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A Child With Metabolic Syndrome and Diabetes: Management Strategy
By Kulkanya Chokephaibukit, MD
Professor of PediatricsFaculty of Medicine Siriraj Hospital
Mahidol University, Bangkok, Thailand7th IAS 2013, KL, Malaysia, 30 June-3 July 2013.Session TUWS05: Optimizing pediatric treatment strategies: Case study for the clinicians
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DisclosureNo conflict of
interest
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Scope of discussion
• Clinical picture of metabolic complications in HIV-infected children and adolescents receiving ART
• How to make diagnosis of insulin resistance, diabetes, and metabolic syndrome
• How to manage metabolic complications of children/adolescents with HIV infection receiving ART
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Metabolic Complications of HIV Infection and Its Therapy
• HIV/HAART-associated lipodystrophy syndrome
• Insulin resistance and glucose homeostasis abnormalities
• Dyslipidemia• Metabolic syndrome
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Let’s start when he was 9 A 9 year-old boy with perinatal HIV
Chief Complaint: Hyperpigmentation of neck and armpit for 2 yearsHistory: • Maternal HIV without perinatal treatment• Diagnosis of HIV infection by serology at 18 month-old , CD4:
256 cell/mm3 (12.39%) • He was started on AZT+3TC (in 1998), then changed to HAART • At 7 year-old, started to gain weight, very good appetite, and
noticed hyperpigmentationFamilial Hx: Mom died from AIDS. Live with grandparents, both
had DM
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Age %CD4 CD4 count VL ART
18 mo 12.39 256 - AZT+3TC
3 Y 2.03 48 - d4T+ddI+EFV
4.5 Y 2.79 72 504,000M41L, D67N
K101E, V179D
d4T+3TC+EFV
5.5 Y - - - AZT+3TC+IDV/r
5.6 Y 3.04 137 <40 AZT+3TC+IDV/r
The 9 year-old boy with dark neck for 2 years
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Date %CD4 CD4 count VL ART
5.6 Y 3.04 137 <40 AZT+3TC+IDV/r
8.5 Y 19.63 930 - AZT+3TC+IDV/r
9Y 19.35 592 - AZT+3TC+LPV/r
9.5 Y 23.86 679 <40 AZT+3TC+LPV/r
The 9 year-old boy with dark neck for 2 years
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Physical Examination:• Wt 46.9 kg (>P97), Ht 140.8 cm (P97), 146% Ideal
BW, BMI 23.9 kg/m2, WC 76.5 cm, HC 73.7 cm
W/H ratio 1.04• GA: loss of pad of fat/ lower limbs,
dorsocervical hump• Chest: gynecomastia• GU: testes 5 cc, PH Tanner II• Normal findings for heart, lungs, abdomen, and
neuro examinations
The 9 year-old boy with dark neck
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Hyperpigmentation of the neck and
armpits, dorsocervical hump
hump
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What is your diagnosis of his skin hyperpigmentation?
• A. genetic plus poor hygeine• B. Acanthosis nigricans
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What is the common condition associated with this skin
hyperpigmentation?
• A. Insulin resistance and diabetes• B. Dyslipidemia
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Acanthosis nigricansA clue for IR
• Hyperpigmented velvety macules and patches and progress to palpable plaques. Mostly observed at the intertriginous areas of the axilla, groin, and posterior neck
• Causes:- Obesity, particularly with darker skin color. Children BMI>98th tile have AN in 62%.1
- Diabetes and Insulin resistance.2
- Polycystic ovarian syndrome- Malignancy: adenocarcinomas of the GI tract
(70-90%), and others 1.Krawczyk M. Pol Arch Med Wewn. Mar 2009;119(3):180-3. 2. Sadeghian G. J Dermatol. Apr 2009;36(4):209-12
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Problem Lists
• Obesity
• Acanthosis nigricans
• Lipodystrophy (mild facial lipoatrophy)
• FBS = 159mg/dl (Provisional DM)
• Metabolic syndrome?
