Choosing a better basal insulin.

1. Addressing Barriers in Achieving Optimal
Glycemic Target with Ideal Basal Insulin,
Degludeg & its Clinical Experience in
Glycemic Control
1
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
BSMMU

2. Objectives
• To obtain insights on the existing insulin therapy
barriers and to understand the need for a better insulin
• To learn about the new ultra-long-acting basal insulin -
the molecule of Insulin Degludec
• Pharmacokinetics/Pharmacodynamics
• Clinical efficacy and safety
• Flexibility in dosing
• Clinical use, dosing and titration

3. What are problems encountered…
3

4. Canada 7.36–8.7%11
Latin America 7.6%1
US 7.2%7
China 9.5%11
India 8.7–9.6%9,11
Japan 7.05–9.6%11
Korea 7.9–8.7%4
Russia 9.6%11
Spain 9.2%8
Sweden 8.7%3
Turkey 10.6%3
UK 8.510–9.8%2
Germany 8.42–9.2%8
Greece 8.911–9.7%3,8
Italy 8.4%11
Poland 9.0%11
Portugal 9.7%3
Romania 9.9%3
1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev & Rathmann Primary Care Diabetes 2013;7:229–33; 3. Oguz et al. Curr Med Res Opin
2013;29:911–20; 4. Ko et al. Diabet Med 2007;24:55–62; 5. Arai et al. Diabetes Res Clin Prac 2009;83:397–401; 6. Harris et al. Diabetes Res Clin Pract 2005;70:90–7; 7.
Hoerger et.al. Diabetes Care 2008;31:81–6; 8. Liebl et al. Diabetes Ther 2012;3:e1–10; 9. Shah et al. Adv Ther 2009;26:325–35; 10. Blak et al. Diabet Med 2012;29:e13–20;
11. Valensi et al. Int J Clin Pract 2008;62:1809–19
Poor glycemic control:
A worldwide problem
Reported mean HbA1c in T2D patients exceeds local targets in nearly all countries

5. But why are we not getting to goal?
5
The glucose targets are known…

6. Patients have poor blood glucose control
Patients struggle to remain fully
compliant with their insulin regimens
Patients and physicians are concerned
about hypoglycemia
User friendly insulin regimens would
help empower patients and physicians
Insulin doses are being missed or not
taken as prescribed
Treatments are
needed that
respond to the
functional and
emotional
needs of people
with diabetes.
The need for
treatment
options that
could help
improve
compliance and
ultimately long
term health
outcomes.
Key global findings from the Survey

7. Barriers to achieving optimal glycemic
control
• Risk of Hypoglycemia
• Suboptimal dosing & titration
• Glucose Variability
Hypoglycemia
• Fear of Hypoglycemia
• Complexity of Regimen
• Lack of Flexibility
Adherence to
Treatment

8. Limitations with current basal insulin therapy
• Basal insulins must be administered
at the same time every day1
• Variability of glucose lowering
effect of current insulins (inter-
patient and intra-patient)2
• Currently available long-acting
insulin analogues do not always
last 24 hours2
• Reducing variability and
extending duration of action
could simplify titration and reduce
the incidence of hypoglycemia2
1. Joshi et al. SA Fam Pract 2009;51:97–102; 2. Evans et al. Diab Obesity Metab 2011;13:677–684

9. 9
Longer
duration
of action
Controls
fasting
blood
glucose
with 1
injection
per day in
all
individuals
Flat time-
action
profile
Lower risk of
hypoglycemia
Less day-
to-day
variability
Lower hypo-
and
hyperglycemia
Ideal
Basal
Insulin
Clinical
Benefit
Development of an ideal basal insulin to meet
these challenges

10. Novel agent to address insulin barriers
10
Optimal Glycemic
Control
Optimal
dosing &
titration
Greater
flexibility
for better
adherence
Lower
hypoglycemi
a risk

11. Hypoglycaemia Risk and
Glucose Variability
BARRIER
11

12. Hypoglycemia continues to be a problem with
current basal insulin analogues
12
1 of 4 patients on basal-only therapy had a
self-treated hypoglycemic event in the past 30 days
Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians.
Current Medical Research and Opinion. 2012;28(12):1947-1958.
Percentage of patients who reported having at least one
self-treated hypoglycemic event in the past 30 days
All
Basal
only
Basal
+bolus
36% 45%25%

