Role of sodium-glucose cotransporter 2 inhibitors in liver diseases

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors compete with the SGLT2 protein for glucose binding in the renal tubules, reducing glucose reabsorption in the kidneys. This in turn leads to increased excretion of glucose, sodium, and water into the urine. These inhibitors, initially developed for diabetes management, have shown potential benefits beyond glycemic control, impacting liver health through various mechanisms. They have emerged as promising agents in managing liver conditions, including fatty liver disease, cirrhosis, and the prevention of hepatocellular carcinoma (HCC). They modulate processes like oxidative stress, inflammation, and autophagy, which are implicated in metabolic dysfunction-associated steatotic liver disease pathogenesis, potentially reducing steatosis and inflammation and preventing progression to more severe liver conditions. In patients with liver cirrhosis, SGLT2 inhibitors have been associated with a reduced need for large-volume paracentesis and lower mortality rates, indicating their potential in managing diuretic-resistant ascites. SGLT2 inhibitors have shown potential in modulating molecular pathways involved in HCC, such as inflammatory responses and oxidative stress, that could justify their use in the prevention of HCC and improving survival in patients with HCC. The present review synthesized findings from multiple studies to elucidate the role of SGLT2 inhibitors in these liver conditions.

Key Words: Sodium-glucose cotransporter 2 inhibitors; Dapagliflozin; Empaglifozin; Metabolic dysfunction-associated steatotic liver disease; Cirrhosis

Core Tip: Sodium-glucose cotransporter 2 inhibitors, primarily developed for diabetes, have shown potential benefits in managing liver conditions. Studies report improved liver enzymes, lipid profile, insulin sensitivity, and stiffness in steatotic liver disease. In patients with decompensated cirrhosis of the liver with refractory ascites, sodium-glucose cotransporter 2 inhibitors reduce the need for paracentesis due to their natriuretic and diuretic effects. Emerging evidence also suggests a role in preventing hepatocellular carcinoma. However, associated adverse events necessitate careful consideration. Further research is crucial to fully understand their mechanisms, optimize treatment strategies, and establish clear clinical guidelines, especially regarding the benefit-risk ratio and combination therapies.

INTRODUCTION

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of oral antidiabetic medications, have garnered increasing interest for their potential benefits beyond glycemic control, particularly in liver diseases such as metabolic dysfunction-associated liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (known as MASH). SGLT2 inhibitors, including dapagliflozin and empagliflozin, primarily work by inhibiting glucose reabsorption in the kidneys, leading to enhanced urinary glucose excretion (UGE) and improved glycemic control[1]. However, recent studies have demonstrated that these medications offer several metabolic advantages, such as weight loss, reduced blood pressure, and improved insulin sensitivity, all of which are relevant in managing metabolic disorders like MASLD[2].

MASLD, characterized by fat accumulation in the liver, is closely linked to conditions such as insulin resistance, type 2 diabetes mellitus (T2DM), and obesity and can progress to more severe conditions like non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. The growing prevalence of MASLD, particularly in patients with T2DM, underscores the need for effective treatments. While no Food and Drug Administration-approved pharmacological therapies are currently available for NAFLD, SGLT2 inhibitors have shown promise in the management of MASLD and MASH by reducing liver fat, lowering liver enzymes, and modulating inflammatory pathways[3]. Additionally, emerging evidence suggests that these drugs may also help mitigate hepatic fibrosis, a key factor in liver disease progression[4].

Despite promising results from preclinical and clinical studies, the role of SGLT2 inhibitors in liver disease remains under investigation. Although some randomized controlled trials (RCTs) have shown benefits, further research is required to fully understand their impact on liver fibrosis and steatosis and their long-term safety in liver disease populations. This growing body of evidence positions SGLT2 inhibitors as a potentially valuable therapeutic option for patients with MASLD and MASH, especially those with concurrent T2DM.

MECHANISM OF ACTION OF SGLT2 INHIBITORS

SGLT2 inhibitors, including dapagliflozin, empagliflozin, and canagliflozin, exert their effects by targeting SGLT2, a protein located in the proximal tubule of the nephron in the kidneys[5]. SGLT2 is responsible for reabsorbing approximately 90% of filtered glucose back into the bloodstream. By inhibiting this transporter SGLT2 inhibitors block glucose reabsorption, increasing UGE and reducing blood glucose levels. This mechanism results in a modest decrease in hemoglobin A1c by approximately 0.5%-1.0%[6].

Beyond their antidiabetic effects SGLT2 inhibitors also interact with the renin-angiotensin-aldosterone system (RAAS)[7]. When sodium reabsorption is inhibited in the proximal tubule, there is an increase in sodium delivery to the macula densa. This leads to a reduction in renin secretion and attenuation of RAAS activity. The inhibition of RAAS reduces afferent arteriole vasodilation and hyperfiltration injury, providing a potential renoprotective effect, particularly beneficial in conditions like chronic kidney disease and cirrhosis.

Additionally, SGLT2 inhibitors have diuretic effects, contributing to natriuresis and osmotic diuresis[8]. These actions help to lower blood volume and blood pressure that may be beneficial in conditions like heart failure in which fluid retention is common. The diuretic effects are also thought to be influenced by changes in hormones such as arginine vasopressin and atrial natriuretic peptide, which play roles in fluid homeostasis.

Moreover, SGLT2 inhibitors may exert beneficial effects on liver function and nutritional status, especially in patients with diabetes and cirrhosis. The improvement in liver function, potentially indicated by increased serum albumin concentrations, may contribute to the reduction of ascites, a common complication in cirrhosis[9]. SGLT2 inhibitors activate adenosine monophosphate-activated kinase (AMPK), which is a highly conserved enzyme that detects changes in cellular energy levels. AMPK is known to increase glucose and fatty acid transport, fatty acid oxidation, autophagy, mitochondrial synthesis, and oxidative metabolism to preserve ATP during times of energy deficiency[10]. AMPK-induced inhibition of NF-kB has anti-inflammatory effects via IL-6 suppression, inhibition of tumor necrosis factor-α release, and stimulation of IL-10 formation[11]. Through these multifaceted mechanisms, SGLT2 inhibitors not only address hyperglycemia but also offer promising benefits in conditions such as heart failure, chronic kidney disease, and liver disease (Figure 1).

