Analogue Insulin, The new tools

to challenges Diabetes

Pugud Samodro
Endocrine Metabolic Division
Internal Medicine Department
Faculty of Medicine and Health Sciences Soedirman
University
Prof Margono Soekarjo general Hospital
Purwokerto - 2010
 Presentation Point of View

1. Rationality of Insulin Therapy for Type 2 DM

2. What is Analogue Insulin?
3. How & strategy of Insulin treatment ?
4. Barrier of using insulin
5. Take Home Message
 RISKESDAS
RISKESDAS 2008
2008

Indonesian Basic Health Diagnosed patients

Research (RISKESDAS)

Total DM = 5,7%
Diagnosed DM = 1,5%
Undiagnosed DM = 4,2%
IGT = 10,2 %
Undiagnosed patients

DM patients estimated
(WHO)
8 million >21
million

2000 22030
Natural History of Type 2
Diabetes
Insulin
 Natural History of Type 2 DM

Normal islet cell

Deposition of amyloid
in T2DM
 Glucose Homeostasis and
Pathophysiology of Hyperglycemia
 The Physiological Requirement for Insulin

Basal

Pancreatic output :
basal  prandial

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis
• Prandial insulin : the amaount of insulin necessary to cover meals without
development of posprandial hyperglycemia
 Insulin Deficiency

Basal insulin Prandial insulin

Basal Prandial
hyperglycemia hyperglycemia
Insulin and Glucose Patterns in Type 2
Diabetes : Basal vs Mealtime

■ Basal hyperglycemia ■ Mealtime hyperglycemia

 
(Moderate) Type
2 diabetes

                                                                                                                   

                                                                
Treatment Based on Pathophysiology
of Hyperglycemia
 Treatment Based on the Pathophysiology of
Hyperglycemia in Type 2 Diabetes

Deficiency Deficiency
basal insulin prandial insulin

Fasting Hyperglycemia
Prandial Hyperglycemia
(Postabsorbtive/Basal) (Meal-related)

Insulin basal/NPH/Long-acting Insulin prandial Short-/Rapid-acting

analog Insulin
Long-acting SU, Metformin Short-acting SU, Glinide, Glitazones,
Glitazone
Acarbose
Policy for the Selection of Glucose Lowering Therapy

Glucometabolic Situation Policy

Postprandial hyperglycemia -glucosidase inhibitors, Short-acting
SU, Glinides, Short-/rapid-acting
insulin

Fasting hyperglycemia Biguanides, long-acting SU,

glitazones, long-acting insulin

Insulin resistant Biguanides, glitazones,

-glucosidase inhibitors

Insulin deficiency SU, glinides, insulin

Reyden L. Eur Heart J 2007; 28: 88-136

 Potential Downsides of
Pharmacological Treatment Modalities in Type 2
diabetes
Potential Problems Avoid or reconsider
Weight gain SU, glinides, glitazones, insulin

GI symtoms Biguanides, -glucosidase inhibitors

Hypoglycemia SU, glinides, insulin

Impaired kidney function Biguanides, SU

Imapired liver function Glinides, glitazones, biguanides, -glucosidase

inhibitors

Impaired cardio- Biguanides, glitazones

pulmonary function

Reyden L. Eur Heart J 2007; 28: 88-136

When to start combination ?

Any single oral therapy is unlikely to lower

A1c > 1.5%, it is logical to consider initial
combination therapy for patients presenting with an
A1c > 8.5%

Dailey GE. Diabetes Care 2005; 28:220-221

Nathan DM et al. Diabetes Care 2006; 29:1963-1972
 OAD :
Kegagalan sekunder sesudah beberapa tahun

8.0
ADOPT
ADOPT study
study
7.6

7.2
HbA 1c (%)

6.8

6.4

6.0
0 Rosiglitazone
Metformin
Glybenclamide

0 1 2 3 4 5
Time (Years)

ADOPT: Kahn SE et al. N Engl J Med 2006;355:2427-43.

 Early Addition of Insulin
Can Optimize Glycemic Control

50 p=0.011 Early addition of insulin

Proportion of Patients with HbA1c

when OAD is inadequate

can improve glycemic control
<7% at 6 Years (%)

without weight gain

25 or hypoglycemia

0
n=242 n=245 n=339
SU = sulfonylurea
al

ne

n
on

uli
A lo
nti

I ns
uli n
n ve

±
SU
I ns
Co

UKPDS 57: Adapted from Wright A et al. Diabetes Care 2002;25:330-6.

