Impact of currently prescribed lipid-lowering drugs on plasma PCSK9 concentration: single or in combination study in rats

Abstract

BackgroundAn emerging data suggested a significant impact of statins on PCSK9 concentration, while the rapid impacts of other lipid-lowering drugs such as ezetimibe and xuezhikang alone or in combination on PCSK9 and lipid profile have not been assessed. This study aims to investigate whether an enhanced PCSK9 concentration by single or combined therapy of lipid-lowering drugs currently used precedes the changes of lipid profile in rats.MethodsSixty-three rats were randomly divided into six groups and orally administrated with placebo (N = 13), ezetimibe 10 mg/kg daily, Xuezhikang 1200 mg/kg daily, ezetimibe 10 mg/kg plus Xuezhikang 1200 mg/kg daily, pitavastatin 10 mg/kg daily or pitavastatin 10 mg/kg plus ezetimibe 10 mg/kg daily for 3 days (N = 10 for each group respectively). Blood samples were obtained at day 3 after orally administration. Plasma PCSK9 levels were determined by ELISA and lipid profile were measured by enzymatic assay.ResultsEzetimibe, Xuezhikang and pitavastatin alone and Xuezhikang plus ezetimibe as well as pitavastatin plus ezetimibe increased PCSK9 levels by 124%, 56%, 111%, 63% and 204% respectively (p < 0.05 compared with placebo). However, Xuezhikang plus ezetimibe did not enhance greater PCSK9 levels compared to monotherapy. Ezetimibe and pitavastatin in combination induced higher PCSK9 levels than pitavastatin monotherapy or co-therapy with ezetimibe plus Xuezhikang. There was no significant difference between any groups with regard to lipid profile levels at day 3 (P > 0.05).ConclusionsElevated PCSK9 concentration by ezetimibe, Xuezhikang and pitavastatin alone or in combination was found prior to the alterations of lipid profile in rats. Combination of Xuezhikang and ezetimibe significantly attenuated increase in PCSK9 compared to ezetimibe plus pitavastatin, suggesting that the former combination may be better than the latter in future clinical application.

Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolaemic non-obese subjects. The BLOOD FLOW intervention study

“…In an in vitro study by the same group, ezetimibe had no effect on PCSK9 protein secretion by HepG2 or Caco-2 cells [23]. In an animal study, 3-day ezetimibe consumption significantly increased control-related plasma PCSK9 concentration in rats before any lipid changes could be observed [24]. On the whole, the reason for these contradictory results extending from in vitro studies to clinical interventions remains open.…”

Relationship Between Low‐Density Lipoprotein Cholesterol, Free Proprotein Convertase Subtilisin/Kexin Type 9, and Alirocumab Levels After Different Lipid‐Lowering Strategies

“…It has been proposed that the effect of fenofibrate on PCSK9 is indirect, rather than a direct effect on gene transcription as is observed with statins . There is some evidence from animal studies that ezetimibe upregulates the PCSK9 and LDLR genes; however, a previous study in humans did not find an effect of ezetimibe on PCSK9 . Increases in PCSK9 concentrations of 13% to 41% (versus placebo) have been reported after treatment with simvastatin or atorvastatin .…”

“…The effect of ezetimibe and fenofibrate on PCSK9 is unclear. Animal studies suggest that ezetimibe increases PCSK9 levels, but no effect was seen in humans . The change in PCSK9 levels with fibrates varies widely among reports …”

Impacts of ezetimibe on PCSK9 in rats: study on the expression in different organs and the potential mechanisms

“…Ezetimibe, an inhibitor of intestine cholesterol absorption, can decrease cholesterol synthesis and reduce circulating LDL-C concentration whenever it is prescribed alone or in combination with statins in controlling dyslipidemia [ 24 , 25 ]. Recently, several researchers have described that ezetimibe or the combination of ezetimibe and statin stimulates the expression of PCSK9 [ 12 , 26 ]. A study from Davignon J et al reported that patients treated with statins alone had a 45% increase in PCSK9 levels and those treated with statin plus ezetimibe showed an approximately 77% increase in PCSK9 concentrations [ 27 ].…”

“…Our previous study showed that ezetimibe induced a rapid increase of plasma PCSK9 concentration prior to the decrease of LDL-C levels in rats, even after 3 days of administration [ 12 ]. Hence, the aim of the present study was to investigate (1) the rapid impacts of ezetimibe on PCSK9 expression in different organs; (2) the underlying mechanisms for the elevated plasma PCSK9 levels after ezetimibe treatment using this 3-days’ rat model.…”