Diabetes:
The Burden of Disease
Fall, 2007
NUR464
1
Prevalence of Diabetes Is Escalating
1990
1995
2001
(Includes Gestational Diabetes)
No Data
< 4%
4%-6%
6%-8%
8%-10%
Source: Mokdad A, et al. Diabetes Care. 2000;23:1278-1283; Mokdad A, et al. J Am Med Assoc.
2001;286:10; Mokdad A, et al. JAMA. 2003;289:76-79.
> 10%
2
Diabetes Mortality Continues Unabated
140
Diseases of the
Heart
Malignant
Neoplasms
Cerebrovascular
Diseases
Diabetes Mellitus
120
AgeAdjusted
Death Rate
Relative to
1980
100
80
60
40
1980
1990
2000
Year
Freid VM, et al. National Center for Health Statistics, 2003.
3
Type 2 Accounts for the Vast Majority
of Diabetes Mellitus Cases
• Type 2 diabetes
•
•
•
•
•
About 90% of the diabetes population
Dual impairment: Insulin deficiency & Insulin resistance
No longer a disease of adults only
Obesity
Genetic link
• Type 1 diabetes
• Approximately 10% of diabetes population
• Absolute insulin requirement
• Autoimmune mediated
CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for
Disease Control and Prevention 2003.
4
Link Between Obesity and
Type 2 Diabetes: Harvard Nurses’
Health Study
120
100
80
60
AgeAdjusted
Relative Risk for 40
Diabetes Mellitus
20
0
< 22
22
22.9
23
23.8
24
24.9
25
26.9
27
28.9
29
30.9
31
32.9
33 > 35
34.9
BMI (kg/m2)
Colditz GA, et al. Ann Intern Med. 1995;122:481-486.
5
2002 — Total Per Capita Health Care
Expenditures
14,000
$13,243
12,000
10,000
8,000
Dollars
6,000
4,000
$2,560
2,000
0
Diabetes
ADA. Diabetes Care. Mar. 2003;26(3):917-932.
Without Diabetes
6
Physiologic Blood Insulin Secretion
Profile
75
Breakfast
Lunch
Dinner
50
Plasma
Insulin
(µU/mL)
25
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine.
June 2003;113(6):30-36.
7
Normal Physiologic Insulin
Sensitivity and Cell Function
Produce Euglycemia
Normal Cell Function
Normal Insulin Sensitivity
Decreased
Lipolysis
Pancreas
Liver
↓ Glucose
Islet Cell Degranulation;
Insulin Released in Response to
Elevated Plasma Glucose
Production
Decreased
Plasma FFA
↑ Glucose
Uptake
Muscle
Adipose Tissue
Decreased Glucose Output
Normal Physiologic
Plasma Insulin
Increased Glucose
Transport
Euglycemia
8
Cell Dysfunction and Insulin
Resistance Produce Hyperglycemia in
Type 2 Diabetes
Cell Dysfunction
Insulin Resistance
Increased
Lipolysis
Pancreas
Liver
Islet Cell Degranulation;
Reduced Insulin Content
↑Glucose
Production
Increased Glucose Output
Reduced
Plasma Insulin
Hyperglycemia
Elevated
Plasma FFA
↓Glucose
Uptake
Muscle
Adipose Tissue
Decreased Glucose
Transport & Activity
(expression)
of GLUT4
9
Frequent Symptoms of Type 2
Diabetes
• Usually slow onset • Weakness/fatigue
• May be
• Glycosuria
asymptomatic
• Dry, itchy skin
• 3 P’s:
• Visual changes
• polyuria,
• Skin and mucous
• polydipsia,
• polyphagia
membrane
infections
10
Stages of Type 2 Diabetes Related to
Beta-Cell Function
100
75
BetaCell
Function 50
(%)
Type 2
Phase 1
IGT
25
Postprandial
Hyperglycemia
0
12 10
6
2
Type 2
Phase 3
Type 2
Phase 2
0
2
6
10
14
Years from Diagnosis
Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).
11
Significant Loss of BetaCell Function at
Diagnosis
• UKPDS
• At the time diabetes was diagnosed, 50% of
betacell function was lost
• Betacell function continued to decline over
the 10-year course of the study
• Correlated with loss of response to oral therapy
• Secondary failure (progressive loss of
beta cell)
UKPDS 16. Diabetes. 1995;44:1249-1258
Turner RC, et al. JAMA. 1999 Jun 2;281(21):2005-2012.
12
Glucose Excursions in Type 2 Diabetes
400
Meal
Meal
Meal
300
Diabetic
Glucose
(mg/dL) 200
100
Normal
0
0600
1000
1400
1800
2200
0200
0600
Time of Day
Polonsky KS, et al. NEJM. 1988;21;318(19):1237-1239.
