Insulin Resistance and Cardiovascular Disease:

1
Insulin Resistance and Cardiovascular
Disease New Perspectives FromVascular Biology

2
Contents
I. CV disease and insulin resistance
Challenges and opportunities II. New
perspectives in cardioprotection Focus on
PPAR? activation III. Insulin sensitizers
Surrogate and clinical outcomes
studies IV. Identifying and treating patients
with insulin resistance
3
Cardiovascular Disease and Insulin
ResistanceChallenges and Opportunities
4
The majority of Americans do not follow a
healthy lifestyle
2000 Behavioral Risk Factor Surveillance System
N 153,805
100
77.8
76.7
80
59.9
60
Respondents
40
24
20
0
Smokers
BMI 25 kg/m2
Consumes fruits/vegetables lt5x/day
Infrequentexercise(lt5x/week)
Reeves MJ, Rafferty AP. Arch Intern Med.
2005165854-7.
5
Numbers of persons with diabetes will more than
double by 2030
40
118 increase
30.3
30
US population with diabetes(millions)
20
13.9
10
0
2002
2030
Year
AHA. Heart Disease and Stroke Statistics2005
Update.Wild S et al. Diabetes Care.
2004271047-53.
6
Increasing problem of obesity and diabetes among
US adults
Obesity (BMI 30 kg/m2)
Diabetes
36 increase
30
8
7.2
31 increase
USadults()
25.4
5.3
19.4
15
4
0
0
1997
2005
1997
2005
JanSep
CDC. 2005 NHIS. www.cdc.gov/nchs/nhis/released2006
03.htm. Accessed April 2006.
7
Cumulative lifetime risk for diagnosis of
diabetes
55
Hispanic females
50
NonHispanic black females
Hispanic males
45
NonHispanic black males
40
Risk ofdiagnosisof diabetes ()
35
NonHispanic white females
30
NonHispanic white males
25
20
15
10
5
0
0
10
20
30
40
50
60
70
80
90
100
Age (years)
Adapted from Narayan et al. JAMA.
20032901884-90.
8
Over half of patients referred to cardiologists
have insulin resistance syndrome
Cardiac rehabilitation
Acute MI
59
58
60
50
Patients withinsulin resistance syndrome ()
40
20
0
N 1912Savage, 2005
N 235 Milani, 2003
N 85 Curran, 2004
Savage PD et al. Am Heart J. 2005149627-31. Mila
ni RV, Lavie CJ. Am J Cardiol. 20039250-4. Curra
n PJ et al. J Am Coll Cardiol. 200443(suppl
A)249A.
9
Almost 70 of patients with first MI have IGT or
undiagnosed diabetes
N 181 consecutive patients admitted to CCU
66
70
Undiagnosed diabetes
31
50
Patients ()
30
Impaired glucose tolerance (IGT)
35
10
0
Glucose tolerance test results
Norhammar A et al. Lancet. 20023592140-4.
10
Role of obesity in insulin resistance
? Caloric intake Sedentarylifestyle Genetic
factors
? Free fatty acids ? Glucose ? Lipids
Oxidativestress Inflammation
VisceralObesity
Insulinresistance
Adapted from Wellen KE, Hotamisligil GS. J Clin
Invest. 20051151111-9.
11
Elevated glucose increases risk in elderly
patients with acute MI
Cooperative Cardiovascular Project 19941996 N
141,680
100
80
Mortalityrate ()
60
40
20
0

110
gt110140
gt140170
gt170240
gt240
Glucose groups (mg/dL)
Without diabetes
With diabetes
Kosiborod M et al. Circulation. 20051113078-86.
12
Insulin resistance associated with coronary
vasomotor abnormalities
Myocardial blood flow (MBF) response to cold
pressor test
75
P 0.003
50
? MBF ()
25
0
Insulin sensitive
Insulin resistant
Quiñones MJ et al. Ann Intern Med. 2004140700-8.
vs baseline
13
Insulin resistance to diabetes Coronary
vasomotor abnormalities progressively worsen
40
Cold pressor test
44
30
? MBF ()

