insulin clinical case starting insulin th

insulin

1. Clinical Case Starting Insulin Therapy:
What You Need to Know?
dr. Leny Puspitasari SpPD-KEMD, FINASIM

2. Disclosure
I have received honorarium as speaker/consultant, support for research/attendance at
educational meetings from:
•Novo Nordisk
•List names of companies

3. Key Challenges for type 2 diabetes patient needing
insulin treatment
Our
Realities
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
ObesMetab. 2017 Aug;19(8):1155-1164 4. Adapted from American Diabetes Association. Diabetes Care 2017;40(Suppl.1):S64 –S74
42
%
Patients with T2DM had
HbA
1c >9%
1
before
they start insulin
70
%
patients on basal insulin
FAILED to achieved HbA1C
target
3
Asian populations generally shown a
high-carbohydrate consumption, it
leads to high insulin resistance and
PPG levels.
2
Intensification from basal to basal
plus/bolus is COMPLEX.
4
3-4
injections

4. 70
%
Patients in Indonesia
fail to achieve
HbA
1c <7%
4
Despite clinical guideline
recommendations and the
benefits of good glycaemic
control,
target HbA
1c levels are often
not met
2-3
Patients progress through
a sequence of medications over several years
1*
COMBINATION
INJECTABLE THERAPY
TRIPLE THERAPY
If HbA
1c
above target
DUAL THERAPY
If HbA
1c
above target
If HbA
1c
above target
MONOTHERAPY
TREATMENT INTENSIFICATION
*Figure adapted from ADA guidelines (Davies et al. Diabetes Care 2018;41(12):2669 -2701)
Abbreviations: HbA
1c, glycated haemoglobin; T2D, type 2 diabetes.
References: 1. Davies et al. Diabetes Care 2018;41(12):2669-2701. 2. de Pablos-Velasco et al. Clin Endocrinol. 2014 ;80(1):47-56. 3. Stratton IM et al. BMJ 2000 ;321(7258):405-12.
Soetedjo et al, Trop Med and Int Health. 2018 (23): 1118-1128 4. Soetedjo et al, Trop Med and Int Health. 2018 (23): 1118-1128
The burden of inadequate glycaemic control in Indonesia is a challenge

5. Treatment is not intensified in a timely manner in people
with T2D with inadequate glycemic control
Of people with T2D with
HbA
1c ≥7.0%... … median time to intensification
with insulin is
>7.2 years
†1
References: 1. Khunti et al. Diabetes Care 2013;36(11):3411-7.
… many patients remain on OAD despite
failure to achieve HbA1C
42
%
Patients with T2DM had
HbA
1c >9%
1
before
they start insulin

6. †M e dia n study f o llo w-up 5.3 y e a rs.
Ab b revi at i o n s: C I, co nf ide nce inte rv a l; HbA1c, gly ca te d ha e m o glo bin; HR , ha za rd ra tio ; T2D, ty pe 2 dia be te s.
Referen c es: 1. P a ul e t a l. C a rdio v a scula r Dia be to lo gy 2015; 14: 100.
Even a 1 year delay in treatment intensification is associated with
an increased risk of diabetes-related complications in people with T2D
A 1-year delay in
treatment intensification
in people with
T2D with HbA
1c ≥7%
is associated with a
INCREASED RISK OF
myocardial infarction
(HR 1.67, 95% CI 1.39–2.01)
1
67
%
INCREASED RISK OF
heart failure
(HR 1.64, 95% CI 1.40–1.91)
1
64
%
INCREASED RISK OF
stroke
(HR 1.51, 95% CI 1.25–1.83)
1
51
%
….compared with those with HbA
1c <7%
1†

