FEATURE
Management of Pediatric Patients with Type 1 Diabetes Steven Ghanny, MD; and Javier Aisenberg, MD
O
ne of the many consequences of the worldwide increase in obesity rates is increased rates of diabetes in both adults and children.1 In 2010, approximately 215,000 people younger than age 20 years in the United States had type 1 diabetes mellitus (T1D) or type 2 diabetes.2 In children and adolescents, T1D is the most frequently diagnosed type of diabetes.3 In the United States, the incidence of T1D in children younger than age 10 years was estimated to be 19.7 per
100,000 each year from 2002 to 2005,2 and this rate increases with age. Within the age group of 0 to 14 years, the highest incidence is found among children age 10 to 14 years, followed by those age 5 to 9 years, and then those age 0 to 4 years.4 METHODOLOGY A PubMed literature search was conducted to identify relevant peer-reviewed clinical and review articles published between January 2000 and May 2013 related to T1D in children. Search terms included
“type 1 diabetes,” “children,” “pediatric,” “insulin,” “insulin analogues,” “rapid-acting,” “long-acting,” “basal insulin,” “bolus insulin,” “aspart,” “lispro,” “glulisine,” “glargine,” “detemir,” “multiple daily injections or MDI,” and “external pumps, continuous subcutaneous insulin infusion, or CSII.” Case studies and editorials were excluded. Clinical study design, methodology, and clinical relevance were assessed. Additionally, the bibliographies of articles of interest were reviewed. A total of 37 articles were selected and analyzed.
Steven Ghanny, MD, is Research Director, Pediatric Endocrinology, The Molly Center for Children with Diabetes and Endocrine Disorders, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ. Javier Aisenberg, MD, is Chief, Pediatric Endocrinology, The Molly Center for Children with Diabetes and dren’s Hospital, Hackensack, NJ. Address correspondence to: Javier Aisenberg, MD, Chief, Pediatric Endocrinology, The Molly Center for Children with Diabetes and Endocrine Disorders, Joseph M. Sanzari Children’s Hospital, Department of Pediatrics - WFAN Building, Room 251, 30 Prospect Avenue, Hackensack, NJ 07601; email: [email protected]. Disclosure: Dr. Ghanny has no relevant financial relationships to disclose. Dr. Aisenberg has received financial compensation as a speaker for Novo Nordisk. doi: 10.3928/00904481-20140221-11
PEDIATRIC ANNALS 43:3 | MARCH 2014
© Shutterstock
Endocrine Disorders, Joseph M. Sanzari Chil-
Healio.com/Pediatrics | 115
FEATURE TABLE 1.
Basal Bolus Insulin Analogues in Children with Type 1 Diabetes Basal Analogue
Onset of Effect
Duration of Effect
Dosing Schedule
Peak
Delivery System(s)
2-4 hours
Up to 24 hours
Once daily; SC
No pronounced peak
Pen, vial
0.8-2 hours
Up to 24 hours
Once or twice daily; SC
Relatively flat
Pen, vial
Lispro12,15
5-15 minutes
4-6 hours
15 minutes preprandial; immediately 30-90 minutes postprandial; SC
MDI, CSII, pen
Aspart12,16
5-15 minutes
3-5 hours
Within 5-10 minutes preprandial; SC
30-90 minutes
MDI, CSII, pen
Glulisine17,18
15 minutes
5.3 hours
Within 15 minutes preprandial; within 20 minutes after starting a meal; SC
40-120 minutes
MDI, CSII, pen
Long-acting Glargine11,12 13,14
Detemir
Rapid-acting
CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; SC = subcutaneous.
TREATMENT CHALLENGES T1D in pediatric patients presents unique treatment challenges. For example, management of T1D must account for differences among children of various ages and adults, and insulin doses based only on body size are likely to be incorrect.5 This “one size fits all” strategy does not work well for pediatric patients because of the gamut of sizes and ages in patients with diabetes. However, health care providers must have generalized ways of managing pediatric patients with T1D in order to have systemization. Puberty, which may dictate the need for a higher dose of insulin due to hormonal changes,5 can impact the risk for diabetic complications. The “dawn phenomenon” — a steep rise in glucose levels in the early morning — has been reported in children younger than age 6 years.5,6 Achieving tight glycemic control while reducing the risk for hypoglycemia is challenging because young patients depend on caregivers (eg, parents, daycare providers, school nurses) at home and school for diabetes care.7 Furthermore, young patients have variable patterns regarding mealtime and exercise, and the general fear of hypoglycemia and its sequelae increases the risk of hyperglycemia. Thus, diabetes management should be adjusted to the age and developmental 116 | Healio.com/Pediatrics
stage of the patient, so involving and engaging parents and caregivers is crucial.5 Current clinical evidence supports the use of intensive diabetes management to slow the progression of vascular and neurologic complications of diabetes in adults and adolescents.8 Benefits of tighter glycemic control also have been observed in pre-adolescent patients.9 Therefore, guidelines from the American Diabetes Association (ADA) recommend glycated hemoglobin (HbA1c) levels of < 8.5% for toddlers and preschool children, < 8% for school-aged children, and < 7.5% for adolescents and young adults.8 However, the drawbacks of intensive insulin therapy can include hypoglycemia and weight gain.8 The risk for adverse neurologic effects of hypoglycemia may be greatest in very young children.8 Appropriate use of insulin pumps may assist in avoiding these complications. INSULIN ANALOGUES Basal-bolus insulin dosing provides the greatest level of glucose control7,9 and flexibility.10 For children or adolescents with T1D, the American Association of Clinical Endocrinologists (AACE) recommends basal-bolus insulin regimens delivered through either multiple daily injections (MDI) or external pumps (continuous subcutaneous
insulin infusion [CSII]).3 The potential benefits and drawbacks of each should be considered when choosing therapy for individual patients (Table 1).11-18 The long-acting (basal) insulin analogues, glargine and detemir,11,13 are approved for use in children with T1D either alone or in combination with prandial (rapid-acting) insulin analogues.19 The long-acting analogues have onsets of effect from ≤ 1 to 4 hours, but the effects can last up to 24 hours.20 The rapidacting analogues, lispro, aspart, and glulisine,15,16,18 are also approved for use in children with T1D and have an onset of action of 5 to 15 minutes, with a duration of effect of a few hours.20 The favorable pharmacologic attributes of rapid-acting analogues when administered in a basalbolus regimen led to superior or equal efficacy compared with regular human insulin in patients with T1D.21 Moreover, long-acting insulin analogues are injected once daily, are associated with a lower incidence of hypoglycemia,22-24 and are available in a pen device (as are the rapid-acting analogues), all of which are advantageous for pediatric patients. Clinical Studies of Rapid-Acting Analogues in Pediatric Patients A study of children with T1D younger than age 7 years compared CSII with
