ppar in cvs

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VBWG Potential role of PPAR activation in CV risk reduction Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72 Atherosclerosis Atherosclerosis Insulin resistance Hyperinsulinemia Hyperinsulinemia Obesity Obesity Food intake Food intake excess excess Genetic Genetic background background Physical Physical inactivity inactivity PPAR modulation Dyslipidemia Dyslipidemia Hyperglycemia Hyperglycemia Inflammation Inflammation Hypercoagulation Hypercoagulation Hypertension Hypertension

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PPAR IN CVS

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Page 1: PPAR In CVS

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Potential role of PPAR activation in CV risk reduction

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

AtherosclerosisAtherosclerosis

Insulin

resistance

HyperinsulinemiaHyperinsulinemia

ObesityObesity

Food intake Food intake excessexcess

GeneticGeneticbackgroundbackground

Physical Physical inactivityinactivity

PPARmodulation

DyslipidemiaDyslipidemia

HyperglycemiaHyperglycemia

InflammationInflammation

HypercoagulationHypercoagulationHypertensionHypertension

Page 2: PPAR In CVS

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

Peroxisome proliferator-activator receptors (PPARs): Overview

• Family of steroid hormone nuclear receptors

• Three isotypes identified

– PPAR

– PPAR

– PPAR

• Ligand-activated transcription factors regulatingmetabolic processes

Page 3: PPAR In CVS

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

PPAR activation and atherosclerosis: A hypothesis

Blunts atherosclerosis

IndirectFat, liver, skeletal muscle

Ligand

endogenous

or synthetic

Activated PPAR receptor

Reducesinflammation

DirectVascular and inflammatory cells

FFA

Glucose

Insulin sensitivity

Triglycerides

HDL

Cytokines

Chemokines

Cholesterol efflux

Adhesion molecules

??

??

Page 4: PPAR In CVS

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Focus on PPAR activation

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

• 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

Page 5: PPAR In CVS

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PPAR modulators

*Withdrawn March 2000†Also available in combination with metformin or sulfonylurea‡ Also available in combination with metformin§Dual PPAR/ agonist

Name Trade name Manufacturer Approval status

Troglitazone Rezulin Parke-Davis 1997*

Rosiglitazone† Avandia GlaxoSmithKline 1999

Pioglitazone‡ Actos Eli Lilly/ 1999Takeda Pharmaceuticals

Muraglitazar§ Pargluva Bristol-Myers Squibb/ NDA Merck submitted

2004

Page 6: PPAR In CVS

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PPAR modulation: Newest strategy in CV risk reduction

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

Insulin

resistance

HypercoagulationHypercoagulation

InflammationInflammation

HypertensionHypertension

DyslipidemiaDyslipidemia

PPARmodulation

HyperglycemiaHyperglycemia HyperinsulinemiaHyperinsulinemia

Page 7: PPAR In CVS

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Factors that may drive the progressive decline of -cell function

Adapted from Kahn SE. J Clin Endocrinol Metab. 2001;86:4047-58.Adapted from Ludwig DS. JAMA. 2002;287:2414-23.

Hyperglycemia(glucose toxicity)

-cell

Insulinresistance

“Lipotoxicity”(elevated FFA, TG)

Page 8: PPAR In CVS

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TRIPOD: Evidence that insulin resistance causes -cell failure

• PPAR activation: 55% relative risk reduction for new-onset diabetes (HR 0.45; 0.25–0.83)

• 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

N = 266 Hispanic women with gestational diabetes randomized to troglitazone 400 mg or placebo for median 30 months

Buchanan TA et al. Diabetes. 2002;51:2796-803.TRIPOD = Troglitazone in Prevention of Diabetes

Page 9: PPAR In CVS

VBWGDPP: Improving insulin sensitivity/secretion prevents diabetes N = 3234

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

pyr = person yearsIGR = insulin-to-glucose ratioDPP = Diabetes Prevention Program

Diabetes hazard

rate (per

100 pyr)

Placebo Metformin LifestyleInsulin

secretion(IGR)

Low Low High High

Insulin sensitivity (1/fasting insulin)

