Circulating N-Linked Glycoprotein Side-Chain Biomarker, Rosuvastatin Therapy, and Incident Cardiovascular Disease: An Analysis From the JUPITER Trial

Abstract

Background: GlycA, a novel protein glycan biomarker of N-acetyl side chains of acute-phase proteins, was recently associated with incident cardiovascular disease (CVD) in healthy women. Whether GlycA predicts CVD events in the setting of statin therapy in men and women without CVD but with evidence of chronic inflammation is unknown.

Methods and results: In the Justfication for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681), participants with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to rosuvastatin 20 mg/day or placebo. GlycA was quantified by nuclear magnetic resonance spectroscopy in 12 527 before randomization and 10 039 participants at 1 year. A total of 310 first primary CVD events occurred during maximum follow-up of 5.0 years (median, 1.9). GlycA changed minimally after 1 year on study treatment: 6.8% and 4.7% decrease in the rosuvastatin and placebo groups, respectively. Overall, baseline GlycA levels were associated with increased risk of CVD: multivariable-adjusted hazard ratio (HR) per SD increment, 1.20 (95% CI, 1.08-1.34; P=0.0006). After additionally adjusting for hsCRP, this was slightly attenuated (HR, 1.18; 95% CI, 1.04-1.35; P=0.01). On-treatment GlycA levels were also associated with CVD; corresponding multivariable-adjusted HRs per SD before and after additionally adjusting for hsCRP: 1.27 (95% CI, 1.13-1.42; P<0.0001) and 1.24 (95% CI, 1.07-1.44; P=0.004), respectively. Tests for heterogeneity by treatment arm were not significant (P for interaction, >0.20).

Conclusion: In the JUPITER trial, increased levels of GlycA were associated with an increased risk of CVD events independent of traditional risk factors and hsCRP.

Clinical trials registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: cardiovascular disease; epidemiology; glycoprotein; metabolomics; statin intervention.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

Baseline to 1‐year median percent change in GlycA with error bar indicating limit of 75th percentile according to randomized treatment, among individuals with both baseline and 1‐year measurements (n=10 039). P values from the Wilcoxon signed‐rank test comparing baseline and year 1 values were P<0.0001. P values from the Wilcoxon rank‐sum test comparing the change among the rosuvastatin group with the change among the placebo group were <0.0001. hsCRP indicates high‐sensitivity C‐reactive protein.

Figure 2

Cumulative incidence rates of the primary endpoint according to baseline quartiles of GlycA.

Figure 3

A, Stratified hazard ratios (95% CIs) per SD of baseline GlycA with the primary endpoint adjusted for age, race, sex, randomization treatment assignment, smoking, blood pressure, body mass index, fasting glucose, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, family history of premature coronary disease, and high‐sensitivity C‐reactive protein. B, Stratified hazard ratios (95% CIs) per SD of on‐treatment GlycA with the primary endpoint adjusted for age, race, sex, randomization treatment assignment, smoking, blood pressure, body mass index, fasting glucose, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, family history of premature coronary disease, and high‐sensitivity C‐reactive protein. CHD indicates coronary heart disease; HR, hazard ratio.

Figure 4

A, Hazard ratios (95% CIs) for the primary endpoint according to baseline GlycA levels events in relation to randomized treatment assignment, adjusted for age, race, sex, smoking, blood pressure, body mass index, fasting glucose, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, high‐sensitivity C‐reactive protein, and family history of premature coronary disease. B, Efficacy of rosuvastatin for the primary endpoint according to baseline GlycA levels adjusted for age, race, sex, smoking, blood pressure, body mass index, fasting glucose, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, high‐sensitivity C‐reactive protein, and family history of premature coronary disease.