Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension.

The effect of topiramate on weight and blood pressure (BP) was examined in a randomized, placebo-controlled trial in obese subjects who had hypertension. After a 4-week, placebo, run-in period, 531 obese subjects (body mass index 27 to 50 kg/m(2)) who had established hypertension were randomly assigned to placebo or 96 or 192 mg/day of topiramate. All subjects received a standardized diet, exercise advice, and behavioral modification from run-in through study end. Initially scheduled for 60 weeks on medication, the sponsor ended the study early to develop a new controlled-release formulation. As a consequence, efficacy was assessed within a predefined modified intent-to-treat population (subjects who enrolled early enough to potentially complete 28 weeks on medication). The placebo and 96- and 192-mg groups had respective weight losses of 1.9%, 5.9%, and 6.5% from baseline (p <0.001 for each comparison with placebo) and decreases in diastolic BP of 2.1, 5.5, and 6.3 mm Hg (p <0.015 vs placebo). Systolic BP was decreased by 8.6 and 9.7 mm Hg in the 96- and 192-mg groups and 4.9 mm Hg in the placebo group (p = NS). Compared with placebo, the topiramate groups had larger proportions of subjects whose weight decreased by > or =5% and 10%, whose diastolic BP decreased by > or =5 and 10 mm Hg, and who achieved normalization of BP (BP <130/85 mm Hg). Adverse events included paresthesia, fatigue, taste perversion, loss of appetite, and difficulty with concentration and attention. In conclusion, topiramate produced clinically relevant effects in reducing body weight and BP, with generally mild to moderate adverse effects.

Antianginal efficacy of omapatrilat in patients with chronic angina pectoris.

Angiotensin-converting enzyme inhibition is not an effective antianginal therapy. Experimental data suggest that broader vasopeptidase inhibition may decrease the magnitude of demand-induced myocardial ischemia. A randomized, double-blind, placebo controlled parallel study evaluated omapatrilat, an inhibitor of angiotensin-converting enzyme and neutral endopeptidase. The primary objective was to compare maximum duration of exercise at peak plasma concentrations. Exercise treadmill studies were performed in 348 patients who had chronic angina at baseline and after 4 weeks of therapy with 80 mg/day omapatrilat or placebo. Safety data were collected and reported for all patients. Treadmill exercise duration at peak was significantly prolonged in the omapatrilat group compared with the placebo group (76.6 +/- 84.2 vs 28.7 +/- 82.2 seconds difference from baseline, p <0.001). Similar statistically significant increases were seen in time to onset of level III/IV angina and time to onset of >/=0.1-mV ST-segment depression (p <0.001). The significant improvements in exercise duration and measurements of myocardial ischemia were not sustained 20 to 28 hours after dosing. Omapatrilat was generally well tolerated in this predominantly normotensive population. The incidence of serious adverse events was 5.2% in the 2 groups. Thus, omapatrilat, an investigational vasopeptidase inhibitor, is effective in prolonging exercise duration and parameters of demand-induced myocardial ischemia in patients who have chronic angina at peak concentrations. The data confirm the proof of principle that broader vasopeptidase inhibition beyond angiotensin-converting enzyme inhibition is required to alleviate symptoms of chronic angina.