Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association

Transcription

1 Diabetes Care 1 Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the Amerian Diabetes Assoiation Silva Arslanian, 1,2 Fida Baha, 3 Margaret Grey, 4,5 Marsha D. Marus, 6 Neil H. White, 7 and Philip Zeitler 8 Although all types of diabetes result in hyperglyemia, the pathophysiology of eah type of diabetes is different. These guidelines summarize available data speifi to the omprehensive are of youth with type 2 diabetes. The objetive is to enrih the reognition of type 2 diabetes in youth, its risk fators, its pathophysiology, its management, and the prevention of assoiated ompliations. PATHOPHYSIOLOGY Gluose homeostasis is maintained by a balane between insulin seretion from the panreati b-ells and sensitivity to insulin in skeletal musle, adipose tissue, and liver (1). When insulin sensitivity delines, insulin seretion must inrease to maintain gluose tolerane, and, in most youth, dereased insulin sensitivity due to puberty and/or obesity is ompensated by inreased insulin seretion. However, when b-ells annot serete suffiient insulin to ompensate for insulin resistane, abnormalities in gluose homeostasis ensue, potentially progressing to prediabetes and type 2 diabetes as b-ell funtion deteriorates further (2 9). The relationship between b-ell funtion and insulin sensitivity in adults and youth has been demonstrated to be a hyperboli funtion and an be desribed mathematially as the produt of insulin sensitivity and b-ell funtion, alled the disposition index (DI) (1). The DI essentially expresses the amount of insulin being sereted relative to the degree of insulin resistane and is a onstant for a given degree of gluose tolerane in any one individual. Overweight and obesity are major aquired ontributors to the development of insulin resistane, partiularly in the fae of the physiologi insulin resistane harateristi of puberty. Robust panreati b-ell ompensatory insulin seretion maintains normal gluose homeostasis. However, in adolesents with obesity who develop type 2 diabetes, there is severe peripheral and hepati insulin resistane, with ;50% lower peripheral insulin sensitivity than peers with obesity without diabetes, along with inreased fasting hepati gluose prodution and inadequate first- and seond-phase insulin seretion, resulting in ;85% lower DI (2). Additional abnormalities in youth with type 2 diabetes inlude impaired gluose sensitivity of insulin seretion, lower serum adiponetin onentrations, and redued inretin effet (3,9 13). While upregulation of a-ell funtion with hypergluagonemia has been impliated in the pathophysiology of type 2 diabetes in adults (14,15), there are limited data in youth with type 2 diabetes, with studies showing either hypergluagonemia or no differene from ontrol subjets without diabetes (3,11,16,17). Cross-setional and longitudinal studies in youth with obesity along the spetrum of glyemia from normoglyemia to prediabetes to type 2 diabetes show, as in adults, that b-ell failure with delining insulin seretion relative to insulin sensitivity results in prediabetes and type 2 diabetes in high-risk youth (5 9,18 21). Importantly, however, prior to reahing the Amerian Diabetes Assoiation (ADA)-defined fasting and oral gluose tolerane test (OGTT)-stimulated glyemi ut points for the diagnosis of prediabetes, youth, like adults, already demonstrate delining b-ell funtion relative to insulin sensitivity (6 8). Also, youth with A1C in the at-risk/ prediabetes ategory ($5.7 to,6.5%) demonstrate impaired b-ell funtion ompared with those with A1C,5.7% (22). A ombination of obesity, genetis, Diabetes Care Publish Ahead of Print, published online November 13, Division of Pediatri Endorinology, Metabolism, and Diabetes Mellitus, University of Pittsburgh, Pittsburgh, PA 2 Center for Pediatri Researh in Obesity and Metabolism, UPMC Children s Hospital of Pittsburgh, Pittsburgh, PA 3 Children s Nutrition Researh Center, Texas Children s Hospital and Baylor College of Mediine, Houston, TX 4 Yale Shool of Nursing, New Haven, CT 5 Yale Shool of Mediine, New Haven, CT 6 University of Pittsburgh Shool of Mediine, Pittsburgh, PA 7 Washington University Shool of Mediine in St. Louis, St. Louis, MO 8 Children s Hospital Colorado and University of Colorado Shool of Mediine, Aurora, CO Corresponding author: Silva Arslanian, silva. arslanian@hp.edu. This position statement was reviewed and approved by the Amerian Diabetes Assoiation Professional Pratie Committee and ratified by the Amerian Diabetes Assoiation Board of Diretors in September For further information on the ADA evidenegrading system and the levels of evidene, please see Table 1 in the Amerian Diabetes Assoiation s Introdution setion of the Standards of Medial Care in Diabetesd2017. Diabetes Care 2018;41(Suppl. 1):S1 S2, d18-sint01. The authors are solely responsible for the ontents of this artile, whih do not neessarily represent the offiial views of the NIDDK by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. More information is available at POSITION STATEMENT

2 2 Position Statement Diabetes Care the hormonal milieu, inretins and/or their effet, and metaboli alterations, suh as gluotoxiity and/or lipotoxiity, are likely to ontribute to deteriorating b-ell funtion against the bakdrop of insulin resistane, eventually ulminating in prediabetes and type 2 diabetes in atrisk youth. Based on the baseline data from the Restoring Insulin Seretion (RISE) study (23,24), there appear to be important differenes in insulin sensitivity and b-ell funtion between youth and adults with similar degrees of dysglyemia, inluding greater insulin resistane for any degree of adiposity and greater insulin seretion for any degree of insulin resistane in youth ompared with adults. RISK, SCREENING, AND DIAGNOSIS Risk Fators Nonmodifiable risk fators for youthonset type 2 diabetes inlude genetis/ epigenetis, manifested as a strong family history of type 2 diabetes in first- or seond-degree relatives; being the offspring of a pregnany ompliated by gestational diabetes mellitus (GDM); minority rae/ethniity; and physiologi insulin resistane of puberty. Metaboli evidene of geneti suseptibility an be deteted in the first deade of life, manifested as impaired insulin sensitivity and redued insulin seretion in otherwise healthy youth with a family history of type 2 diabetes (25). This geneti suseptibility, when ombined with environmental fators onduive to obesity and a sedentary lifestyle, may ultimately translate to type 2 diabetes. Indeed, in a study of youth with obesity, a geneti risk sore for b-ell dysfuntion from five single nuleotide polymorphisms