Illuminating the full side effect profile of GLP-1 drugs

When Lili Zarghami walked out of her doctor’s office with a free box of Mounjaro — a glucagon-like peptide-1 (GLP-1) agonist from Eli Lilly — she felt hopeful that the drug might help her shed extra pounds she had gained related to having polycystic ovary syndrome (PCOS). She injected herself with the first dose on a Saturday afternoon, and by Sunday, her appetite — and any thoughts about food whatsoever — had vanished. “There was literally no desire to eat anything,” said Zarghami. “It feels like a switch in your brain has flipped.”

 Zarghami had good reason to be optimistic that this switch would lead to significant weight loss. GLP-1 agonists were first approved to treat type 2 diabetes in 2005 and have since proven to be extremely effective for weight loss too. In clinical trials, the drugs have led to patients losing up to 18 percent of their bodyweight compared to placebo (1).

“These are the most efficacious medications that I have seen in my clinical practice in almost five decades,” said Michael Camilleri, a gastroenterologist studying gastrointestinal diseases and obesity at the Mayo Clinic. “I graduated from medical school very young in 1975, so I can honestly say that these are the medications that have had the greatest benefits for obesity and the associated complications.”

Yet, GLP-1 drugs are not without side effects. For Zarghami, the early bliss of no longer thinking about or desiring food was soon replaced by concern about not being able to eat even tiny amounts — like one eighth of a normal portion of scrambled eggs. “It wasn’t that I just wasn’t hungry anymore, but it felt like I couldn’t swallow food anymore. Like the food was literally up to my throat, which is an awful feeling, especially when you know you haven’t been able to eat today or yesterday or the day before,” she said.

Zarghami also developed the kind of muscle weakness that would be expected only after running a marathon. But, she was just trying to walk her daily routine of six to eight miles. Initially thinking it must just be dehydration, she began drinking lots of fluids, but she then began experiencing whole-body weakness during her third week of Mounjaro. At that point, she called off work and mostly stayed in bed feeling sick.

The only side effect that Zarghami’s doctor had warned her about was pancreatitis. When she called him to update him on her symptoms, he said that since she was not vomiting, she was probably fine.

Zarghami is not the typical case, however. The most common side effects are gastrointestinal (GI) symptoms like nausea, vomiting, diarrhea, constipation, and bloating (2). But for most people, “it happens very, actually suddenly, and it goes away absolutely, completely despite continuation of the drug,” said Marzieh Salehi, an endocrinologist and researcher studying the cross-communication between the gut and other organs at the University of Texas Health at San Antonio. “There are so many mysterious parts here which we don’t know.”

The completed clinical trials for GLP-1 drugs only focused on patients with type 2 diabetes or obesity. As more real-world data continues to pour in, researchers are now meticulously studying side effects and potential complications. They’re also interested in finding out how the drugs are tolerated in patients with a variety of other conditions — and what the consequences might be for people who will take GLP-1 drugs for the rest of their lives.

A slowed stomach

When Zarghami’s third dose of the injection wore off and she finally began to feel normal again, she decided to stop taking the drug for good. “If I have to choose between feeling the way that I felt towards the end of being on that drug and being the size that I am now and feeling healthy and strong and capable, this is what I will choose every single time,” she said.

Salehi noted that in the clinical trials, depending on the drug, only about five to ten percent of patients stopped using them, but “when you go to the real-world studies, almost actually 50 percent of people, they stop these drugs by six months to 12 months.” Salehi explained that it’s unclear if that is because of the side effects, though they could be playing a role. She thinks there are also likely financial and accessibility issues at play.

To ease the intensity of any side effects, Camilleri emphasized the importance of starting out at a lower dose or escalating the dosage at a slower rate than what is recommended by the Food and Drug Administration (FDA). “We learned this by experience. We were able to take virtually all the patients up to the highest dose recommended by the FDA,” he said.

But that wouldn’t have fixed Zarghami’s symptoms, since she already started at the lowest dose possible. When she went to her annual appointment this year, she and her physician now believe that her side effects were unfortunately exacerbated by acid reflux that was not well controlled. It’s likely related to a finding that Camilleri and other researchers have repeatedly shown, which is that GLP-1 agonists slow down gastric emptying, the amount of time it takes the stomach to empty its contents into the small intestine (3). With more food sitting in the stomach for longer, there is more stomach acid that can reflux and shoot back up into the esophagus.

Food sitting for longer in the stomach has also led to concerns about a life-threatening condition during procedures that require anesthesia called aspiration, whereby patients vomit stomach contents into their lungs. Camilleri recently reviewed multiple studies that assessed lung aspiration in endoscopic procedures and found the risk to be low, with studies showing rates that were similar to patients not taking GLP-1 drugs: 4.8 versus 4.6 cases per 10,000 patients, respectively (4). However, he cautioned that it’s still important to follow the guidelines set by the American Society of Anesthesiologists, and there may be times where the procedure needs to be delayed if too much food is still in the stomach (5).

