new insulins - adaendo.com filehba1c and plasma glucose 26,056 data points (a1c and 7-point glucose...

New Insulins and

Insulin Delivery Systems

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

ADA: Clinical Practice Recommendations. 2001.

Goals of Intensive DiabetesManagement

● Near-normal glycemia– HbA1c less than 6.5 to 7.0%

● Avoid short-term crisis– Hypoglycemia– Hyperglycemia– DKA

● Minimize long-term complications

● Improve QOL

1

3

5

7

9

11

13

15

6 7 8 9 10 11 12

Retinop

Neph

Neurop

Microalb

RE

LA

TIV

ER

ISK

HbA1cSkyler, Endo Met Cl N Am 1996

Relative Risk of Progression ofDiabetic Complications by Mean HbA1CBased on DCCT Data

HbA1c and Plasma Glucose

● 26,056 data points (A1c and 7-point glucoseprofiles) from the DCCT

● Mean plasma glucose = (A1c x 35.6) – 77.3

● Post-lunch, pre-dinner, post-dinner, andbedtime correlated better with A1c thanfasting, post-breakfast, or pre-lunch

Rohlfing et al, Diabetes Care 25 (2) Feb 2002

Emerging Concepts

The Importance of

Controlling Postprandial Glucose

ACE / AACE Targets for Glycemic Control

HbA1c < 6.5 %

Fasting/preprandial glucose < 110 mg/dL

Postprandial glucose < 140 mg/dL

ACE / AACE Consensus Conference, Washington DC August 2001

Insulin

The most powerful agent wehave

to control glucose

Fred Fred BantingBanting (1891–1941) Charles H. (1891–1941) Charles H. BestBest (1899-1978) John J.R. (1899-1978) John J.R. McLeodMcLeod (1876-1935) (1876-1935)

James B. James B. CollipCollip(1892-1965)(1892-1965)

MarjorieMarjorie (?-?) (?-?)

The discovery of insulin(Toronto 1921)

Patient J.L., December 15, 1922 February 15, 1923

The Miracle of Insulin

Comparison of HumanInsulins / Analogues

Insulin Onset of Duration ofpreparations action Peak action

Regular 30–60 min 2–4 h 6–10 h

Lispro/aspart 5–15 min 1–2 h 4–6 h

NPH/Lente 1–2 h 4–8 h 10–20 h

Ultralente 2–4 h Unpredictable 16–20 h

Glargine 1–2 h Flat ~24 h

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

Breakfast Lunch Dinner

8:0012:008:00

Time

Pla

sma

insu

linIdeal Basal/Bolus InsulinAbsorption Pattern

5/8/20025/8/2002 1313

Rapid-acting Insulin Analogs:Medical Rationale

● Administration at mealtime

● Mimic physiological insulin profile

● Improved postprandial glycemic control

● Lower risk of late hypoglycemia

Gly ThrGlu Phe Tyr Pro Lys Thr

Gly ThrGlu Phe Tyr Lys Pro Thr

23 24 25 26 27 28 29 30

Insulin

Lispro

Primary Structure ofLys(B28), Pro(B29)-Insulin

Gly ThrGlu Phe Tyr Pro Lys Thr

Gly ThrGlu Phe Tyr Asp Lys Thr

23 24 25 26 27 28 29 30

Insulin

Aspart

Primary Structure ofAsp(B28)-Insulin

Dissociation & Absorption of NovoLog

Insulin Aspart (NovoLog )

Regular Human Insulin

Peak Time = 80-120 min

Peak Time = 40-50 min

CapillaryMembrane

Su

bcu

tan

eou

s T

issu

eS

ub

cuta

neo

us

Tis

sue

800

700

600

500

400

300

200

100

0

Ser

um

insu

lin (

pm

ol/L

)

0.2 U/kg SQTime (h)

0 2 4 6 8 10

Insulin aspartRegular insulin

Heinemann L, et al. Diabetes Care. 1998;21:1910.

Insulin Aspart: Mean Serum InsulinProfiles During Euglycemic Clamp inHealthy Volunteers

Glucose Area Under the Curve

60

70

80

90

100

110

120

130-3

0

Fas

t

30 60 90 120

240

Time (min)

Glu

cose

(m

g/d

L) None

RegularAspart

Home PD, et al. Diabetes Care. 1998;21:1904-1909.

