New generation insulins

lecture on new generation insulin

2. 7in 10
People with diabetes do not
achieve desired treatment
outcomes
2
4 MILLION
Deathswere caused by diabetes
in 2017
1
1. International Diabetes Federation. IDF Diabetes Atlas, 8
th
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 MILLION
people will have diabetes globally
1
BY 2045, it’s estimated that
TODAY, more than 425 MILLION people have diabetes
1
1in 2
People with type 2 diabetes
do not know they have it
1
?

3. Prevalence of Type 1 Diabetes

4. The worldwide challenge of glycaemic control
HbA
1cin T1D and T2D
*Data are median and in adults (25+ years)
T1D, type 1 diabetes; T2D, type 2 diabetes
1. McKnight et al. DiabetMed 2015;32:1036–50; 2. Oguz et al. CurrMed Res Opin2013;29:911–20;3. Polinskiet al. BMC EndocrDisord
2015;15:46; 4. Mendivil et al. CurrMed Res Opin2014;30:1769–76
T1D
1* T2D
2–4
France: 8.0%
Norway: 7.9%
Sweden: 8.0%
Ukraine: 7.4%
Italy: 7.5%
New Zealand: 8.3%
USA: 7.5%
Greece: 7.6%
Denmark: 7.9%
UK: 8.3–8.5%
Netherlands: 7.5%
Russia: 7.7%
3
India: 8.6%
3
Sweden: 8.7%
2
Poland: 9.0%
2
Portugal: 9.7%
2
UK: 8.4%
3
USA: 8.0%
3
Canada: 7.9%
3
China: 7.6%
3
South Korea: 8.0%
3
Romania: 9.9%
2
Turkey: 8.9–10.6%
2,3
Greece: 9.0%
2
Latin America: 8.5%
4

5. Intensive vs. conventional treatment in T1D and T2D
DCCT/EDIC and UKPDS follow -up data
†p<0.05; intensive vs. conventional treatment; DCCT, Diabetes Control and Complications Trial; EDIC, European Diploma in Intensive Care Medicine;
T1D, type 1 diabetes; T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study. 1. DCCT/EDIC Group. JAMA2002;287:2563–9; 2. Martin et al.
Diabetes Care2006;29:340–4; 3. UKPDS Study Group. Lancet1998;352:837–53; 4. Holman et al. N EnglJ Med 2008;359:1577–89
Retinopathy Neuropathy Renal
*66%
***76%
**53%
***86%****62%
****36%
% of patients who progressed
*p=0.006 **p=0.002 ***p<0.001 ****p<0.0001
T1D
DCCT/EDIC –microvascular complications
1,2
(4-years post-EDIC trial)
Any diabetes-related endpoint
Myocardial infarction
Microvascular disease
1977–1991
Randomisation
2007
(30 years)
10-years post-trial follow-up period
(non-interventional)
12%†
25%†
16%
1997
(20 years)
9%†
24%†
15%†
Improvements in glycaemic
control reduce the risk of
complications
T2D
UKPDS –macrovascular complications
3,4
UKPDS original results:
Intensive vs. conventional
treatment

6. Patients experience frequent hypoglycaemic events,
some of which are severe
HAT, Hypoglycaemia Assessment Tool; T1D, type 1 diabetes; T2D, type 2 diabetes
Khunti et al. Diabetes Obes Metab 2016;18:907–15; Khuntiet al. Poster presented at the 10th International Diabetes Federation-Western Pacific Region
Congress, 21–24 November 2014, Singapore
Results from the HAT study
HAT study
•Non-interventional, global, 6-month retrospective and 1-month
prospective study of patient self-reported hypoglycaemic events
•n=27,585 (T1D: 8,022; T2D: 19,563)
T1D, prospective (n=7,108)
T2D, prospective (n=18,518)
T1D, retrospective (n=8,022)
T1D, prospective (n=7,108)
T2D, retrospective (n=19,563)
T2D, prospective (n=18,518)
Severe hypoglycaemia

7. Fear of hypoglycaemia conflicts with treatment success
for both patients and clinicians
Total patient sample, n=335 (T1D, n=202; T2D, n=133) GAPP™ (A global internet survey of patient and physician beliefs
T1D, type 1 diabetes; T2D, type 2 diabetes regarding insulin therapy): n=1250 physicians
Leiter et al. Can J Diabetes 2005;29:186–92 Peyrot et al. Diabet Med 2012;29:682–9
T1D
T2D
I would treat my patients more aggressively if
there was no concern about hypoglycaemia
Percentage of patients decreasing their insulin
dose following a hypoglycaemic event
Primary care physicians
Diabetes specialists

