Over the next 24 hours

1
Over the next 24 hours

• 4110 diabetic patients newly diagnosed
• 614 diabetic patients will die
• 66 diabetic patients will go blind
• 122 diabetic patients diagnosed with ESRD
• 225 diabetes-related amputations

The Epidemic Called Diabetes
http//www.diabetes.org/uedocuments/NationalDiabet
esFactSheetRev.pdf. Accessed May 11, 2006.
2
Lifetime Risk for Diabetes in the US
For individuals born in 2000 Males
32.8 Females 38.5 Estimated loss of life
expectancy if diagnosed at age 40 Males 11.6
years Females 14.3 years
Narayan JAMA 2003
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Diabetic Patients High Risk for Cardiovascular
Mortality
The greatest cause of mortality in type 2
diabetes is atherosclerotic vascular disease .

• Diabetic patients have
• (2- to 4-fold greater risk of CVD)
• Poorer prognosis for survival
• 3-fold greater mortality from stroke
• Greater risk of permanent brain damage and
  recurrent stroke
• 3-fold risk of sudden death

Sowers JR 2006
4
Diabetes Just the Tip of the Iceberg of the
CardioMetabolic Syndrome
5
The Ticking Clock ? CV Risk Before ? Glucose
Nurses Health Study 20-year follow-up of
117,629 women
6
5.0
3.7
4
Relative risk ofMI orstroke
2.8
2
1.0
0
No diabetesthroughoutstudy
Risk of event prior to diabetesdiagnosis
Risk of eventafter diabetesdiagnosis
Diabetesat baseline
Hu FB, et al. Diabetes Care. 2002251129-1134.
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Metabolic Syndrome

• Convenient Packaging or True Syndrome of
  Specific Risk?

7
What causes the rising incidence of diabetes
mellitus (DM) and the cardiometabolic syndrome ?
8
Insulin ResistanceInherited and Acquired
Influences
Acquired
Inherited

• Overeating
• Overweight
• Inactivity
• Aging
• Medications
• Illness
• Hyperglycemia/
• glucose toxicity
• Elevated FFAs

• Rare Mutations
• Insulin receptor
• Glucose transporter
• Signaling proteins
• Common Forms
• Largely unidentified

INSULIN RESISTANCE
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Adults With Diagnosed Diabetes
1990
No dataavailable
Less than 4
4-6
Above 6
Includes women with a history of gestational
diabetes.
Mokdad AH, et al. Diabetes Care.
200023(9)1278-1283.
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Adults With Diagnosed Diabetes
2000
4-6
Above 6
Includes women with a history of gestational
diabetes.
Mokdad AH, et al. Diabetes Care.
200023(9)1278-1283.
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National Center for Health Statistics, Centers
for Disease Control and Prevention, CDC.gov
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FRENCH (Freedom?) FRIES
Today
20 Years Ago
210 Calories 2.4 ounces
How many calories are in these fries?
610 Calories 6.9 ounces
Calorie Difference 400 Calories
How to burn 400 calories Walk 2 hr 20 Minutes
Based on 130 pound person.
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JNC 7 CVD Risk Factors

• Hypertension
• Cigarette smoking
• Obesity (BMI gt30 kg/m2)
• Physical inactivity
• Dyslipidemia Components
  of CMS
• Diabetes mellitus
• Microalbuminuria
• Estimated GFR lt60 ml/min
• Age (gt55 yr for men, gt65 yr for women)
• Family history of premature CVD (men lt55 yr or
  women lt65 yr)

BMI body mass index GFR glomerular
filtration rate
JAMA. 20032892560-2572.
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Impaired Endothelium-dependent Vasodilation in
People at Risk for T2 DM

Increase over baseline of brachial artery
diameter ()

1st-degree relatives
Plt.01 versus other three arms.One or both
parents. IGTimpaired glucose tolerance.
Caballero AE et al. Diabetes. 1999481856-1862.
16

• What Causes Endothelial Dysfunction in Persons
  with Cardiometabolic Syndrome and Diabetes
  Mellitus?

