Skip to main content

Advertisement

Log in

The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications

  • Obesity Treatment (CM Apovian, Section Editor)
  • Published:
Current Obesity Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

There is currently a steep rise in the global prevalence of obesity. Pharmaceutical therapy is a valuable component of conservative obesity therapy. Herein, medications currently in the phase of preclinical or clinical testing are reviewed, along with an overview of the mechanisms that regulate energy intake and expenditure. In addition, the current and potential future directions of obesity drug therapy are discussed.

Recent Findings

Although the current arsenal of obesity pharmacotherapy is limited, a considerable number of agents that exert their actions through a variety of pharmacodynamic targets and mechanisms are in the pipeline. This expansion shapes a potential near future of obesity conservative management, characterized by tailored combined therapeutic regimens, targeting not only weight loss but also improved overall health outcomes.

Summary

The progress regarding the elucidation of the mechanisms which regulate the bodily energy equilibrium has led to medications which mimic hormonal adaptations that follow bariatric surgery, in the quest for a “Medical bypass.” These, combined with agents which could increase energy expenditure, point to a brilliant future in the conservative treatment of obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

AgRP:

Agouti-related peptide

BAT:

Brown adipose tissue

BMI:

Body mass index

cGMP:

Cyclic guanosine monophosphate

CVD:

Cardiovascular disease

DACRA:

Dual amylin/calcitonin receptor agonists

DIO:

Diet-induced obesity

DPP4:

Dipeptidyl-peptidase-4

EE :

Energy expenditure

EI:

Energy intake

FDA:

Food and Drug Administration

GCGR :

Glucagon receptor

GHSR1a:

Growth hormone secretagogue receptor type 1a

GIP:

Glucose-dependent insulinotropic peptide

GLP-1:

Glucagon-like peptide 1

GLP1R:

Glucagon-like peptide 1 receptor

GOAT:

Ghrelin-O-acyltransferase

NPY:

Neuropeptide Y

OXM:

Oxyntomodulin

POMC:

Proopiomelanocortin

PYY:

Peptide tyrosine-tyrosine

RYGB:

Roux-en-Y gastric bypass

SCT:

Secretin

SG:

Sleeve gastrectomy

T2DM:

Type 2 diabetes mellitus

References

  1. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes. 2008;32(9):1431–7. https://doi.org/10.1038/ijo.2008.102.

    Article  CAS  Google Scholar 

  2. Anderson JW, Konz EC, Frederich RC, Wood CL. Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr. 2001;74(5):579–84. https://doi.org/10.1093/ajcn/74.5.579.

    Article  PubMed  CAS  Google Scholar 

  3. Dombrowski SU, Knittle K, Avenell A, Araujo-Soares V, Sniehotta FF. Long term maintenance of weight loss with non-surgical interventions in obese adults: systematic review and meta-analyses of randomised controlled trials. BMJ. 2014;348:g2646. https://doi.org/10.1136/bmj.g2646.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am. 2018;102(1):183–97. https://doi.org/10.1016/j.mcna.2017.08.012.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597–604. https://doi.org/10.1056/NEJMoa1105816.

    Article  PubMed  CAS  Google Scholar 

  6. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9774):1341–52. https://doi.org/10.1016/S0140-6736(11)60205-5.

    Article  PubMed  CAS  Google Scholar 

  7. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bohula EA, Wiviott SD, McGuire DK, Inzucchi SE, Kuder J, Im K, et al. Cardiovascular safety of lorcaserin in overweight or obese patients. N Engl J Med. 2018;379(12):1107–17. https://doi.org/10.1056/NEJMoa1808721.

    Article  PubMed  CAS  Google Scholar 

  9. Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, et al. Effect of naltrexone-bupropion on major adverse cardiovascular events in overweight and obese patients with cardiovascular risk factors: a randomized clinical trial. JAMA. 2016;315(10):990–1004. https://doi.org/10.1001/jama.2016.1558.

    Article  PubMed  CAS  Google Scholar 

  10. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443(7109):289–95. https://doi.org/10.1038/nature05026.

    Article  PubMed  CAS  Google Scholar 

  11. van den Top M, Spanswick D. Integration of metabolic stimuli in the hypothalamic arcuate nucleus. Prog Brain Res. 2006;153:141–54. https://doi.org/10.1016/S0079-6123(06)53008-0.

