Exploring Promising Therapies for Non-Alcoholic Fatty Liver Disease: A ClinicalTrials.gov Analysis

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a common disease today, reflecting the increasing rates of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM).^1,2 The pathophysiology of NAFLD includes multifaceted interactions between insulin resistance, abnormal lipid homeostasis, oxidative stress, and inflammation.^3,4 While non-pharmacological interventions, especially dietary and weight loss strategies, are the foundational management techniques for NAFLD, the persistence and adherence to such measures remain a challenge.⁵

Several promising therapeutic agents such as Peroxisome proliferator-activated receptor agonists, Farnesoid X receptor agonists, Glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors are undergoing further analysis for their potential efficacy to counteract NAFLD progression. They work by modulating insulin sensitivity, rectifying lipid metabolism, abating hepatic inflammation, and reducing the risk of fibrosis and cirrhosis.^6–8 Current management emphasizes lifestyle modification including weight management. For instance, the Mediterranean diet, abundant in whole foods and beneficial fats, has shown promise in ameliorating hepatic lipid content and insulin dynamics in NAFLD individuals.^9,10

Clinical trial databases, with ClinicalTrials.gov leading the cohort, serve as indispensable repositories for gauging the efficacy and safety of innovative interventions.¹¹ As of today, ClinicalTrials.gov alone encompasses a large range of clinical trials. Despite the growing amount of literature highlighting the potential of pharmacological interventions for NAFLD, the methodical assessment of clinical trials assessing these remedies is conspicuously lacking. Although ClinicalTrials.gov serves as an invaluable corpus of such trials, a dedicated review encapsulating the role of pharmacotherapeutics within the NAFLD therapeutic landscape is still awaited.

Methodological Framework and Research Design

Search Strategy and Inclusion Criteria

On August 24, 2023, a thorough search of ClinicalTrials.gov was conducted using the keywords “Non-alcoholic Fatty Liver Disease” and “NAFLD”. Two evaluators reviewed the trials using established eligibility standards to ensure objectivity. To qualify, studies needed to focus predominantly on NAFLD and be interventional, in addition to being in Phase IV and being concluded.

Results

The preliminary search of the ClinicalTrials.gov database yielded 1364 trials. These were subsequently screened and filtered. Exclusion criteria were applied, eliminating trials that were incomplete (n = 762), non-interventional (n = 98), or outside of phase IV (n = 473). Initially, 31 studies met the inclusion parameters for our review. Upon further examination, 12 trials were excluded due to their inadequate focus on NAFLD. Thus, a total of 19 clinical trials were finalized for evaluation. The stepwise selection methodology is graphically represented in Figure 1, detailing the approach used to discern the pertinent clinical trials for this study.

Figure 1 Flow diagram of trial selection process.

Characteristics of Included Studies

Table 1 shows the description of the clinical trials studied. Most studies (89.5%) were randomized, while 10.5% were non-applicable regarding allocation. The primary intervention model used was Parallel (84.2%), followed by Single Group (10.5%) and Crossover (5.3%).

Table 1 Trial Characteristics

In terms of masking, nearly half (47.4%) had no masking, and the remaining studies employed Single (10.5%), Double (5.3%), Triple (15.8%), or Quadruple (21.1%) masking techniques. Geographically, Korea was the most common location for these studies, hosting just over one quarter (26.3%). China followed with 21.1%, and other countries, including Egypt and Germany, ranged from 5.3% to 10.5% of the studies.

Various interventions were used, with metformin being the most prevalent (12.1%). Other interventions such as Exenatide and Pioglitazone were used in 9.1% of the trials, and a diversity of other treatments appeared in 3.0% to 6.1% of the studies. Further details can be found in Table 2.

Table 2 Overview of the Clinical Trials

Pharmacological Treatment and Management Strategies

Allopurinol

Allopurinol, a xanthine oxidase inhibitor, is used mainly for hyperuricemia and gout. Other indications include cardiovascular and kidney diseases.^12,13 Allopurinol exerts its therapeutic effect by inhibiting xanthine oxidase, a critical enzyme in the metabolic pathway that transforms hypoxanthine into xanthine and subsequently into uric acid.¹³ Through this inhibition, allopurinol not only effectively lowers serum uric acid concentrations but also diminishes the production of reactive oxygen species.^14,15

Elevated serum uric acid levels correlate independently with a heightened severity of hepatic steatosis and fibrosis.^16–18 The underlying pathophysiological mechanisms that might bridge hyperuricemia with NAFLD include insulin resistance and oxidative stress.¹⁹ Notably, one specific trial incorporated allopurinol to evaluate the impact of xanthine oxidase inhibitors on MAFLD by regulating uric acid concentrations.

