INSULIN

Dr. Widyaningsih, SpPD

 (OAD)

I Insulin Secretagogues : - Sulphonylureas (Gen I, II, III : Glimepiride)

- Non-Sulphonylureas (Metaglinides : Nateglinide, Repaglinide)
II Insulin Sensitizers :
1 Thiazolidinediones (TZDs): Glitazone Class (Rosiglitazone, Pioglitazone)
2 Non-TZDs :
a Glitazar Class (Muraglitazar*), Ragaglitazar, Tesaglitazar) : MRT
b Non-Glitazar Class (Metaglidasen : Non Edema and Non Weight Gain)
3 Biguanide : - Metformin XR (Glucophage® XR)
- 3-Guanidinopropionic-Acid *) Withdrawn

III Intestinal Enzyme Inhibitors : 1 -Glucosidase Inhibitor : Acarbose

2 -Amylase Inhibitor : Tendamistase
IV Fixed Dose Combination Types :
Glucovance, Avandamet, Avandaryl, Amaryl-M, Duet act, Actoplusmet
V Other Specific Types : DPP-IV Inhibitors (Vilda-, Sita-, Alo-, Saxa-gliptin)
 INSULIN IN CLINICAL USE

PAST AND PRESENT PRESENT AND FUTURE

NATIVE HUMAN INSULINS INSULIN ANALOGUES

Clinical Use : Since Early 1922s Recombinant Human Insulin: Since 1980s

Actrapid, Insulatard-Monotard, Mixtard RAPID-ACTION : 7 LONG ACTION : 7

1 Lispro (LysB28, ProB29)
Regular-Semilente, NPH-Lente, Ultralente Humalog 2006
2 AspB9
3 AspB10
4 AspB28 (Aspart)
5 Glu B21 NovoRapid 2007
6 Glu B27
7 Glulisine (Apidra,2007)
1 GLARGINE (2000)
2 Detemir (2007)
3 Humalog Mix25(2006)
4 NovoMix30 (2006)
5 Novo Sol BASAL
6 W99-S32
7 C16-HI
 Pharmacokinetics of Human Insulin and Insulin Analogues

ONSET OF PEAK OF ACTION DURATION OF

INSULIN PREPARATION
ACTION (HRS) ACTION (HRS)
RAPID-ACTING
Regular Human Insulin = RHI*) 30-60 mins 2-4 6-8
Insulin Glulisine (Apidra) 5-15 mins 1-2 3-4
Insulin Lispro (Humalog) 5-15 mins 1-2 3-4
Insulin Aspart (NovoRapid) 5-15 mins 1-2 3-4
INTERMEDIATE-ACTING
NPH 1-3 hrs 5-7 13-16
Lente 1-3 hrs 4-8 13-20
LONG-ACTING
Insulin Glargine (LANTUS) 1-3 hrs No Peak 24
Detemir (Levemir) 1-3 hrs Dose Dependent 20-24
Peak
Ultralente PEAKLESS INSULIN 2-4 hrs 8-14 22-26 hrs
PREMIXED
Insulin Lispro 75-25 (Humalog Mix25) 10 mins 1-4 10-20
Insulin Aspart 70/30 (NovoMix) 10 mins 1-4 16-20
 INDIKASI TERAPI INSULIN
 DM tipe 1
 DM tipe 2:
- GAGAL dg OADKendali GD yg buruk: GDP > 250 mg/dl , GDA
menetap > 300 mg/dl, A1C > 6,5% ,ketonuria, dlm jangka wkt 3
bln dg OAD
- Gejala 3P ( defisiensi insulin yg berat), jika gx hilang bisa
kembali ke OAD
- Riwayat pankreotomi disfungsi pankreas, Riwayat fluktuasi GD
yg lebar, Riwayat KAD
- Penyandang DM > 10th
- * Px kritis/akut spt hiperglikemia gawat darurat, IMA,
kardiogenik syok, CVA, fraktur, infeksi sistemik, transplan organ,
edema anasarka, kln kulit yg luas, persalinan, pengguna steroid
ds tinggi, perioperatif
- INSULIN DINI: perbaikan luaran klinis yi:
perbaikan fs pancreas, mencegah kerusakan
endotel, menekan inflamasi, mengurangi
apoptosis & perbaikan profil lipid
INSULIN ANALOG  lbh FISIOLOGIS
 The 17 BENEFICIAL EFFECTS OF INSULIN

