Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials

Abstract

Recent randomized controlled trials (RCTs) tested the efficacy of sodium-glucose cotransporter-2 (SGLT-2) inhibitors to specifically treat nonalcoholic fatty liver disease (NAFLD). We systematically searched three electronic databases (up to 31 October 2020) for identifying placebo-controlled or head-to-head RCTs that used SGLT-2 inhibitors for treatment of NAFLD. No published RCTs with paired liver biopsy data were available for the meta-analysis. Primary outcome measures were changes in serum liver enzyme levels and liver fat content on imaging techniques. Overall, we included a total of twelve RCTs testing the efficacy of dapagliflozin (n = six RCTs), empagliflozin (n = three RCTs), ipragliflozin (n = two RCTs) or canagliflozin (n = one RCT) to specifically treat NAFLD for a median period of 24 weeks with aggregate data on 850 middle-aged overweight or obese individuals with NAFLD (90% with type 2 diabetes). Compared to placebo/reference therapy, treatment with SGLT-2 inhibitors significantly decreased serum alanine aminotransferase (weighted mean differences (WMD): -10.0 IU/L, 95%CI -12.2 to -7.79 IU/L; I² = 10.5%) and gamma-glutamyltransferase levels (WMD: -14.49 IU/L, 95%CI -19.35 to -9.63 IU/L, I² = 38.7%), as well as the absolute percentage of liver fat content on magnetic resonance-based techniques (WMD: -2.05%, 95%CI -2.61 to -1.48%; I² = 0%). In conclusion, SGLT-2 inhibitors seem to be a promising treatment option for NAFLD.

Keywords: NAFLD; SGLT-2 inhibitors; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; nonalcoholic steatohepatitis (NASH); type 2 diabetes mellitus.

Figure 1

Forest plot of the effect of SGLT-2 inhibitors on serum liver enzyme levels (i.e., serum alanine aminotransferase (ALT) (n = 9 randomized controlled trials (RCTs), panel A), aspartate aminotransferase (AST) (n = 9 RCTs, panel B), and gamma-glutamyltransferase (GGT) (n = 6 RCTs, panel C)) as compared with placebo or reference therapy. The pooled (green diamond) and individual effect sizes for RCTs included were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI). Note: If not available, the SDs of the weighted mean difference were estimated using a specific formula (as reported in the Methods section).

Figure 2

Forest plot of the effect of SGLT-2 inhibitors on the absolute percentage of liver fat content assessed by magnetic resonance-based techniques (n = 7 RCTs using either magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or magnetic resonance spectroscopy (MRS)). The effect size was expressed as weighted mean difference (WMD) and 95% confidence intervals for all RCTs included. Note: If not available, the SDs of the weighted mean difference were estimated using a specific formula (as reported in the Methods section). In the study of Bolinder et al. [19], the investigators reported only the placebo-corrected difference in mean percent MRI-PDFF with dapagliflozin.