At the same time, Camilleri pointed out that the gastric slowing is also related to the benefits of the drug. “We look at the delayed stomach emptying as a positive attribute, as one of the mechanisms that’s causing the patient to lose weight because they feel full after they eat, or they can’t eat the next meal,” said Camilleri. His team recently published work showing that delayed gastric emptying during treatment with the GLP-1 agonist liraglutide can be temporary for many, although 30 percent continued to have delayed gastric emptying at 16 weeks (6). In those patients, there may be concerns of gastroparesis, which occurs when the delay gets bad enough — or the stomach stops emptying completely — leading to uncomfortable symptoms like nausea and vomiting. “This still requires further assessment,” said Camilleri, who noted that so far, the data show only a very small increased risk of gastroparesis.

Assessing the risks

Beyond effects on the stomach, there have been concerns in the community about repercussions for other organs — chief among them being the pancreatitis that Zarghami’s physician had warned her about. Salehi said, “For a period of time, we were just sitting on the edge of the chair, all of us, because there was a comment about pancreatitis. And to this day, we still actually follow the algorithm: If there was a history of pancreatitis, do not use.”

The concern stemmed from early case reports suggesting that patients developed pancreatitis while taking GLP-1 agonists. “Case reports don’t prove causality, because you don’t know if that person would have developed pancreatitis otherwise,” said Ronald Goldenberg, a consultant endocrinologist emeritus at LMC Diabetes & Endocrinology who was involved in some of the earliest clinical trials testing GLP-1 drugs. Randomized clinical trials are the gold standard for proving causality because they control for confounders. “The large, randomized trials that have been done with GLP-1 receptor agonists versus placebo show no signal for pancreatitis. So scientifically, that has not been proven, even though there are warnings in the product monographs,” said Goldenberg.

It feels like a switch in your brain has flipped.
 – Lili Zarghami, a GLP-1 patient

Salehi said that in addition to pancreatitis, physicians were also initially concerned about pancreatic cancer and thyroid cancer. “They were absolutely three alarming complications, … but then we have enough evidence on all three to believe that we really do not have increased risk of any of them.”

However, one organ that has been affected by GLP-1 agonists in randomized trials is the gallbladder (7). “These include things like gallstones or biliary colic,” said Goldenberg. “It’s something like 27 more gallbladder-related events per every 10,000 patients treated per year, so it’s a pretty small absolute risk.” He added that the incidence of gallbladder events often increases after weight loss in general, but some studies suggest that GLP-1 drugs slow down gallbladder motility which could create a sludge that leads to gallstones (8).

There has also been a lot of attention paid to the effects that GLP-1 drugs may have on the mind — particularly whether they increase suicidal thoughts. In 2023, the FDA and European Medicines Agency (EMA) began investigating a possible relationship after receiving reports of suicidal thoughts while patients were taking the drugs. However, both agencies concluded that the currently available evidence does not support a causal relationship between GLP-1 drugs and suicidal thoughts or actions (9,10). Yet, the FDA stated, “because of the small number of suicidal thoughts or actions observed in both people using GLP-1 [receptor agonists] and in the comparative control groups, we cannot definitively rule out that a small risk may exist; therefore, FDA is continuing to look into this issue.”

The majority of real-world studies using electronic health records reached the same conclusion (11). Some studies, including one in adolescents taking GLP-1 receptor drugs, found reduced risk of suicidal thoughts (12). Still, psychiatrists like Georgios Schoretsanitis at the University of Zurich and Chiara Gastaldon at the University of Verona saw a need for additional analyses while the regulatory agencies were reviewing their own datasets. They were interested in whether there were subgroups of patients that may be at risk, with the goal of identifying them so that clinicians could have a better idea for who they should monitor more closely. Using data from the World Health Organization, they performed a disproportionality analysis, which sought to determine whether there were more reports of suicidal ideation in people taking GLP-1 drugs than would be expected compared to other types of drugs that people with obesity are commonly prescribed, like metformin (13). This kind of analysis, however, cannot prove causality or estimate the amount of risk present.

Schoretsanitis and Gastaldon found that patients who are co-prescribed antidepressants and the GLP-1 agonist semaglutide may be at risk of developing suicidal ideation. The disproportionality signal they identified disappeared only when they removed this subgroup of patients from their analysis. Yet, Schoretsanitis clarified that their findings absolutely do not mean that someone taking antidepressants should not take semaglutide or other GLP-1 drugs. “What we are saying is that if you have these people, you need to monitor for changes in the mood, for changes like suicidal thoughts. You have to assess a baseline,” said Schoretsanitis. He and Gastaldon added that ideally, patient monitoring should take place within an interdisciplinary team that includes a psychiatrist or psychologist.