was assoiated with a higher hane of prediabetes and type 2 diabetes (26). Dozens of speifi geneti variants linked to type 2 diabetes have been identified in adults (27,28), but these only aount for about 10% of its heritability (29,30). Partiular geneti variants that predispose to diabetes in youth have been identified in Oji-Cree Native Canadians (31) and Afrian Amerian youth (32), but information in other populations is only now emerging. Evidene from both animal and human studies suggests that maternal obesity and GDM ontribute to obesity and type 2 diabetes in youth (33,34). In the Treatment Options for Type 2 Diabetes in Adolesents and Youth (TODAY) ohort, one-third were born after a pregnany ompliated by preexisting diabetes or GDM (35). In the SEARCH for Diabetes in Youth (SEARCH) study, a population-based study of the epidemiology of type 1 and type 2 diabetes in youth in the U.S., exposure to maternal GDM or pregestational diabetes and maternal obesity were independently assoiated with type 2 diabetes in adolesents, with intrauterine exposure to these two risk fators present in 47.2% of type 2 diabetes in the ohort (36). Age of onset of type 2 diabetes was also younger in those exposed to diabetes during gestation. Inidene and prevalene of type 2 diabetes are highest among youth from a minority rae/ethniity (37), likely as a onsequene of many fators, inluding genetis, metaboli harateristis, ultural/environmental influenes, and quality of and aess to health are. Several studies have demonstrated signifiant differenes by rae/ethniity in insulin sensitivity and seretion that might heighten the risk of type 2 diabetes (38 42). Type 2 diabetes typially ours in adolesents at midpuberty (for example, the mean age of diagnosis was 14 years in the TODAY study) (43), most likely preipitated by the physiologi, but transient, pubertal insulin resistane aggravating the preexisting metaboli hallenges of obesity. Cross-setional and longitudinal studies show that insulin sensitivity delines by 25 30% as youth transition from prepuberty to puberty (44 46). In the presene of normally funtioning b-ells, puberty-related insulin resistane is ompensated by inreased insulin seretion/hyperinsulinemia, suh that DI remains normal. In youth who are predisposed to develop prediabetes and/or type 2 diabetes, b-ell ompensation is inadequate with progressive deline in the DI, ultimately resulting in dysglyemia (46,47). In youth-onset type 2 diabetes, the major modifiable risk fators are obesity and lifestyle habits of exess nutritional intake, low physial ativity, and inreased sedentary behaviors with dereased energy expenditure, resulting in the surplus of energy being stored as body fat. Other potentially modifiable risk fators for type 2 diabetes in adolesents and young adults inlude hroni stress and/or depressed mood (48,49) and sleep-related disorders (50 52). Risk Assessment and Diagnosti Criteria Reommendations Risk-based sreening for prediabetes and/or type 2 diabetes should be onsidered after the onset of puberty or after 10 years of age, whihever ours earlier, in hildren and adolesents who are overweight (BMI $85th perentile) or obese (BMI $95th perentile) A and who have additional risk fators for diabetes (see Table 1 for evidene grading of other risk fators). If tests are normal, repeat testing at a minimum of 3-year intervals E, or more frequently if BMI is inreasing. C Fasting plasma gluose, 2-h plasma gluose after 75-g OGTT, or A1C an be used to test for prediabetes or diabetes. B Risk-based sreening for prediabetes and/or type 2 diabetes is timed after the onset of puberty or after 10 years of age, whihever ours earlier, beause the majority of youth-onset type 2 diabetes ours during puberty, as stated above, and rarely in prepubertal hildren. However, some youth with obesity may have earlier onset of puberty than usual, neessitating sreening before 10 years of age. In addition, in North Ameria almost all youth with type 2 diabetes are overweight/obese, hene the reommendation to sreen youth with overweight/obesity. In other parts of the world where youth with type 2 diabetes are not neessarily overweight and/or obese, linial judgment should guide whom to sreen. Although there is no robust evidene-based rationale for the proposed frequeny of testing, inreasing BMI has been shown to be a preditor of deteriorating glyemia and progression to type 2 diabetes (21). Therefore, liniians aring for youth with overweight/obesity with ontinued inrease in their BMI should be aware of the need for more frequent sreening. The laboratory glyemia-based diagnosti riteria for diabetes and prediabetes are the same for youth and adults, regardlessoftypeofdiabetes(table 2) (53). However, these riteria are

3 are.diabetesjournals.org Arslanian and Assoiates 3 Table 1 Risk-based sreening for type 2 diabetes or prediabetes in asymptomati hildren and adolesents in a linial setting* Criteria Overweight (BMI.85th perentile for age and sex, weight for height.85th perentile, or weight.120% of ideal for height). A Plus additional risk fators based on the strength of their assoiation with diabetes: Maternal history of diabetes or GDM during the hild s gestation. A Family history of type 2 diabetes in first- or seond-degree relative. A Rae/ethniity (Native Amerian, Afrian Amerian, Latino, Asian Amerian, Paifi Islander). A Signs of insulin resistane or onditions assoiated with insulin resistane (aanthosis nigrians, hypertension, dyslipidemia, polyysti ovary syndrome, or small-for-gestationalage birth weight). B *Persons aged,18 years. extrapolated from adults, and the epidemiologial studies that formed the basis for both gluose and A1C definitions of diabetes did not inlude pediatri populations. Therefore, the exat relevane of these definitions for pediatri populations remains unlear until more data beome available. The A1C test is universally available and an be performed any time of the day without need for fasting. However, several studies have questioned its validity in the pediatri population beause of poor sensitivity for identifying hildren with dysglyemia and underestimation of the prevalene of prediabetes and diabetes (54 56). Fasting and OGTT riteria have not been validated in youth, either. Studies using ontinuous gluose monitoring (CGM) in youth with obesity demonstrated that A1C and OGTT are equally effetive at identifying glyemi abnormalities on CGM, but the glyemi patterns differ (57); abnormal A1C was assoiated with higher overall and nighttime average gluose on CGM, while abnormal OGTT was assoiated with more time spent above the normal gluose range during the day. Institution of A1C sreening in a large primary are network inreased provider adherene to sreening reommendations ompared with OGTT sreening while identifying the same prevalene of type 2 diabetes (58). Furthermore, in this ohort, the progression to linially onfirmed diabetes was substantially more likely for those with A1C.6% (18.4%) than for those with levels % (1.3%). Therefore, sreening with fasting Table 2 Criteria for the diagnosis of prediabetes and diabetes Prediabetes A1C 5.7% to,6.5% (39 to,48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP ertified and standardized to the DCCT assay. IFG: fasting gluose $100 but,126 mg/dl ($5.6 but,7.0 mmol/l). IGT: 2-h plasma gluose $140 but,200 mg/dl ($7.8 but,11.1 mmol/l) during an OGTT. The test should be performed as desribed by the World Health Organization, using a gluose load ontaining the equivalent of 1.75 mg/kg (max 75 g) anhydrous gluose dissolved in water.