8. The consequences of hypoglycaemia
Desouza et al. Diabetes Care 2010;33:1389–94; Frier et al. Diabetes Care 2011;34(Suppl. 2):S132–7; Frier. Nat Rev Endocrinol 2014;10:711–22; Gjedde et
al. Diabetologia2018;61:551-561
Brain
Heart
Increased risk of myocardial ischaemia
Circulation
Musculoskeletal

9. The consequences of hypoglycaemia present
a considerable burden to patients and society
CVE, cardiovascular events; ER, emergency room; SMBG, self -measured blood glucose
1. Heller et al. Diabet Med2016;33:471–7; 2. Johnston et al. Diabetes Obes Metab2012;14:634–43; 3. Ward et al. J Med Econ2014;17:176–83; 4. Khunti
et al. Diabetes Care2015;38:316–22; 5. Leiter et al. Can J Diabetes2005;29:186–92; 6. UK Prospective Diabetes Study (UKPDS) Group. Lancet
1998;352:837–53; 7. American Diabetes Association. Diabetes Care2017;40(Suppl. 1):S75–S87; 8. The Diabetes Control and Complications Trial Research
Group. N Engl J Med1993;329:977–86; 9. Brod et al. Value Health2011;14:665–71; 10. Davis et al. Curr Med Res Opin2005;21:1477–83; 13. Jönsson et
al. J Value Health 2006;9:193–198; 14. Farmer et al. Curr Med Res Op 2008;24:3097–3104; 15. Amiel et al. Diabet Med 2008;25:245–254. 16. Leese et al.
Diabetes Care. 2003;26:1176–80; 17. Curkendall et al. JCOM2011;18:455–62
CVE
4
ER Visits
3
Ambulance
1
Hospitalisation
1
Falls and
Fractures
2
Emotional
Well-being
9
Sleep
9
Productivity
9,10
Suboptimal
Control
5-8
Social
Activities
9
Ambulance
Emergency
care
Frequency
of SMBG
Physician
visit
Hospitalisation
Direct costs
13-17
Absence
from work
Work
disability
Reduced
working
capacity
Accidents
Indirect costs
13-17

10. Objectives of developing the ideal basal insulin
PD, pharmacodynamic; PK, pharmacokinetic
Ideal PK/PD profile
Flat time–action profile
Low variability
Half-life >24 hours
Potency (total glucose-lowering effect)
Glycaemic control
Simplicity
(once-daily and flexible dosing)
Predictability
Low risk of hypoglycaemia

11. Discovery of insulin
First human patient
Karamitsos, D.T. (2011). The story of insulin discovery. Diabetes Res Clin Pract, 93,S2-S8; Rosenfeld, L. (2002). Insulin: discovery and controversy. Clin
Chem, 48(12), 2270-88.

12. IDegAsp, insulin degludec/insulin aspart
Significant space for innovation within insulin
1922 1977 1990s 2000s 2010s
Isolation
of Insulin
(Banting & Best)
Animal
Insulin
Preparations
Recombinant
Human
Insulin
Rapid-
acting
analogues
Biphasic
analogues
Basal
analogues
New generation
analogues
Premixed animal
insulin
Premixed human
insulin
Premixed insulin
analogue
1950s 1980s 2002 2013
IDegAsp
co-formulation
Evolution of combination insulins
1950s 1980s

13. The quest for the ideal basal insulin
Detemir, insulin detemir; glargine U100, insulin glargine 100 units/mL; glargine U300, insulin glargine 300 units/mL; NPH, neutral protamine Hagedorn;
SmPC, summary of product characteristics; NPH insulin SmPC. https://www.ema.europa.eu/documents/product -information/insulatard-epar-product-
information_en.pdf; Detemir SmPC. https://www.ema.europa.eu/documents/product -information/levemir-epar-product-information_en.pdf; Glargine U100
SmPC. https://www.ema.europa.eu/documents/product -information/lantus-epar-product-information_en.pdf; Glargine U300 SmPC.
https://www.ema.europa.eu/documents/product -information/toujeo-epar-product-information_en.pdf; Degludec SmPC.
https://www.ema.europa.eu/documents/product -information/tresiba-epar-product-information_en.pdfAll accessed December 2018
Animal
insulin
preparations
First-generation
basal insulin
analogues
Isolation of insulin
(Banting & Best)
Ultra-long-acting
basal insulin
analogues
NPH insulin
High
Half-life (hours):
Variability: Medium Low
λ 5–10 12–19 25
Glargine
U300
Detemir
Degludec
Glargine
U100

