Insulin regimens
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Transcript of Insulin regimens
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Objectives
1. Discuss the different types of insulin preparations available to manage types 1 and 2 diabetes
2. Review the various insulin protocols and address appropriate patient selection for each
3. Address how to design and adjust insulin regimens
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What Type of Insulins Are Available?
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Normal Pancreas
Insulin is released in response to varying blood glucose levels and hypoglycemia does not occur
Insu
lin
Eff
ect
Basal Insulin (~0.5-1.0 U/hr.)
‘Bolus’ Insulin (Meal Associated)
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Basal vs Bolus Insulin
BASAL INSULIN• Suppress hepatic glucose
production (overnight and intermeal)
• Prevent catabolism (lipid and protein)– Ketosis– Unregulated amino
acid release• Reduce glucolipotoxicity
BOLUS INSULIN• Meal-associated CHO
disposal
• Storage of nutrients
• Help suppress inter-meal hepatic glucose production
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Insulin Profiles
Rosenstock J. Clin Cornerstone. 2001;4:50-61.
0 2 4 6 8 10 12 14 16 18 20 22 24
Pla
sma In
sulin
Levels
Time (hr)
NPH (10–20 hr)
Regular (6–10 hr)
Ultralente (~16–20 hr )
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The Diffusion Of Insulin
Holleman F. NEJM 1997;337(3):176-83Tuesday, April 11, 2023
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Insulin Self Association Sites
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Newer Insulins
MODIFCATION
ONSET (hr)
PEAK (hr)
DURATION (hr)
LISPRO (Humalog)
-chain Pro Lys28 -chain LysPro29
0.25-0.5 1-2 3-5
ASPART (NovoLog)
-chain ProAsp28
0.25-0.5 1-2 2-4
GLULISINE (Apidra)
-chain LysAsn 3 -chain LysGlu 29
Similar Simil ar Similar
GLARGINE (Lantus)
-chain AspGly 21 -chain Arg31/Arg32
1 None 24
DETEMIR (Levemir)
-chain Lys29(N-
tetradecanoyl)des( -thr 30) 2 6-8 18
NPH Native insulin complexed with protamine
1-4 8-10 12-20 Tuesday, April 11, 2023
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Analog Insulin Profiles
Rosenstock J. Clin Cornerstone. 2001;4:50-61.
0 2 4 6 8 10 12 14 16 18 20 22 24
Pla
sma In
sulin
Levels
Time (hr)
NPH (10–20 hr)
Regular (6–10 hr)
Ultralente (~16–20 hr )
Glargine (~24 hr)
Aspart, Lispro, Glulisine (4–5 hr)
Detemir ~18hr
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Rapid-Acting Analogs and RHI in Obese Subjects
Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.
0 120 240 360 480 600
Time, min
0
1
2
3
4
5
6
N=18
GlulisineLisproRegular human insulin
BMI=30 kg/m2 to 40 kg/m2
Dosage=0.3 U/kg GIR=Glucose Infusion Rate
GIR
, m
g.k
g-1.m
in-1
60
**
* p< .05 GIR-t20% vs RHI and LisproTuesday, April 11, 2023
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Fatty Meals---Rapid Acting Insulin
TIME
INS
UL
IN A
CT
IVIT
Y
GL
UC
OS
E L
EV
EL
SHYPERGLYCEMIA
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1. Hedman CA et al. Diabetes Care 2001;24:1120-1121 2. Home PD et al. Eur J Clin Pharm 1999;55:199-201 3. Novo Nordisk, data on file
