Transcript Polling Question

Concentrated
Insulin:
Deciphering the When and
the How for Better Patient
Outcomes
Sunday, June 12, 2016
Faculty
Chair
Robert R. Henry, MD
Professor of Medicine
University of California at San Diego
Chief, Section of Diabetes,
Endocrinology, and Metabolism
VA San Diego Healthcare System
San Diego, California
Clinical Endocrinologist
Mountain Diabetes and Endocrine Center
Asheville, North Carolina
Expert Panelists
Timothy S. Bailey, MD
Anne L. Peters, MD
Clinical Associate Professor
UCSD School of Medicine
Director, AMCR Institute
Escondido, California
3
Wendy S. Lane, MD
Professor
Keck School of Medicine of the University
of Southern California
Director, USC Clinical Diabetes Programs
University of Southern California
Los Angeles, California
Agenda
7:30 PM - 7:45 PM
Robert R. Henry, MD
Welcome and Introductions
7:45 PM – 8:15 PM
Timothy S. Bailey, MD
Concentrated Insulin in the Modern Diabetes Treatment
Era
8:15 PM – 8:45 PM
Wendy S. Lane, MD
Patient Selection, Dosing, and Delivery Devices Debate:
Asking the Experts
8:45 PM – 9:15 PM
Anne L. Peters
Making the Switch in Clinical Practice: Achieving a
Successful Transition for Your Patients
9:15 PM – 9:30 PM
Robert R. Henry, MD & Faculty
Questions and Answers Session
9:30 PM – 9:45 PM
Robert R. Henry, MD
Summary and Closing Remarks
Concentrated Insulin
in the Modern
Diabetes Treatment
Era
Timothy S. Bailey, MD
Clinical Associate Professor
UCSD School of Medicine
Director, AMCR Institute
Escondido, California
Concentrated Insulin in the Modern
Diabetes Treatment Era
Outline
• History of concentrated insulins
• How we understand insulin action (PK/PD)
– Overview of clamps
• Compare/contrast available concentrated insulins
– To each other (potency, PK/PD)
– To same molecule, different concentrations (potency, PK/PD)
– Caveat in comparing studies (ie, differing [clamp] methodology
makes comparison BETWEEN studies difficult)
• Conclusions
Insulin Concentration History
Insulin First
Dosed
U40
1922
1930’s
U500 U500
U300
U500
U100
(beef) Standard (pork) (human) Glargine
1952
1973
1980
1997
2/2015
U200
U200
Lispro Degludec
5/2015
More compounds
under investigation…
9/2015
• U400 Biodel-531
• U200 BioChaperone®
lispro
• U500 Fluorolog®
1985 -- Insulin Pens -- Key to
Avoid Dosing Confusion
Why Study PK/PD of Basal
Insulin Analogues?
PK = plasma insulin
concentration over
time
PK influences PD
PD established by assessing
• Onset of action
• Duration of action
• Peak action (if any)
• Total metabolic activity
(determined by amount
of glucose infused to
maintain euglycemia)
PD points to clinical
outcomes of the
insulin
In normal volunteers or T2D, endogenous insulin
contributes to PK and interferes with PD.
Porcellati F, et al. Diabetes Care. 2015:38:2237-2240.
Principle of the Euglycemic Glucose
Clamp
BG, mg/dL
BG-Lowering Agent
Without Glucose Infusion
0
60
120
180
Time, min
240
Principle of the Euglycemic Glucose
Clamp (cont)
BG-Lowering Agent
GIR, mg/min
BG, mg/dL
With Glucose Infusion
0
60
120
180
Time, min
240
Principle of the Euglycemic Glucose
Clamp (cont)
GIR
8
GIR,
mg/kg/min
7
6
50
Cmax (PK)
3
40
35
30
25
2
20
1
15
0
-30
Note: Space between
bars is due to a series
of insulin-specific
phenomena
45
5
4
GIR: Key PD parameter
Insulin, μU/mL
9
Serum insulin:
Key PK parameter
Insulin
Distribution
0
30
SC injection
(12 IU regular insulin)
60
Elimination
90
120
150
Tmax (PK)
Arnolds S, et al. Int J Clin Pract. 2010;64:1415-1424.
180
210
240 270
Time, min
300
330
360
Principle of the Euglycemic Glucose
Clamp (cont)
GIR
8
GIR,
mg/kg/min
7
6
50
Cmax (PK)
3
40
35
30
25
2
20
1
15
0
-30
Note: Space between
bars is due to a series
of insulin-specific
phenomena
45
5
4
GIR: Key PD parameter
Insulin, μU/mL
9
Serum insulin:
Key PK parameter
Insulin
Distribution
0
30
SC injection
(12 IU regular insulin)
60
Elimination
90
120
150
Tmax (PK)
Arnolds S, et al. Int J Clin Pract. 2010;64:1415-1424.
