Post on 15-Nov-2014
More Effective Glycaemic Control Turning Theory into Practice
Dr. I Gede Palgunadi, Sp.PDDr. I Gede Palgunadi, Sp.PDSMF Penyakit Dalam RSUD MataramSMF Penyakit Dalam RSUD Mataram
Current and Projected Prevalence
Rates for Diabetes80
0
10
20
30
40
50
Africa Americas EasternMediterranean
Europe SoutheastAsia
Est
imat
ed P
reva
len
ce (
mil
lio
ns) 1995 2000 2025
60
70
WesternPacific
World Health Organization. World Health Report 1997: Message from the Director-General. Available at www.who.int/whr/1997/message.pdf. Accessed November 8, 2002.
50 Million
100 Million
150 Million
200 Million
250 Million
110,5
140
175,4
239,3
1994 1997 2000 2003
2,5
1994
3
1997
4
2000
5
2003
1 Mill
2 Mill
3 Mill
4 Mill
5 Mill
ESTIMATE DIABETES IN INDONESIA
Top ten countries for estimated number of adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)
Rank
1 India 19.4 India 57.2
2 China 16.0 China 37.6
3 U.S. 13.9 U.S. 21.9
4 Russian Fed. 8.9 Pakistan 14.5
5 Japan 6.3 Indonesia 12.4
6 Brazil 4.9 Russian Fed. 12.2
7 Indonesia 4.5 Mexico 11.7
8 Pakistan 4.3 Brazil 11.6
9 Mexico 3.8 Egypt 8.8
10 Ukraine 3.6 Japan 8.5
All other countries 49.7 103.6
Total 135.3 300.0
DEFINISI ADA 2003
• Diabetes mellitus adalah sekelompok penyakit metabolik ditandai hiperglikemia, karena defek sekresi insulin, kerja insulin, atau keduanya
• Gangguan kronik – jangka panjang dan berhubungan erat dengan kerusakan organ tubuh tertentu, mis : mata, ginjal, saraf, jantung serta pembuluh darah
Makna : • Kronik – tidak dapat sembuh• Progresif• Untuk mencegah komplikasi perlu dicegah hiperglikemia
Klasifikasi diabetes mellitus
1. DM tipe 1 : kerusakan sel beta karena sebab (a) imunologis (b) idiopatik
• Diabetes tidak bisa sembuh namun dapat dikendalikan • Pada saat diagnosis, sebagian DM tipe 2 sudah mengalami komplikasi
• Perubahan telah terjadi 5 – 12 tahun sebelum diagnosis ditegakkan
2. DM tipe 2 : karena resistensi insulin yang dominan (dengan defisiensi insulin relatif) sampai gangguan sekresi sel beta dengan resistensi insulin
3. DM tipe lain : a, b, c, d, e, f, g, h
4. Gestational DM
Perkembangan DM Tipe 2
DM Tipe 2
Adapted from Diabetes 1996;45:1661
Resistensi Insulin
Resistensi insulin
Hiperinsulinemia
Toleransi glukosa normal
Kegagalan fungsi sel Beta
Resistensi insulin
Penurunan kadar insulin
Gangguan toleransi glukosa
Diabetes Obes Metab 1999; 1(1): S1
Sensitivitas Insulin Sekresi Insulin
T2DM30% 50%50%
Impaired glucose metabolism
70% 150%150%
Normal glucose metabolism100% 100%100%
IGT50% 70-100%70-100%
Perjalanan Alami DM Tipe 2
ABNORMALITAS METABOLIK DM TIPE 2
OTOT
Jar. Lemak
Penurunan Penggunaan Glukosa Perifer
Penurunan Penggunaan Glukosa Perifer
PANKREASHATI
Peningkatan Produksi Glukosa Hepar
Kegagalan Fungsi Sel Beta
DM tipe 2
RESISTENSI INSULIN
Definisi :
kegagalan terhadap efek fisiologi insulin,
termasuk terhadap metabolisme glukosa,
lipid, protein, serta fungsi endotel vaskuler
Defek utama pada sebagian besar DM tipe 2
Diab Care 1999;22:562Diab Care 2000; 23(Suppl 1):54
Insulin resistance
Glucose uptake Glucose oxidation
Lipolysis Free fatty acid
Glucose uptake Glucose production
VLDL synthesis
HyperinsulinemiaHyperglycemiaDyslipidemia
EFEK RESISTENSI INSULIN
Cardiovascular disease
Interrelation Between Atherosclerosis and Insulin Resistance