14. New Generation of
Basal insulins

15. Degludec GlargineU100 Glargine U300
Type of
insulin
New-generation long-acting
basal insulin analogue
First-generation basal insulin
analogue
Up-concentratedformulation
of first-generation basal
insulin analogue
Modeof
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 Toxicol2015;11:1193–201; Heise et al. Diabetes Obes Metab2012;14:859–
64
Diameter 64.10 μm
Diameter 67.45 μm
Diameter 49.52 μm
500 μm

16. For internal Medical Affairs training only
Hyperglycaemia
Glycaemic control: variability
BG, blood glucose; HbA
1c, 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
0123456789101112131415161718192021 2324
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 ≈ HbA
1c7.8%
(61.7 mmol/mol)
8
0
Patient A
Low variability
Patient B
High variability

17. For internal Medical Affairs training only
Hyperglycaemia
Hypoglycaemia
0123456789101112131415161718192021 2324
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 ≈ HbA
1c7.8%
(61.7 mmol/mol)
8
0
Patient A
Low variability
Patient B
High variability
Glycaemic control: similar HbA
1c, different profile
BG, blood glucose; HbA
1c, 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.

18. Lower day-to-day glucose variability with first-
generation basal insulin analogues versus NPH insulin
CV, coefficient of variation; detemir, insulin detemir; GIR, glucose infusion rate; glargine U100; insulin glargine 100 units/mL; NPH, neutral protamine
Hagedorn; Heise et al. Diabetes 2004;53:1614–20
GIR (mg/kg/min)
GIR (mg/kg/min)
GIR (mg/kg/min)
Time (hours) Time (hours) Time (hours)
0 168 24
6
4
2
0
0 168 24
0
6
4
2
0 168 24
0
6
4
2
0 168 24
6
4
2
0
0 168 24
6
4
2
0
0 168 24
6
4
2
0
0 168 24
6
4
2
0
0 168 24
6
4
2
0
0 168 24
6
4
2
0
NPH insulin 0.4 U/kg
Glargine U100 0.4 U/kg
Detemir 0.4 U/kg

19. 0
25
50
75
100
125
150
175
200
225
250
275
Day
-
to
-
day variability in
AUC
GIR
(CV%)
Lower day-to-day variability in glucose-lowering effect
for degludec versus glargine U100/U300
AUC, area under the curve; CV, coefficient of variation; GIR, glucose infusion rate; glargine U100, insulin glargine 100 units/mL; glargine U300, insulin
glargine 300 units/mL
1.Heise et al. Diabetes Obes Metab2012;14:85–64; 2. Heiseet al. J Diabetes Sci Technol 2018;12:356-363; 3. Heiseet al. Diabetes Obes Metab
2017;19:1032–9
Time interval (hour)Time interval (hour)
Degludec vs. glargine U300
2,3Degludec vs. glargine U100
1,2
Degludec
Glargine U300
Glargine U100

20. Glucose-lowering effect is more consistent with IDeg
than IGlar U100
Proportion of effect in 6-hour time intervals across one dosing interval (%)
Patients with T1D (n=66)
AUC, area under the curve; GIR, glucose infusion rate; IDeg, insulin degludec; IGlarU100, insulinglargineU100; T1D, type 1 diabetes
Heiseet al. Expert OpinDrug MetabToxicol2015;11:1193–201
IDeg0.4 U/kg
IGlarU100 0.4 U/kg

21. FLEX
BOT, n=687
BB
Basal–bolus,
n=1006
ONCE LONG
Basal start,
n=1030
EARLY
Basal start, n=458
LOW VOLUME
U200 basal start,
n=460
ONCE ASIA
Basal start, n=435
ONCE SIMPLE USE
Basal start, n=222
Simple vs. step-wise
Flexibility and
simple titration
in Japan, n=458
HIGH DOSE
degludec U200 vs.
glargine U100,
n=145
VICTOZA
®
ADD-ON
BOT, n=413
SWITCH 2
Basal switch, n=721
COMPARE
BOT, n=373
degludec U100 vs.
U200
DEVOTE
Cardiovascular
outcomes study
ADD-ON TO GLP-1
BOT, n=346
BB T1 LONG
Basal–bolus,
n=629
FLEX T1
Basal–bolus,
n=493
BB T1
Basal–bolus,
n=456
SWITCH 1
Basal switch, n=501
Exercise study
n=40
YOUNG 1
Basal–bolus,
n=350
Degludec phase 3 clinical trial programme overview
BB, basal–bolus; BOT, basal-oral therapy; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T1D, type 1 diabetes; T2D, type 2 diabetes
vs. detemir vs. DPP-4 inhibitors and
T1
D
vs. glargine U100
T2
D
Degludec + liraglutide
Comparators
vs. degludec*
Type 1 diabetesType 2 diabetes