180
210
240 270
Time, min
300
330
360
Euglycemic Clamp
Experimental Setup
Glucose
infusion
Computer
algorithm
Blood
sampling
Glucose
analyzer
Comparison of PK for U500 and U100
Human Regular Insulin
U500 = 500 units/mL, U100 = 100 units/mL
50-Unit Dose
100-Unit Dose
1400
Mean Serum IRI
Concentration, pmol/L
1400
U-500R
U-100R
1200
1000
1000
800
800
600
600
400
400
200
200
0
0
0
4
8
12
16
Time, h
20
U-500R
U-100R
1200
24
de la Peña A, et al. Diabetes Care 2011;34:2496-2501.
0
4
8
12
Time, h
16
20
24
Comparison of PD for U500 and U100
Human Regular Insulin
U500 = 500 units/mL, U100 = 100 units/mL
50-Unit Dose
100-Unit Dose
1000
1000
U-500R
U-100R
GIR, mg/min
800
800
600
600
400
400
200
200
0
0
0
4
8
12
Time, h
16
20
U-500R
U-100R
24
de la Peña A, et al. Diabetes Care 2011;34:2496-2501.
0
4
8
12 16
Time, h
20
24
PK/PD Modeling of U500R Doses at Steady-State
During 24 h of Day 5: 500 U QD, 250 U BID, 165 U TID
PD
6000
3000
Glucose Infusion Rate, mg/min
Serum Insulin Concentration, pmol/L
PK
5000
4000
3000
2000
1000
0
6AM
12PM
6PM
12AM
6AM
Time of day
13
de la Peña A, et al. J Diabetes Sci Technol. 2014;8:821-829.
2500
2000
1500
1000
500
0
6AM
12PM
6PM
12AM
6AM
Time of day
U300 Glargine
14
Insulin Glargine U300 European Patent Application, European Patent Office.
Date of publication: November 23, 2011. EP 2 387 989 A2.
U300 Glargine: Single-Dose Clamp Profile
PK and PD profiles in a single dose clamp study (T1D)
INS, µU/mL
20
U100 0.4 U/kg
U300 0.4 U/kg
U300 0.6 U/kg
U300 0.9 U/kg
SC Injection
10
≤LLOQ
0
GIR, mg/kg/min
0
3
6
12
18
24
30
Time, h
SC Injection
36
U100 0.4 U/kg
U300 0.4 U/kg
U300 0.6 U/kg
U300 0.9 U/kg
2
1
0
0
6
12
18
Time, h
15
Tillner J, et al. Diabetes. 2013;62:A234.
24
30
36
• U100 glargine and
U300 glargine are not
equivalent in
bioavailability
(exposure) and bioefficacy (activity)
• Exposure and activity
after administration of
U300 were less by
~40% compared with
exposure and activity
after administration of
the same amount (0.4
U/kg) from U100
Gla-300 Has a Flatter, More Prolonged Time Action Profile Than
Gla-100 in Clamp Studies in T1D After 8 Days of Treatment
20
Serum insulin
mU/L
10
0
GIR
0
6
12
18
24
30
36
0
6
12
18
24
30
36
0
6
18
24
30
36
3
2
mg/kg/min
1
0
BG
mg/dL
160
140
120
100
Gla-300
0.4 U/kg
16
Becker RH, et al. Diabetes Care. 2015;38:637-643.
12
Time, h
Gla-100
0.4 U/kg
EDITION 1
Basal and Mealtime Insulin Doses
Mean Final Dose, U/kg/d
1.2
1.2
Basal
.9
.9
.6
.6
.3
.3
0
0
Baseline
12 Weeks
6 Months
Mean Final Dose (U/kg/d)
Mealtime
Baseline
12 Weeks
Gla-300
Gla-100
Basal
0.97
0.88
Mealtime
0.55
0.55
Total Daily Dose
1.53
1.43
17
Riddle MC, et al. EASD 2013;OP37.
Gla-300
Gla-100
6 Months
IDeg Serum Concentration, pmol/L
PK/PD Profile of U200 Degludec Is
Bioequivalent to U100 Degludec
AUC t,SS,GIR (%)
Time since injection, h
18
Interval, h
0-6 6-12 12-18 18-24
Interval, h
0-6 6-12 12-18 18-24
Ideg U100
Ideg U200
Korsatko S, et al. Clin Drug Investig. 2013;33:515-521.