HypertensionHypertension
ObesityObesity
HyperinsulinemiaHyperinsulinemia
DiabetesDiabetes
HypertriglyceridemiaHypertriglyceridemia
Small, dense LDLSmall, dense LDL
Low HDLLow HDL
HypercoagulabilityHypercoagulability
InsulinInsulinResistanceResistance
AtherosclerosisAtherosclerosis
STRATEGI TERAPI DM TIPE 2
Pengelolaan :Hiperglikemia
Hiperinsulinemia / Resistensi Insulin Dislipidemia
Komplikasi Mikrovaskuler
Komplikasi Makrovaskuler
Mencegah terjadinya
Prinsip Dasar Terapi Diabetes Mellitus
2
PENGATURAN MAKAN
3
LATIHAN OBAT - OBATAN
4
1
PENYULUHAN
1. Mengurangi resistensi insulin : derivat biguanide dan thiazolidinedione
2. Mengubah metabolisme asam lemak : menghambat keluarnya NEFA, penghambat oksidasi asam lemak
3. Stimulasi sekresi insulin : sulfonilurea, antagonis -2 adrenergik
4. Penghambat naiknya glukosa post prandial : guar gum, -glukosidase inhibitor, -amylase inhibitor
5. Mengurangi berat badan : bahan anorektik, -3 agonist, antagonis neuropeptide Y
6. Memberikan suplementasi insulin basal : glukagon like-peptide I (GLP-I), insulin secretagogue non-sulfoilurea (meglitinide, repaglinide)
Berdasarkan titik tangkapnya telah dikembangkan berbagai obat dengan khasiat sebagai berikut :
MEKANISME KERJA OHO
Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5
Hyperglycemia
GLUCOSE ABSORPTION
alpha-glucosidase inhibitors
INTESTINE
PANCREAS
INSULIN SecretionSulphonylurea (SU)
Non-SU : Meglitinides & Nateglinide
GLUCOSE PRODUCTION
BiguanidesBiguanidesThiazolidinedionesThiazolidinediones
LIVER MUSCLE
PERIPHERAL GLUCOSE UPTAKEThiazolidinedionesThiazolidinediones
BiguanidesBiguanides
ADIPOSE TISSUE
1. Menurunkan absorpsi karbohidrat • Acarbose• Metformin
2. Meningkatkan sekresi insulin (Insulin Secretagogues)• Sulfonilurea : Glibenclamide, glipizide, gliclazide, gliquidone, glimepirid• Non-Sulfonilurea : Nateglinide, Repaglinide
3. Menurunkan produksi glukosa hepar • Metformin• Thiazolidinediones : Pioglitazone
4. Meningkatkan ambilan glukosa perifer • Thiazolidinediones : Pioglitazone • Metformin• Sulfonilurea : Glibenclamide, glipizide, gliclazide, gliquidone, glimepirid
OHO di Indonesia
Obat Anti-hiperglikemia Oral Yang Ideal
Dapat mengontrol gula darah puasa & 2 jam SM
Tidak ada risiko hipoglikemia
Mempunyai dampak yang menguntungkan pada
parameter lipid
Aman dan dapat ditoleransi dengan baik
Pemberian sederhana
Dapat digunakan oleh semua penderita DM tipe 2
Menurunkan morbiditas/ mortalitas kardiovaskuler
dan mikrovaskuler
KRITERIA PENGENDALIAN DMKonsensus PERKENI 2002
Gula Darah Puasa
Gula Darah 2 JSM
HbA1C (%)
Kolesterol Total
Kolesterol LDL
Kolesterol HDL
Trigliserida
BMI
Tekanan Darah
80 - 109
80 - 144
< 6,5
< 200
< 130
> 45
< 150
18,5 - 22,9
< 130 / 80
BAIK
110 - 125
145 - 179
6.5 - 8
200 - 239
100 - 129
150 - 199
23 - 25
130-140/ 80-
90
SEDANG
> 126
> 180
> 8
> 240
> 130
> 200
> 25
> 140 / 90
BURUK
TARGETS FOR GLYCEMIC TARGETS FOR GLYCEMIC CONTROLCONTROL
ADAADA11
IDF (Europe)IDF (Europe)22
HbA1c%HbA1c% FPG mmol/LFPG mmol/L
< 7< 7 < 6.7 (120)*< 6.7 (120)*
<< 6.5 6.5 << 6.0 6.0 (110)*(110)*
*mg/dl*mg/dl
11Diabetes Care 1999;22(Suppl 1):S1-S114. Diabetes Care 1999;22(Suppl 1):S1-S114. 22Diabetic Medicine 1999;16:716-30Diabetic Medicine 1999;16:716-30
What level of glycaemic control should we aim for ?
