J Korean Diabetes.  2024 Jun;25(2):69-75. 10.4093/jkd.2024.25.2.69.

GLP-1 Receptor Agonist

• Chung SM

• KMID: 2556756
• DOI: http://doi.org/10.4093/jkd.2024.25.2.69

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by food intake from L cells of the ileum. GLP-1 contributes to blood glucose control through three main mechanisms: promoting glucose-dependent insulin secretion from pancreatic beta cells, suppressing glucagon hypersecretion from pancreatic alpha cells, and delaying gastric emptying time. GLP-1 receptor agonists (RAs) have been developed for administration twice daily, once daily, and once weekly as subcutaneous injection formulation and as a daily oral formulation. GLP-1 RAs have benefits in reducing glycated hemoglobin, weight, and blood pressure, as well as in managing lipid profiles. Additionally, some GLP-1 RAs have demonstrated cardiovascular benefits. Therefore, the guidelines recommend GLP-1 RA treatment of type 2 diabetes patients with preexisting atherosclerotic vascular disease. GLP-1 RA may also improve renal outcomes. The most frequently reported side effects of GLP-1 RA are gastrointestinal symptoms, which can be minimized by gradually starting treatment at a low concentration and then increasing to the final dosage. Considering the efficacy, administration frequency, and cost of each GLP-1 RA treatment, it can be selected as monotherapy or in combination with oral hypoglycemic agents and basal insulin in free or fixed dose formulation.

Keyword

Blood glucose; Cardiovascular system; Diabetes mellitus, type 2; Glucagon-like peptide-1 receptor agonists; Obesity

Reference

1.Korean Diabetes Association. Diabetes. 6th ed. Seoul: Panmun Education;2023.

2.Kim HJ. Recent updates on glucagon-like peptide 1 receptor agonist. J Korean Diabetes. 2021. 22:126–33.

3.Korean Diabetes Association. Clinical practice guidelines for diabetes. 8th ed. Seoul: Korean Diabetes Association;2023. 124-76:p. 358–69.

4.Davies MJ., Aroda VR., Collins BS., Gabbay RA., Green J., Maruthur NM, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022. 65:1925–66.

5.Kolterman OG., Kim DD., Shen L., Ruggles JA., Nielsen LL., Fineman MS, et al. Pharmacokinetics, pharmacodynam-ics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005. 62:173–81.

6.Ratner RE., Rosenstock J., Boka G; DRI6012 Study Investigators. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med. 2010. 27:1024–32.

7.Fonseca VA., Alvarado-Ruiz R., Raccah D., Boka G., Miossec P., Gerich JE; EFC6018 GetGoal-Mono Study Investigators. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, dou-ble-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care. 2012. 35:1225–31.

8.Nauck MA., Quast DR., Wefers J., Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021. 46:101102.

9.Damholt B., Golor G., Wierich W., Pedersen P., Ekblom M., Zdravkovic M. An open-label, parallel group study inves-tigating the effects of age and gender on the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide. J Clin Pharmacol. 2006. 46:635–41.

10.Kim D., MacConell L., Zhuang D., Kothare PA., Trautmann M., Fineman M, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007. 30:1487–93.

11.Drucker DJ., Buse JB., Taylor K., Kendall DM., Trautmann M., Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008. 372:1240–50.

12.Geiser JS., Heathman MA., Cui X., Martin J., Loghin C., Chien JY, et al. Clinical pharmacokinetics of dulaglutide in patients with type 2 diabetes: analyses of data from clinical trials. Clin Pharmacokinet. 2016. 55:625–34.

13.Marbury TC., Flint A., Jacobsen JB., Derving Karsbøl J., Las-seter K. Pharmacokinetics and tolerability of a single dose of semaglutide, a human glucagon-like peptide-1 analog, in subjects with and without renal impairment. Clin Pharmacokinet. 2017. 56:1381–90.

14.Granhall C., Donsmark M., Blicher TM., Golor G., Sønder-gaard FL., Thomsen M, et al. Safety and pharmacokinetics of single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 diabetes. Clin Pharmacokinet. 2019. 58:781–91.

