Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

PPT Vascular Biology Working Group - PowerPoint - PowerPoint

VIEWS: 73 PAGES: 30

									                         VBWG




 Insulin Sensitizers:
Surrogate and Clinical
  Outcomes Studies
                                                                                                VBWG
Metformin improves endothelial function

                      400              Metformin                              Placebo
                                        1000 mg
                      350              (3 months)

                      300
                                                          *

      Increase in     250
        forearm
                      200
          blood
        flow (%)      150                       *
                      100
                                   *
                          50

                          0
                               3           10          30                 3          10      30
                                                      Acetylcholine (g/min)
                                        Before treatment           After treatment


* P = 0.0027 vs placebo                             Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50.
                                                                                             VBWG
PPAR activation improves renal endothelial
function and reduces proteinuria
N = 19 with type 2 diabetes with/without microalbuminuria

                        P < 0.05                   P < 0.05
       140     133
                              120            119
       120                                                                  Treatment with
                                                          103             rosiglitazone was
       100
  GFR                                                                      followed by 60%
         80
(mL/min)                                                              reductions in albuminuria
         60                                                               and proteinuria in
        40                                                              diabetic patients with
        20                                                                microalbuminuria.
         0
              Placebo     Rosiglitazone   Nateglinide Rosiglitazone

                Microalbuminuria            No microalbuminuria




                                                         Pistrosch F et al. Diabetes. 2005;54:2206-11.
                                                                                             VBWG
PPAR activation normalizes coronary
vasomotor abnormalities in insulin resistance
N = 16 with insulin resistance; rosiglitazone 8 mg for 3 months

                  50                   P < 0.01                   P < 0.01


                  40                                    40.3
                                                      (±31.3)
                 30
         MBF*
          (%)
                  20
                           19.6
                          (±24.3)
                  10                                                              8.7
                                                                                (±18.9)

                   0
                       Pre-Treatment          Post-Treatment                 Off-Treatment


* from rest                                       Quiñones MJ et al. Ann Intern Med. 2004;140:700-8.
                                                                                     VBWG
PPAR activation: Consistent reduction
in carotid atherosclerosis
                                            Patients (n)
 Study (year)     Treatments                 duration               IMT (mm)
 Minamikawa     Troglitazone 400 mg        Type 2 diabetes         0.080, troglitazone
 (1998)         Usual care                 (n = 135)               0.027, usual care
                                           6 mos                   P < 0.001

 Koshiyama      Pioglitazone 30 mg         Type 2 diabetes         0.084, troglitazone
 (2001)         Usual care                 (n = 106)               0.022, usual care
                                           6 mos                   P < 0.001

 Sidhu          Rosiglitazone 8 mg         Stable CAD              0.012, rosiglitazone
 (2004)         Placebo                    (n = 92)                0.0031, placebo
                                           12 mos                  P = 0.03
 Langenfeld     Pioglitazone 45 mg         Type 2 diabetes         0.054, pioglitazone
 (2005)         Glimepiride 2.7 mg         (n = 173)               0.011, glimepiride
                                           6 mos                   P < 0.001

                              Minamikawa J et al. J Clin Endocrinol Metab. 1998;83:1818-20.
                               Koshiyama H et al. J Clin Endocrinol Metab. 2001;86;3452-6.
                               Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4.
                                        Langenfeld MR et al. Circulation. 2005;111:2525-31.
                                                                                                   VBWG
PPAR activation blunts progression of
carotid atherosclerosis in stable CAD
N = 92 without diabetes

                      0.04
                                                                            Placebo
                      0.03                                                  Progression rate =
                                                                            0.031 mm/48 wks
                      0.02
             
           Carotid    0.01                                                  Rosiglitazone 8 mg
             IMT                                                            Progression rate =
            (mm)                                                            0.012 mm/48 wks
                        0

                     –0.01

                             0                    24                   48

                                           Time (weeks)


P = 0.03                         Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24:930-4.
                                                                                VBWG
PPAR activation blunts progression
of carotid atherosclerosis
N = 173 with type 2 diabetes
                0.08
                                            ns
                0.04

                0.00
         
       Carotid –0.04                                           P < 0.001
      IMT (mm)
               –0.08

               –0.12
                                        P < 0.005

               –0.16
                           0                12               24
                                        Weeks

                       Pioglitazone 45 mg        Glimepiride 2.7 mg

                                     Langenfeld MR et al. Circulation. 2005;111:2525-31.
                                                                                                 VBWG
Additive effect of statin and PPAR
activation on atherosclerosis
Rabbit model
                                Changes in maximal vessel wall thickness
                   High-
                 cholesterol
                    diet
          20       (n = 6)                         Normal diet                   Normal diet +
                                                    + PPAR-       Normal diet +  simvastatin
          10                         Normal diet    agonist*       simvastatin + PPAR agonist *
                                       (n = 6)       (n = 7)          (n = 6)       (n = 6)
           0
                   P < 0.01
                                          †            †
 (%) –10
                                                                        †‡
        –20
                                                                                           †‡
        –30
                                                                                P = 0.04
                                                                                P = 0.03

