CLINICAL USE OF INSULIN IN DAILY PRACTICE

(PDCI: MEMULAI DAN INTENSIFIKASI INSULIN)

2015
34-1083-K
Presented and Provided by :
Prof. Dr. dr. Askandar Tjokroprawiro Sp.PD, K-EMD, FINASIM
SURABAYA DIABETES AND NUTRITION CENTRE - Dr. SOETOMO TEACHING HOSPITAL
FACULTY OF MEDICINE AIRLANGGA UNIVERSITY, SURABAYA

SANOFI PDCI WORKSHOP FOR GENERAL PRACTITIONS

PDCI
Partnership for Diabetes Control in Indonesia
ASKES / BHAKTI HUSADA, MoH, PERKENI, ADA, SANOFI
TUBAN (MUSTIKA HOTEL), 18-20 DECEMBER 2015
ASK-SDNC

TUJUAN PEMBELAJARAN PDCI-WORKSHOP

1. Memahami Peran Insulin dalam Pengendalian
Glukosa Darah

2. Meningkatkan Kemampuan dalam Memulai

dan Mentitrasi Dosis Insulin, Menggunakan
Insulin Basal dan Premixed
3. Mampu Melakukan Monitoring dan Evaluasi
Penggunaan Insulin

ASK-SDNC

Pancreatic Islet Cells: Cell, Cell, Cell, Cell, PP-Cell. APA ITU INSULIN?

(Molina 2010, Masharani et al 2011, Summarized : Tjokroprawiro 2015)

Insulin

Hormon yang disekresikan oleh sel Beta Pankreas ( Cell)

Cell Types in Adult Human Pancreatic Islet of Lengerhans, in
approximately % of Islet volume : Cell (25%, Glucagon, Proglucagon),
Cell (55%, Insulin, C Peptide, Proinsulin, IAPP, GABA), Cell (10%,
Somatostatin-14), Cell (3%, Ghrelin), PP-Cell (5%, Pancreatic
Polypeptide)
First-Phase Secretion (a period of minutes, < 5%) and SecondPhase Secretion (over an hour or more, > 95%)
Disekresikan sebagai Respon terhadap Glukosa atau Rangsangan
lainnya, seperti Asam Amino

60
40
20

0
ASK-SDNC

Sarapan

Makan siang

Makan malam

TINJAUAN TERHADAP PROFIL FISIOLOGIS INSULIN

(Molina *2010, Summarized : Tjokroprawiro 2015)
50

Saat makan, insulin meningkat dengan cepat,

durasi pendek (First Phase Secretion, <5%*)

Serum Insulin (mU/L)

40

30

Halus, Stabil
Profil Insulin Basal
(Second Phase Secretion, > 95%*)

20

10
0

0800
1200
1600
2000
2400
MAKAN PAGI MAKAN SIANG MAKAN MALAM
BP=blood pressure;
QOL=quality of life
Adapted from Kruszynska Y et al. Diabetologia 1987;30:16.

ASK-SDNC

0400

0800

Daly A, Power MA. Medical Nutrition Therapy.

Diabetes Mellitus and Related Disorders; Medical
Management of Type 2 Diabetes, 7th Edition.
American Diabetes Association, 2012.

TYPE 2 DIABETES IS PROGRESSIVE

DIAGNOSIS

100

-cell Function, %

MONOTHERAPY

80

COMBINATION
ORAL THERAPY

60
40

T2DM
Phase-I

20

INSULIN
T2DM
Phase-II

0
-12

-6

T2DM
Phase-III

12

Time, Years
HbA1c Not at Target: < 7.0%
Based on data from UKPDS. Diabetes. 1995;44:149-1258(1); Kendall DM, et al. Am J Med.
2009; 122:S37-S50(2); Kendall DM, et al. Am J Manag Care. 2001;7:S327-S343(3)
ASK-SDNC

MEKANISME KERJA INSULIN

(PDCI-2014, Provided 2014-2015)

INSULIN

GLUCOSE

INSULIN
RECEPTORS

GLUT4

ACTIVE

INACTIVE
A
B

ASK-SDNC

MAPK PATHWAY
GENE EXPRESSION
GROWTH REGULATION
ATHEROGENIC & MITOGENIC

A1

P13K PATHWAYS
SIGNAL
TRANSDUCTION
A2

GLUCOSE UTILIZATION
+
GLYCOGEN / LIPID / PROTEIN SYNTHESIS
METABOLIC & ATHEROPROTECTIVE

THE 6 SITES OF ACTIONS OF INSULIN RESISTANCE

(Kim et al 2008, Circ Res. 2008;102:401-414, Provided : Tjokroprawiro 2014-2015)

1

INSULIN RECEPTOR

3 DEGRADATION

IRS-1/2

2 SERINE PHOSPHORYLATION

Pi 3-Kinase
6A ACTIVATION Akt

PDK-1

4 PTP-1B
5 PTEN

PKB
FOXO1

G6P /PEPCK

Gluconeogenesis

LIVER

eNOS

NO

Vasodilation
HEART, ENDOTHELIUM

FOXO1 inhibits Cell Survival & Proliferation

Akt inhibits FOXO1

6B ACTIVATION
aPKC

PKC

GLUT4

Glukose Uptake
ADIPOSE TISSUE,
HEART, SKELETAL
MUSCLE

MOLECULAR MECHANISM OF INSULIN RESISTANCE : (1)

1 decreased activation of receptor binding
2 increased serine phosphorylation of IRS proteins (Zick 2005); (3)
3 increased degradation of IRS proteins
(Zhande et al 2002); increased activity of phosphatases including (src homology 2 domain containing inositol
5-phosphatase 2 [SHIP2], 4
4 phospho-tyrosine phosphatase 1B [PTP-1B]), and 55 phosphatase tensin
homolog deleted on chromosome ten [PTEN] (Egawa et al 2001); (5)
6 decreased activation of insulin receptor
downstream signaling molecules including 6A Akt and 6B atypical PKC (Stratford et al 2004)
ASK-SDNC

