Initiations & Switching to Co-Formulation

Insulin
ARISE Study
dr. Budianto Sigalingging, Sp.PD
Mei 2023

For Healthcare Professional Only

Disclosures

I have received honorarium as speaker/consultant, support for research/attendance at educational meetings

from:

• List names of companies

Presentations Outline

1 Key Challenges for T2DM patient needing insulin treatment

2 IDegAsp Co-formulation Insulin

3 IDegAsp summary results from Randomised Controlled Trial

4 Real world evidence of ARISE study

5 Implication of ARISE data in clinical practice

 Key Challenges for type 2 diabetes patient needing
insulin treatment

Delay insulin use High Carbohydrate

(Therapeutic inertia)1 Consumption2

Our
Realities
Complex
Basal Insulin alone
Treatment4,5
Does not enough3

References: 1. Khunti et al. Diabetes, obesity and metabolism 14:654-661, 2012. 2. Lee YJ Yonsei Med J 2018 Sep;59(7):834-842 3. Mauricio D, et al. Diabetes Obes Metab. 2017
Aug;19(8):1155-1164. 4. Peyrot et al. Diabet Med. 2012;29: 682–9 5. Jarab et al. Int J Clin Pharm. 2014;36(4):725-33
Key Challenges for type 2 diabetes patient needing
insulin treatment

42%
Asian populations generally shown a high-
carbohydrate consumption, it leads to high
insulin resistance and PPG levels. 2

Patients with T2DM had

HbA1c >9%1 before they
start insulin
Our
Realities

70%
Intensification from basal to basal
plus/bolus is COMPLEX.4

patients on basal insulin

FAILED to achieved HbA1C
target3

References: 1. Khunti et al. Diabetes, obesity and metabolism 14:654-661, 2012. 2. Kumar, et al. J Diabetol 2020;11:148-57 3. Mauricio D, et al. Diabetes Obes Metab. 2017
Aug;19(8):1155-1164 4. Adapted from American Diabetes Association. Diabetes Care 2017;40(Suppl.1):S64–S74
Total Glycemic Control: Need for Co-Formulation Insulin

Glycaemic control requires attention to both FPG and PPG1

HbA1c

Clinical evidence suggests that reducing PPG excursions is as

important
as reducing FPG for achieving HbA1c goals1,2

PPG FPG

1. Riddle M, et al. Diabetes Care 34:2508–2514, 2011 | 2. Monnier et al. Endocr Pract. 2006;12:S1:42–63.
 Limitations on current insulin regimens 1-3

Basal Insulin Pre-mix Insulin Basal – Bolus Regimen

• Not covering 24 hours basal • Not covering 24 hours basal • Treatment complexity due to
• Fixed administration time • Require 1-2 injections multiple injections
• Higher variability • Shoulder effect

1.Peyrot et al. Diabet Med 2012;29:682–9; 2. Peyrot et al. Diabetes Care 2010;33:240–5; 3. Elizarofa S, et al. Journal of Diabetes (6) 2014; 100-110 (2)
 13

Clinical Needs
Looking for effective and simpler options
Conceptual: Co-Formulation Insulin will address our
problem on

Glycaemic Control Assurance of

Simplifying Insulin Therapy
Hypoglycaemia
Providing basal and prandial
coverage in one injection1 Associated with simple regimen
Co-formulation Insulin contain
and fewer injection3
Insulin Degludec with flat and
low variability profile2

References: 1. Haahr H et al. Clin Pharmacokinet 2017;56(4):339–354 2. Heise et al. Diabetes Obes Metab 2012;14:859-64 3. Sajay Karla.
Diabetes Ther (2014) 5:65-72
IDegAsp: First in Class Co-Formulation Insulin 1

2,3

1. Kalra et al. Adv Ther (2018) 35:928-936. 2. Heise T, et al. Diabetes Care. 2011; 34(3): 669-74. 3. Jonassen I, et al. Pharm Res. 2012; 29(8):
2104-14. 4. Heller S, et al. Diabetes Metab Res Rev. 2012; 28: 50-61.
IDegAsp OD gives patient basal & prandial coverage
at the largest meal
Glucose-lowering effect of IDegAsp given once daily

0.6 U/kg OD

1. Haahr H et al. Clin Pharmacokinet 2017;56(4):339–354

Intensification with Co-formulation insulin could allow for
SIMPLE regimen with fewer injection1

IDegAsp Basal Basal Plus

VS

IDegAsp Basal Bolus

Co-Formulation

Basal

Bolus
VS

Kalra S, et al. Adv Ther (2018) 35: 928-936

 13

ARISE: insights from the real world

Perkeni Guideline 2021 - INITIATION

HbA1C
Basal Co-Formulation FRC

≥ 7.5 %
Dosis 10U malam hari atau
0.2 unit/Kg/BB

Pasien DM lama + OHO (dual/triple)

