Nonglycemic Nonglycemic Effects of Effects of Thiazolidinedion Thiazolidinedion es es Thomas Repas D.O. Thomas Repas D.O. Diabetes, Endocrinology and Nutrition Center, Affinity Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin Medical Group, Neenah, Wisconsin Member, Inpatient Diabetes Management Committee, St. Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WI Elizabeth’s Hospital, Appleton, WI Member, Diabetes Advisory Group, Wisconsin Diabetes Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Prevention and Control Program Website: www.endocrinology-online.com Website: www.endocrinology-online.com
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 - PowerPoint PPT Presentation
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Nonglycemic Effects of Nonglycemic Effects of ThiazolidinedionesThiazolidinediones
Thomas Repas D.O.Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinDiabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin
Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program
Please Note:Please Note: This presentation discusses investigational, off label This presentation discusses investigational, off label
and non-FDA indicated effects of thiazolidinediones and non-FDA indicated effects of thiazolidinediones (glitazones). Please be aware that TZDs are FDA (glitazones). Please be aware that TZDs are FDA approved for treatment of hyperglycemia in type 2 approved for treatment of hyperglycemia in type 2 diabetes only. This presentation is for informational diabetes only. This presentation is for informational and educational purposes only and is not intended and educational purposes only and is not intended to encourage or recommend any off label uses of to encourage or recommend any off label uses of any pharmaceutical product (s). any pharmaceutical product (s).
Saltiel AR, Olefsky JM. Saltiel AR, Olefsky JM. DiabetesDiabetes. 1996;45:1661-1669.. 1996;45:1661-1669.Suter SL et al. Suter SL et al. Diabetes CareDiabetes Care. 1992;15:193-203.. 1992;15:193-203.
Whitcomb RW et al. In: Whitcomb RW et al. In: Diabetes MellitusDiabetes Mellitus. 1996:661-668.. 1996:661-668.
TZDs : Mechanisms of ActionTZDs : Mechanisms of Action
M uscle and adipose tissue: insulin resistance g lucose uptake
Effects of thiazolidinediones on cardiovascular risk Effects of thiazolidinediones on cardiovascular risk factors and atherosclerotic mechanismsfactors and atherosclerotic mechanisms
PPARs are mediators of vascular disease, inflammation and endothelial dysfunction dysfunction
Promotor C3P
Promotor C3P
CIII GeneCIII Gene
mRNAmRNA
Thiazolidinedione
PPARPPARRXRRXRRetinoic Acid
X ReceptorRetinoic Acid X Receptor
AdipogenesisGlucose TransportMonocyte DifferentiationInduction of Scavenger ReceptorInhibition of Cytokine Production
AdipogenesisGlucose TransportMonocyte DifferentiationInduction of Scavenger ReceptorInhibition of Cytokine Production
Thiazolidinediones and PPAR
Thiazolidinediones and “Insulin Resistance”
Thiazolidinediones and “Insulin Resistance”
GLUT-4
InsulinInsulin
GlucoseGlucoseX
ThiazolidinedioneThiazolidinedione
Thiazolidinediones and “Insulin Resistance”
Thiazolidinediones and “Insulin Resistance”
GLUT-4 GLUT-1
InsulinInsulin
GlucoseGlucoseX
Effect of Pioglitazone on Insulin Resistance: HOMA-IR
Effect of Pioglitazone on Lipid Levels
Lipid Effects of Pioglitazone with Metformin
Reaven GM, et al. J Clin Invest. 1993;92:141-146.
Association Between sdLDL and Insulin ResistanceM
ean
ste
ad
y s
tate
pla
sm
a g
lucose
(mm
ol/
L)
at
iden
tical
pla
sm
a in
su
lin
ALarger LDL particle
pattern
Intermediatepattern
BSmall LDL particle
pattern
0
2
6
10
12
8
4
LDL-size phenotype
(n=52)
(n=29)
(n=19)
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
% o
f P
atie
nts
Study Entry Week 8 - Rosiglitazone
020: LDL/ApoB Ratio Baseline to Wk 26
Glyburide RSG 2mg bd RSG 4mg bd
Mean
Ch
an
ge in
LD
L/A
poB
-0.04
-0.02
0.00
0.02
0.04
0.06
0.08
(Error Bars = 95% CI)(ROSIGLITAZONE/020 - ITT Population)
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-2 HDL-3HDL-3
Mea
n p
erce
nta
ge
chan
ge
(+
95%
CI)
Week 8Week 8
Week 24Week 24
Pioglitazone effects on Small, Dense LDL
Winkler, K et al. Diabetes Care. 2003;26: 2588-2593.Winkler, K et al. Diabetes Care. 2003;26: 2588-2593.
