ESW/MAR-17/RTD LVM-2017/001

Early Insulin Initiation in type 2

DM Management
ESW/MAR-17/RTD LVM-2017/001

Indonesia is One of The Largest Diabetes Population

Top 10 Countries/Territories of number

Of people with diabetes (20-79 years), 2014

China 96,2

India 66,8

USA 25,7

Brazil 11,6

Indonesia 9,1 5
Mexico 9

7 Egypt 7,5

German 7,2
7
Turkey 7,2

Japan 7,2

Prevalence: 5,55% (adult pop.) Prevalence: 5,55% (adult pop.)

Sources :
1. IDF Diabetes Atlas, 6th ed
2. IDF Diabetes Atlas 6th ed UPDATE
3. IDF Diabetes Atlas, 7th ed
 3

DIABETES MENJADI ANCAMAN KESEHATAN DI

SELURUH DUNIA !!!

55.2
66.2
37.4 +20%
53.2
Africa +42%
Middle East and
North Africa 76.7
112.8
Europe
26.5 +47%
North America 51.7
+94%
South and Central America 58.7
101.0
South-East Asia
12.1 +72%
Western Pacific 23.9
16.0
29.6 +98%
+65%

Seluruh dunia :
284.6 juta orang tahun 2010
438.4 juta orang diperkirakan tahun 2030
IDF. Diabetes Atlas 4th Edition 2009 Meningkat 54%
 KLASIFIKASI DM

prevalensi 10%, seringkali terdiagnosis

DM tipe 1 pada usia anak-anak, dan seumur
hidupnya tergantung dengan insulin

DM tipe 2
prevalensi 90%, pada usia dewasa

DM tipe lain : tumor, infeksi, obat-obatan, penyakit sistem imune

DM gestasional : DM saat kehamilan

 SIAPA SAJA YANG BISA TERKENA
DM ?
1. Usia 45 tahun
2. Usia < 45 tahun, terutama dengan kegemukan, yang disertai dengan
faktor resiko :
kebiasaan tidak aktif
turunan pertama dari orang tua dengan DM
riwayat melahirkan bayi dengan BB lahir bayi > 4000 gram, atau
riwayat DM gestasional
hipertensi ( 140/90 mmHg)
kolesterol HDL 35 mg/dL dan atau trigliserida 250 mg/dL
menderita polycystic ovarial syndrome (PCOs) atau keadaan lain
yang terkait dengan resistensi insulin
adanya riwayat toleransi glukosa terganggu (TGT) atau glukosa darah
puasa terganggu (GDPT) sebelumnya Prediabetes
memiliki riwayat penyakit jantung
 BAGAIMANA DIAGNOSIS DM
DITEGAKKAN ?

1. Gejala klasik DM + GDA 200 mg/dL

atau
2. Gejala klasik DM
+
GDP 126 mg/dL dengan puasa 8 jam
atau
3. 2 jam PP TTGO 200 mg/dL
TTGO dengan beban 75 g glukosa

Keluhan klasik DM : rasa haus yang berlebihan, sering kencing terutama malam hari dan
berat badan menurun dengan cepat.
Keluhan lain dapat berupa lemah badan, kesemutan, gatal, mata kabur, gairah seks
menurun, luka sukar sembuh.
 DIAGNOSTIC CRITERIA FOR
PREDIABETES

Pre-Diabetes Diabetes
100 < FBG < 126 > 126
140 < PPG < 200 > 200
5.7 < A1C < 6.5%* > 6.5%*

* A1C not yet recommended in Indonesia

PERKENI Consensus Guidelines, 2011.

 DIABETES : A MALIGNANT VASCULAR DISORDER

Stroke
Menyebabkan Resiko stroke dan
kebutaan peny. jantung
koroner meningkat
Diabetic 2-4x lipat
Retinopathy

Cardiovascular
disease

Diabetic
Myocardiac infarct
Nephropathy Penyebab kematian
utama pasien DM
Merupakan 40% penyebab
gagal ginjal, sehingga Diabetic
pasien harus menjalani cuci Neuropathy
darah/hemodialisis.
Penyebab utama
tindakan amputasi

National Diabetes Information Clearinghouse. Diabetes StatisticsComplications of Diabetes.

http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.
ESW/MAR-17/RTD LVM-2017/001

Type 2 Diabetes is a Progressive Disease

HOMA: homeostasis model assessment

Lebovitz. Diabetes Reviews 1999;7:13953 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:124958)
 MANAJEMEN DIABETES MELLITUS TIPE 2