    Article  PubMed  CAS  Google Scholar 

  12. Heisler LK, Lam DD. An appetite for life: brain regulation of hunger and satiety. Curr Opin Pharmacol. 2017;37:100–6. https://doi.org/10.1016/j.coph.2017.09.002.

    Article  PubMed  CAS  Google Scholar 

  13. Timper K, Bruning JC. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech. 2017;10(6):679–89. https://doi.org/10.1242/dmm.026609.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31(4):506–43. https://doi.org/10.1210/er.2009-0037.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):531–43. https://doi.org/10.1016/s0092-8674(01)00240-9.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang W, Bi S. Hypothalamic regulation of brown adipose tissue thermogenesis and energy homeostasis. Front Endocrinol. 2015;6:136. https://doi.org/10.3389/fendo.2015.00136.

    Article  Google Scholar 

  17. Contreras C, Gonzalez F, Ferno J, Dieguez C, Rahmouni K, Nogueiras R, et al. The brain and brown fat. Ann Med. 2015;47(2):150–68. https://doi.org/10.3109/07853890.2014.919727.

    Article  PubMed  CAS  Google Scholar 

  18. Li Y, Schnabl K, Gabler SM, Willershauser M, Reber J, Karlas A, et al. Secretin-activated brown fat mediates prandial thermogenesis to induce satiation. Cell. 2018;175(6):1561–74 e12. https://doi.org/10.1016/j.cell.2018.10.016.

    Article  PubMed  CAS  Google Scholar 

  19. Kokkinos A, Tsilingiris D, le Roux CW, Rubino F, Mantzoros CS. Will medications that mimic gut hormones or target their receptors eventually replace bariatric surgery? Metab Clin Exp. 2019;100:153960. https://doi.org/10.1016/j.metabol.2019.153960.

    Article  PubMed  CAS  Google Scholar 

  20. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22. https://doi.org/10.1056/NEJMoa1411892.

    Article  PubMed  CAS  Google Scholar 

  21. Lau J, Bloch P, Schaffer L, Pettersson I, Spetzler J, Kofoed J, et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem. 2015;58(18):7370–80. https://doi.org/10.1021/acs.jmedchem.5b00726.

    Article  PubMed  CAS  Google Scholar 

  22. Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, 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(9):1242–51. https://doi.org/10.1111/dom.12932.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. O'Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392(10148):637–49. https://doi.org/10.1016/S0140-6736(18)31773-2.

    Article  PubMed  CAS  Google Scholar 

  24. Goldenberg RM, Steen O. Semaglutide: review and place in therapy for adults with type 2 diabetes. Can J Diabetes. 2019;43(2):136–45. https://doi.org/10.1016/j.jcjd.2018.05.008.

    Article  PubMed  Google Scholar 

  25. Aroda VR, Ahmann A, Cariou B, Chow F, Davies MJ, Jodar E, et al. Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: insights from the SUSTAIN 1-7 trials. Diabetes Metab. 2019;45(5):409–18. https://doi.org/10.1016/j.diabet.2018.12.001.

    Article  PubMed  CAS  Google Scholar 

  26. Jones ES, Nunn N, Chambers AP, Ostergaard S, Wulff BS, Luckman SM. Modified peptide YY molecule attenuates the activity of NPY/AgRP neurons and reduces food intake in male mice. Endocrinology. 2019;160(11):2737–47. https://doi.org/10.1210/en.2019-00100.

    Article  PubMed  PubMed Central  Google Scholar 

  27. van Witteloostuijn SB, Dalboge LS, Hansen G, Midtgaard SR, Jensen GV, Jensen KJ, et al. GUB06-046, a novel secretin/glucagon-like peptide 1 co-agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice. Journal of Peptide Science : an Official Publication of the European Peptide Society. 2017;23(12):845–54. https://doi.org/10.1002/psc.3048.

    Article  CAS  Google Scholar 

  28. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018;391(10140):2607–18. https://doi.org/10.1016/S0140-6736(18)30726-8.

