STAR STUDY.

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1
The Study of Trandolaprilverapamil And insulin Resistance
STAR determined whether glycaemic control was maintained to a
greater degree by an RAS inhibitor/non-DHP CCB than an RAS
inhibitor/thiazide diuretic in hypertensive patients
with metabolic syndrome
2
STAR: rationale
Metabolic syndrome associated with increased risk of
new-onset diabetes and cardiovascular disease
Antihypertensive therapy may be beneficial in
reducing cardiovascular risk in subjects with
metabolic syndrome
Certain antihypertensive agents may decrease insulin
sensitivity and impair glycaemic control
3
STAR: primary objective
To compare the effect of an RAS inhibitor
combined with a non-dihydropyridine calcium
channel blocker and an RAS inhibitor
combined with a thiazide diuretic on
glycaemic control in hypertensive patients
with metabolic syndrome
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
4
STAR: primary and secondary endpoints
Primary endpoint
Change from baseline to end of study on 2-hour postprandial
plasma glucose, using an oral glucose tolerance test (OGTT)
Secondary endpoints
Changes in BP, pulse rate, and BP control
Change in insulin and glucose levels
Effect on HbA1c levels
Fasting glucose ≥126mg/dl and/or 2-hour OGTT ≥200mg/dl
(new-onset diabetes)
Insulin sensitivity and release
Albuminuria
Lipid profile
Safety profile
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
5
STAR: study drugs
Verapamil SR
(non-DHP CCB)
+
Trandolapril
(ACE inhibitor)
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Losartan
(angiotensin II receptor
blocker)
+
Hydrochlorothiazide
(thiazide diuretic)
6
STAR: patients and methods
Prospective, randomized, open-label, multicentre design with blinded
outcome evaluation (PROBE) trial
Approx. 30 US study sites
240 patients randomized to receive:
Verapamil SR/trandolapril (n=119)
Losartan/HCTZ (n=121)
52 weeks of treatment
OGTT and lab tests carried out at baseline, week 12, and
week 52/final visit
Assumptions:
Baseline 2-hour OGTT mean blood glucose level of 170mg/dl
(SD ± 25mg/dl)
Type 1 error of 0.05 for two-tailed test
100 patients per treatment group
Provides 80% power to detect treatment difference of 10mg/dl (6%) in
2-hour OGTT mean change in blood glucose from baseline to end of
study
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
7
STAR: key inclusion criteria
Male or female ≥21 years of age
Metabolic syndrome defined as:
Fasting blood glucose ≥100-≤125mg/dl
Controlled hypertension on two antihypertensive medications
(SBP <140mmHg) or SBP ≥130 and <160mmHg on monotherapy
Plus at least one of the following criteria:
HDL-cholesterol <40mg/dl (men) or <50mg/dl (women)
Triglycerides ≥150mg/dl
Waist circumference >40 inches (102cm): men, >35 inches
(89cm): women
Female patients could not be pregnant or breast-feeding
Data on file, Abbott Laboratories.
8
STAR: key exclusion criteria
Patients with diabetes or secondary hypertension
Those taking more than two antihypertensive agents
Patients with renal insufficiency (i.e. serum creatinine >1.4mg/dl
and/or urine albumin:creatinine ratio >0.3g/g)
Patients who required the following therapy:
NSAIDs or COX-2 inhibitors
Niacin >100mg/day
Loop diuretics or multiple diuretics for severe oedema
Data on file, Abbott Laboratories.
9
STAR: study design
Washout
period
Verapamil SR/trandolapril
180/2mg (od)
**Verapamil SR/trandolapril
180/2mg (od) or 240/4mg (od)
***
*
Losartan/HCTZ 50/12.5mg
(od)
Subject
screened
Weeks -4
Subject
randomized
0
***
**Losartan/HCTZ 50/12.5 mg
(od) or 100/25mg (od)
End of treatment
4
12
52
*If SBP ≥160 and <180mmHg or DBP ≥100mmHg and <110mmHg 2 weeks after discontinuing antihypertensive
therapy, subjects received clonidine 0.1mg bid. Subjects were to discontinue clonidine 2 days prior to baseline. If
