The global clinical trial landscape for non-alcoholic fatty liver disease (NAFLD): current status and future prospects

Abstract

Purpose:

This study comprehensively analyzed the global clinical trials and depicted a landscape for non-alcoholic fatty liver disease (NAFLD) therapy.

Methods:

Using the Trialtrove database, we collected trial information of 2242 clinical trials. Using molecular docking analysis, we investigated the pharmacological properties of glucagon-like peptide-1 receptor (GLP-1R) agonist such as semaglutide and its binding affinity to GLP-1R protein. Based on the transcriptome data of NAFLD-related datasets, we analyzed the expression profile of GLP-1R across healthy liver and NAFLD samples.

Results:

Our clinical trial landscape revealed significant geographic disparities in NAFLD trials, with the US and China leading globally with 488 and 384 trials respectively. Phase IV accounted for the largest proportion (34.10%) among all trials. Among all the NAFLD-related agents, GLP-1R agonists were the most frequently used. In addition, GLP-1R was significantly and widely downregulated in NAFLD, especially in advanced stages such as non-alcoholic steatohepatitis.

Conclusion:

This study offers some valuable insights into the current status and future prospects of NAFLD clinical trials.

Non-alcoholic fatty liver disease (NAFLD) is a serious public health problem that affects approximately a quarter of the global population^[1]. However, at present, there is no globally recognized “first-line agent” for NAFLD, and lifestyle modifications remain the foundation of treatment^[2]. Recently, an increasing number of studies have focused on NAFLD-related therapeutic agents, especially regarding their clinical trials and future prospects, which have attracted significant attention. For example, Wang et al^[3] summarized the potential anti-NAFLD natural products and their targets, discussed the discovery of new targets and docking of active lead compounds, and highlighted the importance of exploring natural products as new drug development against NAFLD in clinical settings. In addition, Li et al^[4] conducted a systematic review and meta-analysis to evaluate the efficacy of SGLT-2 inhibitors in NAFLD treatment and found that SGLT-2 inhibitors could be a promising clinical therapeutic strategy for NAFLD patients, particularly those with type 2 diabetes. These studies offer valuable insights into the promising future of emerging therapies for NAFLD in clinical trials.

HIGHLIGHTS

• This study comprehensively analyzes 2242 global clinical trials for non-alcoholic fatty liver disease (NAFLD) therapies up to May 2025, revealing significant geographic disparities in trial distribution.

• A key finding is the prominent role of GLP-1 receptor agonists (GLP-1RAs) in current trials, with semaglutide and liraglutide emerging as the most frequently used drugs for NAFLD.

• We innovatively visualized the dynamic trends and proportional distribution of Phase I–IV clinical trials from 1998 to 2024 using a streamplot.

• The research demonstrates that GLP1R is significantly downregulated in NAFLD, especially in advanced stages such as non-alcoholic steatohepatitis, providing significant evidence for the use of GLP-1RAs in NAFLD treatment.

• This work emphasizes the urgent need for equitable trial distribution and combination therapies to address unmet clinical challenges in NAFLD treatment.

However, comprehensive analyses regarding the clinical trials of these NAFLD-related therapeutic agents are scarce. Consequently, in this study, we conducted an extensive analysis of the global clinical trials landscape for NAFLD therapy, and we ensure that our study is compliant with the TITAN Guidelines 2025^[5].

Using the Trialtrove database (https://clinicalintelligence.citeline.com/), we employed the search terms “NAFLD,” “MAFLD,” and “MASLD” to conduct this analysis. After a thorough screening process, we identified 2242 relevant clinical trials up to May 2025 (Fig. 1A). The data we collected included trial ID, drug names, targets, mechanisms of action (MoAs), and other relevant clinical information. We comprehensively analyzed the proportions and trends across clinical trial phases, drug-targets, and additional parameters to evaluate the current landscape of clinical trials for NAFLD treatment. When mapping them to each country, we observed that the distribution of NAFLD-related clinical trials globally is uneven: the US and China have the highest number of trials globally, with 488 and 384 trials, respectively. All other countries have fewer than 300 trials, especially regions such as Africa, West Asia, and Southeast Asia have a negligible number of trials (Fig. 1B). In addition, we constructed a bar chart that displays the distribution of clinical trials in the top 20 countries to make the statistical results more intuitive (Fig. 1C). A streamplot illustrated the dynamic changes and proportional distribution of Phase I–IV clinical trials from 1998 to 2024. Beginning with the first clinical trial launched in 1998, an overall rapid growth trend is evident. In recent years, Phase IV trials have shown a proportional expansion, while Phase I trials have displayed a slight shrinking trend (Fig. 1D). In addition, a double-layer pie chart was generated to show the proportion of clinical trials in different phases and statuses (the inner ring represents the phase, and the outer ring represents the status). Among all the trials, Phase IV accounted for the largest proportion (34.10%), followed by Phase II (25.02%), Phase I (23.85%), and Phase III (10.87%). The outer ring includes five statuses (in each phase), and the color gradient from deep to shallow represents the terminated, planned, open, completed, and closed status, respectively. In each phase, the status of completed trials accounts for the largest proportion (Fig. 1E). A proportional pie chart depicts the distribution of sponsor types in all these trials, with academic institutions leading the proportion, followed by industry and government (Fig. 1F).

Figure 1.

