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Diabetes Melitus Lita Septina

SMF Penyakit Dalam


(Peran Dokter Umum RS Haji Medan

dalam Penatalaksanaan DM)


Permasalahan dan Tantangan
Saat ini
Prevalensi Diabetes Melitus (DM) di Indonesia usia diatas
15 tahun sebesar 5,7%. (Riskesdas 2007)1
Data Badan Pusat Statistik Indonesia 2003 penduduk
usia diatas 20 tahun 133 juta dan tahun 2030 : 194 juta
( ± diabetes 11,05 juta)1
Kontrol diabetes : OAD ( efektif dan efikasi berbeda tiap
pasien); diperlukan terapi tambahan insulin 2-3
Pemahanan terapi insulin : inisiasi, optimalisasi dan
intensif 2-3

1. Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Di Indonesia, 2015, Perkumpulan Endokrinologi
Indonesia

2. CPG on Management of type 2 diabetes mellitus, 2009, Malaysian Endocrine and Metabolic Society.

3. Juliana Chan et al. The International Diabetes Management Practice Study (IDMPS). Diab Care 2009; (32):227-233.
Estimated number of people with diabetes worldwide and per region in 2015 and 2040
(20-79 years)

North America and


Caribbean
2015 44.3 million
2040 60.5 million
Europe
2015 59.8 million
2040 71.1 million

Middle East and


North Africa
2015 35.4 million Western Pacific
2040 72.1 million 2015 153.2 million
2040 214.8 million

South East
Asia
2015 78.3 million
South and Africa 2040 140.2 million
Central America
2015 14.2 million
2015 29.6 million
2040 34.2 million
2040 48.8 million 13

World
2015 415 million
2040 642 million
Diabetes by gender
Diabetes by gender

Number of men with diabetes Number of women with diabetes


Number of men with diabetes Number of women with diabetes

2015 215.2 million 2015 199.5 million


2015 215.2 million 2015 199.5 million
2040 328.4 million 2040 313.3 million
2040 328.4 million 2040 313.3 million

Diabetes in urban and rural environments 15


Diabetes in urban and rural environments 15

Diabetes in urban areas Diabetes in rural areas


Diabetes in urban areas Diabetes in rural areas

2015 269.7 million 2015 145.1 million


2015 269.7 million 2015 145.1 million
2040 477.9 million 2040 163.9 million
2040 477.9 million 2040 163.9 million

One inin two


One two adults
adults with
with
IDF Executive summary diabetes report 2015
Diabetes Melitus

Suatu keadaan terjadi TINGGINYA KADAR GULA DARAH


(hiperglikemia), akibat kurang insulin yang beredar dalam
pembuluh darah (gangguan pengeluaran insulin), atau insulin
yang beredar dalam jumlah cukup (malahan bisa berlebih) tetapi
tidak mampu bekerja efektif (gangguan aktifitas insulin /
resistensi insulin), atau kedua-duanya.
Faktor - faktor yang mempengaruhi progresivitas DMT2

Perubahan gaya hidup


Glukosa toksisitas
diet, aktivitas, merokok, alkohol

Lipo-toksisitas

Resistensi Insulin Disfungsi sel Beta


Deposisi Amyloid

Faktor Genetik Penurunan fungsi sel Beta

Progresivitas Diabetes Tipe 2

Vincent P et al. Endocrine Review, 2008, 29(3):351–366


T2DM: Progressive loss of insulin

secretion with increasing insulin resistance

Uncontrolled
Obesity IGT Diabetes hyperglycemia
350 – Postprandial
300 – glucose
250 –
Glucose 200 –
Fasting
(mg/dl) glucose
150 –
100 – Macrovascular
50 – Complication

250 –
200 – Insulin resistance
Relative
function 150 –

(%) 100 –
Clinical Insulin secretion
50 – diagnosis
0– Microvascular
Complication
-10 -5 0 5 10 15 20 25 30
Years of diabetes

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate


metabolism and lipid disorders. In Endocrinology. 4th ed. 2001.
Komplikasi Diabetes

Kronis
Akut

Hipoglikemia
Makrovaskular
KetoAsidosis Diabetik
Mikrovaskular
Hiperglikemia Hiperosmolar
Komplikasi Kronis Diabetes

Mikro-angiopati Makro-angiopati
(pembuluh darah kecil) (pembuluh darah besar)

