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The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 diabetes
JDC-107519; No of Pages 6 Journal of Diabetes and Its Complications xxx (xxxx) xxx
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The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 diabetes☆ Stuart Chalew a,⁎, Jodi Kamps b, Brittney Jurgen b, Ricardo Gomez a, James Hempe a a b
Division of Endocrinology and Diabetes, Children's Hospital of New Orleans and The Louisiana State University Health Sciences Center, New Orleans, LA, United States of America Department of Psychology, Children's Hospital of New Orleans, New Orleans, LA, United States of America
a r t i c l e
i n f o
Article history: Received 19 August 2019 Received in revised form 25 November 2019 Accepted 30 December 2019 Available online xxxx
a b s t r a c t Introduction: Black youth with T1D have been reported to experience more episodes of hypoglycemia than white patients, despite blacks having higher levels of HbA1c. We hypothesized that black patients may be prescribed higher daily doses of insulin putting them at greater higher risk for hypoglycemia. Methods: We performed a retrospective analysis of data from a study of social and environmental factors influencing HbA1c in a biracial pediatric population with T1DM. Changes in patient insulin dose were made at clinic visit based on their self-monitored glucose (SMG) data. Insulin dose (units/kg/d) was compared with HbA1c, reported hypoglycemic episodes and occurrence of low blood glucose from SMG data. Results: Age, duration of diabetes and BMI-z were similar for black and white patients. Black patients had higher levels of HbA1c and mean blood glucose (MBG). HbA1c was higher in blacks even after adjustment for MBG. Reported insulin dose increased with increasing HbA1c (ρ = 0.30, p = 0.0052) or MBG (ρ = 0.36, p b 0.0008). There was no difference in insulin dose between blacks and whites. Reported hypoglycemia was inversely associated with HbA1c and MBG, but there was no racial difference. Occurrence of low glucoses from meter data was slightly higher in whites (p = 0.047). Conclusion: Insulin dose increased with increasing HbA1c or MBG for both groups. Occurrence of hypoglycemia was inversely related to glycemic control. There was slightly higher occurrence low glucose meter readings in white patients. Reported racial disparities in occurrence of hypoglycemia and insulin dosing may be due to clinic specific factors. © 2020 Elsevier Inc. All rights reserved.
1. Introduction Over the years, multiple studies from various clinical centers have found racial disparity in glycemic control between black and white youth with type 1 diabetes (T1D) in the US. HbA1c levels being consistently higher in black patients compared to whites, despite technological advances in glucose monitoring and insulin delivery.1–7 Multiple factors have been associated with this disparity. Families of black patients typically have lower income, lower education level and higher measures of disadvantage compared to white families.8,9 Black patients are more likely to rely on assistance programs like Medicaid than commercial insurance to cover the medical expenses of diabetes.9 Black patients are less likely to be using insulin pumps and perform capillary glucose testing less often than white patients.3,9
☆ Conflict of interest statement: The authors report no relationships that could be construed as a conflict of interest. ⁎ Corresponding author at: Division of Endocrinology and Diabetes, Children's Hospital of New Orleans and The Department of Pediatrics, The Louisiana State University Health Sciences Center, 200 Henry Clay Avenue, New Orleans, LA 70118, United States of America. E-mail address: [email protected] (S. Chalew).
Besides socio-economic and behavioral differences, there are also biological factors contributing to racial disparity in HbA1c. When HbA1c is adjusted for concurrent blood glucose or fructosamine levels, HbA1c is higher in black patients than white patients with the same MBG or fructosamine level.6,10,11 Thus black patients tend to be so-called “high glycators,” where HbA1c overestimates their true mean blood glucose levels.12 Potentially “high glycators” are at greater risk for hypoglycemia when the primary treatment goal is HbA1c.13,14 If clinicians are not aware that a patient is a “high glycator” they may be tempted to increase total insulin dose in order to reduce patient HbA1c toward published glycemic goals. In two multi-center studies with large multiracial populations it has been noted that black children with T1D paradoxically report greater occurrence of hypoglycemia than white patients despite blacks having higher HbA1c.3,15 We have hypothesized that black patients may receive disproportionately higher insulin doses due to the fact that HbA1c overestimates their true MBG.13,14 This would potentially lead to higher occurrence of hypoglycemia in black patients.14,16 Alternatively patients with poor glycemic control may experience symptoms of hypoglycemia at higher glucose levels than patients with good control.17,18 As black patients typically have higher HbA1c and MBG compared to white patients this may account
https://doi.org/10.1016/j.jdiacomp.2019.107519 1056-8727/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
Table 1 Comparison of characteristics of black and white patient groups. Pct BGs b 50 mg/dL Pt* = percent BG b 50 mg/dL per patient. Pct BGs b 70 mg/dL Pt* = percent BG b 70 mg/dL per patients. Pct patients w BG b 50 mg/dL** = percent of total patients with at least one reading BG b 50 mg/dL. Pct patients w BG b 70 mg/dL** = percent of total patients with at least one reading BG b 70 mg/dL. %Pts = percent of patients. Black n = 33
Age (yrs) Males/females Number pts at income level: b$25K $25–75K N$75K Diabetes duration (yrs) BMI z-score HbA1c % MBG (mg/dL) Insulin units/kg/d Pct BGs b 50 mg/dL Pt* Pct BGs b 70 mg/dL Pt* Pct patients w BG b 50 mg/dL** Pct patients w BG b 70 mg/dL** BG measures per day Insulin delivery method % pts: 2 or 3 injections/day N3 injections/day Pump
White n = 52
p=
Mean
SD
Mean
SD
12.8 14/19
±3.6
14.1 30/22
±3.4
19 11 1 8.6 0.87 10.4 255 1.0 1.1 5.9 33.3. 63.6 2.6
±3.8 ±0.9 ±2.1 ±92 ±0.4 ±2.3 ±7.6
±1.7
55 36 9
1 20 30 8.4 0.34 8.9 198 0.8 1.7 5.7 40.4 82.7 4.4
NS NS b0.0001
±3.7 ±1.1 ±1.3 ±44 ±0.3 ±4.0 ±6.0
±2.9
NS NS 0.0013 0.0018 NS NS NS NS 0.0471 0.0004 b0.0001
13 23 64
for higher reports of hypoglycemia in black children despite higher HbA1c. In order to evaluate these hypotheses we retrospectively analyzed insulin dosing data, reported and observed occurrence of hypoglycemia during a study of outcome disparities conducted in a biracial population of youth with type 1 diabetes in New Orleans.
