5/16/2018. Blake. Pediatric Case Studies. Blake

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1 Pediatric Case Studies PHIL ZEITLER MD, PHD SECTION OF ENDOCRINOLOGY DEPARTMENT OF PEDIATRICS UNIVERSITY OF COLORADO DEPARTMENT OF ENDOCRINOLOGY CHILDREN S HOSPITAL COLORADO Blake 15 yo NHW male with long history of overweight and two year increase in weight gain Denies change in eating or activity habits Small breakfast, school lunch, large dinner Fast food once a week PE at school every day 4-5 hours/day of screen time No medications. Depakote two years ago (one year) ROS: daytime sleepiness, snoring. Otherwise negative Blake Past Hx: Uncomplicated pregnancy, BW 5lbs 12 oz, no GDM Asperger s syndrome Fam Hx: Paternal grandmother with T2DM Father with elevated cholesterol Mat uncle with HTN, MI at 45, elevated cholesterol Maternal GF with MI at 61, HTN, elevated cholesterol 1

2 Blake Exam Ht 75%ile Wt > 95%ile BMI 35.7 BP 135/72 Acanthosis nigricans at neck, IP joints, axillae Tanner 5 Of the following, which is the best way to diagnose diabetes in obese youth Fasting glucose Random/post-prandial glucose OGTT Hemoglobin A1c Defining diabetes and prediabetes Remember - diabetes is defined by increased risk for microvascular complications (initially retinopathy) 1979: National Diabetes Data Group. Random or OGTT >200 Fasting glucose > : Based on incidence of retinopathy FPG >126 OGTT >200 Ethnic variation in all parameters was noted (FPG, 2HPG, and A1c) 2009: A1c 6.5 assay concordant with the DCCT National Glycohemoglobin Standardization Program Confirmed on a second test 2

3 International Expert Committee Specificity over sensitivity and regarded 6.5% as conservative A1c is at least as predictive as FPG and 2HPG for development of retinopathy Not a continuum below a certain A1c, you have no risk of retinopathy Committee acknowledged that the tests do not always correlate Prediabetes increased risk for diabetes By fasting and glucose tolerance test Impaired fasting glucose (IFG): mg/dl Impaired glucose tolerance (IGT): mg/dl at 2 hours post challenge By A1c 5.7% correlates with abnormal FPG ( 100) or 2HPG ( 140) Why define prediabetes? Strong data supporting treatment in adults Advantages of adding A1c to diagnostic algorithms The primary benefits of HbA1c are practical The patient does not need to be fasting Testing does not require a return visit HbA1c has less variability and is more reproducible than glucose HbA1c is less subject to acute changes Studies demonstrate that the total number of patients who receive at least some screening increases 3

Effect of use of A1c on frequency of screening in primary care The number of at-risk children screened increased No change in prevalence of pathology There is a difference between

4 Effect of use of A1c on frequency of screening in primary care The number of at-risk children screened increased No change in prevalence of pathology There is a difference between < 6% and > 6% Love-Osborne K et al Pediatr Diabetes 2017 Disadvantages of A1c HbA1c may miss cases of acute onset of diabetes (i.e., type 1) Diseases such as anemia, CF, sickle-cell disease, thalassemia, and other hemoglobinopathies alter HbA1c results There is ethnic variation in HbA1c A1c may cost more Test name Cost* Hemoglobin A1c $70.40 Fasting glucose $ hour glucose tolerance, both specimens plus dextrose drink $46.09 A1C FOR DIAGNOSIS OF DIABETES AND PREDIABETES IN OBESE ADOLESCENT Nowicka P et al. Diabetes Care

But All of these studies use FPG and/or OGTT as the Gold Standard FPG and OGTT are not considered a gold standard in adults Diabetes is diagnosed by risk for complications A1c predicts risk for

