Pediatric Obesity and Metabolic Syndrome - PowerPoint Presentation

Slide1

Pediatric Obesity and Metabolic Syndrome

Chhavi Agarwal, MD, FAAP, MRCP (UK)

Assistant ProfessorDivision of Pediatric EndocrinologySlide2

Objectives

Metabolic SyndromeEtiology

Relationship of various components Primary care setting- Screening for the risk factors Management Slide3

Metabolic SyndromeMetabolic syndrome is a name for a group of risk factors that occur together and increase the risk for cardiovascular disease, stroke, and type 2 diabetes

Formerly called Insulin resistance syndrome; Syndrome XCentral Obesity and Insulin resistance-most important underlying factors of the syndrome

Prevalence in the adult population is 34%2X higher risk of dying from heart attack, 3X likely to have a heart attack or stroke, 5 fold greater risk of developing diabetesSlide4

DefinitionConfusing multiple definitions

WHOEuropean Group for study of Insulin resistanceNational Cholesterol Education Program

International Diabetes FederationSlide5

Metabolic syndrome: The NCEP ATP III definitionSlide6

Metabolic syndrome: IDF consensus definition (2005)Slide7

Metabolic syndrome: Prevalence in the US as defined by NCEP ATP IIISlide8

Pediatric Definition- NCEP ATP III According to the ATP III, metabolic syndrome is present if you have three or more of the following signs:

Systolic Blood pressure ≥ 90th

percentile for gender, age and heightFasting blood sugar ≥ 100 mg/dLLarge waist circumference: ≥ 75th percentile for age and gender

(

J Pediatr. 2004 Oct;145(4):439-44

).

Low HDL cholesterol:

Boys 15-19 years - under 45 mg/dL

Others - under 50 mg/dL

Triglycerides

≥

100 mg/dLSlide9

Pediatric Definition-Weiss et al. According to the Weiss et al, metabolic syndrome is present if there are 3 or more of the following signs:

Systolic Blood pressure ≥95th percentile for gender, age and height

Fasting blood sugar ≥ 100 mg/dLLarge waist circumference ≥ 75th percentile for age and genderFasting Triglycerides ≥5th percentile for age and sex

HDL ≤ 5th percentile for age and sexSlide10

Prevalence of Metabolic SyndromeNHANES III-Among 1960 children aged ≥12 years who fasted ≥8 hours-

two thirds had at least 1 metabolic abnormality, nearly 1 in 10 had Metabolic Syndrome.

The racial/ethnic distribution was similar to adults: Mexican-Americans, followed by non-Hispanic whites, had a greater prevalence of MetS compared with non-Hispanic blacksSlide11

Prevalence in obese adolescents as per NHANES 99-2002 DATACook/Ford 44.2%NCEP ATPIII 26.2%

Caprio 14.1%Cruz 12.4%Slide12

SEARCH-for Diabetes in Youth study Children and Adolescents with newly diagnosed T2DM-92% had≥2 of the following components-abdominal obesity, high BP, high TG, low HDL

73% high BP;65% TG≥110 mg/dl;60%HDL≤40mg/dl;95% waist circumference>90th%ile for age/sexSlide13

Risk Factors

The two most important risk factors for metabolic syndrome are:

Insulin resistance: blood sugar and fat levels rise.

Central obesity (BMI >25): The body may be described as "apple-shaped.”Slide14

Measuring obesity Body Mass Index

Obesity is most commonly assessed by a single measure, the Body Mass Index (BMI), which uses a mathematical formula based on a person’s height and weight.

BMI = weight (kg)/height (m

²

)

Individuals with a BMI

between 25 to 29.9 are considered overweight

of 30 and above are considered obese.

The risk of serious health consequences such as type 2 diabetes, coronary heart disease, hypertension, dyslipidaemia, albuminuria and a wide range of other conditions increases with BMI. Slide15

BMI

DOES NOT

show the difference between excess fat and muscle. identify whether the fat is laid down in particular sites. For example, abdominal fat has more serious health consequences than fat located elsewhere. The relation between fatness and BMI differs with age, race and gender.

Measuring obesity up to here

The limitations of the Body Mass IndexSlide16

Fat distributionGoodpaster

et al 2005 3035 adults-aged 70 to 79, of whom 42% were African Americans.Prevalence of MS was 39% in the entire cohort and highest in obese men and women. CT findings- visceral adipose tissue was nearly 50% higher in participants with MS.