17
Sowers JR. N Engl J Med. 20023461999-2001.
18
Role of the NADPH Oxidase and Angiotensin II
Generation of ROS
Ang II
Gp91 NOX
p22
AT1R
p47
p67?
p47
P67?
ANGangiotensin ROSreactive oxygen species.
19
Arterial Superoxide Production
Human internal mammary arteries incubated with
Ang II ARB
1500

1000
Superoxide anion,pmol/min/mg tissue
500
0
Control
Ang II ARB
Ang II
P.0001. Berry C et al. Circulation.
20001012206-2212.
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Endothelial Progenitor Cells and Vascular
Diseases
Risk factors
Oxidative stress
Endothelial Progenitor Cells
Endothelial injury
Endothelial dysfunction,inflammation
Vascular Repair
Atherogenesis
Hill JM et al. N Engl J Med. 200313593-600.
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Relation Between Endothelium-dependent Function
and Endothelial Progenitor Cells
Endothelial progenitor?cell counts (colony-forming
units)
Flow-mediated dilation
Hill JM et al. N Engl J Med. 200313593-600.
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Diabetics Exhibit Impaired Proliferation of
Human Endothelial Progenitor Cells
Control
Diabetic patient
Tepper OM et al. Circulation. 20021062781-2786.
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FFAs Pathogenesis of NIDDM and CVD
24
How to Measure Waist Circumference

• Place a measuring tape, held parallel to the
  floor, around the patients abdomen at the level
  of the iliac crest
• The tape should fit snugly around the waist
  without compressing the skin
• Take the measurement at the end of a normal
  expiration

Waist circumference of 40 inches in men or 35
inches in women is component of abdominal obesity
/ cardiometabolic syndrome
Circulation. 20051122735-2752.
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Adipose Tissue Secretory Organ
J Clin Invest. 2000106473-481.
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Adiponectin In Humans

• Low levels associated with
• Central adiposity
• Insulin resistance
• Type 2 diabetes
• Hypertriglyceridemia
• Small dense LDL particles
• Patients with CHD
• High levels associated with
• High HDL cholesterol levels
• Insulin sensitivity
• Weight reduction

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Adiponectin
Exercise, weight loss, TZD, ARB
ARBangiotensin receptor blocker FFAfree fatty
acids TGtriglycerides. Modified from Chandran M
et al. Diabetes Care. 2003262442-2450.
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Bergman-R, 2005
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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
30
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

31
DPP (Benefits of Diet and Exercise)

• DM developed in
• 29 of the DPP standard group
• 14 of the diet exercise group
• 22 of the metformin group
• RRR of lifestyle 58
• RRR of metformin 31

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Obesity and Inflammation Reversal by Dietary
Weight Loss
Esposito K, et al. JAMA. 20032891799-1804.
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Systolic HTN and Diabetes Incur Greater CV Risk
Together than Either Alone
250
Men without diabetes
Men with diabetes
200
150
CV Mortality Rate per 10,000 Person-Years
100
50
0
?200
lt120
120-139
140-159
160-179
180-199
Systolic BP (mm Hg)
5,163 men reported taking medication for diabetes
and 342,815 men reported not taking medications
for diabetes average follow-up was 12 years.
Stamler J et al. Diabetes Care. 199316434-444.
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HOT BP control reduces cardiovascular events in
diabetics
Major CV Events 1000 Patient-Yrs
Includes all myocardial infarction, all strokes,
and all other CV deaths.
Hansson L, et al. Lancet. 199835117551762.
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Syst-Eur Outcomes in Diabetic and Nondiabetic
Patients
Overall Mortality
Mortality From Cardiovascular Causes
All Cardiovascular Events
Relative Risk Reduction
P 0.04
P 0.02
P 0.01
Includes fatal and non-fatal events.
Tuomilehto J, et al. N Eng J Med.
1999340677-684.
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Goals of Antihypertensive Rx

• Reduce CVD and renal morbidity and mortality
• Treat to BP lt140/90 mmHg or BP lt130/80 mmHg in
  patients with diabetes or chronic kidney disease
• Achieve SBP goal especially in persons ?50 years
  of age

Chobanian AV et al. JAMA. 200328925602572. Doug
las JG et al. Arch Intern Med. 2003163525541.
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Epiphenomena?Causatively related?All organs
are connected by the same blood vessels!
CKD CVD