 Presentation Point of View

1. Rationality of Insulin Therapy for Type 2 DM

2. What is Analogue Insulin?
3. How & Strategy of Insulin Treatment
4. Barrier of using insulin
5. Take Home Message
 Sejarah Perkembangan
insulin

 1921 : penemuan insulin

 s/d 1983 : era insulin hewan
Menggunakan ekstrak pankreas hewan (sapi / babi)
 1983 : era Human insulin
Menggunakan rDNA manusia untuk menghasilkan insulin
 1999 : era insulin modern (analog) dimulai
Menggunakan teknologi bioengineering untuk memodifikasi
rantai DNA human insulin untuk membuat insulin baru yang
lebih baik dalam hal farmakologi
Saccharomyces cerevisiae
HUMAN INSULIN NOVO NORDISK
ANALOG INSULIN

ACTRAPID – SHORT ACTING

Actrapid/Mixtard/
Insulatard
Novolet
akan habis stoknya
(discontinue)
MIXTARD per bulan juni 2010
- PREMIX

INSULATARD – NPH - INTERMEDIATE

 Kelemahan Human Insulin
(Actrapid/Mixtard)
Period of unwanted
hyperglycemia
Normal insulin secretion
at mealtime
Change in serum insulin

Human insulin

Period of unwanted
hypoglycemia

Human Insulin HARUS

Baseline
disuntikkan 30 menit
sebelum level
makan

Time (h)
SC injection
 Kelemahan Human Insulin Insulatard (NPH)
Memiliki puncak  risiko nokturnal hipo sangat tinggi

Absorbsi insulin bervariasi, bahkan

di pasien yang sama kendali gula darah
tidak terprediksi

tidak bekerja 24 jam

ANALOG INSULIN NOVO NORDISK
ANALOG INSULIN

NOVORAPID - RAPID ACTING

NOVOMIX - PREMIX

LEVEMIR -LONG ACTING ANALOG

NovoRapid
Levemir (Insulin
Structural(Insulin
DesignDetemir)
Aspart)
Human Insulin

C1 Asp
4
cha fatt
ya
(My in cid
ris Phe Gly Arg
tic Phe
ac Glu
id) Tyr
Thr Gly
Pro
Pro Cys
Lys
Thr Val
B29 A21 Asn Cys
Tyr Leu
Gly Lys
A1 Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu
Gln Glu
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Leu
B1 Phe Val Asn Gln His
Profil Insulin Analog sangat mirip dengan Insulin Endogen

---- Insulin endogen

Levemir

---- NovoRapid

NovoMix

Makan Makan Makan Sebelum tidur

Pagi Siang Malam
Analog vs Human Insulin
Profil farmakokinetik analog yang lebih mirip insulin
alami, sehingga menghasilkan : Efektivitas, Keamanan
dan Flexibility lebih baik dibanding human Insulin

 Efektivitas :
 Superior mengendalikan GD 2 jam pp
 Superior mengendalikan GD puasa
 Superior mengendalikan HbA1c
 Keamanan  Risiko Hipoglikemi lebih minimal
 Fleksibilitas  Waktu penyuntikan lebih fleksibel
(tidak menunggu 30 menit)
Pasien sudah menggunakan Human Insulin?

Dose to Dose (1:1)

Sebelumnya Actrapid 10 unit 3x sehari  NovoRapid 10 unit 2 x sehari
Mixtard 14 unit malam dan 16 unit siang  NovoMix 14 unit malam dan 16 unit siang
Insulatard 14 unit malam  Levemir 14 unit malam
 Presentation Point of View

1. Rationality of Insulin Therapy for Type 2

DM
2. What is Analogue Insulin?
3. How & Strategy of Insulin Treatment ?
4. Barrier of using insulin
5. Take Home Message
 The Paradigm of (Type 2) Diabetes Treatment

• Aggressive Treatment – Driven by Target

(AIC < 7%)

• Early Combinations
– Oral agent – oral agent
– Oral agent – insulin

• Aggressive Insulin Treatment

 HbA1c targets should be individualized

• Goal of therapy
– In general: HbA1c <7%
– In the individual patient: HbA 1c as close to 6% as possible without
significant hypoglycemia
• Call to action: HbA1c 7%
• Less stringent goals may be appropriate for:
– Patients with a history of severe hypoglycemia
– Patients with limited life expectancies
– Very young children or older adults
– Individuals with co-morbid conditions

Nathan DM, et al. Diabetes Care 2009;32 193-203.

