Does the Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Events Depend on Haptoglobin Phenotype Within the Action for Health in Diabetes (look AHEAD) Study?

Background Our previous research has identified the haptoglobin (Hp) phenotype as a potential biomarker that could be used to personalize glycemic control in type 2 diabetes mellitus (T2DM) to prevent coronary artery disease (CAD), the most common cardiovascular disease (CVD). We observed that attaining HbA1c ≥8.0% compared with 7.0–7.9% was consistently associated with incident CAD risk among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study with the Hp2-2 type(1). No similar association was observed among participants without the Hp2-2 type. However, most ACCORD participants were middle-aged and older males who were at high risk of CVD. Therefore, the optimal glycemic target for CAD prevention for the Hp types remains unclear among women, younger adults, and those at lower risk of CVD. Objective To explore the relationship between achieving specific clinically relevant HbA1c targets and risk of incident CAD in separate Hp types in a diverse cohort of individuals living with T2DM (the Action for Health in Diabetes (Look AHEAD) study(2)). Methods Hp type was measured in 4,539 blood samples from the Look AHEAD study using a validated assay. Cox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA1c (<6.5%, 6.5-6.9% and ≥8.0% compared to 7.0-7.9%), updated at years 1-4 and biennially thereafter, and incident CAD in the Hp2-2 (n=1,590) and non-Hp2-2 (n=2,949) types separately. Further pre-specified subgroup analyses by age, sex, and history of CVD were performed in each Hp type group separately. Results During 16 years of follow-up, 744 incident CAD cases were documented. Compared with HbA1c 7.0-7.9%, having HbA1c <6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 type (adjusted HR 0.71, 95% CI 0.55-0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 type who were male (0.58, 0.42-0.80), who did not have a history of CVD (0.67, 0.49-0.93), and who were aged ≥65 years at baseline (0.64, 0.43-0.95). HbA1c ≥8.0% was associated with CAD risk among participants with the Hp2-2 type who had a history of CVD (1.81, 1.02-3.21). No associations were observed between the other HbA1c targets and CAD risk when Hp2-2 participants were combined or partitioned into subgroups. Conclusion Achieving HbA1c <6.5% compared with 7.0–7.9% reduced the risk of CAD events in Look AHEAD participants with the non-Hp2-2 type, but not in participants with the Hp2-2 type. HbA1c ≥8.0% was associated with higher CAD risk among participants who had the Hp2-2 type and a history of CVD.