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Drug Safety

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Benefit-Risk Assessment of Obesity Drugs: Focus on Glucagon-like Peptide-1 Receptor Agonists

  • Rasmus M. Christensen
  • Christian R. Juhl
  • Signe S. TorekovEmail author
Review Article

Abstract

The prevalence of obesity and related comorbidities is increasing worldwide. Furthermore,  clinically meaningful body weight losses has proven difficult to achieve and especially to maintain through sustained lifestyle change in the form of diet and exercise. Pharmacotherapy against obesity is a non-invasive treatment as an adjunct to lifestyle changes, but approved anti-obesity drugs are currently few. This article reviews the major anti-obesity drugs and the benefit-risk profiles of the long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide (a modified version of liraglutide with longer half-life and tripled receptor affinity). Generally, GLP-1 RAs are well tolerated and induce significant weight loss and lowering of comorbidities. Studies with liraglutide 3.0 mg/day have shown an average placebo-subtracted weight loss of 5.5 kg (range 4.6–5.9) in 1- to 3-year duration trials. One trial using semaglutide 0.4 mg once daily reported an average weight loss of 11.6% (~ 13.1 kg) after 1 year. Furthermore, semaglutide induced a ~ 6 percentage point larger placebo-subtracted body weight loss in a head-to-head comparison with liraglutide (11.6 vs. 5.5% weight loss, respectively). The safety profiles for both drugs were similar, with transient gastrointestinal disorders being the most commonly reported adverse events. The longest running trial and the most recent trials have not raised any new safety concerns. Long-term trials and post-marketing surveillance is warranted to fully assess both long-term efficacy and safety. Future combinational therapies of mimicked gut hormones involved in regulation of energy homeostasis and/or additional lifestyle change in the form of exercise might further improve efficacy.

Notes

Author contributions

Conceptualisation and methodology: SST. Writing first draft: RMC. Critically editing, re-writing, analysing and reviewing the manuscript: SST, RMC, and CRJ.

Compliance with Ethical Standards

Funding

This work was supported by the Tripartite Immunometabolism Consortium [TrIC], Novo Nordisk Foundation; grant number NNF15CC0018486.

Conflict of interest

Rasmus Michael Christensen was supported by the Novo Nordisk Foundation, grant number NNF15CC0018486. Christian Rimer Juhl has no conflicts of interest that are directly relevant to the content of this article. Signe Sørensen Torekov has received research grants from the Novo Nordisk Foundation and Novo Nordisk A/S.

