Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry.
References
[1]
Global Strategy on Diet, Physical Activity and Health; World Health Organization: Geneva, Switzerland, 2010. Available online: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/print.html/ (accessed on 12 June 2010).
[2]
Flegal, K.M.; Graubard, B.I.; Williamson, D.F.; Gail, M.H. Cause specific excess deaths associated with underweight, overweight and obesity. J. Am. Med. Assoc.?2007, 298, 2028–2037, doi:10.1001/jama.298.17.2028.
[3]
Douketis, J.D.; Macie, C.; Thabane, L.; Williamson, D.F. Systematic review of long-term weight loss studies in obese adults: Clinical significance and applicability to clinical practice. Int. J. Obes. (Lond.)?2005, 29, 1153–1167, doi:10.1038/sj.ijo.0802982.
[4]
Rucker, D.; Padwal, R.; Li, S.K.; Curioni, C.; Lau, D.C.W. Long term pharmacotherapy for obesity and overweight: Updated meta-analysis. Br. Med. J.?2007, 335, 1194–1199, doi:10.1136/bmj.39385.413113.25.
[5]
Bray, G.A. Lifestyle and pharmacological approaches to weight loss: Efficacy and safety. J. Clin. Endocrinol. Metab.?2008, 93, S81–S88, doi:10.1210/jc.2008-1294. 18987274
[6]
Cercato, C.; Roizenblatt, V.A.; Lean?a, C.C.; Segal, A.; Lopes Filho, A.P.; Mancini, M.C.; Halpern, A. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects. Int. J. Obes.?2009, 33, 857–865, doi:10.1038/ijo.2009.124.
[7]
Padwal, R.; Kezouh, A.; Levine, M.; Etminan, M. Long-term persistence with orlistat and sibutramine in a population based cohort. Int. J. Obes.?2007, 31, 1567–1570, doi:10.1038/sj.ijo.0803631.
[8]
Sj?str?m, L.; Narbro, K.; Sj?str?m, C.D.; Karason, K.; Larsson, B.; Wedel, H.; Lystig, T.; Sullivan, M.; Bouchard, C.; Carlsson, B.; Bengtsson, C.; Dahlgren, S.; Gummesson, A.; Jacobson, P.; Karlsson, J.; Lindroos, A.K.; L?nroth, H.; N?slund, I.; Olbers, T.; Stenl?f, K.; Torgerson, J.; Agren, G.; Carlsson, L.M.; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med.?2007, 357, 741–752. 17715408
[9]
U.S. Food and Drug Administration (FDA). Follow-Up to the November 2009 Early Communication about an Ongoing Safety Review of Sibutramine, Marketed as Meridia, 2009. Available online: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/DrugSafetyInformationforHeathcareProfessionals/ucm198206.htm/ (accessed on 12 June 2010).
[10]
Halpern, A.; Pepe, R.B.; Monegaglia, A.P.; Beyruti, M.; de Melo, M.E.; Mancini, M.C. Efficacy and tolerability of the association of sibutramine and orlistat for 6 months in overweight and obese patients. J. Obes.?2010.
[11]
Hendricks, E.J.; Rothman, R.B.; Greenway, F.L. How physician obesity specialists use drugs to treat obesity. Obesity (Silver Springs)?2009, 17, 1730–1735, doi:10.1038/oby.2009.69.
Munro, J.F.; MacCuish, A.C.; Wilson, E.M.; Duncan, L.J.P. Comparison of continuous and intermittent anorectic therapy in obesity. Br. Med. J.?1968, 1, 352–354, doi:10.1136/bmj.1.5588.352. 15508204
[14]
Truant, A.P.; Olon, L.P.; Cobb, S. Phentermine resin as an adjunct in medical weight reduction: A controlled randomized, double-blind prospective study. Curr. Ther. Res. Clin. Exp.?1972, 14, 726–738. 4629111
[15]
Halford, J.C.G.; Harrold, J.A.; Boyland, E.J.; Lawton, C.L.; Blundell, J.E. Serotonergic drugs: Effects on appetite expression and use for the treatment of obesity. Drugs?2007, 67, 27–55, doi:10.2165/00003495-200767010-00004. 17209663
[16]
Guy-Grand, B.; Apfelbaum, M.; Crepaldi, G.; Gries, A.; Lefebvre, P.; Turner, P. International trial of long-term dexfenfluramine in obesity. Lancet?1989, II, 1142–1145.