HAMBATAN DALAM INISIASI INSULIN

MASALAH KLINIS
Klinisi mengkhawatirkan kondisi
hipoglikemia, kenaikan berat badan

MASALAH PASIEN
Takut suntikan / jarum
Takut hipoglikemia

Kesalahpahaman bahwa peningkatan

insulin meningkatkan risiko
kardiovaskular

Menganggap insulin sebagai tanda

kegagalan pasien pribadi untuk
mengendalikan penyakit

Rumit dan labor-intensive

Rumit dan labor-intensive

Kurangnya pengetahuan/pengalaman

Mahal

Tidak cukup waktu untuk edukasi

pasien

Takut kualitas hidup menurun

Keuangan
Teknis (buta dan hidup sendiri)

ASK-SDNC

KAPAN INSULIN DIPERLUKAN?

(PERKENI Consensus Guidelines, 2015)

1.
1
2.
2
3
3.
4.
4
5.
5
6.
6
7
7.
8
8.

Penurunan berat badan secara drastis

Hiperglikemia berat diikuti dengan ketosis
Ketoasidosis Diabetes (KAD)
Kondisi hiperglikemia Hiper Osmolar Non Ketotik (HONK)
Hiperglikemia diikuti dengan laktat asidosis
Kegagalan kombinasi OAD dengan dosis optimal
Infeksi sistemik, pembedahan mayor, Miokardiak Infark Akut, stroke
Gestational DM dengan kadar gula darah yang tidak terkendali
dengan diet.
9 Kerusakan berat fungsi ginjal dan hati
9.
10.
10 Kontraindikasi dan/atau hipersensitivitas terhadap OAD
ASK-SDNC

PRACTICAL INDICATIONS OF BASAL INSULIN

FORMULA : PBB (ESWL), 2-4-9-9, HOMA-B 35
(Clinical Experiences : Tjokroprawiro 2003-2015)
PRIMARY INDICATIONS OF BASAL INSULIN

(When Any of the Six Following Items are Exceeded)

LIFE STYLE MODIFICATION

1 PBB*) Means: Penurunan Berat Badan*) (Kg) > 10% (within 3 months)
2 2 Means: FPG > 200 mg/dL
3 4 Means: 1h-PG > 400 mg/dL
4 9 Means: A1C

*) or ESWL / 3 months
Estimated Significant
Weight Loss > 10%

> 9%

5 9 Means: A1C for Nave T2DM > 9%

6 HOMA-B 35 Means: HOMA-B < 35% (Normal : 70-150%)
SOMETIMES EARLY INSULINIZATION IS INITIATED if : HOMA-B < 50%
ASK-SDNC

10

11

INSULIN DI INDONESIA
(PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015)
JENIS INSULIN

AWITAN
(ONSET)

PUNCAK
EFEK

LAMA
KERJA

KEMASAN

Kerja pendek
(Insulin manusia, Insulin regular)
Humulin R
Actrapid
Insuman*

30-45
menit

2-4 jam

6- 8 jam

Vial
Penfill

4-6 jam

Vial/pen
Flexpen
Pen/vial

8-12 jam

Vial
Penfill
Vial

Kerja cepat (Insulin Analog)

Insulin lispro (Humalog)
Insulin aspart (Novorapid)
Insulin glulisin (Apidra)
Kerja menengah (Insulin
manusia, NPH)
Humulin N
Insulatard
Insuman Basal*
ASK-SDNC

5-15
menit

1,5-4 jam

1-2 jam

4-10 jam

12

INSULIN DI INDONESIA (LANJUTAN)

(PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015)
JENIS INSULIN

Kerja panjang (Insulin Analog)

Insulin glargine (Lantus)
Insulin detemir (Levemir)
Kerja ultra-panjang (Insulin Analog)
Degludec (Tresiba)*
Glargine U300 (Lantus XR, Toujeo)*

AWITAN PUNCA
(ONSET) K EFEK

1-3 jam

Hampir
tanpa
puncak

LAMA
KERJA

KEMASAN

12-24 jam

Pen/vial 100
IU/mL
Pen 100
U/mL

30 -60
menit

Hampir Sampai 48
tanpa
jam
puncak
1-3 jam Tanpa
24 jam
puncak

NPH: Neutral Protamine Hagedorn;. *belum tersedia di Indonesia

ASK-SDNC

Pen

Pen
300U/mL

13

INSULIN DI INDONESIA (LANJUTAN)

(PERKENI, Petunjuk Praktis Terapi Insulin pada pasien DM, 2015)
JENIS INSULIN

Campuran (Premixed, Insulin Manusia)

Humulin 30/70 (30% Regular, 70% NPH)
Mixtard 30/70 (30% Regular, 70% NPH)
Campuran (Premixed Insulin Analogue)
Humalog Mix75/25TM (75% Protamin
Lispro, 25% Lispro)
NovoMix 30 (30% Aspart, 70% Protamin
Aspart)
50/50 PreMix

AWITAN PUNCAK LAMA

EFEK
KERJA
(ONSET)

30 60
menit

12-30
menit

3-12 jam

Vial 30/70
Penfill

1-4 jam

Vial 10 mL,
Pen 3 mL
Penfill/
flexpen

NPH: Neutral Protamine Hagedorn;. *belum tersedia Indonesia

ASK-SDNC

KEMASAN

14

INSULIN IN CLINICAL USE

Lee et al 1998, Hirsch 1998, Bolli et al 1999, Gillies et al 2000
Heinemann 1996, Fineberg et al 2003, Malone et al 2000, 2004
(Summarized : Tjokroprawiro 2003-2015)

