Abdulmoein Al-Agha discusses the use of insulin degludec in managing pediatric diabetes. Insulin degludec is an ultra-long acting basal insulin that provides over 42 hours of basal insulin coverage and achieves similar glycemic control to insulin glargine with less overnight hypoglycemia. Insulin degludec has a half-life of approximately 25 hours, double that of insulin glargine. It also has significantly less day-to-day variability in glucose-lowering effect compared to insulin glargine. These properties allow for more flexibility in dosing time compared to other basal insulins.

1. Abdulmoein Al-Agha, MBBS,DCH, FRCP(UK)
Professor & Pediatric Endocrinologist
aagha@kau.edu.sa
The Use of Insulin Degludec in Management of
Pediatric Diabetes

2. Overview
• Introduction on high rate of diabetes globally.
• History of insulin industry.
• Prevalence of diabetes worldwide.
• Ultra-long acting basal insulin Degludec.
• Review of benefits of insulin Degludec.
• Conclusion.

3. 7 in 10
People with diabetes do not
achieve desired treatment
outcomes2
4 MILLION
Deaths were caused by diabetes
in 20171
1. International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium: International Diabetes Federation. 2017. 2. Hart JT.
Rule of halves: implications of increasing diagnosis and reducing dropout for future workload and prescribing costs in primary care. Br J Gen
Pract. 1992;42(356):116–119.
736 MILLIONpeople will have diabetes globally1
BY 2045, it’s estimated that
TODAY, more than 425 MILLION people have diabetes1
1 in 2
People with type 2 diabetes
do not know they have it1
?

4. Prevalence of Type 1 Diabetes

5. Managing pediatric patients with type 1 DM is challenging!!

6. WHAT ?!
Did you say
INSULIN !?
Barriers to the use insulin in
children

7. Banting Best
192
1
Insulin was the first discovered (late
1920dna rotcod eht now hcihw )s'
eht ti derevocsid ohw tneduts lacidem
)tseB dna gnitnaB( ezirP leboN

8. Banting & Best

9. Patient J.L., December 1922 ,15 February 15, 1923
The Miracle of Insulin

10. Human insulin
• The human insulin protein is composed of 51 amino acids, and has
a molecular size of 5808 Da.
• It is a heterodimer of an A-chain and a B-chain, which are linked
together by disulphide bonds.
• Insulin's structure varies slightly between species of animals.
• Porcine insulin is especially close to the human version, and was
widely used to treat type 1 diabetics before human insulin could
be produced in large quantities by recombinant DNA technologies

11. 2015
Insulin glargine
U300
Long-acting
Evolution of insulin therapy since 1922
Futurure
First clinical
use of insulin
1922
Biosynthetic
human insulin
1982
Rapid-acting
insulin analogue
1996
Exubera inhaled insulin
(withdrawn 2007)
2006
Afrezza
inhaled insulin
2015
Short-acting
1950
NPH insulin
1953
Lente insulin
2013
Insulin degludec
1920 1940 1960 1980 2000
2000
Insulin glargine
U100
Ultra-fast-acting
2005
Insulin detemir
Faster aspart
2017
2017
Adapted from Cahn et al. Lancet Diabetes Endocrinol 2015;3:638–52,notiacilppa tnetaP .ylliL ilE;12 November 2015,esaeler sserP .ylliL ilE;4 December 2015D&R yaD stekraM latipaC .ksidroN ovoN ;
,etadpu19 November 2015
Faster aspart, fast-acting insulin aspart; NPH, neutral protamine Hagedorn

12. Long(Detemir)
Rapid (Lispro, Aspart,Glulisine)
Short (Regular)
Long (Glargine)
0 2 4 6 8 10 12
14 16 18 20 22 24
Hours after injection
Insulinlevel
(Degludec)
Various insulin preparations available so far as
basal – bolus insulin therapy

13. The most important fact is Everyone has different needs!

14. 1
3
7
5
9
15
13
11
6 7 8 9 10 11
Level of Diabetes Control =HbA1c
12
Retinopaty
Nephropaty
Neuropathy
Microalbuminuria
RelativeRiskofcomplications
Good glycemic control will lead to low risk of complications (DCCT)

15. Ultra-long acting basal insulin Degludec.
Tresiba® (insulin degludec
injection) 100 U/mL, 200 U/mL

16. 5
/
1
2
/
2
0
2
0
1
6

17. • Novel ultra long-acting insulin analogue.
• Insulin Degludec provides basal insulin coverage for more
than 42 hours, and achieves similar glycaemic control with
less overnight hypoglycemia than glargine.
• Half life is about 25 hours.
• FDA approved (September, 2015).
• Degludec is approved for use in Europe, Saudi Arabia&
Gulf countries.
Insulin Degludec