[17]
Weintraub, M.; Hasday, J.D.; Mushlin, A.I.; Lockwood, D.H. A double-blind clinical trial in weight control: Use of fenfluramine and phentermine alone or in combination. Arch. Intern. Med.?1984, 144, 1143–1148, doi:10.1001/archinte.1984.00350180055008. 6375610
[18]
Connolly, H.M.; Crary, J.L.; McGoon, M.D. Valvular heart disease associated with fenfluramine-phentermine. N. Engl. J. Med.?1997, 337, 581–588, doi:10.1056/NEJM199708283370901. 9271479
[19]
Astrup, A.; Toubro, S.; Christensen, N.; Quaade, F. Pharmacology of thermogenic drugs. Am. J. Clin. Nutr.?1992, 55, 246S–248S. 1345887
Astrup, A.; Breum, L.; Toubro, S.; Hein, P.; Quaade, F. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine an placebo in obese subjects on an energy restricted diet. A double-blind trial. Int. J. Obes. Relat. Metab. Disord.?1992, 16, 269–277. 1318281
[22]
Shekelle, P.G.; Hardy, M.L.; Morton, S.C.; Maglione, M.; Mojica, M.A.; Suttorp, M.J.; Rhodes, S.L.; Jungvig, L.; Gagné, J. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: A meta-analysis. J. Am. Med. Assoc.?2003, 289, 1537–1545.
[23]
McBride, B.F.; Karapanos, A.K.; Krudysz, A.; Kluger, J.; Coleman, C.I.; White, C.M. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: A randomized controlled trial. J. Am. Med. Assoc.?2004, 291, 216–221, doi:10.1001/jama.291.2.216.
[24]
Connoley, I.P.; Liu, Y.L.; Frost, I.; Reckless, I.P.; Heal, D.J.; Stock, M.J. Thermogenic effects of sibutramine and its metabolites. Br. J. Pharmacol.?1999, 126, 1487–1495, doi:10.1038/sj.bjp.0702446. 10217544
[25]
Mancini, M.C.; Halpern, A. Orlistat in the prevention of diabetes in the obese patient. Vasc. Health Risk Manag.?2008, 4, 325–336. 18561508
[26]
Wadden, T.A.; Berkowits, R.I.; Wonble, L.G. Effects of sibutramine plus orlistat in obese women following 1 year of treatment by sibutramine alone: A placebo controlled trial. Obes. Res.?2000, 6, 431–437.
[27]
Kaya, A.; Aydin, N.; Topsever, P.; Filiz, M.; ?ztürk, A.; Da?ar, A.; K?l?n?, E.; Ekmekcioglu, C. Efficacy of sibutramine, orlistat and combination therapy on short-term weight management in obese patients. Biomed. Pharmacother.?2004, 58, 582–587. 15589067
[28]
Sari, R.; Balci, M.K.; Cakir, M.; Altunbas, H.; Karayalcin, U. Comparison of efficacy of sibutramine or orlistat versus their combination in obese women. Endocr. Res.?2004, 30, 159–167. 15473126
[29]
Bray, G.A. Is new hope on the horizon for obesity? Lancet?2008, 372, 1859–1860, doi:10.1016/S0140-6736(08)61792-4. 19041787
[30]
Greenway, F.L.; Bray, G.A. Combination drugs for treating obesity. Curr. Diab. Rep.?2010, 10, 108–115, doi:10.1007/s11892-010-0096-4. 20425569
[31]
Sari, R.; Balci, M.K.; Coban, E.; Yazicioglu, G. Comparison of the effect of orlistat vs orlistat plus metformin on weight loss and insulin resistance in obese women. Int. J. Obes. Relat. Metab. Disord.?2004, 28, 1059–1063, doi:10.1038/sj.ijo.0802707. 15211369
[32]
Knowler, W.C.; Barrett-Connor, E.; Fowler, S.E. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med.?2002, 346, 393–403, doi:10.1056/NEJMoa012512. 11832527
[33]
Contrave and Empatic. Orexigen Therapeutics, Inc. Available online: http://www.orexigen.com/ (accessed on 16 Mar 2010).