Figure 1 Beneficial effect of sodium-glucose cotransporter 2 inhibitors in various liver diseases. The blue text box indicates the effect on the liver, and the green text box indicates the effect on the kidney. AMPK: Adenosine monophosphate-activated kinase; HCC: Hepatocellular carcinoma; RAAS: Renin-angiotensin-aldosterone system; SGLT2: Sodium-glucose cotransporter 2.

PHARMACOKINETICS

SGLT2 inhibitors, including drugs such as dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, and tofogliflozin, share several key pharmacokinetic characteristics. These drugs are rapidly absorbed following oral administration with peak plasma concentrations (C_max) typically occurring within 1-2 h[12]. The elimination half-life of these medications is relatively long, supporting once-daily dosing.

The majority of SGLT2 inhibitors undergo extensive hepatic metabolism, primarily via glucuronidation to form inactive metabolites. Only a small fraction of the parent drug is excreted unchanged through the kidneys[13]. This metabolic pathway suggests that the pharmacokinetics of SGLT2 inhibitors are primarily influenced by liver function rather than renal function.

Hepatic impairment

The pharmacokinetics of SGLT2 inhibitors are generally impacted by hepatic impairment with varying degrees of effect across different drugs. In subjects with moderate hepatic impairment, an increase in systemic exposure to these drugs has been observed.

Dapagliflozin: Systemic exposure to dapagliflozin has been shown to correlate with the degree of hepatic impairment[14]. In mild hepatic impairment exposure area under the curve (AUC) increases by 3% while C_max becomes 12% lower. In moderate and severe cases AUC rises by 36% and 67%, respectively; C_max increases by 12% (moderate) and 40% (severe)[15]. Caution may be exercised in severe hepatic impairment due to dose-dependent exposure increase; however, long-term safety has not been well studied for severe cases. Therefore, the increase in systemic exposure in mild to moderate hepatic impairment probably does not warrant any reduction in dosing.

Empagliflozin: In mild hepatic impairment exposure AUC increases by 23% while C_max becomes 4% higher. In moderate and severe cases AUC rises by 47% and 75%, respectively; C_max increases by 23% (moderate) and 48%[16]. However, despite up to two times exposure increase, it is considered well-tolerated. These findings suggest that these increases were not substantial enough to require a dose adjustment. The drug was well tolerated even in patients with moderate and severe hepatic impairment with adverse events being mild to moderate in intensity[16].

Canagliflozin: In mild hepatic impairment exposure AUC increases by 10%-11% while C_max becomes 7%-10% higher. In moderate cases AUC rises by 11%; C_max remains more or less unchanged[17]. These pharmacokinetics of canagliflozin were also not found to have many clinical implications. It was observed that the C_max and AUC values differed by < 11% between subjects with normal hepatic function and those with mild and moderate hepatic impairment[14].

Tofogliflozin: There was a 47% increase in C_max and a 70% increase in the AUC. Despite these increases, UGE did not significantly change, and the drug remained well tolerated without any clinically significant adverse events[18].

Ipragliflozin: There was a slight increase in systemic exposure in moderate hepatic impairment with geometric mean ratios of 127% for C_max and 125% for AUC. However, no clinically significant effects on the pharmacokinetics of ipragliflozin or its major metabolite were noted, supporting that dose adjustments are generally unnecessary for patients with moderate hepatic impairment[19].

Ertugliflozin: No dose adjustment has been recommended for mild-to-moderate hepatic impairment. It is well tolerated up to moderate hepatic impairment; however, there is a lack of data in cases of severe hepatic impairment[17].

In summary regarding the use of these drugs in hepatic impairment, clinical decisions should weigh individual patient factors, including the severity of hepatic and renal impairment.

Renal impairment

In patients with renal impairment, the pharmacokinetics of SGLT2 inhibitors can be influenced by reduced renal clearance. Canagliflozin for instance demonstrated an increase in systemic exposure in individuals with renal impairment[14]. The amount of UGE declined as renal function decreased, whereas the renal threshold for glucose excretion was not suppressed to the same extent in the moderate-to-severe renal impairment groups. Despite this a single dose of canagliflozin was found to be well-tolerated by subjects with renal impairment.

Dose adjustments and clinical considerations

There have been a few case reports documenting incidents of liver injury induced by SGLT2 inhibitors, especially in subjects with cirrhosis or preexisting compensated liver disease[20,21]. However, these incidents are rare, and the fact remains that for most SGLT2 inhibitors, no dose adjustments are required in patients with mild hepatic or renal impairment. However, patients with moderate hepatic impairment or severe renal impairment may experience increased drug exposure, necessitating a more cautious approach to dosing. Given that the long-term safety and efficacy profiles of SGLT2 inhibitors in patients with significant hepatic impairment are not fully established, it is crucial for clinicians to assess the benefit-risk ratio on an individual basis, especially for drugs like dapagliflozin.

EFFECT IN MASLD

SGLT2 inhibitors, primarily used for managing T2DM, have shown promising effects in treating MASLD. These effects extend beyond glucose control, influencing various metabolic pathways involved in liver steatosis and fibrosis.