    Article  PubMed  CAS  Google Scholar 

  29. Larsen AT, Sonne N, Andreassen KV, Gehring K, Karsdal MA, Henriksen K. The dual amylin and calcitonin receptor agonist KBP-088 induces weight loss and improves insulin sensitivity superior to chronic amylin therapy. J Pharmacol Exp Ther. 2019;370(1):35–43. https://doi.org/10.1124/jpet.119.257576.

    Article  PubMed  CAS  Google Scholar 

  30. 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(10):E821–7. https://doi.org/10.1152/ajpendo.00514.2015.

    Article  PubMed  Google Scholar 

  31. Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, et al. Ibipinabant attenuates beta-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012;14(6):555–64. https://doi.org/10.1111/j.1463-1326.2012.01563.x.

    Article  PubMed  CAS  Google Scholar 

  32. Ma H, Zhang G, Mou C, Fu X, Chen Y. Peripheral CB1 receptor neutral antagonist, AM6545, ameliorates hypometabolic obesity and improves adipokine secretion in monosodium glutamate induced obese mice. Front Pharmacol. 2018;9:156. https://doi.org/10.3389/fphar.2018.00156.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 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(3):629–42. https://doi.org/10.1111/j.1476-5381.2010.00908.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Knani I, Earley BJ, Udi S, Nemirovski A, Hadar R, Gammal A, et al. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol Metab. 2016;5(12):1187–99. https://doi.org/10.1016/j.molmet.2016.10.004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16(2):167–79. https://doi.org/10.1016/j.cmet.2012.07.002.

    Article  PubMed  CAS  Google Scholar 

  36. Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SO, et al. Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the PIONEER 2 trial. Diabetes Care. 2019;42(12):2272–81. https://doi.org/10.2337/dc19-0883.

    Article  PubMed  CAS  Google Scholar 

  37. Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394(10192):39–50. https://doi.org/10.1016/S0140-6736(19)31271-1.

    Article  PubMed  CAS  Google Scholar 

  38. Pieber TR, Bode B, Mertens A, Cho YM, Christiansen E, Hertz CL, et al. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2019;7(7):528–39. https://doi.org/10.1016/S2213-8587(19)30194-9.

    Article  PubMed  CAS  Google Scholar 

  39. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771. https://doi.org/10.1136/bmj.d7771.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Su N, Li Y, Xu T, Li L, Kwong JS, Du H, et al. Exenatide in obese or overweight patients without diabetes: a systematic review and meta-analyses of randomized controlled trials. Int J Cardiol. 2016;219:293–300. https://doi.org/10.1016/j.ijcard.2016.06.028.

    Article  PubMed  Google Scholar 

  41. Price SL, Bloom SR. Protein PYY and its role in metabolism. Front Horm Res. 2014;42:147–54. https://doi.org/10.1159/000358343.

    Article  PubMed  Google Scholar 

  42. Ueno H, Yamaguchi H, Mizuta M, Nakazato M. The role of PYY in feeding regulation. Regul Pept. 2008;145(1–3):12–6. https://doi.org/10.1016/j.regpep.2007.09.011.

    Article  PubMed  CAS  Google Scholar 

  43. Ballantyne GH. Peptide YY(1-36) and peptide YY(3-36): part I. Distribution, release and actions. Obes Surg. 2006;16(5):651–8. https://doi.org/10.1381/096089206776944959.

    Article  PubMed  Google Scholar 

  44. Sam AH, Gunner DJ, King A, Persaud SJ, Brooks L, Hostomska K, et al. Selective ablation of peptide YY cells in adult mice reveals their role in beta cell survival. Gastroenterology. 2012;143(2):459–68. https://doi.org/10.1053/j.gastro.2012.04.047.

    Article  PubMed  CAS  Google Scholar 

  45. Shi YC, Loh K, Bensellam M, Lee K, Zhai L, Lau J, et al. Pancreatic PYY is critical in the control of insulin secretion and glucose homeostasis in female mice. Endocrinology. 2015;156(9):3122–36. https://doi.org/10.1210/en.2015-1168.

    Article  PubMed  CAS  Google Scholar 

  46. Gantz I, Erondu N, Mallick M, Musser B, Krishna R, Tanaka WK, et al. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults. J Clin Endocrinol Metab. 2007;92(5):1754–7. https://doi.org/10.1210/jc.2006-1806.

