Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

Table 1 The main phase II and phase III randomized controlled trials investigating glucagon-like peptide 1 receptor agonist, glucagon-like peptide 1 receptor agonist/glucose-dependent insulinotropic polypeptide receptor agonist, or glucagon-like peptide 1 receptor agonist/glucagon receptor agonist in metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis

Ref. (trial phase)	Intervention (n)	Comparator (n)	Participants	Duration	Primary hepatic outcome measures	Major adverse events
GLP-1 RAs (n = 13 trials)
Armstrong et al[93] (2016) (phase II)	Liraglutide 1.8 mg/d (26)	Placebo (26)	Biopsy-confirmed MASH with or without T2DM	48 wk	Liraglutide use was associated with greater histological MASH resolution (39%) than placebo use (9%, P = 0.019). Fibrosis progression occurred in 9% of the liraglutide group vs 36% in placebo (P = 0.04)	Moderate gastrointestinal AEs in the liraglutide group (81%) vs placebo group (65%)
Dutour et al[87] (2016) (phase II)	Exenatide 5-10 µg twice a day (22)	Placebo (22)	T2DM and 95% with MASLD (assessed by MRS)	26 wk	LFC was reduced with exenatide (-23.8% [SD 9.5] more than placebo (+12.5% [9.6]; P = 0.007)	Not reported
Yan et al[88] (2019) (phase II)	Liraglutide 1.8 mg/d (24)	Insulin glargine 0.2 IU/kg/d (24) or Satigliptin 100 mg/d (27)	T2DM and MASLD (assessed by MRI-PDFF)	26 wk	In the liraglutide and sitagliptin groups, LFC decreased from baseline to week 26 (liraglutide: from 15.4% [SD 5.6] to 12.5% [6.4], P < 0.001; sitagliptin: from 15.5% [5.6] to 11.7% [5.0]; P = 0.001). Delta MRI-PDFF was greater with liraglutide than sitagliptin, but was not significantly different between the two groups (-4.0 vs -3.8; P = 0.911). MRI-PDFF did not change significantly from baseline in the insulin glargine group	Not reported
Khoo et al[95] (2019) (phase II)	Liraglutide 3 mg/d (15)	Lifestyle modifications (diet and exercise) (15)	Obesity and MASLD without T2DM (assessed by MRS)	26 wk	Both treatment groups showed similar reduction in LFC at 26 wk (-8.1% [SD 13.2] vs -7.0% [7.1]) P = 0.78	Nausea, abdominal discomfort, and diarrhea in the liraglutide group
Liu et al[96] (2020) (phase II)	Exenatide 5-10 µg twice a day (38)	Insulin glargine 0.1-0.3 IU/kg per day (38)	T2DM and MASLD (assessed by MRS)	24 wk	LFC was not significantly reduced after exenatide treatment (change in LFC: -17.6% [SD 12.9]) compared with insulin glargine (change in LFC -10.49 [SD 11.38]) P = 0.1248	Similar between the two groups
Binzino et al[94] (2020) (phase II)	Liraglutide 1.8 mg/d (23)	Placebo (26)	T2DM and MASLD (assessed by MRS)	26 wk	Reduction in LFC was not different between the two groups (liraglutide: from 18.1% [SD 11.2] to 12.0% [7.7]; placebo: from 18.4% [9.4] to 14.7% [10.0%]; estimated treatment effect -2.1% [95% CI -5.3 to 1.0]) P = 0.17	No serious AEs were reported
