Increased LDL-C reduction with ezetimibe in ketogenic diet-induced hypercholesterolemia

Several case reports and a meta-analysis have documented significant increases in cholesterol levels among individuals following a ketogenic diet. However, the mechanistic drivers of this phenotype remain incompletely understood. Here, we describe a retrospective case series of 14 patients with ketogenic diet-induced hypercholesterolemia who experienced larger-than-expected LDL-C reductions after ezetimibe therapy. In a subset of participants with available genetic data, no biallelic sitosterolemia-associated variants were identified in the loci assessed. We hypothesize that chronically low insulin levels may alter hepatic cholesterol homeostasis through changes in ACAT2-mediated cholesterol esterification and in NPC1L1/ABCG5/G8-mediated cholesterol handling. The magnitude of LDL-C reduction achieved with ezetimibe in this cohort suggests that altered cholesterol absorption may contribute importantly to this phenotype. This hypothesis-generating framework offers a plausible mechanistic explanation and supports further prospective study of precision lipid management in ketogenic diet-induced hypercholesterolemia.