22. HbA
1c FPG Hypoglycaemia
ONCE LONG
1
Conf: –16%
Noct: –43%*
Sev: –69%*
ONCE ASIA
2
Conf: –18%
Noct: –38%
Sev: N/A
LOW VOLUME
3
Conf: –14%
Noct: –36%
Sev: N/A
FLEX
4
Conf: +3%
Noct: –23%
Sev: N/A
BB
5
Conf: –24%*
Noct: –31%*
Sev: –34%
SWITCH 2
6
Overall: –23%*†
Noct: –25%*†
Sev: –51%*†
DEVOTE
7
Noct sev: –53%*
Sev: –40%*
Degludec phase 3 T2D trial overview
*Statistically significant difference; †full treatment period; ‡at the end of treatment period 1, mean FPG was 5.96 mmol/L for degludec and 5.94 mmol/L for IGlaU100
At the end of treatment period 2, mean FPG increased slightly to 5.97 mmol/L for degludec, whereas FPG increased to 6.33 mmol/L for glargine U100
Conf, confirmed; FPG, fasting plasma glucose; N/A, not analysed due to few or no severe events recorded; noct, nocturnal; sev, severe
1. Rodbard et al.Diabet Med 2013;30:1298–304; 2. Onishi et al. J Diab Invest 2013;4:605–12; 3. Gough et al. Diabetes Care 2013;36:2536–42; 4. Meneghini et al.
Diabetes Care 2013;36:858–64; 5. Hollander et al. Diabetes Obes Metab 2014;17:202–6; 6. Wysham et al. JAMA 2017;318:45–56; 7. Marso et al. N Engl J Med
2017;377:723–32
Favours
degludec
Favours
glargine U100
Favours
degludec
Favours
glargine U100
Favours
degludec
Favours
glargine U100
*
*
*
‡

23. BEGIN: YOUNG 1 AND EXTENSION
NN1250-3561
Thalange et al. Pediatr Diabetes. 2015;16:164-176.

24. BID, twice-daily; IAsp, insulin aspart; IDeg, insulin degludec; IDet, insulin detemir; QD, once-daily; T1DM, type 1 diabetes mellitus
NovoLog
®
(insulin aspart) [US Prescribing Information]. Plainsboro, New Jersey: NovoNordisk; Feb 2015.
Levemir (insulin detemir) [US Prescribing Information]. Plainsboro, New Jersey: NovoNordisk; Feb 2015.
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
Rationale
•IDegmay offer treatment
benefits to pediatric patients
with T1DM relative to existing
insulin-based therapies
•IDetis widely used in the
treatment of pediatric patients
and is a suitable comparator
•IAspmay be used in children in
preference to soluble human
insulin when a rapid onset of
action might be beneficial
Objective
•To compare the efficacy and
safety of IDegversus IDet, both
given with meal-time IAsp
(basal–bolus therapy) in children
and adolescents with T1DM
YOUNG 1 AND EXTENSION
Background
NovoLog
®
US Prescribing Information: Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4)
Levemir
®
US Prescribing Information: Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4)

25. YOUNG 1 AND EXTENSION
Study design
BID: twice-daily; HbA
1c; glycated hemoglobin;IAsp, insulin aspart; IDeg, insulin degludec; IDet, insulin detemir; NPH: neutral protamine Hagedorn; OAD, oral anti-diabetic drug; QD, once-daily; T1DM, type 1
diabetes mellitus
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
Inclusion/exclusion criteria
•T1DM
•Age 1–17 years
•Ongoing treatment with insulin (any
regimen) for ≥3 months
•No OADs allowed
•HbA
1c≤11.0%
Age stratification groups
•1–5 years
•6–11 years
•12–17 years
People with T1DM
(1-17 years of age)
(n=350)
Continue main
phase treatment
(n=152)
Continue main
phase treatment
(n=128)
IDeg QD + IAsp
(n=174)
Extension phase –26 weeksMain phase –26 weeks
0 26*27
IDet(QDor BID) +
IAsp(n=176)
52†53
weeks
Open label
* Follow-up and 1 week NPH + IAsp washout period to minimize
interference with antibody measurements taken at Week 27. Only
applicable for patients NOTcontinuing in extension period.
† 1 week NPH + IAsp wash out at Week 52

