Current Obesity Reports

, Volume 7, Issue 2, pp 147–161 | Cite as

Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon

Obesity Treatment (CM Apovian, Section Editor)

Abstract

Purpose of Review

Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity. This development is preceded by increased understanding of the underpinnings of energy regulation and neurohormonal pathways involved in energy homeostasis.

Recent Findings

Though there are approved anti-obesity drugs available in the USA, newer drugs are now in the pipeline for development given the urgent need. This review focuses on anti-obesity drugs in the pipeline including centrally acting agents (setmelanotide, neuropeptide Y antagonist [velneperit], zonisamide-bupropion [Empatic], cannabinoid type-1 receptor blockers), gut hormones and incretin targets (new glucagon-like-peptide-1 [GLP-1] analogues [semaglutide and oral equivalents], amylin mimetics [davalintide, dual amylin and calcitonin receptor agonists], dual action GLP-1/glucagon receptor agonists [oxyntomodulin], triple agonists [tri-agonist 1706], peptide YY, leptin analogues [combination pramlintide-metreleptin]), and other novel targets (methionine aminopeptidase 2 inhibitor [beloranib], lipase inhibitor [cetilistat], triple monoamine reuptake inhibitor [tesofensine], fibroblast growth factor 21), including anti-obesity vaccines (ghrelin, somatostatin, adenovirus36).

Summary

With these new drugs in development, anti-obesity therapeutics have potential to vastly expand allowing better treatment options and personalized approach to obesity care.

Keywords

Anti-obesity drugs Weight loss medications Novel targets Phase 1 and phase 2 trials Obesity pharmacotherapy Weight management 

Notes

Acknowledgements

The authors thank A. McCarthy for editorial and administrative assistance.

Funding

No funding was provided for the drafting of this manuscript.

Compliance with Ethical Standards

Conflict of Interest

Gitanjali Srivastava has received compensation from Rhythm Pharmaceuticals for service on an advisory board.

Caroline Apovian has received research funding through grants from Orexigen, Aspire Bariatrics, GI Dynamics, MYOS, Takeda, Gelesis, Vela Foundation, Dr. Robert C. and Veronica Atkins Foundation, Coherence Lab, Energesis, Patient-Centered Outcomes Research Institute (PCORI), and the National Institutes of Health (NIH); has received compensation from Nutrisystem, Zafgen, Sanofi-Aventis, Orexigen, Novo Nordisk, GI Dynamics, Takeda, Scientific Intake, Gelesis, Merck, and Johnson & Johnson for service on advisory boards; and owns stock in Science-Smart LLC.