• 8-day crossover euglycemic
clamp study comparing PK
profile of U100 to U200 IDeg
at 0.4 U/kg in patients with
T1D (n = 33) showed flat,
stable PK/PD profiles for
both insulin concentrations
PK and PD Profiles of U100 and
U200 Lispro
600
Glucose Infusion Rate, mg/min
Mean Free Serum IRI Concentration, pmol/L
1000
800
600
400
200
500
400
300
200
100
0
0
0
1
2
3
5
4
Time, h
6
7
8
de la Peña A, et al. Clin Pharmacol Drug Dev. 2016;5:69-75.
0
1
2
3
5
4
Time, h
6
7
8
Conclusions
• Concentrated insulin is entering the mainstream in diabetes therapy
• Insulin pens have eliminated many dosing challenges for patients
• U500 regular: lower volume, BID/TID provides basal effect
• U300 glargine: longer-acting, flatter, but less potent
• U200: degludec and lispro interchangeable with U100
• These insulins offer additional features that will benefit our patients
• Clinicians need to understand how to use concentrated insulins
effectively
Polling Question
Do the differences between concentrated insulin products
affect your use of these formulations in clinical practice?
A. Yes
B. No
C. I don’t know; I need more information
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Polling Question
What most influences your use of concentrated insulin
formulations?
A. Improved pharmacodynamics vs U100 formulations
B. Ability to administer higher dose in lower volume
C. Ability to use pen for a longer period of time (ie, pens
contain more than the typical 300 units)
D. All of the above
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Concentrated Insulin in the Modern
Diabetes Treatment Era
Faculty Discussion
• What are the key differences between concentrated insulin
products on the market?
• How do those differences affect use in clinical practice?
27
Patient Selection,
Dosing, and Delivery
Devices Debate:
Asking the Experts
Wendy S. Lane, MD
Clinical Endocrinologist
Mountain Diabetes and Endocrine Center
Asheville, North Carolina
Polling Question
What percentage of patients with T2D use > 100 units of insulin
per day?
A. 8%
B. 17%
C. 26%
D. 40%
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17% of Patients Use > 100 U/d
14
Frequency of total daily insulin units, % -- T2D only
Frequency, %
12
10
17% of T2D insulin users (injectors and pumpers) use
> 100 U/d.
8
6
4
N = 595
2
0
10
40
70
100
130
160
190
220
250
280
310
Total Daily Insulin, U
2011 US Roper Diabetes Patient Market Study provided by GfK Custom Research LLC.
340
370
400
Insulin Doses Are Increasing
• Obesity-induced insulin resistance has led to high insulin
requirements in a sizable percentage of people with T2D
• Approximately 35% of subjects with T2D require a basal insulin
maintenance dose of 60 U or more[a]
• In a treat-to-target basal insulin trial involving insulin-naive
patients with T2D, 21% of patients required > 80 U of basal
insulin at the end of the trial[b]
a. Rodbard HW, et al. Endocr Pract. 2014;20:285-292.
b. Gough SCI, et al. Diabetes Care. 2013;36:2536-2542.
Polling Question
What is the average total daily insulin dose in your patients
with T2D?
A. < 20 U
B. 20 to < 60 U
C. 60 to < 100 U
D. 100 to 200 U
E. > 200 U
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Most Common Potential Candidates
for Concentrated Insulin
Obese T2D with severe insulin resistance[a]
• Multiple daily injections
• CSII*
T2D requiring high-dose insulin[a,b]
• Postoperatively or posttransplant
• On high-dose glucocorticoid therapy
• Severe systemic infection
*Off-label use.
a. Cochran E, et al. Diabetes Care. 2005;28:1240-1244.
b. Garg R, et al. Diabetes Metab Res Rev. 2007;23:265-268.
Potential Advantages of Concentrated
Insulin Use in Patients With Severe IR
• Improved insulin absorption from smaller volume injection
leads to more predictable insulin action and improved
glycemic control
• Fewer injections and lower volume injections enhance
patient comfort and enhance adherence
• Concentration of the insulin can prolong the insulin action,
depending on the method of protraction[a] (U500R insulin
and U300 glargine)
• Protracted PD profile of U300 glargine results in less
hypoglycemia than U100 glargine
• Cost savings when used in CSII (fewer cartridge and
battery changes)
a. Sindelka G, et al. Diabetelogia. 1994;37:377-380.
Why Do We Need a Concentrated
Basal Insulin?
