Role of sodium-glucose cotransporter 2 inhibitors in liver diseases

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.

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.

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.

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.