2. Methods This study was a retrospective analysis of patient data collected in study of biochemical, social and environmental factors influencing glycemic control in a biracial population of youth with T1D. Details of the study design have been previously reported.8,9 Type 1 diabetes patients self-identified as either black or white were recruited from the Pediatric Diabetes Center at Children's Hospital of New Orleans, New Orleans, LA. The Children's Diabetes Center at the Children's Hospital of New Orleans is a multidisciplinary referral center. The majority of patients were from the New Orleans metropolitan area. The regular clinic staff included 3 pediatric CDE nurse educators, 1 pediatric nutritionist and 4 pediatric diabetology attendings and 3 pediatric endocrine fellows under their supervision. Patients have continuity of care by one of the attendings supported by the CDE team and nutritionist. The goal of clinical management was to help patients attain optimal glycemic control without undo occurrence of hypoglycemia. Point of care HbA1c are not done in clinic and the lab HbA1c was not available until clinic is over and patients have been discharged. Changes in insulin management were based on review of home glucose records downloaded for the management team at the time of the clinic visit. Patients without self-monitored glucose records were not included in this study. The study was approved by the Institutional Review Board at the Louisiana State University Health Sciences Center as well as Children's Hospital IRB. Informed consent for participation in the study was obtained from the patient's parent/guardian and assent from the patient. Patients included in this study were aged 5–20 yr with duration of type 1 diabetes of at least 1 yr. Diagnosis of type 1 diabetes was based on typical clinical presentation, need for exogenous insulin for metabolic control and presence of one or more anti-pancreatic antibodies. Age, gender, self-identified race, duration of diabetes, height, weight, reported total daily insulin dose administered at home or total infused insulin from pump download, insulin delivery method, family income and medical insurance were recorded at the time of clinic visit.
Table 2 Simple Spearman correlations of study variables. Spearman correlation coefficients Prob N |r| under H0: Rho = 0 Number of observations Insulin U/kg/d Insulin units/kg/day
HbA1c %
MBG (mg/dL)
BMI-z score
Glucoses per day
Percent glucoses b 50 mg/dL
Percent glucoses b 70 mg/dL
Parent reported hypos per week
Patient reported hypos per week
HbA1c % 0.30064 0.0052 85
0.30064 0.0052 85 0.35830 0.0008 85 0.02041 NS 84 −0.18222 NS 85 −0.18028 NS 85 −0.21737 0.0457 85 −0.25970 0.0226 77 −0.19573 NS 77
0.63771 b0.0001 85 0.18079 NS 84 −0.57732 b0.0001 85 −0.21607 0.0470 85 −0.25950 0.0165 85 −0.50685 b0.0001 77 −0.37406 0.0008 77
MBG 0.35830 0.0008 85 0.63771 b0.0001 85
0.11129 NS 84 −0.26812 0.0131 85 −0.25310 0.0194 85 −0.34878 0.0011 85 −0.44762 b0.0001 77 −0.37431 0.0008 77
BMI-z 0.02041 NS 84 0.18079 NS 84 0.11129 NS 84
−0.24338 0.0257 84 0.00552 NS 84 0.05763 NS 84 −0.11946 NS 76 −0.21877 NS 76
BG/day
BG b 50
BG b 70
−0.18222 NS 85 −0.57732 b0.0001 85 −0.26812 0.0131 85 −0.24338 0.0257 84
−0.18028 NS 85 −0.21607 0.0470 85 −0.25310 0.0194 85 0.00552 NS 84 0.20102 NS 85
−0.21737 0.0457 85 −0.25950 0.0165 85 −0.34878 0.0011 85 0.05763 0.6025 84 0.17956 0.1001 85 0.74380 b0.0001 85
0.20102 NS 85 0.17956 NS 85 0.36272 0.0012 77 0.19547 NS 77
0.74380 b0.0001 85 0.27932 0.0139 77 0.20071 NS 77
0.28817 0.0110 77 0.08929 NS 77
Parent hypo
Patient hypo
−0.25970 0.0226 77 −0.50685 b0.0001 77 −0.44762 b0.0001 77 −0.11946 NS 76 0.36272 0.0012 77 0.27932 0.0139 77 0.28817 0.0110 77
−0.19573 NS 77 −0.37406 0.0008 77 −0.37431 0.0008 77 −0.21877 0.0576 76 0.19547 NS 77 0.20071 NS 77 0.08929 NS 77 0.51677 b0.0001 72
0.51677 b0.0001 72
MBG = mean blood glucose BMI = body mass index NS = p N 0.05.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
2.1. Family income
3. Results
Information was collected on family income by questionnaire. Annual family income was grouped into three broad levels $25K and under, over $25K to $75K and over $75K.
3.1. Patients characteristics
2.2. Assessment of hypoglycemia Patients over 8 years of age and their accompanying parent were asked to respond to a simple questionnaire about hypoglycemic events. 1-whether they had ever had a hypoglycemic event associated with seizure or loss of consciousness, and 2-to estimate the number of hypoglycemic episodes per week without seizure or loss of consciousness. The number of respondents to these questions were less than the total number of patients as not all families responded or had children younger than 8 yo. One of the investigators (BJ) reviewed each patient's glucose meter down-load for the 30 days prior to the clinic visit and recorded the number and percentage of readings b70 mg/dL and b50 mg/dL which was used as another metric of occurrence of hypoglycemia. The total number of self-monitored glucose measures per day was also recorded for each patient. Data accuracy and validity was reviewed by author (JK). 2.3. Insulin dose and insulin delivery method The total units of insulin injected per day was the dose reportedly taken by the patient at the clinic visit intake assessment. In the case of patients using insulin pump daily units of insulin used was obtained from the pump download. The total units of insulin taken per day was divided by patient weight in kilograms. Subjects without insulin dose data were not included in the analysis.
