Abstract
We aimed to investigate if estimated hemoglobin A1c (eHbA1c) levels determined using a flash continuous glucose monitoring system could be an indicator of glycemic control status in hemodialysis patients with diabetes. Hemodialysis patients with type 2 diabetes were recruited. eHbA1c levels were measured using the FreeStyle Libre Flash Glucose Monitoring System®. A total of 18 hemodialysis patients with diabetes were included in the study. The eHbA1cGA – calculated based on glycated albumin level, and body mass index and serum hemoglobin concentration were also included in the formula – was higher than the eHbA1c in most patients. Furthermore, the eHbA1cGA – eHbA1c values were >2% in all patients with body mass index <18.5 kg/m2; the maximal value was 4.1%. This study shows that eHbA1c can be used as a reliable indicator for evaluating glycemic control and avoiding hypoglycemia in hemodialysis patients with diabetes, particularly those with decreased body mass index.
Keywords: Continuous glucose monitoring, Estimated hemoglobin A1c, Hemodialysis
There are discrepancies between glycated albumin and self‐measurement of blood glucose levels in hemodialysis patients with diabetes. Estimated hemoglobin A1c levels are determined using a flash continuous glucose monitoring system. Estimated hemoglobin A1c levels could be a reliable indicator for evaluating glycemic control status. Estimated hemoglobin A1c should be used for avoiding hypoglycemia in patients with decreased body mass index.
Introduction
As glycated albumin (GA) levels are unaffected by the shortened lifespan of red blood cells 1 and are associated with increased mortality in hemodialysis patients with diabetes 2 , GA is considered a desirable indicator of glycemic control in diabetic hemodialysis patients 3 , 4 . However, discrepancies have been reported between GA levels and blood glucose or self‐measurement of blood glucose levels in hemodialysis patients with diabetes 5 , 6 , 7 , 8 . This study aimed to investigate whether estimated hemoglobin A1c (eHbA1c) levels, determined using a flash glucose monitoring (FGM) system, could be an indicator of glycemic control status in hemodialysis patients with diabetes, particularly in those with decreased body mass index (BMI), who might show discrepant GA and blood glucose levels in clinical settings.
Methods
We randomly recruited hemodialysis patients with type 2 diabetes. All patients were receiving oral hypoglycemic agents, insulin or both. Patients received hemodialysis treatment at the outpatient dialysis units of Tojinkai Hospital in Kyoto, Japan. The inclusion criterion was stable glycemic control, as evidenced by two GA values within 5 percentage points of each other in 6 months before recruitment. Those using systemic corticosteroids or those with chronic liver disease, thyroid disorders, or malignant diseases were excluded. The study protocol was approved by the ethics committee of the Tojinkai Hospital (2019–05), and the study was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient.
Patients provided medical and demographic information. Blood was drawn from the dialyzer circuit before starting dialysis for analysis. Patients were provided with the FreeStyle Libre™ of the first generation, a sensor‐based FGM system (FSL FGM; Abbott, Diabetes Care, Witney, UK). The system consists of a glucose oxidase‐based electrochemical sensor that measures glucose levels every 15 min, placed subcutaneously, and a receiver that transmits and stores interstitial glucose measurements wirelessly. Patients were instructed to use the device for 14 days. The results from the FGM were downloaded to a research computer in the outpatient clinic. The eHbA1c level based on the average glucose levels from the FGM data was calculated using the following equation: eHbA1c (%) = (average glucose [mg/dL] + 46.7) × 28.7−1. 9
The GA levels were measured within 1 week before or after FGM use by an enzymatic method involving ketoamine oxidase, albumin‐specific proteinase and serum albumin assay reagent (Lucica® GA‐L Kit; Asahi Kasei Pharma Co., Tokyo, Japan) 10 . The eHbA1c level based on the GA level (eHbA1cGA) was calculated using the following equation: 11 eHbA1cGA − 1 (%) = GA × (4.688 − 18.833 × GA−1 − 0.015 × BMI − 0.037 × Hb)−1. BMI and serum Hb concentration, which were included in the equation, were significantly lower in the end‐stage renal disease group than in the normal renal function group, and showed significant negative correlations with the GA/HbA1c ratio 11 .
Regression models were used to evaluate the effects of factors, such as BMI and hemoglobin, on the difference between eHbA1cGA and eHbA1c, and on the ratio of eHbA1cGA to eHbA1c. The mean values were compared using the unpaired Student’s t‐test. The χ2–test was used to compare categorical variables between patients with BMI <18.5 kg/m2 and ≥18.5 kg/m2 12 , 13 . The SPSS statistical package, version 19.0J (SPSS, Inc., Chicago, IL, USA) was used for all statistical analyses. All tests were two‐sided, and P‐values < 0.05 were considered statistically significant.