5 But All of these studies use FPG and/or OGTT as the Gold Standard FPG and OGTT are not considered a gold standard in adults Diabetes is diagnosed by risk for complications A1c predicts risk for complications as well as FPG and OGTT in adults FPG and OGTT are not entirely reproducible. Reproducibility of the Oral Glucose Tolerance Test in Overweight Children Libman et al JCEM 2008 A1c and OGTT as predictors of glycemia 98 obese kids had OGTT and wore CGM for 7 days Chan et al JCEM

Using A1c for diagnosis of diabetes and prediabetes

adults A1c, FPG, and 2HPG are likely measuring different

underlying abnormal glycemia Risk of complications correlates

but neither is OGTT or FPG, A1c is affected by ethnicity,

in healthy lean adolescents 2% of non-obese participants had

6 Using A1c for diagnosis of diabetes and prediabetes Correlations among A1c, FPG,and 2HPG may be less than in adults A1c, FPG, and 2HPG are likely measuring different things Abnormalities in any of them likely indicate underlying abnormal glycemia Risk of complications correlates strongly with A1c in adults A1c is not always reproducible: but neither is OGTT or FPG, A1c is affected by ethnicity, underlying disease But so are FPG and 2HPG HbA1c distribution in healthy lean adolescents 2% of non-obese participants had HbA1c > 5.7% - all less than 6.0% White Hispanic NHB Kelsey et al IMPE 2017 Treating Prediabetes 6

dietary interventions Eliminate liquid calories Reduce or eliminate eating out Reduce portion sizes Evidence based activity interventions Reduce sedentary time/screen time Encourage attainment of

7 In principle, it s easy! Reduce the accretion of visceral fat through lifestyle modification Reverse the trends in the toxic environment Reduce caloric intake Increase caloric expenditure AAP Expert Committee: Evidence based dietary interventions Eliminate liquid calories Reduce or eliminate eating out Reduce portion sizes Evidence based activity interventions Reduce sedentary time/screen time Encourage attainment of recommended activity goals. Barlow et al Pediatrics 2007 Effects of lifestyle intervention in obese children and adults weight change (kg) Standard Moderate Intensive Children Intensive Children Standard years Godoy-Matos et al. JCEM 90: 1460, 2005 Tuomilehto, et al. N Eng J Med 344: 1343, 2001 Van Gaal et al. Lancet 365: 1389, 2005 Poston et al. Int J Obes 27: 1486, 2003 Knowler et al (DPP). N Eng J Med 346: 393, 2002 Despres et al. N Eng J Med 353: 2121, 2005 Berkowitz et al. JAMA 289: 1805, 2003 Torgersen et al. Diab Care 27: 155, 2004 Pi-Sunyer et al. JAMA 295: 761, 2006 Nemet et al. Pediatrics 115: e443, 2005 Chanoine et al. JAMA 293: , 2005 School Interventions 7

Cochrane Meta-analyses Summerbell 2007 No evidence for effectiveness of school-based interventions for the prevention of obesity Some evidence for reported changes in

8 Cochrane Meta-analyses Summerbell 2007 No evidence for effectiveness of school-based interventions for the prevention of obesity Some evidence for reported changes in dietary habits Summberbell 2007 No evidence for effectiveness of school-based interventions for the treatment of obesity The Healthy Study 42 middle schools randomized to multi-modal intervention or control. Baseline in 6 th grade and retested in 8 th grade Small decrease in overweight/obesity in both intervention and control schools, with intervention slightly better HEALTHY did not show: Reduction in CVD risk factor rates Except for BP in Black and White males Improvements in fitness 23 Pharmacologic intervention 8

