The global prevalence of diabetes mellitus (DM) is growing rapidly (Mobasseri et al., 2020[59]). This chronic disorder has adverse effects on most metabolic processes and induces many pathophysiological pathways mediating diabetic complications (Forbes and Cooper, 2013[28]). DM is recognized as a key risk factor for several life-threatening disorders such as cardiovascular and hepatic disorders (Fujii et al., 2020[30]). DM-induced hepatic disorders are a group of complications such as non-alcoholic fatty liver (NAFLD), cirrhosis and fibrosis, hepatocellular carcinoma, acute liver failure, hepatitis, bile duct disease, and jaundice that occur in many patients with uncontrolled DM. These disorders reduce or destroy liver sufficiency and significantly threaten patients' survival or quality of life (Tolman et al., 2007[87]). Thus, hepatic disorders are an important cause of death in patients with DM (Tolman et al., 2007[87]). The value of cirrhosis SMR (standardized mortality ratio; the relative rate of an event compared with the background one) was estimated to be 2.52 compared with 1.34 for cardiovascular complications in diabetic patients (Tolman et al., 2007[87]). Moreover, cirrhosis is suggested as the fourth leading cause of death in diabetic patients (Ramachandran et al., 2017[69]). There are strong relationships between DM and hepatitis as well as hepatocellular carcinoma (Hammerstad et al., 2015[35]; Tingting et al., 2018[86]). Therefore, the management of liver function and prevention of hepatotoxicity in the diabetic milieu is of major importance for the prevention of diabetes-induced hepatic disorders (Tingting et al., 2018[86]).

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a potent class of antidiabetic drugs that act by glycosuria induction via glucose reabsorption inhibition in renal proximal tubules (Figure 1(Fig. 1)) (Yaribeygi et al., 2020[104]). These drugs have a significant impact on blood glucose levels as well as insulin sensitivity in peripheral tissues (Yaribeygi et al., 2020[104]). Moreover, they are now recognized as efficacious agents in diabetic patients with cardiovascular and renal complications owing to their many pleiotropic effects (Yaribeygi et al., 2019[96][98][105], 2020[95][97], 2023[102][101]; Ravindran and Munusamy, 2022[70]). Moreover, recent evidence suggests that SGLT2 inhibitors interact with hepatic functions in the diabetic milieu (Scheen, 2019[76]; Wei et al., 2021[90]). These studies suggest that SGLT2 inhibition modulates liver function through as yet not-well-defined pathways (Wei et al., 2021[90]). In the current study, we discuss the possible liver benefits of SGLT2 inhibitors and elaborate on possible mechanisms involved in such hepatoprotective effects.

DM is classically categorized into three main classes: type 1, type 2, and gestational diabetes (American Diabetes Association, 2017[4]). Type 1 DM (T1DM) or insulin-dependent diabetes mellitus (IDDM) mainly refers to reduced circulating insulin due to pancreatic beta cell failure (American Diabetes Association, 2017[4]). Type 2 DM (T2DM) or non-insulin-dependent diabetes mellitus (NIDDM); that is, the most prevalent form of DM; is primarily related to reduced insulin sensitivity and increased insulin resistance in peripheral tissues (American Diabetes Association, 2017[4]). Gestational diabetes is the other form of DM, which develops in pregnant women probably due to hormonal changes (Maraschin, 2012[57]). There are other forms of DM with minor frequency such as LADA (Latent Autoimmune Diabetes in Adults), Maturity-Onset Diabetes of the Young (MODY), secondary diabetes to different conditions such as pancreatitis, and secondary diabetes to some drugs, e.g. corticosteroids (American Diabetes Association, 2014[5]; O'Neal et al., 2016[62]).

