DIAGNOSIS AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN

DIAGNOSIS AND TREATMENT OF TYPE 2 DIABETES IN CHILDREN Asheesh Dewan, M.D. Outline of Discussion  The importance of the problem  Diagnosis of type 2 diabetes in children  Special problems in children with T2DM  Management based on presentation  The metformin trial  Comorbid conditions Pathogenesis of Type 2 Diabetes MUSCLE  LIVER 1. Increased Hepatic Glucose Production ELEVATED GLUCOSE   3. Peripheral Insulin Resistance PANCREAS 2. Impaired Pancreatic Insulin Secretion Outline of Discussion  The importance of the problem  Diagnosis of type 2 diabetes in children  Special problems in children with T2DM  Management based on presentation  The metformin trial  Comorbid conditions Diabetes Trends in the United States  Prevalence of diagnosed diabetes increased by 33% from 1990 to 1998 Age (y) 30–39 40–49 50–59 % Increase 70 40 31  Highly correlated with prevalence of obesity (r = 0.64, P < 0.001) Mokdad et al. Diabetes Care. 2000;23:1278. Diabetes Trend with Obesity World wide trend of Type 2 Diabetes from 2000 to 2010 Numbers of people with diabetes (in millions) for 2000 and 2010 (top and middle values, respectively), and the percentage increase. Source : Nature 414, 782 - 787 (2001) Projected Obesity prevalence from 1960 to 2025 Source: Nature 404, 2000 Type 2 Diabetes in Children Epidemiology: Population-Based Population Navajo Indians Pima Indians Cree and Ojibway Age (y) 12–19 10–14 15–19 4–19 10–19 Sample Size 142 672 530 717 – Prevalence per 1000 14.1 22.3 50.9 11.1 0 for males 36 for females 4.1 US Caucasians, African Americans (AA), and Mexican Americans (MA) 12–19 2867 J Pediatr. May 2000. Type 2 Diabetes in Children Epidemiology: Case Studies Location Cincinnati, OH Charleston, SC Little Rock, AR San Diego, CA San Antonio, TX Ventura, CA Population Caucasians and AA AA Caucasians, AA, and Latinos MA MA MA New Diabetes Cases (%) 33 46 – 18 18 45 Fagot-Campana et al. J Pediatr. Type 2 Diabetes in Children: Diagnosis by Year 16 14 12 10 8 6 4 2 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 Prevalence of IFG in Nondiabetic US Adolescents (Aged 12–19 Yrs) ADA Guidelines for Screening, Treatment of Children, Adolescents ADA Guidelines for Screening, Treatment of Children, Adolescents (cont.) Outline of Discussion  The importance of the problem  Diagnosis of type 2 diabetes in children  Special problems in children with T2DM  Management based on presentation  The metformin trial  Comorbid conditions ADA Criteria for the Diagnosis of Type 2 Diabetes* T1DM and T2DM: Differential Diagnosis  T1DM – Younger children – Short duration of symptoms  T2DM – Adolescents – Longer duration and more – – – – Frequent diabetic ketoacidosis – – – – (DKA) Caucasian/European descent Weak family history Lean BMI No acanthosis nigricans (AN) – – weight loss Infrequent or mild DKA Mexican, African, or Asian ancestry Strong family history Obese BMI AN Acanthosis Nigricans Acanthosis Nigricans T1DM and T2DM: Differential Diagnosis  T1DM – Subnormal insulin and/or C-peptide – Positive immune markers  Islet cell antibodies  Insulin autoantibodies  Anti-GAD antibodies  T2DM – Normal or elevated insulin and C-peptide – Absent immune markers – Autoimmune thyroid disease infrequent – Autoimmune thyroid disease common GAD=glutamic acid decarboxylase. T2DM in Children: Clinical Features Location Cincinnati Charleston Little Rock San Diego San Antonio Ventura Ethnicity Female/ Family % Male History AA 69 Cau 31 AA 100 AA 74 Cau 24 MA 67 Cau 17 MA 83 MA 100 1.7 1.3 1.6 2.0 3.0 0.8 85% 95% – 87% 74% 100% Mean age Mean Acanthosis (y) BMI % 14 13 14 13 13 14 38 30 35 27 – 33 60 56 86 67 92 – Fagot-Campana et al. J Pediatr. Ketoacidosis in Type 2 Diabetes in Children  6 of 58 patients presented in mild to moderate DKA  5 had HCO3s of 5–19; one patient presented with a pH of 7.18  All had probable concurrent illnesses  All had negative immune markers  Many centers report frequency of 10-15% C-Peptide Values at Diagnosis in T1DM and T2DM Unstimulated C-peptide values 140 120 P<0.001 C-peptide (%ULN) 100 80 60 40 20 0 N=38 N=42 T1DM T2DM Outline of Discussion The importance of the problem Diagnosis of type 2 diabetes in children Special problems in children with T2DM Management based on presentation The metformin trial Comorbid conditions Special Issues In Children  Risk of misdiagnosis  Need for initial use of insulin because of uncertainty or DKA  Lack of information regarding safety and efficacy of oral agents Special Issues in Children With T2DM  Risk of misdiagnosis  Need for initial use of insulin because of uncertainty or DKA  Lack of information regarding safety and efficacy of oral agents Misdiagnosis?  