PEDIATRIC ANNALS 43:3 | MARCH 2014
FEATURE aspart, MDI with aspart (with intermediate-acting neutral protamine Hagedorn [NPH]), and MDI with recombinant human insulin (with NPH). The mean age of participants was 5.2, 5.4, and 5.7 years in the three groups, respectively. Efficacy was equivalent among the three groups, although caregivers reported greater satisfaction with treatment with aspart CSII.25 Similarly, a large noninferiority study (n = 572) of glulisine and lispro as part of a basal-bolus regimen in children and adolescents with T1D (mean age, 12.5 years) found comparable efficacy between the two rapidacting analogues.26 To reduce the number of daily injections, some practitioners may combine long- and rapid-acting insulin analogues into one injection,27 although this is not recommended by the manufacturers. A study of 11 adolescents (mean age, 15.1 years) with T1D demonstrated that coadministration of lispro with glargine reduced the early pharmacodynamic peak of lispro and caused a shift to the right in the glucose infusion rate curve.28 Similarly, a study of eight adolescents (mean age, 17.3 years) with T1D found that the co-administration of aspart with detemir as a single mixed injection diminished the early action of aspart and prolonged its time action profile.27 However, another study of adolescents (n = 14; mean age, 14.75 years) found equivalent effects of co-administration on blood glucose compared with separate administration.29 Clinical Studies of Long-Acting Analogues in Pediatric Patients One pharmacokinetic study of children and adolescents (mean age, 13 years) compared the profiles of detemir and glargine. In this study, detemir was associated with a more reproducible pharmacokinetic profile than glargine in children and adolescents.30 A subanalysis of patients with T1D age 2 to 5 years from a randomized,
PEDIATRIC ANNALS 43:3 | MARCH 2014
open-label trial comparing detemir with NPH was conducted.7 In this limited age group (n = 82; mean age, 4.4 years), detemir provided similar glycemic control compared with NPH. Another study in children age 2 to 16 years demonstrated that detemir was non-inferior to NPH after 52 weeks and was associated with a significantly lower risk of hypoglycemia and significantly lower weight standard deviation score compared with NPH.23
All of our patients whose initial treatment is insulin therapy are started on longacting insulin, along with a rapid-acting insulin. A study of 34 children and adolescents (mean age, 12.7 years) found that switching from NPH to glargine or detemir resulted in a significant reduction in HbA1c levels (P < .05 for both).31 Significant differences were not observed between the glargine and detemir groups, although the detemir group had a smaller increase in body mass index (BMI) compared with either the NPH or glargine groups (P < .05 for both). Because this study lasted for 6 months, the BMI results may have been influenced by growth during the study. Moreover, a large prospective study (n = 10,682) examined the use of glargine or detemir compared with NPH in children and adolescents with T1D (mean age, 15.0 and 13.5 years in the long-acting and NPH groups, respectively).32 In this study, the incidence of diabetic ketoacidosis was higher in patients using insulin glargine or detemir compared with those using NPH (6.6 ± 0.4 vs 3.6 ± 0.3; P < .001). An ultra-long-acting insulin analogue, degludec, has been approved for the treatment of adults with T1D in Europe, Japan, and Mexico. In the
United States, the Food and Drug Administration has requested more data to complete its review. No efficacy studies of degludec in children have been reported, although a study of degludec in children and adolescents with T1D is in progress.33 Another novel long-acting basal insulin in development consists of pegylated lispro, a large hydrodynamic molecule that slows absorption and reduces clearance, resulting in a prolonged duration of action.34 Likewise, no efficacy studies of pegylated lispro in children have been reported. AUTHORS’ CLINICAL EXPERIENCE IN DIABETES MANAGEMENT All of our patients whose initial treatment is insulin therapy are started on long-acting insulin, such as glargine or detemir, along with a rapid-acting insulin such as aspart, lispro, or glulisine. We begin treatment with insulin pens because they are easy to use for patients or caregivers. Ideally, we also have the patients take insulin before meals in order to achieve blood sugar control. Because glycemic control in the first year after diagnosis of diabetes is predictive of future glycemic control,35 we provide the most intensive patient education during this time. The decision to switch to CSII may be made after this time if the patient and family are well educated regarding diabetes care and are interested in switching. CSII can be initiated at any age, and it may particularly benefit younger children, as very small doses and dose changes can be implemented. Additionally, CSII eliminates multiple injections per day, as the insertion site only has to be changed every 2 to 3 days. However, use of CSII may be limited by the maturity and experience of the child and his or her caregivers.7,9 Also, because CSII does not provide a reserve of insulin, as does a basal insulin, risk for diabetic ketoacidosis is increased if insulin delivery is disrupted.10,19 However, some patients Healio.com/Pediatrics | 117
FEATURE TABLE 2.
Methods to Engage Caregivers of Children with Type 1 Diabetes • Emphasize a team approach (including a social worker or psychologist to identify needs of the family). • Provide parents with good access to the diabetes team. • Consider nurse-centered care to ensure provider continuity. • Use an endocrinology hospitalist (so the same attending physician covers all inpatient diabetes patients). • Encourage new patients/families to go to a diabetes education center. • Inform parents/patients about support groups for parents and children. • Share the responsibilities of total patient care with your team and encourage them to further their own knowledge of the condition.
