Pharmacotherapy for obesity: a field in crisis?

References

• Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA289(1), 76–79 (2003).
   PubMed Web of Science ®Google Scholar
• Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. JAMA303(3), 235–241 (2010).
   PubMed Web of Science ®Google Scholar
• Wu T, Gao X, Chen M, Van Dam RM. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes. Rev.10(3), 313–323 (2009).
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on clinical evaluation of medicinal products used in weight control (CPMP/EWP/281/96 Rev. 1). London, UK, 15 November 2007. Doc. Ref. EMEA/CHMP/EWP/517497/2007 (2007).
   Google Scholar
• Rossner S, Sjostrom L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes. Res.8(1), 49–61 (2000).
   PubMedGoogle Scholar
• Heymsfield SB, Segal KR, Hauptman J et al. Effects of weight loss with orlistat on glucose tolerance and progression to Type 2 diabetes in obese adults. Arch. Intern. Med.160(9), 1321–1326 (2000).
   PubMed Web of Science ®Google Scholar
• Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of Type 2 diabetes in obese patients. Diabetes Care27(1), 155–161 (2004).
   PubMed Web of Science ®Google Scholar
• Field BC, Chaudhri OB, Bloom SR. Bowels control brain: gut hormones and obesity. Nat. Rev. Endocrinol.6(8), 444–453 (2010).
   PubMed Web of Science ®Google Scholar
• Balthasar N, Dalgaard LT, Lee CE et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell123(3), 493–505 (2005).
   PubMed Web of Science ®Google Scholar
• Gropp E, Shanabrough M, Borok E et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci.8(10), 1289–1291 (2005).
   PubMed Web of Science ®Google Scholar
• Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature443(7109), 289–295 (2006).
   PubMed Web of Science ®Google Scholar
• Keen-Rhinehart E, Bartness TJ. NPY Y1 receptor is involved in ghrelin- and fasting-induced increases in foraging, food hoarding, and food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol.292(4), R1728–R1737 (2007).
   Google Scholar
• Berthoud HR, Morrison C. The brain, appetite, and obesity. Annu. Rev. Psychol.59, 55–92 (2008).
   PubMed Web of Science ®Google Scholar
• Huszar D, Lynch CA, Fairchild-Huntress V et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell88(1), 131–141 (1997).
   PubMed Web of Science ®Google Scholar
• Farooqi S, O’Rahilly S. Genetics of obesity in humans. Endocr. Rev.27(7), 710–718 (2006).
   PubMed Web of Science ®Google Scholar
• Krishna R, Gumbiner B, Stevens C et al. Potent and selective agonism of the melanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects: energy intake predicts lack of weight loss efficacy. Clin. Pharmacol. Ther.86(6), 659–666 (2009).
   PubMed Web of Science ®Google Scholar
• Heisler LK, Jobst EE, Sutton GM et al. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron51(2), 239–249 (2006).
   PubMed Web of Science ®Google Scholar
• Clifton PG, Kennett GA. Monoamine receptors in the regulation of feeding behaviour and energy balance. CNS Neurol. Disord. Drug Targets5(3), 293–312 (2006).
   PubMedGoogle Scholar
• Rolls BJ, Shide DJ, Thorwart ML, Ulbrecht JS. Sibutramine reduces food intake in non-dieting women with obesity. Obes. Res.6(1), 1–11 (1998).
   PubMedGoogle Scholar
• Barkeling B, Elfhag K, Rooth P, Rossner S. Short-term effects of sibutramine (Reductil) on appetite and eating behaviour and the long-term therapeutic outcome. Int. J. Obes. Relat. Metab. Disord.27(6), 693–700 (2003).
   PubMedGoogle Scholar
• James WP, Caterson ID, Coutinho W et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N. Engl. J. Med.363(10), 905–917 (2010).
   PubMed Web of Science ®Google Scholar
• Thatte U. NS-2330 (Neurosearch). Curr. Opin. Investig. Drugs2(11), 1592–1594 (2001).
   PubMedGoogle Scholar
• Astrup A, Meier DH, Mikkelsen BO, Villumsen JS, Larsen TM. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity16(6), 1363–1369 (2008).
   PubMed Web of Science ®Google Scholar
• Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet372(9653), 1906–1913 (2008).