Diabetik Stroke
Retinopati
meningkat 2 – 4 kali
Dapat lipat pada kejadian
menyebabkan penyakit pembuluh
kebutaan 1,2 darah dan stroke. 5

Diabetik
Penyakit Jantung
Nefropati
8 dari 10 penderita
Penyebab gagal diabetes meninggal
ginjal kronis 3,4 karena penyakit jantung /
pembuluh darah 6

Diabetik Penyakit pembuluh


Neuropati darah perifer penyebab
~60–70% dari pasien 60% amputasi anggota
mengalami kerusakan gerak bawah bukan
saraf ringan sampai akibat trauma /
berat1 kecelakaan. 7,8

1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study Group. J

25 Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676.
6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of

non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
Terapi antihiperglikemi pada Diabetes Tipe 2
1434 SECTION VIII Disorders of
Rekomendasi Carbohydrate
ADA and Fat Metabolism
(American Diabetic Association) dan EASD (European Association for the Study of Diabetes ) 2015

Healthy eating, weight control, increased physical activity, and diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI/lactic acidosis
Costs* low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference–choice dependent on a variety of patient- and disease-specific factors):

Metformin Metformin Metformin Metformin Metformin Metformin


! ! ! ! ! !
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
Weight gain gain neutral loss loss gain
Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs* low low high high high variable

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference–choice dependent on a variety of patient- and disease-specific factors):

Metformin Metformin Metformin Metformin Metformin Metformin


! ! ! ! ! !
Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
! dione inhibitor inhibitor agonist !
Triple ! ! ! !
TZD SU SU SU SU TZD
therapy†
or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i


§ §
or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA
§ §
or Insulin or Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables;
(2) on GLP-1-RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin, in Monotherapy
refractory patients consider adding TZD or SGLT2-I:
Dualtherapy
Metformin Tripletherapy
! Combination Injectable

Combination
injectable Basal insulin ! Mealtime insulin or GLP-1-RA
therapy‡ Polonsky KS , Williams Text Book of
Endocrinology. 2016 : 1386 – 1450.

ADA, Diabetes Care 2016;39(Suppl.


Figure 31-21 Antihyperglycemic therapy in type 2 diabetes: general recommendations of the ADA and EASD. The order in the chart was determined by historical availability 1):S52–S59
Algoritme Pengelolaan DM Tipe 2 Konsensus PERKENI 2015

Modifikasi pola hidup sehat

HbA1c < 7,5% HbA1c ≥ 7,5% HbA1c ≥ 9,0%


Gejala (-) Gejala (+)

Kombinasi 2 obat
Monoterapi dengan salah satu Kombinasi 2 obat* dengan Insulin +/- obat
dibawah ini mekanisme kerja yang berbeda jenis lain
Kombinasi 3 obat Kombinasi 3 obat
Metformin Agonis GLP - 1
Metformin atau obat lini pertama yang lain +

Metformin atau obat lini pertama yang lain +


Agonis GLP - 1
Agonis GLP - 1 Penghambat DPP-IV
Penghambat DPP-IV
Penghambat DPP-IV Tiazolidindion
Tiazolidindion
Penghambat Glikosidase Penghambat SGLT-2**
Mulai atau intensifikasi
Alfa Penghambat SGLT-2**
insulin
Insulin Basal
Penghambat SGLT-2** Insulin Basal
SU / Glinid
Tiazolidindion Kolsevelam **

Obat lini ke 2 +
Kolsevelam **
Sulfonilurea Bromokriptin - QR
Bromokriptin - QR
Keterangan
Glinid Penghambat Glikosidase
* Obat yang terdaftar pemilihan dan
Penghambat Glikosidase Alfa penggunaannya disarankan
Jika HbA1c > 6,4% Alfa mempertimbangkan faktor
Jika belum memenuhi keuntungan dan kerugian biaya
dalam 3 bulan Jika belum memenuhi sasaran dalam 3 bulan dan ketersediaannya

tambahkan obat ke 2 sasaran dalam 3 bulan mulai terapi insulin atau * ** Kolseveam belum tersedia di
Indonesia. Bromokriptin QR
(kombinasi 2 obat) masuk ke kombinasi 3 intensifikasi terapi umumnya digunakanpada terapi
tumor hiposis
obat insulin

Konsensus Pengelolaan dan Pencegahan DMT2 di Indonesia, PERKENI 2015


Multiple mechanism of hyperglycemia in type 2
diabetes
Decreased incretin effect / increase
glucose absorption

