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Joint Inhibition of CETP, PCSK9 Concentrations Linked to Lower Risk of CAD

The combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes.

New findings suggest a joint inhibition of cholesteryl ester transfer protein inhibition (CETP) and PCSK9 inhibitor had additive effects on lipid concentrations and clinical outcomes, including a lower risk of coronary artery disease (CAD).

However, the association of CETP with age-related macular degeneration (AMD) was not observed to be mitigated, as genetically lower CETP concentrations were associated with increased odds for AMD.

“To our knowledge, our 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,” wrote study author Arjen J. Cupido, MD, Amsterdam University Medical Centers.

Previous data has shown CETP may 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 with agents including PCSK9 inhibitors. Thus, novel phase 3 trials are underway to investigate whether CETP leads to reduction of cardiovascular disease (CVD) risk in high-risk patients.

The design for the current study was a two-sample 2x2 factorial Mendelian randomization study in a general population sample that included data for UK Biobank participants of European ancestry. Investigators constructed separate genetic scores for CETP and PCSK9 plasma protein concentrations and combined them to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease.

Then, investigators studied the association of lower PCSK9 and CETP concentrations with lipids, blood pressure, CAD, type 2 diabetes, age-related macular degeneration (AMD), ischemic stroke, any stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis.

A total of 425,354 individuals from the UK Biobank were included in the study, with a median age of 59 years and 229,399 (53.9%) female. Data show the associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled to a 10-mg/dL reduction in LDL-C (for CETP: OR, 0.74; 95% CI, 0.67 - 0.81; for PCSK9: OR, 0.75; 95% CI, 0.71 - 0.79).

In order to evaluate the effect of joint inhibition of PCSK9 and CETP, investigators conducted interaction tests and divided UKB participants into 4 groups, based on median genetically predicted CETP and PCSK9 concentrations.

Investigators found no evidence for nonadditivity in the association with lipoprotein or lipids, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82 mg/dL and PCSK9 effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84 mg/dL). The combined effect size was identified as –3.47 mg/dL (95% CI, -3.76 to -3.18 mg/dL; P = .34 for interaction).

They noted that most importantly, an additive pattern for CAD compared with the group with higher CETP and PCSK9 concentrations were observed. Data show an odds ratio [OR] of 0.96 (95% CI, 0.94 - 1.00) for the group with lower CETP concentrations or PCSK9 concentrations and an OR of 0.90 (95% CI, 0.87 - 0.93) for the group with both lower CETP and PCSK9 concentrations (P = .83 for interaction).

“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,” Cupido added.

The study, “Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study,” was published in JAMA Cardiology.