Download Diabetes Type2

James W. Reed, M.D., MACP, FACE
Professor of Medicine, Associate Chair of Medicine
Chief of Endocrinology & Metabolism
Chief of Medicine Service at Grady for MSM
Global Projections for the Diabetes Epidemic:
1995-2010
26.5
32.9
24%
14.2
17.5
23%
84.5
132.3
57%
9.4
14.1
50%
15.6
22.5
44%
1.0
1.3
33%
World
2000 = 151 million
2010 = 221 million
Increase 46%
Diabetes in the United States

>30% of individuals aged >60 y have diabetes
mellitus or impaired fasting glucose

23.6 million have diabetes

Millions of these people are unaware they
have diabetes

>1.3 million Americans develop diabetes yearly,
>2,800 daily
Harris et al. Diabetes Care. 1998;21:518. 2002 update.
Costs of Diabetes (US)

1 in every 7 health care dollars spent

10-15% of Medicare population has diabetes, but 25%
of Medicare budget is spent on diabetes

Estimated total costs attributable to diabetes (direct
and indirect) ~ $174 billion (2007)

Ranks #1 in direct health care costs of any disease
category ~ $174 billion (2007)

Ranks #2 in total health care costs (direct and indirect,
diabetes and other) ~ $262 billion (2007)
Songer TJ, Ettaro L. Studies on the cost of diabetes. Centers for Disease Control. Atlanta, GA. 1998.
Centers for Disease Control and Prevention. Chronic diseases and conditions. Online edition. Atlanta, GA. 2000.
American Heart Association. Heart and stroke statistical update. Dallas, TX. 1999.
American Diabetes Association. Diabetes Facts and Figures. March 2000. Online edition.
Diabetes: The Burden of Disease
In 2007, diabetes-related economic
losses were estimated to be:
• $174 billion direct health care costs
• 13.9 million hospital days
• 30.3 million office visits
• 120 million work-loss days
• 88 million disability days
Diabetes Facts and Figures, American Diabetes Association, 2000.
Genes
Insulin
Resistance
Normal -cell
function
Compensatory Hyperinsulinemia
Normoglycemia
Lifestyle
and diet
Abnormal -cell
function
Relative insulin deficiency
Hyperglycemia
Type 2 diabetes
Insulin Resistance:
Inherited and Acquired Influences
Acquired
Inherited
Rare Mutations
• Insulin receptor
• Glucose transporter
• Signaling proteins
Common Forms
• Largely unidentified
•
•
•
•
•
•
•
Overeating
Overweight
Inactivity
Aging
Medications
Illness
Hyperglycemia/
glucose toxicity
• Elevated FFAs
INSULIN RESISTANCE
Cardiovascular Disease
US Leading Cause of Death (1998)
Deaths (thousands)
800
700
600
500
400
300
200
100
0
Heart disease
Cancer
Stroke
COPD
Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases.
NHLBI. May 2000.
Prevalence of Diabetic Tissue Damage
at Diagnosis of Type 2 Diabetes
Urine Albumin
4%
Absent Reflexes
8%
Absent Foot Pulses
12%
Cardiovascular
17%
Retinopathy
18%
0%
2%
4%
6%
8% 10% 12% 14% 16% 18% 20%
Prevalence
Dagogo-Jack et al. Arch Int Med. 1997;157:1802-1817.
UKPDS: Complications at Diagnosis
Tissue Damage
Prevalence (%)*
Retinopathy (>1 microaneurysm)
Abnormal ECG
Other macrovascular complication
Absent foot pulses (2) and/or ischemic feet
Impaired reflexes and/or decreased vibration sense
50% of patients had some form of diabetic
complication at time of diagnosis.
*Some patients had more than 1 complication at diagnosis.
Adapted from UKPDS. Diabetologia. 1991;34:877-890.
21
18
9
14
7
Framingham Study and Joslin Patients
Diabetes Is a CV Risk Factor
Women
Men
60
50
2x
40
30
20
10
0
Mortality rate per 1,000
Mortality rate per 1,000
60
50
40
4-5x
30
20
10
0
0-3
4-7 8-11 12-15 16-19 20-23
0-3
Duration of follow-up (y)
Diabetes
4-7 8-11 12-15 16-19 20-23
Duration of follow-up (y)
No Diabetes
Krolewski AS et al. Am J Med. 1991;90(suppl 2A):56S-61S.
