Anti-obesity Drug Discovery: Advances and Challenges

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2021 Nov 24

PMID 34815532

Citations 274

Authors

Timo D Muller

Matthias Bluher

Matthias H Tschop

Richard D DiMarchi

Affiliations

Soon will be listed here.

Abstract

Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.

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References

Muller T, Clemmensen C, Finan B, DiMarchi R, Tschop M . Anti-Obesity Therapy: from Rainbow Pills to Polyagonists. Pharmacol Rev. 2018; 70(4):712-746. DOI: 10.1124/pr.117.014803. View

Hendricks E, Greenway F, Westman E, Gupta A . Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring). 2011; 19(12):2351-60. DOI: 10.1038/oby.2011.94. View

Kjeldsen-Kragh J, Hvatum M, Haugen M, Forre O, Scott H . Antibodies against dietary antigens in rheumatoid arthritis patients treated with fasting and a one-year vegetarian diet. Clin Exp Rheumatol. 1995; 13(2):167-72. View

Clement K, van den Akker E, Argente J, Bahm A, Chung W, Connors H . Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020; 8(12):960-970. DOI: 10.1016/S2213-8587(20)30364-8. View

Tschop M, Speakman J, Arch J, Auwerx J, Bruning J, Chan L . A guide to analysis of mouse energy metabolism. Nat Methods. 2011; 9(1):57-63. PMC: 3654855. DOI: 10.1038/nmeth.1806. View

Geisler J . 2,4 Dinitrophenol as Medicine. Cells. 2019; 8(3). PMC: 6468406. DOI: 10.3390/cells8030280. View

Xue A, Wu Y, Zhu Z, Zhang F, Kemper K, Zheng Z . Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018; 9(1):2941. PMC: 6063971. DOI: 10.1038/s41467-018-04951-w. View

Skibicka K, Hansson C, Alvarez-Crespo M, Friberg P, Dickson S . Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience. 2011; 180:129-37. DOI: 10.1016/j.neuroscience.2011.02.016. View

Clement K, Biebermann H, Farooqi I, van der Ploeg L, Wolters B, Poitou C . MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24(5):551-555. DOI: 10.1038/s41591-018-0015-9. View

10.

Collet T, Dubern B, Mokrosinski J, Connors H, Keogh J, Mendes de Oliveira E . Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017; 6(10):1321-1329. PMC: 5641599. DOI: 10.1016/j.molmet.2017.06.015. View

11.

Yanovski S, Yanovski J . Obesity. N Engl J Med. 2002; 346(8):591-602. DOI: 10.1056/NEJMra012586. View

12.

Frias J, Davies M, Rosenstock J, Perez Manghi F, Lando L, Bergman B . Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021; 385(6):503-515. DOI: 10.1056/NEJMoa2107519. View

13.

Greenway F, Fujioka K, Plodkowski R, Mudaliar S, Guttadauria M, Erickson J . 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. Lancet. 2010; 376(9741):595-605. DOI: 10.1016/S0140-6736(10)60888-4. View

14.

Riediger T, Schmid H, Lutz T, Simon E . Amylin potently activates AP neurons possibly via formation of the excitatory second messenger cGMP. Am J Physiol Regul Integr Comp Physiol. 2001; 281(6):R1833-43. DOI: 10.1152/ajpregu.2001.281.6.R1833. View

15.

Arnold M, Leitzmann M, Freisling H, Bray F, Romieu I, Renehan A . Obesity and cancer: An update of the global impact. Cancer Epidemiol. 2016; 41:8-15. DOI: 10.1016/j.canep.2016.01.003. View

16.

Haqq A, Grambow S, Muehlbauer M, Newgard C, Svetkey L, Carrel A . Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development. Clin Endocrinol (Oxf). 2008; 69(6):911-20. PMC: 2614621. DOI: 10.1111/j.1365-2265.2008.03385.x. View

17.

Maes H, Neale M, Eaves L . Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997; 27(4):325-51. DOI: 10.1023/a:1025635913927. View

18.

Lowe M, Phelan S . Weight-loss maintenance in overweight individuals one to five years following successful completion of a commercial weight loss program. Int J Obes Relat Metab Disord. 2001; 25(3):325-31. DOI: 10.1038/sj.ijo.0801521. View

19.

Clapper J, Athanacio J, Wittmer C, Griffin P, DSouza L, Parkes D . Effects of amylin and bupropion/naltrexone on food intake and body weight are interactive in rodent models. Eur J Pharmacol. 2012; 698(1-3):292-8. DOI: 10.1016/j.ejphar.2012.11.010. View

20.

Nissen S, Wolski K, Prcela L, Wadden T, Buse J, Bakris G . 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. DOI: 10.1001/jama.2016.1558. View