SGLT2 inhibitors are a newly introduced class of antidiabetic drugs that diminish serum glucose by preventing tubular glucose reabsorption and inducing glycosuria (Davidson and Kuritzky, 2014[23]; Yaribeygi et al., 2018[99]). SGLT2s have two types of active cotransporters (types 1 and 2) that are mainly located in S2 and S3 segments of renal proximal tubules (as well as in small intestines) and reabsorb the filtrated tubular glucose (Figure 1(Fig. 1)) (Yaribeygi et al., 2019[96]). SGLTs can transport glucose, galactose, and sodium ions against concentration gradients (one sodium ion with one D-glucose) (Chao, 2014[15]). Moreover, they are involved in gluconeogenesis, improvement of peripheral insulin sensitivity, glucagon release, and insulin secretion (Han et al., 2008[37]; Ferrannini et al., 2014[27]; Wilding et al., 2014[92]; Kern et al., 2016[45]). Since discovering phlorizin as the first SGLT2 inhibitor, several forms of these agents have been introduced, which all reduce blood glucose to near physiological levels (Chao and Henry, 2010[16]; Clar et al., 2012[20]). SGLT2 inhibitors work completely independently of insulin, and thus have a lower risk of inducing hypoglycemia (Chao, 2014[15]). However, using these drugs may be followed by some side effects such as dehydration, dizziness, hypotension, urinary tract infections, and fainting (Reddy and Inzucchi, 2016[71]). Empagliflozin, dapagliflozin, and canagliflozin are the main approved forms of SGLT2 inhibitors (Reddy and Inzucchi, 2016[71]).

The liver is a highly specialized and vital organ that is only developed in vertebrates (Parker and Picut, 2005[66]). It is located in the right upper quadrant of the abdominal cavity, beneath the diaphragm, and on top of the right kidney, stomach, and intestines (Abdel-Misih and Bloomston, 2010[1]; Zong and Friedman, 2014[109]). Anatomically, the liver consists of two greater main lobes each made up of eight segments consisting of about 1000 smaller segments as lobules (Guyton and Hall, 2006[34]). The lobules are connected with the narrower ducts and then to a larger one to form the common hepatic (biliary) duct that transports the produced bile to the gallbladder and duodenum (Guyton and Hall, 2006[34]). It has two distinct blood circulation sources: oxygenated blood flows from the hepatic artery and nutrient-rich blood flows from the hepatic portal vein (Guyton and Hall, 2006[34]). The liver has several important physiological functions in both metabolic and immune-related processes as well as in detoxification, synthesizing, and storing activities (Parker and Picut, 2005[66]; Abdel-Misih and Bloomston, 2010[1]). It is involved in protein and hormone synthesis, glycogen synthesis and storage, blood clotting, vitamin storage, detoxification of the portal and hepatic circulation, clearing drugs and pharmacological agents, and carbohydrate and lipid metabolism (Guyton and Hall, 2006[34]; Zong and Friedman, 2014[109]). Moreover, the liver is involved in cholesterol and lipid homeostasis and the excretion of toxins and ingested heavy metals by producing bile and releasing it into the gallbladder (Guyton and Hall, 2006[34]). Moreover, mesenchymal cells of the liver (known as hepatocytes) control many biochemical activities such as the synthesis and breakdown of small and complex molecules via a system of highly fenestrated vessels (Schulze et al., 2019[77]). Estimates have counted about five hundred different activities for the liver (Sakka, 2007[74]). Therefore, a healthy functioning liver is an important issue in body homeostasis.

