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New Insulins and
Insulin Delivery Systems
Bruce W. Bode, MD, FACE
Atlanta Diabetes Associates
Atlanta, Georgia
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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
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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
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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
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Emerging Concepts
The Importance of
Controlling Postprandial Glucose
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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
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Insulin
The most powerful agent wehave
to control glucose
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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)
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Patient J.L., December 15, 1922 February 15, 1923
The Miracle of Insulin
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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)
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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
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4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Time
Pla
sma
insu
lin
Lispro Lispro Lispro
Aspart Aspart Aspartor oror
Rapid-acting Insulin Analogues ProvideIdeal Prandial Insulin Profile
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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
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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
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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
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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
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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
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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
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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
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Type 2 Diabetes …A Progressive Disease
Over time,most patients will need insulin
to control glucose
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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
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Mimicking NatureThe Basal/Bolus Insulin
Concept
6-16
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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
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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%
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When Basal Corrected
Plas
ma
Glu
cose
(mg/
dL)
200
100
00600 1200
Time of Day1800 2400 0600
150
250
50
Basal hyperglycemia Mealtime hyperglycemia
6-18
Normal
Basal vs Mealtime Hyperglycemia in Diabetes
∆ AUC from normal basal 900 mgm/dL.hr; Est HbA1c 7.2%
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When Mealtime Hyperglycemia Corrected
Plas
ma
Glu
cose
(mg/
dL)
200
100
00600 1200
Time of Day1800 2400 0600
150
250
50
Basal hyperglycemia Mealtime hyperglycemia
6-18
Normal
Basal vs Mealtime Hyperglycemia in Diabetes
∆ AUC from normal basal 1425 mgm/dL.hr; Est HbA1c 7.9
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When Both Basal & Mealtime Hyperglycemia Corrected
Plas
ma
Glu
cose
(mg/
dL)
200
100
00600 1200
Time of Day1800 2400 0600
150
250
50
Basal hyperglycemia Mealtime hyperglycemia
6-18
Normal
Basal vs Mealtime Hyperglycemia in Diabetes
∆ AUC from normal basal 225 mgm/dL.hr; Est HbA1c 6.4%
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MIMICKING NATURE WITH INSULIN THERAPY
Over time,
most patients will need
both basal and mealtime insulin
to control glucose
6-19
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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
![Page 43: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/43.jpg)
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
- if 120-140 mg/dL, increase 4 units
- if 140-160 mg/dL, increase 6 units
- if 160-180 mg/dL, increase 8 units
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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%
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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
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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?
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Starting With Bolus Insulin
Combination Oral Agents
+
Mealtime Insulin
6-46
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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
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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
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Case #1: DM 2 on SU withinfection
● 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
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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
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Case #1: DM 2 on SU withinfection
● Started on MDI
● Did well, average BG 138 mg/dL at 1month and 117 mg/dL at 2 monthspost episode with HbA1c 6.1%
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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
![Page 54: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/54.jpg)
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
![Page 55: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/55.jpg)
Options in Insulin Therapy
● Current
– Multiple injections
– Insulin pump (CSII)
● Future
– Implant (artificial pancreas)
– Transplant (pancreas; islet cells)
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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
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
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
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4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
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
![Page 59: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/59.jpg)
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Time
REG REGREG
NPH/Lente
Pla
sma
insu
linBasal/Bolus Insulin Absorption PatternStandard Insulin Preparations
![Page 60: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/60.jpg)
4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
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
![Page 61: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/61.jpg)
Novo Nordisk devices in diabetes care
•First pen (NovoPen 1) launched in 1985•Committed to developing one new insulin administration system per year.
![Page 62: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/62.jpg)
Lilly Insulin Pens
![Page 63: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/63.jpg)
Introducing InDuo™
● The world’s firstcombined insulindoser and bloodglucose monitoringsystem
● A major break-through in DiabetesCare
![Page 64: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/64.jpg)
InDuo™ - IntegrationFeature
● Combined insulin doserand blood glucosemonitor
![Page 65: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/65.jpg)
InDuo™ - Compact Size
Feature
● Compact, discreet design
Benefit
● Allows discreet testing andinjecting anywhere, anytime
![Page 66: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/66.jpg)
InDuo™ - Doser RemembersFeature
● Remembers amount ofinsulin delivered and timesince last dose
Benefit
● Helps people inject theright amount of insulin atthe right time
![Page 67: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/67.jpg)
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
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
![Page 68: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/68.jpg)
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%
![Page 69: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/69.jpg)
History of Pumps
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PARADIGM PUMP
Paradigm. Simple. Easy.
![Page 72: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/72.jpg)
Pump Infusion Sets
Softset QR Silhouette
![Page 73: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/73.jpg)
Metabolic Advantages with CSII
● Improved glycemic control
● Better pharmacokinetic delivery of insulin
– Less hypoglycemia
– Less insulin required
● Improved quality of life
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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
![Page 75: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/75.jpg)
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
![Page 76: New Insulins · Post-lunch, pre-dinner, post-dinner, and bedtime correlated better with A1c than fasting, post-breakfast, or pre-lunch Rohlfing et al, Diabetes Care 25 (2) Feb 2002](https://reader033.vdocuments.us/reader033/viewer/2022060817/6095c688b90feb1e0e0248a8/html5/thumbnails/76.jpg)
● 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
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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
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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
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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
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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
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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)
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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%
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Case Study: 54 year old DM1 on CSII withLipoatrophy and Insulin Antibodies
● 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
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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
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Case Study: 54 year old DM1 on CSII withLipoatrophy and Insulin Antibodies
● 2-5-02 A1C 6.3% on 20 units per day
● SMBG Avg BG 104, SD 74 based on 3.1tests/day
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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 (%)
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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
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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)
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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
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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
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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.
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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
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Pump Therapy Indications
● HbA1c >7.0%
● Frequent hypoglycemia
● Dawn phenomenon
● Exercise
● Pediatrics
● Pregnancy
● Gastroparesis
● Hectic lifestyle
● Shift work
● Type 2
Marcus. Postgrad Med. 1995.
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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
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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
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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:
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Future ofDiabetes Management
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Improvements in Insulin & Delivery
● Insulin analogs and inhaled insulin
● External pumps
● Internal pumps
● Continuous glucose sensors
● Closed-loop systems
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GLUCOSE MONITORING SYSTEMS -Telemetry
● “Real time” glucosereadings
● Wireless communicationfrom sensor to monitor
● High and low glucosealarms
● FDA panel pending
Consumer Product
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Closed-loop control using an external insulinpump and a subcutaneous glucose sensor
subcutaneousglucose sensor
Insulin infusion pump(currently MiniMed 508)
+
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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
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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)
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Implantable Pump
● AverageHbA1c 7.1%
● Hypoglycemicevents reduceto 4 episodesper 100 pt-years
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MiniMed 2007 System
ImplantableInsulin PumpPlacement
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Long-Term Glucose Sensor
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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
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Combine Pump and Sensor Technology
+
LTSS => Long Term SensorSystem (“Open Loop Control”)
Using an RF Telemetry Link…...
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Medtronic MiniMed’s ImplantableBiomechanical Beta Cell
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Today’s RealityOpen-Loop Glucose Control
Sensor # - 6347
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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
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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
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Conclusion
Intensive therapy is
the best way to treat
patients with diabetes
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QUESTIONS
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● WWW.adaendo.com