20
14


10
10
7
Diabetes Hypertension
0
Insulinsensitive
Insulinresistant
IGT
Diabetes
2

10

• vs baseline
• P lt 0.05 vs insulin sensitive

Prior JO et al. Circulation. 20051112291-8.
14
Insulin resistance increases risk of target
organ damage in hypertension
N 354 with untreated hypertension
P 0.003
59
60
45
40
Patients ()
P 0.04
30
19
15
10
0
Microalbuminuria
LV hypertrophy
With insulin resistance syndrome
Leoncini G et al. J Intern Med. 2005257454-60.
Modified ATP III definition
15
Clinical manifestations of insulin resistance

• Type 2 diabetes and glycemic disorders
• Dyslipidemia
• Low HDL
• Small, dense LDL
• Hypertriglyceridemia
• Hypertension
• Endothelial dysfunction/inflammation (hsCRP)
• Impaired thrombolysis
• ? PAI-1

Insulin resistance Glucotoxicity Lipotoxicity ?
Adiponectin
VisceralObesity
Atherosclerosis
Courtesy of Selwyn AP, Weissman PN.
16
New perspectives in cardioprotection Focus on
PPAR? activation
17
Potential role of PPAR activation in CV risk
reduction
Geneticbackground
Food intake excess
Physical inactivity
Obesity
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Atherosclerosis
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
18
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.
19
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.
20
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.
21
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
22
PPAR activation Newest strategy in CV risk
reduction
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
23
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.
24
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.
25
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.
26
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
27
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.
28
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
29
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.
30
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.
31
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
32
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.
33
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.
34
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Inflammation
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
35
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.
36
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.
37
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.
38
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.
39
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
40
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.
41
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.
42
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Dyslipidemia
Inflammation
PPAR activation
Hypercoagulation
Hypertension
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
43
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.
44
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.
45
CV implications of insulin resistance and PPAR?
activation
Hyperinsulinemia
Hyperglycemia
Insulin
Inflammation
Dyslipidemia
PPAR activation
Hypercoagulation
Hypertension
resistance
Adapted from Tenenbaum A et al. Intl J Cardiol.
200497167-72.
46
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.
47
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
48
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
49
Insulin Sensitizers Surrogate and Clinical
Outcomes Studies
50
Metformin improves endothelial function
Metformin 1000 mg (3 months)
Placebo
400
350

