RTD NovoMix 2017

ESW/MAR-17/RTD NMX-2017/003
INTENSIFICATION
WITH PREMIX
INSULIN
Nama: dr Putu Arya Nugraha
SpPD
Pendidikan:
1. S1 Kedokteran Universitas Udayana
2. Ahli Penyakit Dalam Universitas Udayana
3. Kursus : Kemoterapi (Jakarta), TB Paru
(Jakarta), Diabetes (Jakarta), Hemodialisis
(Denpasar), Hospital Bylaws (Semarang)
4. Konferensi : IDF (Melbourne) 2013, APDW
(Kobe) 2016
Pekerjaan:
1. Staf SMF Penyakit Dalam RSUD Buleleng
2. Koordinator Pendidikan dan Pengajar di
Jejaring Pendidikan FK Universitas Udayana
3. Dosen AKBID Depkes Prop Bali
4. Ketua TKMKB BPJS Singaraja
5. Konsultan Prodia Singaraja
6. Wakil Ketua IDI Cabang Buleleng
7. Ketua Komite Medik RSUD Buleleng
8. Kepala Instalasi Unit Hemodiaisis RSUD
Buleleng
Outlines
Rationale to intensify and guideline

Patient characteristic
BIAsp30 profile
Intensification with biphasic insulin aspart 30 glycaemic control,
hypoglycaemia
Intensification and optimisation guidance with BIAsp30
Switching from basal bolus to premix
Summary
Why do we need to intensify treatment?
100 Lifestyle Mono- Dual Insulin oral

Beta-cell function (%) therapy therapy drugs for
lowering
blood glucose
HbA1c (%)
9
7
HbA1c
Beta-cell function
0 6
0 >15
Time (years)
Adapted from Heine et al. BMJ 2006;333:12004

Jml injeksi
PERKENI Consensus on Insulin Management Kompleksitas
Insulin basal
1 Biasanya dengan metformin +/- non-insulin lainnya Rendah
Awal: 10 U/hari atau 0,1-0,2 U/kgBB/hari

Penyesuaian: 10-15% atau 2-4 U, 1-2 kali/minggu sampai tercapai sasaran GD puasa
Hipoglikemia: tentukan dan atasi penyebab, turunkan dosis 4 U atau 10-20%
Jika setelah GD puasa

tercapai tidak terkendali
(atau jika dosis >0,5
U/kgBB/hari), atasi
ekskursi GD pp dengan
insulin waktu makan
(pertimbangkan untuk
memberikan GLP-1-RA)
Tambahkan 1 injeksi insulin Ganti dengan insulin

cepat sebelum makan terbesar premixed 2x/hari
Awal: 4 U, 0,1 U/kgBB, atau 10%
Awal: bagi dosis basal menjadi 2/3
2 dosis basal. Jika A1C<8%
siang, 1/3 malam atau siang, Sedang
pertimbangkan untuk menurunkan
malam
basal dalam jumlah yang sama
Penyesuaian: naikkan dosis 1-2 U
atau 10-15%, 1-2 kali/minggu
sampai sasaran SMBG tercapai
Hipoglikemia: tentukan dan atasi
Penyebab, turunkan dosis 2-4 U
penyebab, turunkan dosis 2-4 U
atau 10-20%
atau 10-20%
Jika tidak Tambahkan 2 Jika tidak

terkendali, terkendali,
injeksi insulin
pertimbangkan pertimbangkan
basal bolus rapid sebelum
makan (basal basal bolus
bolus)
3+
3+ Tinggi
Awal: 4 U, 0,1 U/kgBB, atau 10%

dosis basal. Jika A1C<8%
pertimbangkan untuk menurunkan
dosis basal dengan jumlah yang
sama
penyebab, turunkan dosis 2-4 U
atau 10-20%
Fleksibilitas
Lebih fleksibel Kurang fleksibel
Outlines

BIAsp30 profile
hypoglycaemia
Summary
Recommendations: Considerations for Future

Intensification
Factors that will determine whether future intensification should be with basalbolus or premix
insulin analog therapy
Favours premix Considerations Favours basal-bolus
Patient preference regarding Comfortable with more frequent

Prefers fewer injections
number of injections injections
Patient preference regarding self- Comfortable with more frequent

Prefers less frequent monitoring
monitoring of blood glucose monitoring
Patient ability to inject (e.g.

