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5/16/2018 1 PHIL ZEITLER MD, PHD SECTION OF ENDOCRINOLOGY DEPARTMENT OF PEDIATRICS UNIVERSITY OF COLORADO DEPARTMENT OF ENDOCRINOLOGY CHILDREN’S HOSPITAL COLORADO Pediatric Case Studies Blake 15 yo NHW male with long history of overweight and two year increase in weight gain Denies change in eating or activity habits Small breakfast, school lunch, “large” dinner Fast food once a week PE at school every day 4-5 hours/day of screen time No medications. Depakote two years ago (one year) ROS: daytime sleepiness, snoring. Otherwise negative Blake Past Hx: Uncomplicated pregnancy, BW 5lbs 12 oz, no GDM Asperger’s syndrome Fam Hx: Paternal grandmother with T2DM Father with elevated cholesterol Mat uncle with HTN, MI at 45, elevated cholesterol Maternal GF with MI at 61, HTN, elevated cholesterol

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5/16/2018

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PHIL ZEITLER MD, PHD

SECTION OF ENDOCRINOLOGY

DEPARTMENT OF PEDIATRICS

UNIVERSITY OF COLORADO

DEPARTMENT OF ENDOCRINOLOGY

CHILDREN’S HOSPITAL COLORADO

Pediatric Case Studies

Blake

15 yo NHW male with long history of overweight and two year increase in weight gain

Denies change in eating or activity habits Small breakfast, school lunch, “large” dinner

Fast food once a week

PE at school every day

4-5 hours/day of screen time

No medications. Depakote two years ago (one year)

ROS: daytime sleepiness, snoring. Otherwise negative

Blake

Past Hx:

Uncomplicated pregnancy, BW 5lbs 12 oz, no GDM

Asperger’s syndrome

Fam Hx:

Paternal grandmother with T2DM

Father with elevated cholesterol

Mat uncle with HTN, MI at 45, elevated cholesterol

Maternal GF with MI at 61, HTN, elevated cholesterol

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Blake

Exam

Ht 75%ile

Wt > 95%ile

BMI 35.7

BP 135/72

Acanthosis nigricans at neck, IP joints, axillae

Tanner 5

Of the following, which is the best way to diagnose diabetes in obese youth

Fasting glucose

Random/post-prandial glucose

OGTT

Hemoglobin A1c

Defining diabetes and prediabetes

Remember - diabetes is defined by increased risk for microvascular complications (initially retinopathy)

1979: National Diabetes Data Group.

Random or OGTT >200

Fasting glucose >140

1997: Based on incidence of retinopathy

FPG >126

OGTT >200

Ethnic variation in all parameters was noted (FPG, 2HPG, and A1c)

2009: A1c ≥ 6.5

assay concordant with the DCCT

National Glycohemoglobin Standardization Program

Confirmed on a second test

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International Expert Committee

• Specificity over sensitivity and regarded 6.5% as ‘conservative’ • A1c is at least as predictive as FPG and 2HPG for development of

retinopathy• Not a continuum – below a certain A1c, you have no risk of retinopathy• Committee acknowledged that the tests do not always correlate

Prediabetes – increased risk for diabetes

By fasting and glucose tolerance test Impaired fasting glucose (IFG): 100 – 125 mg/dl

Impaired glucose tolerance (IGT): 140 – 200 mg/dl at 2 hours post challenge

By A1c

≥ 5.7%

correlates with abnormal FPG (≥100) or 2HPG (≥140)

Why define prediabetes? Strong data supporting treatment in adults

Advantages of adding A1c to diagnostic algorithms

The primary benefits of HbA1c are practical The patient does not need to be fasting

Testing does not require a return visit

HbA1c has less variability and is more reproducible than glucose

HbA1c is less subject to acute changes

Studies demonstrate that the total number of patients who receive at least some screening increases

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Effect of use of A1c on frequency of screening in primary care