Medium

Insulinsecretion

(IGR)

High MediumMedium Low0

5

10

15

20

25

30

Low

Medium

High

Page 10: PPAR In CVS

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PPAR activation blunts progression to diabetes

DPP Research Group.Diabetes. 2005;54:1150-6.*Terminated early after 1.5 years

Diabetes Prevention Program

10

15

5

01.5

Cumulativeincidence

(%)

Years

1.00.50.0

Placebo

Metformin850 mg

Lifestyle

Troglitazone400 mg*

23773915682343n =

75% vs placeboP < 0.001

Page 11: PPAR In CVS

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PPAR activation improves -cell function

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

Acute insulin response to glucose (µIU/mL/10 min)

–1

0

1

2

3

4

5

Insulin

Rosiglitazone 8 mg

P = 0.02

Dispositionindex

HOMA-IR

N = 17 with type 2 diabetes

HOMA-IR = Homeostasis model assessment of insulin resistance

Disposition index =

Page 12: PPAR In CVS

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CV implications of insulin resistance and PPAR activation

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

Insulin

resistance

HyperinsulinemiaHyperinsulinemia

HypercoagulationHypercoagulation

InflammationInflammation

HypertensionHypertension

HyperglycemiaHyperglycemia

DyslipidemiaDyslipidemia

PPARmodulation

DyslipidemiaDyslipidemia

Page 13: PPAR In CVS

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Importance of LDL particle density

• 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.

Page 14: PPAR In CVS

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Greater atherogenicity of small, dense LDL vs normal LDL

Adapted from Sniderman AD et al. Ann Intern Med. 2001;135:447-59.

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

Page 15: PPAR In CVS

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Increased small, dense, LDL particles associated with reduced IHD survival

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

N = 2072 men without IHD at baseline;13-year follow-up

1.00

0.90

0.80

Survivalprobabilities

Follow-up (years)

0 2 4 6 8 10 12

P < 0.001

Tertiles of LDL-C255Å <1.07 mmol/l 1.07–1.86 mmol/l ≥1.86 mmol/l

IHD = ischemic heart disease

Page 16: PPAR In CVS

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PPAR activation increases LDL size and buoyancy

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

N = 302; rosiglitazone 8 mg

4.8

0

4

8

0.019

0

0.02

0.04

LDL particle size LDL density

Diameter

vs baseline (Angstroms)

Relativeflotation

vs baseline

P < 0.0001

P < 0.0001

Page 17: PPAR In CVS

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Comparative effects of PPAR activators on lipids in diabetes

1Goldberg RB et al. Diabetes Care. 2005;28:1547-54.2Plotkin DJ et al. Diabetes. 2005;54(suppl 1):A232.

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

• 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

Page 18: PPAR In CVS

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CV implications of insulin resistance and PPAR activation

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

Insulin

resistance

HyperinsulinemiaHyperinsulinemia

HypercoagulationHypercoagulation

InflammationInflammation

HypertensionHypertension

HyperglycemiaHyperglycemia

DyslipidemiaDyslipidemia

PPARmodulation

InflammationInflammation

Page 19: PPAR In CVS

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Adipokines: An overview

• 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.

Atherogenic Antiatherogenic

Page 20: PPAR In CVS

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Adiponectin associated with decreased risk of MI

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

Adjusted relative risk (P < 0.001) Lipid-adjusted relative risk (P < 0.02)

1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Quintile of adiponectin (95% CI)

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

7.9 12.6 16.5 21.1 29.2 g/mL

Relativerisk

Page 21: PPAR In CVS

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Improved insulin sensitivity associated with increased adiponectinN = 40 women with gestational diabetes treated with troglitazone for 3 months

Pajvani UB et al. J Biol Chem. 2004;279:12152-62.

