Insulin for outpatient setting

Presentation Point of View

1.
2.
3.
4.
5.

Rationality of Insulin Therapy for Type 2 DM

What is Analogue Insulin?
How & strategy of Insulin treatment ?
Barrier of using insulin
Take Home Message

Type 2 Diabetes is NOT a Mild

Disease Macrovascular
Microvascular
Stroke
Diabetic
retinopathy

1.2- to 1.8-fold
increase in stroke3

Leading cause
of blindness
in working-age
adults1

Cardiovascular
disease
75% diabetic patients
die from CV events4

Diabetic
nephropathy
Leading cause of
end-stage renal disease2

Diabetic
neuropathy

Erectile Dysfunction
The most secretive
Complication of DM

Diabetic Foot

Leading cause of
non-traumatic lower
extremity amputations5

Fong DS, et al. Diabetes Care 2003;e 26 (Suppl. 1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98.
3
Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.

Incidence per 1000 Person Years (%)

Incidence Rates of MI and Microvascular

Endpoints by Mean Hemoglobin A1c: UKPDS

Myocardial
Infarction

Microvascular
Endpoints
5

10

Updated Mean Hemoglobin A1c Concentration (%)

Adjusted for age, sex, and ethnic group

Stratton IM et al. BMJ. 2000;321:405-12.

11

Disappointing Outcomes from Recent Major

Trials of Intensive Glycaemic Control
HbA1C
(%)a
ACCORD b

1.1

Hazard ratios (95% CI) vs. control

Macrovascular

Microvascular

Mortality

10 (- 22 to 4)

NR

22 (1 to 46)

14 (3 to 23)

7 (6 to 17)

Intensive R/ (A1c 6.3-6.4%) vs. Standard R/ (A1c 7.4%)

ADVANCEc

0.8

6 (6 to 16)

(Intensive R/ A1c 6.5% vs. Standard R/ A1c 7.3%)

a

Average difference between intensive and conventional glycaemic interventions at stud

Action to Control Cardiovascular Risk in Diabetes Study;

c
Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Controlled Evaluation. NR: not reported.
b

Beneficial Effect: in Less Disease Duration (ACCORD), without Macrovascular Disease

(ADVANCE). HYPOGLYCEMIA is important and should be considered
ACCORD study. N Engl J Med. 2008; 358: 2545-59; ADVANCE study. N Engl J Med.

Goal Values for Glycaemia in

Major Guidelines

HbA1C

Plasma
glucose

IDF Asia-Pacific
(2005)

IDF global
(2005)

ADA/EASD (2008)

<6.5%

<7.0%

FPG 4.46.1 mmol/L

(80110 mg/dL)
Non-fasting glucose
4.48.0 mmol/L
(80145 mg/dL)

<6.0 mmol/L
(110 mg/dL)
pre-breakfast or
evening meal

FPG 3.97.2 mmol/L

(70130 mg/dL)
Peak PPG <10.0 mmol/L
(180 mg/dL)

FPG: fasting plasma glucose (pre-prandial capillary glucose)

PPG: postprandial plasma glucose
Asian-Pacific Type 2 Diabetes Policy Group 2005; International Diabetes Federation 2005;
American Diabetes Association. Diabetes Care. 2008;31 (Suppl 1):S12-S54;
Nathan DM et al. Diabetologia. 2008;51:8-11.

Kriteria Pengendalian DM
Baik

Sedang Buruk

Glukosa Darah Puasa (mg/dL)

80-109

110-125

>126

Glukosa Darah 2 jam PP (mg/dL)

80-144

145-179

>180

A1c (%)

<6,5

6,5-8

>8

Kolesterol Total (mg/dL)

<200

200-239

> 240

Kolesterol LDL (mg/dL)

<100

100-129

> 130

Kolesterol HDL (mg/dL)

>45

Trigliserida (mg/dL)

<150

150-199

>200

IMT (Kg/M2)

18,5-22,9

Tekanan Darah (mmHg)

<130/80

23-25
130-140/80-90

> 25
>140/90

Konsensus Pengelolaan DM
Di Indonesia PERKENI 2006

Legacy Effect of Earlier Glucose Control

After median 8.5 years post-trial follow-up
Aggregate Endpoint

1997

2007

Any diabetes related endpoint

RRR:
P:

12%
0.029

9%
0.040

Microvascular disease

RRR:
P:

25%
0.0099

24%
0.001

Myocardial infarction

RRR:
P:

16%
0.052

15%
0.014

All-cause mortality

RRR:
P:

