Objectives. Objectives. Alejandro J. de la Torre, MD Cook Children s Hospital May 30, 2015

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1 Alejandro J. de la Torre, MD Cook Children s Hospital May 30, 2015 Presentation downloaded from Objectives Understand that the obesity epidemic is also affecting children and adolescents with resultant metabolic abnormalities. Be able to identify the factors used to define metabolic syndrome in children. Understand the effects obesity and genetic factors can have on insulin sensitivity. Objectives Understand the effects insulin resistance can have on glucose homeostasis. Be able to identify medications used in the treatment of Type 2 diabetes in children and adolescents. Understand that Type 2 diabetes in children has been shown to have a more aggressive course towards diabetic complications than Type 1 diabetes. 1

2 Obesity United States (NHANES): - 1/3 children overweight - 17% children obese African American and Hispanic children have increased risk of being overweight or obese Obesity Overweight at age 5 years = 4 x likelihood of obesity at age 14 years Cunningham S et al, New England Journal of Medicine, 2014; 370: Metabolic (Insulin Resistance) Syndrome Cluster of risk factors believed to predict future cardiovascular disease and Type 2 diabetes More than 46 different pediatric definitions for metabolic syndrome Factors: Abdominal adiposity, dyslipidemia, hypertension, glucose intolerance 2

3 Metabolic (Insulin Resistance) Syndrome International Diabetes Foundation (10 to < 16 years): Waist circumference 90% plus any two: 1) TG > 150 mg/dl or treatment for elevated triglycerides 2) HDL < 40 mg/dl men or < 50 mg/dl women or treatment for low HDL 3) Systolic blood pressure > 130, diastolic blood pressure > 85, or treatment for hypertension 4) Fasting plasma glucose > 100 mg/dl or previously diagnosed with Type 2 diabetes Excess weight gain (genetic risk and environment) Visceral Fat Accumulation Insulin resistance Insulin resistance abnormalities Insulin Resistance Abnormalities Glucose Abnormalities - Impaired glucose tolerance to Type 2 DM - Impaired fasting glycemia Lipid Abnormalities - Increased triglycerides/low HDL - Small dense LDL-C Increased Coagulation Factors - Plasminogen activator inhibitor-1 - Fibrinogen 3

4 Insulin Resistance Abnormalities Hemodynamic Changes - Increased renal Na absorption - Increased sympathetic activity Inflammation Increased Hepatic Fat Deposition PCOS Glucose Abnormalities Fasting Blood Glucose Normal < 100 mg/dl Impaired Fasting Glucose (Pre-diabetes) mg/dl Diabetes 126 mg/dl Glucose Abnormalities Non-Fasting Blood Glucose Normal < 140 mg/dl Impaired Glucose Tolerance (Pre-diabetes) mg/dl Diabetes 200 mg/dl 4

5 Glucose Abnormalities- HbA1C HBA1C Normal 5.7% Pre-diabetes % Diabetes 6.5% Type 2 Diabetes Insulin Resistance: - Decreased muscle glucose uptake - Increased hepatic glucose production - Increased adipose tissue breakdown Type 2 Diabetes Type 2 diabetes rarely occurs prior to puberty. Strong family history of Type 2 diabetes in first and second-degree relatives. Prevalence is higher in certain groups: African American, Hispanic, Native American, Asian, South Asian, Pacific Islander. 5

6 Type 2 Diabetes Most common cause of insulin resistance in children is obesity Degree of insulin resistance likely depends on distribution of fat accumulation. Increased visceral fat accumulation leads to more insulin resistance. Cruz ML et al, Diabetes Care 2002; 25 (9): Type 2 Diabetes Type 2 diabetes develops when insulin secretion is not sufficient to meet the needs of the body that are increased by insulin resistance. Type 2 Diabetes Diagnosis ADA Criteria: - Diagnosis can be made on fasting, 2-hour oral glucose tolerance test, or HbA1C. - If there are no diabetic symptoms (weight loss, polyuria, polydipsia, weight loss), testing should be confirmed on different day. 6

7 Type 2 Diabetes Diagnosis Auto-antibody testing should be considered in all pediatric patients with clinical diagnosis of Type 2 diabetes Auto-antibodies are detected in 10-20% of patients thought to have Type 2 diabetes Zeilter P et al, Pediatric Diabetes 2014, 15: Screening at Diagnosis Lipid panel Urine albumin/creatinine ratio Obstructive Sleep Apnea Pregnancy Depression Zeilter P et al, Pediatric Diabetes 2014, 15: Type 2 Diabetes Management Pharmacotherapy Glucose Monitoring Dietary Management Exercise Management Monitoring of comorbidities and complications Zeilter P et al, Pediatric Diabetes 2014, 15:

