Test Your Knowledge Answer #639

The use of any medication comes with inherent risk. It is understandable for patients to be curious and even apprehensive about what unintended effects these medications may have. It is our job as healthcare professionals to warn them what is to be expected and when to seek medical attention.

The most common adverse events experienced with GLP-1 agonists are gastrointestinal, including nausea, vomiting, and diarrhea or constipation. These adverse events can be severe and may cause patients to wish to discontinue therapy. While uncomfortable, these reactions tend to dissipate over time and occur in a dose-dependent manner. They usually occur in the first few months and tend to decline in those who experience them. Beginning at the lowest possible dose before increasing to higher doses can also help avoid these adverse reactions.

GLP-1 agonists have a low propensity to cause hypoglycemia when used alone. Addition of these agents to other medications, however, can increase the likelihood of a hypoglycemic event. Because most patients beginning a GLP-1 agonist are already taking other antidiabetic medications, such as sulfonylureas, it is important to remind them of the signs of hypoglycemia and the actions to take if hypoglycemia occurs. Doses of sulfonylureas are often lowered upon initiation of a GLP-1 agonist.

Injection site reactions such as itching and redness are not uncommon. They occur more frequently with Byetta (exenatide) and Bydureon (extended-release exenatide) than with Victoza (liraglutide). Although rare, GLP-1 agonists can cause a hypersensitivity reaction; these are also more common with exenatide than with liraglutide. Patients should be warned to discontinue the medication and seek medical attention in the event of angioedema or anaphylaxis.

When the subject of cancer arises in relation to a drug, lawyers get excited and prescribers get reluctant. Use of both Bydureon and Victoza is contraindicated in patients with a history, or family history, of medullary thyroid carcinoma or multiple endoctine neoplasia syndrome type 2. It may be helpful to explain two key points to your patients: the actual studies these concerns arose from and the absolute risk of developing these cancers. The studies that provoked this concern were done in rats and mice. The rodents were chronically treated with liraglutide at levels 8 times greater than the highest dose used in humans. Human studies have shown no significant correlation between liraglutide and medullary thyroid cancer. That being said, the incidence of this cancer in the United States is about 600 cases per year. This means a patient's chance of being diagnosed with it is virtually non-existent, regardless of the use of a GLP-1 agonist. One must always weigh the risks and the benefits.

1. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373:473—81
2. Buse JB, Garber A, Rosenstock J, Schmidt WE, Brett JH, Videbæk N, Holst J, Nauck M. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011 Jun;96(6):1695-702. Epub 2011 Mar 30
3. Byetta (exenatide) package insert. Amylin Pharmaceuticals, Inc. 2011
4. Victoza (liraglutide) package insert. Princeton, NJ: Novo Nordisk Inc; 2012 April.
5. McConnell EE, Solleveld HA, Swenberg JA, Boorman GA. Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. J Natl Cancer Inst 1986;76:283-289
6. Mary Parks, M.D., and Curtis Rosebraugh, M.D., M.P.H. Weighing Risks and Benefits of Liraglutide -- The FDA's Review of a New Antidiabetic Therapy. N Engl J Med 2010; 362:774-777