300
250
Increase in forearm blood flow ()
200

150
100

50
0
3
10
30
3
10
30
Acetylcholine (?g/min)
Before treatment
After treatment
Mather KJ et al. J Am Coll Cardiol.
2001371344-50.
P 0.0027 vs placebo
51
PPAR? activation improves renal endothelial
function and reduces proteinuria
N 19 with type 2 diabetes with/without
microalbuminuria
P lt 0.05
P lt 0.05
140
133
120
Treatment with rosiglitazone was followed by 60
reductions in albuminuria and proteinuria in
diabetic patients with microalbuminuria.
119
120
103
100
GFR(mL/min)
80
60
40
20
0
Placebo
Rosiglitazone
Nateglinide
Rosiglitazone
Microalbuminuria
No microalbuminuria
Pistrosch F et al. Diabetes. 2005542206-11.
52
PPAR? activation normalizes coronary vasomotor
abnormalities in insulin resistance
N 16 with insulin resistance rosiglitazone 8
mg for 3 months
50
P lt 0.01
P lt 0.01
40
40.3(31.3)
?MBF ()
30
20
19.6(24.3)
10
8.7(18.9)
0
Pre-Treatment
Post-Treatment
Off-Treatment
Quiñones MJ et al. Ann Intern Med. 2004140700-8.
from rest
53
PPAR? activation Consistent reduction in
carotid atherosclerosis
Patients (n)duration
Study (year)
Treatments
? IMT (mm)
?0.080, troglitazone?0.027, usual careP lt 0.001
Type 2 diabetes (n 135)6 mos
Minamikawa(1998)
Troglitazone 400 mgUsual care
Type 2 diabetes(n 106) 6 mos
?0.084, troglitazone?0.022, usual careP lt 0.001
Koshiyama(2001)
Pioglitazone 30 mgUsual care
?0.012, rosiglitazone?0.0031, placeboP 0.03
Stable CAD(n 92)12 mos
Sidhu(2004)
Rosiglitazone 8 mgPlacebo
?0.054, pioglitazone?0.011, glimepirideP lt 0.001
Langenfeld(2005)
Type 2 diabetes(n 173)6 mos
Pioglitazone 45 mgGlimepiride 2.7 mg
Minamikawa J et al. J Clin Endocrinol Metab.
1998831818-20.Koshiyama H et al. J Clin
Endocrinol Metab. 2001863452-6.Sidhu JS et al.
Arterioscler Thromb Vasc Biol. 200424930-4.Lang
enfeld MR et al. Circulation. 20051112525-31.
54
PPAR? activation blunts progression of carotid
atherosclerosis in stable CAD
N 92 without diabetes
0.04
PlaceboProgression rate 0.031 mm/48 wks
0.03
0.02
? Carotid IMT (mm)
Rosiglitazone 8 mgProgression rate 0.012
mm/48 wks
0.01
0
0.01
0
24
48
Time (weeks)
Adapted from Sidhu JS et al. Arterioscler Thromb
Vasc Biol. 200424930-4.
P 0.03
55
PPAR? activation blunts progression of carotid
atherosclerosis
N 173 with type 2 diabetes
0.08
ns
0.04
0.00
?CarotidIMT (mm)
P lt 0.001
0.04
0.08
0.12
P lt 0.005
0.16
0
12
24
Weeks
Glimepiride 2.7 mg
Pioglitazone 45 mg
Langenfeld MR et al. Circulation.
20051112525-31.
56
Additive effect of statin and PPAR? activation
on atherosclerosis
Rabbit model
Changes in maximal vessel wall thickness
High- cholesterol diet (n 6)
20
Normal diet simvastatin PPAR? agonist (n
6)
Normal diet PPAR?-agonist (n 7)
Normal diet simvastatin (n 6)
10
Normal diet(n 6)
0
? ()
P lt 0.01

10



20
30
P 0.04
P 0.03
L-805645
P lt 0.05 vs high-cholesterol diet
Corti R et al. J Am Coll Cardiol. 200443464-73.
P lt 0.05 vs normal diet
57
PPAR? activation reduces intimal hyperplasia
Balloon injury in mouse model
Rosiglitazone 8 mg/kg
Control
4
3.1
3
I/M ratio()
2
P lt 0.001
0.98
1
0
Intimal area Medial area
Control
Rosiglitazone
I/M
Wang C-H et al. Circulation. 20041091392-400.
58
PPAR? activation Consistent ? in neointimal
proliferation (stented patients with T2D)
Intimal index ()
Trialduration
Study, year (n)
Treatments
Randomization
6 mos
2 days prior
Diet Troglitazone 400 mg
27.1, troglitazone49.0, controlP lt 0.001
Takagi,2000(n 52)
Ins/SU/Acar Troglitazone400 mg
6 mos
39.1, troglitazone71.5, controlP lt 0.0001
1 day prior
Takagi,2002(n 55)
6 mos
Takagi,2003(n 44)
28, pioglitazone48, controlP lt 0.0001
8 days prior
Ins/SU/Acar Pioglitazone 30 mg
Trend to benefit
Placebo Rosiglitazone4 mg/ 8 mg
After stenting
Osman,2004(n 16)
6 mos(first mo at 4 mg)
Takagi T et al. J Am Coll Cardiol.
2000361529-35.Takagi T et al. Am J Cardiol.
200289318-22.Takagi T et al. Am Heart J.
2003146e5. Osman A et al. Am Heart J.
2004147e23.
Intimal area
Intimal index
Stent area
59
PPAR? activation reduces in-stent restenosis
N 95 with type 2 diabetes
25
P 0.03
21
20
15
Restenosis ( stents)
9
10
5
0
Control(n 45)
Rosiglitazone(n 38)
8-mg dose before catheterization 4 mg daily
thereafter
Choi D et al. Diabetes Care. 2004272654-60.
60
Preliminary data support reduction in MIwith
PPAR? activation
Favors oral therapy
Favors insulin
0.62
Sulfonylurea
0.61
Metformin
Sulfonylurea metformin
0.56
0.51
Thiazolidinedione
0.5
0.75
1.25
1
0.25
Odds ratio for MI
Koro CE et al. Diabetes. 200453(suppl 2)A247.
61
PPAR? activation associated with lower mortality
N 16,417 with diabetes and HF
1.0
0.9
0.8
Proportion of patientssurviving
Thiazolidinedione (n 2226)
0.7
13 Relative risk reduction
0.6
No insulin sensitizer (n 12,069)
0.5
50
100
300
150
200
250
0
350
Time (days)
Masoudi FA et al. Circulation. 2005111583-90.
62
Metformin associated with lower mortality
N 16,417 with diabetes and HF
1.0
0.9
0.8
Metformin (n 1861)
Proportion of patientssurviving
0.7
13 Relativerisk reduction
No insulin sensitizer (n 12,069)
0.6
0.5
0
50
150
200
250
300
350
100
Time (days)
Masoudi FA et al. Circulation. 2005111583-90.
63
Neutral effect of PPAR? activationand metformin
on hospital readmission
N 16,417 with diabetes and HF
Hospital readmission

