1 The Study of Trandolapril- verapamil 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 HbA 1c 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) Losartan (angiotensin II receptor blocker) + Hydrochlorothiazide (thiazide diuretic) Bakris G, et al. J Clin Hypertens 2006; May(Suppl.).

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 Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories. *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 Weeks * Verapamil SR/trandolapril 180/2mg (od) **Verapamil SR/trandolapril 180/2mg (od) or 240/4mg (od) Losartan/HCTZ 50/12.5mg (od) **Losartan/HCTZ 50/12.5 mg (od) or 100/25mg (od) Subject screened *** *** 12 Washout period 0 Subject randomized End of treatment

10 Baseline patient characteristics No significant differences were seen between groups at baseline Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories. Characteristic (mean)* Verapamil SR/trandolapril n=119 Losartan/ HCTZ n=121 Female gender (%) Age (years) Systolic BP (mmHg) Diastolic BP (mmHg) Pulse rate (bpm) BMI (kg/m 2 ) Male waist circumference (cm) Female waist circumference (cm) *p=NS

11 39 No clinically significant difference in office BP at baseline or study end* 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 Blood pressure (mmHg) 160 Mean systolic BP Mean diastolic BP End of study* Losartan/HCTZ Verapamil SR/trandolapril Verapamil SR/ trandolapril n= Losartan/HCTZn= Time (weeks) P=0.179 P=

12 Proportion of patients with systolic office blood pressure <130mmHg by visit *P≤0.05; **P≤0.01 (between groups) Data on file, Abbott Laboratories. Verapamil SR/ trandolapriln= Losartan/HCTZ n= Baseline % of patients Week 2 Week 4 Week 6 Week 8 Week 12 Week 26 Week 39 Week 52 Losartan/HCTZ Verapamil SR/trandolapril * ** End of study*** ***Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ

13 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.

14 Primary endpoint result Losartan/HCTZ increased blood plasma glucose significantly more than verapamil SR/trandolapril following OGTT by study end* Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories Change in blood glucose at 2 hours after OGTT (mg/dl) 30 Losartan/HCTZ Verapamil SR/trandolapril 15 n=108 n=107 P<0.001 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 AUC 120 from baseline to study end* with verapamil SR/trandolapril v losartan/HCTZ (P=0.003) Data on file, Abbott Laboratories. *Mean period of follow-up was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ Mean blood glucose (mg/dl) Time (minutes) Losartan/HCTZ baseline Losartan/HCTZ end of study* Verapamil SR/trandolapril baseline Verapamil SR/trandolapril end of study*

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 Low-dose combinations compared with high-dose combinations Data on file, Abbott Laboratories Low dose throughout trial Change in blood glucose at 2 hours after OGTT (mg/dl) Low dose titrated to high dose -20 Losartan/HCTZ Verapamil SR/trandolapril n=85n=84 n=22 n=24

18 Effect on HbA 1c Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories. Baseline values: Verapamil SR/trandolapril 5.8% Losartan/HCTZ 5.7% *Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ HbA 1c (%) Week 12 Week Losartan/HCTZ Verapamil SR/trandolapril n=109 n=97 n=94 P<0.001 vs baseline P=0.055 vs baseline n=112 End of study* n=115 n=115 P=0.027 vs baseline

19 Effect on blood insulin levels Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories. Baseline values: Verapamil SR/trandolapril 112µIU/ml Losartan/HCTZ 106µIU/ml *Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ Week 12 Change in blood insulin at 2 hours after OGTT (µIU/ml) Week Losartan/HCTZ Verapamil SR/trandolapril n=100 n=99 n=83 n=86 P=0.037 P=0.014 End of study* n=105 n=102 P=0.025

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)* Data on file, Abbott Laboratories. *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 Week 12 % of patients Week Losartan/HCTZ Verapamil SR/trandolapril 6/86 20/93 10/72 20/83 P=0.007 P=0.048 End of study** 10/91 25/94 P=0.002

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 Adverse event Number (% of patients) P value Verapamil SR/ trandolapril (n = 119) Losartan/HCTZ (n= 121) Constipation 11 (9%) 4 (3%) NS Cough 7 (6%) 1 (1%) 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%) Sinusitis 3 (2%) NS Upper respiratory tract infection 7 (6%) 6 (5%) NS Urinary tract infection 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), HbA 1c, 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.