13. Fear of hypoglycemia is a concern for patients
taking basal insulin analogues
15
Percentage of patients worried about experiencing
self-treated nocturnal hypoglycemia
Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians.
Current Medical Research and Opinion. 2012;28(12):1947-1958.
42%
57% of patients reported being concerned about
the potential negative impact of nocturnal
hypoglycemic events on their long-term health

14. Risk of hypoglycemia affects dose of insulin
initiated by HCPs
16
Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians.
Current Medical Research and Opinion. 2012;28(12):1947-1958.
Percentage of HCPs who adjust initial dose of insulin
due to risk of hypoglycemia
56%
42%
56%
Initiated patients on a
lower insulin dose than
recommended due to
risk of hypoglycemic
events

15. Glucose variability (GV) predicts hypoglycemia
risk before starting and during insulin therapy
Qu et al. Diab Tech Therapeutics 2012;14:1008–12
Numbers next to bars are p values
GV is therefore likely to be a significant player in overall
treatment success

16. Variability of FPG and cardiovascular mortality
10-year survival
Group 1 (8.5%)
Group 2 (14.8%)
Group 3 (27.7%)
1.0
0.7
0.6
0.5
0.0
0 2 4 6 8 10
Time (years)
0.8
0.9
Survival
probability
Mean CV of FPG*
Variability in blood glucose is an
independent risk factor for mortality
*Significant differences in the CV of FPG (p<0.001)
Muggeo et al. Diabetes Care 2000;23:45–50

17. 19
BARRIERS
Optimal
Glycemic
Control
Hypoglycemia
Risk and Glucose
Variability
GOAL

18. Need for an ideal basal insulin
What is Insulin Degludec?
20

19. Degludec:
Multi-hexamer formation key
to protraction mechanism
Degludec molecules form
hexamers
The side chain (linker) forms an accurate
fit between Degludec hexamers to form
multi-hexamers

20. Degludec association
Proposed steps from injection
to absorption
Degludec multi-hexamers
Degludec monomers
-Zn2+
Degludec di-hexamers
-Phenol
Injected
formulation
S.C. depot
formation
Absorption

21. Capillary membrane
Subcutaneous tissue
Insulin degludec in blood Albumin binding
Monomers
Cell membrane
Capillary blood
Insulin receptors
Multi-hexamers
Degludec:
Mode of action

22. PK/PD in T1DM: Half-life greater than
25 hours
24
2x longer half-life vs insulin glargine
(25.4 hours vs 12.5 hours)
Heise T, Hövelmann U, Nosek L, Bøttcher S, Granhall C, Haahr H. Insulin degludec has a two-fold longer half-life and a more consistent
pharmacokinetic profile than insulin glargine. Poster presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011;
San Diego, California, USA.

23. PK/PD in T1DM: Four times less variability
in glucose-lowering effect over 24 hours
vs insulin glargine
25
Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin
glargine under steady-state conditions in type 1 diabetes. Diabetes, Obesity and Metabolism. 2012;14(9):859-864.
GIR=glucose infusion rate; AUC GIR (GIR in subscript) =Area under the curve for glucose infusion rate; CV%= coeffecient of variation

24. Insulin degludec provides four times lower day-
to-day variability vs insulin glargine
Mean within-subject variability at steady state*
Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin
glargine under steady-state conditions in type 1 diabetes. Diabetes, Obesity and Metabolism. 2012;14(9):859-864.
4x less variability with insulin degludec vs insulin glargine

25. PK/PD in Type 2 DM: A flat, stable
glucose-lowering effect
27Insulin degludec [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2012.
GIR, glucose infusion rate

26. PK/PD in T2DM: Concentration reaches steady
state in 3 days
54320 1 6
Days since first dose
SerumIDegconcentration
ProportionofDay6level(%)
120
110
100
90
80
70
60
50
40
30
20
10
0
T2D
0 1 2 3 4
SerumIDegconcentration
ProportionofDay4level(%)
120
110
100
90
80
70
60
50
40
30
20
10
0
Days since first dose
T1D
T1D trial, n=66; T2D 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(Suppl. 1):A259

