Semaglutide Popularity: Serious Rare Adverse Effects Are Emerging

Amid this fervor, rare but serious adverse effects have recently emerged for this class of hormone-mimicking medications, called glucagon-like peptide 1 (GLP-1) receptor agonists, which in different forms have been on the market for diabetes treatment for almost 2 decades. In its recent blogs critically discussing semaglutide as a weight loss miracle and asking the question on whether there existed an effective pharmacogenovigilance behind semaglutide-based therapies, thasso rose the issue of adverse drug reactions (ADR’s) possibly emerging, even though somewhat hidden and/or at low frequency in treated individuals populations.

Such ADR’s could include those which have been previously been recognised in therapies involving GLP-1 as target. However, when treating millions of people with  semaglutide containing medications as it happens under condition of the presently ongoing surge, relatively unknown or new rare adverse effects may be discovered and, among millions of otherwise successfully treated individuals, amount to a large number of people affected.

Obviously, this is happening here under Wegovy (Semaglutide). Thus, in June 2023, the American Society of Anesthesiologists issued new guidance to stop taking GLP-1 agonists before elective surgery because of safety concerns about vomiting while under anesthesia. Moreover, in October 2023, a Research Letter in JAMA reported dangerous stomach complications in some patients with obesity using GLP-1 agonists. Although their incidences are low, people as well as their physicians should know about the possibility of such serious adverse effects although for many people with obesity, particularly those with more severe obesity who have related complications, the benefits of these medications are quite likely to seemingly outweigh the risks.

In fact, on the one hand, semaglutide, the agent in Wegovy and Ozempic, has been found highly effective for many many patients looking to manage their weight. In clinical trials, people who received it alongside a standard diet and exercise intervention shed an average of about 15% of their body weight while also seeing improvements in cardiovascular and glycemic health and physical functioning. Semaglutide is one of several GLP-1 agonists, including liraglutide (marketed as Victoza for diabetes and Saxenda for weight loss) and dulaglutide (marketed as Trulicity for diabetes), that work by curbing appetite and delaying stomach emptying. These medications simulate gut hormones, and most of their adverse effects are gastrointestinal, including nausea, vomiting,   constipation, and diarrhea. But besides these common issues, the rarer and more serious complications are gaining attention.

On the other hand showed research in Canada on the safety of GLP-1 agonists and bupropion-naltrexone, an older class of weight-loss medication, retrospectively analysing 4144 people with obesity who were prescribed liraglutide, 613 prescribed semaglutide, and 654 prescribed the older treatment  that the GLP-1 group had a 9 times greater risk of pancreatitis, a 4 times greater risk of bowel obstruction, and a more than 3 times greater risk of gastroparesis, which causes stomach paralysis. As characteristic for rare yet possibly serious ADR’s, the absolute risks in the GLP-1 group, however, were all about 1% or less per year of GLP-1 use. While acute pancreatitis and acute gallbladder disease are known adverse effects of GLP-1 agonists, gastroparesis and bowel obstruction are newly adverse conditions when using semaglutide for weight loss.

A third  additional emerging adverse condition are unexpected anesthesia complications where the unexpected expulsion of stomach contents caught the attention of anesthesiologists. Pulmonary aspiration is a rare but potentially fatal complication of anesthesia. According reports of people using GLP-1 agonists who regurgitated or aspirated food during anesthesia surfaced this spring in scientific journals. Some of the reports were striking due to the volume of stomach contents the patients regurgitated despite having fasted. Consequently, in June this year, the American Society of Anesthesiologists warned physicians about these concerns in a statement that also provided updated guidance to not use daily GLP-1 agonists on the day of elective surgery and to stop weekly formulations, like Wegovy and Ozempic, 7 days before surgery.

Last but not least, case reports of depression and suicidality prompted the European Medicines Agency to review about 150 instances of possible self-injury and suicidal thoughts among people using liraglutide or semaglutide. The review will also include other GLP-1 receptor agonists and is expected to conclude in November this year. Already the Wegovy, Saxenda, and Zepbound drug labels include a warning to monitor for depression or suicidal thoughts, but other GLP-1 agonists do not carry the warning. Intended or not, companies excluded people with a history of depression or suicidal behavior or ideation from clinical trials of Wegovy and Saxenda. According to Saxenda’s label, 9 of 3384 people, or 0.3%, who received the drug in clinical trials reported suicidal ideation vs 2 of 1941 participants, or 0.1%, who received a placebo. In any case,  clinicians should use these drugs with caution in people who have a history of suicidality or are currently suicidal and to monitor patients for such predispositions.

What About Long-Term Risks? GLP-1 agonists like semaglutide are meant to be long-term and potentially lifelong weight-management medications. Yet there’s still not much known about adverse effects that may play out over time, especially among people taking the drugs for obesity for long time.