• In a basal/bolus regimen, the largest daily injection for
continuous background glucose control is the basal injection
(usually 50% total daily insulin dose and 2 to 3 times average
bolus dose)
• Current U100 insulin syringes deliver a maximum of 100 U of
insulin, and all but 1 current pen device delivers a maximum
dose of 80 U
• Insulin-resistant patients requiring > 100 U of basal insulin will
need > 1 injection (1 mL) of insulin by syringe, and may require
> 1 pen injection in patients requiring > 80 U/d
• There is some evidence that large insulin volumes are poorly
and inconsistently absorbed, leading to suboptimal glycemic
control[a]
a. Binder C, et al. Diabetes Care. 1984;7:188-199.
Currently FDA-Approved
Concentrated Basal Insulins
• U500 regular human insulin (Lilly) (basal and prandial)
• U300 glargine (sanofi)
• U200 degludec (Novo Nordisk)
U500 R Is Highly Concentrated
U500 R contains 500
units of insulin in each
mL (5 times more
concentrated than
U100)
U500 R allows a patient
to inject one-fifth the
insulin volume
compared with injecting
the same dose of a
U100 insulin
=
100 units
of U100 insulin
in a U100
insulin syringe
(100 unit markings)
OR
100 units
of U500 insulin
in a U100
insulin syringe
(20 unit markings)
100 units
of U500 insulin
in a volumetric
syringe
(0.2 mL)
This shows the same dose
(actual units)
Humulin® R U500 PI. 2016.
Do We Need a Concentrated Prandial
Insulin?
• In MDI regimens, possibly to keep the injection volume
comfortable for patients injecting large (> 35 U) doses of
mealtime insulin, and to make the injection pen last longer
• In CSII, definitely, to facilitate adequate insulin absorption of
high basal and bolus infusion rates and allow adequate insulin
pump operability
• Currently FDA-approved concentrated prandial insulins: U200
lispro
Case 1: Mary
• 59-year-old woman with 17-year history
of T2D
• She has sequentially progressed through
OHAs plus basal insulin and is now on
basal/bolus insulin therapy
• She was initially managed with U100
insulin glargine and insulin lispro, but
required more than 100 units of basal
insulin per day and was taking a total of 6
insulin injections per day. Her fasting BGs
remained elevated (between 150 and 200
mg/dL) on BID glargine, so her PCP placed
her on a U100 N and R insulin regimen as
follows: 50 N/20 R with breakfast, 20 R
with lunch, 20 R with supper, 40 N/10 R at
39
hs, "sliding scale" R prn
Case 1: Mary
History and Physical Examination
Physical
Exam:
Findings:
Height 65", Weight 221 lb, BMI 36.8 kg/m2
Abdominal obesity, advanced peripheral neuropathy
History of UTIs
Medications: N and R insulin, 4 injections daily (170 to 180 U/d, 1.8 U/kg);
furosemide, benazepril, metformin, amitriptyline,
atorvastatin, aspirin
40
Diabetes
Self-Care:
Monitors BG reliably 4 times daily. No omitted insulin doses. Is
committed to improving BG control and lives with supportive
spouse. She would like a more comfortable and convenient
insulin regimen
HbA1c:
7.1%
Case 1: Mary
Polling Question
What are the shortcomings of using insulin glargine in a patient
requiring high basal insulin doses such as Mary?
A. It will require more than a single injection per day
B. It is associated with more hypoglycemia than NPH insulin
C. At high doses it is incompletely absorbed/bioavailable,
reaching a point at which uptitration affords no further
benefit
D. A and C
37
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Increasing Glargine Dose > 0.5 U/kg Does
Not Result in Further Glucose Reduction
Changes are from baseline to indicated time point
Ratio FPG Change,
mg/dL/insulin dose
change, IU/kg
Insulin dose (IU/kg) 0.11 0.22 0.31 0.29
Time, wk 0
2
4
6
0.42
0.43
0.46
0.50
8
12
18
24
-100
-200
N = 458
HbA1c = 8.7%
FPG = 199.6 mg/dL
-300
-400
-500
N = 458
HbA1c = 8.7%
FPG = 199.6 mg/dl
38
Shaefer C, et al. ADA 2015. Poster 995-P.
Case 1: Mary
Polling Question
Choose the INCORRECT answer for the following: Is Mary a
candidate for an insulin pump?