“There is no consistent, reproducible body of evidence [supporting increased suicidal ideation]. In fact, most reports show a reduction in rates, but I would never argue with someone who says we need to learn more. We should continue to monitor this,” said Daniel Drucker, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute who was part of the foundational research on GLP-1 agonists. “There’s no reason to think that if you treat hundreds of thousands of people, there wouldn’t be a spectrum of responses.” Based on the available evidence though, Drucker emphasized it would be an extremely rare side effect.

Side effects in subgroups

So far, researchers have only studied GLP-1 drugs in randomized clinical trials in the context of diabetes and obesity. That means that a big open question is whether the side effect profiles may differ in subgroups of people that scientists have not directly studied, which include a large swath of people now taking these drugs to lose only about 10 to 15 pounds. This has led to ethical concerns, as the increased demand helped create a shortage of these drugs around the world in recent months. “These drugs should be reserved for the people that really need them, and that’s basically type 2 diabetes or obesity,” said Goldenberg.

There also may not be enough information yet for groups who scientists are just now beginning to study in clinical trials — like adolescents with type 2 diabetes or obesity, though the FDA has already approved several GLP-1 agonists for these groups (14,15). “I would argue that we don’t have enough information about young people who might be 12, 14, 16. They’re going through puberty. Their organs are still developing,” said Drucker. “We don’t have 15 years and hundreds of thousands of people that age treated with these medicines.” He also said that researchers don’t know how these drugs will affect people with neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease, in which trials are now ongoing. Similarly, Salehi is studying the use of these drugs in patients with spinal cord injury, who have different levels of gut motility and glucose profiles that may put them at risk of adverse side effects.

“As we extend the use of these medicines in new populations, our clinical experience in those populations will be even thinner,” said Drucker. “I will never stop thinking about, what is the safety of the medicines? What don’t we know? What’s the risk-benefit ratio? Where are the gaps? That’s our job as responsible scientists.”

It also remains unknown whether there will be any new side effects that pop up if people remain on these drugs for 30, 40, or 50 plus years. Clinical trials stop after a few years, and some of the currently FDA-approved drugs have only been around for a couple years. “If you have a serious adverse event that only happens after five years in one in 25,000 people, of course, you’re not going to see that signal in a clinical trial,” said Drucker.

I will never stop thinking about, what is the safety of the medicines? What don’t we know? What’s the risk-benefit ratio? Where are the gaps? That’s our job as responsible scientists.
 – Daniel Drucker, Lunenfeld-Tanenbaum Research Institute

Zarghami still wishes that the GLP-1 approach to weight loss had worked for her. “I hate that it didn’t work. I hate it because there is so much promise around them,” she said. Zarghami encouraged other patients to report side effects, as she did. “It’s super important if you have a side effect that is not listed, and you’re getting brushed off, report it to the pharmaceutical companies because there might be hundreds or thousands of other people feeling the same,” she said. She remains hopeful that a future version of the drugs may be more tolerable for her and others with reflux or other conditions who may have had a similar reaction.

“The next generation of the drugs, to me, would be … coming up with the recipe where we can actually utilize what we have learned already to balance the benefit and complications to a much better degree,” Salehi said.

References

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2. Wharton, S. et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med  134, 14–19 (2021).
3. Maselli, D.B. & Camilleri, M. Effects of GLP-1 and Its Analogs on Gastric Physiology in Diabetes Mellitus and Obesity in Diabetes: from Research to Clinical Practice: Volume 4  (ed. Islam, Md. S.) 171–192 (Springer International Publishing, 2021).
4. Camilleri, M. Definite benefits of GLP-1 receptor agonists: what is the risk of gastroparesis and lung aspiration? Gut  (2024).
5. American Society of Anesthesiologists Consensus-Based Guidance on Preoperative Management of Patients (Adults and Children) on Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists. at <https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative>
6. Camilleri, M., Carlson, P. & Dilmaghani, S. Prevalence and variations in gastric emptying delay in response to GLP-1 receptor agonist liraglutide. Obesity  32, 232–233 (2024).
7. He, L. et al.  Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med  182, 513–519 (2022).
8. Nerild, H. H. et al.  Liraglutide changes postprandial responses of gut hormones involved in the regulation of gallbladder motility. Diabetes Obese Metab  25, 1632–1637 (2023).
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10. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 April 2024. European Medicines Agency (EMA). (2024). at <https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-8-11-april-2024>
11. Wang, W. et al.  Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med  30, 168–176 (2024).
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14. FDA Approves First Generic of Once-Daily GLP-1 Injection to Lower Blood Sugar in Patients with Type 2 Diabetes. FDA  (2024). at <https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-once-daily-glp-1-injection-lower-blood-sugar-patients-type-2-diabetes>
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