#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

New horizons in the drug treatment of obesity


Authors: V. Hainer;  R. Taxová Braunerová;  P. Kalousková;  M. Kunešová
Authors‘ workplace: Endokrinologický ústav Centrum pro diagnostiku a léčbu obezity Ředitelka: doc. RNDr. Běla Bendlová, CSc.
Published in: Prakt. Lék. 2023; 103(4): 163-169
Category: Reviews

Overview

Only modest or transient weight loss achieved with most anti-obesity medications available in the past failed to meet expectations of both patients and physicians. Drug combinations and gut hormone analogues represent a new, more efficient and safe approach to the treatment of obesity and related health risks. Initially, gut hormone analogues, e.g. glucagon like peptide-1 (GLP-1) agonist liraglutide, have successfully been applied for the treatment of type 2 diabetes and later on for the treatment of obesity. The paper reports on the phase 3 clinical trials in obesity management with novel gut hormone analogues, GLP-1 agonist semaglutide and dual gut hormone agonist tirzepatide, a single molecule which targets receptors of two gut hormones, GLP1-1 and glucose-dependent insulinotropic polypeptide (GIP). Both semaglutide and tirzepatide are applied subcutaneously once-weekly. Weight loss achieved with these new drugs, particularly with tirzepatide, is comparable to that observed with less invasive bariatric procedures and is accompanied by significant improvements in cardiometabolic risks and favorable safety profile. Observed gastrointestinal adverse events with these medications were usually transient and mild to moderate in severity. Semaglutide has been approved as an anti-obesity drug for long-term weight management by the European Medicines Agency (EMA) while tirzepatide is waiting for its approval. Clinical studies with oral semaglutide, triple incretin agonist retatrutide, non-peptide GLP-1 oral agonist orforglipron and cagrilintide/semaglutide combination also provided promising results in the weight management. On the other hand, setmelanotide is a drug that acts on the melanocortin-4 receptor (MC4R) and is designated for the treatment of very rare monogenic disorders exhibiting severe obesity in early childhood, e.g. deficiency of proopiomelanocortin or leptin receptor. Individually tailored treatment with antiobesity drugs should be an integral part of the comprehensive obesity management which includes diet, exercise and cognitive behavioral intervention. Well educated physicians should ensure the success of treatment by antiobesity drugs. In addition, health authorities and health insurance companies should consider that the cost of new antiobesity drugs prevents such efficient treatment in most of indicated patients and therefore the measures to arrange appropriate availability of these drugs should be adopted.

Keywords:

semaglutide – Weight loss – antiobesity drugs – tirzepatide – setmelanotide – gut hormone analogues – cardiometabolic risks