   PubMed Web of Science ®Google Scholar
• Lehr T, Staab A, Tillmann C et al. Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic–pharmacodynamic modelling approach. Br. J. Pharmacol.153(1), 164–174 (2008).
   PubMed Web of Science ®Google Scholar
• Nisoli E, Carruba MO. An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action. Obes. Rev.1(2), 127–139 (2000).
   PubMedGoogle Scholar
• Willett F, Curzen N, Adams J, Armitage M. Coronary vasospasm induced by subcutaneous sumatriptan. BMJ304(6839), 1415 (1992).
   PubMed Web of Science ®Google Scholar
• Lloyd DK, Simmons V. Adverse reactions associated with sumatriptan. Lancet341(8852), 1091–1092 (1993).
   Google Scholar
• Ottervanger JP, Stricker BH. Sumatriptan and chest pain. Lancet342(8864), 176 (1993).
   PubMedGoogle Scholar
• Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H. Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacol. Ther.117(2), 207–231 (2008).
   PubMed Web of Science ®Google Scholar
• Fitzgerald LW, Burn TC, Brown BS et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol. Pharmacol.57(1), 75–81 (2000).
   PubMed Web of Science ®Google Scholar
• Goodall EM, Cowen PJ, Franklin M, Silverstone T. Ritanserin attenuates anorectic, endocrine and thermic responses to D-fenfluramine in human volunteers. Psychopharmacology112(4), 461–466 (1993).
   PubMedGoogle Scholar
• Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med.144(6), 1143–1148 (1984).
   PubMed Web of Science ®Google Scholar
• Connolly HM, Crary JL, Mcgoon MD et al. Valvular heart disease associated with fenfluramine-phentermine. N. Engl. J. Med.337(9), 581–588 (1997).
   PubMed Web of Science ®Google Scholar
• Abenhaim L, Moride Y, Brenot F et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N. Engl. J. Med.335(9), 609–616 (1996).
   PubMed Web of Science ®Google Scholar
• Launay JM, Herve P, Peoc’h K et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med.8(10), 1129–1135 (2002).
   PubMed Web of Science ®Google Scholar
• Rutz S, Riegert C, Rothmaier AK, Jackisch R. Presynaptic modulation of 5-HT release in the rat septal region. Neuroscience146(2), 643–658 (2007).
   PubMedGoogle Scholar
• Smith SR, Weissman NJ, Anderson CM et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med.363(3), 245–256 (2010).
   PubMed Web of Science ®Google Scholar
• Erondu N, Gantz I, Musser B et al. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell Metab.4(4), 275–282 (2006).
   PubMed Web of Science ®Google Scholar
• Antal-Zimanyi I, Bruce MA, Leboulluec KL et al. Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y(1) receptor antagonist. Eur. J. Pharmacol.590(1–3), 224–232 (2008).
   PubMedGoogle Scholar
• Chen X, Dimaggio DA, Han SP, Westfall TC. Autoreceptor-induced inhibition of neuropeptide Y release from PC-12 cells is mediated by Y2 receptors. Am. J. Physiol.273(4 Pt 2), H1737–H1744 (1997).
   Google Scholar
• Batterham RL, Cowley MA, Small CJ et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature418(6898), 650–654 (2002).
   PubMed Web of Science ®Google Scholar
• Abbott CR, Monteiro M, Small CJ et al. The inhibitory effects of peripheral administration of peptide YY(3–36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal–brainstem–hypothalamic pathway. Brain Res.1044(1), 127–131 (2005).
   PubMed Web of Science ®Google Scholar
• Koda S, Takeda S, Onimaru H, Akada S, Sakamoto A. Cannabinoid suppressed bicuculline-induced convulsion without respiratory depression in the brainstem-spinal cord preparation from newborn rats. Biomed. Res.26(6), 241–247 (2005).
   PubMedGoogle Scholar
• Korner J, Inabnet W, Febres G et al. Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int. J. Obes.33(7), 786–795 (2009).
   PubMed Web of Science ®Google Scholar
• Batterham RL, Cohen MA, Ellis SM et al. Inhibition of food intake in obese subjects by peptide YY3–36. N. Engl. J. Med.349(10), 941–948 (2003).