Atherogenic Index of Plasma
Lee, C. et al. Abstract 688-P . American Diabetes Association 63rd Scientific Sessions. 6/03 Lee, C. et al. Abstract 688-P . American Diabetes Association 63rd Scientific Sessions. 6/03
Atherogenic index of plasma = the logarithmic transformation of the triglyceride:HDL cholesterol ratio (correlates inversely with the LDL particle size)
Atherogenic index of plasma = the logarithmic transformation of the triglyceride:HDL cholesterol ratio (correlates inversely with the LDL particle size)
Satoh, et al. Diabetes Care. 2003; 26: 2493-2499.
Potential Antiatherogenic Effects of Pioglitazone
Satoh, et al. Diabetes Care. 2003; 26: 2493-2499.
Occur Independent of Antidiabetic Effect
Multiple Factors May Drive Progressive Multiple Factors May Drive Progressive Decline of Decline of -Cell Function-Cell Function
Intra-abdominal Intra-abdominal Fat Area (MRI)Fat Area (MRI)
0
5
10
15
20
25
30
35
40
Mean C
hange f
rom
Base
line (
cm2 )
Placebon=14
RSG 4 mg bdn=10
p=0.652 p=0.695
0
5
10
15
20
25
30
35
40
Placebon=14
RSG 4 mg bdn=10
p=0.559
p=0.022
Carey D et al. Carey D et al. DiabetologiaDiabetologia 2000. 2000.
Mean C
hange f
rom
Base
line (
cm2 )
Subcutaneous Subcutaneous Fat Area (MRI)Fat Area (MRI)
-12
-10
-8
-6
-4
-2
0
2
4
6
Mean C
hange f
rom
Base
line (
%)
Placebon=16
RSG 4 mg bdn=12
p=0.036
p=0.692
Intrahepatic Fat Intrahepatic Fat (MRS)(MRS)
Effects of TZDs on Hepatic Fat
0
5
10
15
20
25
Baseline 16 weeks
Perc
ent H
epat
ic Fa
t Con
tent
Perc
ent H
epat
ic Fa
t Con
tent
21 + 4%21 + 4%
11 + 2%11 + 2%
N=11P< 0.01N=11P< 0.01
Type 2 diabetics on 45 mg/d pioglitazone for 16 weeks Type 2 diabetics on 45 mg/d pioglitazone for 16 weeks
Bajaj, M. et al. Abstract P-597-P.ADA 63rd Scientific Sessions. 6/03. Bajaj, M. et al. Abstract P-597-P.ADA 63rd Scientific Sessions. 6/03.
Effects of Pioglitazone on Microalbuminuria
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
-15
-10
-5
0
5
10
Urquhart, R. et al. Abstract 585-P . American Diabetes Association 63 rd Scientific Sessions. 6/03 Urquhart, R. et al. Abstract 585-P . American Diabetes Association 63 rd Scientific Sessions. 6/03
PioPio
MetMet
SUSU
-17%-17%
-20%-20%
-1%-1%Met/SUMet/SU
Pio/SUPio/SU
Pio/MetPio/Met
-15%-15%
-10%-10%
+6%+6%
Chan
ge in
Urin
ary
Alb/
Cr R
atio
from
Bas
elin
eCh
ange
in U
rinar
y Al
b/Cr
Rat
io fr
om B
asel
ine
Four long-term studies-the "Quartet studies" involved more than 3,700 patients from 28 countries across Europe
Four long-term studies-the "Quartet studies" involved more than 3,700 patients from 28 countries across Europe
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
Mea
n ch
ange
in a
lbum
in:c
reat
inin
e at
26
wee
ks (
%)
All patients
n = 132*
*n = 142
*n = 145
P < 0.001-60
-50
-40
-30
-20
-10
0
Mea
n ch
ange
in a
lbum
in:c
reat
inin
e at
26
wee
ks (
%)
Patients with MA at baseline
*n = 33
*n = 36 *
n = 35
* Error bars = 94% confidence intervals
Effects of Rosiglitazone on Microalbuminuria
-3
-2
-1
0
1
2
3
4
5 RSG (8 mg/day)
Optimally titrated SU
Cha
nge
in b
lood
pre
ssur
e at
52
wee
ks (
mm
Hg)
Systolic BP Diastolic BP
P = 0.0016
Bakris GL, et al. Diabetes 2000; 49 (Suppl. 1):A96.
Mean Ambulatory Blood Pressure
Effect of RSG on FibrinolysisEffect of RSG on FibrinolysisStudy 127Study 127