9 Diabetes Prevention Program (DPP) Compared Intensive Lifestyle, metformin, and placebo in adults with impaired glucose tolerance 3,234 participants, years old, 45% from minority groups, overweight (BMI > 25 kg/m 2 ) Impaired glucose tolerance Glucose mg/dl 2 hrs after 75g glucose Fasting glucose < 140 mg/dl Intervention - tailored dietary and exercise advice by nutritionists - 7 times in 1 st year, every 3 months thereafter Endpoint Diagnosis of diabetes DSMB stopped the trial a year early DPP: estimated cumulative incidence of type 2 diabetes in 3 years 30 * percent ** 0 placebo metformin lifestyle DPP (Knowler et al) N Engl J Med 2002 DPP: effects of treatment on body weight change in weight (kg) placebo metformin lifestyle DPP (Knowler et al) N Engl J Med

10 DPP: incidence of type 2 diabetes in subjects aged years 15 cases/100 person-yr 10 5 * * 0 placebo metformin lifestyle DPP (Knowler et al) N Engl J Med 2002 DPP: incidence of type 2 diabetes in subjects with BMI > cases/100 person-yr 10 5 * * 0 placebo metformin lifestyle DPP (Knowler et al) N Engl J Med 2002 Metformin in Youth Non-controlled case studies Freemark and Bursey 29 obese adolescents white and black boys and girls BMI > 30 kg/m2, Fasting insulin > 15 At least 1 1 st or 2 nd degree relative with T2DM Metformin 500 mg BID or placebo for 6 months BMI decreased 0.12 SD (1%) vs. increase of 0.23 SD (2%) Decreased fasting glucose (all normal) and insulin Freemark and Bursey Pediatrics

Metformin in Youth Double blind placebo controlled 6 month-crossover trial Metformin 1000 mg twice a day or placebo 28 obese adolescents randomized 22 analyzed (78%) Size of treatment effect P value

11 Metformin in Youth Double blind placebo controlled 6 month-crossover trial Metformin 1000 mg twice a day or placebo 28 obese adolescents randomized 22 analyzed (78%) Size of treatment effect P value Weight (kg) Weight z-score BMI (kg/m 2 ) BMI z-score Waist circumference (cm) Waist circumference z-score Fasting glucose (mmol/liter) Srinivasan et al JCEM 2006 Metformin in Youth 85 obese insulin-resistant adolescents BMI > 95%ile Fasting insulin > 15 or HOMA > 2.5 Randomized to receive metformin (1000 mg a day) or placebo for 6 months All participants received office-based lifestyle intervention 80% of metformin and 64% of placebo subjects completed 6 months Love-Osborne et al J. Pediatr 2008 Metformin in Youth Decrease in BMI Metformin (N= 48) Placebo (N= 16) p-value Mean change in BMI (Kg/m 2 ) BMI decrease of > 5% 11(22.9%) 0 (0.0%) 0.001* Increase in BMI 20 (41.7%) 11 (68.8%) 0.06 No change in any measure of glucose/insulin metabolism Love-Osborne et al J. Pediatr

12 DPP for Youth? Progression to diabetes is ~10% in 2 years among obese NHB youth in 2 years Progression to diabetes is ~ 7% in 8 years in insulinresistant Hispanic adolescents with NGT Assume metformin reduces progression by the same order of magnitude as in IGT adults (~0.3% progression vs ~0.5% every 6 months) Assume 5% dropout every 6 months Study would need 5000 kids and last 6 years to get 80% power to see the difference. Implications Prediabetes is a high risk state for progression to diabetes in adults, but implication in kids is unclear high-normal glucose and A1c may be normal in puberty More likely to regress due to changes in insulin resistance of puberty Value of screening is unclear Overt diabetes remains rare (< 0.4% in high-risk kids) Value of identifying prediabetes in kids is unclear all obese kids deserve intervention A1c an imperfect, but efficient, approach to evaluation of high-risk kids A1c > 6% has increased risk for progression Other abnormalities associated with obesity are more common than pre-diabetes and there is evidence base for treatment Hypertension, dyslipidemia, hepatic steatosis, sleep disturbance, mood disorder, disturbed eating etc Deanna 16 year old Latina female diagnosed with type 2 diabetes 3 years ago by primary doctor Started on metformin 2000 mg/d, but reports that she took this for only a few months One month ago, she was admitted to hospital following a suicide attempt Noted to have a glucose of 550 ng/dl (30.5 mmol/l) and glucosuria, with small ketones, normal ph, and normal electrolytes HbA1c 12.5% Started on basal insulin and discharged 12