elect to use a long-acting basal insulin in select cases, while using their insulin pumps for food and blood sugar boluses. Although advances in CSII have led to greater convenience and flexibility, these advances are associated with increased treatment complexity. Therefore, care and good clinical judgment must be taken in choosing between MDI and CSII.19 Once the patient has switched to CSII, we provide the patient and family with support through good rapport between staff and patient, preparatory classes, and follow-up between appointments to monitor blood glucose and determine whether changes in the insulin regimen are necessary. We teach our patients how to download their results from their devices and print out reports for review, and then reward them with small tokens such as gift cards to Target® and other stores. In this way, it incentivizes patients to download their device and gives them, as well their health care providers, useful data. This can then demonstrate to patients the importance of these data in their care 118 | Healio.com/Pediatrics
and may prompt them to continue to download. In addition, we recommend the use of a continuous glucose monitoring system. This device connects to the patient like an insulin pump, where a small, subcutaneous catheter is placed and provides continuous blood sugar measurements from the interstitial fluid. This valuable information helps both the patients and health care providers identify blood sugar trends and can also aid in adjustments to their insulin regimen. ENGAGING CAREGIVERS The chronic care model36 must be applied to both the patients with T1D and their caregivers. Engaging the caregivers is most important in the youngest patients, whereas management of older children and adolescents can include increased focus on the patient. However, caregivers are intermediaries between the pediatric endocrinology team and the patients, and they must achieve confidence in implementing recommended treatment strategies (Table 2). Treatment strategies consistent with the needs of the patient and the parents should be developed. A team approach should be implemented soon after diagnosis. This includes early psychosocial assessment of the family and involvement of a social worker or psychologist who can identify the needs of the family and transmit those needs to the team.3,8,10 In our practice, we have found that a small proportion of patients often make up a large percentage of diabetes re-admissions. Implementing the team approach is important in addressing the patients’ needs and psychosocial issues, and in breaking the cycle of inadequate treatment. Treatment of T1D in infants is focused on providing parents with immediate access to the diabetes team.10 Because toddlers cannot yet understand the need for glucose monitoring and insulin injections, they require consistent care and can benefit from a positive approach from parents. As children mature, the
responsibility for care shifts from the caregivers to the patient (the “emerging adulthood” stage).37 This stage requires patients, their families, and healthcare providers to find a balance between respecting the patient’s independence and providing oversight and support.8,10,37 Additionally, our clinic is nurse-centered to ensure provider continuity and achieve better diabetes care. We empower nurses by allowing them to “adopt” these patients and see them on their own under the health care provider’s supervision during certified diabetes educator visits. We also have extended this model to include an endocrinology hospitalist, such that the same attending physician covers all inpatient diabetes patients and helps to implement the best care possible. New patients are sent to a diabetes education center to begin their diabetes education, learn about insulin pumps, or just to review daily diabetic management. Support groups and other activities provided for our patients allow children to meet other children with diabetes and parents to meet other parents of children with diabetes. A transition clinic is available for the older adolescent patients with diabetes to transition them to adult endocrinologists. Also, an adult endocrinologist sees transitioning patients with us to develop a rapport with the patient and address issues that may occur in adult patients with diabetes. To engage the members of our team, we share the responsibilities of total patient care with nurses, nutritionists, and social workers. Therefore, the members of the team have a sense of responsibility for the well-being of their patients. We also allow, encourage, and support the members of the team to further explore diabetes care through conferences and other educational forums. UNDERSTANDING POOR DIABETES MANAGEMENT Many endocrinology healthcare providers contemplate why their patients
PEDIATRIC ANNALS 43:3 | MARCH 2014
FEATURE are nonadherent with their diabetes regimen. What makes them not take their insulin, check their blood sugars, or not do the other aspects of their diabetes care? In a meta-analysis of pediatric observational studies, it was found that only approximately 38% of patients on pump therapy achieved the ADA HbA1c goal when a sensor-augmented pump was used.38 The SEARCH for Diabetes in Youth Study demonstrated that in 2999 youths, only 44% met the ADA glycemic goals for their age.39 Elevated HbA1c levels and hyperglycemia are symptoms, and it is important to determine the root of these symptoms. Is it because we are not providing patients with adequate education to manage their diabetes? Could it be that they are not motivated to care? Is it lack of home supervision by parents or, more seriously, is it a mental health issue that we are not addressing? By finding out the root of the problem and addressing it, we can help patients to achieve better control of their diabetes. However, because this root can be multifaceted, it takes a team of nurses, doctors, social workers, and others to address these issues, and that is why a multidisciplinary approach to diabetes is key. Screening Screening is key to the proper care of patients with diabetes. Early detection of diabetes is important to avoid the co-morbidities of diabetes. In addition, proper diagnosis of diabetes is equally as important as early detection. For example, many studies have shown that maturity-onset diabetes of the young (MODY), or monogenic diabetes, has been erroneously diagnosed as T1D. The fundamental issue is that MODY, unlike T1D, is treated with oral medication and these patients tend to respond better to oral medications than to insulin. Whether this is from better adherence or better response, the end result is that these patients have improvement in their
PEDIATRIC ANNALS 43:3 | MARCH 2014
HbA1c level. In one study conducted by our group and a collaborating center, we found that we were able to diagnose MODY in patients whose original diagnosis was T1D, and then successfully switched these patients to oral medication. This patient group had near normalization of their HbA1c levels. This again illustrates the importance of screening in diabetes management and care. In addition, we perform an annual screening on all of our patients with diabetes to monitor the development of co-morbidities. This screening includes evaluation for other autoimmune diseases such as celiac disease, autoimmnune thyroiditis, and Addison’s disease, as well as screening for lipid levels and urine microalbumin. We also monitor blood pressure, and for those who are found to have elevated blood pressure on multiple visits, we have them perform ambulatory blood pressure monitoring. CONCLUSION Many challenges surround implementation of effective care in children with T1D that are not encountered with adult patients. Moreover, changes in the population, such as increasing rates of obesity, further complicate the diagnosis and treatment of T1D in children. However, evolving diagnostic and treatment options provide opportunities for improving and individualizing care. The favorable pharmacological attributes of insulin aspart, glulisine, and lispro, as well as several advantages of long-acting insulin analogues, including oncedaily injection of insulin glargine, lower incidence of hypoglycemia, and availability in a pen device, are attractive options for pediatric patients. In addition to advances in pharmacological therapy, diabetes education, CSII, CGMS technology, and caregiver involvement in the treatment of the youngest patient group are important aspects of disease management. Finally, additional studies
are needed to determine the efficacy and long-term effects of newer insulin analogues in young children with T1D. ACKNOWLEDGMENTS Jennifer Steeber, PhD, and Heba Costandy of MedVal Scientific Information Services, LLC, provided medical writing and editorial assistance, funding for which was provided by Novo Nordisk Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines.” REFERENCES 1. Zhang ZY, Wang MW. Obesity, a health burden of a global nature. Acta Pharmacologica Sinica. 2012;33:145-147. 2. Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011: national estimates and general information on diabetes and prediabetes in the United States, 2011. Available at: http://www.cdc.gov/diabetes/ pubs/pdf/ndfs_2011.pdf. Accessed February 21, 2014. 3. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53. 4. Soltesz G, Patterson CC, Dahlquist G; EURODIAB Study Group. Worldwide childhood type 1 diabetes incidence - what can we learn from epidemiology? Pediatr Diabetes. 2007;8(suppl 6):6-14. 5. Silverstein J, Klingensmith G, Copeland K, et al; American Diabetes Association. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186-212. 6. de Beaufort CE, Bruining GJ, Home PD, Houtzagers CM, van Strik R. Overnight metabolic profiles in very young insulin-dependent diabetic children. Eur J Pediatr. 1986;145(12):73-76. 7. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes. 2011;12(7):632-641. 8. American Diabetes Association. Standards of medical care in diabetes–2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 9. International Diabetes Federation. IDF/ISPAD 2011 Global Guideline for Diabetes in Childhood and Adolescence. Available at: http://
Healio.com/Pediatrics | 119
FEATURE www.ispad.org/resources/idfispad-2011-global-guideline-diabetes-childhood-and-adolescence. Access on February 21, 2014. 10. Gan MJ, Albanese-O’Neill A, Haller MJ. Type 1 diabetes: current concepts in epidemiology, pathophysiology, clinical care, and research. Curr Probl Pediatr Adolesc Health Care. 2012;42(10):269-291. 11. Lantus® (insulin glargine [rDNA origin] injection) [prescribing information]. Bridgewater, NJ: sanofi-aventis; 2010. 12. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174-183. 13. Levemir® (insulin detemir [rDNA origin] injection) [prescribing information]. Princeton, NJ: Novo Nordisk Inc; 2012. 14. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the longacting insulin analog detemir. Diabetes Care. 2005;28(5):1107-1112. 15. Humalog® (insulin lispro[rDNA origin] injection) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2011. 16. NovoLog® (insulin aspart [rDNA origin] injection) [prescribing information]. Princeton, NJ, Novo Nordisk Inc; 2011. 17. Levy P. Insulin analogs or premixed insulin analogs in combination with oral agents for treatment of type 2 diabetes. Med Gen Med. 2007;9(2):12. 18. Apidra® (insulin glulisine) [prescribing information]. Bridgewater, NJ: sanofi-aventis; 2009. 19. Moser EG, Morris AA, Garg SK. Emerging diabetes therapies and technologies. Diabetes Res Clin Pract. 2012;9791):16-26. 20. Griffin S. Insulin treatment of type 2 diabetes: considerations when converting from human insulin to insulin analogs. Ann Med. 2013;4592):129-140. 21. Reynolds NA, Wagstaff AJ. Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus. Drugs. 2004;64(17):1957-1974. 22. Robertson KJ, Schoenle E, Gucev Z, et al. Insulin detemir compared with NPH insulin in children and adolescents with type 1 diabetes. Diabet Med. 2007;24(1):27-34. 23. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial. Diabet Med.
