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

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.clinicaltrials.gov; Unique identifier: NCT00239681.