemia/new onset diabetes mellitus for OCA 25 mg daily compared to placebo was 1.08 (CI 0.91–1.29)

Abbreviations: MRI-PDFF (Magnetic Resonance Imaging—Proton Density Fat Fraction), NAS (Non-Alcoholic Fatty Liver Disease Activity Score), NASH (Non-Alcoholic Steatohepatitis), T2DM (Type 2 Diabetes Mellitus), LSM (Least Squares Mean), CI (Confidence Interval), ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase), LDL (Low-Density Lipoprotein), TG (Triglycerides), VCTE (Vibration-Controlled Transient Elastography), MRE (Magnetic Resonance Elastography), HDL (High-Density Lipoprotein), CAP (Controlled Attenuation Parameter), OCA (Obeticholic Acid), CRN (Clinical Research Network), HbA1c (Hemoglobin A1c), and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance).

).

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. Drugs affecting de novo lipogenesis.

Study	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
De novo lipogenesis inhibitors
ACC Inhibitors [122]	126 patients with hepatic steatosis of 8% or greater, and liver stiffness of 2.5 kPa	12 weeks	GS-0976 at doses of 20 mg, 5 mg, or placebo	Trial indicated that there was a 30% or greater decrease in MRI-PDFF in 48% of patients given 20 mg dosage, 28% decrease given 5 mg, and 15% decrease with placebo therapy	No additional metabolic endpoints were reported in this investigation.
FAS Inhibitors [123]	Study Arm 1: 10 male patients/cohort with a total of 3 sequential cohorts Study Arm 2: 14 male and female patients	12 weeks	Arm 1: single dose of FT-4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days Arm 2: intermittent once daily variable dosing or placebo medication	Outcomes showed inhibition of hepatic DNL with single and repeat dosing of agent with a dose dependent relationship 3 mg dosing produced a statistically significant reduction in hepatic steatosis on MRI-PDFF from a baseline of 20.1 ± 7.0 to 16.7 ± 7.0 at week 12 and hepatic DNL	Biomarkers of glucose and lipid metabolism were unchanged with interventions
Aramchol (SCD1 Inhibitor) [126]	247 patients with known NASH	52 weeks	Randomly assigned to received either 400 mg, 600 mg, or placebo medication	Resolution of NASH was seen in 16.7% of patients receiving 600 mg group in comparison to 5% of the placebo arm ALT was reduced by a placebo corrected −29.1 IU l-1 (95% CI = −41.6 to −16.5)	600 mg trial group produced a reduction in liver triglycerides
DGAT Inhibitors [127]	44 patients between 18 and 75 with a BMI between 27 and 19 kg/m2, and HbA1c from 7.3 to 9.5%	13 weeks	Stratified based on liver fat content greater than or less than 20% and then randomized to receive either placebo or 250 mg of the experimental agent	Mean reduction in liver fat from baseline was −5.2% compared to −0.6% in the placebo group.	No changes to plasma glucose, bodyweight, or GI side-effects were observed in comparison to the placebo agent.
DGAT Inhibitors [120]	Patients with NAFLD	Variable in 2 parallel reported studies	First study focused on evaluating monotherapy with variable doses of ACC inhibitor Second study followed effects of 15 mg BID ACC inhibitor in combination with 300 mg DGAT2 inhibitor BID	First study found that there was a dose dependent reduction in the liver fat with monotherapy doses of >10 mg The second study found that combination therapy lowered liver fat by −44.5% and −35.4% at 6 weeks of therapy	No additional metabolic endpoints were reported in this investigation.
Ketohexokinase Inhibitor [128]	158 patients screened and narrowed to 53 patients, 48 of which completed the trial	6 weeks	75 mg or 300 mg of KHK inhibitor in comparison to a placebo trial group	Therapy produced a significant reduction in whole liver fat at the 300 mg dosing (−18.73%; p = 0.04) but not with the 75 mg dosing	Significant reduction in overall inflammatory markers in patients with the use of these inhibitors

Abbreviations: ACC (Acetyl-CoA Carboxylase), MRI-PDFF (Magnetic Resonance Imaging—Proton Density Fat Fraction), FAS (Fatty Acid Synthase), DNL (De Novo Lipogenesis), SCD1 (Stearoyl-CoA Desaturase-1), DGAT (Diacylglycerol Acyltransferase), NAFLD (Non-Alcoholic Fatty Liver Disease), BMI (Body Mass Index), HbA1c (Hemoglobin A1c), KHK (Ketohexokinase).

).

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. Other drugs under investigation.

Study	Study Population	Duration	Intervention	Liver Outcomes	Metabolic Outcomes
Fibroblast growth factors
Pegozafermin [131]	222 patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis	24 weeks	Pegozafermin 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks	Fibrosis improvement was 7% in the pooled placebo group, 22% in the 15 mg pegozafermin group, 26% in the 30 mg pegozafermin group, 27% in the 44 mg pegozafermin group. NASH resolution was seen in 2% in the placebo group, 37% in the 15-mg pegozafermin group, 23% in the 30-mg pegozafermin group, 26% in the 44-mg pegozafermin group.	Treatment with pegozafermin compared to placebo was not associated with significant changes in glycated hemoglobin A1c and body weight.
Aldafermin [132]	171 patients with (49%) and without T2DM with biopsy-proven NASH with F2 or F3 fibrosis	24 weeks	Aldafermin 0.3 mg or 1 mg or 3 mg or placebo	Fibrosis improvement by at least one stage without worsening of steatohepatitis: no significant difference compared to placebo for all doses Liver fat content (MRI-PDFF): significant reduction in absolute change with aldafermin 1 mg (−3.9% (1.4), p = 0.0031) and aldafermin 3 mg (−7.9% (1.4), p < 0.0001)	HbA1c, glucose, insulin: no significant change in any group compared to placebo Weight: significant reduction in the aldafermin 3 mg group compared to placebo only (−2.8 kg, p = 0.0054)

Abbreviations: NASH (Non-Alcoholic Steatohepatitis), T2DM (Type 2 Diabetes Mellitus), F2/F3 Fibrosis (Moderate or Severe Fibrosis), MRI-PDFF (Magnetic Resonance Imaging-Proton Density Fat Fraction), and HbA1c (Hemoglobin A1c).

).

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.