Side Effects of GLP-1 Drugs: What Physicians Need to Know

Just a few years after TikTok videos raised demand, one in eight people in the US has tried Ozempic (semaglutide) or another drug in its class. Glucagon-like peptide 1 (GLP-1) receptor agonists have revolutionized obesity medicine.

But they have no problems. In the early days of the social media craze, news reports often featured patients whose gastrointestinal side effects sent them to the emergency room (ER).

“A lot happened at that time. Patients didn’t want to complain because they were losing weight, and they ended up in the ER with excessive constipation or small bowel obstruction,” said Caroline Apovian, MD, director of the Center for Weight and Health at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

“But that doesn’t really happen now,” he added.

Research backs up his claim: A recent review of studies found that many patients still experience side effects, but only to a mild to moderate degree, as doses increase – and discomfort diminishes over time. About 7% of patients stop taking medication because of these symptoms.

Here’s what the latest research shows about the side effects of GLP-1s.

Most Common: Gastrointestinal Disorders

Depending on the symptoms and the particular medication, anywhere from a third to a half of patients will have some type of bowel problem.

• In that clinical trial, which looked at studies of three GLP-1 drugs — semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Saxenda, Victoza), and tirzepatide (Mounjaro, Zepbound) — semaglutide users got worse. when compared.
• Nausea was reported more often – 44.2% of semaglutide users experienced it, compared to 40.2% for liraglutide and 31% for tirzepatide. Diarrhea, constipation, and vomiting also affected a quarter to a third of patients on semaglutide, and slightly less for the other two medications.

Apovian finds that careful dosing helps her patients avoid side effects.

He said: “We do not know who will work well and who will not work well. We start slowly, and things usually go well.

If the patient does not respond well, he will stop increasing the dose until he agrees and advises to use drugs sold like MiraLAX to deal with the symptoms.

Few reported adverse gastrointestinal events appeared in the data, affecting less than 1% of liraglutide and tirzepatide patients and 2.6% of semaglutide users. Most of these events were related to the gallbladder.

Questions About Cause: Depression and suicide

About a year ago, a study used 18 years worth of data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to examine how often patients report suicidal thoughts. and/or depression while using GLP-1 medications. When comparing metformin and insulin, researchers found an unequal response by patients using semaglutide and liraglutide. Other GLP-1 drugs do not show this effect. The researchers pointed out: These statistics do not show causation – there is no clear reason why the two drugs were associated with other reports.

Other research has been even more encouraging:

• Another study also used FAERS but only looked at data from 2018 to 2022, when the use of these drugs increased, and found no relationship between suicidal behavior or self-harm and GLP-1.
• A recent group study, which looked at data from about 300,000 people, found that GLP-1 users are not at greater risk of death by suicide.
• Both the FDA and the European Medicines Agency have issued statements that the evidence does not support a causal association.

There are several factors at play here. People with obesity and diabetes are more likely to develop depression at first. More importantly, even if there is a link, the cause remains unclear. For example, patients who lose weight through bariatric surgery are at increased risk for depression, substance abuse and self-harm. These symptoms may be related to the weight loss itself, not the medication.

“Some people use food as something other than nutrition. They use food to soothe other mental issues,” Apovian said. “When that is removed, the mental problems are still there.”

In his practice, he has seen the risk of mental health problems rise with a large weight loss – 50-100 lb.

This lack of clarity about causation means that it is important to take a full patient history before prescribing, so you can carefully monitor for existing psychiatric disorders.

Possible link: Ocular symptoms

Here, again, the research is inconclusive but has no clear correlation. Several studies have looked for a link between GLP-1 and vision-related issues:

• Another analyzed data from FAERS and online pharmacology and found semaglutide and lixisenatide were significantly associated with adverse events such as blurred vision, visual impairment, and diabetic retinopathy.
• This summer, a cohort study of nearly 17,000 people with diabetes or overweight/obesity suggested a link between semaglutide and nonarteritic anterior ischemic optic neuropathy (NAION), a common cause of blindness. due to optic nerve damage. The study found “a greater risk of NAION among people prescribed semaglutide relative to those given other drugs to treat type 2 diabetes and obesity or obesity.”
• But this month, another cohort study with 135,000 participants looked at NAION in people with type 2 diabetes, obesity, or both. It compared the results with conventional non-GLP-1 drugs and found the opposite: No increased risk for NAION.

Another concern with all of these studies is that they are based on large databases rather than randomized controlled trials (RCTs). When researchers focused on RCTs in a 2023 meta-analysis, they found a significant association with only one type of GLP-1, albiglutide – which was taken off the market in 2017. The other six drugs approved by The FDA did not disclose the statistics. important connection.

Possible Complication: Pulmonary Aspiration Under Sedation

Earlier this month, the FDA updated the labeling for semaglutide, liraglutide, and tirzepatide to include a warning about the risk of aspiration during surgery. Although there are no published studies, several case reports have appeared.

GLP-1 drugs are slow to leave the stomach, so even if the patient would have fasted before surgery as usual, food or water may remain. In order to respond to this opportunity, a group of professional medical associations issued guidelines for using these drugs during the perioperative period. They include:

• Factors, symptoms, and other medical conditions are considered: Risk is higher during exacerbations, and in general, higher levels mean greater risk.
• GLP-1 may be discontinued if the test shows a high risk.
• Assessment on the day of the procedure for delayed gastric emptying.
• Dietary changes before the procedure, which may include switching to a liquid diet.

Rare: Serious Effects

And then there are the outliers, the scary stories that make the headlines. By themselves, none of these are common enough to affect consideration of GLP-1 use:

• Studies in rats have shown an increased risk of thyroid cancer, but subsequent research has found no evidence.
• Colonic ischemia in combination with tirzepatide.
• Acute pancreatitis leading to death in association with semaglutide.
• Speaking of pancreatitis, that clinical review of studies found that liraglutide and semaglutide led to a higher risk of pancreatitis, bowel obstruction and gastroparesis. But the numbers were so small that they were nothing – for example, only 0.2% of patients with pancreatitis.

The Benefits Outweigh the Risks

When you put these side effects against the many known benefits of weight loss and blood sugar control – lower risk of high blood pressure, heart disease, stroke, metabolic syndrome, liver disease of fat, many cancers, and others – benefits of GLP. -1 drugs seem obvious. Ultimately, it is the patient’s decision whether to start and continue taking any chronic disease medication.

Apovian recommends having a serious discussion before writing that first letter — he compares the situation to taking antidepressants. If your patient understands the potential side effects, they are more likely to adhere to the regimen long-term.

“We teach our patients how to use these drugs, indefinitely, if you want to maintain a low, healthy weight,” he said. “I don’t see patients who stop using them, but they are there. These are people desperate to lose weight, who have not been educated to understand that we are treating disease. It’s not a matter of determination.”

And once the patient starts taking GLP-1, monitor it closely, by visiting each person instead of talking to the doctor, while increasing the dosage. If they have side effects, stay in that position until they are comfortable. And if the patient has a good response to low-dose weight loss, stay there. Because only you I can go up, it doesn’t mean you have to.