1. The Metabolic Syndrome
andd
Cardiovascular Risk
Vivian Fonseca
Tulane University
Texas A & M University
Scott and White Clinic

2. Type 2 Diabetes Mellitus Is a
yp
Progressive Disease
Diagnosis
350
Postprandial
300
Glucose
Glucose
(mg/dL)
250 Fasting
200 Glucose
150
G
(
100
50
250 Insulin Resistance
200
150 Insulin Relative
100 Level
L l Insulin
50 Inadequate Resistance
β-Cell Function Decreasing β-Cell Function
0
Uncontrolled
Obesity
y IGT Diabetes
Hyperglycemia
Clinical Macrovascular Changes
Features Microvascular Changes
Years –10 –5 0 5 10 15 20 25 30
Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.

3. Insulin Resistance Syndrome and Risk
Factors for CVD in Type 2 Diabetes
Hypertension Hyperglycemia
Hyperinsulinemia
yp Dyslipidemia
– decreased HDL
Altered – increased
fibrinolysis, triglycerides
Inflammation, Insulin
Endothelial resistance
i t Genetics
dysfunction Aging
Obesity
Ob it
Sedentary lifestyle

4. Metabolic Syndrome: NCEP Criteria
Diagnosis requires three or more of the following features
• Waist ≥40” in males or ≥35” females
≥40 ≥35
• Triglycerides ≥150 mg/dL (or treatment)
• HDL <40 mg/dL in males and <50 mg/dL in females
(or t t
( treatment) t)
• SBP ≥130 or DBP ≥85 mmHg (or treatment)
• Fasting plasma glucose (FPG) ≥100 mg/dL (or treatment)
100
Issues
• Great
G t concept for professional and patient education:
tf f i l d ti t d ti
clustering of risk factors relate to poor lifestyle habits
• Providers do not measure waist and many lipid panels
are non-fasting
f ti
Grundy S, et al. Circulation 2005;112:2735

5. WHO and NCEP ATP III Criteria
for the Metabolic Syndrome
Criteria WHO NCEP
Glucose status or IR plus 3
or more of others: 3 or more of:
Glucose Status IGT/IFG/DM IFG/DM
HOMA IR Highest 25%
g N/A
Blood Pressure (mmHg) ≥140/90 ≥130/85
Triglycerides (mg/dL) ≥150 ≥150
HDL (mg/dL) <35 (M) <40 (M)
<39 (F)
( ) <50 (F)
( )
Obesity WHR>0.9 (M) WC>102 cm (M)
WHR>0.85 (F) WC>88 cm (F)
or BMI>30 kg/m^2
Microalbuminuria ≥30 mg/g N/A

6. Nuances in the definitions can
have huge effects
SBP>130 AND DBP>85
or
SBP>130 OR DBP>85
The latter scoops up about 60% more people
than the former
Does it matter? We don’t know.
6 of 22

7. Associated with insulin resistance?
Then how about adding…
Adiponectin
p
C-reactive protein
Age
Others?
Oth ?
7 of 22

8. Insulin resistance in those with MS
Author Sensitivity Specificity PPV Comment
Cheal et al. 46% 93% 76% N=443, no diabetes,
Diabetes 40% overweight
53:1195,2004
3 119 2004
Liao et al. 20 - 50% 92% 56% N=74,
Diabetes Care no diabetes
27:978,2004
McLaughlin 52% 85% 78% N=258,
N=258
et al. Ann no diabetes,
Intern Med 100% overweight
,
139:802,2003 or obese
Sierra-Johnson
42% 94% 72% N=256,
et al.
no HBP,
Diabetes C
Di b t Care
no diabetes
29:668,2006
8 of 22

9. Likelihood of IR* in
overweight / obese people
Marker Positive Predictive Value
Overweight / Obese alone 50%
Triglyceride > 130 mg/dl 70%
Triglyceride / HDL ratio >3.0 67%
ATP III Criteria 78%
*Insulin resistance = highest tertile
McLaughlin T et al. Ann Intern Med 139:802,2003 9 of 22

10. Prevalence of Metabolic Syndrome
One in four Americans have metabolic syndrome by
NCEP criteria
Approximately 80% of adults over the age of 20 have
one or more of th components of metabolic syndrome
f the t f t b li d
In addition to 21 million people with diabetes, there are
approximately 50 million people with pre-diabetes or
metabolic syndrome
Ford et al. JAMA 2002;287:356
http://www.diabetes.org/diabetes-statistics/prevalence.jsp