26. Titration algorithm IDegand IDet
Current dose <5U 5–15U >15U
Pre-breakfast/pre-dinner plasma
glucose (IDegand IDet)or
Lowest pre-meal/bedtime plasma
glucose (IAsp)
Adjustment
mg/dL mmol/L U
<90 <5.0 -½ -1 -2
90–145 5.0–8.0 0 0 0
146–180 8.1–10.0 +½ +1 +2
181–270 10.1–15.0 +1 +2 +4
>270 >15.0 +1½ +3 +6
YOUNG 1 AND EXTENSION
Titration
Titration of IAsp, IDeg, and IDet was done once weekly based on lowest of SMPG values measured prior to visit/phone contact.
Basal insulin titration was done according to the lowest pre-breakfast SMPG value measured on the three days prior to the visit/phone contact for IDeg and IDet QD. For IDet BID the morning dose adjustment will be
based on the lowest pre-dinner SMPG value measured on the three days prior to the visit/phone contact.
IAsp titration will be done once weekly based on the lowest of three SMPG values measured prior to the next meal and bedtime on the three days prior to the visit/phone contact:
• Pre-breakfast IAsp was adjusted according to lowest SMPG measured pre -lunch
• Pre-lunch IAsp was adjusted according to lowest SMPG measured before main evening meal
• Before main evening meal IAsp was adjusted according to lowest SMPG measured at bedtime
BID, twice daily; IAsp, insulin aspart; IDeg, insulin degludec; IDet, insulin detemir; QD, once-daily, SMPG, self-measured plasma glucose; U, unit
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
IAsp(sliding scale)
≤5U >5U
Adjustment
U
-1 -2
0 0
+0.5 +1
+1 +2
+1.5 +3

27. Key secondary endpoints
•HbA
1cafter 52 weeks
•Fasting plasma glucose (FPG)
•8-point self-measured plasma glucose (SMPG) profiles
•Hypoglycemia
•Hyperglycemia with ketosis
•Adverse events
•Prandial increment
•Insulin dose
•Weight
In these results presentations, p-values are shown for results that show statistically significant differences, and not for results that are not statistically significant.
HbA
1c, glycated hemoglobin
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
Halvorson et al. Diabetes Spectrum. 2005;18:167-173.
Wolfsdorf JI et al. Pediatr Diabetes. 2014;15 Suppl 20:154-179.
Primary endpoint: HbA
1cchange from baseline after 26 weeks
Achieving good glycemic control in children and
adolescents is challenging due lifestyle factors,
physiological changes, and developmental
changes. Poor control poses a risk of
hyperglycemia with ketosis, which may progress
to diabetic ketoacidosis and eventually death.
YOUNG 1 AND EXTENSION
Endpoints

28. YOUNG 1 AND EXTENSION
HbA
1cover time
FAS, Full analysis set; LOCF, last observation carried forward; Mean±SEM
HbA
1c, glycated hemoglobin; IDeg, insulin degludec; IDet, insulin detemir
a
Calculated, not measured
Comparisons: Estimates adjusted for multiple covariates by ANCOVA
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
IDeg (n=174)
IDet (n=176)
Time (weeks)
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
HbA
1c
(%)
0.0
Treatment difference
(52 weeks):
–0.04%-points (ns)
Treatment difference
(26 weeks):
0.15 %-points
(non-inferior, p<0.05)
HbA
1c
(
mmol
/
mol
)
a
59
0
43
55
75
67
51
35
71
63
47
39
EOT IDeg
7.8±1.1%
EOT IDet
7.9±1.1%

29. YOUNG 1 AND EXTENSION
Fasting plasma glucose over time
FAS, full analysis set; LOCF, last observation carried forward; Mean±SEM
Comparisons: Estimates adjusted for multiple covariates
FPG, fasting plasma glucose; IDeg, insulin degludec; IDet, insulin detemir
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
IDeg (n=174)
IDet (n=176)5.0
6.0
7.0
8.0
9.0
10.0
11.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
FPG (mmol/L)
Time (weeks)
0.0
Treatment difference:
–29.24 mg/dL [95% CI: -51.1; 7.38]
(–1.62 mmol/L [95% CI: −2.84; −0.41])
p<0.05
162
114
150
174
126
102
138
186
FPG (mg/
dL
)
0
198
EOT IDet
171±126 mg/dL
(9.5±7.0 mmol/L)
EOT IDeg
140±77.4 mg/dL
(7.8±4.3 mmol/L)