3
Demographic information regarding the patients by race is shown in Table 1. Patients included for analysis in this study, self-identified as either white n = 52, or black n = 33. There were no differences in age, gender distribution, duration of diabetes, or BMI-z between the groups. White families had markedly higher income distribution than black families (p b 0.0001) and more likely to be using insulin pumps. 3.2. Glycemic control Both HbA1c and mean blood glucose (MBG) were higher in black compared to white patients (Table 1). In multiple variable analysis HbA1c was higher in black patients than whites even after statistical adjustment for chronologic age, MBG, and gender. The number of capillary glucose tests per day (BG measures per day) was nearly 70% higher in white patients compared to blacks (p = 0.0004). 3.3. Insulin usage and reported hypoglycemia Reported units of insulin injected per kilogram body weight per day were similar for black and white patients (Table 1). The percent of a
a ρ=0.36, p=0.0008
2.4. Mean blood glucose (MBG) Capillary blood glucose data were downloaded from each patient home glucose meter using manufacturer's proprietary software. Selfmonitored mean blood glucose (MBG) was calculated for the 30 days prior to the clinic visit as previously described.6,8 2.5. Hemoglobin A1c HbA1c was measured by immunoassay in the Children's Hospital laboratory using the VITROS 5, 1 FS Chemistry System (Ortho-Clinical Diagnostics, Rochester, NY, USA) with an upper reporting limit of 16%. The assay is compliant with the National Glycohemoglobin Standardization Program (NGSP) and the results are reported as NGSP equivalents.19
b ρ=0.30, p<0.0052
2.6. Statistical analysis Initial statistical analysis was performed by assessing normality of continuous variables (PROC UNIVARIATE) Variables which were not normally distributed or were not be normally distributed after log transform were analyzed nonparametrically. Simple correlation between continuous normally distributed variables were evaluated by Spearman ρ (PROC CORR) Differences in the means of variables of interest between blacks and whites were tested by t-test (PROC TTEST) or nonparametric test (PROC NPAR1WAY) if variables were not normally distributed. Differences in proportions of discrete variables were tested using CHI-square test (PROC FREQ). Variables (gender, age, income, insulin delivery method) potentially influencing insulin dose per kg per day in addition to race were analyzed as covariates in a general linear model (PROC GLM). Statistical analysis was performed using SAS software 9.4 (SAS Institute, Cary NC). BMI z-score was calculated from height and weight data using CDC methodology and their SAS program (https://www.cdc.gov/ nccdphp/dnpao/growthcharts/resources/sas.htm).
Fig. 1. Insulin dose (units/kg/day) and glycemia were significantly correlated (Spearman ρ). 1a). Insulin dose versus mean blood glucose (MBG), ρ = 0.36, p = 0.0008. 1b) Insulin dose vs HbA1c, ρ = 0.30, p b 0.0052. There was no difference between black and white patients.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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patient's capillary glucoses (Pct BGs) found to be below 50 mg/dL and below 70 mg/dL respectively were not different between groups (Table 1). Patients were also compared categorically by whether or not there were any glucoses (Pct Patients w BG) below 50 mg/dL or below 70 mg/dL found during inspection of their glucose meter download. There was no difference at the 50 mg/dl threshold. But proportionately more whites (82.7%) had at least one or more glucose measures below 70, compared to the black patients (63.6%) p = 0.0471. Number of glucose tests per day did not have a statistically significant relationship with frequency of hypoglycemia from the meter data. Table 2 presents simple Spearman correlation (ρ) analysis of variables of interest in the study. Reported average daily insulin usage (units/kg/d) was correlated with both HbA1c and MBG, insulin dose increasing with increased HbA1c or MBG (Fig. 1). However, there was no difference in reported daily units of insulin/kg/d injected between black and white youth (Table 1). In subsequent covariate analysis, there was no association of insulin dosage with race, income level, gender, age or mode of insulin delivery in covariate analysis. Insulin dose units/kg/ day was correlated with HbA1c (ρ = 0.3, p =0.0052), MBG (ρ = 0.36, p = 0.0008), percent of glucose readings under 70 mg/dL (ρ = −0.22, p = 0.0457) and parental report of hypoglycemia (ρ = −0.026, p = 0.026) but not with the other continuous variables. Reported
occurrence of non-severe hypoglycemia was inversely associated with HbA1c and MBG, that is lower glycemic levels were associated with more episodes of recalled hypoglycemia by both parents and patients (Fig. 2). Fig. 3 shows the relationship of the percent of a patient's glucoses below 70 mg/dL from the patient's glucose meter data with HbA1c (ρ = −0.26, p = 0.0165) and MBG (ρ = −0.35, p = 0.0011). Further, there was no difference between white and black patients in reported occurrence of severe hypoglycemia. Sixteen percent of black patients (total n = 30) reported having had a prior severe hypoglycemic episode which was similar to the 15.7% of white patients (total n = 51) who reported such episodes. There was no statistical difference in the percent (12.5%) of black parents (total n = 32) who reported that their child had ever had a severe hypoglycemic episode compared to 14% of white parents. 4. Discussion In this biracial population of youth with type 1 diabetes, we in general found no difference in occurrence of symptoms of hypoglycemia, frequency of hypoglycemia on glucose meters or the reported injected insulin dose in units/kg body weight/day between black and white patients. When patient glucose meter data was compared more whites
b
a
ρ=-0.45, p<0.0001
ρ=-0.51, p<0.0001
c
d ρ=-0.37, p=0.0008
ρ=-0.37, p=0.0008
Fig. 2. Parent and patient estimates of occurrence of non-severe hypoglycemia per week and association with glycemia. Parental and patient estimates of occurrence of non-severe hypoglycemic episodes per week were significantly and inversely correlated with both HbA1c and mean blood glucose (MBG) by Spearman correlation (ρ). 2a). Parental estimate of hypoglycemia per week vs HbA1c, 2b). Parental estimate of hypoglycemia per week vs MBG, 2c). Patient estimate of hypoglycemia per week vs HbA1c, 2d). Patient estimate of hypoglycemia per week vs MBG. Circles represent white patients, dots represent black patients.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
were found to have had at least one BG measure below 70 mg/dL compared to blacks. The reported injected insulin dose in units/kg body weight/day was highly correlated with the level of glycemia whether determined by HbA1c or MBG. We found, as has been reported before, that black patients had higher HbA1c and MBG compared to white patients. Furthermore, as also previously noted, when HbA1c was adjusted for MBG and other covariates HbA1c overestimated MBG among black patients in this population.6,10,11 Contrary to our working hypothesis, we did not find a racial disparity in the units of insulin/kg/day injected. Neither did we find a higher reported occurrence of hypoglycemia in blacks compared to whites as has been reported from two prior studies.3,15 Our data indicates that hypoglycemia was more likely to be reported in patients with better glycemic control, i.e. lower HbA1c and MBGs. This observation is consistent with other studies, such as in the Diabetes Control and Complications Trial (DCCT), where the reported occurrence of hypoglycemia was inversely correlated with better glycemic control.20 Our methodology for ascertainment of episodes of hypoglycemia was from questionnaires of patients and parents which was similar to the methods used in Type 1 Diabetes Exchange Group (TDEX) and Pediatric Diabetes Consortium (PDC).3,15 In addition we also reviewed patient glucose meter data for occurrence of biochemical hypoglycemia which was not available in TDEX or PDC. We found that trends in