11. CHD Associated with High Insulin
Levels in Nondiabetic Subjects
1.00
0.95
Proportion Q1
0.90
0 90 Increasing
Without
Major CHD insulin
0.85 Q2
Event levels
0.80
Log rank: associated
Overall P=.001 Q3
with insulin
Q5 vs. Q1 P <.001 Q4 resistance
0.75
Q5
0
0 5 10 15 20 25
Years
Pyörälä M et al. Circulation 1998;98:398

12. Cardiovascular Disease Mortality
and the Metabolic Syndrome
15
Metabolic
RR=3.55
Syndrome
10 (95% CI, 1.96-6.43)
Cumulative
Hazard Ratio
5
Controls
0
0 2 4 6 8 10 12
Follow-up (Years)
Metabolic Yes 866 852 834 292
Syndrome? No 288 279 234 100
Lakka HM et al. JAMA 2002;288:2709

13. Dysglycemia in Patients with Acute MI
y gy
Consecutive patients presenting with acute MI, n = 181
Oral Glucose
Tolerance Test
20% 25%
80% 40% 35%
Diabetic
DM by OGTT
No DM (by History)
IGT by OGTT
Normal OGTT
Norhammar A et al. Lancet. 2002;359:2140

14. Metabolic Syndrome and the risk
of di b t
f diabetes
(San Antonio Heart Study)
Sens. Spec. PPV
ATP III 53 85 31
WHO 43 87 30
FPG ≥ 97 mg/dl 43 92 39
Lorenzo C, et al. Diabetes Care. 26:3153, 2003.
14 of 22

15. Metabolic Syndrome and the risk of diabetes
(Insulin Resistance Atherosclerosis Study*)
Variable OR** (95% CI)
ATPIII 4.14 (2.79 6.16)
4 14 (2 79 – 6 16)
3.84 (2.59 – 5.69)
AHA/NHLBI
3.40 (2.28 – 5.06)
IDF
IGT alone 5.42 (3.60 – 8.17)
* Incident of diabetes in 822 subjects followed for a mean of 5.2 years
j y
** Adjusted for age, sex and ethnicity
Hanley et al., Circulation 112:3713-3721,2005 15 of 22

16. Does the Metabolic Syndrome Predict
CVD?
(Data from San Antonio Heart Study*)
Variable Odds Ratio**(CI) P-Value
ATP III definition 1.56 .028
Adjusted for diabetes
Adj t d f di b t 1.11
1 11 .658
658
Diabetes 2.63
2 63 <0.0001
<0 0001
* CVD mortality i 5 158 people f ll
t lit in 5,158 l followed f 7 8 years
d for 7-8
** Adjusted for age and gender
Stern MP et al. Atheroscler Suppl. 6:3-6, 2005. 16 of 22

17. Glucose Levels and Cardiovascular
Events
3 3
2 h Glucose Fasting Glucose
2.5 2.5
2
RR 2 RR
1.5 1.5
1 1
72 108 144 180 198 72 90 108 126 144 163
2hPG = 140 mg/dL; RR = 1 58 (1.19-2.10)
1.58 (1 19 2 10)
19- FPG = 110 mg/dL; RR = 1 33 (1 06-1.67)
1.33 (1.06 1 67)
06-
2hPG=2-hour plasma glucose; FPG=fasting plasma glucose; RR=risk ratio
Yellow lines are 95% Confidence Intervals
Coutinho MS et al. Diabetes Care. 1999;22:233-242
17 of 22

18. Relation of Waist:Hip Ratio to MI
and Mortality in Women
dM li i W
20
15 Mortality
MI
Incidence 10
(%)
5
0
0-20 21-40 41-60 61-80 81-90 91-95 96-100
Centiles of waist-to-hip ratio
Lapidus L et al. BMJ. 1984;289:1257-1261.
18 of 22

19. Relationship between insulin
resistance and obesity
Helke MF et al., Am J Clin Nutr 83:47, 2006 19 of 22

20. The Adipocyte as an Endocrine Cell
FFA adiponectin PAI-1
leptin
RPB-4
resistin omentin
apelin
li adipsin
di i
SAA
TNF-α
IL-6 visfatin MCP-1

21. Metabolic Syndrome: ADA/EASD View
Adults with any major CVD risk factor should be evaluated
for the presence of other CVD risk factors
Lifestyle modification should be advised for patients with
CVD risk factors above the “normal” cut-point
p
Pharmacological treatment should be administered if the
CVD risk factor is indicative of frank disease
All CVD risk factors should be treated individually
Until randomized controlled trials have been completed,
there is no indication for the pharmacological
treatment for the metabolic syndrome
Kahn R et al. ADA/EASD. Diabetes Care 2005;28:2289

