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Diabetes Mellitus Evidence and Guidelines Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, & Roger S. Blumenthal. Insulin Resistance. Dyslipidemia. HTN Endothelial dysfunction. LDL TG HDL. Thrombosis. PAI-1 TF tPA. Disease Progression. - PowerPoint PPT Presentation
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Diabetes Mellitus Evidence and Diabetes Mellitus Evidence and GuidelinesGuidelines
Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell,
& Roger S. Blumenthal
2
AGE=Advanced glycation end products, CRP=C-reactive protein, CHD=Coronary heart disease HDL=High-density lipoprotein, HTN=Hypertension, IL-6=Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1, SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator
Subclinical Atherosclerosis
Atherosclerotic Clinical Events
Hyperglycemia
AGE Oxidative
stress
Inflammation
IL-6 CRP SAA
Infection
Defensemechanisms
Pathogen burden
Insulin Resistance
HTN Endothelial dysfunction
Dyslipidemia
LDL TG HDL
Thrombosis
PAI-1 TF tPA
Disease Progression
Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077
Mechanisms by which Diabetes Mellitus leads to CHDMechanisms by which Diabetes Mellitus leads to CHD
3
• Consists of a constellation of major risk factors, life-habit risk factors, and emerging risk factors
• Over-represented among populations with CVD
• Often occurs in individuals with a distinctive body-type including an increased abdominal circumference
The Metabolic SyndromeThe Metabolic Syndrome
4
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497
Risk Factor Defining Level
Waist circumference (abdominal obesity) >40 in (>102 cm) in men
>35 in (>88 cm) in women
Triglyceride level >150 mg/dl
HDL-C level <40 mg/dl in men
<50 mg/dl in women
Blood pressure >130/>85 mmHg
Fasting glucose >100 mg/dl
ATP III Definition of the Metabolic SyndromeATP III Definition of the Metabolic Syndrome
Defined by the presence of >3 risk factors
HDL-C=High-density lipoprotein cholesterol
5
40–49
Ford ES et al. JAMA 2002;287:356-359
Pre
vale
nce,
%
20–70+Age, yrs
20–29 30–39 50–59 60–69 700%
10%
20%
30%
40%
50%
National Health and Nutrition Examination Survey (NHANES)
Metabolic Syndrome: Prevalence in U.S. AdultsMetabolic Syndrome: Prevalence in U.S. Adults
Men
Women
6
CH
D P
reva
lenc
e
No MS/No DM
54%
MS/No DM
29%
DM/No MS
2%
DM/MS
15%
8.7%
13.9%
7.5%
19.2%
0%
5%
10%
15%
20%
25%
Metabolic Syndrome: CHD Prevalence*Metabolic Syndrome: CHD Prevalence*
National Health and Nutrition Examination Survey (NHANES)
% of Population =
Alexander CM et al. Diabetes 2003;52:1210-1214
*Among individual >50 years
CHD=Coronary heart disease, DM=Diabetes mellitus, MS=Metabolic syndrome
7
0
1
2
3
4CVD*
CHD†
0 1 2 3 4 5
Mo
rta
lity
haz
ard
ra
tio
Number of Metabolic Syndrome Criteria
*Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C level, recreational and non-recreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke †Similar adjustments except for prevalent stroke
Ford ES et al. Atherosclerosis 2004;173:309-314
Metabolic Syndrome: Risk of DeathMetabolic Syndrome: Risk of Death
CHD=Coronary heart disease, CVD=Cardiovascular disease
Risk is Proportional to the Number of ATP III Criteria
8Tuomilehto J et al. NEJM 2001;344:1343-1350
0
0.05
0.1
0.15
0.2
0.25
InterventionControl
11%
23%
% with Diabetes Mellitus
Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM
Finnish Diabetes Prevention Study
†Defined as a glucose >140 mg/dl 2 hours after an oral glucose challenge
522 overweight (mean BMI=31 kg/m2) patients with impaired fasting glucose† randomized to intervention‡ or usual care for 3 years
Lifestyle modification reduces the risk of developing DM
‡Aimed at reducing weight (>5%), total intake of fat (<30% total calories) and saturated fat (<10% total calories); increasing uptake of fiber (>15 g/1000 cal); and physical activity (moderate at least 30 min/day)
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Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM
Diabetes Prevention Program (DPP)
Knowler WC et al. NEJM 2002;346:393-403
0 1 2 3 4
0
10
20
30
40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Percent developing diabetes
All participants
All participants
Years from randomization
Cu
mu
lativ
e in
cid
en
ce (
%)
*Includes 7% weight loss and at least 150 minutes of physical activity per week
Placebo
Metformin
Lifestyle modification
Inci
denc
e of
DM
(%
)
0
20
30
10
40
00 1 42 3
Years
3,234 patients with elevated fasting and post-load glucose levels randomized to placebo, metformin (850 mg bid), or lifestyle modification*
for 3 years
Lifestyle modification reduces the risk of developing DM
10
Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM
Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) Trial
Gerstein HC et al. Lancet 2006;368:1096-1105
CVD=Cardiovascular disease, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance
0.6
0.4
0.2
0.00 1 2 3 4
PlaceboRosiglitazone
Inci
dent
DM
or
Dea
th
Years
60% RRR, P<0.0001
5,269 patients with IFG and/or IGT, but without known CVD randomized to rosiglitazone (8 mg) or placebo for a median of 3 years
Thiazolidinediones reduce the risk of developing DM
11
Diabetes Mellitus: Lifetime RiskDiabetes Mellitus: Lifetime Risk
Narayan et al. JAMA 2003;290:1884-1890
12
19911991 20012001
< 4-6% 7-8% 9-10%No Data < 4% >10%
Mokdad AH et al. JAMA 2003;289:76-79
Diabetes Mellitus: Prevalence in U.S. AdultsDiabetes Mellitus: Prevalence in U.S. Adults
13
109
20
11
9 6 38 19
3*
30
Total CVD CHD Cardiac failure Intermittent claudication
CVA
Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.
