Tratamento farmacológico da obesidade: passado, presente e futuro.

  • Bruno Geloneze Universidade de Campinas - UNICAMP
Palavras-chave: Obesidade, diabetes, incretinas, anorexígenos, hipotálamo

Resumo

O tratamento da obesidade deve ser baseado na percepção de que a obesidade é uma enfermidade crônica, neuroquímica e recidivante. Sendo assim, a combinação de eficácia, sustentabilidade de longo prazo e perfil de segurança de excelência devem nortear a utilização dos medicamentos disponíveis assim como das novas moléculas vindouras. No momento, a liraglutida parece ser a mais completa droga para a obesidade como doença crônica, mas certamente deverá ser superada pelos novos peptídeos de múltiplo agonismo e/ou pela combinação de várias medicações ainda não disponíveis em baixas dosagens para pacientes precisa e individualmente selecionados.

Biografia do Autor

Bruno Geloneze, Universidade de Campinas - UNICAMP
Professor Livre-Docente em Endocrinologia pela UNICAMP Coordenador do Laboratório de Investigação em Metabolismo e Diabetes - LIMED - UNICAMP

Referências

Adan RA (2013) Mechanisms underlying current and future anti-obesity drugs. Trends Neurosci 36:133–140.

Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, Tsai LF, Robertson D, Jain M, Petrone M, Rondinone C, Hirshberg B, Jermutus L. (2018) MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 30;391(10140):2607-2618.

Altabas V, Zjacic-Rotkvic V. (2015) Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy. Immunotargets Ther 4:123–30.

Aronne LJ, Wadden TA, Peterson C, Winslow D, Odeh S, and Gadde KM (2013) Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring) 21:2163–2171.

Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. (2008) Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 372:1906–13.

Astrup A (2010) Drug management of obesity–efficacy versus safety. N Engl J Med 363:288–290.

Bello NT and Liang NC (2011) The use of serotonergic drugs to treat obesity–is there any hope? Drug Des Devel Ther 5:95–109.

Burke LK and Heisler LK (2015) 5-Hydroxytryptamine medications for the treatment of obesity. J Neuroendocrinol 27:389–398.

Cannistra LB, Davis SM, and Bauman AG (1997) Valvular heart disease associated with dexfenfluramine. N Engl J Med 337:636.

Centers for Disease Control and Prevention (CDC) (1997) Cardiac valvulopathy associatedwith exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 46:1061–1066.

Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. (2015). RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab; 100:1639–45.

Colman E (2005) Anorectics on trial: a half century of federal regulation of prescription appetite suppressants. Ann Intern Med 143:380–385.

Colman E (2007) Dinitrophenol and obesity: an early twentieth-century regulatory dilemma. Regul Toxicol Pharmacol 48:115–117.

Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, and Schaff HV (1997) Valvular heart disease associated with fenfluraminephentermine. N Engl J Med 337:581–588.

Costa E, Groppetti A, and Revuelta A (1971) Action of fenfluramine on monoamine stores of rat tissues. Br J Pharmacol 41:57–64.

Cota D, Tschöp MH, Horvath TL, and Levine AS (2006) Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Brain Res Rev 51:85–107.

Davies MJ, Bergenstal R, Bode B, et al. (2015) Efficacy of liraglutide for weight loss among patients with type 2 diabetes. The SCALE diabetes randomized clinical trial. JAMA 314:687-699.

Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, Findeisen H, Bruemmer D, Drucker DJ, Chaudhary N, et al. (2009) A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 5:749–757.

Després JP, Golay A, and Sjöström L; Rimonabant in Obesity-Lipids Study Group (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134.

Drent ML, Larsson I, William-Olsson T, Quaade F, Czubayko F, von Bergmann K, Strobel W, Sjöström L, and van der Veen EA (1995) Orlistat (Ro 18-0647), a lipase inhibitor, in the treatment of human obesity: a multiple dose study. Int J Obes Relat Metab Disord 19:221–226.

Dunlop DM (1934) The use of 2-4 dinitrophenol as a metabolic stimulant. BMJ 1: 524–527. Finan B, Clemmensen C, Zhu Z, Stemmer K, Gauthier K, Muller L, De Angelis M, Moreth K, Neff F, Perez-Tilve D, et al. (2016a) Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167: 843–857.e14.

Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, et al. (2015) A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 21(1):27-36.

Finer N, Craddock D, Lavielle R, and Keen H (1988) Effect of 6 months therapy with dexfenfluramine in obese patients: studies in the United Kingdom. Clin Neuropharmacol 11 (Suppl 1):S179–S186.

Fujioka K, Seaton TB, Rowe E, Jelinek CA, Raskin P, Lebovitz HE, and Weinstein SP; Sibutramine/Diabetes Clinical Study Group (2000) Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2:175–187.

Gadde KM, Yonish GM, Foust MS, Wagner HR. (2007) Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. J Clin Psychiatry; 68:1226–9.

Garattini S, Mennini T, Bendotti C, Invernizzi R, and Samanin R (1986) Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system. Appetite 7 (Suppl):15–38.

Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, and Bowden CH (2012) Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 95:297–308,

Geloneze B, de Lima-Júnior JC, Velloso LA (2017). Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain-Adipocyte Axis. Drugs. 2017;77(5):493-503

Giralt M, Gavalda-Navarro A, Villarroya F. (2015) Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol 418(Pt 1):66–73.

Götestam KG and Andersson BE (1975) Self-administration of amphetamine analogues in rats. Pharmacol Biochem Behav 3:229–233.

Grundlingh J, Dargan PI, El-Zanfaly M, and Wood DM (2011) 2,4-Dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol 7:205–212.

Harper JA, Dickinson K, and Brand MD (2001) Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev 2:255–265.

Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, and Cheetham SC (1998) Sibutramine: a novel anti-obesity drug: a review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 22 (Suppl 1):S18–S28; discussion S29.

Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, et al. (2002) Activation of central melanocortin pathways by fenfluramine. Science 297:609–611.

Holdaway IM, Wallace E, Westbrooke L, and Gamble G (1995) Effect of dexfenfluramine on body weight, blood pressure, insulin resistance and serum cholesterol in obese individuals. Int J Obes Relat Metab Disord 19:749–751.

Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, and Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271:665–668.

James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp- Pedersen C, Sharma AM, Shepherd GM, Rode RA, et al.; SCOUT Investigators (2010) Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 363:905–917.

Jones BJ and Bloom SR (2015) The new era of drug therapy for obesity: the evidence and the expectations. Drugs 75:935–945.

Khera R, Murad MH, Chandar AK, Dulai PS,Wang Z, Prokop LJ, Loomba R, Camilleri M, and Singh S (2016) Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 315: 2424–2434.

Kim DD, Krishnarajah J, Lillioja S, de Looze F, Marjason J, Proietto J, et al. (2015) Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial. Diabetes Obes Metab. 17:566–72.

Kluger AY, McCullough PA.(2018) Semaglutide and GLP-1 analogues as weight-loss agents. Lancet 392(10148):615-616

Kopelman P, Bryson A, Hickling R, Rissanen A, Rossner S, Toubro S, et al. (2007) Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes 31:494–9.

Kuo DY, Chen PN, Yu CH, Kuo MH, Hsieh YS, and Chu SC (2012) Involvement of neuropeptide Y Y1 receptor in the regulation of amphetamine-mediated appetite suppression. Neuropharmacology 63:842–850.

Kurt TL, Anderson R, Petty C, Bost R, Reed G, and Holland J (1986) Dinitrophenol in weight loss: the poison center and public health safety. Vet Hum Toxicol 28:574–575.

le Roux CW, Astrup A, Fujioka K, et al. (2017) 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: arandomized, double-blind trial. Lancet 389:1399-1409.

Lopes T, Rimland C, Nagassaki S, Geloneze B, Marsaioli A. (2013) A chemometric model applied to fatty acid determination in blood. J. Braz. Chem. Soc., Vol. 24, No. 10, 1599-1605.

MacBryde CM and Taussig BL (1935) Functional changes in liver, heart and muscle, and loss of dextrose tolerance resulting from dinitrophenol. JAMA 6:13–17.

