Potential role of PPAR activation

in CV risk reduction
Genetic
background

Food intake
excess

VBWG

Physical
inactivity

Obesity

Hyperglycemia

Hyperinsulinemia

Insulin
Dyslipidemia

Inflammation

PPAR
modulation
Hypertension

Hypercoagulation

resistance

Atherosclerosis
Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

Peroxisome proliferator-activator
receptors (PPARs): Overview

VBWG

Family of steroid hormone nuclear receptors

Three isotypes identified
PPAR
PPAR
PPAR
Ligand-activated transcription factors regulating
metabolic processes

Plutzky J. Science. 2003;302:406-7.

PPAR activation and atherosclerosis:

A hypothesis

VBWG

Ligand
Activated PPAR receptor

endogenous
or synthetic

Direct
Vascular and inflammatory cells
Cytokines

Chemokines

Indirect
Fat, liver, skeletal muscle
Reduces
inflammation

FFA

Glucose

Cholesterol efflux

Insulin sensitivity

Adhesion molecules

Triglycerides

HDL

Blunts atherosclerosis
Adapted from Plutzky J. Science. 2003;302:406-7.

VBWG

Focus on PPAR activation

Reduces insulin resistance
Preserves pancreatic -cell function
Improves CV risk profile
Improves dyslipidemia ( HDL, LDL density, or TG)
Renal microalbumin excretion
Blood pressure
VSMC proliferation/migration in arterial wall
PAI-1 levels
C-reactive protein levels
Adiponectin
Free fatty acids

Inzucchi SE. JAMA. 2002;287:360-72.

VBWG

PPAR modulators
Name

Trade name

Manufacturer

Approval status

Troglitazone

Rezulin

Parke-Davis

1997*

Rosiglitazone

Avandia

GlaxoSmithKline

1999

Pioglitazone

Actos

Eli Lilly/
Takeda Pharmaceuticals

1999

Muraglitazar

Pargluva

Bristol-Myers Squibb/
Merck

NDA
submitted
2004

*Withdrawn March 2000

Also available in combination with metformin or sulfonylurea

Also available in combination with metformin

Dual PPAR/ agonist

PPAR modulation: Newest strategy

in CV risk reduction

Hyperglycemia

Dyslipidemia

VBWG

Hyperinsulinemia

Insulin
Inflammation

PPAR
modulation
Hypercoagulation

Hypertension
resistance

Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

Factors that may drive the progressive

decline of -cell function

VBWG

Hyperglycemia
(glucose toxicity)

Insulin
resistance

-cell

Lipotoxicity
(elevated FFA, TG)
Adapted from Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-58.
Adapted from Ludwig DS. JAMA. 2002;287:2414-23.

TRIPOD: Evidence that insulin

resistance causes -cell failure

VBWG

N = 266 Hispanic women with gestational diabetes randomized

to troglitazone 400 mg or placebo for median 30 months
PPAR activation: 55% relative risk reduction for
new-onset diabetes (HR 0.45; 0.250.83)
Effect was most prominent in women with initial increase
in insulin sensitivity and accompanying large reduction in
insulin output
Protection persisted 8 months after cessation of
active treatment
PPAR activation associated with preserved
-cell function
TRIPOD = Troglitazone in Prevention of Diabetes

Buchanan TA et al. Diabetes. 2002;51:2796-803.

VBWG

DPP: Improving insulin sensitivity/

secretion prevents diabetes
N = 3234
30

Placebo

Metformin

Lifestyle
Insulin
secretion
(IGR)

25
20
Diabetes
hazard
rate
15
(per
100 pyr)
10

Low
Medium
High

Insulin
secretion
(IGR)

5
0

Low

Medium High

Low

Medium

High

Low Medium

High

Insulin sensitivity (1/fasting insulin)

pyr = person years

IGR = insulin-to-glucose ratio
DPP = Diabetes Prevention Program

DPP Research Group. Diabetes. 2005;54:2404-14.

PPAR activation blunts progression

to diabetes

VBWG

Diabetes Prevention Program

Cumulative
incidence
(%)

15

Placebo

10

Metformin
850 mg
Lifestyle
Troglitazone
75% vs placebo
400 mg*
P < 0.001

5
0
0.0

0.5

1.0

1.5

739

237

Years
n=

2343

1568

*Terminated early after 1.5 years

DPP Research Group.