• The number of at-risk children screened increased

• No change in prevalence of pathology

• There is a difference between < 6% and > 6%

Love-Osborne K et al Pediatr Diabetes 2017

Disadvantages of A1c

HbA1c may miss cases of acute onset of diabetes (i.e., type 1)

Diseases such as anemia, CF, sickle-cell disease, thalassemia, and other hemoglobinopathies alter HbA1c results

There is ethnic variation in HbA1c

A1c may cost more

Test name Cost*

Hemoglobin A1c  $70.40

Fasting glucose $25.09

2 hour glucose tolerance, both 

specimens plus dextrose drink

$46.09

Nowicka P et al. Diabetes Care 2011

A1C FOR DIAGNOSIS OF DIABETES AND PREDIABETES IN OBESE ADOLESCENT

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But

All of these studies use FPG and/or OGTT as the “Gold Standard”

FPG and OGTT are not considered a “gold standard” in adults

Diabetes is diagnosed by risk for complications

A1c predicts risk for complications as well as FPG and OGTT in adults

FPG and OGTT are not entirely reproducible.

Reproducibility of the Oral Glucose Tolerance Test in

Overweight Children

Libman et al JCEM 2008

A1c and OGTT as predictors of glycemia 98 obese kids had OGTT and wore CGM for 7

days

Chan et al JCEM 2015

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Using A1c for diagnosis of diabetes and prediabetes

Correlations among A1c, FPG ,and 2HPG may be less than in adults

A1c, FPG, and 2HPG are likely measuring different things Abnormalities in any of them likely indicate underlying abnormal

glycemia

Risk of complications correlates strongly with A1c in adults

A1c is not always reproducible: but neither is OGTT or FPG,

A1c is affected by ethnicity, underlying disease But so are FPG and 2HPG

HbA1c distribution in healthy lean adolescents

2% of non-obese participants had HbA1c > 5.7% - all less than 6.0%

Kelsey et al IMPE 2017

White Hispanic NHB

Treating Prediabetes

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In principle, it’s easy! Reduce the accretion of visceral fat through lifestyle

modification Reverse the trends in the toxic environment

Reduce caloric intake

Increase caloric expenditure

AAP Expert Committee:

Evidence based dietary interventions

Eliminate liquid calories

Reduce or eliminate eating out

Reduce portion sizes

Evidence based activity interventions

Reduce sedentary time/screen time

Encourage attainment of recommended activity goals.

Barlow et al Pediatrics 2007

Effects of lifestyle intervention in obese children and adults

Godoy-Matos et al. JCEM 90: 1460, 2005Poston et al. Int J Obes 27: 1486, 2003Berkowitz et al. JAMA 289: 1805, 2003Nemet et al. Pediatrics 115: e443, 2005Chanoine et al. JAMA 293: 2873-2883, 2005

0 1 2 3 4 5-7.5

-5.0

-2.5

0.0Standard

Moderate

Intensive

Children Intensive

Children Standard

years

we

igh

t ch

an

ge

(kg

)

Tuomilehto, et al. N Eng J Med 344: 1343, 2001Knowler et al (DPP). N Eng J Med 346: 393, 2002Torgersen et al. Diab Care 27: 155, 2004

Van Gaal et al. Lancet 365: 1389, 2005Despres et al. N Eng J Med 353: 2121, 2005Pi-Sunyer et al. JAMA 295: 761, 2006

School Interventions

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Cochrane Meta-analyses

Summerbell 2007 – No evidence for effectiveness of school-based interventions for the prevention of obesity

Some evidence for reported changes in dietary habits

Summberbell 2007 – No evidence for effectiveness of school-based interventions for the treatment of obesity

The Healthy Study

42 middle schools randomized to multi-modal intervention or control. Baseline in 6th grade and retested in 8th grade

Small decrease in overweight/obesity in both intervention and control schools, with intervention slightly better

HEALTHY did not show:

Reduction in CVD risk factor rates

Except for BP in Black and White males

Improvements in fitness

23

Pharmacologic intervention

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Compared Intensive Lifestyle, metformin, and placebo in adults with impaired glucose tolerance

