Management of Type 2
diabetes in Youth
Cindy Cain RN, PNP
Phil Zeitler MD, PhD
University of Colorado Denver
Aurora, CO
Progression of insulin resistance
to glucose intolerance
Obesity
Genetics
lifestyle
Obesity with
Insulin resistance
Obesity and
hyperinsulinemia
NGT
Metabolic syndrome
T2DM
Compensatory
secretion
Worsening
resistance
Obesity and
hyperinsulinemia
cell failure
IFG
cell failure
HGO
Obesity and
hyperinsulinemia
IGT
Metabolic Syndrome


A clustering of cardiovascular risk factors first
noted in large epidemiologic studies

Visceral adiposity

Insulin resistance

Low HDL

Systemic pro-inflammatory state
Subsequently also associated with

Elevated triglycerides

dysglycemia

PCOS

Fatty liver disease
Mortality Associated With
Metabolic "syndrome"
20
Mortality (% of patients)
18
Metabolic "syndrome"
No metabolic "syndrome"
18
16
14
12
10
8
8
9
6
6
4
3
2
0
2
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All-cause mortality*
CVD mortality*
CHD mortality*
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*Adjusted for known CHD risk factors.
2003®PPS
Lakka H-M et al. JAMA. 2002;288:2709-2716.
Effect of diabetes and metabolic
"syndrome" on cardiovascular disease
Alexander et al. Diabetes 52:1210-1214, 2003
Metabolic syndrome and
vascular complications
in type 2 youth
Fasting Lipid Profiles
(N = 480)
Total cholesterol (mg/dL)
Median
Range
% abnormal
156
62-873
3.1
(>95th %ile)
HDL cholesterol (mg/dL)
40
10-82
23.5
(<5th %ile)
LDL cholesterol (mg/dL)
90
23-449
36.5
(>100)
Triglycerides (mg/dL)
107
27-9688
27.6
(>150)
Dyslipidemia (at least 1
abnormal value)
--
--
59.6
Type 2 youth with Hypertension and
Dyslipidemia (N=480)
Dyslipidemia
No
Dyslipidemia
Yes
TOTAL
BP <95th %ile
154
(32%)
202
(42%)
356
(74%)
BP >95th %ile
42
(9%)
82
(17%)
124
(26%)
TOTAL
196
(41%)
284
(59%)
480
(100%)
Hypertension and nephropathy in adolescents with type 2 vs type 1 diabetes
HT at
MIC at
Yrs
HT at
MIC at
MAC at
DX
DX
F/U
F/U
F/U
F/U
Age at
Dx/
comparison
Pt #
8-19
49
13.9±0.4
50
Arkansas
Scott et al
1997
T1
4
T2
32
NZ - Maori
McGrath et al
1999
T1
0
8.4
11%
18%
17%
12.4/20.9
18
T2
14%
10.1
39%
62%
35%
19.5/29.5
28
Korea
Yoo et al
2004
T1
8.1±3.4
11.3%
2.8%
8-28
141
T2
5.5±3.9
18.2%
4.5%
Australia
Eppens et al
2006
T1
6.8
16
6%
8.1/15.7
1433
T2
1.3
36
28%
13.2/15.3
68
NZ
Scott et al
2006
T1
6
T2
3±0.3
8
20%
22
17 %
4%
16-25
662
72%
12.8%
20±0.4
105
Pinhas-Hamiel and Zeitler. The Lancet 369:1823-1831, 2007
Type 1 versus Type 2 Outcomes in Youth
Results
Type 1 n-1433
Type 2 n-68
Retinopathy
20%
4%
p<0.0001
Microalbuminuria
6%
28%
p<0.0001
Hypertension
16%
36%
p<0.0001
Neuropathy, peripheral
27%
21%
Neuropathy, autonomic
61%
57%
A1c
8.5%
7.3%
Hypertriglyceridemia
53%
Hypercholesterolemia
32%
Eppen, et al Diabetes Care 29:1300,06
Time to onset of nephropathy
Pinhas-Hamiel and Zeitler. The Lancet 369:1823-1831, 2007
Treatment
Treatment Approach – Diabetes
– Lifestyle change must be part of any
intervention
• Standard diabetes education
• Intensive intervention
– Little evidence that this is effective on its
own in children
– In patients with overt diabetes, lifestyle
change should be used in combination with
drug therapy
Glycemic Targets
Glucose
– Target
• Primary - Hemoglobin A1c < 6.5%
• Secondary
