Glucagon-Like Peptide-1 Receptor Agonist-Associated Hepatotoxicity

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of obesity, type 2 diabetes and metabolic dysfunction-associated steatohepatitis. Despite their numerous clinical benefits they are not without risk. Although the product labels contain multiple organ-specific warnings and precautions, the liver is not identified as a target organ of safety concern. Drug-induced liver injury (DILI) is a leading safety-related cause of pipeline attrition, boxed warnings and postmarketing drug withdrawal. This review explores GLP-1RA associated hepatotoxicity.

A comprehensive literature search of PubMed, Medline, EMBASE, Web of Science, SCOPUS and Google Scholar was conducted to identify relevant publications. Searches were conducted using all possible pairwise combinations of the drug or drug class terms with liver safety terms. Product labels, the Food and Drug Administrations Adverse Event Monitoring System for approved drugs and LiverTox®, the online resource for information on DILI were searched.

Thirty-one case reports of suspected GLP-1RA or dual GLP-1/GIP RA-associated hepatotoxicity were identified. The specific term "DILI" related to GLP-1RAs was reported to the Adverse Event Monitoring System 232 times and 3 GLP-1RA drug development programs were terminated due to liver safety. Results from the combined 31 case reports revealed that ages ranged from 17 to 79 years with a female predominance. Although some patients presented with asymptomatic liver tests elevations, most patients were symptomatic with abdominal pain, nausea and vomiting, mimicking GLP-1RA-associated gastrointestinal symptoms of early satiety. Presentation with acute liver failure or hepatic decompensation events also occurred. Treatment-emergent liver test elevations also occurred with dose escalation and switch to a different GLP-1RA. Severity of liver test elevations were most commonly grade 4. Latency ranged from 2 weeks to 6 months. Most cases demonstrated a hepatocellular pattern of liver injury, although cholestatic or mixed injury also occurred. Most liver test elevations resolved upon GLP-1RA or dual GLP-1/GIPRA discontinuation with dechallenge occurring between 1 week to 6 months.

DILI can occur with GLP-1 or GLP-1/GIP RAs. However, the true incidence is likely rare, although is unknown and probably underestimated. Among populations at higher risk may include females, patients with metabolic dysfunction-associated steatotic liver disease, patients experiencing rapid and substantial weight loss, and patients undergoing dose escalation or transitioning between different GLP-1RAs. Recognition of this association is crucial as the mainstay of treatment is prompt drug discontinuation. However, since GLP-1RAs are generally considered hepatoprotective, a potential causal relationship may not be readily suspected, which could delay withdrawal and lead to liver-related adverse events. This review underscores the importance of ongoing postmarketing safety surveillance despite reassuring clinical trial data to further elucidate the risk of GLP-1RA and GLP-1/GIP RA hepatotoxicity. Further research is needed to better understand the mechanism of suspected GLP-1RA and GLP-1/GIP RA-associated hepatotoxicity. As access expands via unregulated compounding pharmacies, patient education is key.