Experts Discuss Serious Adverse Events for GLP-1 Medications

Daniel J. Drucker, MD, from Mt. Sinai Hospital, said, for glucagon-like peptide-1 (GLP-1) medications, the brain is responsible for many of the common gastrointestinal adverse events (AEs) of the medications. He added that aversive centers in brain can be activated, which could make patients have AEs due to the medications.¹

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Some potential concerns surrounding GLP-1 medications are the long-term effects of using these medications, including the risk of pancreatitis, pancreatic cancer, colorectal cancer, gallbladder emptying, aspiration, suicide and other phycological effects, and thyroid cancer.¹

At the American Diabetes Association 84th Scientific Sessions, experts discuss the data around these events and whether or not they can be supported by scientific evidence.¹

Drucker covered the effects on the pancreas and gallbladder. In experiments on rats, Drucker and fellow investigators found that GLP-1 medications generally reduced inflammation in the pancreas. At the time, the anti-inflammatory effects of GLP-1 medications was not as well known.¹

“We did not see an increase in pancreatitis of clinical severity in the animals, but interestingly, we did see an increase in amylase ,and this has always been one of the confounders clinically that people will come in to the doctor's office with the [emergency room] saying, ‘I have abdominal pain.,’” Drucker said. “What's often lacking is imaging criteria for an increase in pancreatic mass and that complicates whether or not the pancreatitis is real.”¹

Drucker stated amylase and lipase levels rising is a normal effect of GLP-1 medications. He said that the effects are rarely more than 3-fold elevated, so there is no reason to be concerned. As for pancreatic cancer, the investigators examined pancreatic cancer cell lines, finding that the cancer cells did not grow in nude mice. In fact, he stated that some cancer cells actually grew smaller.¹

In colorectal cancer, GLP-1 medication was found to reduce the rates of cancer compared to individuals who were on insulin. Further, in the gallbladder, GLP-1 did not promote gallbladder filling, according to Drucker; however, GLP-2 does promote it.¹

The American Society of Anesthesiologists recommended stopping GLP-1 medications if patients plan on having a lot of surgery, but there has been no data linking GLP-1 with an increased risk of aspiration for upper endoscopy. Drucker concluded that it is essential to educate patients on information regarding GLP-1 medication, so they are aware, especially with the increase rates of more spontaneous reports of pregnancy in women.¹

John-Michael Gamble, PhD, from the University of Waterloo, detailed what research suggests about the link between suicide risk and GLP-1s. Although the Icelandic Medicines Agency, FDA, European Medicines Agency (EMA), and Health Canada, have started to examine reports of an increase of suicide and GLP-1 medications, most hypothesis around GLP-1 medication have actually been on the benefits of the medications for psychiatric conditions.¹

In 3 cohort studies, 2 were United States-based and 1 was United Kingdom based. In a study published in Nature Medicine, investigators examined the outcome of suicidal ideation within 6 months with semaglutide in populations that were either overweight or obese or had type 2 diabetes (T2D). For a study in the Journal of Diabetes, investigators evaluated the suicide attempts within 5 years for GLP-1 medications in individuals with T2D and T2D with a history of depression or suicide attempts. In the EMA Final Study Report 2024, investigators evaluated the suicide related or self-harm events with GLP-1s for those with T2D.^1-3

For Nassar, Misra, and Bloomgarden, they found that GLP-1s were associated with lower risks of suicide attempts compared to dipeptidyl peptidase 4 inhibitors, especially for those in the high-risk group. For Wang et al, in patients who were overweight or obese, semaglutide was associated with lower risk for incidence and recurrent suicidal ideation, with similar findings observed in the diabetes cohort.^2,3

“This is reassuring data in that we do not see a signal of suicidality. Their confidence intervals all are below 1, except the EMA final report shows the confidence interval standing 1, the upper 95% value, which is important here, when looking at a serious adverse event does still go in the plausibly concerning number but, overall, this data is reassuring,” Gamble said.¹

Another potential risk for GLP-1 medications is thyroid cancer, with liraglutide even including a black box warning on the risk. However, the warning is only on liraglutide in the United States and Canada, but not in Europe. The EMA also released a statement in October 2023, stating that available evidence does not support causal association between GLP-1 and thyroid cancer.¹

Elizabeth N. Pearce, MD, MSc, from Boston University, said that evidence is lacking due to the exclusion of patients with a history or family history of various thyroid cancer, so most data sets have not been able to investigate the risk factor.¹

Furthermore, GLP-1 studies for T2D have not been able to conclude the incidence due to sample sizes being too small.¹

“The prevalence of medullary thyroid cancer in the general adult population is somewhere on the order of 1 in 30,000 to 1 and 40,000 people, so you would need enormous trials to actually see a signal for safety for this,” Pearce said.¹

Pearce also added the covariates need to be taken into account to properly evaluate the risk. She stated that obesity and hyperglycemia are risk factors for thyroid cancer, so in order to properly evaluate the risk, the underlying effects of diabetes and obesity need to be disentangled.¹

For treating patients, Beverly G. Tchang, MD, from Weill Cornell, gave some insight on best practices, including that personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 2 are contraindications to GLP-1s and should not be used. Furthermore, health care providers should ask patients non-leading questions to figure out their history with pancreatitis, cancer risks, and other factors that could contraindicate the use of GLP-1 medications. For mental health concerns, she said the providers should monitor patients for changes in mood.¹

For the most common gastrointestinal related AEs, she stated that AEs seem to be dose dependent or dependent on dose escalation in her clinic. It’s also best to remind patients to have fiber and stay hydrated. The use of OTC agents to alleviate symptoms can also be used.¹

References

1. Patti ME, Drucker DJ, Gamble JM, Pearce EN, Tchang BG. Severe GLP-1RA Side Effects in Obesity Treatment—Fact or Fiction? Presented At: ADA 84th Scientific Sessions; June 21-June 24, 2024; Orlando, Florida.

2. Nassar M, Misra A, Bloomgarden Z. Impact of treatment with GLP-1RAs on suicide attempts in adults persons with type 2 diabetes: A retrospective comparative effectiveness study based on a global TriNetX health research database. J Diabetes. 2024;16(3):e13547. doi:10.1111/1753-0407.13547

3. Wang W, Volkow ND, Berger NA, Davis PB, Kaelber DC, Xu R. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med. 2024;30(1):168-176. doi:10.1038/s41591-023-02672-2