Reduction in liver fat content

Clinical trials have consistently demonstrated that SGLT2 inhibitors significantly reduce hepatic fat content[22,23]. In particular dapagliflozin and empagliflozin have shown notable reductions in liver steatosis as assessed by non-invasive imaging techniques such as controlled attenuation parameter scores and magnetic resonance imaging proton density fat fraction[24,25]. For instance, dapagliflozin significantly reduced the controlled attenuation parameter score from baseline (266.3 ± 57.8 dB/m to 298.6 ± 59.0 dB/m, P = 0.002)[23]. Additionally, treatment with empagliflozin demonstrated a significant reduction in liver fat fraction compared with control groups[26]. Canagliflozin has also been associated with a reduction in hepatic fat fraction over time with significant decreases in liver fat observed after 6 months and 12 months of treatment (P < 0.0005)[27]. Studies indicate that SGLT2 inhibitors, either as monotherapy or in combination with other agents, reduce liver fat by promoting increased fatty acid oxidation and enhancing insulin sensitivity[28]. This reduction in liver fat is observed even in patients without diabetes, suggesting that the benefits of these drugs extend beyond blood glucose regulation[29].

Improvement in liver enzymes and fibrosis markers

SGLT2 inhibitors have been associated with improvements in liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase[30-32]. In a meta-analysis SGLT2 inhibitor therapy was observed to cause a statistically significant improvement in ALT [standardized mean difference: -0.21, 95% confidence interval (CI): -0.32 to -0.10, P < 0.01] and AST (standardized mean difference: -0.15, 95%CI: -0.24 to -0.07, P < 0.01) when compared with standard of care or placebo[33]. In another study 24 weeks of dapagliflozin therapy led to significant reductions in serum concentrations of AST, ALT, ferritin, and type IV collagen 7S[34]. The decrease in serum levels of liver enzymes in subjects with diabetes using SGLT2 inhibitors has also been found to be superior when compared with other drugs like dipeptidyl peptidase-4 (DPP-4) inhibitors[35].

Additionally, some studies have suggested that SGLT2 inhibitors may attenuate liver fibrosis, particularly in individuals with advanced liver disease or those with significant hepatic fibrosis at baseline[36,37]. While effects on the fibrosis index (e.g., fibrosis-4 index, AST to platelet ratio index, NAFLD fibrosis score) have been variable, there is evidence supporting a reduction in liver stiffness measurements (LSM) in patients who have received treatment, suggesting a potential for halting or even reversing fibrosis progression.

In one study dapagliflozin led to a reduction in liver stiffness as measured by transient elastography. LSM decreased from 9.49 ± 6.05 kPa to 8.01 ± 5.78 kPa in the dapagliflozin group. In addition in the dapagliflozin group in subjects with significant liver fibrosis, LSM decreased significantly from 14.7 ± 5.7 kPa to 11.0 ± 7.3 kPa (P = 0.0158)[36]. However, this significant reduction in LSM occurred only in a specific subgroup (baseline LSM ≥ 8.0 kPa). Similar results have also been observed with empagliflozin therapy, with 24-week therapy significantly ameliorating hepatic fibrosis[26].

Furthermore, meta-analyses have demonstrated a reduction in liver stiffness in patients treated with SGLT2 inhibitors; a random-effects model indicated a decrease in LSM in the dapagliflozin group compared with controls (mean difference = -0.82, P = 0.005)[37]. This suggests that SGLT2 inhibitors may have a role in improving liver stiffness, potentially through the attenuation of hepatic inflammation and fibrosis. In another meta-analysis several indicators of liver fibrosis, LSM, serum ferritin, serum type IV collagen 7S, and fibrosis-4 index, were found to be considerably reduced by SGLT2 inhibitors while subgroup analysis showed marked dose-dependence[38]. Thus, there is evidence suggesting that SGLT2 inhibitors may attenuate liver fibrosis in patients with significant liver injury, particularly through mechanisms such as reduced hepatic lipid accumulation, improved insulin sensitivity, and decreased oxidative stress. Table 1 summarizes the studies on the effect of SGLT2 inhibitors on liver stiffness and fibrosis as assessed by elastography or biopsy in patients with MASLD.

Table 1 Studies on the effect of sodium-glucose cotransporter 2 inhibitors on liver stiffness and fibrosis as assessed by elastography or biopsy in patients with metabolic dysfunction-associated steatotic liver disease.

