Type 1 Diabetes in Adults
Francine Ratner Kaufman, M.D.
Distinguished Professor of Pediatrics
The Keck School of Medicine of USC
Head, Center for Diabetes and
Endocrinology
Childrens Hospital Los Angele
Prevalence of Diabetes
in the United States
US Population: 275 Million in 2000
Undiagnosed
diabetes
5.2 million
Diagnosed
type 2 diabetes
12 million
Diagnosed
type 1 diabetes
~1.0 million
Type 1 diabetes
misdiagnosed as
type 2 diabetes
~1.0 million
Centers for Disease Control. Available at: http://www.cdc.gov/diabetes/pubs/estimates.htm;
EURODIAB ACE Study Group. Lancet. 2000;355:873-876; Harris MI. In: National
Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK;
1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001
Incidence of Type 1 Diabetes
• Incidence increasing by 3.4% per year
• 50% of patients diagnosed before age 20 years
• 50% of patients diagnosed after age 20 years
— Often mistaken for type 2 diabetes—may make up
10% to 30% of individuals diagnosed with type 2
diabetes
— Oral agents ineffective; insulin therapy required
— Autoimmune process slower and possibly different
— Can usually be confirmed by beta cell antibodies
— Loss of c-peptide
EURODIAB ACE Study Group. Lancet. 2000;355:873-876;
Naik RG, Palmer JP. Curr Opin Endocrinol Diabetes. 1997;4:308-315
Making the Diagnosis of Type 1 Diabetes
Symptoms of diabetes
plus
Polyuria, polydipsia,
polyphagia, diabetic
ketoacidosis (DKA)
Random plasma glucose
200 mg/dL*
Fasting plasma glucose (FPG)
126 mg/dL*
Oral glucose tolerance
test (OGTT) with 2-hour value
200 mg/dL*
Loss of c-peptide
c-peptide<0.8 ng/dL
Presence of islet autoantibodies
GADA, ICA, IA-2A, IAA
*Requires confirmation by repeat testing
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10
Natural History of “Pre”–Type 1
Diabetes
-Cell
mass 100%
Putative
trigger
Cellular autoimmunity
Circulating autoantibodies (ICA, GAD65, ICA512A, IAA)
Loss of first-phase
insulin response (IVGTT)
Abnormal glucose
tolerance (OGTT)
Genetic
predisposition
Insulitis
-Cell injury
Time
Eisenbarth GS. N Engl J Med. 1986;314:1360-1368
-Cell
insufficienc
y
Diabetes
Clinical
onset
Rationale for Intensive Therapy
of Type 1 Diabetes
Glucose Control Is Critical
Cumulative Incidence of Nephropathy
DCCT
Cumulative
percentage
40%
Combined Primary Prevention and Secondary
Intervention Cohorts
Intensive
Conventional
30%
Microalbuminuria
P<0.001
20%
10%
Albuminuria
P=0.006
0%
0
1
2
3
4
5
Years
DCCT Research Group. N Engl J Med. 1993;329:977-986
6
7
8
9
Risk of Progression of Microvascular
Complications vs A1C
DCCT
Relative 20
risk
Retinopathy
Neuropathy
Microalbuminuria
15
10
5
0
1
5
6
7
8
9
A1C (%)
A1C=hemoglobin A1c
Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254
10
11
12
Intensive Therapy for Diabetes:
Reduction in Incidence of Complications
T1DM
DCCT
T2DM
Kumamoto
T2DM
UKPDS
9%  7%
9%  7%
8%  7%
Retinopathy
63%
69%
17%–21%
Nephropathy
54%
70%
24%–33%
Neuropathy
60%
58%
–
Cardiovascular
disease
41%*
52*
16%*
A1C
T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.
*Not statistically significant due to small number of events.
†Showed statistical significance in subsequent epidemiologic analysis.
