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 high-density lipoprotein (HDL) in hyperglycemia and may explain why drugs designed to pharmacologically raise HDL-cholesterol and lower triglycerides have not reliably prevented cardiovascular disease (CVD) 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 ACCORD lipid trial (NCT00000620).

Research Design and Methods: Cox proportional hazards regression models quantitfied 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 to 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 most effective in participants with severe dyslipidemia (p, interaction=0.01), and 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.