Disclosure

GS reports personal fees from Rhythm Pharmaceuticals, outside the submitted work. Dr. Apovian reports personal fees from Nutrisystem, personal fees from Zafgen, personal fees from Sanofi-Aventis, grants and personal fees from Orexigen, personal fees from NovoNordisk, grants from Aspire Bariatrics, grants and personal fees from GI Dynamics, grants from Myos, grants and personal fees from Takeda, personal fees from Scientific Intake, grants and personal fees from Gelesis, other from Science-Smart LLC, personal fees from Merck, personal fees from Johnson & Johnson, grants from Vela Foundation, grants from Dr. Robert C. and Veronica Atkins Foundation, grants from Coherence Lab, grants from Energesis, grants from PCORI, and grants from NIH, outside the submitted work. However, the authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gregg EW, Shaw JE. Global health effects of overweight and obesity. N Engl J Med. 2017;377:80–1.  https://doi.org/10.1056/NEJMe1706095.PubMedCrossRefGoogle Scholar
  2. 2.
    Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 2016;315:2284–91.  https://doi.org/10.1001/jama.2016.6458.PubMedCrossRefGoogle Scholar
  3. 3.
    •• Apovian CM, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–62.  https://doi.org/10.1210/jc.2014-3415. Provides current guidelines for clinical application of approved anti-obesity drugs. PubMedCrossRefGoogle Scholar
  4. 4.
    Van Gaal LF, Broom JI, Enzi G, Toplak H. Efficacy and tolerability of orlistat in the treatment of obesity: a 6-month dose-ranging study. Orlistat Dose-Ranging Study Group. Eur J Clin Pharmacol. 1998;54:125–32.PubMedCrossRefGoogle Scholar
  5. 5.
    James WP, Avenell A, Broom J, Whitehead J. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord. 1997;21(Suppl 3):S24–30.PubMedGoogle Scholar
  6. 6.
    Weintraub M, Sundaresan PR, Schuster B, Ginsberg G, Madan M, Balder A, et al. Long-term weight control study. II (weeks 34 to 104). An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin Pharmacol Ther. 1992;51:595–601.PubMedCrossRefGoogle Scholar
  7. 7.
    Aronne LJ, et al. Evaluation of phentermine and topiramate versus phentermine/topiramate extended-release in obese adults. Obesity (Silver Spring, Md.). 2013;21:2163–71.  https://doi.org/10.1002/oby.20584.CrossRefGoogle Scholar
  8. 8.
    Aronne L, Shanahan W, Fain R, Glicklich A, Soliman W, Li Y, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials. Postgrad Med. 2014;126:7–18.  https://doi.org/10.3810/pgm.2014.10.2817.PubMedCrossRefGoogle Scholar
  9. 9.
    Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067–77.  https://doi.org/10.1210/jc.2011-1256.PubMedCrossRefGoogle Scholar
  10. 10.
    Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687–99.  https://doi.org/10.1001/jama.2015.9676.PubMedCrossRefGoogle Scholar
  11. 11.
    Wadden TA, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes. 2015;39:187.  https://doi.org/10.1038/ijo.2014.88.CrossRefGoogle Scholar
  12. 12.
    •• Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinology. 2017;  https://doi.org/10.1038/nrendo.2017.122. Most recent review on current anti-obesity drugs in regard to efficacy, safety, and clinical application.
  13. 13.
    Apovian CM. Naltrexone/bupropion for the treatment of obesity and obesity with type 2 diabetes. Futur Cardiol. 2016;12:129–38.  https://doi.org/10.2217/fca.15.79.CrossRefGoogle Scholar
  14. 14.
    Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E, Stubbe S, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245–56.  https://doi.org/10.1056/NEJMoa0909809.PubMedCrossRefGoogle Scholar
  15. 15.
    Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. 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. 2012;95:297–308.  https://doi.org/10.3945/ajcn.111.024927.PubMedCrossRefGoogle Scholar
  16. 16.
    Kang JG, Park CY. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J. 2012;36:13–25.  https://doi.org/10.4093/dmj.2012.36.1.13.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100:1639–45.  https://doi.org/10.1210/jc.2014-4024.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. Int J Obes. 2014;38:163–9.  https://doi.org/10.1038/ijo.2013.80.CrossRefGoogle Scholar
