1. The Metabolic Syndrome
Gil C. Grimes, MD
September 2006

2. Objectives Define Metabolic Syndrome
Review the prevalence in our population
Discuss the proposed pathophysiology
Review associated morbidity and mortality
Define treatment strategies
Define the metabolic syndrome.
Review the prevalence in our population.
Discuss the proposed pathophysiology.
Define treatment strategies and paradigms

3. Definitions

4. World Health Organization Definition
One of these
Insulin resistance
Impaired glucose regulation
FPG ≥ 110 mg/dl and/or
2 hour PG ≥ 140 mg/dl
Two of these
Hypertension SBP ≥ 140 DBP ≥ 90
Elevated Triglycerides (≥ 150 mg/dl) and/or low HDL (≤35 mg/dl males and ≤39 mg/dl females)
Central Obesity waist to hip ratio >0.90 males, >0.85 females, or BMI>33 kg/m2
Microalbuminuria urinary albumin excretion rate ≥ 20 mg/min or albumin/creatinine ratio ≥ 30 mg/g
Insulin resistance is defined originally as by the use of an insulin clamp
In many studies surrogate markers of insulin resistance are utilized
Fasting insulin levels
Insulin after a 75 gm glucose challenge
Albert KGMM et al Diabetic Med 1998;15: [Level 5]

5. National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATPIII) Definition
Three of the following
Abdominal circumference
Men > 40 inches
Women >35 inches
Triglycerides > 150 mg/dl
HDL Cholesterol
Men < 40 mg/dl
Women <50 mg/dl
Blood Pressure > 130/85 mm Hg
Glycemia >110mg/dl
Abdomen measurements at umbilicus
Correlates better than BMI
Expert panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:
[Level 5]

6. Prevalence This is from the New York Time September 2003
A new food item deep fried with the taste of a cheeseburger and fries all in one
Decline in the amount of exercise
Segway may make things worse
Look at the people in these photos
How many can you identify that are at risk for metabolic syndrome

7. Obesity US 1991
Data from the behavior risk factor surveillance survey
Telephone survey people >18 who were non-institutionalized
[Level 2b]

8. Obesity US 1992
[Level 2b]

9. Obesity US 1993
[Level 2b]

10. Obesity US 1994
[Level 2b]

11. Obesity US 1995
[Level 2b]

12. Obesity US 1996
[Level 2b]

13. Obesity US 1997
[Level 2b]

14. Obesity US 1998
[Level 2b]

15. Obesity US 1999
[Level 2b]

16. Obesity US 2000
[Level 2b]

17. Obesity US 2001
[Level 2b]

18. Texas 2001
Texas subset from the Behavioral Risk Factor Surveillance System
Look closely at the number of those obese
White 60%
Black 75%
Hispanic 70%
Multiracial 55%
Other 46%
Behavioral Risk Factor Surveillance System, 2001 CDC [Level 2b]

19. Prevalence in FOS and SAHS populations
Frammingham offspring study
Prospective community study
Looked at 3,224 patients
Virtually all white
85% of those eligible participated
data
San Antonio Heart Study
Prospective community based study
Data from the survivors (73.7%)
1988 to 1996 data
Looked at a total of 1081 Non-hispanic
Looked at a total of 1656 hispanic
Range is up to 33%
Note the increased number of Mexican Americans with metabolic syndromes
Meigs J et al Diabetes 2003; 52: [Level 2c]

20. Prevalence Metabolic Syndrome in NHANES III
Metabolic Syndrome increases with age
Based on NHANES II data
data set
Ford ES et al JAMA 2002;287: [Level 2 c]

21. Prevalence Metabolic Syndrome in NHANES III by Race
Note the over-representation of hispanics
Ford ES et al JAMA 2002;287: [Level 2 c]

22. Prevalence in Adolescents from NHANES III
5 percent prevalence rate for Metabolic syndrome
Data from
Cook S et al Arch Pediatric Adolec Med 2003;157: [Level 2c]

23. Pathophysiology

24. Proposed Pathophysiology
Role of adipose tissue and inflammation
IL-6 (pro-inflammatory compound)
Produces 25% of IL-6
Stimulate acute phase hepatic protein production
Obesity associated with increased C-reactive protein
Represents chronic low level inflammation
More related to Waist to hip ratio than BMI
This is speculative.
Based on blood samples from NHANES III
The black bars are raised CRP levels in this group
Increased with increased BMI especially in females
There are several lines of evidence that inflammation plays an integral role in the syndrome
Unclear on whether it is a chicken egg thing
Does metabolic syndrome predispose you to low level inflammation?
Doe low level inflammation lead to metabolic syndrome?
Is is adipose poisoning?
Visser M et al JAMA 1999;282: [Level 2b]

25. CRP and BMI Visser M et al JAMA 1999;282:2131-2135 [Level 2b]
NHANES III data
Closer look at BMI vs Waist Hip in women
BMI correlates better for Women than Waist Hip Ratio for increased CRP
Women faired worse than men
Both groups showed increase with obesity
Change remained significant after adjustment for comorbid conditions
Visser M et al JAMA 1999;282: [Level 2b]