a ρ=-0.26, p=0.0165
b ρ=-0.35, p=0.0011
5
patterns of reported hypoglycemia from questionnaires were correlated with the more objective meter data. There are several factors that may explain why our findings differ from those of two multicenter studies with larger numbers of patients and why we could not confirm our hypothesis of higher insulin dose and more hypoglycemia among blacks in our clinic population. The two recent multicenter studies, the Type 1 Diabetes Exchange Group (TDEX) n = 10,704 (697 black patients, 8841white patients, 1166 Hispanic patients) from 60 pediatric sites3 and the Pediatric Diabetes Consortium (PDC) n = 927, (80 black patients, 631 white patients, 216 Hispanic patients) from seven centers.15 found higher occurrence of reported hypoglycemia in black patients, despite blacks having higher HbA1c levels than whites. The PDC study also found higher insulin dosages (units/kg/day) for black patients. While black patients in TDEX overall had slightly lower insulin doses than whites. Although these two studies overall enrolled large numbers of patients the average number of black patients at each clinic of ~11 individuals was low. Between clinic variation in outcomes was not examined and potentially there may have been considerable variation between clinics in approach to therapy and outcomes achieved especially in minority patients. In contrast our study data represents the experience of a single center with the advantage of a relatively large representation of black patients (39%) compared to 6.5% and 8.6% overall for the TDEX and PDC respectively. Furthermore, changes in insulin dose for all patients in this clinic were based on the pattern of the patient's self-monitored glucose data reviewed at the time of clinic visit. HbA1c data was not available to providers or patients until after the clinic visit. This insulin management approach may have helped eliminate disparity in the occurrence of hypoglycemia between white and black patients. Potentially in clinics where point of care HbA1c is available there may be the temptation for providers to treat higher HbA1c21 especially in the absence of good home glucose data as might occur more often in black patients.9 Unfortunately our study was not designed to answer this hypothesis and compare decisions made on changes in insulin dosing with and without the availability of point of care HbA1c. It should be pointed out that ascertainment of units of insulin was different between patients using and not using pumps. Units of insulin delivered per day was directly from pump download, whereas patients not usually pumps the number of units used per day was per patient/parent report. Potentially analysis of between site difference in TDEX and PDC might help clarify whether differences in hypoglycemia and insulin dosing is a site specific phenomenon or is generalizable across sites in the larger studies. Clarification of the relationship between hypoglycemia, measures of glycemia and how insulin dosing decisions by providers are made are potentially important to understand reported racial disparity in these indices. If there is a provider basis for higher occurrence of hypoglycemia in black patients with higher HbA1c this could be changed by adjustment of management approach. It would be important to clarify this issue as it is possible that parents of patients and patients who experience frequent hypoglycemia may not be willing to implement increased insulin doses for fear of more hypoglycemia. This may be a potential barrier to optimizing glycemic control in high risk patients. CRediT authorship contribution statement
Fig. 3. Inverse relationship of percentage glucose meter readings below 70 mg/dL with HbA1c and mean blood glucose (MBG) by Spearman correlation (ρ). 3a). Percent of total meter readings below 70 mg/dL vs HbA1c, 3b). Percent of total meter readings below 70 mg/dL vs mean blood glucose (MBG). Circles represent white patients, dots represent black patients.
Stuart Chalew: Conceptualization, Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing. Jodi Kamps: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing. Brittney Jurgen: Data curation, Investigation, Methodology, Writing - review & editing. Ricardo Gomez: Investigation, Project administration. James Hempe: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing - review & editing.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
Acknowledgements Research reported in this paper was supported by the Mid-South Transdisciplinary Collaborative Center for Health Disparities Research through the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health under Award Number U54MD008176. Dr. Chalew is supported in part by NIH: U54 GM104940. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would also like to acknowledge support from Children's Special Health Services of Louisiana, Children's Hospital of New Orleans, the Louisiana State University Health Sciences Center, and the P and C Carroll Foundation, New Orleans, LA. References 1. Delamater AM, et al. Racial differences in metabolic control of children and adolescents with type I diabetes mellitus. Diabetes Care 1991;14:20-5. 2. Chalew SA, et al. Predictors of glycemic control in children with type 1 diabetes: the importance of race. J Diabetes Complications 2000;14:71-7. 3. Willi SM, et al. Racial-ethnic disparities in management and outcomes among children with type 1 diabetes. Pediatrics 2015;135:424-34. 4. Hanson CL, Henggeler SW, Burghen GA. Race and sex differences in metabolic control of adolescents with IDDM: a function of psychosocial variables? Diabetes Care 1987;10:313-8. 5. Auslander WF, et al. Risk factors to health in diabetic children: a prospective study from diagnosis. Health Soc Work 1990;15:133-42. 6. Kamps JL, Hempe JM, Chalew SA. Racial disparity in A1C independent of mean blood glucose in children with type 1 diabetes. Diabetes Care 2010;33:1025-7.
7. Petitti DB, et al. Glycemic control in youth with diabetes: the SEARCH for diabetes in youth study. J Pediatr 2009;155:668-72. 8. Coulon SJ, et al. Racial differences in neighborhood disadvantage, inflammation and metabolic control in black and white pediatric type 1 diabetes patients. Pediatr Diabetes 2017;18:120-7. 9. Chalew S, et al. Hemoglobin A1c, frequency of glucose testing and social disadvantage: metrics of racial health disparity in youth with type 1 diabetes. J Diabetes and Its Complications 2018;19:p1243-8. 10. Bergenstal RM, et al. Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels. Ann Intern Med 2017;167:95-102. 11. Chalew SA, Hamdan MA. Racial disparity in HbA1c persists when fructosamine is used as a surrogate for mean blood glucose in youth with type 1 diabetes. Pediatr Diabetes 2018;19:1243-8. 12. Hempe J, et al. High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control. J Diabetes Complications 2002;16:313-20. 13. Hempe JM, et al. The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial. Diabetes Care 2015;38:1067-74. 14. Chalew SA. The continuing challenge of outcome disparities in children with diabetes. Pediatrics 2015;135:552-3. 15. Redondo MJ, et al. Racial/ethnic minority youth with recent-onset type 1 diabetes have poor prognostic factors. Diabetes Care 2018;41:1017-24. 16. Chalew SA, McCarter RJ, Hempe JM. Biological variation and hemoglobin a1c: relevance to diabetes management and complications. Pediatr Diabetes 2013;14:391-8. 17. Boyle PJ, et al. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988;318:1487-92. 18. Jones TW, et al. Independent effects of youth and poor diabetes control on responses to hypoglycemia in children. Diabetes 1991;40:358-63. 19. National Glycohemoglobin Standardization Program. , www.ngsp.org. 20. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in IDDM. N Engl J Med 1993;329:977-83. 21. IDF/ISPAD. Global IDF/ISPAD guideline for diabetes in childhood and adolescence. , www.ispad.org/page/IDFISPAD2011 2011.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