References

  1. 1.
    World Health Organization. Obesity and overweight. 2018. http://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 28 Mar 2019.
  2. 2.
    World Health Organization. Prevalence of obesity among adults, BMI ≥ 30, age-standardized Estimates by WHO region. 2017. http://apps.who.int/gho/data/view.main.REGION2480A?lang=en. Accessed 28 Mar 2019.
  3. 3.
    Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009;9:88.  https://doi.org/10.1186/1471-2458-9-88.Google Scholar
  4. 4.
    Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121(6):21–33.  https://doi.org/10.3810/pgm.2009.11.2074.Google Scholar
  5. 5.
    Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Affairs (Project Hope). 2009;28(5):w822–31.  https://doi.org/10.1377/hlthaff.28.5.w822.Google Scholar
  6. 6.
    Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003;138(1):24–32.Google Scholar
  7. 7.
    Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985–3023.  https://doi.org/10.1016/j.jacc.2013.11.004.
  8. 8.
    The Look AHEAD Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity (Silver Spring, Md). 2014;22(1):5–13.  https://doi.org/10.1002/oby.20662.Google Scholar
  9. 9.
    Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34(7):1481–6.  https://doi.org/10.2337/dc10-2415.Google Scholar
  10. 10.
    Fildes A, Charlton J, Rudisill C, Littlejohns P, Prevost AT, Gulliford MC. Probability of an obese person attaining normal body weight: cohort study using electronic health records. Am J Public Health. 2015;105(9):e54–9.  https://doi.org/10.2105/AJPH.2015.302773.Google Scholar
  11. 11.
    Fried M, Yumuk V, Oppert JM, Scopinaro N, Torres A, Weiner R, et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg. 2014;24(1):42–55.  https://doi.org/10.1007/s11695-013-1079-8.Google Scholar
  12. 12.
    Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for medical care of patients with obesity. Endocr Pract. 2016;22(Suppl 3):1–203.  https://doi.org/10.4158/EP161365.GL.Google Scholar
  13. 13.
    Onakpoya IJ, Heneghan CJ, Aronson JK. Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review. BMC Med. 2016;14(1):191.  https://doi.org/10.1186/s12916-016-0735-y.
  14. 14.
    Haslam D. Weight management in obesity—past and present. Int J Clin Pract. 2016;70(3):206–17.  https://doi.org/10.1111/ijcp.12771.Google Scholar
  15. 15.
    Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337(9):581–8.  https://doi.org/10.1056/nejm199708283370901.Google Scholar
  16. 16.
    US Food and Drug Administration. Full prescribing information Suprenza (phentermine hydrochloride) orally disintegrating tablet. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202088s005lbl.pdf. Accesssed 28 Mar 2019.
  17. 17.
    European Medicines Agency. The European Agency for the Evaluation of Medicinal Products. 1999. https://www.ema.europa.eu/documents/press-release/extraordinary-meeting-finalise-review-anorectic-agents_en.pdf. Accessed 28 Mar 2019.
  18. 18.
    Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. 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.Google Scholar
  19. 19.
    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.Google Scholar
  20. 20.
    European Medicines Agency. Acomplia. https://www.ema.europa.eu/en/medicines/human/EPAR/acomplia. Accessed 28 Mar 2019.
  21. 21.
    European Medicines Agency. Zimulti. https://www.ema.europa.eu/medicines/human/EPAR/Zimulti. Accessed 28 Mar 2019.
  22. 22.
    Rolls BJ, Shide DJ, Thorwart ML, Ulbrecht JS. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res. 1998;6(1):1–11.Google Scholar
  23. 23.
    Luque CA, Rey JA. The discovery and status of sibutramine as an anti-obesity drug. Eur J Pharmacol. 2002;440(2):119–28.  https://doi.org/10.1016/S0014-2999(02)01423-1.Google Scholar
  24. 24.
    European Medicines Agency. European Medicines Agency recommends suspension of marketing authorisation for sibutramine. 2010. https://www.ema.europa.eu/news/european-medicines-agency-recommends-suspension-marketing-authorisation-sibutramine?fbclid=IwAR0j-JZEdrJ3qbW2iDOGiVJoiIPZVKuJSZkV5j9a438Lt9h6O6lMP0c34qA. Accessed 28 Mar 2019.
  25. 25.
    US Food and Drug Administration. FDA Drug Safety Communication: FDA Recommends Against the Continued Use of Meridia (sibutramine). 2010. https://www.fda.gov/Drugs/DrugSafety/ucm228746.htm. Accessed 28 Mar 2019. 
  26. 26.
    James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363(10):905–17.  https://doi.org/10.1056/NEJMoa1003114.Google Scholar
  27. 27.
    US Food and Drug Administration. Center for Drug Evaluation and Research 208524Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208524Orig1s000Approv.pdf. Accessed 28 Mar 2019.
  28. 28.
    European Medicines Agency. Withdrawal assessment report for Belviq. 2013. https://www.ema.europa.eu/documents/withdrawal-report/withdrawal-assessment-report-belviq_en.pdf. Accessed 28 Mar 2019. 
  29. 29.
    Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature. 1995;374(6522):542–6.  https://doi.org/10.1038/374542a0.Google Scholar
  30. 30.
    Porter RJ, Dhir A, Macdonald RL, Rogawski MA. Chapter 39—mechanisms of action of antiseizure drugs. In: Stefan H, Theodore WH, editors. Handbook of clinical neurology. Amsterdam: Elsevier; 2012. p. 663–81.Google Scholar
  31. 31.
    European Medicines Agency. Refusal of the marketing authorisation for Qsiva (phentermine / topiramate). 2013. https://www.ema.europa.eu/documents/smop-initial/questions-answers-refusal-marketing-authorisation-qsiva-phentermine/topiramate_en.pdf. Accessed 28 Mar 2019.
  32. 32.
    Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med. 2004;164(9):994–1003.  https://doi.org/10.1001/archinte.164.9.994.Google Scholar
  33. 33.
    Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–34.  https://doi.org/10.1001/jama.2016.7602.Google Scholar
  34. 34.
    Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281(3):235–42.  https://doi.org/10.1001/jama.281.3.235.Google Scholar
  35. 35.
    Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring, Md). 2013;21(5):935–43.  https://doi.org/10.1002/oby.20309.Google Scholar
  36. 36.
    Agerso H, Jensen LB, Elbrond B, Rolan P, Zdravkovic M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia. 2002;45(2):195–202.  https://doi.org/10.1007/s00125-001-0719-z.Google Scholar
  37. 37.
    Madsbad S, Holst JJ. Treatment with GLP-1 receptor agonists. In: Bonora E, DeFronzo R, editors. Diabetes. Epidemiology, genetics, pathogenesis, diagnosis, prevention, and treatment. Cham: Springer International Publishing; 2018. p. 1–45.Google Scholar
  38. 38.
    Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–39.  https://doi.org/10.1152/physrev.00034.2006.Google Scholar
  39. 39.
    Torekov SS, Madsbad S, Holst JJ. Obesity—an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obes Rev. 2011;12(8):593–601.  https://doi.org/10.1111/j.1467-789X.2011.00860.x.Google Scholar
  40. 40.
    Madsbad S. The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabetes Obes Metab. 2014;16(1):9–21.  https://doi.org/10.1111/dom.12119.Google Scholar
  41. 41.
    Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017;28(2):88–103.  https://doi.org/10.1016/j.tem.2016.10.001.Google Scholar
  42. 42.
    Iepsen EW, Zhang J, Thomsen HS, Hansen EL, Hollensted M, Madsbad S, et al. Patients with obesity caused by melanocortin-4 receptor mutations can be treated with a glucagon-like peptide-1 receptor agonist. Cell Metab. 2018;28(1):23–32.  https://doi.org/10.1016/j.cmet.2018.05.008.Google Scholar
  43. 43.
    Knudsen LB, Secher A, Hecksher-Sørensen J, Pyke C. Long-acting glucagon-like peptide-1 receptor agonists have direct access to and effects on pro-opiomelanocortin/cocaine- and amphetamine-stimulated transcript neurons in the mouse hypothalamus. Journal of diabetes investigation. 2016;7 Suppl 1(Suppl Suppl 1):56–63.  https://doi.org/10.1111/jdi.12463.
  44. 44.
    Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Investig. 2014;124(10):4473–88.  https://doi.org/10.1172/JCI75276.Google Scholar
  45. 45.
    Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut. 1997;40(5):597–601.Google Scholar
  46. 46.
    Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4. Endocrinology. 2011;152(8):3103–12.  https://doi.org/10.1210/en.2011-0174.Google Scholar
  47. 47.
    Halawi H, Khemani D, Eckert D, O’Neill J, Kadouh H, Grothe K, et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial. Lancet Gastroenterol Hepatol. 2017;2(12):890–9.  https://doi.org/10.1016/s2468-1253(17)30285-6.Google Scholar
  48. 48.
    Jelsing J, Vrang N, Hansen G, Raun K, Tang-Christensen M, Knudsen LB. Liraglutide: short-lived effect on gastric emptying—long lasting effects on body weight. Diabetes Obes Metab. 2012;14(6):531–8.  https://doi.org/10.1111/j.1463-1326.2012.01557.x.Google Scholar
  49. 49.
    Iepsen EW, Lundgren J, Dirksen C, Jensen JE, Pedersen O, Hansen T et al. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int J Obes (2005). 2015;39(5):834–41.  https://doi.org/10.1038/ijo.2014.177.
  50. 50.
    Bradley DP, Kulstad R, Racine N, Shenker Y, Meredith M, Schoeller DA. Alterations in energy balance following exenatide administration. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2012;37(5):893–9.  https://doi.org/10.1139/h2012-068.
  51. 51.
    van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (2005). 2014;38(6):784–93.  https://doi.org/10.1038/ijo.2013.162.
  52. 52.
    Pannacciulli N, Bunt JC, Koska J, Bogardus C, Krakoff J. Higher fasting plasma concentrations of glucagon-like peptide 1 are associated with higher resting energy expenditure and fat oxidation rates in humans. Am J Clin Nutr. 2006;84(3):556–60.  https://doi.org/10.1093/ajcn/84.3.556.Google Scholar
  53. 53.
    Harder H, Nielsen L, Tu DT, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004;27(8):1915–21.Google Scholar