Regional fat distribution clearly discriminates those with MS, particularly among the non-obese.This implies that older men and women can have normal body weight and even have relatively lower total body fat but still have MS.Slide17

Waist circumference and the metabolic syndrome

The presence of abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated BMI.

The new NCEP consensus definition of the metabolic syndrome stipulates the following as a pre-requisite for a diagnosis of metabolic syndrome:

≥ 88 cm for women

≥ 102 cm men

Waist circumference is calculated by comfortably measuring the waist halfway between the bottom of the rib cage and the top of the pelvis. Slide18

Type II

Diabetes

Natural History of Obesity

x 2 early childhood

x10 age 10 years

x20 adolescence

Obesity tracks into adulthood

Type 2 Diabetes

Obesity

Obesity, IGT

+ complicationsSlide19
Slide20

Risk FactorsOther risk factors include:Aging

Ethnic: Hispanic, South AsianLack of exerciseHypertensionPCOS

OSASlide21

PathogenesisSlide22

Inflammation: the missing link?The adipose tissue is a source of several molecules,such as leptin, (PAI-1),TNF-α, angiotensinogen and IL-6, that are collectively called adipokines and directly contribute to oxidative damage and vascular inflammation

Highly sensitive CRP (hsCRP) levels in plasma tend to be elevated in subjects with insulin resistance and obesity;

elevated levels of hsCRP are predictors of both CHD and diabetes. Dandona et al 2005.Slide23

The inflammatory component of the metabolic syndromeVascular dysfunctionEndothelial dysfunction

MicroalbuminuriaProinflammatory state

Elevated hsCRP and SAAElevated inflammatory cytokines (TNF-α, IL-6)Decreased adiponectin levelsProthrombotic

state

Increased

antifibrinolytic

factors (PAI-1)

Increased fibrinogenSlide24

Overall conceptual framework of new concepts in the patho-physiology of cardiovascular disease (CVD)

Balagopal P ( et al. Circulation 2011;123:2749-2769

Copyright © American Heart AssociationSlide25

EvaluationAnthropometric measurements including BMI and Waist CircumferenceVitals- Blood pressure measurement

Blood glucose (Fasting or OGTT)Lipid ProfileSlide26

Hypertension screeningChildren >3 years who are seen in medical care settings should have their BP measured at least once during every health care episode. Children <3 years should have their BP measured in special circumstancesSlide27

Hypertension screeningSlide28

HypertensionHypertension is defined as average systolic BP (SBP) or diastolic BP that is ≥95th percentile for gender, age, and height on more than three occasions

 Data on healthy adolescents obtained in school health-screening programs demonstrate that the prevalence of hypertension increases progressively with increasing BMI, and hypertension is detectable in ∼30% of obese children (BMI ≥95th percentile). Slide29

PreventionPreventing (and managing) the condition involves:Eating a diet low in fat, with a variety of fruits, vegetables, and whole-grain products

Getting regular exercise, at least 30 minutes of moderate activity almost every day, in children 60 minutes of moderate activity almost every dayLosing weight so that your body mass index (BMI) is less than 25 or less than 90

th percentile.Slide30

Blood pressure ManagementGoal<95%ile for

age,sex and heightConsider pharmacotherapy if>95%ile &

-No improvement with life style intervention -Evidence of target organ damage (microalb.)Slide31

Management of HypertensionPharmacologic therapy, when indicated, should be initiated with a single

drug Acceptable drug classes for use in children include angiotensin-converting enzyme inhibitors,

angiotensin-receptor blockers, β-blockers, calcium channel blockers, and diuretics. ACE first line drug -Titrate until BP< 95%ileSlide32

Dyslipidemia screeninguniversal screening of non-fasting non-HDL cholesterol in children 9 to 11 years old (prior to onset of puberty) and again in individuals 17 to 21 years.