PAST AND PRESENT

PRESENT AND FUTURE

NATIVE HUMAN INSULINS

Clinical Use : Since 1922s

INSULIN ANALOGUES
Recombinant Human Insulin: Since 1980s

ACTRAPID,INSULATARD-MONOTARD,MIXTARD

Regular-Semilente, NPH-Lente, Ultralente

THE 3 OF 34 PROPERTIES OF INSULIN
1 ANTI-INFLAMMATION
2 ANTI-OXIDANT
3 ANTI-APOPTOSIS (Brain, Heart, -Cell)
ASK-SDNC

RAPID-ACTION : 7

LONG ACTION : 8

1 Lispro : LysB28, ProB29 1 Glargine (Lantus, 2003)

(Humalog, 2006)
2 Insulin Aspart 70/30
2 AspB9
(NovoMix30, 2006)
3 AspB10
3 Humalog Mix25 (2006)
4 Asp B28-Aspart
(NovoRapid, 2007) 4 Detemir (Levemir, 2007)
5 Glu B21
5 Degludec (Expected 2016?)
6 Glu B27
6 Novo Sol BASAL 8 C16-HI
7 Glulisine
7 W99-S32 9 Glargine 300U
(Apidra, 2007)

(Toujeo)

PHARMACOKINETICS OF HUMAN INSULIN AND INSULIN ANALOGUES

15

(Summarized : Tjokroprawiro 2008-2015)

INSULIN PREPARATION
SHORT ACTING *)

ONSET OF
ACTION

PEAK OF ACTION
(HRS)

DURATION OF
ACTION (HRS)

30-60 mins
5-15 mins
5-15 mins
5-15 mins

2-4
1-2
1-2
1-2

6-8
3-4
3-4
3-4

RAPID ACTING **)

Regular Human Insulin = RHI*)

INSULIN GLULISINE : APIDRA **)
Insulin Aspart : Novorapid **)
Insulin Lispro : Humalog **)

INTERMEDIATE-ACTING
1-3 hrs
5-7
13-16
NPH
1-3 hrs
4-8
13-20
Lente
LONG-ACTING
INSULIN GLARGINE (LANTUS)
1-3 hrs
No Peak
24
Detemir (Levemir)
1-3 hrs
No Peak
24
Ultralente
2-4 hrs
8-14
22-24 hrs
Ultra-long-acting insulin DEGLUDEC : New Gen. Basal Ins. that forms Soloble Hexamers upon SC inj.
PREMIXED = Biphasic
Insulin Lispro 75/25 (Humalog Mix25)

Insulin Aspart 70/30 (Novomix30)

ASK-SDNC

10 mins
10 mins

1-4
1-4

10-20
16-20

MEMULAI DAN MENTITRASI INSULIN BASAL

16

(Nathan et al. Diabetes Care 2009;32:193-203, Provided : Tjokroprawiro 2013-2015)

Mulai dgn insulin basal

suntikan tunggal,
contoh: pagi hari insulin
glargine

Malam hari atau Pagi hari (lebih baik)

Insulin kerja panjang (siang dan malam dengan OAD)
Malam Insulin kerja menengah
))
), Slide
Dosis harian: 10 U atau 0.2 U/kg*) (atau
Formula
atau Formula
1/3**1/3**
19, 20, 21

Cek
GDP perhari
Naikkan dosis 2 U per 3 hari
(Formula
3.3.5), Slide
Slide 21
19 sampai
(Formula
3.3.5**),
GDP 3.97.2 mmol/L (80130 mg/dL)
Jika GDP >10 mmol/L (>180 mg/dL),
Naikkan dosis 4 U per 3 hari

Lanjutkan regimen dan

cek HbA1c tiap 3 bulan
ASK-SDNC

Jika terjadi hipoglikemia atau

GDP <3.9 mmol/L (<80 mg/dL),
kurangi dosis insulin di pagi hari
4 unit, atau 10% jika >60 unit

*) Body Weight Oriented

**) Blood Sugar Level Oriented

PENYESUAIAN DOSIS INSULIN

MENURUT ADA-2006
Jika A1C tidak tercapai setelah 2-3 bulan pengobatan dan GDP
masih dlm rentang target, tambahkan suntikan sesuai kadar
glukosa darah sebelum makan (pre-meal)
GD pre-meal makan siang yg meningkat: Tambahkan insulin
rapid-acting saat makan pagi
GD pre-meal makan malam yg meningkat: Tambahkan NPH
saat makan pagi atau insulin rapid-acting saat makan siang*
GD sebelum tidur yg meningkat: Tambahkan insulin rapidacting saat makan malam

Premixed insulin tidak dianjurkan pd penyesuaian dosis; namun

dapat digunakan sebelum makan pagi dan/atau makan malam
jika proporsi kerja singkat-menengah nya sama dg proporsi
campuran yg tersedia
Nathan DM et al. Diabetes Care 2006;29:1963-72.
ASK-SDNC

17

18

PENYESUAIAN DOSIS INSULIN

MENURUT ADA-2006
Periksa kembali glukosa darah sebelum makan
untuk melihat apakah diperlukan suntikan lagi.
Jika A1C tetap tidak tercapai, cek glukosa darah
2 jam, atau 1 jam (Tjokroprawiro 2014) setelah
makan dan sesuaikan dengan insulin kerja singkat

Nathan DM et al. Diabetes Care 2006;29:1963-72.

