Association of Sickle Cell Trait With Hemoglobin A1c in African Americans

Abstract

Importance: Hemoglobin A1c (HbA1c) reflects past glucose concentrations, but this relationship may differ between those with sickle cell trait (SCT) and those without it.

Objective: To evaluate the association between SCT and HbA1c for given levels of fasting or 2-hour glucose levels among African Americans.

Design, setting, and participants: Retrospective cohort study using data collected from 7938 participants in 2 community-based cohorts, the Coronary Artery Risk Development in Young Adults (CARDIA) study and the Jackson Heart Study (JHS). From the CARDIA study, 2637 patients contributed a maximum of 2 visits (2005-2011); from the JHS, 5301 participants contributed a maximum of 3 visits (2000-2013). All visits were scheduled at approximately 5-year intervals. Participants without SCT data, those without any concurrent HbA1c and glucose measurements, and those with hemoglobin variants HbSS, HbCC, or HbAC were excluded. Analysis of the primary outcome was conducted using generalized estimating equations (GEE) to examine the association of SCT with HbA1c levels, controlling for fasting or 2-hour glucose measures.

Exposures: Presence of SCT.

Main outcomes and measures: Hemoglobin A1c stratified by the presence or absence of SCT was the primary outcome measure.

Results: The analytic sample included 4620 participants (mean age, 52.3 [SD, 11.8] years; 2835 women [61.3%]; 367 [7.9%] with SCT) with 9062 concurrent measures of fasting glucose and HbA1c levels. In unadjusted GEE analyses, for a given fasting glucose, HbA1c values were statistically significantly lower in those with (5.72%) vs those without (6.01%) SCT (mean HbA1c difference, -0.29%; 95% CI, -0.35% to -0.23%). Findings were similar in models adjusted for key risk factors and in analyses using 2001 concurrent measures of 2-hour glucose and HbA1c concentration for those with SCT (mean, 5.35%) vs those without SCT (mean, 5.65%) for a mean HbA1c difference of -0.30% (95% CI, -0.39% to -0.21%). The HbA1c difference by SCT was greater at higher fasting (P = .02 for interaction) and 2-hour (P = .03) glucose concentrations. The prevalence of prediabetes and diabetes was statistically significantly lower among participants with SCT when defined using HbA1c values (29.2% vs 48.6% for prediabetes and 3.8% vs 7.3% for diabetes in 572 observations from participants with SCT and 6877 observations from participants without SCT; P<.001 for both comparisons).

Conclusions and relevance: Among African Americans from 2 large, well-established cohorts, participants with SCT had lower levels of HbA1c at any given concentration of fasting or 2-hour glucose compared with participants without SCT. These findings suggest that HbA1c may systematically underestimate past glycemia in black patients with SCT and may require further evaluation.

Figure 1. Scatterplot of Observed Data Model of Hemoglobin A_1c vs Fasting and 2-Hour Glucose Measures in Participants With or Without Sickle Cell Trait

Scatterplot of observed data points along side unadjusted and adjusted regression lines examining the association between sickle cell trait (SCT) and hemoglobin A_1c (HbA_1c), controlling for fasting or 2-hour glucose values was obtained using generalized estimating equations (GEE) with an exchangeable correlation matrix to account for correlation of repeated measures. All continuous covariates are centered at the population mean. The solid blue lines represent the regression line for those for who did not have SCT and the dashed orange lines for those who had SCT. BMI indicates body mass index; CARDIA, Coronary Artery Risk Development in Young Adults study. To convert glucose from mg/dL to mmol/L, multiply by 0.0555. A, Included 9062 observations, 720 from participants with SCT and 8342 from participants without SCT. The regression equation: predicted HbA_1c = 6.01 + (−0.28 × SCT) + (0.03 × fasting glucose) + (−0.004 SCT fasting glucose). B, Included 8460 observations, 683 from participants with SCT and 7777 from participants without SCT. The regression equation: predicted HbA_1c = 5.93 + (−0.32 × SCT) + (0.03 × fasting glucose) + (−0.005 × SCT × fasting glucose) + (0.04 × 1 if male) + (0.008 × age) + (0.01 × BMI) + (−0.0004 × ferritin) + (0.001 × estimated glomerular filtration rate) + (−0.08 × 1 if a CARDIA participant) + (0.46 × 1 if currently using diabetes medications) + (0.14 × 1 if previous diabetes diagnosis). C, Included 2001 observations, 127 from participants with SCT and 1874 from participants without SCT. Regression equation: predicted HbA_1c = 5.65 + (−0.28 × SCT) + (0.01 × 2-hour glucose) + (−0.004 × SCT × 2-hour glucose). D, Included 1712 observations, 109 from participants with SCT and 1606 from participants without SCT. Regression equation: predicted HbA_1c = 5.66 + (−0.36 × SCT) + (0.01 × 2-hour glucose) × (−0.004 × SCT × 2-hour glucose) + (0.24 × 1 if male) + (0.02 × age) + (0.006 × BMI) + (−0.0006 × ferritin) + (0.0003 × eGFR) + (0.07 × 1 if previous diabetes diagnosis).

Figure 2. Prevalence of Prediabetes and Diabetes by Sickle Cell Trait Status Among Participants Not Taking Diabetes Medications and With No Prior Diagnosis of Diabetes

Fasting glucose and hemoglobin A_1c analyses included 7499 total observations (6877 observations from participants without sickle cell trait [SCT] and 572 from participants with it). Analyses for 2-hour glucose concentrations were only available from CARDIA participants and included 1869 total observations (1752 observations from participants without SCT and 117 from participants with SCT). For the definition of prediabetes and diabetes by glucose measures, see the Methods section. The prevalence of prediabetes and diabetes by fasting glucose and 2-hour glucose concentration was similar in those with and without SCT (P > .10 for all comparisons). However, the prevalence of prediabetes and diabetes as defined by hemoglobin A_1c was significantly higher among participants with vs without SCT (P < .001 for both). Error bars indicate 95% CIs.

Figure 3. Comparison of the Diagnostic Sensitivity of Hemoglobin A_1c to Identify Combined Prediabetes or Diabetes by Sickle Cell Trait Status

A, For fasting glucose of 100mg/dL or higher, the area under the receiver operating characteristic (AUROC) of hemoglobin A_1c (HbA_1c) was 0.77 (95% CI, 0.75–0.78) among those without sickle cell trait (SCT) and 0.70 (95% CI, 0.65–0.74) among those with SCT. An unpaired comparison of the AUROC curves indicated that the diagnostic ability of HbA_1c to identify fasting glucose–defined prediabetes or diabetes was significantly lower among those with SCT than among those without it (P = .007). B, For 2-hour glucose levels of 140mg/dL or higher, the AUROC of HbA_1c was 0.74 (95% CI, 0.71–0.78) among those without SCT and 0.60 (95% CI, 0.47–0.72) among those with SCT. An unpaired comparison of the AUROC curves indicated that the diagnostic ability of HbA_1c to identify 2-hour glucose-defined prediabetes or diabetes was significantly lower in those with SCT than in those without it (P = .03). To convert glucose from mg/dL to mmol/L, multiply by 0.0555.