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Joslin Diabetes CenterAdvances in Diabetes and Thyroid Disease 2013Pediatric Diabetes: Realistic Expectations in the 21st Century

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Pediatric Diabetes: Realistic Expectations is the 21st Century

Sanjeev Mehta, MD, MPH

Director of Quality, Joslin Diabetes Center

Staff Physician, Pediatric, Adolescent, and Young Adult Section

Assistant Investigator, Genetics and Epidemiology Section

Disclosure Statement

I have no financial disclosures.

Pediatric Diabetes: Lecture Overview

Epidemiology: Incidence / Prevalence

Diagnostic criteria

Glycemic outcomes

Intensive diabetes management• Blood glucose (BG) monitoring

• Nutrition and meal planning

• Insulin regimens

• Continuous glucose monitoring (CGM)

Comorbidities

Abbreviations: type 1 diabetes (“T1D”), type 2 diabetes (“T2D”)

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Q1: In the US, what percentage of African American or Hispanic youth aged <10 years with new-onset diabetes will have type 2 diabetes?

1. 50%

2. 25%

3. 10%

4. 5%

Epidemiology of Pediatric Diabetes

Incidence: 15,000 T1D/yr vs. 3,700 T2D/yr

Prevalence*: 215,000 youth with diabetes

Age at diagnosis• ~75% T1D diagnosed at age <18 years old

• The majority of people with T1D are adults

• Majority of T2D is diagnosed in adults

Female to male ratio: 1 in T1D vs. 1.6 in T2D

Race / Ethnicity • T1D more common in non-Hispanic whites

• T2D more common in minority groups

*2010

Incidence (United States)

2,435 youth <20 years with newly diagnosed diabetes between 2002–2003 (10 locations)

78% T1D and 22% T2D

Writing Group for the SEARCH for Diabetes in Youth Study. JAMA. 2007;297:2716-2724.

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Incidence (Finland)

10,737 youth <15 years diagnosed diabetes between 1980-2005

Incidence (per 100,000/yr) more than doubled from 31.4 in 1980 to 64.2 in 2005 (US ~25)

The rise in incidence was greatest among young children ages 0-4 years

Conclusions• Number of new cases diagnosed <14 years of age

will double again in the next 15 years

• Age of onset will be younger (0-4 years)

Harjutsalo, Lancet 2008; 371: 1777-82

Incidence (Finland)

Recent evidence suggests possible plateau following rapid rise in incidence...too early?

Harjutsalo, Lancet 2008; 371: 1777-82Harjutsalo, JAMA 2013; 310: 427-428

2008 2013

Prevalence (United States)

154,369 youth age <20 years with diabetes in the US; overall prevalence was 0.18%

0-9 years 10-19 years

SEARCH for Diabetes in Youth Study Group. Pediatrics. 2006;118:1510-1518.

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ADA Diagnostic Criteria

Prediabetes• Impaired fasting glucose (IFG): ≥100 and <126

mg/dL• Impaired glucose tolerance (IGT): 2-hour blood

glucose during OGTT ≥140 and <200 mg/dL

Diabetes• Fasting blood glucose ≥126 mg/dL• 2-hour blood glucose during OGTT ≥200 mg/dL• Random blood glucose ≥200 mg/dL associated with

polydipsia, polyuria, and/or weight loss• Hemoglobin A1c ≥6.5% on two occasions

American Diabetes Association. Diabetes Care. 2009; 32:S62-S67. Diabetes Care. 2009;32:1327-1334.

Differentiating Pediatric T1D and T2DType 1 Diabetes Type 2 Diabetes

Diagnosis age<10; Caucasians if age at diagnosis >10 years

Racial/ethnic minority and age at diagnosis >10 years

Not usually overweight; proportionate to obesity in general population

85% are overweight

35-40% present with ketoacidosis 33% with ketonuria;5-25% may have ketoacidosis

5% with a 1st- or 2nd-degree relative with T1D

74-100% with 1st- or 2nd-degree relative with T2D

Increased incidence of other autoimmune diseases

Increase in PCOS; acanthosisnigricans (up to 90%)

Decreased c-peptide and insulin;no increase with glucose challenge

Normal or increased c-peptide and insulin; increased with glucose challenge

Goals of Pediatric Diabetes Management

Utilize intensive therapy aimed at near-normal BG and hemoglobin A1c levels

Prevent diabetic ketoacidosis and severe hypoglycemia

Achieve the highest quality of life compatible with the daily demands of diabetes management

In children, achieve normal growth and physical development and psychological maturation

Establish realistic goals adapted to each individual’s circumstances

ADA Standards of Care 2013.ADA Position Statement. Care of children with diabetes, 2005;28:186–212, updated 2012.

