Type 1 Diabetes in AdultsType 1 Diabetes in Adults

Andrej Janež, MD PhD

Dept. of Endocrinology Diabetes and Metabolic Diseases

University Medical Center Ljubljana

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

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

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