  54. 54.
    Shalev A, Holst JJ, Keller U. Effects of glucagon-like peptide 1 (7-36 amide) on whole-body protein metabolism in healthy man. Eur J Clin Invest. 1997;27(1):10–6.Google Scholar
  55. 55.
    Williams DL, Baskin DG, Schwartz MW. Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety. Endocrinology. 2009;150(4):1680–7.  https://doi.org/10.1210/en.2008-1045.Google Scholar
  56. 56.
    Tran KL, Park YI, Pandya S, Muliyil NJ, Jensen BD, Huynh K, et al. Overview of glucagon-like peptide-1 receptor agonists for the treatment of patients with type 2 diabetes. Am Health Drug Benefits. 2017;10(4):178–88.Google Scholar
  57. 57.
    European Medicines Agency. Ozempic. https://www.ema.europa.eu/en/medicines/human/EPAR/ozempic. Accessed 28 Mar 2019.
  58. 58.
    US Food and Drug Administration. Full prescribing information saxenda (liraglutide [rDNA origin] injection), solution for subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000lbl.pdf. Accessed 28 Mar 2019.
  59. 59.
    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.Google Scholar
  60. 60.
    Guo JJ, Pandey S, Doyle J, Bian B, Lis Y, Raisch DW. A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group. Value Health. 2010;13(5):657–66.  https://doi.org/10.1111/j.1524-4733.2010.00725.x.Google Scholar
  61. 61.
    European Medicines Agency. Assessment report for GLP-1 based therapies. 2013. https://www.ema.europa.eu/documents/report/assessment-report-article-53-procedure-glp-1-based-therapies_en.pdf. Accessed 28 Mar 2019. 
  62. 62.
    Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse Effects of GLP-1 Receptor Agonists. Rev Diabetic Stud. 2014;11(3–4):202–30.  https://doi.org/10.1900/RDS.2014.11.202.Google Scholar
  63. 63.
    Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374(9701):1606–16.  https://doi.org/10.1016/s0140-6736(09)61375-1.Google Scholar
  64. 64.
    Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (2005). 2012;36(6):843–54.  https://doi.org/10.1038/ijo.2011.158.
  65. 65.
    Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (2005). 2013;37(11):1443–51.  https://doi.org/10.1038/ijo.2013.120.
  66. 66.
    Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjoth TV, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314(7):687–99.  https://doi.org/10.1001/jama.2015.9676.Google Scholar
  67. 67.
    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.
  68. 68.
    Blackman A, Foster GD, Zammit G, Rosenberg R, Aronne L, Wadden T et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (2005). 2016;40(8):1310–9.  https://doi.org/10.1038/ijo.2016.52.
  69. 69.
    le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, et al. 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. 2017;389(10077):1399–409.  https://doi.org/10.1016/s0140-6736(17)30069-7.Google Scholar
  70. 70.
    European Medicines Agency. Summary of produce characteristics. https://www.ema.europa.eu/documents/product-information/saxenda-epar-product-information_en.pdf. Accessed 28 Mar 2019. 
  71. 71.
    Rigato M, Fadini GP. Comparative effectiveness of liraglutide in the treatment of type 2 diabetes. Diab Metabol Syndr Obesi. 2014;7:107–20.  https://doi.org/10.2147/DMSO.S37644.Google Scholar
  72. 72.
    Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, 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.
  73. 73.
    Rompianesi G, Hann A, Komolafe O, Pereira SP, Davidson BR, Gurusamy KS. Serum amylase and lipase and urinary trypsinogen and amylase for diagnosis of acute pancreatitis. Cochrane Database Syst Rev. 2017.  https://doi.org/10.1002/14651858.cd012010.pub2.
  74. 74.
    Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med. 2014;370(9):794–7.  https://doi.org/10.1056/nejmp1314078.
  75. 75.
    Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE Clinical Development Program. Diabetes Care. 2017;40(7):839–48.  https://doi.org/10.2337/dc16-2684.Google Scholar
  76. 76.
    Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368(9531):230–9.  https://doi.org/10.1016/s0140-6736(06)69044-2.Google Scholar
  77. 77.
    Nexøe-Larsen CC, Sørensen PH, Hausner H, Agersnap M, Baekdal M, Brønden A, et al. Effects of liraglutide on gallbladder emptying: a randomized, placebo-controlled trial in adults with overweight or obesity. Diabetes Obes Metab. 2018;20(11):2557–64.  https://doi.org/10.1111/dom.13420.Google Scholar
  78. 78.
    Smits MM, Tonneijck L, Muskiet MHA, Hoekstra T, Kramer MHH, Diamant M, et al. Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients. Diabetes Obes Metab. 2016;18(12):1217–25.  https://doi.org/10.1111/dom.12748.Google Scholar
  79. 79.
    Madsen LW, Knauf JA, Gotfredsen C, Pilling A, Sjogren I, Andersen S, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology. 2012;153(3):1538–47.  https://doi.org/10.1210/en.2011-1864.Google Scholar
  80. 80.