3,234 participants, 25-65 years old, 45% from minority groups, overweight (BMI > 25 kg/m2)

Impaired glucose tolerance Glucose 140-200 mg/dL 2 hrs after 75g glucose

Fasting glucose < 140 mg/dL

Intervention - tailored dietary and exercise advice by nutritionists - 7 times in 1st year, every 3 months thereafter

Endpoint – Diagnosis of diabetes

DSMB stopped the trial a year early

Diabetes Prevention Program (DPP)

DPP: estimated cumulative incidence of type 2 diabetes in 3 years

DPP (Knowler et al) N Engl J Med 2002

placebo metformin lifestyle

*

**

0

10

20

30

perc

ent

DPP: effects of treatment on body weight

0 1 2 3 4 5-7.5

-5.0

-2.5

0.0

2.5

placebo

metformin

lifestyle

chan

ge in

wei

ght

(kg)

DPP (Knowler et al) N Engl J Med 2002

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DPP: incidence of type 2 diabetesin subjects aged 25-44 years

placebo metformin lifestyle

* *

0

5

10

15

case

s/10

0

pers

on-y

r

DPP (Knowler et al) N Engl J Med 2002

DPP: incidence of type 2 diabetesin subjects with BMI > 34.9

placebo metformin lifestyle

* *

0

5

10

15

case

s/10

0

pers

on-y

r

DPP (Knowler et al) N Engl J Med 2002

Metformin in Youth

Non-controlled case studies

Freemark and Bursey

29 obese adolescents

white and black

boys and girls

BMI > 30 kg/m2, Fasting insulin > 15

At least 1 1st or 2nd degree relative with T2DM

Metformin 500 mg BID or placebo for 6 months

BMI decreased 0.12 SD (1%) vs. increase of 0.23 SD (2%)

Decreased fasting glucose (all normal) and insulin

Freemark and Bursey Pediatrics 2001

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Metformin in Youth

Size of treatment effect

Pvalue

Weight (kg) – 4.35 0.02

Weight z-score – 0.09 0.009

BMI (kg/m2) – 1.26 0.002

BMI z-score – 0.12 0.005

Waist circumference (cm) – 2.8 0.003

Waist circumference z-score – 0.05 0.005

Fasting glucose (mmol/liter) – 0.2 0.048

Srinivasan et al JCEM 2006

•Double blind placebo controlled 6 month-crossover trial•Metformin 1000 mg twice a day or placebo•28 obese adolescents randomized•22 analyzed (78%)

Metformin in Youth

85 obese insulin-resistant adolescents

BMI > 95%ile

Fasting insulin > 15 or HOMA > 2.5

Randomized to receive metformin (1000 mg a day) or placebo for 6 months

All participants received office-based lifestyle intervention

80% of metformin and 64% of placebo subjects completed 6 months

Love-Osborne et al J. Pediatr 2008

Metformin (N= 48)

Placebo (N= 16)

p-value

Mean change in BMI(Kg/m2)

-0.16 1.89 0.63 1.29 0.11

BMI decrease of > 5% 11(22.9%) 0 (0.0%) 0.001*

Increase in BMI 20 (41.7%) 11 (68.8%) 0.06

Metformin in Youth– Decrease in BMI

Love-Osborne et al J. Pediatr 2008

No change in any measure of glucose/insulin metabolism

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DPP for Youth?

Progression to diabetes is ~10% in 2 years among obese NHB youth in 2 years

Progression to diabetes is ~ 7% in 8 years in insulin-resistant Hispanic adolescents with NGT

Assume metformin reduces progression by the same order of magnitude as in IGT adults (~0.3% progression vs ~0.5% every 6 months)

Assume 5% dropout every 6 months

Study would need 5000 kids and last 6 years to get 80% power to see the difference.