22. Prevention of Type 2 Diabetes:
Results f Recent R d i d T i l
R l of R Randomized Trials
Relative Risk
Study Subjects Intervention Reduction NNT
Behavioral
Finnish DPS IGT Lifestyle 58%
4-8
US DPP IGT y
Lifestyle 58%
%
US DPP IGT Metformin 31% 14
STOP-NIDDM IGT Acarbose 32% 11
edication
TRIPOD Troglitazone
Prior 56% 6
GDM
Orlistat 45%
XENDOS
Me
10
IGT
Ramipril /
DREAM Rosiglitazone NS / 62% 7
IGT
Nathan DM et al. Diabetes Care 2007 30:753

23. Steps to Obesity Management
p y g
Recognition
BMI, waist circumference obesity-related complications
BMI circumference, obesity-
Commitment
Patient, and nutrition team (MD, NP-PA, RD, PhD)
NP-
Realistic expectations
Reduction in health risks, 5% to10% initial weight loss
A multi-disciplined treatment approach
multi-
Behavior modification
Physical activity
y y
Diet
Pharmacotherapy

24. What is Known about
Weight Management?
• Modest weight loss is beneficial especially in the prevention
o chronic diseases c ud g
of c o c d seases including type 2 d abetes a d for
diabetes and o
lowering blood pressure
• At ~6 months individuals can lose 5% to 10% of their
6
starting weight
• Regardless of the intervention, plateaus and regain of
weight loss are expected; compensatory mechanisms
protect against weight loss
• If treatment is discontinued, weight gain occurs
• With support modest weight loss can be maintained
support,
Franz M et al. J Am Diet Assoc 2007:107:1736

25. Being Fit Reduces the Hazards
of Obesity in Males
25,389 males followed for 8 years
Physical fitness, regardless of body mass index (BMI)
fitness (BMI),
decreases risk of mortality from all chronic diseases
3
RR Of All-Cause Mortality including CVD
2.5
Relative
2
Risk
Fit
1.5
Unfit
1
0.5
0
Lean Normal Obese
Lee CD et al. Am J Clin Nutr 1999;69:373; Sui X et al. JAMA 2007;298:2507

26. Comparison of Popular Weight Loss
Diets
• Subjects (n=160) utilized one of the following diets
– Atkins (carbohydrate restricted)
– Zone (macronutrient balanced)
– Weight Watchers (calorie restriction)
– O i h (fat restriction)
Ornish (f t t i ti )
• Weight loss and completers at 1 year
– Atkins 2.1 kg (4.6 lb) [53%]
– Zone 3.2 kg (7.0 lb) [65%]
– Weight Watchers 3 0 kg (6 6 lb) [65%]
3.0 (6.6
– Ornish 3.3 kg (7.3 lb) [50%]
• Each popular diet modestly reduced body weight
weight.
Amount of weight lost was associated with self-
Dansinger M et al. JAMA 2005;293:43 diet but not with diet type
reported adherence to

27. Predictors of Successful Weight Loss
Maintenance in National Weight Control
Registry
• Continue to eat lower energy diets (average energy intake
~1400 kcal/day); eat a low-fat, moderate-carbohydrate
diet (24% of energy from fat)
•F
Frequently self-monitor weight and f d i t k
tl lf it i ht d food intake
• Participant in a minimum of 60 to 90 minutes of physical
activity nearly every d of th week
ti it l day f the k
(2800 kcal/week; 28 miles of walking/week)
• Eat breakfast every day (contrary to the typical eating
pattern for dieters)
Wing RR, Hill JO. Ann Rev Nutr 2001;21:323. Wyatt H et al. Obes Res 2002;2:78

28. What is the Effect of Weight Loss and
Weight Loss Medications on A1C in Type
2 Diabetes?
12-mo
12 mo Weight 12-mo
12 mo Weight
Change (Type 2 12-mo A1C Change (Without
Interventions Diabetes) Change Diabetes)
Weight Loss Diet
g – 2.6 kg (
g (5.7 lb)
) – 0.4% –4.6-7.6 kg (
g (10-17 lb)
)
(n=532)
Orlistat 120 mg tid – 5.0 kg (11 lb) – 0.8% –8.2 kg (18 lb)
(n=574) (Alli)
Sibutramine 15-20 – 7.2 kg (15.8 lb) – 0.4% –8.2 (18 lb)
mg (n=152)
Franz M. On the Cutting Edge. Diabetes Care and Education 2006;6:27

