Intensification with Bolus Insulin

Therapy
Structure of insulin aspart molecule

• Insulin aspart is a
biosynthetically modified
analogue of human insulin
• 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 human insulin are
structurally identical
Pharmacokinetics of NovoRapid® vs. RHI
600 NovoRapid®, t=0 min
Plasma insulin (pmol/L)

500 Human insulin, t=0 min

Human insulin, t=–30 min

400
(insulin dose 0.15 U/kg)
300
n=22
200

100

0
0 1 2 3 4 5 6
Time (hours)
Lindholm et al. Diabetes Care 1999;22:801–5
Aim of insulin therapy
Short-lived, rapidly
generated meal-related
70 insulin peaks (prandial)
• To recreate the normal
60
blood insulin profile
Insulin (µU/mL)

50

40 Sustained
insulin profile (basal)
30

20

10

0
6:00 10:00 14:00 18:00 22:00 2:00 6:00
Time of day
Breakfast Lunch Dinner

Polonsky et al. J Clin Invest 1988;81:442–48

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
* * *
Post-prandial glycaemic excursions were
50020% lower with* *insulin aspart

Insulin (pmol/l)
12
(IAsp) compared with regular human
400 insulin (HI) treatment
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
 6

What are the PK/PD Differences Between Insulin Aspart and

RHI?

Insulin Aspart:
• Has approximately 2x faster absorption than RHI
• Has approximately 2x higher peak insulin concentration than RHI
• Has a more consistent time to peak than RHI
• Mimics the normal prandial response

Parameter Insulin Aspart RHI

Onset of action 10−20 minutes 30 minutes
Peak concentration 40−50 minutes 80−120 minutes

Duration of action 3−5 hours 5−8 hours

Better postprandial blood glucose control with insulin
aspart vs human insulin in a meta-analysis
Change in average blood glucose level (mmol/L) after breakfast, lunch and dinner:
per-trial and overall analysis of treatment differences at week 16
Treatment difference
Trial (%) [95% CI] P
Type 1
035 -0.57 [-0.75; -0.39] <0.001
036 -0.87 [-1.07; -0.68] <0.001
064 -0.43 [-0.54; -0.32] <0.001
065 -0.18 [-0.29; -0.06] 0.003
Type 2
037 -0.20 [-0.62; 0.21] 0.33
1198 -0.72 [-1.65; 0.20] 0.12
1266 0.53 [-2.46; 1.40] 0.59
All
Fixed effects -0.41 [-0.48; -0.35] <0.001
Random effects -0.47 [-0.70; -0.25] <0.001
Test of heterogeneity: P<0.001

-3 0
Favours IAsp + NPH Favours RHI + NPH
IAsp, insulin aspart , NPH, neutral protamine Hagedorn RHI, regular human insulin
Heller et al. J Diabetes 2013; 5:482-491
Lower HbA1c with insulin aspart than human insulin in a
meta-analysis
Hypoglycaemic episodes comparable with insulin aspart and
human insulin in a meta-analysis
Per-trial and overall analysis of all hypoglycaemic episodes
Treatment difference
Trial (%) [95% CI] P
Type 1
035 1.18 [0.98; 1.42] 0.08
036 0.94 [0.79; 1.11] 0.44
054 0.72 [0.36; 1.45] 0.36
064 0.83 [0.64; 1.08] 0.17
065 0.84 [0.65; 1.08] 0.17
066 1.05 [0.72; 1.53] 0.81
Type 1 and Type 2
1634 2.97 [1.40; 6.32] 0.005
Type 2
037 1.11 [0.64; 1.94] 0.70
1198 0.89 [0.44; 1.78] 0.74
1266 1.26 [0.17; 9.06] 0.82
All
Fixed effects 0.99 [0.90; 1.09] 0.81
Random effects 1.00 [0.86; 1.16] 0.97
Test of heterogeneity: P=0.092

0.1 1 10
Favours IAsp + NPH Favours RHI + NPH

IAsp, insulin aspart

NPH, neutral protamine Hagedorn RHI,
regular human insulin
Heller et al. J Diabetes 2013; 5:482-491
Lower rate of nocturnal hypoglycaemic episodes with insulin
aspart vs human insulin in a meta-analysis
Per-trial and overall analysis of all nocturnal hypoglycaemic episodes
Treatment difference
Trial (%) [95% CI] P
Type 1
035 0.75 [0.60; 0.93] 0.01
036 0.69 [0.56; 0.86] <0.001
064 0.79 [0.59; 1.06] 0.11
065 0.79 [0.59; 1.06] 0.12
066 0.83 [0.50; 1.38] 0.48
Type 1 and Type 2
1634 0.97 [0.59; 1.58] 0.89
Type 2
037 0.54 [0.24; 1.22] 0.14
1198 0.68 [0.16; 2.85] 0.59
All
Fixed effects 0.76 [0.67; 0.85] <0.001
Random effects 0.76 [0.67; 0.85] <0.001
Test of heterogeneity: P=0.092

