Thiazolidinediones

BY KUMAR SUDESH
FSO Trainee
Presentation Plan
 Introduction
 About Peroxisome Proliferator Activated
Receptors
 Mechanism of action of thiazolidinediones
 Indications
 Side effects of TZD
 Advantages of TZD
 Problems with TZD
 Pleiotropic effects of TZD
 Evidences of efficacy for thiazolidinediones
 Thiazolidinediones: Present Practice
Introduction
 Thiazolidinediones are also known as glitazones

 Are used in treatment of diabetes mellitus type 2

 High affinity ligand for Peroxisome Proliferator-activated

Receptor γ (PPARγ)

 Most of antidiabetic action of thiazolidinediones is through

stimulation of PPAR – γ (peroxisome proliferator activated
receptor- γ) leading to increased insulin sensitivity

 Troglitazone was first drug in this class to be marketed, but

removed from the market because it caused liver
dysfunction & liver failure.
Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ, eds. Text
Book of diabetes. 4th ed. Singapore: Wiley Blackwell; 2010: 465 – 466
 Peroxisome Proliferator
Activated Receptors
 A group of nuclear receptor proteins that
function as transcription factors regulating
expression of genes

 PPARs play essential roles in regulation of

cellular differentiation, development, and
metabolism (carbohydrate, lipid, protein),
and tumorigenesis

Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ, eds. Text Book of
diabetes. 4th ed. Singapore: Wiley Blackwell; 2010: 465 – 467
 Peroxisome Proliferator
Activated Receptors (Contd….)
Type of PPARs Site of expression Function
PPAR α Tissues with intensive Involved in fatty acid
fatty acid oxidation metabolism, lipid
(liver, heart, muscle, homeostasis, and
kidney and arterial wall peroxisome proliferation
cells)
PPAR β/δ Markedly in brain, Involved in fatty acid
adipose tissue and skin metabolism, lipid
homeostasis, skin
proliferation and
inflammation

PPAR γ Highest expression Involved in adipocyte

levels in adipose tissues differentiation, glucose
and insulin homeostasis,
macrophage function
and inflammation
Mechanism Of Action Of
Thiazolidinediones
 Insulin sensitizer

 Act through stimulation of PPAR γ

 PPAR - γ is highly expressed in adipose

tissue, and to a lesser extent in muscle and
liver

Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ, eds. Text Book of
diabetes. 4th ed. Singapore: Wiley Blackwell; 2010: 465 – 466
Mechanism Of Action Of
Thiazolidinediones (Contd….)
Mechanism Of Action Of
Thiazolidinediones (Contd….)

Presentation1.pptx

Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ, eds. Text Book of diabetes.
4th ed. Singapore: Wiley Blackwell; 2010: 465 – 466
Mechanism Of Action Of
Thiazolidinediones (Contd….)
 Thiazolidinediones also increase production of
adiponectin which has insulin sensitizing, anti-
atherogenic and anti-inflammatory properties

 Thus, stimulation of PPAR – γ by TZD leads to:

 Increased glucose utilisation by skeletal muscle and fat cells

 Increased uptake of free fatty acids and reduced lipolysis by
fat cells
 Reduced hepatic gluconeogenesis
 Apoptosis of larger insulin-resistant cells and proliferation of
smaller insulin-sensitive adipocytes
 Shift in distribution of fat from central to peripheral depots

Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ, eds. Text Book of diabetes. 4th
ed. Singapore: Wiley Blackwell; 2010: 465 – 466
 Thiazolidinediones: Indications

MacIsaac RJ, Jerums G. Clinical indications for thiazolidinediones. Australian prescriber. 2004; 27 (3): 70 – 74
 Thiazolidinediones: Indications
(Contd….)
 Patients must have an intolerance or contraindication to
either metformin or a sulfonylurea to qualify for
treatment with thiazolidinediones

 TZDs can be given in combination with metformin only in

obese patients

 Pioglitazone plus sulphonylurea may be offered to

patients who are unable to take metformin

 Clinical studies have shown that addition of a

thiazolidinedione to combination of metformin and a
sulfonylurea decreases HbA1clevels by 0.6–1.8% over 6–36
months
MacIsaac RJ, Jerums G. Clinical indications for thiazolidinediones. Australian prescriber. 2004; 27 (3): 70 – 74
 Side Effects of TZD
 Weight gain
 Fluid retention leading to Edema
 Mild anemia
 Hypoglycemia if on combined therapy
 Resumption of ovulation/ diminished
effectiveness of birth control pills

Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure. Journal of the
American Heart Association. 2003;108 : 2941-2948
 Advantages Of TZD
1. Thiazolidinediones may decrease Cardiovascular events
Mechanisms by Which Thiazolidinediones May decrease Cardiovascular Events:
CVD risk factor Beneficial Effect of Thiazolidinediones
Hyperglycemia Reduction in HbA1C
Hypertension Reduction in blood pressure
Dyslipidemia Reduction in triglycerides
Increase in HDL cholesterol
Increase in LDL particle size (less atherogenic
particles)
Decrease LDL oxidation
Markers of Endothelial inflammation Decreased C- reactive proteins
Decreased white blood cell count
Decreased fibrinogen
Decreased matrix metalloproteinases- 9
Decreased tumour necrosis factor-α
Markers of elevated thrombotic risk Decreased plasminogen activator inhibitor-1
Decreased platelet aggregation

Kendall DM. Thiazolidinediones the case for early use. Diabetes Care. 2006; 29 (1): 154 - 157
 Advantages Of TZD (Contd…..)
2 Thiazolidinediones increase production of adiponectin which has
.

insulin sensitizing, anti-atherogenic and anti-inflammatory properties

3. Preserves β-cell function and hence prevents secondary failure

4. TZDs do not cause hypoglycemia when used as monotherapy

5. Decrease insulin and sulfonylurea requirements as TZDs improves

insulin sensitivity

6. Administration of TZDs induce ovulation and increase ovulation rate

and pregnancy in PCOS

7. Pioglitazone ameliorates diabetic nephropathy via cell cycle–

dependent mechanisms

Kendall DM. Thiazolidinediones the case for early use. Diabetes Care. 2006; 29 (1): 154 – 157
Okada T, Wada J, Hida K. Thiazolidinediones Ameliorate Diabetic Nephropathy via Cell Cycle–Dependent Mechanisms.
 Problems With TZDs
 Thiazolidinediones produce a slowly generated antihyperglycemic
effect which usually requires 2 – 3 months to reach maximum
effect

 PPAR α and PPAR γ activation by TZD stimulates neoangiogenesis

through a VEGF dependent mechanism – a pathologic event in type
2 DM

 TZDs have been shown to have an association with an increased

risk of fractures particularly in women

 TZDs cause weight gain with an increase in subcutaneous adiposity

 Also cause fluid retention which typically manifests as peripheral

edema
Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure. Journal of the
American Heart Association. 2003;108 : 2941-2948
Problems With TZDs (Contd….)
 Can diminish effectiveness of birth control
pills

 Can cause hypoglycemia if on combined

therapy

 TZDs probably exacerbate macular edema

 TZDs should be used cautiously in patients

with heart failure
Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure. Journal
of the American Heart Association. 2003;108 : 2941-2948
 Pleiotropic Effects Of TZDs
 Improve lipid profile

 Reduce cardiovascular risk factors

 Administration of TZDs induce ovulation and increase

ovulation rate and pregnancy in PCOS

 Useful in Non-alcoholic steatohepatitis

 Pioglitazone ameliorates diabetic nephropathy via cell

cycle–dependent mechanisms

 Decrease microalbuminuria
Kendall DM. Thiazolidinediones the case for early use. Diabetes Care. 2006; 29 (1): 154 – 157
Okada T, Wada J, Hida K. Thiazolidinediones Ameliorate Diabetic Nephropathy via Cell Cycle–Dependent Mechanisms.
Diabetes. 2006; 55:1666–1677
 Thiazolidinediones : Evidences
Of Efficacy: ADOPT Study
 FPG over Time

Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group: Glycemic duration of rosiglitazone, metformin, or glyburide
monotherapy. N.Eng.J.Med. 2006; 355: 2427-43
Thiazolidinediones : Evidences
Of Efficacy - ADOPT Study
 HbA1C over Time

Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group: Glycemic duration of rosiglitazone, metformin, or
 Thiazolidinediones : Evidences
Of Efficacy - ADOPT Study
 Insulin sensitivity over Time

Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group: Glycemic duration of rosiglitazone, metformin, or glyburide
monotherapy. N.Eng.J.Med. 2006; 355: 2427-43.
 Thiazolidinediones : Evidences
Of Efficacy - ADOPT Study
 Thus, ADOPT study showed superiority of
rosiglitazone over metformin and glibenclamide
in reducing progression of type 2 diabetes

Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group: Glycemic duration of rosiglitazone, metformin, or
glyburide monotherapy. N.Eng.J.Med. 2006; 355: 2427-43.
 Thiazolidinediones : Evidences
Of Efficacy - DREAM STUDY
 Showed that with rosiglitazone therapy, there
is reduced risk of developing diabetes in
subjects with impaired glucose tolerance

 With rosiglitazone therapy, Diabetes risk

reduction increased in those with greater body
weight
 Risk reduction for diabetes or death
 40% in people with body mass index <28 kg/m2

