CVD RISK WITH METABOLIC SYNROME and DIABETES

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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,Mis
  souri

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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
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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.
2002287356-359.
4

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

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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
hours TV per day
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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
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Walking the dog
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Causes of Mortality in Patients With Diabetes
Diabetes in America.. NIH No. 95-1468.
1995233-257.
10
CV Events in People With Diabetes Framingham
Heart Study 30-y Follow-up
10
Men
9
Women
11
Risk ratio
19
30
9
38
6
3
20
Total CVD
CHD
Cardiac failure
Intermittent claudication
Stroke
Age-adjusted annual rate/1,000
P lt .001 for all values except P lt .05
Wilson PWF, Kannel WB. In Ruderman N et al,
eds. Hyperglycemia, Diabetes, and Vascular
Disease. Oxford 1992.
11
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

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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) 2.43 (1.64-3.61)
RR (95 CI) 3.55 (1.96-6.43)
Cumulative Hazard ()
Follow-up (years)
Follow-up (years)
Follow-up (years)
Lakka H-M et al. JAMA. 20022882709-2716.
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JNC 7 CVD Risk Factors

• Hypertension
• Cigarette smoking
• Obesity (BMI gt30 kg/m2)
• Physical inactivity
• Dyslipidemia
• Diabetes mellitus
• Microalbuminuria
• estimated GFR lt60 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 20032892560
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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.
15
James Sowers. N Engl J Med. 2002.
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Markers of Inflammation Thrombosis
Vulnerable plaque
Activated Adipocytes, 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
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CV (Metabolic) Risk Factors in Diabetics Linked
to Vascular Dysfunction

• Microalbuminuria
• ?coagulation/?fibrinolysis
• Increased Inflamation
• (NASH)(fatty liver)
• ROS Generation

• Central obesity
• Insulin resistance
• ? Triglycerides
• ? HDL-C
• (Small Dense LDL particals)
• Absent nocturnal drop in BP/HR

? CV Oxidative Stress/ Impaired Endothelial
Function
Sowers J, Haffner S Hypertension 2002.
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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
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• How can we reduce the CVD risk in persons with
  Cardiometabolic Syndrome_at_ Diabetes Mellitus?

20
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

21
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
lt 120
120 -139
140 -159
160 -179
180 -199
gt 200
Systolic Blood Pressure (mm Hg)
Stamler J, et al. Diabetes Care. 199316434-444.
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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
lt120
120139
140159
160179
180199
200
Systolic Blood Pressure (mmHg)
Stamler J et al. Diabetes Care. 199316434444.
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Tight BP Control vs Tight Glucose Control
Any DM
Microvascular
Stroke
DM Death
Complications
End Point

0
10 -
20 -
Reduction in Risk ()
30 -
Tight Glucose Control
40 -
Tight BP Control
P lt 0.05
50 -
UKPDS Group. BMJ. 1998317703713.
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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. 199835117551762.
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Multiple Antihypertensive Agents are Needed to
Achieve Target BP
Target BP(mmHg)
No. of antihypertensive agents
Trial
1
2
3
4
McFarlane1 BP 130/85
ABCD DBP lt75
MDRD MAP lt92
HOT DBP lt80
AASK MAP lt92
UKPDS DBP lt85
DBPdiastolic blood pressure MAPmean arterial
pressure.
Bakris GL et al. Am J Kidney Dis.
200036646661. 1. McFarlane SI et al. Diabetes
Care. 200225718723.
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Key Points for Optimal Hypertension Management
lt130/80 mm Hg in diabetes or renal disease
lt140/90mm Hg
JNC 7BPGoals
JNC 7 recommends If SBP gt20 mm Hg, DBP gt10 mm Hg
over goal, consider initiating with 2-drug
combination
JNC 7 Report. Hypertension. 200342(6)1206-1252.
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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
r299.8
0
1984
1988
1992
1996
2000
2004
2008
United States Renal Data System. Annual data
report. 2000.
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CVD Risks that Cluster with Microalbuminuria

• Absent nocturnal drop in BP/HR
• Increased CV oxidative stress
• Impaired endothelial function
• Abnormal coagulation/ fibrinolytic profiles
• Left ventricular hypertrophy

• Central obesity
• Insulin resistance
• Low HDL cholesterol levels
• High triglyceride levels
• Small dense LDL particles
• Systolic hypertension
• Salt sensitivity
• Elevated CRP other inflammatory markers