Dengan HbA1C >7.5% - <9%
Optimasi Dosis
Dosis maksimal:
0.5 unit/kgBB/hari

Titrasi:
Target:
(Jika nilai GDP atau pre-prandial)
GDP/ Pre-prandial: 80-130 mg/dL
> 180 mg/dL : +4 Unit
GDP 1 – 2 PP : <180 mg/dL
130 – 180 mg/dL : +2 Unit
HbA1C : <7% (evaluasi 3 bulan)
< 130 mg/dL : dosis tetap

1. Perkeni Guideline consensus Insulin 2021.

Perkeni Guideline 2021 - INITIATION

HbA1C
Co-Formulation FRC Basal Plus Basal Bolus

≥ 9 % Mulai dosis 10 Unit Mulai dosis 10 Unit

+ Prandial pada jadwal makan
terbesar.
Basal malam hari
Dosis prandial mulai
+ Prandial pada ke3 jadwal
makan. Basal malam hari

Basal 10U (bedtime)

4U/hari atau 10% dosis Prandial 4U
Pasien DM Baru
basal
Dengan HbA1C >9% atau GDP >250
mg/dL
Atau GDS >300 mg/dL
Optimasi dosis Optimasi dosis Optimasi dosis
OD  BID OD
Atau disertai gejala dekompensasi
Metabolik
Titrasi:
Target:
(Jika nilai GDP atau pre-prandial)
GDP/ Pre-prandial: 80-130 mg/dL
> 180 mg/dL : +4 Unit
GDP 1 – 2 PP : <180 mg/dL
130 – 180 mg/dL : +2 Unit
HbA1C : <7% (evaluasi 3 bulan)
< 130 mg/dL : dosis tetap

1. Perkeni Guideline consensus Insulin 2021.

 Novo Nordisk®

Key findings IDegAsp co-formulation 3 clinical

programme Vs Basal or Basal – Bolus regimen

OD vs basal insulin OD (IGlar U100)1

Superior HbA1C reductions BF L D

Lower PPG excursions (at the meal administered)
Numerically lower risk nocturnal Hypoglycemia

Split dose vs basal plus/basal-bolus2 [INTENSIFICATION]

Similar HbA1C with less injections

BF L D
Significantly lower nocturnal hypoglycaemia
and lower insulin doses

BID, twice-daily; BIAsp, biphasic insulin aspart; BF, breakfast; D, dinner; FPG, fasting plasma glucose; IDegAsp, insulin degludec/insulin aspart; IGlar U100, insulin glargine U100; L, lunch; OD, once-daily; PPG,
postprandial glucose.
1.. Onishi et al. Diabetes Obes Metab 2013;15:826–832; 2. P Tsimikaset al. Diabetes Res and Clin Pract. 2019;147:157-165.
 ARISE
A multi-centre prospective non-interventional study
investigating the clinical effectiveness of IDegAsp (Insulin
Degludec/Insulin Aspart) in patients with type 2
diabetes mellitus in a real-world setting

NIS, non-interventional study; RCT, randomised controlled trials.

Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021.
 Primary objective

To investigate the effectiveness of IDegAsp on glycaemic control in a real-world population of T2D patients, who have
initiated or switched to IDegAsp from previous anti-hyperglycaemic treatment according to local clinical practice

Secondary objective

• To investigate the effectiveness of IDegAsp on glycaemic control in a real-world population of T2D patients treated
with IDegAsp according to local label at the discretion of the treating physician in each individual country as well as in
groups of patients coming from different previous anti-hyperglycaemic treatments

• To investigate the effectiveness of IDegAsp in other clinical parameters and safety in the population previously
referred and to describe the clinical use of IDegAsp in the local clinical practice

NIS, non-interventional study; RCT, randomised controlled trials.

Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021.
 Novo Nordisk®

Study design

T2D adult patients IDegAsp as per local practice*

Week 0 (visit 1) Observation period (visit 2.x) Week 26–36 (visit 3)

Informed Consent & End of Study
Treatment Initiation

Study information Key inclusion criteria Countries

• Physician’s decision to initiate treatment with Australia

• Non-interventional
IDegAsp India
• Multi-centre
• Age ≥18 years
• Prospective, primary data collection • Diagnosed with T2D and treated with any anti- Malaysia
• Visit frequency according to the local standard of hyperglycaemic medication(s) other than IDegAsp Philippines
care • Available HbA1c value ≤12 weeks
Saudi Arabia
South
Africa

*Visit 1 (treatment initiation visit) and visit 3 (end of study visit) were mandatory for all patients. Visit 2 was intermediary and only warranted as per clinical practice
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021..
Endpoints

PRIMARY HbA1C (change in %)

HbA1c less than Change in Change in insulin dose Change in Number of Treatment
HbA1C
FPG (total, basal, prandial) body weight hypo events discontinuation
less than 7% predefined target

SECONDARY

Resource HbA1C < 7%

utilisation without hypo

EXPLORATORY

FPG, fasting plasma glucose.

Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021.
Baseline characteristic

Mean, ± SD Sex Mean, ± SD Mean, ± SD Mean, ± SD

Age, years % Female BMI, kg/m2 Duration of T2D, HbA1C
years
%

Overall
(n = 1102) 58.6 46.4% 29.2 13.3 9.8%
(12.23) (46,4) (5.85) (8.33) (1.99)

BMI, body mass index; FPG, fasting plasma glucose; HbA1c; glycated haemoglobin; N, total number of patients in full analysis set; SD, standard deviation.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six countries. Abstract and oral
presentation at Australasian Diabetes Congress, August 13, 2021.
Previous anti-hyperglycaemic treatment

OAD Basal
Only GLP-1 RA Basal - Bolus Pre-mix
Only

Overall
(n = 1102) 35.1% 21.8% 8.2% 13% 21.9%

Full analysis set includes all eligible patients who signed the informed consent and initiated treatment with IDegAsp.
GLP-1RA, glucagon-like peptide-1 receptor agonist; n, number of patients; OAD, oral antidiabetic drug.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021.
 Novo Nordisk®

Reasons for initiating IDegAsp treatment

To improve patient's glycaemic
control
1026

49
To lower the risk of
291
hypoglycaemia

Flexibility in the dosing %

regimen
286

Fewer injections than basal and

277
bolus therapy Major reason
No reconstitution To improve patient’s glycemic control
98
needed
Change in coverage status 82
favouring IDegAsp

Other 54

0 200 400 600 1000 1200

800
Number of patients with response
IDegAsp, insulin degludec/insulin aspart
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six
countries. Abstract and oral presentation at Australasian Diabetes Congress, August 13, 2021..
Statistically significant change in HbA1C from baseline

Overall OADs only Basal only GLP-1RA Basal + bolus Premix Baseline (%):
9.7 10.2 9.7 9.2 9.3 9.4 0.0
0

Mean change in HbA1c from baseline (%)

-0.5

[-1.20; -0.52]* [-1.17; -0.64]*

-1.4%
-1

[-1.57; -1.10]* [-1.58; -1.03]*

-0.9% -0.9%
-1.5
-1.3% -1.3%
[-2.17; -1.85]*
-2
[-1.51; -1.29]*
-2%
-2.5

Some data may differ from the original abstract due to correction of statistical analyses
Data are change from baseline to Week 36 [95% CI]. The full adjusted model included baseline value, time, time squared of HbA 1c measure, age, sex, BMI, previous anti-hyperglycaemic treatment regimen and study site. To handle (quadratic) deviation from
linearity, a random coefficient model with time and time squared as fixed coefficients, and patient and patient time as random coefficients was used. An unstructured covaria nce matrix was used to describe the variability for the repeated measurements for
patients. *P-value <0.0001.
CI, confidence interval; BMI, body mass index; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c; glycated haemoglobin; OAD, oral antidiabetic drug.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six countries. Abstract and oral presentation at Australasian
Diabetes Congress, August 13, 2021.
Statistically significant change in FPG from baseline
By country

Overall Baseline
196.2 (mg/dL): Australia India Malaysia Philippines Saudi A South A
0.0 158.4 189 190.8 198 207 196.2
0

Mean change in FPG from baseline

-10

-20

-48.6
[-44.82; -11.34]*
-30 [-47.52; -16.56]*

(mg/dL)
-40 -28.8 † -32.4* [-59.76; -34.2]*

[-61.2; -42.48]*

-46.8*
-50
[-67.86; -45.54]*
[-53.64; -44.28]* -52.2* [-81.54; -44.82]*

-57.6*
-60

-70
-63*
Some data may differ from the original abstract due to correction of statistical analyses
Data are change from baseline to Week 36 [95% CI]. The full adjusted model included baseline value, time, time squared of FPG measure, age, sex, BMI, previous anti-hyperglycaemic treatment regimen and study site. To handle (quadratic) deviation from linearity, a random
coefficient model with
time and time squared as fixed coefficients, and patient and patient time as random coefficients was used. An unstructured covariance matrix was used to describe the variability for the repeated measurements for patients. *P<0.0001; †P<0.01.
CI, confidence interval; BMI, body mass index; FPG, fasting plasma glucose.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six countries. Abstract and oral presentation at Australasian Diabetes
Congress, August 13, 2021.
Statistically significant change in FPG from baseline
By previous anti-hyperglycemic treatment