Poor cognitive ability, manual dexterity, Good
need for carer)
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

Outlines

BIAsp30 profile
hypoglycaemia
Summary
BIAsp 30: The molecule
Insulin aspart differs from human

insulin by the single amino-acid
substitution of a proline by an
aspartic acid residue at B28
The B28 position is implicated in the

formation of dimers but not implicated
in pharmacological activity
Insulin aspart is monomeric at

pharmacological concentrations,
allowing rapid absorption into the
bloodstream
Brange et al. Nature 1988;333:67982

Pharmacological profile
Compared with biphasic human insulin, BIAsp 30 has:
More rapid
Similar
and
duration of
Faster Higher peak pronounced
action of
absorption concentration glucose-
basal
lowering
component
effect
BIAsp, biphasic insulin aspart
Jacobsen et al. Eur J Clin Pharmacol 2000;56:399403

Outlines

BIAsp30 profile
Intensification with biphasic insulin aspart 30 glycaemic
control, hypoglycaemia
Summary
1-2-3 study
Objectives
Traditional therapy for patients with type 2 diabetes has focussed on
controlling FPG levels with one or more OADs and/or basal insulin
The IDF has recommended the use of premixed insulin formulations as a
treatment option to initiate insulin in people with type 2 diabetes
This study in patients with type 2 diabetes failing on OADs ( basal
insulin) was conducted to assess whether addition and self-titration of
NovoMix 30 could enable patients to achieve glycaemic targets
Garber et al. Diabetes Obes Metab 2006;8:5866

Design and Methods

Phase 1
End
Pre-dinner x 16 week HbA1c 6.5%
OD of
Start with 12 U at dinner
Study
If HbA1c> 6.5%, go to BID,

stop secretagogues
Phase 2
Pre-breakfast & dinner x 16 week End
BID HbA1c 6.5% of
Add 3 U at breakfast and titrate
Study
If HbA1C> 6.5%, go to TID

Phase 3
TID x 16 week
TID Add 3 U at lunch and titrate
Titrate according to schedule every 3 days

N=100 patients with type 2 diabetes 12 months with HbA1c 7.5 10%, 2
OADs or 1 OAD plus basal insulin OD (max 60 U)
Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Results: Subject characteristics

Number enrolled 100
Mean age (years SD) 56.7 11.5 Of the 100 patients
Gender (%): M/F 50/50 enrolled, 74 patients
Ethnicity (%): B/C/H/O 12/73/13/2 completed
Mean weight (kg SD) 98.5 21.4
Reasons for withdrawal
Mean BMI (kg/m2 SD) 34.2 6.7 were: ineffective therapy
Prior OAD use (%): (1), adverse events (5),
OAD only 72
non-compliance (7), other
OAD + NPH 10
(13)
OAD + glargine 18
Mean diabetes duration
(years SD) 11.1 7.1
Mean HbA1c (% SD) 8.6 0.8
B, Black; C, Caucasian; H, Hispanic; O, Other

Cumulative proportion of patients

achieving targets
HbA1c 6.5 HbA1c < 7%
(AACE, IDF goal) (ADA goal)
OD 21% 41%
BID 52% 70%
TID 60% 77%
Baseline HbA1c was 8.6%

Mean HbA1c value for all subjects

Baseline vs end of treatment
10
8.6%
8
6.6%
HbA1c (%)
0
Baseline end of treatment

Reduced FPG with NovoMix 30

12
* p < 0.001
9.7
10
FPG (mmol/L)
8 6.9
6
0
Baseline OD, BID, TID

Improved 8-point blood glucose profile

with NovoMix 30 BID
Blood glucose (mmol/L) Baseline
14 Twice-daily dosing
12
10
8
6
4
p < 0.001
2
0
Before After Before After Before After Bedtime 3 AM
Breakfast Lunch Dinner
Time of monitoring

Improved 8-point blood glucose profile

with NovoMix 30 TID
Blood glucose (mmol/L) Baseline
14 Three times-daily
12 dosing
10
8
6
4
p < 0.001
2
0
Before After Before After Before After Bedtime 3 AM
Time of monitoring

Similar low hypoglycaemia rate

between phases
Phase 1 Phase 3
Phase 2 BID
OD TID
Number of patients with major

3 3 1
hypoglycaemic events
Rate of minor hypoglycaemic

15 22 12
episodes
Major nocturnal hypoglycaemia

0 0 0
episodes
Stepwise regression showed that there was no correlation of

hypoglycaemia with number of injections
Improved lipid profile and blood pressure

