DIAB-6266; No. of Pages 7 diabetes research and clinical practice xxx (2015) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes Tama´s Ferenci a, Anna Ko¨rner b, Levente Kova´cs a,* a ´ Obuda University, John von Neumann Faculty of Informatics, Physiological Controls Group, Be´csi u´t 96/b, H-1034 Budapest, Hungary b Semmelweis University, 1st Department of Paediatrics, Bo´kay Ja´nos u. 53-54, H-1083 Budapest, Hungary
article info
abstract
Article history:
Aims: The aim of this observational study is to investigate the relationship between age,
Received 29 October 2014
duration of diabetes, HbA1c and the parameters of glucose levels measured with real-time
Received in revised form
CGM in children with type 1 diabetes.
3 December 2014
Methods: Glucose level was characterized with the relative time spent in hyper- and
Accepted 15 January 2015
hypoglycemia, central tendency, variability and MAGE during (real-time) CGM. These
Available online xxx
parameters were measured in 57 children with type 1 diabetes mellitus. The univariate association of the measured parameters was investigated with scatterplots as well as with
Keywords:
linear and distance correlation coefficients.
Pediatric type 1 diabetes mellitus
Results: Age and duration of diabetes were not clinically relevantly associated with any
Continuous glucose monitoring
descriptor of glucose level. HbA1c had an overall positive association with variability and
Glucose variability
MAGE observed during CGM. Slight, but non-significant, positive association of HbA1c was
Hawthorne effect
observed with the time spent in hyperglycemia and the central tendency of glucose level.
HbA1c
With the exception of MAGE, the associations of the descriptors with HbA1c are nonmonotonic, with a temporary break in the positive correlation at 10%. Conclusions: The results confirmed the well-known positive association of HbA1c with the central tendency of glucose level. The non-monotonic relationship between HbA1c and the indicators of the central tendency of glucose level might be caused by the changed adherence of the patients during the period of CGM. HbA1c’s positive association with MAGE without non-monotonicity underlines MAGE’s usefulness in the reliable assessment of the patients’ glycemic state. # 2015 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Type 1 diabetes is one of the most common chronic disorders in children and adolescents. Several factors play a role in the
pathogenesis of the complications in diabetes. Improved metabolic control in particular might prevent or postpone late vascular complications, as has been demonstrated by many studies, mainly by the Diabetes Control and Complications Trial [1] as well as by Epidemiology of Diabetes
* Corresponding author. Tel.: +36 1 666 5585; fax: +36 1 666 5522. E-mail addresses: [email protected] (T. Ferenci), [email protected] (A. Ko¨rner), [email protected] (L. Kova´cs). http://dx.doi.org/10.1016/j.diabres.2015.01.019 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ferenci T, et al. The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.01.019
DIAB-6266; No. of Pages 7
2
diabetes research and clinical practice xxx (2015) xxx–xxx
Interventions and Complications [2]. Glycemic control is usually determined by measurement of glycated hemoglobin (HbA1c). However, patients with similar glycated hemoglobin levels and mean glucose values can experience different glycemic fluctuations. Evidence implicates glycemic variability, mostly present in the form of postprandial glycemic spikes, as a key factor in the development of the complications of diabetes [3]. New technological improvements, especially continuous glucose monitoring (CGM) technique, which consists of a disposable transcutaneous glucose sensor along with an electronic transmitter/receiver unit [4], allows a more precise follow-up of the glucose evolution in vivo. Monitoring might be blinded to the patient which is used to inform healthcare professionals about the patient’s glucose evolution, or nonblinded, also called personal or real-time CGM (RT-CGM), where the receiver is supplemented with a graphical display which allows the patients to have a direct, almost minute-tominute observation of their own glucose level, thus enabling better management of their diabetes which has been demonstrated to improve glucose control [5,6]. By its 5 min measurement frequency (288 measurements per day) CGM has a direct effect on short term monitoring, but questions are raised on its usefulness for evaluating long-term outcome. The most important classical indicator in this sense is HbA1c that reflects the average glucose level of a patient over 120 days (the ‘‘life cycle’’ of red blood cells) [7]. Beside HbA1c, glycemic variability is now suggested to play role in the appearance of long-term complications of diabetes [8,9]. Correlation of HbA1c and glucose itself is well known, but CGM opens new horizons for a more thorough investigation of this issue [10-12]. The aim of the current work is to evaluate the relationship between age, duration of diabetes and HbA1c on the one hand, and glycemia measured with CGM on the other hand in children with type 1 diabetes.