Sources
  1. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label randomized clinical trial. Diabetes Care 2018; 41(2): 258–266.
  2. Ahrén B, Masmiquel L, Kumar H, 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 trial. Lancet Diabetes Endocrinol. 2017; 5(5): 341–354.
  3. Aldhoon-Hainerová I. Obezita v dětství a dospívání. Geneticky podmíněná obezita. In: Hainer V, a kol. Základy klinické obezitologie. 3., zcela přepracované a doplněné vydání. Praha: Grada Publishing 2022; 432–435.
  4. Aroda VR, Bain SC, Cariou B, 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(5): 355–366.
  5. Clément K, Biebermann H, Farooqi IS, et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24: 551–555.
  6. Davies M, Faerch L, Jeppesen OK. 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 Diabetes Endocrinol. 2021; 397: 971–984.
  7. Eliaschewitz FG, Canani LH. Advances in GLP-1 treatment: focus on oral semaglutide. Diabetol Metab Syndr 2021; 13(1): 99.
  8. Farooqi IS, Jebb SA, Langmack G, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999; 341: 879–894.
  9. Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022; 28: 2083–2091.
  10. Hainer V. Comparative efficiency and safety of pharmacological approaches to the management of obesity. Diabetes Care. 2011; 34 (Suppl 2): S349–S354.
  11. Hainer V, Haluzík M. Farmakoterapie obezity. In: Hainer V, a kol. Základy klinické obeziotologie. 3., zcela přepracované a doplněné vydání. Praha: Grada Publishing 2022; 341–372.
  12. Hainer V, Kunešová M, Taxová Braunerová R, AldhoonHainerová I. Duální agonista inkretinových recptorů tirzepatid: nové antidiabetikum je nadějnou perspektivou v léčbě obezity. DMEV. 2022; 25: 136–140.
  13. Haluzík M, Müllerová D, Sucharda P, a kol. Farmakoterapie obezity-update 2023. Čas. Lék. čes. 2023; 162: 19–31.
  14. Haluzík M. Semaglutid. Remedia. 2019; 29: 25–31.
  15. Haqq AM, Chung WK, Dolfuss H, et al. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022; 10: 859–868.
  16. Haws R, Brady S, Davis E, et al. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020; 22: 2133–2140.
  17. Chao AM, Tronieri JS, Amaro A, Wadden TA. Clinical insight on semaglutide for chronic weight management in adults: Patient selection and special consideration. Drug Design Develop Ther. 2022; 16: 4449–4461.
  18. Chavda VP, Ajabiya J, Teli D, et al. Tirzepatide, a new era of dual-targeted treatment for diabetes and obesity: A mini-review. Molecules. 2022; 27: 4315.
  19. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022; 387(3): 205–216.
  20. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormonereceptor agonist retatrutide for obesity – A phase 2 trial. N Engl J Med. 2023; 389(6): 514–526.
  21. Jendle J, Birkenfeld AL, Polonsky WH, et al. Improved treatment satisfaction in patients with type 2 diabetes treated with once-weekly semaglutide in the SUSTAIN trials. Diabetes Obes Metab. 2019; 21: 2315–2326.
  22. Jeon E, Lee KY, Kim K-K. Approved anti-obesity medications in 2022 KSSO guidelines and promise of phase 3 clinical trials: Anti-obesity drugs in the sky and on the horizon. J Obes Metab Syndr. 2023; 32: 106–120.
  23. Karagiannis T, Avgerinos I, Liakos A, et al. Management of type 2 diabetes with dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia. 2022; 65: 1251–1261.
  24. Knop FK, Aroda VR, de Vale RD, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 402(10403): 705–719.
  25. Kunešová M, Müllerová D, Hainer V. Epidemiologie a zdravotní rizika obezity. In: Hainer V, a kol. Základy klinické obezitologie. 3., zcela přepracované a doplněné vydání. Praha: Grada Publishing 2022; 19–43.
  26. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2,4 mg for the treatment of obesity: Key elements of the STEP trials 1 to 5. Obesity. 2020; 28: 1050–1061.
  27. Kühnen P, Clément K, Wiegand S, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Eng J Med. 2016; 375: 240–246.
  28. Kühnen P, Wabitsch M, von Schnurbein J, et al. Quality of life outcomes in two phase 3 trials of setmelanotide in patients with obesity due to LEPR or POMC deficiency. Orphanet J Rare Dis. 2022; 17(1): 38.
  29. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375: 1834–1844.
  30. Murvelashvili N, Xie L, Schellinger JN, et al. Effectiveness of semaglutide versus liraglutide for treating post-metabolic and bariatric surgery weight recurrence. Obesity (Silver Spring). 2023; 31: 1280–1289.
  31. Nauck MA, D´Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regarding glycaemic control and body weight reduction. Cardiovasc Diabetol. 2022; 21: 169.
  32. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label phase 3b trial. Lancet Diabetes Endocrinol. 2018; 6: 275–286.
  33. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial. J Clin Endocrinol Metab. 2018; 103: 2291–2301.
  34. Rubino D, Abrahamsson N, Davies M, 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.
  35. Ryan DH, Lingvay I, Colhoun HM, et al. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am Heart J. 2020; 229: 61–69.
  36. Seyd YY. Tirzepatide: First approval. Drugs. 2022; 82: 1213–1220.
  37. Singh G, Krauthamer M, Bjalme-Evans M. Wegovy (semaglutide): a new weight loss drug for chronic weight management. J Invest Med. 2022; 70: 5–13.
  38. Sorli S, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once-weekly semaglutide monotherpy versus placebo in patients with type 2 diabetes (SUSTAIN 1) a double-blind, randomised, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017; 5: 251–260.
  39. Wabitsch M, Farooqi S, Flück CE, et al. Natural history of obesity due to POMC, PCSK1, and LEPR deficiency and the impact of setmelanotide. J Endocr Soc. 2022; 6: 1–9.
  40. Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity. Am Psychol. 2020; 75: 235–251.
  41. Wadden TA, Bailey TS, Billings LK, 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 STEP3 randomized clinical trial. JAMA. 2021; 325: 1403–1413.
  42. Weghuber D, Barrett T, Barrientos-Pérez M, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. 2022; 387: 2245–2257.
  43. Wharton S, Blevins T, Connery L, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023 Jun 23. doi: 10.1056/NEJMoa2302392 [Online ahead of print].
  44. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384: 989–1002.
Labels
General practitioner for children and adolescents General practitioner for adults
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#