Type 1 Diabetes in Adults

Type 1 Diabetes in AdultsType 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

Undiagnosed diabetes

5.2 million

Prevalence of DiabetesPrevalence of Diabetesin the United Statesin the United States

Diagnosed type 2 diabetes

12 million

Diagnosed type 1 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: NationalDiabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: NIDDK;1995:15-36; U.S. Census Bureau Statistical Abstract of the U.S.; 2001

US Population: 275 Million in 2000

Type 1 diabetes misdiagnosed as type 2 diabetes

~1.0 million

Incidence of Type 1 DiabetesIncidence 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

American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10

*Requires confirmation by repeat testing

Making the Diagnosis of Type 1 DiabetesMaking the Diagnosis of Type 1 Diabetes

Symptoms of diabetes Polyuria, polydipsia,polyphagia, diabetic

plus ketoacidosis (DKA)

Random plasma glucose 200 mg/dL*

Fasting plasma glucose (FPG) 126 mg/dL*

Oral glucose tolerancetest (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

Putativetrigger

Circulating autoantibodies (ICA, GAD65, ICA512A, IAA)Cellular autoimmunity

Loss of first-phase insulin response (IVGTT)

Abnormal glucosetolerance (OGTT) Clinical

onset

Time

-Cell mass 100%

-Cell insufficienc

y

Geneticpredisposition

Insulitis-Cell injury

Eisenbarth GS. N Engl J Med. 1986;314:1360-1368

Diabetes

Natural History of “Pre”Natural History of “Pre”––Type 1 Type 1 DiabetesDiabetes

Rationale for Intensive TherapyRationale for Intensive Therapyof Type 1 Diabetesof Type 1 Diabetes

Glucose Control Is CriticalGlucose Control Is Critical

Cumulative Incidence of NephropathyDCCT

Years

10%

20%

30%

40%

Microalbuminuria

Albuminuria

0%

0 1 2 3 4 5 6 7 8 9

Cumulative percentage

Intensive

Conventional

Combined Primary Prevention and Secondary Intervention Cohorts

P<0.001

P=0.006

DCCT Research Group. N Engl J Med. 1993;329:977-986

Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254

RetinopathyNeuropathyMicroalbuminuria

20

15

10

5

051

Relative risk

A1C (%)

6 7 8 9 10 11 12

Risk of Progression ofRisk of Progression of Microvascular Microvascular Complications vs A1C DComplications vs A1C DCCTCCT

A1C=hemoglobin A1c

*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.

Intensive Therapy for Diabetes:Intensive Therapy for Diabetes:Reduction in Incidence of ComplicationsReduction in Incidence of Complications

T1DM DCCT

T2DMKumamoto

T2DMUKPDS

A1C 9% 7% 9% 7% 8% 7%

Retinopathy 63% 69% 17%–21%

Nephropathy 54% 70% 24%–33%

Neuropathy 60% 58% –

Cardiovascular disease

41%* 52* 16%*

T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

Long-term Microvascular Risk Reduction Long-term Microvascular Risk Reduction in Type 1 Diabetesin Type 1 DiabetesCombined DCCT-EDICCombined DCCT-EDIC

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569

0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4 5 6 7

Years in EDICNo. EvaluatedConventional 169 203 220 581 158 192

200Intensive 191 222 197 596 170 218

180

DCCTEnd of

randomized treatment

EDICYear 1

EDICYear 7

6%

8%

10%

12%

A1C Retinopathy progression(incidence)

Intensive Conventional

P<0.001

P<0.001

P=0.61

Cost-Effectiveness of IntensiveCost-Effectiveness of IntensiveTherapy in Type 1 Diabetes Therapy in Type 1 Diabetes DCCT Modeling StudyDCCT Modeling Study

Years Free From Complication(Projected Average)

Conventional treatment

Intensivetreatment

Proliferative retinopathy 39.1 53.9

Blindness 49.1 56.8

Microalbuminuria 34.5 43.7

End-stage renal disease (ESRD)