• Microalbuminuria

Sowers and Haffner Hyp. 2002
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Proteinuria Is an Independent Risk Factor for
All-cause Mortality in NIDDM
Normoalbuminuria (n191)
Microalbuminuria (n86)
Probability of Survival
Macroalbuminuria (n51)
Plt0.01 normoalbuminuria vs microalbuminuria and
macroalbuminuria Plt0.05 microalbuminuria vs
macroalbuminuria
Years
Gall MA et al. Diabetes. 1995441303-1309.
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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. 2004140167-174.
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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
• (n6,217), microalbuminuria (n6,125)
• Metabolic syndrome as previously defined
• CKD as previously defined

Chen et al. Annals Intern Med. 2004140167-174.
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Multivariate Odds Ratio for CKD or
Microalbuminuria Based on Presence of Components
of the Metabolic Syndrome
Chen et al. Annals Intern Med. 2004140167-174.
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Greater Benefit on CV Events with in Patients
with Renal Insufficiency in HOPE .
Plt0.05



Hazard ratio
Primary outcome
MI
Stroke
CV death
All death
Hosp HF
Revasc
Mann JE et al.Ann Intern Med 2001
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Progression of Renal Disease
CV Events Death
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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

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Biochemical Results(AllHAT)
plt.05 compared to chlorthalidone Ann Intern
Med. 1999130461-470
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Development of Diabetes in ALLHAT
plt.05 compared to chlorthalidpone
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VALUE Incidence of New-onset Diabetes
23 Risk Reduction With Valsartan
P lt 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. 20043632022-2031.
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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

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LIFE New-Onset Diabetes
Intention-to-Treat
0.10
0.09
Atenolol (N3979)
0.08
Losartan (N4019)
0.07
0.06
End Point Rate
0.05
0.04
0.03
0.02
Adjusted Risk Reduction 25, Plt.001 Unadjusted
Risk Reduction 25, Plt.001
0.01
0.00
Study Month
0
6
12
18
24
30
36
42
48
54
60
66
Dahlöf. 2002.
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Prevention of Type 2 Diabetes by Inhibition of
the RASResults

• Study Treatment 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 lt
0.00001)
0.78 0.72, 0.84
Scheen A. Diabetes 200453(S2)A169.
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DREAM NAVIGATOR

• Valsartan
• Nateglinide 22

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Steno-2 Multifactorial Intervention on Macro
and Microvascular Outcomes
160 patients with type 2 diabetes/microalbumin
uria
Conventional therapy
53 risk reduction P0.01
Composite CVD outcome ()
Intensive therapy
Follow-up (months)
Conventional therapy better
Intensive therapy better
CV death, MI, stroke, revascularization,
amputation Total fat intake lt30, gt30 min
excersise 3-5 x weekly, ACE inhibitor, ASA, BP
lt130/80 mm Hg, total-C lt175 , TG lt150 mg/dL, A1c
lt 6.5 N Engl J Med. 20033483831393.
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Prevention of CVD in Diabetes

• No Smoking
• ASA
• Lipid Control (Statin)
• LDL lt70, HDL gt45-50, TG lt150 mg/dl (HMG
  CoA Reductase Inhibitors)
• Blood Pressure lt130/80 mm Hg
• Glycemic Control A1Clt7
• Dash Diet and increased Aerobic Excercise

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Metabolic factors associated with CVD in
postprandial state
Endotheial Dysfunction ? Platelet
activation ? Fibrinolytic resistance
? coagulability
?Postprandial Glycemia ?Postprandial lipemia
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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
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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. 1999341410-418.
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ANG II - SUPEROXIDE PRODUCTION IN HUMAN
VASCULATURE.
Human Internal Mammary Arteries incubated with
Angiotensin II
02-

plt 0.01
N 11
N 11
N 15
.
Ang II ARB
Ang II
CONTROL
Circ. 20001012206-2212
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Role of the NADPH oxidase and p47phox in Ang
II-induced Generation of ROS.
Gp91 NOX
p22
AT1R
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CV Risk Factors in Diabetic and
Cardiometabolic-Syndrome-Linked Vascular
Dysfunction

• 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)

• Microalbuminuria
• Impaired Endothelial Mediated Vasodilation
• Abnormal coagulation /fibrinolytic profiles
• RAS-Mediated ROS Inflammation
• LVH,CHF,Stroke

? CV Oxidative Stress / Impaired Endothelial
Function

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• How Do Statins inhibitors reduce Stroke?
• Are there non-lipid lowering Effects of Statins

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Summary

• Patients with diabetes/ dyslipidemia have a high
  risk of CVD, and should be treated
  aggressively- - LDLlt 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