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

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.