Potential role of PPAR activation in CV risk reduction

1
Potential role of PPAR activation in CV risk
reduction
Geneticbackground
Food intake excess
Physical inactivity
Obesity
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR modulation
Hypercoagulation
Hypertension
resistance
Atherosclerosis
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
2
Peroxisome proliferator-activator receptors
(PPARs) Overview

• Family of steroid hormone nuclear receptors
• Three isotypes identified
• PPAR?
• PPAR?
• PPAR?
• Ligand-activated transcription factors
  regulatingmetabolic processes

Plutzky J. Science. 2003302406-7.
3
PPAR activation and atherosclerosis A hypothesis
Ligandendogenous or synthetic
Activated PPAR receptor
DirectVascular and inflammatory cells
IndirectFat, liver, skeletal muscle
? FFA ? Glucose ? Insulin sensitivity ?
Triglycerides ? HDL
? Cytokines ? Chemokines ? Cholesterol
efflux ? Adhesion molecules
Reducesinflammation
?
?
?
?
Blunts atherosclerosis
Adapted from Plutzky J. Science. 2003302406-7.
4
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. 2002287360-72.
5
PPAR? modulators
Name Trade name
Manufacturer Approval status
Troglitazone Rezulin? Parke-Davis 1997
Rosiglitazone Avandia? GlaxoSmithKline 1999
Pioglitazone Actos? Eli
Lilly/ 1999 Takeda Pharmaceuticals Muraglit
azar Pargluva? Bristol-Myers Squibb/ NDA
Merck submitted
2004
Withdrawn March 2000 Also available in
combination with metformin or sulfonylurea Also
available in combination with metforminDual
PPAR?/? agonist
6
PPAR modulation Newest strategy in CV risk
reduction
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR modulation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
7
Factors that may drive the progressive decline of
?-cell function
Insulinresistance
Hyperglycemia (glucose toxicity)
?-cell
Lipotoxicity (elevated FFA, TG)
Adapted from Kahn SE. J Clin Endocrinol Metab.
2001864047-58. Adapted from Ludwig DS. JAMA.
20022872414-23.
8
TRIPOD Evidence that insulin resistance causes
?-cell failure
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. 2002512796-803.
9
DPP Improving insulin sensitivity/secretion
prevents diabetes
N 3234
Diabetes hazard rate (per 100 pyr)
pyr person years IGR insulin-to-glucose
ratio DPP Diabetes Prevention Program
DPP Research Group. Diabetes. 2005542404-14.
10
PPAR? activation blunts progression to diabetes
Diabetes Prevention Program
15
Placebo
Metformin 850 mg
10
Cumulative incidence ()
Lifestyle
Troglitazone400 mg
5
?75 vs placeboP lt 0.001
0
1.5
1.0
0.5
0.0
Years
237
1568
2343
n
739
DPP Research Group. Diabetes. 2005541150-6.
Terminated early after 1.5 years
11
PPAR? activation improves ?-cell function
N 17 with type 2 diabetes
5
P 0.02
4
3
Disposition index
2
1
0
Rosiglitazone 8 mg
Insulin
1
Acute insulin response to glucose (µIU/mL/10 min)
Disposition index
HOMA-IR
HOMA-IR Homeostasis model assessment of
insulin resistance
Ovalle F, Bell DSH. Diabetes Care. 2004272585-9.
12
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Dyslipidemia
Inflammation
PPAR modulation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
13
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. 200514933-45.
14
Greater atherogenicity of small, dense LDL vs
normal LDL
Susceptible to oxidation Binds to arterial
wallPenetrates arterial wall Toxic to
endothelial cells Promotes PAI-1 production by
endothelial cellsPromotes thromboxane production
by endothelial cellsAccumulates Ca2 in vascular
smooth muscle cellsBinds to LDL scavenger
receptor
Adapted from Sniderman AD et al. Ann Intern Med.
2001135447-59.
15
Increased small, dense, LDL particles associated
with reduced IHD survival
N 2072 men without IHD at baseline13-year
follow-up
1.00
Survivalprobabilities
0.90
P lt 0.001
0.80
0
2
4
6
8
10
12
Follow-up (years)
Tertiles of LDL-C255Å
lt1.07 mmol/l
1.071.86 mmol/l
1.86 mmol/l
St-Pierre AC et al. Arterioscler Thromb Vasc
Biol. 200525553-9.
IHD ischemic heart disease
16
PPAR? activation increases LDL size and buoyancy
N 302 rosiglitazone 8 mg
LDL density
LDL particle size
0.04
8
P lt 0.0001
P lt 0.0001
? Relativeflotation vs baseline
? Diametervs baseline (Angstroms)
4.8
0.019
4
0.02
0
0
Brunzell JD et al. Circulation.
2004110(suppl)III-143.
17
Comparative effects of PPAR? activators on
lipids in diabetes