A. Yes
B. No
C. Maybe
D. It depends what you put in her pump
39
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Case 1: Mary
Initiating CSII With U500 Insulin
Initial U500 pump* settings
• 180 U total daily insulin dose; reduce dose by 15% to 20% for baseline
HbA1c < 8% = approximately 150 U/d insulin requirement (50% basal,
50% bolus); basal requirement = 75 U/24 h = approximately 3 U/h;
divide by 5 = 0.6 U/h
• Set basal rate at 0.6 "pump units" per hour (equivalent to 3.0 U
insulin/h)
• Set meal doses at 5 "pump units" per meal (equal to 25 U insulin) for
breakfast and lunch and 7 "pump units" (equal to 35 U) for supper
• Set target BG = 100; set insulin sensitivity factor = 100; set insulin on
board for 6 h
40
*Off-label use.
Case 1: Mary
Polling Question
Mary was using 90 U of basal insulin on her MDI regimen. Why
was her 24-h basal insulin dose reduced to 75 U (0.6 "pump
units"/h) on U500 by CSII*?
A. To allow for a single daily cartridge change in her pump
B. To prevent hypoglycemia if her insulin absorption
improves with U500 in CSII
C. To save money on insulin
41
*Off-label use.
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Case 1: Mary
Polling Question
What other instructions should Mary receive upon initiation of
U500 via CSII*?
A. Importance of regular SMBG
B. Review of recognition and treatment of hypoglycemia
C. Importance of regular phone contact with pump
nurse/CDE after pump initiation, especially if she
experiences hypoglycemia
D. All of the above
42
*Off-label use.
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Case 1: Mary
Follow-Up on U500 by CSII*
• 3 months: HbA1c 6.0%; no hypoglycemia (lowest BGs [mg/dL]
in 60s only after exercise); weight 226 lb (5-lb increase); Mary
states, "I love the pump!"
• 6 months: HbA1c 5.8%; no hypoglycemia; weight 221 lb
• Over next 5 years: HbA1c range, 5.0% to 7.5%; no significant
hypoglycemia; weight increases to 230 lb and a slight increase
in insulin dose is required; Mary is concerned about her weight
increase, her need for more insulin, and her HbA1c of 7.5% (the
highest it has been since beginning U500 insulin by CSII*)
43
*Off-label use.
Case 1
Mary’s CGM on U500/CSII*
Sunday
Blood Glucose, mg/dL
400
Tuesday
Monday
Thursday
Saturday
Wednesday
Friday
300
200
100
0
3 AM
44
*Off-label use.
HbA1c = 7.5%
6 AM
Courtesy of Wendy Lane, MD.
9 AM
12 PM
3 PM
Time of Day
6 PM
9 PM
Case 1: Mary
Polling Question
What adjunct therapies are options for Mary to limit insulininduced weight gain, reduce her insulin dose, and lower her
HbA1c?
A. Metformin
B. GLP-1 RAs
C. SGLT2 inhibitors
D. All of the above
45
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Case 1: Mary
Plan
Mary is already on metformin and has a history of
recurrent UTIs. Therefore, we added a GLP-1 RA
(liraglutide) at 0.6 mg/d, increasing to 1.2 mg/d in 1 wk.
46
Case 1: Mary
Polling Question
How should Mary’s insulin infusion rates be reduced upon
addition of liraglutide to her U500 CSII* regimen?
A. Reduce basal insulin only by 30%
B. Reduce bolus insulin only by 25%
C. Reduce basal and bolus insulin by 10%
D. Reduce basal and bolus insulin by 20% to 25%
47
*Off-label use.
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Addition of Liraglutide to High-Dose Insulin Therapy
Results in Reductions in Basal and Bolus Insulin
In a study of 37 patients with T2D on high-dose basal/bolus
insulin therapy (mean insulin dose 200 U/d), addition of
liraglutide resulted in an overall 35% insulin reduction at 6
months (38% to 44% reduction in bolus insulin and 29% to 31%
reduction in basal insulin).[a]
In a study of 124 subjects with T2D on basal/bolus insulin
therapy (mean insulin dose 101 U/d), addition of liraglutide
resulted in an 18% overall insulin reduction at 24 weeks.[b]
48
a. Lane W, et al. Diabetes Obes Metab. 2014;16:827-832.
b. Lind M, et al. BMJ. 2015;351:h5364.
Case 1: Mary
Follow-Up U500/CSII* Plus Liraglutide
Basal and bolus insulin reduced by 20 % to 25% on liraglutide. No
change in correction bolus.
Follow-up visits: 4 weeks: HbA1c 6.0%; weight 223 lb. 8 weeks:
HbA1c 5.4%, weight 221 lb; mild-to moderate nocturnal
hypoglycemia noted (lowest BG 52 mg/dL; several in 60s). Basal,
bolus settings reduced.