6%
0.44

13%
0.007

RRR = Relative Risk Reduction, P = Log Rank

UKPDS 80. N Eng J Med. 2008; 359

Therapy for Glycaemia at 5 Years

Proportion of patients

100%

Conventional**

Intensive*

Basal + soluble

80%

Basal insulin

60%

Oral + insulin

40%

Combined oral

20%
0%

77%

Oral monotherapy
Diet alone
Original randomisation

UKPDS 80. N Eng J Med. 2008; 359

*Combination Oral+/Insulin 64 %
**Combination Oral +/Insulin 46 %

Pengelolaan Hiperglikemia
Pasien Rawat Jalan:
Umumnya tidak perlu tergesa-gesa menurunkan kadar
glukosa darah. Tidak harus segera dengan insulin
Moto: Start Low GO Slow, walaupun harus tetap agresif:
early diagnosis
early treatment
early combination
early insulin

Pasien Rawat Inap:

Umumnya memerlukan penurunan kadar glukosa darah
segera. Sasaran kadar glukosa darah lebih agresif.
Umumnya memerlukan insulin
Untuk yang dirawat karena hal lain, dan kadar glukosanya
sudah baik, modalitas pengelolaan hiperglikemia tidak
harus diubah

Strategy to Prevent the Deterioration

of Type 2 Diabetes

Life Style
Beta Cell
Function
(%)

IGT

-12 10

Monotherapy

T2DM phase III

Postprandial T2 DM
Hyperglycemiaphase I

-6

-2

Oral Hypo(s)
Combination

T2DM
phase II

Years from Diagnosis

Lebovitz H. Diabetes Review 1999;7:139-53

Insulin with
or without
Oral Hypo
Glycemic agent

10

14

Insulin

OAD :

Kegagalan sekunder sesudah beberapa

tahun
8.0

ADOPT
ADOPT
study
study

7.6

HbA1c (%)

7.2
6.8
6.4
6.0
0

Rosiglitazone
Metformin
Glybenclamide

Time (Years)

ADOPT: Kahn SE et al. N Engl J Med 2006;355:242743.

ORAL AGENT FAILURE IN

UKPDS
% requiring additional
insulin

60

Taking
insulin
chlorpropamide

Refusing
insulin

glipizide
40

20

159159 152150 143 138 126 132 121127 116123

1
2
3
4
5
6
Years from randomisation

number of
patients/year

Wright et al. Diabetes Care. 2002;25:330-36.

ADOPT TRIAL
Cumulative Incidence of Monotherapy
Failure

15

Kahn: NEJM. 2006; 355:2427- 43

Insulin Use in the United States Remains Low

Despite Poor Glycemic Control
70

NHANES 1999-2000

Patients (%)

60

53

57 59

NHANES 2001-2002
NHANES 2003-2004

50
40

Patients treated with insulin

30
20

20

18 18

16 16
11 10

10

14

Diet only

Oral agents

Oral agents +
insulin

Insulin only

Hoerger TJ et al. Diabetes Care. 2008;31:81- 6.

16

Choosing Insulin for your Patient?

Tahap 1

Tahap 2

Tahap 3

Gaya hidup +
Saat diagnosis:

Metformin +

Gaya hidup

Insulin basal

Gaya hidup +
Metformin +

Insulin intensif

+
Metformin
Well validated
core therapies

Gaya hidup +
Metformin +

Sulfonilurea
Gaya hidup +
Metformin +

Less well
validated core
therapies

Gaya hidup +
Metformin +

Pioglitazon

Pioglitazon +
sulfonilurea

Gaya hidup +

Gaya hidup +

Metformin +

Metformin +

GLP-1 agonis

Basal insulin
Nathan DM et al, Diabetes Care 32:193203, 2009

Presentation Point of View

1.
2.
3.
4.
5.

Rationality of Insulin Therapy for Type 2 DM

What is Analogue Insulin?
How & Strategy of Insulin Treatment
Barrier of using insulin
Take Home Message

Sejarah Perkembangan
insulin

s/d 1983

1921
: penemuan insulin
: 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

Kelemahan Human Insulin

(Actrapid/Mixtard)
Period of unwanted
hyperglycemia

Change in serum insulin

Normal insulin secretion

at mealtime
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

NovoRapid
Levemir
Structural(Insulin
Design
(Insulin
Human
Detemir)
Aspart)
Insulin
C14
Asp
(My fatty
a
rist
ic a cid ch
cid
ain
)

Thr

Lys

Pro
Pro

Thr

Phe

A21

B29
A1

Tyr

Phe

Asn

Gly

Cys

Lys

Gly

Arg

Glu

Gly

Cys
Val
Leu

Tyr
Asn

Tyr

Ile

Glu

Leu

Val

Leu

Ala

Gln

Glu

Glu
Gln
Cys

Tyr
Cys

Thr

Ser

Ile

Cys

Ser

Val

Leu

Leu
His
Gly

B1

Phe

Val

Asn Gln

His

Leu

Cys

Ser

Profil Insulin Analog sangat mirip dengan Insulin Endogen

-------

Insulin endogen
Levemir
NovoRapid
NovoMix

Makan
Pagi

Makan
Siang

Makan
Malam

Sebelum tidur

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 6 unit 3x sehari NovoRapid 6 unit 3 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

How to Start
Insulin Therapy ?