Kendali Glukosa Kendali Penyakit Penyerta Penapisan/Pengelolaan

Diet/gaya hisup sehat Dislipidemia Komplikasi
Aktifitas jasmani Hipertensi Retinopati
Obat/insulin Obesitas Nefropati
Penyakit jantung koroner Neuropati
Peny.kardiovaskular
Komplikasi lain
 terapi diabetes mellitus

1. Diit 2. Olah raga

3. Pengendalian BB 4. Obat : Pil / Insulin 5. Kontrol teratur

 INTERVENSI FARMAKOLOGIS
INTERVENSI FARMAKOLOGIS DITAMBAHKAN JIKA SASARAN KADAR
GLUKOSA DARAH BELUM TERCAPAI DENGAN PENGATURAN MAKAN
DAN LATIHAN JASMANI

1. Obat anti diabetes (OAD) dalam bentuk tablet

2. Insulin

Apabila dokter menyarankan anda

menggunakan insulin, maka bukan
berarti penyakit Diabetes anda
memburuk.
Melainkan, semata-mata untuk
mencapai target glukosa darah.
 1. OBAT HIPOGLIKEMIK ORAL

Digolongkan berdasarkan cara kerjanya:

1. Pemicu sekresi insulin/secretagogue (Sulfonilurea dan Glinit)

2. Penambah sensitifitas terhadap insulin: Metformin dan Tiazolidindion
3. Penghambat absorbsi glukosa:penghambat oksidase alfa
 INSULIN
Cara kerja Insulin: Fungsi utama mengkounter hormon peningkat glukosa
dan mempertahankan gula darah normal, menstimulasi lipogenesis,
menurunkan lipolisis dan meningkatkan transport asam amino ke dalam sel,
menstimulasi pertumbuhan, sintesis DNA dan replikasi sel.

Indikasi terapi insulin:

DM tipe 1/IDDM
DM tipe 2/NIDDM yang tidak berespon dengan pengobatan OHO
DM tipe 2 dengan stress berat
Penurunan BB yang cepat
Ketoasidosis diabetik/HHS
DM pada kehamilan
Gangguan fungsi ginjal atau hati yang berat
/LEVEMIR /NOVO
ESW/MAR-17/RTD LVM-2017/001

Insulin remains the most efficacious glucose

lowering agent
Decrease in HbA1c: Potency of monotherapy
HbA1c %

CHOOSING INSULIN EARLIER

FOR BETTER EFFICACY

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

SOLVE: HbA1c at time of insulin initiation

Baseline HbA1c at time of

insulin initiation The average HbA1c was 8.9%
Prior to insulin initiation, patients
had received OAD therapy for
8.76.7 years
HbA1c (%)

Patients remain poorly controlled

on OAD treatment for prolonged
periods of time

Khunti et al. Diabetes Obes Metab 2012;14(7):65461

T2DM Antihyperglycemic Therapy: General Recommendations
Healthy eating, weight control, increased physical activity
Initial Drug Initial Drug Monotherapy Metformin

Monotherapy Efficacy (HbA1c) High

Hypoglycemia Low risk

Weight Neutral / loss

Side effects GI / lactic acid

Costs Low

If needed to reach individualized HbA1c target after -3 months, proceed to 2-

drug combination (order not meant to denote any specific preference)

Two Drug Two drug combinations Sulfonylurea Thiazolidine-dione DPP-4 Inhibitor GLP-1 receptor Insulin (usually
agonist basal)
Combinations
Efficacy (HbA1c) High High Intermediate HIgh Highest

Hypoglycemia Moderate risk Low risk Low risk Low risk High risk

Weight Gain Gain Neutral Loss Gain

Side effects Hypoglycemia Edema, HF Rare GI Hypoglycemia

Costs Low High High High Variable

Sulfonylurea + Thiazolidine-dione + DPP-4 Inhibitor + GLP-1 receptor Insulin (usually

agonist + basal)
Three Drug
Combinations TZD SU SU SU TZD

Or DPP-4-i Or DPP-4-i Or TZD Or TZD Or DPP-4-i

Or GLP-1-RA Or GLP-1-RA Or Insulin Or Insulin Or GLP-1-RA

Or Insulin Or Insulin

If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents

More complex Insulin

insulin strategies (multiple daily doses)
Diabetes Care. Diabetologia 19 June 2012
MANAGING INPATIENT
HYPERGLYCEMIA
 27