   PubMed Web of Science ®Google Scholar
• Degen L, Oesch S, Casanova M et al. Effect of peptide YY3–36 on food intake in humans. Gastroenterology129(5), 1430–1436 (2005).
   PubMed Web of Science ®Google Scholar
• Gantz I, Erondu N, Mallick M et al. Efficacy and safety of intranasal peptide YY3–36 for weight reduction in obese adults. J. Clin. Endocrinol. Metab.92(5), 1754–1757 (2007).
   PubMed Web of Science ®Google Scholar
• Le Roux CW, Borg CM, Murphy KG, Vincent RP, Ghatei MA, Bloom SR. Supraphysiological doses of intravenous PYY3–36 cause nausea, but no additional reduction in food intake. Ann. Clin. Biochem.45(Pt 1), 93–95 (2008).
   PubMed Web of Science ®Google Scholar
• Dumont Y, Martel JC, Fournier A, St-Pierre S, Quirion R. Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues. Prog. Neurobiol.38(2), 125–167 (1992).
   PubMed Web of Science ®Google Scholar
• Flood JF, Morley JE. Dissociation of the effects of neuropeptide Y on feeding and memory: evidence for pre- and postsynaptic mediation. Peptides10(5), 963–966 (1989).
   PubMedGoogle Scholar
• Jacques D, Abdel-Samad D. Neuropeptide Y (NPY) and NPY receptors in the cardiovascular system: implication in the regulation of intracellular calcium. Can. J. Physiol. Pharmacol.85(1), 43–53 (2007).
   PubMedGoogle Scholar
• Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J. Comp. Neurol.403(2), 261–280 (1999).
   PubMed Web of Science ®Google Scholar
• Larsen PJ, Fledelius C, Knudsen LB, Tang-Christensen M. Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes50(11), 2530–2539 (2001).
   PubMed Web of Science ®Google Scholar
• Turton MD, O’Shea D, Gunn I et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature379(6560), 69–72 (1996).
   PubMed Web of Science ®Google Scholar
• Tang-Christensen M, Larsen PJ, Goke R et al. Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am. J. Physiol.271(4 Pt 2), R848–R856 (1996).
   PubMed Web of Science ®Google Scholar
• Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in Type 2 diabetes: a parallel-group study. Lancet359(9309), 824–830 (2002).
   PubMed Web of Science ®Google Scholar
• Ratner RE, Maggs D, Nielsen LL et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with Type 2 diabetes mellitus. Diabetes Obes. Metab.8(4), 419–428 (2006).
   PubMed Web of Science ®Google Scholar
• Riddle MC, Henry RR, Poon TH et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with Type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab. Res. Rev.22(6), 483–491 (2006).
   PubMed Web of Science ®Google Scholar
• Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with Type 2 diabetes. Diabetes Care27(11), 2628–2635 (2004).
   PubMed Web of Science ®Google Scholar
• Defronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with Type 2 diabetes. Diabetes Care28(5), 1092–1100 (2005).
   PubMed Web of Science ®Google Scholar
• Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in Type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care32(1), 84–90 (2009).
   PubMed Web of Science ®Google Scholar
• Zinman B, Gerich J, Buse JB et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with Type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care32(7), 1224–1230 (2009).
   PubMed Web of Science ®Google Scholar
• Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride monotherapy for Type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet373(9662), 473–481 (2009).
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Buse JB, Taylor K et al. Exenatide once weekly versus twice daily for the treatment of Type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet372(9645), 1240–1250 (2008).
   PubMed Web of Science ®Google Scholar
• Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with Type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet375(9733), 2234–2243 (2010).
   PubMed Web of Science ®Google Scholar
• Skyler JS, Bergenstal R, Bonow RO et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation119(2), 351–357 (2009).
   PubMed Web of Science ®Google Scholar
• Bergenstal RWC, Yan P, Macconell L, Malloy J, Porter L. DURATION-2: exenatide once weekly demonstrated superior glycemic control and weight reduction compared with sitagliptin or pioglitazone after 26 weeks of treatment. Presented at: American Diabetes Association 2009 Scientific Sessions. New Orleans, LA, USA, 7 June 2009.