McCone JF (1897) Thyroid extract in obesity, with report of a case. Pac Rec Med Sur 12:288–289.

McDuffie JR, Calis KA, Booth SL, Uwaifo GI, and Yanovski JA (200) Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy 22: 814–822.

Mack CM, Soares CJ, Wilson JK, Athanacio JR, Turek VF, Trevaskis JL, et al. (2010) Davalintide (AC2307), a novel amylinmimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int J Obes 34:385-95.

Monteiro MP. (2014) Obesity vaccines. Hum Vaccin Immunother. 10:887–95.

Na HN, Nam JH. (2014) Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36. Int J Obes 38:1470–4.

Perkins RG (1919) A study of munitions intoxications in France. Public Health Rep 34:2335.

Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, and Rosenstock J; RIO-North America Study Group (2006) Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295:761–775.

Powell AG, Apovian CM, Aronne LJ. (2011) New drug targets for the treatment of obesity. Clin Pharmacol Ther 90:40–51.

Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, et al. (2010) The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav 97:179–84.

Rodgers RJ, Tschöp MH, and Wilding JP (2012) Anti-obesity drugs: past, present and future. Dis Model Mech 5:621–626.

Simon V and Cota D (2017) Mechanisms in endocrinology: endocannabinoids and metabolism: past, present and future. Eur J Endocrinol 176:R309–R324.

Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, Bays H, and Shanahan WR; Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group (2010) Multicenter, placebo controlled trial of lorcaserin for weight management. N Engl J Med 363:245–256.

Tainter ML (1935) Treatment of acute dinitrophenol poisoning. JAMA 104: 1071–1072.

Tainter ML, Cutting WC, and Stockton AB (1934) Use of dinitrophenol in nutritional disorders: a critical survey of clinical results. Am J Public Health Nations Health 24:1045–1053.

Tainter ML, Stockton AB, and Cutting WC (1933) Use of dinitrophenol in obesity and related conditions. JAMA 101:1472–1475.

Tambascia MA, Geloneze B, Repetto EM, Geloneze SR, Picolo M, Magro DO (2003). Sibutramine enhances insulin sensitivity ameliorating metabolic parameters in a double-blind, randomized, placebo-controlled trial. Diabetes Obes Metab; 5(5):338-44.

Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, and Rössner S; RIO-Europe Study Group (2005) Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study Lancet 365:1389–1397.

Wadden TA, Hollander P, Klein S, et al. (2013) NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes 37(11):1443-1451.

Weintraub M, Sundaresan PR, Madan M, Schuster B, Balder A, Lasagna L, and Cox C (1992) Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 51:586–594.

Weissman NJ, Tighe JF Jr, Gottdiener JS, and Gwynne JT Sustained-Release Dexfenfluramine Study Group (1998) An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. N Engl J Med 339:725–732.

Weissman NJ, Tighe JF Jr, Gottdiener JS, and Gwynne JT (1999) Prevalence of valvular-regurgitation associated with dexfenfluramine three to five months after discontinuation of treatment. J Am Coll Cardiol 34:2088–2095.

Winslow DH, Bowden CH, DiDonato KP, and McCullough PA (2012) A randomized, double-blind, placebo-controlled study of an oral, extended-release formulation of phentermine/topiramate for the treatment of obstructive sleep apnea in obese adults. Sleep (Basel) 35:1529–1539.

Wooltorton E (2002) Obesity drug sibutramine (meridia): hypertension and cardiac arrhythmias. CMAJ 166:1307–1308.

Yukioka H. (2010). A potent and selective neuropeptide Y Y5-receptor antagonist, S-2367, as an anti-obesity agent. Nihon yakurigaku zasshi Folia Pharmacologica Japonica.; 136:270–4.

Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, Leshno M, Blendis L, Halpern Z, and Oren R (2006) A double-blind randomized placebo controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 4:639–644.

Publicado
2019-04-04
Como Citar
Geloneze, B. (2019). Tratamento farmacológico da obesidade: passado, presente e futuro. HU Revista, 44(2), 261 - 268. https://doi.org/10.34019/1982-8047.2018.v44.13989
Seção
Artigos de Revisão da Literatura