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The Role of TZDs in the Management of Type 2
Diabetes
Dr. Eny Ambarwati, SpPD, FINASIMDep. Peny. Dalam, Jantung & Paru, RS. Ridwan
Meuraksa, Jakarta
Nama : Dr. Eny Ambarwati, SpPD, FINASIMTempat/Tgl. Lahir : Jogjakarta, 30 Maret 1966Pendidikan : Dokter Umum, FK - UGM, th 1992 Internis, FK-UGM, th 2005Dinas : Dep. Peny. Dalam RS. M. Ridwan Meuraksa,
Kesdam Jaya/Jayakarta
1. Pendahuluan 2. Management T2DM 3. Peranan TDZs dlm Management
T2DM
Definisi ??
DM Kelompok peny. Metabolik kronik yg
ditandai dgn hiperglikemia ok. gangguan sekresi
& / fungsi (resistensi insulin) (ADA,2005)
PENDAHULUAN
Negara 1995 (juta) Negara 2025 (juta)
Urutan 1 India 19.4 India 57.22 China 16.0 China 37.63 U.S. 13.9 U.S. 21.94 Russian Fed. 8.9 Pakistan 14.55 Japan 6.3 Indonesia 12.46 Brazil 4.9 Russian Fed. 12.27 Indonesia 4.5 Mexico 11.78 Pakistan 4.3 Brazil 11.69 Mexico 3.8 Egypt 8.810 Ukraine 3.6 Japan 8.5
Negara Lainnya 49.7 103.6
Total 135.3 300.0
Sepuluh Negara dengan Perkiraan Jumlah Pasien DM Dewasa Terbanyak, 1995 and 2025
Epidemiology of T2DM in Indonesia
Urban Indonesia Basic Health Research/Riskesdas1 :
Prevalence of DM → 5.7% [♀ : 6.4%; ♂ : 4.9%] Prevalence of IGT → 10.2% Age, central obesity, HT, smoking & obesity were determinant factors for
DM & IGT
West Java study2 :
Prevalence of isolated IFG → 4,13% (n=40) Prevalence of isolated IGT → 24,25% (n=243) Prevalence of mixed IFG/IGT → 5,68% (n=55) Total prevalence of pre-DM → 33,96%
IGT : Impaired Glucose Tolerance ; IFG : Impaired Fasting Glucose1. Mihardja L et al. Acta Med Indones-Indones J Intern Med 2009;41:169–174; 2. Yunir E et al. Acta Med Indones-Indones J Intern Med 2009;41:181–185
Faktor genetik
Faktor lingkungan
Gaya hidup berisiko :
Makan >>Aktivitas <<StressJumlah Insulin : ↓
Fungsi/kerja (RI) : ↓
↑ kadar gula darah → DM
Etiologi DM ?
Insulin resistance & -cell dysfunction are linked and are underlying factors in T2DM
Insulinresistance
High insulin demand
glucoto
xicity
lipotoxicity
Increased lipolysis & release of FFA
Elevated circulating FFA
Decreased glucose uptake into muscle & adipose tissue & raised hepatic glucose output
Hyperglycemia
Type 2 diabetes
-Cell dysfunction
Atherosclerosis
Type 2 diabetesImpaired
glucose tolerance
Polycysticovary disease
Obesity (central)
Dyslipidemia Hypertension
Acanthosisnigricans
Hyperuricemia
Decreasedfibrinolytic activity
InsulinResistance
KLINIS
Insulin Resistance : Associated Conditions
Not specified
Others
Tuberculosis
Accident / suicide
Gangrene
Renal insufficiency
Diabetic coma
Infections
Tumors
Stroke
Myocardial infarction
0 10 20 30 40% deaths in diabetics
3.4
11.4
0.9
2.1
2.7
2.9
3.1
6.7
1022
34.7
Panzram G. Diabetologia 1987; 30: 120-31
Causes of Mortality in Diabetic Patients
2. Management T2DM
HbA1c ≥7%
Lifestyle intervention + metformin
Diagnosis
No
No No
Add glitazone*– no hypoglycaemia
HbA1c ≥7%
HbA1c ≥7%
No
No
No
Intensive insulin + metformin +/- glitazone*
HbA1c ≥7%
Yes
Add basal insulin– most effective
Yes
HbA1c ≥7% Yes
Intensify insulin Add glitazone*
Yes
Add basal or intensify insulin
Yes
Add sulfonylurea
HbA1c ≥7%
Add sulfonylurea– least effective
Yes
Add basal insulin
Associated with increased risk of fluid retention, CHF, & fractures. Rosiglitazone, but probably notpioglitazone, may be associated with an increased risk of MI
ADA/EASD Guidelines 2008
Nathan et al. Diabetes Care 2008;31:173–175
PERKENI T2DM Management 2011
TZDs memiliki posisi = OAD lain
Oral Antidiabetic Drugs (OAD)
1. Gol. Insulin secretagogue : - Sulfonilurea :
* Gen. I : klorpropamide, tolbutamide. * Gen. II : glibenklamid, glipizid, glikazid,
glikuidon, glimepirid- Glinid : repaglinid, nateglinit.