• All-cause HF
• TZD 1.04 (0.991.10) 1.06 (1.001.12)
• Metformin 0.94 (0.891.01) 0.92 (0.860.99)

TZD thiazolidinedione
Masoudi FA et al. Circulation. 2005111583-90.
64
Thiazolidinediones in patients with type 2
diabetes and HF
AHA/ADA consensus statement summary

• NYHA class I/II HF Thiazolidinediones may be
  used cautiously, with initiation of treatment at
  the lowest dose and gradual dose escalation
• Allow more time than usual to achieve target A1C
• NYHA class III/IV HF Thiazolidinediones should
  not be used at this time

Nesto RW et al. Circulation. 20031082941-8.
65
Mortality benefit with combined
insulin-sensitizing therapy
8872 acute MI patients, mean age 76.4 years,
discharged on glucose-lowering medication
No insulin sensitizer (n 6641)Thiazolidinedione
s (n 1273) Metformin (n 819) TZD MET (n
139)
1.00
0.95
Proportion of patientssurviving
0.90
48 Relativerisk reduction
0.85
0.80
0
50
200
250
300
350
100
150
Days from discharge
Inzucchi SE et al. Diabetes Care. 2005281680-9.
66
Insulin sensitizers vs other glucose-lowering
agents following AMI
8872 acute MI patients, mean age 76.4 years,
discharged on glucose-lowering medication
Metformin
TZD
Both
Mortality
0.92 (0.811.06)
0.92 (0.801.05)
0.52 (0.340.82)
Myocardial infarction readmission
1.02 (0.861.20)
0.92 (0.771.10)
0.88 (0.561.37)
Heart failurereadmission
1.06 (0.951.18)
1.17 (1.051.30)
1.24 (0.941.63)
All-cause readmission
1.04 (0.961.13)
1.09 (1.001.20)
1.06 (0.871.30)
Inzucchi SE et al. Diabetes Care. 2005281680-9.
67
UKPDS Risk reduction with metformin in
overweight patients
N 4075 with type 2 diabetes
Aggregate endpoints
P
Favors metforminor intensive
Favors conventional
All-cause mortality Metformin Intensive Myocardia
l infarction Metformin Intensive Stroke Metformin
Intensive
0.021 0.021 0.021
0.1
1
10
Relative risk reduction(95 CI)
UKPDS Group. Lancet. 1998352854-65.
metformin vs intensive therapy
68
Evolution of clinical evidence supporting PPAR?
activation
Surrogate outcomes studies
Ongoing clinical outcomes studies
Large observational studies
2000 2005 and beyond
?Mortality in patients with diabetes HF or AMI
?Endothelialfunction ?Carotid atherosclerosis ?Re
stenosis
69
Anticipated results from large multicenter trials
in diabetes and prediabetes
NAVIGATOR VADT RECORD
ACT-NOW PERISCOPE
ADOPTAPPROACH CHICAGO
ACCORDBARI-2DORIGIN
DREAM
PROactive
2005 2006 2007 2008 2009
Clinical outcomes
Surrogate outcomes
70
PROactive Study design
Objective Assess the effects of pioglitazone
on reducing macrovascular events in type 2
diabetes Design Randomized double-blind,
controlled outcome Population N 5238 with
type 2 diabetes and history of macrovascular
disease Treatment Pioglitazone (up to 45 mg)
or placebo Primary outcome Composite of
all-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation,
stroke Secondary outcomes Individual
components of primary outcome, CV
mortality Follow-up 4 years
Charbonnel B et al. Diabetes Care.
2004271647-53. Dormandy JA et al. Lancet.
20053661279-89.
71
PROactive Baseline CV history

