BASAL BOLUS AND

PREMIX INSULIN

R BOWO PRAMONO
Sardjito Hospital/Faculty of Medicine Gadjah
Mada University -YOGYAKARTA
 CV: dr. R Bowo Pramono SpPD K-EMD
• Lahir TEGAL 27-jan 1959
• Istri: dr. Astuti, SpS, 2 putri
• Dokter Umum: FK UGM
• 17-01-1985
• SpPD : FK UGM 24-11-1997
• K-EMD : 14-05-2008
Pekerjaan:
• 1987-2002 PKM Kedung Waringin Bekasi
• 1999-2004 RSU Selong Lombok Timur
• 2004-2009 RS DR Sardjito/FK UGM

2
 Pemilihan terapi yang TEPAT pada DM
(ADA/EASD)
Perubahan gaya hidup dan metformin

If HbA1c ≥7%*

+ BASAL INSULIN + sulfonylurea + TZD**

(Paling efektif) (lebih murah) (hipo minimal)

If HbA1c ≥7%

Intensifkan + basal
insulin*** + TZD** insulin*** + sulfonylurea

Jika HbA1c ≥7%

+ basal atau intensifkan

Intensive insulin + metformin +/− TZD** insulin
*Cek HbA1c setiap 3 bulan sampai HbA1c <7%, dan selanjutnya stelah 6 bulan
**Berhubungan dengan ↑ resiko dari retensi cairan, CHF dan Fraktur. Rosiglitazone, kemungkinan bukan pioglitazone, mungkin berhubungan dengan ↑ resiko
DM T1
***Dipilih berdasarkan efektifitas dan biaya
1. Nathan D et al. Diabetes Care 2006;29(8):1963–1972. 2. Nathan D et al. Diabetes Care 2008;31(1):173–175
 Both fasting and postprandial blood glucose

levels are elevated in T2DM

Uncontrolled diabetes (HbA1c ~8%)
300

200
Plasma glucose (mg/dl)

Postprandial
hyperglycaemia
Fasting
100
hyperglycaemia

Normal
HbA1c ~5%
0
  
06.00 B 12.00 L 18.00 D 24.00 06.00
Time of day (hours)
B=breakfast; L=lunch; D=dinner.
Adapted from Riddle M. Diabetes Care 1990;13:67686.
 Treating fasting hyperglycaemia lowers
the entire 24-hour plasma glucose profile

400

Plasma glucose (mmol/l)

20

300 T2DM
Plasma glucose (mg/dl)

15

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0 0
6 10 14 18 22 2 6
Time of day (hours)

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001).
Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―9.
 HbA1c  HbA1c

HbA1c
135 mg/dl
7.8%

HbA1c
135 mg/dl
7.8%

Time
 Stage1 Stage2 Stage3

Lifestyle+
Lifestyle +
Diagnosis: Metformin +
Metformin +
Lifestyle+ Insulin basal
Insulin intensif
Metformin
Lifestyle+

Well validated Metformin +

core therapies
Sulfonilurea
Lifestyle+
Lifestyle+
Metformin +
Metformin +
Pioglitazon +
Pioglitazon
sulfonilurea

Lifestyle+ Lifestyle+
Less well Metformin + Metformin +
validated core
therapies GLP-1 agonis Basal insulin
Nathan DM et al, Diabetes Care 32:193–203, 2009
Sequential Insulin Strategies in Type 2 Diabetes
(ADA EASD Position Statement 2012)

NovoMix
One insulin One Device
 Terapi insulin yang ideal harus menyerupai sekresi
insulin fisiologis oleh pankreas
Rejimen insulin Basal-Bolus

Breakfast Lunch Dinner Physiological insulin

Ideal basal insulin
45
Ideal prandial insulin
Insulin (mU/L)

30

15

0
06:00 12:00 18:00 24:00 06:00
Time
Di adaptasi dari Kruszynska YT, et al. Diabetologia 1987;30:16–21
 Insulin Profiles – Schematic (duration)

Aspart, Lispro, Gluisyne (4–5 hr)

Regular (6–8 hr)

NPH (12–16 hr)

Ultralente (~16–20 hr )
Plasma Insulin Levels

Levemir (~24 hr)

Glargine (~24 hr)