 68% in subjects with body mass index >32

kg/m2
Gerstein HC, Yusuf S, Bosh J, et al. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trail
Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired fasting glucose tolerance or
impaired fasting glucose: A randomized controlled trial. Lancet. 2006; 368:1096-1105.
 Thiazolidinediones : Evidences
Of Efficacy - DREAM STUDY
 Despite increase in body weight and body
mass index, rosiglitazone therapy showed a
significant decrease in waist to hip ratio
 Indicated redistribution of fat from the more
harmful central (abdominal) areas to the
peripheral areas (hip)

Gerstein HC, Yusuf S, Bosh J, et al. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication)
Trail Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired fasting glucose
tolerance or impaired fasting glucose: A randomized controlled trial. Lancet. 2006; 368:1096-1105.
Thiazolidinediones : Evidences
Of Efficacy – PROactive Study
 PROactive study (PROspective Pioglitazone
Clinical Trial In Macrovascular Events) showed
that Pioglitazone
 Reduces risk of non- fatal MI, stroke and death by
16%
 Reduces risk of recurrent stroke, with a 47%
reduction in fatal or non fatal stroke

 Pioglitazone reduced blood glucose in a

sustained manner over three years of
PROactive Study (HbA1c reduced by 0.5%
more than placebo)
Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in
people with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2003; 26:2983–2989
Thiazolidinediones : Evidences
Of Efficacy – PROactive Study
 Pioglitazone improved diabetic dyslipidaemia
by
 IncreasingHDL cholesterol by 19% (9% more than
placebo) and
 Reducing triglycerides by 11% (13% more than
placebo) over three years of the PROactive Study

 There was a significant (p=0.03) decrease in

systolic blood pressure (median change 3
mmHg more than produced by placebo) in
patients treated with pioglitazone
Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS. Use of thiazolidinediones and risk of heart failure in people
with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2003; 26:2983–2989
Thiazolidinediones : Evidences
Of Efficacy – PROactive Study
 Long-term Durable Reduction in HbA1c with the
Addition of Pioglitazone to Metformin and SU
Thiazolidinediones : Evidences
Of Efficacy (Contd…..)
 Rosiglitazone Treatment Improves LDL Particle
Density Phenotype
Thiazolidinediones : Evidences
Of Efficacy (Contd…..)
 Effect of Pioglitazone on Abdominal fat
distribution:
Thiazolidinediones : Evidences
Of Efficacy (Contd…..)
 Effect of Rosiglitazone on microalbuminuria:
Thiazolidinediones : Evidences
Of Efficacy (Contd…..)
 Effect of Pioglitazone on recurrent MI in
patients with previous MI:
Thiazolidinediones: Present
Practice
 Because of two already banned drugs
(Troglitazone & Rosiglitazone) in TZDs Class,
doctors don’t prioritize prescribing TZD class of
drug

 Thiazolidinediones prescribed only when

patients have an intolerance or contraindication
to either metformin or a sulfonylurea

 Use of TZDs is limited because of its side effects

(weight gain, edema, anemia, heart failure in
some cases, etc.)
References
 Bailey CJ, Krentz AJ. Oral Antidiabetic Agents. In: Holt RIG, Cockram CS,
Flyvbjerg A, Goldstein BJ, eds. Text Book of diabetes. 4th ed. Singapore: Wiley
Blackwell; 2010: 465 – 468

 MacIsaac RJ, Jerums G. Clinical indications for thiazolidinediones.

Australian prescriber. 2004; 27 (3): 70 – 74

 Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione Use, Fluid

Retention, and Congestive Heart Failure. Journal of the American Heart
Association. 2003;108 : 2941-2948

 Kendall DM. Thiazolidinediones the case for early use. Diabetes Care.
2006; 29 (1): 154 – 157

 Okada T, Wada J, Hida K. Thiazolidinediones Ameliorate Diabetic

Nephropathy via Cell Cycle–Dependent Mechanisms. Diabetes. 2006;
55:1666–1677
 Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group:
Glycemic duration of rosiglitazone, metformin, or glyburide
monotherapy. N.Eng.J.Med. 2006; 355: 2427-43.

 Gerstein HC, Yusuf S, Bosh J, et al. DREAM (Diabetes

Reduction Assessment with ramipril and rosiglitazone
Medication) Trail Investigators. Effect of rosiglitazone on the
frequency of diabetes in patients with impaired fasting
glucose tolerance or impaired fasting glucose: A randomized
controlled trial. Lancet. 2006; 368:1096-1105.

 Delea TE, Edelsberg JS, Hagiwara M, Oster G, Phillips LS.

Use of thiazolidinediones and risk of heart failure in
people with type 2 diabetes: a retrospective cohort study.
Diabetes Care. 2003; 26:2983–2989