Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type 2 diabetes: the ADVANCE study

Objective: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype, but not in participants without the Hp2-2 phenotype. It is unknown if and how these results translate across different demographic/clinical characteristics and treatment strategies.

Research Design and Methods: Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models evaluated the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n=1,327) and without (n=2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol.

Results: While the hazard ratios (HR, 95% CI) were in the hypothesized differing directions, compared to standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 0.82-1.32) or with the Hp2-2 phenotype (0.84, 0.63-1.14, p-interaction=0.27) overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, p-interaction=0.01).

Conclusions: Our findings suggest that intensive glycemic control contributes to the prevention of major CAD among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.