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
3
Diabetes Prevalence, 1990-1998
4
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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Natural History of Type 2 Diabetes
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Development of Type 2 Diabetes
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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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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).
21
International Diabetes Federation Definition
Abdominal obesity plus two other components
elevated BP, low HDL, elevated TG, or impaired
fasting glucose
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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
36
28
26
25
23
21
20
Prevalence,
16
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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ThiazolidinedionesRationale for Type 2 Diabetes
Therapy
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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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PROACTIVE Study Secondary Prevention of
Macrovascular Events in Persons with Diabetes
from Pioglitazone

• 5238 patients with type 2 diabetes who had
  evidence of macrovascular disease assigned to
  oral pioglitazone titrated from 15 mg to 45 mg
  (n2605) or matching placebo (n2633), taken
  w/existing drugs.
• Primary endpoint combined all-cause mortality,
  non fatal myocardial infarction (including silent
  myocardial infarction), stroke, acute coronary
  syndrome, endovascular or surgical intervention
  in the coronary or leg arteries, and amputation
  above the ankle.
• Over an average of 34.5 months. 514 of 2605
  patients in the pioglitazone group and 572 of
  2633 patients in the placebo group achieved the
  primary endpoint (HR 0.90, 95 CI 0.80-1.02,
  p0.095).

Lancet 2005 366 1279-89
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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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UKPDS Effects of Tight vs Less-Tight Blood
Pressure Control
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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)
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ADA 2007 Algorithm for Glycemic Management of
Type 2 DM (Diabetes Care, 2007)
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Rationale for the ADA Goal of HbA1c UKPDS Results

• On the basis of the DCCT and UKPDS, the ADA
  recommended the HbA1c goal to be adults with diabetes
• DCCT involving Type 1 diabetes patients showed an
  approximately 60 reduction in development or
  progression of diabetic retinopathy, nephropathy,
  and neuropathy between intensively treated pts
  (goal A1cgroup (A1c9) over 6.5 Years (NEJM 1993 329
  977-986). A 9-year follow-up of this cohort has
  now shown a 42 reduction (p0.02) in CVD
  outcomes and a 57 reduction (p0.02) in risk of
  nonfatal MI, stroke, or CVD death compared to
  those in the standard arm (NEJM 2005 353
  2643-2653).

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Rationale for HbA1cEffect of Intensive Glycemic Control

• The UKPDS involving newly diagnosed patients with
  Type 2 diabetes followed for 10 years showed
  microvascular complications to be reduced by 25
  in the intensive control (mean A1c7) vs.
  conventional arm (mean A1c7.9). There was a
  nonsignificant (p0.052) reduction in
  cardiovascular complications (Lancet 1998 352
  854-65).
• Epidemiologic analysis of the UKPDS cohort
  showed, however, that for every percentage point
  reduction in A1c level, there was a statistically
  significant 18 reduction in CVD events with no
  glycemic threshold.
• Several large-scale clinical trials have since
  been launched to better address the question of
  intensive glycemic control on CVD outcomes.

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ACCORD Is too aggressive lowering of HbA1c
harmful?

• NHLBI-sponsored ACCORD study randomized 10,251
  participants with T2DM with hx of CVD,
  significant CVD risk or 2 risk factors and
  tested control of HbA1c to strategy for HbA1c 7-7.9.
• Median HbA1c achieved 6.4 vs. 7.5.
• The primary outcome of MI, stroke, or CVD death
  was reduced in the intensive vs. control group
  due to fewer nonfatal MIs, but was not
  significant (HR0.90, p0.16)
• But the trial was stopped early due to increased
  all-cause mortality (5.0 vs. 4.0, HR1.2,
  pintensive arm, despite a reduction in non-fatal
  MI (3.6 vs. 4.6). Major hypoglycemia
  requiring assistance was also significantly
  higher (3.1 vs. 1.0).

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ACCORD (cont.)

• But in those without a prior CVD event and who
  had a baseline HbA1c reduction in the primary CVD outcome suggesting a
  possible benefit of intensive therapy this
  subgroup of T2DM pts.
• In both arms of the study, those with vs. without
  severe hypoglycemia had a higher mortality.

