PPAR In CVS
description
Transcript of 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
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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
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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
??
??
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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
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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*Withdrawn March 2000†Also available in combination with metformin or sulfonylurea‡ Also available in combination with metformin§Dual PPAR/ agonist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
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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
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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)
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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
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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
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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
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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 =
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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(%)
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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
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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
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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
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Nonmodulators Low-renin hypertension
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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
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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
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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
*
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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.
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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