Pediatric Diabetes 2015 doi: 10.1111/pedi.12264 All rights reserved
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Pediatric Diabetes
Original Article
Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler PS, White NH. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatric Diabetes 2015. Objective: The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. Research design and methods: Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. Main outcome measures: Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. Results: Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. Conclusions: Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.
Megan M Kelseya , Mitchell E Geffnerb , Cynthia Guandalinic , Laura Pyled , William V Tamborlanec , Philip S Zeitlera , and Neil H Whitee for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group† a Department of Pediatrics, University of Colorado, Aurora, CO, USA; b The Saban Research Institute of Children’s Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, USA; c Department of Pediatric Endocrinology, Yale University, New Haven, CT, USA; d Biostatistics Center, George Washington University, Rockville, MD, USA; and e Department of Pediatrics, Washington University, St. Louis, MO, USA † Members of TODAY Study Group are listed in the Appendix
Key words: diabetes education – insulin therapy – metformin Corresponding author: Laura Pyle, PhD, Department of Pediatrics, School of Medicine, Department of Biostatistics and Informatics, Colorado School of Public Health, AMC Building 406, Mail Stop B119-406, 12477 E 19th Avenue, Aurora, CO 80045, USA. Tel: 303-724-4355; Fax: 303-724-6858; e-mail: [email protected]
1
Kelsey et al. Submitted 24 September 2014. Accepted for publication 21 January 2015
Although it is still considered relatively uncommon in children, type 2 diabetes (T2D) has become recognized as a disease with increasingly significant impact in youth (1, 2), particularly among racial/ethnic minorities; T2D represents more than half of all newly diagnosed cases of diabetes in Black, Hispanic, Asian/Pacific Islander, and Native American youth aged 10–19 yr (1, 3). The potential impact of the early development of T2D on future morbidity/mortality owing to the associated macro- and microvascular complications is significant (4). The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study was designed to evaluate three treatments for T2D in 10- to 17-yr-old youth: metformin, metformin + lifestyle intervention, and metformin + rosiglitazone. The intervention has been described in detail (5), and primary outcome results have been published (6). Prior to randomization, potential subjects participated in a run-in phase focused on establishing consistent dosing of metformin, delivering standard diabetes education, and weaning insulin in individuals who were receiving it at the time of screening. We previously compared the characteristics of those who successfully completed run-in and those who did not, including change in hemoglobin A1c (HbA1c) levels and body mass index (BMI) (7). The objectives of these current secondary analyses were to (i) provide a more complete description of a large geographically and ethnically diverse cohort of youth with recent-onset T2D receiving routine clinical care in the USA, (ii) assess the effect of short-term (8 wk) standardized diabetes management, including education and treatment with metformin, on clinical and biochemical parameters, and (iii) identify potential predictors of improvement in HbA1c and BMI during this short-term intervention.
