Tahir Mahmood1, Jessica Minnier1,2, Matthew K Ito3, Qian H Li4, Andrew Koren3, Ivy W Kam4, Sergio Fazio1, Michael D Shapiro5. 1. Oregon Health & Science University, Knight Cardiovascular Institute, Center for Preventive Cardiology, USA. 2. Oregon Health & Science University, OHSU-PSU School of Public Health, USA. 3. Sanofi, USA. 4. Regeneron Pharmaceuticals Inc., USA. 5. Center for Preventive Cardiology, Wake Forest University Baptist Medical Center, Section on Cardiovascular Medicine, USA.
Abstract
AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50-60% and lipoprotein(a) (Lp(a)) by 20-30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab. METHODS: This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%. RESULTS: Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance. CONCLUSION: A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors consistently reduce low-density lipoprotein cholesterol (LDL-C) by 50-60% and lipoprotein(a) (Lp(a)) by 20-30%, but the mechanism of Lp(a) lowering remains unclear. If Lp(a) is cleared by the LDL receptor, similar to LDL-C, then one would expect PCSK9 inhibition to induce a concordant LDL-C/Lp(a) response in an approximately 2:1 ratio. We aim to determine the prevalence of discordant plasma LDL-C/Lp(a) response to the PCSK9 inhibitor alirocumab. METHODS: This is a post hoc, pooled analysis of 10 randomized controlled trials from the ODYSSEY Phase 3 clinical trial program for alirocumab. Patients enrolled in the trials were high cardiovascular risk and/or with heterozygous familial hypercholesterolemia. The primary end point was prevalence of discordant LDL-C/Lp(a) response to alirocumab at 24 weeks. Discordant response was defined as LDL-C reduction >35% and Lp(a) reduction ≤10%, or LDL-C reduction ≤35% and Lp(a) reduction >10%. RESULTS: Of the 1709 patients in the pooled study cohort, 62.4% were male, and the mean age was 59.2 (SD: 11.0) years. Baseline mean LDL-C was 126.5 (SD: 46.3) mg/dL and baseline median Lp(a) was 46.9 (interquartile range: 21.8-89.0) mg/dL. Total prevalence of discordant LDL-C/Lp(a) response was 21.5% (12.6% with LDL-C >35% reduction and Lp(a) ≤10% reduction; 8.9% with LDL-C ≤35% reduction and Lp(a) >10% reduction). Baseline Lp(a) and familial hypercholesterolemia status did not affect discordance. CONCLUSION: A high prevalence of discordant LDL-C/Lp(a) response was observed with alirocumab, further suggesting that PCSK9 inhibitor therapy with alirocumab reduces plasma Lp(a) through alternative pathways to LDL receptor clearance. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Anindita Chakraborty; Jing Pang; Dick C Chan; Wendy Barnett; Ann Marie Woodward; Mary Vorster; Gerald F Watts Journal: Clin Cardiol Date: 2021-05-06 Impact factor: 3.287