120 | Healio.com/Pediatrics
2013;30(2):216-225. 24. Chase HP, Dixon B, Pearson J, et al. Reduced hypoglycemic episodes and improved glycemic control in children with type 1 diabetes using insulin glargine and neutral protamine Hagedorn insulin. J Pediatr. 2003;143(6):737-740. 25. Pankowska E, Nazim J, Szalecki M, Urban M. Equal metabolic control but superior caregiver treatment satisfaction with insulin aspart in preschool children. Diabetes Technol Ther. 2010;12(5):413-418. 26. Philotheou A, Arslanian S, Blatniczky L, et al. Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a basal-bolus iInsulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. Diabetes Technol Ther. 2011;13(3):327-334. 27. Cengiz E, Swan KL, Tamborlane WV, et al. The alteration of aspart insulin pharmacodynamics when mixed with detemir insulin. Diabetes Care. 2012;3594):690-692. 28. Cengiz E, Tamborlane WV, Martin-Fredericksen M, Dziura J, Weinzimer SA. Early pharmacodynamic and pharmacokinetic effects of mixing lispro with glargine insulin: results of glucose clamp studies in youth with type 1 diabetes. Diabetes Care. 2010;33(5):1009-1012. 29. Nguyen TM, Renukuntla VS, Heptulla RA. Mixing insulin aspart with detemir does not affect glucose excursion in children with type 1 diabetes mellitus. Diabetes Care. 2010;33(8):1750-1752. 30. Danne T, Datz N, Endahl L, et al. Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial. Pediatr Diabetes. 2008;9(6):554-560. 31. Dundar BN, Dundar N, Eren E. Comparison of the efficacy and safety of insulin glargine and insulin detemir with NPH insulin in children and adolescents with type 1 diabetes mellitus receiving intensive insulin therapy. J Clin Res Pediatr Endocrinol. 2009;1(4):181-187. 32. Karges B, Kapellen T, Neu A et al. Longacting insulin analogs and the risk of diabetic ketoacidosis in children and adolescents with type 1 diabetes: a prospective study of 10,682 patients from 271 institutions. Diabetes Care. 2010;33(5):1031-1033.
33. Clinicaltrials.gov. A Trial Investigating the Efficacy and Safety of Insulin Degludec in Children and Adolescents With Type 1 Diabetes Mellitus (BEGIN™). Available at: http:// www.clinicaltrials.gov/show/NCT01513473. Accessed February 21, 2014. 34. Bergenstal RM, Rosenstock J, Arakaki RF et al. A randomized, controlled study of once daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care. 2012;35(11):2140-2147. 35. Jackson C, Wernham EM, Elder CJ, Wright MP. Early glycaemic control is predictive of long-term control: a retrospective observational study. Pract Diabetes. 2013;30:16-18. 36. Warm EJ. Diabetes and the chronic care model: a review. Curr Diabetes Rev. 2007;3(4):219-225. 37. Peters A, Laffel L; American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: recommendations for transition from pediatric to adult diabetes care systems: a position statement of the American Diabetes Association, with representation by the American College of Osteopathic Family Physicians, the American Academy of Pediatrics, the American Association of Clinical Endocrinologists, the American Osteopathic Association, the Centers for Disease Control and Prevention, Children with Diabetes, The Endocrine Society, the International Society for Pediatric and Adolescent Diabetes, Juvenile Diabetes Research Foundation International, the National Diabetes Education Program, and the Pediatric Endocrine Society (formerly Lawson Wilkins Pediatric Endocrine Society). Diabetes Care. 2011;34(11):2477-2485. 38. Nørgaard K, Scaramuzza A, Bratina N et al; Interpret Study Group. Routine sensor-augmented pump therapy in type 1 diabetes: the INTERPRET Study. Diabetes Technol Ther. 2013;15(4):273-280. 39. Klingensmith, G. Pediatric HbA1c levels in 2010: Goals vs. what is being achieved. Available at: http://www. healio.com/endocrinology/diabetes/news/ p r i n t / e n d o c r i n e - t o d a y / % 7 B d 6 fa a 7 1 f 0223-4d02-992e-92b4d63aa795%7D/pediatric-hba1c-levels-in-2010-goals-vs-what-isbeing-achieved. Accessed February 21, 2014.
PEDIATRIC ANNALS 43:3 | MARCH 2014
ONLINE CE Healio.com tracks your progress and credits for you
The education you need. The subspecialty focus you want.