  19. 19.
    Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62:490–7.  https://doi.org/10.2337/db12-0598.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Yukioka H. A potent and selective neuropeptide Y Y5-receptor antagonist, S-2367, as an anti-obesity agent. Nihon yakurigaku zasshi Folia pharmacologica Japonica. 2010;136:270–4.PubMedCrossRefGoogle Scholar
  21. 21.
    George M, Rajaram M, Shanmugam E. New and emerging drug molecules against obesity. J Cardiovasc Pharmacol Ther. 2014;19:65–76.  https://doi.org/10.1177/1074248413501017.PubMedCrossRefGoogle Scholar
  22. 22.
    Powell AG, Apovian CM, Aronne LJ. New drug targets for the treatment of obesity. Clin Pharmacol Ther. 2011;90:40–51.  https://doi.org/10.1038/clpt.2011.82.PubMedCrossRefGoogle Scholar
  23. 23.
    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 Psychiatry. 2007;68:1226–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Release, O. P. I. P. Orexigen (R) Therapeutics phase 2b trial for Empatic(TM) meets primary efficacy endpoint demonstrating significantly greater weight loss versus comparators in obese patients. http://ir.orexigen.com/phoenix.zhtml%3Fc=207034%26p=irol-newsArticle%26ID=1336796%26highlight= Accessed September 13, 2017.
  25. 25.
    Guide to receptors and channels (GRAC), 4th Edition. Br J Pharmacol 2009;158 Suppl 1, S1–254, doi: https://doi.org/10.1111/j.1476-5381.2009.00499.x.
  26. 26.
    Jarbe TU, DiPatrizio NV. Delta9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta9-THC and the CB1 receptor antagonist SR-141716 (rimonabant) in rats. Behav Pharmacol. 2005;16:373–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Salamone JD, McLaughlin PJ, Sink K, Makriyannis A, Parker LA. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol Behav. 2007;91:383–8.  https://doi.org/10.1016/j.physbeh.2007.04.013.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63:Pl113–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology. 2003;167:103–11.  https://doi.org/10.1007/s00213-002-1384-8.PubMedCrossRefGoogle Scholar
  30. 30.
    Hildebrandt AL, Kelly-Sullivan DM, Black SC. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur J Pharmacol. 2003;462:125–32.PubMedCrossRefGoogle Scholar
  31. 31.
    European Medicines Agency: European Public Assessment Report (EPAR) Acomplia. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf Accessed September 27, 2017 (2007).
  32. 32.
    Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370:1706–13.  https://doi.org/10.1016/S0140-6736(07)61721-8.PubMedCrossRefGoogle Scholar
  33. 33.
    Mitchell PB, Morris MJ. Depression and anxiety with rimonabant. Lancet. 2007;370:1671–2.  https://doi.org/10.1016/S0140-6736(07)61705-X.PubMedCrossRefGoogle Scholar
  34. 34.
    • Blundell J, et al. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017;19:1242–51.  https://doi.org/10.1111/dom.12932. The aim of this trial was to investigate the mechanism of action of body weight loss with semaglutide, a new drug which has shown significant weight loss potential of almost 16% in clinical trials. PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Aroda VR, Bain SC, Cariou B, Piletič M, Rose L, Axelsen M, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017;5:355–66.  https://doi.org/10.1016/S2213-8587(17)30085-2.PubMedCrossRefGoogle Scholar
  36. 36.
    Seino Y, Terauchi Y, Osonoi T, Yabe D, Abe N, Nishida T, et al. Safety and efficacy of semaglutide once weekly versus sitagliptin once daily, both as monotherapy in Japanese subjects with type 2 diabetes. Diabetes Obes Metab. 2017;20:378–88.  https://doi.org/10.1111/dom.13082.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ahren B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5:341–54.  https://doi.org/10.1016/S2213-8587(17)30092-X.PubMedCrossRefGoogle Scholar
  38. 38.
    Lutz TA. Control of food intake and energy expenditure by amylin-therapeutic implications. Int J Obes (Lond). 2009;33(Suppl 1):S24–7.  https://doi.org/10.1038/ijo.2009.13.CrossRefGoogle Scholar
  39. 39.
    Wilson JL, Enriori PJ. A talk between fat tissue, gut, pancreas and brain to control body weight. Mol Cell Endocrinol. 2015;418(Pt 2):108–19.  https://doi.org/10.1016/j.mce.2015.08.022.PubMedCrossRefGoogle Scholar