7. Asian vs Western Difference to
Achieve Glycaemic Control

8. Characteristic T2DM difference between
Caucasian and Asian patients
1.Hussain, Akhtar, Diabetes in Asia: Special Challenges and Solutions. Journal of Diabetology 9(3):p 69-72, Sep–Dec 2018. | DOI: 10.4103/jod.jod_22_18
2.Tan, V., Lee, Y., Venkataraman, K. et al . Ethnic differences in insulin sensitivity and beta-cell function among Asian men. Nutr & Diabetes 5, e173 (2015). https://doi.org/10.1038/nutd.2015.24
3.Kalra S, et al. Choice of Insulin in Type 2 Diabetes: A Southeast Asian Perspective. Indian J Endocrinol Metab. 2017 May-Jun;21(3):478-481. doi: 10.4103/ijem.IJEM_82_17. PMID: 28553609; PMCID: PMC5434737.
Additional prandial
control is often a
treatment consideration
since Melayu ethnicity
have lower beta-cell
function
2
Differences in patient
characteristics reflected
in choices of insulin
regimen for initiation and
intensification
3
Asian Phenotype
Young age of onset,
predisposition to beta-cell
failure and visceral
adiposity, and lower BMI
1
Country Phenotype
1
-South Asian: less muscle and more abdominal
fat, which increases insulin Resistance
-Chinese: 50% normoweight, low BMI
correlating with low level of plasma C-Peptide
and high HbA1C
-Japanese US: visceral fat area and reduced
incremental insulin response were
independent predictors for diabetes.

9. High carbohydrate consumption in Indonesia
1
1.United Nations World Food Programme - Strategic Review of Food Security and Nutrition in Indonesia: 2019–2020
2.Hu EA, Pan A, Malik V, Sun Q. White rice consumption and risk of type 2 diabetes: meta-analysis and systematic review. BMJ. 2012 Mar 15;344:e1454. doi: 10.1136/bmj.e1454. PMID: 22422870; PMCID: PMC3307808.
Intake of rice and other cereals is ~65.7% of the total calorie
intake (50% recommended, already higher than international standards
1
)
Annual average rice
consumption per person
Annual average wheat flour
consumption per person
97 kg
18 kg
One additional serving
(150 gr) of white rice intake
increase risk of T2D by:
2
11%

10. Initiation with basal insulin is not enough
Greater contribution to HbA1c
from PPG
2
31.5 30.8
35.4 34.3
41.1
68.5 69.2
64.6 65.7
58.9
0
10
20
30
40
50
60
70
80
<6.5 6.5 - <7.0 7.0 - <7.5 7.5 - <8.0 ≥8.0
Total hyperglycaemia (%)
Week 24 HbA1c category (%)
After 24/28 weeks of basal insulin treatment
Basal hyperglycaemiaPostprandial hyperglycaemia
References: 1. Mauricio D, et al. Diabetes Obes Metab. 2017 Aug;19(8):1155-1164 2. Riddle M, et al. Diabetes Care 34:2508–2514, 2011
More than ≥70% patients on basal
insulin FAILED to achieved HbA1C target
1

11. Total Glycemic Control: Need for Co -Formulation Insulin
HbA
1c
PPG FPG
Glycaemic control requires attention to both FPG
and PPG
1
Clinical evidence suggests that reducing PPG excursions
is as important
as reducing FPG for achieving HbA1c goals
1,2
1. Riddle M, et al. Diabetes Care 34:2508–2514, 2011 | 2. Monnier et al. Endocr Pract. 2006;12:S1:42–63.

12. Clinical Needs
Looking for effective and simpler options
13

13. IDegAsp: First in Class Co-Formulation Insulin
1
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. DiabetesMetabResRev.2012;28:50-61.
2,3
4

14. IAsp, insulin aspart; IDegAsp, insulin degludec/insulin aspart
Havelund et al. Pharm Res. 2015;32:2250–8
Insulin degludec
dihexamers IAsp hexamers
In the formulation
IDegAsp = Insulin degludec (70%) + IAsp
(30%) existing separately in one formulation
Slow
dissociation
Subcutis
Capillary
Rapid
dissociation
Insulin degludec IAsp
In the subcutaneous depot
Co-formulation of insulin degludec with rapid -acting insulin
possible because of stable dihexamers in solution

