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Eva M. Lonn, MD, MSc, FRCPC, FACC Professor of Medicine McMaster University Hamilton, Ontario, Canada

Eva M. Lonn, MD, MSc, FRCPC, FACC Professor of Medicine McMaster University Hamilton, Ontario, Canada. STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone . STARR. Study of Atherosclerosis with Ramipril and Rosiglitazone.

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Eva M. Lonn, MD, MSc, FRCPC, FACC Professor of Medicine McMaster University Hamilton, Ontario, Canada

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  1. Eva M. Lonn, MD, MSc, FRCPC, FACCProfessor of MedicineMcMaster UniversityHamilton, Ontario, Canada STARR: The Study of Atherosclerosis with Ramipril and Rosiglitazone

  2. STARR Study of Atherosclerosis with Ramipril and Rosiglitazone Eva M. Lonn, Hertzel C. Gerstein, Jackie Bosch, Gilles Dagenais, Rafael Diaz, Patrick Sheridan, Salim Yusuf The STARR Investigators

  3. Background and Rationale • Blood pressure and glucose are risk factors for vascular disease and increase the risk for CV events • People with prediabetes defined as impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are at increased long-term risk for CVD and frequently exhibit a cluster of cardiometabolic risk factors • Dysglycemia • Atherogenic lipid abnormalities • Hypertension or prehypertension • Abdominal obesity • Atherogenic lifestyle habits

  4. ACE-I block the RAAS and decrease the breakdown of bradykinin Lower blood pressure Favourable effects on glucose metabolism Vascular protective effects Decrease inflammation Improve endothelial function Randomized controlled trials reported reduced carotid IMT progression and CV risk reduction in high-risk people with vascular disease and/or diabetes treated with ACE-I Thiazolidinediones bind to PPAR  receptors Increase insulin sensitivity Lower glucose Decrease inflammation Lower blood pressure Improve lipids (HDL, LDL density,  or  TG, FFA)  Adiponectin Improve endothelial function Several previous trials reported reduced rates of carotid IMT progression in people with diabetes treated with TZDs; one small trial in CAD Background and Rationale

  5. The STARR Trial

  6. Study Outcomes Primary CIMT Measurement: Aggregate IMT1 = ∑ Segment Max IMT / Nr. of visualized segments Secondary CIMT Measurement: CCF IMT = ∑ Average CCF IMT/2 Other CIMT Measurements: Single Max IMT = Single Segment Maximum IMT Aggregate IMT2 =∑ Segment Max IMT CCA+BIF / Nr. of visualized segments

  7. Statistical Analysis • Sample size • Double placebo primary CIMT slope = 0.016 mm/year; SD of the slope=0.025; 30% treatment effect at the margins; no interaction; 5% attrition rate; α=0.05 • Amendment: •  Sample Size to 1400 (for primary CIMT slope=0.012) • Allow baseline CUS to be done up to maximum 6 months post randomization • Primary Analysis • Population: Participants with ≥ 2 adequate CUS exams after the baseline CUS • Annualized slopes of the primary, secondary and other CIMT measurements computed for each participant from all serial CUS data by least-squares regression and compared between treatment groups • Confirmatory Analysis • Regression analysis using repeated mixed effect linear models with IMT as the dependent variable (fixed effects: treatment, time, time*treatment interaction term; unstructured covariance matrix) • Sensitivity Analysis • All participants with ≥ 1 CUS after baseline

  8. STARR – Study Population

  9. STARR: 2 x 2 Factorial Design STARR N = 1256 subjects with IGT and/or IFG and baseline + ≥ 2 adequate CUS examinations Rosiglitazone N=621 Placebo N=635 Ramipril N= 637 Ramipril Active + Rosiglitazone Active n=316 Ramipril Active + Rosiglitazone Placebo n=321 Placebo N=619 Rosiglitazone Active + Ramipril Placebo n=305 Rosiglitazone Placebo + Ramipril Placebo n=314 Ramipril: 5 mg/day x 2 months; 10 mg X 10 months; 15 mg after 1 year Rosiglitazone: 4 mg X 2 months; 8 mg thereafter

  10. Baseline Characteristics

  11. Baseline Characteristics

  12. Baseline Characteristics

  13. Baseline CIMT Univariate Associations with Aggregate IMT1: Age (p<0.0001) Sex (p<0.0001) Systolic BP (p<0.0001) Diastolic BP (p<0.0001) FPG (p<0.0001) Region (p<0.0001)

  14. Ramipril: Adherence/Adverse Effects

  15. Ramipril Effect on Blood Pressure Systolic BP (mmHg) Mean Final Systolic BP (mmHg) Ramipril Placebo p 126.1±17.2 132.4 ± 18.0 <0.0001 Placebo Ramipril Diastolic BP (mmHg) Mean Final Diastolic BP (mmHg) Ramipril Placebo p 75.5 ± 10.9 78.9 ±11.1 <0.0001 Placebo Ramipril