  40. 40.
    Bailey RJ, Walker CS, Ferner AH, Loomes KM, Prijic G, Halim A, et al. Pharmacological characterization of rat amylin receptors: implications for the identification of amylin receptor subtypes. Br J Pharmacol. 2012;166:151–67.  https://doi.org/10.1111/j.1476-5381.2011.01717.x.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mack CM, Soares CJ, Wilson JK, Athanacio JR, Turek VF, Trevaskis JL, 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. 2010;34:385–95.  https://doi.org/10.1038/ijo.2009.238.CrossRefGoogle Scholar
  42. 42.
    Mack CM, Smith PA, Athanacio JR, Xu K, Wilson JK, Reynolds JM, et al. Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide. Diabetes Obes Metab. 2011;13:1105–13.  https://doi.org/10.1111/j.1463-1326.2011.01465.x.PubMedCrossRefGoogle Scholar
  43. 43.
    Gydesen S, Andreassen KV, Hjuler ST, Christensen JM, Karsdal MA, Henriksen K. KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Am J Physiol Endocrinol Metab. 2016;310:E821–7.  https://doi.org/10.1152/ajpendo.00514.2015.PubMedCrossRefGoogle Scholar
  44. 44.
    Hjuler ST, Andreassen KV, Gydesen S, Karsdal MA, Henriksen K. KBP-042 improves bodyweight and glucose homeostasis with indices of increased insulin sensitivity irrespective of route of administration. Eur J Pharmacol. 2015;762:229–38.  https://doi.org/10.1016/j.ejphar.2015.05.051.PubMedCrossRefGoogle Scholar
  45. 45.
    Hjuler ST, Gydesen S, Andreassen KV, Karsdal MA, Henriksen K. The dual amylin- and calcitonin-receptor agonist KBP-042 works as adjunct to metformin on fasting hyperglycemia and HbA1c in a rat model of type 2 diabetes. J Pharmacol Exp Ther. 2017;362:24–30.  https://doi.org/10.1124/jpet.117.241281.PubMedCrossRefGoogle Scholar
  46. 46.
    Hjuler ST, et al. The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity (Silver Spring). 2016;24:1712–22.  https://doi.org/10.1002/oby.21563.CrossRefGoogle Scholar
  47. 47.
    Norregaard PK, et al. A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents. Diabetes Obes Metab. 2017;20:60–8.  https://doi.org/10.1111/dom.13034.PubMedCrossRefGoogle Scholar
  48. 48.
    Parker JA, McCullough KA, Field BCT, Minnion JS, Martin NM, Ghatei MA, et al. Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala. Int J Obes. 2013;37:1391–8.  https://doi.org/10.1038/ijo.2012.227.CrossRefGoogle Scholar
  49. 49.
    Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2014;3:241–51.  https://doi.org/10.1016/j.molmet.2013.12.001.PubMedCrossRefGoogle Scholar
  50. 50.
    Cohen MA, Ellis SM, le Roux CW, Batterham RL, Park A, Patterson M, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003;88:4696–701.  https://doi.org/10.1210/jc.2003-030421.PubMedCrossRefGoogle Scholar
  51. 51.
    Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54:2390–5.PubMedCrossRefGoogle Scholar
  52. 52.
    R&D Pipeline. https://www.novonordisk.com/rnd/rd-pipeline.html Novo Nordisk Accessed August 28, 2017 (2017).
  53. 53.
    Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C, Geary N. Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev. 2017;97:411–63.  https://doi.org/10.1152/physrev.00031.2014.PubMedCrossRefGoogle Scholar
  54. 54.
    Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854–9.  https://doi.org/10.1038/nature05484.PubMedCrossRefGoogle Scholar
  55. 55.
    Batterham RL, Cohen MA, Ellis SM, le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003;349:941–8.  https://doi.org/10.1056/NEJMoa030204.PubMedCrossRefGoogle Scholar
  56. 56.
    Troke RC, Tan TM, Bloom SR. The future role of gut hormones in the treatment of obesity. Ther Adv Chronic Dis. 2014;5:4–14.  https://doi.org/10.1177/2040622313506730.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    van der Klaauw AA, et al. High protein intake stimulates postprandial GLP1 and PYY release. Obesity (Silver Spring). 2013;21:1602–7.  https://doi.org/10.1002/oby.20154.CrossRefGoogle Scholar
  58. 58.
    Meguid MM, Glade MJ, Middleton FA. Weight regain after Roux-en-Y: a significant 20% complication related to PYY. Nutrition. 2008;24:832–42.  https://doi.org/10.1016/j.nut.2008.06.027.PubMedCrossRefGoogle Scholar