15.Meier JJ., Menge BA., Schenker N., Erdmann S., Kah-le-Stephan M., Schliess F, et al. Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes. Diabetes Obes Metab. 2020. 22:599–611.

16.Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012. 8:728–42.

17.Huthmacher JA., Meier JJ., Nauck MA. Efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists on a background of basal insulin in type 2 diabetes: a meta-analysis. Diabetes Care. 2020. 43:2303–12.

18.Tsapas A., Avgerinos I., Karagiannis T., Malandris K., Manolopoulos A., Andreadis P, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020. 173:278–86.

19.Baggio LL., Drucker DJ. Glucagon-like peptide-1 recep-tors in the brain: controlling food intake and body weight. J Clin Invest. 2014. 124:4223–6.

20.Tsapas A., Karagiannis T., Kakotrichi P., Avgerinos I., Mantsiou C., Tousinas G, et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Obes Metab. 2021. 23:2116–24.

21.Kadowaki T., Isendahl J., Khalid U., Lee SY., Nishida T., Ogawa W., STEP 6 investigators, et al. Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-con-trolled, phase 3a trial. Lancet Diabetes Endocrinol. 2022. 10:193–206.

22.Pfeffer MA., Claggett B., Diaz R., Dickstein K., Gerstein HC., Køber LV., ELIXA Investigators, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015. 373:2247–57.

23.Álvarez-Villalobos NA., Treviño-Alvarez AM., González-González JG. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016. 375:1797–8.

24.Marso SP., Bain SC., Consoli A., Eliaschewitz FG., Jódar E., Leiter LA., SUSTAIN-6 Investigators, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016. 375:1834–44.

25.Holman RR., Bethel MA., Mentz RJ., Thompson VP., Lokhnygina Y., Buse JB., EXSCEL Study Group, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017. 377:1228–39.

26.Hernandez AF., Green JB., Janmohamed S., D'Agostino RB Sr., Granger CB., Jones NP., Harmony Outcomes committees and investigators, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a dou-ble-blind, randomised placebo-controlled trial. Lancet. 2018. 392:1519–29.

27.Gerstein HC., Colhoun HM., Dagenais GR., Diaz R., Laksh-manan M., Pais P., REWIND Investigators, et al. Dulaglu-tide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019. 394:121–30.

28.Husain M., Birkenfeld AL., Donsmark M., Dungan K., Eliaschewitz FG., Franco DR., PIONEER 6 Investigators, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019. 381:841–51.

29.Gerstein HC., Sattar N., Rosenstock J., Ramasundarahettige C., Pratley R., Lopes RD., AMPLITUDE-O Trial Investigators, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021. 385:896–907.

30.Sattar N., Lee MMY., Kristensen SL., Branch KRH., Del Prato S., Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-anal-ysis of randomised trials. Lancet Diabetes Endocrinol. 2021. 9:653–62.

31.Gragnano F., De Sio V., Calabrò P. FLOW trial stopped ear-ly due to evidence of renal protection with semaglutide. Eur Heart J Cardiovasc Pharmacother. 2024. 10:7–9.

32.Armstrong MJ., Gaunt P., Aithal GP., Barton D., Hull D., Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016. 387:679–90.

33.Newsome PN., Buchholtz K., Cusi K., Linder M., Okanoue T., Ratziu V., NN9931-4296 Investigators, et al. A place-bo-controlled trial of subcutaneous semaglutide in nonal-coholic steatohepatitis. N Engl J Med. 2021. 384:1113–24.

34.Bettge K., Kahle M., Abd El Aziz MS., Meier JJ., Nauck MA. Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of pub-lished clinical trials. Diabetes Obes Metab. 2017. 19:336–47.

35.Abd El Aziz M., Cahyadi O., Meier JJ., Schmidt WE., Nauck MA. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-anal-ysis based on cardiovascular outcomes trials. Diabetes Obes Metab. 2020. 22:699–704.

36.Bjerre Knudsen L., Madsen LW., Andersen S., Almholt K., de Boer AS., Drucker DJ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010. 151:1473–86.