* Diabetes A1C $6.5% ($48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP ertified and standardized to the DCCT assay.* OR FPG $126 mg/dl (7.0 mmol/l). Fasting is defined as no alori intake for at least 8 h.* OR 2-h plasma gluose $200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as desribed by the World Health Organization, using a gluose load ontaining the equivalent of 1.75 mg/kg (max 75 g) anhydrous gluose dissolved in water* OR In a patient with lassi symptoms of hyperglyemia or hyperglyemi risis, a random plasma gluose.200 mg/dl (11.1 mmol/l). FPG, fasting plasma gluose; IFG, impaired fasting gluose; IGT, impaired gluose tolerane; max, maximum. *In the absene of unequivoal hyperglyemia, result should be onfirmed by repeat testing. gluose, OGTT, or A1C is an aeptable approah but should be based on sound linial judgment, reognition of the strengths and weaknesses of eah test, and the failities and resoures available. Confirming Diabetes Type Reommendations Children and adolesents with overweight/obesity in whom the diagnosis of type 2 diabetes is being onsidered should have a panel of panreati autoantibodies tested to exlude the possibility of autoimmune type 1 diabetes. B Geneti evaluation to exlude monogeni diabetes should also be based on linial harateristis and presentation. B As stated above, youth with type 2 diabetes in the U.S. are harateristially overweight and/or obese, in mid- to late puberty, with overrepresentation of minority ethni/raial groups and females (4,43,59). The linial presentation varies widely from asymptomati or minimally symptomati, diagnosed inidentally during routine laboratory testing, to a severe presentation with symptomati hyperglyemia, weight loss, metaboli deompensation, diabeti ketoaidosis (DKA), or hyperglyemi hyperosmolar nonketoti (HHNK) syndrome (4). Obesity is a onsistent feature of youth-onset type 2 diabetes in the U.S. However, beause of the esalating rates of obesity in the general population, hildren with both type 1 diabetes and monogeni diabetes are also more likely to be overweight/obese than in the past (60), making the linial distintion between type 2 diabetes and obese type 1 or monogeni diabetes diffiult. This was illustrated in the TODAY study in whih, of the 1,206 youth linially diagnosed with type 2 diabetes and sreened for irulating GAD65 and IA2 antibodies, 118 (9.8%) were antibody positive (Ab 1 ) (61). Even though these Ab 1 individuals had linial harateristis that overlapped with the antibodynegative (Ab 2 ) youth, they were less likely to be obese, have features of metaboli syndrome, have a family history of diabetes, be female, or be from a minority rae/ethniity, indiating a phenotype more similar to their peers with type 1 diabetes. Pathophysiologially,

4 4 Position Statement Diabetes Care Ab 2 youth with obesity are more insulin resistant than Ab 1 youth with obesity, while Ab 1 youth have more severe insulin defiieny (61 64). Fasting and stimulated C-peptide are signifiantly lower in Ab 1 youth with obesity and diabetes, though with appreiable overlap (63). Moreover, Ab 2 youth are more likely to exhibit features of the metaboli syndrome (elevated systoli blood pressure and ALT), while Ab 1 youth have signifiantly more frequent ketonuria at initial presentation (61,64). The reported rates of positive panreati autoantibodies in youth linially diagnosed with type 2 diabetes vary from 10% to 75% (4,62), likely depending on the ratio of type 1 and type 2 diabetes in the population. The linial distintion between youth with type 2 diabetes and youth with obesity and type 1 or monogeni diabetes is further blurred beause youth with type 2 diabetes often present with some degree of ketosis, inluding DKA (65). The distintion between these forms of diabetes in youth with obesity has important impliations for treatment (66), sine Ab 1 youth present more like individuals with type 1 diabetes, progressing to insulin requirement more rapidly (61), and are at risk for other autoimmune disorders. Therefore, measurement of panreati autoantibodies is reommended in all youth with linial harateristis of type 2 diabetes. This testing should inlude GAD65 and IA2 antibodies, along with insulin autoantibody in individuals who have not yet been exposed to exogenous insulin. The benefit of measurement of ZnT8 antibody in individuals with phenotypi type 2 diabetes is not yet lear. We further reommend that antibodies be measured in a laboratory aligned with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Panreati Autoantibody Standardization Program beause urrently available ommerial assays may not be suffiiently sensitive or speifi. However, in all ases, linial judgment and the presene of other risk fators for type 1 diabetes or type 2 diabetes should be onsidered in making the diagnosis, and the health are team should remain open to reonsidering the initial diagnosis. Sine % of youth with linial features suggestive of type 2 diabetes have been found to have monogeni diabetes, geneti testing for monogeni forms of diabetes should be onsidered as well (67 69). GLYCEMIC TARGETS Reommendations A1C should be measured every 3 months. E A reasonable A1C goal for most hildren and adolesents with type 2 diabetes treated with oral agents alone is,7%. More stringent A1C goals (suh as,6.5%) may be appropriate for seleted individual patients if they an be ahieved without signifiant hypoglyemia or other adverse effets of treatment. Appropriate patients might inlude those with short duration of diabetes and lesser degrees of b-ell dysfuntion and patients treated with lifestyle or metformin only who ahieve signifiant weight improvement. E A1C targets for youth on insulin should be individualized, taking into aount the relatively low