Implications

Prediabetes is a high risk state for progression to diabetes in adults, but implication in kids is unclear

“high-normal” glucose and A1c may be normal in puberty

More likely to regress due to changes in insulin resistance of puberty

Value of screening is unclear

Overt diabetes remains rare (< 0.4% in high-risk kids)

Value of identifying prediabetes in kids is unclear – all obese kids deserve intervention

A1c an imperfect, but efficient, approach to evaluation of high-risk kids

A1c > 6% has increased risk for progression

Other abnormalities associated with obesity are more common than pre-diabetes and there is evidence base for treatment

Hypertension, dyslipidemia, hepatic steatosis, sleep disturbance, mood disorder, disturbed eating etc

Deanna

16 year old Latina female diagnosed with type 2 diabetes 3 years ago by primary doctor

Started on metformin 2000 mg/d, but reports that she took this for only a few months

One month ago, she was admitted to hospital following a suicide attempt Noted to have a glucose of 550 ng/dL (30.5 mmol/L) and

glucosuria, with small ketones, normal pH, and normal electrolytes

HbA1c 12.5%

Started on basal insulin and discharged

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Of the following, which is the most important next test to order?

A. Fasting lipid panel

B. Liver enzymes

C. Pancreatic autoantibodies

D. Self-monitored glucose for one week

E. Stimulated C-peptide

Lessons from TODAY Screening

Of the 1206 children referred by their

pediatric endocrinologist for screening,

119 (9.8%) were positive for diabetes

autoimmunity

Klingensmith et al Diabetes Care 2010

Antibody Negative vs. Positive Subjects

Antibody negative(N=1092)

Antibody positive(N=119)

Age 14.0 (9,17) 13.0 (10, 17)

Years since diagnosis 0.2 (0,2.7) 0.2 (0, 6.5)

BMI Z-score** 2.3 (-0.3, 3.2) 1.9 (0.5, 2.9)

C-peptide (nmol/L)** 1.26 (0,6.39) 0.66 (0, 2.88)

HbA1c* 6.9 (4.5, 17.4) 7.6 (4.8, 19.9)

Cholesterol (mmol/L) 4.04 (1.61, 22.61) 3.9 (2.2, 6.89)

Trigycerides (mmol/L)** 1.2 (0.31, 109.5) 0.87 (0.16, 10.7)

HDL (mmol/L)** 1.01 (0.26, 2.46) 1.11 (0.65, 2.02)

LDL (mmol/L) 2.38 (0.54, 11.63) 2.25 (0.57, 4.30)

SBP** 115.0 (84, 184) 110.7 (86, 144)

DBP** 68.3 (43, 109) 64.7 (44, 90)

*p<0.05

**P < 0.005

Median (min,max)

Klingensmith et al Diabetes Care 2010

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Antibody Negative vs. Positive Subjects

Antibody negative(N=1092)

Antibody positive(N=119)

% female* 64.3 48.7

%non-white** 81.0 59.7

% insulin use* 38.6 53.8

% mother with diabetes** 40.0 21.0

% father with diabetes* 22.7 15.1

% with acanthosis** 83.1 68.1

*p<0.05

**P < 0.005

Klingensmith et al Diabetes Care 2010

Summary

At least 9.8% of US youth identified with T2D by pediatric endocrinologists on clinical grounds are antibody positive some potential subjects were prescreened for DAA

insulin auto-antibodies were not measured

anti ZnT8 (and other unknown antibodies were not measured)

Although antibody positive youth with diabetes are clearly different from antibody negative youth, antibody positive youth are clinically indistinguishable from antibody negative youth

Youth who were ZnT8 positive or who converted to GAD positivity had more rapid loss of glycemic control

Antibody measurement should be considered in obese youth diagnosed with type 2 diabetes

