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Effects of Diabetes, Obesity,
Metabolic Syndrome on
Cardiovascular Health
Filipino American Cardiovascular Health Summit
July 9, 2011
Washington, D.C.
Socorro Juan Vargas, M.D., F.A.C.P., F.A.C.E
Section of Diabetes and Endocrinology
St. Francis Hospital and Medical Center
Assistant Professor of Medicine
University of Connecticut School of Medicine
Disclosure of Conflicts of Interest
• Nothing to disclose
Outline
• Diabetes:
– Definition
– Complications
– Burden of disease
• Cardiometabolic risk factors
• Metabolic Syndrome
• Effects of intensive glycemic control on
cardiovascular risk
• Primary prevention of cardiovascular risk in
diabetes patients
• Treatment goals
What is Diabetes?
• Diabetes is a state characterized by an
absolute or relative deficiency of insulin
relative to the physiological needs of a
given individual
GI
Hormones
Too much
Glucagon
Not enough
insulin
Hyperglycemia
Prevalence and Incidence of Diabetes
and Pre-diabetes in the U.S.A.
• 25.8 million people have diabetes
• Diagnosed: 18.8 million people
• Undiagnosed: 7.0 million people
• A total of 1.9 million new cases of diabetes
were diagnosed in 2010 in the United States
among people aged 20 years and older
• 79 million U.S. adults ages 20 and older have
pre-diabetes
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.
Diabetes in Asian Americans and
Pacific Islanders
• 8.4% of all Asian Americans have
diagnosed diabetes
• Prevalence data for diabetes among
Pacific Islanders is limited
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.
Diabetes Care 2001; 24:2054-2058
Diagnostic Criteria for
Pre-diabetes and Diabetes
Category
A1C
Fasting Plasma
Glucose Test
(FPG)
2-Hour Oral
Glucose
Challenge
Acceptable
N/A
Below 100 mg/dl
Below 140 mg/dl
5.7% - 6.4%
100-125 mg/dl
(IFG)
140-199 mg/dl
(IGT)
≥ 6.5%
126 mg/dl or
above
200 mg/dl or
above
Pre-diabetes
Diabetes
American Diabetes Association. Diabetes Care 2011; 34;(Suppl.1):S11-61.
Diabetes Complications
• Diabetes is the leading cause of:
– kidney failure
• 48,374 people with diabetes began treatment
for end stage kidney disease in 2008
– new cases of adult blindness
• 4.2 million people with diabetes aged 40 and
older had diabetic retinopathy in 2005-2008
– nontraumatic lower-limb amputations
• Over 65,000 nontraumatic lower-limb
amputations were performed in people with
diabetes in 2006
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.-
Diabetes Complications
• The risk of periodontal disease is two to three times
higher in adults with diabetes
• About one-third of people with diabetes have
severe periodontal disease
• 60% to 70% of people with diabetes have mild to
severe nervous system damage
• Almost 30% of people with diabetes aged 40
years and older have impaired sensation in the
feet
• People with diabetes are twice as likely to have
depression
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.
Cardiovascular disease is leading
cause of death in patients with
Type 1 and Type 2 Diabetes
• Framingham study: CVD incidence in diabetics 1
– Males: 2-fold increase
– Females: 3-fold increase
– Women had greater cardiovascular mortality
• CVD morbidity and mortality greater for diabetic
women than non-diabetic men 2
• MRFIT: Absolute risk of CVD death 3X higher in
diabetic men at every age, race, income, cholesterol
and blood pressure 3
1
Kannel WB, McGee DL. Diabetes Care 1979; 2:120-126
Lee WL et al. Diabetes Care 2000; 23:962-968
3 Stamler J et al. Diabetes Care 1993;16:434-444
2
Diabetes is a CVD Risk Equivalent
• Subjects with diabetes have the same
7-year risk for future MI as nondiabetic
individuals who have had a previous MI
Haffner SM et al. N Engl J Med 1998;339:229-234
Diabetes and Risk for Cardiovascular
Disease (CVD)
• Cardiovascular disease (CVD) a major
complication of diabetes and leading cause
of death in patients with diabetes
• In adults with diabetes
– 68% die of heart disease or stroke
– the risk for stroke is 2 to 4 times higher
– 67% have high blood pressure
– smoking doubles the risk for heart disease
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.