27. Reaching steady state with insulin degludec
Units added each day
Units remaining
from prior
injections
(t1/2~24 h) Units absorbed into circulation
5 UDay 1 10 U
~9 U
7.5 U5 U
7.5 U
~9 U
10 U
10 U
15 U
17.5 U
19 U
20 U
10 U
10 UDay 5
Day 4
Day 3
Day 2
Insulin in s.c. depot
10 U
5050%
5050%
5050%
5050%
5050%
Insulin in circulationInjected insulin
Maximum units
present in 24h
interval
10 U
10 U
10 U
10 U
Therefore
there is no
stacking
Figure adapted from Heise and Meneghini Endocr Pract 2014;20:75–83

28. Pharmacokinetics of insulin degludec in special
populations Age
Hepatic function
Renal function
Geriatric (≥65)
Younger adults (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 8 12 16 20 24
IDegconcentration
(pmol/L)
Time since injection (hours)
Normal
Mild
Moderate
Severe
0
2000
4000
6000
8000
10000
0 4 8 12 16 20 24
IDegconcentration
(pmol/L)
Time since injection (hours)
Normal
Child-Pugh A
Child-Pugh B
Child-Pugh C
0 4 8 12 16 20 24
Time since injection (hours)
2000
4000
6000
8000
10000
IDegconcentration(pmol/L)
0
PK, pharmacokinetic
Kupčová et al. Clin Drug Investig 2014;34:127–33; Kiss et al. Clin Pharmacokinet 2014;53:175–83; Korsatko et al. Drugs Aging 2014;31:47–53

29. 31
Efficacy in reaching the target HbA1c
How well does IDeg achieve
glycemic control for patients?

30. 32
BEGIN™ phase 3 program
Investigating the efficacy and safety of Insulin
Degludec in type 1 and type 2 diabetes

31. USA
Russia
France
Denmark
Poland
Romania
Israel
Finland
India
Malaysia
Norway
Taiwan
Thailand
Spain Turkey
Austria
South Korea
South Africa
Japan
Hong Kong
Germany
Canada
Mexico
Brazil
Argentina
Greece
Macedonia
United
Kingdom
Ireland
Italy
Ukraine
Czech Republic
Slovakia
Hungary
Bulgaria
Serbia &
Montenegro
Belgium
Netherlands
Multinational clinical trial program
33
Australia
China
Sweden
Croatia
Largest clinical trial program
for any basal insulin
40 countries
>11,000 subjects

32. Regulatory guidance recommends that insulin be tested in
a treat-to-target design:
BEGIN™ program designed to meet
noninferiority insulin trial standards
34
Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and
prevention (draft guidance). Rockville, MD: Food and Drug Administration, U.S. Dept of Health and Human Services; February 2008.

33. Summary of insulin degludec BEGIN™ phase 3
program
35
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Ocampo Francisco AM, Pei H, Bode B. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-1497; Data on file NN1250-3770. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo
Nordisk for additional information; Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-
target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde
L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract
presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB; Data on file NN1250-3668. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional
information; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with
mealtime insulin aspart in type 2 diabetes. Lancet. 2012;379(9825):1498-1507; Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a
randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia, Pennsylvania, USA. 1059-P.
OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipeptidyl peptidase-4
inhibitor; SU=sulphonylurea; TZD=thiazolidinedione.