Islet β cell
Increased lipolysis
and reduced
glucose uptake

Impaired
Islet cell insulin
secretion

Increased hyperglycemia
glucagon
secretion
Increased glucose
reabsorption

Decrease glucose
uptake
Increased hepatic
glucose
production

Neurotransmitter
dysfunction
RESUME MECHANISM OF Blocks
ACTION OF RECENT OAD Promotes

Liver Muscle
Adipose

Biguanide TZD
FFA release

GLP-1 analog/ Circulation


DPP IV INHIBITOR Biguanide
⇓Glucose TZD
⇓FFA
FFA absorption

Glucose Intestinal lipase inhibitor


absorption

AGI Fat
Pancreas Insulin secretagogues
Carbohydrates Intestines
Sasaran glikemik penderita Diabetes

ADA 2015 PERKENI IDF NICE

A1c (%) < 7,0 < 7,0 6,2 - 7,5 ≤ 6,5 - 7,5

Glukosa Puasa
pra - prandial 80 - 130 80 - 110 91 - 120 72 - 144
(mg/dL)

Glukosa post
prandial (mg/dL)
< 180 < 180 136 - 160 < 180

ADA = American Diabetes Association; IDF = International Diabetes Federation; NICE = National institute of Health and Clinical Excellence

Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus, PERKENI 2015
Tipe dan Sediaan Insulin
Sediaan Insulin
Insulin Type Conventional Analogue

Rapid - acting
Short - acting regular human insulin
Novorapid®(Aspart)
Prandial Actrapid®
Humalog®(Lispro)
Humulin R®
Apidra®(Glulisine)

Intermediate - acting or Neutral Protaminated


Long - acting
Hagerdon (NPH) Insulin
Basal Lantus®(Glargine)
Insulatard®
Levemir®(Detemir)
Humulin N®

Combination of rapid - acting &


Combination of short & intermediate - acting : protaminated analogue
30%regular insulin + 70% NPH Novomix 30® (30% aspart + 70% aspart
Premixed
Mixtard® 30 protamine)
Humulin® 30/70 Humalog Mix® 25 (25% lispro + 75%
Lispro protamine)
Pharmacokinetic profiles of various types of insulin

Brand (Generic) Name Onset Peak (hr) Duration (hr) Timing of Insulin

a) Short - acting, regular


Actrapid® 30 min 1-3 8 30 mins before meal
Humulin R® 30 min 2-4 6-8

b) Rapid - acting analogue


Novorapid® (Aspart) 10 - 20 min 1-3 3-5 5 - 15 mins before or
Humalog® (Lispro) 0 - 15 min 1 3,5 - 4,5 immediately after meals
Apidra® (Glulisine) 5 - 15 min 1-2 3-5

c) Intermediate - acting, NPH


Insulatard® 1,5 hr 4 - 12 18 - 23 Pre - breakfast / pre bed
Humulin N® 1 hr 4 - 10 16 - 18

d) Long - acting analogue


same time everyday at
Glargine® 2 - 4 hr peak less 20 - 24
anytime of the day
Detemir® 1 hr peak less 17 - 23

e) Premixed human (30% regular


Insulin + 70% NPH)
30 min dual 18 - 23 30 - 60 mins before meals
Mixtard 30® 30 min dual 16 - 18
Humulin 30/70®

f) Premixed analogue
Novomix 30® (30% aspart + 70%
10 - 20 min dual 18 - 23
aspartprotamine) 5 - 15 mins before meals
Humalog Mix® 25 (25% lispro + 75% 0 - 15 min dual 16 - 18
lispro - protamine

DeWitt DE et al. J Am Med Assoc. 2003; 289: 2254-64


Inisiasi Insulin
Selecting initial insulin regimen based on blood sugar profile

Blood Glucose Profile


Preferred insulin regiment

Pre - breakfast Daytime

High Normal Pre - bed intermediate / long acting insulin (Basal)

Pre - bed intermediate / long acting insulin and


later add on prandial short / rapid acting insulin
High High
(Basal —> basal Plus / Basal Bolus) or (Pre -
Breakfast and Pre - Dinner Premixed Insulin)

Prandial short / rapid acting insulin and later add


Normal High on basal insulin
(Prandial —> Basal Plus / Basal Bolus)
Pre - bed Intermediate / Basal Insulin
Dosis awal pre - bed intermediate / insulin basal 10 U/hari (0,2 U/
kgBB ; khusus usia tua 0,1 U/kg menghindari hipoglikemia)

Target : 4 - 6 mmol/L (72 - 108 mg/dL)

Monitoring : SMBG puasa, perubahan dosis minimal 3 kali


pemerikasaan berbeda.

