Transcript Targeting Insulin Resistance for Vascular Protection
CV Risk Reduction, Diabetes Prevention, and TZDs
UKPDS 34: Intensive glucose control and CV protection n = 1704 overweight, with diabetes; n = 342 metformin group Aggregate endpoints Favors metformin or intensive Favors usual care All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive P* 0.02
0.12
0.08
0 1 Relative risk (95% CI) 2 *Metformin vs other intensive therapy (sulfonylurea or insulin)
UKPDS Group.
Lancet
. 1998;352:854-65.
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 (1983 –1993) † EDIC n = 1394 (97%) All patients offered intensive treatment Follow-up: 11 yr (1994 –2005)
Primary outcome:
Nonfatal MI, stroke, CV death, confirmed angina, revascularization * ≥3 insulin injections or pump admin/day † 1 –2 injections/day
DCCT/EDIC Study Research Group.
N Engl J Med
. 2005;353:2643-53.
DCCT/EDIC: Intensive glucose control reduces long-term CV risk N = 1441 with type 1 diabetes 0.12
0.10
0.08
Cumulative incidence of any first CV event 0.06
0.04
0.02
0 0
42% (95% CI 9% –63%) P = 0.02
Conventional 52 events 5 10 Time (years) 15 Intensive 31 events 20 0.12
0.10
0.08
Cumulative CV death, nonfatal MI, stroke 0.06
0.04
0.02
0 0
57% (95% CI 12% –79%) P = 0.02
Conventional 25 events 5 10 Time (years) 15 Intensive 11 events 20
DCCT/EDIC Study Research Group.
N Engl J Med
. 2005;353:2643-53.
DCCT/EDIC: Intensive treatment slows renal changes N = 1441 with type 1 diabetes 20 DCCT EDIC year 11 * 17 15 Patients (%) 10 * 13 9 * 6 5 0 5 5 7 † 3 0 0 Baseline End Microalbuminuria Conventional Baseline End Albuminuria Intensive 1 2 Microal buminuria Albumin uria Microalbuminuria: albumin excretion rate ≥40 mg/24 hr Albuminuria: albumin excretion rate ≥300 mg/24 hr *P < 0.01, † P < 0.05 vs intensive treatment
DCCT/EDIC Study Research Group.
N Engl J Med
. 2005;353:2643-53.
Vascular effects of thiazolidinediones (TZDs) Examining the clinical impact of TZDs
TZDs impact carotid IMT Study (year) Minamikawa (1998) Koshiyama (2001) Sidhu (2004) Langenfeld (2005) TRO = troglitazone PIO = pioglitazone ROSI = rosiglitazone GLIM = glimepiride Treatment TRO 400 mg Usual care PIO 30 mg Usual care ROSI 8 mg Placebo PIO 45 mg GLIM 2.7 mg (mean) Patients (Duration) DM2 (6 mo) DM2 (6 mo) Stable CAD (48 wk) DM2 (6 mo)
IMT (mm)
0.08, TRO
0.03, Usual care P < 0.001
0.08, PIO
0.02, Usual care P < 0.001
0.01, ROSI
0.03, Placebo P = 0.03
0.05, PIO
0.01, GLIM P < 0.005
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.
TZD impact on restenosis in type 2 diabetes N = 95 with DM2 and CAD 50 P = 0.03
P = 0.004
40.4
38.2
40 Change at 6 months (%) 30 20 17.6
23.0
10 0 Restenosis rate at ≥50% stenosis Control (n = 45 w/55 lesions) *8 mg before catheterization, 4 mg/d thereafter, combined with conventional antidiabetic therapy Stent diameter reduction ROSI* (n = 38 w/51 lesions)
Choi D et al.
Diabetes Care
. 2004;27:2654-60.
TZDs consistently reduce restenosis after coronary stenting in patients with diabetes TRO* TRO
†
PIO
†
ROSI
†
0 -10 -20 Reduction over 6 mo (%) -30 -40 -50 -60 Endpoint -43 P < 0.0001
Neointimal area -50 P < 0.0001
Neointimal area -39 P < 0.0001
Neointimal area -54 P = 0.03
Restenosis *vs diet † vs other anti-diabetes therapy
1 Takagi T et al.
J Am Coll Cardiol
3 Takagi T et al.
Am Heart J
2000. 2 Takagi T et al.
Am J Cardiol
2003. 4 Choi D et al.
Diabetes Care
2002.
2004.
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
. 2005;366:1279-89.
Major TZD outcome trials PROactive 2005 ADOPT CHICAGO DREAM APPROACH ACT-NOW VADT PERISCOPE RECORD ACCORD BARI-2D ORIGIN 2006 2007 2008 2009
Major TZD outcome trials PROactive 2005 ADOPT CHICAGO DREAM APPROACH ACT-NOW VADT PERISCOPE RECORD ACCORD BARI-2D ORIGIN 2006 2007 2008 2009
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 qd titrated 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
. 2005;366:1279-89.