34. 36
BEGIN™ Once Long Study
Efficacy and Safety in Type 2 Diabetes

35. Insulin-naïve T2D: study design
BEGIN ONCE LONG – 2 years
IDeg OD + metformin
± DPP-4 (n=773)
IGlar OD + metformin
± DPP-4 (n=257)
Insulin-naïve
patients with
type 2 diabetes
(n=1030)
Inclusion criteria
• Type 2 diabetes ≥6
months
• Insulin naïve, treated with
metformin ± SU, DPP-4 or
acarbose for ≥3 months
• HbA1c 7.0–10.0%
• BMI ≤40 kg/m2
• Age ≥18 years
Randomised 3:1 (IDeg OD: IGlar OD)
*1 week wash-out (week 52) to allow for antibody measurement, hence
105 weeks = 104 weeks’ exposure
Continue core phase
treatment (n=551)
Continue core phase
treatment (n=174)
Core phase – 52 weeks Extension phase – 52 weeks
105 weeks0 52* 53
OD, once daily
Zinman et al. Diabetes Care 2012;35:2464–71; Rodbard et al. Diabet Med 2013;30:1298–304

36. Equivalent reductions in HbA1c vs insulin
glargine
38
Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-
naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

37. Significant reductions in FPG vs insulin
glargine
39
Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in
insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

38. Significantly lower risk of nocturnal
hypoglycemia vs insulin glargine
40
• 36% lower risk of nocturnal confirmed hypoglycemia vs insulin glargine (P=0.038)
• 86% lower risk of severe hypoglycemia vs insulin glargine (P=0.017)
• 18% lower risk of overall confirmed hypoglycemia vs insulin glargine (P=NS)
Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in
insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

39. Low Adherence to Treatment
BARRIER
41

40. Patients are not taking basal insulin
as prescribed
42
Brod M, Rana A, Barnett AH. Adherence patterns in patients with type 2 diabetes on basal insulin analogues: missed, mistimed and
reduced doses. Current Medical Research and Opinion. 2012;28(12):1933-1946.
Percentage of patients reporting at least one basal
insulin dosing irregularity in the past 30 days
Almost 1 of 4 patients have mistimed* at least
one basal insulin dose in the past 30 days
22%
14%
24%
Missed
a dose
Mistimed
a dose
Reduced
a dose
*by ±2 hours from prescribed time.

41. 33.2% of patients
reported insulin omission ⁄
non-adherence at least 1
day in the last month,
with an
average of 3.3 days
73%
27%
67%
33%
73% of physicians reported
that their typical patient
does not take their insulin
as prescribed
Insulin doses are being missed or not taken as
prescribed
Too busy
18.9%
Travelling
16.2%
Challenging to
take at same
time each day
9.4%
Forgot
7.4%
Regimen too
complicated
3.8%
Peyrot et al. Diabet Med 2012;29:682–9
GAPP™
• A global internet
survey of patient
and physician
beliefs regarding
insulin therapy
• n=1250
physicians

42. 46
BARRIERS
Optimal
Glycemic
Control
Complex
Regimens & Low
Treatment
Adherence/user
friendly
GOAL

43. Fixed administration time for basal insulin is difficult for
patients
1. Peyrot et al. Diabetic Medicine 2012;29:682–9; 2. Peyrot et al. Diabetes Care 2010;33:240–5
22% of patients said they planned
their daily activities around insulin
injections2
28% of patients said they find it
difficult to take insulin at the
prescribed time daily or with meals
every day1

44. 2-in-5 patients had missed a dose of
basal insulin within the last 30 days
Basal insulin
Missed, mis-timed (by more than 2 hours)
and reduced doses of basal insulin
Data on file.
Insulin analogue patients

45. 44% I had skipped a meal
39% I had exercised recently
81% I had exercised recently
71% I had skipped a meal
37% I had exercised recently
31% I had skipped a meal
On the last occasion that patients had missed, mis-
timed or reduced their basal insulin dose, 37%, 21%
and 68% (respectively) had done so intentionally
Proportion of patients intentionally
missing, mistiming or reducing a dose of
basal insulin the last time they did this
TOP 2 reasons for intentionally missing,
mistiming or reducing a dose of basal
insulin the last time they did this
Basal insulin
Insulin analogue patients
Data on file.

