Table 2

Systematic reviews that have assessed the liver effects associated with SGLT2 inhibitors in patients with T2D with NAFLD

Author (year)	Study type	Studies, n (subjects, n)	Country	Exposure	Duration	Summary findings
Kumar et al (2020)21	RCTs	7 studies (n=255)	Germany (n=1), Japan (n=3), India (n=1), Sweden (n=1), multination (n=1)	Dapagliflozin (n=3), empagliflozin (n=2), ipragliflozin (n=1), luseogliflozin (n=1)	20 weeks–6 months	SGLT2 inhibitors significantly reduced: ALT levels (WMD: −16.17 U/L, 95% CI −21.74 to −10.60). GGT levels (WMD: −19.31 U/L, 95% CI −21.13 to −17.49). SGLT2 inhibitors did not significantly reduce: AST levels (WMD: −7.09 U/L, 95% CI −17.03 to 2.85). Liver fibrosis (SMD: −0.07, 95% CI −0.33 to 0.19). Liver steatosis (SMD: −4.64, 95% CI −9.53 to 0.25).
Dougherty et al (2020)25	Clinical trials	7 studies (n=330)	Japan (n=4), Korea (n=1), Germany (n=1), India (n=1)	Canagliflozin (n=2), dapagliflozin (n=1), empagliflozin (n=2), ipragliflozin (n=2)	20–56 weeks	SGLT2 inhibitors effectively reduced hepatosteatosis in NAFLD, and one single-arm trial demonstrated histological improvement after repeat liver biopsy.
Xing et al (2020)23	RCTs	6 studies (n=309)	Japan (n=4), India (n=1), Sweden (n=1)	Dapagliflozin (n=2), empagliflozin (n=1), ipragliflozin (n=2), luseogliflozin (n=1)	12 weeks–6 months	SGLT2 inhibitors significantly reduced: ALT levels (WMD −11.05 IU/L, 95% CI −19.85 to −2.25). MRI proton density fat fraction (WMD −2.07%, 95% CI −3.86 to −0.28). SGLT2 inhibitors did not significantly reduce: AST levels (WMD −1.11 IU/L, 95% CI −2.39 to 0.17).
Mantovani et al (2020)39	RCTs	7 studies (n=579)	Germany (n=1), Japan (n=2), India (n=1), Sweden (n=1), USA (n=1), multination (n=1)	Canagliflozin (n=1), dapagliflozin (n=3), empagliflozin (n=2), ipragliflozin (n=1)	12–24 weeks	SGLT2 inhibitors significantly reduced ALT levels.
Pan and Stanley (2020)24	Clinical trials	6 studies (n=498)	Japan (n=5), India (n=1)	Dapagliflozin (n=1), empagliflozin (n=1), ipragliflozin (n=1), luseogliflozin (n=2), non-specific (n=1)	20 weeks–6 months	No data for histological inflammation and fibrosis. Insufficient data for liver fat content: 2 studies suggest benefit (vs metformin and standard care), but 1 study shows no relative benefit (vs pioglitazone). Insufficient data for serum markers of liver injury: 3 studies suggest modest benefit, but the other 3 suggest no benefit over different comparators.
Raj et al (2019)40	RCTs	4 studies (n=232)	Japan (n=2), India (n=1), Sweden (n=1)	Dapagliflozin (n=1), empagliflozin (n=1), ipragliflozin (n=1), luseogliflozin (n=1)	12–24 weeks	SGLT2 inhibitors improve the liver enzymes (eg, AST, ALT and GGT), and decrease liver fat and fibrosis.
Tang et al (2016)22	RCTs	1 study (n=67)	Multination (n=1)	Dapagliflozin (n=1)	24 weeks	Dapagliflozin showed no benefit on hepatic fat content.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; NAFLD, non-alcoholic fatty liver disease; RCT, randomized controlled trial; SGLT2, sodium glucose co-transporter 2; SMD, standard mean difference; T2D, type 2 diabetes; WMD, weighted mean difference.