Mean change from baseline (%)
15
10
9.0
4.9 4.9 p < 0.001
5 p = 0.003
0.7
0
p < 0.02
-5 -3.1 -3.0 Parameter (baseline value)
-4.8
-10 HDL (45 mg/dL)
LDL (97 mg/dL)
-15 Triglycerides (258 mg/dL)
-20 Total cholesterol (188 mg/dL)
-19.9
-25 Systolic BP (133 mmHg)
Diastolic BP (79 mmHg)
Weight (99 kg)
BMI (34 kg/m2)

Average insulin dose of NovoMix 30

by phase of study
OD 0.60
BID 0.51 0.64
TID 0.58 0.25 0.70
Mean dose (U/kg) for subjects reaching HbA1c < 6.5%

Summary of 1-2-3 study

On NovoMix 30 OD, 41% of patients achieved HbA1c <7.0%
On OD/BID/TID, 77% of patients achieved HbA1c <7.0% and 60%
achieved 6.5%
On OD/BID/TID, FPG levels were reduced from 173 mg/dL (9.7
mmol/L) at baseline to 125 mg/dL (6.9 mmol/L)
The addition of a second or third injection of NovoMix 30 provides
additional benefit, in terms of FPG, PPG and HbA1c reductions, with no
increased risk of hypoglycaemia
Lipid profile and blood pressure significantly improved, potentially
reducing cardiovascular risk
Garber et al. Diabetes Obes Metab 2006;8:5866

Intensifying insulin regimen after basal insulin

optimization in adults with type 2 diabetes: a 24-week,
randomized, open-label trial comparing insulin
glargine plus insulin glulisine with biphasic insulin
aspart (LanScape)
J. Vora, N. Cohen, M. Evans, A. Hockey, J. Speight, C. Whately-Smith
Diabetes Obes Metab. 2015 Jun 18. doi: 10.1111/dom.12528.

Background
Type 2 diabetes patients who are uncontrolled on OADs may need to be

initiated on Insulin- and may require further intensification for optimal
glycaemic control
Adding one or more prandial injections the basal plus regimen, the basal
bolus regimen or the twice daily premixed insulin regimen are the common
intensification strategies adopted
In patients failing on basal insulin there is a lack of RCT evidence comparing a
Basal Plus and Premix regimens for intensification- This study looks at
addressing this gap
RCT, Randomized clinical trial; OADs, Oral antidiabetic drugs

Study overview
IGlar + IGlu OD at main meal (n=170)
UK and Australian 24-week,
randomised, open-label,
active-controlled, parallel-group study;
BIAsp 30 BID (n=165)
non-inferiority trial
Treatment
Weeks 0 8 or 12 12 24
Run-in period: Randomisation 1:1
IGlar titrated to for patients with
FPG <7.0 mmol/L. FPG <7.0 mmol/L but
All OADs except met HbA1c >7.0%
discontinued
Inclusion criteria Insulin titration

During run in basal insulin was titrated to achieve FPG < 7.0 mmol/l
Patients with type 2 diabetes, treated >3 months with After randomisation insulin doses were adjusted every week up-to
basal insulin week 14 and then every 2 weeks till study end
HbA1c 7.511.0%
BID, twice daily; BIAsp, biphasic insulin aspart; FPG, fasting plasma glucose; IGlar, insulin glargine; IGlu, insulin glulisine; met, metformin;
OAD, oral antidiabetic drug; OD, once daily
Baseline characteristics
Characteristic IGlar + IGlu BIAsp 30
N 170 164
Age, years 61.6 (8.0) 61.6 (8.9)
Weight, kg 91.5 (15.7) 90.8 (15.4)
Body mass index, kg/m2 31.2 (4.1) 31.0 (4.3)
Duration of diabetes, years 12.9 (6.2) 13.0 (6.6)
Mean fasting glucose, mmol/l 6.1 (1.6) 6.0 (1.6)
8.6 (0.9)
Mean HbA1c, % 8.6 (0.9)
DTSQ total treatment

satisfaction 31.3 (5.7) 31.4 (5.1)
(scale 036)
Intention-to-treat population, Data are Means ( Standard deviation), N, number of patients; DTSQ, Diabetes treatment satisfaction questionare
Comparable HbA1c reductions with both groups

Primary endpoint: HbA1c change
Baseline 8.6 8.6
0.0
Change from baseline in HbA1c (%)

-0.2
-0.4
-0.6
-0.8
-1.0
-1
-1.2
Mean (SE) difference: -1.22
0.21 (0.09), NS
-1.4
IGlar + IGlu BIAsp 30
NS, not significant; SE, standard error of the mean; IGlar, insulin glargine; IGlu, insulin glulisine

