2026 Diabetes Care Volume 41, September 2018

Type 1 Diabetes in Children and Jane L. Chiang,1 David M. Maahs,2 Katharine C. Garvey,3 Korey K. Hood,2 Adolescents: A Position Statement Lori M. Laffel,4 Stuart A. Weinzimer,5 Joseph I. Wolfsdorf,3 and Desmond Schatz6 by the American Diabetes Association

Diabetes Care 2018;41:2026–2044 | https://doi.org/10.2337/dci18-0023

Since the American Diabetes Association (ADA) published the Position Statement “Care of Children and Adolescents With Type 1 Diabetes” (1) in 2005, innovations have transformed the landscape and management of type 1 diabetes: novel autoanti- bodies, sophisticated devices for delivering insulin and measuring glucose, and diabetes registries. However, strategies to prevent or delay type 1 diabetes in youth remain elusive, and meanwhile the number of affected children continues to grow. The SEARCH for Diabetes in Youth (SEARCH) study found a 21.1% rise in the prevalence of type 1 diabetes from 2001 to 2009 in youth aged 0 through 19 years, with increases observed in all sex, age, and race/ethnic subgroups except those with the lowest prevalence (0–4 years old and American Indians) (2). Incidence has also increased; the adjusted risk for developing type 1 diabetes increased 1.4% annually between POSITION STATEMENT 2002 and 2012, with significant increases in all age-groups except those 0–4 years old (3). One theme of this Position Statement is that “children are not little adults”d pediatric-onset diabetes is different from adult diabetes because of its distinct epidemiology, pathophysiology, developmental considerations, and response to ther- apy (4,5). Diabetes management for children must not be extrapolated from adult diabetes care. In caring for children and adolescents, clinicians need to be mindful of the child’s evolving developmental stages and must adapt care to the child’s needs and circumstances. Timely anticipatory guidance and care coordination will enable a seamless child/adolescent/young adult transition for both the developing patient and his or her family. Although the ADA stopped developing new position statements in 2018 (6), this Position Statement was developed under the 2017 criteria (7) and provides rec- 1McKinsey & Company and Diasome Pharma- ommendations for current standards of care for youth (children and adolescents) ceuticals, Inc., Palo Alto, CA 2Department of Pediatrics, Stanford University with type 1 diabetes. It is not intended to be an exhaustive compendium on all aspects School of Medicine, Stanford, CA of disease management, nor does it discuss type 2 diabetes in youth, which is the 3Division of Endocrinology, Boston Children’s subject of an ADA Position Statement currently under review. While adult clinical trials Hospital, Department of Pediatrics, Harvard produce robust evidence that has advanced care and improved outcomes (8), pedi- Medical School, Boston, MA 4 atric clinical trials remain scarce. Therefore, the majority of pediatric recommenda- Joslin Diabetes Center, Harvard Medical School, Boston, MA tions are not based on large, randomized clinical trials (evidence level A) but rely on 5Pediatric Endocrinology & Diabetes, Yale School supportive evidence from cohort/registry studies (B or C) or expert consensus/clinical of Medicine, New Haven, CT experience (E) (Table 1). Please refer to the ADA’s “Standards of Medical Care in 6Division of Endocrinology, Department of Pedi- Diabetes” for updates to these recommendations (professional.diabetes.org/SOC). atrics, University of Florida, Gainesville, FL Corresponding author: Desmond Schatz, schatz@ ufl.edu. DIAGNOSIS This position statement was reviewed and ap- Recommendations proved by the American Diabetes Association c Diagnosis of type 1 diabetes should be pursued expeditiously. E Professional Practice Committee in February 2018 and ratified by the American Diabetes c A pediatric endocrinologist should be consulted before making a diagnosis of Association Board of Directors in April 2018. type 1 diabetes when isolated glycosuria or hyperglycemia is discovered in the C © 2018 by the American Diabetes Association. setting of acute illness and in the absence of classic symptoms. Readers may use this article as long as the work c Distinguishing between type 1 diabetes, type 2 diabetes, monogenic diabetes, is properly cited, the use is educational and not and other forms of diabetes is based on history, patient characteristics, and for profit, and the work is not altered. More infor- laboratory tests, including an islet autoantibody panel. B mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Chiang and Associates 2027

Table 1—ADA evidence-grading system for “Standards of Medical Care in Diabetes” Level of evidence Description A Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered, including c Evidence from a well-conducted multicenter trial c Evidence from a meta-analysis that incorporated quality ratings in the analysis Compelling nonexperimental evidence, i.e., “all or none” rule developed by the Centre for Evidence-Based Medicine at the University of Oxford Supportive evidence from well-conducted randomized controlled trials that are adequately powered, including c Evidence from a well-conducted trial at one or more institutions c Evidence from a meta-analysis that incorporated quality ratings in the analysis B Supportive evidence from well-conducted cohort studies c Evidence from a well-conducted prospective cohort study or registry c Evidence from a well-conducted meta-analysis of cohort studies Supportive evidence from a well-conducted case-control study C Supportive evidence from poorly controlled or uncontrolled studies c Evidence from randomized clinical trials with one or more major or three or more minor methodological flaws that could invalidate the results c Evidence from observational studies with high potential for bias (such as case series with comparison with historical controls) c Evidence from case series or case reports Conflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience

Type 1 Staging provide a framework for an optimized of stage 3 diabetes obvious. Because a Prospective longitudinal studies of in- benefit/risk ratio that will impact regulatory low renal glucose threshold may cause dividuals at risk for developing type 1 approval, reimbursement, and adoption of glycosuria without hyperglycemia or diabetes have demonstrated that the interventions in the early stages of type 1 ketonuria, an elevated PG concentration disease is a continuum that progresses diabetes to prevent symptomatic disease. must be documented in a laboratory to sequentially at variable but predictable Inpatientswithclassicsymptoms, mea- diagnose diabetes. The ADA’s criteria for rates through distinct stages before the surement of blood glucose is sufficient to the diagnosis of stage 3 diabetes are onset of symptoms. According to a new diagnose diabetes (symptoms of hypergly- shown in Table 3. Blood glucose rather staging classification system, type 1 di- cemia or hyperglycemic crisis plus a ran- than A1C should be used to diagnose abetes develops in three stages (Table 2). dom plasma glucose [PG] $200 mg/dL acute onset of type 1 diabetes in indi- Stage 1 is defined as the presence of [11.1 mmol/L]). Classic symptoms, typi- viduals with symptoms of hyperglyce- b-cell autoimmunity as evidenced by cally occurring for several days to a few mia (9). Clinical diagnostic criteria are the two or more islet autoantibodies with weeks prior to diagnosis, may include same for type 1 and type 2 diabetes. normoglycemia and is presymptomatic. polyuria, polydipsia, weight loss, polypha- Because the metabolic state of un- Stage 2 is the presence of b-cell auto- gia, fatigue, and blurred vision from lens treated children with type 1 diabetes immunity with dysglycemia and is pre- swelling caused by the osmotic effects of can deteriorate rapidly, a definitive diag- symptomatic. Onset of symptomatic chronic hyperglycemia (9). Perineal can- nosis should be made immediately. De- disease resulting from insulin deficiency didiasis is a common symptom in young lays in diagnosis and initiation of medical in children with type 1 diabetes occurs at children and girls (10). Approximately treatment, including insulin replacement stage 3. Adoption of this staging classi- one-third of cases present with diabetic therapy (see below), must be avoided. A fication provides a standardized taxon- ketoacidosis (DKA) and, unfortunately, glucose tolerance test is seldom required omy for type 1 diabetes and may aid the the numbers are increasing (11). The except in atypical cases or very early in development of therapies and the design characteristic biochemical featuresd the disease when PG values may be of clinical trials to prevent symptomatic hyperglycemia, glucosuria, ketonemia, normal or only mildly abnormal and disease, promote precision medicine, and and ketonuriadusually make the diagnosis the diagnosis may be uncertain.

Table 2—Staging of type 1 diabetes Stage 1 Stage 2 Stage 3 Stage c Autoimmunity c Autoimmunity c New-onset hyperglycemia c Normoglycemia c Dysglycemia c Symptomatic c Presymptomatic c Presymptomatic Diagnostic criteria c $2 autoantibodies c $2 autoantibodies c Clinical symptoms c No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria c FPG 100–125 mg/dL (5.6–6.9 mmol/L) c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L) c A1C 5.7–6.4% (39–47 mmol/mol) or $10% increase in A1C IFG, impaired fasting glucose; IGT, impaired glucose tolerance. 2028 Position Statement Diabetes Care Volume 41, September 2018

Table 3—Criteria for the diagnosis of diabetes (9) FPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.* OR 2-h PG $200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 1.75 g/kg up to a maximum of 75 g anhydrous glucose dissolved in water.* OR A1C $6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified† and standardized to the DCCT assay.* OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random PG $200 mg/dL (11.1 mmol/L). Definitions are based on venous PG levels. WHO, World Health Organization. *In the absence of unequivocal hyperglycemia, the first three criteria should be confirmed by repeat testing. †See www.ngsp.org.