 How to Start
Insulin Therapy ?
 PRINCIPLES OF INSULIN
TREATMENT

Insulin regiment mimicking normal

(endogenous) physiologic insulin
secretion
 The Physiological Requirement for Insulin

Basal

Pancreatic output :
basal  prandial

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis
• Prandial insulin : the amaount of insulin necessary to cover meals without
development of posprandial hyperglycemia
Insulin Preparation

• Basal Insulin
• Prandial Insulin
• (Pre)mixed Insulin
 Glycemic Control: Recommended goals

Measurement Normal IDF1 ADA/EASD2 AACE3 PERKENI

A1c* <6% <6.5% <7% <6.5% <6.5%

Fasting Gluc <100 <110 90-130 <110 80-110

PP (2h) Gluc <140 <155 <180 <140 80-145

* Realistic Target: Lowest A1c possible without unacceptable adverse effects

 IDF = International Diabetes Federation

 ADA = American Diabetes Association.
 AACE = American Association of Clinical Endocrinology
1. Global guideline for type 2 diabetes clinical guidelines taskforce (Brussels: IDF,2005)
2. Nathan DM et al. Diabetologia 2006;49:1711-21.
3. http://www.aace.com/pub/odimplementation/roadmap.pdf
Insulin can be initiated anytime
• Traditionally, insulin had been reserved as the last line of therapy
• Considering the benefits of normal glycemic status,
insulin can be initiated earlier, as soon as is required.

Inadequate + + +
Lifestyle 1 OAD 2 OAD 3 OAD

Initiate Insulin
Indication: Permanent Not permanent
T1DM Infection
OAD failure Pregnancy
OAD Contra Indication Hospitalized
Diabetic Ketoacidosis Perioperative
 Strategy of
Insulin Treatment ?
 Grading of Type 2 Diabetes Based on Level of Fasting
Glycaemia and Suggestion of Insulin Treatment

FBG (mg/dl) Grade Insulin Therapy & Dosis required

< 126 Mild Virtually never needed

126 - 200 Moderate Basal insulin is needed :

Intermediate acting insulin at bed time or
Long-acting insulin 1 – 2X/day
Doses required : 0.3 – 0.4 /kg/day

> 200 Severe Intermediate-acting 2X/day + short-acting insulin

Doses required : 0.5 – 1.5 /kg/day
>250 Very severe Treat as Type 1 diabetes (initially)
1 – 2X basal + 3X bolus (pre-meal)

Skyler,2005
1. If Fasting BG is elevated, start for basal insulin
with long acting insulin (Levemir)

2. If Prandial BG is elevated, start for prandial

/bolus insulin with rapid acting insulin
(NovoRapid)
3. If Fasting and Post Prandial are elevated :
- Oral agent with basal insulin
- premix insulin (NovoMix)
- basal/bolus as in multiple daily injection (MDI)
 Treatment Based on Type of Hyperglycemia

BASAL – PRANDIAL CONCEPT

Prandial Hyperglycemia Basal

Treat fasting hyperglyc. first

Continue oral agent
SMBG is important

Prandial Insulin (NovoRapid) Basal Insulin (Levemir)

Untuk men’simple’kan terapi gunakan NovoMix

(30% : Prandial Insulin & 70% : Basal Insulin)
Strategies for initiation &
intensification of insulin therapy in
patients with type 2 diabetes mellitus
Increasing
need to
Disease cover PPG

progression

Intensification Intensification
Premix once
daily start* Premix twice- Premix three-
daily times daily

Basal bolus Basal bolus

Basal once therapy therapy
daily start* (+ Prandial (+ Prandial
Insulin) Insulin)

*continue with appropriate OAD

Recommendation
“Fix the Fasting First”
Start with basal insulin
 Starting Basal (NPH Insulin or
Long-acting Insulin Analogs)
• Start dose around 10 
• Adjust dose by fasting/preprandial SMBG
• Increase dose (2 – 4 ) every 3 to 5 days as
needed
• Treat to target basal (fasting/preprandial 70 -
130 mg%)
Choose the insulin basal
analogue as a starter
 Suntikkan 10 iu Levemir sekali sebelum tidur.
Atur dosisnya (+3 atau -3) setiap 3 hari sd.
Fix the
GDPFasting Firsttarget GDP 80-110 mg/dL
mencapai
(Perkeni 2006)
400
20

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

300 target T2DM

GDP, mencapai
15
Profile T2DM

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0 0
06.00 10.00 14.00 18.00 22.00 02.00 06.00
Time of day (hours)
 After fasting glucose has
been controlled, then what?
Cek PPG, if it is high goes to
Basal – Bolus or switch to
Premix
Regimen Basal – Bolus

REGIMEN BASAL-BOLUS ---- Insulin endogen

Levemir
Kelebihan :
---- NovoRapid
1. Sangat ideal, dapat menghasilkan terapi yang
menyerupai profil insulin endogen
2. Sangat mudah mengatur dosis insulin basal maupun
bolusnya

