Metabolic Syndrome, Diabetes, and Cardiovascular Disease: Implications for Preventive Cardiology

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Metabolic Syndrome, Diabetes, and Cardiovascular
Disease Implications for Preventive Cardiology

• Nathan D. Wong, PhD, FACC, FAHA
• Professor and Director
• Heart Disease Prevention Program
• Division of Cardiology
• University of California, Irvine

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Overview of Diabetes in the United States
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Diabetes Prevalence, 1990-1998
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Age-adjusted prevalence of physician-diagnosed
diabetes in Adults age 18 and older by
race/ethnicity and sex (NHANES 1999-2004).
Source NCHS and NHLBI. NH non-Hispanic.
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Risk of Cardiovascular Events in Diabetics
Framingham Study
__________________________________________________
_______________

• Age-adjusted
• Biennial Rate Age-adjusted
• Per 1000 Risk Ratio
• Cardiovascular Event Men Women Men
  Women
• Coronary Disease 39 21 1.5
  2.2
• Stroke 15 6 2.9 2.6
• Peripheral Artery Dis. 18 18 3.4
  6.4
• Cardiac Failure 23 21 4.4
  7.8
• All CVD Events 76 65
  2.2 3.7
• Subjects 35-64 36-year Follow-up
  P

__________________________________________________
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Insulin Resistance
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Hyperglycemia in Type 2 Diabetes Results From
Three Major Metabolic Defects
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Relationship Between Obesity andInsulin
Resistance and Dyslipidemia
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Insulin Resistance Associated Conditions
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New Cases of ESRD in the United States
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New Cases of ESRD in the United States by Cause
and Ethnicity, 1998
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Microalbuminuria
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Cardiovascular Disease and Diabetes
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Probability of Death From CHD in Patients With
Type 2 Diabetes With or Without Previous MI
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Framingham Heart Study 30-Year Follow-UpCVD
Events in Patients With Diabetes (Ages 35-64)
10
10
9
Men
Women
8
11
Risk ratio
6
30
19
4
9
6
38
20
3
2
0
Total CVD
CHD
Cardiac failure
Intermittent claudication
Stroke
Age-adjusted annual rate/1,000
PPWF, Kannel WB. In Hyperglycemia, Diabetes and
Vascular Disease. Ruderman N et al, eds. Oxford
1992.
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The Metabolic Syndrome
Endothelial
Systemic
Complex
Dysfunction
Inflammation
Dyslipidemia
TG, LDL
HDL
Athero- sclerosis
Insulin
Disordered
Resistance
Fibrinolysis
Hypertension
Visceral
Obesity
Type 2 Diabetes
Adapted from the ADA. Diabetes Care.
199821310-314Pradhan AD et al. JAMA.
2001286327-334.
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Revised ATP III Metabolic Syndrome Oct 2005
Diagnosis is established when ?3 of these risk
factors are present. Abdominal obesity is more
highly correlated with metabolic risk factors
than is ?BMI. Some men develop
metabolic risk factors when circumference is only
marginally increased.
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA. 20012852486-2497 Updated AHA/NHLBI
Statement Oct 18, 2005 Grundy et al. Circulation
2005 112 (epub).
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International Diabetes Federation Definition
Abdominal obesity plus two other components
elevated BP, low HDL, elevated TG, or impaired
fasting glucose
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Intra-abdominal (Visceral) FatThe dangerous
inner fat!
Front
Visceral AT
Subcutaneous AT
Back
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Relationship Between Visceral Adipose Tissue and
Insulin Action
18 16 14 12 10 8 6 4 2 0
Glucose disposal (mg/kg LBM/min)
1,000
2,000
3,000
4,000
5,000
Visceral adipose tissue volume per unit surface
area (mL/m2)
Banerji M, et al. Am J Physiol. 1997273(2 pt
1)E425-E432.
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Prevalence of the Metabolic Syndrome Among US
Adults NHANES 1988-1994
Age (years)
Ford E et al. JAMA. 2002(287)356.
1999-2002 Prevalence by IDF vs. NCEP Definitions
(Ford ES, Diabetes Care 2005 28 2745-9)
(unadjusted, age 20) NCEP 33.7 in men and
35.4 in women IDF 39.9 in men and 38.1
in women
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Prevalence of the NCEP Metabolic Syndrome
NHANES III by Sex and Race/Ethnicity
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28
26
25
23
21
20
Prevalence,
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Men
Women
Ford ES et al. JAMA 2002287356-359.
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Cardiovascular Disease (CVD) and Total Mortality
US Men and Women Ages 30-74(age, gender, and
risk-factor adjusted Cox regression) NHANES II
Follow-Up (n6255)(Malik and Wong, et al.,
Circulation 2004 110 1245-1250)



