Methods for Diagnosing Diabetes
• FPG 126 mg/dL (after 8-h fast, confirmed)
• Casual plasma glucose 200 mg/dL with
classic diabetes symptoms (confirmed):
– increased urination
– increased thirst
– unexplained weight loss
• OGTT value of  200 mg/dL in the 2-h sample
• Don’t use for diagnosis, but still suggestive:
– Fingerstick glucose
– A1c
ADA. Diabetes Care. 2003;26:S5-S20.
National Cholesterol Education Program
RISK FACTOR
DEFINING MEASURES
Abdominal obesity
Men
Waist circumference:
>40 in (>102 cm)
Women
>35 in (>88 cm)
Triglycerides
HDL-C Men
150 mg/dL
<40 mg/dL
HDL-C Women
<50 mg/dL
Blood pressure
Fasting glucose
130/85 mm Hg
110 mg/dL
3 Risk factors comprise the metabolic syndrome. ICD-9 Code 277.7
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA. 2001. 285:2486-2497.
Aggressive Control of Diabetes:
Goals of Treatment
NORMAL
GOAL
AMERICAN DIABETES ASSOCIATION
HbA1C (%)
Preprandial plasma glucose (mg/dL)
Peak postprandial plasma glucose (mg/dL)
<6
<110
<140
<7
90-130
< 180
AMERICAN ASSOCIATION OF CLINICAL
ENDOCRINOLOGISTS (AACE)
HbA1C (%)
Preprandial plasma glucose (mg/dL)
2-hour postprandial glucose
<6
<110
<140
 6.5
<110
<140
HbA1c is “gold standard” measure of diabetes control over previous 2-3 months
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50;
American College of Endocrinology Consensus Conference on Guidelines for Glycemic Control. August
2001, Washington, DC.
Lower A1C Reduces
Incidence of Complications
A1C
DCCT
9  7%
Kumamoto
9  7%
UKPDS
8  7%
63%
54%
60%
41%*
69%
70%
–
–
17-21%
24-33%
–
16%*
Retinopathy
Nephropathy
Neuropathy
Macrovascular
disease
*Not statistically significant.
Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:977-986.
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103-117.
UK Prospective Diabetes Study Group (UKPDS) 33. Lancet. 1998;352:837-853.
15
Relative Risk of Death*
DECODE Trial: Relative Risk of Death*
Shown by Blood Glucose Level
2.4
*All causes,
2.0
adjusted for
age, sex,
study center
1.6
1.2
1.0
< 110
110-125 126- 139
>140
> 199
140-198
2-h Postprandial
< 140
Fasting Plasma Glucose
(mg/dL)
Adapted from Decode Study Group. Lancet. 1999;354:617-621.
Glucose (mg/dL)
Postprandial Glucose Is a Better
Predictor of Myocardial Infarction and Death
Glycemic Control
(Blood Glucose Level, mg/dL)
Good
Borderline
Poor
P Value
Fasting
80–109
MI per 1,000
123
Death per 1,000 164
110–139
147
220
>140
183
203
—
NS
NS
Postprandial
80–144
MI per 1,000
120
Death per 1,000 167
145–179
165
199
>180
209
262
—
<.05
<.05
Hanefeld M et al. Diabetologia. 1996;39:1577-1583.
Effects of Risk Factors on CVD Mortality
in Type 2 Diabetes - MRFIT
140
120
Nondiabetic
Diabetic
100
CVD death
rate* per
10,000
person-years
80
60
40
20
0
None
One
Two
Number of risk factors
*Age adjusted
Adapted from Stamler J et al. Diabetes Care. 1993;16:434-444.
Three
Atherosclerosis Timeline
Foam
cells
Fatty
streak
Intermediate
lesion
Atheroma
Complicated
lesion/rupture
Fibrous
plaque
Endothelial dysfunction
From First Decade
From Third Decade
Growth Mainly by Lipid Accumulation
From Fourth Decade
Thrombosis
Hematoma
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.
Smooth
Muscle &
Collagen
UKPDS: Metformin Study Results
in Overweight Patients
Metformin
A1C = 7.4%
Conventional
A1C = 8.0%
Risk* P value
Risk*
P value
Any diabetes-related
end point
32%
.0023
7%
NS
Diabetes-related
deaths
42%
.017
20%
NS
Myocardial infarction
39%
.01
21%
NS
Stroke
41%
NS
14%
NS
Microvascular disease
29%
NS
16%
NS
*Compared with conventional therapy.
UKPDS Group. Lancet. 1998;352:854-865.
.
Thiazolidinediones in
Diabetes Therapy