BreakfastBreakfast LunchLunch DinnerDinner NPHNPH

mU/LmU/L

8080

6060

4040

2020

00

100100

06:0006:00 12:0012:00 18:0018:00 24:0024:00 06:0006:00

Ser

um

insu

linS

eru

m in

sulin

1010

mmol/Lmmol/L

1616

1414

1212

88

66

1818

Pla

sma

glu

cose

Pla

sma

glu

cose

250250

200200

150150

300300

mg/mg/dLdL

Insulin Aspart

Human Regular

Insulin Aspart vs Human Regular:Glycemic Control

Prandial increment isthe increase in bloodglucose from premealto 90 minutes postmeal

European trial North American trial

Incr

emen

t (m

mol

/L)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

P<0.001 P<0.001

Postprandial Blood Glucose Increment(Mean over the 3 Meals at 6 Months)

NovoLog®

Regular human insulin

Raskin P, et al. Diabetes Care. 2000;23:583.Home PD, et al. Diabetic Medicine. 2000;17:762.

NovoLog®Regular human insulin

100

Study 1 Study 2 Study 3 Study 4

•

•••

0

200

300

400

500

•• Outliers

Median•• ••

Tm

ax (

min

)

Data from: Home, Eur J Clin Pharmacol 1999; 55:199-203, Heinemann, Diab Med 1996; 13:683-4,Mudaliar, Diabetes Care 1999; 22:1501-6, Heinemann, Diabetes Care 1998; 21(11):1910-14.

Decreased Inter-individual Variability inNovoLog® Values for Tmax

Healthy Volunteers

Frequency of Minor* HypoglycemiaObserved by Level of Glycemic Control

Novo Nordisk (data on file,studies 035/EU, 036/US )

Frequency of Events:

7.9

7.8

7.7

7.6

0

Hb

A1c

(%

)

NovoLog® Regularinsulin

NovoLog® Regularinsulin

8.0

8.1

8.20 / year0–10 / year10–30 / year>30 / year

Type 1 Diabetes

* symptoms or blood glucose < 45 mg/dL

Study 035/EU Study 036/US

Reduced Reporting of Major NocturnalHypoglycemia

NovoLog® Regular human insulin

14

10

0

% Patients with MajorHypoglycemic Episodes

Night-time

4

12

Day-time

8

6

2

p<0.005 NS

Novo Nordisk(data on file, studies 035/EU, 036/US)

Reduced Risk of Major NocturnalHypoglycemia

0.7

0.5

Relative RiskNovoLog Compared to Regular

Human Insulin (1.0 = equal)NovoLog®

Humaninsulin

(N of patients with events)

Home 8%(54/707)

11%(39/358)

Raskin 4%(24/596)

8%(23/286)

Novo Nordisk(data on file, studies 035/EU, 036/US)

Study 035/EU Study 036/US

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


8:0012:008:00

Time

Pla

sma

insu

lin

Lispro Lispro Lispro

Aspart Aspart Aspartor oror

Rapid-acting Insulin Analogues ProvideIdeal Prandial Insulin Profile

400

350

300

250

200

150

100

MealSC injection

50

00 30 60

Time (min)90 120 180 210150 240

Regular Lispro

500450400350300250

150

50

200

100

00 50 100

Time (min)150 200 300250

Pla

sm

a in

sulin

(p

mo

l/L)

Pla

sm

a in

sulin

(p

mo

l/L)

MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care. 1999;22:1501–1506.

Short-Acting Insulin AnalogsLispro and Aspart Plasma Insulin Profiles

Regular Aspart

Pharmacokinetic ComparisonNovoLog® vs Humalog®

300

350

250

200

150

100

50

0

7 8 9 10 11 12 13

NovoLog®

Humalog®

Fre

e In

sulin

(p

mo

l/L)