P<0.001 for all values except *P<0.05
Ris
k ra
tio
Men Women
0
2
4
10
8
6
Age-adjusted Annual Rate/1000
Diabetes Mellitus: Risk of CVD EventsDiabetes Mellitus: Risk of CVD Events
CHD=Coronary heart disease, CVD=Cardiovascular disease
Framingham Heart Study: 30 year follow-up
14Haffner SM et al. NEJM 1998;339:229–234
Patients with DM but no CHD experience a similar rate of MI as patients without DM but with CHD
Eve
nts
*/1
00
per
son-
yea
rs
Prior CHD
45 DMNo DM
No prior CHD
50
40
30
20
10
0
19 20
3.5
Diabetes Mellitus: Risk of Myocardial InfarctionDiabetes Mellitus: Risk of Myocardial Infarction
*Fatal or non-fatal MI
CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction
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0 1 2 3 4 5 6 7 8
20
40
60
80
100
Nondiabetic subjects without prior MI
Diabetic subjects without prior MI
Nondiabetic subjects with prior MI
Diabetic subjects with prior MI
Years
Sur
viva
l (%
)
Diabetes Mellitus: Risk of DeathDiabetes Mellitus: Risk of Death
Haffner SM et al. NEJM 1998;339:229–234
Patients with DM but no CHD experience a similar rate of death as patients without DM but with CHD
CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction
16
WOMENWOMENMENMEN
Sprafka JM et al. Diabetes Care 1991;14:537-543
100
80
60
40
0
Sur
viva
l (%
)
Months Post-MI
No diabetes
n=228
n=1628
Months Post-MI
0 20 40 60
Diabetes
80 0 20 40 60 80
Diabetes
No diabetes
n=156
n=568
Survival post-MI in Diabetics and Non-diabeticsSurvival post-MI in Diabetics and Non-diabetics
Minnesota Heart Survey
MI=Myocardial infarction
17
-25-21
-16-12
-33
-50
-40
-30
-20
-10
0
Microalbuminuria at 12 years Microvascular complicationsRetinopathy Myocardial infarctionAny DM endpoint
% r
ela
tive
ris
k re
du
ctio
n
P=0.03
P<0.01
P<0.01
P=0.05
P=0.02
UKPDS Group. Lancet 1998;352:837-853
A lower HbA1c is associated with reduced vascular risk in diabetics
Intensity of Glucose Control in DM in UKPDSIntensity of Glucose Control in DM in UKPDS
DM=Diabetes mellitus, HbA1C=Glycosylated hemoglobin
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*Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD
Prim
ary
End
poin
t* (
%)
Months of Follow-Up
20
12 24 36 48 60 72 84 96
Intensity of Risk Factor Control in DMIntensity of Risk Factor Control in DM
STENO-2 Study
40
60
0
Intensive Therapy†
Conventional Therapy
†Aggressive treatment of dyslipidemia, hyperglycemia, hypertension, microalbuminuria, and secondary prevention of CV disease
Gaede P et al. NEJM 2003;348:383-393
CABG=Coronary artery bypass graft surgery, CV=Cardiovascular, DM=Diabetes mellitus MI=Myocardial infarction, PAD=Peripheral artery disease, PCI=Percutaneous coronary intervention
160 patients with type 2 DM randomized to targeted intensive multifactorial intervention† or conventional treatment of CV risk factors for 8 years
Lifestyle modification reduces the risk of developing DM
HR=0.47, P=0.008
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Goals Recommendations
Diabetes Mellitus GuidelinesDiabetes Mellitus Guidelines
Goal HbA1C <7% Intensive lifestyle modification to prevent the development of DM (especially in those with the metabolic syndrome)
Aggressive management of CV risk factors
Hypoglycemic Rx to achieve a normal to near normal fasting plasma glucose as defined by the HbA1C
• Weight reduction and exercise• Oral hypoglycemic agents• Insulin therapy
Coordination of diabetic care with the patient’s primary physician and/or endocrinologist
CV=Cardiovascular, DM=Diabetes mellitus, HbA1C=Glycosylated hemoglobin, Rx=Treatment
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
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