15. GIR, glucose infusion rate; IGlar U100, insulin glargine U100; T1D, type 1 diabetes; T2D, type 2 diabetes
Heise et al. Expert Opin Drug Metab Toxicol2015;11:1193–201; Heise et al. Diabetes2012;61(Suppl. 1):A259; Heise et al. Diabetes Obes Metab2012;14:859-64
Insulin degludec IGlar U100
0.4
U/kg
0.6
U/kg
0.8
U/kg
0.4
U/kg
0.6
U/kg
0.8
U/kg
Half-life (hours) 25.9 27.0 23.6 11.5 12.9 11.9
Mean half-life 25.4 12.1
0
40
80
120
160
200
Area under the GIR curve (time interval, hours)
Day
-
to
-
day variability
(coefficient of variation %)
Variability in glucose-lowering effect
over 24 hours at steady state
Insulin degludec variability is four-fold
lower than IGlar U100
0 24 681012141618202224
Time (hours)
0
1
2
3
4
5
6
GIR (mg/kg/min)
Flat time-action profile in T1D
at steady state
Insulin degludec concentration reaches
clinical steady state in 2–3 days
Twice as long half-life of insulin degludec compared with
IGlar U100
Insulin degludec
IGlar U100
540 1 6
Days since first dose
Serum insulin degludec concentration
Proportion of Day 6 level (%)
0
T2D
0 1 2 3 4
Proportion of
Day 4 level (%)
120
0
Days since first dose
T1D
120
32
Pharmacological characteristics of insulin degludec

16. How does the data?
13

17. Insulin Naïve T2D: Study Design
IDegAsp OD  OADs (n=147)
IGlar U100 OD  OADs (n=149)
Insulin-naïve
patients with
type 2 diabetes
(n=296)
0
26
weeks
Inclusion criteria
•Type 2 diabetes ≥6 months
•Previously treated with ≥1 OAD
for at least 12 weeks with at
least recommended
maintenance dose per local
labelling
•HbA
1c 7.0–10.0%
•BMI ≤35 kg/m
2
•Age ≥20 years
Open-label
Prior to randomisation, SUs, DPP-4 inhibitors and glinides were discontinued
Starting dose was 10 U for both treatment arms
IDegAsp was administered with the largest meal of the day; the dosing time was chosen
at the discretion of the patient
IGlarU100 was administered according to label (either before breakfast or at bedtime at
the discretion of the patient
The timing of the dosing was not to be changed during the trial
ETD, estimated treatment difference; FPG,
Onishi et al. Diabetes Obes Metab 2013;15:826–32

18. Mean HbA
1c vs insulin glargine U100
IDegAsp Offers Flexibility in the Timing of Insulin Administration
1
Significantly reduced HbA1c and better PPG
control after dinner with IDegAsp OD
Estimated treatment difference: -0.28% (95% Cl-0.46, -0.10);
??????<0.01 Superiority confirmed, ”vs insulin glargine U100 mean
reduction from baseline
IDegAsp OD (n=147)
RESULT - RCT’s: ONISHI
Onishi et al. Diabetes Obes Metab 2013;15:826–32

19. Novo Nordisk
®
ARISE: Studydesign
*Visit1(treatmentinitiationvisit)andvisit3(endofstudyvisit)weremandatoryforallpatients.Visit2wasintermediaryandonlywarrantedasperclinicalpractice
FulcherG,AkhtarS,Al-JaserS,etal.Improvedglycaemiccontrolinpeoplewithtype2diabetesinitiatingorswitchingtoIDegAspfromanyanti-hyperglycaemictreatmentinareal-worldsettingacrosssix
countries.Abstract andoralpresentationat AustralasianDiabetesCongress,August13,2021..
•Non-interventional
•Multi-centre
•Prospective,primarydatacollection
•Visit frequency according to the local standard of
care
•Physician’sdecisionto initiatetreatmentwith
IDegAsp
•Age≥18years
•Diagnosedwith T2Dandtreatedwith any anti-
hyperglycaemic medication(s)otherthanIDegAsp
•AvailableHbA
1cvalue≤12weeks
Studyinformation Keyinclusioncriteria Countries
Australia
India
Malaysia
Philippines
SaudiArabia
SouthAfrica
T2Dadultpatients IDegAspasper localpractice
*
Week0(visit1)
InformedConsent&
TreatmentInitiation
Observation period (visit 2.x) Week 26–36(visit3)
EndofStudy