Screening and Testing for Type 1 should be used to diagnose type 1 di- prepubertal child with classic symptoms Diabetes in Asymptomatic Children abetes in children and adolescents (15). and without a family history suggestive Screening for type 1 diabetes in asymp- The studies that formed the basis for of a monogenic form of diabetes. How- tomatic children with a panel of auto- recommending A1C for the diagnosis of ever, observational studies show increas- antibodies is currently recommended diabetes included only adults, primarily ing numbers of overweight and obese only in the setting of research studies in those with type 2 diabetes. Also, A1C children and adolescents with type 1 di- first-degree family members of a proband alone may be a poor diagnostic tool for abetes (20), similar to the general pop- with type 1 diabetes (9). The incidental dis- prediabetes and type 2 diabetes in obese ulation, and recent data from the T1D covery of hyperglycemia without classic children and adolescents (16). In a cohort Exchange clinic registry indicate that symptoms does not necessarily indicate of newly diagnosed children and adoles- in more than 11,000 U.S. children and new-onset diabetes, especially in young cents with type 1 diabetes, all had an A1C adolescents with type 1 diabetes, 24% children with an acute illness who may value .6.6% (measured with a point-of- are overweight and an additional 15% experience “stress hyperglycemia.” The care [POC] device), whereas A1C levels are obese (21). Moreover, in patients risk of eventually developing diabetes, in children with transient hyperglycemia aged 10–17 years with a type 2 diabetes however, may be increased in some chil- were between 4.5% and 6.1%. An A1C phenotype, 10% have evidence of islet dren with incidental or stress hyperglyce- cutoff level of 6.35% had a 100% sensi- autoimmunity (22) and some patients mia, especially those with immunological, tivity and specificity for the diagnosis of have pathophysiological features of both metabolic, or genetic markers for type 1 type 1 diabetes (17). Data from four sep- type 1 and type 2 diabetes (i.e., insulin diabetes (12–14), and consultation with a arate prospective studies of high-risk deficiency and increased insulin resis- pediatric endocrinologist is indicated. subjects ,21 years of agedthe Diabe- tance). Distinguishing between type 1 In the asymptomatic child or adoles- tes Prevention Trial–Type 1 (DPT-1), The and type 2 diabetes in an overweight cent screened because of a high risk for Environmental Determinants of Diabetes or obese adolescent, therefore, may be diabetes, a test with fasting plasma glu- in the Young (TEDDY), Trial to Reduce IDDM challenging, especially in ethnic/racial cose (FPG) $126 mg/dL (7 mmol/L), in the Genetically at Risk (TRIGR), and minorities. In such patients, a detailed 2-h PG $200 mg/dL (11.1 mmol/L), or Type 1 Diabetes TrialNet Natural History family history and measurement of islet A1C $6.5% should be repeated on a sep- Study (A1C measured within 90 days of autoantibodies is recommended, and arate day to confirm the diagnosis. The ADA a diagnostic oral glucose tolerance test plasma or urinary C-peptide concentra- $ d recommends that the same test be re- [OGTT] or fasting PG 126 mg/dL) tions also may be helpful (22–24). $ fi peated without delay using a new blood show that A1C 6.5% is a highly speci c Monogenic diabetes, which may ac- sample (9). The diagnosis is also confirmed but not sensitive early indicator of type 1 count for ;1.2–4% of pediatric diabetes if two different tests (such as A1C and FPG) diabetes diagnosed by OGTT or asymp- (25), is frequently misdiagnosed as type are both above the diagnostic threshold; tomatic hyperglycemia (18). 1 diabetes and inappropriately treated however, if the results are discordant, then Although POC A1C assays may be with insulin (26). The minimum preva- fi the test whose result is above the diag- certi ed by the NGSP (formerly the Na- lence of monogenic diabetes in the U.S. nostic cut point should be repeated. The tional Glycohemoglobin Standardization pediatric population is approximately fi child or adolescent with typical symptoms Program), pro ciency testing is not man- 2.1 per 100,000 (26). Clinicians should be of diabetes and a random PG $200 mg/dL dated for performing the test; accord- alert to the possibility of maturity-onset ingly, POC assays for diagnostic purposes (11.1 mmol/L) does not require a repeat diabetes of the young (MODY), particu- are not recommended. Further details value on another day or any further testing larly in antibody-negative youth with on factors that may impact hemoglobin to diagnose diabetes. Glucose meters (and diabetes (26), and neonatal diabetes, glycation and thus the A1C test, includ- urine ketone tests) are useful for screening particularly in children diagnosed with ing age, race, and hemoglobinopathies, in clinics and physicians’ offices, but the di- diabetes in the first 6 months of life. can be found in “Standards of Medical agnosis of diabetes must be confirmed by Making the diagnosis of MODY or neo- Care in Diabetes” (19). measurement of venous PG on an analytic natal diabetes has important implica- instrument in a clinical chemistry laboratory. Distinguishing Diabetes Type tions for treatment of the patient and There is still debate over whether A1C One often correctly assumes a diagno- other affected family members (27) (see and the same A1C cut point as in adults sis of type 1 diabetes in the slender Table 4). The online probability calculator care.diabetesjournals.org Chiang and Associates 2029

Table 4—Characteristics of prevalent forms of primary diabetes in children and adolescents Type 1 diabetes Type 2 diabetes MODY* Atypical diabetes** Prevalence ;85% ;12% ;1–4% $10% in African American Age at onset Throughout childhood and adolescence Puberty; rare ,10 years ,25 years Pubertal Onset Acute severe Insidious to severe Gradual Acute severe DKA at onset ;30% ;6% Not typical Common Affected relative 5–10% 60–90% 50–90% .75% Female:male 1:1 1.1–1.8:1 1:1 Variable Inheritance Polygenic Polygenic Autosomal Autosomal dominant dominant HLA-DR3/4 Association No association No association No association Ethnicity All, Caucasian at highest risk All¶ All African American/Asian Insulin (C-peptide) secretion Decreased/absent Variable Variably decreased Variably decreased Insulin sensitivity Normal when controlled Decreased Normal Normal Insulin dependence Permanent Variable Variable Intermittent Obesity No† .90% Uncommon Varies with population Acanthosis nigricans No Common No† No† Islet autoantibodies Yes§ No No No *MODY is maturity-onset diabetes in the young or monogenic diabetes (16). **Atypical diabetes is also referred to as Flatbush diabetes, type 1.5 diabetes,ketosis-prone diabetes, andidiopathic type 1 diabetes.¶In North America, type 2 diabetes predominates in African American,Hispanic,Native American, and Canadian First Nations children and adolescents and is also more common in Asian and South Asian than in Caucasian individuals. †Mirrors rate in general population. §Diabetes-associated (islet) autoantibodies to insulin, islet cell cytoplasmic, glutamic acid decarboxylase, or tyrosine phosphatase (insulinoma-associated) antibody (IA-2, ICA512, ZnT8 antibodies in 85–95%) at diagnosis.

(www.diabetesgenes.org/content/mody- included teenagers, demonstrated that infusion have lower A1C levels, lower probability-calculator) can aid in the iden- intensive insulin regimens achieved near- hypoglycemia rates, improved diabetes- tification of individuals most likely to normal glycemic control and reduced the related quality of life, higher treatment benefit from genetic testing, although the risk of development and progression of satisfaction, and less fear of hypoglyce- tool is still undergoing validation. complications (28). New rapid- and long- mia (34). Insulin pump studies that in- acting insulin analogs with pharmacoki- corporate continuous glucose monitoring BLOOD GLUCOSE MANAGEMENT: netic and pharmacodynamic properties (CGM) devices used continuously demon- MONITORING AND TREATMENT that facilitate near-physiological insulin strate significant improvement in both Insulin delivery are now available. Multiple daily glycemic control and hypoglycemia re- injection basal-bolus regimens of 1–2 in- duction in pediatric patients with sub- Recommendation jections of long-acting insulin daily with optimal blood glucose control at baseline c Most children with type 1 diabetes rapid-acting insulin for meals and snacks (35). should be treated with intensive are now the standard of care. Commer- insulin regimens via either multiple cially available insulin preparations are daily injections of prandial insulin Assessment of Glycemic Control shown in Table 5. and basal insulin or continuous sub- Recommendations cutaneous insulin infusion. A c A1C should be measured in all chil- Continuous Subcutaneous Insulin dren and adolescents with type 1 Insulin therapy is essential for survival Infusion diabetes at 3-month intervals to in all people with type 1 diabetes. The Once considered an alternative form of assess their overall glycemic con- goal of insulin replacement therapy is to insulin delivery, continuous subcuta- trol. E mimic normal physiological insulin se- neous insulin infusion, or insulin pump c An A1C target of ,7.5% should be cretion patterns. Because plasma insulin therapy, is often used for children with considered in children and adoles- levels normally vary widely throughout type 1 diabetes (29). Meta-analyses of cents with type 1 diabetes but the day, with low levels in the fasting and randomized controlled trials have shown should be individualized based on overnight periods and rapid increases in modest differences between insulin the needs and situation of the pa- the postprandial period, combinations of pump therapy and injection regimens tient and family. E short- and long-acting insulin prepara- for improving glycemic control and re- c With increasing use of CGM de- tions are commonly used to replicate ducing hypoglycemia (30–32). Results vices, outcomes other than A1C, these patterns. Historically, children with in children have thus far been equivo- such as time with glucose in target type 1 diabetes were treated with com- cal (30,32,33). Large registries that track range and frequency of hypogly- binations of short- and intermediate- outcomes of type 1 diabetes treatment cemia, should be considered in the acting insulins to minimize the number and long-term single-center observa- overall assessment of glycemic of daily injections. The Diabetes Control tional studies do suggest children treated control. E and Complications Trial (DCCT), which with continuous subcutaneous insulin 2030 Position Statement Diabetes Care Volume 41, September 2018