46. Better Flexibility
How can IDeg improve treatment
adherence of patients?
50

47. Insulin degludec and flexibility in
day-to-day dosing time
On occasions when administration at the same time of the
day is not possible, insulin degludec allows for flexibility in
the timing of insulin administration. A minimum of 8 hours
between injections should always be ensured.
Patients who forget a dose are advised to take it
upon discovery and then resume their usual once-
daily dosing schedule.
Insulin degludec [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2012. 51

48. 52
BEGIN™ Flex T2 Study
Flexibility in Type 1 and Type 2 Diabetes

49. Flexible vs Fixed dosing in T2D: study design
BEGIN FLEX T2D
Inclusion criteria
• Type 2 diabetes ≥6 months
• Previously treated with
OADs and/or basal insulin
• HbA1c:
OADs only 7–11%
Basal insulin ± OADs 7–10%
• BMI ≤40 kg/m2
• Age ≥18 years
Patients with
type 2 diabetes
(n=687)
0 26 weeks
Open label
IGlar OD ± OADs (n=230)
(metformin/SU/pioglitazone)
IDeg Fixed OD ± OADs (n=228)
(metformin/SU/pioglitazone)
IDeg Flexible OD ± OADs (n=229)
(metformin/SU/pioglitazone)
Meneghini et al. Diabetes Care 2013;36:858–64

50. Flexible dosing time
Mon Tue Wed Thu Fri Sat Sun
MorningMorning Morning
Evening Evening Evening Evening
40 h 40 h 40 h
8 h 8 h
24 h
Insulin degludec: Varied daily dosing
intervals (between 8 to 40 hours)
Insulin glargine: Dosed once daily at
the same time each day, per insulin
glargine label
Insulin degludec’s ultra-long duration of action and steady-state profile allows for a forced
flexible dosing interval in patients with diabetes
55
Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does
not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes.
Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

51. Summary of insulin degludec flexible
day-to-day dosing time
• Insulin degludec administered at flexible dosing times provided:
– Effective glycemic control with noninferior HbA1c reductions
compared to insulin glargine, with less nocturnal hypoglycemia
– FPG reductions greater than insulin glargine in patients with
type 2 diabetes
56
Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does
not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes.
Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

52. Flexibility in day-to-day dosing time
57
Establishing a routine is important, but it is not always possible to inject at
the same time each day…
On occasions when administration at the same time of day is not possible,
insulin degludec allows for flexibility in the timing of insulin administration

53. Who could benefit from flexibility in day-to-
day dosing time?
Juggles a busy
family life
Travels
Needs help
injecting
Has unpredictable
work hours
58

54. 59
Ideal
Basal
Insulin
Longer
duration
of action
Controls fasting
blood glucose with
1 injection per day
in all individuals
Has a long
duration of action
(at least 42 hours)
& a half-life twice
as long as that of
insulin glargine
Flat time-
action
profile
Lower risk of
hypoglycemia
Provides a flat and
stable glucose-
lowering effect,
equally distributed
over 24 hours
Less day-
to-day
variability
Lower hypo- and
hyperglycemia
Has 4 times lower
variability in
glucose-lowering
effect compared
with insulin
glargine
Ideal
Basal
Insulin
Clinical
Benefit
Insulin
Degludec
Improved Adherence &
Overall Glycemic Control

55. 60
Controls fasting
blood glucose with 1
injection per day in
all individuals
Has a long duration
of action (at least 42
hours) & a half-life
twice as long as that
of insulin glargine
Lower risk of
hypoglycemia
Provides a flat and
stable glucose-
lowering effect,
equally distributed
over 24 hours
Lower hypo- and
hyperglycemia
Has 4 times lower
variability in
glucose-lowering
effect compared
with insulin glargine
Clinical
Benefit
Insulin
Degludec
Improved Adherence &
Overall Glycemic Control
Lower risk of
complications Improve
Quality of
Life

56. Establishing Safety
How does IDeg address the fear of
hypoglycemia?
61

57. PG <3.1 mmol/La
(56 mg/dL)
Yes
Hypoglycemia classification – consistent and
stringent in phase 3
Suspected hypoglycemia or
routine PG measurement
Patient able
to treat
self? No
Severe
hypoglycemia
Not classified as
confirmed hypoglycemia
Yes
Confirmed hypoglycemia
(including night time)
No
a: With or without symptoms
A nocturnal episode is any confirmed episode with time of onset between 00:01 am and 05:59 am, inclusive.

