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Associate Professor of Medicine
Harvard Medical School
Director, Division of CME
Beth Israel Deaconess Medical Center
Martin J. Abrahamson, MD, FACP, has disclosed that he has received consulting fees from Novo Nordisk.
GLP-1 receptor agonists have become increasingly recommended for people with type 2 diabetes who are not achieving therapeutic goals with lifestyle modification and metformin. Even for those with type 2 diabetes who are at therapeutic goal, if they are at high risk for or have established atherosclerotic cardiovascular disease (ASCVD), drugs in this class are recommended as an add on to metformin. This recommendation is based on demonstrated cardiovascular benefits of this drug class, especially in individuals with established ASCVD.
Gastrointestinal Adverse Events
So, what are the recognized adverse events of these medications? The most common adverse event after initiation of treatment is nausea, which occurs in approximately 10% of patients. The nausea is in part related to delayed gastric emptying caused by GLP-1 receptor agonists. In most cases, it is mild and decreases with continued use of the medication. Rarely, severe nausea with vomiting occurs.
The risk of nausea can be reduced by eating smaller meals and avoiding fatty foods. In my practice, I also start treatment at the lowest dose and gradually increase only when there are no adverse events.
Other gastrointestinal adverse events include diarrhea or constipation. These too usually improve with continued use of the medication.
Although it is important to know which adverse events may occur with initiation of GLP-1 receptor agonists, it is equally important to dispel some misconceptions about purported “side effects,” many of which stem from preclinical studies in rodents.
First, when used alone or with metformin and/or SGLT2 inhibitors, these medications do NOT cause hypoglycemia. The only scenario in which I might be concerned about hypoglycemia is when adding GLP-1 receptor agonists in patients already receiving insulin or sulfonylureas.
Pancreatic Adverse Events?
Second, there is no evidence that these medications increase the risk for either pancreatitis or pancreatic cancer. In patients with type 2 diabetes receiving GLP-1 receptor agonists, long-term, placebo-controlled studies have shown no increased risk for pancreatic cancer and an extremely rare incidence of pancreatitis.
Nonetheless, they should be avoided in anyone with a history of pancreatitis, unless an obvious cause has been identified, such as hypertriglyceridemia, gall stones, hypercalcemia, or alcohol consumption.
Third, these drugs do not appear to increase the risk for any form of thyroid cancer.
True, in a boxed warning, all GLP-1 receptor agonists, except exenatide, are contraindicated in individuals with a personal or family history of a rare form of thyroid cancer—medullary thyroid carcinoma.
However, this warning is based on carcinogenicity studies in rats, which express high levels of GLP-1 receptors on C-cells. C-cells produce calcitonin, and stimulation of these cells can cause hyperplasia and tumor formation.
In human thyroid C-cells, by contrast, GLP-1 receptors are absent, so to my mind the boxed warning about thyroid cancers is included out of an abundance of caution.
A Beneficial Side Effect
Finally, there is one common side effect of GLP-1 receptor agonists that is a clear benefit of this class of medications: weight loss. GLP-1 receptor agonists increase satiety by acting through central neural mechanisms that are not completely understood. In clinical trials, all agents showed weight loss (typically up to 3 kg). Indeed, liraglutide has been approved for the treatment of obesity.
How do you counsel patients about potential adverse events of GLP-1 receptor agonists? Join the discussion by posting a comment below, and by viewing the patient-directed animation.
Having trouble choosing among the available GLP-1 receptor agonists? I encourage you to visit the online decision support tool, “Choosing Among GLP-1 Receptor Agonists for Patients With Type 2 Diabetes” that I developed with my colleagues, Zachary T. Bloomgarden, MD, MACE; Anne Peters, MD; Richard E. Pratley, MD; and Robert S. Zimmerman, MD. In this decision support tool, you can enter the details of your case and learn how 5 experts would proceed.
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