4



AdultsAdolescents

Reichard P et al. N Engl J Med. 1993;329:304-309. DCCT Research Group. J Pediatr. 1994;125:177-188.

Diabetes Control and Complications Trial: Adult and Adolescent Cohorts

Risk of Retinopathy Progression

A1c 10% x 3 yearsvs.

A1c 8% x 8 years

JAMA. 2002:287.

DCCT Research Group. J Pediatr. 1994;125:177-188.DCCT/EDIC Research Group. J Pediatr. 2001; 139: 804-12.

Benefits of Intensive Diabetes Therapy during Adolescence (DCCT/EDIC)

Intensive diabetes management:• improved A1c compared to conventional therapy

• reduced the risk of diabetic eye disease by 53-70%

• reduced the risk of diabetic kidney disease by 55%

Blood glucose monitoring played a major role in intensive therapy, allowing for optimal insulin dosing

Newer insulins and advanced technologies can aid in the achievement of target blood glucose and A1c levels

5



Maintenance of C-Peptide Production with Intensive Therapy (DCCT)

DCCT

Ann Intern Med. 1998;128:517-523.

DCCT: Risk of hypoglycemia as A1c

Reichard P et al. N Engl J Med. 1993;329:304-309.

DCCT (1993): Adolescents (vs Adults)

Significantly higher A1C levels• Intensive 8.1 vs 7.1%

• Conventional 9.8 vs 9.0%

Significantly more hypoglycemia• Intensive 86 vs 57/100 pt-yrs

• Conventional 28 vs 17/100 pt-yrs

Significantly more diabetic ketoacidosis (DKA)• Intensive 2.8 vs 1.8/100 pt-yrs

• Conventional 4.7 vs 1.3/100 pt-yrs

Reichard P et al. N Engl J Med. 1993;329:304-309. Diabetes Control and Complications Trial Research Group. J Pediatr. 1994;125:177-188.

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Incidence of SH, DKA in Current Era

Incidence of severe hypoglycemia (SH)*

Incidence of DKA*

Rewers et al. JAMA. 2002;287(19):2511-2518; *manuscript summarizes literature on published SH, DKA rates

Overall incidence: 19/100 pt-yearsGirls: decreased with ageBoys: no association with age

Associated with psychiatric disorder,underinsured, longer duration, higher A1c

Overall incidence: 8/100 pt-yearsGirls: increased with ageBoys: no association with age

Associated with psychiatric disorder,underinsured, higher daily insulin, higher A1c

Association between A1c and severe hypoglycemia (SH) and DKA in 2013 Youth and young adults aged 2-26 years (n=13,487)

in the T1D Exchange Registry with T1D ≥ 2 years

0

5

10

15

20

25

30

35

% with ≥1 SH event % with ≥1 DKA event

% of Youth

Miller K. Diabetes Care 2013;36:2009-14.

SH frequency: highest in children <6 years old

DKA frequency: highest in adolescents

Q2: What is the average hemoglobin A1c for youth with type 1 diabetes in the US or Europe?

1. 9.4%

2. 8.6%

3. 7.7%

4. 7.2%

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Glycemic Goals in Pediatric Diabetes

“near normalization of blood glucose levels is seldom attainable...after the honeymoon”

A lower goal may be reasonable if it can be achieved without excessive hypoglycemia

Age Group A1cBlood Glucose (before meals)

Blood Glucose(Bedtime/night)

Toddlers and preschoolers(0-5 years) <8.5% 100 – 180 110 – 200

School age (6-12 years) <8.0% 90 – 180 100 – 180

Adolescents and young adults (13-19 years); ISPAD* <7.5% 90 – 130 90 – 150

Adults(≥20 years) <7.0%

ADA Position Statement. Care of Youth with diabetes, 2005;28:186–212, updated 2012*International Society for Pediatric and Adolescent Diabetes

Glycemic Control (International)

2,873 youth with T1D from 18 countries

19958.6 1.7%

20058.7 1.5%

19988.7 1.8%

4 5 6 7 8 9 10 11 12 13 14 15 16 170

5

10

15

20

25

30

% of Youth

Male Female

A1c (%)

Mortensen et al: Diabetes Care 1997; Danne et al: Diabetes Care 2001; de Beaufort et al: Diabetes Care 2007.

