P5328Clinical and demographic predictors of attenuated LDL-C response to PCSK9 inhibition with bococizumab: Insights from the SPIRE trials

Abstract

Abstract Background While there exists significant inter-individual variability in low density lipoprotein cholesterol (LDL-C) response to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, predictors of this response remain uncertain. The Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) randomized control trials evaluated the efficacy of bococizumab, a humanized murine PCSK9 antibody, in patients at high cardiovascular risk. Purpose This study's purpose is to determine predictors of attenuated LDL-C response to bococizumab. Methods SPIRE 1 and 2 trial subjects allocated to bococizumab (n=13,675) were included. Subjects with an increase in LDL-C or non-compliance to bococizumab, or development of anti-drug or neutralizing antibodies were excluded. The remaining 8281 subjects were divided into quintiles of percent LDL-C reduction from baseline to 14 weeks. The first quintile (Q1) was considered an attenuated response. Multivariate logistic regression was used to discern significant predictors of attenuated response (Q1) compared to robust response (Q5). Results Q1 included 1657 subjects with median 35% LDL-C reduction (range 0.4% - 48%), whereas Q5 included 1658 subjects with median 83% LDL-C reduction (range 78% - 99%). Female sex, diabetes, white race, younger age, higher baseline non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein (a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) were significantly associated with an attenuated response compared to a robust response (each p<0.05, Table). Multivariate logistic regression for attenuated percent LDL-C response to bococizumab from baseline to 14 week Baseline characteristic Adjusted odds ratio (95% confidence interval) P-value Female 3.30 (2.72, 4.00) <0.0001 Diabetes 1.57 (1.32, 1.86) <0.0001 White race 1.44 (1.07, 1.93) 0.016 BMI (per 1kg/m2) 1.09 (1.07, 1.11) <0.0001 Age (per year) 0.98 (0.98, 0.99) 0.0005 Ln hs-CRP (per 1mg/L) 1.19 (1.11, 1.29) <0.0001 Lp (a) (per 10mg/dL) 1.11 (1.09, 1.14) <0.0001 Non-HDL-C (per 10mg/dL) 1.05 (1.02, 1.07) <0.0001 Odds ratios mutually adjusted for the listed variables. Conclusions In the SPIRE 1 and 2 trials, excluding subjects with anti-drug and neutralizing antibodies, significant predictors of an attenuated LDL-C response to PCSK9 inhibition with bococizumab included female sex, diabetes, younger age and white race. Acknowledgement/Funding Pfizer