Nonalcoholic fatty liver disease (NAFLD) is an often neglected etiology of chronic liver disease that is prevalent globally, resulting from the liver fatty acid accumulation and fibrosis without overmuch alcohol consumption (1). Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are the two major subtypes of NAFLD. The patients diagnosed with NASH can subsequently progress to liver fibrosis, which increases the risks of cirrhosis and liver cancer (2, 3). NAFLD is also a dangerous factor that obviously grows the risk of cardiovascular and chronic kidney disease (4, 5). The prevalence of NAFLD is approximately 25% worldwide; furthermore, it is estimated that NAFLD shall be the most common index for liver transplantation by 2030 (6, 7).

The pathogenesis of NAFLD is complex, and several factors have been involved, including Western diet, lifestyle, and genetic susceptibility. NAFLD is most closely related to the metabolic environment, such as insulin resistance, abnormal lipid profile, and metabolic dysfunction, which is also why it has an appropriate new nomenclature as MAFLD (8, 9). Additionally, increased risk of more severe NAFLD is strongly associated with type 2 diabetes (T2DM) and diabetes-related complications (10). Currently, no available drug has been approved for the management of NAFLD (11). Although the insulin sensitizer pioglitazone has been proven to enhance metabolism and liver histology among NAFLD patients, it has limitations in clinical use due to significant adverse events including weight gain, lower extremity edema, and heart failure (12, 13).

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, is a novel oral hypoglycemic agent that inhibits glucose reabsorption, improving insulin resistance, leading to downregulation of SREBP-1c and blockage of new hepatic lipogenesis, thereby improving lipid metabolisms (14, 15). Currently, it has been shown that controlled clinical trials (RCTs) have evaluated the role of empagliflozin in NAFLD patients. However, the role of empagliflozin in NAFLD patients is controversial, and there is no comprehensive analysis on RCTs of empagliflozin. Hence, this research aiming to investigate the effectiveness and security of empagliflozin in NAFLD was made.

This systematic review and meta-analysis of four RCTs was designed to assess the effectiveness and safety of empagliflozin in treating NAFLD patients. Most of these patients have T2DM. This analysis comprehensively assessed the impact of NAFLD patients in terms of glycemic control, body composition, biological indicators of liver function, and hepatic steatosis and fibrosis. The results of our research showed that empagliflozin had significant beneficial effects in decreasing body weight and improving liver function, liver fibrosis, and insulin resistance.

NAFLD has been the most prevalent etiology of chronic liver disease, which is a hot issue in recent research. NAFLD always have associations with changes in metabolic and nonmetabolic processes, such as dyslipidemia, oxidative stress, and insulin resistance. Therefore, attention should be paid to correcting all of these disturbances in the treatment of NAFLD. Current guidelines recommend changing life patterns as first-line therapy strategy for NAFLD. Nevertheless, no pharmacological therapy has been approved for NAFLD (21). Currently, studies have proven that liver histology in T2DM patients and non-T2DM patients with NASH confirmed by biopsy was improved by pioglitazone (3, 22). However, the adverse reactions of pioglitazone limit its use, including sodium and water leakage, weight gain, heart failure, and bone damage (3, 23). Moreover, glucagon-like peptide 1 receptor agonists have indicated beneficial effects in patients with T2DM and NAFLD (24). Several meta-analyses have demonstrated that SGLT2 inhibitors can lower liver enzymes, liver fat and improve body composition (25–27). The role of empagliflozin in NAFLD is not yet fully understood and deserves further investigation.

Empagliflozin is an SGLT2 inhibitor that attenuates blood glucose concentrations by restraining glucose reabsorption and accelerating glucose excretion. Additionally, empagliflozin also has exceptional profits, like cardiovascular protective actions (28), renal protection (29), lowering uric acid levels, and healing NAFLD-associated liver injury (30). In this meta-analysis, our results show reductions in liver function markers AST and ALT after empagliflozin treatment, although the change of ALT did not reach a statistical threshold. Changes in these parameters indicate an amelioration in NAFL or NASH (31). This may be due to the fact that empagliflozin can significantly improve NAFLD-related damage by enhancing autophagy by the liver macrophages and further restraining the inflammatory response (32).