Time (min)-60 0 60 120 180 240 300 360 420 480 540
Aspart 1,2
Pla
sma
Insu
lin
Lev
els
Effect of Premixing on Rapid-Acting Analog Properties
Tmax 49-53 min
70/30 NovoLog Mix 3Tmax 2.4 hours
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GLUCOSEINFUSIONRATE
mg
/dl
0.3 U/Kg NPH s.c.
Plasma Glucose
908070
5.0
4.5
4.0
mm
ol/l
Lepore M. et al., Lepore M. et al., unpublished dataunpublished data
4.0
3.0
2.0
1.0
0
24
20
16
12
8
4
0
0 1 2 3 4 5 6 7 8 9Time (hours)
µm
ol/K
g/m
in
mg/
Kg/
min
PEN UP
PEN DOWN
MIX
Effect of NPH on GIR
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Type 1 Diabetes
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Bolus vs Basal Insulin
• Bolus insulins– Regular
– Humalog (lispro)
– NovoLog (aspart)
– Apidra (glulisine)
• Basal insulins– NPH
– Lente
– Ultralente
– Lantus (glargine)
– Levemir (detemir) Combination insulins — 70/30 and 50/50
— Humalog mix (75/25 or NPL)
— NovoLog mix (70/30 or NPA)Tuesday, April 11, 2023
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Basic Insulin Regimen: Split-Mixed Regimen or Premix
• Does not mimic normal physiology
• Requires meal consistency
• Snacking may result in weight gain
• Hypo- and hyperglycemia
Regular
NPH
B DL HS B
Endogenous insulin
Hyperglycemia
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Basal insulin
Basal-Bolus or Physiologic Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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Case---History
25 year old student comes to clinic for management of type 1 diabetes. He was diagnosed approximately 3 years ago and has been managed with twice daily NPH insulin and lispro. He is frustrated because his glucose values fluctuate considerably, and he is having multiple episodes of hypoglycemia.
His most recent A1C returned 7.8%.
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Case---Continuous Monitoring
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Case Study--History
His current insulin regimen consists of 16 U of NPH plus 5 to 15 U of lispro prior to breakfast and 12 U of NPH with a similar amount of lispro prior to supper. He would give correction doses of lispro prior to lunch, bedtime and occasionally at 2-4 AM. If he was ‘low’, he would eat carbohydrate and not take lispro.
His home glucose log documented testing 4 to 5 times a day with values ranging from 40 to 500 mg/dl.
How should his management be approached? Tuesday, April 11, 2023
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Case Study--Approach
• Set a reasonable goal for glycemic control– Initial goal was to avoid hypoglycemia (glucose
targets 120-150 mg/dL)
• Trouble-shoot the insulin regimen– Which type of insulin and which injection is
doing what? – Good luck doing it with this patient!
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Case Study--Approach
• Variables with injected insulin:– Type of insulin and site of injection– Type of food and gastric emptying– Remembering to take injections– Accuracy of HGM
• Designing an insulin regimen– Think in terms of basal and bolus
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Case Study--Approach
• We opted to use glargine as the basal insulin and lispro as the bolus insulin
• Dose calculations:– TDD: 48 to 73 U– Basal (as NPH): 16+12=28 U– Glargine: 28 x 0.8=22.4 U
CURRENT REGIMEN
16/10 and 12/10 (N/H)
TDD≈48 U/day
PLUS up to 25 U H/DTuesday, April 11, 2023
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Case Study--Approach
• Usual insulin regimens are 50:50 or 60:40 basal:bolus– TDD: 48 to 73 U– Glargine: 22 U– Bolus: ~ 22 U (50:50 Rule)
• Per meal 22/3= 7.3 U/meal
• Designed regimen: Glargine 22 U/HS; lispro 7 U BEFORE EACH MAJOR MEAL
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Case Study--Approach
• Correction doses (‘sliding scale’)– 1700 Rule (some modify this as the 1500 Rule
or the 1800 Rule)– 1700/TDD = Expected amount of glucose
lowering per unit of insulin
• Our patient– 1700/44 = 38 1 U insulin would lower his
glucose 38 mg/dl
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Case Study--Approach
• Our goal glucose is ~ 150 mg/dL• Our patient is instructed to:
– Take 22 U glargine at bed time (or ~ 10:00 PM)
– Start with 7 U of lispro before meals• For every 50 mg/dL glucose is above 150, add 1 U lispro or
for every 50 below 150, subtract 1 U lispro
– Have the patient monitor and adjust the regimen based upon results of HGM
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Carbohydrate Counting
• There is no literature to document superiority of CHO counting– Estimation aids many patients with T1DM
– Likely not effective in T2DM
• Establishing insulin:carbohydrate ratio– [Correction factor] x 0.33 = CHO gm covered by 1 unit
of insulin
– Usual ratio is 10-15:1
– Adjust based upon 2 hour postprandial glucose values
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Clinical Secrets
• Plan target glucose goals• Think in terms of basal and bolus insulin• Typical ratio of basal to bolus is 50:50 or 60:40• Correction doses are generally given before meals
• 1700 Rule: 1700/TDD = Glucose lowering/unit insulin
• Adjust basal insulin based upon FBS and bolus insulin based upon preprandial values
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Summary of Key Dose Concepts for Type 1 Diabetes
Parameter Formula Usual Range
Basal insulin requirements
None (weight based 0.2-0.5
U/kg)
12-24 U/day
Bolus requirements (empiric)
Basal dose 3 or number of meals/d
5-10 U/meal
Insulin:CHO ratio CF x 0.33 ~15
Correction factor 1700 TDD 30-50
NOTE: These are approximations on starting a physiologic insulin regimen and must be adjusted based upon SMBG valuesTuesday, April 11, 2023
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When Should Insulin Be Added In Patients With Type 2
Diabetes?
