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Metabolic Syndrome, Diabetes, and Cardiovascular Disease ...
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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
Overview of Diabetes in the United States
Diabetes Prevalence, 1990-1998
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.
6.75.6
10.7
13.2
11.0 10.9
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
Men Women
Per
cen
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op
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NH Whites NH Blacks Mexican Americans
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<.001,***P<.0001
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Insulin Resistance
Hyperglycemia in Type 2 Diabetes Results From Three
Major Metabolic Defects
Relationship Between Obesity and
Insulin Resistance and Dyslipidemia
Insulin Resistance: Associated Conditions
New Cases of ESRD in the United States
New Cases of ESRD in the United States
by Cause and Ethnicity, 1998
Microalbuminuria
Cardiovascular Disease and Diabetes
Probability of Death From CHD in Patients With Type 2 Diabetes With
or Without Previous MI
Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)
109
20
11
9 63819
3*
30
0
2
4
6
8
10
Age-adjusted annual rate/1,000
Men Women
Total CVD
CHD Cardiac failure
Intermittent claudication
Stroke
Riskratio
P<0.001 for all values except *P<0.05.
Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.
The Metabolic Syndrome
InsulinResistance
Hypertension
Type 2 Diabetes
DisorderedFibrinolysis
ComplexDyslipidemia
TG, LDL
HDL
EndothelialDysfunction
SystemicInflammation
Athero-sclerosis
VisceralObesity
Adapted from the ADA. Diabetes Care. 1998;21:310-314;Pradhan AD et al. JAMA. 2001;286:327-334.
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. 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).
<40 mg/dL<50 mg/dL or Rx for ↓ HDL
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
MenWomen
100 mg/dL or Rx for ↑ glucoseFasting glucose130/85 mm Hg or on HTN RxBlood pressure
HDL-C150 mg/dL or Rx for ↑ TGTG
Abdominal obesity† (Waist circumference‡)
Defining LevelRisk Factor
International Diabetes Federation Definition:
Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or impaired fasting glucose
Back
Visceral AT
Subcutaneous AT
Front
Intra-abdominal (Visceral) FatThe dangerous inner fat!
Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994
Pre
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%)
P
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05
10
15
2025
3035
40
45
20-29 30-39 40-49 50-59 60-69 > 70
MenMenWomenWomen
Age (years)Age (years)Ford E et al. JAMA. 2002(287):356.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
0%
10%
20%
30%
40%
Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity
Pre
vale
nce
, %
MenFord ES et al. JAMA 2002;287:356-359.
Women
WhiteAfrican AmericanMexican AmericanOther
25%25%
16%16%
28%28%
21%21%23%23%
26%26%
36%36%
20%20%
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 (n=6255)(Malik and Wong, et al., Circulation 2004; 110: 1245-1250)
0
1
2
3
4
5
6
7
Rel
ativ
e R
isk
CHD Mortality CVD Mortality Total Mortality
None
MetS
Diabetes
CVD
CVD+Diabetes
* p<.05, ** p<.01, **** p<.0001 compared to none
*
***
***
***
**
***
***
***
******
***
Metabolic Syndrome, CVD Events, and Mortality
• European cohort studies (6156 men and 5356 women): Modified WHO definition of MetS associated with all-cause mortality (RR=1.44 [1.17-1.84] in men and 1.38 [1.02-1.87] in women) and CVD mortality (RR=2.26 [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 (p<0.01) of coronary/cerebrovascular events (Scuteri et al., Diab Care 2005; 28: 882-7)
Evidence Supporting Aggressive Glycemic
Control
Treatment of Type 2 Diabetes
Sites of Action of Therapeutic Options for
Type 2 Diabetes
DCCT: Effects of Intensive vs Conventional Glycemic Control
UKPDS: Design
UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment
UKPDS: Effects of Intensive (Metformin)
Treatment*
UKPDS: Effects of Glycemia Exposure
Over Time
UKPDS: Risk Reduction in Diabetes-
Related Complications (A1c)
Diabetes Prevention Program: Protocol Design
Diabetes Prevention Program: Reduction in Diabetes Incidence
Structures of Thiazolidinediones
Thiazolidinediones: Mechanism of Insulin
Sensitization
PPAR α vs. gamma
• PPAR α (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.