rate of hypoglyemia in youthonset type 2 diabetes. E Home self-monitoring of blood gluose (SMBG) regimens should be individualized, taking into onsideration the pharmaologi treatment of the patient. E Previous target A1C guidelines by the ADA and the International Soiety for Pediatri and Adolesent Diabetes for youth with type 2 diabetes ranged from,6.5% to,7.0% (70,71) and,7.5% (72), mostly based on expert opinion and extrapolated from youth with type 1 diabetes and adults with type 2 diabetes. However, aumulating evidene provides support for more appropriate goals. The TODAY study showed that hypoglyemia is rare in adolesents with type 2 diabetes, even with insulin therapy (73), suggesting that more stringent A1C targets are aeptable. Also in TODAY, individuals with an A1C of.6.3% after 3 months of metformin or an inreasing A1C, even in the nondiabetes range (74), had a substantially inreased risk for loss of glyemi ontrol, likely refleting a greater degree of b-ell dysfuntion (75,76). Furthermore, individuals with youth-onset type 2 diabetes have high rates of ompliations (77 79), many of whih are assoiated with poor glyemi ontrol, and rapid deterioration with inreasing A1C. Finally, youth with type 2 diabetes an be expeted to have long disease duration and, therefore, ontinued risk for aumulation of glyemia-related ompliations. Taken together, this evidene suggests that a more stringent A1C target an and should be attained in youth with type 2 diabetes. The evidene is insuffiient regarding the value of SMBG and how often testing should be performed by youth with type 2 diabetes not on insulin therapy. Until suh data beome available, the frequeny of SMBG should be individualized, taking into aount patient and family burden, the value of the information obtained and how it will be used to adjust therapy, and the assoiated hypoglyemia risk. LIFESTYLE MANAGEMENT Diabetes Eduation and Self-Management Skills Reommendation All youth with type 2 diabetes and their families should reeive omprehensive diabetes self-management eduation/support that is speifi to youth with type 2 diabetes and is ulturally ompetent. B It has been well established that diabetes eduation is neessary, but not suffiient, to enhane self-management in people with diabetes (80,81). The majority of these studies, however, foused on adults with type 2 diabetes and/or youth with type 1 diabetes. Sine the population of youth with type 2 diabetes is more likely to be of minority ethni/raial bakground than those with type 1 diabetes, and materials developed for adults may not address issues of development in youth, ulturally appropriate programs speifi to youth with type 2 diabetes and their families are neessary. Unfortunately, there are no randomized linial trials of eduation and support programs for youth with type 2 diabetes. Nonetheless, desriptive reports suggest that programs that fous on building knowledge and skills appropriate to this population are important in ensuring adequate selfmanagement.

5 are.diabetesjournals.org Arslanian and Assoiates 5 In the TODAY trial (81), the diabetes eduation program inluded ontent about type 2 diabetes physiology and treatment, building skills of healthy eating habits, arbohydrate ounting, portion sizes, reading food labels, gluose monitoring, and ketone testing, as well as problem solving, risk redution, and living with diabetes. Full mastery of the program was ahieved in an average of min sessions. Fators assoiated with shorter time to mastery inluded more reent diagnosis and not having to use a translator, while sex, primary language of the youth and family, individual versus group sessions, or site of delivery were not. These program materials are available from the ADA as Be Healthy Today (82). Given the lak of linial trials of various eduational approahes, it is unlear that this program is superior to other approahes. Nonetheless, the program provides effetive, engaging materials for youth with type 2 diabetes that were designed speifially for this population. Until omparative trials of various approahes are ompleted, diabetes eduation using these materials is appropriate (83). Psyhosoial Fators Reommendations Providers should assess soial ontext, inluding potential food inseurity, housing stability, and finanial barriers, and apply that information to treatment deisions. E Use patient-appropriate standardized and validated tools to assess diabetes distress and mental/ behavioral health in youth with type 2 diabetes, with attention to symptoms of depression and disordered eating behaviors, and refer to speialty are when indiated. B When hoosing gluose-lowering or other mediations for youth with overweight/obesity and type 2 diabetes, onsider mediation adherene and treatment effets on weight. E Starting at puberty, preoneption ounseling should be inorporated into routine diabetes lini visits for all females of hildbearing potential. A Patients should be sreened for smoking and alohol use at diagnosis and regularly thereafter. C The ADA position statement on the provision of psyhosoial are for people living with diabetes reognizes the profound influene of psyhosoial fators on health outomes and well-being (84). The reommendations herein are onsistent with those outlined in that position statement, an important resoure for more detailed information about lifeourse issues and assessment of psyhosoial omorbidities. Most youth with type 2 diabetes ome from raial and ethni minority groups, have low soioeonomi status, and have a family history of diabetes (37,85,86). Families often experiene multiple stressors inluding food inseurity, employment and housing instability, and diffiulties with aess to treatment; youth also may have been exposed to early adversity, whih has been shown to affet health over time (87). Providers should personalize approahes to diabetes management to minimize barriers to are, enhane adherene, and maximize response to treatment by taking into onsideration the soioultural ontext of the patient and their family. Youth with type 1 diabetes have high rates of diabetes distress and psyhiatri symptoms and diagnoses (in partiular, depression and disordered eating behaviors) neessitating ongoing surveillane of mental and behavioral health. Evidene about psyhiatri disorders and symptoms in youth with type 2 diabetes is limited (88 92), but given the soioultural ontext and the medial burden, as well as preexisting obesity-assoiated omorbidities together with type 2 diabetes, ongoing surveillane of mental health/behavioral health is also indiated in youth with type 2 diabetes. Symptoms of depression and disordered eating are ommon in youth with type 2 