Type 1 Diabetes and CVD
• The prevalence of coronary artery
disease is 10 times greater among
patients with Type 1 diabetes than ageand gender-matched individuals
without diabetes
• Insulin resistance is not a characteristic
feature of T1DM
• Is hyperglycemia a direct risk mediator?
Estimated Costs of Diabetes and CVD
in the U.S.
Estimated
Direct
Medical
Costs
Estimated
Indirect
Costs †‡
TOTAL
Cardiovascular
disease
$324 B
$179 B
$503 B
Diabetes
$116 B
$58 B
$174 B
TOTAL
$440 B
$237 B
$677 B
† Disability, work loss, premature mortality
‡ Totals do not add up because of rounding and overlap
National Diabetes Fact Sheet, CDC, 2011.
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.
American Heart Association. Circulation 2010; 121:e46-e215
The Evolution of Mankind
The Evolution of Mankind
2.5 Million years
Genes
50 years
Environment
Age-adjusted Percentage of U.S. Adults Who
Were Obese or Who Had Diagnosed Diabetes
Obesity BMI ≥ 30 kg/m2
1994
2000
2008
2000
2008
Diabetes
1994
Centers for Disease Control and Prevention: National Diabetes Surveillance System
http://www.cdc.gov/diabetes/statistics
Definitions of Metabolic Syndrome
Clinical
Measure
Waist
circumference
AHA/NHLBI
Any 3 of 5 features
IDF
Non-Asian
Men ≥102 cm
Women ≥88 cm
Europid, Sub-Saharan Africans,
Middle Eastern
Men ≥94 cm
Women ≥80 cm
East Asian & South Asians
Men ≥90 cm
Women 80 cm
East Asian & South Asians
South & Central Americans
Men ≥90 cm
Women ≥80 cm
Japanese
Men ≥85 cm
Women ≥90 cm
Triglycerides
≥150 mg/dl or on drug therapy for
high triglycerides
≥150 mg/dl or on drug therapy for
high triglycerides
HDL-C
Men <40 mg/dl, Women <50 mg/dL
or on drug therapy for low HDL-C
Men <40 mg/dl, Women <50 mg/dL
or on drug therapy for low HDL-C
Blood pressure
Systolic ≥130 mmHg
Diastolic ≥85 mmHg or
on drug therapy for hypertension
Systolic ≥130 mmHg
Diastolic ≥85 mmHg or
on drug therapy for hypertension
Fasting glucose
≥100 mg/dl or on drug therapy for
elevated glucose
≥100 mg/dl (includes diabetes)
AHA/NHLBI Circulation 2005;112:2735-2752
IDF Lancet 2005;366:1059-1062
Glycemic Control and CV Risk
Clinical Trials
• Hypothesis: Treatment that normalizes blood glucose
will prevent or delay the long term complications of
diabetes mellitus
TYPE
CLINICAL TRIAL
DCCT
T1DM
Diabetes Control and Complications Trial
EDIC
T1DM
Epidemiology of Diabetes Interventions and
Complications
UKPDS
T2DM