Thiazolidinediones:Rationale for Type 2 Diabetes
Therapy
ACTOS, an Insulin Sensitizer
Reduced Insulin Resistance Suggested by HOMA Analysis of
Pioglitazone Therapy
Improved β-Cell Response Suggested by HOMA Analysis of
Pioglitazone Therapy
Changes in A1c From Baseline in All Treated Patients
Endpoint Changes in Patients With
Lower Baseline A1c (Mean 9.0%)*
Change in FPG From Baseline in All Treated Patients
Change in Lipid Profile at Endpoint:
ACTOS 26-Week Monotherapy
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<0.0001).
• 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 2006;368:1096-105.
PERISCOPE:Comparison of Pioglitazone vs.
Glimepirideon Progression of Coronary
Atherosclerosisin Patients with Type 2 Diabetes
Steve E. Nissen, MDCleveland Clinic FoundationCleveland, Ohio
ACC Scientific Sessions, Late BreakerMonday March 31, 2008Chicago, Illinois
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.2008;299(13):1561-1573
543 patients with type 2 diabetes undergoing angiography for clinical indications
Glimepiride 1-4mg(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
Pioglitazone 15-45mg(titrated to maximally
tolerated dose)
PERISCOPEStudy Design
Nissen S. JAMA.2008;299(13):1561-1573
Pioglitazone
PERISCOPEPrimary Efficacy Parameter
Change in Percent Atheroma Volume (%)
-0.3
-0.1
0.1
0.3
0.5
0.7
0.9 Glimepiride (n=181)
Pioglitazone (n=179)
P<0.001
P=0.44
Change in PAV(%)
0.73
-0.16
Difference between groups P=0.002
Nissen S. JAMA.2008;299(13):1561-1573
0.0
-1.0
-2.0
-3.0
-4.0
-5.0
-6.0
-1.5
-5.5
Glimepiride Pioglitazone
Atheroma Thickness (mm) Atheroma Volume (mm3) Most Disease 10mm (mm3)
PERISCOPE
Intravascular Ultrasound. Secondary Endpoints
0.011
-0.011
0.015
0.01
0.005
0
-0.005
-0.01
-0.015
0.0
-0.5
-2.0
-3.0
-4.0
-5.0
-6.0
-2.1-2.0
P=0.006 P=0.06 P=0.93
Nissen S. JAMA.2008;299(13):1561-1573
PERISCOPEOther Adverse Events
Glimepiride (n=273)
Pioglitazone (n=270)
P Value
Hypoglycemia 37.0% 15.2% <0.001
Edema 11.0% 17.8% 0.02
Angina 12.1% 7.0% 0.05
BUN >30 mg/dL
4.8% 10.7% 0.01
Creatinine > 2.0 mg/dL
0.7% 1.1% 0.69
Hypertension 8.8% 4.8% 0.07
Bone Fractures 0% 3.0% 0.004
Change in Body Weight
+1.6kg +3.6kg <0.001
Nissen S. JAMA.2008;299(13):1561-1573
UKPDS: Effects of Tight vs Less-Tight Blood Pressure
Control
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 <6% vs. standard strategy for 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 <7% in most diabetics; in older diabetics with prior CHD or other risk factors like in ACCORD population, less stringent goals of around 7% might be appropriate.
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.
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% (p=0.001),
all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.
Colhoun HM et al., The Lancet 2004; 364: 685-696
Relative Risk of Eventsin 4S Study
Adapted from Haffner et al. Arch Intern Med. 1999;159:2661.
