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CVD RISK WITH METABOLIC SYNROME and DIABETES. James R. Sowers, M.D. Professor of Medicine , Physiology and Pharmacology Director, Diabetes and Cardiovascular Research Center University Of Missouri Medical Center,Columbia,Missouri. Over the next 24 hours:.

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cvd risk with metabolic synrome and diabetes

CVD RISK WITH METABOLIC SYNROME and DIABETES

James R. Sowers, M.D.

Professor of Medicine , Physiology and Pharmacology

Director, Diabetes and Cardiovascular Research Center

University Of Missouri Medical Center,Columbia,Missouri

over the next 24 hours
Over the next 24 hours:
  • 2200 diabetics will be newly-diagnosed
  • 512 diabetics will die
  • 66 diabetics will go blind
  • 77 diabetics will be diagnosed with ESRD
  • 153 diabetes-related amputationsi

Source: American Diabetes Association

slide3

45

40

Men (n=4265)

Women (n=4559)

35

30

25

20

15

10

5

0

20-29

30-39

40-49

50-59

60-69

70

?

Metabolic Syndrome: Prevalence Increases With Age

47 million or 23% of US Adults Have Metabolic Syndrome

Prevalence, %

Age, yr

Adapted from: Ford ES, et al. JAMA. 2002;287:356-359.

slide4
What Causes the Rising Incidence of Diabetics and the metabolic syndrome in the USA and Other Countries?
slide5

Is It Gluttony or Sloth??

Jack in the Box

Bacon Ultimate Cheeseburger

1020 Calories

71 grams of Fat

Average American

child or teen

watches 3-4 hoursTV per day

french freedom fries
FRENCH(Freedom ?) FRIES

20 Years Ago

Today

210 Calories

2.4 ounces

610 Calories

6.9 ounces

How many calories are

in these fries?

Calorie Difference: 400 Calories

How to burn* 400 calories:

Walk 2 hr 20 Minutes

*Based on 130 pound person

causes of mortality in patients with diabetes

Pneumonia/Influenza

Other

MalignantNeoplasms

5%

4%

13%

55%

13%

10%

Diabetes

STROKE

Heart Disease

Causes of Mortality in Patients With Diabetes

Diabetes in America.. NIH No. 95-1468. 1995:233-257.

slide10

CV Events in People With Diabetes:

Framingham Heart Study – 30-y Follow-up

10

Men

9

Women

11

Risk ratio

19

30

38

9

6

3*

20

Total CVD

CHD

Cardiac failure

Intermittent claudication

Stroke

Age-adjusted annual rate/1,000

P < .001 for all values except *P < .05

Wilson PWF, Kannel WB. In: Ruderman N et al, eds.

Hyperglycemia, Diabetes, and Vascular Disease. Oxford; 1992.

slide11

Changing Rate of Stroke

  • Stroke rates are not falling
  • Incidence level or increasing
    • Similar to CHF and atrial fibrillation
  • May be due to increased DIABETES rates
  • Increasing number of elderly with advanced vascular disease
  • Increasing incidence + aging population =

20%-40% increase in the number of strokes/y

adverse prognostic implications of cardiovascular metabolic syndrome
Adverse Prognostic Implications of Cardiovascular Metabolic Syndrome

Population-based observational study in 1209 men

Metabolic syndrome present

Metabolic syndrome absent

Coronary heart disease mortality

Cardiovascular disease mortality

All-cause mortality

RR (95% CI):

3.77 (1.74-8.17)

RR (95% CI):

3.55 (1.96-6.43)

RR (95% CI):

2.43 (1.64-3.61)

Cumulative Hazard (%)

Follow-up (years)

Follow-up (years)

Follow-up (years)

Lakka H-M et al. JAMA. 2002;288:2709-2716.

jnc 7 cvd risk factors
JNC 7: CVD Risk Factors
  • Hypertension*
  • Cigarette smoking
  • Obesity* (BMI >30 kg/m2)
  • Physical inactivity
  • Dyslipidemia*
  • Diabetes mellitus*
  • Microalbuminuria
  • estimated GFR <60 ml/min
  • Age (older than 55 for men, 65 for women)
  • Family history of premature CVD

(men under age 55 or women under age 65)

*Components of the metabolic syndrome.