Contents lists available at ScienceDirect
Journal of Diabetes and Its Complications journal homepage: WWW.JDCJOURNAL.COM
The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 diabetes☆ Stuart Chalew a,⁎, Jodi Kamps b, Brittney Jurgen b, Ricardo Gomez a, James Hempe a a b
Division of Endocrinology and Diabetes, Children's Hospital of New Orleans and The Louisiana State University Health Sciences Center, New Orleans, LA, United States of America Department of Psychology, Children's Hospital of New Orleans, New Orleans, LA, United States of America
a r t i c l e
i n f o
Article history: Received 19 August 2019 Received in revised form 25 November 2019 Accepted 30 December 2019 Available online xxxx
a b s t r a c t Introduction: Black youth with T1D have been reported to experience more episodes of hypoglycemia than white patients, despite blacks having higher levels of HbA1c. We hypothesized that black patients may be prescribed higher daily doses of insulin putting them at greater higher risk for hypoglycemia. Methods: We performed a retrospective analysis of data from a study of social and environmental factors influencing HbA1c in a biracial pediatric population with T1DM. Changes in patient insulin dose were made at clinic visit based on their self-monitored glucose (SMG) data. Insulin dose (units/kg/d) was compared with HbA1c, reported hypoglycemic episodes and occurrence of low blood glucose from SMG data. Results: Age, duration of diabetes and BMI-z were similar for black and white patients. Black patients had higher levels of HbA1c and mean blood glucose (MBG). HbA1c was higher in blacks even after adjustment for MBG. Reported insulin dose increased with increasing HbA1c (ρ = 0.30, p = 0.0052) or MBG (ρ = 0.36, p b 0.0008). There was no difference in insulin dose between blacks and whites. Reported hypoglycemia was inversely associated with HbA1c and MBG, but there was no racial difference. Occurrence of low glucoses from meter data was slightly higher in whites (p = 0.047). Conclusion: Insulin dose increased with increasing HbA1c or MBG for both groups. Occurrence of hypoglycemia was inversely related to glycemic control. There was slightly higher occurrence low glucose meter readings in white patients. Reported racial disparities in occurrence of hypoglycemia and insulin dosing may be due to clinic specific factors. © 2020 Elsevier Inc. All rights reserved.
1. Introduction Over the years, multiple studies from various clinical centers have found racial disparity in glycemic control between black and white youth with type 1 diabetes (T1D) in the US. HbA1c levels being consistently higher in black patients compared to whites, despite technological advances in glucose monitoring and insulin delivery.1–7 Multiple factors have been associated with this disparity. Families of black patients typically have lower income, lower education level and higher measures of disadvantage compared to white families.8,9 Black patients are more likely to rely on assistance programs like Medicaid than commercial insurance to cover the medical expenses of diabetes.9 Black patients are less likely to be using insulin pumps and perform capillary glucose testing less often than white patients.3,9
☆ Conflict of interest statement: The authors report no relationships that could be construed as a conflict of interest. ⁎ Corresponding author at: Division of Endocrinology and Diabetes, Children's Hospital of New Orleans and The Department of Pediatrics, The Louisiana State University Health Sciences Center, 200 Henry Clay Avenue, New Orleans, LA 70118, United States of America. E-mail address: [email protected] (S. Chalew).
Besides socio-economic and behavioral differences, there are also biological factors contributing to racial disparity in HbA1c. When HbA1c is adjusted for concurrent blood glucose or fructosamine levels, HbA1c is higher in black patients than white patients with the same MBG or fructosamine level.6,10,11 Thus black patients tend to be so-called “high glycators,” where HbA1c overestimates their true mean blood glucose levels.12 Potentially “high glycators” are at greater risk for hypoglycemia when the primary treatment goal is HbA1c.13,14 If clinicians are not aware that a patient is a “high glycator” they may be tempted to increase total insulin dose in order to reduce patient HbA1c toward published glycemic goals. In two multi-center studies with large multiracial populations it has been noted that black children with T1D paradoxically report greater occurrence of hypoglycemia than white patients despite blacks having higher HbA1c.3,15 We have hypothesized that black patients may receive disproportionately higher insulin doses due to the fact that HbA1c overestimates their true MBG.13,14 This would potentially lead to higher occurrence of hypoglycemia in black patients.14,16 Alternatively patients with poor glycemic control may experience symptoms of hypoglycemia at higher glucose levels than patients with good control.17,18 As black patients typically have higher HbA1c and MBG compared to white patients this may account
https://doi.org/10.1016/j.jdiacomp.2019.107519 1056-8727/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
Table 1 Comparison of characteristics of black and white patient groups. Pct BGs b 50 mg/dL Pt* = percent BG b 50 mg/dL per patient. Pct BGs b 70 mg/dL Pt* = percent BG b 70 mg/dL per patients. Pct patients w BG b 50 mg/dL** = percent of total patients with at least one reading BG b 50 mg/dL. Pct patients w BG b 70 mg/dL** = percent of total patients with at least one reading BG b 70 mg/dL. %Pts = percent of patients. Black n = 33
Age (yrs) Males/females Number pts at income level: b$25K $25–75K N$75K Diabetes duration (yrs) BMI z-score HbA1c % MBG (mg/dL) Insulin units/kg/d Pct BGs b 50 mg/dL Pt* Pct BGs b 70 mg/dL Pt* Pct patients w BG b 50 mg/dL** Pct patients w BG b 70 mg/dL** BG measures per day Insulin delivery method % pts: 2 or 3 injections/day N3 injections/day Pump
White n = 52
p=
Mean
SD
Mean
SD
12.8 14/19
±3.6
14.1 30/22
±3.4
19 11 1 8.6 0.87 10.4 255 1.0 1.1 5.9 33.3. 63.6 2.6
±3.8 ±0.9 ±2.1 ±92 ±0.4 ±2.3 ±7.6
±1.7
55 36 9
1 20 30 8.4 0.34 8.9 198 0.8 1.7 5.7 40.4 82.7 4.4
NS NS b0.0001
±3.7 ±1.1 ±1.3 ±44 ±0.3 ±4.0 ±6.0
±2.9
NS NS 0.0013 0.0018 NS NS NS NS 0.0471 0.0004 b0.0001
13 23 64
for higher reports of hypoglycemia in black children despite higher HbA1c. In order to evaluate these hypotheses we retrospectively analyzed insulin dosing data, reported and observed occurrence of hypoglycemia during a study of outcome disparities conducted in a biracial population of youth with type 1 diabetes in New Orleans.