Table 5—Types of insulin preparations and approximate insulin action profiles to guide insulin therapy, prevent or re- Onset of action Peak of action Duration of action verse metabolic decompensation, and de- Insulin type (h) (h) (h) termine whether referral for urgent care is required. The availability of blood ketone Rapid-acting analogs b Aspart (Novolog) 0.25–0.5 1–33–5 meters that measure -hydroxybutyrate Lispro (Humalog) 0.25–0.5 1–33–5 in whole blood has practical and clini- Glulisine (Apidra) 0.25–0.5 1–33–5 cal advantages, including easier sampling Regular insulin 0.5–12–45–8 when urine is difficult to obtain (e.g., Intermediate-acting young children) and potentially earlier NPH 2–44–812–18 and more accurate correlation with clin- Long-acting analogs ical status (41,42). It should be noted that Detemir (Levemir) 2–4 none 12–24 fasting morning ketosis may occur in Glargine (Lantus, Basaglar, younger children with type 1 diabetes Toujeo) 2–4 none up to 24 in the absence of illness or metabolic – . Degludec (Tresiba) 2 4 none 24 deterioration (43).

The DCCT showed that the severity and Self-monitoring of blood glucose levels CGM duration of hyperglycemia exposure are (SMBG) is an essential component of directly related to the risk of develop- treatment of type 1 diabetes in children. Recommendation ment and progression of microvascular Routine SMBG is necessary for determi- c CGM should be considered in all complications in both adults and adoles- nation of immediate insulin needs (e.g., children and adolescents with type cents with type 1 diabetes (28,36). To mealtime), assessment of safety (e.g., 1 diabetes, whether using injec- assess average glycemia over the pre- corrective action for or prevention of tions or insulin pump therapy, as ceding 3 months, A1C levels should be hyper- or hypoglycemia), and longer- an additional tool to help improve fi routinely measured for all individuals term adjustment in insulin dosing regi- glycemic control. Bene ts of CGM with type 1 diabetes. Historically, rec- mens based on blood glucose patterns correlate with adherence to ongo- B ommended glycemic targets for children and trends. Studies have shown an asso- ing use of the device. with type 1 diabetes were higher for ciation between the frequency of blood younger children because of concern glucose tests per day and measures Real-time CGM is increasingly used for about severe hypoglycemia and its del- of glycemic control (39,40). Blood glu- routine diabetes care in children and eterious effects on cognitive devel- cose should be measured before each adolescents with type 1 diabetes. The fi opment. Recently, recommended A1C meal (and snack, if using an intensive rst large-scale randomized controlled targets have been adjusted to ,7.5% multiple daily injection or pump regi- trial of CGM use as an adjunct to SMBG owing to improved tools for diabetes men), before bedtime, before (and often in type 1 diabetes demonstrated a posi- management and a greater understand- after) exercise, prior to and hourly while tive impact on A1C reduction in adults, ing and recognition of the adverse ef- driving (unless using CGM), and when but not in the child or adolescent cohorts fects of chronic hyperglycemia on the symptoms of hypoglycemia are pres- (44). A subsequent post hoc analysis, developing brain (37), and a lower goal ent. Blood glucose targets should be accounting for frequency of CGM use, is reasonable if it can be achieved with- individualized for patient age, insulin showed that CGM lowered A1C levels in out excessive hypoglycemia. Individu- regimen, level of supervision, and other any age-group when the devices were alization of glycemic targets, however, lifestyle issues, with the goal of achiev- used consistently. However, consistent for considerations such as hypoglyce- ing as many glucose values as close to CGM use fell below 50% overall in pe- – mia unawareness, medical comorbidities, target as possible without excessive diatric subjects, with 50% of 8 14-year- – or other clinical, family, or environ- hypoglycemia. olds and only 30% of 15 24-year-olds mental factors, is essential (see also 37 demonstrating consistent CGM use over and 38). the study duration (45). Reduced CGM Blood/Urinary Ketone Monitoring use in youth reflected challenges with Recommendation device wear and the accuracy of early Blood Glucose Monitoring c Blood or urine ketone levels should devices, although consistent CGM use, bemonitoredinchildrenwithtype1 defined as 6 or more days per week for Recommendation diabetes in the setting of prolonged/ the 6-month duration of the trial, yielded c All children and adolescents with better glycemic control (46). Similar stud- type 1 diabetes should have blood severe hyperglycemia or acute ill- ies in children under 10 years old dem- glucose levels monitored multiple ness to determine if adjustment to onstrated satisfaction with devices but times daily (up to 6–10 times/day), treatment or referral to urgent care B no measurable impact on A1C or hypo- including premeal and pre-bedtime, is needed. glycemia reduction (47,48). In the pedi- and as needed for safety in specific Routine testing of blood or urine ke- atric cohort of the Sensor-Augmented situations such as exercise, driving, tones is recommended in the setting of Pump Therapy for A1C Reduction (STAR illness, or the presence of symptoms prolonged hyperglycemia or acute illness 3) trial, subjects aged 7–18 years using of hypoglycemia. B (fever, nausea, vomiting, abdominal pain) insulin pumps plus CGM had a 0.6% care.diabetesjournals.org Chiang and Associates 2031