JAMA 2003:289:2560

slide14

Impaired Endothelium-Dependent Vasodilation in People at Risk for Type 2 Diabetes

16

13.7

12

10.5

9.8

8.4

8

% Increase over baseline of brachial artery diameter

4

0

Relatives**

IGT

Diabetes

Control

1st-Degree relatives

*C vs R, IGT, D

**1 or both parents

Caballero AE et al. Diabetes. 1999; 48: 1856-1862.

slide16

Lumen

Lumen

Cytokines

TNF

IL-1

IL6

Liver

Endothelial Cells

Endothelial Cells

Markers of Inflammation & Thrombosis

“Vulnerable” plaque

ActivatedAdipocytes,

T-Lymphocytes, Macrophages

Endothelial Cell

Activation

PAI-1 

t-PA 

 ICAM, VCAM

selectins

CRP

SAA

Gabay C, NEJM 1999; 340: 448

Libby P, Circulation 1999; 100: 1148

cv metabolic risk factors in diabetics linked to vascular dysfunction
Central obesity

Insulin resistance

 Triglycerides

 HDL-C

(Small Dense LDL particals)

Absent nocturnal drop in BP/HR

Microalbuminuria

coagulation/fibrinolysis

Increased Inflamation

(NASH)(fatty liver)

ROS Generation

CV (Metabolic) Risk Factors in Diabetics Linked to Vascular Dysfunction

 CV Oxidative Stress/

Impaired Endothelial Function

Sowers J,Haffner S: Hypertension2002.

chd mortality according to risk factor status
CHD Mortality According to Risk-Factor Status

140

120

100

80

60

40

20

0

Non-Diabetic

Diabetic

CHD Death

Rate* per

10,000

Person-Years

None

One

Two

Three

Risk Factors

*Age adjusted

Stamler et al, Diabetes Care 1993

slide19
How can we reduce the CVD risk in persons with Cardiometabolic Syndrome@ Diabetes Mellitus?
slide20

Strategies for Reducing Macrovascular Complications

Prevention proven by intervention

  • Dyslipidemia
  • Hypertension
  • Antiplatelet therapy

Prevention suggested by epidemiology

  • Disorders of Thrombolysis
  • Endothelial disorders
  • Inflammation/Oxidative Stress
association of sbp and cvd death in type 2 diabetes
Association of SBP and CVD Death in Type 2 Diabetes

250

Non-diabetic

225

Diabetic

200

175

150

Cardiovascular Mortality Rate/10,000 Person-Yr.

125

100

75

50

25

0

< 120

120 -139

140 -159

160 -179

180 -199

> 200

Systolic Blood Pressure (mm Hg)

Stamler J, et al. Diabetes Care. 1993;16:434-444.

association of sbp and cvd death in type 2 diabetes22
Association of SBP and CVD Death in Type 2 Diabetes

250

Non Diabetic

225

Diabetic

200

175

150

Cardiovascular Mortality Rateper 10,000 Person-Years

125

100

75

50

25

0

<120

120–139

140–159

160–179

180–199

≥200

Systolic Blood Pressure (mmHg)

Stamler J et al. Diabetes Care. 1993;16:434–444.

tight bp control vs tight glucose control
Tight BP Control vs Tight Glucose Control

Microvascular

Any DM

Stroke

DM Death

Complications

End Point

0

–10 -

–20 -

Reduction in Risk (%)

–30 -

Tight Glucose Control

–40 -

Tight BP Control

*P < 0.05

–50 -

UKPDS Group. BMJ. 1998:317;703–713.

slide24

25

20

15

10

5

0

HOT: Greatest Benefit at ≤80 mmHg in Diabetes and Hypertension

*

*P = 0.005

24.4

*

18.6

Events per1,000 Patient-Years

11.9

≤90 mmHg

≤85 mmHg

≤80 mmHg

Hansson L et al. Lancet. 1998;351:1755–1762.

slide25

Multiple Antihypertensive Agents are Needed to Achieve Target BP

Trial

Target BP(mmHg)

No. of antihypertensive agents

1

2

3

4

McFarlane1BP 130/85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

AASK MAP <92

UKPDS DBP <85

DBP=diastolic blood pressure; MAP=mean arterial pressure.