DCCT Research Group. N Engl J Med. 1993;329:977-986; Ohkubo Y, et al. Diabetes Res Clin
Pract. 1995;28:103-117; UKPDS 33: Lancet. 1998;352: 837-853; Stratton IM, et al. Brit Med J.
2000;321:405-412.
Long-term Microvascular Risk Reduction
in Type 1 Diabetes
Combined DCCT-EDIC
Intensive
A1C 12
%
Conventional
Retinopathy
progression
(incidence)
0.5
0.4
10
%
0.3
8%
0.2
0.1
6%
P<0.00 P<0.00 P=0.61
1
1
DCCT
EDIC EDIC
End of
Year 1 Year 7
randomized
treatment
0
0
No. Evaluated
Conventional
Intensive
DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569
1
169
191
2
3
4
5
Years in EDIC
203
222
220
197
581
596
158
170
6
7
192
218
200
180
Cost-Effectiveness of Intensive
Therapy in Type 1 Diabetes
DCCT Modeling Study
Proliferative retinopathy
Years Free From Complication
(Projected Average)
Conventional
Intensive
treatment
treatment
39.1
53.9
Blindness
49.1
56.8
Microalbuminuria
34.5
43.7
End-stage renal disease
(ESRD)
Neuropathy
55.6
61.3
42.3
53.2
Amputation
39.1
53.9
DCCT Research Group. JAMA. 1996;276:1409-1415
Principles of Intensive Therapy
of
Type 1 Diabetes
Targets
Current Targets for Glycemic Control
ADA
A1C (%)
ACE
LA
IDF
<7.0
6.5
90-130
<110
110
<100
<180*
<140
140
<135
<6.5
6.5
Normal: 4%–6%
Fasting/Preprandial (mg/dL)
(plasma equivalent)
Postprandial (mg/dL)
(2-hour)
*Peak
American Diabetes Association. Diabetes Care. 2004,27:S15-S35.
The American Association of Clinical Endocrinologists. Endocr Pract. 2002; 8(suppl. 1):40-82.
Chacra AR, et al. Diabetes Obes Metab. 2005;7:148-160.
IDF (Europe) European Diabetes Policy Group. Diabet Med. 1999;16:716-730.
Principles of Intensive Therapy
of
Type 1 Diabetes
Insulin Options
Action Profiles of Insulins
Aspart, glulisine, lispro 4–5 hours
Regular 6–8 hours
Plasma
insulin
levels
NPH 12–16 hours
Detemir ~14 hours
Ultralente 18–20 hours
Glargine ~24 hours
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Hours
Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26:575-598; Barlocco D. Curr Opin Invest
Drugs. 2003;4:1240-1244; Danne T et al. Diabetes Care. 2003;26:3087-3092
Normal Daily Plasma Insulin Profile
Nondiabetic Obese Individuals
U/mL
100
B
L
D
1200
1800
80
60
40
20
0600
0800
Time of day
B=breakfast; L=lunch; D=dinner
Polonsky KS et al. N Engl J Med. 1988;318:1231-1239
2400
0600
Basal/Bolus Treatment Program with Rapidacting and Basal Analogs
Plasma insulin
Breakfast
Lunch
Rapid
Dinner
Rapid
Rapid
Basal
4:00
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
Physiologic Multiple Injection Regimens
The Basal-Bolus Insulin Concept
• Basal insulin
— Controls glucose production between meals and overnight
— Near-constant levels
— Usually ~50% of daily needs
• Bolus insulin (mealtime or prandial)
— Limits hyperglycemia after meals
— Immediate rise and sharp peak at 1 hour postmeal
— 10% to 20% of total daily insulin requirement at each meal
• For ideal insulin replacement therapy, each component
should come from a different insulin with a specific profile
or via an insulin pump (with one insulin)
Basal-bolus Therapy:
— More frequent decision making, testing,
and insulin dosing
— Allows for variable food consumption
based on hunger level
— Ability to skip meal or snack if desired
(bedtime)
— Reduced variability of insulin absorption
— Easy to adapt to acute changes in
schedule (exercise, sleeping in on
weekends)
Insulin Injection Devices
Insulin pens
• Faster and easier
than syringes
— Improve patient