Time (hours)Hedman, Diabetes Care 2001;24(6):1120-21

5/8/20025/8/2002 2828

Long-acting Soluble Insulin Analogs:Medical Rationale

● Mimic basal physiological insulin profile

● Improved glycemic control

● More reproducible insulin delivery

● May be used in insulin pens

Limitations of NPH, Lente,and Ultralente

● Do not mimic basal insulin profile

– Variable absorption

– Pronounced peaks

– Less than 24-hour duration of action

● Cause unpredictable hypoglycemia

– Major factor limiting insulin adjustments

– More weight gain

1 5 10 15 20 25 30

1 5 10 15 20Asp

Gly

ArgExtension

Substitution

Arg

Insulin GlargineA New Long-Acting Insulin Analog

● Modifications to human insulin chain

– Substitution of glycine at position A21

– Addition of 2 arginines at position B30

● Gradual release from injection site

● Peakless, long-lasting insulin profile

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

6

5

4

3

2

1

00 10

Time (h) after SC injection

End of observation period

20 30

GlargineNPH

Glu

cose

uti

lizat

ion

rat

e(m

g/k

g/h

)

Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp

Overall Summary: Glargine

● Insulin glargine has the following

clinical benefits

– Once-daily dosing because of its prolonged

duration of action and smooth, peakless time-

action profile

– Comparable or better glycemic control (FBG)

– Lower risk of nocturnal hypoglycemic events

– Safety profile similar to that of human insulin

Type 2 Diabetes …A Progressive Disease

Over time,most patients will need insulin

to control glucose

Insulin Therapy in Type 2 DiabetesIndications

● Significant hyperglycemia at presentation

● Hyperglycemia on maximal doses of oral agents

● Decompensation– Acute injury, stress, infection, myocardial ischemia– Severe hyperglycemia with ketonemia and/or ketonuria– Uncontrolled weight loss– Use of diabetogenic medications (eg, corticosteroids)

● Surgery

● Pregnancy

● Renal or hepatic disease

Mimicking NatureThe Basal/Bolus Insulin

Concept

6-16

The Basal/Bolus Insulin Concept

● Basal insulin

– Suppresses glucose production betweenmeals and overnight

– 40% to 50% of daily needs

● Bolus insulin (mealtime)

– Limits hyperglycemia after meals

– Immediate rise and sharp peak at 1 hour

– 10% to 20% of total daily insulin requirementat each meal

Basal vs Mealtime Hyperglycemia in Diabetes

Riddle. Diabetes Care. 1990;13:676-686.

Plas

ma

Glu

cose

(mg/

dL)

200

100

00600 1200

Time of Day1800 2400

Type 2 Diabetes

0600

150

250

50

Basal hyperglycemia Mealtime hyperglycemia

6-18

Normal

∆ AUC from normal basal >1875 mgm/dL.hr; Est HbA1c >8.7%

When Basal Corrected

Plas

ma

Glu

cose

(mg/

dL)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50


6-18

Normal


∆ AUC from normal basal 900 mgm/dL.hr; Est HbA1c 7.2%

When Mealtime Hyperglycemia Corrected

Plas

ma

Glu

cose

(mg/

dL)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50


6-18

Normal


∆ AUC from normal basal 1425 mgm/dL.hr; Est HbA1c 7.9

When Both Basal & Mealtime Hyperglycemia Corrected

Plas

ma

Glu

cose

(mg/

dL)

200

100

00600 1200

Time of Day1800 2400 0600

150

250

50


6-18

Normal


∆ AUC from normal basal 225 mgm/dL.hr; Est HbA1c 6.4%

MIMICKING NATURE WITH INSULIN THERAPY

Over time,

most patients will need

both basal and mealtime insulin

to control glucose

6-19

Starting With Basal InsulinAdvantages

● 1 injection with no mixing

● Insulin pens for increased acceptance

● Slow, safe, and simple titration

● Low dosage

● Effective improvement in glycemic control

● Limited weight gain

6-37

Treatment to Target Study: NPH vsGlargine in DM2 patients on OHA

● Add 10 units Basal insulin at bedtime(NPH or Glargine)

● Continue current oral agents

● Titrate insulin weekly to fasting BG < 100 mg/dL

- if 100-120 mg/dL, increase 2 units




Treatment to Target Study;A1C Decrease

8.6

7.5

7.16.9

6.5

7

7.5

8

8.5

9

0 5 10 15 20

W eeks in Study (N = 401)

Mea

n H

bA1c%

Patients in Target (A1c < 7%)

2.5

32.3

48.8

66.2

0

10

20

30

40

50

60

70

P ercentage of P atients

W eek 0 W eek 8 W eek 12 W eek 18

Advancing Basal/Bolus Insulin

● Indicated when FBG acceptable but– HbA1c > 7% or > 6.5%

and/or– SMBG before dinner > 140 mg/dL

● Insulin options– To glargine or NPH, add mealtime aspart / lispro– To suppertime 70/30, add morning 70/30– Consider insulin pump therapy

● Oral agent options– Usually stop sulfonylurea– Continue metformin for weight control– Continue glitazone for glycemic stability?

