Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Table 3 Summary of trials exploring the efficacy of incretin-based therapies in nonalcoholic steatohepatitis

Ref.	Agent	Comparator	Participants	Duration	Outcomes
Newsome et al[50], 2021	Semaglutide 0.1, 0.2 or 0.4 mg s/c once daily	Placebo	NASH with F1, F2, or F3 fibrosis stage	72 wk	NASH resolution without worsening of fibrosis: 40% (0.1 mg), 36% (0.2 mg), 59% (0.4 mg), 33% (placebo); Improvement in fibrosis (P < 0.001 for 0.4 mg vs placebo); 43% (0.4 mg), 33% (placebo) (P = 0.48); Weight loss: 13% (0.4 mg), 1% placebo
Loomba et al[51], 2023	Semaglutide 2.4 mg s/c	Placebo (1: 2)	NASH with compensated cirrhosis	48 wk	Improvement in liver fibrosis by ≥ 1 stage without worsening NASH: 11% Semaglutide, 29% placebo (P = 0.087); Resolution of NASH at 48 wk: 34% semaglutide, 21% placebo (P = 0.29); No new safety concerns
Romero-Gomez et al[52], 2023	Efinopegdutide 10 mg s/c once weekly	Semaglutide 1 mg s/c once weekly	NAFLD with liver fat content (LFC) ≥ 10%	24 wk	Relative reduction in LFC from baseline higher with efinopegdutide (72.7%) than semaglutide (42.3%); Similar reduction in body weight
Alkhouri et al[53], 2022	Semaglutide 2.4 mg s/c + cilofexor once daily (30 or 100 mg)+ fircosostat (20 mg)	Semaglutide alone Semaglutide+cilofexor/fircosostat	NASH (MRI-PDFF > 10%, elastography ≥ 7 kPa	24 wk	Combination well tolerated; Greater reduction in liver fat with combination groups vs semaglutide (10%-11% vs 8.6%); Similar weight loss in all the groups
Flint et al[54], 2021	Semaglutide 0.4 mg s/c once daily	Placebo	NAFLD, steatosis ≥ 10% (MRI-PDFF), MRE: 2.5-4.63 kPa	48 wk	≥ 30% reduction in liver steatosis at 24, 48 and 72 wk (64.7%, 76.5%, 73.5%) significantly higher than placebo; Change in liver stiffness in NAFLD not significantly different compared to placebo; Improvement in liver enzymes, body weight and HbA1c
Armstrong et al[55], 2016	Liraglutide 1.8 mg/d s/c	Placebo	Biopsy proven NASH	48 wk	39% had resolution of NASH (vs 9% placebo); Progression of fibrosis: 9% Liraglutide, 36% placebo
Khoo et al[56], 2017	Liraglutide 3.0 mg/d	Diet and moderate exercise	Obesity and NAFLD (Liver fat content > 5% on MRI)	26 wk	Similar reduction in weight, liver fat, liver enzymes in both the groups without any significant difference between the two
Yan et al[57], 2019	Liraglutide 1.8 mg/d	Insulin glargine or sitagliptin	T2D and NAFLD	26 wk	Liraglutide and sitagliptin along with metformin reduced body weight, liver fat content, visceral adipose tissue in addition to glycemic control in contrast to Insulin, subcutaneous fat also decreased in liraglutide arm
Bizino et al[58], 2020	Liraglutide 1.8 mg/d	Placebo	T2D and NAFLD	26 wk	Liraglutide reduced significantly more body weight and subcutaneous fat but not visceral fat
Guo et al[59], 2020	Liraglutide 1.8 mg/d	Insulin glargine or placebo	T2D and NAFLD	26 wk	Liraglutide plus 2 gm metformin for 26 wk significantly reduced liver, subcutaneous and visceral fat
Zhang et al[60], 2020	Liraglutide 1.8 mg/d	Pioglitazone	T2D and NAFLD	24 wk	Liraglutide reduced liver fat significantly compare to pioglitazone which could be attributed to weight loss
Liu et al[61], 2020	Exenatide 1.8 mg/d	Insulin glargine	T2D and NAFLD	24 wk	Both reduced liver fat but exenatide led to higher reduction in body weight, visceral fat, liver enzymes
Miyake et al[62], 2022 (Trial Registration: jRCTs061210009)	Semaglutide 0.5 mg/wk + Luseogliflozin 2.5 mg/d	Semaglutide 0.5 mg/wk	T2D and NASH	52 wk	Ongoing study
Gastaldelli et al[63], 2022	Dual GIP/GLP-1R agonist: tirzepatide10 mg or 15 mg/wk	Insulin degludec	T2D and NAFLD	52 wk	Significant decrease in liver fat content, visceral and subcutaneous adipose tissue compared to insulin degludec
Kuchay et al[64], 2020	Glucagon-like peptide-1 receptor (GLP-1r) agonist (GLP-1 RA)	Usual care	T2D and NAFLD	24 wk	Dulaglutide significantly reduces liver fat comma gamma glutamyl transpeptidase

GIP: Glucose-dependent insulinotropic polypeptide; MRE: Magnetic resonance elastography; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; PDFF: Proton density fat fraction.