% Change in insulin sensitivity

(Si)

–50

–100

200

400

500

% Change in HMW/total adiponectin (SA)

300

100

–25 25 50 75 100

Page 22: PPAR In CVS

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

Contrasting roles of CRP and PPAR on inflammation and insulin resistance

AdiposetissueLiver IL-6

PPAR CRP

Glucose

Insulin resistance

Page 23: PPAR In CVS

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Direct relationship of CRP to metabolic syndrome Women’s Health Study; N = 14,719

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

8

6

0

MedianCRP

(mg/L)

Components of the metabolic syndrome (n)

4

0 1 2 3 4 5

2

n = 4086 3884 3152 2292 1135 170

Modified ATP III definition

Page 24: PPAR In CVS

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Inflammation is a contributing mechanism in diabetes development

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

0

5

10

15

20

25

Fibrinogen CRP PAI-1

P = 0.06 P = 0.001 P = 0.001

1st 2nd 3rd 4th

N = 1047

Quartiles of inflammatory proteins

Incidence(%)

Page 25: PPAR In CVS

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PPAR activation decreases CRP in patients with diabetes

Mean change

from baseline

(%)

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

27%–50

–40

–30

–20

–10

0Placebo

Rosiglitazone 4 mg

Rosiglitazone 8 mg

22%

P < 0.05

P < 0.05

N = 357; 26 weeks

Page 26: PPAR In CVS

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CV implications of insulin resistance and PPAR activation

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

Insulin

resistance

HyperinsulinemiaHyperinsulinemia

HypercoagulationHypercoagulation

InflammationInflammation

HypertensionHypertension

HyperglycemiaHyperglycemia

DyslipidemiaDyslipidemia

PPARmodulation

HypertensionHypertension

Page 27: PPAR In CVS

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

–20

–10

0

10

20

–2 –1 0 1 2 3Change in insulin sensitivity (mg/kg/min)

in 24-h systolic

BP(mm Hg)

P < 0.005r = –0.59

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

Improved insulin sensitivity associated with reduced BP

VBWG

Nonmodulators Low-renin hypertension

Page 28: PPAR In CVS

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PPAR activation associated with sustained BP reductionN = 668 with type 2 diabetes

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

–6 –5 –4 –3 –2 –1 10

24-h systolic BP*

Reduction from baseline (mm Hg, 95% CI)

–5 –4 –3 –2 –1 10

24-h diastolic BP* Treatment differences (mm Hg, 95% CI)

6 months

12 months

Baseline sulfonylurea

6 months

12 months

Baseline metformin

*Ambulatory BP

Rosiglitazone added to baseline therapy

Page 29: PPAR In CVS

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

CV implications of insulin resistance and PPAR activation

Insulin

resistance

PPARmodulation

HyperinsulinemiaHyperinsulinemia

HypercoagulationHypercoagulation

InflammationInflammation

HyperglycemiaHyperglycemia

DyslipidemiaDyslipidemia

HypertensionHypertension

Page 30: PPAR In CVS

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PPAR activation blunts TNF-–induced PAI-1 secretion

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

Trog = troglitazone *P < 0.001†P < 0.005

Human umbilical-vein endothelial cells

800

600

400

200

0

PAI-1 (ng)

*

TNF-1 ng/mL

TNF-10 ng/mL

TNF-1 ng/mL

+Trog 10 µM

TNF- 10 ng/mL

+Trog 10 µM

TNF- 100 ng/mL

+Trog 10 µM

TNF-100 ng/mL

*

Page 31: PPAR In CVS

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Basal Placebo Metformin 2.5 g

PAI-1 activity (U/mL)

* P = 0.001 vs placebo

Results at 12 weeks

35

30

25

20

15

10

5

0

A1C = –1.3%

FPG = –55 mg/dL

*

N = 27, 12 weeks

Metformin reduces PAI-1 levels in type 2 diabetes

Nagi DK, Yudkin JS. Diabetes Care. 1993;16:621-9.

Page 32: PPAR In CVS

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

–9.8

–0.56

22.2

–40

–30

–20

–10

0

10

20

30

CRP PAl-1

MMP-9

–26.9

–32.76

–14.35

*NS vs baseline

Baseline

(%)

Metformin 2 g (n = 70) Metformin 1 g + rosiglitazone 8 mg (n = 57)

P = 0.026

P < 0.001

P = 0.046

Benefits of combined insulin sensitizer therapy: Effects on CRP, PAl-1, and MMP-9

*

*

Weeks 8–24