Starting With Bolus Insulin

Combination Oral Agents

+

Mealtime Insulin

6-46

Starting With Bolus InsulinMealtime Lispro vs NPH or MetforminAdded to Sulfonylurea

Browdos, et al. Diabetes. 1999;48(suppl 1):A104.

10.0% 10.4%

−1.9%

10.2%−1.9%

−2.3%

12

10

8

6

4

2

0

12

10

8

6

4

2

0Su + Metformin

(n = 40)Su + NPH

(n = 50)Su + LP(n = 42)

Baseline HbA1c

Follow-up HbA1c

Follow-up Weight

0.9 kg2.3 kg3.4 kg

HbA

1c (%

)

Weight G

ain (kg)

6-47

Case #1: DM 2 on SU withinfection

● 49 year old white male

● DM 2 onset age 43, wt 173 lbs, Ht 70 inches

● On glimepiride (Amaryl) 4 mg/day ,HbA1c 7.3% (intolerant to metformin)

● Infection in colostomy pouch (ulcerative colitis)glucose up to 300 mg/dL plus

● SBGM 3 times per day


● Started on MDI; starting dose 0.2 x wgt. in lbs.

● Wgt. 180 lbs which = 36 units

● Bolus dose (lispro/aspart) = 20% of startingdose at each meal, which = 7 to 8 units ac (tid)

● Basal dose (glargine) = 40% of starting dose atHS, which = 14 units at HS

● Correction bolus = (BG - 100)/ SF, whereSF = 1500/total daily dose; SF = 40

Correction Bolus Formula

Example:

–Current BG: 220 mg/dl

– Ideal BG: 100 mg/dl

–Glucose Correction Factor: 40 mg/dl

Current BG - Ideal BGGlucose Correction factor

220 - 100

40=3.0u


● Started on MDI

● Did well, average BG 138 mg/dL at 1month and 117 mg/dL at 2 monthspost episode with HbA1c 6.1%

Strategies to Improve GlycemicControl: Type 2 Diabetes

● Monitor glycemic targets – Fasting andpostprandial glucose, HbA1c

● Self-monitoring of blood glucose is essential

● Nutrition and activity are cornerstones oftherapy

● Combinations of pharmacologic agents areoften necessary to achieve glycemic targets

Intensive Therapy for Type 1 Diabetes

● Careful balance of food, activity, and insulin

● Daily self-monitoring BG

● Patient trained to vary insulin and food

● Define target BG levels (individualized)

● Frequent contact of patient and diabetes team

● Monitoring HbA1c

● Basal / Bolus insulin regimen

Options in Insulin Therapy

● Current

– Multiple injections

– Insulin pump (CSII)

● Future

– Implant (artificial pancreas)

– Transplant (pancreas; islet cells)

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00

BreakfastBreakfast LunchLunch DinnerDinner

Pla

sma

insu

lin (

Pla

sma

insu

lin (µ U

/ml)

U

/ml)

TimeTime

8:008:00

Physiological Serum InsulinSecretion Profile

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


Pla

sma

insu

linP

lasm

a in

sulin

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

TimeTime

REG REG

NPH/LenteNPH/Lente

Classical “Split-mixed”Treatment Program

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


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

TimeTime

REG REG

NPH/Lente

NPH/Lente

Pla

sma

insu

linP

lasm

a in

sulin

“Split-mixed” Program withBedtime Intermediate Insulin

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


8:0012:008:00

Time

REG REGREG

NPH/Lente

Pla

sma

insu

linBasal/Bolus Insulin Absorption PatternStandard Insulin Preparations

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


8:0012:008:00

Time

Glargineor

Detemir

Lispro Lispro Lispro

Aspart Aspart Aspartor oror

Pla

sma

insu

linBasal/Bolus Treatment Program withRapid-acting and Long-acting Analogs

Novo Nordisk devices in diabetes care

•First pen (NovoPen 1) launched in 1985•Committed to developing one new insulin administration system per year.