Ref.	Country, study design	No. of patients	Male sex/age, in years/DM	Drug	Method of assessment	Outcome
Shimizu et al[36], 2019	Japan, RCT	33	57.6%/56.2 ± 11.5/100%	Dapaglifozin for 24 weeks	Transient elastography	LSM was nonsignificantly decreased after 24 weeks in the dapagliflozin group (9.5 ± 6.0 kPa to 8.0 ± 5.8 kPa, P = 0.0539) but significantly reduced in the subgroup of patients with baseline LSM ≥ 8.0 kPa (14.7 ± 5.7 kPa to 11.0 ± 7.3 kPa, P = 0.0158)
		24	62.5%/57.1 ± 13.8/100%	Placebo
Akuta et al[45], 2020	Japan, retrospective	7	71.4%/44-64/100%	Canagliflozin for 1 year	Liver biopsy	≥ 1 point improvement in fibrosis was observed in 2 (29%) at 6 months and 2 (29%) at 1 year (total 3 patients)
Taheri et al[29], 2020	Iran, RCT	43	65.1%/43.8 ± 9.7/0%	Empaglifozin for 24 weeks	Transient elastography	LSM was significantly decreased at 24 weeks in the empagliflozin group from baseline (6.0 ± 1.4 kPa to 5.3 ± 1.1 kPa, P = 0.001) but not in the placebo group
		47	46.8%/44.1 ± 9.3/0	Placebo
Chehrehgosha et al[26], 2021	Iran, RCT	35	42.9%/50.5 ± 8.4/100%	Empaglifozin for 24 weeks	Transient elastography	LSM was significantly decreased after 24 weeks in the empagliflozin group (LSM: 6.8 ± 2.4 to 6.0 ± 1.6 kPa; P = 0.005) while the change in fibrosis score in the pioglitazone group and placebo groups were not significant
		34	50%/52.5 ± 7.9/100%	Pioglitazone
		37	37.8%/51.8 ± 7.8/100%	Placebo
Das et al[39], 2021	India, prospective	100	81%/44.1 ± 8.2/100%	Dapaglifozin for 24 weeks	Transient elastography	LSM was significantly reduced at 24 weeks (6.9 ± 1.4 kPa at baseline to 6.0 ± 1.4 kPa; P = 0.001)
Pokharel et al[25], 2021	Nepal, prospective	84	81%/47.2 ± 10.0/100%	Empaglifozin	Transient elastography	There was a significant reduction in the LSM from 5.9 ± 4.2 kPa to 5.0 ± 1.5 kPa (P = 0.001)
Koullias et al[49], 2024	Greece, prospective	25	72%/63.2 ± 1.4/	Empaglifozin for 52 weeks	2D-shear wave elastography	There was significant reduction in stiffness from 7.1 ± 0.9 kPa to 6.9 ± 1.6 kPa (P = 0.046) in the empagliflozin group but not with dulaglutide or placebo
		25	84%/54.4 ± 2.5/100%	Dulaglutide for 52 weeks
		28	60.7%/55 ± 2.4/100%	Placebo
Stratina et al[48], 2024	Romania, prospective	92	45.7%/61.5 ± 11.2/100%	Dapagliflozin for 24 weeks	Transient elastography	LSM reduced significantly from 8.1 ± 2.9 kPa to 6.5 ± 3.1 kPa (P < 0.001) with semaglutide but not with (8.2 ± 3.1 kPa to 7.9 ± 2.9 kPa, P = 0.074)
		95	45.3%/56.0 ± 9.8/100%	Semaglutide for 24 weeks
Weng et al[24], 2024	Taiwan, RCT	69	57.3%/51 ± 12.6/9.3%	Dapagliflozin for 24 weeks	Transient elastography	Both groups exhibited reductions in LSM from baseline (control group: From 5.4 ± 2.3 to 4.5 ± 1.2 kPa, P = 0.002; dapagliflozin group: From 5.4 ± 2.0 to 4.1 ± 1.0, P < 0.001); however, the between-group difference did not reach statistical significance (P = 0.08)
		62	50.7%/52 ± 12/17.3%	Placebo

2D: Two-dimensional; DM: Diabetes mellitus; LSM: Liver stiffness measurement; RCT: Randomized controlled trial.

Metabolic improvements

Beyond liver-specific effects SGLT2 inhibitors improve systemic metabolic parameters that are crucial for managing MASLD. These include significant reductions in body weight, visceral fat accumulation, and waist circumference as well as improvements in insulin sensitivity[34,39,40]. Canagliflozin has been found to significantly reduce the serum levels of plasma glucose, glycated hemoglobin, triglycerides, uric acid, and ferritin as well as body weight[32]. Empagliflozin has been found to significantly improve hepatic steatosis, conferring protection against subsequent hepatic insulin resistance[41]. Insulin resistance, a key pathogenic factor in NAFLD, is improved by these drugs, contributing to reduced hepatic lipogenesis and enhanced fatty acid oxidation.

Inflammation and oxidative stress

The pathophysiology of MASLD involves chronic low-grade inflammation and oxidative stress, which are thought to exacerbate hepatic injury and fibrosis. SGLT2 inhibitors have demonstrated anti-inflammatory effects, possibly through the reduction of oxidative stress markers such as fibroblast growth factor 21 and DPP-4 in the liver[42]. These effects may contribute to a more favorable liver environment, reducing the risk of progressing from simple steatosis to NASH or fibrosis.

Effects on patients beyond T2DM

Although much of the research on SGLT2 inhibitors and MASLD has focused on patients with T2DM, there is increasing evidence suggesting that these drugs are effective in individuals with fatty liver disease, regardless of diabetes status[43]. Studies involving populations with and without diabetes have shown that SGLT2 inhibitors can reduce hepatic fat, improve liver enzymes, and lower markers of liver fibrosis, emphasizing their potential as a therapeutic option for the broader population with MASLD. Improvement of liver dysfunction after treatment with dapagliflozin was associated with a decrease in serum DPP-4, suggesting that reduction of serum DPP-4 by SGLT2 inhibitors may be a therapeutic strategy for MASLD/MASH in patients with T2DM that is independent of glucose lowering or weight loss[44].

Long-term efficacy

The long-term benefits of SGLT2 inhibitors in managing MASLD remain under investigation, but available data suggest sustained improvements in liver function, metabolic control, and body composition[45,46]. In addition, compared with other medications like DPP-4 inhibitors, SGLT2 inhibitor use has been seen to be associated with a greater decline in fatty liver index (difference at 1-year measurement, -3.8 95%CI: -4.7 to -3.0)[47]. This observed advantage of SGLT2 inhibitors over DPP-4 inhibition was found to be consistent across subgroups. A recent study evaluating the efficacy of an SGLT2 inhibitor vs a GLP-1 receptor agonist seemed to indicate that GLP-1 receptor agonists like semaglutide might provide greater reduction in LSM compared with SGLT2 inhibitors[48]. However, other studies seem to suggest to the contrary[49].

Thus, there is a need to conduct more long-term studies comparing the efficacy of SGLT2 inhibitors vs other drugs in improving liver function. SGLT2 inhibitors are generally well-tolerated with no significant increase in adverse events compared with placebo or other diabetes medications. In a nested case-control study conducted using Taiwan’s National Health Insurance Research Database for 2011-2018, it was observed that the use of SGLT2 inhibitors was associated with a lower risk of developing MASLD/MASH [odds ratio (OR) = 0.84, 95%CI: 0.46-1.52 and OR = 0.85, 95%CI: 0.63-1.14, respectively], and higher cumulative doses of the medication were significantly associated with a reduced risk of MASLD/MASH (OR = 0.61, 95%CI: 0.38-0.97)[50].