Proportion of patients with HbA1c <7%

Patients achieving target HbA1c <7.0%
30 27.9
Patients who achieved target

p = 0.12
25
20.6
20
HbA1c (%) 15
10
Similar proportion of patients achieved HbA1c target < 7% with Basal Plus and Premix regimens
IGlar, insulin glargine; IGlu, insulin glulisine

Lower nocturnal hypoglycaemia with BIAsp 30

Hypoglycaemia
20 NS Basal-plus
18.2
Incidence (episodes/year)
18 BIAsp 30
16 15.3
14
12 Significantly lower with
10 BIAsp: p=0.019
8
5.7
6
3.6
4
2
0
Overall hypoglycaemia Nocturnal hypoglycaemia
No difference in overall hypoglycaemia between treatment groups

Low rates of severe hypoglycaemia with both groups
NS, not significant; SE, standard error of the mean; IGlar, insulin glargine; IGlu, insulin glulisine
No significant difference in weight gain between

treatment groups
Weight change
3.0
Adjusted mean change between

p=0.20 2.5
2.5
baseline and EOT (kg)

2.06
2.0
1.5
1.0
0.5
0.0
EOT, end of treatment; IGlar, insulin glargine; IGlu, insulin glulisine

Change in insulin dose
Change in insulin dose from randomization

40
35.6
35
Mean change, U
30
25.5
25
20
*
15
10
IGlar, insulin glargine; IGlu, insulin glulisine

Patient reported outcomes

Factors IGlar + IGlu BIAsp 30 Difference p value
DTSQc total treatment satisfaction

11.10 7.94 3.16
LS mean score <0.001
(0.63; 9.85, 12.35) (0.66; 6.64, 9.23) (0.84; 1.51, 4.82)
Change in ADDQoL present quality of life
0.09 0.12 0.22
LS mean score 0.017
(0.07; 0.04, 0.23) (0.07; 0.26,0.02) (0.09;0.04,0.39)
Change in ITSQ total insulin treatment satisfaction
10.64
6.62 4.02
LS mean score (1.51; 13.61, 0.036
(1.51; 9.60, 3.64) (1.91; 0.26, 7.78)
7.68)
Change in EQ-5D visual analogue scale
1.82 0.28 1.54
LS mean score 0.355
(1.27; 0.67, 4.32) (1.29; 2.26, 2.83) (1.66; 1.73, 4.81)
Adjusted means and the associated CI were from mixed-effect models with treatment, pooled centre, randomization criteria, baseline score
and the interaction between treatment and baseline as fixed effects. Note that for the analysis of DTSQc, the baseline score was DTSQs.
Changes are calculated as week 24 value minus baseline value, so negative changes reflect a decrease. Differences between treatments are
calculated as basal plus minus biphasic.

Summary of LanScape study
Equivalent and substantial improvements in glycaemia control with both the

Premix and the Basal Plus regimens
Even tough there were more nocturnal hypoglycemia episodes with the basal
plus strategy Patient reported outcome scores favored the basal plus
strategy in this study
Based on the patients profile , physicians need to choose between a basal
plus or premix twice daily regimen for patients as intensification options in
patients uncontrolled on basal insulin

PREFER: study design (BIAsp 30 vs. all-analogue

basalbolus therapy)
BIAsp, biphasic insulin aspart; BID, twice daily; IAsp, insulin aspart; IDet, insulin detemir;
OADs, oral antidiabetic drugs; OD, once daily; TID, three-times daily
Liebl et al. Diabetes Obes Metab 2009;11:4552
PREFER: HbA1c reduction
BIAsp, biphasic insulin aspart; IAsp, insulin aspart; IDet, insulin detemir
PREFER: hypoglycaemia rate in patients previously

treated with insulin
Hypoglycaemia BIAsp 30 IDet/IAsp
Major (%) 0 1
Minor (%) 27 39
Nocturnal minor (%) 5.8 10.3
Incidence of minor
0.049 0.038
(events per subject per week)
Incidence of nocturnal minor

0.011 0.018
(events per subject per week)
Between-treatment differences were not significant