  59. 59.
    Lluis F, Fujimura M, Gómez G, Salvá JA, Greeley GH Jr, Thompson JC. Cellular localization, half-life, and secretion of peptide YY. Rev Esp Fisiol. 1989;45:377–84.PubMedGoogle Scholar
  60. 60.
    Zac-Varghese S, De Silva A, Bloom SR. Translational studies on PYY as a novel target in obesity. Curr Opin Pharmacol. 2011;11:582–5.  https://doi.org/10.1016/j.coph.2011.10.001.PubMedCrossRefGoogle Scholar
  61. 61.
    •• Tchang BG, Shukla AP, Aronne LJ. Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives. Expert Opin Biol Ther. 2015;15:1061–75.  https://doi.org/10.1517/14712598.2015.1052789. This paper covers the physiology of leptin, pharmacological properties of recombinant metreleptin, and its efficacy in the treatment of generalized lipodystrophy. PubMedCrossRefGoogle Scholar
  62. 62.
    Akinci G, Akinci B. Metreleptin treatment in patients with non-HIV associated lipodystrophy. Recent patents on endocrine, metabolic & immune drug discovery. 2015;9:74–8.CrossRefGoogle Scholar
  63. 63.
    Chan JL, et al. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2011;17:922–32.  https://doi.org/10.4158/ep11229.or.CrossRefGoogle Scholar
  64. 64.
    • Brown RJ, et al. Effects of metreleptin in pediatric patients with lipodystrophy. J Clin Endocrinol Metab. 2017;102:1511–9.  https://doi.org/10.1210/jc.2016-3628. Metreleptin also has important implications in children with lipodsytrophy and low levels of leptin, leading to improved metabolic abnormalities. PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Meehan CA, Cochran E, Kassai A, Brown RJ, Gorden P. Metreleptin for injection to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. Expert Rev Clin Pharmacol. 2016;9:59–68.  https://doi.org/10.1586/17512433.2016.1096772.PubMedCrossRefGoogle Scholar
  66. 66.
    Chou K, Perry CM. Metreleptin: first global approval. Drugs. 2013;73:989–97.  https://doi.org/10.1007/s40265-013-0074-7.PubMedCrossRefGoogle Scholar
  67. 67.
    Chan JL, Koda J, Heilig JS, Cochran EK, Gorden P, Oral EA, et al. Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol. 2016;85:137–49.  https://doi.org/10.1111/cen.12980.CrossRefGoogle Scholar
  68. 68.
    Myalept [package insert]. Amylin Pharmaceuticals https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125390s000lbl.pdf Acccessed September 5, 2017 (2014).
  69. 69.
    Lutz TA. Pancreatic amylin as a centrally acting satiating hormone. Curr Drug Targets. 2005;6:181–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Singh-Franco D, Perez A, Harrington C. The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2011;13:169–80.  https://doi.org/10.1111/j.1463-1326.2010.01337.x.PubMedCrossRefGoogle Scholar
  71. 71.
    Chan JL, Roth JD, Weyer C. It takes two to tango: combined amylin/leptin agonism as a potential approach to obesity drug development. J Investig Med: Off Publ Am Fed Clin Res. 2009;57:777–83.  https://doi.org/10.2310/JIM.0b013e3181b91911.CrossRefGoogle Scholar
  72. 72.
    Ravussin E, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity (Silver Spring, Md.). 2009;17:1736–43.  https://doi.org/10.1038/oby.2009.184.CrossRefGoogle Scholar
  73. 73.
    Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY. Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer. 2005;114:124–30.  https://doi.org/10.1002/ijc.20687.PubMedCrossRefGoogle Scholar
  74. 74.
    Kim EJ, Shin WH. General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system. Biol Pharm Bull. 2005;28:217–23.PubMedCrossRefGoogle Scholar
  75. 75.
    Howland RH. Aspergillus, angiogenesis, and obesity: the story behind beloranib. J Psychosoc Nurs Ment Health Serv. 2015;53:13–6.  https://doi.org/10.3928/02793695-20150219-01.CrossRefPubMedGoogle Scholar
  76. 76.
    Hughes TE, et al. Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women. Obesity (Silver Spring). 2013;21:1782–8.  https://doi.org/10.1002/oby.20356.CrossRefGoogle Scholar
  77. 77.
    Kim DD, Krishnarajah J, Lillioja S, de Looze F, Marjason J, Proietto J, et al. Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial. Diabetes Obes Metab. 2015;17:566–72.  https://doi.org/10.1111/dom.12457.PubMedCrossRefGoogle Scholar
  78. 78.
