1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Medicine
  4. Volume 74, 2023
  5. Article

Annual Review of Medicine

Volume 74, 2023

New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics

Abstract

Nearly half of Americans are projected to have obesity by 2030, underscoring the pressing need for effective treatments. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) represent the first agents in a rapidly evolving, highly promising landscape of nascent hormone-based obesity therapeutics. With the understanding of the neurobiology of obesity rapidly expanding, these emerging entero-endocrine and endo-pancreatic agents combined or coformulated with GLP-1 RAs herald a new era of targeted, mechanism-based treatment of obesity. This article reviews GLP-1 RAs in the treatment of obesity and previews the imminent future of nutrient-stimulated hormone-based anti-obesity therapeutics.

Keyword(s): antiobesity medications, dual receptor agonists, GLP-1 receptor agonists, NuSH-based therapies, nutrient-stimulated hormone-based therapies, triple receptor agonists
Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-043021-014919
2023-01-27
2024-05-03
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-043021-014919.html?itemId=/content/journals/10.1146/annurev-med-043021-014919&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Jastreboff AM, Kotz CM, Kahan S et al. 2019. Obesity as a disease: the Obesity Society 2018 position statement. Obesity 27:7–9
     [Google Scholar]
  2. 2.
    Schwartz MW, Seeley RJ, Zeltser LM et al. 2017. Obesity pathogenesis: an Endocrine Society scientific statement. Endocr. Rev. 38:267–96
     [Google Scholar]
  3. 3.
    Khera R, Murad MH, Chandar AK et al. 2016. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 315:2424–34
     [Google Scholar]
  4. 4.
    Chaudhri O, Small C, Bloom S. 2006. Gastrointestinal hormones regulating appetite. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361:1187–209
     [Google Scholar]
  5. 5.
    Nauck MA, Meier JJ. 2016. GLP-1 receptor agonists and SGLT2 inhibitors: a couple at last?. Lancet Diabetes Endocrinol. 4:963–64
     [Google Scholar]
  6. 6.
    Verdich C, Flint A, Gutzwiller JP et al. 2001. A meta-analysis of the effect of glucagon-like peptide-1 (7–36) amide on ad libitum energy intake in humans. J. Clin. Endocrinol. Metab. 86:4382–89
     [Google Scholar]
  7. 7.
    Drucker DJ. 2016. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 24:15–30
     [Google Scholar]
  8. 8.
    Ryan DH, Lingvay I, Colhoun HM et al. 2020. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design. Am. Heart J. 229:61–69
     [Google Scholar]
  9. 9.
    Baggio LL, Drucker DJ. 2014. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. J. Clin. Investig. 124:4223–26
     [Google Scholar]
  10. 10.
    Nauck MA, Quast DR, Wefers J, Meier JJ. 2021. GLP-1 receptor agonists in the treatment of type 2 diabetes—state-of-the-art. Mol. Metab. 46:101102
     [Google Scholar]
  11. 11.
    Gabery S, Salinas CG, Paulsen SJ et al. 2020. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5:e133429
     [Google Scholar]
  12. 12.
    Secher A, Jelsing J, Baquero AF et al. 2014. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Investig. 124:4473–88
     [Google Scholar]
  13. 13.
    Jastreboff AM, Lacadie C, Seo D et al. 2014. Leptin is associated with exaggerated brain reward and emotion responses to food images in adolescent obesity. Diabetes Care 37:3061–68
     [Google Scholar]
  14. 14.
    Grill HJ. 2020. A role for GLP-1 in treating hyperphagia and obesity. Endocrinology 161:bqaa093
     [Google Scholar]
  15. 15.
    Blundell J, Finlayson G, Axelsen M et al. 2017. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes. Metab. 19:1242–51
     [Google Scholar]
  16. 16.
    Friedrichsen M, Breitschaft A, Tadayon S et al. 2021. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes Obes. Metab. 23:754–62
     [Google Scholar]
  17. 17.
    Tronieri JS, Wadden TA, Walsh O et al. 2020. Effects of liraglutide on appetite, food preoccupation, and food liking: results of a randomized controlled trial. Int. J. Obes. 44:353–61
     [Google Scholar]
  18. 18.
    Nauck MA, Quast DR, Meier JJ. 2021. Another milestone in the evolution of GLP-1-based diabetes therapies. Nat. Med. 27:952–53
     [Google Scholar]
  19. 19.
