Nonglycemic Effects of Thiazolidinediones

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).

3
TZDs Mechanisms of Action
Intestine glucose absorption
Blood glucose
Pancreasinsulin secretion
Saltiel AR, Olefsky JM. Diabetes.
1996451661-1669. Suter SL et al. Diabetes Care.
199215193-203. Whitcomb RW et al. In Diabetes
Mellitus. 1996661-668.
4
Effects of thiazolidinediones on cardiovascular
risk factors and atherosclerotic mechanisms
Thiazolidinediones
? monocyte subendothelial transmigration
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
Thiazolidinedione
Retinoic Acid X Receptor
RXR
Promotor C3P
CIII Gene
7
Thiazolidinediones and Insulin Resistance
X
GLUT-4
8
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
(n19)
10
(n29)
8
Mean steady state plasma glucose(mmol/L) at
identical plasma insulin
(n52)
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. 199392141-146.
13
Effect of Rosiglitazone on LDL Particle Density
Rf lt 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
(N234) Study 108. Data on file, GlaxoSmithKline.
14
020 LDL/ApoB Ratio Baseline to Wk 26
(Error Bars 95 CI)
(ROSIGLITAZONE/020 - ITT Population)
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. Geometr
ic Mean (ITT, LOCF)
16
Pioglitazone effects on Small, Dense LDL
Winkler, K et al. Diabetes Care. 200326
2588-2593.
17
Atherogenic Index of Plasma
Atherogenic index of plasma the logarithmic
transformation of the triglycerideHDL
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
199573473486.
21
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/kgMice treated for 28 days beginning _at_ 67
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 DistributionNormal vs Type 2
Diabetes
25
Intra-abdominal Fat Area (MRI)
Subcutaneous Fat Area (MRI)
40
40
p0.022
35
35
30
30
25
25
20
20
15
p0.559
p0.652
p0.695
15
10
10
5
5
0
Placebo
RSG 4 mg bd
0
n14
n10
Placebo
RSG 4 mg bd
n10
n14
Intrahepatic Fat (MRS)
6
4
p0.692
2
0
Fat Distribution Study 083
Mean Change from Baseline ()
-2
-4
-6
-8
-10
p0.036
-12
Carey D et al. Diabetologia 2000.
Placebo
RSG 4 mg bd
n16
n12
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
N11 Plt 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
Pio
-17
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
0
n 132
20
-10
Placebo
10
-20
RSG (4 mg/day)
0
n 33
RSG (8 mg/day)
-30
Mean change in albumincreatinine at 26 weeks ()
Mean change in albumincreatinine at 26 weeks ()
-10
-40
-20
-50
-30
n 142
n 36
n 145 P lt 0.001
-60
n 35
-40
Error bars 94 confidence intervals
Lebovitz HE, et al. J Clin Endocrinol Metab
2001 86280288.
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
Effect of RSG on FibrinolysisStudy 127
PAI-1 Activity
40
p0.357
30
20
p0.037
10
Mean Change ()
0
-10
-20
-30
-40
D
-33.8 (95
CIs
-50.5, -11.6)
p0.006
Study 127 ITT LOCFFreed et al. Diabetologia
2000.