Klingensmith et al Diabetes Care 2010

Non-glycemic evaluation at diagnosis

Blood pressure

(Fasting) lipid panel

AAP: lipid panel between 7-10 and after completion of puberty

Presence of fatty liver

ALT/AST, though low sensitivity

Urine albumin/creatinine ratio

Depression screening

Evaluation for sleep disturbance

Evaluation for PCOS in females

Birth control counseling

Dental evaluation

Burden of family illness

Zeitler et al Pediatr diabetes 2014

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Ongoing screening

HbA1c every 3-4 months

BP – every visit

Lipid panel: annual

Foot exam/MNSI/monofilament testing – annual

Eye exam – annual/every 2 years

Dental cleaning and exam – every 6 months

Sleep apnea screen every visit

? Vitamin D

Depression screen: every visit

Zeitler et al Pediatr diabetes 2014

Katz et al Diabetes Care. 2016

Depression in youth-onset type 2

Depression is common in US youth with type 2 diabetes, though not at higher rates than obese youth without diabetes

A greater percentage of participants with low adherence had clinically significant depressive symptoms at baseline (18% vs. 12%)

The odds of medication nonadherence increased significantly from those reporting ≥ 1 major life stressor (OR 1.58) to those reporting ≥ 4 major life stressors (OR 2.70)

Significant odds of elevated depressive symptoms and impaired QoL were also found with increased reporting of major stressors

Larkin et al Diabetes Manag (Lond). 2015

Depression and quality of life

At baseline, 22.2% of participants demonstrated impaired HRQOL

Depressive symptoms distinguished those with impaired HRQOL and were significantly related to later impaired HRQOL

Other comorbidities did not have a significant impact on HRQOL

Physical Health Psychological Health

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Arturo

15 yo Latino male with fasting glucose of 289 mg/dL (16 mmol/L) at yearly exam

BMI 32 Kg/M2, BP 120/65, Tanner 5.

Antibodies (GAD, IA2, ZnT8, mIAA) negative

Of the following, what hemoglobin A1c would you use to decide to start insulin:

A. I would always start insulin

B. 6.5%

C. 7.5%

D. 8.5%

E. 10%

A1c < 8.5%* A1c > 8.5%No Acidosis with or without ketosis

Acidosisand/or DKA

and/or HHNK

•metformin PO bid•Titrate up to 2000 mg per day as tolerated

•basal insulin: start at 0.5 U/kg/day and escalate every 2-3 days based on meter glucose•metformin

•titrate up to 2000 mg per day as tolerated

•Manage DKA or HHNK•IV insulin until acidosis resolves, then subcutaneous

Pancreatic autoantibodies

Continue metforminwean insulin

A1C goals not met

Initiate or continue add-on insulin therapy - basal insulin to max 1.5 unit/kg/day

Continue or initiate MDI insulin therapy

positivenegative

A1C Goals Not Met

New Onset Diabetes in Overweight Youth

Consider other drug therapy

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Arturo

15 yo Latino male with fasting glucose of 289 mg/dL (16 mmol/L) at yearly exam

BMI 32 Kg/M2, BP 120/65, Tanner 5.

HbA1c 8.7%

You start him on metformin and titrate to 2000 mg a day

He returns in 3 months

HbA1c is 7.0%

He and his mom report good adherence to metformin

Of the following, the BEST next step in management is:

A. Make no changes - patient is at target

B. Start basal insulin

C. Start GLP-1 agonist

D. Start sulfonylurea

E. Start thiazolidinedione

At diagnosis:

Lifestyle+

Metformin

Lifestyle + Metformin+

Basal insulin

Lifestyle + Metformin+

basal insulin+?

>6.5%

Pathophysiology – based treatment algorithm for Pediatric Type 2 diabetes

Metformin intoleranceSevere resistance

TZD

ObesityGLP-1 agonist

Off label

Obesity/hypertensionDKD

SGLT2 inhibitor

Aggressive Disease: Early

Combination therapy?

