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

Abstract

BackgroundGlycA, 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 ResultsIn 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).ConclusionIn 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.

Glycosylation Signatures of Inflammation Identify Cardiovascular Risk

“…GlycA has been correlated with multiple cytokines from various inflammatory pathways, and a relationship with neutrophil activity (through inference form coexpression-based network analysis) has been proposed. 14 Additionally, in several of the outcome studies mentioned above, 7, 8, 10, 11 comparing patterns of risk associations for GlycA with those for other inflammatory biomarkers supports overlap in the risks captured. In these studies, incremental adjustment for these correlated inflammatory markers in many instances attenuates the magnitude of risk associations.…”

“…By comparison, HMG-CoA reductase inhibitors (statins) reduce high-sensitivity C-reactive protein levels by ~20 to 30%, but do not result in clinically meaningful reductions in GlycA. 8 Future prospective studies will be needed to further evaluate this, including in on-going, large-scale clinical trials that are investigating systemic anti-inflammatory therapies among broader, non-rheumatologic populations to reduce residual risk of CVD. The performance of GlycA in reflecting the effects of non-pharmacologic, lifestyle interventions to reduce inflammation and CVD risk also warrants further study.…”

Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer

“…GlycA, the NMR signal derived from multiple inflammatory glycoproteins, was demonstrated to predict future CVD and T2DM (Table 2) [71][72][73]. GlycA was shown to be related to the leptin/adiponectin ratio, suggesting that adipose tissue-associated low-grade inflammation could be involved in the regulation of inflammatory glycoproteins [49].…”

“…In the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, GlycA was associated with incident CVD, defined as the combined end-point of CV morbidity and mortality, independent of clinical and lipid measures as well as renal function [72]. Baseline concentrations of GlycA in the Justification for the Use of Statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) trial were significantly associated with incident CVD events, even when adjusting for established risk factors and a family history of premature coronary heart disease [73]. Remarkably, this association was only slightly attenuated by hsCRP, suggesting that the two biomarkers are reflecting somewhat different pathobiological processes [73].…”

“…Baseline concentrations of GlycA in the Justification for the Use of Statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) trial were significantly associated with incident CVD events, even when adjusting for established risk factors and a family history of premature coronary heart disease [73]. Remarkably, this association was only slightly attenuated by hsCRP, suggesting that the two biomarkers are reflecting somewhat different pathobiological processes [73]. In addition, GlycA was shown to be associated with future major adverse coronary events and mortality in two different cohorts of patients undergoing coronary angiography [1,52,74].…”