reduction in A1C levels as well as signif- have increased time spent within target have been approved for use in this pop- icant reductions in glycemic variability glucose ranges, reduced hyper- and hy- ulation by the FDA at the time of this compared with the group using injection poglycemia exposure, lowered A1C lev- writing. therapy and no CGM; hypoglycemia ex- els, and improved measures of quality of posure was not significantly different life in both adult and adolescent subjects LIFESTYLE MANAGEMENT between groups (35). (55–58). Translation of automated insu- Although it is still under 10%, recent lin delivery from research to clinical care Lifestyle management is important for reports from a U.S. diabetes registry will require patient and provider educa- pediatric patients with type 1 diabetes estimate that CGM use in pediatric pa- tion to optimize outcomes (59). Users and enables health maintenance, CVD tients consistently increased between must still count carbohydrates and bolus prevention, and glycemic control. Life- 2010–2012 and 2012–2014 (29) and manually before meals. Systems that re- style management includes healthful sharply rose in 2014–2016 (49). The duce reliance on carbohydrate counting approaches to nutrition and exercise. largest increase was in very young chil- and systems that administer glucagon Training young patients and their fami- dren (ages 2–5 years), in whom CGM use under automated control to mitigate the lies in medical nutrition therapy and was approaching 40% (49). There have risk of hypoglycemia remain in develop- approaches to mitigating both the hypo- been improvements in CGM accuracy ment (60). A recent systematic review and hyperglycemic effects of exercise and performance (50). CGM is associated and meta-analysis of randomized con- is part of diabetes self-management ed- with lower mean A1C in youth for insulin trolled trials suggests that artificial pan- ucation and support, which should be pump users as well as patients using creas systems uniformly improve glucose provided by a registered dietitian, a dia- multiple daily injection regimens (51). control in outpatient settings despite betes educator, an exercise specialist/ For most CGM systems, confirmatory heterogenous technical and clinical fac- physiologist, and a pediatric endocri- SMBG is required to make treatment tors (61). nologist. Extensive training should oc- decisions. However, the U.S. Food and cur at diagnosis, with annual updates Drug Administration (FDA) recently ap- by the registered dietitian. Quar- proved a CGM device (for ages 2 and Adjunctive Therapies terly visits with the diabetes educator older) for making treatment decisions Recommendation and endocrinologist ensure ongoing without SMBG. c There is insufficient evidence to training throughout childhood and support the routine use of adjunc- adolescence. tive medical therapies in children Automated Insulin Delivery Nutrition Therapy with type 1 diabetes. E Recommendation Recommendations c Automated insulin delivery sys- Adjunctive therapies to treat type 1 c Individualized medical nutrition tems appear to improve glycemic diabetes, primarily targeting insulin re- therapy is recommended for chil- control and reduce hypoglycemia sistance (during puberty and with obe- dren and adolescents with type in children and should be consid- sity), have been investigated to assess 1 diabetes as an essential com- ered in pediatric patients with potential benefit. However, clinical trials ponent of the overall treatment type 1 diabetes. B have failed to demonstrate a glycemic plan. A benefit of adding metformin (the only c Monitoring carbohydrate intake, The combination of continuous glu- approved insulin sensitizer for use in the whether by carbohydrate counting cose sensors with insulin pumps has pediatric age range) to insulin in over- or experience-based estimation, is enabled the development of automated weight and obese adolescents with type key to achieving optimal glycemic insulin delivery systems (“closed-loop” or 1 diabetes, although some studies have control. B “artificial pancreas” devices). A control- shown weight loss and/or reductions in c Comprehensive nutrition educa- ler algorithm adjusts insulin delivery insulin requirements and cardiovascular tion at diagnosis, with annual up- rates based on a continuous stream of disease (CVD) risk factors with adjunctive dates, by an experienced registered glucose sensor data. Suspending basal metformin (62,63). dietitian is recommended to assess insulin delivery for low sensor glucose Pramlintide, an analog of the pancre- caloric and nutrition intake in re- levels has been shown to markedly re- atic polypeptide amylin, has been shown lation to weight status and CVD risk duce hypoglycemia without worsening to improve glycemic control when added factors and to inform macronutri- glycemia (52). Sensor-augmented pumps to insulin in adults with type 1 diabetes, ent choices. E that preemptively suspend insulin de- primarily through dampening glycemic livery when sensor glucose levels are excursions by suppressing glucagon se- Dietary management should be individ- predicted to be low show promise in cretion and delaying gastric emptying. ualized: family habits, food preferences, minimizing hypoglycemia (53,54). The Neither pramlintide nor other poten- religious or cultural needs, schedules, greatest potential for improved glyce- tially useful adjuncts, such as glucagon- physical activity, and the patient’sand mic control is the dynamic regulation like peptide 1 receptor agonists (e.g., family’s abilities in numeracy, literacy, and of insulin delivery for both high and liraglutide, exenatide) or sodium–glucose self-management should be considered. low glucose levels. “Hybrid” closed-loop cotransporter 2 inhibitors, have been Dietitian visits should include assessment systems, which modulate basal insulin thoroughly studied in the pediatric pop- for changes in food preferences over time, delivery based on sensor glucose levels, ulation with type 1 diabetes, and none access to food, growth and development, 2032 Position Statement Diabetes Care Volume 41, September 2018

weightstatus,cardiovascularrisk,andpo- the liver and skeletal muscles to replenish essential, including pre-exercise tential for eating disorders. Dietary adher- glycogen stores. Impaired counterregula- glucose levels of 90–250 mg/dL ence is associated with better glycemic tory hormone release in pediatric patients (5–13 mmol/L) and accessible car- control in youth with type 1 diabetes (64). may include blunting during sleep, ante- bohydrates, individualized accord- Pediatric nutrition management fol- cedent hypoglycemia, and autonomic fail- ing to the type/intensity of the lows the ADA guidelines for dietary ure (79–81). Delayed hypoglycemia often planned physical activity. E management (65). The best approach occurs at night following afternoon phys- c Strategies to prevent hypoglyce- to healthful eating is within the context ical activities. Therefore, exercise-induced mia during exercise, after exercise, of the family, focusing on healthy eating hypoglycemia and fear of hypoglycemia and overnight following exercise for all members. There is no single ideal may limit desire to participate in exercise. include reducing prandial insulin dietary distribution of calories among The following paragraphs outline strat- dosing for the meal/snack preced- carbohydrates, fats, and proteins for egies to mitigate hypoglycemia risk and ing exercise, increasing carbohydrate people with diabetes; therefore, macro- minimize hyperglycemia with exercise. intake, eating bedtime snacks, using nutrient distribution should be individ- For in-depth discussions, see recently pub- CGM, and/or reducing basal insulin ualized while keeping total calorie and lished reviews and guidelines (76,77,82). doses. C metabolic goals in mind. Carbohydrate Overall, it is recommended that youth c Frequent glucose monitoring be- intake from vegetables, fruits, legumes, with type 1 diabetes participate in 60 fore, during, and after exercise, with whole grains, and dairy products, with an min or more of daily physical activity, or without CGM use, is important to emphasis on foods higher in fiber and including resistance and flexibility train- prevent, detect, and treat hypogly- lower in glycemic load, is preferred over ing (83). Although uncommon in the cemia and hyperglycemia with ex- other sources, especially those containing pediatric population, patients should ercise. C added sugars. Saturated fats should be be medically evaluated for comorbid limited. Caloric intake should fuel normal conditions or diabetes complications that Exercise positively affects physical fit- growth and development and avoid over- may restrict participation in an exercise ness, strength building, weight man- weight and underweight, especially given program. As hyperglycemia can occur agement, social interaction, self-esteem the current trends, with at least one-third before, during, and after physical activ- building, and creation of healthful habits of pediatric patients with type 1 diabetes ity, it is important to ensure that the for adulthood, but it also has the po- overweight or obese (21,66,67). elevated glucose level is not related to tential to cause both hypoglycemia and Nutrition education begins with car- insulin deficiency that would lead to hyperglycemia. bohydrate counting, where consistency, worsening hyperglycemia with exercise The type, intensity, and duration of rather than accuracy, results in optimal and ketosis risk. Intense activity should exercise trigger multiple hormones (insu- glycemic outcomes (68). Over- or under- be postponed with marked hyperglyce- lin, glucagon, catecholamines, and gluco- calculating by up to 10 g or 15% of the mia (glucose $350 mg/dL [19.4 mmol/L]), corticoids) that mediate fuel metabolism carbohydrate amount is unlikely to yield moderate to large urine ketones, and/or (75–77). Pancreatic islet cells achieve eu- substantial hypoglycemia or hyperglyce- b-hydroxybutyrate .1.5 mmol/L. Caution mia, respectively (69,70). Persons lacking glycemia by balancing peripheral glucose may be needed when b-hydroxybutyrate numeracy skills may use past experience uptake and hepatic glucose production. levels are $0.6 mmol/L (76,77). to match insulin doses to carbohydrate In type 1 diabetes, this intrinsic balance The prevention and treatment of hy- intake. does not exist. Exogenous insulin adminis- poglycemia associated with physical ac- Recent studies have shown that meals tration inhibits hepatic glucose production tivity include decreasing the prandial with protein, fat, and more complex car- and promotes exercise-induced glucose up- insulin for the meal/snack before exer- bohydrates delay glucose level increases take, both triggering hypoglycemia. Hyper- cise and/or increasing food intake. Pa- and respond well to square-wave or dual- glycemia may occur during high-intensity tients on insulin pumps can lower basal wave bolus doses or the splitting of bolus exercise such as sprints or resistance train- rates by ;10–50% or more or suspend doses given by injection (71–74). ing when there is inadequate delivery of for 1–2 h during exercise (84). Decreasing exogenous insulin and/or an excess of basal rates or long-acting insulin doses by counterregulatory hormones that increase ;20% after exercise may reduce delayed Physical Activity and Exercise hepatic glucose production and inhibit glu- exercise-induced hypoglycemia (85). cose uptake into skeletal muscle. Accessible rapid-acting carbohydrates Recommendations Though the potential for hyperglyce- and frequent blood glucose monitoring c Exercise is recommended for all youth mia can frustrate patients and families, before, during, and after exercise, with with type 1 diabetes with the goal fear of exercise-induced hypoglycemia or without CGM, maximize safety with of 60 min of moderate- to vigorous- dominates clinical concerns. Intense exer- exercise. intensity aerobic activity daily, with cise increases hypoglycemia risk during, Blood glucose targets prior to exercise vigorous muscle-strengthening and immediately following, and 6–12 h after should be 90–250 mg/dL (5.0–13.9 mmol/L). bone-strengthening activities at least physical activity, the “lag effect” (78). This Consider additional carbohydrate intake 3daysperweek.C lag likely results from a combination of im- during and/or after exercise, depending c Education about prevention and proved insulin sensitivity following exer- on the duration and intensity of physi- management of potential hypogly- cise, blunted counterregulatory hormone cal activity, to prevent hypoglycemia. For cemia during and after exercise is release, and increased glucose uptake by low- to moderate-intensity aerobic activities care.diabetesjournals.org Chiang and Associates 2033