Diabetes. 2005;54:1150-6.

VBWG

PPAR activation improves -cell function

N = 17 with type 2 diabetes
5
P = 0.02

4
3
Disposition
index

2
1
0
1

Rosiglitazone 8 mg
Insulin

Disposition index = Acute insulin response to glucose (IU/mL/10 min)

HOMA-IR
HOMA-IR = Homeostasis model assessment
of insulin resistance

Ovalle F, Bell DSH. Diabetes Care. 2004;27:2585-9.

CV implications of insulin resistance

and PPAR activation
Hyperglycemia

Dyslipidemia

VBWG

Hyperinsulinemia

Insulin
Inflammation

PPAR
modulation
Hypercoagulation

Hypertension
resistance

Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

Importance of LDL particle density

VBWG

In insulin resistance, LDL-C levels are similar or only

slightly elevated vs general population
However, atherogenicity of LDL particles varies
according to density
More dense = more atherogenic
Proportion of small, dense LDL particles greater
in patients with insulin resistance or diabetes vs
general population

Miranda PJ et al. Am Heart J. 2005;149:33-45.

Greater atherogenicity of small, dense

LDL vs normal LDL

VBWG

Susceptible to oxidation
Binds to arterial wall
Penetrates arterial wall
Toxic to endothelial cells
Promotes PAI-1 production by endothelial cells
Promotes thromboxane production by endothelial cells
Accumulates Ca2+ in vascular smooth muscle cells
Binds to LDL scavenger receptor
Adapted from Sniderman AD et al. Ann Intern Med. 2001;135:447-59.

VBWG

Increased small, dense, LDL particles

associated with reduced IHD survival
N = 2072 men without IHD at baseline;13-year follow-up
1.00

Survival
probabilities

0.90
P < 0.001

0.80
0

10

12

Follow-up (years)
Tertiles of LDL-C255
IHD = ischemic heart disease

<1.07 mmol/l

1.071.86 mmol/l

1.86 mmol/l

St-Pierre AC et al. Arterioscler Thromb Vasc Biol. 2005;25:553-9.

PPAR activation increases LDL size

and buoyancy

VBWG

N = 302; rosiglitazone 8 mg

LDL density

LDL particle size

8

0.04

P < 0.0001

4.8

P < 0.0001

Diameter
4
vs baseline
(Angstroms)

Relative
flotation 0.02
vs baseline

0.019

Brunzell JD et al. Circulation. 2004;110(suppl):III-143.

Comparative effects of PPAR activators

on lipids in diabetes

VBWG

In patients not receiving statin therapy, studies suggest that

pioglitazone and rosiglitazone have differing effects on lipid
levels and particle size1
In patients receiving statin therapy, some studies suggest
these differences are eliminated, while other studies suggest
they persist2
Clinical implications are not known3

Goldberg RB et al. Diabetes Care. 2005;28:1547-54.

2
Plotkin DJ et al. Diabetes. 2005;54(suppl 1):A232.
3
Khan M et al. Diabetes. 2005;54(suppl 1):A137.

CV implications of insulin resistance

and PPAR activation
Hyperglycemia

VBWG

Hyperinsulinemia

Insulin
Inflammation
Inflammation

Dyslipidemia

PPAR
modulation
Hypertension

Hypercoagulation
resistance

Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

VBWG

Adipokines: An overview
Antiatherogenic

Atherogenic

CRP
IL-6
PAI-1
Angiotensinogen
Leptin
Resistin
MCP-1

Adiponectin

Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.

Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

Adiponectin associated with decreased

risk of MI

VBWG

N = 18,225 men; 6-year follow-up

1.2
1.0
0.8

Relative
risk

0.6
0.4
0.2
0.0

Quintile of adiponectin (95% CI)

g/mL 7.9

12.6

Adjusted relative risk (P < 0.001)

16.5

21.1

29.2

Lipid-adjusted relative risk (P < 0.02)

Pischon T et al. JAMA. 2004;291:1730-7.

Improved insulin sensitivity associated

with increased adiponectin

VBWG

N = 40 women with gestational diabetes treated with troglitazone

for 3 months
500
400
% Change
in insulin
sensitivity
(Si)

300
200
100

50

25

25

50

75

100

100
% Change in HMW/total adiponectin (SA)
Pajvani UB et al. J Biol Chem. 2004;279:12152-62.