Bakris GL et al. Am J Kidney Dis. 2000;36:646–661.

1. McFarlane SI et al. Diabetes Care. 2002;25;718–723.

key points for optimal hypertension management
Key Points for Optimal Hypertension Management

<140/90mm Hg

<130/80 mm Hg in diabetes or renal disease

JNC 7BPGoals

  • JNC 7 recommends:
  • If SBP >20 mm Hg, DBP >10 mm Hg over goal,
  • consider initiating with 2-drug combination

JNC 7 Report. Hypertension. 2003;42(6):1206-1252.

28

diabetes most common cause of esrd

Other

Glomerulonephritis

10%

13%

No. of patients

Diabetes

Hypertension

Projection

27%

95% CI

Diabetes: Most Common Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

700

600

50.1%

500

No. of dialysis patients (thousands)

400

520,240

300

281,355

200

243,524

100

r2=99.8%

0

1984

1988

1992

1996

2004

2000

2008

United States Renal Data System. Annual data report. 2000.

cvd risks that cluster with microalbuminuria
Central obesity

Insulin resistance

Low HDL cholesterol levels

High triglyceride levels

Small dense LDL particles

Systolic hypertension

Salt sensitivity

Elevated CRP & other inflammatory markers

Absent nocturnal drop in BP/HR

Increased CV oxidative stress

Impaired endothelial function

Abnormal coagulation/ fibrinolytic profiles

Left ventricular hypertrophy

CVD Risks that Cluster with Microalbuminuria
  • Microalbuminuria

Sowers and Haffner Hyp. 2002

proteinuria is an independent risk factor for all cause mortality in niddm
Proteinuria Is an Independent Risk Factor for All-cause Mortality in NIDDM

Normoalbuminuria

(n=191)

Microalbuminuria

(n=86)

Probability of Survival

Macroalbuminuria

(n=51)

P<0.01 normoalbuminuria vs microalbuminuria and macroalbuminuria

P<0.05 microalbuminuria vs macroalbuminuria

Years

Gall MA et al. Diabetes. 1995;44:1303-1309.

metabolic syndrome ckd defined
Metabolic Syndrome/CKD Defined
  • Metabolic syndrome is defined as the presence of 3 or more of the following risk factors
    • HTN
    • low HDL-C
    • high triglycerides
    • elevated glucose
    • abdominal obesity
  • CKD is defined as estimated GFR below 60 mL/min/1.73 m2, microalbuminuria(30 mg/g creatinine )

Chen et al. Annals Intern Med. 2004;140:167-174.

metabolic syndrome and chronic kidney disease microalbuminuria in us adults
Metabolic Syndrome and Chronic Kidney Disease/Microalbuminuria in US Adults
  • Metabolic syndrome is a common risk factor for CVD
  • Cross sectional analysis of NHANES III
  • Patients greater than 20 years of age, CKD

(n=6,217), microalbuminuria (n=6,125)

  • Metabolic syndrome as previously defined
  • CKD as previously defined

Chen et al. Annals Intern Med. 2004;140:167-174.

slide33
Multivariate Odds Ratio for CKD or Microalbuminuria Based on Presence of Components of the Metabolic Syndrome

Chen et al. Annals Intern Med. 2004;140:167-174.

slide34

Greater Benefit on CV Events with in Patients with Renal Insufficiency in HOPE .