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Effect of insulin on glycemic and non-glycemic outcomes

No difference in HbA1c 1 year after starting insulin

At failure

9.7 ± 1.7%

1 year later

9.5 ± 2.0%

Insulin improves but does not correct dyslipidemia or inflammatory status

Levitt Kat et al J Pediatr 2018

Anthony

T2D 4 years ago metformin 2000 mg - 4 years

glargine insulin 110 units – 2.5 years

liraglutide 1.8 mg - 1 year

BP 138/92

HbA1c 8.6%

AST 85 U/L (1.42 µkat/L), ALT 110 U/L (1.84 µkat/L)

Fasting triglycerides 320 mg/dL (3.62 mmol/L)

LDL 160 mg/dL (4.14 mmol/L)

Urine albumin/creatinine 40

Of the following, what would be the MOST important next step in management?

A. Increase glargine dose

B. Start ACE inhibitor

C. Start fibric acid

D. Start statin

E. Start vitamin E

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Hypertension

TODAY Diabetes Care 2013

Dyslipidemia

0

2

4

6

8

10

12

14

Base Month 12

Month 24

Month 26

PERC

ENT

LDL> 130

Metformin Met + Rosi Met + L

0

5

10

15

20

25

30

35

Base Month 12 Month 24 Month 36

PERC

ENT

Triglyceride > 150

Metformin Met + Rosi Met + L

TODAY Diabetes Care 2013

ISPAD Lipid Management

LDL Goal: < 130 mg/dL (3.4 mmol/L)

• LDL > goal – diet therapy (7% sat fat, < 200 mg chol)

• LDL > goal after 6 months of TLC

Start statin

Titrate until LDL < 100 mg/dL (2.6 mmol/L)

TG Goal: < 150 mg/dl (1.7 mmol/L) fasting

• TG > 600 mg/dL (6.7 mmol/L)

Start fibrate – to avoid postprandial > 1000 mg/dl

Zeitler et al Pediatr diabetes 2014

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Microalbuminuria

TODAY Diabetes Care 2013

Maahs, Diabetes technology and therapeutics 2012

Development of diabetic kidney disease

Course of albuminuria and risk of glomerular filtration rate (GFR) loss

Perkins BA et al. J Am Soc Nephrol 2007

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Insulin resistance and kidney disease in youth-onset T2D

Clamp measure of insulin sensitivity inversely associated with eGFR.

HbA1c, systolic Blood pressure and LDL-Cholesterol were not.

P<0.05

P<0.05P<0.05

Bjornstad et al. Diabetes Care 2014

Combined effects of albuminuria and low eGFR

Ninomiya T et al. JASN 2009

Survival by GFR and urine ACR

de Boer I H et al. Diabetes Care 2009

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ISPAD: Hypertension and kidney

Blood pressure: Goal < 95%ile for age, sex, and height• if > 95%ile - lifestyle modification

• BP > 95%ile after 6 months

• Start ACE or ARB

• Titrate until BP < 90th %ile

Albumin excretion: goal albumin/creatinine ratio < 30Abnormal: repeat first morning sample; 2 of 3 abnormal is diagnostic

Start ACE - titrate until albumin/creatinine ratio normal

This does not agree with ADA guidelines for adults

ADA

ACR 30-300 – start ACE/ARB if BP elevated

ACR > 300 – start ACE/ARB

Zeitler et al Pediatr diabetes 2014

Retinopathy

Diabetic Retinopathy

HbA1c (%) tertile

N N % OR (95%CL)

4.30-5.92 172 8 4.7

5.93-7.80 173 20 11.6 2.5 (1.1-5.9)

7.81-13.50 172 43 25.0 6.3 (2.8-14.0)

TODAY Diabetes Care 2013

Beyond glycemic control

Morbidity and mortality in adults with type 2 diabetes is predominately related to cardiovascular disease

Hypertension, microalbuminuria, and dyslipidemia are common in youth with T2D at the time of diagnosis

The prevalence of all of these increases over time

In TODAY, glycemic treatment was insufficient to prevent increased prevalence/risk

These results underscore the worrisome prognosis for complications and comorbidities in youth with type 2 diabetes

Kids are going to live a long time with both poor β-cell function and rising comorbidities

More attention is needed to evidence-based approaches to aggressive treatment of comorbidities needed to lower CVD risk in youth with T2D

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Thank you for your attention