Untuk menurunkan komplikasi mikrovaskuler HbA1c harus senormal mungkin
Awas hipoglikemia ! ! ! HbA1c normal 6.1% PERKENI HbA1c menganjurkan < 7%
(Sesuai konsensus ADA).
BMJ 333; 9 Des. 2006
EVERY 1% EVERY 1% reduction in A1Creduction in A1C
REDUCED REDUCED RISK*RISK*
Deaths from diabetesDeaths from diabetes
Heart attacksHeart attacks
Microvascular complicationsMicrovascular complications
Peripheral vascular disordersPeripheral vascular disorders
UKPDS 35. BMJ 2000; 321: 405-12.UKPDS 35. BMJ 2000; 321: 405-12.
LESSONS FROM UKPDS:BETTER CONTROL MEANS FEWER COMPLICATIONS
-37%-37%
-43%-43%
*p<0.0001*p<0.0001
-14%-14%
-21%-21%
1%1%
Treatment algorithm for type 2 diabetes
Aim
Improved control
Diet, exercise, health education
Oral combinations
Insulin
Insulin plus oral agents
Sulphonylurea, metforminGlucosidase InhibitorsGlitinidesThiazolidinediones
Stepped management of type 2 diabetesThis is illogical in most cases of diabetes where there is both insulin deficiency and resistance
UKPDS shows diet therapy alone worsens pancreatic function in 356 patients by 50% in 6 years
Treatment Priority of Type 2 DM
Glucose control as near
to normal as
reasonably possible
Control of Insulin resistance, Hyperinsulinemia, Obesity,
Dyslipidaemia, Hypertension, Procoagulant State
Microvascular Disease
Macrovascular Disease
Normal IFG IGT + Obesity Dx T2DM Progression ofT2DM
Insulin Concentration
-Cell Failure
Euglycaemia
Hyperg
lycaemia
Dual Defect of Type 2 Diabetes : Treating a Moving Target
-cellDysfunction
InsulinResistance
Type 2Diabetes
Insulin Resistance
Insulin Action
Lifestyle change: an option?
The potentially most efective but most dificult !
Chochrane analysis no high quality data to support the efectiveness of dietary treatment.
BMJ 333; 9 Des. 2006
Rationale for Early Combination Therapy
Pathophysiology – dual defects
Glycaemic burden – FPG and PPG
Monotherapy targets one defect and HbA1C < 7.0% seldom achieved
Diabetes is progressive – durable control means multiple therapies
Switch to combined therapy after ‘treatment failure’ leads to excessive hyperglycaemic exposure
Choice of agents in current use
Sulphonylureas
Metformin
Meglitinides
TZDs -glucosidaseinhibitors
AcarboseMiglitolVoglibose
RosiglitazonePioglitazone
GlipizideGliclazideGlimepirideGlibenclamide
RepaglinideNateglinide
Combination therapy and the dual endocrine defect of type 2 diabetes
1Sulphonylurea or meglitinide ; TZD: thiazolidinedione ; AGI: -glucosidase inhibitor
Metformin + insulin secretagogue1
Metformin + TZD
Metformin + AGI
Sulphonylurea + TZD
Sulphonylurea + AGI
TZDs + AGI
Insulinresistance
β-celldeficiency
Is metformin still the first line drug?