Glycemic Control (United States)

A1c levels for 13,487 youth and young adults participating in the T1D Exchange Clinic Registry

36

12

18

31

1614

0

5

10

15

20

25

30

35

A1c (%)

% of Youth

20138.6 1.5%


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Glycemic Control (United States)

Percent of youth (n=13,226) attaining age-specific A1c goals in the T1D Exchange Clinic Registry

% of Youth

ADA Guidelines ISPAD Guidelines

8.2 1.1% 8.3 1.2% 8.8 1.7%

Wood J. Diabetes Care 2013;36:2035-37.

Increasing BG monitoring by 2 checks daily has been associated with a 0.5% absolute reduction in A1c

Blood Glucose Monitoring and A1c

Levine BS. J Pediatr 2001;139:197–203.

n=300 youth with T1D, ages 7-16 yrs

T1D Exchange Clinic Registry (n=20,555)

Blood Glucose Monitoring and A1c


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Q3: What is the largest difference between mealtime carb estimates and actual carb amounts that will support optimal glycemic control?

1. 20-30 grams

2. 10-15 grams

3. 5-8 grams

4. 1-3 grams

*hyperglycemia or hypoglycemia

Dietary Quality in Pediatric Diabetes

SEARCH Study (89% T1D, age 10-19 yrs, n=1697)

Mayer-Davis, J Amer Diet Assoc, 106:689, 2006


Children ages 2-12 years (T1D vs. NHANES*, n=67)

Mehta, unpublished. *National Health and Nutrition Examination Survey, 2005-06.

10




Children with T1DAges 2-12 yearsN=67, 1 center

Children with DMAges 10-19 yearsN=1697, 6 centers

Mehta, unpublished. *National Health and Nutrition Examination Survey, 2005-06. Mayer-Davis, J Amer Diet Assoc, 106:689, 2006.


Summary of overall nutrition• Low intakes of fruit, vegetables, and whole grains

• Very low intakes of daily fiber

• High intakes of total and saturated fat

• Adequate intakes of protein

Stable across populations over time• Children, young adults, and adults with T1D

• United States, Europe, and Asia

• Similar findings published over the last 30 years

Carbohydrate Estimation/Counting

Limited published data on the association between carbohydrate estimation and A1c until 2009

To date, no method of carbohydrate estimation has proven superior in achieving glycemic targets

Carbohydrate counting is commonly used to calculate prandial insulin doses for intensively treated youth with diabetes

Meal estimates for meals within 10-15 grams do not appear to negatively impact glycemic control• Postprandial glucose excursions or hemoglobin A1c

• Precise (consistent) estimation may be more important than accurate estimation in optimizing hemoglobin A1c

Mehta, Diabetes Care, 32:1014, 2009 Bishop, Diabetes Spectrum, 22:56, 2009Smart, Diabetic Medicine, 26:279, 2009 Smart, Diabetic Medicine 27, 348–353 (2010)

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Patient Perspective on Healthy Foods

Focus group analysis • Youth with T1D (n=35) and their parents

• Understand perceptions of healthful eating and the impact of diabetes management

Focus group themes• Defining healthful foods

– Traditional notions (fruits, vegetables, whole grains)

– Foods which did not cause “spikes” in BGs (low carb or easy to estimate carbohydrate amount)

• Use of flexible insulin regimens– Normalcy in dietary behaviors (good and bad)

– Generally, but not always, easier than fixed regimens

Mehta, Diabetes Care, 32:2174, 2009


“It all comes back to what’s on that glucose meter…If that number’s good, then whatever we have [to eat] in the house is good.” [Parent]

“I would say [unhealthy eating] is anything he’s unable to accurately count the carbs on.” [Parent]

“Everyone wants me to eat healthy, but when I try to eat a fruit or something like that…I can’t eat it.” [Child with T1D]

Mehta, Diabetes Care, 32:2174, 2009


Mehta, ADA Scientific Sessions, 2008

Grains

Prepackaged foods

Fruits

Vegetables

Milk

Fast food

FatFiber

Sugar-sweetened

foods

Protein

HEALTHY UNHEALTHY

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Youth with T1D (US, n=2,743)