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Lipodystrophy in HIV-infected children• Incidence vary 10-50%1-4 due to lack of
consensus for definition • Associated with PI and stavudine
– PI: Predominate with truncal obesity, buffalo hump, and less periheral lipoatrophy
– d4T: Predominate with facial, associated with HLA-B*40015 and Fas gene6
• Likely to appear in early adolescence1,7
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004 3. Amaya RA. Pediatr Infect Dis J. 2002. 4. Sawawiboon N. Int J STD AIDS 2012, 5. Wangsomboonsiri W. CID 2010;50(4):597-604, 6.
Likanonsakul S, AIDS Res Hum Retroviruses. 2012 Jul 9., 7. Alam NM. J Acquir Immune Defic Syndr. 2012; 59(3): 314–324
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Characteristics of Lipodystrophy from Protease Inhibitors
• Fat gain on abdomen, breast, and dorsocervical hump
• Fat loss from peripheral extremities• Fat gain in visceral organs
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Facial and peripheral lipoatrophy following >6 months of stavudine treatment, found in 38% of d4T Rx, occur around early adolescence Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501
Lipodystrophy from d4T
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Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324
Body fat abnormality in HIV-infected children and adolescents: The difference of regions
Lipoatrophy 23%
Europe (N= 426, LD = 42% Receiving PI 60%, Received d4T 10%
Thailand, N=202, LD = 25%Receiving PI 41%, Received d4T 60%
Lipohypertrophy or combine 2.5%%
No fat maldistribution 75%
Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501
Study Population
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Facial Lipoatrophy may improve after
stopping d4T Improvement found in 23%,
at mean duration of 45 months after stopping d4T, around early adolescence
Sawawiboon N. International Journal of STD & AIDS 2012; 23: 497–501
Facial lipoatrophyIs it reversible?
Need to stop d4T before reaching
adolescence
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What about impair FBS (FBS=159)? Need to diagnose and treat
impair FBS and DM
What would you do?A. Perform OGTTB. It’s mostly transient, repeat FBS in 6 months
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Interpretation of Fasting Blood Sugar
Provisional DMNormal FBS
Impaired FBS
100 mg/dl 126 mg/dlFBS
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Oral Glucose Challenge Test: Must be done in all cases of impair FBS
Provisional DMNormal OGTT
Impaired OGTT
140 mg/dl 200 mg/dl2 hr PG
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Why do we need to worry about DM?
• A lot of treatment and complication of DM to follow, interrupt normal life
• DM increased risk of ART associated CVD
• Early intervention (exercise and metformin) may prevent or delayed DM and complications
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• Symptoms of DM plus casual BG ≥200 mg/dL (polyuria, polydipsia, and unexplained weight loss) or• FBS ≥126 mg/dL or• 2-hr BS ≥200 mg/dL during an OGTT or• HbA1C ≥ 6.5%
Diagnosis of Diabetes Mellitus
Pre-diabetes• Impaired FBS 100-125 mg/dL• Impaired OGTT: 2 hr glucose 140-199 mg/dL• HbA1c 5.7-6.4%
American Diabetes Association. Diabetes Care 2010
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Oral Glucose Tolerance Test
0 30 60 90 120
BS 58 134 181 165 188
Insulin 88.7 842.3 >1000 >1000 >1000
Normal fasting lipid profileChol LDL-C HDL-C TG
174 120 51 140
Diagnosis: Impaired OGTT with hyperinsulinemia>>Pre-diabetes
9 yo. boy with acanthosis nigricans
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• Prevalence in adults 10-20%– Increase prevalence in patients receiving HAART
with lipodystrophy1
• Incidence in children is much lower• However, 19% of children receiving PI had impair
OGTT2
Insulin Resistance and Type 2 Diabetes in HIV-Infected Children
1.Vigouroux C. Diabetes & Metabolism 19992. Bitnun A. J Clin Endocrinol Metab 2005
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Classical T2DM riskfactors• Obesity (abdominal)• Physical inactivity• Genetic
– Family history– Race
• Older age• Dyslipidemia
HIV-associated risk factors• Peripheral lipoatrophy• Increased liver or muscle fat• Inflammatory cytokines• Low testosterone• Oxidant stress• HCV infection• PIs therapy
Insulin Resistance and HIV
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How can we prevent DM in this patient?
