Pharmacologic management of metabolic and alcohol-associated liver disease

Metabolic and alcohol-associated liver disease (MetALD) is an emerging phenotype within the steatotic liver disease spectrum, characterized by cardiometabolic risk factors coexisting with alcohol exposure, resulting in synergistic liver injury and fibrosis progression. Therapeutic development remains limited because most steatotic liver disease trials exclude patients with ongoing alcohol use. In contrast, alcohol-associated liver disease (ALD) trials have focused primarily on severe alcohol-associated hepatitis. Current management of patients with MetALD relies on an integrated approach that simultaneously controls alcohol use and cardiometabolic risk. In clinical practice, for patients with MetALD and ongoing alcohol use, therapies aimed at controlling alcohol use remain most critical, given the faster, more progressive disease course related to alcohol as compared to metabolic liver injury. Given the dynamic nature of alcohol intake and metabolic risk factors, longitudinal monitoring of disease stage with noninvasive fibrosis tests is essential. Liver-directed therapies with efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), including incretin-based agents, fibroblast growth factor 21 analogs, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor beta agonists, may benefit selected MetALD patients. Several agents may modulate both metabolic pathways and alcohol consumption through central reward mechanisms. Specific pharmacotherapies targeting alcohol use (acamprosate, naltrexone) combined with structured psychosocial interventions are effective in controlling alcohol use. Given the lack of dedicated clinical trials in MetALD patients, we synthesized data from clinical trials in MASLD and ALD. We propose adapting these data to inform the design of future clinical trials in patients with MetALD.