EFFECT IN CIRRHOSIS

SGLT2 inhibitors, primarily used for managing T2DM and heart failure, have recently been explored for their potential therapeutic benefits in patients with liver cirrhosis[51]. Although these agents were primarily designed to lower blood glucose levels, they offer several mechanisms of action that may benefit individuals with cirrhosis, particularly those with complications such as ascites, hepatic hydrothorax, and renal impairment.

Natriuresis and ascites control

SGLT2 inhibitors have demonstrated a natriuretic effect, which can be beneficial in patients with cirrhosis, particularly those with portal hypertension and ascites[52,53]. In cirrhosis the activation of the RAAS and sympathetic nervous system leads to sodium and water retention, exacerbating ascites. SGLT2 inhibitors work by increasing urinary sodium excretion and glucose elimination in the proximal tubule, which can counteract the effects of fluid retention.

Studies have shown that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, are effective in reducing the need for large-volume paracentesis in patients with cirrhosis and ascites[54]. Empagliflozin has also shown significant improvement in the management of ascites with around 24% of patients experiencing total resolution of ascites over 4 weeks of treatment[55,56].

Impact on renal function

Renal impairment is a common complication in patients with cirrhosis, particularly in those with advanced liver disease or hepatic decompensation. Recent data suggest that SGLT2 inhibitors may have a protective role in some cases, particularly when renal impairment is due to nephropathy or secondary to conditions like immunoglobulin A nephropathy in patients with cirrhosis[57]. In a case study dapagliflozin was associated with a marked reduction in proteinuria in a patient with cirrhosis and nephrotic syndrome, highlighting its potential renal benefits in patients with cirrhosis and comorbid kidney disease. The occurrence of acute kidney injury (AKI), although attributed to SGLT2 inhibitors, is doubtful. A pooled analysis of 13 studies using dapagliflozin did not show any significant increase in the occurrence of AKI[58]. However, the risk of infections [particularly urinary tract infections (UTIs)] may increase, necessitating close monitoring of renal function and infection status in patients with cirrhosis on SGLT2 inhibitors[58].

Effect on liver function and disease severity

The effect of SGLT2 inhibitors on liver function and disease progression in cirrhosis is still under investigation. These agents may indirectly benefit liver function by improving metabolic parameters such as insulin resistance and reducing hepatic fat, a key factor in the development of MASH. Furthermore, by controlling ascites and reducing fluid retention, SGLT2 inhibitors may alleviate the burden of decompensated liver disease, potentially improving overall liver function[58,59].

However, the effects of SGLT2 inhibitors on advanced liver disease markers, such as Child-Pugh scores and Model for End-Stage Liver Disease scores, have been less clear. While some studies have not observed significant differences in these scores with SGLT2 inhibitor treatment, other research has shown that these drugs may help slow disease progression and prevent further decompensation[60,61].

Impact on mortality and disease outcomes

Preliminary data have suggested that SGLT2 inhibitors, such as empagliflozin and dapagliflozin, may improve survival rates in patients with cirrhosis, particularly those with diabetes[61]. A recent study showed that SGLT2 inhibitors were associated with a reduced risk of death in patients with cirrhosis compared with other therapies, such as DPP-4 inhibitors[60]. Table 2 summarizes the studies on the role of SGLT2 inhibitors in patients with cirrhosis. However, more extensive studies are needed to confirm these findings and assess the long-term impact of these drugs on disease progression and mortality in cirrhosis. Studies should also examine the impact of SGLT2 inhibitors on liver fibrosis, disease severity, and outcomes such as transplant-free survival while carefully monitoring for potential adverse effects.

Table 2 Studies on the role of sodium-glucose cotransporter 2 inhibitors in patients with cirrhosis.

Ref.	Country, study design	No. of patients	Male sex/age, in years/etiology/DM	Drug	Indication	Outcome
Montalvo-Gordon et al[52], 2020	Mexico, case series	3	33.3%/53-63/NAFLD: 100%/100%	Empaglifozin: 1, canagliflozin: 2	Diuretic intractable ascites	At 12-24 months of follow-up, all 3 patients had resolution of ascites (off-diuretics)
Kalambokis et al[53], 2021	Greece, case report	1	Male/54/PBC/yes	Empaglifozin	Refractory ascites and hepatic hydrothorax	Increased natriuresis with resolution of ascites, hydrothorax within 4 months (off diuretics), and improvement in glycemic control and liver function
Saffo et al[59], 2021	United States, retrospective	78	65%/61 (22-88)/NAFLD: 50%, Alcohol: 19%/NA	Empagliflozin: 33; Canagliflozin: 17; Dapagliflozin: 13; Ertugliflozin: 1; Multiple: 14	NA	7 patients had AEs, including 6 with mycotic genital infections. There were no episodes of AKI, hypotension, significant electrolyte disturbances, or hepatotoxicity
Saffo et al[60], 2021	United States, retrospective	502	99%/67 ± 7/NAFLD: 47%/100%	NA	Prevention of ascites and death in patients with compensated cirrhosis and DM on metformin	Compared to DPP-4 inhibitors, SGLT2 inhibitors had a reduced risk of mortality (aHR: 0.33, 0.11-0.99) but not ascites
Huynh et al[61], 2023	United States, retrospective	1411	48.6%/60.3 ± 11.7/NA/100%	Empagliflozin: 863; Dapagliflozin: 395; Canagliflozin: 175; Ertugliflozin: 12	Prevention of morbidity and mortality in patients with compensated cirrhosis and DM on metformin	Combination of SGLT2 inhibitors with metformin reduced the risk of mortality (HR = 0.57, 0.41-0.81), decompensation (HR = 0.63, 0.43-0.93), and HCC (HR = 0.43, 0.21-0.88) compared with those on metformin monotherapy
Bakosh et al[56], 2024	Egypt, RCT	21	42.9%/65.7 ± 5/MASLD: 52.4%, HCV: 47.6%/42.9%	Empaglifozin	Refractory ascites	The need for LVP (42.9% vs 100%) and the proportion of patients with ascites (76.2% vs 100%) were significantly lower with SGLT2 inhibitors
Shen et al[55], 2024	Australia, prospective	10	60%/58.5 ± 10.1/alcohol: 60%, HCV: 30%/NA	Empaglifozin	NA	8 (80%) reported AEs, and 3 (30%) reported serious AEs with the frequency being similar in those without cirrhosis
Singh et al[54], 2024	India, RCT	20	90%/52.1 ± 8.6/alcohol: 50%, MASLD: 25%/NA	Dapagliflozin	Recurrent ascites	Complete (15% vs 0%) and partial control (55% vs 35%) of ascites at 6 months was significantly better with SGLT2 inhibitors
Yoshimura et al[57], 2024	Japan, case report	1	Male/45/alcohol/no	Dapagliflozin	IgA nephropathy	Significant reduction in proteinuria within 1 week of treatment

