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Nonglycemic Effects of Thiazolidinediones Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member,

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Presentation on theme: "Nonglycemic Effects of Thiazolidinediones Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Member,"— Presentation transcript:

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. Elizabeths 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). 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 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. TZDs : Mechanisms of Action Intestine: glucose absorption Blood glucose Pancreas: insulin secretion

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

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

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

7 Thiazolidinediones and Insulin Resistance GLUT-4 Insulin Glucose X

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

9 Effect of Pioglitazone on Insulin Resistance: HOMA-IR

10 Effect of Pioglitazone on Lipid Levels

11 Lipid Effects of Pioglitazone with Metformin

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

13 Effect of Rosiglitazone on LDL Particle Density * *% 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. Rf < 0.2632 (smaller, dense) Rf 0.2632 (larger, more buoyant) 0 10 20 30 40 50 60 70 80 % of Patients Study Entry Week 8 - Rosiglitazone

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

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

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

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

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

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

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

21 Treatment Weeks 024681216263852 Free Fatty Acids (mg/dL) 0 18 20 22 24 26 28 No. at Baselinewk 52 Glyburide203168 RSG 4 mg*195139 RSG 8 mg* 189145 Effect of TZDs 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/kg Mice 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 Visceral Fat Distribution: Normal vs Type 2 Diabetes NormalType 2 Diabetes

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

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

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

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

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

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


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