Empagliflozin

Empagliflozin, an SGLT2 inhibitor, is predominantly used to manage type 2 diabetes. Its mechanism of action involves inhibiting the SGLT2 protein within the proximal tubules of the kidneys, which in turn facilitates the excretion of glucose via the urine. This results in a notable reduction of blood glucose concentrations.²⁰ Empagliflozin is used also for weight reduction, decreased blood pressure, and enhancements in cardiovascular health outcomes.²¹

The intricate relationship between T2DM and NAFLD has been conclusively identified. NAFLD is currently acknowledged as the hepatic representation of the metabolic syndrome.²² Given the proven efficacy of SGLT2 inhibitors in managing T2DM, there is’ growing interest in their potential applicability in NAFLD therapy.^23,24 Empirical evidence from studies on empagliflozin indicates that its administration is linked to a substantial reduction in hepatic fat accumulation and improved liver enzyme in people with T2DM.²⁵ Moreover, Empagliflozin’s potential to exert anti-inflammatory and antifibrotic effects is a subject of ongoing research. Preliminary findings are pointing toward encouraging results.²⁶ Notably, two clinical trials incorporated empagliflozin to report its influence on liver lipid content, energy metabolism, and overall body composition in recently diagnosed T2DM patients.

Evogliptin

Evogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is predominantly used for managing T2DM by augmenting insulin secretion and reducing glucagon secretion.²⁷ Research has suggested that DPP-4 inhibitors could have therapeutic implications in NAFLD due to their influence on hepatic lipid metabolism and their inherent anti-inflammatory attributes.²⁸ In preclinical models, Evogliptin has demonstrated notable benefits by mitigating hepatic steatosis, inflammation, and fibrosis.²⁹ One trial incorporated Evogliptin to evaluate its efficacy and safety for T2DM patients concurrently diagnosed with NAFLD.

Exenatide

Exenatide, a GLP-1 receptor agonist, is commonly prescribed for managing T2DM. Its mechanism of action involves enhancing insulin release, curbing glucagon secretion, and decelerating gastric emptying.^30,31 Within the realm of NAFLD, Exenatide, alongside other GLP-1 agonists, has attracted attention due to its potential benefits: promoting weight reduction, heightening insulin sensitivity, and exhibiting hepatoprotective properties.^32,33 Notably, the weight reduction achieved via exenatide might indirectly confer advantages to NAFLD patients, considering the pronounced link between obesity and the onset of NAFLD.³³

Three trials integrated exenatide into their experimental designs with varied objectives. One aimed to assess the outcomes of substituting premeal insulin with exenatide in terms of hepatic steatosis, therapeutic efficacy, insulin secretion, weight modulation, rates of hypoglycemia, and pertinent biomarkers in patients with T2DM and NAFLD. Another sought to evaluate whether a 24-week Exenatide regimen ameliorates histological activity in NASH compared to dietary guidance alone. The last delved into the comparative efficacy of exenatide and insulin glargine in diminishing liver fat in patients newly diagnosed with T2DM and NAFLD over 24 weeks.

Febuxostat

Febuxostat, a non-purine selective xanthine oxidase inhibitor, is mainly prescribed for managing hyperuricemia in patients with gout.³⁴ Numerous studies have underscored the potential influence of uric acid on the pathogenesis of NAFLD, pinpointing oxidative stress as a pivotal mechanism.^14,15 Emerging evidence indicates that Febuxostat has the potential to counteract oxidative stress, reduce lipid accumulation in the liver, and alleviate inflammation; factors that are fundamental to the onset and progression of NAFLD.³⁵ One trial incorporated Febuxostat in its design, aiming to evaluate the effects of xanthine oxidase inhibitors on MAFLD through the modulation of uric acid levels.