20. RESULT - Real-life initiation with Co-Formulation
ARISE Study
-2
-2.5
-2
-1.5
-1
-0.5
0
Statistically significant
change in HbA1C from
baseline
Mean
change
in
HbA
1c
from
baseline
(%)
-67.9
-80
-70
-60
-50
-40
-30
-20
-10
0
Statistically significant
change in FPG from
baseline
[-2.17; -1.85]
P-value <0.0001
[-73.90;-61.86]
P-value <0.0001
77 %
Significant reductions on
Nocturnal Non-Severe
hypoglycemic events
Initiation or switching to
IDegAsp
#
Insulin-naïve patients Insulin-naïve patients Overall Patients
Somedatamaydifferfromtheoriginalabstractduetocorrectionofstatisticalanalyses
DataarechangefrombaselinetoWeek36[95%CI].Thefulladjustedmodelincludedbaselinevalue,time,timesquaredofHbA
1cmeasure,age,sex,BMI,previousanti-hyperglycaemictreatmentregimenandstudysite.Tohandle(quadratic)deviationfromlinearity,arandom
coefficientmodelwithtime andtimesquaredasfixedcoefficients,andpatientandpatienttimeasrandomcoefficientswasused.Anunstructuredcovariancematrixwasusedtodescribethevariabilityfor therepeatedmeasurementsfor patients.*P-value<0.0001.
CI,confidenceinterval;HbA
1c;glycatedhaemoglobin;OAD,oralantidiabeticdrug.
#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.
FulcherG,AkhtarS,Al-JaserS,etal.Improvedglycaemiccontrolinpeoplewithtype2diabetesinitiatingorswitchingtoIDegAspfromanyanti-hyperglycaemictreatmentinareal-worldsettingacrosssixcountries.AbstractandoralpresentationatAustralasianDiabetesCongress,
August13,2021.
Mean
change
in
FPG from baseline (mg/dL)

21. Clinical use of IDegAspCo-Formulation Insulin
13

22. Clinical guidance on initiation
References:
1. Onishi et al. Diabetes Obes Metab 2013;15:826–32 2. Sarah Galtras et al. J Clin Med 2020. 3. Roopa M et al. Diabetes Obes Metab. 2020;1-15
…IDegAsp OD to be considered as
2,3

…Clinical evidence support the study of IDegAsp
initiation of people with T2DM [Onishi]
1
:
INITIATION (OAD FAILURE)
PREFERRABLE TO BASAL INSULIN ALONE
Numerical lower risk of Nocturnal
Hypoglycemia 25%
Superior reduction of HbA1C
More patient achieve target
without hypoglycemia 2X
•Max OAD therapy but HbA1C >7 and PPG 180 mg/dL
•Extreme and symptomatic Hyperglycaemia
•Postprandial Hyperglycaemia is a concern
•People with low BMI

23. Recommended starting dose for initiations
10Unit/OD
With largest meals
Followed by subsequent INDIVIDUAL dosage
weekly adjustment until the desired FPG
reached
Starting dose
>10Unit/OD
With largest meals
Severe Hyperglycemia
HbA1c >10% (86 mmol/mol)*
*This posology is based on expert recommendations from
Sarah G et al.
References: 1. Sarah Galtras et al. J Clin Med 2020. 2. Roopa M et al. Diabetes Obes Metab. 2020;1-15 3. Ryzodeg®. Indonesia Prescribing Information. 2021c

24. Sasaran kontrol glikemik (PERKENI, 2021)
Glukosa darah 1-2 jam PP
Glukosa darah puasa/pre-
prandial capillary plasma glucose
HbA1C 7%
80-130
Mg/dL
<180
Mg/dL
+
Target FPG
Dosis
IDegAsp
>130
mg/dL +2
<80
mg/dL -2
80 - 130
mg/dL
Pertahankan
dosis
Suggested once-weekly titration schedule for
IDegAspin T2D
1. Fulcher et al. Diabetes Care 2014;37:2084–90; 2. Gerety et al. Endocr Pract 2016;22:546–54; 3. Konsensus Perkeni 2021