29. Strategies for Changing Behavior
• Self-monitoring (recording behaviors): always rated by
participants as most helpful
• Individuals who recorded food intake frequently lost more than
twice as much weight as those who did so infrequently1
• Realistic goals: 8% to 10% weight loss improves risk f
% % factors
• Stimulus control: environmental restructuring for modification of
eating cues
• Cognitive restructuring: moving from self-rejection to
self-acceptance
p
• Contingency management: rewards by self or professionals
(rated as least helpful)
• Stress management: #1 predictor of relapse
Foreyt JP, Pendleton VR. Primary Care Reports 2000;6:19
1Wadden TA et al. N Eng J Med 2005;353:2111

30. Strategies for Maintenance
of Behavior Change
• Physical activity: major p
y y j predictor of maintenance
• Social support: family “set p , peer support,
pp y point,” p pp ,
self-help or work-site groups
• Relapse prevention: relapse is expected; coping
strategies are needed
– Stress management
– Social situations
– Continuing support from health professionals
Foreyt JP, Pendleton VR. Primary Care Reports 2000;6:19

31. Bariatric Surgery and Diabetes
Swedish Obese Subjects Study (SOS)
• Weight loss at: 10 Years Post Bariatric Surgery
• 1 year: 38%
• 2 years: 23% Post
g y
Surgery
Control
• 10 years: 16%
• All studied risk factors Resolution 36% 13%
improved, except of DM
hypercholesterolemia and
cardiovascular risk Newly 7% 24%
Developed
• Decreased overall mortality DM
Sjostrom L et al. N Engl J Med 2004;351:2683; Sjostrom L et al. N Engl J Med 2007;357:741

32. The STOP-NIDDM Study: Reduction
in Risk of Cardiovascular Disease
0.06
0.05
Probability 0.04 Hazards Ratio RRR
of Any Placebo 0.51 49%
0.03
Cardiovascular
Event 0.02
Acarbose
0.01
0 01
P=0.04 (log-rank test)
0 P=0.03 (Cox proportional model)
Days After Randomization
Patients at risk
Acarbose 686 675 667 658 643 638 633 627 615 611 604 519 424 332 232
Placebo 682 659 635 622 608 601 596 590 577 567 558 473 376 286 203
Chiasson JL, et al. JAMA. 2003;290(4):486-494.

33. NAVIGATOR
2 x 2 Factorial Design
Valsartan comparison
Valsartan/Nateglinide Placebo/Nateglinide
(n = 2,288) (n = 2,288)
Nateglinide
comparison
Valsartan/Placebo Placebo/Placebo
(n = 2,288) (n = 2,288)
Dosages
Nateglinide 60 mg PO ac
Valsartan 160 mg PO qd
All subjects will receive a lifestyle advice program

34. Exenatide + Oral Agents
Summary of Weight Changes
Placebo
“THE 3 AMIGOS TRIALS”
TRIALS” Exenatide 5 μg
30-
30-Week, Randomized, Placebo-Controlled
Placebo- Exenatide 10 μg
0.0
-0.5 -0.3
-0.6
-1.0 -0.9
ght
-0.9
g)
Δ weig
(kg
-1.5
-1.6 -1.6 -1.6 -1.6
-2.0 * * * *
-2 5
2.5
-3.0 -2.8
*
*P<0 05 vs placebo
<0.05 Exenatide + SU Exenatide + Met Exenatide + SU + Met
(n=377) (n=336) (n=733)
Buse JB, et al. Diabetes Care. 2004;27:2628-2635.
Defronzo RA, et al. Diabetes Care. 2005;28:1092-1100. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

35. Rimonabant:Changes From Baseline for
Body Weight for Year 1
0
Change from baseline, kg
,
-2
-4
b
-6
es
-8 Placebo
5 mg Rim.
20 mg Rim.
-10
0 12 24 36 52
No. at Risk Weeks
Placebo 590 496 413 347 309
5 mg Rim. 1191 1104 833 711 619
20 mg Rim. 1189 1017 863 750 672
Pi-Sunyer, F. et al., JAMA 2006; 295:761-75.

36. Source of Proinflammatory Risk Factors
Adipose Tissue
CD40L
Adhesion Interleukins
molecules
TNF-
TNF-alpha
IL-
IL-1 IL-
IL-6 IL-
IL-8
Matrix
Inflammation Metalloproteinases
Liver
Acute phase proteins
Plaque
destabilization
Serum CRP Fibrinogen
amyloid A