Results
A total of 18 hemodialysis patients with type 2 diabetes were included in the study (Table 1). The eHbA1cGA was greater than the eHbA1c. eHbA1cGA – eHbA1c values were >2% in all patients with BMI <18.5 kg/m2, and its maximal value was 4.1%. The eHbA1cGA – eHbA1c value and eHbA1cGA/eHbA1c ratio were significantly high in patients with BMI <18.5 kg/m2 (Table 2). On multivariate analyses, BMI was significantly associated with the eHbA1cGA – eHbA1c value (β = −0.123, P = 0.045) and eHbA1cGA/eHbA1c ratio (β = −0.025, P = 0.023), and hemoglobin was significantly associated with the eHbA1cGA – eHbA1c value (β = −0.426, P = 0.040) and eHbA1cGA/eHbA1c ratio (β = −0.075, P = 0.043). Figure 1 shows the ambulatory glucose profile of a 74‐year‐old female patient with an 8‐year history of dialysis, GA level of 24.6% and eHbA1cGA level of 8.3%. A stable, flat glucose trend was observed with glucose in the target range. Similar findings were observed in all other patients.
Table 1.
Characteristics of the study participants
| Age (years) | Sex | Duration of diabetes (years) | Duration of dialysis (years) | Medications | BMI (kg/m2) | Serum albumin (g/dL) | Blood glucose (mg/dL) | Hb (g/dL) | GA (%) | eHbA1cGA (%) | eHbA1c (%) | eHbA1cGA – eHbA1c (%) | eHbA1cGA/eHbA1c (%) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 76 | Female | 11 | 7 | OHA | 16 | 3.8 | 130 | 11.4 | 19.0 | 7.3 | 4.9 | 2.4 | 1.5 |
| 2 | 63 | Female | 4 | 4 | IT | 22 | 4.4 | 143 | 10.4 | 24.0 | 8.5 | 5.4 | 3.1 | 1.6 |
| 3 | 50 | Female | 30 | 10 | IT | 28 | 4 | 101 | 11.4 | 19.6 | 7.8 | 6.1 | 1.7 | 1.3 |
| 4 | 67 | Female | 30 | 5 | OHA/IT | 32 | 3.3 | 131 | 10.7 | 22.7 | 8.6 | 7.2 | 1.4 | 1.2 |
| 5 | 74 | Female | 24 | 8 | OHA/IT | 15 | 3.4 | 132 | 8.7 | 24.6 | 8.3 | 5.0 | 3.3 | 1.7 |
| 6 | 46 | Male | 26 | 22 | IT | 16 | 3.4 | 181 | 9.4 | 36.0 | 11.1 | 7.3 | 3.8 | 1.5 |
| 7 | 60 | Female | 33 | 20 | OHA/IT | 21 | 3.9 | 156 | 10.5 | 22.0 | 8.0 | 7.4 | 0.6 | 1.1 |
| 8 | 60 | Male | 37 | 2 | OHA/IT | 23 | 3.7 | 196 | 11.1 | 23.0 | 8.4 | 6.3 | 2.1 | 1.3 |
| 9 | 73 | Female | 44 | 11 | OHA | 17 | 3.7 | 147 | 7.5 | 25.2 | 8.4 | 5.0 | 3.4 | 1.7 |
| 10 | 57 | Female | 11 | 11 | OHA/IT | 16 | 4.3 | 137 | 9.9 | 28.3 | 9.3 | 5.2 | 4.1 | 1.8 |
| 11 | 70 | Female | 33 | 18 | OHA/IT | 22 | 3.7 | 96 | 11.2 | 20.5 | 7.8 | 5.3 | 2.5 | 1.5 |
| 12 | 57 | Male | 23 | 4 | IT | 24 | 3.8 | 96 | 9.1 | 19.0 | 7.3 | 6.1 | 1.2 | 1.2 |
| 13 | 67 | Female | 39 | 9 | IT | 22 | 3.7 | 146 | 11 | 23.3 | 8.4 | 7.0 | 1.4 | 1.2 |
| 14 | 55 | Male | 26 | 4 | IT | 24 | 3.7 | 111 | 9.7 | 16.5 | 6.8 | 5.5 | 1.3 | 1.2 |
| 15 | 72 | Male | 21 | 21 | OHA | 18 | 3.7 | 174 | 9.3 | 23.5 | 8.2 | 5.4 | 2.8 | 1.5 |
| 16 | 56 | Male | 36 | 5 | OHA/IT | 25 | 4 | 122 | 13 | 17.7 | 7.4 | 8.6 | −1.2 | 0.9 |
| 17 | 61 | Male | 46 | 13 | OHA/IT | 20 | 3.2 | 132 | 8.2 | 24.6 | 8.4 | 5.2 | 3.2 | 1.6 |
| 18 | 61 | Male | 26 | 9 | OHA/IT | 25 | 3.8 | 102 | 9.9 | 17.0 | 7.0 | 5.0 | 2.0 | 1.4 |
eHbA1c, estimated hemoglobin A1c based on the average glucose levels from FreeStyle Libre Flash Glucose Monitoring System®; eHbA1cGA, estimated hemoglobin A1c based on the glycated albumin level; GA, glycated albumin; Hb, hemoglobin; IT, insulin therapy; OHA, oral hypoglycemic agent.