Follow-up visit, 3 months later: HbA1c 5.8%; weight 215 lb.
Next 5 years: HbA1c range 5.8% to 6.9%; weight stable at 215 to
220 lb. She is pleased with her treatment regimen.
49
*Off-label use.
Case 1: Mary
CGM -- U500/CSII* Plus Liraglutide
400
Sunday
Tuesday
Blood Glucose, mg/dL
Monday
Thursday
Saturday
Wednesday
Friday
300
200
100
0
3 AM
50
*Off-label use.
HbA1c = 7.5%
6 AM
Courtesy of Wendy Lane, MD.
9 AM
12 PM
3 PM
Time of Day
6 PM
9 PM
Case 2: Karen
• Karen is a 54-year-old woman with an 11-year
history of T2D. She is now on basal/bolus
insulin therapy and has had her insulin doses
increased several times without apparent
therapeutic benefit
• She comes to her initial office visit stating that
she is frustrated with her T2D treatment
because "nothing seems to work." She is not
monitoring her glucose levels because "I have
given up." She admits to occasionally skipping
insulin injections
51
Case 2: Karen
History and Physical Examination
Physical
Exam:
Height 65", weight 218 lb, 36.2 kg/m2
Findings:
Central obesity, mild peripheral neuropathy
Medications: Insulin detemir BID (total 120 U), insulin lispro TID (total 66 U)
(TDD = 186 U = 1.9 U/kg); exenatide 5 mcg BID (total of 7 daily
injections)
Omeprazole, trazodone, metformin 500 mg QD, HCTZ,
pregabalin
52
Past medical
history:
T2D with neuropathy, hypertension, GERD, frequent genital
mycotic infections
FBG and
HbA1c:
FBG 315 mg/dL; HbA1c 11.1%
Case 2: Karen
Polling Question
What are the problems with Karen’s present glucose-lowering
regimen?
A. She is on too little prandial insulin
B. She is on an overly complex regimen with too many daily
injections to easily comply with
C. She requires high insulin doses and may not be adequately
absorbing her insulin
D. All of the above
53
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Case 2: Karen
Treatment Plan
• Increase glucose monitoring to QID (ac and hs)
• Stop insulin detemir; begin insulin degludec U200, 96 U q
AM*; change insulin lispro U100 to insulin lispro U200, 24 U
TID before meals (4 daily injections)
• Provide correction dose for hyperglycemia (2 U U200 lispro
per 50 points BG > 150 mg/dL)
• Stop exenatide
• Increase metformin to 1000 mg BID over next 2 weeks
54
*20% dose reduction
Case 2: Karen
4-Week Follow-Up Visit
• Karen is monitoring BG 4 times daily; FBG 101 to 154 mg/dL;
overall BG 61 to 213 mg/dL; weight is up to 232 lb (14-lb
weight gain)
• HbA1c: 8.6%
• Karen is pleased with her improved glycemic control, but
frustrated with her weight gain
• Plan: begin exenatide 2 mg QW; reduce basal and bolus
insulin 10%
55
Polling Question
What is your primary factor in deciding to switch to a
concentrated insulin product?
A. When patients require > 80 units of basal insulin daily
B. In a patient with insulin resistance
C. When patients require multiple injections per insulin dose
D. When adherence is an issue
E. All of the above
56
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High-Dose Insulin Algorithm
≤ 0.5 U/kg/d
≤ 40 U/d
U100 Basal Insulin
Analogue or
U300 Glargine
BASAL INSULIN
DOSE
*Off-label use.
Courtesy of Wendy Lane MD.
60-160 U/d
40-60 U/d
U200 Degludec
or
U300 Glargine
80 - ≤ 320 total U/d
U200 Degludec + U200 Lispro (MDI) OR U500R MDI
OR
U200 RAA/U500R CSII*
and consider adjunct therapies
57
≥ 0.5 U/kg/d
U200 Degludec
IS BOLUS INSULIN NEEDED?
NO
YES
> 320 total U/D
U500R MDI OR U500R
CSII*
and consider adjunct
therapies
Patient Selection, Dosing, and
Delivery Devices
Faculty Discussion
• When would you not switch to concentrated insulin?
• When is concentrated insulin appropriate?
• How do you make the decision to switch?
58
Making the Switch in
Clinical Practice:
Achieving a
Successful Transition
for Your Patients
Anne L. Peters, MD
Professor at the Keck School of Medicine
of the University of Southern California
Director, USC Clinical Diabetes Programs
University of Southern California
Los Angeles, California
General Rule of Switching
Dose of
U300 glargine > U100 glargine
> U100/U200 degludec
60
Lantus® [package insert]. Bridgewater, NJ: sanofi-aventis US; 2016.
