CV: dr. R Bowo Pramono SpPD KEMD • Lahir TEGAL 27-jan 1959 • Istri: dr. Astuti SpS, 2 putri • Dokter Umum: FK UGM • 17-01-1985 • SPPD : FK UGM 24-11-1997 • KEMD : 14-05-2008 Pekerjaan: • 1987-2002 PKM Kedung Waringin Bekasi • 1999-2004 RSU Selong Lombok Timur • 2004-2010 RS DR Sardjito/FK UGM • 2006-2013 Sekretaris Bagian Penyakit Dalam FK UGM • 2007-2011 Sekretaris PAPDI Cabang Yogyakarta 1
DIAGNOSIS & MANAJEMEN DM TIPE 2
DIAGNOSIS: DIAGNOSED
FASTING BG/mg%
POST PRANDIAL BG/mg%
RANDOM BG/mg%
NO DIABETES
80 - <110
80 - <140
80 - <140
PRE DIABETES
110 - 125
140 - 199
DIABETES
≥ 126
≥ 200
≥ 200
Prinsip Dasar Terapi Diabetes Mellitus 1
3
2
PENGATURAN MAKAN 4
LATIHAN JASMANI
PENYULUHAN
5
OBAT HIPOGLIKEMIK
CANGKOK PANKREAS
Correlation between HbA1c level and mean plasma glucosa levels on multiple testing over 2-3 months HbA1c
Mean plasma glucose (mg/dL)
6
135
7
170
8
205
9
240
10
275
11
310
12
345
6
Hasil dari UKPDS: Kontrol yang baik pada DM T2 mampu menurunkan resiko komplikasi Penurunan 1% HbA1c
Menurunkan resiko*
Kematian karena diabetes
‐21%
Infark miokard
‐14%
Komplikasi mikrovaskuler
‐37%
Gangguan pembuluh darah perifer
‐43%
1%
*p<0.0001 n=3,642 type 2 diabetes patients
Stratton IM et al. BMJ 2000;321:405–412
PRINSIP PENGOBATAN DIET Kebutuhan kalori sesuai : kelamin, umur , berat badan, aktifitas fisik, pekerjaan, kehamilan, menyusui, komplikasi 3 kali makan utama dan 3 kali makan kecil Jumlah dan waktu makan harus tepat
JADWAL MAKAN DIABETES Komposisi diet: 60-70 % hidrat arang 20-25 % lemak 10-15 % protein 20%
10%
25%
10%
25%
6.30
9.30
12.00
15.00
19.00
10%
21.00
PRINSIP OLAHRAGA PADA DIABETES Pilih olahraga yang disenangi Melibatkan otot-otot besar Frekuensi
: Teratur 3-5 kali perminggu
Intensitas
: Ringan sampai sedang
Durasi
: 30 –60 menit / 5 X30 menit /minggu
Tipe
: Aerobik (jalan, joging, ber sepeda)
Program Latihan • Teratur (3-4 kali seminggu) • 20- 40 menit didahului pemanasan 5-10 mnt dan cool-down 10 mnt
• CRIPE: Continous Rythmis Interval Progresif Endurance
Treatment options for type 2 diabetes •
Sulfonylureas – 1st generation e.g. chlorpropamide, tolbutamide – 2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone – 3rd generation e.g. glimepiride – Modified release
•
Biguanides – e.g. metformin
•
Thiazolidinediones – e.g. rosiglitazone, pioglitazone
α-glucosidase inhibitors – e.g. acarbose
•
Insulin – – – –
Glinides/meglitinides – Non-sulfonylureic e.g. repaglinide – Amino acid derivatives e.g. nateglinide
•
•
regular intermediate/long acting pre-mixed analogs • •
•
rapid acting long acting
Fixed-dose oral antidiabetic drug combinations – e.g. glyburide/metformin, glipizide/metformin, rosiglitazone/metformin
Metformin How it works
• Decreases hepatic glucose output • Lowers fasting glycemia
Expected HbA1c ~ 1.5% reduction Adverse events • GI side effects
• Lactic acidosis (quite rare)
Weight effects
Weight stability or modest weight loss
CV effects
Unconfirmed beneficial effect demonstrated in UKPDS
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Sulfonylureas How they work
Enhance insulin secretion
Expected HbA1c reduction Adverse events
~ 1.5%
Weight effects
~ 2 kg weight gain common when therapy initiated
CV effects
UGDP suggested potential cause of increased CVD mortality; not substantiated by UKPDS
Hypoglycemia (but severe episodes are infrequent)
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
INCREASED INSULIN SECRETION Sulfonylurea
Length of action
Begins of action
Daily dose (mg)
Route of excretion
Glibenclamide
16 – 24h
2 – 4h
1,25 – 15
R = 50%, B = 50%
Gliclazide
10 – 24h
2 – 4h
40 – 320
R = 70%, B = 30%
Glipizide
6 – 24h
2 – 4h
2,5 – 40
R = 80%, B =20%
Chlorpramide
24 – 72h
2 – 4h
100 – 500
Renal
Tolbutamide
6 – 10h
2 – 4h
100 – 1000
Renal
Glimepiride
24h
2 – 4h
1-6
R = 40%, B =60%
gliquidon
18 - 24h
2 - 4h
30 - 120
R = 5%, B = 95%
15
Glinides How they work
Stimulate insulin secretion (but differently from sulfonylureas)
Expected HbA1c reduction Adverse events