55.6 61.3

Neuropathy 42.3 53.2

Amputation 39.1 53.9

DCCT Research Group. JAMA. 1996;276:1409-1415

Principles of Intensive Therapy Principles of Intensive Therapy ofof

Type 1 DiabetesType 1 Diabetes

TargetsTargets

Current Targets for Glycemic ControlCurrent Targets for Glycemic ControlADA ACE LA IDF

A1C (%) Normal: 4%–6%

<7.0 6.5 <6.5 6.5

Fasting/Preprandial (mg/dL)

(plasma equivalent)

90-130 <110 110 <100

Postprandial (mg/dL)

(2-hour)

<180* <140 140 <135

*PeakAmerican 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 Principles of Intensive Therapy ofof

Type 1 DiabetesType 1 Diabetes

Insulin OptionsInsulin Options

Action Profiles of InsulinsAction Profiles of Insulins

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Plasmainsulinlevels

Regular 6–8 hours

NPH 12–16 hours

Ultralente 18–20 hours

Hours

Glargine ~24 hours

Aspart, glulisine, lispro 4–5 hours

Detemir ~14 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

Polonsky KS et al. N Engl J Med. 1988;318:1231-1239

0600 0600

Time of day

20

40

60

80

100 B L D

Normal Daily Plasma Insulin ProfileNormal Daily Plasma Insulin ProfileNondiabetic Obese IndividualsNondiabetic Obese Individuals

B=breakfast; L=lunch; D=dinner

0800 18001200 2400

U/mL

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Basal

Pla

sma

insu

lin

Basal/Bolus Treatment Program with Rapid-Basal/Bolus Treatment Program with Rapid-acting and Basal Analogsacting and Basal Analogs

Rapid RapidRapid

• 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)

Physiologic Multiple Injection RegimensPhysiologic Multiple Injection RegimensThe Basal-Bolus Insulin ConceptThe Basal-Bolus Insulin Concept

Basal-bolus Therapy: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 DevicesInsulin 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

0.1 110

Mealtime Insulin and Severe HypoglycemiaMealtime Insulin and Severe HypoglycemiaAspart vs Regular InsulinAspart vs Regular Insulin

All severe hypoglycemia

Nocturnal event

Nocturnal, glucagon required

4–6 hours postmeal

Favors Aspart

Favors RegularInsulin

Relative risk

Home PD et al. Diabet Med. 2000;17:762-770

P Values

NS

0.076

<0.050

<0.005

Variable Basal Rate Continuous Subcutaneous Insulin Variable Basal Rate Continuous Subcutaneous Insulin Infusion (CSII)Infusion (CSII)

4:004:00

2525

5050

7575

16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

Pla

sma

Insu

lin

P

lasm

a In

suli

n µ

U/m

l)

U/m

l)

8:008:0012:0012:008:008:00

TimeTime

Basal Infusion

Bolus Bolus Bolus

Insulin PumpsInsulin PumpsContinuous Subcutaneous Insulin Infusion Continuous Subcutaneous Insulin Infusion (CSII)(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

-2 -1 0 12

CSII vs Multiple Injections of InsulinCSII vs Multiple Injections of InsulinMeta-analysesMeta-analyses

Blood glucose concentration

Glycated hemoglobin

A1C

Insulin dose

InjectionTherapyBetter

PumpTherapyBetter

Mean difference

Pickup J et al. BMJ. 2002;324:1-6;Weissberg-Benchell J et al. Diabetes Care. 2003;26:1079-1087

Pickup et al. 12 RCTs Weissberg-Benchell et al. 11 RCTs

RCT=randomized controlled trial

Balancing Risk of Severe Hypoglycemia Against the Risk of Balancing Risk of Severe Hypoglycemia Against the Risk of ComplicationsComplicationsDCCTDCCT