• 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

1Goldberg RB et al. Diabetes Care.
2005281547-54. 2Plotkin DJ et al. Diabetes.
200554(suppl 1)A232. 3Khan M et al. Diabetes.
200554(suppl 1)A137.
18
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Inflammation
Dyslipidemia
Inflammation
PPAR modulation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
19
Adipokines An overview
Atherogenic
Antiatherogenic

• Adiponectin

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

Lau DCW et al. Am J Physiol Heart Circ Physiol.
2005288H2031-41. Wellen KE, Hotamisligil GS. J
Clin Invest. 20051151111-9.
20
Adiponectin associated with decreased risk of MI
N 18,225 men 6-year follow-up
1.2
1.0
0.8
Relative
0.6
risk
0.4
0.2
0.0
1
2
3
4
5
Quintile of
adiponectin
(95 CI)
7.9
12.6
16.5
21.1
29.2

g/mL
m
Adjusted relative risk (P lt 0.001)
Lipid-adjusted

relative risk (P lt 0.02)
Pischon
T et al.
JAMA
. 20042911730-7.
21
Improved insulin sensitivity associated with
increased adiponectin
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. 200427912152-62.
22
Contrasting roles of CRP and PPAR? on
inflammation and insulin resistance
Adipose tissue
? IL-6
Liver
? CRP
PPAR?
? Glucose
Insulin resistance
Lau DCW et al. Am J Physiol Heart Circ Physiol.
2005288H2031-41.
23
Direct relationship of CRP to metabolic syndrome

• Womens Health Study N 14,719

8
6
Median CRP(mg/L)
4
2
0
0
1
2
3
4
5
Components of the metabolic syndrome (n)
n 4086 3884 3152 2292
1135 170
Ridker PM et al. Circulation. 2003107391-7.
Modified ATP III definition
24
Inflammation is a contributing mechanism in
diabetes development
N 1047
25
20
P 0.06
P 0.001
P 0.001
Incidence()
15
10
5
0
Fibrinogen
CRP
PAI-1
Quartiles of inflammatory proteins
1st
2nd
4th
3rd
Festa A et al. Diabetes. 2002511131-7.
25
PPAR? activation decreases CRP in patients with
diabetes
N 357 26 weeks
Rosiglitazone 4 mg
Rosiglitazone 8 mg
Placebo
0
10
Mean change from baseline()
20
30
40
P lt 0.05
50
27
P lt 0.05
22
Haffner SM et al. Circulation. 2002106679-84.
26
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR modulation
Hypercoagulation
Hypertension
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
27
Improved insulin sensitivity associated with
reduced BP
VBWG
N 24 nondiabetic hypertensives rosiglitazone 8
mg, 16 weeks
20
10
?in 24-h systolic BP(mm Hg)
0
10
20
2
1
0
1
2
3
Change in insulin sensitivity (mg/kg/min)
Low-renin hypertension
Nonmodulators
P lt 0.005r 0.59
Raji A et al. Diabetes Care. 200326172-8.
28
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
3
2
1
1
0
5
4
3
2
1
1
0
24-h diastolic BP Treatment differences (mm Hg,
95 CI)
24-h systolic BPReduction from baseline (mm Hg,
95 CI)
Ambulatory BP
Home PD et al. Diabetes. 200554(suppl 1)A134.
29
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Inflammation
Dyslipidemia
PPAR modulation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
30
PPAR? activation blunts TNF-?induced PAI-1
secretion
Human umbilical-vein endothelial cells
800
600
PAI-1 (ng)
400

200


0
TNF-?10 ng/mL
TNF-?1 ng/mLTrog 10 µM
TNF-? 10 ng/mL Trog 10 µM
TNF-?1 ng/mL
TNF-? 100 ng/mL Trog 10 µM
TNF-?100 ng/mL

Trog troglitazone P lt 0.001 P lt 0.005
Hamaguchi E et al. J Pharmacol Exp Ther.
2003307987-94.
31
Metformin reduces PAI-1 levels in type 2 diabetes
N 27, 12 weeks
35 30 25 20 15 10 5 0
PAI-1 activity (U/mL)

Basal Placebo Metformin 2.5 g
Results at 12 weeks
? A1C 1.3 ? FPG 55 mg/dL
Nagi DK, Yudkin JS. Diabetes Care. 199316621-9.
P 0.001 vs placebo
32
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
PAl-1
0
0.56
10
9.8
14.35

20
P 0.046
30
26.9
32.76
P 0.026
40
P lt 0.001
Metformin 2 g (n 70)
Metformin 1 g rosiglitazone 8 mg (n 57)
Weissman PN et al. Diabetes. 200453(suppl 2)A28.
NS vs baseline