TY - JOUR
T1 - Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease
T2 - A Factorial Mendelian Randomization Study
AU - Cupido, Arjen J.
AU - Reeskamp, Laurens F.
AU - Hingorani, Aroon D.
AU - Finan, Chris
AU - Asselbergs, Folkert W.
AU - Hovingh, G. Kees
AU - Schmidt, Amand F.
N1 - Funding Information: reported grants from the Amsterdam University Medical Centers Young Talent fund, Atheros Fund, Prince Bernhard Culture Fund, and Stichting de Drie Lichten during the conduct of the study. Dr Reeskamp reported being a co-founder of Lipid Tools. Dr Hingorani reported grants from Pfizer outside the submitted work and competitive grant support from UK Research and Innovation, British Heart Foundation (BHF), and National Institute for Health and Care Research (NIHR). Dr Finan reported support from the UCL BHF Research Accelerator, UCL NIHR Biomedical Research Centre, and Health Data Research UK. Dr Asselbergs reported support from the UCL Hospitals NIHR Biomedical Research Centre and BigData@Heart Consortium, funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 116074 and National Institutes of Health grant LM010098. Dr Hovingh reported research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative European Union, and the Klinkerpad fonds; institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; Funding Information: speaker’s bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment at Novo Nordisk, Denmark since April 2019. Dr Schmidt reported support from the BHF (grants PG/18/5033837, PG/22/10989) and UCL BHF Research Accelerator (AA/18/6/ 34223), additional support from the UCL Hospitals NIHR Biomedical Research Centre, and grants from Servier Grant for unrelated drug target validation work outside the submitted work. No other disclosures were reported. Publisher Copyright: © 2022 American Medical Association. All rights reserved.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - IMPORTANCE: Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents.OBJECTIVE: To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes.DESIGN, SETTING, AND PARTICIPANTS: Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry.EXPOSURES: Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease.MAIN OUTCOMES AND MEASURES: Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis.RESULTS: Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19).CONCLUSIONS AND RELEVANCE: Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.
AB - IMPORTANCE: Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents.OBJECTIVE: To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes.DESIGN, SETTING, AND PARTICIPANTS: Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry.EXPOSURES: Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease.MAIN OUTCOMES AND MEASURES: Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis.RESULTS: Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19).CONCLUSIONS AND RELEVANCE: Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options.
KW - Cholesterol Ester Transfer Proteins/genetics
KW - Cholesterol, LDL/blood
KW - Coronary Artery Disease/genetics
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Genetic Variation
KW - Humans
KW - Macular Degeneration
KW - Male
KW - Mendelian Randomization Analysis
KW - Middle Aged
KW - Proprotein Convertase 9/genetics
UR - http://www.scopus.com/inward/record.url?scp=85136248359&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamacardio.2022.2333
DO - https://doi.org/10.1001/jamacardio.2022.2333
M3 - Article
C2 - 35921096
SN - 2380-6583
VL - 7
SP - 955
EP - 964
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 9
ER -