Relationship Between Time‐Varying Achieved High‐Density Lipoprotein Cholesterol and Risk of Coronary Events Depends on Haptoglobin Phenotype Within the ACCORD Lipid Study

Background The Hp (haptoglobin)2‐2 phenotype (~40% of people) is associated with dysfunctional high‐density lipoprotein (HDL) that is heavily oxidized in hyperglycemia, which may explain why raising HDL‐cholesterol (HDL‐C) does not reliably prevent coronary artery disease (CAD) in diabetes. Methods and Results In this observational study using longitudinal data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) lipid trial, time‐varying (achieved) HDL‐C updated at 4, 8, and 12 months, and annually thereafter over a mean of 4.7 years, was analyzed in relation to risk of CAD and secondary outcomes using Cox proportional hazards regression with time‐varying covariables among participants with (n=1781) and without (n=3191) the Hp2‐2 phenotype. HDL‐C did not differ between the phenotypes throughout the study. Having low HDL‐C (<40 mg/dL for male participants and <50 mg/dL for female participants) was associated with a greater risk of CAD compared with non‐low HDL‐C among participants with the non‐Hp2‐2 phenotype (hazard ratio [HR], 1.48 [95% CI, 1.18–1.87]) but not among the Hp2‐2 phenotype (HR, 0.97 [95% CI, 0.70–1.35]; P interaction=0.03). Similarly, an inverse relationship was observed between HDL‐C quintiles and CAD risk among participants without the Hp2‐2 phenotype, whereas no significant inverse relationship was observed among participants with the Hp2‐2 phenotype ( P interaction=0.38). Among the Hp2‐2 phenotype group, having low HDL‐C was associated with higher risk of CVD mortality (HR, 2.09 [95% CI, 1.05–4.13]), and compared with the lowest HDL‐C quintile, higher quintiles were associated with lower risk of CVD mortality and congestive heart failure. Conclusions Hp phenotype modified the association between HDL‐C and risk of CAD in the ACCORD lipid study, suggesting that HDL dysfunction in the Hp2‐2 phenotype may hinder CAD‐protective properties of HDL‐C.