RECOMMENDATIONS FOR
MANAGING INPATIENT
Antihyperglycemic Therapy
HYPERGLYCEMIA

Insulin Oral Agents

Recommended Not generally
recommended

IV Insulin SC Insulin:
Critically ill ICU Programmed/Scheduled
patients Non-critically ill patients

Clement S, et al. Diabetes Care 2004; Moghissi ES, et al. Endocr Pract 2009.
 INSULIN THERAPY IN THE HOSPITAL: 28

PRACTICAL GUIDELINES
Programmed/Scheduled Insulin Correction
Basal Nutritional (supplemental)
Long-acting (preferred) Rapid (preferred) Rapid (preferred) or
regular
Glargine or detemir Aspart, glulisine, lispro, or
Usually bedtime or AM regular When fingerstick BG
Before meal above target value
or NPH
BID (or bedtime)

Insulin drip
(Regular or rapid)
Pre-mixed insulins

Clement S, Ahman A, Braithwaite S, Magee MF, Hirsch et al. Diabetes Care 2004;27:553591.
 29

INITIATING INSULIN THERAPY IN THE

Obtain patient weight in kg
HOSPITAL

Calculate total daily dose (TDD) as

recommended by hospital protocol

Choose the dosing schedule

TDD: 50-60% basal insulin; 40-50% bolus
(pre-meal or nutritional) insulin
Correction insulin as needed

Adjust as needed based on BG

monitoring, NPO and clinical status
 30

OAD THERAPIES IN HOSPITALIZED PATIENTS:

CONSIDERATIONS
Sulfonylureas: major cause of hypoglycemia

Metformin: contraindicated if decreased renal blood flow, use of iodinated

contrast dye, and poor tissue perfusion (CHF, sepsis)

Thiazolidinediones: associated with edema and CHF

ESW/MAR-17/RTD LVM-2017/001

Levemir is approved in special population

Levemir can be used in pregnant women and children 2 years

Levemir Indonesia Prescribing Information 2017

ESW/MAR-17/RTD LVM-2017/001

Summary of A1chieve study in Indonesia

Insulin nave participants initiated on IDet (Indonesia)

Efficacy Safety Other

Baseline HbA1c HbA1c FPG PPG Hypoglycaemia Weight

IDet 9.5% 2.2% 101

mg/dL
115
mg/dL
1.0*

Significant improvement
(p<0.001)

*p<0.001

Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47S53
ESW/MAR-17/RTD LVM-2017/001

Summary

Indonesia is one of the largest diabetes population

Diabetes is a progressive disease which will lead to the need of insulin therapy
Insulin therapy is the most efficacious therapy and can reduce HbA1c up to
2,5%
Starting with basal insulin detemir 10 U once daily and titrate based on patient
condition to reach glycemic control
In Indonesia, in real life clinical practice (A1chieve study), Levemir show
significant improvements in overall glycemic control in terms of HbA1c, FPG,
PPG and patient quality of life
ESW/MAR-17/RTD LVM-2017/001

Levemir
LysB29(N-tetradecanoyl)des(B30) human insulin

Phe Phe Gly Arg

Albumin-binding Pro
Thr
Tyr Glu
Gly
Cys
moeity Thr
Lys
Lys
B29 A21 Asn Cys
Val
Tyr Leu
A1 Gly Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu Gln Glu
Gln Tyr Val
Cys Leu
Cys Ser Leu
Thr Ser Ile Cys
His
Ser
Gly
Cys
Asn Gln His Leu
B1 Phe Val

Whittingham et al. Biochemistry 1997;36:2826

ESW/MAR-17/RTD LVM-2017/001

Pharmacological interventions in T2D

Plasma glucose
-Glucosidase Glitazones
Carbohydrate Glucose Glucose
inhibitors absorption production uptake (+)
()

()
Insulin
secretion
Metformin (+)

Insulin
(+)
Sulphonylureas
Meglitinides
GLP-1 analogues
DPP-4 inhibitors
ESW/MAR-17/RTD LVM-2017/001

Type 2 Diabetes is a Progressive Disease

HOMA: homeostasis model assessment

Lebovitz. Diabetes Reviews 1999;7:13953 (data are from the UKPDS population: UKPDS 16.
Diabetes 1995;44:124958)
ESW/MAR-17/RTD LVM-2017/001