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Natural History of Type 2 Diabetes
Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota.
20 10 0 10 20 30
Years of Diabetes
Relative -Cell Function
PlasmaGlucose
Insulin resistance
Insulin secretion
126 mg/dL Fasting glucose
Postmeal glucose
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Therapy In Type 2 Diabetes:Estimated Improvement
HbA1c FBG (mg/dL)Sulfonylurea 1.5% to 2% 50 to 60Metformin 1% to 2% 50 to 60Pioglitazone 0.6% to 1.9% 55 to 60Rosiglitazone 0.7% to 1.8% 55 to 60Glitazones (Troglit) 0.6% to 1.0% 20 to 40Repaglinide 0.8% to 1.7% 30 to 40Acarbose 0.5% to 1.0% 20 to 30Sulfonylurea + Metformin ~1.7% ~65Sulfonylurea + Pioglitazone ~1.2% ~50Sulfonylurea + Troglitazone ~0.9% to 1.8% ~40 - 60Sulfonylurea + Acarbose ~1.3% ~40Repaglinide + Metformin ~1.4% ~40Pioglitazone + Metformin ~0.7% ~40Rosiglitazone + Metformin ~0.8% ~50
Insulin TherapyOral Agents + Insulin Rx Open to Target Open to Target
Mon
oth
erap
yC
omb
inat
ion
T
her
apy
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Evolution of Treatment Strategies
Pre-1995
Diagnosis
SU
Stop SU
Insulin
Pre-1995
Diagnosis
SU
Stop SU
Insulin
2000
Diagnosis
Monotherapy
Dual/Triple Therapy
Stop OHA
Insulin
Diagnosis
Monotherapy
Dual/Triple Therapy
Stop OHA
Insulin
2000 Current
Diagnosis
Prandial and Basal Insulin + OHA
Monotherapy Dual Therapy
Basal Insulin +
OHA
Triple Therapy
Stop SU
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ADA/EASD Position Statement
DiagnosisDiagnosis
Lifestyle Intervention and Metformin
Lifestyle Intervention and Metformin
Check HbACheck HbA1c1c every 3 months and act until every 3 months and act until HbAHbA1c1c is <7% is <7% Nathan DM et al. Diabetes Care. 2006;29:1963-1972
HbAHbA1c1c 7%7%HbAHbA1c1c 7%7%No
Add Basal Insulin − (most
effective)
Add Basal Insulin − (most
effective)
Add Sulfonylurea −
(least expensive)
Add Sulfonylurea −
(least expensive)
Add GLitazone −( no hypoglycemia)
Add GLitazone −( no hypoglycemia)
Yes
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How Is Insulin Employed in Type 2 Diabetes?
Different Regimens
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B DL HS
Insu
lin E
ffe
ct
Sensitizer Basal InsulinSecretagogue
Basal Insulin Regimen
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Basic Insulin Regimen: Split-Mixed Regimen or Premix
Regular
NPH
B DL HS B
Endogenous insulin
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Basal insulin
Basal-Plus Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Inhaled Bolus Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Basal insulin
Basal-Bolus or Physiologic Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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How Effective Are These Regimens?
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B DL HS
Insu
lin E
ffe
ct
Sensitizer Basal InsulinSecretagogue
Basal Insulin Therapy
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Effects Of Basal Insulin
�□□ HS NPH+Gly+Met BID NPH
HS NPH+Metformin HS NPH+Glyburide
Yki-Järvinen et al; Ann Int Med 1999;130:389
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*7.8
8.1
8.3
Time (wk)
0 4 8 12 16 20 24
7.5
8.0
8.5
9.0
9.5
A1
C (
%)
AM GlargineHS GlargineHS NPH
* Decrease in A1C from baseline for AM Glargine: P<0.001 vs HS NPH and P=0.008 vs HS GlargineFritsche A et al. Ann Int Med 2003;138:952-959.