ASK-SDNC

CTOI with FORMULA 1/3 for DISCHARGED-PATIENTS

19

(Clinical Experiences : Tjokroprawiro 2007-2015)

1 INPATIENTS TREATED with APIDRA 3x 20 Units per Day:

Total dose of APIDRA 60 units per Day
CTOI : Combined Therapy USE FORMULA 1/3 *) *) Blood Sugar Oriented
Oral-Insulin
METHOD- A OR B
METHOD- A
(Since-2003)

- LANTUS : 20 units (1/3 of 60) Mornings

- APIDRA : Formula X2
- AMARYL-M : Mornings, or Mornings and Evenings

or
- LANTUS : 20 units Evenings
METHOD- B - APIDRA : Formula X2
(Widely Withdrawn) - AMARYL-M : Mornings, or Mornings and Evenings

PERKENI-CONSENSUS 2006 : Insulin Dose > 30 Units/day in CTOI

is not Recommended
ASK-SDNC

STOP OAD, and Give PREMIX Twice Daily (ADA/EASD-2012)

Continued

20

CTOI with FORMULA 1/3 (LANTUS) for DIABETIC-OUTPATIENTS

(Clinical Experiences : Tjokroprawiro 2007-2015)

2 DIABETIC OUTPATIENTS FAILED with 2-4 OADs*):

depending on 1-h PG (One Hour Plasma Glucose) , and Special attention to

the figures of the first two fe. : 1-h PG 450 mg/dL , the First two is 45
*) 1-h PG Oriented

FORMULA 1/3 (based on the figures of the first two , that is 45):
Thus, the Initial Dose : 1/3 of 45 = 15 Units
- LANTUS : 15 Units Mornings (At the Same Time of the Day)
METHOD- A - APIDRA : Formula X2
Since-2003 & 2007
- AMARYL-M : Mornings, or Mornings and Evenings

or
- LANTUS : 15 units Evenings (At the Same Time of the Day)
METHOD- B - APIDRA : Formula X2
Widely Withdrawn - AMARYL-M : Mornings, or Mornings and Evenings
ASK-SDNC

21

STEP-UP FORMULA : 3-3-5

(Clinical Experiences : Tjokroprawiro 2003-2015)

I STEP-UP FORMULA 3-3-5 WITH LANTUS

THE 1st 3 INDICATES DAY , whereas the 2nd & 3rd 3 & 5 INDICATE LANTUS DOSE

INCREASING INSULIN DOSE : 3 or 5 units after 3 DAY-EVALUATION

INCREASING INSULIN DOSE OF 3 UNITS IF

FPG (Morning-Glucose) : 130-200 mg/dL

INCREASING INSULIN DOSE 5 UNITS IF

FPG (Morning-Glucose) : > 200 mg/dL

DECREASING INSULIN DOSE 3 UNITS IF
FPG (Morning-Glucose) : < 80 mg/dL (ADA-2015)
ASK-SDNC

Continued

STEP-DOWN FORMULA : 2-2 , 2-1 , 1-2 , 1-1

22

(Clinical Experiences : Tjokroprawiro 2003-2015)

II

STEP-DOWN FORMULAS TO END LANTUS INJECTION

THE 1st FIGURE ( 2 or 1 ) INDICATES DAY , whereas :
THE 2nd FIGURE ( 2 or 1 ) INDICATES DECREASE in LANTUS DOSE

FORMULA 2-2 : Every 2 Days

FORMULA 2-1 : Every 2 Days

2 U Decrease ,until LANTUS INJECTION OFF

1 U Decrease , until LANTUS OFF

FORMULA 1-2 : Every Day

2 U Decrease , until LANTUS OFF

FORMULA 1-1 : Every Day

1 U Decrease , until LANTUS OFF

ASK-SDNC

23

LANGKAH-LANGKAH PENDEKATAN TERAPI DMT2

(KONSENSUS PERKENI, 2011; Raccah. Diabetes Ob Met 2008;10:76-82)
ADA-2015
ADA-2015
A1C
<7.0%
Glukosa plasma sebelum makan
80130 mg/dL
Puncak glukosa plasma kapiler setelah makan
(1 jam postprandial) <180 mg/dL

INSULIN
BASAL
OAD
MONOTERAPI
ATAU
KOMBINASI
DIET DAN
LATIHAN FISIK

Sehari 1x
(sampai optimal)

A1C
Tdk terkendali

BASAL
PLUS-1
1 suntikan
prandial utk
asupan
karbohidrat
terbesar

2 suntikan
prandial utk
asupan
karbohidrat
& terbesar

A1C tdk terkendali, GDP sesuai target

GDPP > 180 mg/dL

Waktu
ASK-SDNC

BASAL
PLUS-2

BASAL
BOLUS
Basal +
3 Suntikan
Prandial
BASAL PLUS

24

INTENSIFIKASI INSULIN
(Konsensus PERKENI, 2011)

Dari BASAL ke BASAL-PLUS kemudian BASAL-BOLUS :

Ketika INSULIN BASAL (Suntikan ke-1) ditambahkan
pada OAD TIDAK MENCAPAI TARGET A1C, maka :

Lakukan langkah-langkah PENAMBAHAN

SHORT ATAU RAPID INSULIN (Stepwise) pada MEALTIME
BASAL +1 : SUNTIKAN ke-2 sebelum
sebelum LARGEST
LARGEST MEAL
MEAL
nd MEAL
BASAL +2 : SUNTIKAN ke-3 sebelum
sebelum 22nd
MEAL

BASAL +3 (BASAL-BOLUS) : SUNTIKAN ke-4

sebelum 3rd MEAL
ASK-SDNC

CTOP : Combined Therapy Oral and Premix

25

CTOP with FORMULA 1/3 for DIABETIC-OUTPATIENTS

(Clinical Experiences : Tjokroprawiro 2007-2015)

DIABETIC OUTPATIENTS FAILED with 2-3 OADs*):

depending on 1-h PG (One Hour Plasma Glucose) , and Special attention to

the figures of the first two fe. : 1-h PG 450 mg/dL , the First two is 45
*) 1-h PG Oriented

FORMULA 1/3 (based on the figures of the first two , that is 45):
Thus, the Initial Dose or PREMIX : 1/3 of 45 = 15 Units
- PREMIX : 15 Units MORNINGS (at Breakfast)
(If Insulin Dose < 20U/day) - OAD : LUNCH and DINNER

PREMIX-A

ASK-SDNC

26

CTOP WITH PREMIX A , AB , AND ABC FOR DIABETIC OUTPATIENTS

PREMIXED-INSULIN REGIMEN IN DAILY PRACTICE
(Clinical Experiences : Tjokroprawiro 2014-2015)