    Article  PubMed  CAS  Google Scholar 

  47. Khatib MN, Gaidhane S, Gaidhane AM, Simkhada P, Zahiruddin QS. Ghrelin O acyl transferase (GOAT) as a novel metabolic regulatory enzyme. Journal of Clinical and Diagnostic Research : JCDR. 2015;9(2):LE01–5. https://doi.org/10.7860/JCDR/2015/9787.5514.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, et al. In adults with Prader-Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels. Neuropeptides. 2011;45(4):301–7. https://doi.org/10.1016/j.npep.2011.06.001.

    Article  PubMed  CAS  Google Scholar 

  49. Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010;330(6011):1689–92. https://doi.org/10.1126/science.1196154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: similarities and differences. J Diabetes Investig. 2010;1(1–2):8–23. https://doi.org/10.1111/j.2040-1124.2010.00022.x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Finan B, Ma T, Ottaway N, Muller TD, Habegger KM, Heppner KM, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151. https://doi.org/10.1126/scitranslmed.3007218.

    Article  PubMed  Google Scholar 

  52. Frias JP, Bastyr EJ 3rd, Vignati L, Tschop MH, Schmitt C, Owen K, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 2017;26(2):343–52 e2. https://doi.org/10.1016/j.cmet.2017.07.011.

    Article  PubMed  CAS  Google Scholar 

  53. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14. https://doi.org/10.1016/j.molmet.2018.09.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180–93. https://doi.org/10.1016/S0140-6736(18)32260-8.

    Article  PubMed  CAS  Google Scholar 

  55. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr. 2007;27:79–101. https://doi.org/10.1146/annurev.nutr.27.061406.093734.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Billington CJ, Briggs JE, Link JG, Levine AS. Glucagon in physiological concentrations stimulates brown fat thermogenesis in vivo. Am J Phys. 1991;261(2 Pt 2):R501–7. https://doi.org/10.1152/ajpregu.1991.261.2.R501.

    Article  CAS  Google Scholar 

  57. Kinoshita K, Ozaki N, Takagi Y, Murata Y, Oshida Y, Hayashi Y. Glucagon is essential for adaptive thermogenesis in brown adipose tissue. Endocrinology. 2014;155(9):3484–92. https://doi.org/10.1210/en.2014-1175.

    Article  PubMed  CAS  Google Scholar 

  58. Sanchez-Garrido MA, Brandt SJ, Clemmensen C, Muller TD, DiMarchi RD, Tschop MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia. 2017;60(10):1851–61. https://doi.org/10.1007/s00125-017-4354-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Pocai A. Unraveling oxyntomodulin, GLP1’s enigmatic brother. J Endocrinol. 2012;215(3):335–46. https://doi.org/10.1530/JOE-12-0368.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Perakakis N, Kokkinos A, Peradze N, Tentolouris N, Ghaly W, Pilitsi E, et al. Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: evidence from two independent trials. Metab Clin Exp. 2019;101:153997. https://doi.org/10.1016/j.metabol.2019.153997.

    Article  PubMed  CAS  Google Scholar 

  61. 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(10):4696–701. https://doi.org/10.1210/jc.2003-030421.

    Article  PubMed  CAS  Google Scholar 

  62. 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(8):2390–5. https://doi.org/10.2337/diabetes.54.8.2390.

    Article  PubMed  CAS  Google Scholar 

  63. Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes. 2006;30(12):1729–36. https://doi.org/10.1038/sj.ijo.0803344.

    Article  CAS  Google Scholar 

  64. Scott R, Minnion J, Tan T, Bloom SR. Oxyntomodulin analogue increases energy expenditure via the glucagon receptor. Peptides. 2018;104:70–7. https://doi.org/10.1016/j.peptides.2018.04.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Ambery PD, Klammt S, Posch MG, Petrone M, Pu W, Rondinone C, et al. MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, phase 1 study. Br J Clin Pharmacol. 2018;84(10):2325–35. https://doi.org/10.1111/bcp.13688.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab. 2019;21(1):120–8. https://doi.org/10.1111/dom.13494.