The major underlying pathophysiologic mechanisms of NAFLD are insulin resistance and hepatic steatosis (33, 34). Evidence has demonstrated that patients treated with empagliflozin can improve hypothalamic insulin sensitivity and potentially benefit obesity and systemic metabolism (35). Studies have reported that empagliflozin can reverse fat and insulin resistance through lipid browning and macrophage activation (30). Improvements in obesity and insulin sensitivity may be associated with increased adiponectin levels, a bioactive protein known as adipokines (36). Empagliflozin promoted the replacement activation of macrophages in white adipose tissue and increased the plasma adiponectin level, resulting in obesity-induced inflammation and insulin resistance (30). Our results indicated that empagliflozin could enhance insulin sensitivity, as measured by HOMA-IR and HOMA2-IR, though the differences did not reach statistical significance. Empagliflozin has a beneficial effect on anthropometric parameters; BMI improved significantly in patients after empagliflozin treatment, but the change in weight was not of statistical significance.

Noninvasive biomarkers of liver fibrosis including the FIB-4 index, NFS, and APRI, were used to assess the severity degree of liver fibrosis (37), and the LSM was also adopted to evaluate liver fibrosis (38). End-stage hepatic fibrosis is a key prognostic biomarker for liver-associated outcomes and the total mortality (21). No effective treatment for hepatic fibrosis was found in the guidelines (39). This analysis demonstrated an obvious improvement in LSM scores after empagliflozin treatment; other markers of liver fibrosis including FIB-4 index, APRI, and NFS also depicted an amelioration with empagliflozin, to a large extent, although not statistically significant. This lack of statistically significant difference may be associated with the short duration of follow-up. The development of fibrosis may last for many years, with significant fibrosis reversal observed after long-term treatment (40). Studies with longer follow-up periods are required to verify the role of empagliflozin in the management of liver fibrosis in NAFLD patients. The specific mechanism of action of empagliflozin in liver fibrosis is not clear. However, it is hypothesized that empagliflozin achieves its antifibrosis effect by inhibiting proinflammatory cytokines such as IL-6, TNF-α, and MCP-1 (41)

NAFLD is currently a hot issue in research, and there are no other drugs in the guidelines that could be approved for treating NAFLD. At present, there is no meta-analysis of empagliflozin in the treatment of NAFLD. As we all know, this is the first meta-analysis to evaluate the role of empagliflozin in NAFLD. The advantage of this analysis is to comprehensively assess the roles of empagliflozin in glycemic control, body composition, levels of biological indicators of liver injury, and liver steatosis and fibrosis among patients with T2DM or non-T2DM combined with NAFLD. However, our study has several limitations: (a) Due to the limited large clinical trials, only a few RCTs were eligible, and only four RCTs were included in this paper. Most of the RCTs had small sample sizes, so the results are not significant. (b) The follow-up period of the included studies was short, and the duration was less than 6 months. There is no evidence of additional histological benefits from empagliflozin treatment for more than 6 months. The long-term prognosis and safety of empagliflozin remains unclear, so further research is required. (c) Liver biopsy as a gold standard for evaluating NAFLD (3). The included articles were not based on liver biopsy but relied on ultrasound and proton density fat fraction to diagnose NAFLD.

In conclusion, our results suggest that empagliflozin significantly reduces the BMI, HOMA-IR, CAP score, and LSM score of both diabetic and nondiabetic NAFLD patients. However, the beneficial effects of empagliflozin did not achieve statistical significance in terms of body weight, FBS, HbA1C, LDL, HDL, TG, ALT, AST, insulin, HOMA2-IR, NFS, FIB-4 index, and APRI. Thus, more RCTs with longer duration and larger sample sizes are required to decide the roles of empagliflozin in patients with NAFLD and to establish adequate guidelines for clinical practice.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

YZ conducted a literature search, information extraction and information analysis and wrote the manuscript. XL extracted the data and reviewed the manuscript. XW and HZ were involved in review. All authors made contributions to the article and approved the submitted version.

The Yunnan Provincial Science and Technology Department Project Fund of China (2017FH001-095) funded this study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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