Presentation is loading. Please wait.

Presentation is loading. Please wait.

Nonglycemic Effects of Thiazolidinediones

Similar presentations


Presentation on theme: "Nonglycemic Effects of Thiazolidinediones"— 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. Elizabeth’s Hospital, Appleton, WI Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Website:

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: Suter SL et al. Diabetes Care. 1992;15: Whitcomb RW et al. In: Diabetes Mellitus. 1996:

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

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

6 Thiazolidinediones and PPAR g
Adipogenesis Glucose Transport Monocyte Differentiation Induction of Scavenger Receptor Inhibition of Cytokine Production Thiazolidinedione PPARg Retinoic Acid X Receptor mRNA RXR Promotor C3P CIII Gene PPAR agonists affect glucose transport at the gene level as previously described. The therapeutic agents available to clinicians to modulate PPAR effects are rarely pure PPAR or PPAR agonists. Rather, there is usually some degree of overlap in effect. 3

7 Thiazolidinediones and “Insulin Resistance”
X Glucose GLUT-4 Insulin has many actions in energy metabolism. (See the Core Curriculum Section of this site). Briefly, insulin inhibits the release of glucose from glycogen stores in the liver, increases peripheral glucose uptake by the GLUT-4 transporter, decreases the production of triglyceride-rich lipoproteins and increases peripheral triglyceride disposal. Insulin resistant patients have impaired activity of the GLUT-4 transporter, which leads to hyperglycemia.

8 Thiazolidinediones and “Insulin Resistance”
X Glucose GLUT-1 GLUT-4 Thiazolidinediones (TZDs) are thought of as insulin sensitizers, but in actuality do not affect GLUT-4. Rather, TZDs open a “back door” for glucose transport into the intracellular space by activating the GLUT-1 transporter.

9 Effect of Pioglitazone on Insulin Resistance: HOMA-IR
Rosenstock J for the Pioglitazone HCl Study Group. Diabetologia. 2000;43(suppl 1):A192. Matthews DR et al. Diabetologia. 1985;28:

10 Effect of Pioglitazone on Lipid Levels
W/NDEI/2854/Therapy.ppt 3/8/02 4:47 PM Effect of Pioglitazone on Lipid Levels Rosenblatt S et al. Coron Artery Dis. 2001;12: 10 NATIONAL DIABETES EDUCATION INITIATIVE™ FOR HEALTHCARE PROFESSIONALS

11 Lipid Effects of Pioglitazone with Metformin
Einhorn D et al. Clin Ther. 2000;22:

12 Association Between sdLDL and Insulin Resistance
12 (n=19) 10 (n=29) 8 plasma glucose (mmol/L) at identical plasma insulin Mean steady state (n=52) 6 4 2 Association Between Small, Dense LDL and Insulin Resistance The goal of this study was to see if individuals who were classified as pattern B on the basis of their LDL particle diameter were also insulin resistant. The study population consisted of 100 adults, 52 women and 48 men, who had no history or symptoms of any known disease and had a normal physical examination and routine findings on general blood chemical analyses, hemogram, and resting electrocardiogram. Subjects were not receiving any medicine known to influence lipid metabolism or glucose tolerance. Pattern B subjects had higher total integrated glucose and insulin responses to oral glucose compared with glucose and insulin responses in those with either pattern A or an intermediate pattern. Pattern B individuals were shown to be more insulin resistant and had higher concentrations of triglycerides and lower HDL cholesterol than those with either pattern A or the intermediate. There were also significant correlation coefficients that existed between LDL diameter and steady state plasma glucose concentrations, glucose and insulin responses, triglycerides and HDL cholesterol concentrations, and systolic and diastolic blood pressure. Reaven GM, et al. J Clin Invest ;92: A Larger LDL particle pattern Intermediate pattern B Small LDL particle pattern LDL-size phenotype Reaven GM, et al. J Clin Invest. 1993;92:

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

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

15 Rosiglitazone Effects on HDL Sub-fractions
25 Week 8 20 Week 24 15 Mean percentage change 95% CI) 10 + ( 5 -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:

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

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

20 Multiple Factors May Drive Progressive Decline of -Cell Function
“Glucotoxicity” (hyperglycemia) Insulin Resistance -cell “Lipotoxicity” (elevated FFA, TG) Multiple Factors May Drive Progressive Decline of Beta-Cell Function Insulin resistance can lead to hyperglycemia, elevated free fatty acids, and increased triglycerides. These, along with protein glycation, can contribute to beta-cell decline and apoptosis. Reaven GM. Physiol Rev. 1995;73: Adapted from Reaven GM. Physiol Rev 1995;73:473–486.

21 Effect of TZD’s on Free Fatty Acids
Treatment Weeks 2 4 6 8 12 16 26 38 52 Free Fatty Acids (mg/dL) 18 20 22 24 28 No. at No. at Baseline wk 52 Glyburide RSG 4 mg* RSG 8 mg* 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 mg/kg Mice treated for 28 days ~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
Slide 13 Visceral Fat Distribution: Normal vs Type 2 Diabetes As seen in computed tomographic (CT) scans, the distribution of visceral fat (white areas) differs in a subject with normal glucose tolerance (left) and in a subject with type 2 diabetes (right). The two subjects had similar waist circumferences, but the individual with type 2 diabetes had a larger amount of visceral fat than did the subject with normal glucose tolerance. The amount of subcutaneous fat was larger in the subject with normal glucose tolerance than in the subject with type 2 diabetes.

25 Fat Distribution Study 083 Intra-abdominal Fat Area (MRI)
Subcutaneous Fat Area (MRI) Mean Change from Baseline (cm 2 ) 40 Mean Change from Baseline (cm 2 ) 40 35 p=0.022 35 30 30 25 25 20 20 15 p=0.652 p=0.695 p=0.559 15 10 10 5 5 Placebo RSG 4 mg bd n=14 n=10 Placebo RSG 4 mg bd n=14 n=10 Intrahepatic Fat (MRS) 6 4 p=0.692 2 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
All patients Patients with MA at baseline 30 n = 132 * 20 -10 Placebo 10 -20 RSG (4 mg/day) * n = 33 -30 RSG (8 mg/day) 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 -1 -2 -3 P = Systolic BP Diastolic BP Bakris GL, et al. Diabetes 2000; 49 (Suppl. 1):A96.

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


Download ppt "Nonglycemic Effects of Thiazolidinediones"

Similar presentations


Ads by Google