13
Insulin Secretion in Type 2 Diabetes
Meal
800
Meal
Meal
Normal
Type 2 diabetes
600
Insulin
Secretion 400
(pmol/min)
200
0
0600
1000
1400
1800
2200
0200
Time (24hour clock)
Polonsky KS, et al. N Engl J Med. 1996 Mar 21;334(12):777-783.
14
Normal A1C < 6.0%
A1C =
PPG + FPG
CDC. National Diabetes Fact Sheet. 2003; Atlanta, GA. US Dept. HHS, Center for
Disease Control and Prevention 2003.
15
Relative Risk for Death Increases with
2hour Blood Glucose Regardless of
the FPG Level
2.4
2.0
Relative
Risk of
Death*
1.6
1.2
1.0
< 110
110-125 126- 139
>140
> 199
140-198
< 140
Fasting Plasma Glucose (mg/dL)
*Adjusted for age, sex, study center
Adapted from DECODE Study Group. Lancet. 1999;354:617-621.
16
As Patients Get Closer to A1C Goal, the Need
to Manage PPG Significantly Increases
Increasing Contribution of PPG as A1C Improves
100
30%
80
%
Contribution
60
70%
60%
50%
55%
FPG
PPG
40
20
70%
30%
40%
50%
45%
0
< 10.2
10.2 to 9.3 9.2 to 8.5
8.4 to 7.3
< 7.3
A1C Range (%)
Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and
postprandial plasma glucose increments to the overall diurnal hyperglycemia
of Type 2 diabetic patients: variations with increasing levels of HBA(1c).
Diabetes Care. 2003;26:881-885.
17
Blood Glucose Control Guidelines
American Diabetes American College
of Endocrinology
Association
(ACE)
(ADA)
Preprandial blood
glucose
90–130 mg/dL
< 110 mg/dL
Postprandial blood
glucose
< 180 mg/dL
< 140 mg/dL
(peak)
(2 hour)
< 7%
≤ 6.5%
A1C
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50.
American College of Endocrinology. Endocr Pract. 2002;8(suppl 1):40-82.
18
UKPDS 57: Over Time Increasing
Numbers of Patients Require Insulin
60
Chlorpropamide
Glipizide
Patients
Requiring
Additional
Insulin (%)
40
20
0
1
2
3
4
5
6
Years from Randomization
Adapted from: Wright A, et al. Diabetes Care. 2002;25:330–336.
19
Insulin is Associated with the Most
Profound Effects on A1C
Alpha
Metformin glycosidase TZDs
Inhibitors
Insulin
1.02.0
1.02.0
0.51.0
0.51.0
1.52.5
SU=
2550
mg/day
100 mg w/
meals
1645
None
mg/day
Diet &
SU &
Exercise Glitinides
Typical
Change 0.52.0
in A1C
Max
Dose
2040
mg/day;
Glitinides:
4120 mg
Before
meals
Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.
20
Human Insulins
• Regular
• Neutral Protamine Hagedorn (NPH)
• Premix 70/30 (70% NPH / 30% Regular)
21
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Theoretical representation of
expected insulin release in
nondiabetic subjects
Baseline
Level
Time (hours)
SC injection
22
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Regular insulin (human)
Theoretical representation of
profile associated with Regular
Insulin (human)
Baseline
Level
Time (hours)
SC injection
23
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
NPH insulin (human)
Theoretical representation of
profile associated with NPH Insulin
Baseline
Level
Time (hours)
SC injection
24
Human Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Human Premix 70/30
(70% NPH & 30% Regular)
Theoretical representation of
profile associated with Human
Premix 70/30
Baseline
Level
Time (hours)
SC injection
25
Analog Insulins
• Rapid-acting
• Basal
• Premix
26
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Theoretical representation of
expected insulin release in
nondiabetic subjects
Baseline
Level
Time (hours)
SC injection
27
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Rapid-Acting Insulin Analog
Theoretical representation of
profile associated with rapid-acting
Insulin Analog
Baseline
Level
Time (hours)
SC injection
28
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
QD (basal) Analog Insulin
Theoretical representation
of profile associated with
Basal Analog Insulin
Baseline
Level
Time (hours)
SC injection
29
Analog Insulin Time-Action Patterns
Change in serum insulin
Normal insulin secretion
at mealtime
Insulin Analog Premix
Theoretical representation of
profile associated with Insulin
Analog Premix
Baseline
Level
Time (hours)
SC injection
30
“Although insulin therapy has not
traditionally been implemented early
in the course of Type 2 diabetes,
there is no reason why it should not be…”
Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.
31