Flexible Timing Of Glargine Compared With NPH Insulin
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Treat to Target Trial
6
7
8
9
0 4 8 12 16 20 24
Mea
n A
1C (
%)
Weeks
Insulin glargine
NPH insulin
Target A1C (%)
Riddle et al. Diabetes Care. 2003;26:3080-3086
~60% of patients reached target
Subjects were oral agent failures on SU alone or
SU+metformin and basal insulin was added and aggressively titrated
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DetemirDetemir GlargineGlargine
A1C at endpoint A1C at endpoint (baseline adjusted) (baseline adjusted)
7.16 %7.16 % 7.12%7.12%
Insulin dose at Insulin dose at endpointendpoint
0.63 u/kg (0.02-3.96)0.63 u/kg (0.02-3.96)
[0.43 u/kg (0.02-1.98) [0.43 u/kg (0.02-1.98) detemir QD (45% of pts.)]detemir QD (45% of pts.)]
[0.85 u/kg (0.14-3.96) [0.85 u/kg (0.14-3.96) detemir BID (55% of pts.)detemir BID (55% of pts.)
0.40 u/kg0.40 u/kg
Completion rateCompletion rate 80%80% 87%87%
In-clinic FPG In-clinic FPG (mg/dl)(mg/dl)
129.6129.6 129.6129.6
Rosenstock J et al. ADA 2006; Abstract 555-P
Achieving Glycemic Control (Detemir v Glargine)
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Do Algorithms and Basal Insulin Work?
Start SU
Add metformin
Start insulin
Fanning et al. Diabetes Care 2004;27:1638-1646
Community Center + Algorithm
Community Center
Without Algorithm
University Center + Algorithm
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Gycemia Optimization Trial
Goal FPG (mg/dl)
Glargine Dose (IU)
Proportion With A1C <
7.0%Mean
A1C (%)
Severe Hypoglycemia (Event/patient year)
A1C < 7.0% A1C ≥ 7.0%
120 (n=952) 59.2±37 31.5 7.58±1.1 0.02 0.02
110 (n=974) 62.2±37 32.2 7.52±1.1 0.02 0.08
100 (n=973) 69.6±41 37.5 7.41±1.1 0.04 0.05
90 (n=950) 74.9±53 41.1 7.26±1.1 0.08 0.12
80 (n=975) 78.1±43 44.3 7.32±1.2 0.11 0.19
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Basic Insulin Regimen: Split-Mixed Regimen or Premix
Regular
NPH
B DL HS B
Endogenous insulin
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Aggressively Titrated Premix
70/30+Met+Pio Met+Pio
Baseline A1C 8.1±1.0 7.9±0.9
EOS A1C 6.5±1.0 7.8±1.2
Percentage of Patients With A1C (EOS)
<7.0% 76.3 24.1
≤6.5 59.1 11.5
≤6.0 33.3 2.3
≤5.5 14.0 0
FPG (mg/dl) 130±50 162±41
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When and How Should Prandial Insulin Be Added?
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Contributions of FBG and PPG to Overall Glycemia
Adapted from Monnier, Lapinski, Colette: Diab Care Mar 2003, pg 881
PPG + FBG = HbA1c (%)
010203040
50607080
1 2 3 4 5
A1c Quintiles
Co
ntr
ibu
tio
n (
%)
(<7.3) (7.3-8.4) (8.5-9.2) (9.3-10.2) (>10.2)PPG
FPGTuesday, April 11, 2023
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Basal insulin
Basal-Plus Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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Final Insulin Doses Basal-Plus Regimen
Abstracts of the 66th Scientific Sessions of the ADA. Abstracts of the 66th Scientific Sessions of the ADA. DiabetesDiabetes. 2006; V(suppl X): XX. Abstract XX.. 2006; V(suppl X): XX. Abstract XX.
30 31
0
5
10
15
20
25
30
35
Baseline Endpoint
Insu
lin D
ose
(IU
)
5
Baseline
11
Endpoint
Basal Insulin Dose
Rapid-Acting Dose
● 26 week study (safety analysis) (N=158)● Baseline A1C was 7.4% and fell to 7.0%● 26% achieved A1C < 6.5%
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CHO Counting v Fixed Regimen
Mean A1C Across Study Weeks
Abstracts of the 66th Scientific Sessions of the ADA. Abstracts of the 66th Scientific Sessions of the ADA. DiabetesDiabetes. 2006; V(suppl X): XX. Abstract XX.. 2006; V(suppl X): XX. Abstract XX.