Overall Baseline Basal

OAD Only Basal Premix
196.2 (mg/dL): Insulin Bolus GLP1-RA
N= 371 Insulin
0.0 N=137
N=230 N= 232 N= 87
0

-10

Mean change in FPG from baseline

-44.12;1.26
-20

-43.24;-16.34
-21.4
-48.6
-45.38;-17.77
-30

-29.8*

(mg/dL)
-31.6*
-50.58;-29.71
-40

-50
-40.1* [-59.76; -34.2]*

[-61.2; -42.48]*
-60
-73.90;-61.86
[-53.64; -44.28]* [-81.54; -44.82]*
-70

-80
-67.9*
Some data may differ from the original abstract due to correction of statistical analyses
Data are change from baseline to Week 36 [95% CI]. The full adjusted model included baseline value, time, time squared of FPG measure, age, sex, BMI, previous anti-hyperglycaemic treatment regimen and study site. To handle (quadratic) deviation from linearity, a random
coefficient model with
time and time squared as fixed coefficients, and patient and patient time as random coefficients was used. An unstructured covariance matrix was used to describe the variability for the repeated measurements for patients. *P<0.0001; †P<0.01.
CI, confidence interval; BMI, body mass index; FPG, fasting plasma glucose.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six countries. Abstract and oral presentation at Australasian Diabetes
Congress, August 13, 2021.
 Other Key Secondary Endpoint

Body Weight Hypoglycemia Change in Total Insulin Dose

Overall
Initiation or switching to IDegAsp1
Mean change in body
weight from baseline

79.9 Kg

77 -2.3
(kg)

[-1.51; -0.52]ⱡ %
Basal

Units/Day

-1kg
[-3.51; -1.01]*
Significant reductions on Nocturnal
Non-Severe hypoglycemic events 1.8 units/day
Prandial [0.62; 3.02]**

Data are change from baseline to Week 36 [95% CI]. The full adjusted model included baseline value, time, time squared of total daily insulin measure, age, sex, BMI, previous anti-hyperglycaemic treatment regimen and study site. To
handle (quadratic) deviation from linearity, a random coefficient model with time and time squared as fixed coefficients, and patient and patient time as random coefficients was used. An unstructured covariance matrix was used to
describe the variability for the repeated measurements for patients. N: Number of patients in full analysis set, n: Number of patients contributing to stat analysis ⱡP<0.0001 *P<0.001, **P<0.01
1. Data set total number of patients in full analysis set= 1102, observed within 4 weeks prior to initiations of Idegasp (n=128, events= 364), Observed within 4 weeks prior to EOS or at discontinuations (n= 44, events= 162.
Fulcher G, Akhtar S, Al-Jaser S, et al. Improved glycaemic control in people with type 2 diabetes initiating or switching to IDegAsp from any anti-hyperglycaemic treatment in a real-world setting across six countries. Abstract and oral
presentation at Australasian Diabetes Congress, August 13, 2021.
 Novo Nordisk®

ARISE summary

Initiation with or switch to IDegAsp, led to

STATISTICALLY STATISTICALLY SIGNIFICANT LOWER SIGNIFICANTLY LOWER RATE

SIGNIFICANT REDUCTIONs daily basal but higher of nocturnal non-severe
REDUCTIONs in overall FPG and body prandial insulin dose for hypoglycemic events and no
in HbA1c weight previous insulin users unexpected safety findings

FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonists; IDegAsp, insulin degludec/insulin aspart
 13

Implications of ARISE data for clinical

practice
 Novo Nordisk®

IDegAsp for initiation, intensification or switch of insulin therapy

in patients with T2D1,2

Patients failing to achieve Patients with post-prandial glucose

glycaemic control despite spikes, despite optimising basal
optimising non-insulin therapies insulin

Patients at increased risk of Patients who may benefit Patients requiring flexibility
hypoglycaemia, including from a reduced injection burden in the timing of insulin
nocturnal hypoglycaemia or a less complex regimen dosing

1. Glastras SJ, et al. J Clin Med. 2020;9:1091; 2. Gunton JE, et al. Med J Aust. 2014:201:650–3 (Dec 2016 update), available: http://t2d.diabetessociety.com.au/about-us/
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IDegAsp 2-in-1 Co-Formulation
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For Healthcare Professional Only