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Metabolic Syndrome, CVD Events, and Mortality

• European cohort studies (6156 men and 5356
  women) Modified WHO definition of MetS
  associated with all-cause mortality (RR1.44
  1.17-1.84 in men and 1.38 1.02-1.87 in women)
  and CVD mortality (RR2.26 1.61-3.17 in men and
  2.78 1.57-4.94 in women) (Hu et al. Arch Intern
  Med 2004 164 1066-76)
• Atherosclerosis Risk in Communities (ARIC) study
  (12,089 men and women) 11 year follow-up, ATP
  III MetS associated with 1.5-2-fold greater
  likelihood of developing CHD and stroke, but MetS
  did not improve prediction over FRS (McNeill et
  al. Diab Care 2005 28 385-90)
• Cardiovascular Health Study (CHS) (2,175 elderly
  subjects) ATP III definition associated with 38
  increased risk (pr events (Scuteri et al., Diab Care 2005 28
  882-7)

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Evidence Supporting Aggressive Glycemic Control
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Treatment of Type 2 Diabetes
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Sites of Action of Therapeutic Options for Type
2 Diabetes
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DCCT Effects of Intensive vs Conventional
Glycemic Control
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UKPDS Design
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UKPDS Effects of Intensive (Sulfonylurea/Insulin
) Treatment
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UKPDS Effects of Intensive (Metformin)
Treatment
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UKPDS Effects of Glycemia Exposure Over Time
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UKPDS Risk Reduction in Diabetes-Related
Complications (A1c)
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Diabetes Prevention Program Protocol Design
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Diabetes Prevention Program Reduction in
Diabetes Incidence
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Structures of Thiazolidinediones
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Thiazolidinediones Mechanism of Insulin
Sensitization
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PPAR a vs. gamma

• PPAR a (fibrates) work mostly in the liver and
  lower VLDL triglycerides and increase HDL-C but
  do not affect FFA, glucose, or insulin
  sensitivity
• PPAR gammas (TZDs such as rosiglitazone or
  pioglitazone) promote new fat cells in
  subcutaneous tissue and decrease intramuscular
  and visceral fat.

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ThiazolidinedionesRationale for Type 2 Diabetes
Therapy
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ACTOS, an Insulin Sensitizer
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Reduced Insulin Resistance Suggested by HOMA
Analysis of Pioglitazone Therapy
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Improved ß-Cell Response Suggested by HOMA
Analysis of Pioglitazone Therapy
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Changes in A1c From Baseline in All Treated
Patients
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Endpoint Changes in Patients With Lower Baseline
A1c (Mean 9.0)
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Change in FPG From Baseline in All Treated
Patients
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Change in Lipid Profile at Endpoint ACTOS
26-Week Monotherapy
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DREAM Study for Prevention of Diabetes

• 5,269 persons with pre-diabetes randomized to
  rosiglitazone (8 mg daily) vs. placebo and
  ramipril vs. placebo for median of 3 years
• 10.6 of those on rosiglitazone progressed to
  type 2 diabetes vs. 25 on placebo, a 62 risk
  reduction (p
• Primary endpoint of development of diabetes or
  death from any cause reduced by 60
• 51 of those on rosiglitazone vs. 30 on placebo
  returned to normal blood sugar
• No significant difference in future
  cardiovascular events, but higher rate of new
  heart failure in those on rosiglitazone (0.5)
  vs. placebo (0.1). Body weight increased 2.2kg
  more in the rosiglitazone vs. placebo group.

The DREAM (Diabetes REduction Assessment with
ramipril and rosiglitazone Medication)
investigators. Effect of rosiglitazone on the
frequency of diabetes in patients with impaired
glucose tolerance or impaired fasting glucose a
randomised controlled trial. Lancet
20063681096-105.
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PERISCOPEComparison of Pioglitazone vs.
Glimepirideon Progression of Coronary
Atherosclerosisin Patients with Type 2 Diabetes
Steve E. Nissen, MD Cleveland Clinic
Foundation Cleveland, Ohio ACC Scientific
Sessions, Late Breaker Monday March 31,
2008 Chicago, Illinois
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PERISCOPEBackground

