Timely Intensification using

Bolus Insulin Therapy

DR. Dr. Himawan Sanusi, SpPD-KEMD

Endocrine Metabolic and Diabetes

Internal Medicine Departement
Hasanuddin University
Wahidin Sudirohusodo Hospital
Pengalaman klinik ….
GD pre meal :
80 – 130 mg/dL

Kontrol 2 jam post

Glikemik prandial : 130 –
Baik 180 mg/dL

HbA1c
<7%
Which one do you choose ?

• 1 injection
• 2 injection
• 3 injection
• 4 injection
Insulin in daily practice….

• One injection:
– Intermediate-acting insulin or long-acting analog at bedtime
– Premixed formulation before dinner
• Two injections:
– Breakfast and dinner: premixed formulation
– Breakfast and dinner: short-acting or rapid-acting plus NPH or long-acting insulin
analog
• Three injections
– Add a short- or rapid-acting insulin injection at lunchtime to a 2-injection
premixed regimen
– Add a third premix injection at lunchtime to a 2-injection premixed regimen
– Move the intermediate- or long-acting insulin analog to bedtime with short-
acting or rapid-acting insulin analog at breakfast and dinner
• Multiple injections
– Short-acting or rapid-acting insulin analog at each meal with an intermediate- or
long-acting at bedtime
Outline

• Rationale to Intensify
• Guideline to Intensify
• Insulin Aspart Profile
• Intensification with Insulin Aspart
Rationale to
Intensify
Progression of T2D

Progression of T2D

Insulin resistance
β-cell function
Insulin level
Incretin effect

4–7 years Postprandial glucose

FPG

Development of microvascular complications

Development of macrovascular complications

Impaired glucose tolerance Diabetes

Diabetes diagnosis

FPG, fasting plasma glucose; T2D, type 2 diabetes

Adapted from Kendall et al. Am J Med 2009:122(Suppl. 6):S37–50
Insulin optimisation and intensification should
follow disease progression

Lifestyle + OADs
β-cell function (%)

Basal insulin + OADs

Titrate dose to reach/maintain glycaemic targets

Initiate Basal and 1–3 injections of bolus or premix

Intensify for mealtime insulin coverage

Optimise

Intensify

Treatment optimisation and intensification

OAD, oral antidiabetic drug

Schematic diagram adapted from Kahn. Diabetologia 2003;46:3–19
Inzucchi et al. Diabetologia 2012;55:1577–96
Need for fast onset of action

400
Insulin (pmol/min)

Traditional insulin products do not

mimic the healthy insulin
200
response

Meals

22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00
Time
Healthy insulin response
Soluble human insulin
NPH, neutral protamine Hagedorn; SC, subcutaneous

Adapted from Polonsky et al. N Engl J Med 1988;318:1231–9 NPH insulin

sc insulin replacement
New Slide
Guideline to
Intensify
Kapan Terapi Intensifikasi dilakukan?
Algoritme Pengelolaan DMT2 di Indonesia

Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia. 2015. PB PERKENI.
Bagaimana terapi Intensifikasi dilakukan?
(PERKENI Guideline)

Petunjuk praktis terapi insulin pada pasien diabetes melitus. PERKENI, 2015
Insulin Aspart Profile
Quest to attain ideal bolus insulin

Exubera inhaled insulin

(withdrawn 2007) Faster
Rapid-acting

Ultra-fast-acting
insulin analogue
2006 aspart
BioChaperone lispro
First clinical 1996 2017
Short-acting

use of
Trepostinil lispro (LY900014)
insulin
1922 Biosynthetic human
insulin 1982 Afrezza inhaled Liver-selective prandial insulin
Insulin 2015

1920 1940 1960 1980 2000 2017 Future

Glucose-sensitive insulin

Oral insulin

Faster aspart, fast-acting insulin aspart; NPH, neutral protamine Hagedorn

Adapted from Cahn et al. Lancet Diabetes Endocrinol 2015;3:638–52; Eli Lilly. Patent application, 12 November 2015; Eli Lilly. Press release, 4 December 2015;
Novo Nordisk. Capital Markets Day R&D update, 19 November 2015
Structure of insulin aspart molecule