(30260 min), and if the patient is fasting, possibility of a more serious psychological potential treatment-related effects 10215 g of carbohydrate may prevent issue must be considered and evaluated. on hunger/caloric intake. B hypoglycemia (86). After insulin boluses For these reasons, adolescents should (relative hyperinsulinemia), consider 0.5– be offered time by themselves with their Youth with type 1 diabetes are part of a 1.0 g of carbohydrates/kg per hour of care provider(s) starting at age 12 years. larger ecosystem of family, community, exercise (;30260 g), which is similar to Care should be taken to respect the and peer influences that impact health carbohydrate requirements to optimize privacy of teens/young adults, especially and quality-of-life outcomes. Thus, a performance in athletes without type 1 regarding behaviors that are considered family-centered diabetes care approach diabetes (87–89). taboo or risky (94). Discussions with for youth with type 1 diabetes is essen- adolescents should include questions tial to ensure that all psychosocial influ- about well-being in general, diabetes ences are addressed. For background distress, and risk behaviors (e.g., sub- BEHAVIORAL ASPECTS OF information, please refer to the ADA stance use and sexual activity) (95,96). It SELF-MANAGEMENT Position Statement on the psychosocial is recommended that prior to or shortly Recommendations care of people with diabetes (90) and to after puberty, girls with type 1 diabetes c At diagnosis and during routine “Standards of Medical Care in Diabetes” should be counseled about the impor- follow-up care, assess psychosocial for current general recommendations (65). tance of good metabolic control prior to issues and family stresses that could The sections below offer specificconsid- conception and should be made aware impact diabetes management and erations applicable to providing care to that safe and effective family planning provide appropriate referrals to youth with type 1 diabetes. methods are available should they become trained mental health professionals, sexually active and not desire pregnancy. preferably experienced in childhood Age-Groups diabetes. E Table 6 illustrates typical development Screening, Prevention, and Treatment c Providers should consider asking and diabetes demands and priorities Given the rapid and dynamic nature of youth and their parents about social across childhood, updated from the orig- cognitive, developmental, and emotional adjustment (peer relationships) inal version (1). The responsibility for and changes in youth, early detection of de- and school performance to deter- supervision of type 1 diabetes manage- pression, anxiety disorders, disordered mine whether further evaluation is ment falls largely to the primary care- eating (97), and learning disabilities en- needed. B giver during the early years of childhood, hances the range and effectiveness of po- c Assess youth with diabetes for ge- with a gradual transition to other care- tential treatment options and may help neric and diabetes-related distress, givers and school personnel as the child to minimize adverse effects on diabetes generally starting at 7–8 years of ages. However, the primary caregiver will management and disease outcomes. Al- age. B remain a major part of type 1 diabetes though rates of psychological distress and c Providers should encourage devel- management through adolescence. disordersinchildrenwithtype1diabetes opmentally appropriate family in- may not differ from the general population, volvement in diabetes management Unique Challenges of Adolescence The adolescent years may disrupt diabe- adolescents with type 1 diabetes do tend tasks for children and adolescents, tes care and communication between to show 2–3timestherateofpsychological recognizing that premature trans- family members, youth, and providers. distress as their peers without diabetes fer of diabetes care to the child may Hallmarks of normal adolescence are in- (98–101). Distinguishing between frank de- result in poor self-management be- creased independence in decision mak- pressive or anxiety disorders and diabetes- haviors and deterioration in glyce- ing and reliance on the peer group for related distress should be left to mental mic control. A validation of self-concept and self-worth. health providers so that appropriate treat- c Consider including children in con- Wishingto“fitin”maycontributeto youth ment options can be determined. sent processes as early as cognitive hiding or minimizing diabetes care be- Because youth depend on social sup- development indicates understand- haviors, thereby compromising manage- port systems (family and care providers) ing of health consequences of be- ment in the school setting (91). Cognitive and must eventually transition to inde- havior. E development and medical decision-making pendent diabetes self-management as c Offer adolescents time by them- skills will impact a wide variety of risk- adults, their families and related social selves with their care provider(s) taking behaviors and acceptance of self- networks should be included in psycho- starting at age 12 years, or when management behaviors into daily life social assessment and treatment (102– developmentally appropriate. E (92,93). Suboptimal glycemic manage- 104). Teaching family members effective c Consider screening for disordered ment should not automatically be at- problem-solving and conflict-resolution or disrupted eating behaviors using tributed to adolescent rebellion or lack skills can improve diabetes management validated screening measures when of concern for health. A thorough, age- and facilitate better glycemic control, with hyperglycemia and/or weight loss are appropriate psychosocial evaluation and the potential to reduce diabetes distress unexplained based on self-reported review of the medical regimen will suggest and improve quality of life (102,105,106). behaviors related to medication dos- targets for modification to facilitate self- Parents of children with type 1 diabetes are ing, meal plan, and physical activity. management and well-being. If the ado- prone to high rates of depression, especially In addition, a review of the medical lescent is resistant to accepting support around the time of diagnosis (107,108). regimen is recommended to identify from clinicians, family, and friends, the Persistence of parental depression is 2034 Position Statement Diabetes Care Volume 41, September 2018

Table 6—Typical development and diabetes demands and priorities across childhood Ages and corresponding T1D management priorities (and Family considerations due to developmental level Typical developmental tasks person responsible) presence of T1D 0–2 years; infancy and start of Attachment and development of Reduction of wide fluctuations in Vigilance in identifying child toddlerhood trusting bond with caregivers glucose levels (caregiver) symptoms of hypo- and hyperglycemia Physical development and reaching Prevention of hypoglycemia Coping with stress associated with milestones of first words and (caregiver) management and additional walking responsibilities 2–6 years; end of toddlerhood Often begin formal Reduction of wide fluctuations in Continued vigilance in identifying through early childhood schoolingdpreschool to glucose levels (caregiver, school child symptoms elementary school personnel) Separating from caregivers for Prevention of hypoglycemia Communicating and planning for activities (caregivers, school personnel) monitoring when not with child; coping with stress Physical growth with interests in Trusting others to help with Close monitoring of food intake and exploring new challenges and diabetes management (child) adjustments for variable activities appetites 7–11 years; late childhood Developing skills in physical, social, Sharing in the identification of Teaching child symptoms of and academic areas symptoms of hypo- and hyperglycemia and hypoglycemia hyperglycemia (child and caregiver) Gaining more autonomy from Treating hypoglycemia and carrying Teaching basics of diabetes primary caregivers, yet still very supplies (child with planning/ management and treatment reliant on caregiver supervision supervision from adults) and planning Often engaging in team activities Developing sense of problem Praising conduct of management that promote sharing and solving and flexibility with tasks understanding views of others regimen if plans or activities change (child with guidance/ modeling from caregiver) Modeling problem solving when new diabetes problems arise Helping teach child to disclose to others about diabetes Coping with stress and new challenges of complex schedules and eating patterns 12–15 years; early adolescence Managing changes with body More decision making about Coping with common increase in diabetes management and conflict about diabetes regimen changes (teen) management Attempts at “fitting in” with peer Expectation to monitor and be Developing new forms of groups; peers becoming larger vigilant about glucose excursions monitoring and communicating influence on behavior when away from primary about diabetes caregivers (teen) Developing stronger sense of self Disclose to others about diabetes Supervising enough but attempting and identity for safety (teen) to support growing autonomy in teen Desiring less guidance and supervision from caregivers, yet still needing it 16–19 years; late adolescence Expansion of networks and activities Increasing autonomy for many Balancing need for supervision and management tasks (teen) guidance with less face-to-face time with teen and more teen autonomy Increased thinking and worries Diminishing seeking of guidance and Modeling positive decision making about what is next supervision from caregivers about diabetes and life choices (teens) Expectation to make decisions Discussions about transition to Creating scaffolding for transition based on interests and different diabetes care providers with diabetes and next phase of opportunities (teens, care team, and caregivers) life T1D, type 1 diabetes.