attitude and
adherence
— Have accurate
dosing
mechanisms, but
inadequate
resuspension of
NPH may be a
problem
Mealtime Insulin and Severe Hypoglycemia
Aspart vs Regular Insulin
All severe hypoglycemia
Favors
Aspart
Favors
Regular
Insulin P Values
NS
Nocturnal event
0.076
Nocturnal, glucagon
required
<0.050
4–6 hours postmeal
<0.005
0.1
Home PD et al. Diabet Med. 2000;17:762-770
1
Relative risk
10
Variable Basal Rate Continuous Subcutaneous Insulin
Infusion (CSII)
75
Plasma Insulin µU/ml)
Breakfast
Lunch
Dinner
50
Bolus Bolus
Bolus
25
Basal Infusion
4:00
8:00
12:00
16:00
Time
20:00
24:00
4:00
8:00
Insulin Pumps
Continuous Subcutaneous Insulin Infusion
(CSII)
• For motivated patients
• Expensive
• External, programmable pump
connected to an indwelling
subcutaneous catheter
—Only rapid-acting insulin
—Programmable basal rates
—Bolus dose without extra injection
—New pumps with dose calculator
function
—Bolus history
• Requires support system of qualified
providers
CSII vs Multiple Injections of Insulin
Meta-analyses
Injection
Therapy
Better
Pump
Therapy
Better
Blood glucose
concentration
Glycated hemoglobin
A1C
Insulin dose
-2
-1
0
Mean difference
Pickup et al. 12 RCTs
RCT=randomized controlled trial
1 2
Weissberg-Benchell et al. 11
RCTs
Pickup J et al. BMJ. 2002;324:1-6;
Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087
Balancing Risk of Severe Hypoglycemia Against the Risk of
Complications
DCCT
Retinopathy Progression
Severe
Hypoglycemia
120
100
patien 100
tyears 80
100
16
patient-14
years
60
8
12
10
6
40
4
20
2
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5
0
5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5
A1C (%)
DCCT Research Group. N Engl J Med. 1993;329:977-986
A1C (%)
Hypoglycemia
Risk Factors
Behavioral Factors
Patient Factors
• Hypoglycemia unawareness
• History of previous
hypoglycemia
• Defective glucose
counterregulation
• Long duration of diabetes
• Erratic insulin absorption
• Age less than 5 to 7 years
• Dietary inconsistency
– Prolonged fasting
– Missed meal or snack
• Strenuous exercise
Medical Factors
•
•
•
•
Drug side effects (-blockers)
Dosing errors
Unpredictable insulin kinetics
Inappropriate insulin
distribution
Weight Gain
• Insulin therapy reverses catabolic effects of
diabetes
— Glycosuria reduced
— Normal fuel-storage mechanisms restored
• Risk of hypoglycemia often causes patients to
increase caloric intake and avoid exercise
• Risk of weight gain decreases with more
physiologic insulin administration
— Flexible insulin dosing to meet dietary and exercise
needs
Elderly Treatment Considerations
Special Considerations in the Elderly
With Type 1 Diabetes
• Intensive therapy/tight control for otherwise
healthy elderly patients
• Less strict glycemic goals for elderly patients
with severe complications or comorbidities or
with cognitive impairment
— FPG <140 mg/dL
— PPG <220 mg/dL
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004
Risk of Hypoglycemia in the Elderly
• Erratic eating
(quantities)
Food Intake
• Erratic timing of
meals
Renal
Function
• Renal impairment
40
50
60
Age (years)
70
80
Treatment Challenges in the Elderly
With Type 1 Diabetes
• Lack of thirst perception predisposes to hyperosmolar
state
• Confusion of polyuria with urinary incontinence or
bladder dysfunction
• Increased risk of and from hypoglycemia
— Altered perception of hypoglycemic symptoms
— Susceptibility to serious injury from falls or accidents