United Kingdom Prospective Diabetes Study
ACCORD
T2DM
Action to Control Cardiovascular Risk in
Diabetes Study Group
ADVANCE T2DM
Action in Diabetes and Vascular Disease:
Preterax and Diamicron Controlled
Evaluation
VADT
Veterans Diabetes Trial
T2DM
Diabetes Control and Complications
Trial (DCCT)
• Improved control of blood glucose
reduced the risk of clinically
meaningful:
Retinopathy
76%
P≤0.002
Nephropathy
54%
P<0.04
Neuropathy
60%
P≤0.002
Cardiovascular endpoint
57%
P≤0.007
DCCT. N Engl J Med 1993; 329: 977-986
DCCT/EDIC. N Engl J Med 2005;353:2643-2653
Cumulative Incidence
EDIC Findings: Cardiovascular Events
Cumulative Incidence of First of Any Event
0.12
0.10
Risk reduction 42%
95% CI: 9% to 63%
P = 0.02
0.08
0.06
0.04
Intensive
0.02
0.00
0
Cumulative Incidence
Conventional
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
0.12
0.10
Risk reduction 57%
95% CI: 12% to 79%
P = 0.02
0.08
0.06
0.04
Conventional
0.02
Intensive
0.00
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Years from Study Entry
DCCT/EDIC N Engl J Med 2005;353:2643-2653
14
15
16
17
18
19
20
21
United Kingdom Prospective Diabetes
Study (UKPDS)
Risk reduction with 1% decline in annual mean A1C
P <.0001
P = .035
P = .021 P = .0001
0%
14%
12%
16%
15%
30%
19%
37%
43%
45%
Microvascular
Disease
PVD
UKPDS. BMJ 2000;321:405-412
MI
Stroke
Heart
Cataract
Failure Extraction
UKPDS: Follow-Up Study
Differences in A1C between intensive &
standard glycemia control treatment groups
were lost after one year
Relative Risk Reductions
Intensive
Insulin/Sulfonylurea
Intensive Metformin
Any DM
endpoint
9%
P=0.04
21%
P=0.01
Microvascular
disease
24%
P=0.001
Myocardial
Infarction
15%
P=0.01
33%
P=0.005
Death from
any cause
13%
P=0.007
21%
P=0.002
UKPDS. N Engl J Med 2008;359:1577-1589
ACCORD, ADVANCE and VADT
Characteristic
ACCORD
ADVANCE
VADT
10,251
11,140
1,791
62
66
60
Duration of T2DM
10 yr
8 yr
11.5 yr
History of CVD
35%
32%
40%
BMI
32
28
31
Baseline A1c
8.3
7.5
9.4
A1c achieved
6.4 vs 7.5
6.3 vs 7.0
6.9 vs 8.5
HR CVD Events
0.9 (0.78-1.04)
0.94 (0.84-1.06)
0.88 (0.74-1.05)
HR Mortality
1.22 (1.01-1.46)
0.93 (0.83-1.06)
1.07 (0.81-1.42)
N
Mean age
ACCORD Study Group. N Engl J Med 2008;358:2545-2559
ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572
VADT. N Engl J Med 2009;360:129-139
Effects of Intensive Glycemic Control
Study
Microvascular
Disease
Macrovascular
Disease
Mortality
UKPDS
DCCT/EDIC
ACCORD
?