Methods Study design Details of screening for TODAY and the run-in phase were previously described (5,7). Briefly, subjects were identified from the participating pediatric diabetes centers and partners. Public advertisements were also used, but resulted in very few identified participants. Pancreatic antibody-negative (glutamic acid decarboxylase-65 and tyrosine phosphatase) and c-peptide-positive youth ages 10–17 yr who had less than 2-yr duration of T2D were eligible for inclusion in the study; therefore, T2D diagnosis was consistent with the recently published guidelines for diabetes
2
classification in youth (8). At screening, diabetes medications were recorded and anthropometrics (height, weight, and BMI), blood pressure (BP), and physical examination were performed. BMI z-score was calculated based on age- and gender-stratified normative data. Family history of T2D and gestational diabetes was collected in the form of questionnaire. Fasting blood samples were obtained for measurement of total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and c-peptide. All assays were performed at a centralized laboratory using standard biochemical assays (see www.todaystudy.org) (5). As all participants were overweight or obese (BMI, > 85th percentile for sex and age) and had diabetes, participants were classified as having metabolic syndrome if they also had either dyslipidemia (high total or low HDL cholesterol, according to sex-, race-, and age-based cut-offs) and/or hypertension (BP > 95th percentile for age, sex, and height). Elevated liver transaminases were defined as ≥ 1.5 times the upper limit of normal (ALT: female, ≥75 and male, ≥ 97.5 U/L; AST: female, ≥ 69 and male, ≥97.5 U/L). During the run-in period, participants and an identified and consenting adult family member were given one-on-one standardized diabetes education, including diabetes pathophysiology, medication action, lifestyle guidelines, diabetes self-care, and goal-setting (9). The metformin dose was titrated as tolerated to a maximum dose of 1000 mg twice daily, other oral diabetes medications were discontinued, and insulin was tapered with the goal of discontinuation. Laboratory studies, anthropometrics, and BP measurements were repeated at subsequent run-in visits. In order to successfully complete the run-in period, participants were required to demonstrate ≥ 80% medication adherence for at least 6 wk, tolerate metformin at a dose of at least 500 mg twice daily, miss no more than two run-in visits, maintain a HbA1c of ≤ 8% (64 mM/M) for at least 2 months on metformin alone, and demonstrate mastery of basic diabetes education. The run-in period lasted from 2–6 months during which time participants had a minimum of 6 and maximum of 12 visits for mastery of diabetes education (9); the median time in run-in for all those screened was 2.4 months (25th and 75th percentiles = 2.0 and 3.0 months, respectively) (7). A total of 228 screened participants (24%) failed to meet criteria for randomization, and their characteristics have been previously described (7). The study protocol was approved by the institutional review board of Pediatric Diabetes 2015
Recently diagnosed youth with type 2 diabetes each participating institution. Parents of participants provided written informed consent, and all children and adolescents provided assent according to local guidelines.
Statistical analyses To describe characteristics of T2D in recently diagnosed youth in routine clinical care and before any TODAY interventions were undertaken (objective 1), all diabetes antibody-negative subjects screened for the TODAY study (n = 1092) were included. To describe the changes in subject characteristics during run-in, those who completed at least 8 wk of run-in were included (n = 814), regardless of whether they were ultimately randomized. For comparisons between race/ethnicity groups and medication groups, Kruskal–Wallis tests were used for continuous variables and chi-squared tests were used for categorical variables. Only non-Hispanic Whites, Blacks, and Hispanic Whites were included in the racial/ethnic comparisons, as subject numbers in other racial/ethnic groups were inadequate for a meaningful analysis. For adjusted comparisons, p values from the F-test are reported. McNemar’s test was used to compare the change in the proportion of participants with cardiometabolic risk factors from screening to the end of the run-in phase. Linear models were used to evaluate potential predictors of change in HbA1c and BMI z-score during the run-in period (sas proc glm, version 9.2, SAS Institute Inc., Cary, NC). The TODAY study was powered for the primary outcome only; the outcomes reported herein are considered exploratory. P-values 7.5% (58 mM/M) also decreased from 40.8% to 11.4% (p < 0.0001), and there were small, but statistically significant, improvements in BMI z-score (2A), total [−8.88 mg/dL (−0.23 mM/L), p < 0.0001] and LDL [−5.02 mg/dL (−0.13 mM/L), p < 0.0001] cholesterol, triglycerides [−9.73 mg/dL (−0.11 mM/L), p < 0.0001], systolic BP (−1.0 mm Hg, p = 0.039), and diastolic BP (−1.0 mm Hg, p = 0.002). Again, these improvements remained significant after removing the subjects that remained on insulin therapy at the