FORMULA 1/3 (Formula < 20) : PREMIX-A If Premix Dose < 20 U/day : Breakfast
FORMULA 60-40 : PREMIX-AB

IF PREMIX DOSE (20-40 U/day): Breakfast and Dinner

(Example : 30 U/day Breakfast 18 U, Dinner 12 U)

60% = 18 U Breakfast (A) 40% = 12 U Dinner (B)

FORMULA 50-20-30 : PREMIX-ABC

IF PREMIX (>40 U/day) : Breakfast, Lunch, Dinner

(Example : 50 U/day Breakfarst : 25 U, Lunch 10 U, Dinner 15 U)

50% = 25 U Breakfast (A), 20% = 10 U Lunch (B), 30% = 15 U Dinner (C)

ASK-SDNC

27

THE 3 (THREE) FORMULAS OF PREMIX IN CTOP

PREMIX- A PREMIX- AB PREMIX- ABC

(Clinical Experiences : Tjokroprawiro 2014-2015)

PREMIX-A (IF < 20 /d) PREMIX-AB (IF 20-40 /d) PREMIX-ABC (IF >40 /d)
DOSE: 60% (A) and 40% (B) DOSE: 50%-20%-30%
DOSE 1/3 (A)
(A), (B), (C)

PREMIX-A : 1X
Breakfast Only

PREMIX-AB : 2X
Breakfast 60% (A)
Dinner 40% (B)

(CTOP = Combined Therapy Oral Premixed Insulin)

ASK-SDNC

PREMIX-ABC : 3X
Breakfast 50% (A)
Lunch 20% (B)
Dinner 30% (C)

THE SUMMARIZED USE OF FORMULAS PREMIX-A, AB, ABC

28

(Clinical Experiences : Tjokroprawiro 2015)

PREMIX-A (100% of insulin daily dose) : if the daily insulin

dose < 20 Unit.
Injection of premix (<20 U/day) only once injection per day at
breakfast.

PREMIX-AB (see Slide 26) (60% at breakfast, 40% at dinner) : if

the daily insulin dose between 20-40 Unit, for example 30 unit/day

Injection of premix twice daily. Premix-A 60% (60% of 40 U) :

18 Unit at breakfast and premix-B 40% (12 Unit) at dinner.

PREMIX-ABC
PREMIX-ABC (see Slide 26) (50% at breakfast, 20% at lunch,
30% at dinner) If the daily insulin dose >40 Unit, for example
50 Unit/day, Injection of premix-A (50% of 60 U) : 25 Unit at
breakfast, premix-B (20% of 10 U) : 12 unit, and premix-C
(30% of 60 U) : 15 unit at dinner
ASK-SDNC

Pendekatan dalam Memulai dan Menyesuaikan Insulin pada DMT2

Number of
injections

(usually with metformin +/- other noninsulin agent)

Flexibility
ASK-SDNC

If not controlled after FBG target

is reached (or if dose >0,5
U/kg/day), treat PPG excursions
with mealtime insulin. (Consider
initial GLP-1-RA trial.)

Start: 4 U, 0.1 U/kg, or 10% basal dose. If HbA1c <8%

consider reducing basal by same amount.
Adjust: Increase dose by 1-2 U or 10-15% once-twice
weekly until SMBG target reached.
For hypo: Determine and address cause; reduce
corresponding dose by 2-4 U or 10-20%

If not
controlled,
consider
basal-bolus

3+

low

Start: 10 U/day or 0.1-0.2 U/kg/day

Adjust: 10-15% or 2-4 U once-twice weekly to reach FBG target.
For hypo: Determine and address cause; reduce dose by 4 U or 10-20%

Add 1 rapid insulin injection

before largest meal
(Basal Plus 1 or 2, Basal Bolus)

Regimen
complexity

BASAL INSULIN

Change to
premixed insulin twice daily
(Premix-A, AB, or ABC)

Start: Divide current basal dose into 2/3 AM, 1/3 PM or

1/2AM, 1/2 PM.
Adjust: Increase dose by 1-2 U or 10-15% once-twice
weekly until SMBG target reached.
For hypo: Determine and address cause; reduce
corresponding dose by 2-4 U or 10-20%

ADD 2 RAPID INSULIN* INJECTIONS

BEFORE MEALS (BASAL-BOLUS)

mod.

If not
controlled,
consider
basal-bolus

Start: 4 U, 0.1 U/kg, or 10% basal dose/meal. If HbA1c <8% consider reducing basal by same amount.
Adjust: Increase dose by 1-2 U or 10-15% once-twice weekly until SMBG target reached.
For hypo: Determine and address cause; reduce corresponding dose by 2-4 U or 10-20%

More flexible

29

high

Less flexible
Inzucchi SE, et al. Diabetes Care 2015;38:140149

CORRELATION OF A1C WITH AVERAGE GLUCOSE

30

A calculator for converting A1C results into eAG (estimated Average Glucose), in either mg/dL
or mmol/L, is available at http://professional.diabetes.org/GlucoseCalculator.aspx

A1C
6
7
8
9
10
11
12
ASK-SDNC

MEAN PLASMA GLUCOSE

mg/dL
mmol/L
126
7.0
154
8.6
183
10.2
212
11.8
240
13.4
269
14.9
298
16.5
Diabetes Care 35, Supplement 1, January 2012

MEMBERIKAN PENGOBATAN YANG

TEPAT PADA PASIEN YANG TEPAT

31

KARAKTERISTIK PASIEN

Profil Glucosa Darah Pasien

Faktor Psikososial dan Budaya
Pilihan Pasien
Usia
Penyakit Komorbid
Keinginan untuk Mematuhi Pengobatan

KARAKTERISTIK INSULIN

ASK-SDNC

Kemampuannya utk Menyamai Sekresi Insulin Endogen

Potensi Efek Samping
Biaya
Kompleksitas Komposisinya

Meneghini L. South Med J 2007;100:164-74.