SBP ≥180mmHg and/or DBP ≥110mmHg, the subject was withdrawn from the study
** Uptitration of verapamil SR/trandolapril or losartan/HCTZ for patients not controlled (SBP ≥130mmHg).
Protocol-allowed additional antihypertensive medications to be added if SBP still ≥130mmHg
*** Six-month extension period where all subjects received verapamil SR/trandolapril was available for all
subjects completing the main study
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
10
Baseline patient characteristics
No significant differences were seen between groups at baseline
Verapamil
SR/trandolapril
Losartan/
HCTZ
n=119
n=121
Female gender (%)
53.8
48.8
Age (years)
57.7
55.4
Systolic BP (mmHg)
145.4
146.7
Diastolic BP (mmHg)
86.4
88.2
Pulse rate (bpm)
71.5
70.3
BMI (kg/m2)
33.8
34.6
Male waist circumference (cm)
112.0
114.0
Female waist circumference (cm)
105.0
107.1
Characteristic (mean)*
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
*p=NS
11
No clinically significant difference in office BP
at baseline or study end*
160
Blood pressure (mmHg)
150
Mean systolic BP
140
P=0.179
130
120
Verapamil SR/trandolapril
Losartan/HCTZ
110
100
90
Mean diastolic BP
P=0.605
80
70
60
0 2 4 6 8
12
26
39
52
94
100
93
97
Time (weeks)
Verapamil SR/
trandolapril
n=
Losartan/HCTZ n=
119 116 115 113 113 112
120 119 115 115 113 112
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
100
105
End of
study*
119
120
*Mean period of follow-up for OGTT was 45.5 weeks for
verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ
12
Proportion of patients with systolic office
blood pressure <130mmHg by visit
70
Verapamil SR/trandolapril
% of patients
60
*
**
Losartan/HCTZ
50
40
30
20
10
0
Baseline
Week 2
Week 4
Week 6
Week 8
Week 12
Week 26
Week 39
Week 52
End of
study***
Verapamil SR/
trandolapril
n=119
116
115
113
113
112
100
94
93
119
Losartan/HCTZ n=120
119
115
115
113
112
105
100
97
120
Data on file, Abbott Laboratories.
*P≤0.05; **P≤0.01 (between groups)
***Mean period of follow-up for OGTT was 45.5 weeks for
verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ
Use of concomitant
antihypertensive medications allowed
by protocol
Use of concomitant antihypertensive medications allowed
by protocol to achieve BP goals was similar in both groups
(P=0.053 between groups):
56.3% in the verapamil SR/trandolapril group
43.8% in the losartan/HCTZ group
Data on file, Abbott Laboratories.
13
14
Primary endpoint result
Change in blood glucose at 2 hours after OGTT (mg/dl)
Losartan/HCTZ increased blood plasma glucose significantly more
than verapamil SR/trandolapril following OGTT by study end*
P<0.001
30
n=107
25
20
15
10
Verapamil SR/trandolapril
5
n=108
Losartan/HCTZ
0
-5
-10
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
Baseline values:
Verapamil SR/trandolapril 144mg/dl
Losartan/HCTZ 142mg/dl
* Mean period of follow-up for OGTT was
45.5 weeks for verapamil SR/trandolapril
and 48.3 weeks for losartan/HCTZ
15
OGTT results at baseline and study end*
Significantly greater change in OGTT-glucose AUC120 from baseline to
study end* with verapamil SR/trandolapril v losartan/HCTZ (P=0.003)
220
200
180
Verapamil SR/trandolapril
baseline
160
Verapamil SR/trandolapril
end of study*
Losartan/HCTZ baseline
140
Losartan/HCTZ
end of study*
120
100
0
30
60
Time (minutes)
Data on file, Abbott Laboratories.
90
120
* Mean period of follow-up was 45.5 weeks
for verapamil SR/trandolapril and 48.3
weeks for losartan/HCTZ
16
Requirement for dose titration
Proportions of patients requiring dose titration for BP
control were similar in both groups:
76.5% (91/119) in the verapamil SR/trandolapril
group
73.6% (89/121) in the losartan/HCTZ group
Data on file, Abbott Laboratories.