NEJM 2008 358 2545-9
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ADVANCE

• A larger study, ADVANCE, in 11,140 pts with T2DM
  done in Europe, Australia/NZ, Canada, and Asia
  did not find an increased risk (8.9 vs. 9.6 for
  total deaths, 4.5 vs. 5.2 for CVD death).
• The primary intensive therapy was the
  sulfonylurea gliclizide with addl medications to
  achieve HbA1c
• 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 8
  vs. 10 years and somewhat lower HbA1c at
  baseline.
• A significant reduction in the primary endpoint
  of combined microvascular and macrosvascular
  events was achieved (HR0.90, p0.01) mainly due
  to reduction in microvascular outcomes
  (macrovascular endpoints not reduced,
  HR0.94,p0.32)
• This study also showed those without prior
  macrovascular disease to show a benefit (14 risk
  reduction, pNo benefit seen in those with prior disease.

NEJM 2008 358 2560-2572)
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ACCORD vs. ADVANCE

• One possible explanation of the difference in
  findings between the two studies was that the
  rate of HbA1c reduction was much greater in
  ACCORD (1.4 reduction within 4 months than in
  ADVANCE 0.5 at 6 months and 0.6 at 12 months).
• Experts speculate that more aggressive treatment
  can more likely lead to hypoglycemia requiring
  attention, as was clearly the case in ACCORD.

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VA Diabetes Trial (VADT)

• 1,791 veterans, 97 men, 62 white, mean age 60
  years), 7.5 year intervention
• Intensive HbA1c
• Baseline glycemic control worst of the recent
  trials at 9.5 40 had prior CVD events, 80 had
  HTN, 50 had dyslpidemia, most were obese

N Engl J Med. 2009 Jan 8360(2)129-39
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VADT (cont.)

• No significant difference in primary outcome of
  CVD events 263 in standard control and 231 in
  intensive control, HR0.88, p0.12.
• More CVD deaths in the intensive arm compared to
  the standard arm (38 vs. 29, n.s.)
• Most important finding was that severe
  hypoglycemia (impairment/loss of consciousness
  within prior 3 months) was a power predictor of
  CVD events (HR2.1, p0.02) and occurred in 21
  of intensive control and 10 of standard control
  subjects.
• An ancillary study showed that the primary CVD
  endpoint was significantly reduced in those with
  low, but not high baseline coronary calcium
  scores.

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Why no benefit from these trials?

• Other CVD risk factors were treated to a moderate
  or high degree, so had lower overall rates of CVD
  in the standard arm than originally predicted.
• The additive benefits of intensive glycemic
  control may be smaller and more difficult to show
  in the background of aggressive treatment of
  other risk factors.
• The three trials compared intensive vs.
  conventional treatment in the flatter part of the
  observational glycemic-CVD risk curve.
• The trials were also conducted in persons with
  established diabetes in combination whether with
  CVD or multiple risk factors subset analyses of
  the 3 trials suggested a significant benefit in
  those without known CVD, or with a shorter
  duration of diabetes or lower A1c upon entry.

Circulation 2009 119 351-357
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ADA / AHA / ACC Statement Recommendations(Circula
tion 2009 119 351-357)

• Findings from ACCORD, ADVANCE, and VADT do not
  suggest need for major changes in targets, but
  additionally clarification for individualizing
  therapy.
• General goal of non-complicated DM pts based on benefits seen
  from DCCT and UKPDS for microvascular disease
  (ACC/AHA Class Ia Level of Evidence A) and
  based on follow-up of these trials, macrovascular
  disease (ADA B-Level, ACC/AHA Class IIb - A).
• An additional benefit for microvascular disease
  may be obtained from even lower goals if they can
  be achieved without significant hypoglycemia (ADA
  B-Level, ACC/AHA, Class IIa C).
• Less stringent goals may be appropriate for those
  with a hx of severe hypoglycemia, difficult to
  control DM pts, and those with advanced micro or
  macrovascular complications or major
  comorbidities (ADA, C-level recommendation,
  ACC/AHA, Class IIa C).