26. CRP, IL-6, and subsequent DM
Data from Women’s Health Study
Looked at women who subsequently developed DM and examined Il-6 and CRP
27,628 total patients
Of those 180 developed Diabetes within the trial period
Matched to 362 case control that did not develop diabetes
Looking at two different BMI (darker heavier)
Comparing relative risk of developing diabetes with the Il-6 or CRP level
Higher baseline predictive even with normal BMI
Pradhan AD et al JAMA 2001;286: [Level 2b]

27. Cartoon of mechanism of disease

28. Associated Morbidity and Mortality

29. CHD Morbidity and Mortality
This is from the Kuopio Ischaemic Heart Diease Risk Factor Study
Population based cohort study of 1209 finish men years of age
inception
Follow up through 1998
There is an increased risk of death as a direct result of MI, or as a result of CVD (Heart failure etc).
There is also and increased risk of all cause mortality although not as drastic.
Lakka H et al JAMA 2002; 288: [Level 1b]

30. Metabolic Syndrome as a Risk for CHD and Diabetes
West of Scotland Coronary Prevention Study
5974 men
Followed 4.9 years
Metabolic syndrome conveyed the same risk as smoking or increasing your age by 10 years for CHD
Dramatic increase in risk for DM
Sattar N et al Circulation 2003:108: [Level 2b]

31. Risks for CHD and CVA Morbidity
Botnia Study Group
Examined families goal of identifying early defects in families with DM-2
Examined 4,483 subjects
Looked at the development of Coronary Heart Disease or Cerebral Vascular Disease
Presence of Metabolic syndrome conferred increased risk of both
Isomaa B et al Diabetes Care 2001;24: [Level 2b]

32. Risk for CHD Mortality
Finish Study group Botnia
subjects
10% died
5.8% from CHD
Of those who died metabolic syndrome increased risk of death and of CHD mortality compared with no metabolic syndrome
Isomaa B et al Diabetes Care 2001;24: [Level 1a]

33. Risk for CHD and Diabetes
From the West Scotland Study
Sattar N et al Circulation 2003:108: [Level 2b]

34. Risk for DM from Kuopio IHD Risk Factor Study
Presence of Metabolic Syndrome
Odds Ratio of developing DM 10
4 fold increased risk for DM
WHO Definition with Waist Hip Ratio >0.90
Sensitivity 0.83
Specificity 0.78
NCEP Definition
Sensitivity 0.57
Specificity 0.90
Finish study of 1004 men followed for four years
This is from the Kuopio Ischaemic Heart Diease Risk Factor Study
Population based cohort study of 1209 finish men years of age
inception
Follow up through 1998
Laaksonen D et al Am J Epidemiol 2002;156: [Level 2b]

35. Treatment

36. Treatment Prevention is the Key Diminish the adipose poisoning
Must extrapolate from other studies
Diabetes Prevention Program
Goal 150 minutes of exercise weekly
Low fat diet
Nutrition counseling every 90 days
NNT 8 people for 3 years to prevent 1 new DM
Absolute Risk Reduction 12.77%
Finish Study over six years mean follow up 3.2 years
Recruited high risk individuals (first degree relative with DM), obese patients, those with impaired fasting glucose
172 men 350 women
Randomly assigned to intense intervention vs control
Confidence interval 5.2 to 15.5
Tuomilheto J et al NEJM 2001;344: [Level 1a]

37. Treatment Lifestyle vs. Metformin
Similar design
NNT for 3 years to prevent on case of DM
Lifestyle 6.9
Metformin 13.9
Diabetes Prevention Group
Random Assignment 3234 non-diabetic with increased fasting or post load glucose concentrations
Lifestyle group 150 minutes physical activity weekly vs metformin 850 mg BID
Diabetes Prevention Program Group NEJM 2002;346: [Level 1a]

38. Treatment Lifestyle vs. Xenical
Subgroup analysis of Xenical trial
40% of patients positive for Metabolic syndrome
Type II DM 13.9% lifestyle group
Type II DM 9.8% Xenical group
Industry sponsored study
Never published outside of this presentation.
Torgerson J et al 12th European Congress on Obesity 2003 [Level 2b ?]

39. Statins et al
Presence of Metabolic Syndrome indicates at least 2 risk factors
LDL goal <100 mg/dl
Statins reduce LDL on average 18-55%
Fenofibrate reduce Triglycerides 20-50% and raise HDL 10-35%
Niacin reduce LDL 5-25% Triglycerides 20-50% and raise HDL 15-35%
Combinations work well, caution for increased risk of adverse events
O‘Mara NB Prescriber’s Letter 2003;19:191001

40. Control the Pressure
JNC 7 guidelines and ALLHAT tell us to lower the pressure
Intensive lifestyle modification
HOPE trial 32% reduction in new onset DM for ramipril
LIFE trial
Losartan 6% developed DM
Atenolol 8% developed DM
It appears form recent evidence that it takes High Dose Ramipril to achieve this change
There is an underlying question as to whether Beta Blockers may not be as good as ACE/ARB in Prevention of DM

41. Aspirin Therapy
Routine recommendation for those at increased risk for cardiovascular disease
Unclear if it decreases progression of Metabolic Syndrome
Use based on High Risk status of these patients

42. Sample Patient 38 year old male Weight 250 lbs Height 72 inches BMI 34
BP 140/86
Screen Glucose?
Screen Lipids?
Therapy?

43. Take Home It is common in our patients
The prevalence is expected to increase
The process starts early
The intervention needs to start early
Get your patients up and moving