A. Diet and exercise B. Diet and exercise and metformin
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Reduction in the Incidence of T2 DM with Lifestyle Intervention or
Metformin• 3234 patients with IFG or IGT
• Treatment; placebo, metformin, lifestyle-modification program
• Lifestyle-modification program: 7% weight loss and 150 mins of physical activity per week
• Average follow-up was 2.8 yr
Diabetes Prevention Program. N Engl J Med 2002:346:393-403
Exercise and Metformin can prevent DM
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Diabetes Prevention Program. N Engl J Med 2002:346:393-403
At 3 years
28.9%
21.7%
14.4%
Lifestyle gr.: reduced the risk of converting to DM by 58%Metformin gr.: reduced the risk of converting to DM by 31%
Incidence of DM in lifestyle gr.: 39% lower than metformin gr.
Exercise and Metformin can prevent DM
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None is approved in children•Troglitazone (TRIPOD) (withdrawn due to rare hepatitis)
Hispanic women with GDM 56% risk reductionBuchanan TA et al. Diabetes 2002
•Acarbose (STOPP-NIDDM) Subject with IGT 32% decreased conversion to T2DM
Chiasson JL et al. JAMA 2003•Xenical (XENDOS)
Subject with BMI >29, lifestyle plus xenical vs placebo 37% risk reductionTorgerson JS et al. Diabetes care 2004
Drugs that may delay or prevent the development of Type2 DM
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A 9 Year-Old Boy with Perinatal HIV and Insulin-Resistance
• Treatment: Metformin (500) 1 tab oral bid Encourage healthy life style, exercise
Continue ART: AZT/3TC/LPV/r• Outcomes: 4 mo after treatment
– Wt 44.4 kg (-2 kg),
– Ht 142 cm, BMI 22 kg/m2 (-1.9) – WC 76.2 cm (-0.3 cm)
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OGTT 12/1/070 30 60 90 120
BS 58 95 116 99 99
Insulin 13.19 130.9 249.4 139.3 161.1
0 30 60 90 120
BS 58 134 181 165 188
Insulin 88.7 842.3 >1000 >1000 >1000
OGTT 8/11/06
After 4 months of Metformin Rx and exercise: Improved hyperinsulinemia and BS
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Fasting lipid profile
Date Chol LDL-C HDL-C TG
7/25/06 174 120 51 140
12/7/07 232 138.4 71 113
6 Months later…He developed hyperlipidemia
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NCEP Definition for Dyslipidemia in Children and Adults
TG was not established by NCEP; a TG level of 125 mg/dL approximates the mean 95th percentile for TGs in boys and girls during childhood and adolescence.
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Why do we need to care about dyslipidemia? Should we just leave it for the adult doctors to take care of the business
when the child grown-up!
