Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys: Effects of LDL lowering by ezetimibe in the absence of statins

- We used a dyslipidemia cynomolgus monkey model induced by a high-fat/high-cholesterol diet.
- Animals were treated with ezetimibe (Zetia®, Ezetrol®) by oral gavage or food treats.
- At two weeks, LDL cholesterol was decreased by 58%, total cholesterol by 42% for all animals.
- Inversely, PCSK9 levels were increased by 137% after ezetimibe treatment.
- We conclude that PCSK9 levels are inversely related to LDL cholesterol in this dyslipidemia model.

ObjectivesTo assess the lipid-lowering efficacy of ezetimibe in dyslipidemic cynomolgus monkeys comparing two dosing methods, and to evaluate PCSK9 plasma levels during dyslipidemia induction by feeding a high-fat/high-cholesterol diet (HFD), ezetimibe (Zetia®, Ezetrol®) treatment, ezetimibe washout, and HFD washout.Methods and resultsTwenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100-400 mg/dL) were randomized into two groups and treated with ezetimibe for two weeks, either by oral gavage or by using food treats. The lipid-lowering effects of ezetimibe were identical between the two groups. After treatment, mean LDL cholesterol was decreased by 58% (174-72 mg/dL), total cholesterol by 42% (241-138 mg/dL), and PCSK9 levels were increased by 137% (147-314 ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol.ConclusionsIn a cynomolgus dyslipidemia model, PCSK9 levels are inversely correlated with LDL cholesterol in the absence of statin treatment, regardless whether lipid changes are modulated by diet or ezetimibe treatment.