    Novo Nordisk. CHMP endorses EU label update of Saxenda® based on the LEADER trial. 2017. https://www.novonordisk.com/bin/getPDF.2115243.pdf. Accessed 28 Mar 2019. 
  81. 81.
    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.Google Scholar
  82. 82.
    US Food and Drug Administration. Center for drug evaluation and research 209637Orig1s000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000lbl.pdf. Accessed 28 Mar 2019. 
  83. 83.
    Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard ML, et al. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care. 2016;39(2):231–41.  https://doi.org/10.2337/dc15-0165.Google Scholar
  84. 84.
  85. 85.
    ClinicalTrials.gov. Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT). NCT03574597. 2018.https://clinicaltrials.gov/ct2/show/NCT03574597. Accessed 28 Mar 2019. 
  86. 86.
    Sorli C, Harashima SI, Tsoukas GM, Unger J, Karsbol JD, Hansen T, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5(4):251–60.  https://doi.org/10.1016/s2213-8587(17)30013-x.Google Scholar
  87. 87.
    Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.  https://doi.org/10.1056/NEJMoa1607141.Google Scholar
  88. 88.
    Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017;318(15):1460–70.  https://doi.org/10.1001/jama.2017.14752.Google Scholar
  89. 89.
    Dicembrini I, Nreu B, Scatena A, Andreozzi F, Sesti G, Mannucci E, et al. Microvascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled trials. Acta Diabetol. 2017;54(10):933–41.  https://doi.org/10.1007/s00592-017-1031-9.Google Scholar
  90. 90.
    Hernandez C, Bogdanov P, Corraliza L, Garcia-Ramirez M, Sola-Adell C, Arranz JA, et al. Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes. 2016;65(1):172–87.  https://doi.org/10.2337/db15-0443.Google Scholar
  91. 91.
    Mensberg P, Nyby S, Jorgensen PG, Storgaard H, Jensen MT, Sivertsen J, et al. Near-normalization of glycaemic control with glucagon-like peptide-1 receptor agonist treatment combined with exercise in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19(2):172–80.  https://doi.org/10.1111/dom.12797.Google Scholar
  92. 92.
    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.Google Scholar
  93. 93.
    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.Google Scholar
  94. 94.
    Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105–13.  https://doi.org/10.1016/s2213-8587(17)30412-6.Google Scholar
  95. 95.
    Kaneko M, Narukawa M. Assessment of cardiovascular risk with glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes using an alternative measure to the hazard ratio. Ann Pharmacother. 2018;52(7):632–8.  https://doi.org/10.1177/1060028018757407.Google Scholar
  96. 96.
    The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145–54.  https://doi.org/10.1056/NEJMoa1212914.Google Scholar
  97. 97.
    Finkelstein EA, Verghese NR. Incremental cost-effectiveness of evidence-based non-surgical weight loss strategies. Clin Obes. 2019;0(0):e12294.  https://doi.org/10.1111/cob.12294.
  98. 98.
    ClinicalTrials.gov. Saxenda in obesity services (STRIVE Study) (STRIVE). NCT03036800. 2017. https://clinicaltrials.gov/ct2/show/NCT03036800. Accessed 28 Mar 2019.
  99. 99.
    Basalay MV, Mastitskaya S, Mrochek A, Ackland GL, Del Arroyo AG, Sanchez J, et al. Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning. Cardiovasc Res. 2016;112(3):669–76.  https://doi.org/10.1093/cvr/cvw216.Google Scholar
  100. 100.
    Salcedo I, Tweedie D, Li Y, Greig NH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br J Pharmacol. 2012;166(5):1586–99.  https://doi.org/10.1111/j.1476-5381.2012.01971.x.Google Scholar
  101. 101.
    Vinue A, Navarro J, Herrero-Cervera A, Garcia-Cubas M, Andres-Blasco I, Martinez-Hervas S, et al. The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype. Diabetologia. 2017;60(9):1801–12.  https://doi.org/10.1007/s00125-017-4330-3.Google Scholar
  102. 102.
    Holst JJ, Madsbad S, Bojsen-Møller KN, Svane MS, Jørgensen NB, Dirksen C, et al. Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss. Surg Obes Relat Dis. 2018;14(5):708–14.  https://doi.org/10.1016/j.soard.2018.03.003.Google Scholar
  103. 103.
    Meek CL, Lewis HB, Reimann F, Gribble FM, Park AJ. The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptides. 2016;77:28–37.  https://doi.org/10.1016/j.peptides.2015.08.013.Google Scholar
  104. 104.
    Sadry SA, Drucker DJ. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat Rev Endocrinol. 2013;9(7):425–33.  https://doi.org/10.1038/nrendo.2013.47.Google Scholar
  105. 105.
    Alexiadou K, Anyiam O, Tan T. Cracking the combination: gut hormones for the treatment of obesity and diabetes. J Neuroendocrinol. 2018:e12664.  https://doi.org/10.1111/jne.12664.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Biomedical Sciences and Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagen NDenmark

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