Toujeo® [package insert]. Bridgewater, NJ: sanofi-aventis US; 2016.
Clinical Experience: Switching to and
From Concentrated Insulins
Switch to U100
Glargine
Switch to U300
Glargine
U100 Glargine
--
Switch dose for
dose the same;
likely need to
uptitrate
Consider
downtitrating by
10%
U300 Glargine
Consider
downtitrating by
20%
--
Consider
downtitrating by
20%
Degludec
Switch dose for
dose the same;
likely need to
uptitrate
Switch dose for
dose the same;
likely need to
uptitrate
Current Therapy
61
Switch to Degludec
--
Case 3: Joseph
• Joseph is a 58-year-old white man with an
18-year history of T2D
• He was started on oral agents and over
time switched to orals + a GLP-1 RA and
then to basal insulin
• His BMI = 32 kg/m2 and he is otherwise
healthy
• He is the vice president of a bank, drives
1 hour each way to work in rush hour traffic
and has little time for exercise
• He does, however, try to eat well and
observes a fairly low carbohydrate diet
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Case 3: Joseph
T2D History
• 2 years previously, with an HbA1c of 7.5%, he was started on
U100 glargine and the dose was uptitrated to 50 U at bedtime
• His metformin, SGLT2 inhibitor, and GLP-1 RA were continued
• HbA1c fell to 6.9% with a reduction in FBG to 100 to 120 mg/dL
• However, his target is an HbA1c of 6.5% so he started to
exercise after dinner each evening
• With this change he began to have nocturnal hypoglycemia;
reducing his glargine dose resulted in an increase in FBG
63
Case 3: Joseph
Nocturnal Hypoglycemia on U100 Glargine
400
Blood Glucose, mg/dL
350
300
250
200
150
100
50
3:00
AM
12:00
AM
Fri
64
Courtesy of Anne Peters, MD.
Sat
6:00
AM
Sun
Mon
Tue
9:00
AM
Wed
Thu
Case 3: Joseph
Transition From U100 to U300 Glargine
• To help reduce his nocturnal hypoglycemia he was switched
from U100 to U300 glargine
• His dose remained unchanged from 50 U of U100 to 50 U of
U300
• After the switch his FBG increased to ~160 mg/dL so his dose
was once again uptitrated
• On 60 U of U300 glargine his overnight hypoglycemia was
nearly eliminated and his HbA1c was 6.8%
65
Case 3: Joseph
After Switching to U300
400
Blood Glucose, mg/dL
350
300
250
200
150
100
50
3:00
AM
12:00
AM
Fri
67
Courtesy of Anne Peters, MD.
Sat
6:00
AM
Sun
Mon
Tue
9:00
AM
Wed
Thu
Case 4: Heather
• Heather is a 48-year-old flight
attendant for a major airline
• She has had T1D for the past 20
years
• For much of the time she has had
T1D she has done fairly well on
U100 glargine plus premeal rapidacting insulin
• However, she has had a long, slow
fall in her C-peptide secretion that
has led to increasing "brittleness"
in terms of her BG
68
Case 4: Heather
History
• She loves night flights and historically worked on the overnight flight
from LAX to Miami, but with increasing seniority she has moved up
to international flights
• Her typical schedule is to fly once per week; on a flight from LAX to
somewhere in the world, spend a day resting, and then return to LAX
• When she is working she is often busy and distracted and is very
anxious about hypoglycemia
• When she is back at home she is active, likes to work out, and is on a
normal daytime schedule
69
Case 4: Heather
U100 Glargine to U100 Degludec
• She was not interested in a pump or a sensor, although recently, with
her increasing frequency of lows, she started to wear a CGM
• Her CGM data showed high variability, although her HbA1c was 7.0%
• She was switched from 14 U of U100 glargine to 12 U of U100
degludec given once every 24 hours (more or less)
• This simplified her life and improved her basal values, with less
hypoglycemia
• However, her HbA1c increased to 7.4%, reflecting a need to better
dose her prandial insulin
70
Polling Question
U100 to U500 Regular Insulin
You would like to switch a patient (HbA1c 8.4%) to U500. For a
total daily dose of 300 U given twice daily, how would you
distribute the doses?
