Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy

Abstract

Background Statin‐mediated efficacy of lowering low‐density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine‐protease associated with LDL metabolism, which circulates as mature and furin‐cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin‐naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10‐ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01–1.24 [ P =0.03]), whereas furin‐cleaved level was not (per 10‐ng/mL increase: OR, 1.37; 95% CI, 0.73–2.58 [ P =0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

Population PK/PD modeling of low‐density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti‐PCSK9 monoclonal antibody

“…42 We observed that co-administration of statins increased target-mediated maximum elimination rate V max of bococizumab by 17%. This is consistent with the effect of statins (stimulation of LDL-R and PCSK9 production [43][44][45][46] ) and target-mediated elimination of bococizumab (via binding to PCSK9 1,35 ). Therefore, upregulation of PCSK9 could have resulted in LDL-C increase, but the effect of upregulating LDL-R exceeded the effect of up-regulation of PCSK9, suggesting net enhancement of LDL-C reduction.…”

Impact of conventional lipid-lowering therapy on circulating levels of PCSK9: protocol for a systematic review and meta-analysis of randomised controlled trials

“…14 Although multiple randomised controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of PCSK9 inhibitors in treating dyslipidaemia, several studies have reported that conventional lipid-lowering therapies could lead to increased circulating PCSK9 levels. [15][16][17][18][19][20] On the other hand, it has been reported that statin treatment raises PCSK9 in primarily the inactivated form. 21 Additionally, PCSK9 expression is controlled by the circadian rhythm and is influenced by multiple hormonal and nutritional factors, which further complicates the quantification of its plasma concentration.…”

“…Accumulating evidence has demonstrated that elevated circulating PCSK9 level has been associated with increased CVD risk 14. Although multiple randomised controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of PCSK9 inhibitors in treating dyslipidaemia, several studies have reported that conventional lipid-lowering therapies could lead to increased circulating PCSK9 levels 15–20. On the other hand, it has been reported that statin treatment raises PCSK9 in primarily the inactivated form 21.…”

Metformin-induced PCSK9 inhibition further decreases LDL-C following statin treatment in non-diabetic patients with coronary artery disease and hyperlipoproteinemia(a)

“…Statin therapy has been reported to increase the circulating PCSK9 levels with dose intensi cation, which may limit additional LDL-C reduction [13]. Kuyama et al [14] demonstrated that circulating PCSK9 is correlated with a hypo-response to statins. Some studies showed residual risks partially derived from statin-induced PCSK9 upregulation [14] and associated Lp(a) elevation [10].…”

“…Kuyama et al [14] demonstrated that circulating PCSK9 is correlated with a hypo-response to statins. Some studies showed residual risks partially derived from statin-induced PCSK9 upregulation [14] and associated Lp(a) elevation [10]. Although PCSK9 inhibition with monoclonal antibodies has proven effective and safe in reducing cardiovascular risk by both LDL-C and Lp(a) lowering [15,16], the general administration of PCSK9 inhibitors in clinical remains limited owing to their high cost and inconvenience [17].…”