Efficacy and safety of Topiramate in the treatment of obese subjects with essential hypertension
ABSTRACT 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.
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ABSTRACT: Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.Drug Safety 02/2006; 29(4):277-302. DOI:10.2165/00002018-200629040-00001 · 2.62 Impact Factor
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ABSTRACT: Obesity is a major public health concern and environmental factors are involved in its development. The hypothalamus is a primary site for the integration of signals for the regulation of energy homeostasis. Dysregulation of these pathways can lead to weight loss or gain. Some drugs in development can have favourable effects on body weight, acting on some of these pathways and leading to responses resulting in weight loss. Strategies for the management of weight reduction include exercise, diet, behavioural therapy, drug therapy and surgery. Investigational antiobesity medications can modulate energy homeostasis by stimulating catabolic or inhibiting anabolic pathways. Investigational drugs stimulating catabolic pathways consist of leptin, agonists of melanocortin receptor-4, 5-HT and dopamine; bupropion, growth hormone fragments, cholecystokinin subtype 1 receptor agonist, peptide YY3-36, oxyntomodulin, ciliary neurotrophic factor analogue, beta3-adrenergic receptor agonists, adiponectin derivatives and glucagon-like peptide-1. On the other hand, investigational drugs inhibiting anabolic pathways consist of the ghrelin receptor, neuropeptide Y receptor and melanin-concentrating hormone-1 antagonists; somatostatin analogues, peroxisome proliferator-activated receptor-gamma and -beta/delta antagonists, gastric emptying retardation agents, pancreatic lipase inhibitors, topiramate and cannabinoid-1 receptor antagonists. These differing approaches are reviewed and commented on in this article.Expert Opinion on Investigational Drugs 09/2006; 15(8):897-915. DOI:10.1517/135437184.108.40.2067 · 5.43 Impact Factor