2. Gol. Peripheral insulin sensitivity : - TZDs : troglitazon, rosiglitazon, pioglitazon (R/Actos)- Biguanid : metformin
3. Gol. Hepatic glucose production (Glukoneogenesis inhibitor) : - Biguanid - TZDs
4. Gol. AGI : acarbose 5. Gol. DPP 4 inhibitor(glucagon secretion) :
- saxa/vilda/sita/lina - gliptin
NORMOGLYCEMIA
Increased insulin secretionDecrease in
hepatic glucose production
Increase in glucose uptake
Sulfonylureas Non-sulfonylurea secretagogues
TZDs Biguanides
Alpha-glucosidase inhibitors
Decreased digestion of complex sugars
MEKANISME KERJA OAD
BiguanidesTZDs
Current treatments for T2DM have limitations when renal function declines
30 – 60 <30 Hemodialysis>60
Liraglutide
Metformin
Pioglitazon
AcarboseRepaglinid
e
Exenatide
Dose Reduction
Insulin
Dose Reduction
Gliclazide
Dose ReductionDose Reduction
Glimepiride
Declining GFR
Linagliptin
Ora
l d
rug
sIn
ject
ab
les
Saxagliptin
Dose Reduction
Adapted from: Schernthaner G, et al. Nephrol Dial Transplant. 2011;26(2):454–7 (in press) and respective EMEA SmPCs
SitagliptinVildagliptin
Dose Reduction
19
The treatment :
→ When ?→ How ?
Bali Endocrine Update 2012 Bali Endocrine Update 2012
Fasting plasmaGlucose(FPG) levels
80 - < 140 mg/dl
The Glucose Target
2 Hour Post PrandialGlucose(PPG) levels
Random plasmaGlucoselevels
Glycated hemoglobin (A1C)levels
80 - < 100 mg/dl
< 200 mg/dl < 7 %
Konsensus Perkeni 2011
Target Pengendalian DM (Perkeni, 2011)
Parameter CV Risks
(-)CV Risks
(+)IMT (kg/m2) 18,5 - <23 18,5 - <23
BP Sistolik (mmHg) < 130 < 130
BP Diastolik (mmHg) < 80 < 80
Fasting Blood Glucose (mg/dL) < 100 < 100
Post Prandial Blood Glucose (mg/dL) < 140 < 140
HbA1c (%) < 7 < 7
LDL (mg/dL) < 100 < 70
HDL (mg/dL) Male > 40Female > 50
Male > 40Female > 50
Trigliseride (mg/dL) < 150 < 150
CV = Cardiovascular, BP= Blood Pressure
23
3. Peranan TZDs pada Management T2DM
β-cell dysfunction
Insulin resistance
Increased hepatic glucose
production
the “triumvirate”
The 3 Main Pathophysiological Defects of T2DM
PILIHAN PENGOBATAN
OAD
Mengatasi : Defisiensi Insulin Resistensi Insulin
OAD + OAD
INSULIN
OAD +
INSULIN
INSULIN +
INSULIN
Hyperglycemia
ADIPOSE TISSUE
Lipolysis
FFA Mobilization
T2DM, lipotoxicity & metabolic evils…Can We Prevent It ?? Yes, if we reduce insulin resistance.