18. For internal Medical Affairs training only
Degludec Glargine U100 Glargine U300
Type of
insulin
New-generation long-acting
basal insulin analogue
First-generation basal insulin
analogue
Up-concentrated formulation
of first-generation basal
insulin analogue
Mode of
protraction
Forms soluble multihexamers Precipitates as microcrystals Precipitates as microcrystals
Half life ~25 hours ~12 hours ~19 hours
Degludec and glargine U100 and U300
Glargine U100, insulin glargine 100 units/mL; glargine U300, insulin glargine 300 units/mL
Glargine U100 image data on file; glargine U300 optical microscopy images obtained from European patent application
http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=EP&NR=2387989A2&KC=A2&date=&FT=D&locale=en_EP
Jonassen et al. Pharm Res 2012;29:2104–14; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes Obes Metab 2012;14:859–
64
Diameter 64.10 μm
Diameter 67.45 μm
Diameter 49.52 μm
500 μm

19. Half-life of insulin degludec is double that of insulin glargine
*Insulin glargine was undectable after 48 hours Results from 66 patients with type 1 diabetes (T1D)
IDeg, insulin degludec; IGlar, insulin glargine
Heise et al. Diabetes 2011;60.lppuS(1BL:)11esieH ; et al. Diabetologia 2011;54.lppuS(1S:)425
Insulin degludec Insulin glargine
0.4U/kg 0.6U/kg 0.8U/kg 0.4U/kg 0.6U/kg 0.8U/kg
Half-life )sruoh( 25.9 27.0 23.6 11.5 12.9 11.9
Mean half-life 25.4 12.1

20. Flat time-action profile of insulin Degludec
0
1
2
3
0 4 8 16 20 24
GIR(mg/kg/min)
12
Time (hours)
AUCGIR, 0–12 h
AUCGIR, 0–6 h AUCGIR, 6–12 h AUCGIR, 12–18 h AUCGIR, 18–24 h
AUCGIR, 12–24 h
AUCx–y, area under the curve for a specified time interval after injection
GIR, glucose infusion rate
Type 2 diabetes, 49 patients, randomised, 2-,doirep12-ta dessessa saw ytilibairaV lairt yad
syad no spmalc yb etats ydaets6 and 12

21. Insulin degludec concentration reaches steady state in
3 days
50 1 62 3 4
Days since first dose
SerumIDegconcentration
ProportionofDay6level(%)
120
110
100
90
80
70
60
50
40
30
20
10
0
Type 2 diabetes
0 1 3 4
SerumIDegconcentration
ProportionofDay4level(%)
120
110
100
90
80
70
60
50
40
30
20
10
0
2
Days since first dose
Type 1 diabetes
Type 1 diabetes trial, n= 66epyT ;2 diabetes trial, n=49
T1D trial, 0.4,0.6 or 0.8 U/kg; T2D trial, 0.4,0.6 or 0.8 U/ kg
Estimated ratios and 95% CI
Heise et al. Diabetes 2012;61.lppuS(1A:)259

22. For internal Medical Affairs training only
Hyperglycaemia
Glycaemic control: variability
BG, blood glucose; HbA1c, glycated haemoglobin.
Image adapted from Penckofer S et al. Diabetes Techno Ther 2012;14:303–10; Vora J & Heise T. Diabetes Obes Metab 2013;15:701–12.
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24
0
6
2
4
10
12
14
16
18
22
Time (hours)
BG(mmol/L)
36
72
108
144
180
216
252
288
324
BG(mg/dL)
Mean BG ≈ HbA1c 7.8%
(61.7 mmol/mol)
8
0
Patient A
Low variability
Patient B
High variability

23. For internal Medical Affairs training only
Hyperglycaemia
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24
0
6
2
4
10
12
14
16
18
22
Time (hours)
BG(mmol/L)
36
72
108
144
180
216
252
288
324
BG(mg/dL)
Mean BG ≈ HbA1c 7.8%
(61.7 mmol/mol)
8
0
Patient A
Low variability
Patient B
High variability
Glycaemic control: similar HbA1c, different profile
BG, blood glucose; HbA1c, glycated haemoglobin.
Image adapted from Penckofer S et al. Diabetes Techno Ther 2012;14:303–10; Vora J & Heise T. Diabetes Obes Metab 2013;15:701–12.