2. Methods This study was a retrospective analysis of patient data collected in study of biochemical, social and environmental factors influencing glycemic control in a biracial population of youth with T1D. Details of the study design have been previously reported.8,9 Type 1 diabetes patients self-identified as either black or white were recruited from the Pediatric Diabetes Center at Children's Hospital of New Orleans, New Orleans, LA. The Children's Diabetes Center at the Children's Hospital of New Orleans is a multidisciplinary referral center. The majority of patients were from the New Orleans metropolitan area. The regular clinic staff included 3 pediatric CDE nurse educators, 1 pediatric nutritionist and 4 pediatric diabetology attendings and 3 pediatric endocrine fellows under their supervision. Patients have continuity of care by one of the attendings supported by the CDE team and nutritionist. The goal of clinical management was to help patients attain optimal glycemic control without undo occurrence of hypoglycemia. Point of care HbA1c are not done in clinic and the lab HbA1c was not available until clinic is over and patients have been discharged. Changes in insulin management were based on review of home glucose records downloaded for the management team at the time of the clinic visit. Patients without self-monitored glucose records were not included in this study. The study was approved by the Institutional Review Board at the Louisiana State University Health Sciences Center as well as Children's Hospital IRB. Informed consent for participation in the study was obtained from the patient's parent/guardian and assent from the patient. Patients included in this study were aged 5–20 yr with duration of type 1 diabetes of at least 1 yr. Diagnosis of type 1 diabetes was based on typical clinical presentation, need for exogenous insulin for metabolic control and presence of one or more anti-pancreatic antibodies. Age, gender, self-identified race, duration of diabetes, height, weight, reported total daily insulin dose administered at home or total infused insulin from pump download, insulin delivery method, family income and medical insurance were recorded at the time of clinic visit.
Table 2 Simple Spearman correlations of study variables. Spearman correlation coefficients Prob N |r| under H0: Rho = 0 Number of observations Insulin U/kg/d Insulin units/kg/day
HbA1c %
MBG (mg/dL)
BMI-z score
Glucoses per day
Percent glucoses b 50 mg/dL
Percent glucoses b 70 mg/dL
Parent reported hypos per week
Patient reported hypos per week
HbA1c % 0.30064 0.0052 85
0.30064 0.0052 85 0.35830 0.0008 85 0.02041 NS 84 −0.18222 NS 85 −0.18028 NS 85 −0.21737 0.0457 85 −0.25970 0.0226 77 −0.19573 NS 77
0.63771 b0.0001 85 0.18079 NS 84 −0.57732 b0.0001 85 −0.21607 0.0470 85 −0.25950 0.0165 85 −0.50685 b0.0001 77 −0.37406 0.0008 77
MBG 0.35830 0.0008 85 0.63771 b0.0001 85
0.11129 NS 84 −0.26812 0.0131 85 −0.25310 0.0194 85 −0.34878 0.0011 85 −0.44762 b0.0001 77 −0.37431 0.0008 77
BMI-z 0.02041 NS 84 0.18079 NS 84 0.11129 NS 84
−0.24338 0.0257 84 0.00552 NS 84 0.05763 NS 84 −0.11946 NS 76 −0.21877 NS 76
BG/day
BG b 50
BG b 70
−0.18222 NS 85 −0.57732 b0.0001 85 −0.26812 0.0131 85 −0.24338 0.0257 84
−0.18028 NS 85 −0.21607 0.0470 85 −0.25310 0.0194 85 0.00552 NS 84 0.20102 NS 85
−0.21737 0.0457 85 −0.25950 0.0165 85 −0.34878 0.0011 85 0.05763 0.6025 84 0.17956 0.1001 85 0.74380 b0.0001 85
0.20102 NS 85 0.17956 NS 85 0.36272 0.0012 77 0.19547 NS 77
0.74380 b0.0001 85 0.27932 0.0139 77 0.20071 NS 77
0.28817 0.0110 77 0.08929 NS 77
Parent hypo
Patient hypo
−0.25970 0.0226 77 −0.50685 b0.0001 77 −0.44762 b0.0001 77 −0.11946 NS 76 0.36272 0.0012 77 0.27932 0.0139 77 0.28817 0.0110 77
−0.19573 NS 77 −0.37406 0.0008 77 −0.37431 0.0008 77 −0.21877 0.0576 76 0.19547 NS 77 0.20071 NS 77 0.08929 NS 77 0.51677 b0.0001 72
0.51677 b0.0001 72
MBG = mean blood glucose BMI = body mass index NS = p N 0.05.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
2.1. Family income
3. Results
Information was collected on family income by questionnaire. Annual family income was grouped into three broad levels $25K and under, over $25K to $75K and over $75K.
3.1. Patients characteristics
2.2. Assessment of hypoglycemia Patients over 8 years of age and their accompanying parent were asked to respond to a simple questionnaire about hypoglycemic events. 1-whether they had ever had a hypoglycemic event associated with seizure or loss of consciousness, and 2-to estimate the number of hypoglycemic episodes per week without seizure or loss of consciousness. The number of respondents to these questions were less than the total number of patients as not all families responded or had children younger than 8 yo. One of the investigators (BJ) reviewed each patient's glucose meter down-load for the 30 days prior to the clinic visit and recorded the number and percentage of readings b70 mg/dL and b50 mg/dL which was used as another metric of occurrence of hypoglycemia. The total number of self-monitored glucose measures per day was also recorded for each patient. Data accuracy and validity was reviewed by author (JK). 2.3. Insulin dose and insulin delivery method The total units of insulin injected per day was the dose reportedly taken by the patient at the clinic visit intake assessment. In the case of patients using insulin pump daily units of insulin used was obtained from the pump download. The total units of insulin taken per day was divided by patient weight in kilograms. Subjects without insulin dose data were not included in the analysis.
3
Demographic information regarding the patients by race is shown in Table 1. Patients included for analysis in this study, self-identified as either white n = 52, or black n = 33. There were no differences in age, gender distribution, duration of diabetes, or BMI-z between the groups. White families had markedly higher income distribution than black families (p b 0.0001) and more likely to be using insulin pumps. 3.2. Glycemic control Both HbA1c and mean blood glucose (MBG) were higher in black compared to white patients (Table 1). In multiple variable analysis HbA1c was higher in black patients than whites even after statistical adjustment for chronologic age, MBG, and gender. The number of capillary glucose tests per day (BG measures per day) was nearly 70% higher in white patients compared to blacks (p = 0.0004). 3.3. Insulin usage and reported hypoglycemia Reported units of insulin injected per kilogram body weight per day were similar for black and white patients (Table 1). The percent of a
a ρ=0.36, p=0.0008
2.4. Mean blood glucose (MBG) Capillary blood glucose data were downloaded from each patient home glucose meter using manufacturer's proprietary software. Selfmonitored mean blood glucose (MBG) was calculated for the 30 days prior to the clinic visit as previously described.6,8 2.5. Hemoglobin A1c HbA1c was measured by immunoassay in the Children's Hospital laboratory using the VITROS 5, 1 FS Chemistry System (Ortho-Clinical Diagnostics, Rochester, NY, USA) with an upper reporting limit of 16%. The assay is compliant with the National Glycohemoglobin Standardization Program (NGSP) and the results are reported as NGSP equivalents.19
b ρ=0.30, p<0.0052
2.6. Statistical analysis Initial statistical analysis was performed by assessing normality of continuous variables (PROC UNIVARIATE) Variables which were not normally distributed or were not be normally distributed after log transform were analyzed nonparametrically. Simple correlation between continuous normally distributed variables were evaluated by Spearman ρ (PROC CORR) Differences in the means of variables of interest between blacks and whites were tested by t-test (PROC TTEST) or nonparametric test (PROC NPAR1WAY) if variables were not normally distributed. Differences in proportions of discrete variables were tested using CHI-square test (PROC FREQ). Variables (gender, age, income, insulin delivery method) potentially influencing insulin dose per kg per day in addition to race were analyzed as covariates in a general linear model (PROC GLM). Statistical analysis was performed using SAS software 9.4 (SAS Institute, Cary NC). BMI z-score was calculated from height and weight data using CDC methodology and their SAS program (https://www.cdc.gov/ nccdphp/dnpao/growthcharts/resources/sas.htm).