0.1 1 10
Favours IAsp + NPH Favours RHI + NPH

Heller et al. J Diabetes 2013; 5:482-491

4T: summary of efficacy and safety at 3 years
Biphasic insulin Prandial insulin Insulin detemir
20 aspart aspart
8
Mean relative change (%)

10

No. of events per

6
0

patient/year
–10 4

–20
2
–30

0
HbA1c FPG PPG Body weight Hypoglycaemia

Baseline value 8.5% 9.6 mmol/L 12.6 mmol/L 85.8 kg

p-value 0.28 0.83 <0.001 0.20

Holman et al. N Engl J Med 2007;357:1716–30; Holman et al. N Engl J Med 2009;361:1736–47
Basal+insulin aspart: Efficacy results
HbA1c FPG PPG
n= 1127 1869 1221 1905 917 1447
0 0

24 weeks FPG/PPG (mg/dL)

-0.5 -20
Change from baseline to

Change from baseline to

24 weeks HbA1c (%)

-40
-1
-60
-1.5 -59.4
-80
-2 -88.2* -88.2*
-2.0 * -100

-2.5 -120
-120.6*
-3 -2.8 * -140
Baseline values 10.1 9.4 214.2 185.4 282.6 248.4
Insulin-naïve Insulin-experienced
*p<0.001
Home et al. Diabetes Res Clin Pract 2011;94:352–63
Insulin Aspart in special population:

1. Maternal
2. Elderly
3. Hepatic impairment
Maternal glycaemic control and hypoglycaemia in type 1
diabetes pregnancy: a randomised trial of insulin aspart vs.
human insulin in 322 pregnant women
Mathiesen et al. Diabetes Care 2007;30:771–6
Insulin aspart provide better postprandial
control compared to human insulin
Visit P2 Visit P4
0.0

-0.1
Plasma glucose

-0.2
(mmol/l)

-0.3

-0.4
p = 0.044 in favour
-0.5 of insulin aspart
-0.6

-0.7

-0.8 p = 0.003 in favour

of insulin aspart
Difference between IAsp and HI in mean prandial glucose increments
Mathiesen ER et al. Diabetes Care 2007;30(4):771-6.
Severe hypoglycaemia in subjects randomised prior to
pregnancy

Insulin aspart
4 Human insulin
(episodes/patient/year)
Rate of hypoglycaemia

3
2.4 2.4
2.2
2
1.2
0.9 0.9
1
0.3 0.2
0
Pre-conception 1st half 2nd half Post-partum
pregnancy pregnancy

All differences NS
Subjects were randomised prior to pregnancy

Heller et al. Diabetes Care 2010;33:473–77

Congenital malformations
Insulin aspart Human insulin
n n
Total (n=15) 6/138* 9/136*
Percentage 4.3% 6.6%

Cardiac-related malformations 5 4

Anencephaly/CNS malformations 1 1

Congenital hydronephrosis 0 1
Congenital tongue anomaly 0 1
Talipes 0 1

Fetal chromosomal abnormality 0 1

*Including liveborn and stillborn infants and terminations of pregnancy due to antenatally diagnosed congenital
malformations
Hod et al. Am J Obstet Gynecol 2008;198:186.e1–7
The rapid-acting properties of insulin
aspart are preserved in elderly people
with type 2 diabetes
Krones et al. Diabetes Obes Metab 2009;11:41–4
PD profiles in the elderly
GIRmax higher and earlier with Insulin aspart (smoothed)
insulin aspart vs. RHI RHI (smoothed)
6
**
GIR (mg/(min*kg)

5 *
***
4

0
0 60 120 180 240 300 360 420 480 540 600
Nominal time (min)
*AUCGIR(0-120 min) greater with insulin aspart vs. RHI (p<0.0001), **AUCGIR(0-300 min) greater with insulin aspart vs. RHI
(p=0.0001), ***AUCGIR(300-600 min) greater with RHI vs. insulin aspart (p=0.0006)
AUC, area under the curve; GIR, glucose infusion rate; INS, insulin; PD, pharmacodynamic; RHI, regular human
insulin
Krones et al. Diabetes Obes Metab 2009;11:41–4
Conclusions
• Compared with RHI, insulin aspart showed greater PD activity in the early
phase
• Improved meal-time coverage with insulin aspart vs. RHI
• Insulin aspart resulted in significantly lower PD activity in the late phase
compared with RHI
• It may reduce the risk of late postprandial and, when injected at dinner
time, nocturnal hypoglycaemia
• Absorption of insulin aspart was faster and greater in the early phase vs. RHI
• The PK/PD properties of insulin aspart are preserved in elderly patients with
T2DM
PK/PD, pharmacokinetic/pharmacodynamic; RHI, regular human insulin; T2DM, type 2 diabetes mellitus
Krones et al. Diabetes Obes Metab 2009;11:41–4
Pharmacokinetics of insulin aspart in
hepatic impairment
Patient demographics