0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
 Dosis Insulin
• Kebutuhan insulin 0,3 – 0,5 Unit/KgBB/Hari
• Pertama kali diberikan dengan dosis yang kecil,
biasanya dimulai insulin aksi pendek 3X2n/hari
(n=angka ratusan KGD)
• Dinaikkan 2-4 unit setiap sekitar 3 hari bila KGD
target belum tercapai
• Dosis Insulin jangka menengah 75-80% jumlah insulin
jangka pendek perhari, dapat diberikan 2 dosis pagi
dan malam (dosis malam<pagi nocturnal
cicardian)
 Basal insulin limitations

• When we add once-daily basal injection to existing OAD regimen

• Inadequate postprandial glycaemic control1
• Significant postprandial hyperglycemia2
• To overcome the above shortcomings, bolus therapy (rapid acting
insulin injections) added for prandial hyperglycemia
• More number of injections2
• Increased self monitoring2
• Patient motivation, educational-emotional support and good cognitive
function is needed – increased burden on healthcare resources2

1. Barnett A et al. Int J Clin Pract 2008; 62:1647-1653

2. Liebl A. Int J Clin Pract 2009; 63 (Suppl 164):1-5
PPG contributes up to ~70% of
glucose load

100
PPG
30% FPG
Contribution (%)

80 45% 40%
50%
60 70%

40
70%
55% 60%
20 50%
30%
0
< 7.3 7.3–8.4 8.5–9.2 9.3–10.2 > 10.2

HbA1c quintiles

Monnier et al. Diabetes Care 2003;26:881–5

 Insulin Intensification:
Common Strategies

Starting regimens: Intensification regimens:

Basal insulin + Premix

OADs BD or TD

Premix insulin OD Basal–bolus

or BD therapy
International guidelines says about
intensification :

ADA: FPG on target but HbA1c >7

Add 4U rapid-acting insulin at breakfast, lunch or dinner
add rapid-acting
AAFP: FPG on target but HbA1c >7
Add 4U rapid-acting insulin at breakfast, lunch or dinner

AACE: High HbA1c

Support intensification from basal to premix or basal-bolus
Support intensification from premix to basal-bolus

IDF: High HbA1c switch to premix

Support intensification from basal to premix or basal-bolus
Support intensification from premix to basal-bolus

EASD: Refer to IDF guidelines

 AACE

• Transition from a long-acting insulin • Transition from a once-daily premixed

analogue to a premixed insulin insulin analogue to a twice-daily
analogue twice daily (1:1 dose premixed insulin analogue
transfer)

• Split 50:50 between prebreakfast and predinner

• Titrate based on self-monitored blood glucose data and diet history
• Reduce the total dose by 20% if the patient experiences recurrent
hypoglycaemia

AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13 (Suppl 1)

Postprandial hyperglycaemia: Role
in diabetic complications-
• Postprandial hyperglycaemia: An independent risk factor for
macro vascular complications
• Postprandial hyperglycaemia is associated with increased
risk of retinopathy
• Postprandial hyperglycaemia causes oxidative stress,
inflammation and endothelial dysfunction
• Postprandial hyperglycaemia is associated with increased
CIMT
• Postprandial hyperglycaemia is associated with decreased
myocardial blood volume and myocardial blood flow

Guideline for Management of Postmeal Glucose (IDF, 200

Studies linking postprandial hyperglycaemia with risk
of cardiovascular disease and all-cause mortality
The Dual-Release Insulin Concept Of
Insulin Biaspart 30
• Physiological insulin
profile: Profiles are schematic
– Meal-related peak
– Basal component
• Rapid-acting insulin
analogue, together with a
basal insulin analogue,
provides physiological insulin
replacement Physiological insulin profile
Soluble insulin aspart
• Premix analogues, Protamine-crystallised
such as Biaspart 30, insulin aspart
mimic physiological
Biaspart 30
insulin secretion
Pharmacokinetics:
Twice as rapid onset & as high peak

Biaspart 30
25 *** Premix human Insulin30
Serum insulin (mU/l)

20 ***p < 0.0001

15

10

0
8:00 11:0 14:0 17:0 20:0 23:0 2:00 5:00 8:00
0 0 0 0 0
Time of day
Jacobsen et al. Eur J Clin Pharm 2000;56:399-403
 Efficacy of Biphasic Insulin Aspart 30
in Patients with T2DM Not Achieving
Glycemic Targets on OADs with/without
Basal Insulin Therapy