associated with poorer child adjustment Emerging technologies, like phone and in maintaining communication of infor- and diabetes management, especially in computer transmission of glucose and mation through nonconfrontational chan- younger children (109). insulin management data, can be useful nels and may provide a means for youth care.diabetesjournals.org Chiang and Associates 2035

to communicate directly with care providers The risk of hypoglycemia limits optimal access to medical support to assist as they transition to more independent treatment of type 1 diabetes. Because with sick-day management. C self-management (110). Remote monitor- current methods of blood glucose mon- c Standard pediatric-specific proto- ing of glucose levels should be discussed itoring and insulin replacement are im- cols for DKA treatment should be with the child and family to determine perfect, hypoglycemia risk is invariably availableinemergencydepartments “rules of engagement” about acceptable present. Registry data suggest that se- and hospitals. E times and situations to monitor. vere hypoglycemia has decreased with advances in care since the DCCT (113). DKA is an acute complication usually Patient education, frequent SMBG, and Anticipatory Guidance associated with new-onset type 1 diabe- CGM may detect hypoglycemia and help Immunization tes, insulin omission, and increased adjust insulin dosing and carbohydrate Children with diabetes should receive all levels of stress-related counterregula- intake. Closed-loop systems with pre- immunizations in accordance with the tory hormones/cytokines (e.g., infection) dicted low glucose suspend reduce hy- recommendations of the Advisory Com- (112). Mild cases may be safely and ef- poglycemia in children and adolescents mittee on Immunization Practices, Cen- fectively treated in an acute care setting in research studies (57). ters for Disease Control and Prevention, with appropriate resources and may not fl Clinicians should ask patients about including annual vaccination against in u- require hospitalization. Education must their symptoms of hypoglycemia and at enza for children with diabetes who are be provided to families to prevent DKA, what threshold of glycemia these occur; at least 6 months of age. The child and which may have serious sequelae, partic- if the threshold is suggestive of hypo- adolescent vaccination schedule is avail- ularly in young children. Refer to guide- glycemia unawareness, then the treat- able at www.cdc.gov/vaccines/schedules/ lines for DKA management (112). hcp/child-adolescent.html. Large studies ment regimen and glycemia goals should have shown no causal relationship be- Hypoglycemia be adjusted upwards (114). Oral carbo- tween childhood vaccination and type 1 hydrate (15 g) is the preferred treatment Recommendations for patients with blood glucose ,70 diabetes (111). c Individuals with type 1 diabetes, or mg/dL (3.9 mmol/L) or those with symp- Growth their caregivers, should be asked toms of hypoglycemia who are alert and Normal linear growth and appropriate about symptomatic and asymptom- able to eat. Glucagon is used for severe weight gain throughout childhood and atic hypoglycemia at each encounter. E hypoglycemia. In children, small stud- adolescence are excellent indexes of c Glucose (15 g) is the preferred ies have led to age-based minidoses of general health and reasonable markers treatment for the conscious indi- glucagon (0.02–0.15 mg) if the child is of metabolic control. Height and weight vidual with hypoglycemia (blood alert but not able to eat (115). Alternate should be measured at each visit and glucose ,70 mg/dL [3.9 mmol/L]), delivery methods for glucagon are in tracked via appropriate height and although any form of carbohy- development (116). weight growth charts (www.cdc.gov/ drate may be used. If the SMBG growthcharts/clinical_charts.htm). Over- result 15 min after treatment shows weight and obesity are emerging issues continued hypoglycemia, the treat- Microvascular Complications in youth with type 1 diabetes (21,66,67) ment should be repeated. Once Retinopathy, diabetic kidney disease and should be considered as part of blood glucose concentration re- (DKD) (previously referred to as “ne- dietary counseling. turns to normal, the individual phropathy”), and neuropathy are rarely should consider a meal or snack reported in prepubertal children and COMPLICATIONS AND and/or reduce insulin to prevent children with diabetes duration of only COMORBIDITIES hypoglycemia recurrence. E 1–2 years; however, complications may c Glucagon should be prescribed for Acute Complications occur after the onset of puberty or after all individuals with type 1 diabe- 5–10 years of diabetes (117). It is rec- DKA tes. Caregivers or family members ommended that clinicians with expertise Recommendations of these individuals should be in- in diabetes management should counsel c Individuals and caregivers of indi- structed in its administration. E the pediatric patient and family on the viduals with type 1 diabetes should c Hypoglycemia unawareness or one importance of early prevention and be educated annually on DKA pre- or more episodes of severe hypo- intervention. vention, including sick-day manage- glycemia should trigger reevalua- ment, the importance of insulin tion of the treatment regimen. E DKD administration, and glucose and c Insulin-treated patients with hypo- ketone level monitoring. B glycemia unawareness or an epi- Recommendations c All individuals with type 1 diabetes sode of severe hypoglycemia should c Annual screening for albuminuria should have access to an uninter- be advised to raise their glycemic witharandom(morningsam- rupted supply of insulin. Lack of targets to avoid further hypoglyce- ple preferred to avoid effects of access and insulin omissions are mia for at least several weeks to exercise) spot urine sample for major causes of DKA. A partially reverse hypoglycemia un- albumin-to-creatinine ratio should c Patients and families with type 1 awareness and reduce the risk of be considered at puberty or at diabetes should have continual future episodes. B age .10 years, whichever is earlier, 2036 Position Statement Diabetes Care Volume 41, September 2018

(eGFR)(131)canbeapproximatedbased practices and cost-effectiveness are once the child has had diabetes on measurement of serum creatinine needed (137). for 5 years. B concentration along with consideration c An ACE inhibitor or an angioten- Neuropathy sin receptor blocker (ARB), titrated of clinical status, age, diabetes duration, to normalization of albumin ex- and therapies. Improved methods are Recommendation cretion, may be considered when needed to screen for early GFR loss since c Consider an annual comprehensive elevated urinary albumin-to-creatinine eGFR is inaccurate at GFR .60 mL/min/ foot exam for the adolescent at 2 ratio (.30 mg/g) is documented 1.73 m (132). the start of puberty or at age (two of three urine samples ob- 10 years, whichever is earlier, once tained over a 6-month interval Retinopathy the youth has had type 1 diabetes B following efforts to improve glyce- Recommendations for 5 years. mic control and normalize blood c An initial dilated and comprehensive pressure). E eye examination is recommended Neuropathy rarely occurs in prepubertal – at age 10 years or after puberty has children or after only 1 2 years of di- Screening provides an opportunity to started, whichever is earlier, once abetes (117). A comprehensive foot detect albuminuria early, initiate ACE the youth has had diabetes for 3–5 exam, including inspection, palpation inhibitor or ARB therapy, particularly years. B of dorsalis pedis and posterior tibial in the presence of hypertension, and en- c After the initial examination, an- pulses, assessment of the patellar and fl courage meticulous attention to achiev- nual routine follow-up is generally Achilles re exes, and determination of fi ing glycemic goals, especially during the recommended. Less frequent ex- proprioception, vibration, and mono la- reversible phase of DKD (118). Evalu- aminations, every 2 years, may be ment sensation, should be performed ation for possible nondiabetic kidney acceptable on the advice of an eye annually along with assessment of symp- disease should be considered as part care professional and based on risk toms of neuropathic pain. The SEARCH of the clinical evaluation. If females are factor assessment. E study reported a 7% prevalence of diabe- prescribed ACE inhibitors/ARBs, they tic peripheral neuropathy with poorer glu- should be counseled on the teratogenic In children and adolescents, most pa- cose control, older age, longer diabetes risks associated with pregnancy (refer to tients with retinopathy have either duration, smoking, increased diastolic “Standards of Medical Care in Diabetes” nonproliferative or preproliferative blood pressure, obesity, increased LDL for additional guidance on pharmaco- retinopathy. Retinopathy (like albu- cholesterol and triglycerides, and lower logic treatment of hypertension [119]). minuria) most commonly occurs after HDL cholesterol as risk factors (138). The ADA has published clinical practice recom- Hypertension, or even a rise in blood the onset of puberty and after 5–10 mendations for preventive foot care in pressure within the normal range, may years of diabetes duration (117,133). adults with diabetes (122) and for diabetic accompany progression to albuminuria Hypertension, poor metabolic control, (120) or its persistence (121). Risk fac- neuropathy (139); for future updates to albuminuria, hyperlipidemia, smoking, ’ torsforDKDincludepoorglycemic these recommendations, see the ADA s diabetes duration, and pregnancy all “ ” control, smoking, a parent with essential Standards of Medical Care in Diabetes confer increased retinopathy risk (122, (professional.diabetes.org/SOC). hypertension, and a family history of 134). ACE inhibitors slow retinopathy DKD or CVD (122). Even in the absence progression, even in normotensive pa- of hypertension, an ACE inhibitor or tients (135). Macrovascular Complications ARB may reverse increased albumin Early referrals establish appropriate CVD, cerebrovascular disease, and pe- excretion or delay the progression to follow-up patterns for ophthalmologic ripheral vascular disease resulting from albuminuria (123–125). In adults with examinations by eye care professionals atherosclerosis are leading causes of diabetes, treatment of elevated albumin with expertise in diabetic retinopathy, morbidity and mortality in adults with excretion in the absence of hyperten- – particularly in the pediatric patient, and type 1 diabetes (140 142). Factors con- sion is not recommended (126). Data on engage and educate the pediatric pa- tributing to atherosclerosis and elevated the long-term benefitofthesetherapies plasma lipid concentrations in children tient and family about diabetes man- are needed to support the benefiton and youth include smoking, hyperten- agement and its comorbidities. Fundus long-term vascular disease risk reduc- sion, obesity, family history of heart photography, including nonmydriatic tion (127,128). The Adolescent type 1 disease, and diabetes (143,144). Diabe- modalities, may be an additional helpful Diabetes cardio-renal Intervention Trial tes is an independent risk factor for CVD (AdDIT) in adolescents with type 1 di- educational tool for the adolescent. A in adults, conferring a two- to fourfold 5 abetes demonstrated safety of ACE in- recent report of a large study (n 5,453) increased incidence of CVD. There is hibitor treatment but did not change indicated that only 64.9% of youth with unequivocal evidence that the athero- the albumin-to-creatinine ratio over type 1 diabetes and 42.2% of youth with sclerotic process begins in childhood the course of the study (129). The T1D type 2 diabetes received retinal screening (145–147), and although CVD events Exchange clinic registry reported only by 6 years postdiagnosis and that getting are not expected to occur during child- 36% of those diagnosed with albumin- screened was particularly challenging for hood, various methodologies show that uria or greater were treated (130). An racial minorities and less affluent fami- youth with type 1 diabetes may have estimation of glomerular filtration rate lies (136). More data on best screening subclinical CVD abnormalities within the care.diabetesjournals.org Chiang and Associates 2037