Kuchay et al[89] (2020) (phase II)	Dulaglutide 1.5 mg/wk (32)	Standard of care for T2DM (32)	T2DM and MASLD (assessed by MRI-PDFF)	26 wk	Dulaglutide resulted in a control-corrected absolute reduction in LFC -3.5% (95% CI -6.6 to -0.4; P = 0.025) and relative reduction of -26.4% (-44.2 to -8.6; P = 0.004) compared with placebo; absolute changes in liver stiffness on VCTE (-1.31 kPa [-2.99 to 0.37]; P = 0.12) with no difference between two treatment groups	No serious AEs were reported
Guo et al[90] (2020) (phase II)	Liraglutide 1.8 mg/wk (32)	Insulin glargine once a day (32); Placebo (32)	T2DM and MASLD (assessed by MRS) treated with metformin	26 wk	Liraglutide resulted in a control-corrected absolute reduction in LFC of -6.3% (P < 0.05) and relative reduction of -24% (P < 0.05); reduction in liver fat content was greater with liraglutide (-6.3%) than with insulin glargine (-3.4%) with no difference between the two treatment groups (P > 0.05)	No serious AEs; mild-to-moderate gastrointestinal AEs were reported in the liraglutide group
Zhang et al[91] (2020) (phase II)	Liraglutide 1.2 mg/wk (30)	Pioglitazone 30 mg a day (30)	T2DM and MASLD (assessed by MRS) treated with metformin	24 wk	Liraglutide resulted in a control-corrected absolute reduction in LFC of -4.0% (95% CI -6.6 to -0.4; P < 0.05) and relative reduction of -17% (P < 0.05); this reduction in LFC was greater with liraglutide than pioglitazone	No serious AEs; mild-to-moderate gastrointestinal AEs were reported in the liraglutide group
Newsome et al[84] (2021) (phase II)	Semaglutide 0.1 mg/d (80); 0.2 mg/d (78); 0.4 mg/d (82)	Placebo (80)	Biopsy-proven MASH and liver fibrosis with or without T2DM	72 wk	Among patients with stage F2 or F3 fibrosis, the percentage of patients with MASH resolution and no worsening of fibrosis was 40% in the 0.1 mg group, 36% in the 0.2 mg group, 59% in the 0.4 mg group, and 17% in placebo (P < 0.001 for semaglutide 0.4 mg vs placebo); fibrosis stage improvement occurred in 43% of the 0.4 mg group and in 33% of the placebo group (P = 0.48)	No serious AEs; nausea, constipation, and vomiting was higher in the 0.4 mg group than in the placebo group
Flint et al[92] (2021) (phase II)	Semaglutide 0.4 mg/d (34)	Placebo (33)	MASLD (assessed by MRI-PDFF and MRE) with or without T2DM	72 wk	Semaglutide significantly reduced LFC compared with placebo and more patients had a ≥ 30% reduction in LFC with semaglutide at 24, 48, and 72 wk (with an estimated treated ratio of 0.50 at week 72 with P < 0.0001); changes in liver stiffness were not different between the two groups	Gastrointestinal AEs (diarrhea and nausea) were more frequently reported in the semaglutide group than the placebo group