diabetes and assoiated with poorer glyemi ontrol (89). The prevalene of linially signifiant symptoms of depression among youth with type 2 diabetes was reported to be 8.6% in the SEARCH ohort of youth with type 1 and type 2 diabetes (89) and 14.8% in the TODAY ohort of youth with type 2 diabetes (93). In addition, more than 25% of females and males in the SEARCH ohort of youth with type 2 diabetes reported symptoms of disordered eating behaviors, suh as skipping insulin, vomiting, and using diet pills or laxatives, and these behaviors were assoiated with poorer glyemi ontrol in females (89). Binge eating rates in the TODAY ohort were high (26%) and were assoiated with more severe obesity, psyhologial symptoms of disordered eating, and symptoms of depression (94). More researh is needed to evaluate rates of diagnosable psyhiatri disorders, trauma, vitimization, and psyhotropi drug use in youth with type 2 diabetes. It also is important to eluidate the relationships among obesity, psyhiatri disorders, and mediation regimens beause many of the drugs presribed for diabetes and psyhiatri disorders are assoiated with weight gain and inreased onerns about eating, shape, and weight (95,96). Finally, in aord with the ADA s Standards of Medial Care in Diabetesd2018 (97), preoneption ounseling should be provided starting at puberty for all girls of hildbearing potential in order to inrease understanding of risk related to diabetes and improve health prior to oneption. In the TODAY study (98), despite ounseling on pregnany redution designed speifially for youth with type 2 diabetes, 10.2% of the females in the ohort beame pregnant over an average of 3.8 years of study partiipation. Of note, 26.4% of pregnanies ended in a misarriage, stillbirth, or intrauterine death, and 20.5% of the liveborn infants had a major ongenital anomaly. These data onfirm the importane of eduating young women with type 2 diabetes to time their pregnanies to redue risks to themselves and their offspring. More researh regarding pregnany outomes in youth with type 2 diabetes is needed. Lifestyle Modifiation, Weight Management, Exerise, and Nutrition Reommendations Youth with overweight/obesity and type 2 diabetes and their families should be provided with developmentally and ulturally appropriate omprehensive lifestyle programs that are integrated with diabetes management aiming to ahieve 7 10% derease in exess weight. C

6 6 Position Statement Diabetes Care Given the neessity of long-term weight ontrol and lifestyle management for hildren and adolesents with type 2 diabetes, lifestyle intervention should be based on a hroni are model and offered in the ontext of diabetes are. E Youth with diabetes, like all hildren, should be enouraged to partiipate in at least min of moderate to vigorous physial ativity at least 5 days per week (and strength training on at least 3 days per week) B and should be enouraged to derease sedentary behavior. C Nutrition for youth with type 2 diabetes, like all hildren, should fous on healthy eating patterns that emphasize onsumption of nutrient-dense, high-quality foods and derease onsumption of alorie-dense, nutrient-poor foods, partiularly sugar-added beverages. B The utility of pharmaotherapy for weight redution in youth with type 2 diabetes remains limited in the absene of approved, effetive, and safe mediations and the lak of linial trials in youth with type 2 diabetes. B Lifestyle modifiation programs that inorporate evidene-informed behavioral strategies to promote hanges in diet and physial ativity (99) are a ornerstone of treatment for adults with type 2 diabetes beause the resulting redutions of 5 7% of initial body weight are assoiated with improvements in blood gluose levels and other risk parameters. Muh less is known about the impat of lifestyle interventions in youth with type 2 diabetes, although 90% are overweight or obese. Family-based behavioral weight management programs in shool-aged hildren without diabetes have a modest, but positive, impat on weight and ardiometaboli risk fators but are less effetive in adolesents and hildren with more severe obesity ( ). Intensive weight management, when ompared with usual treatment, an have sustained benefits over a 2- year period for ethnially and raially diverse inner-ity hildren and adolesents with an average BMI.35 (102,103). Although BMI hanges in treated youth were modest (103), those who reeived usual are showed inreases in BMI over the period of observation, while the intervention group had ontinued improvements in body omposition and insulin resistane relative to those who did not reeive weight management. The most pertinent evidene regarding the impat of lifestyle interventions for youth with type 2 diabetes omes from the TODAY study (104), where the goal was to ahieve 7 10% derease in perent overweight. The addition of lifestyle intervention to metformin monotherapy was not assoiated with durable metaboli ontrol beyond that of metformin alone. Youth reeiving metformin plus lifestyle intervention showed shortterm, but not sustained, weight loss and improvements in body omposition relative to those in the two other intervention groups (105). While 31% of youth who reeived lifestyle intervention ahieved the preplanned goal of a derease of $7% in perent overweight through 24 months of intervention, this result did not differ signifiantly from that obtained with metformin monotherapy and no preditors of suessful weight loss were identified. However, irrespetive of treatment assignment, sustained weight losses $7% of exess body weight were assoiated with improvements in A1C, HDL, and C-peptide (105), indiating that obesity management remains a ruial goal. Components of a omprehensive pediatri lifestyle intervention are well established (106,107), inluding those for youth with severe obesity (108). These inlude the involvement of family at a developmentally appropriate level and evidene-based behavioral strategies to failitate enduring hanges in nutrition and physial ativity. Guidelines for physial ativity and nutrition are based on those reommended by the Amerian Aademy of Pediatris (2007) (107) and the Endorine Soiety (2017) (106). Youth with type 2 diabetes frequently have severe obesity, and it is partiularly important that behavior hange goals for diet and ativity inorporate stepwise, ahievable targets developed in onjuntion with the youth and family members, as appropriate. Youth with type 2 diabetes will fae inreasing severity of obesity and diabetes ompliations as they age ( ). An important first step is to integrate diabetes are and eduation, suh as the approah used in the TODAY trial, with ongoing lifestyle