Gliclazide

Gliclazide is an oral sulfonylurea antidiabetic agent that stimulates insulin secretion from the pancreatic beta cells by binding to specific receptors on these cells, causing ATP-sensitive potassium channels to close.^36,37

Intriguingly, research has shed light on gliclazide’s potential for mitigating liver steatosis and inflammation, especially as evidenced in rodent models.³⁸ Key mechanisms that have been posited include enhancing insulin sensitivity, promoting antioxidant actions, and modulating the release of proinflammatory cytokines.^39–41 In a singular trial, gliclazide was incorporated to compare its effects with those of liraglutide and metformin, specifically addressing diabetes concomitant with NAFLD over 24 weeks.

Glimepiride

Glimepiride is an oral medication often used for treating T2DM. It operates similarly to gliclazide, enhancing insulin release from the pancreas by specifically interacting with the sulfonylurea receptor. This interaction leads to the shutting down of ATP-sensitive potassium channels.⁴² Notably, glimepiride exhibits a range of additional effects, including significant anti-inflammatory and antioxidative properties. Emerging research suggests that glimepiride may also protect the liver. This potential benefit is primarily due to its ability to reduce oxidative stress and inflammation, key factors in the development of NAFLD.⁴³ Moreover, glimepiride’s role in improving blood sugar control and increasing insulin sensitivity could indirectly help in alleviating NAFLD.⁴⁴ In one study, the effectiveness of glimepiride was compared to that of tofogliflozin, focusing on their effects on liver health and metabolic indicators in NAFLD patients with T2DM over a period of 48 weeks.

Insulin Glargine

Insulin glargine, a long-acting insulin, is used for DM. Its relevance in NAFLD is notable, as it may counteract fat buildup in the liver by improving blood sugar control.^45–47 While there is’ a theory that exogenous insulin administration might intensify hepatic steatosis,⁴⁸ insulin glargine, through its potential to enhance glycemic control and reduce glycemic variability, might counteract these adverse effects.^49,50 This aspect was investigated in two studies: one compared the efficacy of liraglutide with metformin against that of sitagliptin and insulin glargine, for treating T2DM patients with NAFLD. The other study evaluated whether exenatide is more effective than insulin glargine in reducing liver fat in newly diagnosed T2DM and NAFLD patients over 24 weeks.

Ipragliflozin

Ipragliflozin, part of the SGLT2 inhibitor medication class, is noted for its promising effects on liver steatosis and fibrosis.^51,52 Extensive studies indicate that Ipragliflozin can reduce liver fat, improve liver enzyme levels, and potentially reduce signs of liver fibrosis.^52–54 These positive effects are thought to stem from several mechanisms, such as weight reduction, increased insulin sensitivity, and direct anti-inflammatory effects on the liver.^53,55 One trial incorporated Ipragliflozin to investigate its impact on visceral fat and the extent of fatty liver in T2DM patients undergoing metformin and pioglitazone treatment.

Liraglutide

Liraglutide, a GLP-1 receptor agonist similar to Exenatide, has garnered attention in the study of NAFLD. The LEAN trial highlighted its effectiveness, demonstrating liraglutide’s ability to resolve non-alcoholic steatohepatitis more effectively than a placebo, without worsening fibrosis.⁵⁶ The positive effects of liraglutide in patients with NAFLD/NASH may be attributed to various factors including weight loss promotion, reduction in liver fat accumulation, anti-inflammatory properties, and possible direct antifibrotic effects.^57–61 Two trials incorporated liraglutide into their study design with distinct objectives. One trial sought to compare the effects of gliclazide, liraglutide, and metformin on diabetes patients afflicted by NAFLD over 24 weeks. Another aimed to compare the efficacy of combining liraglutide with metformin with the effectiveness of sitagliptin and insulin glargine, specifically targeting NAFLD patients diagnosed with T2DM.

Lobeglitazone

Lobeglitazone is a member of the thiazolidinedione family, known for enhancing insulin sensitivity.⁶² These medications work by activating the peroxisome proliferator-activated receptor gamma, leading to improved insulin response in peripheral tissues.⁶³ Research indicates that Lobeglitazone may reduce liver fat, improve the histological characteristics of NASH, and potentially have antifibrotic effects.^64,65 One study was conducted to evaluate the effectiveness and safety of Lobeglitazone in reducing intrahepatic fat in patients with T2DM patients and NAFLD over 24 weeks.