With so much online education available, it can be difficult to find exactly what you need. That’s why we’ve tailored our content specifically for you. At the INFECTIOUS DISEASES IN CHILDREN Education Lab at Healio.com, you’ll gain immediate access to interactive CE activities that are focused on your subspecialty. • Adolescent Medicine • Allergy, Asthma & Immunology • Dermatology • Developmental and Behavioral Medicine • Emerging Diseases • Gastrointestinal Conditions • General Pediatrics • Respiratory Infections • Vaccine-preventable Diseases
Your education is just a click away at Healio.com/Pediatrics/Education-Lab
HT_11-1144 HT_11-
Management of Pediatric Patients with Type 1 Diabetes Steven Ghanny, MD; and Javier Aisenberg, MD
O
ne of the many consequences of the worldwide increase in obesity rates is increased rates of diabetes in both adults and children.1 In 2010, approximately 215,000 people younger than age 20 years in the United States had type 1 diabetes mellitus (T1D) or type 2 diabetes.2 In children and adolescents, T1D is the most frequently diagnosed type of diabetes.3 In the United States, the incidence of T1D in children younger than age 10 years was estimated to be 19.7 per
100,000 each year from 2002 to 2005,2 and this rate increases with age. Within the age group of 0 to 14 years, the highest incidence is found among children age 10 to 14 years, followed by those age 5 to 9 years, and then those age 0 to 4 years.4 METHODOLOGY A PubMed literature search was conducted to identify relevant peer-reviewed clinical and review articles published between January 2000 and May 2013 related to T1D in children. Search terms included
“type 1 diabetes,” “children,” “pediatric,” “insulin,” “insulin analogues,” “rapid-acting,” “long-acting,” “basal insulin,” “bolus insulin,” “aspart,” “lispro,” “glulisine,” “glargine,” “detemir,” “multiple daily injections or MDI,” and “external pumps, continuous subcutaneous insulin infusion, or CSII.” Case studies and editorials were excluded. Clinical study design, methodology, and clinical relevance were assessed. Additionally, the bibliographies of articles of interest were reviewed. A total of 37 articles were selected and analyzed.
Steven Ghanny, MD, is Research Director, Pediatric Endocrinology, The Molly Center for Children with Diabetes and Endocrine Disorders, Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ. Javier Aisenberg, MD, is Chief, Pediatric Endocrinology, The Molly Center for Children with Diabetes and dren’s Hospital, Hackensack, NJ. Address correspondence to: Javier Aisenberg, MD, Chief, Pediatric Endocrinology, The Molly Center for Children with Diabetes and Endocrine Disorders, Joseph M. Sanzari Children’s Hospital, Department of Pediatrics - WFAN Building, Room 251, 30 Prospect Avenue, Hackensack, NJ 07601; email: [email protected]. Disclosure: Dr. Ghanny has no relevant financial relationships to disclose. Dr. Aisenberg has received financial compensation as a speaker for Novo Nordisk. doi: 10.3928/00904481-20140221-11
PEDIATRIC ANNALS 43:3 | MARCH 2014
© Shutterstock
Endocrine Disorders, Joseph M. Sanzari Chil-
Healio.com/Pediatrics | 115
FEATURE TABLE 1.
Basal Bolus Insulin Analogues in Children with Type 1 Diabetes Basal Analogue
Onset of Effect
Duration of Effect
Dosing Schedule
Peak
Delivery System(s)
2-4 hours
Up to 24 hours
Once daily; SC
No pronounced peak
Pen, vial
0.8-2 hours
Up to 24 hours
Once or twice daily; SC
Relatively flat
Pen, vial
Lispro12,15
5-15 minutes
4-6 hours
15 minutes preprandial; immediately 30-90 minutes postprandial; SC
MDI, CSII, pen
Aspart12,16
5-15 minutes
3-5 hours
Within 5-10 minutes preprandial; SC
30-90 minutes
MDI, CSII, pen
Glulisine17,18
15 minutes
5.3 hours
Within 15 minutes preprandial; within 20 minutes after starting a meal; SC
40-120 minutes
MDI, CSII, pen
Long-acting Glargine11,12 13,14
Detemir
Rapid-acting
CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; SC = subcutaneous.
TREATMENT CHALLENGES T1D in pediatric patients presents unique treatment challenges. For example, management of T1D must account for differences among children of various ages and adults, and insulin doses based only on body size are likely to be incorrect.5 This “one size fits all” strategy does not work well for pediatric patients because of the gamut of sizes and ages in patients with diabetes. However, health care providers must have generalized ways of managing pediatric patients with T1D in order to have systemization. Puberty, which may dictate the need for a higher dose of insulin due to hormonal changes,5 can impact the risk for diabetic complications. The “dawn phenomenon” — a steep rise in glucose levels in the early morning — has been reported in children younger than age 6 years.5,6 Achieving tight glycemic control while reducing the risk for hypoglycemia is challenging because young patients depend on caregivers (eg, parents, daycare providers, school nurses) at home and school for diabetes care.7 Furthermore, young patients have variable patterns regarding mealtime and exercise, and the general fear of hypoglycemia and its sequelae increases the risk of hyperglycemia. Thus, diabetes management should be adjusted to the age and developmental 116 | Healio.com/Pediatrics
stage of the patient, so involving and engaging parents and caregivers is crucial.5 Current clinical evidence supports the use of intensive diabetes management to slow the progression of vascular and neurologic complications of diabetes in adults and adolescents.8 Benefits of tighter glycemic control also have been observed in pre-adolescent patients.9 Therefore, guidelines from the American Diabetes Association (ADA) recommend glycated hemoglobin (HbA1c) levels of < 8.5% for toddlers and preschool children, < 8% for school-aged children, and < 7.5% for adolescents and young adults.8 However, the drawbacks of intensive insulin therapy can include hypoglycemia and weight gain.8 The risk for adverse neurologic effects of hypoglycemia may be greatest in very young children.8 Appropriate use of insulin pumps may assist in avoiding these complications. INSULIN ANALOGUES Basal-bolus insulin dosing provides the greatest level of glucose control7,9 and flexibility.10 For children or adolescents with T1D, the American Association of Clinical Endocrinologists (AACE) recommends basal-bolus insulin regimens delivered through either multiple daily injections (MDI) or external pumps (continuous subcutaneous
