CV Risk Reduction, Diabetes Prevention, and TZDs

1
CV Risk Reduction, Diabetes Prevention, and TZDs
2
UKPDS 34 Intensive glucose control andCV
protection
n 1704 overweight, with diabetes n 342
metformin group
Favors metforminor intensive
Favors usual care
Aggregate endpoints
P
All-cause mortality Metformin Intensive Myocardia
l infarction Metformin Intensive Stroke Metformin
Intensive
0.02 0.12 0.08
0
1
2
Relative risk(95 CI)
Metformin vs other intensive therapy
(sulfonylurea or insulin)
UKPDS Group. Lancet. 1998352854-65.
3
DCCT/EDIC Lower glucose lower long-term CV
risk
DCCT Type 1 diabetes, ages 13 to 40 yr N 1441
Intensive diabetes therapy
Conventional diabetes therapy
Mean follow-up 6.5 yr (19831993)
EDIC n 1394 (97)
All patients offered intensive treatment
Follow-up 11 yr (19942005)
Primary outcome Nonfatal MI, stroke, CV death,
confirmed angina, revascularization
3 insulin injections or pump admin/day 12
injections/day
DCCT/EDIC Study Research Group. N Engl J Med.
20053532643-53.
4
DCCT/EDIC Intensive glucose control reduces
long-term CV risk
N 1441 with type 1 diabetes
0.12
0.12
? 42 (95 CI 963) P 0.02
? 57 (95 CI 1279) P 0.02
0.10
0.10
0.08
0.08
Cumulative incidence of any first CV event
Cumulative CV death, nonfatal MI, stroke
Conventional 52 events
0.06
0.06
Conventional 25 events
0.04
0.04
Intensive 31 events
Intensive 11 events
0.02
0.02
0
0
0
5
10
15
20
0
5
10
15
20
Time (years)
Time (years)
DCCT/EDIC Study Research Group.N Engl J Med.
20053532643-53.

5
DCCT/EDIC Intensive treatment slows renal changes
N 1441 with type 1 diabetes
EDIC year 11
DCCT

20
17

15
13
Patients ()
9

10
7
6

5
5
5
3
2
1
0
0
0
Microal-buminuria
Albumin-uria
End
Baseline
End
Baseline
Microalbuminuria
Albuminuria
Intensive
Conventional
Microalbuminuria albumin excretion rate 40
mg/24 hr Albuminuria albumin excretion rate 300
mg/24 hr P lt 0.01, P lt 0.05 vs intensive
treatment
DCCT/EDIC Study Research Group.N Engl J Med.
20053532643-53.
6
Vascular effects of thiazolidinediones (TZDs)

• Examining the clinical impact of TZDs

7
TZDs impact carotid IMT
Patients (Duration)
Study (year)
Treatment
? IMT (mm)
Minamikawa(1998)
TRO 400 mgUsual care
DM2 (6 mo)
?0.08, TRO?0.03, Usual careP lt 0.001
Koshiyama(2001)
PIO 30 mgUsual care
DM2(6 mo)
?0.08, PIO ?0.02, Usual careP lt 0.001
Sidhu(2004)
ROSI 8 mgPlacebo
Stable CAD(48 wk)
?0.01, ROSI ?0.03, PlaceboP 0.03
Langenfeld(2005)
PIO 45 mgGLIM 2.7 mg (mean)
DM2 (6 mo)
?0.05, PIO ?0.01, GLIMP lt 0.005
TRO troglitazone PIO pioglitazone ROSI
rosiglitazone GLIM glimepiride
Minamikawa J et al. J Clin Endocrinol Metab
1998.Koshiyama H et al. J Clin Endocrinol Metab
2001.Sidhu JS et al. Arterioscler Thromb Vasc
Biol 2004.Langenfeld MR et al. Circulation 2005.
8
TZD impact on restenosis in type 2 diabetes

