Transcript Metabolic Syndrome – Dr Agarwal

Pediatric Obesity and Metabolic Syndrome
Chhavi Agarwal, MD, FAAP, MRCP (UK)
Assistant
Professor
MARCH
3, 2011
Division of Pediatric Endocrinology
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Objectives
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Metabolic Syndrome
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Etiology
Relationship of various components
Primary care setting- Screening for the risk
factors
Management
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Metabolic Syndrome
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Metabolic 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
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Formerly called Insulin resistance syndrome; Syndrome X
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Central Obesity and Insulin resistance-most important underlying factors of
the syndrome
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Prevalence in the adult population is 34%
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2X higher risk of dying from heart attack, 3X likely to have a heart attack or
stroke, 5 fold greater risk of developing diabetes
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Definition
• Confusing multiple definitions
> WHO
> European Group for study of Insulin resistance
> National Cholesterol Education Program
> International Diabetes Federation
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Metabolic syndrome:
The NCEP ATP III definition
Risk Factor
Defining Level
Abdominal obesity
Men
Women
Waist circumference
>102 cm (>40 in)
>88 cm (>35 in)
Triglycerides
≥150 mg/dL (1.7 mmol/L)
HDL cholesterol
Men
Women
<40 mg/dL (1.04 mmol/L)
<50 mg/dL (1.29 mmol/L)
Blood pressure
≥130/ ≥85 mmHg
Fasting glucose
≥100 mg/dL (5.6 mmol/L)
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Metabolic syndrome:
IDF consensus definition (2005)
Central Obesity
Waist circumference
- ethnicity specific*
- for Europids:
Male ≥ 94 cm
Female ≥ 80 cm
plus any two of the following:
Raised Triglycerides
≥150mg/dL (1.7mmol/L)
or specific treatment for this lipid abnormality
Low HDL Cholesterol
<40mg/dL (1.03 mmol/L) in males
<50mg/dL (1.29 mmol/L) in females
or specific treatment for this lipid abnormality
Raised blood pressure
Systolic : ≥130 mmHg
or
Diastolic: ≥85 mmHg
or
Treatment of previously diagnosed hypertension
Impaired fasting
glycaemia
Fasting plasma glucose ≥100 mg/dL (5.6 mmol/L)
or previously diagnosed type 2 diabetes
If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended
but is not necessary to define presence of the syndrome.
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Prevalence (%)
Metabolic syndrome:
Prevalence in the US as defined by NCEP ATP III
45
40
35
30
25
20
15
10
5
0
Men
Women
20-29
30-39
40-49
50-59
60-69
>70
Age
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Pediatric Definition- NCEP ATP III
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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 height
Fasting blood sugar ≥ 100 mg/dL
Large waist circumference: ≥ 75th percentile for age and gender
(J Pediatr. 2004 Oct;145(4):439-44).
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Low HDL cholesterol:
Boys 15-19 years - under 45 mg/dL
Others - under 50 mg/dL
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Triglycerides ≥ 100 mg/dL
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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:
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Systolic Blood pressure ≥95th percentile for gender, age and height
Fasting blood sugar ≥ 100 mg/dL
Large waist circumference ≥ 75th percentile for age and gender
Fasting Triglycerides ≥5th percentile for age and sex
HDL ≤ 5th percentile for age and sex
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Prevalence of Metabolic Syndrome
NHANES 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: MexicanAmericans, followed by non-Hispanic whites, had a greater prevalence
of MetS compared with non-Hispanic blacks
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Prevalence in obese adolescents as per
NHANES 99-2002 DATA
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Cook/Ford 44.2%
NCEP ATPIII 26.2%
Caprio
14.1%
Cruz
12.4%
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SEARCH-for Diabetes in Youth study
Children and Adolescents with newly diagnosed
T2DM• 92% had≥2 of the following componentsabdominal 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/sex
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Risk Factors
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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.”
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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 (m²)
• 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.
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Measuring obesity up to here
The limitations of the Body Mass Index
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.
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Fat distribution
Goodpaster 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.
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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.
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Natural History of Obesity
Obesity
Obesity, IGT
+ complications
Type 2 Diabetes
Type II
Diabetes
Obesity tracks into adulthood
– x 2 early childhood
– x10 age 10 years
–x20 adolescence
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Risk Factors
• Other risk factors include:
> Aging
> Ethnic: Hispanic, South Asian
> Lack of exercise
> Hypertension
> PCOS
> OSA
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Pathogenesis
Stress
Visceral
adiposity
Dyslipidemia
Metabolic
Syndrome
Insulin
Resistance
Type 2 Diabetes
Hypertension
Cardiovascular disease
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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.
