Type 2 Diabetes in Children and Youth

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  • IGT = Impaired Glucose Tolerance
  • Metformin improves glycaemia in type 2 diabetic adolescents This slide shows the principal results from the study in type 2 diabetic adolescents. As the study was terminated early, as described above, data are presented for baseline and the last double-blind measurement. Treatment with metformin significantly improved fasting plasma glucose and HbA 1C , compared with placebo (p<0.001 for each). Jones KL, Arslanian S, Peterokova VA, Park J-S, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25: 89-94.
  • Metformin is well tolerated in paediatric subjects Both studies included an evaluation of the tolerability of metformin. The most common side-effects observed were gastrointestinal, as would be expected for this agent. However, most of these side-effects were transient, and no treatment-related gastrointestinal side-effect led to withdrawal of therapy. There were also no treatment-related serious adverse events in either study. Overall, the tolerability profile of metformin was similar to that observed in adults. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001; 107: e55. Jones KL, Arslanian S, Peterokova VA, Park J-S, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25: 89-94.
  • We explored whether the observed difference were due to prior therapy of subjects. analysis of these sub-populations, show a clear difference. The drug-naïve group showed a more homogeneous response throughout the study—both groups behaved similarly Both met and rsg groups were well-matched at screening and bl and achieved similar values by study end (week 24) Both groups showed a decline in A1c from screening through week 24 that was statistically significant (though study not powered for this analysis) On the other hand, subjects who were on prior therapy, showed a more heterogeneous response; especially during pbo run-in there was an increase in A1c from screening & baseline. By week 24, there was no improvement in A1c values from screening OR baseline
  • Overall weight gain of 3kg in rsg group.

Transcript

  • 1. Francine Ratner Kaufman, MD Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens Hospital Los Angeles Type 2 Diabetes in Children and Youth Paula Jameson, ARNP, MSN, CDE Nemours Children’s Clinic Division of Endocrinology
  • 2. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 3. Question What Do We Know About Type 2 Diabetes in Youth?
  • 4. Is it an epidemic?
    • The incidence is increasing and probably underestimated
      • Population based estimates indicate an ~10-fold increase in incident cases over the past 10-15 years
      • 8% to 43% of all new cases of diabetes in the United States depending on ethnicity
      • The SEARCH Trial
      • What about prevalence??
      • Bloomgarden ZT. Diabetes Care . 2004;27:998-1010 Centers for Disease Control. Diabetes Fact Sheet. 2005
  • 5. Diabetes Trends Among Adults in the US BRFSS 1990, 1995 and 2001
  • 6. Changing Face of Diabetes in Youth in US 0 5 10 15 20 25 30 35 % with type 2 87 88 89 90 91 92 93 94 95 96 Cincinnati <19 years Little Rock 8-21 years San Antonio <19 years Source: Fagot-Campagna et al., J Pediatr 136:664-672, 2000
  • 7. Question Is the Pathophysiology the Same as in Adults?
    • Associated with significant ß-cell failure as well as insulin resistance
      • Occurs at the time of intense insulin resistance due to puberty
  • 8. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 9. Insulin Resistance Age Puberty Type 2 Diabetes Prediabetes Beta Cell Defect Obesity BP, Lipids Gender – Girls Polycystic ovary syndrome Genetics Ethnicity Sedentary Lifestyle Beta Cell Defect
  • 10.  
  • 11. Insulin Resistance Autoimmunity Type 2 Diabetes Prediabetes Beta Cell Defect Genetic Defect Intrauterine IUGR, DM Glucose toxicity Beta Cell Defect Fat cell toxicity
  • 12. Question Is the Presentation the Same as in Adults?
    • Does not appear to be preceded by long asymptomatic period
      • Do not find undiagnosed cases on screening
  • 13. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 14. Pre-diabetes (IGT) and T2D 0% 33% 15 subjects Weninger et al, 1980 4% 21% 112 multi-ethnic teens (>95 th %ile) Sinha et al, 2002 0% 28% 150 Hispanic +FH (8-13 years >85 th %ile) Goran et al, 2004 0% 25% 55 multi-ethnic youth (>95 th %ile) Sinha et al, 2002 6% 17% 66 multi-ethnic youth (4-16 years) Paulsen et al, 1968 T2D IGT Overweight Sample
  • 15.  
  • 16. Years from Clinical Diagnosis B-cell Function (%) UKPDS Data Type 2 Diabetes Progressive Pancreatic B-cell Failure ? Curve for Youth Prevention and Early Treatment
  • 17. Question What distinguishes type 1 from type 2 diabetes in youth?