    Ard J, Fitch A, Fruh S, Herman L. 2021. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv. Ther. 38:2821–39
     [Google Scholar]
  20. 20.
    Almandoz JP, Lingvay I, Morales J, Campos C. 2020. Switching between glucagon-like peptide-1 receptor agonists: rationale and practical guidance. Clin. Diabetes 38:390–402
     [Google Scholar]
  21. 21.
    Gossmann M, Butsch WS, Jastreboff AM. 2021. Treating the chronic disease of obesity. Med. Clin. North Am. 105:983–1016
     [Google Scholar]
  22. 22.
    Knudsen LB, Lau J. 2019. The discovery and development of liraglutide and semaglutide. Front. Endocrinol. 10:155
     [Google Scholar]
  23. 23.
    Bode B. 2012. An overview of the pharmacokinetics, efficacy and safety of liraglutide. Diabetes Res. Clin. Pract. 97:27–42
     [Google Scholar]
  24. 24.
    Pi-Sunyer X, Astrup A, Fujioka K et al. 2015. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373:11–22
     [Google Scholar]
  25. 25.
    Davies MJ, Bergenstal R, Bode B et al. 2015. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE Diabetes randomized clinical trial. JAMA 314:687–99
     [Google Scholar]
  26. 26.
    Wadden TA, Tronieri JS, Sugimoto D et al. 2020. Liraglutide 3.0 mg and intensive behavioral therapy (IBT) for obesity in primary care: the SCALE IBT randomized controlled trial. Obesity 28:529–36
     [Google Scholar]
  27. 27.
    Wadden TA, Hollander P, Klein S et al. 2013. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int. J. Obes. 37:1443–51
     [Google Scholar]
  28. 28.
    le Roux CW, Astrup A, Fujioka K et al. 2017. 3 Years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389:1399–409
     [Google Scholar]
  29. 29.
    Kelly AS, Auerbach P, Barrientos-Perez M et al. 2020. A randomized, controlled trial of liraglutide for adolescents with obesity. N. Engl. J. Med. 382:2117–28
     [Google Scholar]
  30. 30.
    Christou GA, Katsiki N, Blundell J et al. 2019. Semaglutide as a promising antiobesity drug. Obes. Rev. 20:805–15
     [Google Scholar]
  31. 31.
    Lau J, Bloch P, Schaffer L et al. 2015. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J. Med. Chem. 58:7370–80
     [Google Scholar]
  32. 32.
    Kushner RF, Calanna S, Davies M et al. 2020. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP Trials 1 to 5. Obesity 28:1050–61
     [Google Scholar]
  33. 33.
    Wilding JPH, Batterham RL, Calanna S et al. 2021. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384:989–1002
     [Google Scholar]
  34. 34.
    Davies M, Faerch L, Jeppesen OK et al. 2021. 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 397:971–84
     [Google Scholar]
  35. 35.
    Wadden TA, Bailey TS, Billings LK et al. 2021. Effect of subcutaneous semaglutide versus placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 325:1403–13
     [Google Scholar]
  36. 36.
    Rubino D, Abrahamsson N, Davies M et al. 2021. Effect of continued weekly subcutaneous semaglutide versus placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 325:1414–25
     [Google Scholar]
  37. 37.
    Rubino DM, Greenway FL, Khalid U et al. 2022. Effect of weekly subcutaneous semaglutide versus daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA 327:138–50
     [Google Scholar]
  38. 37a.
    Garvey WT, Batterham RL, Bhatta Met al 2022. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat. Med 28:2083–91
     [Google Scholar]
  39. 38.
    Wilding JPH, Batterham RL, Davies M et al. 2022. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes. Metab. 24:1553–64
     [Google Scholar]
  40. 39.
    Aronne LJ, Hall KD, Jakicic JM et al. 2021. Describing the weight-reduced state: physiology, behavior, and interventions. Obesity 29:Suppl. 1S9–24
     [Google Scholar]
  41. 40.
    Kim HS, Jung CH. 2021. Oral semaglutide, the first ingestible glucagon-like peptide-1 receptor agonist: Could it be a magic bullet for type 2 diabetes?. Int. J. Mol. Sci. 22:ijms22189936
     [Google Scholar]
  42. 41.
    Bucheit JD, Pamulapati LG, Carter N et al. 2020. Oral semaglutide: a review of the first oral glucagon-like peptide 1 receptor agonist. Diabetes Technol. Ther. 22:10–18
     [Google Scholar]
  43. 42.