ADVANCE
VADT
UKPDS. Lancet 1998; 352:837-853
UKPDS. N Engl J Med 2008; 359:1577-1589
DCCT. N Engl J Med 1993; 329: 977-986
DCCT/EDIC. N Engl J Med 2005;353:2643-2653
ACCORD. N Engl J Med 2008; 358(24):2545-59
ADVANCE. N Engl J Med 2008; 358 (24): 2560-72
VADT. N Engl J Med 2009;360:129-139
Initial Trial
Long-term
Follow-up
Effects of Intensive Glycemic Control
• Benefit from intensive therapy when
initiated earlier in the course of disease
• CV benefit may be evident only after an
extended period of time
• Effect may be sustained for period
longer than 10 years after intensive
therapy is discontinued
Intensive Glycemic Control in Diabetes:
Implications of ACCORD, ADVANCE and VADT
• Clinical implication = individualized goals
and care
• General A1c goal of <7%
– For microvascular disease prevention
– Reasonable for macrovascular risk reduction,
pending more evidence
• A1c goals closer to normal for some patients
– Short duration of diabetes, long life expectancy,
no significant CVD
– Levels reached without significant adverse
treatment effects
ADA/ACC/AHA Position Statement. Diabetes Care 2009;32:187-192
Intensive Glycemic Control in Diabetes:
Implications of ACCORD, ADVANCE and VADT
• Less stringent goals for some patients
–
–
–
–
–
History of severe hypoglycemia
Limited life expectancy
Advanced micro- or macrovascular complications
Extensive comorbid conditions
Long-standing diabetes with difficulty achieving
glycemic goals
ADA/ACC/AHA Position Statement. Diabetes Care 2009;32:187-192
Targets for Glycemic, Blood Pressure
and Lipid Control
ADA
AACE
<7.0%
≤6.5%
Premeal PG
70-130 mg/dL
<110 mg/dL
Postmeal PG
<180 mg/dL
<140 mg/dL
< 130/80 mmHg
< 130/80 mmHg
LDL-C
<100 mg/dL
<70 (CVD)
<100 mg/dL
<70 (CVD)
HDL-C
>40 mg/dL (M)
>50 mg/dL (F)
>40 mg/dL (M)
>50 mg/dL (F)
<150 mg/dL
<150 mg/dL
HbA1c
BP
Lipids
Triglycerides
American Diabetes Association. Diabetes Care. 2011;34(suppl 1):S11-S61
American College of Endocrinology. Endocr Pract. 2007;13(suppl 1):1-68
GI Effects
Incretins
Amylin
α Glucosidase
inhibitors
Bile acid
sequestrant
Insulin Secretion
↑ Sulfonylureas
↑ Meglitinides
↑ Incretins
Glucagon Secretion
↓ Incretins
↓ Amylin
Appetite Control
Incretins
Amylin
HYPERGLYCEMIA
Hepatic Glucose
Output
↓ Metformin
↓ Thiazolidinediones
Lipotoxicity
Thiazolidinediones
Glucose reabsorption
↓SGLT2 Inhibitors
Glucose uptake and utilization
↑Thiazolidinediones
↑ Metformin
Primary Prevention of CVD in People
with Type 1 and Type 2 Diabetes
Intervention
Recommended Goals
Weight
Moderate weight loss (5-7% of
starting weight)
Medical
nutrition
therapy
Saturated fat <7% of energy
intake
Dietary cholesterol <200 mg/day
Trans-unsaturated fats <1% of
energy intake
Physical
activity
150 min moderate intensity
aerobic activity or
90 minutes vigorous aerobic
activity
Distributed over at least 3
days/wk
Tobacco
Tobacco cessation
AHA/ADA Circulation 2007;115:114-126
Recommended Agents
Primary Prevention of CVD in People
with Type 1 and Type 2 Diabetes
Intervention
Recommended Goals
Blood
pressure
<130/80 mmHg
Lipids
LDL < 100 mg/dL
If TG 200-499 mg/dL
Non-HDL target ≤130 mg/dL
If TG ≥500 mg/dL
Treat prior to LDL reduction
TG ≤150 mg/dL
HDL: men >40 mg/dL
Women >50 mg/dL
Antiplatelets
> 40 yrs of age or if increased CV
risk
Glycemic
control
HgbA1c <7%
AHA/ADA Circulation 2007;115:114-126
Recommended Agents
ACE-I, ARB
(β-blockers, thiazides,
CCB added as needed)
Aspirin 75-162 mg/day
Summary
• A comprehensive approach to the prevention
and management of cardiovascular disease
in diabetes patients is best accomplished
through a combination of lifestyle
modification and targeting of multiple
cardiometabolic risk factors and
comorbidities
• Focus on individualizing therapy: choose the
appropriate A1c target, cardiometabolic
goals and proper drug regimen for each
patient
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