Jika pemeriksaan > 2x GDP < 80 mg/dl maka turunkan dosis


intermediate / insulin basal 2 U.

Jika hasil GDP > 6 mmol/L (110 mg/dl) tanpa riwayat hipoglikemia,
naikkan dosis 2U

Swinnen SGHA et al. Diabetologia 2009; 52(11):2324-2327.


Initiating insulin with basal insulin

Treatment Dose

10 units or 0,2 U/kg at bedtime


Initiation
0,1 units /kg if higher risk for hypos

Monitoring pre-breakfast BG
Monitoring and targets
Target pre-breakfast BG is at 4 - 6 mmol/L (72 - 108 mg/dL)

Adjust insulin doses after 3 consecutive BG values obtained


(every 3 - 7 days)
Optimisation < 4 mmol/L (>1 value) → reduce doses by 2 units
4 - 6 mmol/L (all values) → maintain current dose
> 6 mmol/L (>1 value, no hypos) → increase by 2 units

0,2 - 0,3 units / kg in lean patients


Optimal dose 0,4 - 0,5 units / kg in most patients
Up to 0,7 units / kg in obese patients

Watch for nocturnal hypoglycaemia. If hypoglycaemia is the limiting


Caution factor to achieve optimum dose, conventional intermediate - acting
insulin may be switched to basal insulin analogue
Bu BY. Australian Family Physician 2007; 36(7):549-553.

Swinnen SGHA et al. Diabetologia 2009; 52(11):2324-2327.


Strategi urutan terapi Insulin pada DMT2 Kompleksitas
Jumlah injeksi

Insulin basal
Biasanya dengan metformin +/- non insulin lainnya
Rendah
1
Awal : 10 U / hari atau 0,1 - 0,2 U/kg BB/hari
Penyesuaian : 10 - 15% atau 2 - 4 U, 1 - 2 kali/minggu sampai tercapai sasaran GD puasa
hipoglikemia : tentukan dan atasi penyebeb, turunkan dosis 4 U atau 10 - 20%

Jika setelah GD
Tambahkan 1 injeksi insulin cepat Ganti dengan insulin premixed
sebelum makan besar puasa tercapai tidak terekendali 2x/hari
(atau jika dosis > 0,5U/kg BB/hari)
atasi ekskursi GD pp dengan insulin

Awal 4 U, 0,1 U/kg BB atau 10% dosis basal. Jika waktu makan (pertimbangkan Sedang
2 Awal : bagi dosis basal menjadi 2/3 siang, 1/3
A1C <8% pertimbangkan untuk menurunkan basal
untuk memberikan malam atau1/2 siang, 1/2 malam.
dalam jumlah yang sama
GLP1 - RA Penyesuaian naikkan dosis 1-2U atau 10-15%, 1-2
Penyesuaian : naikkan dosis 1 - 2U atau 10 - 15%,
kali/minggu sampai sasaran SMBG tercapai
1-2 kali/minggu sampai sasaran SMBG tercapai
Hipoglikemia : tentukan dan atasi penyebab,
Hipoglikemia : tentukan dan atasi penyebeb,
turunkan dosis 2-4 U atau 10-20%
turunkan dosis 2-4 U atau 10 - 20%

Tambahkan ≥ 2 injeksi insulin rapid Jika tidak


Jika tidak
sebelum makan (basal bolus) terkendali, pertimbangkan
terkendali, pertimbangkan
basal bolus
basal bolus
Awal 4 U, 0,1 U/kg BB atau 10% dosis basal. Jika
A1C <8% pertimbangkan untuk menurunkan basal
dalam jumlah yang sama
3+ Penyesuaian : naikkan dosis 1 - 2U atau 10 - 15%, Tinggi
1-2 kali/minggu sampai sasaran SMBG tercapai

Hipoglikemia : tentukan dan atasi penyebeb,


turunkan dosis 2-4 U atau 10 - 20%
Fleksibilitas

Lebih Fleksibel Kurang Fleksibel


ADA, Diabetes Care 2016;39(Suppl. 1):S52–S59
Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus, PERKENI 2015
Terima kasih