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