Metformin biguanide yg diterima secara luas sbg first line drug. Safe, effective, dan murah.
Menurunkan resiko penyakit kardiovaskuler pada pasien obese dengan DM type 2.
Metformin: foundation therapy for prevention of type 2 diabetes and its complications
Reduced morbidity and mortality in the UKPDS
– Unique reduction of cardiovascular complications beyond that expected from blood glucose control
IDF and ADA guidelines favour the use of metformin as foundation therapy for type 2 diabetes where possible
The antihyperglycaemic efficacy of metformin is dose-related with an optimal daily dose of 2000 mg/day
Metformin is well tolerated across its dosage range
– Gastrointestinal side-effects are usually transient
– Minimised by slow dosage titration
– Only about 5% of patients cannot tolerate metformin
Proven to prevent or delay type 2 diabetes (DPP)
UKPDS clinical outcomes for metformin
Any diabetes-related complication
Diabetes deaths
Myocardial infarction
Stroke
Microvascular complications
Retinal photocoagulation
Clinical endpoints
aCompared with conventional diet-based therapy (overweight patients)
UKPDS 34. Lancet 1998;352:854-65
riska
32%
42%
39%
41%
29%
31%
p
0.002
0.017
0.01
0.13
0.19
0.17
Metformin therapy
Metformin and myocardial infarction
Follow-up 3 years
Clinical endpoints (%)
Reinfarction Symptoms of angina Acute cardiovascular eventsFatalities
Controls(n=123)
8.910.6 6.510.3
Metformin(n=187)
1.64.84.08.0
Diabetic 34% / IGT 52% / Normal 14%
Sgambato et al. Clin Ter 1980;94:77-85
Kontrol Metabolik Metformin pada DM Tipe 2
Metformin
Glucose uptake & utilisation
Muscle
Glucose uptake
VLDL synthesis
Liver
Fat storage Lipolysis Free fatty acids
Adipose
EuglycaemiaNormolipidaemia
Metformin: multiple mechanisms for vascular protection
Insulin sensitivity Fibrinolysis Nutritive capillary flow Haemorrheology Postischaemic flow
Metformin addresses CV risk by a range of direct and indirect mechanisms
Improved Reduced Hypertriglyceridaemia AGE formation Crosslinked fibrin Neovascularisation Oxidative stress
Reduced cardiovascular risk
100100
ß C
ell f
unct
ion
(%)
ß C
ell f
unct
ion
(%)
Glycated haemoglobinGlycated haemoglobin
ß Cell functionß Cell function
InsulinInsulinLifestyle Monotherapy Dual Lifestyle Monotherapy Dual ± oral drugs± oral drugs
Therapy for loweringTherapy for lowering Blood glucoseBlood glucose
99
88
77
66
55
Gly
cate
d ha
emog
lobi
n (%
)G
lyca
ted
haem
oglo
bin
(%)
>15>150000
Traditional treatment strategy for type 2 diabetes and its consequences. In type 2Traditional treatment strategy for type 2 diabetes and its consequences. In type 2Diabetes Diabetes ß cell function declines over the years, irrespective of treatment with metformin,ß cell function declines over the years, irrespective of treatment with metformin,Sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to beSulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to beAdjusted at regular intervals according to the level of glycaemia. Because doctor and patientAdjusted at regular intervals according to the level of glycaemia. Because doctor and patientRecurrently fail to reach target.Recurrently fail to reach target. BMJ 333; 9 Des 2006. BMJ 333; 9 Des 2006.
Sulfonylurea, thiazolidinedion, or insulin ? add to metformin !