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The inflammatory component of the
metabolic syndrome
• Vascular dysfunction
> Endothelial dysfunction
> Microalbuminuria
• Proinflammatory state
> Elevated hsCRP and SAA
> Elevated inflammatory cytokines (TNF-α, IL-6)
> Decreased adiponectin levels
• Prothrombotic state
> Increased antifibrinolytic factors (PAI-1)
> Increased fibrinogen
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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 Association
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Evaluation
• Anthropometric measurements including BMI
and Waist Circumference
• Vitals- Blood pressure measurement
• Blood glucose (Fasting or OGTT)
• Lipid Profile
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Hypertension screening
• Children >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 circumstances
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Hypertension screening
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Hypertension
• Hypertension 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).
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Prevention
• Preventing (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 day
• Losing weight so that your body mass index (BMI) is less than 25 or
less than 90th percentile.
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Blood pressure Management
• Goal<95%ile for age,sex and height
• Consider pharmacotherapy if>95%ile &
-No improvement with life style intervention
-Evidence of target organ damage (microalb.)
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Management of Hypertension
• Pharmacologic 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%ile
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Dyslipidemia screening
• universal 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.
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Dyslipidemia screening
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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 dyslipidemia
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Recommended Cut Points for Lipid and
Lipoprotein Levels (mg/dL) in Children and
Adolescents
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Dyslipedemia management
• Goal
-LDL <100mg/dl
-TG <150mg/dl
-HDL> 35mg/dl
• Consider pharmacotherapy-No improvement with life style intervention and LDL 130-159mg/dl
with risk factors
-LDL>160mg/dl
• Statins first line drug
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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.
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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 specialist
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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 FLP
– LDL <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 therapy
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Side effects
• Headaches, 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.
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Follow up
A child or adolescent should be seen 6 weeks after
starting a medication and approximately every three
months thereafter
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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 possible
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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 FLP
– TG <100 mg/dL =continue CHILD 2-TG, monitor q6
months
– TG >100 mg/dL= re-consult dietician for intensified
CHILD 2-TG diet
• TG ≥200-499 mg/dL, non HDL ≥145 mg/dL = consider fish oil,
consult lipid specialist
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Drug intervention for treatment of individual
components
Atherogenic dyslipidemia
• Statins
• Fibrates
• Nicotinic acid
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Management of Dyslipidemia
• ARBITER-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 thickness
• in 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).
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Management of dyslipidemia
• A 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).
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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.
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Recommendations for Screening for Type 2
DM in Children
Screened 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.
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Prevention of T2DM
• Obesity 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.
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Recent Trials Relevant to the
Primary Prevention of Type 2 Diabetes
Study
Year
Interventions
Outcome
DaQing
(China)
1997
Diet, physical
activity or both
(control group:
general)
Reduction in diabetes incidence
31% in diet group, 46% in
physical activity and 42% in diet
and physical activity compared to
control group
Finnish
2001
Diabetes
Prevention
Study
Diet and physical
activity (control
group: general
advice)
Reduction by 58% of the risk of
diabetes compared to control
group
Diabetes
2002
Prevention
Program
(USA)
Diet, physical
activity,
metformin and
placebo
58% reduction in incidence of
diabetes with lifestyle
intervention, 31% with metformin
STOPNIDDM
Acarbose or
placebo
32% patients randomised to
acarbose and 42% randomised to
placebo developed diabetes
2002
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Treatment – Lifestyle Changes
• DPP- 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 baseline
1. 53% of those in the placebo group went on to develop MS over the
mean 3.2 years of follow-up,
2. compared with 47% in the metformin group and
3. 38% in the lifestyle intervention group.
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Drug Treatment
Insulin resistance and hyperglycemia
•Metformin
•Thiazolidinediones
•GLP-1 agonist (Exenatide, Liraglutide, Bydureon)
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Management of Hyperglycemia
• Mild 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 - insulin
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Metformin
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Metformin: Pediatric studies
Pediatric population demonstrated beneficial
effects on:
• fasting glucose
• BMI
• fasting insulin
• waist circumference
• and body weight
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Thiazolidinediones
• PPAR gamma agonists
• Alter adipocyte and muscle metabolism to promote
increased insulin sensitivity
• Pioglitazone
• Well studied in adults• -lower A1c ~ 1%
• Beneficial effects on lipids
• May prolong β cell function
• Not approved for use in youth with T2DM
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GLP-1 Agonists
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↑ glucose dependent insulin secretion
↓ inappropriate glucagon
↓ gastric emptying
Byetta: 5 or 10 mcg SC bid, 30-60 min before breakfast,
dinner
• Victoza: 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
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Future medications
• New 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.
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Cardiovascular Disease Prevention
should begin in Childhood
• Subclinical Atherosclerosis, the pathologic basis for
clinical CVD, begins in childhood.
• Risk factors for the development of atherosclerosis can
be identified in childhood
• Development 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 life
• Interventions exist for management of identified risk
factors and should be implemented.
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Controversy?
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Criteria are ambiguous or incomplete. Rationale for
thresholds are ill defined.
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Insulin resistance as the unifying etiology is uncertain..
• Inflammatory markers should be included
• Cumulative risk score approach
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