N 95 with DM2 and CAD
P 0.004
P 0.03
Change at 6 months ()
Restenosis rate at 50 stenosis
Stent diameter reduction
ROSI (n 38 w/51 lesions)
Control (n 45 w/55 lesions)
8 mg before catheterization, 4 mg/d thereafter,
combined with conventional antidiabetic therapy
Choi D et al. Diabetes Care. 2004272654-60.
9
TZDs consistently reduce restenosis after
coronary stenting in patients with diabetes



-39
-43
P lt 0.0001
P lt 0.0001
-50
-54
P lt 0.0001
P 0.03
Neointimalarea
Neointimalarea
Neointimalarea
Restenosis
Endpoint
vs diet vs other anti-diabetes therapy
1Takagi T et al. J Am Coll Cardiol 2000. 2Takagi
T et al. Am J Cardiol 2002. 3Takagi T et al. Am
Heart J 2003. 4Choi D et al. Diabetes Care 2004.
10
Surrogate outcome results driving major TZD trials
TZDs are associated with reductions in
atherosclerotic progression and restenosis
TZDs reduce inflammatory markers (CRP, TNF?)
independent of glycemic control
Reducing CV risk factors with TZDs may also
reduce CV morbidity and mortality
Dormandy JA et al. Lancet. 20053661279-89.
11
Major TZD outcome trials
ACT-NOW VADT PERISCOPE RECORD
ADOPT CHICAGO DREAM
ACCORDBARI-2DORIGIN
APPROACH
PROactive
2005 2006 2007 2008 2009
12
Major TZD outcome trials
ACT-NOW VADT PERISCOPE RECORD
ADOPT CHICAGO DREAM
ACCORDBARI-2DORIGIN
APPROACH
PROactive
2005 2006 2007 2008 2009
13
PROactive Study design
PROspective pioglitAzone Clinical Trial In
macroVascular Events
Randomized, double-blind controlled trial N
5238 with type 2 diabetes and macrovascular
disease
Pioglitazone 15 mg qdtitrated to 45 mg qd
Placebo
Primary outcome Composite of all-cause
mortality, MI (including silent MI), ACS,
stroke, revascularization, leg amputation
Secondary outcome All-cause mortality,MI
(excluding silent MI), stroke
Mean follow-up 34.5 months
Dormandy JA et al. Lancet. 20053661279-89.
14
PROactive CV history at baseline

Pioglitazone n 2605 Placebo n 2633
MI 47 46
Stroke 19 19
PCI or CABG 31 31
Acute coronary syndromes 14 14
Coronary artery disease 48 48
Peripheral arterial disease 19 20
History of hypertension 75 76
2 macrovascular disease criteria 47 49
Dormandy JA et al. Lancet. 20053661279-89.
15
PROactive CV medications at baseline

Pioglitazonen 2605 Placebon 2633
?-blockers 55 54
ACEIs 63 63
ARBs 7 7
CCBs 34 37
Nitrates 39 40
Thiazide diuretics 15 16
Antiplatelets 85 83
Aspirin 75 72
Statins 43 43
Fibrates 10 11
Dormandy JA et al. Lancet. 20053661279-89.
16
PROactive Nonsignificant reduction in primary
outcome
All-cause mortality, nonfatal MI, ACS, stroke,
coronary or peripheral revascularization, leg
amputation
25
10 RRR HR 0.90 (0.801.02) P 0.095
20
Placebo572 events
Pioglitazone514 events
15
Events()
10
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Including silent MI
Dormandy JA et al. Lancet. 20053661279-89.
17
PROactive Significant reduction in secondary
outcome
All-cause mortality, nonfatal MI, stroke
25
20
Placebo358 events
16 RRR HR 0.84 (0.720.98) P 0.027
15
Events()
10
Pioglitazone301 events
5
0
6
0
12
18
24
30
36
Time from randomization (months)
Excluding silent MI
Dormandy JA et al. Lancet. 20053661279-89.
18
PROactive Subgroup analysisPrevious MI
n 2445 with previous MI (6 mo)

