Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: Pathophysiology, diagnosis, and emerging therapeutic strategies

Table 3 Timeline of key clinical trials in metabolic dysfunction-associated steatotic liver disease: Drug classes, endpoints, and outcomes[84,117,123,129,133,139,163-166]

Year	Trial	Drug/class	Primary endpoint	Key outcome	Ref.
2015	LEAN	Liraglutide (GLP-1 RA)	NASH resolution without fibrosis worsening	Met endpoint; improved NASH resolution	Armstrong et al[84]
2019	REGENERATE (Interim)	Obeticholic acid (FXR agonist)	Fibrosis improvement without NASH worsening	Improved fibrosis in 23% vs 12% placebo	Ratziu et al[163]
2020	REVERSE	Lanifibranor (pan-PPAR agonist)	Improvement in NAS and fibrosis	Significant histologic improvement	Francque et al[129]
2021	FLINT	Obeticholic acid	NAS improvement ≥ 2 points without fibrosis worsening	Positive results in steatosis and inflammation	Sanyal et al[164]
2022	MAESTRO-NAFLD-1	Resmetirom (THR-β agonist)	Liver fat reduction via MRI-PDFF	Significant reduction in liver fat content	Harrison et al[165]
2022	MAESTRO-NASH	Resmetirom (THR-β agonist)	NASH resolution and fibrosis improvement	Met both primary endpoints	Harrison et al[123]
2022	SYNERGY	Semaglutide + cagrilintide	Liver fat reduction	Significant additive effect on steatosis	Frias et al[166]
2023	SURMOUNT-1	Tirzepatide (GLP-1/GLP RA)	Weight reduction	Robust weight loss and decrease liver fat (MRI)	Loomba et al[117]
2023	ESSENCE	Efruxifermin (FGF-21 analogue)	Histologic NASH resolution and fibrosis improvement	Positive early-phase results	Harrison et al[133]
2023	CENTURION	Survodutide (GLP-1/glucagon RA)	Liver fat reduction	Marked liver fat loss on imaging	Sanyal et al[139]

This table presents a chronological overview of major clinical trials conducted in metabolic dysfunction-associated steatotic liver disease, highlighting the evolving therapeutic landscape. Each trial is listed with its year of publication, pharmacologic class, primary endpoints, and key outcomes. Studies such as LEAN, REGENERATE, and MAESTRO-NASH have laid the foundation for understanding drug efficacy in nonalcoholic fatty liver disease resolution and fibrosis improvement. Newer trials like SURMOUNT-1 and ESSENCE continue to explore novel agents, including dual incretin therapies and fibroblast growth factor-21 analogues, with promising metabolic and histologic effects. This timeline illustrates the progression from early histologic endpoints to robust, non-invasive imaging and metabolic markers. GLP-1 RA: Glucagon-like peptide-1 receptor agonists; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; THR: Thyroid hormone receptor; FGF: Fibroblast growth factor; NASH: Nonalcoholic fatty liver disease; NAS: Nonalcoholic fatty liver disease activity score; MRI: Magnetic resonance imaging; MRI-PDFF: Magnetic resonance imaging-proton density fat fraction.