Insulin Degludec

dr. Taufik Hidayat

Regional Medical Advisor
Novo Nordisk Indonesia
 2

Current unmet needs with basal insulin

Glycaemic control

Injection Risk of
flexibility hypoglycaemia
 Poor glycaemic control in T2DM patients in Indonesia

90
81.01
80

70
67.85 68.78

60
% OF PATIENTS

50 47.22
40

30

20

10

0
ADA (≥ 7%) AACE/IDF/APDPG ADA (> 7.22) AACE/IDF/APDPG
(≥ 6.5%) (≥ 6.1)
HbA1c (%) FPG (mmol/l)

Soewondo, P, et al. The DiabCare Asia 2008 Study – Outcomes on control and complications of type 2 Diabetets patients in Indonesia. Med J Indones 2010; 19:235-44)
High incidence of hypoglycaemia in insulin-
treated T2DM patients in Indonesia
Retrospective (n=357)
Prospective (n=347)
RR 2.30
p<0.001
30
(events per patient-year)
Hypoglycaemic rates

25
25.7
RR 4.61
20
p<0.001
15
RR 1.25 13.0
10 11.2 p=0.252
5
3.1 3.9
0
Patients with hypoglycaemia (%): 39.5Any99.4 Nocturnal
13.4 15.3 Severe
59.0 75.1

Any Nocturnal Severe*

‘Any’ and ‘Nocturnal’ based on 4-week period for both retrospective and prospective analyses.
*Retrospective data based on 6-month period and prospective data based on 4-week period.
RR, rate ratio; T1DM, type 1 diabetes mellitus.

Rudijanto A, et al. Acta Med Indones. 2018 Jan;50(1):26-37.

Fear of hypoglycaemia conflicts with treatment success
for both patients and clinicians

Percentage of patients decreasing their insulin I would treat my patients more aggressively if
dose following a hypoglycaemic event1 there was no concern about hypoglycaemia2

100 T1D (n=202) Primary care physicians

Patients modifying insulin dose (%)

T2D (n=133) Diabetes specialists

80
79%
74%
72%
60
58%

40 43%
79%

20

0
Non-severe episodes Severe episodes 0 20 40 60 80 100
Proportion of patients (%)

Data based on GAPP™ study, a global internet survey of patient and physician beliefs regarding insulin therapy, n=1250 physicians.
1. Leiter L et al. Can J Diabetes. 2005;29:186–92; 2. Peyrot M et al. Diabet Med. 2012;29:682–9.
Association between glycaemic variability,
hypoglycaemia and outcomes: the hypo triad

Hypoglycaemia

Glycaemic Outcomes
variability

1. Desouza CV et al. Diabetes Care 2010;33:1389–94; 2. Driesen NR et al. J Neurosci Res 2007;85:575–82;
3. Mooradian AD. Brain Res Brain Res Rev 1997;23:210–8; 4. Sanon VP et al. Clin Cardiol 2014;37:499–504;
5. Dhalla NS et al. J Hypertens 2000;18:655–73; 6. Pieber et al. Diabetologia 2017; DOI 10.1007/s00125-017-4422-0; 7. Zinman et al. Diabetologia 2017; DOI 10.1007/s00125-017-
4423-z.
Glycaemic control: similar HbA1c, different profile

18 324
Hyperglycaemia
16 288
14 252
Patient A Patient B
12 HbA1c 7.8% HbA1c 7.8% 216
BG (mmol/L)

BG (mg/dL)
(61.7 mmol/mol) (61.7 mmol/mol)
10 180

8 144

6 108

4 72

2 36
Hypoglycaemia
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Time (hours)

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.
Increasing glycaemic variability significantly increases the
risk of hypoglycaemia, MACE and all-cause mortality
Pre-specified analyses of the DEVOTE trial

Low variability
p = 0.0038 Medium variability
6 p < 0.0001 High variability
Rate (events/100 patient-years

5
p = 0.0068
of observation)

0
Severe hypoglycaemia MACE All-cause mortality

Rate, events per 100 patient-years of observation.

MACE, major adverse cardiovascular event.
Adapted from Zinman B et al. Diabetologia. 2017; doi: 10.1007/s00125-017-4423-z.
Severe hypoglycaemia and the association to MACE and
all-cause mortality
Systematic review: hypoglycaemia is ACCORD: the association between
associated with adverse outcomes1 hypoglycaemia* and mortality in T2D2

ORIGIN: severe hypoglycaemia is associated ADVANCE: severe hypoglycaemia is associated

with increased risk of adverse outcomes3 with increased risk of adverse outcomes4

MACE, major adverse cardiovascular event; T2D, type 2 diabetes.