58. 0.25 0.5 1 2 4
Pre-specified meta-analyses: overall confirmed
hypoglycemia
In favour of IDeg In favour of IGlar
1.10 [0.96;1.26] Not significant
0.91 [0.83;0.99] Significant*
0.83 [0.70;0.98] Significant*
0.83 [0.74;0.94] Significant*
T2D
LOW VOLUME
BB
FLEX T2D
ONCE ASIA
ONCE LONG
Pooled T2D
FLEX T1D
BB T1D LONGT1D
Pooled T1D
Pooled T1D & T2D
52
26
26
26
52
52
26
Pooled insulin-naïve T2D
Weeks
Adjusted for trial, type of diabetes, anti-diabetes therapy at screening, sex, region and age. Flexible arm not included in analysis. *Significantly lower risk based on 95% CI
Ratner et al. Diabetes Obes Metab 2013;15:175–84

59. 0.25 0.5 1 2 4
Pre-specified meta-analyses: nocturnal
confirmed hypoglycemia
0.83 [0.69;1.00] Not significant
0.74 [0.65;0.85] Significant*
0.64 [0.48;0.86] Significant*
0.68 [0.57;0.82] Significant*
T2D
LOW VOLUME
BB
FLEX T2D
ONCE ASIA
ONCE LONG
Pooled T2D
FLEX T1D
BB T1D LONGT1D
Pooled T1D
Pooled T1D & T2D
26
26
26
52
52
26
Pooled insulin-naïve T2D
In favour of IDeg In favour of IGlar
52
Weeks
Adjusted for trial, type of diabetes, anti-diabetes therapy at screening, sex, region and age. Flexible arm not included in analysis. *Significantly lower risk based on 95% CI
Ratner et al. Diabetes Obes Metab 2013;15:175–84

60. Meta-analyses: severe hypoglycemia in type 1
and type 2 diabetes
0.03125 0.0625 0.125 0.25 0.5 1 2 4 8
Significant*0.14 [0.03;0.70]
Not significant0.81 [0.42;1.56]
Not significant1.12 [0.68;1.86]
Not significant0.97 [0.66;1.44]
In favour of IDeg In favour of IGlar
T2D
Pooled T2D
T1D Pooled T1D
Pooled T1D & T2D
Pooled insulin
-naïve T2D
Adjusted for trial, type of diabetes, anti-diabetes therapy at screening, sex, region and age. Flexible arm not included in analysis. *Significantly lower risk based on 95% CI
Ratner et al. Diabetes Obes Metab 2013;15:175–84

61. Nocturnal confirmed hypoglycemia
Definition
0.0 0.2 0.4 0.6 0.8 1 1.2 1.4
T2D Insulin-naïve
0.64 [0.48; 0.86]*
0.56 [0.39; 0.80]*
0.73 [0.56; 0.97]*
Nocturnal confirmed hypoglycemia
(original definition) (0:01–5:59)
Nocturnal confirmed symptomatic
hypoglycemia (0:01–5:59)
Nocturnal ADA documented symptomatic
hypoglycemia (0:01–5:59)
In favour of IDeg In favour of IGlar
0.51 [0.36; 0.72]*
0.43 [0.28; 0.64]*
0.62 [0.45; 0.84]*
0.75 [0.58; 0.99]*
0.68 [0.51; 0.91]*
0.72 [0.55; 0.93]*
0.72 [0.51; 1.00]
0.65 [0.45; 0.93]*
0.70 [0.51; 0.96]*
0.0 0.2 0.4 0.6 0.8 1 1.2 1.4
In favour of IDeg In favour of IGlar
Nocturnal confirmed hypoglycemia
(original definition) (0:01–5:59)
Nocturnal confirmed symptomatic
hypoglycemia (0:01–5:59)
Nocturnal ADA documented symptomatic
hypoglycemia (0:01–5:59)
T2D Basal–bolus
Entire trial period
Maintenance period only
Heller et al. Diabetes 2014;63(Suppl. 1):A106