17 RESTORE LH, FSH, 1 GLYCEMIC CONTROL 2 CARDIO-PROTECTION

TESTOSTERON  AIC (ANIMALS, HUMAN)

16  LIPOLYSIS
(FFA Rel., TG,HDL-C)
15  ADMA IN PLASMA
AND ENDOTHELIUM
14  BONE ANABOLIC
( OSTEOGENESIS)
3 ANTI-ATHEROSCLEROSIS
4 PROFIBRINOLYSIS
( PAI-I)
17 INSULIN 5 ANTI-THROMBOSIS
( TISSUE FACTOR)
BENEFITS
6 ANTI-PLATELET
( c-AMP)

13  PLASMA ARGINASE
7 VASODILATATION
( UREA)
( NO,  eNOS)
9 ANTI-INFLAMMATION
12 ANTI-OXIDANT IB, NFB, MCP-1, 8 ANTI-APOPTOSIS
( ROS) TNF, ICAM-1, CRP (Heart, Brain,  Cell)

11 VASPIN IS INCREASED WITH INSULIN INJECTION 10 ↑ “LIPOGENESIS”

HAKEKAT

 Menurunkan kadar glukosa PUASA dan

PRANDIAL
mk diperlukan INSULIN BASAL + INSULIN
PRANDIAL
 Glukosa darah prandial dipengaruhi basal
maka Penurunan kadar glukosa basal jg
diikuti penurunan kadar glukosa pandrial
CARA PEMBERIAN INSULIN BASAL

 Insulin kerja cepat iv (RCI): novorapid (Rawat

Inap)

 Insulin kerja panjang sc yi LEVEMIR

 PEMBERIAN INSULIN IDEAL SESUAI
KEADAAN FISIOLOGIS TUBUH
 INSULIN BASAL 1X
 INSULIN PRANDIAL 3X

Dapat divariasi sesuai dg kenyamanan px seperti INSULIN 2x

sblm makan PAGI & MALAM dianggap mendekati fisiologis
kecuali DM tipe 1 kr sangat sulit mencapai kendali glukosa
darah baik, sedangkan pd DM tipe 2 kekurangan insulin tdk
mutlak
INSULIN BASAL malam 1x + OAD (metformin) 
mengurangi ES Insulin spt BB yg meningkat
INSULIN BASAL + OAD (Met/glitazon) u/ resistensi insulin
INSULIN BASAL + met + Sulfoniluria
DM tipe 1

Insulin Total Harian = 0,5 unit/BB

miss BB=60 kg 30 unit
Insuli Prandial = 60 %= 18 unit 3 x 6 u ac
Insulin basal = 40% = 12 unit malam
 VARIASI GDP dan 2JPP
 GDP & 2 JPP tinggi
ICU: RI iv
DM tipe 1: (1) LEVEMIR 1x mlm
+ NOVORAPID 3x
DM tipe 2: (1) LEVEMIR 1 x mlm
+ NOVORAPID 3x + OAD
(2) Novomix 2x pagi & malam ac
Usia lanjut: LEVEMIR 1x pagi
GDM: LEVEMIR 1x + NOVORAPID 3x
 VARIASI GDP dan 2JPP

 GDP tinggi & 2 JPP baik

mkn malam besar/spjg: LEVEMIR 1x malam
 VARIASI GDP dan 2JPP

 GDP baik & 2 JPP tinggi

DM tipe 2 dg gagal parsial dg OAD, SH, CKD:
(1) levemir 1x (2) Novorapid 3x
Tx steroid pagi:
levemir 1x pagi + novorapid 3x
GDM: levemir 1x pagi
+ novorapid (jika diperlukan)
SASARAN KENDLI GLUKOSA DARAH