1. Adapted from Yeh JS et al. Acta Diabetol 2016;53:377–92; 2. Adapted from Bonds DE et al. BMJ 2009;339:b4909;
3. Adapted from Mellbin LG et al. Eur Heart J 2013;34:3137–44 for the ORIGIN Trial Investigators;
4. Adapted from Zoungas S et al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group.
Fixed administration time for basal insulin is difficult for
patients

28% of patients find it difficult to take

insulin at the prescribed time daily or
with meals every day1

22% of patients planned their daily

activities around insulin injections2

1. Peyrot et al. Diabet Med 2012;29:682–9; 2. Peyrot et al. Diabetes Care 2010;33:240–5
Need for ultra-long-acting
basal insulin
 Slide no 12

The quest for the ideal basal insulin

From first generation analogues to ultra-long acting analogues

IDet
Animal
Isolation of insulin insulin
(Banting & Best) preparations NPH insulin IGlar U100 IGlar U300 IDeg

First generation Ultra-long-acting

basal insulin basal insulin
analogues analogues

λ Half life (hours): 5–10 12–19 25

Variability: High Medium Low

NPH SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000441/WC500033307.pdf;

IDet SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000528/WC500036662.pdf;
IGlar U100 SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000284/WC500036082.pdf;
IGlar U300 SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000309/WC500047935.pdf;
IDeg SmPC. http://ec.europa.eu/health/documents/community-register/2013/20130121124987/anx_124987_en.pdf. All accessed December 2016
Insulin degludec
Rationally designed, beyond sequence modification

Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin

A1 s s
G I V E Q C C T S I C S L Y Q L E N Y C N
A21
s s DesB30
B1 s s
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K T

DesB30 insulin

L-γ-Glu
O NH

Glutamic acid
O ‘spacer’
HO OH
N
H

Hexadecandioyl
O O

Fatty diacid side

chain
Jonassen et al. Pharm Res 2012;29:2104–14
 The stable dihexamers formed
Insulin degludec in solution in the pen are
Mode of protraction injected into the subcutaneous
[ Phenol; Zn2+] space

fatty acid
side-chains

monomers

Jonassen et al. Parm Res 2012;29:2104–14

Insulin degludec
Mode of protraction
[ Phenol; Zn2+]

Jonassen et al. Pharm Res 2012;29:2104–14

 After injection, the insulin degludec
Insulin degludec dihexamers adapt to an open
Mode of protraction conformation after phenol has rapidly
diffused from the vehicle
[ Phenol; Zn2+]

Jonassen et al. Pharm Res 2012;29:2104–14

 After the diffusion of phenol and
Insulin degludec conformation change, the dihexamers link
together via single side-chain contacts. Long
Mode of protraction multihexamer chains assemble
[ Zn2+]

Jonassen et al. Pharm Res 2012;29:2104–14

 Zinc diffuses slowly causing
Insulin degludec Monomers arehexamers
individual absorbed to
from
Mode of protraction thedisassemble,
depot into the circulation
releasing
[ Zn2+] monomers

Jonassen et al. Pharm Res 2012;29:2104–14

 Slide no 19

Longer duration of action and lower glucose variability with ultra-long-

acting basal insulin analogues versus first generation insulin analogues

Twice as long half-life of IDeg Flat time-action profile in T1D

compared with IGlar U100 6
at steady state

GIR (mg/kg/min)
5
IDeg IGlar U100
4
0.4 0.6 0.8 0.4 0.6 0.8 3
U/kg U/kg U/kg U/kg U/kg U/kg
2
Half-life 1
25.9 27.0 23.6 11.5 12.9 11.9
(hours)
0
Mean half-life 25.4 12.1 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)

*IGlar U100 was undetectable after 48 hours

Heise et al. Diabetes 2011;60(Suppl. 1):LB11; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes 2012;61(Suppl. 1):A259;
Heise et al. Diabetes Obes Metab 2012;14:859-64; Heise et al. Poster presentation at DTM 2016
Reaching steady state with degludec without stacking

Injected insulin Insulin in s.c. depot Insulin in circulation

Units remaining Maximum units
from prior injections present in 24 h
Units added each day (t1/2 ~24 h) interval Units absorbed into circulation

Day
1 10 U 10 50% 5U
U

Day
2 10 + 5U 15 50%
7.5
U U U

Day
3 10 + 7.5 17.5 50%
~9
U U U U

Day
4 10 + ~9 19 50%
~10
U U U U
Elimination of any
insulin follows
Day
5 10 + ~10 20 50%
10 first order
U U U U kinetics
Therefore there is
10 no stacking
s.c., subcutaneous
U 2014;20:75–83
Figure adapted from Heise and Meneghini. Endocr Pract
 Insulin degludec provides equivalent reductions in HbA1c
with a lower risk of hypoglycaemia, and at a lower daily dose vs IGlar U1001-3

