Updates in Metabolic Syndrome

1
Updates in Metabolic Syndrome

• Omer Junaidi, M.D.
• Amanda Ryan, D.O.
• Internal Medicine Chief Residents

2
Group of Metabolic Risk Factors

• Abdominal obesity
• Atherogenic dyslipidemia
• Elevated blood pressure
• Insulin resistance or glucose intolerance
• Prothrombotic state
• Proinflammatory state

3
(No Transcript)
4
Objectives

• Defining and classifying metabolic syndrome
• Understanding the basic science
• Learning the prevalence and incidence
• Reviewing the clinical relevance
• Discussing treatment options

5
(No Transcript)
6
WHO Criteria 1999

• Insulin resistance (type 2 diabetes, IFG, IGT)
• Plus any 2 of the following
• Elevated BP (gt140/90 or drug Rx)
• Plasma TG gt150 mg/dL
• HDL lt35 mg/dL in men and 40 in women
• BMI gt30 and/or W/H ratio gt0.9 men and 0.85 women
• Urinary albumin gt20mcg/min or Alb/Cr gt30mcg/g

7
NCEP ATP III Guidelines
8
AHA Guidelines for Diagnosis

• Three of More of the Following Components
• Elevated waist circumferenceMen  Equal to or
  greater than 40 inches (102 cm)Women  Equal to
  or greater than 35 inches (88 cm)
• Elevated triglyceridesEqual to or greater than
  150 mg/dL
• Reduced HDL cholesterolMen  Less than 40
  mg/dLWomen  Less than 50 mg/dL
• Elevated blood pressureEqual to or greater than
  130/85 mm Hg
• Elevated fasting glucoseEqual to or greater
  than 100 mg/dL

9
New Guidelines Needed

• Identify those at high risk for developing
  cardiovascular disease and diabetes
• Be useful for international comparisons
• Be useful for clinicians

10
International Diabetes Federation 2005 Consensus
11
IDF Waist Circumference
12
Prevalence of Metabolic Syndrome

• 3rd National Health and Nutrition Examination
  Survey
• Data collected between 1988-1994
• 3 or more of the following criteria
• Abdominal obesity waist circumference gt102cm in
  men and gt88cm win women
• Hypertriglyceridemia gt150mg/dL
• HDL lt40 in men and lt50 in women
• High blood pressure gt130/85 mm Hg
• High fasting glucose gt110mg/dL
• 8814 men and women gt20 years old studied
• Ford, E et al Prevalence of the Metabolic
  Syndrome Among US Adults. JAMA 2002297356-59.

13
Prevalence of Metabolic Syndrome

• Results indicated 22-24 prevalence
• 6.7 among 20-29 year olds
• 43 among 60-69 year olds
• Similar for men and women 24 and 23.4
• African American women compared to men had a 57
  higher prevalence
• Mexican American women compared to men had a 26
  increase
• Using these numbers, approximately 47 million US
  residents have metabolic syndrome

14
(No Transcript)
15
Clinical Implications

• Cardiovascular disease
• Diabetes
• Liver Disease
• Cognitive Function

16
NHANES Applied to MS CV Risk

• Logistic regression was used to estimate the
  cross-sectional association of the syndrome and
  each of its 5 component conditions separately
  with history of myocardial infarction (MI),
  stroke, and either MI or stroke (MI/stroke).
• Models were adjusted for age, sex, race, and
  cigarette smoking. The metabolic syndrome was
  significantly related in multivariate analysis to
  MI. The syndrome was significantly associated
  with MI/stroke in both women and men.
• Ninomiya et al. Association of the Metabolic
  syndrome with history of myocardial infarction
  and stroke in the third national health and
  nutrition examination survey. Circulation
  200410942-46.

17
(No Transcript)
18
INTERHEART

• Purpose of this trial was to assess if common
  risk factors identified in developed countries
  can be appropriately applied on a global scale.
• Smoking, hx of HTN of DM, W/H ratio, dietary
  patterns, physical activity, consumption of EtOH,
  apolipoproteins, and psychosocial factors all
  studied.
• Included nearly 15,000 both case and control
• Yusuf et al. Effect of potentially modifiable
  risk factors associated with myocardial
  infarction in 52 countries (the INTERHEART
  study) case-control study. Lancet
  2004364937-44.

19
Results

• Everything except alcohol was a significant risk
  factor for acute MI across all groups
• Smoking and raised ApoB/ApoA1 ratio were two
  strongest predictors
• DM, HTN, and psychosocial factors were next
  strongest.
• W/H ratio stronger than BMI

20
(No Transcript)
21
Metabolic Syndrome Hypertension

• Randomized prospective study in Italy with gt1700
  people with HTN (mean 155/95) no CVD, followed
  for a mean of 4 years
• During follow up, 162 pts developed CV events, a
  total of 593 pts had metabolic syndrome using
  NCEP guidelines
• Those with MS had an almost double CV event rate
  3.23 vs 1.76per 100pt years.