13 Of the following, which is the most important next test to order? A. Fasting lipid panel B. Liver enzymes C. Pancreatic autoantibodies D. Self-monitored glucose for one week E. Stimulated C-peptide Lessons from TODAY Screening Of the 1206 children referred by their pediatric endocrinologist for screening, 119 (9.8%) were positive for diabetes autoimmunity Klingensmith et al Diabetes Care 2010 Antibody Negative vs. Positive Subjects Antibody negative (N=1092) Antibody positive (N=119) Age 14.0 (9,17) 13.0 (10, 17) Years since diagnosis 0.2 (0,2.7) 0.2 (0, 6.5) BMI Z-score** 2.3 (-0.3, 3.2) 1.9 (0.5, 2.9) C-peptide (nmol/l)** 1.26 (0,6.39) 0.66 (0, 2.88) HbA1c* 6.9 (4.5, 17.4) 7.6 (4.8, 19.9) Cholesterol (mmol/l) 4.04 (1.61, 22.61) 3.9 (2.2, 6.89) Trigycerides (mmol/l)** 1.2 (0.31, 109.5) 0.87 (0.16, 10.7) HDL (mmol/l)** 1.01 (0.26, 2.46) 1.11 (0.65, 2.02) LDL (mmol/l) 2.38 (0.54, 11.63) 2.25 (0.57, 4.30) SBP** (84, 184) (86, 144) DBP** 68.3 (43, 109) 64.7 (44, 90) Median (min,max) *p<0.05 Klingensmith et al Diabetes Care 2010 **P <

14 Antibody Negative vs. Positive Subjects Antibody negative (N=1092) Antibody positive (N=119) % female* %non-white** % insulin use* % mother with diabetes** % father with diabetes* % with acanthosis** *p<0.05 **P < Klingensmith et al Diabetes Care 2010 Summary At least 9.8% of US youth identified with T2D by pediatric endocrinologists on clinical grounds are antibody positive some potential subjects were prescreened for DAA insulin auto-antibodies were not measured anti ZnT8 (and other unknown antibodies were not measured) Although antibody positive youth with diabetes are clearly different from antibody negative youth, antibody positive youth are clinically indistinguishable from antibody negative youth Youth who were ZnT8 positive or who converted to GAD positivity had more rapid loss of glycemic control Antibody measurement should be considered in obese youth diagnosed with type 2 diabetes Klingensmith et al Diabetes Care 2010 Non-glycemic evaluation at diagnosis Blood pressure (Fasting) lipid panel AAP: lipid panel between 7-10 and after completion of puberty Presence of fatty liver ALT/AST, though low sensitivity Urine albumin/creatinine ratio Depression screening Evaluation for sleep disturbance Evaluation for PCOS in females Birth control counseling Dental evaluation Burden of family illness Zeitler et al Pediatr diabetes

Ongoing screening HbA1c every 3-4 months BP every visit Lipid panel: annual Foot exam/mnsi/monofilament testing annual Eye exam annual/every 2 years Dental cleaning and exam every 6 months Sleep

Vitamin D Depression screen: every visit Zeitler et al Pediatr diabetes 2014 Depression in youth-onset type 2 Depression is common in US youth with type 2 diabetes, though not at higher rates than