Kelemahannya :
1. Pasien tidak menyukainya karena 4 x suntik
2.Makan
Pasien Makan
harus menggunakan
Makan 2 jenisSebelum
insulin (berisiko
tidur
Pagi Siang Malam
pasien salah suntik) dan biaya terapi lebih mahal
 Suntikkan 10
Tambahkan iu Levemir
Injeksi sekalidi
NovoRapid sebelum tidur.
setiap makan
Atur
(2-6 iu)dosisnya
untuk (+3 atau -3) setiap
mengendalikan Gula 3 hari 2sd.
darah jam
Basal –
GDP Bolus Concept
mencapai dengan
target GDPmg/dL
80-110 mg/dL
PP mencapai target
Levemir - NovoRapid < 180 (Perkeni
(Perkeni 2006)
2006)
400
20

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

300 T2DM
15
Profile T2DM

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0 0
06.00 10.00 14.00 18.00 22.00 02.00 06.00
Time of day (hours)
Regimen Premix

REGIMEN PREMIX ---- Insulin endogen

NovoMix 1 x sehari (mulai 12 iu)
Kelebihan : NovoMix 2 x sehari (mulai 3 iu)
NovoMix 3 x sehari (mulai 3 iu)
• Sangat disukai pasien karena cukup menggunakan 1
jenis insulin dan 1 jenis pen (Data Diabcare 2008, pada
1829 pasien Indonesia menunjukkan premix paling
banyak digunakan)
Kelemahannya :
• Pengaturan dosis kurang fleksibel

Makan Makan Makan Sebelum tidur

Pagi Siang Malam
Premix Concept dengan NovoMix

400
20

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

300 T2DM
15
Profile T2DM

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0 0
06.00 10.00 14.00 18.00 22.00 02.00 06.00
Time of day (hours)
 Presentation Point of View

1. Rationality of Insulin Therapy for Type 2

DM
2. What is Analogue Insulin?
3. How & Strategy of Insulin treatment ?
4. Barrier of using insulin
5. Take Home Message
Kendala dalam terapi Insulin

I don’t want it.!

It hurts ! Expensive !

Drug
addiction ?
 Kendala dalam terapi Insulin

1. “Sekali mulai terapi insulin, tidak bisa di stop lagi ”

(Persepsi yang salah, seperti “kecanduan” obat )
– Berikan insulin dengan “percobaan” jangka pendek :
“Cobalah suntik insulin selama 1 bulan saja, lalu kita evaluasi lagi”

2. “ Suntik insulin sangat merepotkan”

( Pasien merasa tidak sanggup suntik sendiri)
• Demonstrasikan kepada pasien betapa simple nya suntikan insulin
• Berikan insulin 1x /hari untuk mengurangi ketidaknyamanan

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

 Kendala dalam terapi Insulin
3. “Kegagalan terapi adalah kesalahan saya”
(suntikan insulin sebagai hukuman karena kegagalan pribadi)
Jelaskan bahwa insulin diperlukan karena perjalanan penyakit DM yg progresif,
bukan karena kegagalan pasien mengelola penyakitnya)

4. “Famili saya disuntik insulin sebelum diamputasi kakinya”

(Insulin diberikan bila Diabetes sudah berat)
Jelaskan bahwa suatu saat insulin diperlukan karena perjalanan alamiah penyakit
DM yg progresif

5. “ Saya tidak berani suntik insulin sendiri, karena nyeri..! ”

(Anxietas terhadap suntik insulin)
Show patient that insulin injection is less painful than BG monitoring with a
glucose meter

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

HIPOGLIKEMIA
 Presentation Point of View

1. Rationality of Insulin Therapy for Type 2

DM
2. What is Analogue Insulin?
3. How & Strategy of Insulin treatment ?
4. Barrier of using insulin
5. Take Home Message
 Take Home Messages

1. DM tipe 2 adalah penyakit kronik yang progresif

2. Terapi DM –perlu “timing” yg tepat untuk mencapai target
3. Bila target belum tercapai, harus meningkat ke langkah berikutnya
4. Terapi Insulin sering diperlukan untuk mencapai target glikemik
5. Titrasi dosis insulin dilakukan sesuai algoritme (perlu SMBG) sehingga risiko hipoglikemia
dapat ditekan
6. Edukasi sangat penting sebelum & selama terapi insulin

7. Mulailah dengan mengendalikan gula darah puasa,

Setelah GDP mencapai target (80-110 mg/dL) selama 3 bulan namun HbA1c masih tinggi,
segeralah menambahkan penyuntikkan bolus (terapi basal-bolus) atau mengganti terapi
dengan premix insulin (untuk pertimbangan yang lebih simpel untuk pasien)

Setelah 3 bulan menggunakan premix 2 x sehari tidak juga mencapai target HbA1c segeralah
meningkatkan premix menjadi 3 x sehari atau menggunakan terapi Basal-Bolus MDI
THANK YOU