Haptoglobin Phenotype Modifies the Effect of Fenofibrate on Risk of Coronary Event: ACCORD Lipid Trial

OBJECTIVE The haptoglobin (Hp)2-2 phenotype (∼35–40% of people) is associated with increased oxidation and dysfunctional HDL in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL cholesterol and lower triglycerides have not reliably prevented cardiovascular disease in diabetes. We aimed to determine whether the effect of adding fenofibrate versus placebo to simvastatin on the risk of coronary artery disease (CAD) events depends on Hp phenotype in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. RESEARCH DESIGN AND METHODS Cox proportional hazards regression models quantified the relationship between fenofibrate therapy and CAD events in the ACCORD lipid trial in participants with the Hp2-2 phenotype (n = 1,795) separately from those without (n = 3,201). RESULTS Fenofibrate therapy successfully lowered the risk of CAD events in participants without the Hp2-2 phenotype (multivariable adjusted hazard ratio 0.74 [95% CI 0.60–0.90] compared with no fenofibrate therapy) but not in participants with the Hp2-2 phenotype (1.16 [0.87–1.56]; P interaction = 0.009). Subgroup analyses revealed that this protective effect of fenofibrate against CAD events among the non–Hp2-2 phenotype group was pronounced in participants with severe dyslipidemia (P interaction = 0.01) and in males (P interaction = 0.02) with an increased CAD risk from fenofibrate treatment observed in females with the Hp2-2 phenotype (P interaction = 0.002). CONCLUSIONS The effect of fenofibrate added to simvastatin on risk of CAD events depends on Hp phenotype in the ACCORD lipid trial.