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Microalbuminuria and ChronicKidney Disease
Chronic Kidney Disease
Microalbuminuria
OR
Components
OR
Components
2
2.2
2
1.2
3
3.4
3
1.6
4
4.2
4
2.5
5
5.9
5
3.2
Adjusted for age, race or ethnicity, sex,
nonsteroidal anti-inflammatory drug use in past
month, high school education, physical
inactivity, and current or former
smoking. Compared with those with 0 or 1
component of the metabolic syndrome. ORodds
ratio. Chen J et al. Ann Intern Med.
2004140167-174.
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Microalbuminuria A Manifestation of Diffuse
Endothelial Cell Injury
Injured Endothelium
Renal Vasculature
Systemic Vasculature
Cardiovascular Risk Factors Age
Diabetes Hypertension Smoking Absent
nocturnal BP dipping Salt sensitivity Left
ventricular hypertrophy Dyslipidemia Central
obesity Insulin resistance Elevated CRP
Sympathetic dysfunction Hyperuricemia
Interstitial Albumin Leak
Microalbuminuria
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Proteinuria Predicts Stroke and CHD Events in
Type 2 DM
1
40
34.8
Plt.001
0.9
A
30
0.8
25.7
23.0
B
Survival Curves For CV Mortality
20
0.7
Incidence ()
18.4
0.6
11.1
C
10
7.2
Overall Plt.001
0.5
0
0
80
60
20
Stroke
40
100
CHD Events
Months
CHD, coronary heart disease CV, cardiovascular
U-Prot, urinary protein concentration.
Miettinen H, et al. Stroke. 1996272033-2039.
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Microalbuminuria Predicts CV Risk at Levels Below
Current Definition
Microalbuminuria assessment in patients with
hypertension and diabetes improves CV risk
stratification.
Quintile of urine A/C ratio (mg/g) among 1,063
hypertension patients with diabetes
10
Wachtell K et al. Ann Intern Med. 2003139901-6.
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Effects of ARBs on Progression to ESRD in
Diabetic Nephropathy
RENAAL
IDNT
p0.003
p0.006
plt0.001
Brenner et al. N Engl J Med 2001345861869.
Lewis et al. N Engl J Med 2001345851860.
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Heart Protection Study Coronary Events by Prior
Disease
Heart Protection Study Collaborative Group.
Lancet. 20033612005-2016.
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Secondary End Point Fatal and Nonfatal Stroke
Sever PS, et al. for the ASCOT Investigators.
Lancet. 20033611149-1158.
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HPS Microvascular Events in Diabetics
Heart Protection Study Collaborative Group.
Lancet. 20033612005-2016.
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Adding a Statin to RAS Blockade
Zoja C, et al. J Am Soc Nephrol. 200112A4344.
47

• Reduce Stroke and Microalbuminuria?
• Are There Non-lipid Lowering (Pleiotrophic)
  Effects?

48
Beneficial Effects of Statins on Endothelial
Function
Sowers JR. Am J Cardiol. 200391(suppl
4A)14B-22B.
49
Priorities for the Treatment of Dyslipidemia in
DM and CMS ?
Therapy
Goal level, mg/dL (mmol/L)
Priorities
Lower LDL cholesterol 100 (lt 70 mg/dl) Statin
(HMG-CoA reductase inhibitor) levels Bile acid
sequestrant (binding resin) added if
needed Raise HDL-cholesterol gt45 in men
Behavioral interventions levels gt55 in women
Glycemic control Difficult to increase
HDL-cholesterol level except with nicotinic
acid (niacin) Lower triglyceride levels lt400
(lt150 mg/dl) Glycemic control Fibric
acid derivative (fibrate) Statin in patients
who have high LDL- cholesterol
levels Treat combined Same as above Glycemic
control hyperlipidemia Statin Fenofibrate
Niacin
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CV Risk Factor Levels Among Adults With Diagnosed
Diabetes
Fewer than half of the adults with diabetes
achieve treatment goals for CV risk factors
A1C Levellt7
Blood Pressure lt130/80 mm Hg
Total Cholesterol lt200 mg/dL
Achieved All 3 Treatment Goals
Saydah SH et al. JAMA. 2004291335-342.
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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 P .01
Composite CVD outcome ()
Intensive therapy
Follow-up (months)
Intensive therapy better
Conventional therapy better
CV death, MI, stroke, revascularization,
amputation. Total fat intake lt30, gt30 min
exercise 3-5 x weekly, ACE inhibitor, ASA, BP.
lt130/80 mm Hg, total-C lt175, TG lt150 mg/dL, A1c
lt6.5 Gaede P, et al. N Engl J Med.
2003348383-393.
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