• Insulin aspart is a biosynthetically

modified analogue of RHI
Asp

Asp

• A single proline amino acid at position

28 of the insulin B-chain has been
replaced with an aspartic acid residue
• In all other respects, insulin aspart and
RHI are structurally identical

RHI, regular human insulin

1. Owens D, Vora J. Insulin aspart: a review. Expert Opin. Drug Metab. Toxicol. 2006; 2(5):793-804
Insulin aspart: rapid dissociation into monomers

B29
Lys B21’
Glu
B30
Thr
B22’
Arg

B28
Pro/Asp
3.7 Å
B23’ Gly

B27
Thr
Hexamer Dimer Monomer

Reproduced from Brange & Vølund. Adv Drug Delivery Rev 1999;35:307–335
Insulin aspart: a more physiological insulin
response in T2DM compared with human insulin
Insulin aspart
*p<0.05 vs. human insulin Human insulin
Mean serum glucose (mmol/l)

14 600
* * *
500 lower with
Post-prandial glycaemic excursions were 20% insulin
** aspart (IAsp)
12

Insulin (pmol/l)
compared with regular human insulin (HI) treatment
400
10 300
* * * * *
8 200

100
6
0 0
0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Time (min) Time (min)
Perriello et al. Diabet Med 2005;22:606–11
Intensification with
Insulin Aspart
Options for insulin intensification
with insulin aspart (FullSTEP)
• STEPwise
• Complete basal-bolus
Insulin intensification strategies

• Starting insulin regimens and their stepwise intensification have

been suggested by international guidelines
• The regimens outlined in these guidelines are the premixed,
basal, basal-plus and basal–bolus regimens
• Stepwise insulin intensification using basal to basal-plus or a QD
or BID premixed insulin regimen are simplified potential
alternatives to full basal–bolus or TID premixed regimens

BID, twice daily; QD, once daily; TID, three times daily
Treatment intensification with stepwise addition of
prandial insulin aspart boluses compared with full
basal–bolus therapy (FullSTEP Study): a
randomised, treat-to-target clinical trial
Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–7
FullSTEP: trial design
Main inclusion criteria
• Age ≥18 years
• Type 2 diabetes for ≥12 months
• Basal insulin treatment for ≥6 months
• HbA1c 7.0–9.0%
• BMI <40 kg/m2
• Willing and able to eat three meals each day

If HbA1c ≥7.0%
Screening Randomisation 1:1 IDet QD + 3rd IAsp
± OADs
If HbA1c ≥7.0%
Run-in IDet QD + 2nd IAsp
± OADs

IDet QD + 1st IAsp

± OADs
IDet OD ± OADs

IDet QD + IAsp (breakfast, lunch, dinner) ± OADs

Week –10 –8 0 11 22 32
n=401

Treat to target

BMI, body mass index; IAsp, insulin aspart; IDet, insulin detemir; OAD, oral antidiabetic drug; QD, once daily

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

Baseline characteristics
Basal–bolus Stepwise

Number of subjects 200 201

Age, years 59.6 (9.5) 60.0 (9.1)

Sex, n (%)
Female 101 (50.5) 97 (48.3)
Male 99 (49.5) 104 (51.7)

Body weight, kg 86.1 (15.2) 88.9 (18.7)

BMI, kg/m2 30.7 (4.6) 31.5 (4.8)

Duration of diabetes, years 12.5 (8.4) 12.8 (7.7)

HbA1C % 7.9 (0.6) 7.9 (0.6)

FPG, mmol/L 6.9 (1.6) 7.0 (1.9)

FPG, mg/dL 124 (29) 126 (34)