Insulin ditambahkan bila HbA1C > 8,5% tapi komorbid yang menyertai DM type 2 lebih dipertimbangkan!
Bila tidak ada komorbid yang gawat maka kombinasi Su + Met lebih disukai pasien dibandingkan insulin.
BMJ 333; 9 Des. 2006
And then? 3oral agents, insulin as add-on, or insulin alone?
Kombinasi (Su + Met + Thz) lebih mahal dibandingkan insulin + Met.
Bila target HbA1C tak tercapai dg dual terapi mulai basal insulin atau Intermediate/long acting insulin.
Inhaled insulin baru2 ini di US mulai dipakai. Belum tau keberhasilan dan efek samping.
Lifestyle counselling and metforminLifestyle counselling and metformin
Add sulfonylurea or or thiazolidinedione or basal insulinAdd sulfonylurea or or thiazolidinedione or basal insulin
Metformin +Metformin +Sulfonylurea +Sulfonylurea +Basal insulinBasal insulin
Metformin +Metformin +ThiazolidenedioneThiazolidenedione
+ sulfonylurea + sulfonylurea OrOr
Metformin +Metformin +ThiazolidinedioneThiazolidinedione
+ basal insulin+ basal insulin
IntensifyIntensifyInsulinInsulin
TherapyTherapy
Intensive insulin + metformin Intensive insulin + metformin ± thiazolidinedione± thiazolidinedione
GlycatedGlycatedHaemoglobin Haemoglobin ≥ 7%≥ 7%
Goal of treatment should be a glycated haemoglobin value as close to the non-diabeticGoal of treatment should be a glycated haemoglobin value as close to the non-diabeticRange (<6,1%) as possible; treatment should be started or changed if the value is Range (<6,1%) as possible; treatment should be started or changed if the value is ≥ 7%≥ 7%Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5%Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is > 8,5%Insuli can be started at any poit in the course of diabetes, including at the time of diagnosisInsuli can be started at any poit in the course of diabetes, including at the time of diagnosisInsulin treatment (plus metformin) is generally preferred to three oral agent as it is at least Insulin treatment (plus metformin) is generally preferred to three oral agent as it is at least As effective in lowering glycamia and is much cheaper.As effective in lowering glycamia and is much cheaper.
GlycatedGlycatedHaemoglobin Haemoglobin ≥ 7%≥ 7%
BMJ 333; 9 Des.2006.BMJ 333; 9 Des.2006. Management of hyperglycaemia in type 2 diabetes Management of hyperglycaemia in type 2 diabetes
Obat Baru
Vildagliptin 50mg/tablet, Sitagliptin, Saxagliptin Bekerja pada sel α & sel ß pankreas suatu
DPP-4 inhibitor oral (dipeptidyl peptidase IV). Meningkatkan sekresi insulin dan menurunkan
sekresi glukagon obat ini merupakan kandidat sebagai obat
pilihan pertama selain regulasi gula darah dan tidak meningkatkan berat badan.
Suastika, Konas VII PERSADIA 2008
RINGKASAN• DM tipe 2 merupakan ~95 dari seluruh kasus DM
• DM tipe 2 terutama disebabkan oleh resistensi insulin
• Adanya resistensi insulin akan berpengaruh terhadap jaringan otot, lemak dan liver dengan akibat terjadinya hiperinsulinemia, hipergikemia dan dislipidemia
• Adanya resistensi insulin akan berpengaruh terhadap perkembangan komplikasi vascular diabetik
• Setiap terapi DM tipe 2 haruslah selalu mengingat pada perbaikan resistensi insulin
Summary points Initial treatment should consist of lifestyle
intervention and metformin Treatment should aim to keep blood glucose
concentrations as close to the non-diabetic range as possible
The relentless decline of ß cell function requires early intervention, regular monitoring of glycaemia, and prompt adjustment of the (combination of) blood glucose lowering drugs, including insulin
Good glycaemia control will reduce the occurrence of inicrovascular and perhaps cardiovascular complications of type 2 diabetes
Scientific evidence for any algorithm is largely lacking