   Google Scholar
• Sebokova E, Benardeau A, Sprecher U, Sewing S, Tobalina L, Migliorini C. Taspoglutide, a novel human once-weekly analogue of glucagon-like peptide-1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat. Diabetes Obes. Metab.12(8), 674–682 (2010).
   PubMedGoogle Scholar
• Ratner R, Nauck M, Kapitza C, Asnaghi V, Boldrin M, Balena R. Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study. Diabet. Med.27(5), 556–562 (2010).
   PubMed Web of Science ®Google Scholar
• Kolterman OG, Kim DD, Shen L et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with Type 2 diabetes mellitus. Am. J. Health Syst. Pharm.62(2), 173–181 (2005).
   PubMed Web of Science ®Google Scholar
• Astrup A, Rossner S, Van Gaal L et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet374(9701), 1606–1616 (2009).
   PubMed Web of Science ®Google Scholar
• Byetta® package insert. Amylin Pharmaceuticals, Inc., San Diego, CA, USA (2007).
   Google Scholar
• Bjerre Knudsen L, Madsen LW, Andersen S et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology151(4), 1473–1486 (2010).
   PubMed Web of Science ®Google Scholar
• Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide – the FDA’s review of a new antidiabetic therapy. N. Engl. J. Med.362(9), 774–777 (2010).
   PubMed Web of Science ®Google Scholar
• Victoza® (liraglutide [rDNA origin] injection) Prescribing Information. Novo Nordisk A/S, Princeton, NJ, USA (2011).
   Google Scholar
• Baggio LL, Huang Q, Brown TJ, Drucker DJ. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology127(2), 546–558 (2004).
   PubMed Web of Science ®Google Scholar
• Dakin CL, Gunn I, Small CJ et al. Oxyntomodulin inhibits food intake in the rat. Endocrinology142(10), 4244–4250 (2001).
   PubMed Web of Science ®Google Scholar
• Dakin CL, Small CJ, Park AJ, Seth A, Ghatei MA, Bloom SR. Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. Am. J. Physiol. Endocrinol. Metab.283(6), E1173–E1177 (2002).
   Google Scholar
• Dakin CL, Small CJ, Batterham RL et al. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology145(6), 2687–2695 (2004).
   PubMed Web of Science ®Google Scholar
• Cohen MA, Ellis SM, Le Roux CW et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J. Clin. Endocrinol. Metab.88(10), 4696–4701 (2003).
   PubMed Web of Science ®Google Scholar
• Wynne K, Park AJ, Small CJ et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes54(8), 2390–2395 (2005).
   PubMed Web of Science ®Google Scholar
• Wynne K, Park AJ, Small CJ et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int. J. Obes.30(12), 1729–1736 (2006).
   PubMed Web of Science ®Google Scholar
• Kerr BD, Flatt PR, Gault VA. (D-Ser2)Oxm[mPEG-PAL]: a novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions. Biochem. Pharmacol.80(11), 1727–1735 (2010).
   PubMedGoogle Scholar
• Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron69(4), 664–679 (2011).
   PubMed Web of Science ®Google Scholar
• Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br. J. Pharmacol.134(6), 1151–1154 (2001).
   PubMed Web of Science ®Google Scholar
• Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol.136(4), 550–557 (2002).
   PubMed Web of Science ®Google Scholar
• Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. 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. Lancet365(9468), 1389–1397 (2005).
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with Type 2 diabetes: a randomised controlled study. Lancet368(9548), 1660–1672 (2006).
   PubMed Web of Science ®Google Scholar
• Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. 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. JAMA295(7), 761–775 (2006).
   PubMed Web of Science ®Google Scholar
• Blundell JE. Perspective on the central control of appetite. Obesity14(Suppl. 4), 160S–163S (2006).
   Google Scholar
• Van Gaal LF, Scheen AJ, Rissanen AM, Rossner S, Hanotin C, Ziegler O. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur. Heart J.29(14), 1761–1771 (2008).
   PubMed Web of Science ®Google Scholar
• Addy C, Wright H, Van Laere K et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab.7(1), 68–78 (2008).
   PubMed Web of Science ®Google Scholar
• Addy C, Li S, Agrawal N et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J. Clin. Pharmacol.48(4), 418–427 (2008).
   PubMed Web of Science ®Google Scholar
• Addy C, Rothenberg P, Li S et al. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers. J. Clin. Pharmacol.48(6), 734–744 (2008).
   PubMed Web of Science ®Google Scholar
• Aronne LJ, Tonstad S, Moreno M et al. A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int. J. Obes.34(5), 919–935 (2010).
   Web of Science ®Google Scholar
• Proietto J, Rissanen A, Harp JB et al. A clinical trial assessing the safety and efficacy of the CB1R inverse agonist taranabant in obese and overweight patients: low-dose study. Int. J. Obes.34(8), 1243–1254 (2010).
   Web of Science ®Google Scholar
• Kipnes MS, Hollander P, Fujioka K et al. A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with Type 2 diabetes. Diabetes Obes. Metab.12(6), 517–531 (2010).
   PubMed Web of Science ®Google Scholar
• Gadde KM, Franciscy DM, Wagner HR 2nd, Krishnan KR. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA289(14), 1820–1825 (2003).
   PubMed Web of Science ®Google Scholar
• Van Ameringen M, Mancini C, Pipe B, Campbell M, Oakman J. Topiramate treatment for SSRI-induced weight gain in anxiety disorders. J. Clin. Psychiatry63(11), 981–984 (2002).
   PubMedGoogle Scholar
• Bray GA, Hollander P, Klein S et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes. Res.11(6), 722–733 (2003).
   PubMedGoogle Scholar
• Zernig G, De Wit H, Telser S et al. Subjective effects of slow-release bupropion versus caffeine as determined in a quasi-naturalistic setting. Pharmacology70(4), 206–215 (2004).
   PubMed Web of Science ®Google Scholar
• Okada M, Kaneko S, Hirano T et al. Effects of zonisamide on dopaminergic system. Epilepsy Res.22(3), 193–205 (1995).
   PubMed Web of Science ®Google Scholar
• Okada M, Hirano T, Kawata Y et al. Biphasic effects of zonisamide on serotonergic system in rat hippocampus. Epilepsy Res.34(2–3), 187–197 (1999).
   PubMed Web of Science ®Google Scholar
• Gadde KM, Yonish GM, Foust MS, Wagner HR. Combination therapy of zonisamide and bupropion for weight reduction in obese women: a preliminary, randomized, open-label study. J. Clin. Psychiatry68(8), 1226–1229 (2007).
   PubMed Web of Science ®Google Scholar
• Roose SP, Dalack GW, Glassman AH, Woodring S, Walsh BT, Giardina EG. Cardiovascular effects of bupropion in depressed patients with heart disease. Am. J. Psychiatry148(4), 512–516 (1991).
   PubMed Web of Science ®Google Scholar
• Aubin HJ. Tolerability and safety of sustained-release bupropion in the management of smoking cessation. Drugs62(Suppl. 2), 45–52 (2002).
   PubMed Web of Science ®Google Scholar
• Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf.30(7), 555–567 (2007).
   PubMed Web of Science ®Google Scholar
• Ohtahara S, Yamatogi Y. Safety of zonisamide therapy: prospective follow-up survey. Seizure13(Suppl. 1), S50–S55; discussion S56 (2004).
   PubMed Web of Science ®Google Scholar
• Greenway FL, Whitehouse MJ, Guttadauria M et al. Rational design of a combination medication for the treatment of obesity. Obesity17(1), 30–39 (2009).
   PubMed Web of Science ®Google Scholar
• Wadden TA, Foreyt JP, Foster GD et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity19(1), 110–120 (2011).
   PubMed Web of Science ®Google Scholar
• Smith SR. Naltrexone–buproprion causes weight loss in overweight and obese adults. Evid. Based Med.16(2), 53–54 (2011).
   PubMedGoogle Scholar
• Greenway FL, Fujioka K, Plodkowski RA et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet376(9741), 595–605 (2010).
   PubMed Web of Science ®Google Scholar
• Gomez R, Navarro M, Ferrer B et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J. Neurosci.22(21), 9612–9617 (2002).
   PubMed Web of Science ®Google Scholar
• Nogueiras R, Veyrat-Durebex C, Suchanek PM et al. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes57(11), 2977–2991 (2008).
   PubMed Web of Science ®Google Scholar
• Randall PA, Vemuri VK, Segovia KN et al. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol. Biochem. Behav.97(1), 179–184 (2010).
