What are the gastrointestinal adverse effects of the glucagon-like peptide 1 receptor agonists, and how should they be managed?

Gastrointestinal (GI) adverse effects are frequently reported treatment-related side effects of the glucagon-like peptide 1 receptor agonists (GLP-1 RA) and contribute to non-adherence and discontinuation of these agents.^1,2 Gastrointestinal adverse effects caused fewer than 5% of discontinuations in most GLP-1 RA clinical trials; however, clinical practice shows discontinuation rates of 5% to 10%.^1,3-11 Therefore, it is important for providers to discuss the possibility of GI adverse effects with their patients before starting GLP-1 RA therapy to improve understanding, adherence, and discontinuation rates.¹

The GLP-1 RA are incretin mimetics that bind to glucagon-like peptide 1 (GLP-1) receptors, thereby exerting the following pharmacological effects: increase glucose-dependent insulin secretion, inhibit glucagon secretion, slow gastric emptying, and promote satiety.^2,12 GLP-1 RA are divided into short-acting (e.g., exenatide twice daily, lixisenatide) and long-acting agents (e.g., dulaglutide, liraglutide, semaglutide, exenatide extended-release [ER]).^2-9 Table 1 provides the dosing and pharmacokinetic properties of the GLP-1 RA.^3-9,13 Of note, most of the agents require dosage up-titration to lessen GI intolerance, and both semaglutide formulations (tablet and injection) and liraglutide have non-therapeutic starting doses for initial titration to reduce GI adverse effects.^3-10,14 Exenatide ER is formulated as microspheres suspended in a medium-chain triglycerides oil, which leads to a gradual release of exenatide, and therefore, does not require a dose titration due to a slow rise to steady-state concentrations.^9,13 At recommended doses, short-acting GLP-1 RA lead to intermittent drug exposure, while long-acting GLP-1 RA result in more steady drug exposure.^13,15 Over time, continuous exposure with the long-acting GLP-1 RA leads to a reduced effect on slowing gastric emptying due to tachyphylaxis, which has not been observed with the short-acting agents because of their pharmacokinetic profiles. Long-acting GLP-1 RA have lower rates of GI adverse effects (especially nausea) due to their lesser effect on gastric emptying compared to short-acting GLP-1 RA.^{2,12,13,15,16}

Table 1. Dosing and pharmacokinetics of GLP-1 RA.^3-9,13

The most common GI adverse effects of GLP-1 RA include nausea, vomiting, and diarrhea, with rates dependent on the medication and dose (Table 2).^2-9,13,17 Short-acting GLP-1 RA are associated with more nausea and vomiting, possibly due to slowed gastric emptying; however, long-acting GLP-1 RA are associated with more diarrhea.^12,13,15

Among the short-acting GLP-1 RA, a meta-analysis by Bettge and colleagues found that lixisenatide was associated with a lower risk of nausea (p = 0.0038) and diarrhea (p = 0.0018) but found no difference in risk of vomiting (p = 0.42) compared to exenatide twice daily.¹⁵

When comparing long-acting GLP-1 RA, exenatide ER appears to have a favorable GI safety and tolerability profile compared to some long-acting agents due to a lower risk of nausea and vomiting.^16,17 A meta-analysis by Htike and colleagues found that exenatide ER was associated with a lower odds of nausea and vomiting compared to liraglutide and dulaglutide.16 Additionally, Bettge and colleagues found a significantly lower risk of nausea with exenatide ER than liraglutide (p < 0.0001).¹⁵ A meta-analysis including data with injectable semaglutide found that subcutaneous semaglutide was associated with higher incidences of nausea (odds ratio [OR], 1.72; 95% CI, 1.38 to 2.14) and vomiting (OR, 1.52; 95% CI, 1.12 to 2.07), but not diarrhea (OR, 1.24; 95% CI, 0.96 to 1.61), compared to other long-acting agents (liraglutide, exenatide ER, and dulaglutide).¹⁸ Additionally, a meta-analysis of the PIONEER trials found that oral semaglutide was associated with an increased risk of vomiting compared to other GLP-1 RA (liraglutide and dulaglutide) (relative risk [RR], 1.96; 95% CI, 1.06 to 3.64), but no difference in risk of nausea and diarrhea.¹⁹ Compared to liraglutide, dulaglutide has shown similar risks of nausea and vomiting; however, Bettge and colleagues found a lower risk of diarrhea with dulaglutide.^15,16

There can be an increase in reported GI adverse effects when GLP-1 RA are used concurrently with background antihyperglycemic therapies such as metformin or insulin due to similar GI adverse effect profiles (metformin) and possibly a more advanced stage of diabetes (use of insulin).^13,15 The meta-analysis by Bettge and colleagues found that background metformin increased the risk of nausea (p = 0.04) and vomiting (p = 0.0009) for all GLP-1 RA, and background insulin increased the risk of nausea (p = 0.0009).¹⁵ These findings were mainly driven by the short-acting GLP-1 RA; in particular, exenatide twice daily was associated with significantly higher rates of nausea (p < 0.0001), vomiting (p = 0.0026) and diarrhea (p = 0.0005) with background insulin, and nausea (p = 0.0005) and diarrhea (p = 0.0038) with concurrent metformin.