PROactive: CV history at baseline MI Stroke PCI or CABG Acute coronary syndromes Coronary artery disease Peripheral arterial disease History of hypertension ≥2 macrovascular disease criteria % Pioglitazone n = 2605 47 19 31 14 48 19 75 47 Placebo n = 2633 46 19 31 14 48 20 76 49
Dormandy JA et al.
Lancet
. 2005;366:1279-89.
PROactive: CV medications at baseline
-blockers ACEIs ARBs CCBs Nitrates Thiazide diuretics Antiplatelets Aspirin Statins Fibrates % Pioglitazone n = 2605 55 63 7 34 39 15 85 75 43 10 Placebo n = 2633 54 63 7 37 40 16 83 72 43 11
Dormandy JA et al.
Lancet
. 2005;366:1279-89.
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 (0.80
–1.02) P = 0.095
20 Events (%) 15 Placebo 572 events Pioglitazone 514 events 10 5 0 0 *Including silent MI 6 12 18 24 Time from randomization (months) 30 36
Dormandy JA et al.
Lancet
. 2005;366:1279-89.
PROactive: Significant reduction in secondary outcome All-cause mortality, nonfatal MI*, stroke 25 20 Events (%) 15 10 16% RRR HR 0.84 (0.72
–0.98) P = 0.027
5 0 0 *Excluding silent MI Placebo 358 events Pioglitazone 301 events 6 12 18 24 Time from randomization (months) 30 36
Dormandy JA et al.
Lancet
. 2005;366:1279-89.
PROactive: Subgroup analysis –Previous 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.
PROactive: HF hospitalization and mortality N = 5238 HF leading to hospital admission* Fatal HF Pioglitazone n (%) 149 (5.7) 25 (0.96) Placebo n (%) 22 (0.84) P NS *Non-adjudicated
Dormandy JA et al.
Lancet
. 2005;366:1279-89.
PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes 30 Vascular events (%) 20 10 0 0 HPS 22% RRR P < 0.0001
1 Placebo Simvastatin 2 3 Years 4 5 6
Lancet
. 2003;361.
CHD death, MI*, revasc (%) 40 30 20 10 0 0 CARE 25% RRR P = 0.05
1 Placebo Pravastatin 2 3 Years 4 5
Circulation
. 1998;98.
25 20 MI, stroke, 15 CV death 10 (%) 5 0 0 MICRO-HOPE 25% RRR P = 0.0004
1 Placebo Ramipril 2 Years 3 4
Lancet
. 2000;355.
5 Cardiac 20 death, MI*, 15 coronary 10 revasc, ACS (%) 5 0 0 PROactive 19% RRR P = 0.034
Placebo Pioglitazone 1 2 3 Years
www.proactive-results.com.
*Nonfatal
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
. 2005;366:1279-89.
Fonseca V et al.
J Clin Endocrinol Metab
. 2006;91:25-7.
Meisner F et al.
Arterioscler Thromb Vasc Biol
. 2006;26:845-50.
Fluid retention after TZD use tends to be peripheral n = 99 with diabetes, chronic systolic HF, and fluid retention; 34% NYHA III –IV 100 95 80 80 73 63 60 Patients (%) 40 32 18 20 11 0 0 Pulmonary edema Jugular venous distention Ascites Peripheral edema No TZD (n = 80) TZD (n = 19)
Tang WHW et al.
J Am Coll Cardiol
. 2003;41:1394-8.
Managing TZD-related fluid retention n = 260 with type 2 diabetes 0.50
0.24
0.25
0 Change in Hct (%) -0.25
-0.50
-0.02
-0.75
-1.00
-0.89
ROSI -0.70
ROSI + furosemide 40 mg/d ROSI + HCTZ 25 mg/d -0.12
ROSI + spironolactone 50 mg/d Placebo (ROSI discontinued) Hct = hematocrit ROSI = rosiglitazone 4 mg bid
Karalliedde J et al.
Diabetes
. 2005;54(suppl 1):A20-1.
Collecting duct (CD) PPAR
: Potential mechanism for volume expansion CD-specific PPAR
knockout (KO) mouse model vs control 100
32.2% P < 0.001
80
15.5% P = NS 60 Plasma volume ( µL/g body wt) 40 20 0 Vehicle Control Rosiglitazone 320 mg/kg diet
Zhang H et al.
Proc Nat Acad Sci. USA
. 2005;102:9406-11.
TZDs associated with lower mortality N = 16,417 Medicare patients with diabetes and HF (1998 –1999, 2000 –2001) 1.0
0.9
Proportion of patients surviving 0.8
0.7
0.6
0 0 13% RRR HR 0.87 (0.80
–0.94) Thiazolidinedione (n = 2226) No insulin sensitizer (n = 12,069) 50 100 150 200 Follow-up (days) 250 300 350
Masoudi FA et al.