Fig. 1. Insulin dose (units/kg/day) and glycemia were significantly correlated (Spearman ρ). 1a). Insulin dose versus mean blood glucose (MBG), ρ = 0.36, p = 0.0008. 1b) Insulin dose vs HbA1c, ρ = 0.30, p b 0.0052. There was no difference between black and white patients.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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patient's capillary glucoses (Pct BGs) found to be below 50 mg/dL and below 70 mg/dL respectively were not different between groups (Table 1). Patients were also compared categorically by whether or not there were any glucoses (Pct Patients w BG) below 50 mg/dL or below 70 mg/dL found during inspection of their glucose meter download. There was no difference at the 50 mg/dl threshold. But proportionately more whites (82.7%) had at least one or more glucose measures below 70, compared to the black patients (63.6%) p = 0.0471. Number of glucose tests per day did not have a statistically significant relationship with frequency of hypoglycemia from the meter data. Table 2 presents simple Spearman correlation (ρ) analysis of variables of interest in the study. Reported average daily insulin usage (units/kg/d) was correlated with both HbA1c and MBG, insulin dose increasing with increased HbA1c or MBG (Fig. 1). However, there was no difference in reported daily units of insulin/kg/d injected between black and white youth (Table 1). In subsequent covariate analysis, there was no association of insulin dosage with race, income level, gender, age or mode of insulin delivery in covariate analysis. Insulin dose units/kg/ day was correlated with HbA1c (ρ = 0.3, p =0.0052), MBG (ρ = 0.36, p = 0.0008), percent of glucose readings under 70 mg/dL (ρ = −0.22, p = 0.0457) and parental report of hypoglycemia (ρ = −0.026, p = 0.026) but not with the other continuous variables. Reported
occurrence of non-severe hypoglycemia was inversely associated with HbA1c and MBG, that is lower glycemic levels were associated with more episodes of recalled hypoglycemia by both parents and patients (Fig. 2). Fig. 3 shows the relationship of the percent of a patient's glucoses below 70 mg/dL from the patient's glucose meter data with HbA1c (ρ = −0.26, p = 0.0165) and MBG (ρ = −0.35, p = 0.0011). Further, there was no difference between white and black patients in reported occurrence of severe hypoglycemia. Sixteen percent of black patients (total n = 30) reported having had a prior severe hypoglycemic episode which was similar to the 15.7% of white patients (total n = 51) who reported such episodes. There was no statistical difference in the percent (12.5%) of black parents (total n = 32) who reported that their child had ever had a severe hypoglycemic episode compared to 14% of white parents. 4. Discussion In this biracial population of youth with type 1 diabetes, we in general found no difference in occurrence of symptoms of hypoglycemia, frequency of hypoglycemia on glucose meters or the reported injected insulin dose in units/kg body weight/day between black and white patients. When patient glucose meter data was compared more whites
b
a
ρ=-0.45, p<0.0001
ρ=-0.51, p<0.0001
c
d ρ=-0.37, p=0.0008
ρ=-0.37, p=0.0008
Fig. 2. Parent and patient estimates of occurrence of non-severe hypoglycemia per week and association with glycemia. Parental and patient estimates of occurrence of non-severe hypoglycemic episodes per week were significantly and inversely correlated with both HbA1c and mean blood glucose (MBG) by Spearman correlation (ρ). 2a). Parental estimate of hypoglycemia per week vs HbA1c, 2b). Parental estimate of hypoglycemia per week vs MBG, 2c). Patient estimate of hypoglycemia per week vs HbA1c, 2d). Patient estimate of hypoglycemia per week vs MBG. Circles represent white patients, dots represent black patients.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
S. Chalew et al. / Journal of Diabetes and Its Complications xxx (xxxx) xxx
were found to have had at least one BG measure below 70 mg/dL compared to blacks. The reported injected insulin dose in units/kg body weight/day was highly correlated with the level of glycemia whether determined by HbA1c or MBG. We found, as has been reported before, that black patients had higher HbA1c and MBG compared to white patients. Furthermore, as also previously noted, when HbA1c was adjusted for MBG and other covariates HbA1c overestimated MBG among black patients in this population.6,10,11 Contrary to our working hypothesis, we did not find a racial disparity in the units of insulin/kg/day injected. Neither did we find a higher reported occurrence of hypoglycemia in blacks compared to whites as has been reported from two prior studies.3,15 Our data indicates that hypoglycemia was more likely to be reported in patients with better glycemic control, i.e. lower HbA1c and MBGs. This observation is consistent with other studies, such as in the Diabetes Control and Complications Trial (DCCT), where the reported occurrence of hypoglycemia was inversely correlated with better glycemic control.20 Our methodology for ascertainment of episodes of hypoglycemia was from questionnaires of patients and parents which was similar to the methods used in Type 1 Diabetes Exchange Group (TDEX) and Pediatric Diabetes Consortium (PDC).3,15 In addition we also reviewed patient glucose meter data for occurrence of biochemical hypoglycemia which was not available in TDEX or PDC. We found that trends in
a ρ=-0.26, p=0.0165
b ρ=-0.35, p=0.0011
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patterns of reported hypoglycemia from questionnaires were correlated with the more objective meter data. There are several factors that may explain why our findings differ from those of two multicenter studies with larger numbers of patients and why we could not confirm our hypothesis of higher insulin dose and more hypoglycemia among blacks in our clinic population. The two recent multicenter studies, the Type 1 Diabetes Exchange Group (TDEX) n = 10,704 (697 black patients, 8841white patients, 1166 Hispanic patients) from 60 pediatric sites3 and the Pediatric Diabetes Consortium (PDC) n = 927, (80 black patients, 631 white patients, 216 Hispanic patients) from seven centers.15 found higher occurrence of reported hypoglycemia in black patients, despite blacks having higher HbA1c levels than whites. The PDC study also found higher insulin dosages (units/kg/day) for black patients. While black patients in TDEX overall had slightly lower insulin doses than whites. Although these two studies overall enrolled large numbers of patients the average number of black patients at each clinic of ~11 individuals was low. Between clinic variation in outcomes was not examined and potentially there may have been considerable variation between clinics in approach to therapy and outcomes achieved especially in minority patients. In contrast our study