6.5
7.0
7.5
8.0
8.5
0 2 6 12 18 24
Week
A1C
(%
) ALG
Carb Count
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0
20
40
60
80
100
120
ALG Carb Count
P=0.04
Insulin DosesD
os
e (I
U)
Abstracts of the 66th Scientific Sessions of the ADA. Abstracts of the 66th Scientific Sessions of the ADA. DiabetesDiabetes. 2006; V(suppl X): XX. Abstract XX.. 2006; V(suppl X): XX. Abstract XX.
110.294.3
Rapid-Acting
ALG Carb Count
Basal Insulin
103.4
86.8
P<0.0001
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Insu
lin E
ffe
ct
B DL HS
Bolus insulin
Inhaled Bolus Insulin Therapy
Endogenous insulin
Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193
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Inhaled Insulin (Exubera)
• Uses powdered native human insulin– 1 and 3 mg blister
packs
3mg Blister
0.15U/Kg (~10U Reg)
(3) 1mg Blister
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Inhaled Insulin (Exubera) and OHA
*P < .001
Weiss, et al. Diabetes. 1999;48(suppl 1):A12.
10
9
8
7
5Baseline
(0)Follow-up
(12)
Oral Agents +Inhaled Insulin
Oral Agents AloneSU and/or Met
Baseline(0)
Follow-up(12)
2.3%*
Weeks
6
Hb
A1c
(%
)
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FPG: Exubera vs SC Insulin at End Point
Hollander PA, et al. Diabetes Care. 2004;27:2356-2362.Data on file.
Exubera SCMea
n
FPG
(m
g/dL
)
-40
-35
-30
-25
-20
-15
-10
-5
0Standard Intensive
Type 2 DM
194
163
203
190
201
167
209
207
152
132
158
149
Type 1 DM
On insulin
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What Are the Side Effects of Exogenous Insulin?
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Hypoglycemia
Severe insulin reactions per 100 patient-yr
7.8
3
2.3
110
62
0 20 40 60 80 100 120
VA IIIP
VA CSDM
UKPDS
SDIS
DCCT Type 1 diabetes
Type 2 diabetes
Adapted with permission from McCall A. In: Leahy J, Cefalu W eds. Insulin Therapy. New York, NY:Marcel Dekker, Inc.; 2002:193
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Total Weight Gain andTotal Insulin Dose
Adapted from Henry RR, et al. Diabetes Care. 1993;16:21-31.
0
100
200
300
400
0 10 20 30 40 50
Total insulin dose (U/d)
Total weight gain (lb)Tuesday, April 11, 2023
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0.5
0
1
1.5
2
Weight v Delta A1C
Studies with Type 2 Diabetes
1 2 3 4
Glargine
NPH
1
14
2
2
3 3
4
2
6
5
6
5
Detemir1. Yki-Jarvinen Diabetes Care 2000;23:1131 2. Rosenstock Diabetes Care 2001;24:631 3. Riddle Diabetes Care 2003;26: 3079 4. Fritsche Ann Int Med 2003;138: 952 5.Raslova Diab Res Clin Pract 2004;66:193 6. Haak Diab Obes Clin Pract 2005;7:56 R
educ
tion
in A
1C (
%)
Weight Gain (kg)
7. Study 1530 8. Study 1337 9. Study 1373; Rosenstock, 2006
77
8
8 99
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How Do The Various Approaches Compare?
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Comparison of Common Insulin Regimens*
Variable Glargine* NPH1 Premix2,3 Detemir4
Efficacy Insulin Works
Hypoglycemia† 1.0 1.4X 2.5-5.0X 1.0
Insulin Dose 1.0 1.0 1.5-2.0X 1.6-2.1X
Weight Gain 1.0 1.0 1.5X 0.7-1.0X
*Normalized to glargine; sponsored comparator trials †Confirmed hypoglycemia1Riddle MC et al. Diabetes Care 2003;26:3080-3086 2Janka HU et al. Diabetes Care 2005;28:254-259 3Raskin P et al. Diabetes Care 2005;28:260-265 4Rosenstock J et al. ADA 2006; Abstract 555-P
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Conclusions
• Adjunctive therapy with insulin in type 2 diabetes is both safe and effective
• Instead of being the ‘last resort’, early insulin use is being encouraged by national organizations
• Choice of insulin and/or regimen is dependent upon:– The patient
– Pre-existing glycemic control
– Duration of illness
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