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.
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Notes
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Acknowledgements
Professor Proietto is the chair of the Medical Advisory Board for Optifast for Novartis, a member of the Australian Advisory Boards for Reductil® (Abbott) and Xenical® (Roche) and on the medical advisory board for rimonabant (Sanofi-Aventis), and Professor John McNeil was a member of the Reductil® (Abbott) Advisory Board. The authors have no conflicts of interest that are directly relevant to the content of this manuscript. Funds to assist in the preparation of the review were received from Monash University, Department of Epidemiology & Preventive Medicine. No external sources of funding were obtained to assist in the preparation of this review.
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Ioannides-Demos, L.L., Proietto, J., Tonkin, A.M. et al. Safety of Drug Therapies Used for Weight Loss and Treatment of Obesity. Drug-Safety 29, 277–302 (2006). https://doi.org/10.2165/00002018-200629040-00001
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DOI: https://doi.org/10.2165/00002018-200629040-00001