17
Change in blood glucose
at 2 hours after OGTT (mg/dl)
Low-dose combinations compared with
high-dose combinations
n=85
30
20
n=22
10
0
n=84
-10
-20
Losartan/HCTZ
n=24
Low dose
Low dose
throughout trial titrated to high dose
Data on file, Abbott Laboratories.
Verapamil SR/trandolapril
18
Effect on HbA1c
HbA1c (%)
6.5
P<0.001
vs baseline
P=0.055
vs baseline
P=0.027
vs baseline
n=115
n=97
Verapamil SR/trandolapril
n=112
6.0
n=94
Losartan/HCTZ
n=115
n=109
5.5
Week 12
Week 52
End of study*
Baseline values:
Verapamil SR/trandolapril 5.8%
Losartan/HCTZ 5.7%
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
* Mean period of follow-up for OGTT was
45.5 weeks for verapamil SR/trandolapril
and 48.3 weeks for losartan/HCTZ
19
Effect on blood insulin levels
Change in blood insulin
at 2 hours after OGTT (µIU/ml)
P=0.037
n=99
25
P=0.014
P=0.025
20
n=86
15
10
n=102
Verapamil SR/trandolapril
n=100
Losartan/HCTZ
5
n=83
n=105
0
-5
-10
Week 12
Week 52
End of
study*
Baseline values:
Verapamil SR/trandolapril 112µIU/ml
Losartan/HCTZ 106µIU/ml
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
* Mean period of follow-up for OGTT was
45.5 weeks for verapamil SR/trandolapril
and 48.3 weeks for losartan/HCTZ
20
Development of new-onset diabetes*
More than three times as many patients in the losartan/HCTZ group
developed new-onset diabetes at 12 weeks than in the verapamil
SR/trandolapril group (using ADA definition)*
P=0.002
30
P=0.048
P=0.007
20/83
25
% of patients
25/94
20/93
20
Verapamil SR/trandolapril
10/72
15
10/91
Losartan/HCTZ
10
6/86
5
0
Week 12
Data on file, Abbott Laboratories.
Week 52
End of
study**
* Fasting blood glucose ≥126mg/dl and/or
2-hour blood glucose levels after OGTT
≥200mg/dl based on ADA definition
** Mean period of follow-up for OGTT was 45.5
weeks for verapamil SR/trandolapril and 48.3
weeks for losartan/HCTZ
21
Incidence of treatment-emergent adverse
events occurring in 5% or more of patients
Overall incidence of treatment-emergent adverse events was similar
in both treatment groups
Number (% of patients)
Adverse event
Verapamil SR/
trandolapril (n = 119)
Losartan/HCTZ
(n= 121)
P value
Constipation
11 (9%)
4 (3%)
NS
Cough
7 (6%)
1 (1%)
0.035
Diabetes mellitus
10 (8%)
16 (13%)
NS
Dizziness
9 (8%)
5 (4%)
NS
Dry mouth
8 (7%)
7 (6%)
NS
Fatigue
6 (5%)
7 (6%)
NS
Headache
6 (5%)
5 (4%)
NS
Pain in extremity
6 (5%)
0
0.014
Sinusitis
6 (5%)
3 (2%)
NS
Upper respiratory tract infection
7 (6%)
6 (5%)
NS
Urinary tract infection
6 (5%)
6 (5%)
NS
Data on file, Abbott Laboratories.
22
The STAR trial: summary
STAR compared the effect of an RAS inhibitor/non-DHP CCB
and an RAS inhibitor/thiazide diuretic on glycaemic control in
hypertensive patients with metabolic syndrome
Little or no change in glucose tolerance was demonstrated with
verapamil SR/trandolapril, whereas glucose levels (2-hour OGTT),
HbA1c, and insulin levels were significantly increased with
losartan/HCTZ
Significantly higher incidence of new-onset diabetes was seen in
losartan/HCTZ group (using ADA definition)
Blood pressure was significantly reduced with both
combination treatments
Overall safety profiles were comparable between groups
Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).
Data on file, Abbott Laboratories.
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