“First, do no harm” is a fundamental tenet in medicine. As the arsenal of incretin therapies targeting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors continues to expand, clinicians need to balance the myriad clinical benefits with potentially severe adverse effects (AEs) to put this principle into practice.

A diverse lineup of experts took a deep dive into the data on known and potential AEs of GLP-1 receptor agonist therapies in the Sunday, June 23, symposium Severe GLP-1 RA Side Effects in Obesity Treatment—Fact or Fiction? The symposium can be viewed on-demand by registered meeting participants on the virtual meeting platform. If you haven’t registered for the 84^th Scientific Sessions, register today to access the valuable meeting content through Aug. 26.

“We’ve had these drugs for more than 19 years,” said Daniel J. Drucker, MD, Professor of Medicine at the Lunenfeld-Tanenbaum Research Institute of Mt. Sinai Hospital, who provided an overview of the known and potential AEs of GLP-1-based therapies. “Obviously, the drugs have gotten better, and we do have to be vigilant, but nausea, vomiting, diarrhea, constipation, and gallbladder events are some of the best described, most common AEs.”

Dr. Drucker reviewed evidence from clinical trials and real-world datasets. Overall, no increased risk of pancreatitis, pancreatic/hepatocellular/colorectal cancer, aspiration/pneumonia, or diabetic retinopathy is seen in patients on GLP-1 receptor agonist therapies.

 “The data we have on gallbladder events is real,” said Dr. Drucker, adding that it is important for clinicians to have a conversation with their patients about potential gallbladder events, especially in those with a history of gallbladder disease. Discussion of the benefits and risks is also important for people who are pregnant or may become pregnant while on incretin therapy.

As novel incretin therapies are developed, Dr. Drucker said that it is critical to keep investigating not just their mechanisms of action and potential benefits, but also their safety.

John-Michael Gamble, PhD, Clinical Associate Professor at the University of Waterloo, Canada, discussed the origin and biological plausibility of the concern over suicide risk in people using GLP-1 receptor agonists, relevant scientific evidence and its limitations, and the implications for prescribers and their patients.

“Detection of suicidality is difficult in clinical practice,” Dr. Gamble said.

Patients often do not report suicidal ideation, consideration, or attempts to their health care providers. In addition, data on suicide risk in patients on incretin therapies may be confounded by underlying conditions, including obesity and diabetes, which have been linked to increased suicide risk.

In a preliminary evaluation, the U.S. Food and Drug Administration (FDA) did not find a causal link between the use of GLP-1 receptor agonists and suicidal thoughts or actions. The European Medicines Agency (EMA) came to a similar conclusion. The FDA added that it could not definitively rule out a small risk and the agency continues to assess this concern.

Elizabeth N. Pearce, MD, MSc, Professor of Medicine at Boston University, spoke about the challenges in investigating causal associations between incretin therapies and a rare solid tumor, like thyroid cancer.

Thyroid cancers have a low prevalence of about one in 30,000−40,000 in the general population. “Observational data are a mixed bag and probably do not account for all the confounding factors,” said Dr. Pearce. The pharmacovigilance data are interesting but are more hypothesis generating, rather than definitive, she added.

Dr. Pearce said that in the U.S., it may be advisable to not use GLP-1 receptor agonists in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 given the inclusion of a black box warning regarding thyroid C-cell tumors in the FDA labeling information for several incretin therapies. She also cautioned against screening for thyroid nodules before ordering these medications to avoid contributing to the “epidemic of overdiagnosis of thyroid cancer.”

Beverly G. Tchang, MD, Assistant Professor of Clinical Medicine at Weill Cornell Medicine, explored general principles for how clinicians can integrate current evidence on thyroid cancer, pancreatitis, gallbladder disease, gastrointestinal effects, mood changes, and hypoglycemia into clinical practice.

She highlighted prescriber-directed medication adjustments—such as slow dose escalation, use of the lowest therapeutic dose, microdosing/intermediate dosing, and supportive measures, such as anti-emetics/prokinetics—as  effective strategies for side-effect management. She also spoke on the importance of being mindful of mood changes in patients, and anticipating changes in the patient’s insulin needs to prevent hypoglycemia.