By Seema Gupta, MD, MSPH

Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV

Dr. Gupta reports no financial relationships relevant to this field of study.

SYNOPSIS: In patients with type 1 diabetes, hemoglobin A1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin.

SOURCE: Bergenstal RM, Gal RL, Connor CG, et al. Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels. Ann Intern Med 2017;167:95-102.

Based on data from early studies, including the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, it has been established that in patients with diabetes, intensive therapy targeting lower levels of glycemia delays onset effectively and slows the progression of microvascular complications such as diabetic retinopathy, nephropathy, and neuropathy.1,2 Glycated hemoglobin A1c (A1c) measurement, as the standard glycemic marker for the assessment of diabetes and prediabetes status, remains the most widely used clinical test to estimate the degree to which this is achieved. A1c is hemoglobin with glucose attached to the N-terminal valine of the beta chain and is expressed as the proportion of total hemoglobin. The lifespan of red blood cells is about 120 days; therefore, A1c reflects mean blood glucose levels over the past two to three months.

Despite the broad acceptance of A1c as the gold standard of blood glucose control and its wide use to judge the efficacy of diabetes treatment and to adjust therapy, many recognize that levels may vary substantially between individuals, even those who exhibit similar blood glucose levels.3 Several studies have shown that this glycation gap in terms of demonstrating higher A1c concentrations may be significant in some ethnic groups when compared to white patients with similar blood glucose concentrations. Genetic factors substantially determine A1c, and studies have shown that in patients with type 1 diabetes, genetic effects or heritability could explain approximately 62% of population variance in A1c, while the remainder may be attributable to the influence of unique environment and age.4 Researchers have found that between-patient variation in derived mean red blood cell age may explain all glucose-independent variations in A1c.5

Bergenstal et al conducted a prospective, 12-week observational study across 10 diabetes centers in the United States to determine whether a racial difference exists in the relationship between mean glucose concentrations and A1c levels and to explain the observed differences in A1c levels between non-Hispanic black persons and non-Hispanic white persons with type 1 diabetes. The authors recruited 104 black participants and 104 participants ≥ 8 years of age who had suffered from type 1 diabetes for at least two years and presented with A1c levels between 6-12%. Investigators measured mean glucose concentrations using continuous glucose monitoring, then compared by race with A1c, glycated albumin, and fructosamine values.

Researchers found that the mean A1c level was higher among black participants (9.1%) than white participants (8.3%), and the mean glucose concentration for a given A1c was significantly lower in black participants than in white participants (P = 0.013). This lower concentration level was reflected in mean A1c values among black participants, which were 0.4% higher than those among white participants (95% confidence interval, 0.2-0.6) for a given mean glucose concentration. However, the researchers observed no significant racial differences in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.2 for both comparisons).

COMMENTARY

There has been a long debate about why African-American patients with diabetes exhibit a higher A1c than their white counterparts. Is it because of biological differences, or do African-Americans demonstrate higher blood glucose because they may not have the same access to care or insurance? Or is it some combination of several factors? Bergenstal et al certainly provided evidence that in addition to environmental and other socioeconomic factors, biological factors play a critically significant role in this difference. This is noteworthy because we should no longer dismiss these differences as normal and inconsequential. The findings of this study should help us provide some direction in the clinical management of certain populations. For patients with difficult-to-control diabetes, it may be essential to spend more time studying the individual blood glucose readings to help better personalize the patient’s blood glucose management. At the same time, it’s important to understand that intrapatient variability, interpatient variability, and racial variability are critical factors of which all clinicians should be aware, including the differences between black and white patients. Finally, it is important to note that there were too few participants in the study with A1c levels < 6.5% to generalize the results to such individuals.

REFERENCES

  1. Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
  2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853.
  3. Wilson DM, Xing D, Cheng J, et al. Persistence of individual variations in glycated hemoglobin: Analysis of data from the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Trial. Diabetes Care 2011;34:1315-1317.
  4. Snieder H, Sawtell PA, Ross L, et al. HbA(1c) levels are genetically determined even in type 1 diabetes: Evidence from healthy and diabetic twins. Diabetes 2001;50:2858-2863.
  5. Malka R, Nathan DM, Higgins JM. Mechanistic modeling of hemoglobin glycation and red blood cell kinetics enables personalized diabetes monitoring. Sci Transl Med 2016;8:359ra130.