• Compounding of diabetic complications by effects of
aging
• Frequent concurrent illnesses and/or medications
• More frequent and severe foot problems
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004
Monitoring Outcomes and
Managing Risk Factors
Follow-up Visits
Monitoring of Target Values:
Cardiovascular Risk Factors
Frequency
Goal
Blood pressure
Quarterly
<130/80 mm Hg
HDL cholesterol
Annually (more often >40 mg/dL, males
if control poor)
>50 mg/dL, females
LDL cholesterol
Annually (more often <100 mg/dL
if control poor)
May be different in young
children
Triglycerides
Annually (more often <150 mg/dL
if control poor)
Creatinine
Annually
<1.3 mg/dL
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004
Follow-up Visits
Quarterly Evaluations
Frequency
Assessment
General checkup
(including
weight/BMI, A1C)
Quarterly
General health
Foot exam
Quarterly
(or every visit)
Peripheral neuropathy
and infection
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004
Follow-up Visits
Annual Evaluations
Frequency
Assessment
Skin examination
Annually
Peripheral neuropathy
Neurologic examination
Annually
Autonomic and peripheral
neuropathy
Dilated eye
examination
Annually (in adolescents and
>3 years after type 1
diagnosis)
Annually (in adolescents and
>3 years after type 1
diagnosis)
Annually (more often if CVD
present)
Retinopathy
Annually
Thyroid disease,
celiac disease, etc
Microalbuminuria
Cardiac examination
Screening for other
autoimmune conditions
Target <30 mg/g creatinine
Development/
progression of CVD
Cefalu WT et al, eds. CADRE Handbook of Diabetes Management. New York, NY:
Medical Information Press; 2004
Diabetes as a Risk Equivalent of CAD
7-Year Incidence of
Myocardial Infarction (%)
Nondiabetic, n=1373
45
45.0%
Diabetic, n=1059
40
35
30
25
18.8%
20.2%
No DM, +MI
+DM, No MI
20
15
10
5
3.5%
0
No DM, No MI
DM=diabetes mellitus; MI=myocardial infarction.
Haffner SM, et al. N Engl J Med. 1998;339:229-234.
+DM, +MI
ABCs of CVD Risk Management
Intervention
A
• A1c
• Antiplatelets/anticoagulants
• ACE inhibitors/ARBs
• Antianginals
B
• BP control
• -blockers
Goals
• Treat all high-risk patients with
one of these
• Optimize BP especially if CVD,
type 2 diabetes, or low EF
present
• Relieve anginal symptoms, allow
patient to exercise
• Aim for BP <130/85 mm Hg, or
<130/80 mm Hg for type 2
diabetes
• Post MI or low EF
CVD=cardiovascular disease; ACE=angiotensin converting enzyme;
ARB=angiotensin receptor blocker; BP=blood pressure; EF=ejection fraction;
MI=myocardial infarction.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
ABCs of CVD Risk Management (cont.)
Intervention
C
• Cholesterol management
Goals
• LDL-C targets, ATP III guidelines
— CHD, CHD risk
equivalents: <100 mg/dL
— 2 RF: <130 mg/dL
— 0-1 RF: <160 mg/dL
• Cigarette-smoking cessation
• HDL-C: 40 mg/dL (men)
50 mg/dL (women)
• TG: <150 mg/dL
• Long-term smoking cessation
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
ABCs of CVD Risk Management (cont.)
Intervention
D
• Dietary/weight counseling
• Diabetes management
E
• Exercise
• Education of patients and
families
Goals
• Achieve optimal BMI
•  saturated fats;  fruits,
vegetables, fiber
• Achieve HbA1c <7%
• Improve physical fitness
(aim for 30 min/d on most
days per week)
• Optimize awareness of CAD
risk factors
BMI=body mass index; HbA1c=glycosylated hemoglobin;
CAD=coronary artery disease.