37. Selected NF-κB responsive genes with potential roles
in insulin resistance and T2D (•) or CHD (♦)
IKKβ
NF-κB
Cytokines Chemokines Surface Proteins Others
•♦IL-6 •♦MCP-1 ♦E-Selectin •♦PAI1
•♦IL 1β
•♦IL-1β ♦MIP 1α,
♦MIP-1α, β ♦P Selectin
♦P-Selectin •♦SAA
•♦TNF-α ♦MIP-2 ♦ICAM1 •♦CRP
•Resistin ♦MIP-3α ♦VCAM1 ♦Cox2
♦IFN-γ ♦CD40 ligand •♦iNOS
Receptors
♦Lymphotoxins ♦IgGs ♦VEGF
♦CD40
IL-7, 8 ♦A20
IL-6R, IL-1R Transcription
IL-11, 12 ♦MMPs
•TNFR p75
p •IKKβ
IL-13,
IL 13 15
•TNFR p55 •♦NF-κB RelA, p50
IL-4
IFNα,β,γR c-Jun, FosB, JunB

38. Effect of Pioglitazone
on Cardiovascular Risk Markers
rom baseline
% change fr
pioglitazone
glimepiride
hsCRP
h CRP MCP-1
MCP 1 MMP-9
MMP 9 IMT
Pfützner A J Am Coll Cardiol. 2005;45(12):1925-31

39. Glucose Metabolism Before and After
Aspirin
Hundal RS et al. J Clin Invest. 2002;109:1321-1326.

40. TINSAL T2D – Targeting Inflammation with Salsalate in Type 2 Diabetes
Salsalate is a covalent, head-to-tail dimer between two salicylic acid moieties.
Salsalate is insoluble at acidic pH so it doesn’t irritate the stomach
pH, stomach.
OH CH 3 CO 2 OH CO 2 H
CO 2 H CO 2 H CO 2
Salicylic Aspirin Salsalate
Acid (Disalcid)

41. 4.5 vs. 3.0 g/day Salsalate in patients with T2D
Glucose utilization Salicylate
FBS (mg/dl) C-peptide (nM) (mg/kg/min) (mg/dl)
3 8
200
Pre
* * 20
Post 6
2 *
4 Pre
100 * 1
* 10
2 Post
19% 9% 40% 50% 15%
0 0 0 0
4.5 3.0 4.5 3.0 4.5 3.0 4.5 3.0
Adiponectin
FFA (mEq/l) TG (mg/dl) CRP (mg/dl) (mg/dl)
1.2
12
6
200 20
0.8
* *
* * 4
*
100 10
0.4 2
28% 40% 50% 40% 35%
0 0 0 0
4.5
45 30
3.0 4.5
45 30
3.0 4.5
45 30
3.0 4.5
45 30
3.0
Salsalate dose (g/d)
Goldfine & Shoelson et al, Clinical and Translational Science, 2008;1;36

42. Salsalate Improves Glycemia During Oral
Glucose Tolerance Testing in Ob it
Gl T l T ti i Obesity
Salsalate Placebo
* p<0 01
p<0.01
10
** **
9 9
Percent Change
e
5
**
mol/L)
8 8 0
lucose (mm
7 7 5
-5
-10
6 6
-15
15
Gl
5 5 Baseline
Post Therapy -20
0 60 120 0 60 120 Salsalate
Placebo
Time (minutes)
Fleischman et al Diabetes Care 2008; 31:289

43. Free Fatty Acids and Inflammatory Mediators
Improve With Salsalate in Obesity
**
0.6
20
6
* p<0.05
*
Salsalate
*
0.3
10
3
** p<0.01
14% 34% 56%
FFA CRP Adiponectin
0.6
20
6
Placebo
0.3
3
10
3
Baseline
Salsalate
FFA CRP Adiponectin
(mEq/L) (mg/L) (mg/L)
Fleischman et al Diabetes Care 2008; 31:289

44. TINSAL-
TINSAL-T2D Stage 1:
HbA1c (primary endpoint)
0.2
hange fro baseline)
Placebo
0
om
-0.2
*P vs placebo
vs.
ercent HbA1c (ch
3.5 g *0.02
-0.4 3.0 g *0.02
4.0 g *0.001
Pe
-0.6 *Holm’s procedure
0 4 8 14
Trial week

45. TINSAL-
TINSAL-T2D Trial Design
Stage I: 14-week multicenter, double-masked, placebo-controlled
dose ranging study in inadequately controlled T2D (7.0 ≤ HbA1c ≤ 9.5)
Screen n=240, Randomize n=108
Placebo 3.0g 3.5g 4.0g
n=27 n=27 n=27 n=27
52
Stage II: 26-week multicenter, double-masked,
placebo-controlled phase III trial
Screen n=564 Randomize n=282
n=564,
Placebo Salsalate 3.5 g/d
n=141 randomized n=141 randomized
Placebo Salsalate
n=113 complete n=113 complete