    Elfers CT, Roth CL. Robust reductions of excess weight and hyperphagia by beloranib in rat models of genetic and hypothalamic obesity. Endocrinology. 2017;158:41–55.  https://doi.org/10.1210/en.2016-1665.PubMedCrossRefGoogle Scholar
  79. 79.
    The Boston Globe: Zafgen drug halted after second patient dies. https://www.bostonglobe.com/business/2015/12/03/fda-orders-zafgen-halt-clinical-trial-for-obesity-drug/PwGxnqvLoIYpXZN59hPT6M/story.html Accessed September 27, 2017 (2015).
  80. 80.
    Yamada Y, Kato T, Ogino H, Ashina S, Kato K. Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats. Horm Metab Res. 2008;40:539–43.  https://doi.org/10.1055/s-2008-1076699.PubMedCrossRefGoogle Scholar
  81. 81.
    Kopelman P, Bryson A, Hickling R, Rissanen A, Rossner S, Toubro S, et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes. 2007;31:494–9.  https://doi.org/10.1038/sj.ijo.0803446.CrossRefGoogle Scholar
  82. 82.
    Kopelman P, et al. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical). Obesity (Silver Spring). 2010;18:108–15.  https://doi.org/10.1038/oby.2009.155.CrossRefGoogle Scholar
  83. 83.
    Hansen HH, Jensen MM, Overgaard A, Weikop P, Mikkelsen JD. Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat. Pharmacol Biochem Behav. 2013;110:265–71.  https://doi.org/10.1016/j.pbb.2013.07.018.PubMedCrossRefGoogle Scholar
  84. 84.
    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. Lancet. 2008;372:1906–13.  https://doi.org/10.1016/S0140-6736(08)61525-1.PubMedCrossRefGoogle Scholar
  85. 85.
    Doggrell SS. Tesofensine—a novel potent weight loss medicine. Evaluation of: Astrup A, 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. Lancet 2008;372:1906-13. Expert Opin Investig Drugs. 2009;18:1043–6.  https://doi.org/10.1517/13543780902967632.PubMedCrossRefGoogle Scholar
  86. 86.
    Giralt M, Gavalda-Navarro A, Villarroya F. Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol. 2015;418(Pt 1):66–73.  https://doi.org/10.1016/j.mce.2015.09.018.PubMedCrossRefGoogle Scholar
  87. 87.
    Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol. 2016;78:223–41.  https://doi.org/10.1146/annurev-physiol-021115-105339.PubMedCrossRefGoogle Scholar
  88. 88.
    Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology. 2009;150:4931–40.  https://doi.org/10.1210/en.2009-0532.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr. 2011;93:901s–905.  https://doi.org/10.3945/ajcn.110.001941.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Cuevas-Ramos D & Aguilar-Salinas CA Modulation of energy balance by fibroblast growth factor 21. Horm Mol Biol Clin Inv 2016, 30, doi: https://doi.org/10.1515/hmbci-2016-0023.
  91. 91.
    Gomez-Samano MA, et al. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol. 2017;11:335–41.  https://doi.org/10.1016/j.redox.2016.12.024.PubMedCrossRefGoogle Scholar
  92. 92.
    Fisher FM, et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes. 2010;59:2781–9.  https://doi.org/10.2337/db10-0193.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Altabas V, Zjacic-Rotkvic V. Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy. Immunotargets Ther. 2015;4:123–30.  https://doi.org/10.2147/ITT.S60398.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Colon-Gonzalez F, Kim GW, Lin JE, Valentino MA, Waldman SA. Obesity pharmacotherapy: what is next? Mol Asp Med. 2013;34:71–83.  https://doi.org/10.1016/j.mam.2012.10.005.CrossRefGoogle Scholar
  95. 95.
    Takagi K, Legrand R, Asakawa A, Amitani H, François M, Tennoune N, et al. Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans. Nat Commun. 2013;4:2685.  https://doi.org/10.1038/ncomms3685.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Monteiro MP. Obesity vaccines. Hum Vaccin Immunother. 2014;10:887–95.PubMedCrossRefGoogle Scholar
  97. 97.