VBWG

Contrasting roles of CRP and PPAR

on inflammation and insulin resistance
Liver

Adipose
tissue

IL-6

CRP

PPAR

Glucose
Insulin resistance
Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.

VBWG

Direct relationship of CRP

to metabolic syndrome
Womens Health Study; N = 14,719
8
6
Median
CRP
(mg/L)

4
2
0
0

Components of the metabolic syndrome (n)

n=
Modified ATP III definition

4086

3884

3152

2292

1135

170

Ridker PM et al. Circulation. 2003;107:391-7.

VBWG

Inflammation is a contributing mechanism in

diabetes development
N = 1047
25
20

Incidence 15
(%)

P = 0.06

P = 0.001

P = 0.001

10
5
0

Fibrinogen

CRP

PAI-1

Quartiles of inflammatory proteins

1st

2nd

3rd

4th

Festa A et al. Diabetes. 2002;51:1131-7.

VBWG

PPAR activation decreases CRP

in patients with diabetes
N = 357; 26 weeks
0

Rosiglitazone
4 mg

Placebo

Rosiglitazone
8 mg

10
Mean
change
from
baseline
(%)

20
30
40
P < 0.05

50

27%

P < 0.05

22%
Haffner SM et al. Circulation. 2002;106:679-84.

CV implications of insulin resistance

and PPAR activation
Hyperglycemia

Dyslipidemia

VBWG

Hyperinsulinemia

Insulin
Inflammation

PPAR
modulation
Hypertension

Hypercoagulation

resistance

Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

VBWG

Improved insulin sensitivity associated

with reduced BP

N = 24 nondiabetic hypertensives; rosiglitazone 8 mg, 16 weeks

20

in 24-h
systolic
BP
(mm Hg)

10
0
10
20
2

Change in insulin sensitivity (mg/kg/min)

P < 0.005
r = 0.59

Nonmodulators

Low-renin hypertension
Raji A et al. Diabetes Care. 2003;26:172-8.

VBWG

PPAR activation associated with

sustained BP reduction
N = 668 with type 2 diabetes
Rosiglitazone added to baseline therapy
Baseline metformin
6 months
12 months
Baseline sulfonylurea
6 months
12 months
6

5 4

24-h systolic BP*

24-h diastolic BP*

Reduction from baseline (mm Hg, 95% CI)

Treatment differences (mm Hg, 95% CI)

Ambulatory BP

Home PD et al. Diabetes. 2005;54(suppl 1):A134.

CV implications of insulin resistance and

PPAR activation
Hyperglycemia

VBWG

Hyperinsulinemia
Insulin

Dyslipidemia

Hypertension

Inflammation

PPAR
modulation

Hypercoagulation

resistance

Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

PPAR activation blunts TNF-induced

PAI-1 secretion

VBWG

Human umbilical-vein endothelial cells

800
600

PAI-1
(ng)

400

200

*
0
TNF-
1 ng/mL

Trog = troglitazone
*P < 0.001

P < 0.005

TNF-
1 ng/mL
+
Trog 10 M

TNF-
10 ng/mL

TNF-
10 ng/mL
+
Trog 10 M

TNF-
TNF-
100 ng/mL 100 ng/mL
+
Trog 10 M

Hamaguchi E et al. J Pharmacol Exp Ther. 2003;307:987-94.

VBWG

Metformin reduces PAI-1 levels

in type 2 diabetes
N = 27, 12 weeks
35
30
PAI-1
activity
(U/mL)

25

20
15
10
5
0

A1C = 1.3%
FPG = 55 mg/dL
* P = 0.001 vs placebo

Basal

Placebo

Metformin 2.5 g

Results at 12 weeks
Nagi DK, Yudkin JS. Diabetes Care. 1993;16:621-9.

VBWG

Benefits of combined insulin sensitizer

therapy: Effects on CRP, PAl-1, and MMP-9
Weeks 824

MMP-9

30

22.2

20
10

Baseline
(%)

CRP

0
10
20
30
40

0.56
9.8

14.35

P = 0.046

26.9
P = 0.026

32.76
P < 0.001

Metformin 2 g (n = 70)
*NS vs baseline

PAl-1

Metformin 1 g + rosiglitazone 8 mg (n = 57)

Weissman PN et al. Diabetes. 2004;53(suppl 2):A28.