Targeted screening should occur in children 2 to 8 years old and adolescents 12 to 16 years old with two fasting lipid profiles (between 2 weeks and 3 months apart, results averaged) for the risk factors.Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics. 2011;128;S213–S256.Slide33

Dyslipidemia screening have a moderate- or high-risk medical condition

have other cardiovascular risk factors (diabetes, hypertension, BMI ≥ 95th percentile, or smoke cigarettes) or have a family history of early CVD or severe hypercholesterolemia. A significant family history includes:

 a. parent or grandparent who at <55 years for males or <65 years for females had suffered a myocardial infarction or sudden death, had undergone a coronary artery procedure, or who otherwise had evidence of coronary atherosclerosis, peripheral vascular disease, or cerebrovascular disease

b.

parent with total cholesterol ≥ 240mg/dL or known dyslipidemiaSlide34

Recommended Cut Points for Lipid and Lipoprotein Levels (mg/dL) in Children and AdolescentsSlide35

Dyslipedemia managementGoal

-LDL <100mg/dl-TG <150mg/dl

-HDL> 35mg/dlConsider pharmacotherapy- -No improvement with life style intervention and LDL 130-159mg/dl with risk factors

-LDL>160mg/dl

Statins first line drug Slide36

Dietary management of dyslipedemia

Diet with: total fat at 25-30% of calories, saturated fat <10% of calories, and cholesterol intake

<300 mg/d, (CHILD 1)In children with identified ↑ TC and ↑ LDL-C, a more stringent diet with saturated fat ≤ 7% of calories and dietary cholesterol limited to 200 mg/d has been shown to be safe and modestly effective in lowering the LDL-C level.

(

CHILD 2 – LDL

)

In children with elevated TG, reduction of simple carbohydrate intake and weight loss are associated with decreased TG

levels

The CHILD 2 -TG diet

is

recommended as the primary diet therapy in this setting. Slide37

Lipid treatment recommendations Birth-10 y/o: Pharmacologic treatment limited to children with severe primary hyperlipidemia

≥ 400 hypercholesterolemia, or hypertriglyceridemia (TG≥ 500), high risk condition, cardiovascular disease under care of lipid specialistSlide38

Lipid treatment recommendations

10-21 y/o:LDL: average results≥250 mg/dL = consult lipid specialist

≥130-250 mg/dL or non-HDL ≥145 mg/dL = refer to dietician for medical nutrition therapy with CHILD 1 CHILD 2 x 6 months, then repeat FLPLDL <130 mg/dL = continue CHILD 2-LDL, re-eval in 12 months

LDL ≥130 ≤189 mg/dL with neg family hx & no other risk factors = continue CHILD 2-LDL, re-eval in 6 months

LDL ≥130 ≤189 mg/dL + ≥2 high level RF + 2 moderate RF = consider statin therapy

LDL ≥190 mg/dL= consider initiation of statin therapySlide39

Side effectsHeadaches, rash Elevated hepatic aminotransferases

Elevated muscle enzymes – myositis (muscle aches) can progress to rhabdomyolysis (life threatening) Side effects are reversible with discontinuation of the medication Teratogenicity – unknown. These drugs are not recommended for adolescent females who are sexually active without contraceptives and are at risk of becoming pregnant.Slide40

Follow up A child or adolescent should be seen 6 weeks after starting a medication and approximately every three months thereafter

 Fasting lipid profile Height, weight Safety labs include LFTs and CPK

 Other tests as indicated Once the target has been achieved, follow-up every 6 months if possibleSlide41

Lipid treatment recommendations Triglycerides: average results

≥500 mg/dL = consult lipid specialist≥100 mg/dL <10 y/o or ≥130 mg/dL 10-19 y/o = refer to dietician for medical nutrition therapy with CHILD 1

 2 for 6 months, repeat FLPTG <100 mg/dL =continue CHILD 2-TG, monitor q6 monthsTG >100 mg/dL= re-consult dietician for intensified CHILD 2-TG dietTG ≥200-499

mg/dL, non HDL ≥145 mg/dL = consider fish oil, consult lipid specialistSlide42

Drug intervention for treatment of individual components

Atherogenic dyslipidemia

StatinsFibratesNicotinic acidSlide43

Management of DyslipidemiaARBITER-2 trial (Taylor et al 2004) supporting the addition of extended-release niacin to statin therapy to increase HDL-C in patients with abnormal glucose tolerance,

changes in HDL-C were independently associated with changes in carotid intima-media thicknessin the past, been considered problematic due to its glucose-raising effects.

Recent data, however, indicate that despite the modest increase in serum glucose levels the overall benefit of nicotinic acid treatment is a marked reduction in cardiovascular events (Canner et al 2005).Slide44

Management of dyslipidemiaA new post-hoc analysis of the Bezafibrate

Infarction Prevention (BIP) trial 1470 patients with MS when treated with bezafibrate (400 mg/d) - a reduced risk of MI as compared with placebo, and cardiac mortality showed borderline significance towards reduction

(Tenenbaum et al 2005).Slide45

Management of dyslipidemia statins remain the drug of choice for patients who need to achieve the LDL-C goal,

fibrate therapy may represent an alternative for those with a lipid profile typical of MS (Robins 2003). The concomitant use of fibrates could be attractive in patients whose LDL-C is controlled by statin therapy but whose HDL-C and/or triglycerides are still inappropriate.Slide46

Recommendations for Screening for Type 2 DM in ChildrenScreened for DM beginning at age 10 years or at onset of puberty (if puberty occurs at a younger age).