Confidential
Confirmed by plasma glucose <3.1 mmol/L; Calculated for the final 20 weeks of the study
PREFER: change in body weight in patients

previously treated with basal insulin
Liebl et al. Diabetes Obes Metab 2009;11:4552; Liebl et al. Diabetes 2010;59(Suppl. 1):A4552
Summary of PREFER study
Both insulin analogue regimens enabled patients with type 2 diabetes to

reach an HbA1c target of 7.0%
Rates of hypoglycaemia were low and comparable between insulin analogue

regimens
Patients not reaching target on NPH insulin or insulin glargine (+OADs)

benefited more from intensification to basalbolus IDet/IAsp than to
BIAsp 30 BID
BIAsp, biphasic insulin aspart; BID, twice daily; IAsp, insulin aspart; IDet, insulin detemir; NPH, neutral protamine
Hagedorn; OAD, oral antidiabetic drug
Outlines

BIAsp30 profile
hypoglycaemia
Summary
Practical guidance on intensification of BIAsp 30: a

consensus statement
BIAsp, biphasic insulin aspart; BID, twice daily; FPG, fasting plasma glucose; OD, once daily
Unnikrishnan et al. Int J Clin Pract 2009;63:15717
Switching from basal insulin OD or BID to

BIAsp 30 BID
1:1 total dose transfer to BIAsp 30

Split the dose 50:50 pre-breakfast and
pre-dinner
Titrate the dose preferably once a week

Discontinue sulphonylureas
Continue metformin
Consider discontinuing TZDs as per local guidelines and
practice
Administer BIAsp 30 just before meals
BIAsp, biphasic insulin aspart; BID, twice daily; OD, once daily; TZDs, thiazolidinediones
Practical guidance on intensification of BIAsp 30: a

consensus statement
BIAsp, biphasic insulin aspart; BID, twice daily; FPG, fasting plasma glucose; OD, once daily
Intensifying from BIAsp OD to BID or from BID to

TID
BIAsp, biphasic insulin aspart; BID, twice daily; OD, once daily; TID, three-times daily;
TZDs, thiazolidinediones
Outlines

BIAsp30 profile
hypoglycaemia
Summary

Sub-analysis of the A1chieve study
A1chieve was an international, open-label, prospective, non-interventional,
24-week study in people with type 2 diabetes starting/switching to biphasic
insulin aspart 30, insulin detemir or insulin aspart.
The objective of this sub-analysis of the A1chieve study was to evaluate the
safety (primary endpoint) and effectiveness (secondary endpoints) of biphasic
insulin aspart 30 in patients switching from basal-bolus insulin regimens that
included insulin glargine or NPH insulin.
A total of 1024 people with type 2 diabetes were switched from basal-bolus
insulin therapy to receive biphasic insulin aspart 30 on entering the study;
240 and 784 participants received insulin glargine-based (BB-GLA group) and
NPH insulin-based basal-bolus insulin regimens (BB-NPH group) before the
switch, respectively
Dieuzeide G. Safety and effectiveness of biphasic insulin aspart 30 in people with type 2 diabetes switching from basal-bolus insulin regimens in the
A1chieve study. Primary Care Diabetes 2014; 8: 111117
Glycaemic Control
Glycaemic Control and QoL
Measurement Insulin glargine based basal bolus NPH based basal bolus regimen
regimen
baseline 24 weeks P value baseline 24 weeks P value
HbA1c (%) 10.2 7.7 p < 0.001 9.5 7.6 p < 0.001
FPG before breakfast (mmol/l) 11.7 7.5 p < 0.001 10.1 7.2 p < 0.001
FPG after breakfast (mmol/l) 14.4 9.2 - 13.6 9.1 p < 0.001
FPG after lunch (mmol/l) 12.8 8.7 - 11.8 8.8 p < 0.001
FPG after dinner (mmol/l) 11.6 8.3 - 12.1 8.5 p < 0.001
HRQoL (VAS) 70.6 76.5 p < 0.001 64.7 76.4 p < 0.001
Hypoglycaemia and Body Weight
Measurement Insulin glargine based basal bolus regimen NPH based basal bolus regimen
baseline 24 weeks P value baseline 24 weeks P value
Overall hypoglycaemia (% patients with at 17.1 8.1 p < 0.01 23.2 11.1 p < 0.001
least one event)
Major hypoglycaemia (% patients with at 1.7 0 p < 0.05 4.6 0.2 p < 0.001
least one event)
Nocturnal hypoglycaemia (% patients with 5.4 0 p < 0.01 13.1 3.9 p < 0.001
at least one event)
body weight, kg (% patients with at least 70.3 71.4 p < 0.001 77.3 77.0 p < 0.05
one event)
Summary of sub-analysis A1chieve
Intensification of insulin regimens also need to take into consideration the

complexity of the regimens and the likelihood that patients will be able to
adhere to the therapy
In people with inadequately controlled hyperglycaemia, biphasic insulin aspart