30. YOUNG 1 AND EXTENSION
8-point self-measured plasma glucose
FAS, full analysis set; LOCF, last observation carried forward
*p<0.05; Comparisons: Estimates adjusted for multiple covariates
BF, breakfast; IDeg, insulin degludec; IDet, insulin detemir; SMPG, self-measured plasma glucose
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
IDeg (n=174)
IDet (n=176)
Week
0
Week
52
6
7
8
9
10
11
12
13
14
Pre BF 90 mins
after BF
Pre lunch 90 mins
after lunch
Pre dinner 90 mins
after dinner
Bedtime Pre BF
SMPG (mmol/L)
0
*
*
*
162
216
180
126
234
198
144
SMPG (mg/
dL
)
252
0

31. YOUNG 1 AND EXTENSION
Hypoglycemia
SAS, safety analysis set
Comparisons: Estimates adjusted for multiple covariates
a
Definition of severe hypoglycemia is according to ISPAD guidelines
Nocturnal hypoglycemia is between 11pm to 7am
% patients, proportion of patients with events; # patients, number of patients with events; ERR, estimated rate ratio; IDeg, insulin degludec; IDet, insulin detemir; PYE, patient-year of exposure, ns, not
statistically significant
Statistics based on FAS population
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
Confirmed hypoglycemia
End of extension
(Week 52)
IDeg rate: 57.7/PYE
IDet rate: 54.1/PYE
ERR (IDeg/IDet): 1.11
[95% CI: 0.89; 1.38]
(ns)
Nocturnal confirmed
hypoglycemia
End of extension (Week 52)
IDeg rate: 6.03/PYE
IDet rate: 7.60/PYE
ERR (IDeg/IDet): 0.99
[95% CI: 0.72; 1.34]
(ns)
IDeg (n=174)
IDet (n=175)
IDeg
(n=174)
Incidence
% patients
(# patients)
Rate
episodes/
PYE
Severe
17.8%
(31/174)
0.51
IDet
(n=175)
Incidence
% patients
(# patients)
Rate
episodes/
PYE
13.7%
(24/175)
0.33
IDegvs. IDet
Rate
ratio
ΔRisk
1.30 +30%
Child has altered mental status
and cannot assist in his own
care, is semi-or unconscious, or
in coma ±convulsions and may
require parenteral therapy
a

32. Insulin degludec
(n=174)
Insulin detemir
(n=175)
n % E R n % E R
All confirmed hypoglyemia 171 98.3 9317 5771 168 96.0 7967 5405
Nocturnal confirmed hypoglycemia 133 76.4 973 603 125 71.4 1120 760
All reported severe hypoglycemia 31 17.8 82 51 24 13.7 48 33
Externally classified severe episodes 28 16.1 61 38 22 12.6 38 26
Altered mental status and cannot assist in
his care
21 12.1 46 28 11 6.3 18 12
Semiconscious or unconscious 7 4.0 7 4 6 3.4 10 7
Coma ±convulsions 6 3.4 8 5 7 4.0 10 7
Not severe hypoglycemia 5 2.9 13 8 5 2.9 8 5
Not possible to classify 5 2.9 8 5 1 0.6 2 1
YOUNG 1 AND EXTENSION
Hypoglycemia including pre -specified external classification
SAS, safety analysis set
n, number of participants; %, percentage of participants; E, number of events; R, event rate per 100 patient-years of exposure
IDeg, insulin degludec; IDet, insulin detemir
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
Data are from the end of the extension trial (Week 52).

33. YOUNG 1 AND EXTENSION
Hyperglycemia with ketosis
Mean±SEM
p-values are from an ANCOVA model
IDeg, insulin degludec; IDet, insulin detemir
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
End of extension (Week 52)
Rate ratio 0.41
[95% CI: 0.22; 0.78]
p<0.05
IDeg (n=174)
IDet (n=175)

34. YOUNG 1 AND EXTENSION
Conclusion
•A1c control was comparable between treatment arms
•Overall rates of adverse events, severe adverse events, and safety parameters were
comparable between treatment arms
•IDegoffers a new addition to the treatment of T1DM in children
HbA
1c, glycated hemoglobin. IDeg, insulin degludec; IDet, insulin detemir; EMA, European Medicines Agency; T1DM, type 1 diabetes mel litus
Tresiba
©
(insulin degludec) [European Public Assessment Report (EPAR) —Product Information]. Bagsværd, Denmark: NovoNordisk; Mar 2015.
NovoLog
®
(insulin aspart) [US Prescribing Information]. Plainsboro, New Jersey: NovoNordisk; Feb 2015.
Levemir (insulin detemir) [US Prescribing Information]. Plainsboro, New Jersey: NovoNordisk; Feb 2015.
Thalange et al. Pediatr Diabetes. 2015;16:164-176.
•Based on this trial, Tresiba
®
(IDeg) was approved by the EMA for use in pediatric patients
who are ≥1 year of age
NovoLog
®
US Prescribing Information: Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4)
Levemir
®
US Prescribing Information: Pediatric: Has not been studied in children with type 2 diabetes. Has not been studied in children with type 1 diabetes <2 years of age (8.4)