• Pioglitazone reduced risk of CV events,
  including Fatal/nonfatal MI by 28 (P
  0.045) ACS by 37 (P 0.035)
• Over 3 years, pioglitazone added to medication in
  1000 patients could prevent
• 22 recurrent MIs
• 23 ACS events
• Future studies are needed to further elucidate
  the underlying mechanism(s) of these clinical
  results

Excluding silent MI
Adapted from Erdmann E. AHA 2005.
www.PROactive-results.com.
19
PROactive HF hospitalization and mortality
N 5238
Pioglitazone n () Placebo n () P
HF leading to hospital admission Fatal HF 149 (5.7) 25 (0.96) 108 (4.1) 22 (0.84) 0.007NS
Non-adjudicated
Dormandy JA et al. Lancet. 20053661279-89.
20
PROactive vs landmark clinical trials
Comparative benefit in patients with diabetes
Placebo
CARE
30
Placebo
HPS
40
CHD death, MI, revasc ()
25 RRR P 0.05
22 RRR P lt 0.0001
30
Vascular events ()
20
20
Pravastatin
Simvastatin
10
10
0
0
0
1
2
3
4
5
0
1
2
3
4
5
6
Years
Years
Circulation. 199898.
Lancet. 2003361.
MICRO-HOPE
PROactive
25
Cardiac death, MI,coronary revasc, ACS()
20
Placebo
Placebo
25 RRR P 0.0004
20
19 RRR P 0.034
15
MI, stroke, CV death ()
15
10
10
Ramipril
Pioglitazone
5
5
0
0
0
1
2
3
4
5
0
1
2
3
Years
Years
www.proactive-results.com.
Lancet. 2000355.
Nonfatal
21
PROactive in perspective

• Significant 16 reduction in secondary
  outcome(MI, stroke, or death) despite
  nonsignificant 10 reduction in primary outcome
• HF hospitalizations increased vs placebo, though
  HF deaths were similar
• TZD effect on plaque stability and inflammation
  might contribute to CV benefits
• 3-year trial may be too short to definitively
  evaluate CV treatment effect event curves did
  not begin to separate until 18 months

Dormandy JA et al. Lancet. 20053661279-89. Fonse
ca V et al. J Clin Endocrinol Metab.
20069125-7. Meisner F et al. Arterioscler
Thromb Vasc Biol. 200626845-50.
22
Fluid retention after TZD use tends to be
peripheral
n 99 with diabetes, chronic systolic HF, and
fluid retention 34 NYHA IIIIV
95
100
80
73
80
63
60
Patients()
40
32
18
20
11
0
0
Pulmonary
Jugular venous
Ascites
Peripheral
edema
distention
edema
No TZD (n 80)
TZD (n 19)
Tang WHW et al. J Am Coll Cardiol. 2003411394-8.
23
Managing TZD-related fluid retention
n 260 with type 2 diabetes
0.50
0.25
0
Change in Hct ()
-0.25
-0.50
-0.75
-1.00
ROSI
ROSI furosemide 40 mg/d
ROSI HCTZ 25 mg/d
ROSI spironolactone 50 mg/d
Placebo (ROSI discontinued)
Hct hematocrit ROSI rosiglitazone 4 mg bid
Karalliedde J et al. Diabetes. 200554(suppl
1)A20-1.
24
Collecting duct (CD) PPAR? Potential mechanism
for volume expansion
CD-specific PPARg knockout (KO) mouse model vs
control
? 32.2
P lt 0.001
? 15.5
P NS
Plasma volume (µL/g body wt)
g
Vehicle
Rosiglitazone 320 mg/kg diet

Zhang H et al. Proc Nat Acad Sci. USA.
20051029406-11.
25
TZDs associated with lower mortality
N 16,417 Medicare patients with diabetes and HF
(19981999, 20002001)
1.0
0.9
0.8
Proportion of patientssurviving
Thiazolidinedione (n 2226)
0.7
13 RRR HR 0.87 (0.800.94)
0.6
No insulin sensitizer (n 12,069)
0
50
100
300
150
200
250
0
350
Follow-up (days)
Masoudi FA et al. Circulation. 2005111583-90.
26
TZDs in type 2 diabetes and HF
AHA/ADA consensus statement, NYHA HF
classification

