THIAZOLIDINEDIONES (TZDs)

Dr. dr. Mgs. IRSAN SALEH, M. Biomed

4/26/2017
Tim Penyusun
• Dr. Nita Parisa
• Dr. Fauziah, M.Bmd
• Yeni Agustin, S.Si., M.Kes

4/26/2017
OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 ↓ 𝐼𝑛𝑠𝑢𝑙𝑖𝑛
↑ 𝐿𝑖𝑝𝑜𝑙𝑦𝑠𝑖𝑠
𝑠𝑒𝑐𝑟𝑒𝑡𝑖𝑜𝑛
TZDs + - TZDs
↑ 𝐺𝑙𝑢𝑐𝑎𝑔𝑜𝑛 ↑ 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
𝑠𝑒𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑝𝑡𝑖𝑜𝑛

HYPER
TZDs - GLYCEMIA + TZDs
↑ 𝐺𝑙𝑢𝑐𝑜𝑠𝑒 ↓ 𝐺𝑙𝑢𝑐𝑜𝑠𝑒
𝑝𝑟𝑜𝑐𝑢𝑐𝑡𝑖𝑜𝑛 𝑢𝑝𝑡𝑎𝑘𝑒

↑ 𝑛𝑒𝑢𝑟𝑜𝑡𝑟𝑎𝑛𝑠𝑚𝑖𝑡𝑡𝑒𝑟 ↓ 𝐼𝑛𝑐𝑟𝑒𝑡𝑖𝑛
𝑑𝑦𝑠𝑓𝑢𝑛𝑐𝑡𝑖𝑜𝑛 𝑒𝑓𝑓𝑒𝑐𝑡
Multiple defects type 2 diabetes: from Triumvirate to ominus
octet (DeFronzo, 2010)
Obesity-induced macrophage infiltration into
adipose tissue causes insulin resistance

normal adipocytes hypertrophied adipocytes

insulin-sensitive tissue
(Tateya et al, 2013)
 Insulin Resistance Mechanism

(Samuel and Shulman, 2012).

OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
TZDs  insulin sensitiser/glitazone

TZDs compound: troglitazone (Hepatotoxic)

FDA 1996 - Withdrawal, pioglitazone and
rosiglitazone (White , 2014)
can be used as:
monotherapy
combination (Metformin, Sulfonylureas)
ADA recommends pioglitazone as a second-
or third-line agent for type 2 DM (HF and MI)
 TZDs

insulin sensitisers  beta-cell  bind to

the (PPAR-y)I n muscle and liver 
forms a complex with the retinoid X
receptor (RXR)  enhanced expression
of certain insulin-sensitive genes, such
as GLUT- 4, lipoprotein lipase, fatty acid
transporter protein and fatty acyl CoA
synthase.

This increases insulin sensitivity in

adipose tissue, liver and skeletal muscle
(glucose uptake and utilisation),
increases adipocyte lipogenesis and
decreases circulating fatty acid levels.
Bilous and Donelly, 2015 There is also decreased production of
the cytokine TNF-and of resistin.
OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 PHARMACOKINETICS

well absorbed after oral administration

extensively bound to serum albumin
Rosiglitazone and pioglitazone are
metabolised via various cytochrome P450
isoenzymes
pioglitazone: CYP2C8 and CYP3A4
rosiglitazone: CYP2C9 and CYP2C8

(Rang et al, 2007; Brunton et al, 2010; Katzung et al, 2012)

 PHARMACOKINETICS

Pioglitazone: excreted in the bile and

eliminated in the feces
Rosiglitazone: metabolites are primarily
excreted in the urine
no dosage adjustment is required in renal
impairment
avoided in nursing mothers

(Rang et al, 2007; Katzung et al, 2012)

OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 THERAPEUTIC USES AND DOSAGE

Pioglitazone and Rosiglitazone are dosed Once Daily

Starting Dose
Rosiglitazone 4mg (not exceed 8 mg)
Pioglitazone 15-30 mg (not exceed 45 mg)

(Track et al, 2006; Brunton et al, 2010)

OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 EFFICACY TZD

DIABETES PREVENTION  STUDY SUBJET WITH IGT  PIO

(45 MG/DAY) REDUCED THE RISK OF CONVERSION FROM
IGT TO T2DM BY 72%, CONVERSION TO NORMAL GLUCOSE
TOLERANCE: 48%, REDUCED LEVELS OF FASTING GLUCOSE
AND GLYCATED HEMOGLOBIN (HbA1C)  SIMILARY
BENEFICIAL EFFECT WITH ROSIGLITAZONE (8 MG/DAILY)
DIABETES PROGRESSION  ROSIGLITAZONE (UP TP 4 MG
TWICE DAILY) DECREASED THE RISK OF MONOTHERAPY
FAILURE BY 32% VERSUS METFORMIN (UP TO 1 G TWICE
DAILY) AND BY 63% VERSUS GLYBURID (UP TO 7.5 MG
TWICE DAILY), A BETTER glycemic control
(Nesto et al, 2003; Pastromas et al, 2006; Brunton et al, 2010; Khrishnaswami et al, 2010;
Katzung et al, 2012; Rizos et al, 2016)
 PLEIOTROPIC EFFECTS

FAT REDISTRIBUTION --> DISTRIBUTION FAT FROM THE

VISCERAL TO THE SUBCUTANEOUS STORAGE DEPOT,
REDUCED INTRAHEPATIC FAT LEVELS
RENOPROTECTIVE ABILITY  SUITABLE CHOICE FOR
PATIENTS WITH RENAL FAILURE; DECREASE URINARY
ALBUMIN EXCRETION AND URINARY PROTEIN
12 WEEKS: DECREASE SERUM HIGH SENSITIVITY CRP
LEVELS AND IMPROVED GLYCEMIC CONTROL (FASTING
GLUCOSE AND HbA1C) AND LIPID PROFILE

(Nesto et al, 2003; Pastromas et al, 2006; Brunton et al, 2010; Khrishnaswami et al, 2010;
Katzung et al, 2012; Rizos et al, 2016)
OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 ADVERSE EFFECTS

HEART FAILURE  Fluid Retention

PERIPHERAL EDEMA AFTER 1 YEAR OF
PIOGLITAZONE TREATMENT  Adiposa
Differentiation and similar CCB
BONE FRACTURES  Osteoblast Osteoklast
CANCER
WEIGHT GAIN  Diferensiasi Adiposa
MACULAR EDEMA  Fluid Retention

(Nesto et al, 2003; Pastromas et al, 2006; Brunton et al, 2010; Khrishnaswami et al, 2010;
Katzung et al, 2012; Rizos et al, 2016)
OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 CONTRA INDICATIONS

Hypersensitivity to product or components

Patients at risk of Heart Failure
Established NYHA class III/IV Heart Failure

(Pastromas et al, 2006; Rizos et al, 2016)

OUTLINES
PATHOGENESIS OF TYPE 2 DIABETES
MECHANISM OF ACTION
PHARMACOKINETICS
THERAPEUTIC
PHARMACODYNAMICS
USES AND DOSAGE

PLEIOTROPIC EFFECTS
ADVERSE EFFECTS

CONTRA INDICATIONS

DRUG INTERACTIONS
 DRUG INTERACTIONS

In Europe, rosiglitazone and pioglitazone are

contraindicated for use with insulin (Risk
Heart Failure)
Gemfibrozil and Trimetoprim increased
concentrations of rosiglitazone
Rifampicin decreased concentration of
rosiglitazone

(Scheen, 2007)
DRUG INTERACTIONS
DRUG INTERACTIONS
 DRUG INTERACTIONS

Rosiglitazone  decrease bioavailabilitas

dari nevirapine
Pioglitazone  decrease concentration
plasma of midazolam and nifedipine
There is no food interaction

(Scheen, 2007)
 Regimen in Indonesia

Generic: Thiazolidinedion
Patent : Actos (15-30 mg), Gliabetes 30 mg,
Prabetic (15-30 mg), Deculin (15-30 mg),
Pionix (15-30 mg)
Once daily
With or Without Food

(Perkeni, 2011)
 Metformin VS TZD

Source: Adapted from slide deck that accompanies Inzucchi SE, et.al. Diabetes Care 2015;38:140-49.
4/26/2017
Available at: http://care.diabetesjournals.org/content/38/1/140/suppl/DC2.
4/26/2017 (Perkeni, 2011)
 CAUTION

Liver function test (SGOT and SGPT) before

and after treatment (3 months)
Visus and Funduscopy Check Regularly
THANK YOU