Dormandy JA et al. Lancet. 20053661279-89.
72
PROactive CV medications at study entry

Dormandy JA et al. Lancet. 20053661279-89.
73
PROactive Reduction in primary outcome
All-cause mortality, MI, ACS, coronary or
peripheral revascularization, amputation, stroke
25
10 Relative risk reduction HR 0.90
(0.801.02)P 0.095
Placebo(572 events)
20
Pioglitazone(514 events)
15
Proportionof events()
10
5
0
6
0
12
18
24
30
36
Time from randomization
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
Dormandy JA et al. Lancet. 20053661279-89.
Unadjusted
74
PROactive Reduction in secondary outcome
All-cause mortality, MI (excluding silent MI),
stroke
25
20
Placebo(358 events)
16 Relative risk reduction HR 0.84
(0.720.98)P 0.027
15
Proportionof events()
10
Pioglitazone(301 events)
5
0
6
0
12
18
24
30
36
Time from randomization
Number at risk
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
Dormandy JA et al. Lancet. 20053661279-89.
Unadjusted
75
PROactive Summary

• Pioglitazone added to standard antidiabetic and
  CV therapies showed
• 10 RRR in primary outcome Composite
  all-cause mortality, nonfatal MI (including
  silent MI), stroke, ACS, leg amputation,
  coronary or leg revascularization
• 16 RRR in secondary outcome All-cause
  mortality, nonfatal MI (excluding silent MI) or
  stroke
• No difference between groups in HF mortality
• Continued divergence in survival
  curves Greater benefit with longer treatment
  duration hypothesized

PROactive results support use of PPAR? modulator
in patients with diabetes at high CVD risk May
improve CVD outcomes and need to add insulin
Dormandy JA et al. Lancet. 20053661279-89.
76
DREAM
Diabetes REduction Assessment with ramipril and
rosiglitazone Medication
Objective Assess efficacy of rosiglitazone and
ramipril in diabetes prevention Design
N 5269 with IGT or IFG, randomized (2x2
factorial design) to Treatment
Rosiglitazone 8 mg vs placebo or
ramipril 15 mg vs placebo Primary
outcomes New-onset diabetes and all-cause
mortality Secondary outcomes Combined MI,
stroke, CV death, PCI/CABG, HF, angina,
ventricular arrhythmia Combined
microalbuminuria/macroalbuminuria
development, 30 decrease in CrCl STARR
substudy Change in carotid atherosclerosis Foll
ow-up 4 years (anticipated) Completion 2006
The DREAM Trial Investigators. Diabetologia.
2004471519-27.
77
DREAM Baseline characteristics
Age (years) 54.7 Hypertension () 43.5 Hyperlipi
demia () 35.5 BP (mm Hg) 136/83 BMI
(kg/m2) 30.5 Waist circumference
(inches) Men 34.3 Women 32.6
The DREAM Trial Investigators. Diabetologia.
2004471519-27.
78
ADOPT Study design
A Diabetes Outcome Progression Trial
Objective Assess effect on glucose control of
rosiglitazone, metformin, or glyburide
monotherapy Design N 3600 with type 2
diabetes of ?3 years duration, drug-naïve
Treatment Randomized to rosiglitazone 8 mg,
metformin 2 g, or glyburide 15 mg Primary
outcome Time to need for combination
therapy Secondary outcomes ?-cell function,
insulin sensitivity, dyslipidemia, albumin
excretion, PAI-1, fibrinogen, CRP Follow-up 4
years Completion 2007
Viberti G et al. Diabetes Care. 2002251737-43.
79
Identifying and Treating Patients with Insulin
Resistance
80
Diagnosis of diabetes, IFG, and IGT
Plasma glucose (mg/dL)
Fasting
2-hr postload
Casual
126 100 to 125 (ADA) gt110 to 126 (AACE)