2.
Materials and methods
2.1.
Study population and design
Fifty-seven children with type 1 diabetes mellitus (DM) were selected as a convenience sample from the database of the 1st Department of Paediatrics of Semmelweis University (Budapest, Hungary), with CGM measurement data between July 2009 and February 2011. Only patients with at least 1 year of DM duration were included so that even HbA1c had time to reach its characteristic levels. The majority of the patients were poorly controlled (according to the guidelines [13] of the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes [14–16]) with CGM performed to optimize therapy. CGM measurements were non-blinded to the patients, i.e. real time (RT)-CGM was employed. The sample included patients using continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) treatment regimes. The CGM sensors were accurate and reliable, time to sensor failure, frequency and duration of data gaps were negligible, the alarms worked properly. Sex, age, duration of diabetes and HbA1c at the time of the CGM
Table 1 – Most important descriptive statistics of the patients’ characteristics. Patient characteristics in mean (median) W SD (IQR) [min–max] format for continuous variables and as frequency tables for discrete variables. Parameter Total number of patients Treatment regime Length of CGM measurement [h] Type of device
Sex Age [year] Duration of DM [year] HbA1c [%] HbA1c [mmol/mol]
Descriptive statistics 57 30 (52.6%) MDI, 27 (47.4%) insulin pump 216.9 (161.6) 166.7 (258.1) [19.5– 705.5] 47 (82.5%) Guardian REAL-Time 9 (15.8%) Paradigm 522 and 722 1 (1.8%) Paradigm Veo-554 36 (63.2%) female, 21 (36.8%) male 12.5 (13.0) 3.5 (6.0) [4–18] 5.1 (4.0) 3.5 (6.0) [1–18] 8.6 (8.2) 1.5 (1.7) [5.9–12.1] 70.8 (66.1) 16.1 (18.6) [41.0–108]
measurement were extracted for each patient from the electronic records of the hospital information system. HbA1c was measured with NGSP certified method. The summary of these patient characteristics is shown in Table 1. CGM recordings were electronically processed (by exporting them to comma separated values format using the software of the device manufacturer) and the following parameters were extracted from the time series of glucose measurements to characterize the clinically relevant aspects of the patients’ glucose evolution:
Time spent in hyperglycemia and hypoglycemia relative to the whole length of recording (hypoglycemia was defined as glucose level 10 mmol/l) in [%]. Central tendency of glucose levels (quantified with mean and median glucose level) in [mmol/l]. Dispersion, i.e. variability of glucose levels (quantified with standard deviation and interquartile range of glucose level) in [mmol/l]. Mean Amplitude of Glycemic Excursions (MAGE), calculated according to the algorithm of Baghurst [17,18]. While there are many glycemic variability metrics described in the literature [19], MAGE was chosen due to its widespread use despite its limitations [20], i.e. to show a representative example of glycemic variability metrics to illustrate their application. Comparison of these metrics is extensively covered in the literature [21]. Summary of these parameters is presented in Table 2.
2.2.
Statistical analysis
A pairwise analysis was performed between every possible variable (altogether 3 7 = 21 pairs). As every variable was quantitative, this was essentially a question of correlation, which was investigated with graphical (scatter plot) and analytical (calculation of correlation coefficients) methods. Scatter plots sometimes revealed not simply non-linear, but markedly non-monotonic relationships, so the calculation
Please cite this article in press as: Ferenci T, et al. The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.01.019
DIAB-6266; No. of Pages 7
3
diabetes research and clinical practice xxx (2015) xxx–xxx
Table 2 – Most important descriptive statistics of the investigated CGM parameters. Descriptive statistics of the indicators derived from CGM-measured glucose evolution in mean (median) W SD (IQR) [min–max] format. Parameter
Descriptive statistics
Percentage of time spent in hyperglycemia (>10 mmol/l) [%] Percentage of time spent in hypoglycemia (10 mmol/l) [%]
r p
0.04 0.7403
0.01 0.9514
0.24 0.0775
0.21 0.5540
0.18 0.7953
0.27 0.1642
Ratio of hypoglycemia (
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes Tama´s Ferenci a, Anna Ko¨rner b, Levente Kova´cs a,* a ´ Obuda University, John von Neumann Faculty of Informatics, Physiological Controls Group, Be´csi u´t 96/b, H-1034 Budapest, Hungary b Semmelweis University, 1st Department of Paediatrics, Bo´kay Ja´nos u. 53-54, H-1083 Budapest, Hungary
article info
abstract
Article history:
Aims: The aim of this observational study is to investigate the relationship between age,
Received 29 October 2014
duration of diabetes, HbA1c and the parameters of glucose levels measured with real-time
Received in revised form
CGM in children with type 1 diabetes.