15 Ongoing screening HbA1c every 3-4 months BP every visit Lipid panel: annual Foot exam/mnsi/monofilament testing annual Eye exam annual/every 2 years Dental cleaning and exam every 6 months Sleep apnea screen every visit? Vitamin D Depression screen: every visit Zeitler et al Pediatr diabetes 2014 Depression in youth-onset type 2 Depression is common in US youth with type 2 diabetes, though not at higher rates than obese youth without diabetes A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%) The odds of medication nonadherence increased significantly from those reporting 1 major life stressor (OR 1.58) to those reporting 4 major life stressors (OR 2.70) Significant odds of elevated depressive symptoms and impaired QoL were also found with increased reporting of major stressors Katz et al Diabetes Care Depression and quality of life At baseline, 22.2% of participants demonstrated impaired HRQOL Depressive symptoms distinguished those with impaired HRQOL and were significantly related to later impaired HRQOL Other comorbidities did not have a significant impact on HRQOL Physical Health Psychological Health Larkin et al Diabetes Manag (Lond)

16 Arturo 15 yo Latino male with fasting glucose of 289 mg/dl (16 mmol/l) at yearly exam BMI 32 Kg/M 2, BP 120/65, Tanner 5. Antibodies (GAD, IA2, ZnT8, miaa) negative Of the following, what hemoglobin A1c would you use to decide to start insulin: A. I would always start insulin B. 6.5% C. 7.5% D. 8.5% E. 10% New Onset Diabetes in Overweight Youth A1c < 8.5%* A1c > 8.5% No Acidosis with or without ketosis Acidosis and/or DKA and/or HHNK metformin PO bid Titrate up to 2000 mg per day as tolerated basal insulin: start at 0.5 U/kg/day and escalate every 2-3 days based on meter glucose metformin titrate up to 2000 mg per day as tolerated Manage DKA or HHNK IV insulin until acidosis resolves, then subcutaneous Pancreatic autoantibodies negative positive Continue metformin wean insulin Continue or initiate MDI insulin therapy A1C goals not met Consider other drug therapy Initiate or continue add-on insulin therapy - basal insulin to max 1.5 unit/kg/day A1C Goals Not Met 16

17 Arturo 15 yo Latino male with fasting glucose of 289 mg/dl (16 mmol/l) at yearly exam BMI 32 Kg/M 2, BP 120/65, Tanner 5. HbA1c 8.7% You start him on metformin and titrate to 2000 mg a day He returns in 3 months HbA1c is 7.0% He and his mom report good adherence to metformin Of the following, the BEST next step in management is: A. Make no changes - patient is at target B. Start basal insulin C. Start GLP-1 agonist D. Start sulfonylurea E. Start thiazolidinedione Pathophysiology based treatment algorithm for Pediatric Type 2 diabetes At diagnosis: Lifestyle + Metformin >6.5% Lifestyle + Metformin + Basal insulin Off label Lifestyle + Metformin + basal insulin +? Metformin intolerance Severe resistance TZD Obesity GLP-1 agonist Aggressive Disease: Early Combination therapy? Obesity/hypertension DKD SGLT2 inhibitor 17

18 Effect of insulin on glycemic and nonglycemic outcomes No difference in HbA1c 1 year after starting insulin At failure 9.7 ± 1.7% 1 year later 9.5 ± 2.0% Insulin improves but does not correct dyslipidemia or inflammatory status Levitt Kat et al J Pediatr 2018 Anthony T2D 4 years ago metformin 2000 mg - 4 years glargine insulin 110 units 2.5 years liraglutide 1.8 mg - 1 year BP 138/92 HbA1c 8.6% AST 85 U/L (1.42 µkat/l), ALT 110 U/L (1.84 µkat/l) Fasting triglycerides 320 mg/dl (3.62 mmol/l) LDL 160 mg/dl (4.14 mmol/l) Urine albumin/creatinine 40 Of the following, what would be the MOST important next step in management? A. Increase glargine dose B. Start ACE inhibitor C. Start fibric acid D. Start statin E. Start vitamin E 18

Hypertension TODAY Diabetes Care 2013 Dyslipidemia 14 LDL> 130 35 Triglyceride > 150 12 30 10 25 PERCENT 8 6 4 20 15 PERCENT 2 10 0 Base Month Month Month 5 12

130 mg/dl (3.4 mmol/l) LDL > goal diet therapy (7% sat fat, < 200 mg chol) LDL > goal after 6 months of TLC Start statin Titrate until LDL < 100 mg/dl (2.

