Combined genetic CETP and PCSK9 inhibition additively associated with lower CAD risk
Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study
Introduction and methods
As only one-third of patients on PCSK9is meet LDL-c targets [1-3], additional therapies are needed to further lower their CVD risk. Inhibition of cholesteryl ester transfer protein (CETP) appears to be a promising strategy. A recent Mendelian randomization (MR) study suggested that while PCSK9 and CETP both affect the risk of coronary artery disease (CAD), they may act through different pathways and could therefore have additive benefits .
Aim of the study
The study aim was to evaluate the associations of combined reduction of CETP and PCSK9 protein plasma concentrations with lipid levels, CAD, and other clinical outcomes known to be associated with CETP or PCSK9.
This was a two-sample, 2 × 2 factorial MR study that consisted of 3 parts. The research focused on the investigation of: (1) the associations of genetically predicted lower CETP or PCSK9 concentrations with lipids and CAD risk, using external, summary-level genome-wide association study data; (2) the associations of individually genetically predicted lower CETP or PCSK9 concentrations with lipids and clinical outcomes, using data of 425,354 UK Biobank participants of White ancestry; and (3) the associations of the combined exposure to genetically predicted lower CETP and PCSK9 concentrations with lipids and clinical outcomes, using factorial MR.
Using summary data from previous MR studies [5,6], genetic scores were constructed for both CETP and PCSK9 plasma protein concentrations. These 2 genetic scores were then combined to model the expected effects of combined lower PCSK9 and CETP concentrations.
The authors assessed the associations of lower CETP and/or PCSK9 concentrations with blood lipid and lipoprotein concentrations, blood pressure, CAD, T2DM, age-related macular degeneration (AMD), ischemic stroke, any stroke, Alzheimer disease, vascular dementia, HF, AF, CKD, asthma, and multiple sclerosis.
Associations of lower CETP or PCSK9 concentrations with lipid levels and clinical outcomes
- The genetic scores for CETP and PCSK9 protein concentrations were validated using the external, non–UK Biobank data.
- This showed that lower CETP plasma concentrations were associated with decreased LDL-c, triglyceride, and apoB levels and with increased HDL-c and apoA1 levels, whereas lower plasma PCSK9 concentrations were associated with decreased total cholesterol, LDL-c, apoB, and apoA1 levels.
- Analyses of the UK Biobank data revealed similar effects of lower CETP or PCSK9 concentrations on lipid levels.
- When corrected for multiple testing, genetically predicted lower CETP concentrations were associated with lower odds of CAD (odds ratio (OR): 0.96; 95%CI: 0.94–0.99) and higher odds of AMD (OR: 1.11; 95%CI: 1.04–1.19) compared with higher genetically predicted concentrations, while lower genetically predicted PCSK9 concentrations were associated with lower odds of CAD (OR: 0.94; 95%CI: 0.92–0.96). There were no significant associations between lower CETP or PCSK9 concentrations and the other clinical outcomes.
- When scaled to a 10-mg/dL LDL-c reduction, the associations of lower CETP and lower PCSK9 concentrations with CAD were also comparable (OR for lower CETP: 0.74; 95%CI: 0.67–0.81; OR for lower PCSK9: 0.75; 95%CI: 0.71–0.79).
Associations of combined lower CETP and PCSK9 concentrations with lipid levels and clinical outcomes
- There was no evidence for nonadditivity in the association of combined CETP and PCSK9 inhibition with lipids or lipoproteins, particularly for LDL-c (effect size for lower CETP: –1.11 mg/dL; 95%CI: –1.40 to –0.82; effect size for lower PCSK9: –2.13 mg/dL; 95%CI: –2.43 to –1.84; effect size for combination: –3.47 mg/dL; 95%CI: –3.76 to –3.18; P=0.34 for interaction).
- An additive effect was also seen for the association of combined lower CETP and PCSK9 concentrations with CAD compared with higher CETP and PCSK9 concentrations (OR for lower CETP: 0.96; 95%CI: 0.94–1.00; OR for lower PCSK9: 0.94; 95%CI: 0.91–0.97; OR for combination: 0.90; 95%CI: 0.87–0.93; P=0.83 for interaction). Similar additive effects were found for the other clinical outcomes.
In this MR and factorial MR study, genetically lower CETP and PCSK9 concentrations were associated with lower LDL-c and apoB concentrations and lower risk of CAD, and genetically lower CETP concentrations were associated with higher risk of AMD. The authors believe their “data provide the first suggestion that the combination of CETP inhibition with PCSK9 inhibition will result in an independent and additive effect on the reduction of atherogenic lipids and a proportional clinically relevant reduction of CAD risk.”