Mooradian AD et al. Ann Intern Med 2006;145:125-34.
Hirsch IB et al. Clin Diabetes 2005;23:78-86.

INSULIN DAN WAKTU PEMERIKSAAN

GLUKOSA DARAH MANDIRI
PEMBERIAN

MONITORING GULA
DARAH

Sebelum atau
setelah makan

Setelah makan

1-2 jam setelah suntikan

atau segera sebelum
makan

Sebelum makan

Diantara makan/makan
berikutnya atau pada saat
akan tidur

Segera sebelum makan

berikutnya; biasanya 1-2
jam setelah suntikan

Kerja
Menengah

Sebelum sarapan,
Sebelum makan
malam,
pada saat akan
tidur

Diantara makan siang/malam

Diantara tengah malam/
sarapan,
Diantara pukul 04:00/sarapan

Sebelum sarapan,
sebelum tidur, midsleep,
dan sarapan, sebelum
sarapan

Kerja
Panjang

Sebelum sarapan,
atau pada saat
akan tidur

Kebanyakan pada malam hari

Sebelum sarapan

(Pengalaman Klinik : Pagi Hari)

(Tergantung Jam Suntik)

INSULIN

Kerja
Singkat

Regular

ASK-SDNC

WAKTU
SUNTIKAN

32

Medical Management of Type 2 Diabetes. 7th Edition. American Diabetes Association, 2012.

PRACTICAL INDICATIONS OF BASAL INSULIN

FORMULA : PBB (ESWL), 2-4-9-9, HOMA-B 35
(Clinical Experiences : Tjokroprawiro 2003-2015)
PRIMARY INDICATIONS OF BASAL INSULIN

(When Any of the Six Following Items are Exceeded)

LIFE STYLE MODIFICATION

1 PBB*) Means: Penurunan Berat Badan*) (Kg) > 10% (within 3 months)
2 2 Means: FPG > 200 mg/dL
3 4 Means: 1h-PG > 400 mg/dL
4 9 Means: A1C

*) or ESWL / 3 months
Estimated Significant
Weight Loss > 10%

> 9%

5 9 Means: A1C for Nave T2DM > 9%

6 HOMA-B 35 Means: HOMA-B < 35% (Normal : 70-150%)
SOMETIMES EARLY INSULINIZATION IS INITIATED if : HOMA-B < 50%
ASK-SDNC

33

34

PRACTICAL TOOL FOR INSULIN RESISTANCE AND -CELL FUNCTION

(Mathews et al 1985, Falutz et al 2002, Summarized : Tjokroprawiro 2005-2015)

HOMA-R

Fasting Insulin (U/mL) x FPG (mmol/L)

22.5

Insulin Resistance

HOMA-B

:
-Cell Function

20 x Fasting Insulin (U/mL)

FPG (mmol/L) 3.5

Clinical Use in Daily Practice

HOMA-R and HOMA-B

ASK-SDNC

(N: < 2.0)

(N: 70150%)

1 RATIONALE TREATMENT
2 FOLLOW-UP OF TREATMENT

MECHANISMS BY WHICH HYPOGLYCAEMIA MAY

AFFECT CARDIOVASCULAR EVENTS

35

(Desouza et al 2010, Provided : Tjokroprawiro 2013-2015)

VEGF
CRP
IL6
INFLAMMATION

NEUTROPHIL
ACTIVATION
BLOOD COAGULATION
ABNORMALITIES

PLATELET FACTOR VII

ACTIVATION

HYPOGLYCEMIA

ENDOTHELIAL
DYSFUNCTION
Vasodilation

3
SYMPATHOADRENAL
RESPONSE

RHYTHM ABNORMALITIES

ASK-SDNC

HEMODYNAMIC CHANGES
Adrenaline
Contractility
Oxygen Consumption
Heart Workload
HEART RATE VARIABILITY

CLINICAL MANIFESTATIONS of POSTmeal HYPERGLYCEMIA (PmH) IDF 2007

36

(IDF-2007, Summarized : Tjokroprawiro 2010-2015)

OTHER EVIDENCE of STATEMENT on POSTmeal HYPERGLYCEMIA

1 PmH causes OXIDATIVE STRESS, INFLAMMATION, and
ENDOTHELIAL DYSFUNCTION

2 PmH is Associated with IMPAIRED COGNITIVE FUNCTION

in ELDERLY PEOPLE with T2DM
3 PmH is Associated with :
INCREASED RISK OF RETINOPATHY
4 PmH is Associated with INCREASED CIMT
5 PmH is Associated with MYOCARDIAL BLOOD
VOLUME and REDUCED MYOCARDIAL BLOOD FLOW
6 PmH is Associated with INCREASED RISK OF CANCER
ASK-SDNC

PROSEDUR PEMANTAUAN (MONITORING)

37

(Konsensus PERKENI-2015, Provided : 2015)

1 Tergantung dari tujuan pemeriksaan tes dilakukan pada waktu (B):
1.
Sebelum makan
2 jam sesudah makan. Tjokroprawiro sejak 2014 (E) : 1 jam sesudah makan
lebih akurat, based on Peak Prandial Plasma Glucose (ADA, 2015)
Sebelum tidur malam
2 Pasien dengan kendali buruk/tidak stabil dilakukan tes setiap hari
2.
3 Pasien dengan kendali baik/stabil sebaiknya tes tetap dilakukan secara rutin.
3.
Pemantauan dapat lebih njarang (minggu sampai bulan) apabila pasien
terkontrol baik secara konsisten
4 Pemantauan glukosa darah pada pasien yang mendapat terapi insulin, ditujukan
4.
juga untuk penyesuaian dosis insulin dan memantau timbulnya hipoglikemia (E)
5 Tes lebih sering dilakukan pada pasien yang melakukan aktivitas tinggi , pada
5.
keadaan krisis , atau pada pasien yang sulit mencapai target , atau (sering
hiperglikemi/sering hipoglikemia ), juga pada saat perubahan dosis terapi
*ADA menganjurkan pemeriksaan kadar glukosa darah malam hari (bed-time) dilakukan pada jam 22.00
ASK-SDNC