• Background
• Cardiovascular disease is the leading cause of
  death in patients with diabetes
• Few studies have compared outcomes for diabetes
  medications beyond their glucose lowering
  efficacy
• Sought to compare coronary disease progression
  measured by intravascular ultrasound for two
  alternative treatment strategies
• Glimepiride (an insulin secretagogue)
• Pioglitazone (an insulin sensitizer)
• Hypothesis
• To directly compare the effectiveness of these 2
  alternative approaches, an insulin-providing vs
  an insulin-sensitizing strategy, in reducing
  progression of atherosclerosis in patients with
  type 2 diabetes and coexisting coronary artery
  disease

Nissen S. JAMA.2008299(13)1561-1573
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PERISCOPE Study Design
543 patients with type 2 diabetes undergoing
angiography for clinical indications
Glimepiride 1-4mg (titrated to maximally
tolerated dose)
Pioglitazone 15-45mg (titrated to maximally
tolerated dose)
Repeat Intravascular Ultrasonography Examination
at 16 weeks
Primary Outcome Measure Change in percent
atheroma volume (PAV) from baseline to study
completion
Nissen S. JAMA.2008299(13)1561-1573
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PERISCOPEPrimary Efficacy ParameterChange in
Percent Atheroma Volume ()
P
0.73
Change in PAV()
-0.16
P0.44
Difference between groups P0.002
Pioglitazone
Nissen S. JAMA.2008299(13)1561-1573
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PERISCOPEIntravascular Ultrasound. Secondary
Endpoints
Atheroma Thickness (mm)
Atheroma Volume (mm3)
Most Disease 10mm (mm3)
P0.93
P0.006
P0.06
Nissen S. JAMA.2008299(13)1561-1573
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PERISCOPEOther Adverse Events
Nissen S. JAMA.2008299(13)1561-1573
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UKPDS Effects of Tight vs Less-Tight Blood
Pressure Control
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ACCORD Is too aggressive lowering of HbA1c
harmful?

• NHLBI-sponsored ACCORD study of approx. 10,000
  T2DM pts with CHD or 2 risk factors tested
  control of HbA1c to HbA1c 7-7.9.
• Median HbA1c achieved 6.4 vs. 7.5
• The trial was stopped early (Feb 6, 2008) due to
  more deaths in intensive arm (257, or 14/1000
  person years) vs. standard arm (203, or 11/1000
  person years).
• There were, however, 10 fewer MIs in intensive
  arm and no link to any particular medication
  causing increases in deaths was noted.
• No change in general recommendation by ADA to
  achieve for HbA1c diabetics with prior CHD or other risk factors
  like in ACCORD population, less stringent goals
  of around 7 might be appropriate.

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ADVANCE and VADT

• In light of ACCORD, a larger study, ADVANCE, in
  progress of 11,140 pts with T2DM also did an
  interim analysis reported February 14 but did not
  find any evidence of increased risks.
• These pts achieved the same HbA1c of 6.4 as
  achieved in the ACCORD intensive therapy arm, but
  ADVANCE pts had less severe diabetes--duration
  shorter (8 vs. 10 years) and somewhat lower HbA1c
  at baseline.
• It is possible that it is the intensity of
  treatment or rather than the HbA1c achieved which
  is the problem but that will need to be examined
  further.
• The U.S. VA Diabetes Trial, also examining the
  relation of intensive glycemic control to
  cardiovascular outcomes will report its results
  soon.
• The ADA plans to evaluate the results from all
  these studies before making further
  recommendations.

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Collaborative Atorvastatin Diabetes Study (CARDS)

• 2838 patients aged 40-75 with type 2 diabetes, no
  prior CVD, but at least 1 of the following
  retinopathy, albuminuria, smoking, or
  hypertension
• Randomization to 10 mg atorvastatin or placebo
• Mean follow-up 3.9 years
• Reduction in all CVD events of 37 (p0.001), all
  cause mortality 27 (p0.059). CHD events
  reduced 36 and stroke 48.

Colhoun HM et al., The Lancet 2004 364 685-696
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Relative Risk of Eventsin 4S Study
Placebo
Simvastatin
40
CAD Events
26.2