62. Nocturnal confirmed hypoglycemia
Time period
0.0 0.2 0.4 0.6 0.8 1 1.2 1.4
T2D Insulin-naïve
0.64 [0.48; 0.86]*
0.60 [0.45; 0.80]*
0.93 [0.75; 1.15]
Nocturnal confirmed hypoglycemia
(original definition) (0:01–5:59)
Nocturnal confirmed hypoglycemia
(21:59–5:59)
Nocturnal confirmed hypoglycemia
(0:01–7:59)
In favour of IDeg In favour of IGlar
0.51 [0.36; 0.72]*
0.49 [0.35; 0.69]*
0.76 [0.59; 0.99]*
0.75 [0.58; 0.99]*
0.73 [0.59; 0.91]*
0.77 [0.60; 0.97]*
0.0 0.2 0.4 0.6 0.8 1 1.2 1.4
In favour of IDeg In favour of IGlar
Nocturnal confirmed hypoglycemia
(original definition) (0:01–5:59)
Nocturnal confirmed hypoglycemia
(21:59–5:59)
Nocturnal confirmed hypoglycemia
(0:01–7:59)
T2D Basal–bolus
0.72 [0.51; 1.00]
0.70 [0.54; 0.91]*
0.70 [0.53; 0.92]*
Entire trial period
Maintenance period only
Heller et al. Diabetes 2014;63(Suppl. 1):A106

63. Summary of efficacy and safety in
type 2 diabetes
• In patients with type 2 diabetes, insulin degludec provides
– Effective glycemic control with noninferior HbA1c reductions compared to insulin glargine,
with less hypoglycemia
– FPG reductions greater than insulin glargine
68
Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in
insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-
2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Onishi Y, Park
SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of
a randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia,
Pennsylvania, USA. 1059-P; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco
AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in
type 2 diabetes. Lancet. 2012;379(9825):1498-1507.
OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipetidyl peptidase-4 inhibitor; TZD=thiazolidinedione.

64. Non-inferior HBA1c reduction & Significant
FPG reductions
69
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Ocampo Francisco AM, Pei H, Bode B. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-1497; Data on file NN1250-3770. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo
Nordisk for additional information; Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-
target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde
L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract
presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB; Data on file NN1250-3668. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional
information; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with
mealtime insulin aspart in type 2 diabetes. Lancet. 2012;379(9825):1498-1507; Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a
randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia, Pennsylvania, USA. 1059-P.
OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipeptidyl peptidase-4
inhibitor; SU=sulphonylurea; TZD=thiazolidinedione.

65. Significant reductions in hypoglycemia
70
Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Ocampo Francisco AM, Pei H, Bode B. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin
aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-1497; Data on file NN1250-3770. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo
Nordisk for additional information; Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-
target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde
L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract
presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB; Data on file NN1250-3668. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional
information; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with
mealtime insulin aspart in type 2 diabetes. Lancet. 2012;379(9825):1498-1507; Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a
randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia, Pennsylvania, USA. 1059-P.
OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipeptidyl peptidase-4
inhibitor; SU=sulphonylurea; TZD=thiazolidinedione.

66. Comparable reductions in nocturnal
hypoglycemia vs insulin glargine
71
• 23% lower risk of nocturnal confirmed hypoglycemia vs insulin glargine (P=NS)
• 3% higher risk of overall confirmed hypoglycemia vs insulin glargine (P=NS)
Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does
not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes.
Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

67. Who could benefit from hypoglycemia risk
reduction?
Reports
hypoglycemic events
Admits to lowering
dose to avoid
hypoglycemia
Is afraid of
hypoglycemia
Has higher fasting
target due to
hypoglycemia risk
72

68. Clinical use, dosing and device
How can we use IDeg in practice?
73

69. Clinical Indications
• With intensified glucose monitoring and the insulin
dose adjusted on an individual basis, Insulin
Degludec can be used in:
Renal and Hepatic Impairment
Elderly (>65 years old)
• Safety and efficacy have not been established
in children and adolescents below 18 years of age.
• No clinical experience in pregnant women.
Animal reproduction studies have not revealed any
difference between Insulin Degludec and Human
Insulin regarding embryotoxicity and teratogenicity.
74

