Abstract 15537: Ezetimibe in Combination With Simvastatin Reduces Remnant-cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients

Introduction: Large genetic studies have recently recognized remnant-cholesterol, defined as cholesterol in triglyceride (TG)-rich lipoproteins, as a causal risk factor for ischemic heart disease and low grade inflammation, independently of HDL-cholesterol. NPC1L1 in the intestine is the target of ezetimibe, but its function in the liver is still unknown. Hypothesis: To clarify the function of hepatic NPC1L1 in humans we performed a randomized, single-blind, placebo-controlled study and investigated molecular changes in lipoprotein, lipid and carbohydrate metabolism secondary to combined inhibition of cholesterol synthesis and intestinal cholesterol absorption. Methods: Forty cholesterol gallstone patients (13 men and 27 women) received 80 mg/day simvastatin, 10 mg/day ezetimibe, or a combination of simvastatin and ezetimibe, or placebo for four weeks. Plasma, bile and liver biopsies were collected. Results: The first results showed that ezetimibe treatment alone or in combination with simvastatin did not increase the % molar concentration of cholesterol in bile nor blunted the decrease due to cholesterol synthesis inhibition. Combination therapy led to a 70% decrease in cholesteryl esters (p<0.001) and a 50% decrease in TG (p<0.01) in the core of TG-rich lipoproteins. Negative changes in fasting insulin, c-peptide, or glucose concentrations were not observed. The dramatic changes in the core of TG-rich lipoprotein were not seen in subjects treated with simvastatin or ezetimibe alone, and were not paralleled by changes in HDL-cholesterol. Conclusions: The expected increase in biliary cholesterol following treatment with ezetimibe does not occur in humans, suggesting different functions of NPC1L1 (or ezetimibe action) in the liver and intestine. The results also help to explain why ezetimibe associated to simvastatin was more effective in reducing CVD events in the diabetic patients (IMPROVE-IT), known to have increased levels of TG-rich lipoproteins.