Table 2.
Clinical characteristics of study patients
| Body mass index | P | ||
|---|---|---|---|
| <18.5 | ≥18.5 | ||
| Sex (male/female) | 2/4 | 6/6 | 0.638 |
| Age (years) | 66.3 ± 12.1 | 60.6 ± 5.7 | 0.310 |
| Duration of diabetes (years) | 25.2 ± 12.0 | 30.3 ± 10.4 | 0.772 |
| Duration of dialysis (years) | 13.3 ± 6.5 | 8.6 ± 5.8 | 0.136 |
| Serum albumin (g/dL) | 3.7 ± 0.3 | 3.8 ± 0.3 | 0.758 |
| Hemoglobin (g/dL) | 9.4 ± 1.3 | 10.5 ± 1.2 | 0.083 |
| eHbA1cGA | 7.8 ± 1.3 | 6.9 ± 0.6 | 0.068 |
| eHbA1c | 5.5 ± 0.9 | 6.3 ± 1.1 | 0.148 |
| eHbA1cGA – eHbA1c | 3.3 ± 0.6 | 1.6 ± 1.2 | 0.005 |
| eHbA1cGA/eHbA1c | 1.6 ± 0.1 | 1.3 ± 0.2 | 0.004 |
Data are means ± standard deviation or number. eHbA1cGA, estimated hemoglobin A1c based on the glycated albumin level; eHbA1c, estimated hemoglobin A1c based on the average glucose levels from FreeStyle Libre Flash Glucose Monitoring System®.
Figure 1.
The ambulatory glucose profiles uploaded from the FreeStyle Libre Flash Glucose Monitoring System®.
Discussion
Strict glycemic control is important for reducing microvascular and macrovascular complications 14 , and reducing the risk of mortality in hemodialysis patients with diabetes 15 . In contrast, an increased frequency of hypoglycemia is associated with a high risk of mortality in patients with diabetic kidney disease 16 .
Consensus guidelines for managing diabetes patients have identified GA levels and pre‐dialysis casual plasma glucose levels as indicators of glycemic control in hemodialysis patients with diabetes 17 . However, there is no reliable indicator in patients with discordant GA levels and blood glucose levels or self‐measurement of blood glucose levels. In the present study, the critical discrepancy between blood glucose control levels evaluated by GA and estimated hemoglobin A1c levels determined using a flash continuous glucose monitoring system was observed in hemodialysis patients with type 2 diabetes, particularly those with decreased BMI. This was probably due to elongation of the albumin lifespan, which leads to more increased GA than actual, in those patients associated with common complications experienced by end‐stage renal disease patients, including hypothyroidism and decreased BMI 18 .
GA showed short‐term (~2–4 weeks) glycemic control status, and HbA1c showed long‐term (~3 months) glycemic control status. We added the blood glucose of the enrolled population in short‐term and long‐term periods as confounding factors in multivariate analyses. The result was almost the same (data not shown).
Furthermore, eHbA1c level based on the casual blood glucose was calculated 9 . The difference between eHbA1c and eHbA1c based on casual blood glucose was significantly lower than the difference between eHbA1cGA and eHbA1c based on casual blood glucose (P < 0.001).
The readings from the FGM data for the first 2 days are known to be not entirely precise. We have provided a sensitivity analysis excluding the first 2 days, and the result did not change (data not shown).
There were some limitations of this study. First, FGM might be underestimated when blood glucose levels are low, which could lead to the estimated HbA1c also being lower. However, Yajima et al. 19 reported that FGM might be clinically acceptable. Second, the GA levels were measured within 1 week before or after FGM. Deviations in measurement timing could be a source of bias; however, they do not contribute significantly to the results, as GA levels showed approximately 2–4 weeks of glycemic control status. In conclusion, the current study shows that eHbA1c might be used as a reliable indicator for evaluating glycemic control and for avoiding hypoglycemia in hemodialysis patients with diabetes, particularly those with decreased BMI. Prospective studies are required to establish that the use of eHbA1c as an index of glycemic control will improve microvascular and macrovascular complications, and will result in low mortality rates.
Disclosure
The authors declare no conflict of interest.
Acknowledgments
The authors express their appreciation to the patients who participated in this study and the diabetes educators for the continuous glucose monitoring downloads. The authors also thank Editage (www.editage.com) for English language editing. This research received no specific grant from any funding agency in the public, commercial or not‐for‐profit sectors.
J Diabetes Investig. 2020
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