A real-world analysis of Lomitapide-associated adverse events: Data from FAERS and CVAROD

Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor approved for the treatment of Homozygous Familial Hypercholesterolemia (HoFH), effectively lowers LDL cholesterol but raises safety concerns, particularly regarding hepatic and gastrointestinal adverse events (AEs). We conducted a pharmacovigilance disproportionality analysis using 2 major spontaneous reporting systems: the U.S. FDA Adverse Event Reporting System (FAERS, 2004-2024) and the Canada Vigilance Adverse Reaction Online Database (CVAROD, 2014-2025). All Lomitapide-related reports were extracted and analyzed using 4 statistical algorithms: reporting odds ratio (ROR), proportional reporting ratio, information component (IC), and Empirical Bayes Geometric Mean (EBGM). Signals were assessed at both the system organ class (SOC) and preferred term (PT) levels, with clinical priority scoring applied to rank AEs by relevance and impact. A total of 3665 FAERS and 80 CVAROD reports were analyzed. Gastrointestinal events were most frequent, including diarrhea (n = 1072; LBROR = 7.78), weight loss (n = 832; LBROR = 13.44), and nausea (n = 525; LBROR = 2.87). Hepatic events included elevated liver enzymes (n = 190; LBROR = 11.47) and hepatic steatosis (n = 67; LBROR = 13.01). Metabolic complications such as increased LDL levels (n = 159; LBROR = 85.45) were also observed. Subgroup analyses indicated higher susceptibility in males for diarrhea and weight loss, and in minors for abdominal pain (n = 10; LBROR = 7.53) and vomiting (n = 6; LBROR = 1.96). Novel signals, including renal pain (n = 10; LBROR = 2.33) and intestinal hemorrhage (n = 3; LBROR = 1.98), were identified, previously unreported in clinical trials. Most AEs occurred within the first week of treatment. Lomitapide is associated with clinically significant gastrointestinal, hepatic, and metabolic AEs, with elevated risk in male and pediatric patients. The early onset of reactions and emergence of novel signals highlight the importance of close monitoring, particularly during treatment initiation. Personalized risk mitigation strategies should be implemented to optimize the safety of Lomitapide therapy in HoFH patients.