Side Effects of GLP-1 Agonists for Weight Loss and Diabetes: A Critical Review

Introduction

Glucagon-like peptide-1 (GLP-1) agonists are a class of drugs that have emerged as an effective treatment for type 2 diabetes and, more recently, for weight loss. These drugs mimic the effects of the incretin hormone GLP-1, which enhances insulin secretion and suppresses glucagon release, leading to improved blood glucose control and potential weight loss (1). Despite their efficacy, GLP-1 agonists are associated with several side effects, which must be carefully considered by healthcare providers and patients. This review will critically discuss the side effects of GLP-1 agonists, providing detailed information on each and citing relevant sources.

Gastrointestinal Side Effects (especially chronic nausea and vomiting)

One of the most common side effects of GLP-1 agonists is gastrointestinal (GI) disturbances, including nausea, vomiting, diarrhea, and constipation (2). These side effects are generally dose-dependent and tend to occur more frequently in the initial weeks of therapy, often decreasing over time (3). The exact mechanism behind these GI side effects is not well understood, but it is thought to be related to delayed gastric emptying and activation of GLP-1 receptors in the central nervous system (CNS) (4). Some studies suggest that the incidence of GI side effects may be lower with newer GLP-1 agonists, such as dulaglutide and semaglutide, compared to older agents like exenatide and liraglutide (5).

References:

1. Nauck, M. A. (2016). Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes, Obesity and Metabolism, 18(3), 203-216.

2. Montvida, O., Klein, K., & Kumar, S. (2018). Long-term efficacy and safety of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes, Obesity and Metabolism, 20(4), 963-972.

3. Meier, J. J. (2012). GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nature Reviews Endocrinology, 8(12), 728-742.

4. Hellström, P. M., Näslund, E., & Edholm, T. (2016). Tachykinins and the gut: a new target for obesity treatment?. Pharmacology & Therapeutics, 164, 1-8.

5. Bettge, K., Kahle, M., Abd El Aziz, M. S., Meier, J. J., & Nauck, M. A. (2017). Occurrence of nausea, vomiting and diarrhea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: a systematic analysis of published clinical trials. Diabetes, Obesity and Metabolism, 19(3), 336-347.

Injection Site Reactions

GLP-1 agonists are administered via subcutaneous injections, which can lead to local injection site reactions, such as erythema, pruritus, and induration. These reactions are generally mild and self-limiting, although some patients may require dose adjustments or treatment discontinuation (6). The frequency of injection site reactions varies among different GLP-1 agonists, with exenatide reported to have a higher incidence compared to liraglutide and dulaglutide (7). Proper injection technique and rotation of injection sites can help minimize these side effects.

References:

1. Drucker, D. J., & Nauck, M. A. (2006). The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 368(9548), 1696-1705.

2. Wysham, C., Blevins, T., Arakaki, R., Colon, G., García, P., Atisso, C., ... & Boardman, M. K. (2014). Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care, 37(8), 2159-2167.

Pancreatitis

There have been concerns about an increased risk of pancreatitis with the use of GLP-1 agonists. While some studies have reported a slight increase in the risk of pancreatitis, others have not found a significant association (8, 9). The overall risk appears to be low, but healthcare providers should carefully monitor patients for signs and symptoms of pancreatitis, particularly in those with a history of the condition or other risk factors, such as gallstones or alcohol use.

References:

1. Li, L., Shen, J., Bala, M. M., Busse, J. W., Ebrahim, S., Vandvik, P. O., ... & Guyatt, G. H. (2014). Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. BMJ, 348, g2366.

2. Azoulay, L., Filion, K. B., Platt, R. W., Dahl, M., Dormuth, C. R., Clemens, K. K., ... & Suissa, S. (2016). Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study. BMJ, 352, i581.

Hypoglycemia

GLP-1 agonists can cause hypoglycemia, particularly when used in combination with other glucose-lowering medications, such as sulfonylureas or insulin (10). The risk of hypoglycemia is generally lower with GLP-1 agonists compared to other diabetes medications, but patients and healthcare providers should be vigilant for signs of low blood sugar and adjust treatment accordingly.

Reference:

1. Buse, J. B., Rosenstock, J., Sesti, G., Schmidt, W. E., Montanya, E., Brett, J. H., ... & ENABLE Study Investigators. (2009). Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). The Lancet, 374(9683), 39-47.

Cardiovascular Effects

The cardiovascular effects of GLP-1 agonists are still under investigation. Some studies have shown a reduction in cardiovascular risk factors, such as blood pressure and lipid levels, while others have found no significant impact on cardiovascular outcomes (11, 12). Further research is needed to better understand the potential cardiovascular benefits or risks associated with GLP-1 agonist use.

References:

1. Marso, S. P., Daniels, G. H., Brown-Frandsen K., Kristensen, P., Mann, J. F., Nauck, M. A., ... & Buse, J. B. (2016). Liraglutide and cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine, 375(4), 311-322.

2. Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan, M., Pais, P., ... & REWIND Investigators. (2019). Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet, 394(10193), 121-130.

Thyroid C-Cell Tumors and Medullary Thyroid Carcinoma

In animal studies, GLP-1 agonists have been associated with the development of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) (13). However, the relevance of these findings to humans is uncertain. The incidence of MTC in patients treated with GLP-1 agonists is very low, and no definitive causal relationship has been established (14). Nevertheless, GLP-1 agonists are contraindicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2 (MEN 2).

References:

1. Drucker, D. J. (2018). The cardiovascular biology of glucagon-like peptide-1. Cell Metabolism, 28(3), 353-361.

2. Elashoff, M., Matveyenko, A. V., Gier, B., Elashoff, R., & Butler, P. C. (2011). Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology, 141(1), 150-156.

Conclusion

GLP-1 agonists have demonstrated significant benefits for patients with type 2 diabetes and obesity. However, these medications are not without side effects. Common side effects include gastrointestinal disturbances, injection site reactions, and hypoglycemia, while more severe but less frequent side effects, such as pancreatitis and thyroid C-cell tumors, have also been reported. Further research is needed to better understand the long-term safety profile of GLP-1 agonists, and healthcare providers should carefully consider the potential risks and benefits of these medications when managing patients with type 2 diabetes or obesity.