• Class III
• Use cautiously
• Initiate treatment at lowest dose
• Escalate dose gradually
• Allow more time than usual to achieve A1C target

• Class IIIIV
• TZDs should not be used at this time

Nesto RW et al. Circulation. 20031082941-8.
27
Major TZD outcome trials
ACT-NOW VADT PERISCOPE RECORD
ADOPT CHICAGO DREAM
ACCORDBARI-2DORIGIN
APPROACH
PROactive
2005 2006 2007 2008 2009
28
DREAM Background and study objective
Diabetes REduction Assessment with ramipril and
rosiglitazone Medication

• Previous studies have shown evidence for
  ?new-onset diabetes with RAAS and PPAR agonists
• Does treatment with ramipril and/or rosiglitazone
  prevent or delay the development of diabetes in
  persons with IGT or IFG and no diabetes?

DREAM Trial Investigators. Diabetologia.
2004471519-27.
29
RAAS modulation reduces new-onset diabetes
Treatment with ACE inhibitors or ARBs
SCOPE
CHARM
ANBP2
HOPE
ALLHAT
CAPPP
STOP-2
VALUE
PEACE
LIFE
0
-10
Reduction in new diabetes ()
-20
-30
-40
Adapted from Pepine CJ, Cooper-Dehoff RM. J Am
Coll Cardiol 2004. Julius S et al. Lancet
2004.PEACE Trial Investigators. N Engl J Med
2004.
30
TRIPOD Treating insulin resistance reduces
incidence of type 2 diabetes
TRoglitazone In Prevention Of Diabetesn 236
Hispanic women with gestational diabetes
Annual incidence
60
55 RRR HR 0.45 (0.250.83)P 0.009
40
New-onset diabetes ()
Placebo
20
Troglitazone 400 mg
0
0
12
24
36
48
60
Follow-up (months)
Unadjusted
Buchanan TA et al. Diabetes. 2002512796-803.
31
TZDs blunt diabetes progression
Diabetes Prevention Program
15
Placebo
Metformin 850 mg bid
Cumulative incidence of diabetes ()
10
Lifestyle
?75 vs placeboP lt 0.001
Troglitazone400 mg/d
5
0
1.5
1.0
0.5
0
Years
237
1568
2343
n
739
DPP Research Group.Diabetes. 2005541150-6.
Withdrawn from study after 1.5 yr
32
DREAM Study design
Randomized, double-blind 2 2 factorial designN
5269 with IFG and/or IGT
Ramipril 15 mg/d Rosiglitazone 8 mg/d
Ramipril 15 mg/d Placebo
Placebo Placebo
Rosiglitazone 8 mg/d Placebo
Primary outcomeDiabetes or death from any cause
Secondary outcomes I CV eventsCombined MI,
stroke, CV death, revascularization, HF, angina,
ventricular arrhythmia
Secondary outcomes II Renal eventsCombined
microalbuminuria, macroalbuminuria, or ?30 in
CrCl
Follow-up 35 years
DREAM Trial Investigators. Diabetologia.
2004471519-27.
33
DREAM 2 x 2 factorial design
N 5269 with IFG and/or IGT
Rosiglitazone Placebo
Ramipril Ramipril Rosiglitazone Ramipril Placebo
Placebo Rosiglitazone Placebo Placebo Placebo
DREAM Trial Investigators. Diabetologia.
2004471519-27.
34
DREAM Inclusion criteria
N 5269

• Age 30 years
• IFG and/or IGT
• Fasting plasma glucose 100125 mg/dL
• 2-hour 75 g OGTT 140199 mg/dL

DREAM Trial Investigators. Diabetologia.
2004471519-27.
35
DREAM Key exclusion criteria

