The relationship between repeated measurements of HbA1c and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study

Abstract

Background: In the ACCORD study, participants with the haptoglobin (Hp) 2-2 phenotype and glycated hemoglobin (HbA_1c) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA_1c 7.0-7.9%. However, this association was not observed in participants without the Hp2-2 phenotype. The optimal glycemic target for CAD prevention for the Hp phenotypes remains uncertain and may vary based on demographic and clinical factors.

Objective: To investigate how reaching clinically relevant HbA_1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA_1c ≤ 11% at baseline).

Methods: Cox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA_1c (< 6.5%, 6.5-6.9%, and ≥ 8.0% compared to 7.0-7.9%), updated at years 1-4, 6, 8, and 10, and incident CAD in the Hp2-2 (n = 1,587) and non-Hp2-2 (n = 2,944) phenotypes separately. Further pre-specified subgroup analyses by age, sex, history of cardiovascular disease (CVD), race, and diabetes duration were performed in each Hp phenotype group separately.

Results: Compared with HbA_1c 7.0-7.9%, having HbA_1c < 6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 phenotype (adjusted HR 0.71, 95% CI 0.55-0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 phenotype who were male (0.60, 0.44-0.83), who did not have a history of CVD (0.65, 0.47-0.90), who were aged ≥ 65 years (0.64, 0.44-0.94), who were White (0.68, 0.51-0.91), or who had diabetes duration > 10 years (0.58, 0.35-0.95). HbA_1c ≥ 8.0% was associated with CAD risk only among participants with the Hp2-2 phenotype who had a history of CVD (1.79, 1.00-3.20). No associations were found between the other HbA_1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups.

Conclusion: The differences in our results compared to our previous findings may be due to variations in the study populations and factors associated with weight loss, making it difficult to draw definitive conclusions. Our current findings should be considered in the context of hypothesis generation, and ideally, will encourage additional research in this field.

Keywords: Coronary artery disease; Epidemiology; Genetic association; Glycated hemoglobin; Haptoglobin phenotype; Type 2 diabetes mellitus.

Fig. 1

Mean HbA_1c levels over study duration by haptoglobin phenotype. Mean HbA_1c over study duration did not differ between haptoglobin phenotype groups in Look AHEAD participants. Unadjusted mean HbA_1c levels in participants measured at baseline and years 1–4, 6, 8, and 10 for Look AHEAD trial participants with the non-Hp2-2 phenotype (blue) and with the Hp2-2 phenotype (orange). Mean HbA_1c at each timepoint was compared between Hp phenotype groups using t-tests. The sample size for the non-Hp2-2 and Hp2-2 phenotypes at different time points was as follows: 2,944 and 1,587 at baseline, 2,835 and 1,541 at year 2, 2,795 and 1,501 at year 4, 2,729 and 1,469 at year 6, 2,597 and 1,392 at year 8, and 2,330 and 1,260 at year 10, respectively.

Fig. 2

Association between HbA_1c and CAD in Look AHEAD participants by haptoglobin phenotype group. The solid line represents the fully adjusted hazard ratio, and the dotted lines represent the 95% confidence intervals. The plot was truncated at the 5th and 95th percentiles of HbA_1c (5.5% and 9.7% respectively).