  • 18. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 19. Pediatric Diabetes 2002 Type 1 diabetes Childhood obesity Type 2 Monogenic Diabetes Diabetes + Syndromes “ Pediatric Diabetes is a DIFFICULT diagnostic speciality”
  • 20. Antibody Ethnicity C-peptide Comorbid Relative with DM DKA Course Weight 15% NA, AA, HA, Asian, Pacific Islander 85% Whites predominate Normal or increased C-peptide can be preserved at DX Increase in polycystic ovary syndrome Acanthosis nigricans (90%) thyroid, adrenal, vitiligo, celiac 74%-100% with T2DM 5% with T1DM Up to 20% may have with T2DM Ketonuria (33%) Mild DKA (5%-25%) 35%-40% Indolent Virtually none found on screening Rapid From DPT-1 can be indolent All > 85% overweight 20% may be obese T2DM T1DM
  • 21. Differentiation Between Type 1 and 2
    • 48 with type 2 vs 39 with type 1
    • Type 2
      • Ethnicity, 1 st degree relative, BMI>24, +C-peptide, acanthosis
      • Hathout et al Pediatrics 107e102,June,2001
    85% have islet autoimmunity 8.1% ICA 30% GAD 35%IAA Abs 1.8 + 3.5 ug/l 2.2 + 2.2 ug/l C-peptide 53% 33% DKA Type 1 Type 2
  • 22. Question How Does Type 2 Present in Youth? Is it asymptomatic or symptomatic in youth?
  • 23. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 24. Diagnosis with Type 2 Fagot-Campagna et al J Pediatr 2000
    • Mean Age 12-14 years
    • Girls > Boys 1.7:1
    • Obese BMI >85 th %
    • Minority Groups 94%
    • Strong Family History 74-100%
    • Acanthosis Nigricans 56-92%
    • Diagnosis made by Symptoms, not Screening
    • HbA1c 10-13%
    • Weight loss 19-62%
    • Glucose in urine 95%
    • Ketosis 16-79%
    • DKA 5-10%
  • 25.  
  • 26. Question What Are Treatment Targets in Youth with Type 2 Diabetes? Are they the same as in adults?
  • 27. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 28. TREATMENT GOALS
    • Glucose control, HbA1c <7%
      • Eliminate symptoms of hyperglycemia
    • Maintenance of reasonable body weight
    • Improve cardiovascular risk factors
    • Reduce microvascular complications
    • Improvement in physical and emotional well-being
    A1c <7.0 Bed 100-160 FG 80-120 PP 100-160 Goals (Diabetes Care, 2000)
  • 29. Treatment Issues
    • Self-monitoring of blood glucose
      • Fasting and postprandial
      • Frequency depends on regimen
    • Medical Nutrition Therapy
    • Diabetes Education
      • Involves family
        • Direct family supervision produces better glycemic control outcomes 1
    • Lifestyle Coaching
    • Preconception counseling
    • Immunizations
    • Dental care
    • Smoking and alcohol counseling
        • 1. Bradshaw, J Pediatr Endocrinol Meta 15, 2002
    • 2. Pediatrics 112:2003 Prevention and treatment of type 2 diabetes in children with special emphasis on Native American Youth
  • 30. ROLE OF FAMILY IN MANAGEMENT
    • African-American Family Study
    • Group 1, direct family supervision
    • Group 2, no direct supervision
    • Group 1 ending HbA1c = 7.1 + 0.8%
    • Group 2 ending HbA1c = 12.3 + 0.6%
    • P=<0.0005
    • Bradshaw, J Pediatr Endocrinol Meta 15, 2002
  • 31. Question What are the Treatment Regimens for Youth?
  • 32. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 33.  
  • 34. TZD = thiazolidinedione Silverstein JH, Rosenbloom AL. J Pediatr Endcrinol Metab . 2000;13 Suppl 6:1406-1409. Diagnosis Asymptomatic Start with insulin and diet, exercise Diet and exercise Monthly review, A1C q3mo > 7% Add metformin Add metformin Attempt to wean insulin Add insulin, TZD, sulfonylurea BG 250 mg/dL or 12 mmol/L Add 3rd agent < 7% > 7% > 7% < 7%
  • 35. Metformin improves glycaemia in type 2 diabetic adolescents FPG (mmol/L) HbA 1C (%)  – 3.6 mmol/L (p<0.001)  – 1.2% (p<0.001) Jones KL et al. Diabetes Care 2002; 25: 89–94 Baseline Last double-blind measurement
  • 36. Metformin is well tolerated in pediatric subjects
    • Obese nondiabetic adolescents
      • Transient abdominal discomfort or diarrhea in 21% on metformin vs. 6% on placebo
      • Nausea in 6% on metformin vs. 0% on placebo
    • Type 2 diabetic adolescents
      • Abdominal pain in 25% on metformin vs. 12% on placebo
      • Diarrhea 17% on metformin vs. 10% on placebo
    • No treatment withdrawals for drug-related gastrointestinal side-effects in either trial
  • 37. Use of Rosiglitazone in T2DM Children Drug Naive Prior Therapy
    • More homogeneous response throughout study
    • Both groups well matched at screen and baseline
    • Both groups behaved similarly
    • Increase in HbA 1c at all visits
    • No improvement in HbA 1c from screening
    Visit (weeks) -6 0 4 8 16 24 Mean HbA 1c (%) 6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 Screen Baseline Visit (weeks) -6 0 4 8 16 24 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 9.2 Screen Baseline Mean HbA 1c (%) K. Jones et al, poster 1904-P, 65 th ADA Scientific Sesssions Metformin (N=50) Rosiglitazone (N=55) Error Bar = SE Metformin (N=48) Rosiglitazone (N=42) Error Bar = SE
  • 38. Adverse Events Of Interest K. Jones et al, poster 1904-P, 65 th ADA Scientific Sesssions
  • 39. Glimepiride vs. Metformin as Monotherapy in Pediatric Subjects with T2DM: A Single Blind Comparison Study.
