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

The S tudy of T randolapril-verapamil A nd insulin R esistance. 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. STAR: rationale.

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

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  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 patientswith 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 HbA1clevels • 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. Verapamil SR(non-DHP CCB) + Trandolapril(ACE inhibitor) Losartan(angiotensin II receptor blocker) + Hydrochlorothiazide(thiazide diuretic) STAR: study drugs 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, andweek 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%) in2-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. **Verapamil SR/trandolapril 180/2mg (od) or 240/4mg (od) Verapamil SR/trandolapril180/2mg (od) Washout period *** * Losartan/HCTZ 50/12.5mg (od) *** **Losartan/HCTZ 50/12.5 mg (od) or 100/25mg (od) Subject screened Subject randomized End of treatment Weeks -4 0 4 12 52 STAR: study design *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 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* 160 150 Mean systolic BP 140 P=0.179 130 120 Verapamil SR/trandolapril Blood pressure (mmHg) 110 Losartan/HCTZ 100 Mean diastolic BP 90 P=0.605 80 70 60 0 2 4 6 8 12 26 39 52 End ofstudy* Time (weeks) 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 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 forverapamil 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 ** 60 Losartan/HCTZ 50 40 % of patients 30 20 10 0 End of study*** Baseline Week 2 Week 4 Week 6 Week 8 Week 12 Week 26 Week 39 Week 52 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 *P≤0.05; **P≤0.01 (between groups) ***Mean period of follow-up for OGTT was 45.5 weeks forverapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ Data on file, Abbott Laboratories.

  13. Use of concomitantantihypertensive 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* P<0.001 30 n=107 25 20 15 Change in blood glucose at 2 hours after OGTT (mg/dl) 10 Verapamil SR/trandolapril 5 Losartan/HCTZ n=108 0 -5 Baseline values:Verapamil SR/trandolapril 144mg/dlLosartan/HCTZ 142mg/dl -10 * Mean period of follow-up for OGTT was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories.

  15. Verapamil SR/trandolaprilbaseline Verapamil SR/trandolaprilend of study* 220 200 Losartan/HCTZ baseline Losartan/HCTZend of study* 180 Mean blood glucose (mg/dl) 160 140 120 100 0 30 60 90 120 Time (minutes) 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) * Mean period of follow-up was 45.5 weeks for verapamil SR/trandolapril and 48.3 weeks for losartan/HCTZ Data on file, Abbott Laboratories.

  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. n=85 30 20 n=22 10 Change in blood glucoseat 2 hours after OGTT (mg/dl) 0 Verapamil SR/trandolapril n=84 -10 Losartan/HCTZ -20 n=24 Low dosethroughout trial Low dosetitrated to high dose Low-dose combinations compared withhigh-dose combinations Data on file, Abbott Laboratories.

  18. Effect on HbA1c 6.5 P=0.027vs baseline P=0.055vs baseline n=115 P<0.001vs baseline n=97 n=112 Verapamil SR/trandolapril HbA1c (%) 6.0 n=94 n=115 Losartan/HCTZ n=109 5.5 Week 12 Week 52 End of study* 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 Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories.

  19. P=0.037 n=99 25 P=0.014 P=0.025 20 n=86 n=102 15 Verapamil SR/trandolapril Change in blood insulinat 2 hours after OGTT (µIU/ml) 10 n=100 Losartan/HCTZ 5 n=83 n=105 0 -5 -10 Week 12 Week 52 End ofstudy* Effect on blood insulin levels Baseline values:Verapamil SR/trandolapril 112µIU/mlLosartan/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 Bakris G, et al. J Clin Hypertens 2006; May(Suppl.). Data on file, Abbott Laboratories.

  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 P=0.048 30 P=0.007 25/94 20/83 25 20/93 20 Verapamil SR/trandolapril 10/72 15 % of patients Losartan/HCTZ 10/91 10 6/86 5 0 Week 12 Week 52 End ofstudy** * Fasting blood glucose ≥126mg/dl and/or2-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 Data on file, Abbott Laboratories.

  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 Data on file, Abbott Laboratories.

  22. The STAR trial: summary • STAR compared the effect of an RAS inhibitor/non-DHP CCBand 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 bothcombination 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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