Global landscape of clinical trials on therapeutic agents for NAFLD. (A) A total of 2242 clinical trials of NAFLD were identified worldwide. (B) Global distribution of clinical trials of NAFLD. (C) Top 20 countries in the ranking. (D) A streamplot illustrated the dynamic changes and proportional distribution of Phase I–IV clinical trials from 1998 to 2024. (E) A double-layer pie chart illustrates the proportion of clinical trials in different phases and statuses (the inner ring represents the phase, and the outer ring represents the status). (F) A proportional pie chart depicts the distribution of sponsor types in these trials, with academic institutions leading the proportion, followed by industry and government. (G) Top 5 applied drugs, defined mechanisms of action (MoAs), and targets among all the trials. (H) A gradient treemap summarizes the GLP-1RAs atlas. The color gradient and area size represent usage frequency.

Regarding the drug targets and their MoAs, we found that the most frequently applied drug category is the natural product used in 294 NAFLD-related clinical trials (Fig. 1G, left panel). Interestingly, after excluding drugs that are inapplicable or have unidentified pharmacological activities, GLP-1R agonist (GLP-1RA) was applied in 183 trials and ranks first among all the MoAs (Fig. 1G, middle panel). Consistently, the top target is GLP-1R, followed by PPARγ, NR1H4, SLC5A2, and PPARα (Fig. 1G, right panel). Considering the significance of GLP-1RAs in NAFLD clinical trials, we investigated drug usage across the above-mentioned 183 trials and found semaglutide and liraglutide to be the most and second most used, respectively. A gradient treemap summarizes the GLP-1RAs atlas in the 183 trials, and the color gradient and area size represent the usage frequency (Fig. 1H).

GLP-1RAs were initially developed for type 2 diabetes and obesity, and have emerged as promising candidates because of their pleiotropic metabolic effects including weight loss, insulin sensitization, and anti-inflammatory properties^[6,7]. For example, the LEAN trial demonstrated that liraglutide significantly improved the histological resolution of steatohepatitis (non-alcoholic steatohepatitis [NASH]) in 39% of patients versus 9% with placebo^[8]. Additionally, semaglutide, a long-acting GLP-1RA, showed in a Phase II trial (NCT02970942) that 59% of patients achieved NASH resolution without worsening fibrosis, compared to 17% in the placebo group^[9]. However, the effects on fibrosis regression remain modest, highlighting the need for combination therapies that aim to accelerate the progress of clinical trials and ultimately enhance the therapeutic efficacy of NAFLD treatment.

Using molecular docking analysis, we investigated the structural features and pharmacological properties of GLP-1RAs such as semaglutide and its binding affinity to GLP-1R protein. The 3D structure of GLP-1R protein and the detailed binding of semaglutide to the site with the lowest affinity score (−18.5 kcal/mol) were depicted in Figure 2A,B. The binding details are illustrated in Figure 2C: the blue center represents semaglutide, with surrounding amino acids depicted as well. Red arcs indicate hydrophobic interaction sites between GLP-1R protein amino acids and semaglutide. Subsequently, the expression profile of GLP-1R across normal liver and NAFLD was further investigated. We searched several NAFLD-related datasets with transcriptome profiling data (GSE61260 and GSE89632 were retrieved from the GEO database, and E-MEXP-3291 was retrieved from the EMBL-EBI database). Compared to normal livers, GLP-1R mRNA level is significantly and widely downregulated in NAFLD, especially in advanced stages such as NASH (Fig. 2D–F). This finding further demonstrated that the downregulation of GLP-1R might be closely associated with the pathogenesis and progression of NAFLD, suggesting that the usage of GLP-1RA acts as a promising therapeutic strategy for NAFLD.

Figure 2.

Semaglutide can bind with high affinity to the GLP-1R protein, which is significantly downregulated in NAFLD. (A) The 3D structure of human GLP-1R protein. (B) The binding site of semaglutide with affinity score up to −18.5 kcal/mol. (C) A detailed illustration of the interaction between semaglutide and GLP-1R protein, with the red arcs indicating hydrophobic interaction sites. (D–F) In several NAFLD-related datasets, GLP-1R is significantly downregulated in NAFLD, especially in advanced stages such as NASH.

This study has several limitations. First, a substantial proportion of the trials included in this study employed multi-drug regimens (e.g. GLP-1RA/FXR agonist combination), which complicates data interpretation primarily because of the inherent difficulty in isolating individual drug effects. Furthermore, the heterogeneity in trial designs regarding combination ratios and administration protocols introduced additional confounding variables.

In summary, our study provides several important insights for the field of NAFLD research. First, our study reveals significant geographic disparities in NAFLD clinical trials with the US and China as leading countries, which highlights the need for increased research efforts in some less-developed regions (e.g. Africa, West Asia, and Southeast Asia) to ensure a more balanced allocation of funding and research resources globally. Second, the dominant usage of GLP-1RAs in NAFLD trials highlights their potential as promising therapeutic agents for NAFLD patients. Finally, the expression analysis of GLP-1R in healthy livers and NAFLD reinforces the biological rationale for targeting this receptor in therapeutic interventions. These findings not only depict the current trends in NAFLD trials but also provide evidence-based foundation for future researches. We hope these insights could facilitate the development of next-generation therapeutics and successful clinical translation, ultimately benefiting more patients with NAFLD.

Ethical approval

This study is based on public datasets and does not require ethical approval and consent.

Consent

This study is based on public datasets and does not require ethical approval and consent.

Sources of funding

This study was supported by the National Natural Science Foundation of China (Grant No. 82474318 to X.Z.; Grant No. 82274155 to X.W.).

Author contributions

Not applicable.

Conflicts of interest disclosure

The authors declare that they have no competing interests.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Not applicable.

Provenance and peer review

Not applicable.

Data availability statement

Original data analyzed in this study are available in the Trialtrove database (https://clinicalintelligence.citeline.com/), a publicly accessible repository specializing in global clinical trial intelligence. The codes used in this study are available from the corresponding author upon reasonable request.