Diabetes Mellitus Evidence and Guidelines

1

• Diabetes Mellitus Evidence and Guidelines
• Andrew P. DeFilippis, Ty J. Gluckman, James Mudd,
  Catherine Campbell,
• Roger S. Blumenthal

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Mechanisms by which Diabetes Mellitus leads to CHD
Hyperglycemia
Inflammation
? AGE ? Oxidative stress
? IL-6 ? CRP ? SAA
Infection
? Defensemechanisms ? Pathogen burden
Subclinical Atherosclerosis
Atherosclerotic Clinical Events
AGEAdvanced glycation end products,
CRPC-reactive protein, CHDCoronary heart
disease HDLHigh-density lipoprotein,
HTNHypertension, IL-6Interleukin-6,
LDLLow-density lipoprotein, PAI-1Plasminogen
activator inhibitor-1, SAASerum amyloid A
protein, TFTissue factor, TGTriglycerides,
tPATissue plasminogen activator
Biondi-Zoccai GGL et al. JACC 2003411071-1077
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The Metabolic Syndrome

• 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

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ATP III Definition of the Metabolic Syndrome
Defined by the presence of gt3 risk factors
Risk Factor Defining Level
Waist circumference (abdominal obesity) gt40 in (gt102 cm) in men
gt35 in (gt88 cm) in women
Triglyceride level gt150 mg/dl
HDL-C level lt40 mg/dl in men
lt50 mg/dl in women
Blood pressure gt130/gt85 mmHg
Fasting glucose gt100 mg/dl
HDL-CHigh-density lipoprotein cholesterol
Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults.
JAMA 20012852486-2497
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Metabolic Syndrome Prevalence in U.S. Adults
National Health and Nutrition Examination Survey
(NHANES)
Men
Women
Prevalence,
4049
2070
2029
3039
5059
6069
?70
Age, yrs
Ford ES et al. JAMA 2002287356-359
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Metabolic Syndrome CHD Prevalence
National Health and Nutrition Examination Survey
(NHANES)
19.2
13.9
CHD Prevalence
8.7
7.5
No MS/No DM
MS/No DM
DM/No MS
DM/MS
54
29
of Population
2
15
CHDCoronary heart disease, DMDiabetes mellitus,
MSMetabolic syndrome
Among individual gt50 years
Alexander CM et al. Diabetes 2003521210-1214
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Metabolic Syndrome Risk of Death
Risk is Proportional to the Number of ATP III
Criteria
4
CVD
3
CHD
Mortality hazard ratio
2
1
0
0
1
2
3
4
5
Number of Metabolic Syndrome Criteria
CHDCoronary heart disease, CVDCardiovascular
disease
Adjusted for age, sex, race or ethnicity,
education, smoking status, nonHDL-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 2004173309-314
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Metabolic Syndrome Risk of Developing DM
Finnish Diabetes Prevention Study
522 overweight (mean BMI31 kg/m2) patients with
impaired fasting glucose randomized to
intervention or usual care for 3 years
Lifestyle modification reduces the risk of
developing DM
Intervention Control
23
11
with Diabetes Mellitus
Defined as a glucose gt140 mg/dl 2 hours after an
oral glucose challenge
Aimed at reducing weight (gt5), total intake of
fat (lt30 total calories) and saturated fat (lt10
total calories) increasing uptake of fiber (gt15
g/1000 cal) and physical activity (moderate at
least 30 min/day)
Tuomilehto J et al. NEJM 20013441343-1350
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Metabolic Syndrome Risk of Developing DM
Diabetes Prevention Program (DPP)
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
Placebo Metformin Lifestyle modification
40
30
20
Incidence of DM ()
10
0
0
1
4
2
3
0
Years
Includes 7 weight loss and at least 150 minutes
of physical activity per week
Knowler WC et al. NEJM 2002346393-403
