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Nonglycemic Effects of Thiazolidinediones

Nonglycemic Effects of Thiazolidinediones. Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI

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Nonglycemic Effects of Thiazolidinediones

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  1. Nonglycemic Effects of Thiazolidinediones Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Website: www.endocrinology-online.com

  2. Please Note: • This presentation discusses investigational, off label and non-FDA indicated effects of thiazolidinediones (glitazones). Please be aware that TZDs are FDA approved for treatment of hyperglycemia in type 2 diabetes only. This presentation is for informational and educational purposes only and is not intended to encourage or recommend any off label uses of any pharmaceutical product (s).

  3. TZDs : Mechanisms of Action Intestine: glucose absorption Blood glucose Pancreas:insulin secretion Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669. Suter SL et al. Diabetes Care. 1992;15:193-203. Whitcomb RW et al. In: Diabetes Mellitus. 1996:661-668.

  4.  triglycerides  HDL  FFA  BP  glycemia  LDL  PAI-1  oxidative stress VSMC migration and proliferation Effects of thiazolidinediones on cardiovascular risk factors and atherosclerotic mechanisms Thiazolidinediones  monocyte subendothelialtransmigration

  5. Peroxisome Proliferator-activated Receptors PPAR a AgonistsPPAR a • Fatty Acids • Fibrates Fatty Acid, HDL Metabolism PPAR g AgonistsPPAR g • Oxidized Lipids • Thiazolidinedioines Adipogenesis, insulin sensitivity PPARs are mediators of vascular disease, inflammation and endothelial dysfunction

  6. Adipogenesis Glucose Transport Monocyte Differentiation Induction of Scavenger Receptor Inhibition of Cytokine Production PPARg mRNA Thiazolidinediones and PPARg Thiazolidinedione Retinoic Acid X Receptor RXR Promotor C3P CIII Gene

  7. Insulin Glucose Thiazolidinediones and “Insulin Resistance” X GLUT-4

  8. Insulin Thiazolidinedione Glucose Thiazolidinediones and “Insulin Resistance” X GLUT-1 GLUT-4

  9. Effect of Pioglitazone on Insulin Resistance: HOMA-IR

  10. Effect of Pioglitazone on Lipid Levels

  11. Lipid Effects of Pioglitazone with Metformin

  12. Association Between sdLDL and Insulin Resistance 12 (n=19) 10 (n=29) 8 Mean steady state plasma glucose(mmol/L) at identical plasma insulin (n=52) 6 4 2 0 A Larger LDL particle pattern Intermediate pattern B Small LDL particle pattern LDL-size phenotype Reaven GM, et al. J Clin Invest. 1993;92:141-146.

  13. Effect of Rosiglitazone on LDL Particle Density* Rf < 0.2632 (smaller, dense) Rf  0.2632 (larger, more buoyant) 80 70 60 50 % of Patients 40 30 20 10 0 Week 8 - Rosiglitazone Study Entry *% of patients by particle size before and after 8 weeks of Rosiglitazone 4 mg bid in a randomized placebo-controlled pharmacodynamic study (N=234) Study 108. Data on file, GlaxoSmithKline.

  14. 0.08 0.06 0.04 0.02 Mean Change in LDL/ApoB 0.00 -0.02 -0.04 RSG 2mg bd RSG 4mg bd Glyburide 020: LDL/ApoB Ratio Baseline to Wk 26 (ROSIGLITAZONE/020 - ITT Population) (Error Bars = 95% CI)

  15. Rosiglitazone Effects on HDL Sub-fractions 25 Week 8 20 Week 24 15 95% CI) Mean percentage change 10 + ( 5 0 -5 HDL-2 HDL-3 Data on File (Study 108). GlaxoSmithKline. Geometric Mean (ITT, LOCF)

  16. Pioglitazone effects on Small, Dense LDL Winkler, K et al. Diabetes Care. 2003;26: 2588-2593.

  17. Atherogenic Index of Plasma Atherogenic index of plasma = the logarithmic transformation of the triglyceride:HDL cholesterol ratio (correlates inversely with the LDL particle size) Lee, C. et al. Abstract 688-P . American Diabetes Association 63rd Scientific Sessions. 6/03

  18. Potential Antiatherogenic Effects of Pioglitazone Satoh, et al. Diabetes Care. 2003; 26: 2493-2499.

  19. Occur Independent of Antidiabetic Effect Satoh, et al. Diabetes Care. 2003; 26: 2493-2499.

  20. Multiple Factors May Drive Progressive Decline of -Cell Function “Glucotoxicity” (hyperglycemia) Insulin Resistance -cell “Lipotoxicity” (elevated FFA, TG) Adapted from Reaven GM. Physiol Rev 1995;73:473–486.

