Pioglitazone is a newer thiazolidinedione insulin sensitizer that reduces insulin resistance. It works by activating PPARγ receptors in fat and muscle cells. Studies show pioglitazone improves glycemic control similarly to metformin but is more effective at increasing insulin sensitivity. Pioglitazone also improves lipid profiles and has potential cardiovascular benefits through effects on multiple risk factors, though longer term outcome studies are still needed.

1. Emerging trends in the therapy of DM Better clarity, Better outcomes Dr. B. K. Iyer

2. Diabetes – evolving status as of today Stem cell therapy Therapy based on Glucokinase Therapy based on GLP1 [EXENATIDE] Insulin sensitizers Insulins & OHAs Inhaled insulins Bariatric Surgery Therapy based on Amylin [PRAMILINTIDE] The growing epidemic of type 2 diabetes is prompting the need for a lot of of new therapies

4. Diabetes – evolving therapies today Insulin sensitizers, thus, play a key role in the therapy of diabetes, since they not only help to tackle insulin resistance but also manage the components of metabolic syndrome. Hence, insulin sensitization is the key to effective insulin action

6. What Is Known?

8. Insulin Resistance: Manifestations Hypertension, Atherosclerosis, POS Disturbed glucose tolerance Acanthosis Nigricans, Central obesity. Clinical manifestations Dyslipidaemia Glucose intolerance Biochemical abnormalities Vascular abnormalities High TG, Low HDL-C; Small, dense LDL Insulin resistance, Hyperinsulinaemia Abnormal thrombolysis, ED & VSC dysfunction INSULIN RESISTANCE

15. Insulin Resistance: pathway effects

17. IR and AN “ Velvety, mossy, verrucous, hyperpigmented skin change often found over the nape of the neck, in the axillae or beneath the breasts.”

18. IR and AN more than 90% of patients with IR 21% of diabetic patients 55% of obese patients ?? % of obese, diabetic patients Microscopic acanthosis nigricans in type 2 diabetes, j Cutan med Surg 2001 sep-Oct;5(5):390-3 by manus RM, Gottschalk R, Alanen K, Shum DT, Grundy P I Packianathan, O Stevenson & N finer , Centre for obesity research, Luton and Dunstable hospital NHS trust, Luton, UK, diabetes care 1999 Oct 22 (10) : 1655-9 Studies have revealed that AN is present in

21. IR and hypertension Direct vasodilator Increases sympathetic outflow Increases renal sodium reabsorption Counter the vasodilatory effects and result in elevations of BP in the IR individuals Insulin VSMC hypertrophy Endothelial dysfunction &  production of NO Thus, IR Increases chances of atherogenesis & CAD Insulin resistance

22. The approach to tackle IR

27. PPAR receptors and cholesterol

29. Thiazolidinediones and their role

30. Thiazolidinediones and their role

31. Thiazolidinediones and their role

32. What May Be Unknown? What is the new thiazolidinedione - Pioglitazone?

34. Pioglitazone – Mechanism of action

40. Studies on Pioglitazone

42. Pioglitazone vs. Metformin

48. Pioglitazone or Metformin added to existing SU therapy

55. Pioglitazone vs. Metformin vs. SU

57. Comparison of Pioglitazone with Metformin or SU & combination on CISI Antonio Ceriello et al, Diabetes Care 28: 266-272, 2005

60. Anti-inflammatory and Anti-atherogenic studies

62. Anti-inflammatory and Anti-atherogenic studies Pioglitazone vs. Control

66. Anti-inflammatory and Anti-atherogenic studies Pioglitazone vs. SU

71. PROactive - ( PRO spective A ctos C linical T rial I n macro- V ascular E vents)

78. Pioglitazone - Summary Powers insulin Improves Lipids Confronts challenges of cardiovascular risks Prevents complications The Superior insulin receptor sensitizer Doubly benefits diabetics Reduces small, dense LDL LDL Min. +12.8% HDL Min. -10.1% TG Result Lipid

79. What Needs to Be Known? What is different about Pioglitazone as compared to Rosiglitazone?

80. Second Generation thiazolidinediones – what is known? Yes No Active metabolites 24 16-24 Duration of action High 4 15 / 30 Pioglitazone Low 3 2 / 4 Rosiglitazone Activity on PPAR-  Plasma Peak Doses [mg.] Thiazolidinediones

81. Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.

82. Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.    

83. Rosi vs. Pio study A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia [Diabetes Care. 2005;28(7): 1547-1554.

84. Rosi vs. Pio study Data presented at the American Heart Association’s 2004 scientific session in New Orleans by Ronald Goldberg, University of Miami school of medicine. Rosiglitazone [% changes] Pioglitazone [% changes] LDL- Cholesterol [Mg. ‘ dl.] HDL-cholesterol [Mg. / dl.] Triglycerides [Mg./ dl.] +23.3% +13.7% +7.8% +14.9% +14.0% -12.0% Week 24 changes from baseline

85. Rosi vs. Pio in dyslipidaemia   

86. How does all this affect our knowledge? Which of the 2 currently available thiazolidinediones is the better option? 2 vital questions on Thiazolidinediones Is there a role for thiazolidinedione in regular therapy of diabetes Multi-point fuel injection Carburretor

89. Pionorm - the better Thiazolidinedione – Action on Hba1c Impact on lipid parameters Improvement In FBS, PPBG Impact on Insulin Levels [FSI & HOMA-S] Increased Adiponectinaemia Action on blood pressure Impact on Cardiovascular Risk factors Impact on CRP and PWV Impact on carotid Intima Media Thickness Lesser risks of atherosclerosis New drugs like Muraglitazar and tesaglitazar, non-TZD drugs that inhibit the PPAR-  & -  receptors, are in late stage clinical trials and appear to have greater effect in reducing CV risk factors