      • 26 week randomized, single-blind, parallel-group, forced-titration study to evaluate the efficacy and safety of GLIM and MET in subjects age 9-17 yrs inadequately controlled with diet/exercise and/or failed oral monotherapy
      • Reduction in A1C and SMBG levels similar between groups
      • GLIM and MET have comparable safety profiles
    • Gottschalk M, Danne T, et al
    • Abstract 264-OR (ADA Oral Presentation,
  • 40. LWPES Survey 130 Clinical Practices
    • 48% treated with insulin alone
      • 2 injections
    • 44% with oral agents
      • 71% metformin
      • 46% sulfonylurea
      • 9% TZD
      • 4% meglitinide
    • 8% lifestyle
  • 41. An Answer The Today Trial?
  • 42. Studies to Treat Or Prevent Pediatric Type 2 Diabetes STOPP-T2D Funded by National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health
  • 43. STOPP-T2 TREATMENT PRIMARY AIM
    • To compare the efficacy of 3 treatment regimens
      • Metformin
      • Metformin + lifestyle
      • Metformin + TZD
      • On Time to Treatment Failure and on Glycemic Control
    TODAY
  • 44. Outcome Measures
    • Glycemia
      • HbA1c, fasting and postprandial glucose by home monitoring
    • Insulin sensitivity and secretion
      • OGTT, HOMA, QUICKI, proinsulin, C-peptide
    • Body composition
      • BMI, DEXA, waist circumference, abdominal height
    • Fitness and physical activity
      • PDPAR, PWC 170, accelerometer
  • 45. Outcome Measures (continued)
    • Nutrition
      • food frequency questionnaire
    • Cardiovascular disease risk
      • BP, lipids, inflammatory markers, coagulation factors
    • Microvascular complications
      • microalbuminuria, neuropathy
    • Quality of life
    • Cost
  • 46. Inclusion Criteria
    • Age 10 to 17 years
    • Duration of diabetes < 2 years
    • BMI  85 th percentile
    • Adult involved in the daily activities of the child agrees to participate in the intervention
    • Absence of pancreatic autoimmunity
    • Fasting C-peptide > 0.6 mmol/L
    • Fluency in English or Spanish
  • 47. Question What are the Complications & Co-Morbidities of Type 2 in Youth? Are they the same as in adults?
  • 48. Natural History of Type 2 Diabetes Genetic susceptibility Environmental factors Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy Blindness Renal failure CHD Amputation Onset of diabetes Complications Disability Death Ongoing hyperglycemia PRE Obesity Insulin resistance Risk for Disease Metabolic Syndrome
  • 49. Long term outcome Arslanian S. Hormone Res 2002; 57 Suppl 1: 19-28 Yokoyama H. Kidney Int 2000; 58: 302-311 Dean., Diabetes 2002;51(Suppl 2):A24.
    • Pima Indians - diagnosed < 20 years of age
      • 22% had microalbuminuria at diagnosis
      • Increased to 60% at 20-29 years of age
    • Japan - School Children
      • Retinopathy
        • 36% had incipient retinopathy at diagnosis
        • Increased to 39% at 2 years’ follow-up
      • Young Diagnosed Patients
        • 44% diagnosed at <30 years of age had nephropathy 25 years later
    • Indigenous Canadians - mean age 23 yrs, 9 yrs duration of diabetes
      • HbA1c 10.9%
        • 67% poor glycemic control
      • 45% hypertension requiring treatment
      • 35% microalbuminuria (6% required dialysis)
      • 38% pregnancy loss
      • 9% mortality
  • 50. Are there specific lipid and BP abnormalities documented in children with T2DM?
    • Lipids
      • Same as in adults
      • increased TG, slight elevation LDL, decreased HDL
      • Added risk factor of obesity and metabolic syndrome
    • BP (CHLA)
      • 3.4% systolic > 97 th %ile
      • 20.1% diastolic > 97 th %ile
  • 51. Management of Dyslipidemia in Children and Adolescents with Diabetes
    • A consensus panel – In the absence of data, get experts to give an opinion
    • Consensus panel members – met July 2002
    • Representing Pediatric Endocrinology, Cardiology and Nephrology
      • Kaufman FR, Arslanian S, Berenson G, Clark NG, Gidding S, Jones KL, Lauer R, Schieken R, Sinaiko AR
    • Diabetes Care 26:2194;2003
  • 52. Conclusion
    • Increased incidence
    • Difficult to distinguish from type 1
    • Occurs at the time of intense insulin resistance due to puberty
    • Does not appear to be preceded by long asymptomatic period
    • More insulin deficiency and requirement for exogenous insulin early
    • Safety and efficacy of therapeutic agents
    • Rapid progression of co-morbidities and complications
  • 53. Thank you [email_address]