first decade of diagnosis (148–150). childhood and should be evaluated. Nor- obtaining a fasting lipid panel beginning Population-based studies estimate that mal blood pressure levels for age, sex, at 2 years of age (155). Abnormal results 14–45% of children with type 1 diabetes and height and appropriate methods from a random lipid panel should be have two or more CVD risk factors for measurement are available online confirmed with a fasting lipid panel. (151–153). The American Heart Associ- at www.nhlbi.nih.gov/health/prof/heart/ SEARCH study data show that improved ation published a joint statement with hbp/hbp_ped.pdf. Treatment for hyper- glucose control over a 2-year period is the ADA on CVD in type 1 diabetes (143) tension is generally an ACE inhibitor, but associated with a more favorable lipid and a scientific statement on CVD risk an ARB may be used if the ACE inhibitor is profile; however, improved glycemic factors in youth with diabetes (144). not tolerated. Hypertension diagnosis in control alone is unlikely to normalize children with diabetes is often delayed lipids in youth with type 1 diabetes Hypertension and undertreated (154). If hypertension and dyslipidemia (156,157). Initial treat- Recommendations is documented, pathological causes other ment should include medical nutrition c Blood pressure should be mea- than DKD should be excluded. Laboratory therapy and a diet restricting saturated sured at each routine visit. Children examination should include evaluation of fats (158). found to have high-normal blood renal functional status (urinalysis, serum Neither long-term safety nor cardio- pressure (systolic blood pressure creatinine, and blood urea nitrogen) and vascular outcome efficacy of statin ther- or diastolic blood pressure at the urinary albumin excretion (if not obtained apy has been established for adolescents; 90th percentile for age, sex, and within the previous 6 months). however, studies have shown short-term height) or hypertension (systolic safety equivalent to that seen in adults blood pressure or diastolic blood Dyslipidemia and efficacy in lowering LDL cholesterol levels in familial hypercholesterole- pressure at the 95th percentile for Recommendations age, sex, and height) should have c Obtain a fasting lipid profile in mia or severe hyperlipidemia, improv- blood pressure confirmed on three children 10 years of age or older ing endothelial function, and causing separate days. B as soon as convenient after the regression of carotid intimal thickening c Initial treatment of high-normal diagnosis of diabetes (once gly- (129,159,160). The AdDIT study dem- blood pressure (systolic blood pres- cemic control has been estab- onstrated the safety of statin use over sure or diastolic blood pressure lished). E 2–4 years in adolescents with type 1 consistently at the 90th percentile c If LDL cholesterol values are within diabetes. This study showed significant for age, sex, and height) includes the accepted risk level (,100 mg/ reductions in total, LDL, and non-HDL dietary modification and increased dL [2.6 mmol/L]), a lipid profile cholesterol levels, in triglyceride lev- exercise, if appropriate, aimed at repeated every 3–5 years is reason- els, and in ratios of apolipoprotein B to weight control. If target blood able. E apolipoprotein A1. However, statin use – pressure is not reached with 3 6 c If lipids are abnormal, initial ther- hadnosignificant effects on carotid months of initiating lifestyle inter- apy should consist of optimizing intima-media thickness, other cardio- vention, pharmacologic treatment glucose control and medical nutri- vascular markers, the GFR, or retinop- E should be considered. tion therapy using a Step 2 Amer- athy progression (129). Statins are not c fi In addition to lifestyle modi ca- ican Heart Association diet that approved for patients aged ,10 years, tion, pharmacologic treatment of restricts saturated fat to 7% of and statin treatment should generally hypertension (systolic blood pres- total calories and dietary choles- notbeusedinchildrenwithtype1 sure or diastolic blood pressure terol to 200 mg/day, which is safe diabetes before this age. Statins are consistently at the 95th percentile and does not interfere with normal contraindicated in pregnancy; there- for age, sex, and height) should be growth and development. B fore, pregnancy prevention is of para- considered as soon as hyperten- c After 10 years of age, consider mount importance for postpubertal sion is confirmed. E adding a statin in patients who, girls. c ACE inhibitors or ARBs should be despite medical nutrition therapy considered for the initial pharma- and lifestyle changes for 6 months, Smoking cologic treatment of hypertension, continue to have LDL cholesterol following reproductive counseling .160 mg/dL (4.1 mmol/L) or LDL Recommendation because of the potential terato- cholesterol .130 mg/dL (3.4 mmol/L) c Elicit a smoking history at initial and genic effects of both drug classes. E and one or more CVD risk factors, follow-up diabetes visits, and dis- c Treatment goal is blood pressure following reproductive counseling courage smoking in youth who do consistently ,90th percentile for because of the potential terato- not smoke and encourage smoking age, sex, and height. E genic effects of statins. E cessation in those who do smoke. A c Therapy goal is an LDL cholesterol Blood pressure measurements should value ,100 mg/dL (2.6 mmol/L). E The adverse health effects of smoking be determined using the appropriate are well recognized with respect to fu- size cuff with the child seated and re- For children with a significant family ture cancer and risk of vascular disease laxed. Parental hypertension is a major history of CVD, the National Heart, (161). Cigarette smoking cessation, in- risk factor for elevated blood pressure in Lung, and Blood Institute recommends cluding e-cigarettes, is an important part 2038 Position Statement Diabetes Care Volume 41, September 2018

of routine diabetes care, as is assessment thyroid antibodies, a recent study from type 1 diabetes and confirmed celiac of exposure to secondhand smoke. Sweden indicated TPOAb was more pre- disease, a gluten-free diet reduces symp- dictive than TGAb in multivariate analy- toms and hypoglycemia (175). The chal- Autoimmune Conditions sis (166). Thyroid function tests may be lenging dietary restrictions associated misleading (euthyroid sick syndrome) with having both type 1 diabetes and Recommendation if performed at diagnosis. Therefore, if celiac disease are a significant burden. c Assess for additional autoimmune thyroid function tests are slightly ab- Therefore, a biopsy to confirm the di- conditions soon after the diagnosis normal after diagnosis, they should be agnosis of celiac disease is recommended, of type 1 diabetes and if symptoms repeated upon metabolic stability and especially in asymptomatic children, develop. E achievement of glycemic targets. Sub- before prescribing significant dietary clinical hypothyroidism may be associ- changes (176). Some patients and pro- Screening for thyroid dysfunction and ated with increased risk of symptomatic viders may choose to start a gluten-free celiac disease is recommended because hypoglycemia (167) and reduced linear diet without a biopsy in the presence of of increased risk for additional autoim- growth rate. a high antibody titer and symptoms of mune disorders. Periodic screening in celiac disease. Genetic screening (HLA- asymptomatic individuals has been rec- Celiac Disease DQ2 and HLA-DQ8) confirms high risk ommended, but the optimal frequency for celiac disease (177). and benefit of screening are unclear. Recommendations Although much less common than celiac c Screen children with type 1 diabe- disease and thyroid dysfunction, other tes for celiac disease by measuring TRANSITION FROM PEDIATRIC TO autoimmune conditions, such as Addison IgA tissue transglutaminase (tTG) ADULT CARE disease (primary adrenal insufficiency), antibodies, with documentation of Recommendations normal total serum IgA levels, soon autoimmune hepatitis, autoimmune gas- c Pediatric diabetes providers should after the diagnosis of diabetes, or tritis, dermatomyositis, and myasthenia begin to prepare youth for transi- IgG to tTG and deamidated gliadin gravis, occur more commonly with pa- tion in early adolescence and, at antibodies if IgA deficient. E tients with type 1 diabetes than in the the latest, at least 1 year before the c Repeat screening within 2 years general pediatric population and should transition to adult health care. E of initial screening and then again be assessed and monitored as clinically c Both pediatric and adult diabetes 5 years thereafter and consider indicated. care providers should provide sup- more frequent screening in chil- port and resources for transition- Thyroid Disease dren who have symptoms or a ing young adults. E first-degree relative with celiac Recommendations disease. B c Consider testing children with The developmental stage of emerging c Children with biopsy-confirmed ce- type 1 diabetes for antithyroid adulthood is characterized by compet- liac disease should be placed on a peroxidase and antithyroglobulin ing educational, social, vocational, and gluten-free diet and have a consul- antibodies soon after the diagno- financial priorities (178). During this tation with a dietitian experienced sis. B phase, youth experience decreasing pa- in managing both diabetes and c Measure thyroid-stimulating hor- rental support and become fully respon- celiac disease. B mone concentrations at diagnosis sible for their diabetes care, which may when clinically stable or soon after trigger a decline in medication-taking Celiac disease is an immune-mediated glycemic control has been estab- behavior and difficulty achieving blood disorder that occurs with increased fre- lished. If normal, suggest rechecking glucose targets (179). Consequently, quency in patients with type 1 diabetes every 1–2yearsorsoonerifthe young adults with type 1 diabetes are (1–16% vs. 0.3–1% in the general pop- patient develops symptoms or signs at risk for acute diabetes complications, – suggestive of thyroid dysfunction, ulation) (168 171). Classic symptoms of chronic macrovascular and microvas- thyromegaly, an abnormal growth celiac disease include diarrhea, weight cular complications, psychosocial chal- rate, or unexplained glycemic var- loss or poor weight gain, growth failure, lenges, and early mortality (180–182). iability. E abdominal pain, chronic fatigue, irritability, An ineffective transition from pediat- inability to concentrate, malnutrition due ric to adult diabetes care may contribute Autoimmune thyroid disease is the to malabsorption, other gastrointestinal to fragmentation of health care and in- most common autoimmune disorder as- problems, and occasional skin conditions creased risk for adverse outcomes. Prior sociated with diabetes, occurring in 17– (dermatitis herpetiformis). Unpredictable research has highlighted challenges in the 30% of patients with type 1 diabetes blood glucose levels, unexplained hypogly- transition process, including gaps between (162). At diagnosis, about 25% of children cemia, and glycemic deterioration may pediatric and adult care (183,184), sub- (more females than males) with type 1 occur in patients with diabetes and celiac optimal transition preparation (184), de- diabetes have thyroid autoantibodies disease (172–174). Occasionally, one may terioration of glycemic control (185,186), (163); their presence predicts thyroid seeexcessiveweight,forexample,inolder and increased hospitalizations (187). dysfunctiondmost commonly hypothy- female teens and young adults, associated Available data suggest that many roidism, although hyperthyroidism oc- with gastrointestinal distress leading to young adults in the U.S. do not transi- curs in ;0.5% of cases (164,165). For overeating. In symptomatic children with tion to adult care until their early to care.diabetesjournals.org Chiang and Associates 2039