Braunstein JB et al. Cardiol Rev. 2001;9:96-105.
Management of Cardiovascular Risk in
Diabetes
Blood Pressure Control
Treatment target: Blood pressure <130/80 mm Hg
Standard
methods
(1, 2, or 3
agents may be
needed)
• Angiotensin-converting enzyme (ACE)
inhibitor
• Angiotensin-receptor blocker (ARB)
• Thiazide
• -Blocker
Individualized
options
• -Adrenergic blocker or central adrenergic
agent
• Long-acting calcium channel blocker
(CCB)
• Loop diuretic
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S65-S67;
Arauz-Pacheco C et al. Diabetes Care. 2002;25:134-147
Management of Cardiovascular Risk in Diabetes
LDL Control
Treatment target:
LDL <100 mg/dL, no CVD
LDL <70 mg/dL, with CVD
Standard
method
• HMG-CoA reductase inhibitors (statins)
Individualized
options
• Intestinal cholesterol absorption inhibitors
• Bile acid–binding resins
• Nicotinic acid
HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A
American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S68-S71;
Grundy SM et al. Circulation. 2004;110:227-239; Haffner SM. Diabetes Care.
1998;21:160-178; Lindgärde F. J Intern Med. 2000;248:245-254
The Future of Type 1 Diabetes Care
Emerging Type 1 Diabetes Therapies
Insulins
Aerodose®
AERx®
Exubera®
Oralin®
Technosphere®
insulin
Inhaled liquid aerosol insulin; portable device
delivery
Inhaled liquid aerosol insulin; portable device
delivery
Particulate cloud inhaled insulin; portable device
delivery
Buccally absorbed, liquid aerosol insulin; portable
device delivery
Inhaled dry powder insulin; portable device delivery
Pramlintide
(Symlin®)
Injectable amylin analogue; slows gastric emptying,
suppresses glucagon, and increases satiety
Islet cell transplant
Transplantation of donor pancreatic -cells;
restores endogenous insulin secretion
Inhaled Insulin in Type 1 Diabetes
73 Patients Taking Inhaled Insulin TID in Addition to Injected
Long-Acting Insulin
A1C (%)
Subcutaneous insulin:
16 U regular + 31 U
long-acting
10
9
Inhaled insulin:
12 mg inhaled + 25 U
ultralente
8
7
6
0
4
8
Weeks
Skyler JS et al. Lancet. 2001;357:331-335
12
New Class of Agents for Diabetes
Pramlintide
Glucose Flux in Healthy Subjects
Mixed Meal (with ~85 g Dextrose)
Mixed Meal (with ~85 g Dextrose)
200
0.6
0.4
Grams of Glucose flux/min
Plasma Glucose (mg/dL)
160
120
80
40
Appearance
Meal Derived Glucose
0.2
Hepatic Glucose Production
0
Total Glucose Uptake
-0.2
Disappearance
-0.4
-0.6
0
-30
0
60
120
180
Time (min)
Adapted and calculated from Pehling G., et al. J. Clin. Invest. 1984; 74: 985-991
-30
0
60
120
Time (min)
180
Multihormonal Regulation of Glucose
Appearance and Disappearance
0.6
Mixed Meal (with ~85 g Dextrose)
Regulated by hormones:
amylin, CCK, GLP-1, etc.