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

2 OAD

1 OAD

Initiate

3 OAD

Insulin

Indication: Permanent

Not permanent

T1DM

Infection

OAD failure

Pregnancy

OAD Contra Indication

Hospitalized

Diabetic Ketoacidosis

Perioperative

Strategy of
Insulin Treatment ?

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

Basal Insulin (Levemir)

(NovoRapid)

Untuk mensimplekan 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
cover PPG

Disease
progression

Premix once
daily start*

Basal once
daily start*

Intensification

Intensification

Premix twicedaily

Premix threetimes daily

Basal bolus
therapy
(+ Prandial
Insulin)

Basal bolus
therapy
(+ Prandial
Insulin)

*continue with appropriate OAD

Recommendation

Fix the Fasting First

Start with basal insulin

Tahap 1

Tahap 2

Tahap 3

Gaya hidup +
Saat diagnosis:

Metformin +

Gaya hidup

Insulin basal

Gaya hidup +
Metformin +

Insulin intensif

+
Metformin
Well validated
core therapies

Gaya hidup +
Metformin +

Sulfonilurea
Gaya hidup +
Metformin +

Less well
validated core
therapies

Gaya hidup +
Metformin +

Pioglitazon

Pioglitazon +
sulfonilurea

Gaya hidup +

Gaya hidup +

Metformin +

Metformin +

GLP-1 agonis

Basal insulin
Nathan DM et al, Diabetes Care 32:193203, 2009

Choose the insulin basal

analogue as a starter

ONCE daily
Levemir start

10 U

pada makan malam atau sebelum tidur

Rekomendasi dosis Levemir yang dikombinasikan dengan oral
adalah satu kali sehari, dimulai dengan 10 U atau 0.1 - 0.2 U/Kg. Waktu
Penyuntikan dapat diberikan kapan saja, tetapi harus pada waktu yang
sama setiap harinya.

Suntikkan 10 iu Levemir sekali sebelum tidur.

Atur dosisnya (+3 atau -3) setiap 3 hari sd.
Fix the
Firsttarget GDP 80-110 mg/dL
GDPFasting
mencapai
(Perkeni 2006)
400

Plasma glucose (mg/dl)

T2DM

300 target
GDP, mencapai

200

15
Profile T2DM

Hyperglycaemia due to an increase in fasting glucose

100

10

Normal
0
06.00

Plasma glucose (mmol/l)

20

Meal

Meal

10.00

14.00

Meal

18.00

22.00

Time of day (hours)

02.00

0
06.00

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
Kelebihan :

-------

Insulin endogen
Levemir
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
Makan 2 jenisSebelum
tidur
2.Makan
PasienMakan
harus menggunakan
insulin
(berisiko
Pagi
Siang
Malam
pasien salah suntik) dan biaya terapi lebih mahal

Suntikkan 10
iu Levemir
sekalidisebelum
tidur.
Tambahkan
Injeksi
NovoRapid
setiap makan
Atur
dosisnya
(+3 atau -3) setiap
3 hari 2sd.
(2-6
iu)
untuk
mengendalikan
Gula
darah
jam
Basal

Bolus
Concept
dengan
GDP
mencapai
target
GDPmg/dL
80-110
mg/dL
PP
mencapai
target
<
180
(Perkeni
Levemir - NovoRapid
(Perkeni
2006)
2006)
400

Plasma glucose (mg/dl)

T2DM

300

Plasma glucose (mmol/l)

20

15
Profile T2DM
200

Hyperglycaemia due to an increase in fasting glucose

100

10

Normal
0
06.00

Meal

Meal

10.00

14.00

Meal

18.00

22.00

Time of day (hours)

02.00

0
06.00

Regimen Premix

----

REGIMEN PREMIX
Kelebihan :

Insulin endogen
NovoMix 1 x sehari (mulai 12 iu)
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
Pagi

Makan
Siang

Makan
Malam

Sebelum tidur

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 dont want
it.!
It hurts
!

Drug
addiction ?

Expensive !

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.

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