Lilly Insulin Pens

Introducing InDuo™

● The world’s firstcombined insulindoser and bloodglucose monitoringsystem

● A major break-through in DiabetesCare

InDuo™ - IntegrationFeature

● Combined insulin doserand blood glucosemonitor

InDuo™ - Compact Size

Feature

● Compact, discreet design

Benefit

● Allows discreet testing andinjecting anywhere, anytime

InDuo™ - Doser RemembersFeature

● Remembers amount ofinsulin delivered and timesince last dose

Benefit

● Helps people inject theright amount of insulin atthe right time

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


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

TimeTime

Basal infusion

Bolus Bolus Bolus

Pla

sma

insu

linP

lasm

a in

sulin

Variable Basal Rate: CSII Program

Lauritzen. Diabetologia. 1983;24:326–329.

Fast (n = 12)

Semilente (n = 9)

Intermediate (n = 36)

Fra

ctio

n a

t in

j. si

te

1.00

0.75

0.50

0.25

06 12 18 24 36 42 4830

Hours after single SC injectionsFemoral region

Variability of Insulin Absorption

CSII <2.8%

SubcutaneousInjectable10% to 52%

History of Pumps

PARADIGM PUMP

Paradigm. Simple. Easy.

Pump Infusion Sets

Softset QR Silhouette

Metabolic Advantages with CSII

● Improved glycemic control

● Better pharmacokinetic delivery of insulin

– Less hypoglycemia

– Less insulin required

● Improved quality of life

CSII Reduces HbA1c

5.05.56.06.57.07.58.08.5.099.5

10.0

n = 58 n = 107 n = 116 n = 50 n = 25 n = 56Mean dur. = 36

AdolescentsAdults

Mean dur. = 36 Mean dur. = 54 Mean dur. = 42 Mean dur. = 12 Mean dur. = 12

Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327;Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Bell DSH, et al. Endocrine Practice. 2000;6:357–360;Chase HP, et al. Pediatrics. 2001;107:351–356.

Bell Rudolph Chanteleau Bode Boland Chase

Pre-pump Post-pump

Hb

A1c

CSII Reduces Hypoglycemia

0

20

40

60

80

100

120

140

160

n = 55Mean age 42

n = 107Mean age 36

n = 116Mean age 29

n = 25Mean age 14

n = 56Mean age 17

Eve

nts

per

hu

nd

red

pat

ien

t ye

ars

Chantelau E, et al. Diabetologia. 1989;32:421–426; Bode BW, et al. Diabetes Care. 1996;19:324–327;Boland EA, et al. Diabetes Care. 1999;22:1779–1784; Chase HP, et al. Pediatrics. 2001;107:351–356.

Bode Rudolph Chanteleau Boland Chase

Pre-pump Post-pump

● Monitoring– HbA1c = 8.3 - (0.21 x BG per day)

● Recording 7.4 vs 7.8

● Diet practiced– CHO: 7.2– Fixed: 7.5– Other: 8.0

● Insulin type– Lispro: 7.3– R: 7.7

CSIIFactors Affecting HbA1c

Insulin aspart versus buffered R versusinsulin lispro in CSII study:

Bode et al: Diabetes Care, March 2002

Insulin aspart

Buffered regular human insulin (Velosulin®)Screening

Insulin lispro–2 0 16

weeks weeksweeks

! 146 patients in the USA; 2–25 years with Type 1 diabetes;

7% ≤ HbA1c ≤ 9%; previously treated with CSII for 3 months

Glycemic Control with CSIINovoLog®Human insulinHumalog®

7.0

7.2

7.8

8.0

Hb

A1c

(%

) 7.6

7.4

Baseline Week 8 Week 12 Week 160

Bode, Diabetes 2001 ; 50(S2):A106

Type 1 Diabetes

Self-Monitored Blood Glucose in CSII

NovoLog® Buffered Regular Humalog®

80

100

120

140

160

180

200

220

Blo

od

Glu

cose

(m

g/d

l)

