Plasma PCSK9 is increased by Fenofibrate and Atorvastatin in a non-additive fashion in diabetic patients

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

“…Several reports [8,10] suggest that these effects of PPAR-α on cholesterol and lipoprotein metabolism may lead indirectly to decrease hepatic intracellular cholesterol levels, and thus result in a secondary increase in PCSK9 expression and secretion. Costet et al reported that one-day administration of atorvastatin increased PCSK9 levels whereas that of fenofibrate did not [11], which might support the indirect slower effect of PPAR-α agonist on PCSK9 expression. PPAR-γ is another target of bezafibrate and is expected to have effects on glucose metabolism and insulin resistance [36].…”

“…In contrast to these reports, Mayne et al and Troutt et al represented an increase in circulating PCSK9 level after fenofibrate treatment with 200 mg/day in dyslipidemic patients (+17%; p = 0.031 and +25%; p < 0.01, respectively) [8,10], although the precise mechanism contributing to these increases remains to be clarified. Furthermore, Costet et al reported that 6 weeks of treatment with either 10 mg/day atorvastatin or 160 mg/day fenofibrate increased PCSK9 levels (+14%; p = 0.01 and +26%; p < 0.01, respectively) in T2DM subjects, with no additive effect after 6 weeks of combined therapy [11]. In our study, the effect of fenofibrate treatment with 200 mg/day on plasma PCSK9 level was more prominent (+66.8%) than these reports and was even higher than previously reported value of high dose (80 mg) atorvastatin treatment (+47%) [26], although study population and duration of the treatment were different.…”

“…Recently, it was shown that fenofibrate suppressed PCSK9 expression at the promoter level and reduced statin-induced PCSK9 secretion in vitro [9], whereas, fenofibrate did not suppress and rather increased circulating PCSK9 level in several in vivo studies [8,10,11]. Bezafibrate is another widely used fibrate, and both of which have substantial triglyceride (TG)-reducing-effect and high-density lipoprotein cholesterol (HDL-C)-raising effect.…”

Pcsk9

“…They have been shown to repress PCSK9 gene expression in a human hepatocyte cell line and isolated mouse hepatocytes, 85,86 but the WY14643 agonist had no effect on the level of PCSK9 mRNA in isolated hamster hepatocytes. 87 The reasons for this discrepancy are unclear as are those from clinical studies in fibrate-treated patients, showing increased plasma PCSK9 levels in most studies [88][89][90][91] and a decreased levels in another. 85 PPARγ ligands, 15d-PGJ1 or pioglitazone, have been shown to augment the level of PCSK9 mRNA in HepG2 cells.…”

Proprotein convertase subtilisin/kexin type 9: A new target molecule for gene therapy

“…Caresky et al [9] demonstrated that atorvastatin treatment (10 mg/day) reduced LDL-C levels by 30%, with no significant effect on PCSK9 expression, whereas patients receiving 40 mg/day of atorvastatin displayed a total decrease of 42% in LDL-C level, while plasma PCSK9 concentration increased by 34%. However, Costet et al [10] reported that the same dose of atorvastatin (10 mg/day) increased plasma PCSK9 by 24% by day 1, and by 14% after 6 weeks of administration in patients with type 2 diabetes mellitus. Later studies by Welder et al [11] confirmed that high-dose atorvastatin treatment (80 mg/day) causes a 47% increase in serum PCSK9 after 4 weeks of administration, which was completely sustained at 8-week, 12-week, and 16-week time points.…”