– Fasting BG < 120
– Post-prandial BG < 140
– Monitoring (if not on insulin)
• Finger stick blood glucose
– Twice a day
– 3-5 days a week
– When ill
Metformin
• Mechanism of action
– suppression of HGO
– Secondary decrease in insulin levels
– May have peripheral effects?
• Well-studied in adults and children
– effective, safe, and inexpensive
• Most pediatric experience of oral agents
– Approximately 45% of patients nationally
• Approved for pediatric use in diabetes
Metformin
• Desirable properties –
– weight loss
– Mild improvement in lipids
– Improvement in menstrual irregularities/hirsutism
– ? Improvement in hepatic steatosis
• Minimal side effects –
– GI - can be avoided with slow titration
– Lactic acidosis –metanalysis of 40,000 patients – no
increased lactic acidosis - even when used with
contraindications
• Salpeter et al Arch Intern Med. 2003 163:2594, 2003
Sulfonylureas
• Insulin secretagogues
• Well-studied in adults – effective, safe,
inexpensive
• Side effects significant
– Weight gain
– hypoglycemia
• no effect on lipids
• Rarely used in Pediatrics
– MODY
Thiazolidinediones
• PPARg agonists
– Alter adipocyte and muscle metabolism to promote
increased insulin sensitivity
– rosiglitazone, pioglitazone
• Well-studied in adults
– Lower A1c ~1%
– Beneficial effects on lipids
• May prolong -cell function
• Not approved in Youth
– Very limited pediatric Experience
– One clinical trial – never published
Thiazolidinediones
• Extensive Side effects
– Weight gain
• Visceral vs subcutaneous fat
• may not be deleterious
– Edema
– Decreased bone density?
– Increased cardiac dysfunction
• Implications for youth with “young” hearts but
hypertension and dyslipidemia
– Macular edema
– Liver dysfunction
Metaglinide analogs
• Insulin secretagogues
– Short acting
– Glucose-dependent
– repaglinide, nateglinide
• May be helpful in control of postprandial hyperglycemia
• Compliance before meals difficult for
adolescents
Insulin
• Not generally considered first line
therapy for type 2 in adults
– Weight gain
– Hypoglycemia
– management burden
– ? Increased cardiovascular risk
BUT
• It works!
• It may synergize with other therapies by reducing
glucose toxicity
• Familiar to pediatricians and pediatric diabetologists
– 25-30% of adolescent type 2 patients are being treated
with insulin alone.
• Patients often started on insulin –
– ? Diagnosis, acute metabolic decompensation
• More serious illness = Better compliance?
• Preservation of b-cell function?
Treatment Algorithm:
Current Practice Among Pediatric
Endocrinologists
• No evidence
• New onset
– “Reasonable” control (A1c <8–10, nonketotic)
• Start metformin at 500 mg q/d
• Titrate as tolerated (<500 mg/wk) to maximum
of 2000 mg/d
• Initiate SDE, with additional focus on basic
lifestyle change and weight loss
– Little evidence for efficacy of lifestyle alone
SDE = standard diabetes education.
Treatment Algorithm
• New onset
• “Poor” control (A1c >8–10)
– Without acidosis
• Start metformin at 500 mg q/d and basal insulin
(15-30 units qhs)
– Titrate metformin as tolerated (<500 mg/wk)
to maximum of 2000 mg/d
– Once glucose control is attained, wean insulin as tolerated
– With acidosis
– Treat as you would in type 1 until acidosis resolved
