Haptoglobin Phenotype and Cardiovascular Risk: The ACCORD Blood Pressure RCT

BACKGROUND: A relationship between hypertension and risk of incident cardiovascular disease, coronary artery disease, and stroke is widely reported in type 2 diabetes. However, trials testing intensive blood pressure control therapy versus standard therapy to reduce cardiovascular events have reported conflicting results, which could potentially be due to an unmeasured biological factor such as the common Hp (haptoglobin) phenotype. METHODS: Multivariable-adjusted Cox proportional hazards regression models assessed the relationship between intensive (versus standard) blood pressure control therapy and risk of composite cardiovascular disease, coronary artery disease, and stroke events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure trial in participants with the Hp2-2 phenotype (n=1527) separately from Hp1 allele carriers (n=2748). RESULTS: Intensive blood pressure therapy (versus standard therapy) was associated with a lower risk of composite cardiovascular disease among Hp1 allele carriers (hazard ratio, 0.76 [95% CI, 0.59–0.99]) but not among participants with the Hp2-2 phenotype (hazard ratio, 1.12 [95% CI, 0.80–1.55]; P -interaction=0.07). No significant hazard ratio was observed for intensive therapy versus standard therapy on risk of coronary artery disease (Hp1 allele carriers: hazard ratio, 0.85 [95% CI, 0.67–1.08]; Hp2-2 phenotype: hazard ratio, 1.12 [95% CI, 0.84–1.51]; P -interaction=0.11). Intensive therapy was associated with a lower risk of stroke among Hp1 allele carriers (hazard ratio, 0.53 [95% CI, 0.31–0.91]) but not among Hp2-2 participants (hazard ratio, 0.70 [95% CI, 0.33–1.46]; P -interaction=0.56). CONCLUSIONS: The lack of an effect of intensive blood pressure control on composite cardiovascular disease events in the original ACCORD blood pressure trial may be explained in part by variation in response among the Hp phenotypes. Further study and replication are required. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00000620.