• ACEI/TZD use or contraindication
• LVEF lt40 or other CVD with ACEI indication
• Diabetes
• Renal disease, including renal artery stenosis
• Diseases/medications that affect glucose
  tolerance
• Use of steroids/niacin
• Pregnancy

DREAM Trial Investigators. Diabetologia.
2004471519-27.
36
DREAM Baseline characteristics
Age (years) 54.7
Women () 58.5
Women with prior gestational diabetes () 9.3
Hypertension () 43.5
Hyperlipidemia () 35.5
BP (mm Hg) 136/83
BMI (kg/m2) 30.5
Waist-hip ratio, men 0.96
Waist-hip ratio, women 0.87
Waist circumference, men (in) 34.3
Waist circumference, women (in) 32.6

DREAM Trial Investigators. Diabetologia.
2004471519-27.
37
DREAM Baseline glucose status
n mg/dL

• Isolated IGT 1835 (35)
• Isolated IFG 739 (14)
• IGT and IFG 2692 (51)
• FPG (mean) 104
• 2-hr plasma glucose (mean) 157

Based on 100 mg/dL threshold
DREAM Trial Investigators. Diabetologia.
2004471519-27.
38
DREAM Beyond diabetes prevention

• IFG and IGT are strong risk factors for CV
  disease
• Does treatment with rosiglitazone and/or ramipril
  improve IFG, IGT, and glucose control?
• Positive result for either or both drugs will
• Affirm that links between RAAS, glucose
  homeostasis, andCV disease are clinically
  important
• Highlight relevance of elevated glucose levels as
  modifiablerisk factors for CV disease

DREAM Trial Investigators. Diabetologia.
2004471519-27.
39
DREAM Substudies

• STARR (STudy of Atherosclerosis with Ramipril and
  Rosiglitazone)
• (N 1427)
• Carotid atherosclerosis progression

• EpiDREAM Epidemiologic follow-up of individuals
  screened but
• not randomized for DREAM (N 20,000)
• Environmental/genetic determinants of diabetes,
  obesity, andCV disease

• Effects of rampiril and rosiglitazone
• Conversion of IGT to normal glucose tolerance
• Insulin resistance and ?-cell function
• FPG, 2-hr plasma glucose, A1C

DREAM Trial Investigators. Diabetologia.
2004471519-27.
40
ADOPT Study objective
A Diabetes Outcome Progression Trial

• What is the long-term efficacy of monotherapy
  with rosiglitazone vs metformin or glyburide on
  glucose control in patients with type 2 diabetes
  (diagnosed3 years)?

Viberti G et al. Diabetes Care. 2002251737-43.
41
ADOPT Study design
Randomized, double-blind, parallel group designN
3600, drug naïve with type 2 diabetes lt3 years
Glyburide 15 mg/day
Metformin 2 g/day
Rosiglitazone 8 mg/day
Primary outcomeTime to monotherapy failure
Secondary outcomes Changes in A1C, FPG, ?-cell
function, insulin sensitivity, lipids, BP,
albumin excretion, PAI-1, fibrinogen, CRP
Follow-up 4 years
Titrated to maximum tolerated dose
Viberti G et al. Diabetes Care. 2002251737-43.
42
CHICAGO Study objective
Carotid Intima-Media Thickness in Atherosclerosis
Using Pioglitazone trial

• How effective is pioglitazone in controlling the
  progression of atherosclerosis in patients with
  type 2 diabetes, as measured by carotid artery
  thickness?

NIH. www.clinicaltrials.gov. Mazzone T. Am J
Cardiol. 200493(suppl)27C-31C.

43
CHICAGO Study design
Double-blind, randomized, active control,
parallel-efficacy study Type 2 diabetes,
asymptomatic for CAD N 462
Pioglitazone 15, 30, or 45 mg
Glimepiride 1, 2, or 4 mg
Primary outcome Change in carotid intima-media
thickness at 18 months
Secondary outcome Carotid artery calcium score
NIH. www.clinicaltrials.gov. Mazzone T. Am J
Cardiol. 200493(suppl)27C-31C.

Titrated to reach glycemic control