Table 2. Incidence rates of nausea, vomiting, and diarrhea reported in the prescribing information for the GLP-1 RA.^3-9

The GLP-1 RA-related GI adverse effects are mostly transient and typically lessen within weeks of ongoing treatment.^12,14,17 Gastrointestinal disturbances mainly occur with GLP-1 RA initiation and dose escalations, and higher starting doses of GLP-1 RA may increase the incidence of these adverse effects.¹³ Therefore, starting with lower doses and a slower dose titration may help minimize this risk.^2,3,6-8,13 Table 3 provides patient counseling points to mitigate the GI adverse effects.^2,14,20,21

Table 3. Patient counseling points to help alleviate GI adverse effects.^2,14,20,21

GI gastrointestinal

Patients with gastroparesis and severe gastroesophageal reflux disease should be carefully monitored while taking GLP-1 RA due to the potential for slowed gastric emptying.^2,17,22 The prescribing information for exenatide twice daily, lixisenatide, dulaglutide, and exenatide ER include a warning to avoid use in patients with severe GI disease (e.g., severe gastroparesis).^3-5,9 Patients should also be aware of the potential risk for pancreatitis and the associated signs and symptoms.^3-9 A classic symptom is constant, intense abdominal pain that may penetrate to the back and can occur with vomiting. Patients should be advised to discontinue the GLP-1 RA if this hallmark symptom arises.

In summary, nausea, vomiting, and diarrhea are the main GI adverse effects of GLP-1 RA, with varying rates among agents and doses. Therefore, dose titration and patient counseling are essential for mitigating these GI disturbances.

1. Sikirica MV, Martin AA, Wood R, Leith A, Piercy J, Higgins V. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes. Diabetes Metab Syndr Obes. 2017;10:403-412. doi: 10.2147/dmso.s141235
2. Hinnen D. Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr. 2017;30(3):202-210. doi: 10.2337/ds16-0026
3. Byetta. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021.
4. Adlyxin. Prescribing information. Sanofi-Aventis U.S. LLC; 2021.
5. Trulicity. Prescribing information. Eli Lilly and Company; 2021.
6. Victoza. Prescribing information. Novo Nordisk A/S; 2020.
7. Ozempic. Prescribing information. Novo Nordisk A/S; 2021.
8. Rybelsus. Prescribing information. Novo Nordisk A/S; 2021.
9. Bydureon BCise. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021.
10. Cefalu WT, Buse JB, Del Prato S, et al. Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors' expert forum. Diabetes Care. 2014;37(9):2647-2659. doi: 10.2337/dc14-1395
11. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015;4:212283. doi: 10.7573/dic.212283
12. Trujillo J, Haines S. Diabetes mellitus. In: DiPiro JT, Yee GC, Posey ML, Haines ST, Nolin TD, Ellingrod VL, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. McGraw-Hill; 2020:chap 91. Accessed December 1, 2021. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=228901946
13. Nauck MA, Meier JJ. Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181(6):R211-R234. doi: 10.1530/EJE-19-0566
14. Kane MP, Triplitt CL, Solis-Herrera CD. Management of type 2 diabetes with oral semaglutide: practical guidance for pharmacists. Am J Health Syst Pharm. 2021;78(7):556-567. doi: 10.1093/ajhp/zxaa413
15. 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 published clinical trials. Diabetes Obes Metab. 2017; 19(3):336-347. doi: 10.1111/dom.12824
16. Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon‐like peptide‐1 receptor agonists in type 2 diabetes: a systematic review and mixed‐treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524-536. doi:10.1111/dom.12849
17. Trujillo J. Safety and tolerability of once‐weekly GLP‐1 receptor agonists in type 2 diabetes. J Clin Pharm Ther. 2020;45(Suppl 1):43-60. doi:10.1111/jcpt.13225
18. Andreadis P, Karagiannis T, Malandris K, et al. Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2018;20(9):2255-2263. doi: 10.1111/dom.13361
19. Li J, He K, Ge J, Li C, Jing Z. Efficacy and safety of the glucagon-like peptide-1 receptor agonist oral semaglutide in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2021;172:108656. doi: 10.1016/j.diabres.2021.108656
20. Possible side effects. Victoza® (liraglutide). Accessed December 1, 2021. https://www.victoza.com/faq/Possible-side-effects.html
21. Side effects. Trulicity® (dulaglutide). Accessed December 1, 2021. https://www.trulicity.com/how-to-use/side-effects
22. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107-139. doi: 10.4158/cs-2019-0472