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Redalyc.Update on Pharmacology of Obesity: Benefts and Risks Nutrición Hospitalaria ISSN: 0212-1611 info@nutriciónhospitalaria.com Grupo Aula Médica España Cabrerizo García, Lucio; Ramos-Leví, Ana; Moreno Lopera, Carmen; Rubio Herrera, Miguel A. Update on pharmacology of obesity: Benefts and risks Nutrición Hospitalaria, vol. 28, núm. 5, septiembre, 2013, pp. 121-127 Grupo Aula Médica Madrid, España Available in: http://www.redalyc.org/articulo.oa?id=309229028014 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative 12. Update_15. Update 29/07/13 13:24 Página 121 Nutr Hosp 2013;28(Supl. 5):121-127 ISSN (Versión papel): 0212-1611 ISSN (Versión electrónica): 1699-5198 CODEN NUHOEQ S.V.R. 318 Update on pharmacology of obesity: Benefts and risks Lucio Cabrerizo García1, Ana Ramos-Leví1, Carmen Moreno Lopera2, Miguel A. Rubio Herrera1 1 Servicio de Endocrinología y Nutrición. Hospital Clínico San Carlos. IDISSC. Facultad de Medicina. Universidad Complu - ten se. Madrid. Spain. 2 Centro de Salud Lucero. Madrid. Spain. Abstract FARMACOLOGÍA DE LA OBESIDAD AL DÍA: BENEFICIOS Y RIESGOS The prevalence of obesity in Western countries has increased at a much greater pace than the development of Resumen new efficient and safe drugs, beyond mere lifestyle chan- ges, for the treatment of overweight. Numerous different El incremento de la prevalencia de obesidad en los paí- types of drugs which had been used in the past for the tre- ses occidentales no ha sido paralela al desarrollo de nue- atment of obesity have currently been withdrawn due to vos fármacos eficaces y seguros a largo plazo para el tra- undesirable long-term side effects. The only available tamiento del exceso de peso más allá de los cambios en el drug in Europe is orlistat, which serves only as an aid for estilo de vida. La larga lista de fármacos que se han utili- the treatment of obesity. In the USA, however, a few cen- zado para el tratamiento de la obesidad han tenido que tral adrenergic-mediators, for instance, diethylpropion ser retirados por efectos secundarios indeseables para la and phentermine, have been available for decades to treat salud a largo plazo. En Europa solo contamos con orlistat, obesity during a short-term period (less than 12 weeks). como único fármaco coadyuvante para el tratamiento de The Food and Drug Administration (FDA) has recently la obesidad, mientras que en EEUU hace décadas disponen approved lorcaserin and the combination phentermine/ de unos pocos fármacos adrenérgicos de acción central topiramate for the treatment of obesity. The first one is a (como Dietilpropion o Phentermine) para un tratamiento a selective serotonin 2C receptor agonist that works by corto plazo (inferior a 12 semanas). Recientemente,la decreasing food intake with few side effects. Its outcomes Food and Drug Administration (FDA), acaba de aprobar on weight are modest, but may be helpful in certain selec- la lorcaserina y la combinación de Phentermine y topira- ted patients. The phentermine/topiramate combination mate. Lorcaserine es un agonista específico del receptor has proved to be highly effective, achieving a 10% reduc- serotoninérgico 2c, con actividad anorexígena y pocos tion in weight in the majority of patients, although atten- efectos secundarios. Sus efectos sobre el peso son modera- tion must be drawn to the possible development of side dos, pero pueden ser de utilidad en algunos pacientes effects in both the short and the long-term follow-up. seleccionados. La combinación de phentermine y topira- Further investigation regarding the mechanisms invol- mate es muy eficaz alcanzando un 10% de pérdida de ved in weight balance will anticipate the development of peso en una mayoría de pacientes, aunque debemos estar new expectations for the treatment of obesity in the near atentos acerca de sus potenciales efectos secundarios a future. corto y largo plazo. La profundización en la investigación de los mecanismos implicados en la regulación del peso Nutr Hosp 2013; 28 (Supl. 5):121-127 corporal conllevará nuevas expectativas de tratamientos Key words: Obesity. Pharmacology. Pharmacotherapy. para la obesidad en un futuro próximo. Phentermine topiramate. Lorcaserine. Nutr Hosp 2013; 28 (Supl. 5):121-127 Palabras clave: Fármacos obesidad. Combinación topira- mato-fentermina. Lorcaserina. The historical progress of drug therapy for obesity sibutramine and rimonabant, both with central and pe - has been discouraging, since no drug has achieved a ri pheral action, side effects have repeatedly outwei ghed long-term favorable benefit-risk ratio. Beginning with benefits, forcing international regulatory agencies to the first thyroid hormone extracts that were used in the subsequently proceed to their withdrawal1 (table I). late 19th century, continuing with amphetamines and With the exception of orlistat, which is still available other sympathetic-activator drugs, and the most recent for the long term treatment of obesity (> 12 months), only a few adrenergic drugs are accessible exclusively in the USA