Anti-obesity drug discovery: advances and challenges

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. The development of therapies that are capable of safely achieving sizeable and sustained body weight loss has proved tremendously challenging. Here, Müller et al. provide an overview of the history of anti-obesity drug development, focusing on lessons learned, ongoing challenges and recent advances in the field.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 334

1. 1.
   Health Effects of Overweight and Obesity in 195 Countries over 25 Years · 2017

   No notice
2. 2.

   Bauer UE, Briss PA, Goodman RA, Bowman BA. Prevention of chronic disease in the 21st century: elimination of the leading preventable causes of premature death and disability in the USA. Lancet. 2014;384:45-52.

   Not in our library10.1016/s0140-6736(14)60648-6

3. 3.

   Bjerregaard LG, et al. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N. Engl. J. Med. 2018;378:1302-1312.

   Not in our library10.1056/nejmoa1713231

4. 4.

   Twig G, et al. Body-mass index in 2.3 million adolescents and cardiovascular death in adulthood. N. Engl. J. Med. 2016;374:2430-2440.

   Not in our library10.1056/nejmoa1503840

5. 5.

   Berrington de Gonzalez A, et al. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211-2219.

   Not in our library10.1056/nejmoa1000367

6. 6.

   Calle EE. Obesity and cancer. BMJ. 2007;335:1107-1108.

   Not in our library10.1136/bmj.39384.472072.80

7. 7.

   Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003;348:1625-1638.

   Not in our library10.1056/nejmoa021423

8. 8.

   Belanger MJ, et al. Covid-19 and disparities in nutrition and obesity. N. Engl. J. Med. 2020;383:e69.

   Not in our library10.1056/nejmp2021264

9. 9.

   Arnold M, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 2015;16:36-46.

   Not in our library10.1016/s1470-2045(14)71123-4

10. 10.

    Arnold M, et al. Obesity and cancer: an update of the global impact. Cancer Epidemiol. 2016;41:8-15.

    Not in our library10.1016/j.canep.2016.01.003

11. 11.

    Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003;289:187-193.

    Not in our library10.1001/jama.289.2.187

12. 12.

    Prospective Studies C, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373:1083-1096.

    Not in our library10.1016/s0140-6736(09)60318-4

13. 13.

    Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet. 2002;360:473-482.

    Not in our library10.1016/s0140-6736(02)09678-2

14. 14.

    Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J. Health Econ. 2012;31:219-230.

    Not in our library10.1016/j.jhealeco.2011.10.003

15. 15.

    McAllister EJ, et al. Ten putative contributors to the obesity epidemic. Crit. Rev. Food Sci. Nutr. 2009;49:868-913.

    Not in our library10.1080/10408390903372599

16. 16.

    Cappuccio FP, et al. Meta-analysis of short sleep duration and obesity in children and adults. Sleep. 2008;31:619-626.

    Not in our library10.1093/sleep/31.5.619

17. 17.

    Noh J. The effect of circadian and sleep disruptions on obesity risk. J. Obes. Metab. Syndr. 2018;27:78-83.

    Not in our library10.7570/jomes.2018.27.2.78

18. 18.

    Scott KA, Melhorn SJ, Sakai RR. Effects of chronic social stress on obesity. Curr. Obes. Rep. 2012;1:16-25.

    Not in our library10.1007/s13679-011-0006-3

19. 19.

    Ness-Abramof R, Apovian CM. Drug-induced weight gain. Drugs Today. 2005;41:547-555.

    Not in our library10.1358/dot.2005.41.8.893630

20. 20.

    Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 1997;27:325-351.

    Not in our library10.1023/a:1025635913927

21. 21.

    Bray MS, et al. NIH working group report — using genomic information to guide weight management: from universal to precision treatment. Obesity. 2016;24:14-22.

    Not in our library10.1002/oby.21381

22. 22.
    Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture · 2013

    No notice
23. 23.

    Grjibovski AM, Olsen AO, Magnus P, Harris JR. Psoriasis in Norwegian twins: contribution of genetic and environmental effects. J. Eur. Acad. Dermatol. Venereol. 2007;21:1337-1343.

    Not in our library10.1111/j.1468-3083.2007.02268.x

24. 24.

    Katzmarzyk PT, et al. Familial resemblance for coronary heart disease risk: the HERITAGE Family Study. Ethn. Dis. 2000;10:138-147.

    Not in our library

25. 25.

    Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int. J. Cancer. 2002;99:260-266.

    Not in our library10.1002/ijc.10332

26. 26.

    Bray GA, Kim KK, Wilding JPH, World Obesity F. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes. Rev. 2017;18:715-723.

    Not in our library10.1111/obr.12551

27. 27.

    Burki T. European Commission classifies obesity as a chronic disease. Lancet Diabetes Endocrinol. 2021;9:418.

    Not in our library10.1016/s2213-8587(21)00145-5

28. 28.

    Bluher M. Obesity: global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 2019;15:288-298.

    Not in our library10.1038/s41574-019-0176-8

29. 29.

    Carlsson LMS, et al. Life expectancy after bariatric surgery in the Swedish Obese Subjects Study. N. Engl. J. Med. 2020;383:1535-1543.

    Not in our library10.1056/nejmoa2002449

30. 30.

    Adams TD, et al. Weight and metabolic outcomes 12 years after gastric bypass. N. Engl. J. Med. 2017;377:1143-1155.

    Not in our library10.1056/nejmoa1700459

31. 31.

    Farooqi IS. Defining the neural basis of appetite and obesity: from genes to behaviour. Clin. Med. 2014;14:286-289.

    Not in our library10.7861/clinmedicine.14-3-286

32. 32.
    Efficacy and Safety of Cathine (Nor-Pseudoephedrine) in the Treatment of Obesity: A Randomized Dose-Finding Study · 2017

    Not checked
33. 33.

    Lucchetta RC, et al. Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients. Clinics. 2017;72:317-324.

    Not in our library10.6061/clinics/2017(05)10

34. 34.

    Muller TD, Clemmensen C, Finan B, DiMarchi RD, Tschop MH. Anti-obesity therapy: from rainbow pills to polyagonists. Pharmacol. Rev. 2018;70:712-746.

    Not in our library10.1124/pr.117.014803

35. 35.

    Davies M, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397:971-984.

    Not in our library10.1016/s0140-6736(21)00213-0

36. 36.

    Rubino D, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414-1425.

    Not in our library10.1001/jama.2021.3224

37. 37.

    Wadden TA, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical tTrial. JAMA. 2021;325:1403-1413.

    Not in our library10.1001/jama.2021.1831

38. 38.

    Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 2021;384:989.

    Not in our library10.1056/nejmoa2032183

39. 39.

    Tak YJ, Lee SY. Anti-obesity drugs: long-term efficacy and safety: an updated review. World J. Mens Health. 2020;39:208-221.

    Not in our library10.5534/wjmh.200010

40. 40.

    Bray GA, Fruhbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. 2016;387:1947-1956.

    Not in our library10.1016/s0140-6736(16)00271-3

Cited by papers we hold 8

• Global, regional, and national prevalence of adult overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021 · 2025
  Corrected
• Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial · 2024
  No notice
• Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management · 2023
  No notice
• Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments · 2023
  No notice
• BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy · 2022
  No notice
• Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes · 2022
  No notice
• Signaling pathways in obesity: mechanisms and therapeutic interventions · 2022
  Corrected
• The Related Metabolic Diseases and Treatments of Obesity · 2022
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.