Type 2 Diabetes in Children and Youth

Type 2 Diabetes in Children and Youth
Francine Ratner Kaufman, MD Professor of Pediatrics The Keck School of Medicine of USC Head, Center for Diabetes and Endocrinology Childrens Hospital Los Angeles Paula Jameson, ARNP, MSN, CDE Nemours Children’s Clinic Division of Endocrinology

Natural History of Type 2 Diabetes
Complications Genetic susceptibility Environmental factors Onset of diabetes Disability PRE Obesity Insulin resistance Ongoing hyperglycemia Death Risk for Disease Metabolic Syndrome Blindness Renal failure CHD Amputation Atherosclerosis Hyperglycemia Hypertension Retinopathy Nephropathy Neuropathy

What Do We Know About Type 2 Diabetes in Youth?
Question What Do We Know About Type 2 Diabetes in Youth?

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 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: Centers for Disease Control. Diabetes Fact Sheet. 2005

Diabetes Trends Among Adults in the US BRFSS 1990, 1995 and 2001

Changing Face of Diabetes in Youth in US
35 30 25 20 % with type 2 15 10 5 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: , 2000

Occurs at the time of intense insulin resistance due to puberty
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

Polycystic ovary syndrome
Type 2 Diabetes Prediabetes Beta Cell Defect Beta Cell Defect Age Puberty Obesity BP, Lipids Insulin Resistance Genetics Ethnicity Sedentary Lifestyle Gender – Girls Polycystic ovary syndrome

Insulin Resistance Beta Cell Defect Type 2 Diabetes Prediabetes
Autoimmunity Genetic Defect Beta Cell Defect Fat cell toxicity Intrauterine IUGR, DM Glucose toxicity Insulin Resistance

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

Pre-diabetes (IGT) and T2D
Overweight Sample IGT T2D Paulsen et al, 1968 66 multi-ethnic youth (4-16 years) 17% 6% Weninger et al, 1980 15 subjects 33% 0% Sinha et al, 2002 55 multi-ethnic youth (>95th %ile) 25% 112 multi-ethnic teens (>95th %ile) 21% 4% Goran et al, 2004 150 Hispanic +FH (8-13 years >85th %ile) 28% IGT = Impaired Glucose Tolerance

Type 2 Diabetes ? Curve for Youth B-cell Function (%)
Progressive Pancreatic B-cell Failure Prevention and Early Treatment UKPDS Data B-cell Function (%) ? Curve for Youth Years from Clinical Diagnosis

What distinguishes type 1 from type 2 diabetes in youth?
Question What distinguishes type 1 from type 2 diabetes in youth?

“Pediatric Diabetes is a DIFFICULT diagnostic speciality”
Childhood obesity Type 2 Diabetes + Syndromes Monogenic Diabetes Type 1 diabetes

T1DM T2DM Weight 20% may be obese All > 85% overweight Course Rapid
From DPT-1 can be indolent Indolent Virtually none found on screening DKA 35%-40% Ketonuria (33%) Mild DKA (5%-25%) Relative with DM 5% with T1DM Up to 20% may have with T2DM 74%-100% with T2DM Comorbid thyroid, adrenal, vitiligo, celiac Increase in polycystic ovary syndrome Acanthosis nigricans (90%) C-peptide C-peptide can be preserved at DX Normal or increased Antibody Ethnicity 85% Whites predominate 15% NA, AA, HA, Asian, Pacific Islander

Differentiation Between Type 1 and 2
48 with type 2 vs 39 with type 1 Type 2 Ethnicity, 1st degree relative, BMI>24, +C-peptide, acanthosis Type 2 Type 1 DKA 33% 53% C-peptide ug/l ug/l Abs 8.1% ICA 30% GAD 35%IAA 85% have islet autoimmunity Hathout et al Pediatrics 107e102,June,2001

Question How Does Type 2 Present in Youth?
Is it asymptomatic or symptomatic in youth?