SASARAN (TARGET) PENGENDALIAN DM

38

(Konsensus PERKENI-2015, Provided : 2015)

PARAMETER

SASARAN

IMT (kg/m2)
Tekanan darah sistolik (mmHg)
Tekanan darah diastolik (mmHg)
Glukosa darah preprandial kapiler
(mg/dL)

18,5 - < 23*

< 140 (B)
<90 (B)
80 130**

Glukosa darah (Peak Prandial

Plasma Glucose, ADA-2015) 1-2 jam
PP kapiler (mg/dL)

<180** Peak Prandial biasanya

terjadi 1 jam Post Prandial ***)

HbA1c (%)
Kolesterol LDL (mg/dL)

< 7 (atau individual) (B)

<100 (<70 bila risiko KV sangat
tinggi) (B)

Kolesterol HDL (mg/dL)

Trigliserida (mg/dL)

Laki-laki: >40; Perempuan: >50 (C)

<150 (C)

ASK-SDNC

Keterangan : KV = Kardiovaskular, PP = Post Prandial

*The Asia-Pacific Perspective: Redefining Obesity and Its Treatment, 2000
** Standards of Medical Care in Diabetes, ADA 2015
*** Tjokroprawiro sejak 2014

THE ROLES of

APIDRA

&

LANTUS

39

to TARGET HbA1c<7%

(Monnier et al 2003, Clinical Experience & Provided : Tjokroprawiro 2012-2015)

PPG

FPG

CONTRIBUTION (%)

100
80
60
40
20
0
<7.3
n=58

7.38.4
n=58

PPG
APIDRA
ASK-SDNC

8.59.2
n=58

9.310.2
n=58

HbA1c, %
APIDRA

LANTUS

>10.2
n=58

FPG
LANTUS

TARGET TREATMENT : STANDARDS OF MEDICAL CARE IN DIABETES ADA 2014-2015

(ADA-2015, PERKENI 2015,Summarized : Tjokroprawiro 2010-2015)

GLYCEMIC CONTROL (D) :

ADA 2015, PERKENI 2011

A1C (PRIMARY TARGET FOR GLYCEMIC CONTROL)

PRE PRANDIAL CAPILLARY PLASMA GLUCOSE (PPG)

< 7% *) INA : < 7%

80-130 mg/dL
PEAK PRANDIAL CAPILLARY PLASMA GLUCOSE (1hPG) < 180 mg/dL
BLOOD PRESSURE-ADA 2015 (H) :
< 140/90 mmHg **)

LIPIDS (L) :

LDL-C < 100 mg/dL ***)

Severe Hyper-TG (>1000 mg/dL): Immediate Tx with Fibric Acid

Deriv or Fish Oil to Reduce the Risk of Acute Pancreatitis. If HDLChol < 40 mg/dL and LDL-Chol 100-129 mg/dL a Fibrate or Niacin
might be used. CV Risk is more Important than LDL-C Target ***)

GA : Glycated Albumin
(11-16%)

MAGE : PPG 80-130,

1hPG<180
Mean Amplitude of
Glucose Excursion

TARGET : A1C < 7%

Surabaya (outpatient clinic)
(64.2 %, n : 500)
Tjokroprawiro, 2010

* More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized
based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular
complications, hypoglycemia unawareness, and individual patient considerations.
** Based on patient characteristics and response to therapy, lower SBP targets may be appropriate.
***OVERT
OVERTCVD:
CVD:AALOWER
LOWERLDL
LDLCHOL.
CHOL.GOAL
GOALOF,
OF 70
70 mg/dL,
mg/dL, USING
USINGAA HIGH
HIGH DOSE
DOSE OF
OFAASTATIN,
STATIN, IS
IS AN
AN OPTION
OPTION
***
DMOVERT
OVERTCVD
CVDWITH
WITHHIGH-INTENSITY
HIGH-INTENSITYSTATIN
STATINTHERAPY.
THERAPY.
DM
CLINICAL PRACTICE RECOMMENDATIONS, FOCUS ON GDM ADA 2015
1 GDM was defined as any degree of glucose intolerance with onset or first recognition during pregnancy.
1.
2 Women with diabetes in the First Trimester should receive a diagnosis of OVERT, not gestational, DIABETES.
2.
3.
3 The Diagnosis of GDM (One Step with 2-h 75-g OGTT) is made when ANY of the FOLLOWING PLASMA
GLUCOSE VALUES in mg/dL (week 24-28) are EXCEEDED: Fasting > 92; 1 h > 180; 2 h > 153.
(IADPSG consensus). IADPSG : International Association of Diabetes and Pregnancy Study Groups.
4.
4 TARGET TREATMENT of GDM : Preprandial <95, and either 1-h Postmeal < 140 or 2-h Postmeal < 120

ASK-SDNC

40

METHOD-A : AMGA MORNING LANTUS , with AMARYL-M Metformin, Gliptin, Amaryl-M 41

Lantus with AMGA : Amary-M, Metformin, Gliptin, Amaryl-M
(Clinical Experiences : Tjokroprawiro 2003-2015)

LANTUS plus AMGA (AMARIL-M - METFORMIN GLIPTIN AMARYL-M): SAFE FOR MCR
*) OAD is Given if
HOMA-B > 25%

The ROLE of HOMA-B in CTOI (N: 70-150%)

1. HOMA-B > 25% : Use Basal + Met + Gliptin + OAD*)
FX2 : FORMULA X 2
or
2. HOMA-B > 25% : Use Basal Plus + Met + Gliptin + OAD*)
)
F
X
1:
FORMULA
X1
3. HOMA-B > 25% : Use Basal-Bolus + Met + Gliptin + OAD*
4. HOMA-B < 25% : Use Basal-Bolus + Met + Gliptin + No OAD*)