insulin infusion [CSII]).3 The potential benefits and drawbacks of each should be considered when choosing therapy for individual patients (Table 1).11-18 The long-acting (basal) insulin analogues, glargine and detemir,11,13 are approved for use in children with T1D either alone or in combination with prandial (rapid-acting) insulin analogues.19 The long-acting analogues have onsets of effect from ≤ 1 to 4 hours, but the effects can last up to 24 hours.20 The rapidacting analogues, lispro, aspart, and glulisine,15,16,18 are also approved for use in children with T1D and have an onset of action of 5 to 15 minutes, with a duration of effect of a few hours.20 The favorable pharmacologic attributes of rapid-acting analogues when administered in a basalbolus regimen led to superior or equal efficacy compared with regular human insulin in patients with T1D.21 Moreover, long-acting insulin analogues are injected once daily, are associated with a lower incidence of hypoglycemia,22-24 and are available in a pen device (as are the rapid-acting analogues), all of which are advantageous for pediatric patients. Clinical Studies of Rapid-Acting Analogues in Pediatric Patients A study of children with T1D younger than age 7 years compared CSII with
PEDIATRIC ANNALS 43:3 | MARCH 2014
FEATURE aspart, MDI with aspart (with intermediate-acting neutral protamine Hagedorn [NPH]), and MDI with recombinant human insulin (with NPH). The mean age of participants was 5.2, 5.4, and 5.7 years in the three groups, respectively. Efficacy was equivalent among the three groups, although caregivers reported greater satisfaction with treatment with aspart CSII.25 Similarly, a large noninferiority study (n = 572) of glulisine and lispro as part of a basal-bolus regimen in children and adolescents with T1D (mean age, 12.5 years) found comparable efficacy between the two rapidacting analogues.26 To reduce the number of daily injections, some practitioners may combine long- and rapid-acting insulin analogues into one injection,27 although this is not recommended by the manufacturers. A study of 11 adolescents (mean age, 15.1 years) with T1D demonstrated that coadministration of lispro with glargine reduced the early pharmacodynamic peak of lispro and caused a shift to the right in the glucose infusion rate curve.28 Similarly, a study of eight adolescents (mean age, 17.3 years) with T1D found that the co-administration of aspart with detemir as a single mixed injection diminished the early action of aspart and prolonged its time action profile.27 However, another study of adolescents (n = 14; mean age, 14.75 years) found equivalent effects of co-administration on blood glucose compared with separate administration.29 Clinical Studies of Long-Acting Analogues in Pediatric Patients One pharmacokinetic study of children and adolescents (mean age, 13 years) compared the profiles of detemir and glargine. In this study, detemir was associated with a more reproducible pharmacokinetic profile than glargine in children and adolescents.30 A subanalysis of patients with T1D age 2 to 5 years from a randomized,
PEDIATRIC ANNALS 43:3 | MARCH 2014
open-label trial comparing detemir with NPH was conducted.7 In this limited age group (n = 82; mean age, 4.4 years), detemir provided similar glycemic control compared with NPH. Another study in children age 2 to 16 years demonstrated that detemir was non-inferior to NPH after 52 weeks and was associated with a significantly lower risk of hypoglycemia and significantly lower weight standard deviation score compared with NPH.23
All of our patients whose initial treatment is insulin therapy are started on longacting insulin, along with a rapid-acting insulin. A study of 34 children and adolescents (mean age, 12.7 years) found that switching from NPH to glargine or detemir resulted in a significant reduction in HbA1c levels (P < .05 for both).31 Significant differences were not observed between the glargine and detemir groups, although the detemir group had a smaller increase in body mass index (BMI) compared with either the NPH or glargine groups (P < .05 for both). Because this study lasted for 6 months, the BMI results may have been influenced by growth during the study. Moreover, a large prospective study (n = 10,682) examined the use of glargine or detemir compared with NPH in children and adolescents with T1D (mean age, 15.0 and 13.5 years in the long-acting and NPH groups, respectively).32 In this study, the incidence of diabetic ketoacidosis was higher in patients using insulin glargine or detemir compared with those using NPH (6.6 ± 0.4 vs 3.6 ± 0.3; P < .001). An ultra-long-acting insulin analogue, degludec, has been approved for the treatment of adults with T1D in Europe, Japan, and Mexico. In the
United States, the Food and Drug Administration has requested more data to complete its review. No efficacy studies of degludec in children have been reported, although a study of degludec in children and adolescents with T1D is in progress.33 Another novel long-acting basal insulin in development consists of pegylated lispro, a large hydrodynamic molecule that slows absorption and reduces clearance, resulting in a prolonged duration of action.34 Likewise, no efficacy studies of pegylated lispro in children have been reported. AUTHORS’ CLINICAL EXPERIENCE IN DIABETES MANAGEMENT All of our patients whose initial treatment is insulin therapy are started on long-acting insulin, such as glargine or detemir, along with a rapid-acting insulin such as aspart, lispro, or glulisine. We begin treatment with insulin pens because they are easy to use for patients or caregivers. Ideally, we also have the patients take insulin before meals in order to achieve blood sugar control. Because glycemic control in the first year after diagnosis of diabetes is predictive of future glycemic control,35 we provide the most intensive patient education during this time. The decision to switch to CSII may be made after this time if the patient and family are well educated regarding diabetes care and are interested in switching. CSII can be initiated at any age, and it may particularly benefit younger children, as very small doses and dose changes can be implemented. Additionally, CSII eliminates multiple injections per day, as the insertion site only has to be changed every 2 to 3 days. However, use of CSII may be limited by the maturity and experience of the child and his or her caregivers.7,9 Also, because CSII does not provide a reserve of insulin, as does a basal insulin, risk for diabetic ketoacidosis is increased if insulin delivery is disrupted.10,19 However, some patients Healio.com/Pediatrics | 117
FEATURE TABLE 2.
Methods to Engage Caregivers of Children with Type 1 Diabetes • Emphasize a team approach (including a social worker or psychologist to identify needs of the family). • Provide parents with good access to the diabetes team. • Consider nurse-centered care to ensure provider continuity. • Use an endocrinology hospitalist (so the same attending physician covers all inpatient diabetes patients). • Encourage new patients/families to go to a diabetes education center. • Inform parents/patients about support groups for parents and children. • Share the responsibilities of total patient care with your team and encourage them to further their own knowledge of the condition.