Circulation
. 2005;111:583-90.
TZDs in type 2 diabetes and HF AHA/ADA consensus statement, NYHA HF classification Class I –II
•
Use cautiously
•
Initiate treatment at lowest dose
•
Escalate dose gradually
•
Allow more time than usual to achieve A1C target Class III –IV
•
TZDs should not be used at this time
Nesto RW et al.
Circulation
. 2003;108:2941-8.
Major TZD outcome trials PROactive 2005 ADOPT CHICAGO DREAM APPROACH 2006 2007 ACT-NOW VADT PERISCOPE RECORD ACCORD BARI-2D ORIGIN 2008 2009
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
. 2004;47:1519-27.
RAAS modulation reduces new-onset diabetes Treatment with ACE inhibitors or ARBs 0 -10 Reduction in new diabetes (%) -20 -30 -40
Adapted from Pepine CJ, Cooper-Dehoff RM.
J Am Coll Cardiol
Julius S et al.
Lancet
2004.
2004.
PEACE Trial Investigators.
N Engl J Med
2004.
TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes TRoglitazone In Prevention Of Diabetes n = 236 Hispanic women with gestational diabetes 60 Annual incidence 40 New-onset diabetes (%) 20 55% RRR HR 0.45 (0.25
–0.83)* P = 0.009
Placebo 12.1% 5.4% Troglitazone 400 mg *Unadjusted 0 0 12 24 36 Follow-up (months) 48 60
Buchanan TA et al.
Diabetes
. 2002;51:2796-803.
TZDs blunt diabetes progression Diabetes Prevention Program 15 Cumulative incidence of diabetes (%) 10 5 0 0 n = 2343 *Withdrawn from study after 1.5 yr 0.5
Years 1568 1.0
739 1.5
237 Placebo Metformin 850 mg bid Lifestyle Troglitazone 400 mg/d*
75% vs placebo P < 0.001
DPP Research Group.
Diabetes.
2005;54:1150-6.
DREAM: Study design Randomized, double-blind 2
×
2 factorial design N = 5269 with IFG and/or IGT Ramipril 15 mg/d + Placebo Ramipril 15 mg/d + Rosiglitazone 8 mg/d Rosiglitazone 8 mg/d + Placebo Primary outcome: Diabetes or death from any cause Placebo + Placebo
Secondary outcomes I: CV events
Combined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia
Secondary outcomes II: Renal events
Combined microalbuminuria, macroalbuminuria, or
30% in CrCl Follow-up: 3 –5 years
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
DREAM: 2 x 2 factorial design N = 5269 with IFG and/or IGT Ramipril Placebo Rosiglitazone Ramipril + Rosiglitazone Rosiglitazone + Placebo Placebo Ramipril Placebo + Placebo + Placebo
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
DREAM: Inclusion criteria N = 5269
•
Age ≥30 years
•
IFG and/or IGT
–
Fasting plasma glucose 100 –125 mg/dL
–
2-hour 75 g OGTT 140 –199 mg/dL
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
DREAM: Key exclusion criteria
•
ACEI/TZD use or contraindication
•
LVEF <40% 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
. 2004;47:1519-27.
DREAM: Baseline characteristics Age (years) Women (%) Women with prior gestational diabetes (%) Hypertension (%) Hyperlipidemia (%) BP (mm Hg) BMI (kg/m 2 ) Waist-hip ratio, men Waist-hip ratio, women Waist circumference, men (in) Waist circumference, women (in) 54.7
58.5 9.3
43.5
35.5
136/83 30.5
0.96
0.87
34.3
32.6
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
DREAM: Baseline glucose status
•
Isolated IGT
•
Isolated IFG*
•
IGT and IFG* n 1835 (35%) 739 (14%) 2692 (51%)
•
FPG (mean)
•
2-hr plasma glucose (mean) mg/dL 104 157 *Based on 100 mg/dL threshold
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
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, and CV disease are clinically important
–
Highlight relevance of elevated glucose levels as modifiable risk factors for CV disease
DREAM Trial Investigators.
Diabetologia
. 2004;47:1519-27.
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, and CV 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
. 2004;47:1519-27.
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 (diagnosed ≤3 years)?
Viberti G et al.
Diabetes Care
. 2002;25:1737-43.
ADOPT: Study design Randomized, double-blind, parallel group design N ≈ 3600, drug naïve with type 2 diabetes <3 years Glyburide 15 mg/day* Rosiglitazone 8 mg/day* Primary outcome: Time to monotherapy failure Metformin 2 g/day* 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
. 2002;25:1737-43.
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?
Mazzone T.
Am J Cardiol.
NIH. www.clinicaltrials.gov.
2004;93(suppl):27C-31C.
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 *Titrated to reach glycemic control
Mazzone T.
Am J Cardiol.
NIH. www.clinicaltrials.gov.
2004;93(suppl):27C-31C.