Metformin

Metformin, a biguanide antihyperglycemic agent, is widely used to treat T2DM, mainly by reducing liver glucose production and increasing muscle insulin sensitivity.⁶⁶ Its potential effectiveness in managing NAFLD has become a subject of interest. However, research outcomes have been inconsistent; while some studies suggest benefits like reduced liver enzymes and liver fat, others find its effects comparable to those of lifestyle changes in terms of improving liver health.^67,68 Recent clinical trials have further explored its efficacy, including its use in combination with other treatments like ipragliflozin, pioglitazone, liraglutide, gliclazide, sitagliptin, and insulin glargine, in patients with coexisting T2DM and NAFLD.

Omega-3 Acid Ethyl Esters (OMACOR)

In the field of molecular biochemistry, Omega-3 acid ethyl esters, which are derived from longer-chain omega-3 fatty acids like eicosapentaenoic acid and docosahexaenoic acid, have been recognized for their heart-protective properties.^69,70 Recently, there has’ been growing interest in these fatty acids within the scope of NAFLD, largely due to their reported anti-inflammatory, antioxidative, and lipid-modulating effects.^5,71 In a trial, Omega-3 acid ethyl esters were incorporated to discern the influence of long-chain n-3 fatty acid supplementation on NAFLD biomarkers and the risk factors associated with cardiovascular disease and T2DM over an 18-month span.

Pentoxifylline

Pentoxifylline, a drug derived from methylxanthine, is primarily used to treat intermittent claudication resulting from peripheral artery disease.⁷² Its possible role in treating NAFLD arises from its significant anti-inflammatory and antifibrotic properties. A key mechanism of pentoxifylline involves inhibiting tumor necrosis factor-alpha (TNF-α), a critical cytokine involved in inflammation and the progression of NAFLD. Various clinical studies have assessed its effectiveness in patients with NAFLD/NASH, with initial results highlighting its potential benefits, particularly in reducing liver enzymes and indicators of liver damage. Additionally.⁷³ One trial incorporated pentoxifylline to examine the liver’s contribution to the onset of T2DM and its correlation with the pathogenesis of NAFLD.

Pioglitazone

Pioglitazone, a key drug in the thiazolidinedione class, primarily acts as an insulin sensitizer by targeting the peroxisome proliferator-activated receptor gamma.⁷⁴ The drug helps reduce liver steatosis and inflammation, possibly due to improved insulin sensitivity, reduced inflammation in fat tissue, and altered lipid metabolism.⁷⁵ Recent studies also highlight its potential in managing NAFLD by reducing liver fat and inflammation, attributed to enhanced insulin sensitivity and adjustments in lipid metabolism.⁷⁶ Despite its efficacy in improving NAFLD, particularly in diabetic patients, caution is necessary due to side effects like weight gain and the risks of bone fractures and bladder cancer, underscoring the need for a balanced risk-to-benefit assessment.^8,77 Three clinical trials involving pioglitazone were conducted with distinct goals: assessing ipragliflozin’s impact on visceral fat in T2DM patients on metformin and pioglitazone; evaluating the efficacy and safety of evogliptin in T2DM patients with NAFLD, and examining the effectiveness of pioglitazone hydrochloride and metformin hydrochloride combination therapy in newly diagnosed T2DM patients with NAFLD symptoms.

Rifampicin

Rifampicin is primarily recognized as a potent antibiotic targeting Mycobacterium tuberculosis. Intriguingly, it also is a robust inducer of the liver’s cytochrome P450 system.⁷⁸ Its connection to NAFLD is primarily underscored by its influence on bile acid metabolism and its potential therapeutic role in alleviating pruritus, a symptom often associated with liver diseases, including primary biliary cholangitis.⁷⁹ While direct evidence advocating for rifampicin’s application in NAFLD remains scarce, its ability to regulate bile acid transport and synthesis might indirectly affect the disease’s progression. However, the use of rifampicin for NAFLD must be judiciously considered due to its potent antibiotic nature and the possible hepatotoxic repercussions, particularly with extended usage.⁸⁰ One trial incorporated rifampicin to discern the effects of PXR activation on hepatic fat content by comparing rifampicin with a placebo in volunteers.