AE: Adverse events; aHR: Adjusted hazard ratio; AKI: Acute kidney injury; DM: Diabetes mellitus; DPP-4: Dipeptidyl peptidase 4; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HR: Hazard ratio; IgA: Immunoglobulin A; LVP: Large-volume paracentesis; MASLD: Metabolic dysfunction-associated steatotic liver disease; NA: Not available; NAFLD: Nonalcoholic fatty liver disease; PBC: Primary biliary cirrhosis; RCT: Randomized controlled trial; SGLT2: Sodium-glucose cotransporter 2.

SGLT2 INHIBITORS AND HEPATOCELLULAR CARCINOMA

Preliminary laboratory findings suggest that SGLT2 inhibitor use can improve liver function and suppress the proliferation of hepatocellular carcinoma (HCC) cells[62]. Preclinical studies support the role of these drugs in modulating molecular pathways that are central to HCC pathogenesis, including inflammatory responses, cell proliferation, and oxidative stress[63,64]. This raises enormous promise in the long-term management, monitoring, and prognosis of patients with chronic liver disease. In a study based on the National Surveillance, Epidemiology and End Results database, it was found that initiation of SGLT2 inhibitor therapy was associated with a significantly lower risk of mortality among patients with HCC after adjusting for potential confounders [hazard ratio (HR) = 0.68, 95%CI: 0.54-0.86], and this association was even for longer duration of use (HR = 0.60, 95%CI: 0.41-0.88)[65]. However, this observational study did not sufficiently discuss the potential impact of confounding factors (e.g., baseline characteristics, concomitant medications) on the results. In addition SGLT2 inhibitor initiation was observed to be associated with a lower mortality risk ranging from 14% to 60% independent of patient demographics, tumor characteristics, and cancer treatments.

In another nationwide cohort study in South Korea using propensity scoring, it was seen that in the cohort with fatty liver disease-T2DM-chronic viral hepatitis, there was a significant decrease in HCC occurrence among those receiving SGLT2 inhibitors (P = 0.03); this observation remained valid in the multivariate Cox regression analysis (HR = 2.21, 95%CI: 1.01-4.85, P = 0.048)[66]. Findings from other studies also suggest that SGLT2 inhibitor use was associated with a lower risk of HCC compared with other drugs like DPP-4 inhibitors after adjusting for other variables[67,68]. Table 3 summarizes the studies on the role of SGLT2 inhibitors in relation to HCC. While these are still early days, these findings assume enormous importance in the context of the increasing burden of HCC, especially among patients with MASLD. The use of SGLT2 inhibitors could be a game-changer in our approach to dealing with the rising burden of HCC worldwide.

Table 3 Studies on the role of sodium-glucose cotransporter 2 inhibitors in relation to hepatocellular carcinoma.

Ref.	Country, study design	No. of patients	Male sex/age, in years/cirrhosis/DM	Outcome
Hendryx et al[65], 2022	United States, retrospective	3185	68.3%/74.8 ± 6.5/68.5%/100%	SGLT2 inhibitor use was associated with reduced risk of mortality (HR: 0.58, 0.42-0.89) in patients with HCC, and the association was stronger for longer duration of use (HR: 0.37, 0.19-0.71)
Cho et al[66], 2024	South Korea, retrospective	55770	56.8%/49.7 ± 12.9/0.2%/100%	There was no reduction in the risk of HCC in the overall cohort, but a significant decrease in HCC occurrence was observed among patients using SGLT2 inhibitors with chronic viral hepatitis (P = 0.03)
Chou et al[67], 2024	Hong Kong, retrospective	22154	59.8%/62.8 ± 11.3/2.7%/100%	SGLT2 inhibitor use was associated with a lower risk of HCC (aHR: 0.42, 0.28-0.79), cancer-related mortality (aHR: 0.31, 0.19-0.41), and all-cause mortality (aHR: 0.30, 0.26-0.41) compared with DPP-4 inhibitors
Chung et al[68], 2024	South Korea, retrospective	13227	63.2%/59.8 ± 11.4/NA/100%	SGLT2 inhibitor use was associated with a lower risk of HCC (aHR: 0.68, 0.48-0.95), liver-related complications (aHR: 0.88, 0.79-0.97), and cirrhosis-related complications (aHR: 0.88, 0.79-0.98) compared with DPP-4 inhibitors

aHR: Adjusted hazard ratio; DM: Diabetes mellitus; DPP-4: Dipeptidyl peptidase 4; HR: Hazard ratio; HCC: Hepatocellular carcinoma; NA: Not available; SGLT2: Sodium-glucose cotransporter 2.