Alkhouri et al[86] (2022) (phase II)	Semaglutide 2.4 mg/wk (21)	Semaglutide 2.4 mg/wk plus cilofexor 30 mg/d (22) or Semaglutide 2.4 mg/wk plus cilofexor 100 mg/d (22) or Semaglutide 2.4 mg/wk plus firsocostat 20 mg/d (22) or Semaglutide 2.4 mg plus cilofexor 30 mg/d plus firsocostat 20 mg/d (21)	MASH with mild to moderate fibrosis (assessed by either liver biopsy or MRI-PDFF ≥ 10% and VCTE measured liver stiffness ≥ 7 kPa) with or without T2DM	24 wk	Combination treatments vs semaglutide monotherapy resulted in greater improvements in LFC (least-squares mean of absolute changes: ranging from -9.8% to -12.6% vs -8.6%; the difference was significant only between the semaglutide and semaglutide plus firsocostat groups) and in noninvasive tests of liver fibrosis	Treatment was well tolerated; the incidence of AEs was similar across the groups (73-90%), and most commonly reported AEs were gastrointestinal, including nausea, diarrhea, and constipation
Loomba et al[85] (2023) (phase II)	Semaglutide 2.4 mg/wk (47)	Placebo (24)	Biopsy-proven compensated MASH cirrhosis with or without T2DM	48 wk	Semaglutide, compared to placebo, resulted in no improvement in liver fibrosis (11% vs 29%, OR: 0.28 [95%CI 0.06-1.24]); P = 0.087 and no significant difference between treatments for MASH resolution (34% vs 21%, OR: 1.97 [95%CI 0.56-7.91]); P = 0.29	Mild to moderate transient gastrointestinal AEs occur mainly during treatment initiation or dose escalation
GLP-1RA/GIPRA (n = 1 trial)
Gastaldelli et al[97] (2022) (substudy of phase III)	Tirzepatide 5 mg/wk (71); 10 mg/wk (79); 15 mg/wk (72)	Insulin degludec once a day (74)	T2DM and MASLD (assessed by MRI-PDFF) treated with metformin and/or SGLT2 inhibitors	52 wk	The absolute reduction in LFC at week 52 was significantly higher for the pooled tirzepatide 10 mg and 15 mg groups (-8.1%) vs the insulin degludec group (-3.4%); the estimated treatment difference vs insulin degludec was -4.7% (95%CI -6.7 to -2.7; P < 0.0001); those with at least a 30% relative decrease in LFC at week 52 were higher in each tirzepatide group (ranging from approximately 67% to 81% for tirzepatide doses) vs the insulin degludec group (32%)
GLP-1RA/GCGRA (n = 1)
Romero-Gómez et al[98] (2023) (phase II)	Efinopegdutide 10 mg/wk (72)	Semaglutide 1 mg/wk (73)	MASLD (assessed by MRI-PDFF) with or without T2DM	24 wk	The mean relative reduction in LFC was 72.7% with efinopegdutide and 42.3% with semaglutide. The difference in mean relative reduction from baseline in LFC at week 24 in the efinopegdutide group compared to the semaglutide group was 30.4% (95%CI 22.1-38.7; P < 0.001)	Overall, gastrointestinal AEs were more frequently reported in the efinopegdutide group compared to semaglutide