* **

Bedtime 2 AMBefore and90 min. after

breakfast

Before and90 min. after

lunch

Before and90 min. after

dinner

Type 1 Diabetes

Bode, Diabetes 2001 ; 50(S2):A106

Ep

iso

des

/mo

nth

/pat

ien

t

0

2

4

6

8

10

12

insulin aspart human insulin insulin lispro

pp < 0.05 < 0.05

pp < 0.05 < 0.05

Symptomatic or ConfirmedHypoglycaemia

30% relative reduction

Bode et al: Diabetes Care, March 2002

0

10

20

30

40

50

Insulin aspartBuffered human insulinInsulin lispro

Pat

ien

ts w

ith

tro

ub

le-f

ree

use

(%

)

Insulin aspart versus buffered R versus insulinlispro in CSII study: pump compatibility

Data on file (study ANA 2024)

Case Study: 54 year old DM1 on CSII withLipoatrophy and Insulin Antibodies

● DM 1 onset age 21, 1968

● CSII 1998, A1C 7.8%

● Lipoatrophy with humalog 1999-2000

● Changed to Velosulin BR with still lipoatrophy

● Control suboptimal A1C 7.8%


● 7-10-01 A1C 7.8% on 28.8 units per day

● SMBG Avg BG 140, SD 118 based on 2.9 tests/day

● Insulin antibodies positive 1:32

● Changed to Novolog 1 to 1 transfer

● 10-16-01 A1C 6.5% on 20.8 units per day

● SMBG Avg 118, SD 73 based on 3.0 tests per day

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

5 /9 /20 0 1 5 /2 9/2 0 0 1 6 /1 8/2 0 0 1 7 /8 /20 0 1 7 /2 8/2 0 0 1 8 /1 7/2 0 0 1 9 /6 /20 0 1 9 /2 6/2 0 0 1 1 0 /16 /2 0 0 1 1 1 /5/2 0 0 1

HumalogAverage = 140SD = 118

NovologAverage = 118SD = 73

DM 1 CSII Patient: Humalog to Novolog


● 2-5-02 A1C 6.3% on 20 units per day

● SMBG Avg BG 104, SD 74 based on 3.1tests/day

7.197.57

9.2

5.00

6.00

7.00

8.00

9.00

10.00

Baseline 6 months 18 months

P = 0.026 P = 0.040

N = 11

CSII Usage in Type 2 PatientsAtlanta Diabetes Experience

Mean HbA1c (%)

Glycemic Control in Type 2 DM:CSII vs MDI in 127 patients

● A1C

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

CSII MDI

Baseline

End of Study (24 wks)

Raskin, Diabetes 2001; 50(S2):A106

DM 2 Study: CSII vs MDI

● Overall treatment satisfaction improved in theCSII group: 59% pre to 79% at 24 weeks

● 93% in the CSII group preferred the pump totheir prior regiment (insulin +/- OHA)

● CSII group had less hyperglycemic episodes(3 subjects, 6 episodes vs. 11 subjects, 26episodes in the MDI group)

48.1

34.539.3 40.1 39.8

0

10

20

30

40

50

60

Baseline(MDI)

15 days 6 mos 18 mos 36 mos

-28% -18% -16% -17%

* P <0.001

** * *

n = 389 n = 389 n = 298 n = 246 n = 187

Insulin Reduction Following CSII

Normalization of Lifestyle

● Liberalization of diet — timing & amount

● Increased control with exercise

● Able to work shifts & through lunch

● Less hassle with travel — time zones

● Weight control

● Less anxiety in trying to keep on schedule

N = 165Average Duration = 3.6 yearsAverage Discontinuation <1%/yr

Continued 97%

Discontinued 3%

Current Continuation RateContinuous Subcutaneous Insulin Infusion (CSII)

Bode BW, et al. Diabetes. 1998;47(suppl 1):392.

6,600 8,700 11,40015,000

20,00026,500

35,00043,000

60,000

81,000

120,000

162,000

0

50,000

100,000

150,000

'90 '91 '92 '93 '94 '95 '96 '97 '98 '99 2000 2001

U.S. Pump UsageTotal Patients Using Insulin Pumps

Pump Therapy Indications

● HbA1c >7.0%

● Frequent hypoglycemia

● Dawn phenomenon

● Exercise

● Pediatrics

● Pregnancy

● Gastroparesis

● Hectic lifestyle

● Shift work

● Type 2

Marcus. Postgrad Med. 1995.