Type 1 and type 2 are often difficult to differentiate at diagnosis in children and adolescents  Recent advances have separated forms of diabetes previously classified as T2DM – Identification of MODY genes – Identification of mitochondrial defects  These forms vary in their relative insulin deficiency and insulin resistance, and respond differently to different medications Special Issues in Children  Risk of misdiagnosis  Need for initial use of insulin because of uncertainty or DKA  Lack of information regarding safety and efficacy of oral agents Need for Initial Insulin Use in Children  At least 10% of children with new-onset type 2 diabetes present with DKA  A multicenter therapeutic study found 20% of suspected type 2 adolescents were antibody-positive  Sometimes the diagnosis is just not initially clear and must await the return of immune markers and C-peptide  Some anxious parents want the blood glucose reduced quickly and don’t want to wait for the slower response to oral agents Special Issues in Children with T2DM  Risk of misdiagnosis  Need for initial use of insulin because of uncertainty or DKA  Lack of information regarding safety and efficacy of oral agents Outline of Discussion  The importance of the problem  Diagnosis of type 2 diabetes in children  Treatment approaches  The Metformin Trial  Comorbid conditions Study Objectives  Evaluate the efficacy of metformin (2000 mg/d) in a multicenter, randomized, double-blind, placebocontrolled trial in children with type 2 diabetes  Primary comparison of metformin vs placebo: change from baseline FPG after 16 wk of treatment  Secondary comparisons of metformin vs placebo after 16 wk of treatment: – HbA1c levels – Change from baseline in body weight, BMI, and lipids Subject Disposition 399 not randomized 481 enrolled 82 randomized to double-blind RX Metformin n=42 Placebo n=40 Discontinued during DB period 6 (14%) 4 (10%) Rescue from DB treatment Unblinded by DSMB Completed 16-wk DB treatment 4 (10%) 13 (31%) 19 (45%) 26 (65%) 7 (18%) 3 (8%) Mean FPG Change From Baseline at Week 16 or Last Double-Blind Visit Mean baseline FPG 192 mg/dL 162 mg/dL Mean change from baseline FPG (mg/dL) 40 20 0 -64* -20 -40 -60 Placebo Metformin *P< 0.001 *Significance level: P<0.03355, where the testwise critical value was adjusted for an 8-wk interim analysis of FPG, to preserve an overall alpha level of ≤0.05 using the O’Brien-Fleming method with an alpha of 0.025 at the interim analysis. Mean Adjusted* HbA1c at Week 16 or Last Double-Blind Visit Difference = -1.2% 10 Adjusted mean HbA1c (%) 8.6 9 † 8 7 6 Placebo 7.5 † P< 0.001 Metformin * Mean adjusted for baseline HbA1c. † P value is based on an ANCOVA comparing metformin to placebo using baseline HbA1c as the covariate and treatment as the main effect. Summary  Metformin, titrated up to 2000 mg/d, improved glycemic control (FPG, HbA1c) in children with type 2 diabetes  No adverse effects on body weight, BMI, or lipid profile  Well tolerated; AEs similar to adult population Conclusions  Metformin was shown to be safe and effective for glycemic management of type 2 diabetes in children  The present findings confirm the ADA Consensus Statement recommendation for the use of metformin to treat type 2 diabetes in children Therapy for Type 2 Diabetes Pharmacologic algorithm for treating type 2 diabetes Education, diet, exercise, monitoring Goals: FPG <126 mg/dL HbA1c <7.0% Adequate control: continue therapy, see every 3 mo Inadequate control after 1 mo: intervene with monotherapy-metformin Other monotherapy options: sulfonylureas, acarbose, repaglinide, thiazolidinediones, insulin Monotherapy inadequate after 3 mo: add 2nd agent Outline of Discussion  The importance of the problem  Diagnosis of type 2 diabetes in children  Treatment approaches  Management based on presentation  Comorbid conditions Comorbid Conditions and Concerns  Macrovascular complications  Obesity  Hypertension  Dyslipidemia  Sleep apnea  Hyperandrogenemia and polycystic ovary syndrome Prevalence of fatty liver disease in US adults [1] and adolescents. [2,3] Adult 1. 2. 3. Adolescents Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106-1110. Franzese A, Vajro P, Aregenziana A, et al. Liver involvement in obese children: ultrasonography and liver enzyme levels at diagnosis and during follow-up in an Italian population. Dig Dis Sci. 1997;42:1428-1432. Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97:2460-462. Hypertension Sorof J, Daniels S, Obesity Hypertension in Children. Hypertension. 2002;40:441 Obstructive Sleep Apnea Syndrome Sogut A, Altin R, Uzun L, Ugur MB, Tomac N, Acun C, Kart L, Can G. Prevalence of obstructive sleep apnea syndrome and associated symptoms in 3-11-year-old Turkish children. Pediatr Pulmonol. 2005 Mar;39(3):251-6. Reade EP, Whaley C, Lin JJ, McKenney DW, Lee D, Perkin R. Hypopnea in pediatric patients with obesity hypertension. Pediatr Nephrol. 2004 Sep;19(9):1014-20. Epub 2004 Jun 4. Summary  The occurrence of type 2 diabetes is increasing among children and adolescents  Its distinction from type 1 diabetes can usually be made clinically  When diagnosis is unclear, immune markers and C-peptide can be helpful  Treatment is dictated by presentation Summary  The approaches to glycemic therapy in type 2 diabetes in children do not differ from those in adults  Therapy by lifestyle change is difficult to implement and ineffective in children  A double-blind, placebo-controlled trial of metformin in children showed it to be safe and effective in this age group Summary  Glycemic control is not enough in the treatment of type 2 diabetes  Attention must be paid to comorbid conditions  There is little information about the frequency, consequence, or treatment of the comorbid conditions associated with type 2 diabetes when it occurs in the young