new insulins · 2003-03-20 · new insulins and insulin delivery systems bruce w. bode, md, face...

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

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

Short-Acting AnalogsLispro and Aspart

● Convenient administration immediatelyprior to meals

● Faster onset of action

● Limit postprandial hyperglycemic peaks

● Shorter duration of activity

– Reduce late postprandial hypoglycemia– Frequent late postprandial hyperglycemia

● Need for basal insulin replacement revealed

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

Lispro Mix 75/25Pharmacodynamics

00 44 88 1212 1616 2020 2424

00

22

44

66

88

1010

1212

Glu

cose

infu

sio

n r

ate

mg

/kg

/min

HoursHours

Lispro

Lispro Mix 75/25

NPL

Heise T, et al. Diabetes Care. 1998;21:800–803.

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

Glucose Infusion Raten = 20 T1DMMean ± SEM

SC insulin

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

0 4 8 12 16 20 24Time (hours)

mg

/kg

/min

µm

ol/k

g/m

in

Lepore M, et al. Diabetes. 2000;49:2142–2148.

NPH

Ultralente

CSII

Glargine

Glargine

Plasma Glucose

Time (hours)

220

200

180

160

140

120

12

11

10

9

8

7

0 4 8 12 16 20 24

mg

/dL

mm

ol/

L

Lepore M, et al. Diabetes. 2000;49:2142–2148.

n = 20 T1DMMean ± SEM

SC insulin

NPH

Ultralente

CSII

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

Starting With Basal InsulinBedtime NPH Added to Diet

Cusi & Cunningham. Diabetes Care. 1995;18:843-851.

300

200

00800 1200 1600

Time of Day2000 2400 0400 0800

400

100

Diet onlyBedtime NPH

Plas

ma

Glu

cose

(mg/

dL)

6-38

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

Initial Dosage Calculations

Correction Bolus

"1500 Rule"

•insulin sensitivity factor

•determines the estimated BG drop

per 1.0 unit of insulin

Davidson PC, The Insulin Pum p Therapy Book: Insights from the Experts 1995, 59-71.

Glucose Correction Factor

1500 Rule says:

John Smith is on:

•36 units insulin/day

•1500/36= 40

•1 unit lowers BG 40 mg/dl

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)

1.0

0.8

0.6

0

Insulin

Time

Multiple Injection TherapyIntermediate & Short-Acting Insulin Pre-Meal

Injections1.0

0.8

0.6

0

Insulin

Time

Multiple Injection TherapyIntermediate & Short-Acting Insulin Pre-Meal

Injections1.0

0.8

0.6

0

Insulin

Time

Multiple Injection Therapy Intermediate & Short-Acting Insulin Pre-Meal

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

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%

Pump TherapyBasal & Bolus Short-Acting Insulin

Pump TherapyBasal & Bolus Short-Acting Insulin

● Combined withSMBG, physiologicinsulin requirementscan be achievedmore closely

● Flexibility in lifestyle

History of Pumps

PARADIGM PUMP

Paradigm. Simple. Easy.

Paradigm Pump: Advantages

● 29% smaller, water resistant

● Menu driven:

bolus, suspend, basal, prime, utilities

● Reservoir based (easier to fill)

● Silent motor

● AAA batteries

Paradigm Pump: Advantages

● Various bolus options

normal, square, dual, and “easy bolus”

● Enhanced memory

● Enhanced safety features

(low reservoir alarm, auto off, etc.)

Pump Infusion Sets

Softset QR Silhouette

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

Pharmacokinetic AdvantagesCSII vs MDI

● Uses only regular or very rapid insulin

– More predictable absorption than modifiedinsulins (variation 3% vs 52%)

● Uses 1 injection site

– Reduces variations in absorption dueto site rotation

● Eliminates most of the subcutaneous insulin depot

● Programmable delivery simulates normalpancreatic function

Metabolic Advantages with CSII

● Improved glycemic control

● Better pharmacokinetic delivery of insulin

– Less hypoglycemia

– Less insulin required

● Improved quality of life

8.18

8.58.2

8.9

6.96.977

7.6

6

7

8

9

10

Baseline 1 yr 2 yr 3 yr 4 yr

Adolescent (37) Adult (166)

Glycemic ControlH

bA

1c

Atlanta Diabetes Associates

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

● 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)

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

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

Current Candidate Selection

Patient Requirements

–Willing to monitor and record BG

–Motivated to take insulin

–Willing to quantify food intake

–Willing to follow-up

– Interested in extending life

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

What Type of Bolus Should You Give?

