Liver enzyme elevations during statin-ezetimibe therapy in ABCG2 c.421C>A variant carriers: a case series and narrative review.

INTRODUCTION: Statin-ezetimibe combination therapy is widely used and generally well tolerated; however, liver enzyme elevations may occur during treatment and can be difficult to interpret in patients with polypharmacy and other contributing factors. The potential role of drug-drug-gene interactions (DDGIs) in this context remains insufficiently explored.

MATERIALS AND METHODS: We present a series of 11 patients from the PGx-CardioDrug study, selected for documented liver enzyme elevations during statin-ezetimibe therapy that led to treatment modification and carriage of the ABCG2 c.421A allele. Clinical characteristics, treatment history, laboratory findings, and outcomes were reviewed alongside available pharmacogenetic results for genes involved in drug transport and metabolism. Available records of five additional ABCG2 c.421CA carriers with documented normal liver enzyme findings during combination therapy were reviewed for descriptive comparison. A narrative review of the literature was conducted to provide a mechanistic interpretation for the observed findings.

RESULTS: The series included six women and five men, aged 27-78 years. Muscle symptoms and/or creatine kinase (CK) elevations were observed in six patients, including two with rhabdomyolysis requiring hospitalization. Dose reduction, drug discontinuation, or switching to alternative lipid-lowering therapy resulted in improvement of laboratory parameters in several patients. In two patients, abnormalities persisted or increased during subsequent ezetimibe monotherapy. Follow-up laboratory results were not available for all patients. Eight patients had the ABCG2 c.421CA genotype and three had c.421AA, consistent with the selection criterion. Additional findings included variants in SLCO1B1, ABCC2, ABCB1, and UGT1A1. In the five potential comparators, normal liver enzyme findings during combination therapy were supported by numerical laboratory values in three patients and clinical documentation in two.

DISCUSSION: These cases illustrate the difficulty of interpreting liver enzyme elevations during statin-ezetimibe therapy in patients with concomitant medications and other contributing factors. The narrative review provides a pharmacokinetic rationale for considering DDGIs, but the case series does not establish their contribution to the observed abnormalities. Genotype-based selection, incomplete clinical data, and the small descriptive comparator group limit interpretation. These observations remain hypothesis-generating.