30 can be used effectively and safely as an insulin intensification regimen
requiring fewer daily injections than a basal-bolus regimen
Patient QoL may be improved through the improvement in glycaemic control,

reduction of hypoglycaemia, elimination of unrealistically complex insulin
injection regimens, and reduced insulin injection frequency
Titration Algorithm for Switching from BasalBolus to

Premix Insulin Analog*
General guidance: as always, titration must be tailored to the

individual patient
Switch:
These guidelines do not override clinical judgment and
knowledge
Patient is unwilling or unable
Reduce total daily dose of all insulin by 2030% to use basal-bolus therapy
Then split this value 50/50 to give you the starting dose of HbA1c above target
premix insulin analog at breakfast and evening meal consistently on a basal-bolus
Unusual meal patterns may lead you to reconsider the initial regimen
dose ratio
Patients discharged from
Titrate the dose preferably once or twice a week hospital on a basal bolus
regimen if appropriate
Adjust the evening meal dose first, followed by the breakfast
dose
Safety is key: go slowly
* Based on consensus
Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0
Outlines

BIAsp30 profile
hypoglycaemia
Summary
Summary
Diabetes is a progressive disease which may need insulin

intensification therapy
NovoMix30 can be given OD, BID, TID
Premix insulin analogues are suitable for initiation, intensification,
and can effectively manage HbA1c, with low risk of hypoglycaemia
Patients with poorly controlled type 2 diabetes who have trouble
adhering to their basal-bolus insulin regimen might benefit from
switching to biphasic insulin aspart 30 therapy
Terima Kasih

RTD NovoMix 2017

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

RTD NovoMix 2017

Uploaded by

Copyright:

Available Formats

ESW/MAR-17/RTD NMX-2017/003

Rationale to intensify and guideline

Why do we need to intensify treatment?

100 Lifestyle Mono- Dual Insulin oral

Adapted from Heine et al. BMJ 2006;333:12004

Awal: 10 U/hari atau 0,1-0,2 U/kgBB/hari

Jika setelah GD puasa

Tambahkan 1 injeksi insulin Ganti dengan insulin

Jika tidak Tambahkan 2 Jika tidak

Awal: 4 U, 0,1 U/kgBB, atau 10%

Rationale to intensify and guideline

Recommendations: Considerations for Future

Favours premix Considerations Favours basal-bolus

Patient preference regarding Comfortable with more frequent

Patient preference regarding self- Comfortable with more frequent

Patient ability to inject (e.g.

Ted Wu et al. Diabetes Ther. 2015 Jun 24.DOI 10.1007/s13300-015-0116-0

Rationale to intensify and guideline

BIAsp 30: The molecule

Insulin aspart differs from human

The B28 position is implicated in the

Insulin aspart is monomeric at

Brange et al. Nature 1988;333:67982

Compared with biphasic human insulin, BIAsp 30 has:

BIAsp, biphasic insulin aspart

Jacobsen et al. Eur J Clin Pharmacol 2000;56:399403

Rationale to intensify and guideline

Garber et al. Diabetes Obes Metab 2006;8:5866

Design and Methods

If HbA1c> 6.5%, go to BID,

If HbA1C> 6.5%, go to TID

Titrate according to schedule every 3 days

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Results: Subject characteristics

B, Black; C, Caucasian; H, Hispanic; O, Other

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Cumulative proportion of patients

BID 52% 70%

TID 60% 77%

Baseline HbA1c was 8.6%

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Mean HbA1c value for all subjects

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Reduced FPG with NovoMix 30

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Improved 8-point blood glucose profile

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Improved 8-point blood glucose profile

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Similar low hypoglycaemia rate

Number of patients with major

Rate of minor hypoglycaemic

Major nocturnal hypoglycaemia

Stepwise regression showed that there was no correlation of

Improved lipid profile and blood pressure

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Average insulin dose of NovoMix 30

BID 0.51 0.64

TID 0.58 0.25 0.70

Mean dose (U/kg) for subjects reaching HbA1c < 6.5%

Adapted from Garber et al. Diabetes Obes Metab 2006;8:5866

Summary of 1-2-3 study

Garber et al. Diabetes Obes Metab 2006;8:5866

Intensifying insulin regimen after basal insulin