    Haffer KN. Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice. J Anim Sci Biotechnol. 2012;3:21.  https://doi.org/10.1186/2049-1891-3-21.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Yamada T, Hara K, Kadowaki T. Association of adenovirus 36 infection with obesity and metabolic markers in humans: a meta-analysis of observational studies. PLoS One. 2012;7:e42031.  https://doi.org/10.1371/journal.pone.0042031.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    • Na HN, Kim H, Nam JH. Prophylactic and therapeutic vaccines for obesity. Clin Exp Vaccine Res. 2014;3:37–41.  https://doi.org/10.7774/cevr.2014.3.1.37. This review describes the ongoing development of therapeutic vaccines for the prevention of obesity, and the possibility of using inactivated adenovirus-36 as a vaccine and anti-obesity agent. PubMedCrossRefGoogle Scholar
  100. 100.
    Na HN, Nam JH. Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36. Int J Obes. 2014;38:1470–4.  https://doi.org/10.1038/ijo.2014.41.CrossRefGoogle Scholar
  101. 101.
    Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev. 2006;27:750–61.  https://doi.org/10.1210/er.2006-0032.PubMedCrossRefGoogle Scholar
  102. 102.
    Cone RD. Studies on the physiological functions of the melanocortin system. Endocr Rev. 2006;27:736–49.  https://doi.org/10.1210/er.2006-0034.PubMedCrossRefGoogle Scholar
  103. 103.
    Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8:571–8.  https://doi.org/10.1038/nn1455.PubMedCrossRefGoogle Scholar
  104. 104.
    Rossi M, Kim MS, Morgan DGA, Small CJ, Edwards CMB, Sunter D, et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology. 1998;139:4428–31.  https://doi.org/10.1210/endo.139.10.6332.PubMedCrossRefGoogle Scholar
  105. 105.
    Tolle V, Low MJ. In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes. 2008;57:86–94.  https://doi.org/10.2337/db07-0733.PubMedCrossRefGoogle Scholar
  106. 106.
    Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, et al. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009;30:1892–900.  https://doi.org/10.1016/j.peptides.2009.07.012.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    • Anderson EJ, et al. 60 YEARS OF POMC: regulation of feeding and energy homeostasis by alpha-MSH. J Mol Endocrinol. 2016;56:T157–74.  https://doi.org/10.1530/JME-16-0014. This review discusses the history of POMC mRNA and melanocortin peptides as well as the latest work attempting to unravel feeding and regulation in the CNS by alpha-MSH. PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248–51.PubMedCrossRefGoogle Scholar
  109. 109.
    Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, et al. Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes. 2008;57:3267–72.  https://doi.org/10.2337/db08-0577.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Girardet C, Butler AA. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim Biophys Acta. 2014;1842:482–94.  https://doi.org/10.1016/j.bbadis.2013.05.004.PubMedCrossRefGoogle Scholar
  111. 111.
    Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360:44–52.  https://doi.org/10.1056/NEJMoa0803085.PubMedCrossRefGoogle Scholar
  112. 112.
    Low MJ. Neuroendocrinology: new hormone treatment for obesity caused by POMC-deficiency. Nat Rev Endocrinol. 2016;12:627–8.  https://doi.org/10.1038/nrendo.2016.156.PubMedCrossRefGoogle Scholar
  113. 113.
    Kuhnen P, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375:240–6.  https://doi.org/10.1056/NEJMoa1512693.PubMedCrossRefGoogle Scholar
  114. 114.
    Rhythm Pharmaceuticals, Inc Product pipeline: peptide therapeutics for rare genetic deficiencies resulting in life-threatening metabolic disorders. http://www.rhythmtx.com/pipeline/product-pipeline/ Accessed August 28, 2017 (2017).
  115. 115.
    Double-blind, multi-center, randomized study to assess the efficacy and safety of velneperit (S-2367) and orlistat administered individually or combined with a reduced calorie diet (RCD) in obese subjects. https://clinicaltrials.gov/ct2/show/NCT01126970 Accessed September 13, 2017 (2011).
  116. 116.
    Wharton S, Serodio KJ. Next generation of weight management medications: implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17:35.  https://doi.org/10.1007/s11886-015-0590-z.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Cluny NL, Vemuri VK, Chambers AP, Limebeer CL, Bedard H, Wood JT, et al. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br J Pharmacol. 2010;161:629–42.  https://doi.org/10.1111/j.1476-5381.2010.00908.x.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, et al. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav. 2010;97:179–84.  https://doi.org/10.1016/j.pbb.2010.07.021.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310:R885–95.  https://doi.org/10.1152/ajpregu.00520.2015.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti G, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials. Diabetes Obes Metab. 2017;19:1233–41.  https://doi.org/10.1111/dom.12926.PubMedCrossRefGoogle Scholar
