TY - JOUR
T1 - Inverse relationship between LDL cholesterol and PCSK9 plasma levels in dyslipidemic cynomolgus monkeys
T2 - Effects of LDL lowering by ezetimibe in the absence of statins
AU - Hentze, Hannes
AU - Jensen, Kristian K.
AU - Chia, Ser Mien
AU - Johns, Douglas G.
AU - Shaw, Rachel J.
AU - Davis, Harry R.
AU - Shih, Shian Jiun
AU - Wong, Kenny K.
PY - 2013/11
Y1 - 2013/11
N2 - Objectives: To 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 results: Twenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100-400mg/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% (174-72mg/dL), total cholesterol by 42% (241-138mg/dL), and PCSK9 levels were increased by 137% (147-314ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol. Conclusions: In 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.
AB - Objectives: To 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 results: Twenty dyslipidemic cynomolgus monkeys on HFD for seven months (LDL cholesterol 100-400mg/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% (174-72mg/dL), total cholesterol by 42% (241-138mg/dL), and PCSK9 levels were increased by 137% (147-314ng/mL). PCSK9 levels on regular diet before and after HFD were also inversely correlated to LDL cholesterol. Conclusions: In 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.
KW - Dyslipidemia
KW - Ezetimibe
KW - Non-human primate
KW - PCSK9
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U2 - 10.1016/j.atherosclerosis.2013.08.028
DO - 10.1016/j.atherosclerosis.2013.08.028
M3 - Article
C2 - 24125416
AN - SCOPUS:84885412701
SN - 0021-9150
VL - 231
SP - 84
EP - 90
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -