The S tudy of T randolapril-verapamil A nd insulin R esistance

1

The The SStudy of tudy of TTrandolapril-randolapril-verapamil verapamil AAnd insulin nd insulin RResistance esistance

STAR determined whether glycaemic control was maintained to a STAR determined whether glycaemic control was maintained to a greater degree by an RAS inhibitor/non-DHP CCB than an RAS greater degree by an RAS inhibitor/non-DHP CCB than an RAS

inhibitor/thiazide diuretic in hypertensive patientsinhibitor/thiazide diuretic in hypertensive patientswith metabolic syndromewith metabolic syndrome

2

STAR: rationaleSTAR: rationale

Metabolic syndrome associated with increased risk of Metabolic syndrome associated with increased risk of new-onset diabetes and cardiovascular diseasenew-onset diabetes and cardiovascular disease

Antihypertensive therapy may be beneficial in Antihypertensive therapy may be beneficial in reducing cardiovascular risk in subjects with reducing cardiovascular risk in subjects with metabolic syndromemetabolic syndrome

Certain antihypertensive agents may decrease insulin Certain antihypertensive agents may decrease insulin sensitivity and impair glycaemic controlsensitivity and impair glycaemic control

3

STAR: primary objectiveSTAR: primary objective

To compare the effect of an RAS inhibitor To compare the effect of an RAS inhibitor

combined with a non-dihydropyridine calcium combined with a non-dihydropyridine calcium

channel blocker and an RAS inhibitor channel blocker and an RAS inhibitor

combined with a thiazide diuretic on combined with a thiazide diuretic on

glycaemic control in hypertensive patients glycaemic control in hypertensive patients

with metabolic syndromewith metabolic syndrome

Bakris G, Bakris G, et alet al. . J Clin HypertensJ Clin Hypertens 2006; May(Suppl.). 2006; May(Suppl.).

4

STAR: primary and secondary endpointsSTAR: primary and secondary endpoints

Primary endpointPrimary endpoint

Change from baseline to end of study on 2-hour postprandial Change from baseline to end of study on 2-hour postprandial plasma glucose, using an oral glucose tolerance test (OGTT) plasma glucose, using an oral glucose tolerance test (OGTT)

Secondary endpointsSecondary endpoints

Changes in BP, pulse rate, and BP controlChanges in BP, pulse rate, and BP control

Change in insulin and glucose levelsChange in insulin and glucose levels

Effect on HbAEffect on HbA1c1c levelslevels

Fasting glucose ≥126mg/dl and/or 2-hour OGTT ≥200mg/dlFasting glucose ≥126mg/dl and/or 2-hour OGTT ≥200mg/dl(new-onset diabetes)(new-onset diabetes)

Insulin sensitivity and releaseInsulin sensitivity and release

Albuminuria Albuminuria

Lipid profileLipid profile

Safety profileSafety profileBakris G, Bakris G, et al. J Clin Hypertenset al. J Clin Hypertens 2006; May(Suppl.). 2006; May(Suppl.).Data on file, Abbott Laboratories.Data on file, Abbott Laboratories.

5

STAR: study drugsSTAR: study drugs

Verapamil SRVerapamil SR(non-DHP CCB)(non-DHP CCB)

++

TrandolaprilTrandolapril(ACE inhibitor)(ACE inhibitor)

LosartanLosartan(angiotensin II receptor (angiotensin II receptor

blocker)blocker)

+ +

HydrochlorothiazideHydrochlorothiazide(thiazide diuretic)(thiazide diuretic)

Bakris G, Bakris G, et alet al. . J Clin HypertensJ Clin Hypertens 2006; May(Suppl.). 2006; May(Suppl.).

6

STAR: patients and methodsSTAR: patients and methods

Prospective, randomized, open-label, multicentre design with blinded Prospective, randomized, open-label, multicentre design with blinded outcome evaluation (PROBE) trialoutcome evaluation (PROBE) trialApprox. 30 US study sitesApprox. 30 US study sites240 patients randomized to receive:240 patients randomized to receive:

Verapamil SR/trandolapril (n=119)Verapamil SR/trandolapril (n=119)Losartan/HCTZ (n=121)Losartan/HCTZ (n=121)

52 weeks of treatment52 weeks of treatmentOGTT and lab tests carried out at baseline, week 12, andOGTT and lab tests carried out at baseline, week 12, andweek 52/final visitweek 52/final visitAssumptions:Assumptions:

Baseline 2-hour OGTT mean blood glucose level of 170mg/dlBaseline 2-hour OGTT mean blood glucose level of 170mg/dl(SD ± 25mg/dl) (SD ± 25mg/dl) Type 1 error of 0.05 for two-tailed test Type 1 error of 0.05 for two-tailed test

100 patients per treatment group100 patients per treatment groupProvides 80% power to detect treatment difference of 10mg/dl (6%) inProvides 80% power to detect treatment difference of 10mg/dl (6%) in2-hour OGTT mean change in blood glucose from baseline to end of 2-hour OGTT mean change in blood glucose from baseline to end of study study

Bakris G, Bakris G, et al. J Clin Hypertenset al. J Clin Hypertens 2006; May(Suppl.). 2006; May(Suppl.).Data on file, Abbott Laboratories.Data on file, Abbott Laboratories.

7

STAR: key inclusion criteriaSTAR: key inclusion criteria

Male or female ≥21 years of ageMale or female ≥21 years of age

Metabolic syndrome defined as:Metabolic syndrome defined as:

Fasting blood glucose ≥100-≤125mg/dlFasting blood glucose ≥100-≤125mg/dl

Controlled hypertension on two antihypertensive medicationsControlled hypertension on two antihypertensive medications(SBP <140mmHg) or SBP ≥130 and <160mmHg on monotherapy (SBP <140mmHg) or SBP ≥130 and <160mmHg on monotherapy

Plus at least one of the following criteria:Plus at least one of the following criteria:

HDL-cholesterol <40mg/dl (men) or <50mg/dl (women)HDL-cholesterol <40mg/dl (men) or <50mg/dl (women)

Triglycerides ≥150mg/dlTriglycerides ≥150mg/dl

Waist circumference >40 inches (102cm): men, >35 inchesWaist circumference >40 inches (102cm): men, >35 inches(89cm): women(89cm): women

Female patients could not be pregnant or breast-feedingFemale patients could not be pregnant or breast-feeding

Data on file, Abbott Laboratories.Data on file, Abbott Laboratories.

8

STAR: key exclusion criteriaSTAR: key exclusion criteria

Patients with diabetes or secondary hypertensionPatients with diabetes or secondary hypertension

Those taking more than two antihypertensive agentsThose taking more than two antihypertensive agents

Patients with renal insufficiency (i.e. serum creatinine >1.4mg/dl Patients with renal insufficiency (i.e. serum creatinine >1.4mg/dl and/or urine albumin:creatinine ratio >0.3g/g)and/or urine albumin:creatinine ratio >0.3g/g)

Patients who required the following therapy:Patients who required the following therapy:

NSAIDs or COX-2 inhibitorsNSAIDs or COX-2 inhibitors

Niacin >100mg/dayNiacin >100mg/day

Loop diuretics or multiple diuretics for severe oedemaLoop diuretics or multiple diuretics for severe oedema


9

STAR: study designSTAR: study design


*If SBP ≥160 and <180mmHg or DBP ≥100mmHg and <110mmHg 2 weeks after discontinuing antihypertensive *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. 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 studyIf 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). ** 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 ≥130mmHgProtocol-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 *** Six-month extension period where all subjects received verapamil SR/trandolapril was available for all subjects completing the main studysubjects completing the main study

WeeksWeeks

**

-4-4 44 5252

Verapamil SR/trandolaprilVerapamil SR/trandolapril180/2mg (od)180/2mg (od)

**Verapamil SR/trandolapril **Verapamil SR/trandolapril 180/2mg (od) or 180/2mg (od) or 240/4mg (od)240/4mg (od)

Losartan/HCTZ 50/12.5mg Losartan/HCTZ 50/12.5mg (od)(od) **Losartan/HCTZ 50/12.5 mg **Losartan/HCTZ 50/12.5 mg

(od) or 100/25mg (od)(od) or 100/25mg (od)

Subject Subject screenedscreened

******

******

1212

Washout Washout periodperiod

00

Subject Subject randomizedrandomized End of treatmentEnd of treatment

10

Baseline patient characteristicsBaseline patient characteristics

No significant differences were seen between groups at baselineNo significant differences were seen between groups at baseline


Characteristic (mean)*Characteristic (mean)*Verapamil Verapamil

SR/trandolaprilSR/trandolapriln=119n=119

Losartan/Losartan/HCTZHCTZn=121n=121

Female gender (%)Female gender (%) 53.853.8 48.848.8

Age (years)Age (years) 57.757.7 55.455.4

Systolic BP (mmHg)Systolic BP (mmHg) 145.4145.4 146.7146.7

Diastolic BP (mmHg)Diastolic BP (mmHg) 86.486.4 88.288.2

Pulse rate (bpm)Pulse rate (bpm) 71.571.5 70.370.3

BMI (kg/mBMI (kg/m22)) 33.833.8 34.634.6

Male waist circumference (cm)Male waist circumference (cm) 112.0112.0 114.0114.0

Female waist circumference (cm)Female waist circumference (cm) 105.0105.0 107.1107.1

**pp=NS=NS

11

3939

No clinically significant difference in office BP No clinically significant difference in office BP at baseline or study end*at baseline or study end*


*Mean period of follow-up for OGTT was 45.5 weeks for*Mean period of follow-up for OGTT was 45.5 weeks forverapamil SR/trandolapril and 48.3 weeks for losartan/HCTZverapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ

7070

8080

9090

100100

110110

120120

130130

150150

00

Blo

od

pre

ssu

re (

mm

Hg

)B

loo

d p

ress

ure

(m

mH

g)

160160

Mean systolic BPMean systolic BP

Mean diastolic BPMean diastolic BP

End ofEnd ofstudy*study*

Losartan/HCTZLosartan/HCTZ Verapamil SR/trandolaprilVerapamil SR/trandolapril

606022 44 66 88 1212 2626 5252

Verapamil SR/Verapamil SR/trandolapril trandolapril n=n= 119119 116116 115115 113113 113113 112112 100100 9494 9393 119119Losartan/HCTZLosartan/HCTZ n=n= 120120 119119 115115 115115 113113 112112 105105 100100 9797 120120

Time (weeks)Time (weeks)

PP=0.179=0.179

PP=0.605=0.605

140140

12

Proportion of patients with systolic office Proportion of patients with systolic office blood pressure <130mmHg by visitblood pressure <130mmHg by visit

**PP≤0.05; **≤0.05; **PP≤0.01 (between groups)≤0.01 (between groups)


Verapamil SR/Verapamil SR/trandolapriltrandolapril n=n=119119 116116 115115 113113 113113 112112 100100 9494 9393 119119

Losartan/HCTZ n=Losartan/HCTZ n=120120 119119 115115 115115 113113 112112 105105 100100 9797 120120

BaselineBaseline

% o

f p

atie

nts

% o

f p

atie

nts

6060

4040

2020

00

7070

5050

3030

1010

Week 2Week 2 Week 4Week 4 Week 6Week 6 Week 8Week 8 Week 12Week 12 Week 26Week 26 Week 39Week 39 Week 52Week 52

Losartan/HCTZLosartan/HCTZ

Verapamil SR/trandolaprilVerapamil SR/trandolapril * **

End of End of study***study***

***Mean period of follow-up for OGTT was 45.5 weeks for***Mean period of follow-up for OGTT was 45.5 weeks forverapamil SR/trandolapril and 48.3 weeks for losartan/HCTZverapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ

13Use of concomitantUse of concomitant

antihypertensive medications allowed antihypertensive medications allowed by protocolby protocol

Use of concomitant antihypertensive medications allowed Use of concomitant antihypertensive medications allowed

by protocol to achieve BP goals was similar in both groups by protocol to achieve BP goals was similar in both groups

((PP=0.053 between groups):=0.053 between groups):

56.3% in the verapamil SR/trandolapril group56.3% in the verapamil SR/trandolapril group

43.8% in the losartan/HCTZ group43.8% in the losartan/HCTZ group


14

Primary endpoint resultPrimary endpoint result

Losartan/HCTZ increased blood plasma glucose significantly more Losartan/HCTZ increased blood plasma glucose significantly more than verapamil SR/trandolapril following OGTT by study end* than verapamil SR/trandolapril following OGTT by study end*


-10-10

-5-5

00

55

1010

2020

2525

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2 h

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T (

mg

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2 h

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T (

mg

/dl)

3030


Verapamil SR/trandolaprilVerapamil SR/trandolapril

1515

n=108n=108

n=107n=107

PP<0.001<0.001

Baseline values:Baseline values:Verapamil SR/trandolapril 144mg/dlVerapamil SR/trandolapril 144mg/dlLosartan/HCTZLosartan/HCTZ 142mg/dl 142mg/dl

** Mean period of follow-up for OGTT was Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril 45.5 weeks for verapamil SR/trandolapril

and 48.3 weeks for losartan/HCTZand 48.3 weeks for losartan/HCTZ

15

OGTT results at baseline and study end* OGTT results at baseline and study end*

Significantly greater change in OGTT-glucose AUCSignificantly greater change in OGTT-glucose AUC120120 from baseline to from baseline to study end* with verapamil SR/trandolapril study end* with verapamil SR/trandolapril vv losartan/HCTZ ( losartan/HCTZ (PP=0.003) =0.003)


** Mean period of follow-up was 45.5 Mean period of follow-up was 45.5 weeks for verapamil SR/trandolapril and weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ48.3 weeks for losartan/HCTZ

100100

120120

140140

160160

180180

200200

220220

Mea

n b

loo

d g

luco

se (

mg

/dl)

Mea

n b

loo

d g

luco

se (

mg

/dl)

Time (minutes)Time (minutes)

00 3030 6060 9090 120120

Losartan/HCTZ baselineLosartan/HCTZ baseline

Losartan/HCTZLosartan/HCTZend of study*end of study*

Verapamil SR/trandolaprilVerapamil SR/trandolaprilbaselinebaseline

Verapamil SR/trandolaprilVerapamil SR/trandolaprilend of study*end of study*

16

Requirement for dose titrationRequirement for dose titration

Proportions of patients requiring dose titration for BP Proportions of patients requiring dose titration for BP control were similar in both groups:control were similar in both groups:

76.5% (91/119) in the verapamil SR/trandolapril 76.5% (91/119) in the verapamil SR/trandolapril groupgroup

73.6% (89/121) in the losartan/HCTZ group73.6% (89/121) in the losartan/HCTZ group


17

Low-dose combinations compared withLow-dose combinations compared withhigh-dose combinationshigh-dose combinations


-10-10

00

1010

2020

3030

Low doseLow dosethroughout trialthroughout trial

Ch

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Ch

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T (

mg

/dl)

at 2

ho

urs

aft

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GT

T (

mg

/dl)

Low doseLow dosetitrated to high dosetitrated to high dose

-20-20



n=85n=85

n=84n=84

n=22n=22

n=24n=24

18

Effect on HbAEffect on HbA1c1c


Baseline values:Baseline values:Verapamil SR/trandolapril 5.8%Verapamil SR/trandolapril 5.8%Losartan/HCTZLosartan/HCTZ 5.7% 5.7%

** Mean period of follow-up for OGTT was Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril 45.5 weeks for verapamil SR/trandolapril


Hb

AH

bA

1c1c (

%)

(%

)

5.55.5

6.56.5

Week 12Week 12 Week 52Week 52

6.06.0Losartan/HCTZLosartan/HCTZ


n=109n=109

n=97n=97

n=94n=94

PP<0.001<0.001vs baselinevs baseline

PP=0.055=0.055 vs baselinevs baseline

n=112n=112

End of study*End of study*

n=115n=115

n=115n=115

PP=0.027=0.027 vs baselinevs baseline

19

Effect on blood insulin levels Effect on blood insulin levels


Baseline values:Baseline values:Verapamil SR/trandolapril 112Verapamil SR/trandolapril 112µIµIU/mlU/mlLosartan/HCTZLosartan/HCTZ 106 106µIµIU/mlU/ml** Mean period of follow-up for OGTT was Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril 45.5 weeks for verapamil SR/trandolapril


-5-5

00

55

1010

1515

2020

Week 12Week 12

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T (

at 2

ho

urs

aft

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GT

T (

µIµI U

/ml)

U/m

l)

Week 52Week 52

2525

-10-10



n=100n=100

n=99n=99

n=83n=83

n=86n=86

PP=0.037=0.037

PP=0.014=0.014

End ofEnd ofstudy*study*

n=105n=105

n=102n=102

PP=0.025=0.025

20

Development of new-onset diabetes*Development of new-onset diabetes*

More than three times as many patients in the losartan/HCTZ group More than three times as many patients in the losartan/HCTZ group developed new-onset diabetes at 12 weeks than in the verapamil developed new-onset diabetes at 12 weeks than in the verapamil SR/trandolapril group (using ADA definition)*SR/trandolapril group (using ADA definition)*


** Fasting blood glucose ≥126mg/dl and/orFasting blood glucose ≥126mg/dl and/or2-hour blood glucose levels after OGTT 2-hour blood glucose levels after OGTT ≥200mg/dl based on ADA definition≥200mg/dl based on ADA definition

**** Mean period of follow-up for OGTT was 45.5 Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZweeks for losartan/HCTZ

00

55

1010

1515

2020

2525

Week 12Week 12

% o

f p

atie

nts

% o

f p

atie

nts

Week 52Week 52

3030



6/866/86

20/9320/93

10/7210/72

20/8320/83PP=0.007=0.007

PP=0.048=0.048

End ofEnd ofstudy**study**

10/9110/91

25/9425/94

PP=0.002=0.002

21

Incidence of treatment-emergent adverse Incidence of treatment-emergent adverse events occurring in 5% or more of patientsevents occurring in 5% or more of patients

Overall incidence of treatment-emergent adverse events was similar Overall incidence of treatment-emergent adverse events was similar in both treatment groupsin both treatment groups

Adverse event Adverse event

Number (% of patients)Number (% of patients)

P P valuevalueVerapamil SR/Verapamil SR/trandolapril (n = 119)trandolapril (n = 119)

Losartan/HCTZLosartan/HCTZ(n= 121)(n= 121)

ConstipationConstipation 11 (9%)11 (9%) 4 (3%)4 (3%) NSNS

CoughCough 7 (6%)7 (6%) 1 (1%)1 (1%) 0.0350.035

Diabetes mellitusDiabetes mellitus 10 (8%)10 (8%) 16 (13%)16 (13%) NSNS

Dizziness Dizziness 9 (8%)9 (8%) 5 (4%)5 (4%) NSNS

Dry mouthDry mouth 8 (7%)8 (7%) 7 (6%)7 (6%) NSNS

FatigueFatigue 6 (5%)6 (5%) 7 (6%)7 (6%) NSNS

HeadacheHeadache 6 (5%)6 (5%) 5 (4%)5 (4%) NSNS

Pain in extremityPain in extremity 6 (5%)6 (5%) 00 0.0140.014

SinusitisSinusitis 6 (5%)6 (5%) 3 (2%)3 (2%) NSNS

Upper respiratory tract infectionUpper respiratory tract infection 7 (6%)7 (6%) 6 (5%)6 (5%) NSNS

Urinary tract infectionUrinary tract infection 6 (5%)6 (5%) 6 (5%)6 (5%) NSNS


22

The STAR trial: summaryThe STAR trial: summary

STAR compared the effect of an RAS inhibitor/non-DHP CCBSTAR compared the effect of an RAS inhibitor/non-DHP CCBand an RAS inhibitor/thiazide diuretic on glycaemic control in and an RAS inhibitor/thiazide diuretic on glycaemic control in hypertensive patients with metabolic syndromehypertensive patients with metabolic syndrome

Little or no change in glucose tolerance was demonstrated with Little or no change in glucose tolerance was demonstrated with verapamil SR/trandolapril, whereas glucose levels (2-hour OGTT), verapamil SR/trandolapril, whereas glucose levels (2-hour OGTT), HbAHbA1c,1c, and insulin levels were significantly increased with and insulin levels were significantly increased with losartan/HCTZlosartan/HCTZ

Significantly higher incidence of new-onset diabetes was seen in Significantly higher incidence of new-onset diabetes was seen in losartan/HCTZ group (using ADA definition)losartan/HCTZ group (using ADA definition)

Blood pressure was significantly reduced with bothBlood pressure was significantly reduced with bothcombination treatmentscombination treatments

Overall safety profiles were comparable between groupsOverall safety profiles were comparable between groups


Documents

The S tudy of T randolapril-verapamil A nd insulin R esistance