[34]
Anderson, J.W.; Greenway, F.L.; Fujioka, K. Bupropion SR enhances weight loss: A 48-week double-blind, placebo- controlled trial. Obes. Res.?2002, 10, 633–641, doi:10.1038/oby.2002.86. 12105285
[35]
Lee, M.W.; Fujioka, K. Naltrexone for the treatment of obesity: Review and update. Expert Opin. Pharmacother.?2009, 10, 1841–1845, doi:10.1517/14656560903048959. 19537999
[36]
Grill, H.J. Leptin and the systems neuroscience of meal size control. Front Neuroendocrinol.?2010, 31, 61–78, doi:10.1016/j.yfrne.2009.10.005. 19836413
[37]
Cummings, D.E.; Overduin, J. Gastrointestinal regulation of food intake. J. Clin. Invest.?2007, 117, 13–23, doi:10.1172/JCI30227. 17200702
[38]
Greenway, F.L.; Whitehouse, M.J.; Guttadauria, M.; Anderson, J.W.; Atkinson, R.L.; Fujioka, K.; Gadde, K.M.; Gupta, A.K.; O’Neil, P.; Schumacher, D.; Smith, D.; Dunayevich, E.; Tollefson, G.D.; Weber, E.; Cowley, M.A. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Springs)?2009, 17, 30–39, doi:10.1038/oby.2008.461.
[39]
Padwal, R. Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Curr. Opin. Investig. Drugs?2009, 10, 1117–1125. 19777400
[40]
Greenway, F.L.; Dunayevich, E.; Tollefson, G.; Erickson, J.; Guttadauria, M.; Fujioka, K.; Cowley, M.A.; NB-201 Study Group. Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. J. Clin. Endocrinol. Metab.?2009, 94, 4898–4906. 19846734
[41]
Oommen, K.J.; Mathews, S. Zonisamide: A new antiepileptic drug. Clin. Neuropharmacol.?1999, 22, 192–200. 10442247
[42]
Gadde, K.M.; Franciscy, D.M.; Wagner, H.R., 2nd; Krishnan, K.R. Zonisamide for weight loss in obese adults: A randomized controlled trial. J. Am. Med. Assoc.?2003, 289, 1820–1825, doi:10.1001/jama.289.14.1820.
[43]
McElroy, S.L.; Kotwal, R.; Guerdjikova, A.I.; Welge, J.A.; Nelson, E.B.; Lake, K.A.; D’alessio, D.A.; Keck, P.E.; Hudson, J.I. Zonisamide in the treatment of binge eating disorder with obesity: A randomized controlled trial. J. Clin. Psychiatry.?2006, 67, 1897–1906, doi:10.4088/JCP.v67n1209. 17194267
[44]
Astrup, A.; Toubro, S. Topiramate: A new potential pharmacological treatment for obesity. Obes. Res.?2004, 12, 167S–173S, doi:10.1038/oby.2004.284. 15687413
[45]
Leombruni, P.; Lavagnino, L.; Fassino, S. Treatment of obese patients with binge eating disorder using topiramate: A review. Neuropsychiatr. Dis. Treat.?2009, 5, 385–392. 19649212
[46]
Vivus, Inc. Qnexa Obesity, Available online: http://www.vivus.com/pipeline/qnexa-obesity/ (accessed on 16 Mar 2010).
[47]
Woods, S.C.; D′Alessio, D.A. Central Control of Body Weight and Appetite. J. Clin. Endocrinol. Metab.?2008, 93, S37–S50, doi:10.1210/jc.2008-1630. 18987269
[48]
Ravussin, E.; Smith, S.R.; Mitchell, J.A.; Shringarpure, R.; Shan, K.; Maier, H.; Koda, J.E.; Weyer, C. Enhanced weight loss with pramlintide/metreleptin: An integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring)?2009, 17, 1736–1743, doi:10.1038/oby.2009.184.
[49]
Smith, S.R.; Aronne, L.J.; Burns, C.M.; Kesty, N.C.; Halseth, A.E.; Weyer, C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care?2008, 31, 1816–1823, doi:10.2337/dc08-0029. 18753666
[50]
Heymsfield, S.B.; Greenberg, A.S.; Fujioka, K.; Dixon, R.M.; Kushner, R.; Hunt, T.; Lubina, J.A.; Patane, J.; Self, B.; Hunt, P.; McCamish, M. Recombinant leptin for weight loss in obese and lean adults: A randomized, controlled, dose-escalation trial. J. Am. Med. Assoc.?1999, 282, 1568–75, doi:10.1001/jama.282.16.1568.
[51]
Rosenbaum, M.; Goldsmith, R.; Bloomfield, D.; Magnano, A.; Weimer, L.; Heymsfield, S.; Gallagher, D.; Mayer, L.; Ellen, M.; Leibel, R.L. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest.?2005, 115, 3579–3586, doi:10.1172/JCI25977. 16322796
Aronne, L.J.; Halseth, A.; Burns, C.; Miller, S.; Shen, L.Z. Enhanced weight loss following co-administration of pramlintide with sibutramine or phentermine in obese subjects. Obesity (Silver Spring)?2010.
[54]
Turton, M.D.; O’Shea, D.; Gunn, I.; Beak, S.A.; Edwards, C.M.B.; Meeran, K.; Choi, S.J.; Taylor, G.M.; Heath, M.M.; Lambert, P.D.; Wilding, J.P.H.; Smith, D.M.; Ghatei, M.A.; Herbert, J.; Bloom, S.R. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature?1996, 379, 69–72. 8538742
[55]
Zander, M.; Madsbad, S.; Madsen, J.L.; Holst, J.J. Effect of 6-week course of glucagon-like peptide-1 on glycaemic control, insulin sensivity, and β-cell function in type 2 diabetes: A parallel group study. Lancet?2002, 359, 824–830, doi:10.1016/S0140-6736(02)07952-7. 11897280
[56]
DeFronzo, R.A.; Ratner, R.E.; Han, J.; Kim, D.D.; Fineman, M.S.; Baron, A.D. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care?2005, 28, 1092–1100, doi:10.2337/diacare.28.5.1092. 15855572
[57]
Astrup, A.; R?ssner, S.; van Gaal, L.; Rissanen, A. NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet?2009, 374, 1606–1616. 19853906
[58]
Adran, T.E.; Ferri, G.L.; Bacarese-Hamilton, A.J.; Fuessl, H.S.; Polak, J.M.; Bloom, S.R. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology?1985, 89, 1070–1077. 3840109
[59]
Batterham, R.L.; Cohen, M.A.; Ellis, S.M.; Le Roux, C.W.; Withers, D.J.; Frost, G.S.; Ghatei, M.A.; Blook, S.R. Inhibition of food intake in obese subjects by peptide YY 3-36. N. Engl. J. Med.?2003, 349, 941–948, doi:10.1056/NEJMoa030204. 12954742
[60]
Emisphere Technologies, Inc. Emisphere Technologies Reports Encouraging Data from Independent Clinical Study Assessing the Effects of Oral GLP-1 e PYY3-36, Combined with Eligen, June 2009. Available online: http://ir.emisphere.com/releasedetail.cfm?-ReleaseID=385806/ (accessed on 12 June 2010).
[61]
Turner, E.H.; Loftis, J.M.; Blackwell, A.D. Serotonin a la carte: Supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol. Ther.?2006, 109, 325–338, doi:10.1016/j.pharmthera.2005.06.004. 16023217
[62]
Rothman, R.B. Treatment of obesity with “combination” pharmacotherapy. Am. J. Ther.?2009.
[63]
Jackson, C.W.; Cates, M.; Lorenz, R. Pharmacotherapy of eating disorders. Nutr. Clin. Pract.?2010, 25, 143–159, doi:10.1177/0884533610362239. 20413695
[64]
Berkowitz, R.I.; Fabricatore, A.N. Obesity, psychiatric status, and psychiatric medications. Psychiatr. Clin. North Am.?2005, 28, 39–54, doi:10.1016/j.psc.2004.10.005. 15733610