elect to use a long-acting basal insulin in select cases, while using their insulin pumps for food and blood sugar boluses. Although advances in CSII have led to greater convenience and flexibility, these advances are associated with increased treatment complexity. Therefore, care and good clinical judgment must be taken in choosing between MDI and CSII.19 Once the patient has switched to CSII, we provide the patient and family with support through good rapport between staff and patient, preparatory classes, and follow-up between appointments to monitor blood glucose and determine whether changes in the insulin regimen are necessary. We teach our patients how to download their results from their devices and print out reports for review, and then reward them with small tokens such as gift cards to Target® and other stores. In this way, it incentivizes patients to download their device and gives them, as well their health care providers, useful data. This can then demonstrate to patients the importance of these data in their care 118 | Healio.com/Pediatrics
and may prompt them to continue to download. In addition, we recommend the use of a continuous glucose monitoring system. This device connects to the patient like an insulin pump, where a small, subcutaneous catheter is placed and provides continuous blood sugar measurements from the interstitial fluid. This valuable information helps both the patients and health care providers identify blood sugar trends and can also aid in adjustments to their insulin regimen. ENGAGING CAREGIVERS The chronic care model36 must be applied to both the patients with T1D and their caregivers. Engaging the caregivers is most important in the youngest patients, whereas management of older children and adolescents can include increased focus on the patient. However, caregivers are intermediaries between the pediatric endocrinology team and the patients, and they must achieve confidence in implementing recommended treatment strategies (Table 2). Treatment strategies consistent with the needs of the patient and the parents should be developed. A team approach should be implemented soon after diagnosis. This includes early psychosocial assessment of the family and involvement of a social worker or psychologist who can identify the needs of the family and transmit those needs to the team.3,8,10 In our practice, we have found that a small proportion of patients often make up a large percentage of diabetes re-admissions. Implementing the team approach is important in addressing the patients’ needs and psychosocial issues, and in breaking the cycle of inadequate treatment. Treatment of T1D in infants is focused on providing parents with immediate access to the diabetes team.10 Because toddlers cannot yet understand the need for glucose monitoring and insulin injections, they require consistent care and can benefit from a positive approach from parents. As children mature, the
responsibility for care shifts from the caregivers to the patient (the “emerging adulthood” stage).37 This stage requires patients, their families, and healthcare providers to find a balance between respecting the patient’s independence and providing oversight and support.8,10,37 Additionally, our clinic is nurse-centered to ensure provider continuity and achieve better diabetes care. We empower nurses by allowing them to “adopt” these patients and see them on their own under the health care provider’s supervision during certified diabetes educator visits. We also have extended this model to include an endocrinology hospitalist, such that the same attending physician covers all inpatient diabetes patients and helps to implement the best care possible. New patients are sent to a diabetes education center to begin their diabetes education, learn about insulin pumps, or just to review daily diabetic management. Support groups and other activities provided for our patients allow children to meet other children with diabetes and parents to meet other parents of children with diabetes. A transition clinic is available for the older adolescent patients with diabetes to transition them to adult endocrinologists. Also, an adult endocrinologist sees transitioning patients with us to develop a rapport with the patient and address issues that may occur in adult patients with diabetes. To engage the members of our team, we share the responsibilities of total patient care with nurses, nutritionists, and social workers. Therefore, the members of the team have a sense of responsibility for the well-being of their patients. We also allow, encourage, and support the members of the team to further explore diabetes care through conferences and other educational forums. UNDERSTANDING POOR DIABETES MANAGEMENT Many endocrinology healthcare providers contemplate why their patients
PEDIATRIC ANNALS 43:3 | MARCH 2014
FEATURE are nonadherent with their diabetes regimen. What makes them not take their insulin, check their blood sugars, or not do the other aspects of their diabetes care? In a meta-analysis of pediatric observational studies, it was found that only approximately 38% of patients on pump therapy achieved the ADA HbA1c goal when a sensor-augmented pump was used.38 The SEARCH for Diabetes in Youth Study demonstrated that in 2999 youths, only 44% met the ADA glycemic goals for their age.39 Elevated HbA1c levels and hyperglycemia are symptoms, and it is important to determine the root of these symptoms. Is it because we are not providing patients with adequate education to manage their diabetes? Could it be that they are not motivated to care? Is it lack of home supervision by parents or, more seriously, is it a mental health issue that we are not addressing? By finding out the root of the problem and addressing it, we can help patients to achieve better control of their diabetes. However, because this root can be multifaceted, it takes a team of nurses, doctors, social workers, and others to address these issues, and that is why a multidisciplinary approach to diabetes is key. Screening Screening is key to the proper care of patients with diabetes. Early detection of diabetes is important to avoid the co-morbidities of diabetes. In addition, proper diagnosis of diabetes is equally as important as early detection. For example, many studies have shown that maturity-onset diabetes of the young (MODY), or monogenic diabetes, has been erroneously diagnosed as T1D. The fundamental issue is that MODY, unlike T1D, is treated with oral medication and these patients tend to respond better to oral medications than to insulin. Whether this is from better adherence or better response, the end result is that these patients have improvement in their
PEDIATRIC ANNALS 43:3 | MARCH 2014
HbA1c level. In one study conducted by our group and a collaborating center, we found that we were able to diagnose MODY in patients whose original diagnosis was T1D, and then successfully switched these patients to oral medication. This patient group had near normalization of their HbA1c levels. This again illustrates the importance of screening in diabetes management and care. In addition, we perform an annual screening on all of our patients with diabetes to monitor the development of co-morbidities. This screening includes evaluation for other autoimmune diseases such as celiac disease, autoimmnune thyroiditis, and Addison’s disease, as well as screening for lipid levels and urine microalbumin. We also monitor blood pressure, and for those who are found to have elevated blood pressure on multiple visits, we have them perform ambulatory blood pressure monitoring. CONCLUSION Many challenges surround implementation of effective care in children with T1D that are not encountered with adult patients. Moreover, changes in the population, such as increasing rates of obesity, further complicate the diagnosis and treatment of T1D in children. However, evolving diagnostic and treatment options provide opportunities for improving and individualizing care. The favorable pharmacological attributes of insulin aspart, glulisine, and lispro, as well as several advantages of long-acting insulin analogues, including oncedaily injection of insulin glargine, lower incidence of hypoglycemia, and availability in a pen device, are attractive options for pediatric patients. In addition to advances in pharmacological therapy, diabetes education, CSII, CGMS technology, and caregiver involvement in the treatment of the youngest patient group are important aspects of disease management. Finally, additional studies
are needed to determine the efficacy and long-term effects of newer insulin analogues in young children with T1D. ACKNOWLEDGMENTS Jennifer Steeber, PhD, and Heba Costandy of MedVal Scientific Information Services, LLC, provided medical writing and editorial assistance, funding for which was provided by Novo Nordisk Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines.” REFERENCES 1. Zhang ZY, Wang MW. Obesity, a health burden of a global nature. Acta Pharmacologica Sinica. 2012;33:145-147. 2. Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011: national estimates and general information on diabetes and prediabetes in the United States, 2011. Available at: http://www.cdc.gov/diabetes/ pubs/pdf/ndfs_2011.pdf. Accessed February 21, 2014. 3. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53. 4. Soltesz G, Patterson CC, Dahlquist G; EURODIAB Study Group. Worldwide childhood type 1 diabetes incidence - what can we learn from epidemiology? Pediatr Diabetes. 2007;8(suppl 6):6-14. 5. Silverstein J, Klingensmith G, Copeland K, et al; American Diabetes Association. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186-212. 6. de Beaufort CE, Bruining GJ, Home PD, Houtzagers CM, van Strik R. Overnight metabolic profiles in very young insulin-dependent diabetic children. Eur J Pediatr. 1986;145(12):73-76. 7. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes. 2011;12(7):632-641. 8. American Diabetes Association. Standards of medical care in diabetes–2013. Diabetes Care. 2013;36(suppl 1):S11-S66. 9. International Diabetes Federation. IDF/ISPAD 2011 Global Guideline for Diabetes in Childhood and Adolescence. Available at: http://
Healio.com/Pediatrics | 119
FEATURE www.ispad.org/resources/idfispad-2011-global-guideline-diabetes-childhood-and-adolescence. Access on February 21, 2014. 10. Gan MJ, Albanese-O’Neill A, Haller MJ. Type 1 diabetes: current concepts in epidemiology, pathophysiology, clinical care, and research. Curr Probl Pediatr Adolesc Health Care. 2012;42(10):269-291. 11. Lantus® (insulin glargine [rDNA origin] injection) [prescribing information]. Bridgewater, NJ: sanofi-aventis; 2010. 12. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352(2):174-183. 13. Levemir® (insulin detemir [rDNA origin] injection) [prescribing information]. Princeton, NJ: Novo Nordisk Inc; 2012. 14. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the longacting insulin analog detemir. Diabetes Care. 2005;28(5):1107-1112. 15. Humalog® (insulin lispro[rDNA origin] injection) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2011. 16. NovoLog® (insulin aspart [rDNA origin] injection) [prescribing information]. Princeton, NJ, Novo Nordisk Inc; 2011. 17. Levy P. Insulin analogs or premixed insulin analogs in combination with oral agents for treatment of type 2 diabetes. Med Gen Med. 2007;9(2):12. 18. Apidra® (insulin glulisine) [prescribing information]. Bridgewater, NJ: sanofi-aventis; 2009. 19. Moser EG, Morris AA, Garg SK. Emerging diabetes therapies and technologies. Diabetes Res Clin Pract. 2012;9791):16-26. 20. Griffin S. Insulin treatment of type 2 diabetes: considerations when converting from human insulin to insulin analogs. Ann Med. 2013;4592):129-140. 21. Reynolds NA, Wagstaff AJ. Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus. Drugs. 2004;64(17):1957-1974. 22. Robertson KJ, Schoenle E, Gucev Z, et al. Insulin detemir compared with NPH insulin in children and adolescents with type 1 diabetes. Diabet Med. 2007;24(1):27-34. 23. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial. Diabet Med.