  16. Ramipril Effect on Glucose Fasting PG (mM) 2 Hour PG (mM) Placebo Placebo Ramipril Ramipril

  17. Ramipril Effect on Carotid IMT Primary Analysis *No significant interaction between ramipril and rosiglitazone (p=0.28) Multivariate Adjusted Analysis: No significant treatment effects Confirmatory Analysis: No significant treatment effects Sensitivity Analysis: No significant treatment effects

  18. RamiprilEffect on Carotid IMT Aggregate IMT1 Progression 0.8 0.78 IMT(mm) 0.76 0.74 0.72 0 1 2 3 4 5 Year Primary Analysis Confirmatory Analysis Aggregate IMT1 Slope p=0.45 0.012 p=0.37 0.010 0.008 Placebo mm/year 0.006 Ramipril 0.004 0.002 0 Ramipril Placebo

  19. RosiglitazoneAdherence/Adverse Effects

  20. RosiglitazoneEffect on Blood Pressure Systolic BP (mmHg) Mean Final Systolic BP (mmHg) Rosiglitazone Placebo p 128.4 ± 17.5 130.1 ± 18.1 0.09 Placebo Rosiglitazone Diastolic BP (mmHg) Mean Final Diastolic BP (mmHg) Rosiglitazone Placebo p 76.7 ±11.5 77.7 ± 10.7 0.06 Placebo Rosiglitazone

  21. Rosiglitazone Effect on Glucose Fasting PG (mM) 2 Hour PG (mM) Placebo Placebo Rosiglitazone Rosiglitazone

  22. Rosiglitazone Effect on Carotid IMT Primary Analysis All additional analyses including the confirmatory analysis (mixed models), the sensitivity analysis (in 1347 subjects) and multivariate adjusted analyses showed similar results – trend toward lower CIMT progression with rosiglitazone compared to placebo for the primary measurement (Aggregate IMT1 ) and significant reduction in CIMT progression for the secondary measurement (CCF IMT) and for the Aggregate IMT2 progression

  23. RosiglitazoneEffect on Carotid IMT Aggregate IMT1 Slope 0.012 0.010 0.008 mm/year 0.006 0.004 0.002 0 Rosiglitazone Placebo Primary Analysis Primary Outcome Secondary Outcome CCF IMT Slope p=0.017 0.008 p=0.174 0.006 mm/year 0.004 0.002 0 Rosiglitazone Placebo Difference Active-Placebo (mm/year): -0.00214 ± 0.0016 -0.00421 ± 0.0018

  24. RosiglitazineEffect on Carotid IMT Confirmatory Analysis Primary CIMT Measurement Secondary CIMT Measurement CCF IMT Progression Aggregate IMT1 Progression 0.7 p=0.08 p=0.01 0.8 Placebo Placebo 0.68 0.78 IMT (mm) IMT (mm) 0.76 0.66 Rosiglitazone Rosiglitazone 0.74 0.64 0.72 0.62 0 1 2 3 4 5 0 1 2 3 4 5 Year Year Difference Active-Placebo: -0.00258 ± 0.0015 - 0.00444 ± 0.0017

  25. Rosiglitazone Subgroup Analysis Mean Primary CIMT Slope Difference: Active-Placebo p - interaction 0.36 0.76 0.44 0.59 Age<=54 (n=646) Age>54 (n=610) Women (n=693) Men (n=563) North America (n=472) South America (n=369) Europe/Australia (n=148) India (n=267) Baseline CUS at: Randomization (n=460) Within 3 months from Rand (n=337) 3-6 months from Rand (n=459) -0.014 0.0 0.010

  26. Cardiovascular Events Low Short-term CV Risk

  27. Conclusions • STARR is the largest RCT of the effects of ACE-I and TZD on carotid IMT • Participants with prediabetes without CVD and generally well controlled CV risk factors • Low short-term risk for CV events • Slow rates of subclinical vascular disease progression • Ramipril 15 mg/day was well tolerated, lowered BP by 5.5/2.7 mmHg and resulted in modest trends towards improved glycemia, but had no significant effect on carotid IMT • Study population • Asymptomatic subjects without over-activated RAAS • Low carotid IMT progression - study power

  28. Conclusions • The results of STARR for the ramipril arm are consistent within the trial and are also in general consistent with previous studies • The findings of STARR do not challenge the role of ACE-I in higher risk populations, such as people with CVD, diabetes or uncontrolled hypertension

  29. Conclusions • Rosiglitazone 8 mg/day was well tolerated, lowered FPG by 0.4 (7.2 mg/dl) mmol/L, 2 hr PG by 1.0 mmol/L (18.0 mg/dl) and BP by 1.1/1.1 mmHg • Rosiglitazone - trend towards lower carotid IMT progression for the primary CIMT measurement and significant reductions in the secondary carotid IMT measurement and the additional aggregate carotid IMT measurement • Results for rosiglitazone were consistent within the trial and are also consistent with previous studies of TZDs on carotid IMT in people with diabetes • Further trials of the long-term effects of TZDs on CV events are warranted

  30. Question & Answer

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