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Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian
Arjen J Cupido1,2,3,4, Laurens F Reeskamp1,2, Aroon D Hingorani5,6,7
1Amsterdam UMC location, University of Amsterdam, Department of Vascular Medicine, Amsterdam, the Netherlands.
Insights
Joint inhibition of cholesteryl ester transfer protein (CETP) and PCSK9 shows additive benefits for lipid traits and cardiovascular disease risk, including coronary artery disease (CAD). This suggests potential for combination therapies in high-risk patients.
Area of Science:
- Cardiovascular Genetics
- Lipid Metabolism
- Pharmacogenomics
Background:
- Cholesteryl ester transfer protein (CETP) inhibition raises HDL-C and lowers LDL-C, but current LDL-C target attainment is insufficient for many high-risk patients.
- PCSK9 inhibitors are effective but costly; combined inhibition strategies warrant investigation for enhanced cardiovascular risk reduction.
Purpose of the Study:
- To investigate the association of combined genetically reduced CETP and PCSK9 concentrations with coronary artery disease (CAD) and other clinical outcomes.
- To explore the additive or interactive effects of simultaneous CETP and PCSK9 inhibition on lipid profiles and disease risk.
Main Methods:
- A two-sample, 2x2 factorial Mendelian randomization study utilizing UK Biobank data from European ancestry participants.
- Genetic risk scores for CETP and PCSK9 plasma protein concentrations were constructed and combined to assess their joint effects on various health outcomes.
Main Results:
- Lower CETP and PCSK9 concentrations were individually associated with reduced CAD risk, with similar effects when scaled per 10-mg/dL LDL-C reduction.
- Combined lower CETP and PCSK9 concentrations demonstrated additive effects on lipid levels and disease risk, notably for LDL-C and CAD, without significant interaction.
- Lower CETP concentrations were also associated with an increased risk of age-related macular degeneration.
Conclusions:
- Joint inhibition of CETP and PCSK9 exhibits additive benefits on lipid profiles and cardiovascular disease risk, including CAD.
- Combination therapies targeting both CETP and PCSK9 may offer a promising strategy for high-risk patients who do not achieve treatment goals with existing therapies.
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.
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