120 | Healio.com/Pediatrics
2013;30(2):216-225. 24. Chase HP, Dixon B, Pearson J, et al. Reduced hypoglycemic episodes and improved glycemic control in children with type 1 diabetes using insulin glargine and neutral protamine Hagedorn insulin. J Pediatr. 2003;143(6):737-740. 25. Pankowska E, Nazim J, Szalecki M, Urban M. Equal metabolic control but superior caregiver treatment satisfaction with insulin aspart in preschool children. Diabetes Technol Ther. 2010;12(5):413-418. 26. Philotheou A, Arslanian S, Blatniczky L, et al. Comparable efficacy and safety of insulin glulisine and insulin lispro when given as part of a basal-bolus iInsulin regimen in a 26-week trial in pediatric patients with type 1 diabetes. Diabetes Technol Ther. 2011;13(3):327-334. 27. Cengiz E, Swan KL, Tamborlane WV, et al. The alteration of aspart insulin pharmacodynamics when mixed with detemir insulin. Diabetes Care. 2012;3594):690-692. 28. Cengiz E, Tamborlane WV, Martin-Fredericksen M, Dziura J, Weinzimer SA. Early pharmacodynamic and pharmacokinetic effects of mixing lispro with glargine insulin: results of glucose clamp studies in youth with type 1 diabetes. Diabetes Care. 2010;33(5):1009-1012. 29. Nguyen TM, Renukuntla VS, Heptulla RA. Mixing insulin aspart with detemir does not affect glucose excursion in children with type 1 diabetes mellitus. Diabetes Care. 2010;33(8):1750-1752. 30. Danne T, Datz N, Endahl L, et al. Insulin detemir is characterized by a more reproducible pharmacokinetic profile than insulin glargine in children and adolescents with type 1 diabetes: results from a randomized, double-blind, controlled trial. Pediatr Diabetes. 2008;9(6):554-560. 31. Dundar BN, Dundar N, Eren E. Comparison of the efficacy and safety of insulin glargine and insulin detemir with NPH insulin in children and adolescents with type 1 diabetes mellitus receiving intensive insulin therapy. J Clin Res Pediatr Endocrinol. 2009;1(4):181-187. 32. Karges B, Kapellen T, Neu A et al. Longacting insulin analogs and the risk of diabetic ketoacidosis in children and adolescents with type 1 diabetes: a prospective study of 10,682 patients from 271 institutions. Diabetes Care. 2010;33(5):1031-1033.
33. Clinicaltrials.gov. A Trial Investigating the Efficacy and Safety of Insulin Degludec in Children and Adolescents With Type 1 Diabetes Mellitus (BEGIN™). Available at: http:// www.clinicaltrials.gov/show/NCT01513473. Accessed February 21, 2014. 34. Bergenstal RM, Rosenstock J, Arakaki RF et al. A randomized, controlled study of once daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care. 2012;35(11):2140-2147. 35. Jackson C, Wernham EM, Elder CJ, Wright MP. Early glycaemic control is predictive of long-term control: a retrospective observational study. Pract Diabetes. 2013;30:16-18. 36. Warm EJ. Diabetes and the chronic care model: a review. Curr Diabetes Rev. 2007;3(4):219-225. 37. Peters A, Laffel L; American Diabetes Association Transitions Working Group. Diabetes care for emerging adults: recommendations for transition from pediatric to adult diabetes care systems: a position statement of the American Diabetes Association, with representation by the American College of Osteopathic Family Physicians, the American Academy of Pediatrics, the American Association of Clinical Endocrinologists, the American Osteopathic Association, the Centers for Disease Control and Prevention, Children with Diabetes, The Endocrine Society, the International Society for Pediatric and Adolescent Diabetes, Juvenile Diabetes Research Foundation International, the National Diabetes Education Program, and the Pediatric Endocrine Society (formerly Lawson Wilkins Pediatric Endocrine Society). Diabetes Care. 2011;34(11):2477-2485. 38. Nørgaard K, Scaramuzza A, Bratina N et al; Interpret Study Group. Routine sensor-augmented pump therapy in type 1 diabetes: the INTERPRET Study. Diabetes Technol Ther. 2013;15(4):273-280. 39. Klingensmith, G. Pediatric HbA1c levels in 2010: Goals vs. what is being achieved. Available at: http://www. healio.com/endocrinology/diabetes/news/ p r i n t / e n d o c r i n e - t o d a y / % 7 B d 6 fa a 7 1 f 0223-4d02-992e-92b4d63aa795%7D/pediatric-hba1c-levels-in-2010-goals-vs-what-isbeing-achieved. Accessed February 21, 2014.
PEDIATRIC ANNALS 43:3 | MARCH 2014
ONLINE CE Healio.com tracks your progress and credits for you
The education you need. The subspecialty focus you want.
With so much online education available, it can be difficult to find exactly what you need. That’s why we’ve tailored our content specifically for you. At the INFECTIOUS DISEASES IN CHILDREN Education Lab at Healio.com, you’ll gain immediate access to interactive CE activities that are focused on your subspecialty. • Adolescent Medicine • Allergy, Asthma & Immunology • Dermatology • Developmental and Behavioral Medicine • Emerging Diseases • Gastrointestinal Conditions • General Pediatrics • Respiratory Infections • Vaccine-preventable Diseases
Your education is just a click away at Healio.com/Pediatrics/Education-Lab
HT_11-1144 HT_11-