Regimen intensification was associated with better outcomes in related analysis

Insulin Regimens (SEARCH Study)

Paris, J Pediatr 2009;155:183-9Pihoker, Diabetes Care 2013; 36:27-33

Youth with T1D (Europe, n=1,133)

Acute events• DKA: no difference according to regimen

• Severe hypoglycemia (/100 pt-years)– No events in 96% of cohort

– Lowest in pump (5.4) and highest in pre-mixed (42.4)

Insulin Regimens (Hvidoere Study)

de Beaufort, Pediatric Diabetes 2013: 14: 422–428.

Insulin Pump/CSII

Basal-BolusInjection

Conventional(twice daily)

Conventional (twice+PRN)

Conventional (pre-mixed)

% Youth 32.8 16.9 36.5 7.5 6.3

A1c (%) 7.8 0.9% 8.0 1.0% 8.2 1.0% 7.3 0.5% 8.5 1.7%

Insulin Pump Use

Mehta S. Endocrinol Metab Clin N Am 2010; 39: 573–593

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Challenges of Pump Use vs Injections

53%

79%

23%

47%

0%

20%

40%

60%

80%

100%

Insulin after Eating Forgets Insulin

Pump Injections

P<0.0001 P<0.0001

Courtesy L. Laffel.

Burdick J et al. Pediatrics. 2004;113:e221-e224.

A1C increases 1% / 4 missed boluses/week

Missed Insulin Meal Boluses and A1C

A1C levels correlated with the number of missed meal insulin boluses per day (r = 0.4)

(n=48)

Potential benefits of pump therapy• Lower hemoglobin A1c (0.2-0.5%)

• Less frequent nocturnal hypoglycemia– Similar or lower rate of overall hypoglycemia

– Similar or lower rate of severe hypoglycemia

• Lower total daily insulin dose, but not weight/BMI

• Similar or better quality of life, but need additional studies comparing to flexible injection regimens

Potential risks of pump therapy• Risk of DKA (absence of long-acting insulin)

• Missed insulin boluses (and higher A1c)

Insulin Regimens

Mehta S. Endocrinol Metab Clin N Am 2010; 39: 573–593

14



JDRF Continuous Glucose Monitoring Study Group, NEJM, 2008; 359.

Relationship between Change in A1C and Frequency of CGM Use

Change in A1C-0.9

-0.7

-0.5

-0.3

-0.1

0.1

Ch

ang

e in

A1C

Prevalence of CVD Risk Factors in T1D

Cardiovascular disease risk factors

US (SEARCH)

Norway (NCDQ)

Germany (DPV, F)

Germany (DPV, M)

Above A1c target (ADA)

55.6 71.4 61 59

Dyslipidemia 43.0 41.4 34 22

Obesity 12.6 4.4 23 18

Elevated BP 5.9 6.9 23 19

Microalbuminuria 9.2 1.0 N/A N/A

* Petitti, J Pediatrics, 155:668, 2009 Liu, Pediatric Diabetes, 11:4, 2010 Maahs, Diabetes Care, 30:2593, 2007Kershnar, J Pediatrics, 149:314, 2006 Rodriguez, Pediatrics, 15:245, 2010 Margeirsdottir, Diabetologia, 50:207, 2007Schwab, Pediatric Diabetes, 11:357, 2010

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Prevalence of CVD Risk Factors in T1D

Number of CVD risk factors

Number of CVD risk factors

Norway (NCDQ)n=576

Germany (DPV)n=33,488

0 14.0 26.0

1 41.0 39.0

2 30.0 24.3

3 12.6 8.7

≥4 2.4 2.0

* Margeirsdottir, Diabetologia, 50:207, 2007Schwab, Pediatric Diabetes, 11:357, 2010

Joslin Medalists

Awarded to individuals with physician-confirmed insulin dependence for ≥25 years

25-Year

(1948)

50-Year

(1970)

75-Year

(1995)

80-Year

(2013)

Pediatric Diabetes: Realistic Expectations is the 21st Century

Sanjeev Mehta, MD, MPH

Director of Quality, Joslin Diabetes Center

Staff Physician, Pediatric, Adolescent, and Young Adult Section

Assistant Investigator, Genetics and Epidemiology Section

16

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