    Aroda VR, Rosenstock J, Terauchi Y et al. 2019. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care 42:1724–32
     [Google Scholar]
  44. 43.
    Saxena AR, Gorman DN, Esquejo RM et al. 2021. Danuglipron (PF-06882961) in type 2 diabetes: a randomized, placebo-controlled, multiple ascending-dose phase 1 trial. Nat. Med. 27:1079–87
     [Google Scholar]
  45. 44.
    Butler PC, Chou J, Carter WB et al. 1990. Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes 39:752–56
     [Google Scholar]
  46. 45.
    Hartter E, Svoboda T, Ludvik B et al. 1991. Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans. Diabetologia 34:52–54
     [Google Scholar]
  47. 46.
    Asmar M, Bache M, Knop FK et al. 2010. Do the actions of glucagon-like peptide-1 on gastric emptying, appetite, and food intake involve release of amylin in humans?. J. Clin. Endocrinol. Metab. 95:2367–75
     [Google Scholar]
  48. 47.
    Li Z, Kelly L, Heiman M et al. 2015. Hypothalamic amylin acts in concert with leptin to regulate food intake. Cell Metab. 22:1059–67
     [Google Scholar]
  49. 48.
    Lutz TA. 2012. Control of energy homeostasis by amylin. Cell. Mol. Life Sci. 69:1947–65
     [Google Scholar]
  50. 49.
    Mietlicki-Baase EG, Rupprecht LE, Olivos DR et al. 2013. Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake. Neuropsychopharmacology 38:1685–97
     [Google Scholar]
  51. 50.
    Mietlicki-Baase EG, Reiner DJ, Cone JJ et al. 2015. Amylin modulates the mesolimbic dopamine system to control energy balance. Neuropsychopharmacology 40:372–85
     [Google Scholar]
  52. 51.
    Boccia L, Gamakharia S, Coester B et al. 2020. Amylin brain circuitry. Peptides 132:170366
     [Google Scholar]
  53. 52.
    Lau DCW, Erichsen L, Francisco AM et al. 2021. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet 398:2160–72
     [Google Scholar]
  54. 53.
    Enebo LB, Berthelsen KK, Kankam M et al. 2021. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet 397:1736–48
     [Google Scholar]
  55. 54.
    Pelle MC, Provenzano M, Zaffina I et al. 2021. Role of a dual glucose-dependent insulinotropic peptide (GIP)/glucagon-like peptide-1 receptor agonist (twincretin) in glycemic control: from pathophysiology to treatment. Life 12:29
     [Google Scholar]
  56. 55.
    Dupre J, Ross SA, Watson D, Brown JC. 1973. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab. 37:826–28
     [Google Scholar]
  57. 56.
    Nauck MA, Heimesaat MM, Orskov C et al. 1993. Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Investig. 91:301–7
     [Google Scholar]
  58. 57.
    Piteau S, Olver A, Kim SJ et al. 2007. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochem. Biophys. Res. Commun. 362:1007–12
     [Google Scholar]
  59. 58.
    Baggio LL, Drucker DJ. 2007. Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–57
     [Google Scholar]
  60. 59.
    Usdin TB, Mezey E, Button DC et al. 1993. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 133:2861–70
     [Google Scholar]
  61. 60.
    Nyberg J, Anderson MF, Meister B et al. 2005. Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J. Neurosci. 25:1816–25
     [Google Scholar]
  62. 61.
    Adriaenssens AE, Biggs EK, Darwish T et al. 2019. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab. 30:987–96.e6
     [Google Scholar]
  63. 62.
    Coskun T, Sloop KW, Loghin C et al. 2018. 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. 18:3–14
     [Google Scholar]
  64. 63.
    Rosenstock J, Wysham C, Frias JP et al. 2021. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 398:143–55
     [Google Scholar]
  65. 64.
    Capozzi ME, DiMarchi RD, Tschop MH et al. 2018. Targeting the incretin/glucagon system with triagonists to treat diabetes. Endocr. Rev. 39:719–38
     [Google Scholar]
  66. 65.
    Del Prato S, Kahn SE, Pavo I et al. 2021. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 398:1811–24
     [Google Scholar]
  67. 66.
    Dahl D, Onishi Y, Norwood P et al. 2022. Effect of subcutaneous tirzepatide versus placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA 327:534–45
     [Google Scholar]
  68. 67.