30
20
Patients ()
10
0
NFG
IFG
DM
Revascularization
25
16.6
16.7
20
15
Patients ()
10
5
0
NFG
IFG
DM
Total Mortality
Patients ()
NFG
IFG
DM
Adapted from Haffner et al. Arch Intern Med.
19991592661.
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Reduction in CHD Event Rates With Statin
Treatment (WOSCOPS)
Sattar N, et al. Circulation. 2003108414-419
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Are LDL and HDL Effects Additive?
2nd Order Relationship
Absolute Change in LDLHDL
0
10
20
30
40
50
60
70
80
0
ALLHAT
BIP
CDP
PROSPER
20
CARE, HPS
LIPID
VA HIT
DAIS
4S
HHS
40
CV Event RRR
WOSCOPS
AFCAPS/ TexCAPS
60
ASCOT
80
R2 0.8512
100
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Hypertension Optimal Treatment (HOT) Outcomes in
Patients With Diabetes
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Most CHD Events May be Preventable by Control of
Blood Pressure, HDL-C, LDL-C to Optimal Levels
in Persons with the Metabolic Syndrome (Wong et
al., Am J Cardiol 2003 91 1421-26)


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The endocannabinoid system

• An endogenous signaling system which contributes
  to physiologic regulation of energy balance, food
  intake, and lipid and glucose metabolism through
  both central and peripheral effects

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Effects of cannabinoid-1 receptor blocker
rimonabant on weight reduction and cardiovascular
risk factors over 1 year RIO Europe Study

• 1,507 pts with BMI 30 or 27 with dyslipidemia
  and/or hypertension randomized to placebo, 5mg or
  20 mg rimonabant, w/hypocaloric diet
• Weight loss at 1 year -3.4 kg w/5mg, -6.6 kg
  w/10 mg rimonabant vs. placebo (-1.8 kg)
• Rimonabant 20 mg produced greater improvements in
  waist circumference, HDL-C, triglycerides, LDL-C,
  insulin, and prevalence of metabolic syndrome
  (reduced by 34 w/placebo vs. 64.8 with
  rimonabant)

Van Gaal LF, et al. Lancet 2005 365 1389-97
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Metabolic Syndrome Lifestyle Management

• Obesity / weight management low fat high
  fiber diet resulting in 500-1000 calorie
  reduction per day to provide a 7-10 reduction on
  body weight over 6-12 mos, ideal goal BMI
• Physical activity at least 30, pref. 60 min
  moderate intensity on most or all days of the
  week as appropriate to individual
• Nutritional recommendations per ATP III
  guidelines low intake of saturated fats, trans
  fats, and cholesterol, reduced consumption of
  simple sugars, and increased intakes of fruits,
  vegetables, and whole grains are reasonable

Grundy SM, Hansen B, Smith SC, et al. Clinical
management of metabolic syndrome. Report of the
American Heart Association / National Heart,
Lung, and Blood Institute / American Diabetes
Association Conference on Scientific Issues
Related to Management. Circulation 2004 109
551-556
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Therapeutic Lifestyle ChangesNutrient
Composition of TLC Diet

• Nutrient Recommended Intake
• Saturated fat Less than 7 of total calories
• Polyunsaturated fat Up to 10 of total calories
• Monounsaturated fat Up to 20 of total calories
• Total fat 2535 of total calories
• Carbohydrate 5060 of total calories
• Fiber 2030 grams per day
• Protein Approximately 15 of total calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and
  expenditure to maintain desirable body
  weight/ prevent weight gain

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Effect of Mediterranean-style diet in the
metabolic syndrome

• 180 pts with metabolic syndrome randomized to
  Mediterranean-style vs. prudent diet for 2 years
• Those in intervention group lost more weight
  (-4kg) than those in the control group (0.6kg)
  (pIl-6.
• After 2 years, 40 pts in intervention group still
  had features of metabolic syndrome compared to 78
  pts in the control group

Esposito K et al. JAMA 2004 292(12) 1440-6.
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Therapeutic Goals and Recommendations for
Clinical Management of Metabolic Syndrome (Grundy
et al. Circulation 2005 112 (epub) Oct 18)
Dyslipidemia LDL-C, HDL-C, TG, non-HDL-C
Elevated Blood Pressure
Elevated Glucose
Prothrombotic and Proinflammatory States
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ABCs of Metabolic Syndrome Management
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ABCs of Metabolic Syndrome Management
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Goals for Elevated Glucose

• For IFG delay progression to type 2 diabetes for
  diabetes, HgbA1c
• For IFG encourage weight reduction and increased
  physical activity
• For type 2 diabetes, lifestyle therapy and if
  necessary, pharmacologic therapy to achieve near
  normal HgbA1c behaviors.
• Limited clinical trial data on treatment to
  reduce CVD events neither metformin or
  thiazolidinediones recommended just for
  prevention of diabetes because cost-effectiveness
  and long-term safety not yet documented.

Grundy et al. AHA/NHLBI scientific statement on
diagnosis and management of metabolic syndrome.
Circulation Oct 18, 2005 112 (e pub)