intervention for obesity management (106) to maximize the impat of medial and lifestyle interventions over time. Comprehensive hroni are models have been reommended for youth with obesity and hroni illness (112,113). With the exeption of orlistat, weight loss mediations are not approved for use in youth. The Endorine Soiety guidelines for pediatri obesity (106) review the limited evidene for effetiveness of urrent weight-loss mediations and reommends that their use be restrited to the researh setting. More researh into possible pharmaologi approahes to augment lifestyle interventions and their role in type 2 diabetes in youth is urgently needed. PHARMACOLOGIC APPROACHES TO GLYCEMIC MANAGEMENT Reommendations Initiate pharmaologi therapy, in addition to lifestyle therapy, at diagnosis of type 2 diabetes. A In inidentally diagnosed or metabolially stable patients (A1C,8.5% and asymptomati), metformin is the initial pharmaologi treatment of hoie if renal funtion is normal. A Youth with marked hyperglyemia (blood gluose $250 mg/dl, A1C $8.5%) without aidosis at diagnosis who are symptomati with polyuria, polydipsia, noturia, and/ or weight loss should be treated initially with basal insulin while metformin is initiated and titrated. B In patients with ketosis/ ketoaidosis, treatment with subutaneous or intravenous insulin should be initiated to rapidly orret the hyperglyemia and the metaboli derangement. One aidosis is resolved, metformin should be initiated while subutaneous insulin therapy is ontinued. A In individuals presenting with severe hyperglyemia (blood gluose $600 mg/dl), assess for HHNK syndrome. A

7 are.diabetesjournals.org Arslanian and Assoiates 7 In patients initially treated with insulin and metformin who are meeting gluose targets based on home blood gluose monitoring, insulin an be tapered over 2 6 weeks by dereasing the insulin dose 10 30% every few days. B If the glyemi target is no longer met using metformin alone, or if ontraindiations or intolerable side effets of metformin develop, basal insulin therapy should be initiated. B If the ombination of metformin plus basal insulin is ineffetive at ahieving or maintaining glyemi targets, more intensive approahes to insulin therapy may be initiated. E The use of nonapproved mediations in youth with type 2 diabetes is not reommended outside of researh trials. B In the linial setting, only a minority of youth with type 2 diabetes are on lifestyle management alone (114,115) beause it is often inadequate for ahieving and maintaining the desired level of glyemi ontrol and BMI improvement, with the perentage of patients remaining on lifestyle intervention alone delining further by 1 year (115). Therefore, in most ases, the addition of pharmaologi intervention early in the disease is warranted. As in adults, the pharmaologi intervention should be a stepped proess. However, sine only metformin and insulin are urrently approved for the treatment of diabetes in patients under 18 years old, the approah in youth is more limited. Initial Treatment Initial treatment of youth-onset type 2 diabetes should inlude metformin and/ or insulin alone or in ombination, based on the metaboli status of the patient. Initial treatment of the youth with obesity and diabetes must take into aount that diabetes type is often unertain in the first few weeks of treatment owing to overlap in presentation and that a substantial perentage of youth with type 2 diabetes will present with linially signifiant ketoaidosis (65). Therefore, immediate therapy should address the hyperglyemia and assoiated metaboli derangements irrespetive of ultimate diabetes type, with adjustment of therapy one metaboli ompensation has been established and subsequent information, suh as antibody results, beomes available. Figure1providesanapproahtoinitial treatment. Metformin Metformin is the preferred drug for initial treatment of type 2 diabetes in adults and youth. In the TODAY study, 48.3% of youth with type 2 diabetes who were Figure 1 Management of new-onset diabetes in overweight youth suspeted to have type 2 diabetes based on risk fators listed in Table 1. MDI, multiple daily injetions.

8 8 Position Statement Diabetes Care enrolled, with less than 2 years (median 8 months) of diabetes duration, maintained adequate glyemi ontrol (A1C,8.0%) on metformin alone for up to 6 years (104). However, youth were more likely than adults to require additional pharmaologi treatment to meet glyemi targets, with the other 51.7% of youth on metformin requiring insulin by 4 years, with a median time to treatment failure of 11.8 months. Asymptomati youth with presumptive type 2 diabetes who present in a stable metaboli state and have A1C,8.5% should be started on metformin as initial therapyif renal funtion is normal. Asymptomati patients with A1C $8.5% may also be given an initial trial of metformin monotherapy at the disretion of the health are provider, espeially if the patient and family situation suggest the promise of exellent adherene to lifestyle hange reommendations. The reommended approah to metformin initiation is to start with a dose of 500 1,000 mg/day and gradually esalate it every 1 2 weeks, depending on patient tolerability, to the reommended therapeuti dose of 1,000 mg b.i.d. Slower dosage esalation may be needed if gastrointestinal side effets our and, in some ases, the maximum dose may not be ahievable. Extended-release metformin may have fewer gastrointestinal side effets and be more onvenient for the patient, but there are no studies in youth omparing extended-release metformin to the standard metformin preparation. Metformin Plus Insulin Youthwithmarkedhyperglyemia(blood gluose $250 mg/dl and/or A1C $8.5%) without aidosis at diagnosis but who are symptomati with polyuria, polydipsia, noturia, and/or weight loss should be treated initially with basal insulin while onurrently initiating and titrating metformin. In patients with ketosis/ ketoaidosis at diagnosis, treatment with subutaneous or intravenous insulin should be initiated to rapidly orret the hyperglyemia and the metaboli derangement. One aidosis is resolved, metformin should be initiated while subutaneous insulin therapy is ontinued (116). In individuals presenting with severe hyperglyemia (blood gluose $600 mg/dl), assess for HHNK syndrome. One glyemi stability is ahieved, insulin may not be needed. Limited data suggest that adolesents with type 2 diabetes who present initially with DKA, ketosis, or symptomati hyperglyemia an be managed suessfully with metformin alone, at least initially after a short ourse of insulin therapy to establish glyemi stability (117). For example, in the TODAY study, more