 Puasa : 80 – 110 mg /dl

 1 jam sth makan : < 180 mg / dl
 Pasien Bedah dan keadaan kritis: 80 – 110
mg/ dl
RAWAT INAP

 Insulin Basal : 50% Total keb insulin per hari

 Insulin Prandial : 50 %
 Insulin Koreksi : 10-20%

 15 gram KH = 60 kal dibutuhkan 1 u

 INSULIN IV

INDIKASI
* Px kritis/akut spt hiperglikemia gawatdarurat, IMA,
CVA, fraktur, infeksi sistemik, kardiogenik syok,
transplan organ, edema anasarka, kln kulit yg luas,
persalinan, pengguna steroid ds tinggi, perioperatif

SASARAN
 kritis bedah 80-110
 kritis non bedah /bedah tdk kritis 90-140
 Protokol TX INSULIN IV
 ICU:
- > 220 : mulai 2-4 u/jam
- 110-220 : mulai 1-2 u/jam
- < 110: insulin tdk diberikan, periksa GD tiap 4 jam

- >140 : naikkan 1-2 u /jam

- 110-140: naikkan 0,5-1 u /jam
- tercapai normal:sesuaikan ins 0,1-0,5 u /jam,
dipertahankan, diturunkan setengahnya, GD tiap 1
jam, jka < 80 stop insuli di+ D40% cek tiap jam
IV ke SC

Px dg infus 2 u / jam selama 6 jam terakhir

Sc = 80% x 48 u = 38 u
Basal = 50% = 19 u malam
Bolus = 50% = 19 u  3 x 6 u ac
PROTOKOL TX INSULIN SC

 Levemir: 10 u malam atau 5 u jika khawatir

hipo atau 15 u jika obes, inf, luka terbuka,
pakai steroid, post CABG
dosis disesuaikan sp target 80-110
 Novorapid: 0,1 u /bb tiap mkn
jika 200-299 : tambahkan 0,075 u /bb
> 300 : 0,1 U/BB
dosis disesuaikan sampai target 120-200
KAD

 Awal 10 unit (0,15 u /bb)

 5 u /jam (0,1 u/bb/jam)
 Naikkan 1 u setiap 1-2 jam bila penurunan < 10%
atau status asam basa tdk membaik
 Kurangi 1-2 u/jam bila < 250 atau kx membaik, kadar
gula turun > 75 /jam
 Pertahankan 140-180
 Jika < 80 stop insulin maks 1 jam
 Jika selalu < 100 infus D10 sp kadar 140-180
 Jika px bisa makan ganti dg sc, jika sbelumnya tdk
pernah insulin ds sc total 0,6 u /bb (50%basal 50%
prandial)
 Avoid SIDS ! : Subcutaneous Insulin Degradation Syndrome
Sites of SC Insulin Injection at the Healthy Areas
Distance between the two Sites of Injection : Minimally 2.5 cm

76-90 1-15

61-75 16-30

46-60 31-45

ASK-DNC
 Injeksi Subkutan
NovoMix® 30 (NM)
Human Insulin (HI)
Efek Farmakodinamik

0 2 4 6 8 10 12 14 16 18 20 22 24
Waktu (jam)
Mula Kerja : 10 – 20 menit
Lama Kerja : 24 jam
Aktifitas puncak : 1 – 4 jam
(Weyer et al 1997)
ASK-DNC
INITIATE STUDY : KASUS GAGAL DENGAN OAD
(Raskin et al 2004)

NovoMix® 30

42%*

AIC INSULIN GLARGINE

< 6.5% 28%*

ASK-DNC
 ALGORITHM FOR THE METABOLIC MANAGEMENT OF T2DM
(ADA / EASD Recommendations 2009)
TIER 1 : WELL-VALIDATED CORE THERAPIES
LIFESTYLE – METFORMIN LIFESTYLE – METFORMIN
+ +
At diagnosis: BASAL INSULIN INTENSIVE INSULIN

LIFESTYLE Detemir can be used in

+
LIFESTYLE – METFORMIN Basal / Basal Plus Regimen,
METFORMIN + and Aspart as Prandial Insulin
from Initiation to Insulin Intensification
SULFONYLUREA