24. Insulin Degludec has 4 times lower variability than insulin Glargine
220
200
180
160
140
120
100
80
60
40
20
0
IDeg
IGlar
Area under the GIR curve (time interval, hours)
Day-to-dayvariability
(coefficientofvariation%)
Endpoint IDeg CV)%( IGlar CV)%( p value
AUCGIR, 0-24 h 20 82 p <0.0001
Heise et al. Diabetes Obes Metab 2012;14:859-64; 54 patients with type 1 diabetes

25. For internal Medical Affairs training only

26. Flexible administration of IDeg was tested in both T1D and T2D
Two phase 3a clinical trials (6 and 12 months)
IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes
Meneghini et al. Diabetes Care 2013;36:858–64; Mathieu et al. J Clin Endocrinol Metab 2013;98:1154–62
MON TUE WED THUR FRI SAT SUN
12am
2am
12pm
4am
6am
8am
10am
2pm
4pm
6pm
8pm
10pm
Morning Morning Morning
Evening Evening Evening Evening
40h 8h 40h 40h8h 24h

27. Flexibility can benefit patients who find it challenging to inject
at the same time each day1,2
IDeg, insulin degludec; IGlar U100, insulin glargine U100; NS, not significant; OD, once daily
1. Aye & Atkin. Drug, Healthcare and Patient Safety 2014;6:55–67; 2. Meneghini et al. Expert Rev Endocrinol Metab 2012;7:9–14; 3. Meneghini et al. Diabetes Care 2013;36:858–64
“…In particular, this could include individuals
who travel regularly ... Shift workers may
also greatly benefit from the freedom to
change their dosing schedule…”1
“Flexibility in the timing of insulin
administration can benefit patients who find
it challenging to always inject insulin at
the same time each day.”2
0
45
60
50
75
70
55
40
HbA1c(mmol/mol)
65
35
HbA1c
3
0.0
IDeg Flexible vs IGlar U100
Treatment difference:
non-inferior
NS
Time (weeks)
IDeg Flexible vs IDeg Fixed
Treatment difference:
NS
Confirmed hypoglycaemia3
Time (weeks)
IDeg Flexible OD
IDeg Fixed OD
IGlar U100 OD

28. Pharmacokinetics of insulin degludec in
special populations Age
Hepatic function
Renal function
Geriatric ( ≥65regnuoY )
stluda(18–35)
The PK properties of insulin
degludec are not affected by
increasing age, renal impairment
or hepatic impairment
0
2000
4000
6000
8000
10000
0 4 20 24
Insulindegludec
concentration(pmol/L)
8 12 16
Time since injection
(hours)
Normal
Mild
Moderate
Severe
0
2000
4000
6000
8000
10000
0 4 20 24
Insulindegludec
concentration(pmol/L)
8 12 16
Time since injection (hours)
Normal
Child-Pugh A
Child-Pugh B
Child-Pugh C
0 4 20 248 12 16
Time since injection
(hours)
2000
4000
6000
8000
10000
Insulindegludec
concentration(pmol/L)
0
PK, pharmacokinetic
Kupčová et al. Clin Drug Investig 2014;34:127–33ssiK ; et al. Clin Pharmacokinet 2014;53:175–83oktasroK ; et al. Drugs Aging 2014;31:47–53

29. Initiation of Degludec in T1D
CSI, continuous subcutaneous insulin regimen; degludec, insulin degludec; OD, once daily; T1D, type 1 diabetes
Tresiba® September 2017 (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002498/WC500138940.pdf)
START
SWITCH
FROM OTHER INSULIN
Basal DegludecDegludec
OD
Newly
diagnosed +
Meal-
time
insulin
Individual dose
adjustment
Consider 20% reduction in
insulin dose when switching
from basal insulin or basal
component of CSI
Individual
requirement

30. Summary
Degludec
shows non-inferiority in HbA1c versus glargine U100 HbA1c
shows significant reductions in the rates of overall confirmed
symptomatic, nocturnal confirmed symptomatic, and severe
hypoglycaemia in T1D and T2D versus glargine U100

Degludec, insulin degludec; FPG, fasting plasma glucose; glargine U100, insulin glargine 100 units/mL; T1D, type 1 diabetes; T2D, type 2 diabetes
Confirm the CV safety in patients at high risk of cardiovascular
disease, versus glargine U100

31. Thanks