    Article  PubMed  CAS  Google Scholar 

  67. Britta Goebel MS, Visentin R, Riz M, Man CD, Cobelli C, Klabunde T. Effects of the novel dual GLP-1R/GCGR agonist SAR425899 on postprandial glucose metabolism in overweight/obese subjects with type 2 diabetes. Diabetes. 2018;67(Supplement 1). https://doi.org/10.2337/db18-72-OR.

    Article  Google Scholar 

  68. Korner J, Inabnet W, Febres G, Conwell IM, McMahon DJ, Salas R, et al. Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes. 2009;33(7):786–95. https://doi.org/10.1038/ijo.2009.79.

    Article  CAS  Google Scholar 

  69. Bhat VK, Kerr BD, Vasu S, Flatt PR, Gault VA. A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice. Diabetologia. 2013;56(6):1417–24. https://doi.org/10.1007/s00125-013-2892-2.

    Article  PubMed  CAS  Google Scholar 

  70. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27–36. https://doi.org/10.1038/nm.3761.

    Article  PubMed  CAS  Google Scholar 

  71. Behary P, Tharakan G, Alexiadou K, Johnson N, Wewer Albrechtsen NJ, Kenkre J, et al. Combined GLP-1, oxyntomodulin, and peptide YY improves body weight and glycemia in obesity and prediabetes/type 2 diabetes: a randomized, single-blinded, placebo-controlled study. Diabetes Care. 2019;42(8):1446–53. https://doi.org/10.2337/dc19-0449.

    Article  PubMed  CAS  Google Scholar 

  72. Lutz TA. Control of food intake and energy expenditure by amylin-therapeutic implications. Int J Obes. 2009;33(Suppl 1):S24–7. https://doi.org/10.1038/ijo.2009.13.

    Article  CAS  Google Scholar 

  73. Fu W, Patel A, Jhamandas JH. Amylin receptor: a common pathophysiological target in Alzheimer’s disease and diabetes mellitus. Front Aging Neurosci. 2013;5:42. https://doi.org/10.3389/fnagi.2013.00042.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. American Diabetes A. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90–S102. https://doi.org/10.2337/dc19-S009.

    Article  Google Scholar 

  75. 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 Care. 2008;31(9):1816–23. https://doi.org/10.2337/dc08-0029.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H, et al. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy. Obesity. 2009;17(9):1736–43. https://doi.org/10.1038/oby.2009.184.

    Article  PubMed  CAS  Google Scholar 

  77. 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(12):1105–13. https://doi.org/10.1111/j.1463-1326.2011.01465.x.

    Article  PubMed  CAS  Google Scholar 

  78. 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(2):385–95. https://doi.org/10.1038/ijo.2009.238.

    Article  CAS  Google Scholar 

  79. Hjuler ST, Gydesen S, Andreassen KV, Pedersen SL, Hellgren LI, Karsdal MA, et al. The dual amylin- and calcitonin-receptor agonist KBP-042 increases insulin sensitivity and induces weight loss in rats with obesity. Obesity. 2016;24(8):1712–22. https://doi.org/10.1002/oby.21563.

    Article  PubMed  CAS  Google Scholar 

  80. 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.

    Article  PubMed  CAS  Google Scholar 

  81. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med. 1998;4(6):718–21. https://doi.org/10.1038/nm0698-718.

    Article  PubMed  CAS  Google Scholar 

  82. Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann F, et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med. 1998;4(6):722–6. https://doi.org/10.1038/nm0698-722.

    Article  PubMed  CAS  Google Scholar 

  83. Powell AG, Apovian CM, Aronne LJ. New drug targets for the treatment of obesity. Clin Pharmacol Ther. 2011;90(1):40–51. https://doi.org/10.1038/clpt.2011.82.

    Article  PubMed  CAS  Google Scholar 

  84. Morvan F, Rondeau JM, Zou C, Minetti G, Scheufler C, Scharenberg M, et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci U S A. 2017;114(47):12448–53. https://doi.org/10.1073/pnas.1707925114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Chen JL, Walton KL, Hagg A, Colgan TD, Johnson K, Qian H, et al. Specific targeting of TGF-beta family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease. Proc Natl Acad Sci U S A. 2017;114(26):E5266–E75. https://doi.org/10.1073/pnas.1620013114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Hashimoto O, Funaba M. Activin in glucose metabolism. Vitam Horm. 2011;85:217–34. https://doi.org/10.1016/B978-0-12-385961-7.00011-1.