3 December 2014
Methods: Glucose level was characterized with the relative time spent in hyper- and
Accepted 15 January 2015
hypoglycemia, central tendency, variability and MAGE during (real-time) CGM. These
Available online xxx
parameters were measured in 57 children with type 1 diabetes mellitus. The univariate association of the measured parameters was investigated with scatterplots as well as with
Keywords:
linear and distance correlation coefficients.
Pediatric type 1 diabetes mellitus
Results: Age and duration of diabetes were not clinically relevantly associated with any
Continuous glucose monitoring
descriptor of glucose level. HbA1c had an overall positive association with variability and
Glucose variability
MAGE observed during CGM. Slight, but non-significant, positive association of HbA1c was
Hawthorne effect
observed with the time spent in hyperglycemia and the central tendency of glucose level.
HbA1c
With the exception of MAGE, the associations of the descriptors with HbA1c are nonmonotonic, with a temporary break in the positive correlation at 10%. Conclusions: The results confirmed the well-known positive association of HbA1c with the central tendency of glucose level. The non-monotonic relationship between HbA1c and the indicators of the central tendency of glucose level might be caused by the changed adherence of the patients during the period of CGM. HbA1c’s positive association with MAGE without non-monotonicity underlines MAGE’s usefulness in the reliable assessment of the patients’ glycemic state. # 2015 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
Type 1 diabetes is one of the most common chronic disorders in children and adolescents. Several factors play a role in the
pathogenesis of the complications in diabetes. Improved metabolic control in particular might prevent or postpone late vascular complications, as has been demonstrated by many studies, mainly by the Diabetes Control and Complications Trial [1] as well as by Epidemiology of Diabetes
* Corresponding author. Tel.: +36 1 666 5585; fax: +36 1 666 5522. E-mail addresses: [email protected] (T. Ferenci), [email protected] (A. Ko¨rner), [email protected] (L. Kova´cs). http://dx.doi.org/10.1016/j.diabres.2015.01.019 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ferenci T, et al. The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.01.019
DIAB-6266; No. of Pages 7
2
diabetes research and clinical practice xxx (2015) xxx–xxx
Interventions and Complications [2]. Glycemic control is usually determined by measurement of glycated hemoglobin (HbA1c). However, patients with similar glycated hemoglobin levels and mean glucose values can experience different glycemic fluctuations. Evidence implicates glycemic variability, mostly present in the form of postprandial glycemic spikes, as a key factor in the development of the complications of diabetes [3]. New technological improvements, especially continuous glucose monitoring (CGM) technique, which consists of a disposable transcutaneous glucose sensor along with an electronic transmitter/receiver unit [4], allows a more precise follow-up of the glucose evolution in vivo. Monitoring might be blinded to the patient which is used to inform healthcare professionals about the patient’s glucose evolution, or nonblinded, also called personal or real-time CGM (RT-CGM), where the receiver is supplemented with a graphical display which allows the patients to have a direct, almost minute-tominute observation of their own glucose level, thus enabling better management of their diabetes which has been demonstrated to improve glucose control [5,6]. By its 5 min measurement frequency (288 measurements per day) CGM has a direct effect on short term monitoring, but questions are raised on its usefulness for evaluating long-term outcome. The most important classical indicator in this sense is HbA1c that reflects the average glucose level of a patient over 120 days (the ‘‘life cycle’’ of red blood cells) [7]. Beside HbA1c, glycemic variability is now suggested to play role in the appearance of long-term complications of diabetes [8,9]. Correlation of HbA1c and glucose itself is well known, but CGM opens new horizons for a more thorough investigation of this issue [10-12]. The aim of the current work is to evaluate the relationship between age, duration of diabetes and HbA1c on the one hand, and glycemia measured with CGM on the other hand in children with type 1 diabetes.