~ 1.5% (repaglinide)
Weight effects
~ 2 kg weight gain common when therapy initiated
CV effects
None mentioned in ADA recommendations
Hypoglycemia (may be less frequent than some sulfonylureas)
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Dipeptidyl Peptidase IV Inhibitors How they work
Inhibit degradation of endogenous GLP-1
Expected HbA1c reduction Adverse events
~0.8%
Weight effects
Neutral
CV effects
Unknown
Minimal
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
α-Glucosidase Inhibitors How they work
↓ rate of digestion of polysaccharides in proximal small intestine (primarily lowering PPG levels without causing hypoglycemia)
Expected HbA1c reduction Adverse events
0.5–0.8%
Weight effects CV effects
Weight neutral
• Increased gas production • GI symptoms Unconfirmed report of reduction of severe outcomes in one clinical trial
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Thiazolidinediones How they work
Increase sensitivity of muscle, fat, and liver to endogenous and exogenous insulin
Expected HbA1c reduction
0.5–1.4%
Adverse events
Weight gain and fluid retention
Weight effects
• •
Increase in subcutaneous adiposity Redistribution from visceral deposits
CV effects
•
New / worsened CHF or peripheral edema (due to fluid retention) Reduction in some secondary CV endpoints demonstrated in PROactive study
•
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Glucagon-like Peptide 1 Agonist (exenatide) How it works
Stimulates insulin secretion
Expected HbA1c 0.5–1% reduction Adverse events GI side effects (nausea, vomiting, diarrhea)
Weight effects
Weight loss of ~ 2–3 kg over 6 months (may be result of GI effects)
CV effects
None mentioned in ADA recommendations
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Dipeptidyl Peptidase IV Inhibitors How they work
Inhibit degradation of endogenous GLP-1
Expected HbA1c reduction Adverse events
~0.8%
Weight effects
Neutral
CV effects
Unknown
Minimal
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Amylin Agonists (pramlintide) How it works
Synthetic amylin analogue that inhibits glucagon production in a glucosedependant fashion
Expected HbA1c reduction Adverse events
0.5–0.7%
Weight effects
Weight loss ~ 1–1.5 kg over 6 months (may be due to GI effects)
CV effects
None mentioned in ADA recommendations
GI effects (nausea)
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Insulin How it works
Direct compensation for lack of insulin sensitivity
Expected HbA1c reduction Adverse events
1.5–2.5%
Weight effects CV effects
Weight gain of ~ 2–4 kg
Hypoglycemia
• Beneficial effect on TG and HDL • Weight gain may have an adverse effect on CV risks
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Indikasi terapi Insulin: • DM tipe 1 • DM tipe 2 yang tidak terkontrol diet, olah raga, OHO. • DM gestasional • Gangguan faal hati & ginjal yang berat. • Dengan infeksi akut (selulitis, gangren), TBC berat, penyakit kritis (stroke/AMI) • Dengan KAD/HHS • Dengan fraktur atau pembedahan mayor • Kurus (BB rendah), terkait malnutrisi (DMTM) • Dengan penyakit Grave’s • Dengan tumor ganas • Dengan pemberian kortikosteroid
100
Stages of Type 2 Diabetes
75 Beta Cell Function (%)
IGT
Postpandrial Hiperglycemi
T-2 DM phase I Beta Cell function ± 50 %
50 T2 DM phase I
25
T2 DM phase II T2 DM phase III
0 -12 -10
-6
-2
0
2
Years From Diagnosis Lebovitz, 2000
6
10
14 25
Summary: Expected HbA1c Reduction Intervention
Expected ↓ in HbA1c
Insulin Metformin Sulfonylureas Glinides TZDs α-Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
1.5 to 2.5% 1.5% 1.5% 1 to 1.5%a 0.5 to 1.4% 0.5 to 0.8% 0.5 to 1.0% 0.5 to 1.0% ~0.8%
a
Repaglinide is more effective than nateglinide
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Factors that May Affect Compliance Weight Gain Insulin – intermediate/long
X
Insulin – short/rapid
X
Metformin
GI Side Effects
X X
Sulfonylurea
X
Glinides
X
TZDs
X
2-3x Daily Dosing
X X
α-Glucosidase inhibitors
X