The 1-2-3 Study

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

 1-2-3 Study: Investigation
Of Once-, Twice-, Thrice-Daily Biaspart30
Phase 1
End
Pre-dinner x 16 weeks HbA1c ≤6.5%
OD of
Start with 12 U at dinner
Study
If HbA1c >6.5%, go to BID,
d/c secretagogues
Phase 2
Pre-breakfast & dinner x 16 weeks End
Add 3 U at breakfast and titrate HbA1c ≤6.5% of
BID
Study
If HbA1C >6.5%, go to TID
Phase 3
TID x 16 weeks
TID Add 3 U at lunch and titrate
Titrate according to schedule every 3 days
n=100 type 2 DM 12 months with 7.5  HbA1c 10%, 2 OADs or
1 OAD plus basal insulin OD (max 60 U)

Garber et al. Diabetes, Obesity & Metabolism 2006; 8:58–66.

 Results: Cumulative Percentage of Patients
Achieving A1C Goals

A1C ≤ 6.5 A1C < 7%

(AACE, IDF goal) (ADA goal)

QD 21% 41%

BID 52% 70%

TID 60% 77%

Total 60/100 77/100

Baseline A1C was 8.6%

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

 INITIATE: Significantly more patients met
HbA1c targets with NovoMix® 30 as compared to Glargine

NovoMix® 30 (n = 100)
p = 0.0002
Glargine (n = 109)
70 66%
Patients reaching target

60 p = 0.0356
at Week 28 (%)

50
42%
40%
40
30 28%

20
10
0
HbA1c < 7.0% HbA1c ≤ 6.5%
(ADA goal) (ACE and IDF goal)
HbA1c target

Raskin P et al. Diabetes Care 2005; 28:260-5

INITIATE: Greater reduction in HbA1c with NovoMix® 30/met than
Glarg/glim

BIAspart30/met Glarg/glim
0
HbA1c HbA1c

-0.5 9.2% 8.9%

D H bA1c (% )

7.8%
-1
-0.5%
7.5%
-1.5 p=0.0002

-2 Reduction from
baseline to
end-of-trial
EUROMIX study: Kann P et al. Endocrine Abstracts 2005;10:OC8
NovoMix 30 Twice-A-Day vs Basal-Bolus

Liebl A et al. for the PREFER Diabetes, Obes & Metab 2009; 11(1): 45–52
 PREFER study: Significant reduction in HbA1c with
NovoMix 30 after 26 weeks
NovoMix 30 dose titration was done using 2-0-2 algorithm

NovoMix® 30 Levemir®/NovoRapid®
0
Reduction in HbA1c (%)

8.40% 8.52%
-0.5

-1.0 7.17%
6.96%
-1.5
-0.234%
p=0.0052
-2.0
Baseline-corrected
treatment difference

Liebl et al. Diabetes Obes Metab 2009; 11: 45-52

Dosage Guideline for intensifying with
NovoMix®30

recommendation dose adjustment

Why premixed insulin?
Premixed insulin
•40% of human insulin
used world over

Advantages of premixed
•Increased dosage accuracy
•Increased efficacy
•Enhanced convenience

Increased compliance &

better long-term outcomes1
 DiabCare Asia -2008
COUNTRY RESULTS ON OUTCOME DATA AND ANALYSES
Indonesia

Total number of centers: 18 (incl. Yogyakarta)

Total number of subjects participated: 1829

First patient first visit (FPFV): 17 November

2008

Study completed: February 2009

 Types of Insulin Used

30 27.13
Number of Patients (%)

25
21.34
20

15
8.92
10
6.39 6.39
5.19
5

0
Human Analogue Meal time Premix Basal Basal
insulin bolus

n=497 n=164 n=117 n=391 n=117 n=95

INSULIN ANALOG:
1. NovoRapid
2. NovoMix
3. Levemir
 Summary

• Although basal bolus therapy is considered the optimal

treatment regimen for intensification, premix still has a
place since it is seen as the simplest (shown by extensive
market research). So both the regimens play an
important role in intensification

• In addition:
– The 1-2-3 study highlights the benefits of starting
and intensifying with BIAspart30. In this study
77% patients reached HBA1C goal of <7% with
once, twice or thrice daily BIAspart30

• So there is a wealth of evidence to support the important

role that BIAspart30 plays in intensification treatment
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