A. 180 U in AM; 120 U in PM
B. 160 U in AM; 110 U in PM
C. 250 U in AM; 110 U in PM
D. Not enough experience to know
72
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Algorithm for U500 Regular
Insulin Therapy
TDI Dose
(U/d)
Injection Frequency/
Delivery Method*
Dosage Distribution
(% of TDD)†
150-300
2 injections/d
(AM & PM) with or without
basal insulin
AM injection - 60% TDD
PM injection = 40% TDD
(ie, 60/40)
150-300
3 injections/d
(AM, noon, and PM) with or without
basal insulin
40/30/30 or
45/35/20 or
40/40/20
CSII‡
24-hour basal insulin infusion + 3 mealtime
boluses (eg, 50% TDD for basal rate and
20/15/15 for mealtime boluses or
20% TDD for basal rate and
30/25/25 for mealtime boluses)
150-300
AM refers to pre-breakfast; noon refers to pre-lunch; PM refers to pre-evening meal.
regular boluses recommended at least 30 minutes premeal; dosage titration is according
to frequent SMBG.
†Empirically reduce the conversion dose from U100 insulins by 10% to 20% if baseline HbA is
1c
≤ 8%, and increase the dose by 10% to 20% if HbA1c ≥ 10%.
‡Off-label use.
*U500
Lane WS, et al. Endocr Pract. 2009;15:71-79.
Algorithm for U500 Regular
Insulin Therapy (cont)
Injection Frequency/
Delivery Method*
Dosage Distribution
(% of TDD)†
300-600
3 injections/d
(AM, noon, and PM)
with or without basal
40/30/30 or
45/35/20 or
40/40/20
300-600
4 injections/d
(AM, noon,
PM, bedtime)
30/30/30/10
300-600
CSII‡
Same as above
TDI Dose (U/d)
AM refers to pre-breakfast; noon refers to pre-lunch; PM refers to pre-evening meal.
regular boluses recommended at least 30 minutes premeal; dosage titration is according
to frequent SMBG.
†Empirically reduce the conversion dose from U100 insulins by 10% to 20% if baseline HbA is
1c
≤8%, and increase the dose by 10% to 20% if HbA1c ≥10%.
‡Off-label use.
*U500
Lane WS, et al. Endocr Pract. 2009;15:71-79.
Algorithm for U500 Regular
Insulin Therapy (cont)
TDI Dose (U/d)
Injection
Frequency/
Delivery Method*
Dosage
Distribution
(% of TDD)†
4 injections/d
(AM, noon, PM,
and bedtime)
25/25/25/25 or
30/30/30/10
> 600
AM refers to pre-breakfast; noon refers to pre-lunch; PM refers to pre-evening meal.
regular boluses recommended at least 30 minutes premeal; dosage titration is according
to frequent self-monitored blood glucose.
†Empirically reduce the conversion dose from U100 insulins by 10% to 20% if baseline HbA is
1c
≤ 8%, and increase the dose by 10% to 20% if HbA1c ≥ 10%.
*U500
Lane WS, et al. Endocr Pract. 2009;15:71-79.
Conclusions
• Switching from one basal insulin to another requires attention
to the type of insulin being used
• This can be an issue with variations in insurance coverage
• Overall, switching to a newer basal insulin helps reduce
hypoglycemia, particularly overnight
• However, in patients on prandial insulin, adjustments in rapidacting insulin may be required to fit the new basal levels
76
Polling Question
Do you find that when switching from U100 glargine to U300
glargine the majority of your patients need to uptitrate?
A. Yes
B. No
C. Not enough experience to know
77
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Polling Question
Do you find that when switching from U100 glargine to
degludec, the majority of your patients need to downtitrate?
A. Yes
B. No
C. Not enough experience to know
78
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Polling Question
How comfortable are you with the dosing algorithm for
switching from U100 to U500 regular insulin?
A. Very comfortable
B. Somewhat comfortable
C. Not comfortable
D. Not enough experience to know
79
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Making the Switch in Clinical Practice: Achieving a
Successful Transition for Your Patients
Faculty Discussion
• Is one strategy better than another?
• How do you decide which strategy is best in your patients?
80
Question and
Answer Session
Robert R. Henry, MD
Timothy S. Bailey, MD
Wendy S. Lane, MD
Anne L. Peters, MD
Submitting Questions
A question can be submitted to the panel at any time during
the event.
To submit questions to the panel, please email
[email protected]
Or
Text 530.454.5563
We encourage you to submit questions during the program.
Microphones will also be accessible during Q&A.
Not all questions can be answered, unfortunately, due to time
constraints.
Summary and
Closing Remarks
Robert R. Henry, MD
Professor of Medicine, University of
California at San Diego; Chief, Section of
Diabetes, Endocrinology, and Metabolism
VA San Diego Healthcare System
San Diego, California