Diagnosis with Type 2 Fagot-Campagna et al J Pediatr 2000
Mean Age years Girls > Boys :1 Obese BMI >85th % Minority Groups 94% Strong Family History % Acanthosis Nigricans % Diagnosis made by Symptoms, not Screening HbA1c % Weight loss % Glucose in urine 95% Ketosis % DKA %

Question What Are Treatment Targets in Youth with Type 2 Diabetes?
Are they the same as in adults?

TREATMENT GOALS Glucose control, HbA1c <7%
Goals (Diabetes Care, 2000) FG PP Bed A1c <7.0 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

ROLE OF FAMILY IN MANAGEMENT
African-American Family Study Group 1, direct family supervision Group 2, no direct supervision Group 1 ending HbA1c = % Group 2 ending HbA1c = % P=<0.0005 Bradshaw, J Pediatr Endocrinol Meta 15, 2002

What are the Treatment Regimens for Youth?
Question What are the Treatment Regimens for Youth?

Start with insulin and diet, exercise
Diagnosis BG 250 mg/dL or 12 mmol/L Asymptomatic Start with insulin and diet, exercise Diet and exercise <7% <7% Monthly review, A1C q3mo Add metformin Attempt to wean insulin >7% Add metformin >7% Add insulin, TZD, sulfonylurea >7% Add 3rd agent TZD = thiazolidinedione Silverstein JH, Rosenbloom AL. J Pediatr Endcrinol Metab. 2000;13 Suppl 6:

Metformin improves glycaemia in type 2 diabetic adolescents
D –3.6 mmol/L (p<0.001) D –1.2% (p<0.001) FPG (mmol/L) HbA1C (%) 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 HbA1C, 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: Baseline Last double-blind measurement Jones KL et al. Diabetes Care 2002; 25: 89–94

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 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:

Use of Rosiglitazone in T2DM Children
Drug Naive Prior Therapy Metformin (N=50) Rosiglitazone (N=55) Error Bar = SE 9.2 Metformin (N=48) Rosiglitazone (N=42) Error Bar = SE 8.8 9.0 8.6 8.4 8.8 8.2 Mean HbA1c (%) 8.6 Mean HbA1c (%) 8.0 8.4 7.8 7.6 8.2 7.4 8.0 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 7.2 Screen Baseline 7.0 7.8 6.8 7.6 -6 4 8 16 24 -6 4 8 16 24 Visit (weeks) Screen Baseline Visit (weeks) More homogeneous response throughout study Both groups well matched at screen and baseline Both groups behaved similarly Increase in HbA1c at all visits No improvement in HbA1c from screening K. Jones et al, poster 1904-P, 65th ADA Scientific Sesssions

Adverse Events Of Interest
Overall weight gain of 3kg in rsg group. K. Jones et al, poster 1904-P, 65th ADA Scientific Sesssions

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 Abstract 264-OR (ADA Oral Presentation, Gottschalk M, Danne T, et al

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

An Answer The Today Trial?

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

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

Outcome Measures Glycemia Insulin sensitivity and secretion
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

Outcome Measures (continued)
Nutrition food frequency questionnaire Cardiovascular disease risk BP, lipids, inflammatory markers, coagulation factors Microvascular complications microalbuminuria, neuropathy Quality of life Cost

Inclusion Criteria Age 10 to 17 years
Duration of diabetes < 2 years BMI  85th 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

Question What are the Complications & Co-Morbidities of Type 2 in Youth? Are they the same as in adults?

Long term outcome Pima Indians - diagnosed < 20 years of age
22% had microalbuminuria at diagnosis Increased to 60% at 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 Arslanian S. Hormone Res 2002; 57 Suppl 1: Yokoyama H. Kidney Int 2000; 58: Dean., Diabetes 2002;51(Suppl 2):A24.

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 > 97th%ile 20.1% diastolic > 97th%ile

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

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

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Type 2 Diabetes in Children and Youth

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