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

2. Study of Atherosclerosis with Ramipril and Rosiglitazone
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. Background and Rationale
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

5. The STARR Trial Objectives Design Eligibility Recruitment Organization
To evaluate the effect of Ramipril 15 mg/day on subclinical vascular disease progression
To evaluate the effect of Rosiglitazone 8 mg/day on subclinical vascular disease progression
Design
Double-blind placebo controlled parallel group RCT
2 x 2 factorial; Substudy of DREAM
Average 3 years of follow-up
Eligibility
Men and women ≥ 30 years with IGT (FPG < 7 and 2 hr PG mmol/L) and/or IFG (FPG= mmol/L); no CVD; no DM; Adequate baseline carotid ultrasound exam
Recruitment
Organization
1425 subjects from 32 centers in 10 countries
Coordination: PHRI, McMaster University, Canada
Sponsored by Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, GlaxoSmithKline, sanofi-aventis, King Pharmaceuticals
Outcome
Annualized progression slope of the aggregate carotid intima-media thickness

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 Primary Analysis
Double placebo primary CIMT slope = 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
Total
Rami
Plac
Rosi
Clinical Eligibility + Adequate Baseline CUS
1425
715
710
709
716
Died
Lost to Follow-up 13 7 6 3 4 9
Baseline + ≥ 1 CUS exam
Sensitivity Analysis
1347
681
666
670
677
Baseline + ≥ 2 CUS exams
Primary Analysis
1256
637
619
621
635

9. STARR: 2 x 2 Factorial Design
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
DREAM: 2 x 2 factorial design
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
Active Rami
N=637
Plac Rami N=619
Active Rosi N=621
Plac Rosi
N=635
Age (yrs)
54.6 ± 10.9
54.5 ± 10.6
54.3 ± 10.7
54.8 ± 10.8
Women
373 (58.6%)
320 (51.7%)*
335 (54.0%)
358 (56.4%)
IIGT
383 (60.1%)
378 (61.1%)
374 (60.2%)
387 (60.9%)
IIFG
92 (14.4%)
81 (13.1%)
88 (14.2%)
85 (13.4%)
IGT+IFG
162 (25.4%)
160 (25.9%)
159 (25.6%)
163 (25.7%)
Hypertension
246 (38.6%)
265 (42.8%)
259 (41.7%)
252 (39.7%)
Hyperchol.
204 (32.0%)
203 (32.8%)
194 (31.2%)
213 (33.5%)
Smoking (curr)
62 (9.7%)
74 (12.0%)
68 (11.0%)
Sedentary
190 (29.8%)
182 (29.4%)
178 (28.7%)
194 (30.6%)

11. Baseline Characteristics
Active Rami
N=637
Plac Rami N=619
Active Rosi N=621
Plac Rosi
N=635
North America
243 (38.2%)
229 (37.0%)
240 (38.7%)
232 (36.5%)
South America
187 (29.4%)
182 (29.4%)
183 (29.5%)
186 (29.3%)
Europe/Australia
73 (11.4%)
75(12.1%)
68 (11.0%)
80 (12.6%)
India
134 (21.0%)
133 (21.5%)
130 (20.9%)
137 (21.6%)
ASA/Antiplatelet
76 (11.9%)
65 (10.5%)
76 (12.2%)
65 (10.2%)
Statin
57 (9.0%)
75 (12.1%)
71 (11.4%)
61 (9.6%)
Fibrate
14 (2.2%)
13 (2.1%)
17 (2.7%)
10 (1.6%)
Thiazide diuretic
66 (10.6%)
Beta-blocker
106 (16.6%)
102 (16.5%)
109 (17.6%)
99 (15.6%)
CaChannel Blocker
55 (8.6%)
58 (9.3%)
ARB
42 (6.8%)
33 (5.2%)

12. Baseline Characteristics
Active Rami
N=637
Plac Rami N=619
Active Rosi N=621
Plac Rosi
N=635
BMI (kg /m2)
30.0 ± 5.1
30.4 ± 5.5
30.5 ± 5.4
30.0 ± 5.2
WHR (M)
0.96 ± 0.07
0.96 ± 0.06
0.97 ± 0.07
WHR (F)
0.86 ± 0.07
SBP (mmHg)
134.5 ± 19.1
135.5 ± 19.1
134.7 ± 18.5
135.3 ± 19.7
DBP (mmHg)
81.5 ± 11.3
82.1 ± 11.7
81.8 ± 11.3
81.7 ± 11.7
ABI
1.2 ± 0.2
FPG (mmol/L)
5.75 ± 0.7
5.77 ± 0.7
2 Hr PG (mmol/L)
8.68 ± 1.4
8.77 ± 1.4
8.72 ± 1.3
8.72 ± 1.4
LVH on ECG
25 (3.9%)
26 (4.2%)
21 (3.4%)
30 (4.7%)

