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CV Risk Reduction, Diabetes Prevention, and TZDs

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. P*. All-cause mortality Metformin Intensive

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CV Risk Reduction, Diabetes Prevention, and TZDs

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  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 Aggregate endpoints Favors metforminor intensive Favors usual care P* All-cause mortality Metformin Intensive Myocardial 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. 1998;352:854-65.

  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 (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.

  4. DCCT/EDIC: Intensive glucose control reduces long-term CV risk N = 1441 with type 1 diabetes 0.12 0.12 42% (95% CI 9%–63%) P = 0.02 57% (95% CI 12%–79%) 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. 2005;353:2643-53.

  5. DCCT/EDIC: Intensive treatment slows renal changes N = 1441 with type 1 diabetes DCCT EDIC year 11 * 20 17 * 15 13 Patients (%) 9 * 10 7 6 † 5 5 5 3 2 1 0 0 0 Baseline End Baseline End Microal-buminuria Albumin-uria Microalbuminuria Albuminuria Conventional Intensive 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.

  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 < 0.001 Koshiyama(2001) PIO 30 mgUsual care DM2(6 mo) 0.08, PIO 0.02, Usual careP < 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 < 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 Control (n = 45 w/55 lesions) ROSI* (n = 38 w/51 lesions) *8 mg before catheterization, 4 mg/d thereafter, combined with conventional antidiabetic therapy Choi D et al. Diabetes Care. 2004;27:2654-60.

  9. TZDs consistently reduce restenosis after coronary stenting in patients with diabetes † † † -39 -43 P < 0.0001 P < 0.0001 -50 -54 P < 0.0001 P = 0.03 Endpoint Neointimalarea Neointimalarea Neointimalarea Restenosis *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. 2005;366:1279-89.

  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. 2005;366:1279-89.

  14. PROactive: CV history at baseline % Dormandy JA et al. Lancet. 2005;366:1279-89.

  15. PROactive: CV medications at baseline % Dormandy JA et al. Lancet. 2005;366:1279-89.

  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 (0.80–1.02) P = 0.095 20 Placebo572 events Pioglitazone514 events 15 Events(%) 10 5 0 0 6 12 18 24 30 36 Time from randomization (months) *Including silent MI Dormandy JA et al. Lancet. 2005;366:1279-89.

  17. PROactive: Significant reduction in secondary outcome All-cause mortality, nonfatal MI*, stroke 25 20 Placebo358 events 16% RRR HR 0.84 (0.72–0.98) P = 0.027 15 Events(%) 10 Pioglitazone301 events 5 0 0 6 12 18 24 30 36 Time from randomization (months) *Excluding silent MI Dormandy JA et al. Lancet. 2005;366:1279-89.

  18. 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.

  19. PROactive: HF hospitalization and mortality N = 5238 *Non-adjudicated Dormandy JA et al. Lancet. 2005;366:1279-89.

  20. PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes HPS Placebo CARE Placebo 30 40 CHD death, MI*, revasc (%) 22% RRR P < 0.0001 25% RRR P = 0.05 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 Lancet. 2003;361. Circulation. 1998;98. 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 Lancet. 2000;355. www.proactive-results.com. *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. 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.

  22. Fluid retention after TZD use tends to be peripheral n = 99 with diabetes, chronic systolic HF, and fluid retention; 34% NYHA III–IV 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. 2003;41:1394-8.

  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 (ROSIdiscontinued) Hct = hematocrit ROSI = rosiglitazone 4 mg bid Karalliedde J et al. Diabetes. 2005;54(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 < 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. 2005;102:9406-11.

  25. TZDs associated with lower mortality N = 16,417 Medicare patients with diabetes and HF (1998–1999, 2000–2001) 1.0 0.9 0.8 Proportion of patientssurviving Thiazolidinedione (n = 2226) 0.7 13% RRR HR 0.87 (0.80–0.94) 0.6 No insulin sensitizer (n = 12,069) 0 0 50 100 150 200 250 300 350 Follow-up (days) Masoudi FA et al. Circulation. 2005;111:583-90.

  26. 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 TZDs in type 2 diabetes and HF AHA/ADA consensus statement, NYHA HF classification Nesto RW et al. Circulation. 2003;108:2941-8.

  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. 2004;47:1519-27.

  29. RAAS modulation reduces new-onset diabetes Treatment with ACE inhibitors or ARBs HOPE CAPPP STOP-2 ALLHAT ANBP2 SCOPE CHARM 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 12.1% 5.4% TRoglitazone In Prevention Of Diabetesn = 236 Hispanic women with gestational diabetes Annual incidence 60 55% RRR HR 0.45 (0.25–0.83)*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. 2002;51:2796-803.

  31. TZDs blunt diabetes progression Diabetes Prevention Program 15 Placebo Metformin 850 mg bid Cumulative incidence of diabetes (%) 10 Lifestyle 75% vs placeboP < 0.001 Troglitazone400 mg/d* 5 0 0 0.5 1.0 1.5 Years 1568 n = 2343 237 739 DPP Research Group.Diabetes. 2005;54:1150-6. *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+ Placebo Ramipril 15 mg/d + Rosiglitazone 8 mg/d Rosiglitazone 8 mg/d+ Placebo Placebo+ Placebo Primary outcome:Diabetes or death from any cause Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina, ventricular arrhythmia Secondary outcomesII: Renal eventsCombined microalbuminuria, macroalbuminuria, or 30% in CrCl Follow-up: 3–5 years DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  33. DREAM: 2 x 2 factorial design N = 5269 with IFG and/or IGT DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  34. 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.

  35. 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.

  36. DREAM: Baseline characteristics DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

  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. 2004;47:1519-27.

  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. 2004;47:1519-27.

  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. 2004;47:1519-27.

  40. ADOPT: Study objective ADiabetes 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.

  41. ADOPT: Study design Randomized, double-blind, parallel group designN ≈ 3600, drug naïve with type 2 diabetes <3 years Glyburide 15 mg/day* Rosiglitazone 8 mg/day* Metformin 2 g/day* Primary outcome:Time 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. 2002;25:1737-43.

  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. 2004;93(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. 2004;93(suppl):27C-31C. *Titrated to reach glycemic control

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