X
GLP-1 agonist
X
X
Pramlintide
X
X
DPP-IV inhibitors Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Which second-line therapy? ÐHbA1C
Pros
Cons
SU
1.5
Large clinical database, inexpensive
Weight gain and hypoglycaemia
TZD
0.5–1.4
No hypoglycaemia, some benefits on lipids
Oedema, heart failure, weight gain, expensive
Insulin
1.5–3+
Large clinical database, most effective Hypoglycaemia, weight gain, need for SMBG
AGI
0.5–0.8
No hypoglycaemia, weight neutral
GI side-effects, expensive
GLP-1 analogue
0.5–1.0
No hypoglycaemia, weight loss
GI side-effects, expensive, injected
Meglitinide
1.0–1.5
Fewer hypos than sulfonylurea
TID dosing, expensive
SU: sulfonylurea; TZD: thiazolidinedione; AGI: α-glucosidase inhibitor SMBG: self monitoring of blood glucose ADA/EASD. Diabetes Care 2006; 29: 1963-1972, Diabetologia 2006; 49: 1711-21
100
Stages of Type 2 Diabetes
75 Beta Cell Function (%)
IGT
Postpandrial Hiperglycemi
T-2 DM phase I Beta Cell function ± 50 %
50 T2 DM phase I
25
T2 DM phase II T2 DM phase III
0 -12 -10
-6
-2
0
2
Years From Diagnosis Lebovitz, 2000
6
10
14 29
Effectiveness of Type 2 Diabetes Therapy Starting HbA1c
Diet & Exercise 1.5-2%
Metformin Insulin Secretagogues
1%
TZD Alpha-glucosidase Inhibitors
Combination Oral Agents
Insulin
3-4%
5% or more
<7%
<8% 1-1.5%
<8-10%
>10%
Klasifikasi Insulin Kelas
Mulai efek Puncak Lama
Aksi pendek Actrapid, Humulin R
15-30 mnt 2-4jam 6-8jam
Campuran (premixed) Humulin 30/70,Mixtard 30/70
60 mnt
1-8jam 14-15 jam
Aksi sedang Humulin N, Insulatard
2-4jam
1-8jam 14-15 jam
Aksi panjang Lantus , Levemir
Tanpa Puncak 24 jam
What are the reasons for the shortcomings of insulin? That has to dissolve in SC fluids and dissociate into monomers…….. Dissociation in
subcutaneous tissue
Subcutaneoust issue Mol/l
10‐3
10‐4
10‐5
10‐8
Diffusion
Capillary membrane 32 Adapted from Brange J et al. Diabetes Care 1990;13:923
Klasifikasi Insulin yang baru Kelas Aksi cepat (analog) Lyspro (Humalog) Aspart (Novo Rapid) Apiora Campuran (premixed) Humalog Mix 25/75 Novomix 30/70
Mulai efek Puncak Lama 5-15 mnt
2 jam
4-6jam
5-15mnt
2-4jam
12-14 jam
LOKASI PENYUNTIKKAN
Insulin Regimen Evolution
35
Insulin > Cara pemberian insulin > Semprit dan jarum
Pemakaian semprit dan jarum memungkinkan Anda untuk mengatur dosis dan membuat formulasi campuran insulin. Keterbatasannya adalah membutuhkan ketrampilan yang cukup untuk menarik dosis insulin dengan tepat. Cara menyuntik insulin
Dahulu: Agar tidak salah dosis, kemasan insulin 40U/ml atau 100U/ml disesuaikan dengan skala pada spuit, bisa 40 atau 100 Sekarang: ? Tidak tersedia lagi 38
NovoPen®
39
Sistem NovoLet®
40
INSULIN ANALOG: 1. NovoRapid 2. NovoMix 3. Levemir
45
Summary: Expected HbA1c Reduction Intervention
Expected ↓ in HbA1c
Insulin Metformin Sulfonylureas Glinides TZDs α-Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
1.5 to 2.5% 1.5% 1.5% 1 to 1.5%a 0.5 to 1.4% 0.5 to 0.8% 0.5 to 1.0% 0.5 to 1.0% ~0.8%
a
Repaglinide is more effective than nateglinide
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
Factors that May Affect Compliance Weight Gain Insulin – intermediate/long
X
Insulin – short/rapid
X
Metformin
GI Side Effects
X X
Sulfonylurea
X
Glinides
X
TZDs
X
2-3x Daily Dosing
X X
α-Glucosidase inhibitors
X
X
GLP-1 agonist
X
X
Pramlintide
X
X
DPP-IV inhibitors Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.
ADA/EASD consensus algorithm Tier 1:
Call to action if HbA1c is ≥7%
well-validated therapies At diagnosis: Lifestyle + Metformin
STEP 1
Lifestyle + Metformin + Basal insulin
Lifestyle + Metformin + Intensive insulin
Lifestyle + Metformin + Sulfonylurea STEP 2
STEP 3
Tier 2: Less well validated therapies
Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss
Lifestyle + metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting Nathan DM, et al. Diabetes Care 2009;32 193-203.
Lifestyle + Metformin + Pioglitazone + Sulfonylurea
Lifestyle + metformin + Basal insulin 48
DM tipe 1 49
1980
1980
2009