mid-twenties (186,188), but timing is caregivers must carefully balance au- appropriate insulin therapy and advanced highly variable. There is no clear optimal tonomy with supervision. Caregivers diabetes technologies. transition age, and the overriding prior- should not delegate all diabetes care Parallel to the technological advances, ity is to ensure consistent follow-up. to the youth, as adolescents often need ongoing research is required to better An individualized approach to transition more, not less, support during this understand the complexities involving timing is recommended, prioritizing the challenging developmental period. epidemiology, pathophysiology, compli- developmental needs and preferences There is a dearth of quality research cations, and quality of life and to improve of the patient. on high-risk behaviors (e.g., illicit drug long-term outcomes associated with the The ADA and numerous professional use, alcohol and tobacco use, unpro- disease in pediatrics. Adult diabetes re- societies recommend that pediatric di- tected sexual activity, and disordered search trials often do not include youth, abetes providers begin transition prep- eating) in youth with type 1 diabetes, and it is unclear how many, if any, of the aration during the early adolescent years although the few studies suggest that findings apply to the pediatric popula- but, at the latest, at least 1 year prior rates are similar to the general popu- tion; therefore, inclusion of a diverse to transfer (94). Preparation should in- lation (96). However, in youth with pediatric population is needed. Preserv- clude patient counseling on diabetes self- type 1 diabetes, the combination of ing b-cell function and ultimately pre- management, the differences between high-risk behaviors and dysglycemia venting type 1 diabetes is the aim. pediatric and adult care systems, the co- are potentially disastrous. Health care ordination of transfer, direct communica- providers should meet with youth alone tion with receiving adult providers, and a and conduct a comprehensive HEADSS Funding and Duality of Interest. J.L.C. serves written care summary. (home, education, eating, activities, drugs, as medical consultant for Diasome Pharmaceut- Please refer to ADA’s Position State- sexuality, suicide/depression, and safety) icals, Inc. and McKinsey & Company. D.M.M. has received research support from the National ment (94) for a comprehensive dis- assessment, incorporating diabetes as Institutes of Health (NIH), JDRF, the National cussion regarding the challenges of appropriate. Science Foundation, and the Helmsley Charitable emerging adulthood and specific tran- Engaging youth in highly supervised Trust, and his institution has received research sition care recommendations. Organi- and supportive environments, such as support from Medtronic, Dexcom, Insulet, Big- zations including Got Transition (189) diabetes camps, provides real-time ed- foot Biomedical, and Roche; he has consulted for Abbott, the Helmsley Charitable Trust, Sanofi, and the Endocrine Society (190) have ucation and reinforces the concept that and Eli Lilly and has served on an advisory board developed transition tools for clinicians, they are not alone. A recent study in for Insulet. K.C.G. has received research support patients, and families. Clinical trials to emerging adults with type 1 diabetes from NIH. K.K.H. has received grants from Dexcom study interventional approaches to tran- showed that young adults with diabetes and personal fees from Johnson & Johnson Di- abetes Institute, Lilly Innovation Center, and sition preparation and transfer coordi- fared comparably to their peers without Bigfoot Biomedical, outside the submitted work. nation, in order to optimize biomedical diabetes in life path decisions, health L.M.L. has served as a consultant for Sanofi, and psychosocial outcomes, are still behaviors, and psychological well-being Novo Nordisk, Lilly, Dexcom, Menarini, Roche, needed. (192). Psychosocial research studies that Unomedical, MannKind, Boehringer Ingelheim, evaluate quality-of-life measures and AstraZeneca, Johnson & Johnson, Merck, and Insulet, outside the submitted work. She has also effective behavioral interventions in received research support from NIH, JDRF, and CONCLUSIONS youth with type 1 diabetes are critically the Helmsley Charitable Trust. S.A.W. has received Multicenter collaborative research and important. grants and personal fees from Medtronic and serves technological advances have increased Technological advances have revolu- as a consultant for Tandem, Insulet, and Sanofi, type 1 diabetes disease understanding tionized diabetes management with outside the submitted work. J.I.W. receives roy- alties for his role as an editor for UpToDate. and led to advances in treatment. How- novel hardware, software, and the ability D.S. has served as a consultant to Sanofi, had ever, management of type 1 diabetes to capture endless streams of data. Im- a TrialNet grant in part from Sanofi, has been in youth remains imperfect, requiring proved data quality, including improv- on the external advisory board for Sankyo, unending vigilance and behavioral inter- ing current methods to translate data and had grants from JDRF and the Helmsley fl vention. While it is burdensome to all from diabetes devices to patient, family, Charitable Trust. No other potential con icts of interest relevant to this article were reported. affected individuals and their families, it and provider use, are needed to trans- is particularly challenging to those with form clinical care. Future clinical studies References limited resources and skills. Interdic- should evaluate how best to leverage fi 1. Silverstein J, Klingensmith G, Copeland K, tion studies have yet to accomplish their the technology tools and ef ciently an- et al.; American Diabetes Association. Care of goals of preventing and preserving b-cell alyze and translate the data generated children and adolescents with type 1 diabetes: function. into diabetes management. Patients a statement of the American Diabetes Associa- Type 1 diabetes requires youth to would benefit from device manufac- tion. Diabetes Care 2005;28:186–212 conform their lifestyle and behavior to turers enabling data interoperability, 2. Dabelea D, Mayer-Davis EJ, Saydah S, et al.; SEARCH for Diabetes in Youth Study. Prevalence a diabetes care regimen to control dis- regulatory agencies expediting and har- of type 1 and type 2 diabetes among children ease outcomes. In young children (under monizing approvals, and payors reim- and adolescents from 2001 to 2009. JAMA 6 years old), sick-day management, hy- bursing the numerous supplies needed 2014;311:1778–1786 poglycemia unawareness, and caregiver to optimize type 1 diabetes manage- 3. Mayer-Davis EJ, Lawrence JM, Dabelea D, et al.; SEARCH for Diabetes in Youth Study. issues are common but are manageable ment in a timely manner, especially for Incidence trends of type 1 and type 2 diabetes with education and attentiveness (191). the pediatric population. All patients with among youths, 2002–2012. N Engl J Med 2017; When adolescents seek independence, type 1 diabetes should have access to 376:1419–1429 2040 Position Statement Diabetes Care Volume 41, September 2018

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