STEP 1 STEP 2 STEP 3

TIER 2 : LESS WELL-VALIDATED THERAPIES

LIFESTYLE – METFORMIN LIFESTYLE – METFORMIN
+ + S Sulfonylurea
PIOGLITAZONE PIOGLITAZONE
No Hypoglycaemia + M Metformin
Oedema/CHF SULFONYLUREA
Bone loss I Insulin
LIFESTYLE – METFORMIN L Lifestyle
+ LIFESTYLE – METFORMIN
GLP-1 AGONIST E Exclude Others
No Hypoglycaemia
+
Weight loss BASAL INSULIN
Nausea/vomiting
 Therapeutic Algorithm for CTOI in T2DM

HEALTH EDUCATION, MNT, EXERCISE (TARGET : WEIGHT LOSS 5-10%)

Aim
LIFESTYLE + METFORMIN + SU or Non SU
AIC GLITAZONE GLUCOSIDASE INHIBITORS

ORAL COMBINATIONS : 2-4 COMBINATIONS

INDICATIONS OF CTOI : PRIMARY AND SECONDARY
CRITERIA :FORMULAS 2-4-8 AND/OR HOMA-B
FPG > 200, 2H-PG > 400, AIC > 8%, HOMA-B < 35%-50%

<7% Timely Use of Basal Insulin Reinforced as a Core Therapy for T2DM

Excellent Control Need Insulin : Candidates for CTOI

INSULIN PLUS ORAL AGENTS FOR DIABETES

HOMA-B = Normal 70-150% CTOI : COMBINED THERAPY OAD AND INSULIN
*) EARLY INSULINATION : HOMA-B < 35-50%
 Combined Therapy Oral Agent and Insulin
(CTOI)

I PRIMARY INDICATION : PERKENI-2006 PLUS

1 USE FORMULA 2-4-8 : 2 : FPG > 200 mg/dl
4 : 2h-PG> 400 mg/dl
8 : AIC > 8 %
2 HOMA-B < 35% (Normal : 70-150%)
3 EARLY INSULINATION, if :
- HOMA-B < 50%
- SEVERE UNCONTROLLED WEIGHT LOSS (More than 10%)
Continued
 COMBINED THERAPY OAD AND INSULIN
(CTOI)

II SECONDARY INDICATION for diabetic patients with :

1 Bone Fractures
Hemodialysis Pts with
2 Moderate-Severe Renal Failure Diabetic Nephropathy
3 Advanced Pulmonary Tbc
4 Decompensated or Special Cases of Liver Cirrhosis
5 Uncontrolled or Severe Weight-Loss
6 Other Specific Cases : Non-Active Gangrene, Etc
 METHOD-A with LEVEMIR in the Morning
OAD : ORAL ANTI DIABETES METFORMIN : AFTER MEALS
Breakfast : 6.30 am Lunch : 0.30 pm Dinner : 6.30 pm

9.30 am 3.30 pm 9.30 pm

Snack Snack Snack

LEVEMIR OADS OADS

6-30 u sc METFORMIN METFORMIN
METFORMIN
OADS : OPTIONAL METFORMIN DOSE : 1500 – 2000 mg/day

METHOD-A : CTOI with LEVEMIR and OAD - METFORMIN

 GLIMEPIRIDE COMBINED WITH MORNING INSULIN GLARGINE,
BEDTIME NEUTRAL PROTAMINE HAGEDORN INSULIN, OR
BEDTIME INSULIN GLARGINE IN PATIENTS WITH T2DM
(Fritsche et al. in Ann Intern Med 2003;138:952-959)

RANDOMIZED, CONTROLLED TRIAL

The Risk for Nocturnal Hypoglycemia was Lower with
Glimepiride in Combination with Morning and Bedtime
Insulin Glargine than with Glimepiride in Combination with
Bedtime NPH Insulin in Pts with T2DM.
MORNING INSULIN GLARGINE Provided Better Glycemic
Control than did BEDTIME INSULIN GLARGINE or
BEDTIME NPH INSULIN. (Fritsche et al. 2003)
 21

THE ROLES OF NOVORAPID IN

FORMULA X2 IN DAILY PRACTICE

SC-INJECTION : FORMULA X2 – NOVORAPID ..?.. u/Once (!)