22
Metabolic Syndrome Hypertension

• This increase remained after adjustment for all
  traditional cardiovascular risk factors with a
  hazard ratio of 1.73.
• Metabolic syndrome was an independent predictor
  of both cardiac and cerebrovascular events.
• Schillaci et al. Prognostic value of the
  metabolic syndrome in essential hypertension J.
  Am. Coll. Cardiol., May 2004 43 1817 - 1822.

23
Risks with of MS characteristics
24
Metabolic Syndrome Aortic Stenosis

• Aortic valves sclerosis and progression to aortic
  stenosis may be caused by an atherosclerotic
  process
• 105 consecutive patients with at least moderate
  AS were enrolled and 40 of them had MS per
  NCEP-ATP III.
• End-points included hemodynamic progression of AS
  (per echo) and cardiovascular death and AVR

25
Metabolic Syndrome Aortic Stenosis

• Hemodynamic progression to AS was twice as fast
  in those with MS
• Three year event free survival was markedly lower
  with 44 (those with metabolic syndrome) vs 69
  with p 0.002
• In multivariate analysis, MS was found to be a
  strong independent predictor of both stenosis
  progression (p 0.006) and event-free survival
  odd (p lt 0.001)
• Briand et al. Metabolic syndrome negatively
  influences disease progression and prognosis in
  aortic stenosis. Journal of American College of
  Cardiology 2006 472229.

26
Insulin Resistance

• Numerous trials have demonstrated the
  relationship between impaired glucose tolerance,
  development of DM, and cardiovascular risk.
• Some studies have decreased the fasting glucose
  cutoff to 100mg/dL.

27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
Metabolic Syndrome, Inflammation, and Cognitive
Decline

• Cardiovascular and metabolic risk factors are
  hypothesized to play a role in the pathogenesis
  of Alzheimers and vascular dementia.
• Study designed to test hypothesis that metabolic
  syndrome is a risk factor for cognitive decline
  and whether this association is modified by
  inflammation
• Yaffe et al The metabolic syndrome,
  inflammation, and risk of cognitive decline.
  JAMA 20042922237-42.

31
Cognitive Effects cont

• 5 year prospective observational study conducted
  from 1997 to 2002
• Total of 2632 patients aged 70-79
• Exclusion criteria included clinical dementia,
  inability to communicate with the interviewer,
  difficulty with ADLs, cancer tx within 3 years
• Modified mini-mental state exam (3MS) given at
  baseline and repeated at 3 and 5 year visits
• Cognitive impairment defined as a 3MS change of 5
  or more
• Metabolic syndrome defined using NCEP guidelines
• Inflammatory markers included measurements for
  IL-6 and CRP
• Covariates included characteristics previously
  shown in the literature to be associated with
  cognitive function or metabolic syndrome

32
Results

• Mean age 73.6 52 women, 40 black, 25 high
  markers of inflammation
• Compared with participants without metabolic
  syndrome (n1616), those with metabolic syndrome
  (n1016) were more likely to be
• women and white
• to smoke
• have higher depression scores
• higher BMI
• hx of MI
• to use statins and NSAIDS
• have higher markers of inflammation

33
More Results

• Cognitive decline occurred in 598 participants
  (23)
• Baseline cognitive scores similar for those with
  (90.6) or without (90.4) metabolic syndrome
• RISK OF DEVELOPING COGNITIVE IMPAIRMENT OVER 4
  YEARS ACCORDING TO THE METABOLIC SYNDROME AND
  INFLAMMATION

34
Conclusion

• Among high functioning elders, those with
  metabolic syndrome showed an increased risk of
  developing cognitive impairment and decline over
  four years.

35
Insulin Resistance, Metabolic Syndrome and NASH

• Nonalcoholic fatty liver disease is a common
  condition compromising a wide spectrum of liver
  damage strongly associated with type 2 diabetes,
  obesity, and hyperlipidemia.
• Insulin resistance affects 20 of the nondiabetic
  population and occurs in association with many
  cardiovascular and metabolic abnormalities

36
Purpose and Criteria

• Study designed to assess the relationship of
  different degrees of insulin resistance (IR) and
  fatty liver.
• 308 consecutive patients referred to metabolic
  clinic
• Eligible if no excessive alcohol, hep B/C
  negative, and no US findings of cirrhosis
• ALT, HDL, triglycerides, glucose, insulin, and
  standard glucose tolerance tests
• Angelico et al. Insulin Resistance, the
  metabolic syndrome, and nonalcoholic fatty liver
  disease. Jour Clinical Endocrinology
  Metabolism 2005901578-82.

37
Insulin Resistance

• Homeostasis model of IR based on serum fasting
  glucose and insulin levels was used as a measure
  of IR.
• Liver steatosis was analyzed using ultrasound
  with grading of 0-3 based on intensity of echoes.
• 5 without steatosis
• 59 with mild/moderate steatosis
• 36 with severe

38
Insulin Resistance

• Per WHO criteria, 193 subjects has a normal
  glucose tolerance test
• 43 subjects had impaired glucose tolerance
• 72 subjects had type 2 diabetes
• Strong positive correlation found between insulin
  resistance and severe steatosis

39
Liver Pathology and the Metabolic Syndrome in
Severe Obesity

• 580 subjects undergoing gastric bypass surgery
  had wedge biopsies of liver
• Mean age was 36
• 436 were women
• Steatosis found in 86, risk was 2.6 times higher
  in men
• Fibrosis present in 74 of a subgroup of 82 pts,
  majority with grade 1
• Marceau et al Liver pathology and the metabolic
  syndrome X in severe obesity. Journal of
  Clinical Endocrinology and Metabolism.
  1999841513-17.