2.
Materials and methods
2.1.
Study population and design
Fifty-seven children with type 1 diabetes mellitus (DM) were selected as a convenience sample from the database of the 1st Department of Paediatrics of Semmelweis University (Budapest, Hungary), with CGM measurement data between July 2009 and February 2011. Only patients with at least 1 year of DM duration were included so that even HbA1c had time to reach its characteristic levels. The majority of the patients were poorly controlled (according to the guidelines [13] of the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes [14–16]) with CGM performed to optimize therapy. CGM measurements were non-blinded to the patients, i.e. real time (RT)-CGM was employed. The sample included patients using continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) treatment regimes. The CGM sensors were accurate and reliable, time to sensor failure, frequency and duration of data gaps were negligible, the alarms worked properly. Sex, age, duration of diabetes and HbA1c at the time of the CGM
Table 1 – Most important descriptive statistics of the patients’ characteristics. Patient characteristics in mean (median) W SD (IQR) [min–max] format for continuous variables and as frequency tables for discrete variables. Parameter Total number of patients Treatment regime Length of CGM measurement [h] Type of device
Sex Age [year] Duration of DM [year] HbA1c [%] HbA1c [mmol/mol]
Descriptive statistics 57 30 (52.6%) MDI, 27 (47.4%) insulin pump 216.9 (161.6) 166.7 (258.1) [19.5– 705.5] 47 (82.5%) Guardian REAL-Time 9 (15.8%) Paradigm 522 and 722 1 (1.8%) Paradigm Veo-554 36 (63.2%) female, 21 (36.8%) male 12.5 (13.0) 3.5 (6.0) [4–18] 5.1 (4.0) 3.5 (6.0) [1–18] 8.6 (8.2) 1.5 (1.7) [5.9–12.1] 70.8 (66.1) 16.1 (18.6) [41.0–108]
measurement were extracted for each patient from the electronic records of the hospital information system. HbA1c was measured with NGSP certified method. The summary of these patient characteristics is shown in Table 1. CGM recordings were electronically processed (by exporting them to comma separated values format using the software of the device manufacturer) and the following parameters were extracted from the time series of glucose measurements to characterize the clinically relevant aspects of the patients’ glucose evolution:
Time spent in hyperglycemia and hypoglycemia relative to the whole length of recording (hypoglycemia was defined as glucose level 10 mmol/l) in [%]. Central tendency of glucose levels (quantified with mean and median glucose level) in [mmol/l]. Dispersion, i.e. variability of glucose levels (quantified with standard deviation and interquartile range of glucose level) in [mmol/l]. Mean Amplitude of Glycemic Excursions (MAGE), calculated according to the algorithm of Baghurst [17,18]. While there are many glycemic variability metrics described in the literature [19], MAGE was chosen due to its widespread use despite its limitations [20], i.e. to show a representative example of glycemic variability metrics to illustrate their application. Comparison of these metrics is extensively covered in the literature [21]. Summary of these parameters is presented in Table 2.
2.2.
Statistical analysis
A pairwise analysis was performed between every possible variable (altogether 3 7 = 21 pairs). As every variable was quantitative, this was essentially a question of correlation, which was investigated with graphical (scatter plot) and analytical (calculation of correlation coefficients) methods. Scatter plots sometimes revealed not simply non-linear, but markedly non-monotonic relationships, so the calculation
Please cite this article in press as: Ferenci T, et al. The interrelationship of HbA1c and real-time continuous glucose monitoring in children with type 1 diabetes. Diabetes Res Clin Pract (2015), http://dx.doi.org/10.1016/j.diabres.2015.01.019
DIAB-6266; No. of Pages 7
3
diabetes research and clinical practice xxx (2015) xxx–xxx
Table 2 – Most important descriptive statistics of the investigated CGM parameters. Descriptive statistics of the indicators derived from CGM-measured glucose evolution in mean (median) W SD (IQR) [min–max] format. Parameter
Descriptive statistics
Percentage of time spent in hyperglycemia (>10 mmol/l) [%] Percentage of time spent in hypoglycemia (10 mmol/l) [%]
r p
0.04 0.7403
0.01 0.9514
0.24 0.0775
0.21 0.5540
0.18 0.7953
0.27 0.1642
Ratio of hypoglycemia (