MCR: Metabolic,
Cardioprotective, BREAKFAST : 6.30 am
Renoprotective
Fritsche et al 2003
MORNING LANTUS
(METHOD A) is BETTER
than BEDTIME LANTUS
(METHOD B)

MORNING LANTUS
6-30 u sc
AMARYL-M
ASK-SDNC

LUNCH : 0.30 pm

DINNER : 6.30 pm

PRANDIAL APIDRA ( FX2)

PRANDIAL APIDRA ( FX2)

9.30 am

3.30 pm

9.30 pm

Snack

Snack

Snack

OPTIONAL Tx
METFORMIN (MET), GLIPTIN

AMARYL-M

LANTUS in combination with AMARYL-M in METHOD-A is the rationale

theurapeutic regimen in the management of T2DM for better MCR: glycemic
control (M), for risk reduction of CVDs (C), and for of cancer protection (C)

42

THE ROLES OF RUMUS KALI DUA : FORMULA X2 in RGC

INDICATED FOR HYPERGLYCEMIA*) > 200 mg/dL IN DAILY PRACTICE
(Clinical Experiences : Tjokroprawiro 2007-2015)

*) One Hour Post Prandial or Random Hyperglycemia RC : RAPID CONTROL

SC-INJECTION : FORMULA X2. RC with APIDRA ...Unit/Once (!)

For Out- and In- Patients IF HYPERGLYCEMIA >200 mg/dL
RGC : Rapid Glycemic Control
Exp.: BS 240 mg/dL

APIDRA Dose (SC): 2 x 2 = 4u /once

APIDRA

BS 380 mg/dL

APIDRA Dose (SC): 3 x 2 = 6u /once

APIDRA

BS 450 mg/dL

APIDRA
APIDRA

APIDRA
ASK-SDNC

Dose (SC): 4 x 2 = 8u /once

Onset of Action 5 15 Minutes,

: Peak 1-2 Hours, Duration of Action 3-4 Hours

43

THE ROLES OF RUMUS KALI SATU: FORMULA X1 in RGC

INDICATED FOR HYPERGLYCEMIA*) > 200 mg/dL IN DAILY PRACTICE
(Clinical Experiences : Tjokroprawiro 2007-2015)

*) ONE HOUR POST PRANDIAL OR RANDOM HYPERGLYCEMIA

FORMULA X1 RC with S.C. Rapid - Ins : can be Repeated on Indication

*) For Out- and In- Patients
RGC : Rapid Glycemic Control IF HYPERGLYCEMIA >200 mg/dL
Exp.:

BS 240 mg/dL

APIDRA

Dose : 2 x 1 = 2u /once

BS 380 mg/dL

APIDRA

Dose : 3 x 1 = 3u /once

BS 450 mg/dL

APIDRA

Dose : 4 x 1 = 4u /once

APIDRA:
ASK-SDNC

Onset of Action 5-15 Minutes,

Peak 1-2 Hours, Duration of Action 3-4 Hours

The 34 ENDOCARDIOMETABOLIC PROPERTIES OF INSULIN

(The Multitude of Insulin Effects)

44

(Summarized Illustrated : Tjokroprawiro and Murtiwi 2009-2015)

25
24
23

Cell Cycle and Proliferation

and Diff. of Cell
Uric Acid Clearance
Uric Acid Formation

RESTORE
LH, FSH, TESTOSTERON

21 MATURATION OF ADIPOCYTE
(mTORC1, CREB, C/ EBP, GPDH)
20

LIPOLYSIS via HSL

(Hormone Sensitive Lipase)

19 LIPOGENESIS via LPL

(Lipoprotein Lipase)
18

PROTEIN SYNTHESIS

17

FA & AA to Ketoacids
AA Transport

16
15

GLYCOGEN SYNTHESIS
BONE ANABOLIC
( OSTEOGENESIS)

ASK-SDNC

ANTI-INFLAMMATION
IB, NFB, TNF,
ICAM-1, MCP-1, CRP

Egr : TF, PAI-1, Ap-1 ( MMPs)

(Avogaro et al 2011)

27

HSP 70 / 72 / 90
(Wound Healing, Etc)

30 CORTICOSTERON-DEPENDENT INSULIN RESISTANCE

CARDIO-PROTECTION
(ANIMALS, HUMAN)

29 EPCs SURVIVAL

ANDROGEN :

DHEAS, ANDROSTENE-DIONE,
TESTO, DH TESTOSTERONE
22

1 GLYCEMIC CONTROL
GLUT-4 Synt. & Transl, Glucose, A1C

ANTI-ATHEROSCLEROSIS
5
NADPH oxidase, ROS, IB,
NFB ( ICAM, MCP, CRP)
6

PROFIBRINOLYSIS ( PAI-I)

VASODILATATION
( eNOS, iNOS, NO)

34 Mt Biogenesis, Oxidative Capacity, ATP

ANTI-PLATELET ( c-AMP)

33 Brain : Appetite & Energy Expenditure

34 INSULIN PROPERTIES

32 PLASMA ARGINASE ACTIVITY

10

ANTI-APOPTOSIS
(Heart, Brain, Cell)

11

ANTI-OXIDANT ( ROS)

12

ADMA : PLASMA & END.

( NO : RENOFIBROSIS)

31 GLUCAGON SECRETION
14 GROWTH DEVELOPMENT
HYPOTHETICAL WAY TO TUMOR
VIA IGF1 RECEPTOR ?
28 ARTERIAL VASODILATOR
(SKELETAL MUSCLE VASCULAR BEDS)

ANTI-THROMBOSIS
( TISSUE FACTOR)

13

RONS
( RENAL FIBROSIS)

26 VASPIN mRNA IS INCREASED WITH INSULIN INJECTION IN SEVERE INSULIN RESISTANCE