*P<0.05

*

*

*

Hazard ratio

Primary

outcome

MI

Stroke

CV

death

All

death

Hosp HF

Revasc

Mann JE et al.Ann Intern Med 2001

progression of renal disease

Microalbuminuria

Overt Proteinuria

Doubling of Creatinine

End Stage Renal Disease

Progression of Renal Disease

CV Events

Death

slide36

BP(ACE/ARB)- Reduction for Renal Protection

Hemodynamic Effects

  • Reduction in systemic BP
  • Reduction in glomerular capillary pressure because of efferent glomerular arteriolar dilation
  • Reduction in proteinuria

Nonhemodynamic

  • Inhibition of macrophage/monocyte infiltration
  • Reduction in Inflammation
  • Reduction in Oxidative Stress
biochemical results allhat
Biochemical Results(AllHAT)

* p<.05 compared to chlorthalidone

† Ann Intern Med. 1999;130:461-470

development of diabetes in allhat
Development of Diabetes in ALLHAT

*p<.05 compared to chlorthalidpone

slide39

18

16

14

12

10

8

6

4

2

0

VALUE: Incidence of New-onset Diabetes

23% Risk Reduction With Valsartan

P < 0.0001

New-Onset Diabetes (% of patients in treatment group)

16.4%

13.1%

Valsartan-based Regimen

(n = 5094)

Amlodipine-based Regimen

(n = 5074)

Julius S, et al. Lancet. 2004;363:2022-2031.

slide40

HOPE/HOPE-TOO: Development of diabetes

New Diabetes - All Patients

HOPE Study Ends

0.12

Ramipril

0.10

Placebo

0.08

Hazard

0.06

0.04

ALL: RR: 0.69, CI: (0.57-0.83)

0.02

CONT: RR: 0.70, CI: (0.57-0.86)

0.0

Years

1

2

3

4

5

6

7

Bosch J. European Society of Cardiology C 2003. Vienna, Austria

life new onset diabetes
LIFE: New-Onset Diabetes

Intention-to-Treat

0.10

0.09

Atenolol (N=3979)

0.08

Losartan (N=4019)

0.07

0.06

End Point Rate

0.05

0.04

0.03

0.02

Adjusted Risk Reduction 25%, P<.001

Unadjusted Risk Reduction 25%, P<.001

0.01

0.00

Study Month

0

6

12

18

24

30

36

42

48

54

60

66

Dahlöf. 2002.

prevention of type 2 diabetes by inhibition of the ras results

0.1 0.2 0.5 1 2 5 10

Favors Treatment Favors Control

Prevention of Type 2 Diabetes by Inhibition of the RASResults
  • StudyTreatment Control RR (fixed) 95% CI RR (fixed) 95% CI

ALLHAT 2002 119/5840 302/9733

ALPINE 2003 1/196 8/196

CAPP 1999 227/5184 280/5229

CHARM 2003 163/2715 202/2721

HOPE 102/2837 155/2883

LIFE 2002 241/4006 319/3592

SCOPE 2003 99/2160 125/2170

SOLVD 2003 9/153 31/138

STOP-HTN-2 1999 99/1969 97/1961

.66 [0.53, 0.81]

0.13 [0.02, 0.97]

0.09 [ 0.70, 1.03]

0.01 [0.66, 0.97]

0.69 [0.52, 0.85]

0.75 [0.64, 0.88]

0.81 [0.62, 1.06]

0.26 [0.13, 0.53]

0.95 [0.72, 1.26]

Total (95% CI) 25060 29023

Total events 1158 (Treatment), 1609 (Control)

Test for heterogeneity Chi2 =22.39, df = 8 (p = 0.004),

P = 64.3%

Test for overall effect Z = 6.73 (p < 0.00001)

0.78 [0.72, 0.84]

Scheen A. Diabetes 2004;53(S2);A169.

dream navigator
DREAM NAVIGATOR
  • Valsartan
  • Nateglinide 2#2
steno 2 multifactorial intervention on macro and microvascular outcomes
Steno-2: Multifactorial Intervention on Macro and Microvascular Outcomes