13. Baseline CIMT Univariate Associations with Aggregate IMT1:
CIMT (mm)
Ramipril (n=637)
Rami Placebo
(n=619)
Rosiglitazone (n=621)
Rosi Placebo (n=635)
Aggregate IMT1
0.75 ± 0.19
0.76 ± 0.19
0.75 ± 0.20
0.76 ±0.19
CCF IMT
0.66 ± 0.16
0.67 ± 0.16
Single Max IMT
1.23 ± 0.53
1.25 ± 0.54
1.23 ± 0.52
1.25 ± 0.55
Aggregate IMT2
0.78 ± 0.19
0.79 ±0.19
0.79 ± 0.20
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
Placebo
On Study Drug at 1 year
94.0%
95.5%
at 2 years
90.7%
93.0%
at 3 years
at Final visit
Non – Study ACE-I at Final Visit
83.9%
83.6%
1.3%
91.9%
88.6%
3.6%
Reasons for Stopping Study Drug
Participant Refusal
6.3%
6.5%
MD advice
1.7%
1.9%
Cough
7.4%
1.6%
Fatigue
1.3 %
0.3%
Hypotension
1.1%
0.5%
UPDATED SEPT
Note – Ps/JP given groupings for compliance as individual list indicates categories are not grouped.
Updated Sept 6/06

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

16. Ramipril Effect on Glucose
Fasting PG (mM)
2 Hour PG (mM)
Placebo
Placebo
Ramipril
Ramipril
UPDATED SEPT
Mean Final
Ramipril
Placebo p
Fasting PG (mmol/L)
5.80 ± 1.0
5.88 ± 1.2
0.26
2 Hr PG (mmol/L)
7.37 ± 2.3
7.59 ± 2.7
0.24

17. Ramipril Effect on Carotid IMT
Primary Analysis
IMT Slope (mm/year)
Ramipril (n=637)
Mean ± SE
Placebo (n=619) p
Aggregate IMT1* ± ±
0.45
CCF IMT ± ±
0.36
Single Max IMT
± ) ±
0.38
Aggregate IMT2 ± ±
0.66
*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. Ramipril Effect on Carotid IMT
Primary Analysis
Confirmatory Analysis
Aggregate IMT1 Slope
Year
IMT(mm)
0.72
0.74
0.76
0.78
0.8 1 2 3 4 5
Aggregate IMT1 Progression
0.012
p=0.45
p=0.37
0.010
0.008
Placebo
mm/year
0.006
Ramipril
0.004
0.002
Ramipril
Placebo

19. Rosiglitazone Adherence/Adverse Effects
Placebo
On Study Drug at 1 year
95.8%
97.5%
at 2 years
94.5%
94.8%
at 3 years
at Final Visit
Non study TZD at Final Visit
89.0%
87.7%
91.2%
89.9%
0.3%
Reasons for Stopping Study Drug
Participant Refusal
7.1%
6.8%
Edema
1.8%
1.3%
MD advice
1.9%
1.5%
Weight Gain
0.9%
MD Advice
1.1%
UPDATED SEPT
Note – Ps/JP given groupings for compliance as individual list indicates categories are not grouped.
Updated Sept 6/06

20. Rosiglitazone Effect on Blood Pressure
Systolic BP (mmHg)
Mean Final Systolic BP (mmHg)
Rosiglitazone Placebo p
128.4 ± ±
Placebo
Rosiglitazone
Diastolic BP (mmHg)
Mean Final Diastolic BP (mmHg)
Rosiglitazone Placebo p
76.7 ± ±
Placebo
Rosiglitazone

21. Rosiglitazone Effect on Glucose
Fasting PG (mM)
2 Hour PG (mM)
Placebo
Placebo
Rosiglitazone
Rosiglitazone
UPDATED SEPT
Mean Final
Ramipril
Placebo p
Fasting PG (mmol/L)
5.66 ± 1.1
6.01 ± <0.0001
2 Hr PG (mmol/L)
7.04 ± 2.5
8.00 ± <0.0001

22. Rosiglitazone Effect on Carotid IMT
Primary Analysis
CIMT Slope (mm/year)
Rosiglitazone (n=621)
Placebo
(n=635) p
Aggregate IMT1 ± ±
0.1747
CCF IMT ± ±
0.0171
Single Max IMT ± ±
0.2772
Aggregate IMT2 ± ±
0.0296
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. Rosiglitazone Effect on Carotid IMT
Primary Analysis
Primary Outcome Secondary Outcome
Rosiglitazone
Placebo
0.002
0.004
0.006
0.008
0.010
0.012
Aggregate IMT1 Slope
mm/year
CCF IMT Slope
0.008
p=0.017
p=0.174
0.006
mm/year
0.004
0.002
Rosiglitazone
Placebo
Difference Active-Placebo (mm/year):
± ±

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

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
Rami
Plac
Rosi
Major CV Events 10 11 12 9
CV Death 1 MI
Stroke
New Angina 7 6
Revasc 4
CHF 2
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