Total daily
Trial included Glycaemic control1,3 Confirmed hypoglycaemic events (RR)¶1-3
dose1,3

Non-inf FPG Daytime Nocturnal Dose ratio IDeg significantly

HbA1c (mmol/L) All non-severe non-severe Severe (RR) better

BB T1 LONG
T1DM B/B§ -0.61 1.10 1.14 0.83 1.12 0.88 Not significant
FLEX T1†

ONCE LONG
T2DM BOT ONCE ASIA
IGlar U100
(insulin naïve) ONCE LOW
-0.34 0.83 0.89 0.64 0.14 0.90 significantly better
VOLUME
¶ = Full treatment period
T2DM BOT † = Flex arm excluded;
(insulin experienced) SWITCH 2 -0.14# 0.77 0.80 0.76 0.49 0.96 only OD data included
§ = SWITCH 1 not
included as results not
available at time of
meta-analysis
T2DM B/B BB T2 -0.29 0.82 0.83 0.75 N/A* 1.03 * = Not enough events for
statistical analysis
RR = Rate ratio
NR = Not reported

B/B, basal bolus therapy; BOT, basal oral therapy; FPG, fasting plasma glucose

References: 1. Vora et al. Diabetes Ther 2014;5(2):435-46. 2. Ratner et al. Diabetes Obes Metab. 2013;15:175–184. 3. Wysham et al. JAMA. 2017:318(1):45-56.
 Hypoglycaemia

Insulin degludec delivers significant reductions in hypoglycaemia

in patients with T2DM on basal oral therapy1
Insulin degludec significantly reduces severe, overall confirmed and nocturnal hypoglycaemia, when
compared with IGlar U100, in patients with T2DM BOT (insulin naïve)1

Meta-analysis of patients with T2DM BOT (insulin naïve) - full treatment period:1

Reduction of Reduction of Reduction of

severe nocturnal confirmed all confirmed
hypoglycaemic events hypoglycaemic events hypoglycaemic events

86%* 36%* 17%*

0.14 [0.03-0.70] 0.64 [0.48-0.86] 0.83 [0.70-0.98]

*p < 0.05; B/B, basal bolus therapy; BOT, basal oral therapy

Reference: 1. Ratner et al. Diabetes Obes Metab. 2013;15:175-184.

 Cost-effectiveness

Insulin degludec is cost-effective vs IGlar U1001-4

Clinical Patient
UK Sweden
data population
Cost-effective:
• The extent to which IDeg
interventions represent value RCT T1DM Dominant1 SEK 19,766/QALY2 dominant
(ref year 2016) (ref year 2012)
for money5
• Interventions below IDeg
£20,000/QALY in the UK and cost-effective
T2DM BOT Dominant1 SEK 10,082/QALY2
SEK 500,000/QALY in (ref year 2016) (ref year 2012)
Sweden are considered cost- IDeg
effective6,7 not cost-effective

Dominant: T2DM B/B £15, 983/QALY1 SEK 36,074/QALY2

(ref year 2016) (ref year 2012)
• The intervention is less costly
and more effective6
Dominant3 Dominant4
RWE T1DM
(ref year 2015) (ref year 2014)

B/B, basal-bolus therapy; BOT, basal oral therapy; QALY, quality-adjusted life year; RCT, randomised controlled trial; Ref,
reference; RWE, real-world evidence; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus

References: 1. Evans et al. Diabetes Ther 2017;8:275-291. 2. Ericsson et al. J Med Econ 2013;16(12):1442-52. 3. Evans M, et al. JME 2015;18:96-105. 4. Landstedt-Hallin et al. Curr Med Res Opin. 2017 Apr;33(4):647-
655. 5. Griffiths et al, ClinicoEconomics and Outcomes Research 2015;7: 463-476. 6. McCabe et al. Pharmacoeconomics 2008;26:733-44. 7. National Board of Health and Welfare. 2010 Available from:
http://www.socialstyrelsen.se/nationellariktlinjerfordepressionochangest/Documents/nr-depression-vetenskapligtunderlag.pdf.
CONFIRM: the largest comparative effectiveness study
of degludec versus glargine U300 to date
US, patient-level, longitudinal, real-world study
SECONDARY USE OF DATA

