In this study, we compared changes in liver function in 643 patients who received SGLT2i + GLP1Ra combination treatment for approximately 3 years. Combination treatment significantly improved liver function and prevented increases in FIB-4 index values, which are thought to be caused primarily by aging among patients with FIB-4 index ≥ 1.3. Using a PS-matched model, we noted that the preceding drug (SGLT2i or GLP1Ra) did not significantly affect liver function; however, prior SGLT2i use appeared to be beneficial for improving liver function. The hepatoprotective effects of SGLT2is- and GLP1Ras-only treatments have been reported [13–16]; however, reports on the efficacy of their combined use are limited. Here, we observed that SGLT2i + GLP1Ra combination treatment improved liver function in patients with T2DM, suggesting that these two drugs possibly have a stronger beneficial effect on NAFLD and other liver conditions than their monotherapies. While there are reports of the concurrent administration of SGLT2is and GLP1Ras [13–16], the effect of the drug used preceding the combination treatment on liver function remains unclear. Here, we report for the first time that in clinical practice, the use of SGLT2i prior to SGLT2i + GLP1Ra combination treatment may be more beneficial to liver function.
GLP-1Ras primarily improve liver function by suppressing hepatic glucose production, enhancing insulin sensitivity, alleviating local inflammation, and reducing body weight [13, 16]. These effects result in a decrease in hepatic fat content and liver enzyme levels and hepatoprotective benefits, especially in conditions such as NAFLD. Potential improvements in liver function dependent on weight loss owing to SGLT2i and GLP1Ra use have been reported [14]. However, improvements in liver function independent of weight loss have also been reported [15]. SGLT2is reduce the levels of certain biomarkers of hepatocellular damage, such as cytokeratin 18-M30 and plasma fibroblast growth factor 21 [26]. Histological examinations of liver biopsies from patients with T2DM have also shown that SGLT2is improve NAFLD activity score, steatosis, inflammation, and ballooning, and in some cases, ameliorate fibrosis and modify hepatic gene expression profiles [27]. In particular, in patients with T2DM, before the progression of liver fibrosis, the effect of SGLT2i on steatosis, inflammation, and ballooning, independent of weight loss, may be more beneficial for liver function improvement than that of GLP1Ra.
The strengths of this study include: (i) it is the first report on the assessment of the impact of different prior therapies (SGLT2i or GLP1Ra) on liver function in patients receiving SGLT2i + GLP1Ra combination treatment, (ii) it involves the analysis of data corresponding to a long period of over 3 years; and (iii) the results obtained are based on trend scores obtained using actual clinical data on known background factors, enabling a more practical evaluation of treatment effects.
In daily clinical practice, injectable GLP1Ras are often used in combination with SGLT2is. SGLT2is are frequently administered first, especially in patients with T2DM and hepatic dysfunction owing to cost considerations. Our present results suggest that this administrations order may be appropriate for slowing hepatic dysfunction progression. Moreover, liver dysfunction conditions such as NAFLD are independently associated with cardiovascular diseases [28], and the cardiovascular benefits of GLP-1Ras and SGLT2is are well established [1–3]. Therefore, SGLT2i + GLP1Ra combination treatment, in addition to improving liver function, may also reduce cardiovascular risk in patients with T2DM and NAFLD. Further, given that the results of this study are based on actual clinical data, the accumulation of additional evidence may lead to the establishment of this combination treatment as a standard treatment protocol for obese patients with T2DM.
This study has some limitations. First, it was a retrospective observational study; thus, the data collected may be associated with selection bias. Notably, only patients who continued treatment were included; those who discontinued treatment owing to side effects or poor adherence were excluded. Reportedly, among users of hypoglycemic agents, metformin and SGLT2i users show higher adherence and continuation rates, whereas users of injection therapies, e.g., GLP1Ras, show lower adherence and continuation rates [29]. This study also focused on patients with a BMI close to 30, which is higher than the average BMI of Japanese patients with T2DM (24.3) [30]. Additionally, even though GLP1Ras have been available in Japan since 2010, their use is still limited. Thus, this study possibly included a significant number of severely obese patients with poor adherence to diet and exercise treatment who were compelled to use GLP1Ras in the long term. Second, due to lack of data on abdominal circumference, the presence of metabolic syndrome and albumin levels, fatty liver index, NAFLD-liver fat score (NLFS), and NAFLD-fibrosis score (NFS) were not assessed. Third, the dose of GLP1Ras administered in Japan is lower than that administered in other countries, e.g., most of the patients included in this study did not receive the maximum doses of liraglutide and dulaglutide, which are commonly used in other countries. It remains unclear whether relatively low doses of GLP1Ras can provide sufficient hypoglycemic and organ-protective effects. Thus, it is possible that the observed hepatoprotective effects may be predominantly due to the use of SGLT2i, independent of its weight loss effect.
Regardless of these limitations, this study provides valuable insights into liver function improvement and highlights the potential benefits of the SGLT2i + GLP1Ra combination treatment in patients with T2DM, especially in the context of NAFLD. In future, it would be necessary to conduct further studies, particularly prospective studies, to provide a more comprehensive understanding of the benefits of this combination treatment and identify strategies for its optimal implementation.