35. Flexibility
Possible flexible administration

36. 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

37. Flexibility can benefit patients who find it challenging to
inject at the same time each day
1,2
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 Metab2012;7:9–14; 3. Meneghini et al. Diabetes Care2013;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
HbA
1c
(
mmol
/
mol
)
65
35
HbA
1c
3
0.0
IDeg Flexible vs IGlar U100
Treatment difference:
non-inferior
NS
Time (weeks)
IDeg Flexible vs IDeg Fixed
Treatment difference:
NS
Confirmed hypoglycaemia
3
Time (weeks)
IDegFlexible OD
IDegFixedOD
IGlarU100 OD

38. Summary of US and EU labels –subpopulations
IDeg, insulin degludec
Tresiba
®
September 2015 (http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203314lbl.pdf ); Tresiba
®
August 2015
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_ -_Product_Information/human/002498/WC500138940.pdf )
US EU
Renal indication
No clinically relevant differences in the
pharmacokinetics of IDegwere identified in patients with
renal impairment vs. healthy patients
Can be used in renal impaired patients
Hepatic indication
No clinically relevant differences in the
pharmacokinetics of IDegwere identified in patients with
hepatic impairment vs. healthy patients
Can be used in hepatic impaired patients
Paediatricindication
•Can be used in adolescents and children from the age
of 1 year
•Can be used in adolescents and children from the age
of 1 year
•Safety and efficacy have been demonstrated in a long-
term trial in children aged 1 to less than 18 years
Pregnancy
No clinical studies of the use of IDegin pregnant women.
It should be used during pregnancy only if the potential
benefit justifies the potential risk to the foetus
There is no clinical experience with use of IDegin
pregnant women
Elderly (≥65 years)
No differences in the safety and effectiveness of IDegin
patients ≥65 years vs. younger patients
Can be used in elderly patients
Elderly(≥75 years)
Greater caution is recommended in geriatric patients as
increased sensitivity in some individuals cannot be ruled out

39. 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 Degludec
Degludec
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

40. New Generation of
Bolus insulins

41. Approaching physiological mealtime
insulin therapy
Meals
Normal free insulin levels (mean)
Desired mealtime insulin
10
20
30
40
50
60
70
09:00 12:00 15:00 18:00 21:00 24:00
Insulin (mU/L)
Time of day
Dinner Long-acting insulinBreakfast Lunch
10
0
Adapted from Polonskyet al. N EnglJ Med 1988;318:1231–9

42. 2015
Insulin glargine
U300
Glucose-sensitive
insulin
BioChaperonelispro
Liver-selective prandial insulin
Oral insulin
Long
-
acting
Goal of insulin development: approach endogenous
insulin secretion by healthy pancreatic beta -cells
Future
First clinical
use of insulin
1922
Biosynthetic
human insulin
1982
Rapid-acting
insulin analogue
1996
Exuberainhaled insulin
(withdrawn 2007)
2006
Afrezza
inhaled insulin
2015
Short
-
acting
1950
NPH insulin
1953
Lente insulin
2000
Insulin glargine
U100
2013
Insulin degludec
1920 1940 1960 1980 2000
Ultra
-
fast
-
acting
2005
Insulin detemir
Faster aspart
2017
2017
Adapted from Cahn et al. Lancet Diabetes Endocrinol2015;3:638–52; Eli Lilly. Patent application, 12 November 2015; Eli Lilly. Press release, 4 December 2015;
Novo Nordisk. Capital Markets Day R&D update, 19 November 2015
Faster aspart, fast-acting insulin aspart; NPH, neutral protamine Hagedorn

43. In insulin aspart, B28Pro is substituted with aspartic
acid reducing the strength of the insulin dimer
Reduced monomer –monomer
interaction in the dimer leads
to fast monomer formation
after injection
B28Asp
Dimer interfaceA chain
B chain
ProGIVEQCCTSICSLYQLENYCN
FVNQHLCGSHLVEALYLVCGERGFFYT
Asp
D
KT
ss
s
s
s
s
P
Brangeet al.Diabetes Care 1990;13:923–54
Insulin aspart is currently marketed as NovoRapidand NovoLog
Asp, aspartic acid; faster aspart, fast-acting insulin aspart; pro, proline