Strata, n
HbA1c 7.0–8.0%, % 112 (56.0) 113 (56.2)
HbA1c 8.1–9.0%, % 88 (44.0) 88 (43.8)

Data are mean (SD) unless otherwise stated

Full analysis set
BMI, body mass index

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

 FullSTEP: mean HbA1c over time

8.0
7.9
7.8
7.7
7.6
7.5
HbA1c (%)

7.4
7.3
7.2
7.1
7.0
Stepwise
6.9
6.8
Basal–bolus
6.7
6.6

0 3 6 9 12 15 18 21 24 27 30 33

Time since randomisation (week)

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

FullSTEP: HbA1c reduction from baseline to end of
trial

Treatment difference is from estimated values adjusted for multiple covariates

CI, confidence interval; NS, not significant

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

FullSTEP: patients achieving HbA1c <7%
Stepwise
Basal–bolus

80 OR = 2.38 OR = 1.36
p<0.0001 p=0.15
OR = 6.85
70 p<0.0001
Percentage of subjects

60 65.4 63.3
50 56.3 55.9

40 45.2
30

20
19.2
10

0
Week 10 Week 21 End of trial

OR, odds ratio

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–7

 FullSTEP: significantly less hypoglycaemia with
stepwise approach
Stepwise
Basal–bolus

90

80
(episodes/exposure-year)
Hypoglycaemia rate

70

60

50

40

30

20

10

0
4 8 12 16 20 24 28 32

Time (weeks)

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–7

FullSTEP: FPG, hypoglycaemia incidence and body
weight
FPG

•FPG was comparable between the groups

•Mean treatment difference: 2.1 mg/dL; NS

Hypoglycaemia

•Patients in the stepwise group experienced fewer hypoglycaemic

episodes of all kinds versus those on basal–bolus insulin
•Rate ratio: 0.58 (95% CI: 0.45;0.75); p<0.001

Body weight

•Body weight was comparable between the groups

•Mean treatment difference: −0.48 kg; NS

CI, confidence interval; FPG, fasting plasma glucose; NS, not significant

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

FullSTEP: distribution of bolus injections in the
stepwise treatment group at end of trial
80

70

60
Patients (%)

50

40
40.3
30
27.4
20
17.4
10

0
1 2 3
Number of bolus injections
Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37
FullSTEP: conclusions
• The stepwise regimen was non-inferior to the basal–bolus regimen in terms of
change in HbA1c from baseline to 32 weeks
– Change from baseline in HbA1c after 10 and 21 weeks was significantly smaller in
the stepwise arm versus the basal–bolus arm
– At week 32, there was no difference between treatment arms
• There was no difference in FPG between treatment groups
• There was significantly less hypoglycaemia in the stepwise arm versus the
basal–bolus arm
• More subjects withdrew from the basal–bolus arm than the stepwise arm

FPG, fasting plasma glucose; PRO, patient-reported outcome

Rodbard et al. Lancet Diabetes Endocrinol 2014;2:30–37

Options for STEPwise insulin
intensification with insulin aspart
• ExtraSTEP
• SimpleSTEP
Comparison of two intensification regimens with rapid-acting
insulin aspart in T2D inadequately controlled by once-daily
insulin detemir and oral antidiabetes drugs: the STEPwise
randomised study

Meneghini et al. Endocr Pract 2011;17:727–36

T2D, type 2 diabetes

The STEPwise study: rationale

• Designed in response to guidance from the ADA/EASD

• Optimise (basal dose) and intensify (addition of bolus doses)
treatment when HbA1c is ≥7%
• Insulin aspart administration initially QD, progressing to BID and
then TID as needed

• Addition: with largest perceived meal

SimpleSTEP • Titration: pre-meal SMPG 4–6 mmol/L (72–108 mg/dL)
and/or bedtime SMPG 4-8 mmol/L (72–144 mg/dL)

• Addition: largest measured PPG increment

ExtraSTEP
• Titration: post-meal SMPG 4–8 mmol/L (72–144 mg/dL)