than 90% of the subjets sreened for study partiipation were initially ontrolled adequately on metformin alone regardless of prior insulin therapy (117). However, these TODAY partiipants were frequently ontated and losely monitored by the researh staff, a situation that may not be feasible in a linial setting. Whether or not early treatment with insulin provides unique benefits in youth with type 2 diabetes remains questionable. The reently ompleted RISE Pediatri Mediation Study in youth with obesity with impaired gluose tolerane or reent-onset type 2 diabetes did not demonstrate benefits of 3 months of basal insulin glargine followed by 9 months of metformin ompared with metformin alone for 12 months in preserving or restoring b-ell funtion (118). It remains to be determined if longer periods of insulin treatment may prove benefiial in preserving b-ell funtion. Ongoing Therapy When the individualized glyemi target an no longer be met with metformin alone, or if metformin intolerane or renal insuffiieny develops, insulin therapy should be initiated. This an be done alone or in ombination with metformin, unless metformin is ontraindiated. Beause studies indiate that adherene with insulin therapy is a hallenge in youth with type 2 diabetes (73,119), starting with a single daily dose of a long-ating insulin analog (glargine [Lantus, Basalglar, Toujeo], detemir [Levemir], or deglude [Tresiba]) may be preferred. Premixed insulins may be appropriate in some irumstanes. If the ombination of metformin at the maximum tolerated dose (up to 1,000 mg b.i.d.) plus basal insulin at a maximum dose of 1.5 units/kg/day is ineffetive at ahieving the glyemi target, mediation adherene should be atively addressed. When ombined metformin and basal insulin therapy does not ahieve targets, and in the absene of other approved drugs to treat diabetes in youth (,18 years old), higher doses of long-ating insulin or initiation of multiple daily injetions of basal and premeal rapid-ating insulin should be onsidered, though adherene to the latter may be a barrier. Beause severe insulin resistane is harateristi of youth with type 2 diabetes, basal insulin doses above 1.5 units/kg/day may be required to ahieve adequate glyemi ontrol, partiularly for those youth with elevated A1C and gluotoxiity and youth who are in midto late puberty. In these irumstanes, it may be appropriate to use more onentrated insulin preparations (U-300 glargine [Toujeo], U-200 Tresiba, U-200 Humalog, U-500 regular) to avoid largevolume injetions that may further diminish mediation adherene. The most signifiant adverse effet of insulin therapy in type 2 diabetes, as in type 1 diabetes, is hypoglyemia. Although the inidene of hypoglyemia in youth with type 2 diabetes is low, even with insulin therapy (73), patients treated with insulin should be eduated about avoidane, reognition, and treatment of hypoglyemia and should be instruted on the use of gluagon for treatment of severe hypoglyemia. Also, sine insulin may result in weight gain, involvement of a nutritionist in patient are and eduation is essential when insulin is initiated. Other Therapies Other than insulin and metformin, there are urrently more than 25 mediations in 10 general lasses that are ommerially available and FDA-approved for treatment of type 2 diabetes in adults in the U.S. (Table 3). It should be noted, however, that none of these are urrently approved for use in youth (,18 years old), and while some of these agents have undergone or are urrently undergoing pharmaokineti, pharmaodynamis, and safety/ tolerability testing in small pediatri studies, no effiay or long-term safety results have yet been reported in youth. Although the TODAY study demonstrated that the addition of rosiglitazone to metformin improved the durability of glyemi ontrol (treatment failure rate 38.6% for metformin plus rosiglitazone vs. 51.7% for metformin alone) with no inreased rate of adverse events over a 3 6 year period in youth with reentonset type 2 diabetes, it is premature to reommend its widespread use in

9 are.diabetesjournals.org Arslanian and Assoiates 9 Table 3 Drugs for treating type 2 diabetes in adults (not inluding insulin or insulin analogs) but not yet approved in youth exept for metformin Drug lass Available drugs in this lass Mehanism of ation Signifiant adverse effets Biguanides Metformin Dereases insulin resistane; redues hepati gluose prodution; inreases peripheral gluose uptake; dereases gastrointestinal absorption of gluose Sulfonylureas Meglitinides a-gluosidase inhibitors GLP-1 agonists DPP-4 inhibitors Glipizide Glimepiride Glyburide Repaglinide Nateglinide Aarbose Miglitol Exenatide Liraglutide Dulaglutide Lixisenatide Albiglutide Semaglutide Saxagliptin Sitagliptin Alogliptin Linagliptin Stimulates seretion of insulin from the b-ell Stimulates gluose-dependent seretion of insulin from the b-ell Delays absorption of gluose by intestines by inhibiting breakdown of omplex sugars Inretin effet; slows gastri emptying; enhanes postprandial insulin biosynthesis; improvesb-ell funtion; dereases appetite Inhibits DPP-4 enzyme, reduing endogenous GLP-1 breakdown Amylin analog Pramlintide Inhibits postprandial gluagon seretion; delays gastri emptying; improves satiety Thiazolidinediones SGLT-2 inhibitors Bile aid sequestrant Dopamine-2 agonist Rosiglitazone Pioglitazone Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Colesevelam Bromoriptine (quik release) PPAR-g inhibitor; inreases insulin sensitivity in liver, musle, and adipose tissue; dereases hepati gluose output Allows more gluose to be exreted in the urine and hene lowers blood gluose Mehanism for gluose lowering is unknown Modulates hypothalami regulation of metabolism; inreases insulin sensitivity Gastrointestinal Lati aidosis Hypoglyemia Weight gain Hypoglyemia URI Diarrhea Headahe Flatulene Diarrhea Abdominal ramps Aute panreatitis C-ell hyperplasia/ medullary thyroid arinoma Nausea/vomiting Hypoglyemia Diarrhea Headahe Aute panreatitis URI UTI Nasopharyngitis Headahe Hypoglyemia Nausea Anorexia Abdominal pain Edema Weight gain Anemia Elevated liver enzymes Euglyemi ketoaidosis UTI Candidal vulvovaginitis Gastrointestinal (gas, nausea, diarrhea, abdominal pain) Weakness Musle pain Nausea/vomiting Fatigue Dizziness Headahe Approved in patients,18 years old DPP-4, dipeptidyl peptidase 4; GLP-1, gluagon-like peptide 1; PPAR, peroxisome proliferator ativated reeptor; SGLT2, sodium gluose otransporter 2; URI, upper respiratory infetion; UTI, urinary trat infetion. Yes No No No No No No No No No No youth with type 2 diabetes, espeially sine its use is not approved in the pediatri population. Even though many of the newer agents approved in the adult population are promising and may have partiular benefits in younger individuals with diabetes, we annot reommend widespread use of these mediations until additional studies are ompleted. Unfortunately, implementation and ompletion of suh studies have been slow and many barriers have been identified (111). Therefore, we reommend that the use of these mediations in youth with type 2 diabetes be avoided outside of researh trials. However, ollaboration among investigators, pharmaeutial sponsors, and governmental regulators is urgently needed to expand treatment options for this population of patients. METABOLIC SURGERY Reommendations Metaboli surgery may be onsidered for the treatment of adolesents with type 2 diabetes who are markedly obese (BMI.35 kg/m 2 )