    Article  PubMed  CAS  Google Scholar 

  87. Lach-Trifilieff E, Minetti GC, Sheppard K, Ibebunjo C, Feige JN, Hartmann S, et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol. 2014;34(4):606–18. https://doi.org/10.1128/MCB.01307-13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Rooks DS, Laurent D, Praestgaard J, Rasmussen S, Bartlett M, Tanko LB. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle. 2017;8(5):727–34. https://doi.org/10.1002/jcsm.12205.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hanna MG, Badrising UA, Benveniste O, Lloyd TE, Needham M, Chinoy H, et al. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019;18(9):834–44. https://doi.org/10.1016/S1474-4422(19)30200-5.

    Article  PubMed  CAS  Google Scholar 

  90. Polkey MI, Praestgaard J, Berwick A, Franssen FME, Singh D, Steiner MC, et al. Activin type II receptor blockade for treatment of muscle depletion in chronic obstructive pulmonary disease. A randomized trial. Am J Respir Crit Care Med. 2019;199(3):313–20. https://doi.org/10.1164/rccm.201802-0286OC.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Garito T, Roubenoff R, Hompesch M, Morrow L, Gomez K, Rooks D, et al. Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. Diabetes Obes Metab. 2018;20(1):94–102. https://doi.org/10.1111/dom.13042.

    Article  PubMed  CAS  Google Scholar 

  92. Busko M. Investigational drug reduces body fat in obese patients with diabetes. In: https://www.medscape.com/viewarticle/921019. Accessed 10 Dec 2019.

  93. Dehvari N, da Silva Junior ED, Bengtsson T, Hutchinson DS. Mirabegron: potential off target effects and uses beyond the bladder. Br J Pharmacol. 2018;175(21):4072–82. https://doi.org/10.1111/bph.14121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab. 2015;21(1):33–8. https://doi.org/10.1016/j.cmet.2014.12.009.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Siljee JE, Unmehopa UA, Kalsbeek A, Swaab DF, Fliers E, Alkemade A. Melanocortin 4 receptor distribution in the human hypothalamus. Eur J Endocrinol. 2013;168(3):361–9. https://doi.org/10.1530/EJE-12-0750.

    Article  PubMed  CAS  Google Scholar 

  96. Yang Y. Structure, function and regulation of the melanocortin receptors. Eur J Pharmacol. 2011;660(1):125–30. https://doi.org/10.1016/j.ejphar.2010.12.020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Huvenne H, Dubern B, Clement K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obesity Facts. 2016;9(3):158–73. https://doi.org/10.1159/000445061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Ayers KL, Glicksberg BS, Garfield AS, Longerich S, White JA, Yang P, et al. Melanocortin 4 receptor pathway dysfunction in obesity: patient stratification aimed at MC4R agonist treatment. J Clin Endocrinol Metab. 2018;103(7):2601–12. https://doi.org/10.1210/jc.2018-00258.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Kuhnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375(3):240–6. https://doi.org/10.1056/NEJMoa1512693.

    Article  PubMed  CAS  Google Scholar 

  100. Clement K, Biebermann H, Farooqi IS, Van der Ploeg L, Wolters B, Poitou C et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med 2018;24(5):551–5. doi:https://doi.org/10.1038/s41591-018-0015-9.

    Article  CAS  PubMed  Google Scholar 

  101. Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321–9. https://doi.org/10.1016/j.molmet.2017.06.015.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. 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(4):1639–45. https://doi.org/10.1210/jc.2014-4024.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 inhibitors: a review of their antidiabetic and cardioprotective effects. Int J Environ Res Public Health. 2019;16(16). https://doi.org/10.3390/ijerph16162965.

    Article  CAS  PubMed Central  Google Scholar 

  104. Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open. 2016;6(2):e009417. https://doi.org/10.1136/bmjopen-2015-009417.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity. 2014;22(4):1042–9. https://doi.org/10.1002/oby.20663.