for the short-term treatment of obesity, i.e., Correspondence: Miguel A. Rubio Herrera. < 12 weeks (table II). Servicio de Endocrinología y Nutrición. Hospital Clínico San Carlos. Undoubtedly, obesity entails a major healthcare pro - Martín Lagos, s/n. blem which affects 24% of adult Spanish population2 28040 Madrid. and for which no real effective methods are available E-mail: [email protected] for its management. Conventional approaches based on 121 12. Update_15. Update 29/07/13 13:24 Página 122 Table I Table II Anorexigenic drugs used in the past for obesity Drugs approved by the FDA for weight loss and reasons for their withdrawal Generic names Trademark names Usual doses Drug Year Reason for withdrawal (year) Long-term treatment of obesity (> 12 months) Dinitrofenol 1930s Risk of neuropathy and cataracts Orlistat Xenical 120 mg, 3 times a day Anphetamines 1936 Dependency and abuse, potential cardiovascular adverse effects Sympathomimetic drugs approved for short-term treatment of obesity (< 12 weeks) Aminorex 1965 Pulmonary hypertension (1968) Diethylpropion Mazindol 1970 Discontinued 1993- (Australia) Tablets Tenuate 25 mg, TID Fenfluramine 1963 Europe Valvular heart disease. Pulmonary Extended release Tenuate 75 mg Once daily 1973 US hypertension (1997) Phentermine HCl Dexfenfluramine 1985 Europe Valvular heart disease. Pulmonary Capsules Phentridol 15-37,5 mg QD 1996 US hypertension (1997) Teramine Adipex-P Sibutramine 1997 US 2001 Europe Cardiovascular disease (2010) Tablets Tetramine Adipex-P Rimonabant 2006 Europe Severe psychiatric disorders Extended release Lonamin 15 or 30 mg/day, QD (2009) Benzphetamine Didrex 25 to 150 mg/day, in single or divided doses lifestyle interventions reach, at the most, 5-10% weight Phendimetrazine loss at 6-12 months’ follow-up, but adherence to treat- Capsules, extended Adipost 105 mg/day, in the morning ments is scarce, and weight recovery is commonly release Bontril 3 observed in the long-term. Melfial The search for a drug with the best benefit-risk ratio Prelu-2 should include the achievement of at least a 10-20% X-trozine weight loss, which would imply an intermediate effect Tablets Bontril between the modest outcomes of lifestyle interventions Obezine 35 mg, 2–3 times a day (5-10%) and those of the simplest bariatric surgery technique (20-30%). For this reason, the FDA consi - ders that a suitable drug for the treatment of obesity should comply with the following characteristics: a) a me chanism of action is related to inhibition of fat ab - significantly different weight loss (> 5%) in compar- sor ption to approximately 30% of intake.4 This action ison to placebo after one year of treatment and b) that entails the development of its well-known side effects, the number of individuals reaching > 5% weight loss is such as flatulence, increased bowel habit, voluminous at least 35% in comparison to placebo, with differences stools and steatorrhea, which may occur in up to 15- being statistically significant. In any case, drug treat- 20% of patients; but these have not frequently been a ment for obesity would be indicated in those with a reason for discontinuation of treatment. Orlistat 120 mg body mass index (BMI) ≥ 30 kg/m2 or ≥ 27 kg/m2 with TID achieves a 3% higher weight loss than placebo and obesity-associated major comorbidities. contributes to a decrease of obesity-associated meta- bolic comorbidities. Further sub-analysis demonstra - ted that 26% of those receiving orlistat lost > 10% of Commercially available drugs total body weight, whilst 30% of this group lost > 5%, for the treatment of obesity in comparison to 14% and 19% in the placebo group, respectively. The XENDOS (Xenical in the prevention In Europe, the only available drug for the treatment of diabetes in obese subjects) study, a four-year dou - of obesity is orlistat. The other ones which have been ble-blind placebo-controlled trial of 3305 non-diabetic already approved by the FDA in the USA are still under obese patients, showed that orlistat reduced the risk of evaluation by the European Medicines Agency (EMA). developing type 2 diabetes by 37.3% compared to pla - cebo (lifestyle modification).5 Orlistat is the only currently available drug whose Orlistat technical data sheet includes obesity as an indication of use. However, 32 alerts of severe hepatic failure, toge - Orlistat is a gastric and pancreatic lipase inhibitor, ther with some cases of pancreatitis and renal oxalate which was first introduced in the market in 1998. Its calculi, have decreased its popularity. 122 12. Update_15. Update 29/07/13 13:24 Página 123 Drugs that have been used to treat obesity, The FDA advisory panel voted 13 to 7 in favor of but that are not approved by regulatory agencies approval of this combination in December 2010; howe - for this purpose ver, the FDA declined to approve the drug in February 2011, claiming that cardiovascular safety should be Bupropion proved in a specific large-scale long-term trial, before it could be reconsidered for evaluation.
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