data represents the experience of a single center with the advantage of a relatively large representation of black patients (39%) compared to 6.5% and 8.6% overall for the TDEX and PDC respectively. Furthermore, changes in insulin dose for all patients in this clinic were based on the pattern of the patient's self-monitored glucose data reviewed at the time of clinic visit. HbA1c data was not available to providers or patients until after the clinic visit. This insulin management approach may have helped eliminate disparity in the occurrence of hypoglycemia between white and black patients. Potentially in clinics where point of care HbA1c is available there may be the temptation for providers to treat higher HbA1c21 especially in the absence of good home glucose data as might occur more often in black patients.9 Unfortunately our study was not designed to answer this hypothesis and compare decisions made on changes in insulin dosing with and without the availability of point of care HbA1c. It should be pointed out that ascertainment of units of insulin was different between patients using and not using pumps. Units of insulin delivered per day was directly from pump download, whereas patients not usually pumps the number of units used per day was per patient/parent report. Potentially analysis of between site difference in TDEX and PDC might help clarify whether differences in hypoglycemia and insulin dosing is a site specific phenomenon or is generalizable across sites in the larger studies. Clarification of the relationship between hypoglycemia, measures of glycemia and how insulin dosing decisions by providers are made are potentially important to understand reported racial disparity in these indices. If there is a provider basis for higher occurrence of hypoglycemia in black patients with higher HbA1c this could be changed by adjustment of management approach. It would be important to clarify this issue as it is possible that parents of patients and patients who experience frequent hypoglycemia may not be willing to implement increased insulin doses for fear of more hypoglycemia. This may be a potential barrier to optimizing glycemic control in high risk patients. CRediT authorship contribution statement
Fig. 3. Inverse relationship of percentage glucose meter readings below 70 mg/dL with HbA1c and mean blood glucose (MBG) by Spearman correlation (ρ). 3a). Percent of total meter readings below 70 mg/dL vs HbA1c, 3b). Percent of total meter readings below 70 mg/dL vs mean blood glucose (MBG). Circles represent white patients, dots represent black patients.
Stuart Chalew: Conceptualization, Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing. Jodi Kamps: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing. Brittney Jurgen: Data curation, Investigation, Methodology, Writing - review & editing. Ricardo Gomez: Investigation, Project administration. James Hempe: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Writing - review & editing.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519
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Acknowledgements Research reported in this paper was supported by the Mid-South Transdisciplinary Collaborative Center for Health Disparities Research through the National Institute on Minority Health and Health Disparities (NIMHD) of the National Institutes of Health under Award Number U54MD008176. Dr. Chalew is supported in part by NIH: U54 GM104940. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would also like to acknowledge support from Children's Special Health Services of Louisiana, Children's Hospital of New Orleans, the Louisiana State University Health Sciences Center, and the P and C Carroll Foundation, New Orleans, LA. References 1. Delamater AM, et al. Racial differences in metabolic control of children and adolescents with type I diabetes mellitus. Diabetes Care 1991;14:20-5. 2. Chalew SA, et al. Predictors of glycemic control in children with type 1 diabetes: the importance of race. J Diabetes Complications 2000;14:71-7. 3. Willi SM, et al. Racial-ethnic disparities in management and outcomes among children with type 1 diabetes. Pediatrics 2015;135:424-34. 4. Hanson CL, Henggeler SW, Burghen GA. Race and sex differences in metabolic control of adolescents with IDDM: a function of psychosocial variables? Diabetes Care 1987;10:313-8. 5. Auslander WF, et al. Risk factors to health in diabetic children: a prospective study from diagnosis. Health Soc Work 1990;15:133-42. 6. Kamps JL, Hempe JM, Chalew SA. Racial disparity in A1C independent of mean blood glucose in children with type 1 diabetes. Diabetes Care 2010;33:1025-7.
7. Petitti DB, et al. Glycemic control in youth with diabetes: the SEARCH for diabetes in youth study. J Pediatr 2009;155:668-72. 8. Coulon SJ, et al. Racial differences in neighborhood disadvantage, inflammation and metabolic control in black and white pediatric type 1 diabetes patients. Pediatr Diabetes 2017;18:120-7. 9. Chalew S, et al. Hemoglobin A1c, frequency of glucose testing and social disadvantage: metrics of racial health disparity in youth with type 1 diabetes. J Diabetes and Its Complications 2018;19:p1243-8. 10. Bergenstal RM, et al. Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels. Ann Intern Med 2017;167:95-102. 11. Chalew SA, Hamdan MA. Racial disparity in HbA1c persists when fructosamine is used as a surrogate for mean blood glucose in youth with type 1 diabetes. Pediatr Diabetes 2018;19:1243-8. 12. Hempe J, et al. High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control. J Diabetes Complications 2002;16:313-20. 13. Hempe JM, et al. The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive treatment in the ACCORD trial. Diabetes Care 2015;38:1067-74. 14. Chalew SA. The continuing challenge of outcome disparities in children with diabetes. Pediatrics 2015;135:552-3. 15. Redondo MJ, et al. Racial/ethnic minority youth with recent-onset type 1 diabetes have poor prognostic factors. Diabetes Care 2018;41:1017-24. 16. Chalew SA, McCarter RJ, Hempe JM. Biological variation and hemoglobin a1c: relevance to diabetes management and complications. Pediatr Diabetes 2013;14:391-8. 17. Boyle PJ, et al. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988;318:1487-92. 18. Jones TW, et al. Independent effects of youth and poor diabetes control on responses to hypoglycemia in children. Diabetes 1991;40:358-63. 19. National Glycohemoglobin Standardization Program. , www.ngsp.org. 20. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in IDDM. N Engl J Med 1993;329:977-83. 21. IDF/ISPAD. Global IDF/ISPAD guideline for diabetes in childhood and adolescence. , www.ispad.org/page/IDFISPAD2011 2011.
Please cite this article as: S. Chalew, J. Kamps, B. Jurgen, et al., The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 ..., Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107519