3
4 Median
Q1
64.4 35.6 13.6 12.5 45.3 25.7 2.7 60.0 39.6 60.0 21.9 36.8 26.7 17.7 91.3 91.3 8.2 65.4
149 137 495 281 30 655 432 655 239 402 292 193 997 997 90 714
%
703 389
N
1092 14 13 1047 2 1 1085 34.9 30.4 1085 2.4 2.1 1087 3.8 2.6 1087 6.9 6.0 1087 157.0 135.0 1087 107.0 73.0 1087 92.0 74.0 1087 39.0 33.0 1056 114.0 107.0 1056 68.0 62.0
N 16 6 39.9 2.6 5.2 8.9 179.0 156.0 111.0 46.0 122.0 74.0
Q3
Q1
155 52 141 47 89 82 44 183 183 24 150
38 22 101 39 7
129 78
N
74.9 25.1 68.1 22.7 43.0 39.6 21.3 88.4 88.4 11.6 72.5
18.4 10.6 48.8 18.8 3.4
62.3 37.7
%
207 14 13 201 2 1 207 34.4 30.4 207 2.3 2.0 207 4.1 2.8 207 6.3 5.8 207 162.0 137.0 207 124.0 85.0 207 96.0 74.0 207 37.0 31.0 201 115.5 106.5 201 68.5 62.0
N Median
White
16 5 39.2 2.6 5.4 7.6 194.0 207.0 116.0 43.0 124.5 75.5
Q3
211 184 220 89 151 48 79 385 385 10 254
40 60 155 133 9
270 127
N
397 379 390 390 395 395 395 395 395 395 381 381
N
Race/ethnicity Q1
Q3
N Median
Q1
Hispanic Q3
p-value*
53.1 46.3 55.4 22.4 38.0 12.1 19.9 97.0 97.0 2.5 64.0
10.1 15.1 39.0 33.5 2.3
68.0 32.0
%
223 153 241 103 125 133 51 334 334 42 251
48 45 185 93 6
224 153
N
59.2 40.6 63.9 27.3 33.2 35.3 13.5 88.6 88.6 11.1 66.6
12.7 11.9 49.1 24.7 1.6
59.4 40.6
%
0.1095
0.0052 0.2354 0.0590
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Pediatric Diabetes
Original Article
Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study Kelsey MM, Geffner ME, Guandalini C, Pyle L, Tamborlane WV, Zeitler PS, White NH. Presentation and effectiveness of early treatment of type 2 diabetes in youth: lessons from the TODAY study. Pediatric Diabetes 2015. Objective: The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort. Research design and methods: Descriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening. Main outcome measures: Demographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures. Results: Subjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation. Conclusions: Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.
Megan M Kelseya , Mitchell E Geffnerb , Cynthia Guandalinic , Laura Pyled , William V Tamborlanec , Philip S Zeitlera , and Neil H Whitee for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group† a Department of Pediatrics, University of Colorado, Aurora, CO, USA; b The Saban Research Institute of Children’s Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, USA; c Department of Pediatric Endocrinology, Yale University, New Haven, CT, USA; d Biostatistics Center, George Washington University, Rockville, MD, USA; and e Department of Pediatrics, Washington University, St. Louis, MO, USA † Members of TODAY Study Group are listed in the Appendix
Key words: diabetes education – insulin therapy – metformin Corresponding author: Laura Pyle, PhD, Department of Pediatrics, School of Medicine, Department of Biostatistics and Informatics, Colorado School of Public Health, AMC Building 406, Mail Stop B119-406, 12477 E 19th Avenue, Aurora, CO 80045, USA. Tel: 303-724-4355; Fax: 303-724-6858; e-mail: [email protected]
1
Kelsey et al. Submitted 24 September 2014. Accepted for publication 21 January 2015
Although it is still considered relatively uncommon in children, type 2 diabetes (T2D) has become recognized as a disease with increasingly significant impact in youth (1, 2), particularly among racial/ethnic minorities; T2D represents more than half of all newly diagnosed cases of diabetes in Black, Hispanic, Asian/Pacific Islander, and Native American youth aged 10–19 yr (1, 3). The potential impact of the early development of T2D on future morbidity/mortality owing to the associated macro- and microvascular complications is significant (4). The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study was designed to evaluate three treatments for T2D in 10- to 17-yr-old youth: metformin, metformin + lifestyle intervention, and metformin + rosiglitazone. The intervention has been described in detail (5), and primary outcome results have been published (6). Prior to randomization, potential subjects participated in a run-in phase focused on establishing consistent dosing of metformin, delivering standard diabetes education, and weaning insulin in individuals who were receiving it at the time of screening. We previously compared the characteristics of those who successfully completed run-in and those who did not, including change in hemoglobin A1c (HbA1c) levels and body mass index (BMI) (7). The objectives of these current secondary analyses were to (i) provide a more complete description of a large geographically and ethnically diverse cohort of youth with recent-onset T2D receiving routine clinical care in the USA, (ii) assess the effect of short-term (8 wk) standardized diabetes management, including education and treatment with metformin, on clinical and biochemical parameters, and (iii) identify potential predictors of improvement in HbA1c and BMI during this short-term intervention.