ADA, American Diabetes Association; BID, twice daily; EASD, European Association for the Study of Diabetes; PPG, postprandial glucose; QD, once daily;
SMPG, self-measured plasma glucose; TID, three times daily

Meneghini et al. Endocr Pract 2011;17:727–736

 STEPwise: study design
Inclusion criteria:
• Age >18 years
• T2D for >6 months
• HbA1c 7.5–10.0%
• Basal insulin for ≥3 months + 1–3 OADs ExtraSTEP Largest measured
+ IAsp x3
+ IAsp ×3 PPG increment
ExtraSTEP
Randomisation ExtraSTEP
ExtraSTEP
+ IAsp
+ IAsp ×2x2 TargetPPG :
+ IAsp 4–8 mmol/L
+ IAsp ×1x1

+SimpleSTEP+
IAsp ×1 Largest perceived
meal
IAsp x1
SimpleSTEP
Insulin detemir initiated + SimpleSTEP+
IAsp ×2
Run-in period insulin detemir + OADs
IAsp x2 Target preprandial
SimpleSTEP glucose:
+ IAsp ×3
+ IAsp x3
4–6 mmol/L
Weeks
–12 0 12 24 36
Period 1 Period 2 Period 3

ExtraSTEP – largest measured PPG increment; SimpleSTEP – largest perceived meal

IAsp, insulin aspart (insulin aspart); OAD, oral antidiabetic drug; PPG, postprandial plasma glucose; T2D, type 2 diabetes

Adapted from Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: baseline characteristics
ExtraSTEP SimpleSTEP
Number (female/male) 146 (70/76) 150 (67/83)
Age, years 58.3 58.3
Body weight, kg 88.8 88.0
BMI, kg/m2 31.26 31.38
HbA1c, % 8.9 8.7
FPG, mmol/L (mg/dL) 8.3 (149.0) 8.1 (146.0)
Diabetes duration, years 11.8 12.7
Mean basal insulin dose at baseline, U/kg 0.59 0.58
Mean bolus insulin dose at baseline, U/kg 0.05 0.05

• Primary outcome: HbA1c after 36 weeks of treatment

• Secondary outcomes: FPG, prandial glucose increments, adverse events, laboratory safety parameters,
hypoglycaemia

BMI, body mass index; FPG, fasting plasma glucose

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: treatment targets

FPG PPG
HbA1c
4–6 mmol/L 4–8 mmol/L
<7%
72–108 mg/dL 72–144 mg/dL

Good glycaemic control

FPG, fasting plasma glucose; PPG, postprandial glucose

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: dose and HbA1c in treatment period 1-3
1.5
10.0 10
9.59.5

Dose (IU/kg)
9.0 9 8.9
1.0
HbA1c (%)

8.5
8.5 8.5
8.7
8.0 8 7.8 7.7
8.2
7.5 7.5 7.7 0.5
7.5
7.0 7

6.5 6.5

0 6 Period 1 Period 2 Period 3 0

Treatment period 3

ExtraSTEP Bolus dose Basal dose Total dose

SimpleSTEP Bolus dose Basal dose Total dose
ExtraSTEP – largest measured PPG increment; SimpleSTEP – largest perceived meal
PPG, postprandial plasma glucose

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: FPG reduction from baseline
ExtraSTEP
SimpleSTEP

9 162

8.3 8.2
153
8 7.8
8.1 7.6
7.9

FPG (mg/dL)
144
FPG (mmol/L)

7.7
7 7.5
135

6
126

5
117

0
Baseline Week 12 Week 24 Week 36

Adjusted for baseline FPG

FPG, fasting plasma glucose

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: 24-h PG profiles at end of trial
14
252
13
234
12
216
11
PG (mmol/L)

198

PG (mg/dL)
10
180
9
162
8
144
7
126
6
108
5
90
0
0
Before After Before After Before After Bedtime
breakfast breakfast lunch lunch dinner dinner