Screening should occur with either a fasting plasma glucose measurement or 2-hour oral glucose tolerance test, and should occur every 2 years.

Obese or at risk for overweight (PLUS having any TWO of the following risk factors: Family history of type 2 DM in first- or second-degree relative Race/ethnicity (Native American, African American, Latino, Asian or Pacific Islander) Signs of insulin resistance or conditions associated with insulin resistance (

acanthosis

nigricans

, hypertension, dyslipidemia, polycystic ovary syndrome)

History of DM in the mother or gestational DM during the child's gestation

Diabetes Care. 2011;34(suppl 1):S15.Slide47

Prevention of T2DMObesity is the main modifiable risk factor

for type 2 diabetes. Small amounts of weight loss (5%–10%) can prevent or delay the development of type 2 diabetes in individuals with a high risk of the disease.

Even a 5% weight reduction in those who are overweight or obese improves the risk of complications such as heart disease. Slide48

Recent Trials Relevant to the Primary Prevention of Type 2 Diabetes Slide49

Treatment – Lifestyle ChangesDPP- more than 3200 men and women with impaired glucose tolerance were examined and followed for 3 years (Orchard et al 2005).

These subjects were randomized to intensive lifestyle changes (diet and exercise interventions), metformin therapy or placebo. Incidence of MS at baseline was over 50%.

Among participants who did not have MS at baseline53% of those in the placebo group went on to develop MS over the mean 3.2 years of follow-up, compared with 47% in the metformin group and 38% in the lifestyle intervention group.Slide50
Slide51

Drug Treatment Insulin resistance and hyperglycemiaMetformin

ThiazolidinedionesGLP-1 agonist (Exenatide, Liraglutide, Bydureon)Slide52

Management of HyperglycemiaMild hyperglycemia (126–200 mg/dL) and glycosylated hemoglobin level <8.5% or an incidental diagnosis of type 2 DM -therapeutic lifestyle changes in combination with metformin

severe hyperglycemia (>200 mg/dL), glycosylated hemoglobin level >8.5%, or ketosis - insulinSlide53

MetforminSlide54

Metformin: Pediatric studiesPediatric population demonstrated beneficial effects on: fasting glucose

BMI fasting insulin waist circumferenceand body weightSlide55

ThiazolidinedionesPPAR gamma agonists

Alter adipocyte and muscle metabolism to promote increased insulin sensitivityPioglitazoneWell studied in adults--lower A1c ~ 1%

Beneficial effects on lipidsMay prolong β cell functionNot approved for use in youth with T2DMSlide56

GLP-1 Agonists

↑ glucose dependent insulin secretion↓ inappropriate glucagon

↓ gastric emptyingByetta: 5 or 10 mcg SC bid, 30-60 min before breakfast, dinnerVictoza: Titration dose 0.6 mg, then ↑ to 1.2- 1.8 mg, SC OD

Bydureon: 2 mg, Once weekly, SC

NOT FDA approved for <18 years Slide57

Future medicationsNew generation of PPAR agonists, which interact with both PPARα and γ-receptors (the glitazars), thereby combining lipid and glycaemic effects.

Emerging therapies such as, protein tyrosine phosphatase 1B inhibitors, leptin receptor antagonists, and cannabinoid receptor blocking agents offer potential as future therapies for MS.Slide58

Cardiovascular Disease Prevention should begin in ChildhoodSubclinical Atherosclerosis, the pathologic basis for clinical CVD, begins in childhood.

Risk factors for the development of atherosclerosis can be identified in childhoodDevelopment and progression of atherosclerosis clearly relates to the number and intensity of CV risk factors, beginning in childhood

Risk factors track from childhood into adult lifeInterventions exist for management of identified risk factors and should be implemented.Slide59

Controversy? Criteria are ambiguous or incomplete. Rationale for thresholds are ill

defined. Insulin resistance as the unifying etiology is uncertain..

Inflammatory markers should be includedCumulative risk score approach