Methods Study design Details of screening for TODAY and the run-in phase were previously described (5,7). Briefly, subjects were identified from the participating pediatric diabetes centers and partners. Public advertisements were also used, but resulted in very few identified participants. Pancreatic antibody-negative (glutamic acid decarboxylase-65 and tyrosine phosphatase) and c-peptide-positive youth ages 10–17 yr who had less than 2-yr duration of T2D were eligible for inclusion in the study; therefore, T2D diagnosis was consistent with the recently published guidelines for diabetes
2
classification in youth (8). At screening, diabetes medications were recorded and anthropometrics (height, weight, and BMI), blood pressure (BP), and physical examination were performed. BMI z-score was calculated based on age- and gender-stratified normative data. Family history of T2D and gestational diabetes was collected in the form of questionnaire. Fasting blood samples were obtained for measurement of total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and c-peptide. All assays were performed at a centralized laboratory using standard biochemical assays (see www.todaystudy.org) (5). As all participants were overweight or obese (BMI, > 85th percentile for sex and age) and had diabetes, participants were classified as having metabolic syndrome if they also had either dyslipidemia (high total or low HDL cholesterol, according to sex-, race-, and age-based cut-offs) and/or hypertension (BP > 95th percentile for age, sex, and height). Elevated liver transaminases were defined as ≥ 1.5 times the upper limit of normal (ALT: female, ≥75 and male, ≥ 97.5 U/L; AST: female, ≥ 69 and male, ≥97.5 U/L). During the run-in period, participants and an identified and consenting adult family member were given one-on-one standardized diabetes education, including diabetes pathophysiology, medication action, lifestyle guidelines, diabetes self-care, and goal-setting (9). The metformin dose was titrated as tolerated to a maximum dose of 1000 mg twice daily, other oral diabetes medications were discontinued, and insulin was tapered with the goal of discontinuation. Laboratory studies, anthropometrics, and BP measurements were repeated at subsequent run-in visits. In order to successfully complete the run-in period, participants were required to demonstrate ≥ 80% medication adherence for at least 6 wk, tolerate metformin at a dose of at least 500 mg twice daily, miss no more than two run-in visits, maintain a HbA1c of ≤ 8% (64 mM/M) for at least 2 months on metformin alone, and demonstrate mastery of basic diabetes education. The run-in period lasted from 2–6 months during which time participants had a minimum of 6 and maximum of 12 visits for mastery of diabetes education (9); the median time in run-in for all those screened was 2.4 months (25th and 75th percentiles = 2.0 and 3.0 months, respectively) (7). A total of 228 screened participants (24%) failed to meet criteria for randomization, and their characteristics have been previously described (7). The study protocol was approved by the institutional review board of Pediatric Diabetes 2015
Recently diagnosed youth with type 2 diabetes each participating institution. Parents of participants provided written informed consent, and all children and adolescents provided assent according to local guidelines.
