Transcript Diagnosis of type 2 diabetes in children

DIAGNOSIS AND
TREATMENT OF TYPE 2
DIABETES IN CHILDREN
Dr. Mouna Dakar
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
 Highly
% Increase
70
40
31
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
Age (y)
Sample Size
Prevalence
per 1000
Navajo Indians
12–19
142
14.1
10–14
672
22.3
15–19
530
50.9
4–19
717
11.1
10–19
–
12–19
2867
0 for males
36 for
females
4.1
Pima Indians
Cree and Ojibway
US Caucasians, African
Americans (AA), and
Mexican Americans (MA)
J Pediatr. May 2000.
Type 2 Diabetes in Children
Epidemiology: Case Studies
Population
New Diabetes
Cases (%)
Cincinnati, OH
Caucasians and AA
33
Charleston, SC
AA
46
Little Rock, AR
Caucasians, AA, and
Latinos
MA
–
18
San Antonio, TX
MA
18
Ventura, CA
MA
45
Location
San Diego, CA
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

T2DM
– Younger children
– Adolescents
– Short duration of symptoms
– 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
– Autoimmune thyroid
disease common
GAD=glutamic acid decarboxylase.
 T2DM
– Normal or elevated
insulin and C-peptide
– Absent immune markers
– Autoimmune thyroid
disease infrequent
T2DM in Children: Clinical Features
Location
Ethnicity Female/ Family
%
Male
History
Mean age Mean Acanthosis
(y)
BMI
%
Cincinnati
AA 69
Cau 31
1.7
85%
14
38
60
Charleston
AA 100
1.3
95%
13
30
56
Little Rock
AA 74
Cau 24
1.6
–
14
35
86
San Diego
MA 67
Cau 17
2.0
87%
13
27
67
San Antonio
MA 83
3.0
74%
13
–
92
Ventura
MA 100
0.8
100%
14
33
–
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
P<0.001
140
C-peptide (%ULN)
120
100
80
N=38
60
40
20
0
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
4 (10%)
26 (65%)
Unblinded by DSMB
13 (31%)
7 (18%)
Completed 16-wk DB treatment
19 (45%)
3 (8%)
Mean FPG Change From Baseline
at Week 16 or Last Double-Blind Visit
Mean change from
baseline FPG (mg/dL)
Mean baseline FPG
192 mg/dL
162 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%
Adjusted mean
HbA1c (%)
10
8.6
9
†
7.5
8
7
† P<
0.001
6
Placebo
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
Monotherapy inadequate
after 3 mo: add 2nd agent
Other monotherapy
options: sulfonylureas,
acarbose, repaglinide,
thiazolidinediones,
insulin
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
Thank you