DM is a strong risk factor for liver function with negative effects on hepatic sufficiency (Hammerstad et al., 2015[35]; Ramachandran et al., 2017[69]; Weiler et al., 2020[91]). DM is considered the main common cause of liver disorders in most epidemiological studies (de Vries et al., 2020;[24] Islam et al., 2020[41]). A wide spectrum of liver complications including abnormal liver enzymes, NAFLD, cirrhosis, non-alcoholic steatohepatitis (NASH), hepatocellular carcinoma, acute liver failure, and icterus are directly related to DM, and are more prevalent in diabetic patients compared to non-diabetic population (Figure 2(Fig. 2)) (Tolman et al., 2007[87]; Leite et al., 2009[49]; Ortiz-Lopez et al., 2012[64]). The exact underlying mechanism inducing liver disorders in the diabetic milieu is not well understood, but the roles of insulin resistance, oxidative stress, and inflammation are more emphasized (Forbes and Cooper, 2013[28]; Mohamed et al., 2016[60]). Since the liver is among the most susceptible organs to DM-dependent oxidative stress, insulin resistance, and subsequent compensatory hyperinsulinemia are the major underlying factors inducing hepatic failure (Bugianesi et al., 2005[14], Manna et al., 2010[56]; Palsamy et al., 2010[65]). Insulin resistance and uncontrolled DM induce pathophysiological pathways inducing free radicals' hyper-production and antioxidant defense system (ADS) weakening, which in turn induce oxidative stress and various injuries to biomolecules such as proteins (including liver enzymes), lipids, and carbohydrates in the liver tissue (Mohamed et al., 2016[60]).

Moreover, DM induces different inflammatory pathways such as TNF-α (tumor necrosis factor-alpha), c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κb) cascades (Han et al., 2006[36]; Banerjee and Saxena, 2012[11]; Mohamed et al., 2016[60]). DM modulates the expression and activity of liver enzymes (Mohamed et al., 2016[60]). For example, cytochrome P450 2E1 (CYP2E1), a main metabolic enzyme mostly expressed in the liver; has higher expression and activity in diabetic and obese individuals and induces excessive metabolism of polyunsaturated fatty acids, which in turn increases cytotoxic byproducts, mitochondrial reactive oxygen species (ROS) and oxidative stress (Leung and Nieto, 2013[51]). Furthermore, DM can cause fat aggregation in hepatocytes and induces NAFLD, which in turn exacerbates liver functions (Saponaro et al., 2015[75]). NAFLD may induce NASH by triggering inflammatory events, and necrotic processes in hepatocytes, and then, prolonged NASH may predispose to cirrhosis and hepatocellular carcinoma at advanced levels (Mohamed et al., 2016[60]). Therefore, proper management of DM could effectively prevent the activation of these pathophysiological pathways and improve liver sufficiency in the diabetic milieu.

Using SGLT2 inhibitors in patients with diabetes is increasing and they are now recognized as potent hypoglycemic drugs with minor side effects (Choi et al., 2022[19]). Although they have shown some liver benefits in studies (Latva-Rasku et al., 2019[47], Scheen, 2019[76], Hsiang and Wong, 2020[39]), the involved molecular mechanisms are not well understood. In the following sections, we survey for possible liver benefits of SGLT2 inhibitors in different liver disorders and conclude about possible involved mechanisms.

SGLT2 inhibitors can provide extra-glycemic benefits in the liver tissue (Table 1(Tab. 1); References in Table 1: Aso et al., 2019[8]; Chiang et al., 2020[18]; Coelho et al., 2021[21]; Hendryx et al., 2022[38]; Inoue et al., 2019[40]; Jojima et al., 2019[42]; Leiter et al., 2016[50]; Saffo et al., 2020[72], 2021[73]; Seko et al., 2018[78]; Shiba et al., 2018[80]; Wei et al., 2021[90]). They can normalize LFTs as valuable markers of liver health. Moreover, they can reduce or slow the fibrotic processes and decrease liver tissue stiffness via different pathways. Owing to their fat-burning effects, SGLT2 inhibitors reduce the stored lipid droplets in steatotic hepatocytes and normalize liver tissue composition in patients with NAFLD, which in turn prevents subsequent disorders. Finally, these antidiabetics demonstrated potent anti-carcinogenic effects in the liver (and other tissues) and can inhibit NASH to HCC transition or HCC development in the diabetic milieu through several pathways. Taken together, SGLT2 inhibitors are promising glucose-lowering agents with effective hepatoprotective benefits.

Habib Yaribeygi and Amirhossein Sahebkar (Department of Biotechnology, Mashhad University of Medical Sciences, Mashhad, Iran; E-mail: amir_saheb2000@yahoo.com) contributed equally as corresponding author.

The authors declare that they have no conflict of interest in this study.