Grams of Glucose flux/min
0.4
0.2
Meal-Derived Glucose
Hepatic Glucose Production
0
Balance of insulin
suppression and
glucagon stimulation
Total Glucose Uptake
-0.2
Insulin-mediated
glucose uptake
-0.4
-0.6
-30 0
120
240
360
480
Time (min) From Start of Mixed Meal
Calculated from data in Pehling G, et al. J Clin Invest 1984; 74: 985-991
Pramlintide Improves Postprandial
Glucose
TYPE 1 DIABETES
Lispro Insulin
Pramlintide 60 g + Lispro Insulin
300
Mean (SE)
Plasma Glucose
(mg/dL)
250
200
150
100
0
60
120
240
Regular Insulin
Pramlintide 60 g + Regular Insulin
300
Mean (SE)
Plasma Glucose
(mg/dL)
180
250
200
150
100
0
60
120
180
240
Time Relative to Meal and Pramlintide (min)
Evaluable population; Mean (SE)
Pramlintide + Lispro insulin (n = 20)
Pramlintide + Regular insulin (n = 18)
Pramlintide Acetate Prescribing Information, 2005
Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079
Pramlintide Clinical Effects
TYPE 1 DIABETES COMBINED PIVOTALS
Placebo + Insulin
30 or 60 g Pramlintide TID or QID + Insulin
 Insulin Use (%)
 A1C (%)
Week 4 Week 13 Week 26
0
 Weight (kg)
Week 4 Week 13 Week 26
Week 4 Week 13 Week 26
1
8
6
-0.2
0
4
-0.4
***
-0.6
***
***
-0.8
*
2
***
-1
0
-2
***
**
-4
Placebo + insulin (N = 538), Baseline A1C = 9.0%
Pramlintide + insulin (N = 716), Baseline A1C = 8.9%
*P <0.05, **P <0.01, ***P <0.0001; ITT population; Mean (SE) change from baseline
Pramlintide Acetate Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc.
Data from Whitehouse FW, et al. Diabetes Care 2002; 25:724-730
Data from Ratner R, et al. Diabetic Med 2004; 21:1204-1212
-2
***
Adverse Events* 5%
PRAMLINTIDE TYPE 1 DIABETES STUDIES
Adverse Event
Nausea
Anorexia
Inflicted Injury
Vomiting
Arthralgia
Fatigue
Allergic
Reaction
Dizziness
Pivotal Studies
Pramlintide
Placebo (%)
(%)
(N=538)
(N=716)
17
48
2
17
10
14
7
11
5
7
7
4
5
6
4
5
*Excluding hypoglycemia, indicated dose (ITT)
AE profile for Dose-Titration Study similar to Pivotals
Pramlintide Acetate Prescribing Information, 2005
Clinical Practice
Study
Pramlintide (%)
(N=265)
37
0
8
7
2
5
<1
2
Continuous Glucose Monitoring
• Benefits of continuous glucose monitoring
— More complete glucose profile than with
traditional SMBG
— Tracking of meal-related glycemic trends
— Detection of nocturnal hypoglycemia
— Facilitation of changes in insulin regimens
— Alarm for highs and lows (GlucoWatch)
• Remaining challenges
—
—
—
—
Daily SMBG still required
Not suited to many patients
Limited accuracy, especially for hypoglycemia
Glycemic pattern results confusing, subject to
interpretation
Future Glucose Monitors
Guardian™ CGMS
Freestyle Navigator™
External Closed-Loop
• Minimally invasive
continuous glucose
monitors
• Implanted glucose
sensors
• Implanted insulin
pumps
• “Closed-loop”
systems
Implanted Closed-Loop
Can Type 1 Diabetes Be “Cured?”
Islet Cell Transplantation
7 Type 1 Patients, Aged 29 to 54 Years, With History of
Severe Hypoglycemia and Metabolic Instability
Mean 9
A1C
(%)
8
Mean
6
C-peptide
(ng/mL) 5
8.4
%
5
5.7
4
7
6
*
3
*
*
2
5.7
%
2.5
1
4
0.48
0
Baseline
6 months
after
transplant
*P<0.001 vs baseline
Shapiro AMJ et al. N Engl J Med. 2000;343:230-238
Baseline Fasting 90 min
postmeal
6 months
after
transplant
Opportunities for Intervention in
Type 1 Diabetes
TrialNet
Multiple antibody positive
Genetically at risk
Loss of first-phase
insulin response
-Cell
mass
Newly
diagnosed
diabetes
Genetic
predisposition
Insulitis
-Cell injury
Time
-Cell
insufficienc
y
Diabete
s