(Mostly for Out-Patients) RANDOM GLYCEMIA (>200 mg/dl)
Exp. :  BS 240 mg/dl NOVORAPID  Dose (SC): 2 x 2 = 4 u/once
 BS 380 mg/dl NOVORAPID  Dose (SC): 3 x 2 = 6 u/once
 BS 450 mg/dl NOVORAPID  Dose (SC): 4 x 2 = 8 u/once

These Interventions can be done 1 – 2 – 3 Times/day

Given Anytime as long as Blood Sugar Levels > 200 mg/dl
 RAPID GLYCEMIC CONTROL (RGC) WITH I.V. INSULIN : FORMULA –1 , x12 , 3 , x2
Emergency Cases : Sepsis – Acute Stroke – Hyperglycemic Crisis, Etc.

DIABETIC Pts : f.e. With Blood Glucose 720 mg/dl

Reagen Lactat Infusion 1000 ml/day : NovoRapid I.V. 4 Units per Hour

A B
Rapid Glycemic Control (RGC) Insulin Syringe Pump
FORMULA (-1) FORMULA x12

7 Minus One = 6 7 x 12 = 84
6 Times 4 u NovoRapid IV/Hour 84u NovoRapid /24 ml/24 hours

Recheck Blood Sugar Level Every 3 Hours after A and B Regimens have been Finished
If Blood Sugar Level is still higher than 250 mg/dl, FORMULA -1 ( A ) and x12 ( B ) should be
Repeated until Blood Sugar Levels less than 250 mg/dl

NovoRapid SC : 7 x 2 = 14
Repeat RGC Glucose > 250 mg/dl Glucose < 250 mg/dl
FORMULA (x2)

MAINTENANCE FLUID THERAPY

 34
Clinical Experiences with Formula 1/3 in CTOI

1 Inpatients treated with NovoRapid (NovoR) 60 units/day :

AR 20 units TID
Use Formula 1/3
Methods-A, or B
A - Levemir/NovoMix : 20 units Mornings
- OADs and/or Metformin Afternoon and/or Evenings
or
B - Levemir/NovoMix : 20 units Evenings
- OADs and/or Metformin Evening and/or Afternoons
PERKENI-Consensus 2006 : Insulin Dose > 30 Units/day in CTOI
is not Recommended STOP OAD, and Give Premixed Insulin Twice Daily
ASK-DNC
Continued
Clinical Experiences with Formula 1/3 in CTOI
()

2 Outpatients failed with 2-4 Oral Agents :

depending on 2h-PPG , and Special attention to
the figures of the first two fe. : 2h-PPG 360 mg/dl , the 1st two is 36

Formula 1/3 (based on figures of the first two) :

Use Methods-A or B
- Levemir/NovoMix : 12 Units Mornings (1/3 of 36 = 12)
a
- OADs and/or Metformin
or
b - Levemir/NovoMix : 12 units Evenings
- OADs and/or Metformin
ASK-DNC
 CTOI for Discharged Inpatient and Outpatient

CTOI Levemir or NovoMix with OADs and/or Metformin

INPATIENTS OUTPATIENTS
Well Controlled with NovoR 20 Units tid Failed Pts with OADs (2-4 Combinations)

Total Dose 60 U 2h-PPG = 3 6 0 mg/dl

Formula 1/3 : 20 U Formula 1/3 : 12 U

Methods : A or B Methods : A or B
Lev./N.Mix : 20 U/Mornings or Evenings Lev./N.Mix : 12 U/Mornings or Evenings
CTOI CTOI
OAD and/or Metformin OAD and/or Metformin

Follow-up : Doses of Levemir or NovoMix and OADs are subject to change

Formulas : Step Up : 3-3-5 or Step Down : 2-2, 2-1 , 1-2, 1-1

ASK-DNC