Table 1

Principal phase two placebo-controlled or head-to-head RCTs testing the efficacy and safety of antihyperglycaemic drugs in patients with NAFLD or NASH

Liver enzymesLiver
fat*		Liver inflammation†Liver
fibrosis†		NASH
resolution†		Major adverse
effects
MetforminImprovedImprovedNo effectNo effectNo effectGastrointestinal
Glitazones
(pioglitazone, rosiglitazone)		ImprovedImprovedImprovedImprovedImprovedWeight gain (mild), oedema, heart failure, bone fractures
GLP-1 receptor agonists
(liraglutide, exenatide)		ImprovedImprovedImprovedNo effectImprovedGastrointestinal
DPP-4 inhibitors
(sitagliptin, vildagliptin)		ImprovedNo effectUnknownUnknownUnknownPancreatic, joint pain
SGLT-2 inhibitors
(dapaglifozin, empagliflozin, canaglifozin)		ImprovedImprovedUnknownUnknownUnknownGenitourinary infections, dehydration

  • NB: The aforementioned data are derived by an updated systematic review [104] that included phase 2 head-to-head or placebo-controlled RCTs of adults or children with NAFLD or NASH, which used an European Medicines Agency-approved antihyperglycaemic drug for treatment of NAFLD or NASH. Only RCTs that had at least 20 patients per treatment arms of interest were included in the systematic review.

  • Metformin, n=6 RCTs involving a total of 573 individuals, most of whom (>90%) did not have T2DM, who were treated for a median of 9 months. Four RCTs had liver biopsy data.

  • Glitazones, n=8 (6 pioglitazone and 2 rosiglitazone) RCTs involving a total of 828 individuals, most of whom (85%) did not have T2DM, who were treated for a median of 12 months. Seven RCTs had liver biopsy data.

  • GLP-1 RAs, n= 6 randomised controlled trials involving a total of 396 individuals, most of whom (73%) had T2DM, who were treated for a median of 6 months. Only one RCT had liver biopsy data (ie, the LEAN trial).

  • DPP-4 inhibitors, n=4 RCTs involving a total of 241 individuals with T2DM or pre-diabetes, who were treated for a median of 6 months. No RCTs with liver biopsy data.

  • SGLT-2 inhibitors, n=7 RCTs involving a total of 579 individuals (100% had T2DM), who were treated for a median of 6 months. No RCTs with liver biopsy data.

  • *RCTs where liver fat was determined either by imaging methods (ie, ultrasound and MRI or spectroscopy) or by histology.

  • †RCTs where liver inflammation, fibrosis and resolution of NASH was determined by liver biopsy.

  • DPP-4, dipeptidyl peptidase 4 inhibitors; GLP-1RAs, glucagon-like peptide-1 receptor agonists; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; RCT, randomised controlled trial; SGLT-2, sodium-glucose cotransporter 2 inhibitors; T2DM, type 2 diabetes mellitus.