25. If Adequate glycaemic control is not
achieved with
IDegAsp OD
Treatment can be intensified to….
If HbA1C is not met with IDegAsp OD, glucose monitoring is
needed to determine where hyperglycaemia is occurring.
Treatment can be intensified to
IDegAsp (Split dose)
IDegAsp OD + Iasp at one or
more meals
IDegAsp (split dose) + Iasp at
the third meals
A
B
C
+
TREATMENT INTENSIFICATION
Intensification from IDegAspOD
References: 1. Sarah Galtras et al. J Clin Med 2020. 2. Roopa M et al. Diabetes Obes Metab. 2020;1-15
3
Alternative
Strategy to
achieve adequate
glycaemic control

26. ‘if there are post prandial glucose
excursion after 2 meals’
Recommend a max OD dose 30-
40 unit before splitting.
The dose ratio

not

necessarily

(1:1) with a minimum dosing
interval of 4 hours
*: this may be vary with individualise target and monitoring frequency
When &
How do
you
intensify:
IDegAsp Split
‘if there are persistent
excessive post prandial

glucose excursion’
(i.e 3 reading of >180 mg/dL
over 1 week on

SMBG/capillary blood
glucose)*
IDegAsp split + Iasp IDegAsp OD + Iasp
or
‘if post prandial occurs when

FPG is normal’
(i.e in country where meals
are typically

rich in
carbohydrate)
References: 1. Sarah Galtras et al. J Clin Med 2020. 2. Roopa M et al. Diabetes Obes Metab. 2020;1-15

27. Guideline Recommendation
13

28. ALGORITHM
Insulin
Therapy
Guideline Perkeni 2021. Pedoman Terapi Insulin pada Pasien Diabetes Melitus.
Patients Type 2 DM +
oral (mono/dual/triple)
Basal
Co-Formulation
Or Premix
FRC
Dose 10U at night or
0.2 unit/kg/BW
Maximum dose
0.5 unit/kg/BW
Target:
GDP/ Pre-prandial: 80-130 mg/dL
GDP 1 – 2 PP : <180 mg/dL
HbA1C : <7% (evaluasi 3 bulan)
Titrasi:
(Jika nilai GDP atau pre-prandial)
> 180 mg/dL : +4 Unit
130 – 180 mg/dL : +2 Unit
< 130 mg/dL : dosis tetap
Initiation
Intensification
≥7.5%
HbA1C

29. ALGORITHM
Insulin
Therapy
Guideline Perkeni 2021. Pedoman Terapi Insulin pada Pasien Diabetes Melitus.
Patients Type 2 DM NEW
HbA1C > 9%;
FPG >250 mg/dL ;
BG > 300 mg/dl;
Metabolic Decompensation
Initiation
De-escalation
FRC
Co-Formulation
or Premixed
+ Prandial at the largest
meal
Basal at night
Basal Plus Basal Bolus
Starting dose 10 Unit
Dose optimalization
OD → BID
Starting dose 10 Unit
Dose optimalization
OD → BID
Starting dose
prandial 4U/hari or
10% from basal dose
Optimalization dose
+ Prandial at the third
meal. Basal at night
Basal 10U (bedtime)
Prandial 4U
Intensification
Target:
GDP/ Pre-prandial: 80-130 mg/dL
GDP 1 – 2 PP : <180 mg/dL
HbA1C : <7% (evaluasi 3 bulan)
Titrasi:
(Jika nilai GDP atau pre-prandial)
> 180 mg/dL : +4 Unit
130 – 180 mg/dL : +2 Unit
< 130 mg/dL : dosis tetap
≥9%
HbA1C

30. 56
*versus Glargine; FPG,fastingplasmaglucose;HbA
1c,glycosylatedhaemoglobin;PPG,postprandialplasmaglucose.
1.Ryzodeg
®
indonesia Prescribing Information 2023.2.Onishi,etal. Diabetes Obes Metab 2013;15:826–32.
Benefitsofinitiation with IDegAsp*
Superior Glycemic
Control
IDegAsp targeting
FPG & PPG
2
Numerical lower
risk of Nocturnal
Hypoglycemia
2
Simple to use
OD with largest
meals
1

HbA
1c
OD
Flexibility in the
timing of insulin
adminstrations
1
START with CONFIDENCE

31. Thank you