Salsalate

Salsalate, a derivative of salicylate that does not contain acetyl groups, is primarily known for its anti-inflammatory properties.⁸¹ Recently, it has attracted attention for its potential use in treating metabolic disorders, especially due to its ability to reduce inflammation, a key aspect in conditions like T2DM and NAFLD.^82,83 NAFLD is characterized by chronic, low-level inflammation, and targeting this aspect of the disease could offer significant therapeutic benefits. Studies have shown that salsalate can improve insulin sensitivity and glucose control in people with T2DM. Its effects on NAFLD are believed to stem from its ability to inhibit the nuclear factor-kappa B pathways, leading to a decrease in the release of proinflammatory cytokines from the liver.⁸⁴ In one trial, salsalate was included in a treatment plan for patients with osteoarthritis who also had NAFLD, to observe changes in NAFLD indicators following its administration.

Sitagliptin

Sitagliptin, a type of DPP-4 inhibitor, plays a crucial role in treating T2DM.⁸⁵ Its primary mechanism involves prolonging the action of incretin hormones, which leads to increased insulin production and decreased glucagon release, thereby achieving a balanced metabolic effect.⁸⁶ Recently, the use of DPP-4 inhibitors like sitagliptin has shown promise in treating NAFLD, especially in patients with both T2DM and NAFLD. Studies indicate that sitagliptin can significantly improve liver function and reduce liver fat, as evidenced by advanced imaging methods such as magnetic resonance spectroscopy.⁸⁷ The drug works by reducing cell death in liver cells, decreasing fat production in the liver, and managing oxidative stress and related inflammation.⁸⁸ In one clinical trial, researchers explored the effectiveness of combining sitagliptin with insulin glargine for treating NAFLD in T2DM patients, comparing it to the combination of liraglutide and metformin.

Tofogliflozin

Tofogliflozin, a key SGLT2 inhibitor, is mainly used to treat T2DM.⁸⁹ It works by blocking SGLT2 in the kidney’s proximal tubules. This action significantly lowers glucose reabsorption in the kidneys, leading to increased glucose excretion in urine and improved blood sugar control.⁹⁰ Recent studies also highlight the potential benefits of SGLT2 inhibitors for treating NAFLD.²³ These benefits are thought to arise from reduced visceral fat, lower hepatic glucose production, increased fat oxidation, and decreased fat synthesis in the liver.^91–93 Specific research on tofogliflozin has shown its ability to reduce liver fat and improve indicators of liver damage in patients with both NAFLD and T2DM.⁹⁴ One trial compared tofogliflozin with glimepiride, focusing on their effects on liver histology and metabolic markers in NAFLD patients with T2DM over a 48-week period.

Ursodeoxycholic Acid (UDCA)

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid that is traditionally used to treat primary biliary cholangitis.⁹⁴ Due to its cytoprotective, immunomodulatory, and anti-apoptotic properties, there is growing interest in exploring its use in treating other liver diseases, such NAFLD.^95,96 Preliminary studies have posited that UDCA may improve liver function and reduce liver cell damage in NAFLD by stabilizing cell membranes, reducing harmful bile acids, and protecting against oxidative stress.⁹⁷ One trial incorporated UDCA to understand the hepatic role in the onset of T2DM and its interrelation with NAFLD pathogenesis.

Vitamin E

Vitamin E, recognized for its robust fat-soluble antioxidant qualities, is of interest to researchers due to its possible role in addressing NAFLD and its more advanced form, NASH.⁹⁸ The antioxidant effects of Vitamin E show promise in potentially decelerating or reversing the progression of these conditions. However, it is’ important to approach its use with caution. Certain studies have highlighted possible adverse effects associated with prolonged consumption, such as an increased risk of overall mortality, hemorrhagic stroke, and a greater likelihood of prostate cancer in men, particularly when used in therapeutic doses.^98,99 One trial studied the impact of a tocotrienol-rich fraction of vitamin E on liver enzymes and DNA damage in overweight children with NAFLD over a span of 6 months.