44. Greater early insulin exposure with insulin aspart
compared with human insulin
40
35
30
25
20
15
10
5
0
0 120 240 360 480
Time (min)
Serum insulin (mU/L)
Serum insulin profiles in healthy subjects*
Human soluble insulin
Insulin aspart
Home et al. Eur J Clin Pharmacol 1999;55:199–203
*Corrected for endogenous insulin

45. Clinical and pharmacological improvements with
insulin aspart compared with human insulin
Improved PPG control
1
Can be dosed immediately before a meal or can be
given soon after a meal when necessary*
1
Low number of nocturnal hypoglycaemic events
2
1. Novo Nordisk. Insulin aspart (NovoRapid) summary of product characteristics. 2015; 2. Heller et al. J Diabetes 2013;5:482–91
*Not in US label
PPG, postprandial plasma glucose

46. Building on a strong foundation with
insulin aspart
Treatment of diabetes in adults, adolescents and children
aged ≥1 years
Continuous infusion in a pump system
In iv use
Pregnancy and breastfeeding
Elderly patients
Novo Nordisk. Insulin aspart (NovoRapid) summary of product characteristics. 2016
iv, intravenous

47. Ultra-fast insulin: approaching a physiological
insulin profile even further
Fast-acting insulin
Time (h)
Insulin action (at mealtime)*
From the normal pancreas
‘Ultra-fast’ insulin
Regular human insulin
Ultra-fast insulin should:
•Better approach physiological insulin secretion in
T1D
•Replace early insulin secretion in T2D
•Have a better profile for pump therapy
Adapted from Home. Diabetes ObesMetab2015;17:1011–20
*Schematic representation
T1D, type 1 diabetes; T2D, type 2 diabetes

48. Niacinamide: absorption modifier
Vitamin B3
L-Arginine: added for stability
Naturally occurring
amino acid
Insulin aspart
Changing the formulation: faster aspart is
insulin aspart in a new formulation
FDA. Inactive ingredient search for approved drug products database. www.accessdata.fda.gov/scripts/cder/iig/index.cfm
EDTA, ethylenediaminetetra-acetic acid

49. Niacinamide increases monomer fraction and
permeation rate of insulin aspart
Rate of increase similar as improvement from human insulin to insulin aspart
Monomer fraction
+35%
Permeation rate across
HDMEC cell monolayers
0.00
0.01
0.02
0.03
0.04
0.05
Human
insulin
Insulin
aspart
Faster
aspart
†
0
2x10
-06
4x10
-06
6x10
-06
P
app
(cm/s)
+27%
Volume fraction of
monomers in buffer
Human
insulin
Insulin
aspart
Faster
aspart
†
Buckley et al. ATTD 2016 (ATTD-0083); Novo Nordisk. Data on file
†
Concentration of niacinamidesimulating subcutaneous environment after injection
HDMEC, human dermal microvascular endothelial cells

50. Summary

51. Summary
Degludec
shows non-inferiority in HbA
1cversus glargine U100HbA
1c
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

52. Summary
Degludec
has greater FPG reductions in insulin-naïve patients with T2D versus glargine U100
provides a flat and stable glucose-lowering effect, over 24 hours
FPG
shows non-inferiority in HbA
1cversus glargine U100HbA
1c
shows significant reductions in the rates of overall confirmed symptomatic,
nocturnal confirmed symptomatic, and severe hypoglycaemia in T1D and T2D versus
glargine U100

24 h
Has significantly lower or clinically relevant equal insulin dose versus glargine U100
in T1D and in T2D

dose
Degludec, insulin degludec; FPG, fasting plasma glucose; glargine U100, insulin glargine 100 units/mL; T1D, type 1 diabetes; T2D, type 2 diabetes

53. Summary
Degludec
has a simple titration schedule that has the potential for up to 5 fewer SMBG test
strips/week versus glargine U100
allows for flexibility in the timing of insulin administration when needed, without
compromising the risk of hypoglycaemia
is well tolerated
improves QoLfor patients initiating insulin therapy
does not increase the risk of adverse cardiovascular outcomes in patients at high
risk, versus glargine U100
has lower day-to-day variability in glucose-lowering effect, and higher potency
versus glargine U300
U300
Degludec, insulin degludec; glargine U100, insulin glargine 100 units/mL; glargine U300, insulin glargine 300 units/mL; SMBG, self-measured blood glucose;
QoL, quality of life