*L-805645
†P < 0.05 vs high-cholesterol diet
‡P < 0.05 vs normal diet                                Corti R et al. J Am Coll Cardiol. 2004;43:464-73.
                                                                                     VBWG
PPAR activation reduces intimal hyperplasia
Balloon injury in mouse model

                           Control          Rosiglitazone 8 mg/kg




                                4
                                      3.1
                                3

                       I/M ratio 2                  P < 0.001
                          (%)
                                                      0.98
                                 1

                                0
        Intimal area                 Control      Rosiglitazone
I/M =
        Medial area                            Wang C-H et al. Circulation. 2004;109:1392-400.
                                                                                       VBWG
PPAR activation: Consistent  in neointimal
proliferation (stented patients with T2D)
                                                             Trial             Intimal
 Study, year (n)    Treatments      Randomization          duration           index (%)

   Takagi,          Diet ±           2 days prior           6 mos          27.1, troglitazone
   2000             Troglitazone                                           49.0, control
   (n = 52)         400 mg                                                 P < 0.001
   Takagi,          Ins/SU/Acar ±    1 day prior            6 mos          39.1, troglitazone
   2002             Troglitazone                                           71.5, control
   (n = 55)         400 mg                                                 P < 0.0001

   Takagi,          Ins/SU/Acar ±    8 days prior           6 mos          28%, pioglitazone
   2003             Pioglitazone                                           48%, control
   (n = 44)         30 mg                                                  P < 0.0001
   Osman,           Placebo          After stenting         6 mos          Trend to benefit
   2004             Rosiglitazone                           (first mo
   (n = 16)         4 mg/ 8 mg                              at 4 mg)

                                              Takagi T et al. J Am Coll Cardiol. 2000;36:1529-35.
                                                   Takagi T et al. Am J Cardiol. 2002;89;318-22.
                   Intimal area                         Takagi T et al. Am Heart J. 2003;146:e5.
 Intimal index =
                   Stent area                         Osman A et al. Am Heart J. 2004;147:e23.
                                                                                      VBWG
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               Rosiglitazone*
                                     (n = 45)                (n = 38)


*8-mg dose before catheterization;
4 mg daily thereafter                             Choi D et al. Diabetes Care. 2004;27:2654-60.
                                                                           VBWG
Preliminary data support reduction in MI
with PPAR activation
                                          Favors oral therapy       Favors insulin


                                         0.62
           Sulfonylurea

                                         0.61
              Metformin

            Sulfonylurea            0.56
            + metformin
                                  0.51
       Thiazolidinedione


                           0.25   0.5           0.75            1             1.25
                                                       Odds ratio for MI

                                  Koro CE et al. Diabetes. 2004;53(suppl 2):A247.
                                                                                    VBWG
PPAR activation associated with
lower mortality
N = 16,417 with diabetes and HF
           1.0


           0.9


Proportion 0.8                                        Thiazolidinedione (n = 2226)
of patients
 surviving 0.7
                                13% Relative
                                risk reduction
           0.6
                                                         No insulin sensitizer (n = 12,069)

           0.5
                 0   50   100     150      200     250       300       350
                                   Time (days)

                                            Masoudi FA et al. Circulation. 2005;111:583-90.
                                                                                      VBWG
Metformin associated with lower mortality
N = 16,417 with diabetes and HF


                1.0


                0.9


                0.8
  Proportion                                                    Metformin (n = 1861)
  of patients
   surviving    0.7        13% Relative
                          risk reduction
                0.6                            No insulin sensitizer (n = 12,069)


                0.5
                      0    50      100     150     200       250       300      350
                                           Time (days)


                                               Masoudi FA et al. Circulation. 2005;111:583-90.
                                                                                    VBWG
Neutral effect of PPAR activation
and metformin on hospital readmission
N = 16,417 with diabetes and HF


                                   Hospital readmission
                             All-cause                              HF

 TZD                      1.04 (0.99–1.10)              1.06 (1.00–1.12)

 Metformin                0.94 (0.89–1.01)              0.92 (0.86–0.99)



TZD = thiazolidinedione                      Masoudi FA et al. Circulation. 2005;111:583-90.
                                                                            VBWG
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. 2003;108:2941-8.
                                                                                      VBWG
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)
              1.00
                                                           Thiazolidinediones (n = 1273)
                                                           Metformin (n = 819)
                                                           TZD + MET (n = 139)
              0.95