ExtraSTEP randomisation ExtraSTEP week 36

SimpleSTEP randomisation SimpleSTEP week 36
PG, plasma glucose

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: overall hypoglycaemia rates
9
8.31
8.12
8

6 5.87 5.98
Hypoglycaemia rate
(episodes per year)

2
1.39
1.01 ExtraSTEP
1
SimpleSTEP
0.01 0.04
0
Major Minor Nocturnal Diurnal

Both nocturnal and diurnal rates include all hypoglycaemia (including unclassified and symptoms only)

Meneghini et al. Endocr Pract 2011;17:727–36

STEPwise: increase in hypoglycaemia rates with
treatment intensification
16
14.7
14.1
14
12.9 13

12
Hypoglycaemia rate
(episodes per year)

10

5.9 6.2
6 5.5 5.6

4
ExtraSTEP
2 SimpleSTEP
0
Period 1 Period 3 1 bolus 3 boluses

An increase in hypoglycaemia events was observed from period 1 to period 2 and

as the number of prandial boluses went from one to three injections per day

Meneghini et al. Endocr Pract 2011;17:727–736

STEPwise: conclusions

• An overall reduction in HbA1c of 1.2% was achieved with the addition

of insulin aspart
• The greatest HbA1c reductions were achieved with the first and second
bolus injections
• Improvement in glycaemic control was comparable between
both groups
• The number of hypoglycaemic episodes increased with increasing
number of insulin aspart injections, but the rate of hypoglycaemic
episodes was low
• An intensification regimen of stepwise addition of prandial insulin may
be a more patient-friendly way to achieve full basal–bolus treatment

Meneghini et al. Endocr Pract 2011;17:727–736

 Strategies for dose intensification1
Fix the FPG first using basal insulin (dose optimisation)
Goal: FPG 70-130 mg/dl (3.9-7.2 mmol/l)
Consider adding bolus insulin when :
A1C>7% and FPG at goal or basal insulin dose > 0.5 U/kg
Fix the FPG first using basal insulin (dose optimisation)
Goal: FPG 70-130 mg/dl (3.9-7.2 mmol/l)
Consider adding bolus insulin when :
A1C>7% and FPG at goal or basal insulin dose > 0.5 U/kg

Add bolus 2U at each meal Add bolus 4U at largest meal

Titrate to next pre-prandial goals ( and bedtime) daily Titrate to next pre-prandial (or bedtime) goal daily

If subsequent pre-meal sugars are: If subsequent pre-meal sugars are:

<70mg/dl -1U <70mg/dl -1U
70-130mg/dl 0 70-130mg/dl 0
>130mg/dl +1U >130mg/dl +1U
Discontinue SU on addition of bolus insulin Discontinue SU on addition of bolus insulin
Patients need to monitor up to 4x per day Patients may need monitor up to 4x per day

If A1C>7% after 3 months despite titrating bolus dose, If A1C>7% after 3 months despite titrating bolus dose, or
or bolus dose s are more than 30 U per meal : bolus dose is more than 30 U per meal :
Resume titration of basal insulin and/or consider performing Add 2nd bolus of 4U at 2nd largest meal and titrate as before.
a 7 point profile Repeat for 3rd bolus dose at final meal of the day

Pfutzner A, Forst T. Intensification with prandial insulin. Int J Clin Pract 2009; 63 (Suppl. 164): 11–14
Summary
 We should consider for prandial insulin when basal insulin with any oral
combination could not reach the target

 Insulin Aspart has a mimic with natural insulin secretion for prandial response

 There are two methods for intensification with Insulin Aspart:

 Stepwise
 Complete basal-bolus

 The stepwise regimen was non-inferior to the basal–bolus regimen in terms of

change in HbA1c from baseline to 32 weeks

 An intensification regimen of stepwise addition of prandial insulin may be a more

patient-friendly way to achieve full basal–bolus treatment

 Always Start with a small doses and adjust the doses once or twice a week
 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Figure 1 (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)