Dear Editor,
We appreciate Ren
et al. for their interest in our study and for providing valuable insights into incretin-based therapy for patients with nonalcoholic fatty liver disease (NAFLD), which was referred to as metabolic dysfunctionassociated steatotic liver disease (MASLD) in the editorial [
1,
2]. As the authors indicated, we acknowledged that there are still some issues to be addressed when using incretinbased therapy to treat NAFLD. In our study, glucagon-like peptide-1 receptor agonists (GLP-1RAs) were significantly more effective than thiazolidinediones (TZDs) in reducing liver fat content measured by proton magnetic resonance spectroscopy (1H-MRS) in overweight or obese patients with NAFLD or nonalcoholic steatohepatitis (NASH). For controlled attenuation parameter (CAP) and biopsy-based outcomes including fibrosis stage, the superiority of GLP-1RAs was not statistically significant. In the editorial, the authors noted inconsistencies in study outcomes and called for studies targeting non-obese or lean populations. We would like to go over these issues in detail.
Regarding the disparity between non-invasive and invasive liver outcomes in our study results, the editorial especially focused on liver fibrosis, which can be detected by invasive methods. The authors stated that GLP-1RAs may have a positive effect on metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis, based on the evidence from previous TZD studies and our results showing a trend toward better efficacy of GLP-1RAs than TZDs [
2,
3]. We agree with this suggestion, yet some points need consideration. Previous meta-analysis has shown that TZDs have the potential to improve or prevent the progression of liver fibrosis [
3]. TZDs can improve liver fibrosis in patients with NASH, regardless of whether they have advanced (F3-F4) fibrosis at baseline [
3]. However, GLP-1RAs have shown inconsistent results pertaining to improving liver fibrosis in patients with NAFLD [
4,
5]. A randomized controlled trial reported that patients with more severe baseline fibrosis (F3-F4) are less likely to respond to the GLP-1RAs [
4]. Reportedly, early liver fibrosis is likely to regress and resolve when extracellular matrix crosslinking and angiogenesis are absent [
6]. Therefore, to make an accurate assessment of the treatment effects on fibrosis reduction, patients should be analyzed according to their baseline fibrosis stage before starting the drugs. However, due to a lack of trials reporting the effects of GLP-1RAs on liver histological endpoints, we could not identify how the drugs affected liver fibrosis based on patients’ baseline fibrosis stage in our study. Furthermore, because type 2 diabetes is a potential risk factor for the development and progression of advanced fibrosis, the patients’ diabetic status should also be considered [
7]. More clinical trials analyzing the effect of GLP-1RAs on liver fibrosis according to baseline fibrosis stage and diabetes in patients with NAFLD will lead to more solid conclusions.
When it comes to non-invasive liver outcomes, there was an imbalance between the results from 1H-MRS and CAP in our study. GLP-1RAs had a greater effect than TZDs on reducing liver fat when detected by 1H-MRS in obese or overweight patients with NAFLD/NASH. However, according to CAP, GLP-1RAs only showed a trend of better effects than TZDs and did not reach statistical significance. This inconsistency could be attributed to obese people’s lower CAP accuracy compared to non-obese people [
8,
9]. CAP may struggle to differentiate between steatosis grades S2 and S3 in patients with a BMI ≥28 kg/m [2.10]. Meanwhile, MRS has been reported as a precise and effective method for assessing treatment response in the absence of iron deposition, fibrosis, or coexisting liver pathologies [
9].
In the editorial, the authors emphasized the importance of further research into incretin-based therapy in the management of non-obese or lean subjects with NAFLD. We completely agree with the suggestions. Non-obese individuals with NAFLD are expected to account for approximately 40% of the NAFLD/NASH population, but the majority of the studies on pharmacological treatments for NASH patients have focused on overweight and obese patients [
11]. Due to data scarcity, it was not able to compare the effects of GLP-1RAs and TZDs in non-obese or lean patients with NAFLD/NASH in our study. However, based on previous research, we anticipate that GLP-1RAs can have a promising effect on improving NASH through visceral fat loss in non-obese patients with NAFLD/NASH. There is a strong link between visceral fat obesity and non-obese NAFLD, and GLP-1RAs have been shown to reduce visceral fat mass [
12,
13]. From a mechanistic standpoint, there is evidence that GLP-1RAs may help improve NASH in non-obese individuals. A previous study found that GLP-1RAs can lower leptin levels, a proinflammatory cytokine, regardless of fat mass reduction [
14]. Leptin causes liver fibrosis by inhibiting peroxisome proliferator-activated receptor-γ (PPAR-γ), which prevents hepatic stellate cells from differentiating into myofibroblasts [
15]. Thus, GLP-1RAs may have a therapeutic effect on NASH in non-obese patients by modulating proinflammatory cytokines like leptin, which are involved in NASH development. However, given the lack of evidence, more research into non-obese or lean populations with NAFLD/NASH is needed.
In conclusion, our findings suggest that GLP-1RAs, an incretin-based glucose-lowering drug, may be more effective in overweight or obese NAFLD/NASH patients than TZDs, particularly in terms of reducing liver fat content. For invasive outcomes associated with liver fibrosis, clinical trials investigating the effects of GLP-1RAs in NAFLD/NASH patients based on baseline fibrosis stage and diabetic status are warranted. Furthermore, future research should focus on the effects of GLP-1RAs and TZDs in non-obese or lean NAFLD/NASH patients. Because incretin may have a positive effects on multiple organs involved in NAFLD/NASH pathophysiology, research into the use of various incretinbased therapies in these patients will help to expand the limited therapeutic options.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2020R1F1A1069257) and the Ministry of Education, Science and Technology (NRF-2019R1A6A1A03031807). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
FOOTNOTES
-
Authors’ contribution
Drafting of manuscript: HK, MJP; Critical review of manuscript: All authors.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
controlled attenuation parameter
glucagon-like peptide-1 receptor agonists
proton magnetic resonance spectroscopy
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
nonalcoholic fatty liver disease
nonalcoholic steatohepatitis
peroxisome proliferator-activated receptor-γ
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Citations
Citations to this article as recorded by
- Reply to correspondence on “Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis”
Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan
Clinical and Molecular Hepatology.2024; 30(4): 1039. CrossRef