40
Correlations

• BMI correlated positively with fasting blood
  sugars and degree of steatosis, inversely with
  total and HDL cholesterol.
• Serum ALT and AST highly correlated with
  steatosis.
• Four components of metabolic syndrome
  significantly correlated with grade of fatty
  infiltration.
• Cohort of 104 women with WHR measurements there
  was significant interaction among fasting blood
  sugars, WHR, and relative risk of steatosis
  hepatitis.

41
Economics of Obesity Diabetes

• Contributing factors that have tipped the balance
  between caloric intake and expense into an
  unfavorable area
• Expanding labor market for women
• Increased consumption of food away from home
• Rising cost of healthy foods
• Growing quantity of caloric intake with declining
  overall food prices
• Decreased need of occupational and environmental
  physical activity

42
(No Transcript)
43
Economics

• Diabetes in the US, estimated to account for 1.3
  of our GDP and 31 of total indirect costs (lost
  wages, more people on disability, etc)
• In five years, cost of treating DM went form 44
  to 92 billion in the US.
• Estimated prevalence in US of DM in 2000 was 8.8,
  2030 estimate is 11.2
• Yach et al. Epidemiologic and economic
  consequences of the global epidemics of obesity
  and diabetes. Nature Medicine. 20061262-66.

44
Primary Intervention

• Main principle is healthy lifestyle promotion
  including
• Moderate caloric restriction (goal 5-10 body
  weight loss in 1st year)
• Moderate increase in physical activity
• Change in dietary choices

45
Diet

• Main dietary strategies include adequate
  omega-3-fatty acids intake, reduction of
  saturated and trans-fats, consumption of a diet
  high in fruits, vegetables, nuts, and whole
  grains and low in refined grains. Each of these
  strategies may be associated with reducing
  inflammation.
• Giugliano et al. The effects of diet on
  inflammation focus on metabolic syndrome. Jour
  Amer Coll Card. 200648677-85.

46
(No Transcript)
47
(No Transcript)
48
What to Treat

• There is a definite need for a treatment that can
  modulate the underlying pathophysiologic
  mechanisms in metabolic syndrome as a whole,
  these are not yet completely defined and
  therefore, no specific pharmacotherapy exists
• At this point, goal is to treat each individual
  component to help decrease the cardiovascular and
  diabetes risk

49
Summary of Current Data

• Metformin (UKPDS, DPP)
• Acarbose (Stop-NIDDM)
• Ramipril (HOPE)
• Pravastatin(WOSCOPS)
• Losartan (LIFE)
• Niaspan (HATS)

• ? diabetes, obesity and BP
• ? diabetes, BP, CVD, Lipids
• ? diabetes, CVD
• ? diabetes, CVD
• ? diabetes, CVD, stroke
• ? CVD, TG, ? HDL

50
Glitazones

• Improve insulin sensitivity
• Decrease blood sugar
• Increase healthy fats (HDL, adiponectin)
• Antiinflammatory, anticlotting, antiproliferating
  (CRP, PAI-1, MMP9)
• Improve endothelial dysfunction
• However, may also increase the risk of weight
  gain, edema, and CHF

51
Rimonabant

• Selective cannabinoid-1 receptor blocker that
  reduces body weight and improves cardiovascular
  risk factors in obese patients.
• Study randomly assigned 1036 overweight or obese
  pts with untreated dyslipidemia to either placebo
  or rimonabant in addition to a hypocaloric diet.
  
• Despres et al. Effects of rimonabant on
  metabolic risk factors in overweight patients
  with dyslipidemia. New England Journal of
  Medicine 2005 35320.

52
Results

• Around 60-63 completed trial, most common side
  effects were depression, anxiety, and nausea.
• Rimonabant at 20mg was associated with a
  significant reduction in weight, waist
  circumference, increase in HDL, reduction in
  triglycerides.
• Also resulted in increased adiponectin levels.

53
More Areas to Include in Research
54
What We Would Really Like to Know!!
55
Metabolic SyndromeThe Deadly Quintet Camus 1966,
Reaven 1988
Diabetes Hypertension Hyperuricemia
Insulin Hyperinsulinemia Resistance

• TNF?
• Leptin
• Adiponectin

? Exercise
? PAI-1
Lipid Abnormalities

• triglycerides
• ? HDL
• small dense LDL

Myocardial Infarction
ALSO ASSOCIATED WITH
MYOSTEATOSIS AND NASH
56
The End

• Thank you to Dr.Morley for his guidance while
  preparing this presentation.
• Thank you to all of our mentors here at St.Louis
  University and the VA hospital for being positive
  role models for us as we become the kind of
  clinician educators we strive to be.