Effect of simvastatin and ezetimibe on suPAR levels and outcomes

TY - JOUR

T1 - Effect of simvastatin and ezetimibe on suPAR levels and outcomes

AU - Hodges, Gethin W

AU - Bang, Casper N

AU - Forman, Julie L

AU - Olsen, Michael H

AU - Boman, Kurt

AU - Ray, Simon

AU - Kesäniemi, Y Antero

AU - Eugen-Olsen, Jesper

AU - Greve, Anders M

AU - Jeppesen, Jørgen L

AU - Wachtell, Kristian

N1 - Copyright © 2018 Elsevier B.V. All rights reserved.

PY - 2018/5

Y1 - 2018/5

N2 - Background and aims: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown. Methods: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). Results: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%–11.5%) in the placebo group, but only by 4.1% (1.9%–6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17–3.61); MCE 1.40 (1.01–1.92); and AVE 1.42 (1.02–1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE. Conclusions: Simvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677).

AB - Background and aims: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown. Methods: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). Results: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%–11.5%) in the placebo group, but only by 4.1% (1.9%–6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17–3.61); MCE 1.40 (1.01–1.92); and AVE 1.42 (1.02–1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE. Conclusions: Simvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677).

U2 - 10.1016/j.atherosclerosis.2018.03.030

DO - 10.1016/j.atherosclerosis.2018.03.030

M3 - Journal article

C2 - 29602140

SN - 0021-9150

VL - 272

SP - 129

EP - 136

JO - Atherosclerosis

JF - Atherosclerosis

ER -