Physicians' Academy for Cardiovascular Education

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

Literature - Cupido AJ, Reeskamp LF, Hingorani AD, et al. - JAMA Cardiol. 2022 Sep 1;7(9):955-964. doi: 10.1001/jamacardio.2022.2333

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 [4].

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.

Main results

Associations of lower CETP or PCSK9 concentrations with lipid levels and clinical outcomes

Associations of combined lower CETP and PCSK9 concentrations with lipid levels and 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.”


Show references

Find this article online at JAMA Cardiol.

Share this page with your colleagues and friends: