1. diabetes.ca | 1-800-BANTING (226-8464) Canadian Diabetes Association Clinical Practice Guidelines Type 2 Diabetes in Children and Adolescents Chapter 35 Constadina Panagiotopoulos, Michael C. Riddell, Elizabeth A.C. Sellers

2. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Key Messages Anticipatory guidance regarding healthy eating and active lifestyle is recommended to prevent obesity Regular targeted screening for type 2 diabetes is recommended in children at risk Children with type 2 diabetes should receive care from an interdisciplinary pediatric diabetes healthcare team Early screening, intervention, and optimization of glycemic control are essential, as childhood type 2 diabetes is associated with severe and early onset of microvascular complications 2013

3. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Outline Epidemiology Prevention Screening & Diagnosis Classification Management Immunization Complications Comorbid Conditions

4. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Epidemiology of T2DM in Canada Amed S et al. Diabetes Care 2010;33:786-791.

5. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Minimum Incidence Rates of Non-T1DM in Canadian Children <18 years Amed S et al. Diabetes Care 2010;33:786-791.

6. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Breastfeeding beneficial in reducing risk Obesity is a major modifiable risk factor Family-based lifestyle interventions with a behavioral component aimed at changes in diet and physical activity patterns have been shown to result in significant weight reduction in children and adolescents Prevention

7. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association The role of pharmacotherapy in the treatment of childhood obesity is controversial as there are few controlled trials and no long-term safety or efficacy data Bariatric surgery in adolescents should be limited to exceptional cases and be performed only by experienced teams Prevention

8. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 1.Anticipatory guidance promoting healthy eating, the maintenance of a healthy weight, and regular physical activity is recommended as part of routine pediatric care [Grade D, Consensus]. 2.Intensive lifestyle intervention, including dietary and exercise interventions, family counseling, and family-oriented behaviour therapy, should be undertaken for obese children in order to achieve and maintain a healthy body weight [Grade D, Consensus]. Recommendations 1 and 2: Prevention

9. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screening and Diagnosis … Why is it worthwhile?

10. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Clinical featureProportion (%) Asymptomatic35% Acanthosis nigricans73% Obesity95% Ketosis44% Diabetic ketoacidosis10% PCOS12.1% Dyslipidemia44.8% Hypertension28.3% ALT > 90 IU/L or FLD22.2% Micro-/macroalbuminuria14.2% Clinical Features at Diagnosis of T2DM Amed S et al. Diabetes Care 2010;33:786-791.

11. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Risk factors for childhood type 2 diabetes include: – T2DM in a first- or second-degree relative – High risk ethnic or racial group – Obesity – Impaired glucose tolerance (IGT) – Polycystic ovary syndrome (PCOS) – Exposure to diabetes in utero – Acanthosis nigricans – Hypertension and dyslipidemia – Nonalcoholic fatty liver disease (NAFLD) – Use of atypical antipsychotic medications Screening and Diagnosis

12. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Ethnicity # newly diagnosed (%) % of population diagnosed age <10 years Total (%)227 (100%)8% Aboriginal100 (44.1%)11% Caucasian57 (25%)8.8% African / Caribbean 23 (10.1%)4.3% Asian23 (10.1%)8.7% Mixed ethnicity14 (6.2%)-- Hispanic4 (1.8%)-- Middle Eastern1 (0.4%)-- Ethnicity of Children with Newly Diagnosed T2DM Amed S et al. Diabetes Care 2010;33:786-791.

13. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screening and Diagnosis Fasting plasma glucose (FPG) Recommended screening test Oral glucose tolerance test (OGTT) BMI ≥99 th %ile and/or Multiple risk factors Diagnostic criteria for above same as for adults

14. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association FPG ≥7.0 mmol/L Fasting = no caloric intake for at least 8 hours Or 2hPG in a 75-g OGTT ≥11.1 mmol/L 2hPG = 2-hour Plasma Glucose; FPG = Fasting Plasma Glucose; OGTT = Oral Glucose Tolerance Test; PG = Plasma Glucose Diagnosis of Diabetes

15. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Who to screen? How often to screen? 1.Non-pubertal + ≥3 risk factors 2.Pubertal + ≥2 risk factors 3.IFG or IGT 4.Use of atypical antipsychotic medications Screen with FPG every 2 years

16. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Risk Factors for T2DM Obesity (BMI ≥95 th %ile for age and gender) Member of a high-risk ethnic group Family history of T2DM and/or exposure to hyperglycemia in utero Signs or symptoms of insulin resistance – Acanthosis nigricans – Hypertension – Dyslipidemia – Non alcoholic fatty liver disease (ALT > 3X ULN or fatty liver on ultrasound – Polycystic ovarian syndrome

17. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Presence of clinical risk factors, mode of presentation, and early course of the disease usually indicate whether the child has type 1 or type 2 diabetes. But, children with type 2 diabetes can present with diabetic ketoacidosis (DKA) Testing for absence of islet autoantibodies may be useful Classification

18. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Fasting insulin levels are not helpful at diagnosis, as levels may be low due to glucose toxicity DNA diagnostic testing for genetic defects in beta cell function should be considered in children who have a strong family history suggestive of autosomal- dominant inheritance and who are lacking features of insulin resistance Classification

19. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 3.Screening for type 2 diabetes should be performed every 2 years using an FPG test in children with any of the following: – ≥3 risk factors in non-pubertal or ≥2 risk factors in pubertal (Grade D, Consensus) – Obesity (BMI ≥95th percentile for age and gender) [Grade D, Level 4] – Member of a high-risk ethnic group (e.g. Aboriginal, African, Asian, Hispanic, or South Asian descent) [Grade D, Level 4] – Family history of type 2 diabetes and/or exposure to hyperglycemia in utero [Grade D, Level 4] – Signs or symptoms of insulin resistance (including acanthosis nigricans, hypertension, dyslipidemia, NAFLD [ALT >3X ULN or fatty liver on ultrasound], PCOS) [Grade D, Level 4] b)IFG or IGT [Grade D, Consensus] c)Use of atypical antipsychotic medications [Grade D, Consensus] Recommendation 3: Screening 2013

20. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 4.A 75-gram oral glucose tolerance test may be used as a screening test in very obese children (BMI ≥99 th percentile for age and gender) or those with multiple risk factors who meet the criteria in recommendation 3 [Grade D, Consensus]. Recommendation 4: Screening

21. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management Interdisciplinary pediatric diabetes healthcare team Target A1C ≤7.0% Treatment programs for adolescents with type 2 diabetes should address the lifestyle and health habits of the entire family, emphasizing healthy eating and physical activity

22. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management (Physical Activity) Children with type 2 diabetes should strive to achieve the same activity level recommended for children in general: – 60 minutes / day of moderate-to-vigorous physical activity – Limit sedentary screen time to ≤2 hours per day

23. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management Psychological issues (depression, binge eating, smoking cessation) need to be addressed and interventions offered as required 19.4% have neuropsychiatric disorder at presentation of T2DM Levitt K, et al. Pediatr Diabetes 2005;6(2):84-89.

24. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management – Severe Metabolic Decompensation Severe metabolic decompensation at diagnosis – DKA – A1C ≥9.0% – Symptoms of severe hyperglycemia May wean insulin once glycemic targets are achieved, particularly if lifestyle changes are effectively adopted INSULIN

25. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management – Oral Antihyperglycemic Agents Limited data about the safety or efficacy of oral antihyperglycemic agents in children None of the oral antihyperglycemic agents have been approved by Health Canada for use in children

26. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management – Oral Antihyperglycemic Therapy If glycemic targets are not achieved within 3 to 6 months using lifestyle modifications alone, one of the following should be initiated METFORMIN or GLIMEPIRIDE or INSULIN Metformin may be used at diagnosis in children presenting with A1C >7%

27. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Management - Pharmacotherapy Metformin has been shown to be safe in adolescents for up to 16 weeks, reducing A1C by 1.0 - 2.0% and lowering FPG with similar side effects as seen in adults Glimepiride has also been shown to be safe and effective in adolescents for up to 24 weeks, reducing A1C (-0.54%) but weight gain of 1.3 kg Therefore, metformin preferred over glimepiride Jones KL et al. Diabetes Care 2002;25(1):89-94. Gottschalk M et al. Diabetes Care 2007;30(4):790-794.

28. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 5.Commencing at the time of diagnosis of type 2 diabetes, all children should receive ongoing intensive counseling, including lifestyle modification, from an interdisciplinary pediatric healthcare team [Grade D, Level 4]. 5.The target A1C for most children with type 2 diabetes should be ≤7.0% [Grade D, Consensus]. Recommendations 5 and 6: Management

29. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 7.In children with type 2 diabetes and an A1C ≥9.0%, and in those with severe metabolic decompensation (e.g. DKA), insulin therapy should be initiated, but may be successfully weaned once glycemic targets are achieved, particularly if lifestyle changes are effectively adopted [Grade D, Level 4]. Recommendation 7: Management

30. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 8.In children with type 2 diabetes, if glycemic targets are not achieved within 3 to 6 months using lifestyle modifications alone, 1 of the following should be initiated: – Metformin [Grade B, Level 2 (43)] or – Glimepiride [Grade B, Level 2 (44)] or – Insulin [Grade D, Consensus] Recommendation 8: Management If the decision is made to use an oral antihyperglycemic agent, metformin should be used over glimepiride [Grade D, Consensus]. Metformin may be used at diagnosis in those children presenting with an A1C >7.0% [Grade B, Level 2]. 2013

31. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Immunization Manage the same as in type 1 diabetes Some children with type 2 diabetes may have other factors (e.g. Aboriginal heritage) that may place them at higher risk of increased influenza- and pneumococcal-related morbidity

32. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Complications – Short Term Diabetic ketoacidosis – 10% of Canadian youth present with DKA at diagnosis Hyperglycemic hyperosmolar state (HHS) – High mortality rates (up to 37% in one series) have been reported in youth presenting with combined DKA and HHS at onset of type 2 diabetes Amed S et al. Diabetes Care 2010;33(4)786-791. Rosenbloom AL. J Pediatr 2010;156(2):180-184.

33. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Complications – Longer term Evidence suggests that early-onset type 2 diabetes in adolescence is associated with severe and early- onset microvascular complications, including retinopathy, neuropathy, and nephropathy Therefore, it is prudent to consider screening for these complications at diagnosis and yearly thereafter

34. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screen for microalbuminuria: – first morning urine ACR (preferred). – Abnormal results should be confirmed at least 1 month later with: A repeat first morning ACR If abnormal, follow by timed, overnight urine collection for albumin excretion rate Microalbuminuria (ACR >2.5 mg/mmol ) should not be diagnosed in adolescents unless it is persistent Persistent albuminuria should be referred to a pediatric nephrologist Complications

35. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Aboriginal youth in Canada are at increased risk of renal diseases that are not associated with diabetes Persistent albuminuria may be evidence of other underlying renal disease Referral to a pediatric nephrologist for assessment of etiology and treatment is recommended Complications – Special Populations

36. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screening for dyslipidemia at diagnosis and every 1 to 3 years as clinically indicated thereafter Start a statin if the low-density lipoprotein cholesterol (LDL-C) level remains >4.2 mmol/L after a 3- to 6-month trial of dietary intervention Comorbid Conditions - Dyslipidemia

37. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Screening for high blood pressure should begin at diagnosis and subsequent clinic visits Surveillance should occur for comorbid conditions associated with insulin resistance – Polycystic ovarian syndrome – Non-alcoholic fatty liver disease Comorbid Conditions – Hypertension and Others

38. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association ACR = albumin-creatinine ratio

39. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association

40. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 9.Children with type 2 diabetes should be screened annually for microvascular complications (nephropathy, neuropathy, retinopathy) beginning at diagnosis of diabetes [Grade D, Level 4]. Recommendation 9: Complications

41. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 10.Children with type 2 diabetes should be screened for microalbuminuria with a first morning urine ACR (preferred) [Grade B, Level 2] or a random ACR [Grade D, Consensus]. Abnormal results should be confirmed [Grade B, Level 2] at least 1 month later with a first morning ACR and, if abnormal, followed by timed, overnight urine collection for albumin excretion rate [Grade D, Consensus]. Recommendation 10: Complications

42. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Microalbuminuria (ACR >2.5 mg/mmol) should not be diagnosed in adolescents unless it is persistent as demonstrated by 2 consecutive first morning ACR or timed collections obtained at 3- to 4-month intervals over a 6- to 12-month period [Grade D, Consensus]. Those with persistent albuminuria should be referred to a pediatric nephrologist for assessment of etiology and treatment [Grade D, Level 4]. Recommendation 10: Complications (continued)

43. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 11.Children with type 2 diabetes should have a fasting lipid profile measured at diagnosis of diabetes and every 1 to 3 years thereafter, as clinically indicated [Grade D, Consensus]. 12.Children with type 2 diabetes should be screened for hypertension beginning at diagnosis of diabetes and at every diabetes-related clinical encounter thereafter (at least biannually) [Grade D, Consensus]. Recommendations 11 and 12: Comorbid Conditions

44. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association 13.Children with type 2 diabetes should be screened at diagnosis for comorbid conditions associated with insulin resistance, including non-alcoholic fatty liver disease [Grade D, Level 4] and polycystic ovarian syndrome in pubertal females [Grade D, Level 4] and yearly thereafter, as clinically indicated [Grade D, Consensus]. 2013 Recommendation 13: Comorbid Conditions

45. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association Summary Messages Clinicians must be vigilant for risk factors of type 2 diabetes in children Selected screening and timely diagnosis is important in reducing complications An experienced multidisciplinary team should manage diabetes using a range of interventions from lifestyle to oral agents to insulin Screen for comorbidities and complications

46. guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca Copyright © 2013 Canadian Diabetes Association CDA Clinical Practice Guidelines http://guidelines.diabetes.cahttp://guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) http://diabetes.ca http://diabetes.ca – for patients