DCCT Research Group. N Engl J Med. 1993;329:977-986

2

0

A1C (%)

4

6

8

10

12

14

16

5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5

100 patient-years

0

100 patient-years

5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010.5

20

40

60

80

100

120

A1C (%)

Severe Hypoglycemia

Retinopathy Progression

HypoglycemiaHypoglycemiaRisk FactorsRisk Factors

Patient FactorsPatient Factors• Hypoglycemia unawarenessHypoglycemia unawareness• History of previous History of previous

hypoglycemiahypoglycemia• Defective glucose Defective glucose

counterregulationcounterregulation

• Long duration of diabetesLong duration of diabetes

• Erratic insulin absorptionErratic insulin absorption

• Age less than 5 to 7 yearsAge less than 5 to 7 years

Behavioral FactorsBehavioral Factors• Dietary inconsistencyDietary inconsistency

– Prolonged fastingProlonged fasting

– Missed meal or snackMissed meal or snack

• Strenuous exerciseStrenuous exercise

Medical FactorsMedical Factors• Drug side effects (Drug side effects (-blockers)-blockers)

• Dosing errorsDosing errors

• Unpredictable insulin kineticsUnpredictable insulin kinetics

• Inappropriate insulin Inappropriate insulin distributiondistribution

Weight Gain 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 ConsiderationsElderly Treatment Considerations

Special Considerations in the ElderlySpecial Considerations in the ElderlyWith Type 1 DiabetesWith 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 ElderlyRisk of Hypoglycemia in the Elderly

• Erratic eating (quantities)

• Erratic timing of meals

• Renal impairment

40 50 60 70 80

Risk of H

ypoglycemia

Food Intake

Renal Function

Age (years)

Treatment Challenges in the ElderlyTreatment Challenges in the ElderlyWith Type 1 DiabetesWith 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


Monitoring Outcomes andMonitoring Outcomes andManaging Risk FactorsManaging Risk Factors

Follow-up VisitsFollow-up VisitsMonitoring of Target Values:Monitoring of Target Values:Cardiovascular Risk FactorsCardiovascular Risk Factors

Frequency Goal

Blood pressure Quarterly <130/80 mm Hg

HDL cholesterol Annually (more often if control poor)

>40 mg/dL, males

>50 mg/dL, females

LDL cholesterol Annually (more often if control poor)

<100 mg/dLMay be different in young children

Triglycerides Annually (more often if control poor)

<150 mg/dL

Creatinine Annually <1.3 mg/dL


Frequency Assessment

General checkup (including weight/BMI, A1C)

Quarterly General health

Foot exam Quarterly (or every visit)

Peripheral neuropathy and infection

Follow-up VisitsFollow-up VisitsQuarterly EvaluationsQuarterly 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)

Retinopathy

Microalbuminuria Annually (in adolescents and>3 years after type 1 diagnosis)

Target <30 mg/g creatinine

Cardiac examination Annually (more often if CVD present)

Development/progression of CVD

Screening for other autoimmune conditions

Annually Thyroid disease,

celiac disease, etc

Follow-up VisitsFollow-up VisitsAnnual EvaluationsAnnual Evaluations


Diabetes as a Risk Equivalent of CADDiabetes as a Risk Equivalent of CAD

0

5

10

15

20

25

30

35

40

45

No DM, No MI No DM, +MI +DM, No MI +DM, +MI

DM=diabetes mellitus; MI=myocardial infarction.Haffner SM, et al. N Engl J Med. 1998;339:229-234.

7-Y

ear

Inci

den

ce o

fM

yoca

rdia

l In

farc

tio

n (

%)

Nondiabetic, n=1373

Diabetic, n=1059

3.5%

18.8% 20.2%

45.0%

ABCs of CVD Risk ManagementABCs of CVD Risk Management

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.

• Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes

• Post MI or low EF

• BP control

• -blockers

B

• 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

• A1c

• Antiplatelets/anticoagulants

• ACE inhibitors/ARBs

• Antianginals

A

GoalsIntervention

ABCs of CVD Risk Management ABCs of CVD Risk Management (cont.)(cont.)


Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

• HDL-C: 40 mg/dL (men) 50 mg/dL (women)

• TG: <150 mg/dL

• Long-term smoking cessation• Cigarette-smoking cessation

• LDL-C targets, ATP III guidelines— CHD, CHD risk

equivalents: <100 mg/dL

— 2 RF: <130 mg/dL

— 0-1 RF: <160 mg/dL

• Cholesterol managementC

GoalsIntervention

ABCs of CVD Risk Management ABCs of CVD Risk Management (cont.)(cont.)

BMI=body mass index; HbA1c=glycosylated hemoglobin;CAD=coronary artery disease.


• Improve physical fitness (aim for 30 min/d on most days per week)

• Optimize awareness of CAD risk factors

• Exercise

• Education of patients and families

E

• Achieve optimal BMI saturated fats; fruits,

vegetables, fiber

• Achieve HbA1c <7%

• Dietary/weight counseling

• Diabetes management

D

GoalsIntervention

Treatment target: Blood pressure <130/80 mm HgStandard 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

Management of Cardiovascular Risk in Management of Cardiovascular Risk in DiabetesDiabetesBlood Pressure ControlBlood Pressure Control

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 DiabetesManagement of Cardiovascular Risk in DiabetesLDL ControlLDL Control

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

HMG-CoA=3-hydroxy-3-methylglutaryl coenzyme A

Treatment target: LDL <100 mg/dL, no CVD

LDL <70 mg/dL, with CVD

Standardmethod

• HMG-CoA reductase inhibitors (statins)

Individualized options

• Intestinal cholesterol absorption inhibitors

• Bile acid–binding resins

• Nicotinic acid

The Future of Type 1 Diabetes CareThe Future of Type 1 Diabetes Care

Emerging Type 1 Diabetes TherapiesEmerging Type 1 Diabetes Therapies

Insulins

Aerodose® Inhaled liquid aerosol insulin; portable device delivery

AERx® Inhaled liquid aerosol insulin; portable device delivery

Exubera® Particulate cloud inhaled insulin; portable device delivery

Oralin® Buccally absorbed, liquid aerosol insulin; portable device delivery

Technosphere® insulin

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

Subcutaneous insulin: 16 U regular + 31 U long-acting

Inhaled insulin: 12 mg inhaled + 25 U ultralente

Inhaled Insulin in Type 1 DiabetesInhaled Insulin in Type 1 Diabetes

Skyler JS et al. Lancet. 2001;357:331-335

10

Weeks

A1C (%)

0 4 8 12

73 Patients Taking Inhaled Insulin TID in Addition to Injected Long-Acting Insulin

9

8

7

6

New Class of Agents for DiabetesNew Class of Agents for Diabetes

Pramlintide

Time (min)

Adapted and calculated from Pehling G., et al. J. Clin. Invest. 1984; 74: 985-991

Pla

sma

Glu

cose

(m

g/d

L)

0 1200

40

80

120

160

200

-30 60 180

Mixed Meal (with ~85 g Dextrose)

0 120-0.6

-0.4

-0.2

0

0.2

0.4

0.6

Gra

ms

of

Glu

cose

flu

x/m

in

-30


Meal Derived Glucose

Total Glucose Uptake

60 180

Hepatic Glucose Production

Time (min)

Appearance

Disappearance

Glucose Flux in Healthy SubjectsGlucose Flux in Healthy Subjects

Multihormonal Regulation of Glucose Multihormonal Regulation of Glucose Appearance and DisappearanceAppearance and Disappearance

Time (min) From Start of Mixed Meal


0 120 240 360 480

-0.6

-0.4

-0.2

0

0.2

0.4

0.6G

ram

s o

f G

luco

se f

lux/

min

-30

Calculated from data in Pehling G, et al. J Clin Invest 1984; 74: 985-991

Insulin-mediatedglucose uptake

Balance of insulin suppression and

glucagon stimulation

Regulated by hormones: amylin, CCK, GLP-1, etc.