    Frias JP, Davies MJ, Rosenstock J et al. 2021. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385:503–15
     [Google Scholar]
  69. 68.
    Ludvik B, Giorgino F, Jodar E et al. 2021. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet 398:583–98
     [Google Scholar]
  70. 69.
    Jastreboff AM, Aronne LJ, Ahmad NN et al. 2022. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387:205–16
     [Google Scholar]
  71. 70.
    Sutherland EW, Cori CF. 1948. Influence of insulin preparations on glycogenolysis in liver slices. J. Biol. Chem. 172:737–50
     [Google Scholar]
  72. 71.
    Muller WA, Faloona GR, Aguilar-Parada E, Unger RH. 1970. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N. Engl. J. Med. 283:109–15
     [Google Scholar]
  73. 72.
    Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. 1970. Studies of pancreatic alpha cell function in normal and diabetic subjects. J. Clin. Investig. 49:837–48
     [Google Scholar]
  74. 73.
    Muller WA, Faloona GR, Unger RH. 1971. The influence of the antecedent diet upon glucagon and insulin secretion. N. Engl. J. Med. 285:1450–54
     [Google Scholar]
  75. 74.
    Langhans W, Zeiger U, Scharrer E, Geary N. 1982. Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon. Science 218:894–96
     [Google Scholar]
  76. 75.
    Doi K, Kuroshima A. 1982. Modified metabolic responsiveness to glucagon in cold-acclimated and heat-acclimated rats. Life Sci. 30:785–91
     [Google Scholar]
  77. 76.
    Campbell JE, Drucker DJ. 2015. Islet alpha cells and glucagon—critical regulators of energy homeostasis. Nat. Rev. Endocrinol. 11:329–38
     [Google Scholar]
  78. 77.
    Arrubla J. 2021. Poster 231: Phase I study of glucagon-like peptide-1/glucagon receptor dual agonist BI 456906 in obesity. Obesity 29:Suppl. 2231 (Abstr.)
    [Google Scholar]
  79. 78.
    Coskun T, Urva S, Roell WC et al. 2022. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab 34:1234–47.e9
     [Google Scholar]
  80. 79.
    Muller TD, Finan B, Bloom SR et al. 2019. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30:72–130
     [Google Scholar]
  81. 80.
    Bliss ES, Whiteside E. 2018. The gut-brain axis, the human gut microbiota and their integration in the development of obesity. Front. Physiol. 9:900
     [Google Scholar]
  82. 81.
    Boyle CN, Lutz TA, Le Foll C 2018. Amylin—its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol. Metab. 8:203–10
     [Google Scholar]
  83. 82.
    Lutz TA. 2022. Creating the amylin story. Appetite 172:105965
     [Google Scholar]
  84. 83.
    Christoffersen BO, Skyggebjerg RB, Bugge A et al. 2020. Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Gottingen minipigs. Int. J. Obes. 44:447–56
     [Google Scholar]
  85. 84.
    Zigman JM, Bouret SG, Andrews ZB. 2016. Obesity impairs the action of the neuroendocrine ghrelin system. Trends Endocrinol. Metab. 27:54–63
     [Google Scholar]
  86. 85.
    Holst JJ, Rosenkilde MM. 2020. GIP as a therapeutic target in diabetes and obesity: insight from incretin co-agonists. J. Clin. Endocrinol. Metab. 105:e2710–16
     [Google Scholar]
  87. 86.
    Holst JJ. 2019. The incretin system in healthy humans: the role of GIP and GLP-1. Metabolism 96:46–55
     [Google Scholar]
  88. 87.
    Galsgaard KD, Pedersen J, Knop FK et al. 2019. Glucagon receptor signaling and lipid metabolism. Front. Physiol. 10:413
     [Google Scholar]
  89. 88.
    Koska J, DelParigi A, de Courten B et al. 2004. Pancreatic polypeptide is involved in the regulation of body weight in Pima Indian male subjects. Diabetes 53:3091–96
     [Google Scholar]
/content/journals/10.1146/annurev-med-043021-014919
Loading
New Frontiers in Obesity Treatment: GLP-1 and Nascent Nutrient-Stimulated Hormone-Based Therapeutics
Annual Review of Medicine 74, 125 (2023); https://doi.org/10.1146/annurev-med-043021-014919
/content/journals/10.1146/annurev-med-043021-014919
/content/journals/10.1146/annurev-med-043021-014919
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error