ADVERSE EVENTS

While SGLT2 inhibitors have been well-tolerated in many clinical settings, their safety profile in patients with cirrhosis, especially those with hepatic decompensation, requires careful consideration. Patients with cirrhosis are at a higher risk for infections, particularly genitourinary infections, and SGLT2 inhibitors may exacerbate this risk. The possibility of electrolyte imbalances and AKI, especially when used in conjunction with diuretics or in patients with sepsis, also warrants close monitoring. The common adverse events associated with SGLT2 inhibitors that have been documented to date are summarized below (Table 4).

Table 4 List of adverse events with sodium-glucose cotransporter 2 inhibitors.

Adverse events	Description	Incidence
Genital mycotic infections	Common due to increased glucose in the urine, fostering fungal growth, more frequent in premenopausal females. UTIs are also common, especially in older individuals or those with recurrent infections	Up to 15% for genital mycotic infections; UTIs are common, but the exact incidence varies
DKA	It is rare but serious; it can occur with a modest glucose increase, with a higher risk in patients with cirrhosis during fasting, dehydration, or illness. Canagliflozin and dapagliflozin pose a greater risk of euglycemic DKA than empagliflozin	Rare but reported cases in patients with cirrhosis
Acute kidney injury	Higher risk when combined with diuretics, especially in those with renal impairment (GFR < 60 mL/min/1.73 m2). Patients with sepsis or dehydration need close monitoring	There has not been a significant increase in trials, but caution is to be exercised in high-risk populations
Fractures and amputations	Canagliflozin is linked to increased fracture risk and nearly doubled lower limb amputation risk, particularly in patients with peripheral vascular disease	CANVAS trial: Higher fracture risk (15.4 fractures per 1000 person-years); amputation risk nearly doubled. Incidence of fractures in other trials- not significantly higher
Fournier’s gangrene	Rare but life-threatening necrotizing genital and perineal infection. Food and Drug Administration has issued warnings and requires immediate medical attention if symptoms arise	Extremely rare but serious; the exact incidence is unknown
Hypotension and dehydration	Due to the mild diuretic effect, it causes a 3-5 mmHg drop in BP. Risk increases in patients on antihypertensives or those prone to dehydration. Patients with cirrhosis and splanchnic vasodilation require monitoring	1.2% to 1.5%, especially in patients prone to dehydration or on antihypertensives
Other side effects	Includes mild hypoglycemia (especially with sulfonylureas or insulin), fatigue, arthralgia, and mild allergic reactions (rash, urticaria). Generally mild and reversible	Variable, mild in most cases
Concerns in chronic liver disease	Generally, it is well tolerated in mild-to-moderate liver impairment, but isolated reports of drug-induced liver injury exist. Patients with advanced cirrhosis (Child-Pugh C) require caution [increased risk of infections, particularly UTIs and sepsis, in decompensated cirrhosis]	Study on empagliflozin: 10 patients with cirrhosis, 8 had an adverse event, 3 reported a serious adverse event (1 could be attributed to empagliflozin). The overall frequency of adverse events is similar to earlier phase 3 trials of SGLT2 inhibitors

BP: Blood pressure; DKA: Diabetic ketoacidosis; GFR: Glomerular filtration rate; SGLT2: Sodium-glucose cotransporter 2; UTI: Urinary tract infections.

Genital mycotic infections

One of the most common adverse effects of SGLT2 inhibitors is genital mycotic infections, which occur in up to 15% of users[69]. This is due to the increased glucose load in the urine, which fosters fungal growth. In particular premenopausal females are more frequently affected. UTIs are also common although they are more frequent in older individuals, females, or those with a history of recurrent UTIs[70,71]. These infections are generally mild and can be managed with appropriate antifungal treatment.

Diabetic ketoacidosis

There are reports of development of diabetic ketoacidosis (DKA) in patients with cirrhosis after SGLT2 inhibitors were administered[72]. While rare SGLT2 inhibitors can lead to DKA even with only modest increases in blood glucose. This condition is a serious concern in patients with T2DM who experience intercurrent illnesses, fasting, or dehydration, all of which may precipitate DKA. Canagliflozin and dapagliflozin have been linked to an increased risk of euglycemic DKA (with only mild-to-moderate glucose elevation) although empagliflozin has shown a lower risk[73,74]. This makes close monitoring essential for patients who are prone to dehydration, particularly during illness or fasting periods.

AKI

As discussed earlier SGLT2 inhibitors, especially when combined with diuretics, may increase the risk of AKI, particularly in patients with preexisting renal impairment. Although clinical trials do not show a significant increase in renal dysfunction, caution should be exercised when these agents are used in patients with a glomerular filtration rate below 60 mL/minute/1.73 m². An overwhelming concern in the use of SGLT2 inhibitors in patients with cirrhosis is the potential occurrence of hepatorenal syndrome (HRS) since cirrhosis is accompanied by complex alterations in circulatory systemic hemodynamics-splanchnic vasodilation, decreased cardiac output, and a decrease in effective renal blood flow. However, SGLT2 inhibitors have been shown to primarily alter the volume distribution (from interstitial to intravascular space) rather than causing reductions in effective blood volume and blood pressure. Again, it is presumed that SGLT2 inhibitors slightly reduce the glomerular filtration rate by inducing vasoconstriction in the efferent arteriole, potentially decreasing renal blood flow by augmenting preglomerular pressure, and causing exacerbation of HRS.

However, a randomized trial showed that the renal hemodynamic changes caused by dapagliflozin were due to post-glomerular vasodilatation and not pre-glomerular vasoconstriction[75]. Further, it was seen that dapagliflozin did not affect renal vascular resistance and in fact decreased intraglomerular pressure along with post-glomerular resistance, an effect that might prove to be beneficial in HRS. Further studies are required to clarify these issues although at present SGLT2 inhibitors seem to be safer than loop diuretics and mineralocorticoid antagonists in terms of volume depletion in patients with cirrhosis.