Mechanism of action reverses underlying etiology


Glucose control achieved without hypoglycemia


TZDs improve insulin sensitivity
TZD monotherapy or metformin combination (no increase
in insulin)
Possible secondary benefits include:

Preservation of pancreatic -cell function
 May help reduce progression of disease

Protective cardiovascular effects
 Improve dyslipidemia( ↑HDL,↓TG, ↓LDL density)
 ↓Renal microalbumin excretion
 ↓VSMC proliferation and migration in arterial wall
 Enhance thrombolytic mechanisms
MICRO-HOPE: Primary Outcomes
0
Nonfatal
MI
CV Death
Stroke
Total
mortality
-5
-10
%
-15
-20
-25
22%‡
-30
33%§
-35
-40
24%†
*P<.0001
37%*
The Heart Outcomes Prevention Evaluation (HOPE)
Study Investigators. Lancet. 2000;355:253-259.
‡P<.01
§P<.0074
HOPE and MICRO-HOPE: Event Reductions
for Primary End Points and Total Mortality
25%
Total mortality
16%
33%
32%
Stroke
22%
20%
MI
37%
CV death
26%
0
5
10
15
20
Percent
Diabetic
The HOPE Study Investigators. Lancet. 2000;355:253-259.
25
30
Overall
35
40
The Deadly Quartet
Type 2 Diabetes
Hypercoagulability
Insulin Resistance
Hypertension
Dyslipidemia
Recognizing the
Insulin-Resistant Patient
Insulin resistance is associated with:





Abdominal obesity
Glucose intolerance
First-degree relative
with type 2 diabetes
Absent nocturnal drop in
BP
Salt sensitivity





History of
gestational diabetes
Dyslipidemia
Hypertension
Increased PAI-1/
Platelets
Acanthosis nigricans
C




Nutrition therapy
 decrease fat content and total calories
 decrease saturated fat
 decrease salt for hypertension
 healthy diet
 weight reduction in obese patients
Exercise
 increase energy expenditure with
moderate-intensity exercise
Lifestyle changes to reduce cardiovascular risk factors
(eg, smoking cessation)
Training in self-management and SMBG
©1997 PPS
C
2Muscle and adipose tissue:
glucose uptake
1Intestine: glucose absorption
Insulin resistance
Blood glucose
4Liver: hepatic
glucose output
Insulin
resistance
3 Pancreas: insulin secretion
Sulfonylureas
insulin secretion
©1997 PPS
DeFronzo RA. Diabetes. 1988;37:667-687.
Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529.
C
1Intestine: glucose absorption
2 Muscle and adipose tissue:
glucose uptake
Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
Insulin
resistance
3 Pancreas: insulin secretion
Meglitinides
Insulin secretion
©1998 PPS
Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.
C
2 Muscle and adipose tissue:
glucose uptake
Metformin glucose utilization
1Intestine: glucose absorption
Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
Metformin HGO
Insulin
resistance
3Pancreas: insulin secretion
©1997 PPS
DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.
C
1 Intestine: glucose absorption
Acarbose glucose absorption secondary
to digestion of carbohydrate
2Muscle and adipose
tissue: glucose uptake
Insulin resistance
Blood glucose
4Liver: hepatic
glucose output
Insulin
resistance
3 Pancreas: insulin secretion
©1997 PPS
Amatruda JM. In: Diabetes Mellitus. 1996.