● 9 DM 1 patients on CSII ate pizza and coke on fourconsecutive Saturdays

● Dual wave bolus (70% at meal, 30% as 2-h square):

9 mg/dl glucose rise

● Single bolus: 33 mg/dl rise

● Double bolus at -10 and 90 min: 66 mg/dl rise

● Square wave bolus over 2 hours: 80 mg/dl rise

Chase et al, Diabetes June 2001 #365

Treatment of Hypoglycemia

● Education

–Glucose tablets

–Glucagon

● Call healthcare team

–Any hypoglycemic events requiring assistance

Treatment of Hyperglycemia

● If blood glucose is above 250 mg/dl

– Take a correction bolus by pump

– Check BG again in 1 hr

● If still above 250 mg/dl

– Take correction bolus by syringe

– Change infusion set and reservoir

– Check BG again in 1 hr

● If BG has not decreased

– Increase correction bolus by syringe

– CALL PHYSICIAN

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

Pulmonary Insulin

Oral Agents + Mealtime Inhaled InsulinEffect on HbA1c

*P < .001

Weiss, et al. Diabetes. 1999;48(suppl 1):A12.

10

9

8

7

5Baseline

(0)Follow-up

(12)

Oral Agents +Inhaled InsulinOral Agents Alone

Baseline(0)

Follow-up(12)

−2.3%*

Weeks

6

HbA

1c (%

)

6-55

● Non-invasive

– Near Infrared Spectroscopy (NIR)

● Minimally-invasive (ISF)

– Micropore sampling

– Iontophoresis

– Subcutaneous sensors

Categories of Glucose Monitoring

Cygnus GlucoWatch– Watch Component

– Electrode Component

– Initial calibration takes 3 hours

– Senses glucose and gives anaverage every 20 minutes up to 12hours (r = 0.80 home use)

– Alarm for high, low and rapidlydropping blood sugars

– Indicated for 18 years and older

Cygnus GlucoWatchCygnus GlucoWatch

GLUCOSE MONITORING SYSTEMS -EXTERNAL

● Physician downloads data forretrospective analysis

● Com-Station and softwarepackages combine data from:

– Sensor

– Models 508 and 507Cinsulin pumps

– Traditional glucosemeters

Physician Product

Patient with Type 1 Diabetes

– Practicing MDI

– HbA1C of 8.5%

– Complications

of High BG

Renal

Retinal

Neural

Glucose Profiles

0

50

100

150

200

250

300

350

12:00 Midnight 6:00 AM 12:00 Noon 6:00 PM 12:00 MidnightTim e

Meal Meal Meal MealGlu

cose

Con

cent

ratio

n (m

g/dl

)

Pre-Meal BG Tests

Glucose Profiles

GlucoseMonitorPre-Meal BG Tests

0

50

100

150

200

250

300

350

12:00 Midnight 6:00 AM 12:00 Noon 6:00 PM 12:00 MidnightTim e

Meal Meal Meal MealGlu

cose

Con

cent

ratio

n (m

g/dl

)

Patient with Type 1 Diabetes

– Practicing MDI

– HbA1C of 8.5%

– Complicationsof High BG

Renal

Retinal

Neural

History

● 70 Year-old white male

● Type 2 DM, 15 years

● Current Treatment:

–Glucophage 500mg AM, 1000mg PM

–Glynase 6mg BID

–Rezulin 400mg QD

History

● HgA1c increased to 8.0% from 6.5% 18 months earlier

● SMBG Average: 162 mg/dL

– AM = 137

– Noon = 199

– PM = 151

– HS = 188

● Ht= 73”; Wt= 180 lbs; BMI=23 kg/m2

● CGMS done to determine best course of treatment

Modal Day

-50

0

50

100

150

200

250

300

350

400

12:00A M

4:00 A M 8:00 A M 12:00PM

4:00 PM 8:00 PM 12:00A M

Tim e

1/10/99

1/11/99

1/12/99

Glu

cose

con

cent

ratio

n (M

g/d

l)

-50

0

50

100

150

200

250

300

350

400

12:00 A M 4:00 A M 8:00 A M 12:00 PM 4:00 PM 8:00 PM 12:00 A M

Tim e

Glucose Sensor Profile

11-30-99

Glu

cose

con

cent

ratio

n (M

g/d

l)

Changes to be made

● Options discussed with patient:

1. Add insulin pre-meal

2. Change Glynase to Prandin

● CGMS re-done

six weeks later

-50

0

50

100

150

200

250

300

350

400

12:00A M

4:00 A M 8:00 A M 12:00PM

4:00 PM 8:00 PM 12:00A M

Tim e

-50

0

50

100

150

200

250

300

350

400

12:00

A M

4:00

A M

8:00

A M

12:00

PM

4:00

PM

8:00

PM

12:00

A M

Tim e

3/20/00

3/21/00

3/22/00

3/23/00

Modal Day

Glu

cose

con

cent

ratio

n (M

g/d

l)

Reasons to Use CGMS

● Improve glycemic control

● Reduce risk of hypoglycemicevents

● Minimize risk of futurehypoglycemia

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

Implantable InsulinPumps Indications for Use

" Diabetes out of control (frequent, rapid ρBG)" Frequent hypoglycemic episodes" Subcutaneous insulin absorption resistance" Injection or infusion site reaction

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 these slides, contact

● WWW.adaendo.com

● Email: [email protected]

new insulins · 2003-03-20 · new insulins and insulin delivery systems bruce w. bode, md, face...

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