Meal-Derived Glucose

Hepatic Glucose Production

Total Glucose Uptake

Pramlintide Improves Postprandial Pramlintide Improves Postprandial GlucoseGlucoseTYPE 1 DIABETESTYPE 1 DIABETES

100

150

200

250

300

0 60 120 180 240

Time Relative to Meal and Pramlintide (min)

Mean (SE) Plasma Glucose

(mg/dL)

100

150

200

250

300

0 60 120 180 240

Mean (SE) Plasma Glucose

(mg/dL)

Lispro InsulinPramlintide 60 g + Lispro Insulin

Regular InsulinPramlintide 60 g + Regular Insulin

Evaluable population; Mean (SE)Pramlintide + Lispro insulin (n = 20)Pramlintide + Regular insulin (n = 18)

Pramlintide Acetate Prescribing Information, 2005Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079

Pramlintide Clinical EffectsPramlintide Clinical EffectsTYPE 1 DIABETES COMBINED PIVOTALSTYPE 1 DIABETES COMBINED PIVOTALS

-0.8

-0.6

-0.4

-0.2

0

-4

-2

0

2

4

6

8

-2

-1

0

1

***

***

***

**

*

***

******

Week 4 Week 13 Week 26Week 4 Week 13 Week 26Week 4 Week 13 Week 26

Insulin Use (%) A1C (%) Weight (kg)

Placebo + Insulin30 or 60 g Pramlintide TID or QID + Insulin

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; 25:724-730Data from Ratner R, et al. Diabetic Med 2004; 21:1204-1212

Adverse Events* Adverse Events* 5%5%PRAMLINTIDE TYPE 1 DIABETES STUDIESPRAMLINTIDE TYPE 1 DIABETES STUDIES

275Arthralgia

574Fatigue

7117Vomiting

81410Inflicted Injury

0172Anorexia

374817Nausea

Clinical Practice Study Pivotal Studies

(N=265)(N=716)(N=538)Adverse Event Pramlintide (%)Pramlintide (%)Placebo (%)

*Excluding hypoglycemia, indicated dose (ITT)AE profile for Dose-Titration Study similar to Pivotals

254Dizziness

<165Allergic Reaction

Pramlintide Acetate Prescribing Information, 2005

• 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

Continuous Glucose MonitoringContinuous Glucose Monitoring

Future Glucose Monitors Future Glucose Monitors

• Minimally invasive continuous glucose monitors

• Implanted glucose sensors

• Implanted insulin pumps

• “Closed-loop” systems

External Closed-Loop

Implanted Closed-Loop

Guardian™ CGMS

Freestyle Navigator™

4

5

6

7

8

9

Can Type 1 Diabetes Be “Cured?”Can Type 1 Diabetes Be “Cured?”Islet Cell TransplantationIslet Cell Transplantation

7 Type 1 Patients, Aged 29 to 54 Years, With History of Severe Hypoglycemia and Metabolic Instability

Shapiro AMJ et al. N Engl J Med. 2000;343:230-238

Baseline 6 monthsafter

transplant

MeanA1C (%)

0

1

2

3

4

5

6

Baseline

6 monthsafter

transplant

MeanC-peptide(ng/mL)

Fasting 90 min postmeal

8.4%

5.7% 0.48

2.5

5.7

*

*

*P<0.001 vs baseline

*

Loss of first-phase insulin response

Newly diagnosed diabetes

Genetically at riskMultiple antibody positive

Opportunities for Intervention inType 1 Diabetes

TrialNet

-Cell insufficienc

y

Geneticpredisposition

Insulitis-Cell injury Diabete

s

Time

-Cell mass

Documents

Type 1 Diabetes in Adults