    Article  PubMed  CAS  Google Scholar 

  106. Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition. Diabetes Obes Metab. 2016;18(2):125–34. https://doi.org/10.1111/dom.12578.

    Article  PubMed  CAS  Google Scholar 

  107. Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity. 2012;20(8):1645–52. https://doi.org/10.1038/oby.2012.59.

    Article  PubMed  CAS  Google Scholar 

  108. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1730–5. https://doi.org/10.2337/dc15-0355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Hollander P, Bays HE, Rosenstock J, Frustaci ME, Fung A, Vercruysse F, et al. Coadministration of canagliflozin and phentermine for weight management in overweight and obese individuals without diabetes: a randomized clinical trial. Diabetes Care. 2017;40(5):632–9. https://doi.org/10.2337/dc16-2427.

    Article  PubMed  CAS  Google Scholar 

  110. Lundkvist P, Sjostrom CD, Amini S, Pereira MJ, Johnsson E, Eriksson JW. Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab. 2017;19(1):49–60. https://doi.org/10.1111/dom.12779.

    Article  PubMed  CAS  Google Scholar 

  111. Axel AM, Mikkelsen JD, Hansen HH. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. 2010;35(7):1464–76. https://doi.org/10.1038/npp.2010.16.

    Article  CAS  Google Scholar 

  112. Hansen HH, Hansen G, Tang-Christensen M, Larsen PJ, Axel AM, Raben A, et al. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant. Eur J Pharmacol. 2010;636(1–3):88–95. https://doi.org/10.1016/j.ejphar.2010.03.026.

    Article  PubMed  CAS  Google Scholar 

  113. Sjodin A, Gasteyger C, Nielsen AL, Raben A, Mikkelsen JD, Jensen JK, et al. The effect of the triple monoamine reuptake inhibitor tesofensine on energy metabolism and appetite in overweight and moderately obese men. Int J Obes. 2010;34(11):1634–43. https://doi.org/10.1038/ijo.2010.87.

    Article  CAS  Google Scholar 

  114. 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(9653):1906–13. https://doi.org/10.1016/S0140-6736(08)61525-1.

    Article  PubMed  CAS  Google Scholar 

  115. Bentzen BH, Grunnet M, Hyveled-Nielsen L, Sundgreen C, Lassen JB, Hansen HH. Anti-hypertensive treatment preserves appetite suppression while preventing cardiovascular adverse effects of tesofensine in rats. Obesity. 2013;21(5):985–92. https://doi.org/10.1002/oby.20122.

    Article  PubMed  CAS  Google Scholar 

  116. Koch M. Cannabinoid receptor signaling in central regulation of feeding behavior: a mini-review. Front Neurosci. 2017;11:293. https://doi.org/10.3389/fnins.2017.00293.

    Article  PubMed  PubMed Central  Google Scholar 

  117. 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. 2002;136(4):550–7. https://doi.org/10.1038/sj.bjp.0704767.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001;134(6):1151–4. https://doi.org/10.1038/sj.bjp.0704379.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Kirkham TC, Williams CM. Endocannabinoid receptor antagonists: potential for obesity treatment. Treat Endocrinol. 2004;3(6):345–60. https://doi.org/10.2165/00024677-200403060-00003.

    Article  PubMed  CAS  Google Scholar 

  120. Nagappan A, Shin J, Jung MH. Role of cannabinoid receptor type 1 in insulin resistance and its biological implications. Int J Mol Sci. 2019;20(9). https://doi.org/10.3390/ijms20092109.

    Article  CAS  PubMed Central  Google Scholar 

  121. 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(9600):1706–13. https://doi.org/10.1016/S0140-6736(07)61721-8.

    Article  PubMed  CAS  Google Scholar 

  122. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, Group RI-ES. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389–97. https://doi.org/10.1016/S0140-6736(05)66374-X.

    Article  PubMed  CAS  Google Scholar 

  123. Hollander PA, Amod A, Litwak LE, Chaudhari U, Group AS. Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: the ARPEGGIO trial. Diabetes Care. 2010;33(3):605–7. https://doi.org/10.2337/dc09-0455.