• 200
• 140 to 199 (ADA)
• gt140 to lt200 (AACE)

Diabetes Impaired fasting glucose
(IFG) Impaired glucose tolerance (IGT)
200
Following equivalent of 75 g anhydrous glucose
in water
ADA. Diabetes Care. 200528(suppl 1)S4-36.AACE.
Endocr Pract. 20039240-52.
81
Metabolic syndrome diagnosis ATP III emphasizes
clinical practice

• Risk factor Defining level
• Abdominal obesity (in) Waist Men gt40 Women gt35
  
• Triglycerides (mg/dL) 150
• HDL-C (mg/dL) Men lt40 Women lt50
• BP (mm Hg) 130/85
• Fasting glucose (mg/dL) 110 (ADA 100)

NCEP ATP III. JAMA. 20012852486-97.
82
Metabolic syndrome diagnosis IDF emphasizes
central obesity
International Diabetes Federation

• Central obesity
• Plus any 2 of the following

• Defined according to waist circumference
  (ethnic- and gender-specific)

• Plasma triglycerides gt150 mg/dL
• HDL-C lt40 mg/dL
• BP ?140/90 mm Hg
• Fasting glucose ?100 mg/dL or previously
  diagnosed type 2 diabetes

Or receiving specific treatment for this
abnormality
www.idf.org. Accessed August 2005.
83
IDF ethnic- and gender-specific criteria for
central obesity
Waist circumference (inches)
Men
Women

• European ?37 ?32
• Sub-Saharan African
• Middle Eastern
• South Asian ?35 ?32
• South/Central American
• Chinese ?35 ?32
• Japanese ?34 ?35

www.idf.org. Accessed August 2005.
84
Metabolic syndrome diagnosis WHO emphasizes
central role of insulin resistance

• Insulin resistance
• Type 2 diabetes, or
• Impaired fasting glucose, or
• If fasting glucose lt110 mg/dL, glucose uptake
  below lowest quartile

• Plus any 2 of the following
• Antihypertensive medication and/or BP 140/90 mm
  Hg
• Plasma triglycerides 150 mg/dL
• HDL-C lt35 mg/dL (men) or lt39 mg/dL (women)
• BMI gt30 kg/m2 and/or waist-hip ratio gt0.9 (men)
  gt0.85 (women)
• Urinary albumin excretion rate 20 µg/min or
  albumin-creatinine ratio 30 mg/g

Grundy SM et al. Circulation. 2004109433-8.Adap
ted from Alberti KG, Zimmet PZ. Diabet
Med.199815539-53.
85
Other markers of insulin resistance

• Family history of type 2 diabetes or CAD
• Overactive sympathetic nervous system
• ?Uric acid

Cohn GS et al. Am J Hypertens. 2005181099-103.
86
ABCs of coronary prevention
Adapted from Cohen JD. Lancet. 2001357972-3.
87
Multidisciplinary consensus on managingmetabolic
syndrome
AHA / NHLBI / ADA

• Modify lifestyle (weight loss, physical activity)
• Assess risk
• Framingham Risk Score
• CRP (optional)
• Reduce risk factors (ATP III, JNC 7, ADA)
• Lipids, BP, thrombosis, glucose

There is growing interest in the possibility
that drugs that reduceinsulin resistance will
delay onset of type 2 diabetes and will
reduceCVD risk when the metabolic syndrome is
present.
Grundy SM et al. Circulation. 2004109551-6.
88
DPP Impact of lifestyle intervention or
metformin on diabetes
40
Placebo
N 3234, no diabetes Age 50 207 lbs Glucose 107
P
30
Metformin
lt 0.001
?31
Cumulative incidence of diabetes ()
20
Lifestyle
?58
lt 0.001
10