Insulin detemir molecule: sites of protraction

Subcutaneous Major protraction

depot
Self-association + albumin binding

Minor protraction
Circulation
Albumin binding

Interstitial fluid No further significant protraction

Hamilton-Wessler et al. Diabetologia 1999;42:125463

ESW/MAR-17/RTD LVM-2017/001

PK/PD: dose response in type 2 diabetes

Dose-proportional glucose-lowering effect and duration of action

Insulin detemir
0.4 U/kg 0.8 U/kg 1.4 U/kg
Insulin glargine
3.0
rate (mg/kg/min)

No significant
Glucose infusion

2.5 between-
2.0 treatment
1.5 difference at
each dose
1.0
level
0.5
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time from insulin injection (hours)

PD, pharmacodynamics; PK, pharmacokinetics

Klein et al. Diabetes Obes Metab 2007;9:2909
ESW/MAR-17/RTD LVM-2017/001

PK/PD: duration of action in type 2 diabetes

CGM shows similar blood glucose levels for once-daily insulin detemir and insulin glargine

Insulin injection Insulin detemir once daily

Insulin glargine once daily

12

Blood glucose (mmol/L)

9

Time of day

24-h glucose profiles. Each point represents the treatment groups mean glucose for each hour and standard error of 29 subjects treated with
once-daily insulin detemir or glargine starting at 20:00 hours. The basal period is from 24:00 hours to 06:00 hours.

CGM, continuous glucose monitoring system; PD, pharmacodynamics; PK, pharmacokinetics

King et al. Diabetes Obes Metab 2009;11:6971

ESW/MAR-17/RTD LVM-2017/001

How to Titrate Basal Insulin

Levemir Dose Titration Guidelines:
3-0-3 Algorithm

Simple Dose titration with Levemir

Mean 3-day FPG
(mg/dL)
Start with Levemir 10 U or 0.1-0.2 U per Kg body weight
FPG>110 mg/dL +3U
FPG 80-110 mg/dL 0

FPG <80 mg/dL -3U

Patients who experienced hypoglycemia reduced their daily dose by 3 units

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.

Levemir Indonesia Prescribing Information 2017
ESW/MAR-17/RTD LVM-2017/001

Starting Insulin Detemir from insulin naive patients

A1chieve Indonesia: efficacy results Insulin nave

HbA1c (%) FPG (mg/dl) PPG (mg/dl)

Baseline values 9.5 219 263

n 147 317 295

*p<0.001
Soewondo P, et al. Clinical experience with insulin detemir: Results from the Indonesian cohort of the international A1chieve study.
Diabetes Research and Clinical Practice 2013; 100(S1): S47S53
 ALGORITHM OF T2DM DIAGNOSIS
Diabetes Symptoms
Diabetes Classic Diabetes Classic
Symptoms (+) GDP Symptoms (-)
GDS
FPG 126 < 126 126 100-125 < 100

RBG > 200 < 200 > 200 140-199 < 140

FBG and PPG

OGTT
2 hour BG
FPG 126 < 126

RBG > 200 < 200 > 200 140-199 < 140

Diabetes Mellitus IGT IFG Normal

Evaluation of Nutritional Status Education

Evaluation Diabetic Complications Dietary Planning
Evaluation Dietary Need and Dietary Planning Physical Exercise
Achieving Ideal Body Weight

FBG (Fasting Blood Glucose) IGT (Impaired Glucose Tolerance) PERKENI Consensus Guidelines, 2011.
RBG (Random Blood Glucose) IFG (Impaired Fasting Glucose)
 BIGUANID
Mekanisme kerja terutama menurunkan pengeluaran glukosa hati.

Mampu meningkatkan sensitifitas terhadap insulin dengan meningkatkan

aktifitas reseptor insulin tirosin kinase, meingkatkan sistesis glikogen dan
meningkatkan transport GLUT $4 transporter ke dalam plasma membran.
Contoh: Metformin. Mampu menurunkan GDP sampai 5070 mg/dl dan
the HbA1c sampai 1.41.8%.
Tidak begitu berbahaya dalam menyebabkan hipoglikemi
Efek samping yang sering terjadi: ketidak nyamanan GI dan mual.
Hampir 0.03 kasus/1,000 pasien-tahun, mengalami asidosis laktat
terutama pada pasien yang mengalami renal insufisiensi dan gangguan
hati
Metformin tidak direkomendasikan untuk pasien dengan kreatinin >1.5
mg/dl.
Baik digunakan bagi pasien gemuk.