Poor Candidates for CSII

● Unwilling to comply with medical follow-up

● Unwilling to perform self blood glucosemonitoring 4 times daily

● Unwilling to quantitate food intake

Meal bolus

1

2

3

4

5

6

12 am 12 pm 12 am

Time of day

Basal rate

Pump Therapy

Units

Meal boluses

● Insulin needed pre-meal– Pre-meal BG– Carbohydrates in meal– Activity level

● Correction bolus for high BG

Basal rate

● Continuous flow ofinsulin

● Takes the place of NPHor ultralente insulin

If HbA1c is Not to Goal

● SMBG frequency andrecording

● Diet practiced

– Do they know whatthey are eating?

– Do they bolus for allfood and snacks?

● Infusion site areas

– Are they in areas of lipohypertrophy?

● Other factors:

– Fear of low BG

– Overtreatment of low BG

Must look at:

Future ofDiabetes Management

Improvements in Insulin & Delivery

● Insulin analogs and inhaled insulin

● External pumps

● Internal pumps

● Continuous glucose sensors

● Closed-loop systems

GLUCOSE MONITORING SYSTEMS -Telemetry

● “Real time” glucosereadings

● Wireless communicationfrom sensor to monitor

● High and low glucosealarms

● FDA panel pending

Consumer Product

Closed-loop control using an external insulinpump and a subcutaneous glucose sensor

subcutaneousglucose sensor

Insulin infusion pump(currently MiniMed 508)

+

Closed-Loop Setup for Canine Studies

Q W E R T Y U I O P { } |

A S D F G H J K L : " Enter; 'Z X C V B N M < > ?

/ Shift.,

ESC F1 F2 F3 F4 F5 F6 F7 F8 F 9 F10 F11 F12 Insert Delete Scroll Print

1 2 3 4 5 6 7 8 9 0 _ +

\][

1 2 Alt

Shift

- =

Alt

~`

Tab

6 am noon 6 pm midnight 6 am noon6 am noon 6 pm midnight 6 am noon0

100

200

300

400

500meals YSI GLC

Sensoradjust controlparameters

start control

GL

UC

OS

E (

mg

/dl)

6 am noon 6 pm midnight 6 am noon6 am noon 6 pm midnight 6 am noon0

2

4

6

8

10

12

0

25

50

75

100

µU/ml(U/h)

Time (h)

Clo

sed

Lo

op

Res

on

se(U

/h)

Insu

lin ( µ

U/m

l)

24-h Closed-Loop Control (diabetic canine)

Implantable Pump

● AverageHbA1c 7.1%

● Hypoglycemicevents reduceto 4 episodesper 100 pt-years

MiniMed 2007 System

ImplantableInsulin PumpPlacement

Long-Term Glucose Sensor

0

50

100

150

200

250

300

350

26 Thu 27 Fri 28 Sat 29 Sun 30 Mon 31 Tue 1 Nov 2 Thu 3 Fri 4 Sat 5 Sun 6 Mon 7 Tue

Glu

cose

(m

g/dL

)LONG TERM IMPLANTABLE SYSTEM

Source: Medical Research Group, Inc.

Human Clinical Trial

Combine Pump and Sensor Technology

+

LTSS => Long Term SensorSystem (“Open Loop Control”)

Using an RF Telemetry Link…...

Medtronic MiniMed’s ImplantableBiomechanical Beta Cell

Today’s RealityOpen-Loop Glucose Control

Sensor # - 6347

Source: Medical Research Group, Inc.

50

100

150

200

250

300

350

400

16 Wed 17 Thu 18 Fri 19 Sat 20 Sun 21 Mon 22 Tue 23 WedAugust 2000

Glu

cose

(mg/

dL)

LONG TERM IMPLANTABLE SYSTEMAutomatic Glucose Regulation

in a Fully Pancreatectomized Canine

CLOSED LOOP CONTROL

ManualControl

ManualControl

Automatic ControlBegins

ControlTerminated

Summary

● Insulin remains the most powerful agentwe have to control diabetes

● When used appropriately in a basal/bolusformat, near-normal glycemia can be achieved

● Newer insulins and insulin delivery devicesalong with glucose sensors will revolutionizeour care of diabetes

Conclusion

Intensive therapy is

the best way to treat

patients with diabetes

QUESTIONS

● For a copy or viewing of theseslides, contact

● WWW.adaendo.com

new insulins - adaendo.com filehba1c and plasma glucose 26,056 data points (a1c and 7-point glucose...

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