8 Metformin Pharmacotherapy Insulin Metformin + Insulin Pharmacotherapy. Metformin Liver Muscle and Fat Decreased Gluconeogenesis Increased glucose uptake Pharmacotherapy Metformin: - AMP-kinase - May help lower HbA1C by 1-2% - Side effects: Abdominal pain, diarrhea, nausea - Little risk of hypoglycemia - Dose titrated to max of 1000 mg twice daily over 3-4 weeks 8

9 Insulin: Pharmacotherapy Basal: Lantus, Levemir, NPH Fast-acting: Novolog, Humalog HbA1C < 9% Pharmacotherapy - Metformin monotherapy HbA1C > 9% - Basal Insulin + Metformin - Transition to Metformin monotherapy Goal of treatment HbA1C < 6.5% Pharmacotherapy 90% of Type 2 diabetes in children can be managed with metformin alone Laffel L et al, Pediatric Diabetes 2012:13: If fail to reach HbA1C < 6.5% by 3-4 months, start basal insulin. If goal not reached with metformin and basal insulin, start fast-acting insulin with meals. 9

10 Dietary Management Elimination of sugared beverages Increasing fruits and vegetables Reducing foods with refined, simple sugars Limit distractions while eating Reducing processed, packaged foods Reducing meals not eaten at home Portion control Carbohydrate limits at meals Limit high, high calorie foods Exercise Management Moderate-to-vigorous exercise at least 60 minutes daily Limit daily screen time to < 2 hours Encourage physical activity as a family event Blood Pressure Hypertension present in 13.6% of US youth presenting in Type 2 diabetes. In the TODAY study, hypertension seen in 33.8% of US youth by the end of the study. Males have increased incidence of hypertension. 10

11 Blood Pressure BP should be measured at each visit. BP should be normalized for sex, age, and height. Initial treatment of BP > 95% on three occasions is lifestyle changes. If BP still > 95% after 6 months, ACE inhibitor should be considered. Nephropathy In the TODAY study, microalbuminuria was present in 6.3% of new onset Type 2 diabetes. By 36 months after diagnosis, this increased to include 16.6% of individuals. Factors involved with microalbumin progression are DM duration, HbA1C, diastolic blood pressure. Nephropathy Albuminuria should be checked at diagnosis and then annually. If abnormal, should be repeated on 2-3 different occasions. If persistently abnormal, ACE inhibitor should be considered. Factors that can affect urine microalbumin are exercise, smoking, menstruation, orthostasis 11

12 Dyslipidemia Lipid panel should be obtained soon after diagnosis once glucose controlled and then annually. Other potential useful markers include lipoprotein (a), LDL-P number, small LDL-P number. Goals: Dyslipidemia LDL-C < 100 mg/dl HDL-C > 35 mg/dl Triglycerides < 150 mg/dl Dyslipidemia If LDL-C above goal, initial treatment is dietary counseling. AHA Step 2 Diet: - Cholesterol < 200 mg/day - Saturated fat < 7% of total calories - < 30% of calories from fat 12

13 Dyslipidemia If LDL-C above goal, initial treatment is dietary counseling. AHA Step 2 Diet: - Cholesterol < 200 mg/day - Saturated fat < 7% of total calories - < 30% of calories from fat Dyslipidemia If LDL > 130 mg/dl after 6 months, statin therapy should be considered. Goal of statin therapy is LDL < 130 mg/dl with an ideal target of < 100 mg/dl. If triglycerides > mg/dl, fibric acid medication should be considered. TODAY Study Complications and comorbidities in Type 2 DM in adults and Type 2 DM in children and adolescents are the same. It appears that they occur more rapidly in children and adolescents. Tryggestad JB et al, Journal of diabetes and its complications 2015; 29:

14 TODAY Study Over an average follow-up of 3.86 years - Hypertension 11.6% 33.8% - High-risk LDL 4.5% 10.7% - Microalbuminuria 6.3% 16.6% - Retinopathy present in 13.9% at end of study. Tryggestad JB et al, Journal of diabetes and its complications 2015; 29: Type 1 DM vs Type 2 DM Type 2 diabetic youth compared to Type 1 diabetic youth have increased mortality after a shorter disease duration and had more cardiovascular deaths. Constantino MI et al, Diabetes Care 2013; 36: Question There is consensus on an appropriate definition of metabolic syndrome in children? A) True B) False 14

15 Question There is consensus on an appropriate definition of metabolic syndrome in children? A) True B) False Question If allowed by glucose trends and acceptable HbA1C, the goal of long term pharmacotherapy is? A) Oral monotherapy B) Insulin monotherapy C) Insulin + oral therapy D) None of the above Question If allowed by glucose trends and acceptable HbA1C, the goal of long term pharmacotherapy is? A) Oral monotherapy B) Insulin monotherapy C) Insulin + oral therapy D) None of the above 15

16 Question Current studies indicate that the risk of complications and morbidities is less in Type 2 diabetic youth than Type 1 diabetic youth? A) True B) False 16