160 patients with type 2 diabetes/microalbuminuria

Conventional therapy

53% risk reduction P=0.01

Composite CVD outcome* (%)

Intensive therapy†

Follow-up (months)

Conventional therapy better

Intensive therapy better

*CV death, MI, stroke, revascularization, amputation

†Total fat intake <30%, >30% min excersise 3-5 x weekly, ACE inhibitor, ASA, BP <130/80 mm Hg, total-C <175 , TG <150 mg/dL, A1c < 6.5%

N Engl J Med. 2003;348:383–1393.

prevention of cvd in diabetes
Prevention of CVD in Diabetes
  • No Smoking
  • ASA
  • Lipid Control (Statin) +

LDL <70, HDL >45-50, TG <150 mg/dl (HMG CoA Reductase Inhibitors)

  • Blood Pressure <130/80 mm Hg
  • Glycemic Control: A1C<7%
  • Dash Diet and increased Aerobic Excercise
slide47

Metabolic factors associated with CVD in postprandial state

Endotheial Dysfunction

 Platelet activation

 Fibrinolytic resistance

 coagulability

Postprandial Glycemia

Postprandial lipemia

slide48

Ins/IGF-1 receptor

Glucose Transport

PO4

MAP kinase

AKT

IRS-1

(-)

P13-K

Na-K ATPase

NOS gene / expression & incresed glucose transport

(-)ROS?

(+)

Mitogenesis, hypertrophy & remodeling

Ang II

slide49

25

20

15

10

5

0

VA-HIT: Increasing HDL-C

Reduces Risk of CV Death

RRR 22%

(95% CI, 7-34; P=.006)

Placebo

Cumulative

incidence

(%)

Gemfibrozil

0

1

2

3

4

5

6

Year

Rubins HB et al. N Engl J Med. 1999;341:410-418.

ang ii superoxide production in human vasculature
ANG II - SUPEROXIDE PRODUCTION IN HUMAN VASCULATURE.

Human Internal Mammary Arteries incubated with Angiotensin II

02-

*

p< 0.01

N = 11

N = 11

N = 15

.

Ang II

Ang II + ARB

CONTROL

Circ. 2000;101:2206-2212

role of the nadph oxidase and p47phox in ang ii induced generation of ros

O2•-

O2

e-

Ang II

NAD(P)H

p47

p67?

NADP

Rac

Rac

p47

P67?

Role of the NADPH oxidase and p47phox in Ang II-induced Generation of ROS.

Gp91

NOX

p22

AT1R

cv risk factors in diabetic and cardiometabolic syndrome linked vascular dysfunction
CV Risk Factors in Diabetic and Cardiometabolic-Syndrome-Linked Vascular Dysfunction
  • Microalbuminuria
  • Impaired Endothelial Mediated Vasodilation
  • Abnormal coagulation /fibrinolytic profiles
  • RAS-Mediated ROS Inflammation
    • LVH,CHF,Stroke
  • Central obesity
  • Insulin resistance
  •  LDL-C
  •  Triglycerides
  •  HDL-C
  • Small Dense LDL particles
  • Absent nocturnal drop in BP and heart rate
  • Non-Alcoholic Fatty Liver (NASH)

 CV Oxidative Stress / Impaired Endothelial Function

slide53
How Do Statins inhibitors reduce Stroke?

Are there non-lipid lowering Effects of Statins

summary
Summary
  • Patients with diabetes/ dyslipidemia have a high risk of CVD, and should be treated aggressively- - LDL< 70mg/dl.
  • In clinical trials:
    • HPS results showed significant benefit from lipid-lowering, including nephropathy(All LDL levels)
    • CARDS Benefits in diabetic patients striking-Stroke Reduction 48% with Atorvastatin Rx
    • ASCOT LLA: incidence of nonfatal MI and fatal CHD lower by 36% in atorvastatin group
    • STENO-2: intensive intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduced the risk of CV and microvascular events by 50%