Insulin naïve Degludec

(minimum 12 months) (minimum three months)
Patients with Hypoglycaemia HbA1c Time-to-
Hypoglycaemia HbA1c
T2D 180 days (−90 + 7 days) Discontinuation
180 days 180 (−90 days)
(N=4056 )
Insulin naïve Glargine U300
(minimum 12 months) (minimum three months)

6 months pre-index 3 months Index date 3 months 6 months post-index

Primary endpoint:
• Change in mean HbA1c from the index date until six months of follow-up
Secondary endpoints:
• Rate of overall hypoglycaemic episodes from the index date until six months of follow-up
• Proportion of patients with ≥one hypoglycaemic episodes from the index date until six months of follow-up
• Rate of treatment discontinuation

Tibaldi et al. Diabetes 2018;67 (Suppl. 1A):LB27

CONFIRM: conclusions

Degludec Total number of patients: 4056

vs Real-world evidence HbA1c ETD: –0.3% FAVOURS DEGLUDEC

Glargine U300 Hypoglycaemia RR: 0.70 FAVOURS DEGLUDEC

Discontinuation HR: 0.73 FAVOURS DEGLUDEC

Results from CONFIRM demonstrated improved glycaemic control at

lower insulin doses, lower rates of hypoglycaemia and lower risk of
discontinuation with degludec versus glargine U300

Tibaldi et al. Diabetes 2018;67 (Suppl. 1A):LB27

Clinical use of insulin degludec

Simplicity Convenience Safety

Hypoglycaemia
Flexible dosing reductions across
Once-daily dosing
phase 3 trials
Effective and
No new adverse
predictable glucose-
Simple initiation event profile
lowering profile
and titration
No increase in risk of
Available in adverse CV outcomes
FlexTouch® versus glargine U100

Minimal injection-site
reaction

CV, cardiovascular; glargine U100, insulin glargine 100 units/mL

Which patient groups will benefit from degludec?

Patients whoWhen
need tohypoglycaemia,
start
Varying stages of multiple
beta- injections Patients
When
withFPG and HbA1c
insulin or switch from anotherand lack of
cell dysfunction flexibility are barriers
irregulartolifestyle
are not at target
basal insulin
glycaemic control

FPG, fasting plasma glucose; PPG, postprandial glucose; T1D, type 1 diabetes; T2D, type 2 diabetes
Thalange et al. Pediatr Diabetes 2015;16:164–76; Meneghini et al. Diabetes Care 2013;36:858–64; Mathieu et al. J Clin Endocrinol Metab
2013;98:1154–62; Lane et al. JAMA 2017;318:33–44; Wysham et al. JAMA 2017;318:45–56; Tresiba® March 2018
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203314s008lbl.pdf) Tresiba® November 2017
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002498/WC500138940.pdf)
Initiation of degludec in T1D

SWITCH
START
FROM OTHER INSULIN

Individual dose Most patients = 1:1

adjustment

Newly Degludec Meal- Basal Degludec

diagnosed OD + time
insulin
individual adjusment for
patients transferring from
basal insulin BID or HbA1c <
8.0%.
Dose reduction need to be
considered followed by
individual dosage adjustment
based on the glycemic
response

OD, once daily; T1D, type 1 diabetes; BID, twice daily

Tresiba® Indonesia Prescribing Information. 2018.
Initiation of degludec in T2D

SWITCH
START
FROM OTHER BASAL INSULIN
Changing to insulin degludeg can be done unit-to-unit based on the
previous basal insulin dose followed by individual dosage
adjustments
Recommended
10 U daily. 1:1
Basal Degludec
Followed by
individual dose
adjustment
OAD

Insulin Basal 1:1

+ OR Degludec
naïve Degludec Bolus
−
Bolus
1:1
Premix Degludec

Transferring a patient to another type, brand or manufacturer of

insulin must be done under medical supervision and
may need for a change in dosage.

Consider 20% reduction in insulin dose when switching from

BID insulin or glargine U300
OAD, oral antidiabetic drug; T2D, type 2 diabetes
Tresiba® Indonesia Prescribing Information. 2018.
Suggested titration schedule T2D1,2

• Once-weekly titration based

+ If above target, +2 units on the average of two
preceding FPG measurements2

• FPG target should be

If at target, maintain dose individualised

• ADA/EASD recommend an FPG

– target of 4.4 to 7.2 mmol/L
(80 to 130 mg/dL) for many
If below target, –2 units adult patients with diabetes3*