Fractures and amputations

The use of SGLT2 inhibitors, particularly canagliflozin, has been associated with a heightened risk of fractures and amputations[76]. The Canagliflozin Cardiovascular Assessment Study found that the risk of fractures was significantly higher, and the risk of lower limb amputations was nearly doubled in patients using SGLT2 inhibitors compared with those receiving placebo[77]. These findings suggest that SGLT2 inhibitors should be used with caution in patients with conditions that predispose them to fractures or poor wound healing, such as peripheral vascular disease.

Fournier’s gangrene

Fournier’s gangrene, a rare but severe necrotizing infection of the genital and perineal areas, has been reported in patients taking SGLT2 inhibitors[78]. Although extremely uncommon, it is a serious adverse event that requires immediate medical attention. The Food and Drug Administration has issued a warning regarding this risk, advising that clinicians monitor patients closely for any symptoms of genital infection and provide early intervention if necessary.

Hypotension and dehydration

SGLT2 inhibitors act as mild diuretics, leading to a reduction in blood pressure by 3-5 mmHg. This effect may cause hypotension, especially in patients already on antihypertensive medications or those who are at risk of dehydration. Theoretically speaking, decompensated liver cirrhosis is often associated with hypotension, especially in the setting of adrenal insufficiency, cirrhotic cardiomyopathy, and the use of higher doses of diuretics, and hemodynamic instability could result from SGLT2 inhibitor administration. However, it has been observed that SGLT2 inhibitors have a small, dose-independent impact on blood pressure (a decrease in systolic blood pressure of 3-5 mmHg) with the maximal effect seen in those with preexisting hypertension[79]. Although patients with cirrhosis are prone to hypotension, existing data on SGLT2 inhibitors do not mandate strict monitoring for symptoms of hypotension and dehydration in this subgroup of patients.

Other adverse effects

Other side effects include mild-to-moderate hypoglycemia, particularly in patients who are also taking sulfonylureas or insulin. Some patients may experience nonspecific fatigue, arthralgia (joint pain), and mild allergic reactions such as rashes or urticaria[80,81]. While these side effects are generally mild and reversible with appropriate treatment or discontinuation of the drug, they require attention to ensure patient comfort and prevent further complications.

Concerns and safety in chronic liver disease

To date the long-term safety profile of SGLT2 inhibitors has not been adequately assessed in patients with cirrhosis, and further studies need to be carried out. As previously discussed SGLT2 inhibitors are generally well tolerated in patients with mild-to-moderate hepatic impairment. However, there are isolated reports of drug-induced liver injury, particularly in patients with significant liver disease, such as cirrhosis. Although clinical trials suggest these drugs are safe in patients with mild or moderate hepatic impairment, caution is warranted, especially in patients with advanced cirrhosis (Child-Pugh C) since the long-term safety and efficacy of these drugs in this population remain uncertain.

A recent study evaluated the safety and tolerability of empagliflozin in compensated and decompensated liver disease[55]. Out of 10 patients 8 patients (80%) had an adverse event, and 3 of them (30%) reported a serious adverse event, one of which could be attributed to empagliflozin. However, the overall frequency of adverse events was similar to earlier phase 3 trials of SGLT2 inhibitors, thus implying that 1-month treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease.

Additionally, SGLT2 inhibitors may pose a heightened risk of infections, particularly in patients with chronic liver disease, who are already at a higher baseline risk for infections. Patients with decompensated cirrhosis may experience more frequent infections, particularly UTIs and sepsis. At the moment data regarding long-term safety of SGLT2 inhibitors in patients with cirrhosis is scarce. However, the following conclusions regarding their safety in patients with cirrhosis can be made with a reasonable degree of certainty: (1) SGLT2 inhibitors can be safely used in patients with compensated chronic liver disease; (2) In patients with decompensated chronic liver disease, the safety concerns regarding their usage arise mainly because of the risk of hypotension, renal impairment, and the occurrence of infections; and (3) Existing data although limited show that with a degree of caution, SGLT2 inhibitors may be used in patients with decompensated chronic liver disease without any major risk of hypotension or worsening of HRS. The safety differences between different stages of cirrhosis (Child-Pugh A/B vs C) cannot be more clearly distinguished at this moment, and the current evidence on decompensated cirrhosis will perhaps be discussed in greater detail as newer evidence emerges. More prospective studies are needed to evaluate the risk-benefit ratio for high-risk populations.

CONCLUSION

SGLT2 inhibitors have emerged as a promising therapeutic option for managing various liver conditions, especially in patients with concurrent T2DM. While primarily used for glycemic control, these medications offer several benefits beyond diabetes management. In patients with MASLD SGLT2 inhibitors have demonstrated effectiveness in reducing hepatic fat content and fibrosis as shown by studies using noninvasive imaging techniques. Beyond liver-specific effects these inhibitors improve systemic metabolic parameters like body weight, visceral fat accumulation, and insulin sensitivity. In patients with cirrhosis SGLT2 inhibitors can be beneficial in managing ascites due to their natriuretic effect, reducing the need for large-volume paracentesis. They may have a protective role in cases of renal impairment associated with cirrhosis. Lastly, studies suggest a preventive role of SGLT2 inhibitor for HCC and lower risk of mortality among patients with HCC.

However, SGLT2 inhibitors are associated with multiple adverse events, and caution is warranted in patients with advanced cirrhosis (Child-Pugh C) due to uncertain long-term safety and efficacy. While SGLT2 inhibitors show promise in managing liver diseases, further research is needed to fully understand their long-term impact on liver fibrosis, steatosis, and safety in populations with liver diseases.

The studies included in this review have some obvious limitations, which include but are not limited to small sample size, absence of RCTs, and the presence of potential biases like selection bias, residual confounding, etc. Hence, caution should be exercised in interpreting the results of these studies. These conclusions need to be validated through large-scale, multicentric RCTs. Clinicians should carefully assess the benefit-risk ratio on an individual basis, especially for patients with moderate-to-severe hepatic or renal impairment.