Statin therapy is a major determinant of PCSK9 plasma concentration: data from four clinical trials with AMG 145

Purpose: Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a critical role in the metabolism of low density lipoproteins (LDL), impairing LDL clearance by promoting LDL receptor degradation. Data suggest statins may modify PCSK9 levels. We tested whether PCSK9 levels were associated with the intensity of statin therapy. Method: We analyzed baseline PCSK9 plasma concentrations in 1335 patients, aged 18-80, in four Phase 2 clinical trials (MENDEL, LAPLACE, RUTHERFORD, GAUSS) with AMG 145, a fully human monoclonal antibody to PCSK9, and examined associations with baseline characteristics, including statin therapy (none, non-intensive, or intensive [defined as simvastatin 80 mg QD, atorvastatin ≥40 mg QD, rosuvastatin ≥20 mg QD, or any statin plus ezetimibe]). Results: Baseline PCSK9 concentration varied greatly (median 406 ng/mL, IQR 326-493 ng/mL, range 116-1200 ng/mL), but levels were not associated with age, sex, or LDL-C. PCSK9 levels did significantly differ based on statin therapy; medians were 343 ng/mL (IQR 296-408) in patients on no statin, 421 ng/mL (IQR 346-485) for those on non-intensive statin treatments, and 531 ng/mL (IQR 433-645) for those on intensive statin treatments (p-value < 0.0001). In the analyses of log transformed baseline PCKSK9 levels, baseline statin treatment accounted for more than one-quarter (R2=0.28, p-value < 0.0001) of the variability, more than any other baseline factor. Baseline PCKS9 by Baseline Statin Use Conclusions: PCSK9 plasma concentrations are higher in patients on statin therapy and highest in those on the most intensive statin or statin plus ezetimibe treatments.