70. Dosing of Insulin Degludec
Initiation
Type 2 diabetes
• 10 units starting dose1
• Individual dose
adjustments1
Type 1 diabetes
• Combination with
mealtime insulin1
• Individual dose
adjustment1
Transfer from
other basal insulin
Type 2 diabetes
• Unit-to-unit switch from
prior basal
insulin/component1
Type 1 diabetes
• OD therapy: unit-to-unit
switch1
• BID basal insulin or HbA1c
<8.0%: dose determined on
an individual basis1
BID, twice daily
1. Tresiba® SmPC, Novo Nordisk, May 2013 75

71. How to adjust Insulin Degludec dose
once a week1
1. Get to steady state – typically 2–3 days after first dose
2. Titrate once-weekly based on average of 2 preceding FPG
measurements*
• ADA/EASD recommended FPG goal is 3.9 to 7.7 mmol/L (70
to 130 mg/dL) for many adult patients with diabetes2
22
FPG, fasting plasma glucose; ADA, American Diabetes Association; EASD, European Association for the
Study of Diabetes
If above goal, +2 units
If below goal, -2 units
If at goal, maintain dose
1. Tresiba® SmPC, Novo Nordisk, May 2013
*Fasting plasma glucose (FPG) measurements must be from 2 preceding days

72. Insulin NPH (Not truly basal) Glargine Detemir Degludec
Structure Crystalline suspension
of human insulin with
protamine and zinc
Addition of two
and substitution
of one amino
acid
Addition of
accylated fatty acid
chain at B
Deletion of B30, addition of
glutamic acid spacer and
diacylated fatty acid chain at
B29
Number of amino
acids
51 53 51 50
Carbon in side
chain
0 0 14 16
Mechanism of
protraction
Less solubility in the
extracellular fluid leads
to slower absorption
and a prolonged effect
Precipitation at
acidic pH
Binding to albumin Multihexamer chain formation
Terminal half life Variable 12.5 hrs 12.5 hrs 25.1-25.4 hrs
Duration of action 13-20 hrs Upto 24 hrs Upto 18-23 hrs Upto 42 hrs
Intra-patient
glycemic variability
High High Low Lowest
Exposure ratio: first
12 hrs to second 12
hrs after injection
60:40 50:50 50:50
Timing of
administration
Once or twice or thrice
daily
At the same time
everyday
Once or twice daily At any time, every day
Comparison of various basal insulins

73. Insulin NPH Glargine Detemir Degludec
Risk of hypoglycemia Present Low Low Least
Risk of nocturnal hypoglycemia Present Low Low Least
Risk of severe hypoglycemia Present Low Low Least
Injection site reactions Lesser than glargine Possible, because
of acidic pH
Rare Rare
Weight gain Yes Yes No Yes
Binding of IGF-1R (human
insulin 100)
641+51 18+2 2
Binding affinity to insulin
receptor (human insulin 100)
86+3 16+1 13-15
Use in renal impairment Dose needs to be adjusted Safe Safe Safe
Use in hepatic impairment Dose needs to be adjusted Safe Safe Safe
Miscibility with regular/rapid
acting insulin
Can be mixed with soluble
insulin without affecting
absorption kinetics of
either insulin
No No Yes
Miscibility with Glucagon like
peptide – 1 receptor agonists
Yes No Yes
Comparison of various basal insulins-2

75. Clinical summary of Insulin Degludec
 Successful non-inferior HbA1c reductions in type 1
or type 2 diabetes, based on treat-to-target trial
designs1-3
 Significantly lower risk of nocturnal hypoglycemia
versus insulin glargine1–4
 Flexibility in day-to-day dosing time when needed,
delivered in a once-daily dose4–7
17
1. Zinman et al. Diabetes Care 2012;35:2464–71; 2. Garber et al. Lancet 2012;379:1498–1507; 3. Heller. Lancet 2012;379:1489–97; 4.Keating. Drugs
2013;73:575–93; 5. Meneghini et al. Diabetes Care 2013;36:858–64; 6. Mathieu et al. J Clin Endocrinol Metab 2013;98:1154–62; 7. Tresiba® SmPC, Novo
Nordisk, May 2013

76. Thank you or your kind
attention!
81