Liver InsulinResistance Leading to
Gluconeogen
esis
Adipose TissueInsulin Resistance
Adapted from DeFronzo et al. Diabetes Care. 1992;15:318-368
Lipotoxicity↑ Production of TG-rich lipoproteins
Insulin Resistance leading to
Glucose Utilization
Lipoapoptosis of beta cells
Pioglitazone
Pioglitazone
Metformin
TZDs
Muscle Glucose uptake & adiposal
Liver- Glucose uptake
- VLDL cholesterol
Adipose tissue- Glucose uptake & disposal- Free fatty acid uptake- Alteration of other adipocyte factors
Improvementin metabolicimbalances
DeFronzo R. Diabetes 1988;37:667–687; Reginato & Lazar,.Trends Endocrinol Metab,1999;10:9–13; Saltiel & Olefsky. Diabetes 1996;45:1661–
1669
Metabolic Control in Type 2 Diabetes by TZDs
Pioglitazone vs Metformin as Add-on to SU: HbA1c Results
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6
-1.8
-2.0
0
-
0.
5
-
1.
0
-
1.
5
-
2.
0
-
2.
5
-
3.
0
-
3.
5
-
4.
0
Weeks
Pioglitazone + SU
Metformin + SUChange from baseline in FPG (mmol/L)
0 10 20 30 40 50 60 70 80 90 100110
Change from baseline in HbA1c (%)
Weeks
Pioglitazone + SU
Metformin + SU
Charbonnel B et al. Diabetologia 2005;48:1093–1104
0 10 20 30 40 50 60 70 80 90 100110
HbA1c FPG
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
-1.6 Pioglitazone + metformin
Gliclazide + metformin
Pioglitazone + metformin
Gliclazide + metformin
p :<0.001
Charbonnel B et al. Diabetologia 2005;48:1093–1104
Pioglitazone vs Gliclazide as Add-on to Metformin: HbA1c Results
HbA1c FPG
Weeks
Change from baseline in FPG (mmol/L)
0 10 20 30 40 50 60 70 80 90 100110
Change from baseline in HbA1c (%)
Weeks
0 10 20 30 40 50 60 70 80 90 100110
8
8.5
9
9.5
10
0 4 8 12 16
Mean
Hb
A1
c
(%)
Weeks
† † †
† ††† †
†p0.01 vs baseline
-1.4
-0.8
-0.2
Ch
an
ge f
rom
baselin
eH
bA
1c (
%)
Placebo + insulin Pioglitazone 30mg + insulinPioglitazone 15mg + insulin
*
*
*p<0.01 vs placebo
†
Pioglitazone plus Stable Insulin Therapy : HbA1c Results
-0.4
-1.0-1.2
-0.6
010.5
Rosenstock J et al. Int J Clin Pract 2002;56:251–257
Benefits of Pioglitazone: Lipid Metabolism Pioglitazone improves diabetic dyslipidaemia
Decreasing triglyceride levels Increasing high-density lipoprotein (HDL) cholesterol
levels
Dormandy JA et al., Lancet (2005) 366:1279-1289. Mazzone T et al., JAMA (2006) 296: 2572Nicholls et al., J Am Coll Cardiol (2008) 52:255-62.
Corr
ect
ed
for
Com
para
tor
32
LIPIDS INFLAMMATION ↓ Triglycerides ↓ CRP, Interleukin-6 ↓ LDL ↓ ICAM, VCAM,
MCP-1 ↑ HDL ↓ MMP-9,
Adiponectin ↓ TNFa, soluble
CD40 ligandCOAGULATION ↓ PAI-1 FAT DISTRIBUTION ↓ Fibrinogen ↓ Visceral fat ↓ Platelet aggregation ↓ Hepatic fat ↓ Endothelin 1 ↑ Subcutaneous fat
VASCULAR EFFECTS BONE METABOLISM ↑ Blood volume ↑ Osteoporosis?
↓ Blood pressure ↓ Intima-media thickness ↑ Endothelial function ↑ Vascular permeability Patel CB et al. Diabetes Vasc Dis Res 2006;3:65–71
PPAR Agonists: Pleiotropic Effects
• Individualized tx targets
TREATMENT CHOICE
Principles in Selecting Antihyperglycemic Interventions Safety profiles Effectiveness in lowering blood glucose Extraglycemic effects that may reduce long-
term complications HT, dyslipidemia, BMI, RI, insulin secretory
capacity Tolerability Ease of use Cost
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Kesimpulan
Patogenesis T2DM meliputi RI & disfungsi sel β Penanganan T2DM ditujukan pada upaya
mengatasi RI & disfungsi sel β TZDs : pioglitazone menurunkan HbA1c mll
mekanisme ↑ Insulin receptor sensitivity & efek pleiotropik yg menguntungkan dlm management T2DM, shg komplikasi dpt dicegah
TERIMA KASIH