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Metabolic Syndrome Risk of Developing DM
Diabetes Reduction Assessment with Ramipril and
Rosiglitazone Medication (DREAM) Trial
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
0.6
Placebo Rosiglitazone
0.4
Incident DM or Death
0.2
60 RRR, Plt0.0001
0.0
0
1
2
3
4
Years
CVDCardiovascular disease, DMDiabetes mellitus,
IFGImpaired fasting glucose, IGTImpaired
glucose tolerance
Gerstein HC et al. Lancet 20063681096-1105
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Diabetes Mellitus Lifetime Risk
Narayan et al. JAMA 20032901884-1890
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Diabetes Mellitus Prevalence in U.S. Adults
Mokdad AH et al. JAMA 200328976-79
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Diabetes Mellitus Risk of CVD Events
Framingham Heart Study 30 year follow-up
10
Men
Women
8
6
Risk ratio
4
2
0
Age-adjusted Annual Rate/1000
Plt0.001 for all values except Plt0.05
CHDCoronary heart disease, CVDCardiovascular
disease
Wilson PWF, Kannel WB. In Hyperglycemia,
Diabetes and Vascular Disease. Ruderman N et al,
eds. Oxford 1992.
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Diabetes Mellitus Risk of Myocardial Infarction
50
DM No DM
45
40
30
Events/100 person-years
20
19
20
10
3.5
0
Prior CHD
No prior CHD
Patients with DM but no CHD experience a similar
rate of MI as patients without DM but with CHD
CHDCoronary heart disease, DMDiabetes mellitus,
MIMyocardial infarction
Fatal or non-fatal MI
Haffner SM et al. NEJM 1998339229234
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Diabetes Mellitus Risk of Death
100
80
Survival ()
60
Nondiabetic subjects without prior MI Diabetic
subjects without prior MI Nondiabetic subjects
with prior MI Diabetic subjects with prior MI
40
20
5
6
2
3
4
7
8
0
1
Years
Patients with DM but no CHD experience a similar
rate of death as patients without DM but with CHD
CHDCoronary heart disease, DMDiabetes mellitus,
MIMyocardial infarction
Haffner SM et al. NEJM 1998339229234
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Survival post-MI in Diabetics and Non-diabetics
Minnesota Heart Survey
WOMEN
MEN
100 80 60 40 0
No diabetes
No diabetes
n1628
n568
Diabetes
Survival ()
Diabetes
n228
n156
Months Post-MI
Months Post-MI
0
20
40
60
80
0
20
40
60
80
MIMyocardial infarction
Sprafka JM et al. Diabetes Care 199114537-543
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Intensity of Glucose Control in DM in UKPDS
P0.03
P0.05
P0.02
relative risk reduction
Plt0.01
Plt0.01
A lower HbA1c is associated with reduced vascular
risk in diabetics
DMDiabetes mellitus, HbA1CGlycosylated
hemoglobin
UKPDS Group. Lancet 1998352837-853
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Intensity of Risk Factor Control in DM
STENO-2 Study
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
60
Intensive Therapy Conventional Therapy
40
Primary Endpoint ()
20
HR0.47, P0.008
0
12
24
36
48
60
72
84
96
Months of Follow-Up
Aggressive treatment of dyslipidemia,
hyperglycemia, hypertension, microalbuminuria,
and secondary prevention of CV disease
Death from CV causes, nonfatal MI, CABG, PCI,
nonfatal stroke, amputation, or surgery for PAD
CABGCoronary artery bypass graft surgery,
CVCardiovascular, DMDiabetes mellitus
MIMyocardial infarction, PADPeripheral artery
disease, PCIPercutaneous coronary intervention
Gaede P et al. NEJM 2003348383-393
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Diabetes Mellitus Guidelines

• 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 patients
  primary physician and/or endocrinologist

Goal HbA1C lt7
CVCardiovascular, DMDiabetes mellitus,
HbA1CGlycosylated hemoglobin, RxTreatment