– Start metformin and subcutaneous insulin as needed
– Wean insulin as tolerated
Treatment Algorithm
• Intensification of therapy
– Failure to maintain A1c <6.5
– Add-on insulin
• Once-daily basal insulin (glargine or detemir) –
start at 10–20 units a day
– Given whenever adherence and supervision are
most likely
– Titrate as needed to maintain A1c <6.5
• Addition of short-acting insulin
– Inability to maintain A1c in target despite 1 unit/kg
long-acting insulin
– Evidence for postprandial hyperglycemia
Treatment Algorithm
• Intensification of therapy
– Other options1,2
• Exenatide
– Incretin – GLP-1 analog
» Slows gastric emptying
» Decreases appetite
» Increases glucose-dependent insulin secretion
» Injected bid before meals
» Not FDA approved – pediatric trials pending
• DPP-4 inhibitors
– Sitagliptin
» Inhibits GLP-1 inactivation
» Actions similar to exenatide but no weight loss
» Not FDA approved – pediatric trials pending
1. Holst JJ. Expert Opin Emerg Drugs. 2004;9(1):155-166. 2. Drucker DJ et al. Lancet. 2006;368(9548):1696-1705.
Non-glycemic targets
AHA/ADA Consensus
• Atherosclerotic lesions in youth correlate
with established risk factors
• Risk factors track from childhood into
adulthood
• Behaviors associated with risk acquired
during childhood
• No controlled trial comparing risk
reduction will ever be done
(Kavey et al, Circulation 114:2710-2738, 2006)
Lipids
• LDL < 160 mg/dl (?130) {<100 mg/dL in DM}
• LDL > goal – diet therapy (7% sat fat, < 200 mg
chol)
• LDL > 160 mg/dl after 6 months of TLC
• “It may be appropriate to treat”
• TG < 150 mg/dl fasting
• TG > 400
• treat – to avoid postprandial > 1000 mg/dl
• HDL > 35 mg/dL
Treatment - lipids
• Same as in Adults
– Efficacy in lipid lowering similar
– No evidence for (or against)
cardioprotective effect with any intervention
•
•
•
•
•
Statins
Fish Oil/Omega 3 Fatty acids
Ezetimibe
Nicotinic acid
Fibrates
Blood pressure
• Goal < 95%ile for age
• pharmacologic therapy may be appropriate
if > 95%ile AND
• No improvement with lifestyle modification
• Evidence of target organ damage
(microalbuminuria)
• ACE or ARB first line drug
• Titrate ACE until BP < 90th %ile
Microalbuminuria
• Random urine albumin/creatinine ratio
• Normal < 30
• Abnormal sample repeated fasting
• 2 of 3 abnormal is diagnostic
• Start therapy with ACE and titrate until
microalbumin normal
Treatment – BP, albumin
• Same as adults
– ACE inhibitor
– Angiotensin receptor blocker (ARB)
– Diuretics
– Calcium channel blockers (CaCB)
– Beta adrenergic antagonists
CASE DISCUSSION
Dominick
• 15 yo Hispanic male with long history of
overweight and newly diagnosed
diabetes (Fasting glucose 289)
• Denies change in eating or activity
habits
– “Healthy” diet with large portions sizes
– Fast food 2-3 times a week
– Active in sports (football, lacrosse)
• No medications
• ROS: Polyuria, polydipsia, fatigue for 3
months
Dominick
• Past Hx:
– BW 8 lbs, 2 oz, T2DM
• Fam Hx:
– Mother and father with T2DM (dx 45 and 43)
– T2DM in maternal and paternal grandparents
– Maternal grandfather with MI age 62
Dominick
• Exam
– Ht 75%ile
– Wt > 95%ile
– BMI 32
– BP 120/58
– Acanthosis nigricans at neck, IP joints
– Tanner 5
Dominick
• Laboratory evaluation?
• Other evaluations?
• Interventions?
• Follow-up Care