Normal Mild Moderate Severe

n (female/male) 6 (3/3) 6 (1/5) 6 (3/3) 6 (2/4)

Age (years) 39.7 55.7 49.2 53.5

Weight (kg) 72 89 78 78

Child–Pugh score 0.0 5.7 7.3 10.2

Data are mean, unless otherwise indicated

Holmes et al. Br J Clin Pharmacol 2005;60:469–76
Mean insulin aspart plasma concentration vs.
time profiles by degree of hepatic impairment

35
Normal
concentration (mU/L)
Mean insulin aspart

30 Mild
Moderate
25 Severe
20

15
10
5
0
0 200 400 600 800 1000 1200 1400 1600
Time (min)

Holmes et al. Br J Clin Pharmacol 2005;60:469–76

Effect of hepatic impairment on AUC

In(AUC)

Child–Pugh score
No correlation was observed between Child–Pugh score and AUC0–1440

AUC, area under the plasma concentration curve

Holmes et al. Br J Clin Pharmacol 2005;60:469–76
Effect of hepatic impairment on CL/F
3

(L/min)
(L/min)
2
CLF
CL/F

Child–Pugh score

No correlation was observed between Child–Pugh score and CL/F

CL/F, apparent clearance

Holmes et al. Br J Clin Pharmacol 2005;60:469–76
Conclusions

• Hepatic impairment does not affect the PK of insulin aspart in a

clinically significant manner
• Insulin aspart should be dosed according to individual
requirements

PK, pharmacokinetics
Holmes et al. Br J Clin Pharmacol 2005;60:469–76
STEP-Wise™: study design
ExtraSTEP Largest measured
×
+ IAsp+IAsp
3 x3 PPG increment
Randomisation ExtraSTEP
ExtraSTEP
ExtraSTEP + +IAsp
IAsp x2
2× Target postprandial:
4–8 mmol/L
+ +IAsp
IAsp x1
1 ×
×
+SimpleSTE
IAsp 1 Largest perceived
meal
Insulin detemir initiated
Run-in period detemir + OADs
P+IAsp x1
SimpleSTEP
×
+ SimpleSTE
IAsp 2
Target preprandial:
P+IAsp x2
+ IAsp 3 ×
SimpleSTEP
+IAsp x3
4–6 mmol/L

Weeks
–12 0 12 24 36
Period 1 Period 2 Period 3
Inclusion criteria: ExtraSTEP - Largest measured PPG increment
• Age >18 years SimpleSTEP - Largest perceived meal
• T2DM >6 months
• HbA1c 7.5–10.0%
• Basal insulin ≥3 months + 1–3 OADs

IAsp, insulin aspart (insulin aspart); OAD, oral antidiabetic drug; PPG, postprandial plasma glucose; T2DM, type 2
diabetes mellitus
Adapted from Meneghini et al. Endocr Pract 2011;17:727–36
STEPwiseTM: HbA1c and hypoglycaemia in
treatment period 3 (24-36 weeks)
10.010
10
10
9.59.5

(episodes per year)

9
9.0 9 8.9
8

Hypoglycaemia (episodes/yr)
8.5
8.58.5 7
HbA1c (%)

8.7
7.8
6
8.0 8 8.2 7.7
P=.74 5

Hypolgycaemia
7.57.5 7.7
7.5 4
7.0 7 3
6.56.5 2
1
6
0 0
0-12 12-24 24-36 Minor Nocturnal
Weeks ExtraSTEP
SimpleSTEP

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

Insufficiency of oral+basal Insulin-Current Opinions

The individual is not meeting glycemic

targets on basal insulin1-4
and:

FPG with basal

A1C still not at goal
with 0.5 U/kg/day
of daily basal
insulin3
Elevated A1C
insulin is within Further increases in
despite normal FPG
targeted range, but basal insulin result
(<130mg/dL) with
PPG is persistently in hypoglycemia3
basal insulin2,3
above goal3,4

1. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related Disorders. Alexandria, VA: American Diabetes
Association, Inc.; 2004:207-223.
2. American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
3. Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.
4. Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Combination injectable therapy for
type 2 diabetes.

FBG: fasting blood glucose

GLP-1 RA: GLP-1 receptor agonist
Hypo: hypoglycemia

American Diabetes Association. Pharmacologic approaches to glycemic treatment. Sec. 8. In Standards of

Medical Care in Diabetes - 2017. Diabetes Care 2017; 40(Suppl. 1):S64–S74
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 respons

Prandial insulin with Aspart give more benefits in Maternal, eldery and
hepatic problem with Diabetes compare with Human insulin

Always Start with a small doses and adjust the doses once or twice a week

Hypoglycemia is less common in insulin Aspart than Human Insulin