RR = 0.6895% CI = 0.59-0.79
P <0.001 n = 1631/1606
RR = 0.62 95% CI = 0.46-0.85 P <0.003 n = 335/343
NFG IFG DMRR = 0.58 95% CI = 0.41-0.80P <0.001 n = 232/251
RR = 0.67 95% CI = 0.55-0.80P <0.001 n = 1631/1606
RR = .57 95% CI = 0.37-.87P <0.01 n = 335/343
RR = 0.52 95% CI = 0.32-0.82P <0.005 n = 232/251
RR = 0.72 95% CI = 0.57-0.90P <0.005 n = 1631/1606
RR = 0.57 95% CI = 0.35-0.93 P <0.02 n = 335/343
16.4
7.7 7.312.810.4 13.1
05
10152025
RR = 0.79 95% CI = 0.49-1.27P <0.34 n = 232/251
NFG IFG DM
NFG IFG DM
Patients (%)
CAD Events
Revascularization
Total Mortality
21.1
11.5 10.2 11.616.6 16.7
05
10152025
Patients (%)
30.437.5
18.6 19.523.526.2
010203040
Patients (%)
Placebo Simvastatin
Reduction in CHD Event Rates With Statin Treatment
(WOSCOPS)
Sattar N, et al. Circulation. 2003;108:414-419
10.4
6.2
7.7
4.4
0
2
4
6
8
10
12
CH
D e
ven
t ra
te (
%)
Patients WithMetabolic Syndrome
Patients WithoutMetabolic Syndrome
PlaceboPravastatin
Are LDL and HDL Effects Additive?
R2 = 0.8512
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80
% Absolute Change in LDL+HDL
% C
V E
ven
t R
RR
HATS
FATS
FATS F/U
4SVA HIT DAIS
BIP
AFCAPS/TexCAPS
WOSCOPS
LIPIDCARE, HPS
HHS
CDP
ASCOT
ALLHAT
PROSPER
2nd Order Relationship
Hypertension Optimal Treatment (HOT): Outcomes in Patients
With Diabetes
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)
28.2
51.2 50.646.2
38.1
80.5 82.1
45.1
0
10
20
30
40
50
60
70
80
90
Men Women
Pro
po
rtio
n o
f C
HD
Ev
en
ts P
rev
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ted
(P
AR
%)
BP only HDL-C only LDL-C only All 3 factors
***
* p<0.05, ** p<0.01 compared to men
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
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
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 <25
• 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
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 25–35% of total calories• Carbohydrate 50–60% of total calories• Fiber 20–30 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
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) (p<0.01), and significant reductions in CRP and Il-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.
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
ABC’s of Metabolic Syndrome Management
Intervention Goals / Treatment
A Antiplatelet agent Treat all high-risk patients with low-dose aspirin (or clopidogrel in those with CVD if aspirin is contraindicated) and consider low-dose aspirin in moderately high-risk patients.
B BP Control Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes. Consider ACE-I or ARBs and low dose diuretics in combination rx.
ABC’s of Metabolic Syndrome ManagementIntervention Goals
C Cholesterol Management
LDL-C targets, ATP III guidelines
–High Risk: CHD, CHD risk equivalents (incl. >20% 10-year risk): <100 mg/dL (option <70 mg/dl if CVD present)
– Moderately High Risk (10-20% risk or subclinical disease) 2 RF: <130 mg/dL, option <100 mg/dL
– Moderate Risk (2+ RF, <10%) <130 mg/dL
-- Low Risk: 0-1 RF: <160 mg/dL
Non-HDL-C targets 30 mg/dL higher
HDL-C: >40 mg/dL (men)
>50 mg/dL (women)
TG: <150 mg/dL
Cigarette Smoking
Long term smoking cessation
Goals for Elevated Glucose
• For IFG delay progression to type 2 diabetes; for diabetes, HgbA1c <7.0%
• 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 <7%; modify other risk factors and 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)