    Article  PubMed  CAS  Google Scholar 

  124. Van Gaal L, Pi-Sunyer X, Despres JP, McCarthy C, Scheen A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care. 2008;31(Suppl 2):S229–40. https://doi.org/10.2337/dc08-s258.

    Article  PubMed  CAS  Google Scholar 

  125. Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2013;27(4):1621–30. https://doi.org/10.1096/fj.12-221580.

    Article  CAS  Google Scholar 

  126. Li S, Li Y, Xiang L, Dong J, Liu M, Xiang G. Sildenafil induces browning of subcutaneous white adipose tissue in overweight adults. Metab Clin Exp. 2018;78:106–17. https://doi.org/10.1016/j.metabol.2017.09.008.

    Article  PubMed  CAS  Google Scholar 

  127. Carbone F, Tack J. The effect of sildenafil on gastric motility and satiation in healthy controls. United European Gastroenterol J. 2018;6(6):846–54. https://doi.org/10.1177/2050640618766933.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Liang C, Curry BJ, Brown PL, Zemel MB. Leucine modulates mitochondrial biogenesis and SIRT1-AMPK signaling in C2C12 myotubes. Journal of Nutrition and Metabolism. 2014;2014:239750. https://doi.org/10.1155/2014/239750.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999;443(3):285–9. https://doi.org/10.1016/s0014-5793(98)01705-0.

    Article  PubMed  CAS  Google Scholar 

  130. Fu L, Li F, Bruckbauer A, Cao Q, Cui X, Wu R, et al. Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism. Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy. 2015;8:227–39. https://doi.org/10.2147/DMSO.S82338.

    Article  CAS  Google Scholar 

  131. Zemel MB, Kolterman O, Rinella M, Vuppalanchi R, Flores O, Barritt AS, et al. Randomized controlled trial of a leucine-metformin-sildenafil combination (NS-0200) on weight and metabolic parameters. Obesity. 2019;27(1):59–67. https://doi.org/10.1002/oby.22346.

    Article  PubMed  CAS  Google Scholar 

  132. Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr. 2008;88(4):906–12. https://doi.org/10.1093/ajcn/88.4.906.

    Article  PubMed  CAS  Google Scholar 

  133. Ostendorf DM, Caldwell AE, Creasy SA, Pan Z, Lyden K, Bergouignan A, et al. Physical activity energy expenditure and total daily energy expenditure in successful weight loss maintainers. Obesity. 2019;27(3):496–504. https://doi.org/10.1002/oby.22373.

    Article  PubMed  Google Scholar 

  134. Melby CL, Paris HL, Sayer RD, Bell C, Hill JO. Increasing energy flux to maintain diet-induced weight loss. Nutrients. 2019;11(10). https://doi.org/10.3390/nu11102533.

    Article  CAS  PubMed Central  Google Scholar 

  135. Petridou A, Siopi A, Mougios V. Exercise in the management of obesity. Metab Clin Exp. 2019;92:163–9. https://doi.org/10.1016/j.metabol.2018.10.009.

    Article  PubMed  CAS  Google Scholar 

  136. Foright RM, Presby DM, Sherk VD, Kahn D, Checkley LA, Giles ED, et al. Is regular exercise an effective strategy for weight loss maintenance? Physiol Behav. 2018;188:86–93. https://doi.org/10.1016/j.physbeh.2018.01.025.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(5):356–67. https://doi.org/10.1016/S2213-8587(19)30066-X.

    Article  PubMed  CAS  Google Scholar 

  138. Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–16. https://doi.org/10.1016/S2213-8587(16)30267-4.

    Article  PubMed  CAS  Google Scholar 

  139. Ludvik B, Frias JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370–81. https://doi.org/10.1016/S2213-8587(18)30023-8.

    Article  PubMed  CAS  Google Scholar 

  140. Miras AD, Perez-Pevida B, Aldhwayan M, Kamocka A, McGlone ER, Al-Najim W, et al. Adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(7):549–59. https://doi.org/10.1016/S2213-8587(19)30157-3.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexander Kokkinos.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Obesity Treatment

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsilingiris, D., Liatis, S., Dalamaga, M. et al. The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications. Curr Obes Rep 9, 136–149 (2020). https://doi.org/10.1007/s13679-020-00378-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13679-020-00378-x

Keywords

Navigation