Vitamin D

Vitamin D impacts cellular growth, immune function, and inflammation reduction, suggesting its involvement in the development and progression of NAFLD.^100–102 Epidemiological data reveal an inverse correlation between vitamin D levels and NAFLD prevalence, with deficiencies more prevalent in NAFLD patients.^103,104 This vitamin has shown the potential to inhibit NAFLD progression through anti-inflammatory antifibrotic effects and to improve insulin sensitivity.¹⁰⁵ Rodent studies further support these findings, indicating that vitamin D supplementation reduces liver steatosis and inflammation.^106–108 Two trials explored Vitamin D’s influence on NAFLD and its related metabolic parameters in T2DM patients.

Discussion

An exploration of the therapeutic potential of various agents in managing NAFLD indicates the multifaceted nature of the disease and its intricate interconnections with other metabolic disorders, especially T2DM. This complexity is aptly mirrored in the multitude of therapeutic agents being considered.

Thiazolidinediones like Lobeglitazone and Pioglitazone have traditionally been harnessed for their insulin-sensitizing capacities.^61,73 Their potential utility in NAFLD hinges on enhancing insulin sensitivity in peripheral tissues, consequently diminishing liver fat accumulation and ameliorating histological indicators of the disease.^62,75 Nevertheless, caution is imperative with pioglitazone, given the associated risks of bone fractures, weight gain, and potential long-term safety concerns.⁷⁶

Metformin is a cornerstone for T2DM management in the same metabolic milieu, and its implications for NAFLD management cannot be sidelined.⁶⁵ However, its efficacy is contested, with some studies highlighting its potential advantages in liver aminotransferase reduction and hepatic steatosis mitigation, and others debating its superiority over lifestyle modifications.⁶⁷

A noteworthy entry into this therapeutic spectrum is the Omega-3 acid ethyl esters or OMACOR. These derivatives, notably eicosapentaenoic acid and docosahexaenoic acid, bring cardioprotective capabilities.⁶⁹ Their burgeoning role in NAFLD is rooted in their anti-inflammatory, lipid-regulating, and antioxidative attributes, elucidating their potential as a therapeutic adjunct.^7,70

Agents like Pentoxifylline and Salsalate, despite their primary roles in managing peripheral artery disease and inflammation, respectively, have demonstrated potential benefits in NAFLD due to their anti-inflammatory properties. Their therapeutic impact, especially that of pentoxifylline, can be attributed to their potential to suppress vital inflammatory cytokines, such as TNF-α, which are pivotal in NAFLD progression.^71,83

While rifampicin’s primary role as a potent antibiotic is widely acknowledged, its implications for NAFLD hinge on its influence on bile acid metabolism and potential therapeutic role in alleviating pruritus, a symptom often associated with liver diseases.⁷⁸ However, it must be prescribed with caution due to possible hepatotoxic repercussions.⁷⁹

DPP-4 inhibitors like Sitagliptin and SGLT2 inhibitors such as Tofogliflozin showcase the intertwined pathophysiology of NAFLD and T2DM, underscoring the potential benefits these antidiabetic agents might confer on hepatic steatosis and inflammation.^84,88

Moreover, traditional agents like UDCA and vitamins like Vitamin E and Vitamin D underscore the multifactorial therapeutic approach to NAFLD. While UDCA’s hepatoprotective and anti-apoptotic properties offer therapeutic possibilities, Vitamin E’s antioxidant prowess suggests potential therapeutic benefits. Still, the latter must be approached cautiously, given the potential risks associated with high doses.^96,97 Vitamin D, on the other hand, bridges the realm of bone health with cellular growth, immune function, and inflammation, suggesting an intricate role in NAFLD’s development and progression.¹⁰¹

Future Directions

As NAFLD research and therapy advance, it is’ evident that a multifaceted approach is crucial. Personalized treatments rooted in genomic and metabolic profiling appear to be the way forward, while long-term studies remain vital to establish the safety and efficacy of new agents. Understanding NAFLD’s molecular foundations can lead to novel therapeutic targets, potentially offering more effective treatments. Given the disease’s multifactorial nature, there is’ potential for combining various therapeutic agents and merging them with lifestyle modifications.

Conclusion

Since NAFLD has become a major health concern, more clinical trials and different pharmacological approaches are required to counteract the potential side effects associated with the disease. Agents like Thiazolidinediones, Metformin, Omega-3 acid ethyl esters, and DPP-4 inhibitors, among others, highlight the diverse approaches toward NAFLD management. At the same time, each agent presents potential therapeutic benefits but has associated risks and limitations. Further investigations are definitely warranted.