• It is an important risk factor for CVD in adults– Atherosclerosis starts in childhood, esp. if TC>200 and
LDL-C >130 mg/dl• Very common, found 60%-80% in children receiving HAART,
particularly PI1-3, found more in patients with lipodystrophy– Some PI cause less dyslipidemia: ATV, DRV
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002
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Metabolic complications:
>>Start from lipodystrophy,
>>dyslipidemia, insulin resistance
End up with cardiovascular diseases, stroke, DM
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Prevalence of Dyslipidemia in a European cohort of HIV-infected children and adolescents (N=426), 60% receiving PI4
Fasting Hypertriglyceridemia66%
Hyper-cholesterolemia49%
Glucose intolerance5%
4%
21%
28%
1%
45%
Dyslipidemia found 40%-80% in children, associated with receiving PI and lipodystrophy1-3
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002, 4. Alam NM. J Acquir Immune Defic Syndr. 2012 March 1; 59(3): 314–324
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Frequency of abnormal lipid profile in Thai adolescentsSiriraj, Bangkok, 2013
HIV-infected N = 100
HealthyTotal = 50
P value
CHOL > 200 mg/dl
25 (25%) 12 (24%) 0.867
LDL > 130 mg/dl 16 (16%) 8 (16%) 0.733
HDL < 35 mg/dl 8 (8%) 0 (0) 0.017
TG > 150 mg/dl 37 (37%) 1 (2%) <0.001
V. Poomlek. 7th IAS 2013, KL, MOPE047
49% receiving PI
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Risk of Myocardial Infarction in Patients Exposed to Specific Individual Antiretroviral Drugs : The Data
Collection on Adverse Events of Anti-HIV Drugs (D:A:D)
Worm SW. JID 2010;201:318-30.
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What else can we do other than even more encouraging
lifestyle modification?• A: Change ARV• B: Start statin
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• Exercise at least 1 hr per day• Modified diet (<30% total fat and <7% of sat fat, <200 mg of
cholesterol/day)• Statin only in those with persistent TC>200 mg/dl and LDL-C
>130 mg/dl, not for < 8 yo, unknown long-term effect.• Fibrate for hypertriglyceridemia (>400 mg/dl)• ARV modification
Intervention in this patient:
• Educate for life style modification: Low fat diet and exercise
• Change LPV/r to ATV/r
Treatment of dyslipidemia in children
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Lipid Changes at Week 48 with Baseline in PI Studies
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Date %CD4 CD4 count VL Medication
1/6/2010(12 Y)
20.58 572 - AZT+3TC+ATV/r
7/9/2010(12 Y)
- - - TDF+3TC+ATV/r
18/3/2011(13 Y)
22.88 510 <40 TDF+3TC+ATV/r
He started to be uneasy to take ARV
**Once daily regimen
Fasting Blood Sugar : 138mg/dl Cholesterol 155 mg/dl Triglyceride 159 mg/dl LDL 74 mg/dl HDL 50 mg/dl
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Diet education for dyslipidemia
High Cholesterol
Diet
High Triglyceride Diet
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Diabetic diet education
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He becomes an uneasy adolescent and start to have poor compliance to metformin and diet and weight control
- He continue to gain more weightBP: 130/90 mmHgTG = 202 mg/dl, HDL 52 mg/dl, Cholesterol 224 mg/dL
Follow-up • FBS 400 mg/dl• HbA1C 13.8 %
Does he meet the criteria for metabolic syndrome? …..Yes or No
Dx: DMStart Insulin SC
5 Years after starting treatmentAnd became a teenager
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Metabolic Syndrome
A Cluster of • Abdominal obesity• Increased triglyceride levels• Decreased HDL-cholesterol levels• Hyperglycemia• HypertensionA meta-analysis of the prospective studies has shown that the presence of metabolic syndrome increases the risk of Type2 DM and CVD
Galassi A. Am J Med. 2006
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Metabolic Syndrome in children and adolescents: The clusters of metabolic risk factors (International Diabetes Federation)
Waist circumference >
P90
FBS > 100 mg/dl
TG>150 mg/dl
HDL<40 mg/dl
(<50 mg/dl in female >16 yo
BP>130/85mmHg
Presence of metabolic syndrome increases risk of -CVD (RR 1.53; 1.26-1.87)-CHD(RR 1.52; 1.37-1.69)-Stroke (RR 1.76; 1.37-2.25).
Galassi A. Am J Med 2006;119:812-9
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Criteria Dx Metabolic syndromein this patient
• BW > P97– Triglyceride > 150 mg/dl– FBS > 100 mg/dl– BP 120/80-128/80 mmHg– HDL 45-50 mg/dl
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Jerico C. Diabetes Care. 2005 Jan;28(1):132-7.
