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

Website: www.endocrinology-online.comWebsite: www.endocrinology-online.com

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

Liver: hepatic g lucose output

Intestine: glucose absorptionIntestine: glucose absorption

Blood glucoseBlood glucose

Pancreas:Pancreas:insulin secretioninsulin secretion

glycemiaglycemia

triglyceridestriglycerides

HDLHDL

FFAFFA

BPBP

PAI-1PAI-1

oxidative oxidative stressstress

VSMC migration VSMC migration and proliferationand proliferation

LDLLDL

ThiazolidinedionesThiazolidinediones

monocytemonocyte subendothelialsubendothelial transmigrationtransmigration

Effects of thiazolidinediones on cardiovascular risk Effects of thiazolidinediones on cardiovascular risk factors and atherosclerotic mechanismsfactors and atherosclerotic mechanisms

Peroxisome Proliferator-activated Receptors

PPAR AgonistsPPAR • Fatty Acids• Fibrates

Fatty Acid, HDL Metabolism

PPAR Agonists PPAR • Oxidized Lipids• Thiazolidinedioines

Adipogenesis, insulin sensitivity

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

““Glucotoxicity”Glucotoxicity”(hyperglycemia)(hyperglycemia)

-cell

Insulin Insulin ResistanceResistance

““Lipotoxicity”Lipotoxicity”(elevated FFA, TG)(elevated FFA, TG)

Adapted from Reaven GM. Physiol Rev 1995;73:473–486.

Treatment Weeks0 2 4 6 8 12 16 26 38 52

Fre

e F

atty

Aci

ds

(mg

/dL

)

018

20

22

24

26

28

No. at No. atBaseline wk 52

Glyburide 203 168

RSG 4 mg* 195 139

RSG 8 mg* 189 145

Effect of TZD’s on Free Fatty AcidsEffect of TZD’s on Free Fatty Acids

ITT without LOCF *Given in divided doses

Study 020. Data on file; GlaxoSmithKline.

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.

db/dbdb/db Mouse Mouse Normal MouseNormal Mouse

Visceral Fat Distribution:Visceral Fat Distribution:Normal vs Type 2 DiabetesNormal vs Type 2 Diabetes

Normal Type 2 Diabetes

Fat DistributionFat DistributionStudy 083Study 083

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

-40

-30

-20

-10

0

10

20

30

40

Mea

n C

hang

e (%

)

p=0.152

p=0.428

= -21.8% (95 CIs: -37.5, -2.2)p=0.031

PAI-1 AntigenPAI-1 Antigen

Study 127 ITT LOCFFreed et al. Diabetologia 2000.

PAI-1 ActivityPAI-1 Activity

-40

-30

-20

-10

0

10

20

30

40

Mean

Ch

an

ge (

%)

SU

SU + RSG

p=0.357

p=0.037

= -33.8% (95 CIs: -50.5, -11.6)p=0.006