  121. 121.
    Boess F, Bertinetti-Lapatki C, Zoffmann S, George C, Pfister T, Roth A, et al. Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man. J Mol Endocrinol. 2013;50:325–36.  https://doi.org/10.1530/JME-12-0186.PubMedCrossRefGoogle Scholar
  122. 122.
    Serge Jabbour, T. R. P., Julio Rosenstock, Marie-Louise Hartoft-Nielson, Oluf Kristian Hojbjerg Hansen, and Melanie Davies. Abract OR15-3 Robust dose-dependent glucose lowering and body weight (BW) reductions with the novel oral formulation of semaglutide in patients with early type 2 diabetes (T2D). Endocrine Society 2016 https://endo.confex.com/endo/2016endo/webprogram/Paper25706.html (April 2, 2016).
  123. 123.
    Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20:122–8.  https://doi.org/10.1016/j.drudis.2014.10.003.PubMedCrossRefGoogle Scholar
  124. 124.
    Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1:8–23.  https://doi.org/10.1111/j.2040-1124.2010.00022.x.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Christensen M, Vedtofte L, Holst JJ, Vilsboll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60:3103–9.  https://doi.org/10.2337/db11-0979.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Hansen MSS, Tencerova M, Frolich J, Kassem M, Frost M. Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on bone cell metabolism. Basic Clin Pharmacol Toxicol. 2017;122:25–37.  https://doi.org/10.1111/bcpt.12850.PubMedCrossRefGoogle Scholar
  127. 127.
    Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138:159–66.PubMedCrossRefGoogle Scholar
  128. 128.
    Yip RG, Boylan MO, Kieffer TJ, Wolfe MM. Functional GIP receptors are present on adipocytes. Endocrinology. 1998;139:4004–7.  https://doi.org/10.1210/endo.139.9.6288.PubMedCrossRefGoogle Scholar
  129. 129.
    Knapper JM, Puddicombe SM, Morgan LM, Fletcher JM. Investigations into the actions of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1(7-36)amide on lipoprotein lipase activity in explants of rat adipose tissue. J Nutr. 1995;125:183–8.PubMedGoogle Scholar
  130. 130.
    Paschetta E, Hvalryg M, Musso G. Glucose-dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity-associated disorders. Obes Rev. 2011;12:813–28.  https://doi.org/10.1111/j.1467-789X.2011.00897.x.PubMedCrossRefGoogle Scholar
  131. 131.
    Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. 2002;8:738–42.  https://doi.org/10.1038/nm727.PubMedCrossRefGoogle Scholar
  132. 132.
    Holst JJ. Gut hormones as pharmaceuticals. From enteroglucagon to GLP-1 and GLP-2. Regul Pept. 2000;93:45–51.PubMedCrossRefGoogle Scholar
  133. 133.
    Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2003;284:E671–8.  https://doi.org/10.1152/ajpendo.00492.2002.PubMedCrossRefGoogle Scholar
  134. 134.
    Schulman JL, Carleton JL, Whitney G, Whitehorn JC. Effect of glucagon on food intake and body weight in man. J Appl Physiol. 1957;11:419–21.PubMedCrossRefGoogle Scholar
  135. 135.
    Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M, et al. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes Metab. 2016;18:1176–90.  https://doi.org/10.1111/dom.12735.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    •• Farooqi IS, O'Rahilly S. 20 years of leptin: human disorders of leptin action. J Endocrinol. 2014;223:T63–70.  https://doi.org/10.1530/joe-14-0480. The discovery of leptin has provided a robust framework to build our current understanding of energy regulation. This review describes how the identification of humans with mutations in leptin or leptin receptor has provided insight into leptin-responsive pathways controling eating behavior PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight ManagementBoston University School of MedicineBostonUSA

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