   PubMed Web of Science ®Google Scholar
• Aronne L, Fujioka K, Aroda V et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a Phase 2, randomized, placebo-controlled, dose-escalation study. J. Clin. Endocrinol. Metab.92(8), 2977–2983 (2007).
   PubMed Web of Science ®Google Scholar
• Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care31(9), 1816–1823 (2008).
   PubMed Web of Science ®Google Scholar
• Mack CM, Soares CJ, Wilson JK et al. Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight. Int. J. Obes.34(2), 385–395 (2010).
   Web of Science ®Google Scholar
• Ravussin E, Smith SR, Mitchell JA et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity17(9), 1736–1743 (2009).
   PubMed Web of Science ®Google Scholar
• Symlin® (pramlintide acetate) injection. Prescribing Information. Amylin Pharmaceuticals Inc., CA, USA (2005).
   Google Scholar
• Whitehouse F, Kruger DF, Fineman M et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in Type 1 diabetes. Diabetes Care25(4), 724–730 (2002).
   PubMed Web of Science ®Google Scholar
• Hollander PA, Levy P, Fineman MS et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with Type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care26(3), 784–790 (2003).
   PubMed Web of Science ®Google Scholar
• Ratner RE, Want LL, Fineman MS et al. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with Type 2 diabetes. Diabetes Technol. Ther.4(1), 51–61 (2002).
   PubMedGoogle Scholar
• Ratner RE, Dickey R, Fineman M et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet. Med.21(11), 1204–1212 (2004).
   PubMed Web of Science ®Google Scholar
• Edelman S, Garg S, Frias J et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care29(10), 2189–2195 (2006).
   PubMed Web of Science ®Google Scholar
• Karl D, Philis-Tsimikas A, Darsow T et al. Pramlintide as an adjunct to insulin in patients with Type 2 diabetes in a clinical practice setting reduced A1C, postprandial glucose excursions, and weight. Diabetes Technol. Ther.9(2), 191–199 (2007).
   PubMed Web of Science ®Google Scholar
• Minokoshi Y, Alquier T, Furukawa N et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature428(6982), 569–574 (2004).
   PubMed Web of Science ®Google Scholar
• Bergeron R, Russell RR 3rd, Young LH et al. Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am. J. Physiol.276(5 Pt 1), E938–E944 (1999).
   PubMed Web of Science ®Google Scholar
• Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol.273(6 Pt 1), E1107–E1112 (1997).
   PubMed Web of Science ®Google Scholar
• Salt IP, Connell JM, Gould GW. 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes. Diabetes49(10), 1649–1656 (2000).
   PubMedGoogle Scholar
• Andersson U, Filipsson K, Abbott CR et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem.279(13), 12005–12008 (2004).
   PubMed Web of Science ®Google Scholar
• Chakrabarti R, Misra P, Vikramadithyan RK et al. Antidiabetic and hypolipidemic potential of DRF 2519 – a dual activator of PPAR-α and PPAR-γ. Eur. J. Pharmacol.491(2–3), 195–206 (2004).
   PubMed Web of Science ®Google Scholar
• Jones JR, Barrick C, Kim KA et al. Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc. Natl Acad. Sci. USA102(17), 6207–6212 (2005).
   PubMed Web of Science ®Google Scholar
• Doggrell S. Do peroxisome proliferation receptor-γ antagonists have clinical potential as combined antiobesity and antidiabetic drugs? Expert Opin. Investig. Drugs12(4), 713–716 (2003).
   PubMedGoogle Scholar
• Oberfield JL, Collins JL, Holmes CP et al. A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. Proc. Natl Acad. Sci. USA96(11), 6102–6106 (1999).
   PubMed Web of Science ®Google Scholar
• Mukherjee R, Hoener PA, Jow L et al. A selective peroxisome proliferator-activated receptor-γ (PPARγ) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Mol. Endocrinol.14(9), 1425–1433 (2000).
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in Type 2 diabetes. Lancet368(9548), 1696–1705 (2006).
   PubMed Web of Science ®Google Scholar
• Ahren B. Islet G protein-coupled receptors as potential targets for treatment of Type 2 diabetes. Nat. Rev. Drug Discov.8(5), 369–385 (2009).