Incidence 5.1% in <30 yo., 27% in 50-59 yo.
Metabolic syndrome among HIV-infected patients: related factors
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Pathogenesis of Metabolic Complications in HIV-infected Patients
• HIV infection increase inflammatory cytokines– TNF inhibits the uptake of FFA by adipocyte, increase
lipogenesis– IL-6 and adipocytokines cause dyslipidemia and lipodystrophy– May directly induce insulin resistance
• Protease inhibitor– Effect several steps causing dyslipidemia, IR, and
lipodystrophy• NRTI
– Cause mitochondrial dysfunctionlactic acidosis adipocyte death
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Anuurad E. Curr Opin Endocrinol Diabetes Obes. 2010 Oct;17(5):478-85.
11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; FFA, free
fatty acids; ROS, reactive
oxygen species;
Development of HIV and PI associated lipodystrophy/ IR
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Screening and intervention for metabolic complications in HIV-Infected Patients is needed especially for
patients at risk
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Contribution of risks factors for CAD in HIV-Positive Persons
Rotger M. CID 2013 Jul;57(1):112-21.
1.04
1.25
1.47
Estimated effect (95%CI) on the odds ratio of a first CAD event for:- genetic risk score quartile (black dots), -HIV-related variables (gray triangles)-traditional CAD risk factors (gray squares).
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Impaired FBS
Oral Glucose Tolerance Test (OGTT) • Glucose 1.75g/kg/dose (Max 75g)• Blood for Blood sugar and insulin • (at 0, 60, 120 min)
Impaired OGTT normal
Hyperinsulinemia
F/U FBS, HbA1C q 3 months if• HbA1C > 9 or • FBS > 200 mg/dlStart Insulin SC
• F/U FBS q 3-6 months
• Start Metformin• DM education• Life style modification• ART modification
Physical exam/wt/ht/wcCheck FBS, Lipid q 6 mo.
Dyslipidemia
• Life style modification
• ART modification • Lipid lowering agent
if not response
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Management of Metabolic Complications in HIV-Infected Children and Adolescents
• Step 1– Lifestyle modification with diet and exercise– Weight control – Change PI to NNRTI or ATV/r or DRV/r, may consider
unboosted ATV or low dose LPV/r• Step 2
– Metformin (for >10 yo) if impair OGTT, or Insulin injection if meet criteria for DM
– Fibrate if TG>400 mg/dl – Lowest dose statin (pravastatin or atorvastatin) if TC >
200 mg/dl
Need to work with the family and psychological support
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Therapeutic Goals
Glycemic recommendations• HbA1c <7%• FBG: 70-130 mg/dL• Fed glucose <180 mg/dlWeight/diet• BMI < 25 kg/m2
• Exercise > 150 min/week• Diet <7% saturated fat
Adapted from ADA and EASD consensus 2009
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Therapeutic Goals
Dyslipidemia• LDL-C < 100 mg/dl• HDL-C > 35 mg/dl• TG < 150 mg/dlBlood pressure• Established HT in children: BP < 95th % for age,
sex and height Adapted from ADA and EASD consensus 2009, Libman IM. 2007
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How to treat?• Stop using d4T (do not use d4T for > 6 months) >>
Phasing out d4T
• Avoid PI (may not be possible, or use ATV/r or DRV/r
• Medical: None is really effective and practical
• Liposuction for severe buffalo hump
• Filling therapy for facial lipoatrophy: may consider in
adults
Before After
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Prevention of Metabolic Complicationsin HIV-Infected Children & Adolescents
• Healthy life style– weight control – regular exercise– low saturated fat diet, eat fish and veggies– No smoking
• Avoid PI (25% of Asian children are receiving PI)– Serious with adherence to first line NNRTI regimens,
NVP has the least long-term problem• Screening and early intervention in borderline
dyslipidemia
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Thank you for your kind
attention