19 Hypertension TODAY Diabetes Care 2013 Dyslipidemia 14 LDL> Triglyceride > PERCENT PERCENT Base Month Month Month Base Month 12 Month 24 Month 36 Metformin Met + Rosi Met + L Metformin Met + Rosi Met + L TODAY Diabetes Care 2013 ISPAD Lipid Management LDL Goal: < 130 mg/dl (3.4 mmol/l) LDL > goal diet therapy (7% sat fat, < 200 mg chol) LDL > goal after 6 months of TLC Start statin Titrate until LDL < 100 mg/dl (2.6 mmol/l) TG Goal: < 150 mg/dl (1.7 mmol/l) fasting TG > 600 mg/dl (6.7 mmol/l) Start fibrate to avoid postprandial > 1000 mg/dl Zeitler et al Pediatr diabetes

20 Microalbuminuria TODAY Diabetes Care 2013 Development of diabetic kidney disease Maahs, Diabetes technology and therapeutics 2012 Course of albuminuria and risk of glomerular filtration rate (GFR) loss Perkins BA et al. J Am Soc Nephrol

Insulin resistance and kidney disease in youth-onset T2D Clamp

HbA1c, systolic Blood pressure and LDL- Cholesterol were not.

Diabetes Care 2014 Combined effects of albuminuria and low egfr

21 Insulin resistance and kidney disease in youth-onset T2D Clamp measure of insulin sensitivity inversely associated with egfr. HbA1c, systolic Blood pressure and LDL- Cholesterol were not. P<0.05 P<0.05 P<0.05 Bjornstad et al. Diabetes Care 2014 Combined effects of albuminuria and low egfr Ninomiya T et al. JASN 2009 Survival by GFR and urine ACR de Boer I H et al. Diabetes Care

22 ISPAD: Hypertension and kidney Blood pressure: Goal < 95%ile for age, sex, and height if > 95%ile - lifestyle modification BP > 95%ile after 6 months Start ACE or ARB Titrate until BP < 90 th %ile Albumin excretion: goal albumin/creatinine ratio < 30 Abnormal: repeat first morning sample; 2 of 3 abnormal is diagnostic Start ACE - titrate until albumin/creatinine ratio normal This does not agree with ADA guidelines for adults ADA ACR start ACE/ARB if BP elevated ACR > 300 start ACE/ARB Zeitler et al Pediatr diabetes 2014 Retinopathy Diabetic Retinopathy HbA1c (%) tertile N N % OR (95%CL) ( ) ( ) TODAY Diabetes Care 2013 Beyond glycemic control Morbidity and mortality in adults with type 2 diabetes is predominately related to cardiovascular disease Hypertension, microalbuminuria, and dyslipidemia are common in youth with T2D at the time of diagnosis The prevalence of all of these increases over time In TODAY, glycemic treatment was insufficient to prevent increased prevalence/risk These results underscore the worrisome prognosis for complications and comorbidities in youth with type 2 diabetes Kids are going to live a long time with both poor β-cell function and rising comorbidities More attention is needed to evidence-based approaches to aggressive treatment of comorbidities needed to lower CVD risk in youth with T2D 22

23 Thank you for your attention 23

Type 2 Diabetes Mellitus in Adolescents PHIL ZEITLER MD, PHD SECTION OF ENDOCRINOLOGY DEPARTMENT OF PEDIATRICS UNIVERSITY OF COLORADO DENVER

Type 2 Diabetes Mellitus in Adolescents PHIL ZEITLER MD, PHD SECTION OF ENDOCRINOLOGY DEPARTMENT OF PEDIATRICS UNIVERSITY OF COLORADO DENVER Yes! Is Type 2 diabetes the same in kids as in adults? And No!