Statistical analyses To describe characteristics of T2D in recently diagnosed youth in routine clinical care and before any TODAY interventions were undertaken (objective 1), all diabetes antibody-negative subjects screened for the TODAY study (n = 1092) were included. To describe the changes in subject characteristics during run-in, those who completed at least 8 wk of run-in were included (n = 814), regardless of whether they were ultimately randomized. For comparisons between race/ethnicity groups and medication groups, Kruskal–Wallis tests were used for continuous variables and chi-squared tests were used for categorical variables. Only non-Hispanic Whites, Blacks, and Hispanic Whites were included in the racial/ethnic comparisons, as subject numbers in other racial/ethnic groups were inadequate for a meaningful analysis. For adjusted comparisons, p values from the F-test are reported. McNemar’s test was used to compare the change in the proportion of participants with cardiometabolic risk factors from screening to the end of the run-in phase. Linear models were used to evaluate potential predictors of change in HbA1c and BMI z-score during the run-in period (sas proc glm, version 9.2, SAS Institute Inc., Cary, NC). The TODAY study was powered for the primary outcome only; the outcomes reported herein are considered exploratory. P-values 7.5% (58 mM/M) also decreased from 40.8% to 11.4% (p < 0.0001), and there were small, but statistically significant, improvements in BMI z-score (2A), total [−8.88 mg/dL (−0.23 mM/L), p < 0.0001] and LDL [−5.02 mg/dL (−0.13 mM/L), p < 0.0001] cholesterol, triglycerides [−9.73 mg/dL (−0.11 mM/L), p < 0.0001], systolic BP (−1.0 mm Hg, p = 0.039), and diastolic BP (−1.0 mm Hg, p = 0.002). Again, these improvements remained significant after removing the subjects that remained on insulin therapy at the
3
4 Median
Q1
64.4 35.6 13.6 12.5 45.3 25.7 2.7 60.0 39.6 60.0 21.9 36.8 26.7 17.7 91.3 91.3 8.2 65.4
149 137 495 281 30 655 432 655 239 402 292 193 997 997 90 714
%
703 389
N
1092 14 13 1047 2 1 1085 34.9 30.4 1085 2.4 2.1 1087 3.8 2.6 1087 6.9 6.0 1087 157.0 135.0 1087 107.0 73.0 1087 92.0 74.0 1087 39.0 33.0 1056 114.0 107.0 1056 68.0 62.0
N 16 6 39.9 2.6 5.2 8.9 179.0 156.0 111.0 46.0 122.0 74.0
Q3
Q1
155 52 141 47 89 82 44 183 183 24 150
38 22 101 39 7
129 78
N
74.9 25.1 68.1 22.7 43.0 39.6 21.3 88.4 88.4 11.6 72.5
18.4 10.6 48.8 18.8 3.4
62.3 37.7
%
207 14 13 201 2 1 207 34.4 30.4 207 2.3 2.0 207 4.1 2.8 207 6.3 5.8 207 162.0 137.0 207 124.0 85.0 207 96.0 74.0 207 37.0 31.0 201 115.5 106.5 201 68.5 62.0
N Median
White
16 5 39.2 2.6 5.4 7.6 194.0 207.0 116.0 43.0 124.5 75.5
Q3
211 184 220 89 151 48 79 385 385 10 254
40 60 155 133 9
270 127
N
397 379 390 390 395 395 395 395 395 395 381 381
N
Race/ethnicity Q1
Q3
N Median
Q1
Hispanic Q3
p-value*
53.1 46.3 55.4 22.4 38.0 12.1 19.9 97.0 97.0 2.5 64.0
10.1 15.1 39.0 33.5 2.3
68.0 32.0
%
223 153 241 103 125 133 51 334 334 42 251
48 45 185 93 6
224 153
N
59.2 40.6 63.9 27.3 33.2 35.3 13.5 88.6 88.6 11.1 66.6
12.7 11.9 49.1 24.7 1.6
59.4 40.6
%
0.1095
0.0052 0.2354 0.0590