Titration in patients with T1D must be done by individual

case and in collaboration with the HCP
*Individual patient goals may vary. This is a suggested once-weekly titration schedule. FPG goal should be individualised. If average FPG levels are more than 1
mmol/L below or 2 mmol/L above FPG goal, larger dose changes (e.g., 4, 6, or 8 units) can be considered
ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FPG, fasting plasma glucose; HCP, health care provider; T1D, type 1
diabetes; T2D, type 2 diabetes
1. Endocrinologic and Metabolic Drug Advisory Committee. Insulin degludec and insulin degludec/insulin aspart treatment to improve glycemic control in patients
with diabetes mellitus: NDAs 203314 and 203313 briefing document. Published November 8, 2012; 2. Vora et al. Diabetes Res Clin Pract 2015;109:19–31; 3.
ADA standards of medical care in diabetes – 2016. Diabetes Care 2016;39(Suppl. 1):S39–S46
Flexible administration of insulin degludec
Two phase 3a clinical trials (6 and 12 months)

MON TUE WED THUR FRI SAT SUN

12 am

2 am

4 am Morning Morning Morning

6 am

8 am

10 am

12 pm

2 pm

4 pm Evening Evening Evening Evening

6 pm
40 h 8h 40 h 8h 40 h 24 h
8 pm

10 pm

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
Insulin degludec (Tresiba®) provides flexibility in day-to-day dosing time
when needed, without compromising efficacy or risk of hypoglycaemia1-3

MON TUE WED THURS FRI SAT SUN • Tresiba® is a basal insulin for once-daily
12 AM subcutaneous administration at any time of
2 AM
the day, preferably at the same time
4 AM
every day1
6 AM

8AM • Tresiba® allows for flexibility in the

10 AM timing of insulin administration, when
12 PM administration at the same time of the day
2 PM
is not possible1-3
4 PM

6 PM • A minimum of 8 hours between injections

8 PM should be ensured1
10 PM

Basal insulin analogues such as IGlar U100 and IDet

must be administered at the same time every day to
ensure insulin coverage and predictable glycaemic
response4,5

References: 1. Tresiba® SmPC, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002498/WC500138940.pdf. 2.

Meneghini et al. Diabetes Care. 2013;36:858–864. 3. Mathieu et al. J Clin Endocrinol Metab. 2013;98(3):1154–1162. 4. Levemir® SmPC,
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000528/WC500036662.pdf. 5. Lantus® SmPC,
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000284/WC500036082.pdf.
 Summary

Insulin degludec – effective glycaemic control

with a lower hypoglycaemia risk and a lower daily dose vs IGlar U100

Effective Significantly lower rates Significantly lower daily Cost-effective5,6

glycaemic control1-4 of hypoglycaemia1-4 insulin dose1-3

Additional value:
Real world evidence confirms RCT findings:
switching patients to Tresiba® from other basal Due to its long duration of action and steady-state
insulins improves glycaemic control, at lower total profile, Tresiba® allows flexibility in day-to-day dosing
daily insulin doses and significantly reduces the time when needed, without compromising efficacy or
risk of hypoglycaemia7 risk of hypoglycaemia8

References: 1. Vora et al. Diabetes Ther 2014;5(2):435-46. 2. Lane et al. JAMA. 2017;318(1):33-44. 3. Wysham et al. JAMA. 2017:318(1):45-56. 4. Marso et al. NEJM 2017;377(8):723-732. 5. Evans et al.
Diabetes Ther 2017;8:275-291. 6. Ericsson et al. J Med Econ 2013;16(12):1442-52. 7. Siegmund T, et al. Diabetes Obes Metab 2018; 20(3):689-697. 8. Tresiba® SmPC
Detailed summary – part 1
Degludec

24 h Provides a flat and stable glucose-lowering effect over 24 hours

 HbA1c Shows non-inferiority in HbA1c versus glargine U100

 FPG Has greater FPG reductions in insulin-naïve patients with T2D versus
glargine U100

Shows significant reductions in the rates of overall confirmed symptomatic,

 nocturnal confirmed symptomatic, and severe hypoglycaemia in T1D and T2D
versus glargine U100

 Has significantly lower or clinically relevant equal insulin dose versus glargine
dose U100 in T1D and in T2D

FPG, fasting plasma glucose; glargine U100, insulin glargine 100 units/mL; T1D, type 1 diabetes; T2D, type 2 diabetes
Detailed summary – part 2
Degludec

U300 Has lower day-to-day variability in glucose-lowering effect, and higher potency
versus glargine U300

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

Improves QoL for patients initiating insulin therapy and those switching from
another basal

Does not increase the risk of adverse cardiovascular outcomes in patients at

high risk, versus glargine U100

Is well tolerated

glargine U100, insulin glargine 100 units/mL; glargine U300, insulin glargine 300 units/mL; SMBG, self-measured blood glucose; QoL, quality of life