Anti-Inflammatory HDL Function, Incident Cardiovascular Events, and Mortality: A Secondary Analysis of the JUPITER Randomized Clinical Trial

Abstract

Background High-density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti-inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation. Methods and Results The functional capacity of HDL to inhibit oxidation of oxidized low-density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case-control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all-cause mortality compared to 517 age- and sex-matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50-0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, -8.9% to -1.7%; P=0.005) versus 1.3% (95% CI, -6.5% to 4.0%; P=0.63) with placebo (P=0.22 for between-group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5-1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06-2.21; P=0.02). Furthermore, there was significant (P=0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti-inflammatory. Conclusions In JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti-inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti-inflammatory HDL function with risk may account in part for the HDL paradox. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00239681.

Keywords: HDL function; HDL inflammatory index; HDL particle number; cardiovascular disease risk factors; high‐density lipoprotein.

Conflict of interest statement

Dr Adelman and Dr Collins are employees of Vascular Strategies. Dr Mora received research grant support from Atherotech Diagnostics for work outside the current study, the Molino Family Trust, and NIH, and has served as consultant to Quest Diagnostics for work outside the current study. The remaining authors have no disclosures to report.

Figures

Figure 1. Relationship between HDL inflammatory index at baseline and CVD /all‐cause mortality (A) and CVD only (B).

Conditional logistic regression was used to estimate CVD hazard ratios as a function of baseline HDL inflammatory index adjusted for age, drug (statin vs placebo), race, systolic blood pressure, cigarette smoking, body mass index, glucose level, low‐density lipoprotein cholesterol, family history of premature coronary disease, triglycerides, and high‐sensitivity C‐reactive protein. Regions with sparse data are not displayed (ie, 2.5 SD). CVD indicates cardiovascular disease; HDL, high‐density lipoprotein.

Figure 2. Association of biomarkers with CVD/all‐cause mortality risk by HII categories at baseline.

HR1–Hazard ratio comparing risk in HII category >1.0 to HII category 0 to 0.5; HR2–hazard ratio comparing risk in HII category 0.5 to 1.0 to HII category 0 to 0.5; and P for interactions between HII categories and biomarkers of cardiovascular risk at baseline. HRs were obtained from conditional logistic regression models. (A) Shows the relationship of HDL‐related biomarkers and inflammatory markers with CVD/all‐cause mortality risk by HII categories at baseline. (B, C) Association of HDL‐P and Apo AI with CVD/all‐cause mortality risk within the three categories of HII. Apo AI indicates apolipoprotein AI; CEC, cholesterol efflux capacity; CVD, cardiovascular disease; GlycA, glycoprotein acetylation; HDL, high‐density lipoprotein; HDLC, high‐density lipoprotein cholesterol; HDLP, high‐density lipoprotein particle number; HII, HDL inflammatory index; hsCRP, high‐sensitivity C‐reactive protein; Lp‐PLA2 act., lipoprotein‐associated phospholipase A2 activity; and sPLA2, secretory phospholipase A2.