10 10 Position Statement Diabetes Care and who have unontrolled glyemia and/or serious omorbidities despite lifestyle and pharmaologi intervention. A Metaboli surgery should be performed only by an experiened surgeon working as part of a wellorganized and engaged multidisiplinary team inluding surgeon, endorinologist, nutritionist, behavioral health speialist, and nurse. A Bariatri or metaboli surgery, inluding Roux-en-Y gastri bypass, vertial sleeve gastretomy, laparosopi adjustable gastri banding, laparosopi gastri pliation, and biliopanreati diversion, has been shown to signifiantly redue weight, BMI (120), and ardiovasular omorbidities (121) in adults with obesity and is now onsidered a standard omponent of are for adults with morbid obesity. Metaboli surgery is also an effetive strategy for prevention (122,123) and treatment of type 2 diabetes in obese and severely obese (BMI $30 kg/m 2 ) adults ( ) and is now endorsed as part of the algorithm for treating type 2 diabetes in adults (127). Over the last deade, weight-loss surgery has been inreasingly performed in adolesents with obesity, but the longterm experiene remains limited. The urrent guidelines for metaboli surgery in adolesents generally inlude BMI.35 kg/m 2 with signifiant omorbidities or BMI.40 kg/m 2 with or without omorbidities (106, ). The Endorine Soiety Clinial Pratie Guideline on Pediatri Obesity disusses bariatri surgery for the management of pediatri obesity in detail, and interested readers an refer to it (106). Briefly, positive outomes of metaboli surgery have inluded remission of type 2 diabetes, improvements in gluose homeostasis in youth without diabetes, improvement in surrogate markers of insulin sensitivity and seretion, resolution of sleep apnea, improvements in nonaloholi fatty liver disease (NAFLD), and improvements in ardiovasular disease (CVD) risk fators, among others (106, ). Diret omparison between the medial management of youth with type 2 diabetes and bariatri surgery outome, both short- and long-term, is very limited. A reent study ompared youth with type 2 diabetes from the Teen-Longitudinal Assessment of Bariatri Surgery (Teen-LABS) ohort who had undergone a bariatri surgial proedure with youth with medially treated type 2 diabetes from the TODAY ohort. During 2 years, A1C dereased from 6.8% to 5.5% in Teen-LABS and inreased from 6.4% to 7.8% in TODAY, BMI dereased by 29% in Teen-LABS and inreased by 3.7% in TODAY, elevated blood pressure dereased from 45% to 20% of partiipants in Teen-LABS and inreased from 22% to 41% in TODAY, and dyslipidemia dereased from 72% to 24% in Teen-LAB versus no appreiable hange in TODAY (142). Overall, studies in both adults and adolesents suggest that those who undergo bariatri surgery earlier in the ourse of diabetes (that is, at a younger age or with higher baseline b-ell funtion) have a higher remission rate despite similar weight loss (143). Initial diabetes remission rates in adults range between 40% and 70%, whereas in adolesents the reported initial rates are as high as % (144). The longterm durability of these remissions is unknown and will require longer follow-up. Short-term and long-term ompliations of metaboli surgery need to be taken into onsideration. In Teen-LABS, 13% of adolesents required a seond operative proedure and another 13% required an endosopi proedure beause of a ompliation (145). In the reent Teen-LABS/TODAY omparison, 30% of the youth with diabetes undergoing surgial intervention required readmission and/or reoperation (142). Postoperative nutritional ompliations (vitamin B 12, thiamine, and vitamin D defiieny) are also prevalent. Long-term follow-up and further researh is required to better understand the mehanisms by whih metaboli surgery improves type 2 diabetes and the shortterm and long-term benefits and risks of this proedure in youth. Quality of life and eonomi (ost-benefit) analyses will also be important omponents of ongoing follow-up and researh (146,147). PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS Youth-onset type 2 diabetes is assoiated with signifiant mirovasular and marovasular risk burden and a substantial inrease in the risk of ardiovasular morbidity and mortality at an earlier age than those individuals diagnosed later in life (148). The higher ompliation risk in earlier-onset type 2 diabetes is likely to be related to prolonged lifetime exposure to hyperglyemia and other atherogeni risk fators, inluding insulin resistane, dyslipidemia, hypertension, and hroni inflammation. These diabetes omorbidities also appear to be higher than in youth with type 1 diabetes despite shorter diabetes duration and lower A1C (149). In addition, the progression of vasular abnormalities appears to be more pronouned in type 2 diabetes diagnosed earlier in life ompared with type 1 diabetes of similar duration, inluding ishemi heart disease and stroke (150,151). Nephropathy Reommendations Blood pressure should be measured at every visit. A Blood pressure should be optimized to redue risk and/or slow the progression of diabeti kidney disease. A If blood pressure is.95th perentile for age, sex, and height, inreased emphasis should be plaed on lifestyle management to promote weight loss. If blood pressure remains above the 95th perentile after 6 months, antihypertensive therapy should be initiated. C Initial therapeuti options inlude ACE inhibitors or angiotensin reeptor blokers. Other blood pressure lowering agents may be added as needed. C Protein intake should be at the reommended daily allowane of 0.8 g/kg/day. E Urine albumin/reatinine ratio (UACR) should be obtained at the time of diagnosis and annually thereafter. An elevated UACR (.30 mg/g reatinine) should be onfirmed on two of three samples. B Estimated glomerular filtration rate (egfr) should be determined at the time of diagnosis and annually thereafter. E