Glucagon-like peptide 1 agonists are potentially useful drugs for treating metabolic dysfunction-associated steatotic liver disease

Table 1 Steatotic liver disease, new classification

Subcategories	Etiologies
MASLD	Presence of hepatic steatosis and 1 cardiometabolic risk factor out of 5 (see Table 2) and no other discernible cause for hepatic steatosis. If additional drivers of steatosis are identified, then this is consistent with a combination etiology
MetALD	MASLD and increased alcohol intake: 20-50 g/day (females); 30-60 g/day (males)
Alcohol Associated (Alcohol related liver disease-ALD)	Alcohol intake > 50 g/day (females) and > 60 g/day (males)
Specific etiology SLD	(1) Drug-induced liver injury; (2) Monogenic diseases: Lysosomal acid lipase deficiency, Wilson disease, hypo-betalipoproteinemia, inborn errors of metabolism; and (3) Miscellaneous: Celiac disease, HIV, malnutrition, HCV
Cryptogenic SLD	Those with no identifiable cause (cryptogenic SLD) may be re-categorized in the future pending developments in our understanding of disease pathophysiology

MASLD: Metabolic dysfunction-associated steatotic liver disease; MetALD: Metabolic and alcohol related/associated liver disease; ALD: Alcohol related liver disease; SLD: Steatotic liver disease; HIV: Human immunodeficiency virus; HCV: Hepatitis C virus.

Table 2 Cardio-metabolic risk factors

Risk factors	Cut-off values
BMI	BMI > 25 kg/m2 (23 in Asia) or waist circumference > 94 cm (males)/ > 80 cm (females) or ethnicity-adjusted
Fasting serum glucose	Fasting serum glucose ≥ 5.6 mmol/L (100 mg/dL) or 2-h post-load glucose levels ≥ 7.8 mmol/L (≥ 140 mg/dL) or HbA1c ≥ 5.7% (39 mmol/L) or T2DM or treatment for T2DM
Blood pressure	Blood pressure 130/85 mmHg or specific antihypertensive drug treatment
Plasma triglycerides	Plasma triglycerides ≥ 1.70 mmol/L (≥ 150 mg/dL) or lipid lowering treatment
Plasma HDL cholesterol	Plasma HDL cholesterol ≤ 1.0 mmol/L (≤ 40 mg/dL) (males) and ≤ 1.3 mmol/L (≤ 50 mg/dL) (females) or lipid lowering treatment

BMI: Body mass index; T2DM: Type 2 diabetes mellitus; HDL: High-density lipoproteins.

Table 3 Clinical trials with glucagon-like peptide 1 receptor agonists dual therapy

Molecule and trial	Primary aim	Type of study	Duration of therapy	State of recruitment	Main results
Cotadutide (GLP-1/glucagon receptor agonist)[28]	To evaluate the effects of cotadutide on hepatic and metabolic parameters in participants with overweight/obesity and type 2 diabetes	Randomized, phase 2b study	54 weeks	Completed	Improved glycemic control and weight loss, improvements in hepatic parameters
Cotadutide (GLP-1/glucagon receptor agonist), NCT04019561	To evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects of two dosage levels of cotadutide in obese subjects with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis	Randomized, double-blind, placebo-controlled, phase 2 study		Completed
Tirzepatide (GIP/ GLP-1 receptor agonist)[30]	To determine the effect of tirzepatide on biomarkers of non-alcoholic steatohepatitis and fibrosis in patients with type 2 diabetes	Post hoc analysis in a phase 2 trial	26 weeks	Completed	Higher tirzepatide doses significantly decreased non-alcoholic steatohepatitis-related biomarkers and increased adiponectin in patients with type 2 diabetes
Tirzepatide (GIP/GLP-1 receptor agonist)[31]	To characterize the changes in liver fat content, volume of visceral adipose tissue, and abdominal subcutaneous adipose tissue in response to tirzepatide or insulin degludec in a subpopulation of the SURPASS-3 study	Randomized, open-label, parallel-group, phase 3 study	52 weeks	Completed	Significant reduction in liver fat content and visceral adipose tissue and abdominal subcutaneous adipose tissue volumes compared with insulin degludec in this subpopulation of patients with type 2 diabetes in the SURPASS-3 study
Tirzepatide, (GIP/GLP-1 receptor agonist), NCT04166773 (SYNERGY-NASH)	To determine whether tirzepatide, administered once weekly, is safe and effective as a treatment for non-alcoholic steatohepatitis	Randomized, double-blind, placebo-controlled phase 2 study	52 weeks	Completed
Efinopegdutide (GLP-1/glucagon receptor co-agonist)[32]	To assess the effects of the GLP-1/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content in patients with non-alcoholic fatty liver disease	Randomized, phase 2a, active-comparator-controlled, parallel-group, open-label study	24 weeks	Completed	In patients with non-alcoholic fatty liver disease, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in liver fat content than semaglutide 1 mg weekly

GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent insulinotropic polypeptide.