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

DisclosureNo conflict of

interest

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

Metabolic Complications of HIV Infection and Its Therapy

• HIV/HAART-associated lipodystrophy syndrome

• Insulin resistance and glucose homeostasis abnormalities

• Dyslipidemia• Metabolic syndrome

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

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

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

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

Hyperpigmentation of the neck and

armpits, dorsocervical hump

hump

What is your diagnosis of his skin hyperpigmentation?

• A. genetic plus poor hygeine• B. Acanthosis nigricans

What is the common condition associated with this skin

hyperpigmentation?

• A. Insulin resistance and diabetes• B. Dyslipidemia

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

Problem Lists

• Obesity

• Acanthosis nigricans

• Lipodystrophy (mild facial lipoatrophy)

• FBS = 159mg/dl (Provisional DM)

• Metabolic syndrome?

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

Characteristics of Lipodystrophy from Protease Inhibitors

• Fat gain on abdomen, breast, and dorsocervical hump

• Fat loss from peripheral extremities• Fat gain in visceral organs

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

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

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

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

Interpretation of Fasting Blood Sugar

Provisional DMNormal FBS

Impaired FBS

100 mg/dl 126 mg/dlFBS

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

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

• 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

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

• 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

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

How can we prevent DM in this patient?

A. Diet and exercise B. Diet and exercise and metformin

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

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

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

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)

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

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

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.

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

Metabolic complications:

>>Start from lipodystrophy,

>>dyslipidemia, insulin resistance

End up with cardiovascular diseases, stroke, DM

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

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

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.

What else can we do other than even more encouraging

lifestyle modification?• A: Change ARV• B: Start statin

• 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

Lipid Changes at Week 48 with Baseline in PI Studies

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

Diet education for dyslipidemia

High Cholesterol

Diet

High Triglyceride Diet

Diabetic diet education

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

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

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

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

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

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

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

Screening and intervention for metabolic complications in HIV-Infected Patients is needed especially for

patients at risk

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).

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

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

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

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

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

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

Thank you for your kind

attention