• Lose 510 lbs
• Exercise 2.5 hrs/wk

0
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Year
DPP Diabetes Prevention Program
DPP Research Group. N Engl J Med.
2002346393-403.
89
UKPDS Comparison of tight control of BP vs
glycemia on risk of diabetes complications
Any diabetes-related outcome
Diabetes-related death
Coronaryheart failure
Micro-vascular
Retinopathy
Stroke
0
10
20
Patients
30
40
50
60
Tight BP (144/82 vs 154/87 mm Hg)
Tight glucose (A1C 7 vs 7.9)
UKPDS Group. BMJ. 1998317703-13.
UKPDS UK Prospective Diabetes Study
90
HPS and CARDS Benefits of lowering LDL-C in
diabetes
Event rate ()
? LDL-C(mg/dL)
Statin better
Placebo better
Placebo
Statin
P
HPS
0.73
34.8
lt0.0001 0.0003 0.001
12.6 13.5 9.0
9.4 9.3 5.8
All diabetes
0.67
34.8
Diabetes, no CVD
0.63
46.4
CARDS
0.5
0.7
0.9
1
1.7
Relative risk
Statin vs placebo HPS Heart Protection
Study CARDS Collaborative Atorvastatin Diabetes
Study
HPS Collaborative Group. Lancet.
20033612005-16.Colhoun HM et al. Lancet.
2004364685-96.
91
ASCOT-LLA Atorvastatin reduces CV events in
patients with diabetes and hypertension
N 2532, baseline LDL-C 128 mg/dL
14.0
Placebo
12.0
23 Risk reduction P 0.036
10.0
8.0

6.0
Atorvastatin 10 mg
4.0
2.0
HR 0.77 (0.610.98)
0.0
Years
0.5
0.0
1.0
1.5
2.0
2.5
3.0
3.5
Number at risk
1231
1258
1209
1191
1171
1065
699
370
Placebo
1237
1274
1219
1200
1175
1058
714
375
Atorvastatin
Nonfatal MI, CV mortality, UA, stable angina,
arrhythmias, stroke, TIA, PAD, retinal vascular
thrombosis, revascularization ASCOT-LLA
Anglo-Scandinavian Cardiac Outcomes TrialLipid
Lowering Arm
Sever PS et al. Diabetes Care. 2005281151-7.
92
MICRO-HOPE, PERSUADE Reduction in primary
outcome with ACEI
PERSUADE (N 1502) CV death/MI/cardiac arrest
MICRO-HOPE (N 3577) CV death/MI/stroke
25
Placebo
20
19 Risk reduction P 0.131
15
Perindopril 8 mg
10
5
0
0
1
2
3
4
5
Follow-up (years)
HOPE Study Investigators. Lancet.
2000355253-9. Daly CA et al. Eur Heart J.
2005261369-78.
93
Steno-2 supports aggressive multifactorial
intervention in type 2 diabetes

• Objective Target-driven, long-term,
  intensified intervention aimed at multiple
  risk factors compared with conventional
  therapy
• Design N 160 patients with type 2 diabetes
  and microalbuminuria
• Intensive treatment targets BP lt130/80 mm Hg
• A1C lt6.5
• Total-C lt175 mg/dL
• Triglycerides lt150 mg/dL

Gæde P et al. N Engl J Med. 2003348383-93.
94
Steno-2 Effects of multifactorial intervention
on CV outcomes
N 160 with type 2 diabetes and microalbuminuria
60
50
Conventional
Primary composite outcome ()
40
30
20
Intensive
10
0
0
12
24
36
48
60
72
84
96
Follow-up (months)
Gæde P et al. N Engl J Med. 2003348383-93.
CV death, MI, stroke, revascularization,
amputation
95
Summary

• The majority of patients seen in cardiology
  practices have insulin resistance
• Synergistic interaction of risk factors
  associated with insulin resistance places
  patients at high risk for CV disease
• Current guidelines recommend aggressive
  multi-factorial treatment in patients with
  diabetes or prediabetes
• PPAR? modulation is a potentially important
  strategy for improving insulin sensitivity and
  blunting atherosclerosis progression