  21. No. at No. at Baselinewk 52 Glyburide 203 168 RSG 4 mg* 195 139 RSG 8 mg* 189 145 28 26 24 Free Fatty Acids (mg/dL) 22 20 18 0 0 2 4 6 8 12 16 26 38 52 Treatment Weeks Effect of TZD’s on Free Fatty Acids ITT without LOCF *Given in divided doses Study 020. Data on file; GlaxoSmithKline.

  22. Thiazolidinedione Increases Islet Insulin in db/db Mice 28 days treatment with RSG 1.42 mg/kg MET 100 mg/kg GLI 49.4 mg/kgMice treated for 28 days beginning @ ~6–7 wk of age. Lister CA, Moore GBT, Piercy V, et al. 35th Annual EASD, Brussels, Belgium, Sept 28, 1999: Poster.

  23. db/db Mouse Normal Mouse

  24. Normal Type 2 Diabetes Visceral Fat Distribution:Normal vs Type 2 Diabetes

  25. ) ) 2 2 Mean Change from Baseline (cm Mean Change from Baseline (cm Intra-abdominal Fat Area (MRI) Subcutaneous Fat Area (MRI) 40 40 p=0.022 35 35 30 30 25 25 20 20 15 p=0.559 p=0.652 p=0.695 15 10 10 5 5 0 Placebo RSG 4 mg bd 0 n=14 n=10 Placebo RSG 4 mg bd n=10 n=14 Intrahepatic Fat (MRS) 6 4 p=0.692 2 0 Fat Distribution Study 083 Mean Change from Baseline (%) -2 -4 -6 -8 -10 p=0.036 -12 Carey D et al. Diabetologia 2000. Placebo RSG 4 mg bd n=16 n=12

  26. Effects of TZDs on Hepatic Fat Type 2 diabetics on 45 mg/d pioglitazone for 16 weeks 21 + 4% Percent Hepatic Fat Content 11 + 2% N=11 P< 0.01 Bajaj, M. et al. Abstract P-597-P.ADA 63rd Scientific Sessions. 6/03.

  27. Effects of Pioglitazone on Microalbuminuria Four long-term studies-the "Quartet studies" involved more than 3,700 patients from 28 countries across Europe Met -1% Met/SU +6% Change in Urinary Alb/Cr Ratio from Baseline Pio/SU SU -10% -17% Pio Pio/Met -20% -15% Urquhart, R. et al. Abstract 585-P . American Diabetes Association 63rd Scientific Sessions. 6/03

  28. Effects of Rosiglitazone on Microalbuminuria Patients with MA at baseline All patients 30 0 n = 132 * 20 -10 Placebo 10 -20 RSG (4 mg/day) 0 * n = 33 RSG (8 mg/day) -30 Mean change in albumin:creatinine at 26 weeks (%) Mean change in albumin:creatinine at 26 weeks (%) -10 -40 -20 -50 -30 * n = 142 * n = 36 * n = 145 P < 0.001 -60 * n = 35 -40 * Error bars = 94% confidence intervals Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.

  29. Mean Ambulatory Blood Pressure 5 RSG (8 mg/day) 4 Optimally titrated SU 3 2 Change in blood pressure at 52 weeks (mmHg) 1 0 -1 -2 -3 P = 0.0016 Diastolic BP Systolic BP Bakris GL, et al. Diabetes 2000; 49 (Suppl. 1):A96.

  30. PAI-1 Antigen SU SU + RSG Effect of RSG on FibrinolysisStudy 127 PAI-1 Activity 40 p=0.357 30 20 p=0.037 10 Mean Change (%) 0 -10 -20 -30 -40 D = -33.8% (95 CIs : -50.5, -11.6) p=0.006 Study 127 ITT LOCFFreed et al. Diabetologia 2000.

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