   PubMed Web of Science ®Google Scholar
• Chu ZL, Jones RM, He H et al. A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology148(6), 2601–2609 (2007).
   PubMed Web of Science ®Google Scholar
• Lauffer LM, Iakoubov R, Brubaker PL. GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell. Diabetes58(5), 1058–1066 (2009).
   PubMed Web of Science ®Google Scholar
• Ning Y, O’neill K, Lan H et al. Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells. Br. J. Pharmacol.155(7), 1056–1065 (2008).
   PubMed Web of Science ®Google Scholar
• Overton HA, Fyfe MC, Reynet C. GPR119, a novel G protein-coupled receptor target for the treatment of Type 2 diabetes and obesity. Br. J. Pharmacol.153(Suppl. 1), S76–S81 (2008).
   PubMed Web of Science ®Google Scholar
• Semple G, Fioravanti B, Pereira G et al. Discovery of the first potent and orally efficacious agonist of the orphan G-protein coupled receptor 119. J. Med. Chem.51(17), 5172–5175 (2008).
   PubMed Web of Science ®Google Scholar
• Chu ZL, Carroll C, Alfonso J et al. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology149(5), 2038–2047 (2008).
   PubMed Web of Science ®Google Scholar
• Lan H, Vassileva G, Corona A et al. Mice lacking GPR119 maintain metabolic homeostasis. Presented at: Keystone Symposium. Diabetes: Molecular Genetics, Signalling Pathways and Integrated Physiology 2007. Keystone, CO, USA, 14–19 January 2007.
   Google Scholar
• Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of Type 2 diabetes mellitus. J. Med. Chem.53(17), 6355–6360 (2010).
   PubMed Web of Science ®Google Scholar
• Han S, Hagan DL, Taylor JR et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes57(6), 1723–1729 (2008).
   PubMed Web of Science ®Google Scholar
• Meng W, Ellsworth BA, Nirschl AA et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of Type 2 diabetes. J. Med. Chem.51(5), 1145–1149 (2008).
   PubMed Web of Science ®Google Scholar
• Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with Type 2 diabetes mellitus. Clin. Pharmacol. Ther.85(5), 513–519 (2009).
   PubMed Web of Science ®Google Scholar
• List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium–glucose cotransport inhibition with dapagliflozin in Type 2 diabetes. Diabetes Care32(4), 650–657 (2009).
   PubMed Web of Science ®Google Scholar
• Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with Type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet375(9733), 2223–2233 (2010).
   PubMed Web of Science ®Google Scholar
• Strojek K. Efficacy and safety of dapagliflozin in patients with Type 2 diabetes mellitus and inadequate glycaemic control on glimperide monotherapy. Abstract 870. Presented at: 46th Annual Meeting of the European Association for the Study of Diabetes (EASD). Stockholm, Sweden, 20–24 September 2010 (Abstract 870).
   Google Scholar
• Wilding JP, Norwood P, T’joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with Type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care32(9), 1656–1662 (2009).
   PubMed Web of Science ®Google Scholar
• Bays HE. Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for ‘sick fat’ and metabolic disease. Expert Rev. Cardiovasc. Ther.7(11), 1429–1445 (2009).
   PubMedGoogle Scholar
• Sjostrom L, Narbro K, Sjostrom CD et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med.357(8), 741–752 (2007).
   PubMed Web of Science ®Google Scholar
• Cummings DE, Overduin J, Foster-Schubert KE. Gastric bypass for obesity: mechanisms of weight loss and diabetes resolution. J. Clin. Endocrinol. Metab.89(6), 2608–2615 (2004).
   PubMed Web of Science ®Google Scholar
• Cummings DE, Shannon MH. Roles for ghrelin in the regulation of appetite and body weight. Arch. Surg.138(4), 389–396 (2003).
   PubMed Web of Science ®Google Scholar
• Vincent RP, Le Roux CW. The satiety hormone peptide YY as a regulator of appetite. J. Clin. Pathol.61(5), 548–552 (2008).
   PubMed Web of Science ®Google Scholar
• Le Roux CW, Welbourn R, Werling M et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann. Surg.246(5), 780–785 (2007).
   PubMed Web of Science ®Google Scholar