Proportion
of patients   0.90
 surviving
                          48% Relative
              0.85       risk reduction



              0.80
                     0   50     100 150      200    250     300    350
                                  Days from discharge
                                             Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
                                                                                 VBWG
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          0.92                  0.52
                       (0.81–1.06)   (0.80–1.05)           (0.34–0.82)


       Myocardial          1.02          0.92                  0.88
       infarction      (0.86–1.20)   (0.77–1.10)           (0.56–1.37)
       readmission

       Heart failure       1.06          1.17                  1.24
       readmission     (0.95–1.18)   (1.05–1.30)           (0.94–1.63)


       All-cause           1.04          1.09                  1.06
       readmission     (0.96–1.13)   (1.00–1.20)           (0.87–1.30)

                                        Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.
                                                                                       VBWG
UKPDS: Risk reduction with metformin
in overweight patients
N = 4075 with type 2 diabetes
         Aggregate endpoints                                                    P*
                                       Favors metformin     Favors
                                         or intensive     conventional
            All-cause mortality                                               0.021
                          Metformin
                           Intensive

         Myocardial infarction                                                0.021
                          Metformin
                           Intensive

                             Stroke                                           0.021
                          Metformin
                           Intensive

                                       0.1            1                10
                                             Relative risk reduction
                                                    (95% CI)
*metformin vs intensive therapy                           UKPDS Group. Lancet. 1998;352:854-65.
                                                              VBWG
Evolution of clinical evidence supporting
PPAR activation


          Surrogate            Large       Ongoing clinical
          outcomes         observational     outcomes
           studies            studies         studies


 2000                         2005 and beyond

        Endothelial         Mortality in
         function             patients with
        Carotid              diabetes + HF
         atherosclerosis      or AMI

        Restenosis
                                                                   VBWG
Anticipated results from large multicenter
trials in diabetes and prediabetes


                                         ACT-NOW
                                        NAVIGATOR
                            ADOPT          VADT          ACCORD
                          APPROACH      PERISCOPE        BARI-2D
PROactive   DREAM          CHICAGO       RECORD           ORIGIN


  2005      2006             2007          2008          2009


             Clinical outcomes      Surrogate outcomes
                                                                         VBWG

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. 2004;27:1647-53.
                                   Dormandy JA et al. Lancet. 2005;366:1279-89.
                                                                     VBWG
PROactive: Baseline CV history
                                                  %
                              Pioglitazone                 Placebo
                                n = 2605                   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          47                           49
criteria


                                 Dormandy JA et al. Lancet. 2005;366:1279-89.
                                                                      VBWG
PROactive: CV medications at study entry
                                             %
                        Pioglitazone                 Placebo
                          n = 2605                   n = 2633
   -Blockers               55                           54
   ACEIs                    63                           63
   ARBs                       7                            7
   CCBs                     34                           37
   Nitrates                 39                           40
   Thiazide diuretics       15                           16
   Antiplatelet             85                           83
   Aspirin                  75                           72
   Statins                  43                           43
   Fibrates                 10                           11
                                  Dormandy JA et al. Lancet. 2005;366:1279-89.
                                                                                      VBWG
 PROactive: Reduction in primary outcome
 All-cause mortality, MI, ACS, coronary or peripheral revascularization,
 amputation, stroke
              25
                           10% Relative
                          risk reduction
              20        HR* 0.90 (0.80–1.02)
                                                  Placebo
                             P = 0.095          (572 events)
              15                                                         Pioglitazone
  Proportion                                                             (514 events)
  of events 10
     (%)
              5

              0
                   0        6          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
*Unadjusted                                       Dormandy JA et al. Lancet. 2005;366:1279-89.
                                                                                  VBWG
 PROactive: Reduction in secondary outcome
 All-cause mortality, MI (excluding silent MI), stroke
              25

              20
                                                                  Placebo
                                  16% Relative
              15                 risk reduction
                                                                (358 events)
  Proportion                   HR* 0.84 (0.72–0.98)
  of events 10                      P = 0.027
     (%)                                                              Pioglitazone
                                                                      (301 events)
               5

               0
                   0     6      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
*Unadjusted                                   Dormandy JA et al. Lancet. 2005;366:1279-89.
                                                                              VBWG
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. 2005;366:1279-89.
                                                                                    VBWG
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

Follow-up:             4 years (anticipated)

Completion:            2006

                                The DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
                                                                          VBWG
DREAM: Baseline characteristics
       Age (years)                               54.7

       Hypertension (%)                          43.5

       Hyperlipidemia (%)                        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. 2004;47:1519-27.
                                                                                    VBWG
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. 2002;25:1737-43.

								
To top