Post hoc analyses of randomized controlled trials investigating the effects of incretin receptor agonists (RAs) (e.g., cotadutide) on plasma aminotransferase concentrations in patients with type 2 diabetes mellitus or studies that used liver ultrasound or blood biomarkers or scores for testing the effects of incretin RAs on metabolic dysfunction-associated steatotic liver disease were excluded. AEs: Adverse effects; GLP-1: Glucagon-like peptide 1; GIP: Glucose-dependent insulinotropic polypeptide; GCG: Glucagon; LFC: Liver fat content; MRS: Magnetic resonance spectroscopy; MRI-PDFF: MRI-proton density fat fraction; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; RAs: Receptor agonists; RCT: Randomized controlled trial; SGLT2: Sodium-glucose cotransporter 2; T2DM: Type 2 diabetes mellitus; VCTE: Vibration-controlled transient elastography.

Table 2 The main ongoing randomized controlled trials assessing the efficacy and safety of incretin receptor agonists in metabolic dysfunction-associated steatotic liver disease

Clinical trial registration number	Trial acronym	Status	Study participants	Interventions	Study characteristics	Estimated sample size, n	Primary hepatic outcome measures	Estimated completion date
GLP-1 RAs
NCT04822181	ESSENCE	Recruiting	MASH on liver biopsy	Semaglutide vs placebo	Phase III double-blind, placebo-controlled trial	1200	Histological resolution of MASH with no worsening of liver fibrosis after 72 wk of treatment	July, 2029
							Improvement in liver fibrosis and no worsening of MASH after 72 wk of treatment
							Time to first liver-related clinical events (composite endpoint) after 240 wk of treatment
NCT05016882	N/A	Active not recruiting	MASH on liver biopsy	Semaglutide Plus NNC0194-04991vs placebo	Phase II, randomized, double-blind, active and placebo-controlled, double-dummy, parallel-group, multinational trial	672	Improvement in liver fibrosis and no worsening of MASH after 52 wk of treatment	March, 2025
NCT04971785	N/A	Active not recruiting	MASH-related compensated cirrhosis on liver biopsy	Semaglutide plus cilofexor or fisocostat	Phase II, randomized, double-blind, double-dummy, placebo-controlled trial	440	Percentage of participants who achieve ≥ 1 stage improvement in liver fibrosis without worsening of MASH after 72 wk of treatment	December, 2024
							Histological resolution of MASH after 72 wk of treatment
NCT04639414	COMBATT2NASH	Recruiting	T2DM with MASH on liver biopsy	Semaglutide plus empagliflozine vs placebo and empagliflozine vs placebo	Phase IV, randomized, double-blind placebo-controlled trial	192	Histological resolution of MASH without worsening of fibrosis after 48 wk of treatment	December, 2023
NCT05140694	N/A	Not yet recruiting	T2DM with MASLD on transient elastography with CAP	Dulaglutide vs empagliflozin vs empagliflozin plus dulaglutide	Phase IV, randomized, active-comparator controlled, parallel grouped trial	135	Changes in CAP score after 24 wk of treatment	December, 2025
NCT03648554	REALIST	Not yet recruiting	T2DM with MASH on liver biopsy	Dulaglutide vs placebo	Phase IV, multicenter, open, prospective, randomized, controlled dietary reinforcement trial	93	Histological resolution of MASH with no worsening of fibrosis after 52 wk of treatment	March, 2024
GLP-1RA/GIPRA
NCT04166773	SYNERGY-NASH	Active, not recruiting	MASH on liver biopsy with or without T2DM	Tirzepatide vs placebo	Phase IIb, randomized, double-blind, placebo-controlled trial	196	Histological resolution of MASH with no worsening of fibrosis after 52 wk of treatment	February, 2024
Dual GLP-1RA/GCGRAs
NCT05364931	PROXYMO-ADV	Active, not recruiting	MASH with fibrosis on liver biopsy	Cotudatide vs placebo	Phase IIb/III randomized double-blind, placebo-controlled trial	1860	Histological resolution of MASH with no worsening of fibrosis after 48 wk of treatment	April, 2024
							Histological resolution of MASH with no worsening of fibrosis and improvement in liver fibrosis by at least one stage without worsening of MASH after 84 wk of treatment
NCT05006885	N/A	Completed	MASLD on MRI-PDFF	Pemvidutide vs placebo	Phase I	95	Percentage of change in LFC by MRI-PDFF from baseline to day 85	August, 2022
NCT04771273	N/A	Completed	MASH on liver biopsy	Survodutide (BI456906) vs placebo	Phase IIb, multicenter, double-blind, parallel-group, randomized trial	240	Percentage of patients with histological improvement in MSAH (defined as NAS reduction of two or more points) after 48 wk of treatment	December, 2023
Triple GLP-1RA/GIPRA/GCGRA
NCT04505436	N/A	Recruiting	MASH on liver biopsy	Efocipegtrutide (HM15211) vs placebo	Phase IIb, adaptive, randomized, double-blind, placebo-controlled, parallel-group trial	240	Histological resolution of MASH with no worsening of liver fibrosis after 52 wk of treatment	November, 2025

¹NNC01940499 is a new subcutaneously administered FGF21 analog. The last search on https://clinicalstrial.gov/ was completed on December 21, 2023.

CAP: Controlled attenuation parameter; GIP: Glucose-dependent insulinotropic polypeptide; GLP-1: Glucagon-like peptide 1; GCG: Glucagon; MRI-PDFF: MRI-proton density fat fraction; MASLD: Metabolic dysfunction-associated steatotic liver disease; NAS: NAFLD activity score; MASH: Metabolic dysfunction-associated steatohepatitis.